@article {pmid39653745, year = {2024}, author = {Banu, S and Mk, K and George, JK and Siby, E and Bhagat, R and Ms, S and Patil, SJ and Phadke, SR and Sowpati, DT and Tallapaka, KB}, title = {Enhanced resolution of optical genome mapping utilizing telomere-to-telomere reference in genetic disorders.}, journal = {European journal of human genetics : EJHG}, volume = {}, number = {}, pages = {}, pmid = {39653745}, issn = {1476-5438}, abstract = {Reference genomes serve as a baseline criterion for comparison of personal genomes to deduce clinical variants. The widely used reference genome, GRCh38, contains stretches of gaps and unresolved bases particularly in complex regions which could obscure variant discovery. In contrast, the gapless telomere-to-telomere CHM13 (T2T-CHM13) reference genome can be used to assess difficult regions of the genome. Optical genome mapping (OGM), an imaging technique for structural variation identification has improved resolution compared to traditional cytogenetic methods. Our study showcases the utility of the T2T-CHM13 reference genome for enhanced structural variant (SV) detection in complex regions. We illustrate this through two clinical cases, where improved alignment with T2T-CHM13 led to significantly higher confidence scores for critical SVs. We demonstrate improved clinical diagnostic outcomes with the updated T2T-CHM13 reference and advocate its adoption.}, }
@article {pmid39652599, year = {2024}, author = {Syed, S and Aloe, S and Sutherland, JH and Holloman, WK and Lue, NF}, title = {Ustilago maydis Trf2 ensures genome stability by antagonizing Blm-mediated telomere recombination: Fine-tuning DNA repair factor activity at telomeres through opposing regulations.}, journal = {PLoS genetics}, volume = {20}, number = {12}, pages = {e1011515}, doi = {10.1371/journal.pgen.1011515}, pmid = {39652599}, issn = {1553-7404}, abstract = {TRF2 is an essential and conserved double-strand telomere binding protein that stabilizes chromosome ends by suppressing DNA damage response and aberrant DNA repair. Herein we investigated the mechanisms and functions of the Trf2 ortholog in the basidiomycete fungus Ustilago maydis, which manifests strong resemblances to metazoans with regards to the telomere and DNA repair machinery. We showed that UmTrf2 binds to Blm in vitro and inhibits Blm-mediated unwinding of telomeric DNA substrates. Consistent with a similar inhibitory activity in vivo, over-expression of Trf2 induces telomere shortening, just like deletion of blm, which is required for efficient telomere replication. While the loss of Trf2 engenders growth arrest and multiple telomere aberrations, these defects are fully suppressed by the concurrent deletion of blm or mre11 (but not other DNA repair factors). Over-expression of Blm alone triggers aberrant telomere recombination and the accumulation of aberrant telomere structures, which are blocked by concurrent Trf2 over-expression. Together, these findings highlight the suppression of Blm as a key protective mechanism of Trf2. Notably, U. maydis harbors another double-strand telomere-binding protein (Tay1), which promotes Blm activity to ensure efficient replication. We found that deletion of tay1 partially suppresses the telomere aberration of Trf2-depleted cells. Our results thus point to opposing regulation of Blm helicase by telomere proteins as a strategy for optimizing both telomere maintenance and protection. We also show that aberrant transcription of both telomere G- and C-strand is a recurrent phenotype of telomere mutants, underscoring another potential similarity between double strand breaks and de-protected telomeres.}, }
@article {pmid39650708, year = {2024}, author = {Wang, J and Xie, F and Zhu, W and Ye, D and Xiao, Y and Shi, M and Zeng, R and Bian, J and Xu, X and Chen, L and Zhu, A and Zhu, K and Fan, T and Liu, B and Xiao, L and Zhang, X}, title = {Relationship between serum carotenoids and telomere length in overweight or obese individuals.}, journal = {Frontiers in nutrition}, volume = {11}, number = {}, pages = {1479994}, doi = {10.3389/fnut.2024.1479994}, pmid = {39650708}, issn = {2296-861X}, abstract = {BACKGROUND: Previous researches have demonstrated an association between carotenoids and elongated telomeres. Nonetheless, there is scant scientific evidence examining this relationship in individuals who are overweight or obese, a demographic more predisposed to accelerated aging. This study aims to elucidate the correlation between serum carotenoid concentrations and telomere length within this population group.
METHODS: Data were sourced from the 2001-2002 National Health and Nutrition Examination Survey, encompassing 2,353 overweight or obese participants. The levels of α-carotene, β-carotene (both trans and cis isomers), β-cryptoxanthin, lutein/zeaxanthin, and trans-lycopene were quantified via high-performance liquid chromatography. Telomere length was assessed using quantitative polymerase chain reaction.
RESULTS: Following adjustment for potential confounders, telomere length exhibited an increase of 1.83 base pairs (bp) per unit elevation in β-carotene levels (β = 1.83; 95% CI: 0.48, 3.18). Within the fully adjusted model, telomere length incremented by 1.7 bp per unit increase in serum β-carotene among overweight individuals (β = 1.7; 95% CI: 0.1, 3.3), and by 2.6 bp per unit increase among obese individuals (β = 2.6; 95% CI: 0.1, 5.0). Furthermore, restricted cubic spline analysis revealed a linear relationship between β-carotene levels and telomere length, whereas a non-linear association was observed between β-cryptoxanthin levels and telomere length.
CONCLUSION: This investigation indicates that higher serum β-carotene concentrations are linked with extended telomere length in overweight and obese populations in the United States. These findings warrant further validation through prospective studies.}, }
@article {pmid39647990, year = {2024}, author = {Yang, H and Chen, L and Liu, Y}, title = {Association of leukocyte telomere length with the risk of digestive diseases: A large-scale cohort study.}, journal = {Chinese medical journal}, volume = {}, number = {}, pages = {}, pmid = {39647990}, issn = {2542-5641}, abstract = {BACKGROUND: Leukocyte telomere length (LTL) shortening, a biomarker of telomere attrition, has been linked to multiple diseases. However, the relationship between LTL and digestive diseases remains uncertain. This study aimed to investigate the association between LTL and the risk of digestive diseases.
METHODS: A cohort analysis of over 500,000 participants from the UK Biobank (UKB) between 2006 and 2021 was conducted to estimate the associations of LTL with more than 90 common digestive diseases. LTL was quantified using multiplex quantitative polymerase chain reaction, and cases of each disease were determined according to inpatient and primary care data. Multivariable Cox proportional hazards regression analysis was used to evaluate the associations of LTL with the risk of digestive diseases. Furthermore, such associations were also evaluated after stratification by sex and ethnicity.
RESULTS: After a mean follow-up time of 11.8 years, over 20 the International Classification of Diseases 10th Revision (ICD-10) codes were observed to be associated with telomere attrition. LTL shortening is associated with an increased risk of several digestive diseases, including gastroesophageal reflux disease (K21: hazard ratio [HR] = 1.30, 95% confidence interval [95% CI]: 1.19-1.42), esophageal ulcer (K221: HR = 1.81, 95% CI: 1.22-2.71), Barrett's esophagus (K227: HR = 1.58 95% CI: 1.14-2.17), gastritis (K29: HR = 1.39, 95% CI: 1.26-1.52), duodenal ulcer (K26: HR = 1.55, 95% CI: 1.14-2.12), functional dyspepsia (K30X: HR = 1.36, 95% CI: 1.06-1.69), non-alcoholic fatty liver disease (NAFLD) (K760: HR = 1.39, 95% CI: 1.09-1.78), liver cirrhosis (K74: HR = 4.73, 95% CI: 3.27-6.85), cholangitis (K830: HR = 2.55, 95% CI: 1.30-5.00), and hernia (K43: HR = 1.50, 95% CI: 1.17-1.94; K44: HR = 1.29, 95% CI: 1.17-1.42). The risk of rectal polyps (K621: HR = 0.77, 95% CI: 0.63-0.92) decreased per unit shortening of LTL.
CONCLUSIONS: This study suggests that LTL shortening is associated with an increased risk of most digestive diseases except for rectal polyps. These findings may provide some clues for understanding the pathogenesis of digestive diseases.}, }
@article {pmid39647324, year = {2024}, author = {Li, X and Wang, X and Yu, F and Li, Z and Chen, D and Qi, Y and Lu, Z and Liu, Y and Chen, D and Wu, Y}, title = {Development and validation of a prognostic and drug sensitivity model for gastric cancer utilizing telomere-related genes.}, journal = {Translational oncology}, volume = {52}, number = {}, pages = {102232}, doi = {10.1016/j.tranon.2024.102232}, pmid = {39647324}, issn = {1936-5233}, abstract = {BACKGROUND: Gastric cancer (GC) poses a major global health challenge because of its unfavorable prognosis. Elevated telomerase activity has been linked to the rapid growth and invasiveness of GC tumors. Investigating the expression profiles of telomerase could improve our understanding of the mechanisms underlying telomere-related GC advancement and its applicability as potential targets for diverse therapeutic strategies for GC.
METHODS: The TCGA and GEO databases were utilized to access transcriptome and clinical data related to GC. After assessing differentially expressed genes (DEGs), a prognostic risk model was developed through Cox univariate regression, LASSO-Cox regression. The prognostic risk model was validated using data from the GSE62254 cohort. The significant influence of the risk model on the tumor immune microenvironment (TIME) and its sensitivity to various drugs was assessed.
RESULTS: Differential expression analysis identified 328 significantly telomere-related DEGs in GC, with 35 of them showing a significant association with GC prognosis. A predictive risk model composed of four telomere-related genes (TRGs) was established, enabling the accurate stratification of GC patients into two distinct prognostic groups. The LASSO risk model demonstrated notable variations in immune-cell infiltration and drug sensitivity patterns between high- and low-risk groups.
CONCLUSIONS: The study establishes suggestive relationships between four TRGs (LRRN1, SNCG, GAMT, and PDE1B) and the prognosis of GC. The comprehensive characterization of the TRG model reveals their possible roles in the prognosis, TIME, and drug sensitivity in GC.}, }
@article {pmid39642730, year = {2024}, author = {Li, R and Chen, G and Liao, W and Yuchi, Y and Yang, X and Zhang, Z and Liu, X and Mao, Z and Li, L and Zhao, J and Li, H and Huo, W and Guo, Y and Li, S and Wu, W and Wang, C and Hou, J}, title = {The role of telomere shortening in ambient ozone exposure-related insulin resistance.}, journal = {Journal of hazardous materials}, volume = {484}, number = {}, pages = {136768}, doi = {10.1016/j.jhazmat.2024.136768}, pmid = {39642730}, issn = {1873-3336}, abstract = {BACKGROUND: Ozone (O3) exposure and telomere shortening are associated with insulin resistance (IR). However, the role of telomere shortening in ambient O3 exposure-related IR is largely unclear.
METHODS: The Henan Rural Cohort recruited participants and performed a random forest method to estimate residential O3 concentration. IR was reflected by homeostasis model assessment-IR, quantitative insulin sensitivity check index, triglyceride and glucose index, etc. Generalized linear model, quantile regression model, and mediation effects analysis were utilized to assess the associations of O3 exposure and relative telomere length (RTL) with longitudinal IR markers and their change rates. Furthermore, the role of telomere homeostasis in O3-exposure-induced IR in vivo and in vitro experiments was verified.
RESULTS: O3 exposure was positively associated with longitudinal IR. The proportions of RTL mediated associations between O3 exposure and longitudinal IR markers ranged from 11.92 % to 60.36 %. O3-exposed mice exhibited a higher glucose load, upregulation of GSK-3β and G-6-Pase expression at mRNA levels, glycogen accumulation reduction, telomere shortening, and decreased telomerase reverse transcriptase activity relative to air-exposed mice. In vitro experiments reveal that overexpression of TERT in HepG2 cells up-regulated G-6-Pase mRNA expression level.
CONCLUSIONS: Impaired telomere homeostasis may be involved in O3 exposure-related IR via inhibition of glycogen synthesis and acceleration of gluconeogenesis and the specific mechanisms are still further elucidated.}, }
@article {pmid39639361, year = {2024}, author = {Tan, L and Zhong, MM and Zhao, YQ and Feng, Y and Ye, Q and Hu, J and Ou-Yang, ZY and Chen, NX and Su, XL and Zhang, Q and Liu, Q and Yuan, H and Wang, MY and Feng, YZ and Guo, Y}, title = {The role of circulating polyunsaturated fatty acids in mediating the effect of BMI on leukocyte telomere length: analysis using Mendelian randomization.}, journal = {Nutrition & metabolism}, volume = {21}, number = {1}, pages = {104}, pmid = {39639361}, issn = {1743-7075}, support = {202208043514//The Hunan Provincial Health Commission/ ; 202208043514//The Hunan Provincial Health Commission/ ; 202208043514//The Hunan Provincial Health Commission/ ; 202208043514//The Hunan Provincial Health Commission/ ; 202208043514//The Hunan Provincial Health Commission/ ; 202208043514//The Hunan Provincial Health Commission/ ; 202208043514//The Hunan Provincial Health Commission/ ; 202208043514//The Hunan Provincial Health Commission/ ; 202208043514//The Hunan Provincial Health Commission/ ; 202208043514//The Hunan Provincial Health Commission/ ; 202208043514//The Hunan Provincial Health Commission/ ; 202208043514//The Hunan Provincial Health Commission/ ; 202208043514//The Hunan Provincial Health Commission/ ; 202208043514//The Hunan Provincial Health Commission/ ; 202208043514//The Hunan Provincial Health Commission/ ; (81800788 and 81773339)//the National Natural Science Foundation of China/ ; (81800788 and 81773339)//the National Natural Science Foundation of China/ ; (81800788 and 81773339)//the National Natural Science Foundation of China/ ; (81800788 and 81773339)//the National Natural Science Foundation of China/ ; (81800788 and 81773339)//the National Natural Science Foundation of China/ ; (81800788 and 81773339)//the National Natural Science Foundation of China/ ; (81800788 and 81773339)//the National Natural Science Foundation of China/ ; (81800788 and 81773339)//the National Natural Science Foundation of China/ ; (81800788 and 81773339)//the National Natural Science Foundation of China/ ; (81800788 and 81773339)//the National Natural Science Foundation of China/ ; (81800788 and 81773339)//the National Natural Science Foundation of China/ ; (81800788 and 81773339)//the National Natural Science Foundation of China/ ; (81800788 and 81773339)//the National Natural Science Foundation of China/ ; (81800788 and 81773339)//the National Natural Science Foundation of China/ ; (81800788 and 81773339)//the National Natural Science Foundation of China/ ; (2017WK2041 and 2018SK52511)//the Science and Technology Department of Hunan Province, China/ ; (2017WK2041 and 2018SK52511)//the Science and Technology Department of Hunan Province, China/ ; (2017WK2041 and 2018SK52511)//the Science and Technology Department of Hunan Province, China/ ; (2017WK2041 and 2018SK52511)//the Science and Technology Department of Hunan Province, China/ ; (2017WK2041 and 2018SK52511)//the Science and Technology Department of Hunan Province, China/ ; (2017WK2041 and 2018SK52511)//the Science and Technology Department of Hunan Province, China/ ; (2017WK2041 and 2018SK52511)//the Science and Technology Department of Hunan Province, China/ ; (2017WK2041 and 2018SK52511)//the Science and Technology Department of Hunan Province, China/ ; (2017WK2041 and 2018SK52511)//the Science and Technology Department of Hunan Province, China/ ; (2017WK2041 and 2018SK52511)//the Science and Technology Department of Hunan Province, China/ ; (2017WK2041 and 2018SK52511)//the Science and Technology Department of Hunan Province, China/ ; (2017WK2041 and 2018SK52511)//the Science and Technology Department of Hunan Province, China/ ; (2017WK2041 and 2018SK52511)//the Science and Technology Department of Hunan Province, China/ ; (2017WK2041 and 2018SK52511)//the Science and Technology Department of Hunan Province, China/ ; (2017WK2041 and 2018SK52511)//the Science and Technology Department of Hunan Province, China/ ; (kq2202403 and kq2202412)//the Natural Science Foundation of Changsha City/ ; (kq2202403 and kq2202412)//the Natural Science Foundation of Changsha City/ ; (kq2202403 and kq2202412)//the Natural Science Foundation of Changsha City/ ; (kq2202403 and kq2202412)//the Natural Science Foundation of Changsha City/ ; (kq2202403 and kq2202412)//the Natural Science Foundation of Changsha City/ ; (kq2202403 and kq2202412)//the Natural Science Foundation of Changsha City/ ; (kq2202403 and kq2202412)//the Natural Science Foundation of Changsha City/ ; (kq2202403 and kq2202412)//the Natural Science Foundation of Changsha City/ ; (kq2202403 and kq2202412)//the Natural Science Foundation of Changsha City/ ; (kq2202403 and kq2202412)//the Natural Science Foundation of Changsha City/ ; (kq2202403 and kq2202412)//the Natural Science Foundation of Changsha City/ ; (kq2202403 and kq2202412)//the Natural Science Foundation of Changsha City/ ; (kq2202403 and kq2202412)//the Natural Science Foundation of Changsha City/ ; (kq2202403 and kq2202412)//the Natural Science Foundation of Changsha City/ ; (kq2202403 and kq2202412)//the Natural Science Foundation of Changsha City/ ; }, abstract = {BACKGROUND: polyunsaturated fatty acids (PUFAs) are a category of fatty acids that contain omega-3 and omega-6 fatty acids, which constitute a substantial portion of the Western diet and are vital for maintaining human wellness. The extent to which circulating PUFAs influence the effects of BMI on leukocyte telomere length (LTL) is unknown. Additionally, the impact of circulating PUFA on LTL remains controversial in observational studies.
METHODS: Using publicly accessible datasets, a genome-wide association study (GWAS) was carried out to determine genetic association estimates for BMI, circulating PUFAs, and LTL. The circulating PUFAs considered were omega-3 PUFAs (i.e., docosahexaenoic acid (DHA) and total omega-3 PUFAs) and omega-6 PUFAs (i.e., linoleic acid (LA) and total omega-6 PUFAs). Two-sample Mendelian randomization (MR) was used to investigate the causal relationships between BMI and PUFA with LTL. Additionally, we examined whether certain PUFA mediate the impact of BMI on LTL.
RESULTS: None of the evidence supported a causal effect of genetically predicted DHA and total omega-3 PUFA on LTL (DHA: β = 0.001, 95% CI: -0.023 to 0.026, p = 0.926; total omega-3 PUFA: β = 0.008, 95% CI: -0.013 to 0.029, p = 0.466). After conducting sensitivity analyses to account for various models of horizontal pleiotropy, the causal association between higher levels of LA and longer LTL persisted (β = 0.034, 95% CI 0.016 to 0.052, p < 0.001). Adjusting for LA in genetics reduced the effect of BMI on LTL from β = -0.039 (95% CI: -0.058 to -0.020, p < 0.001) to -0.034 (95% CI: -0.054 to -0.014, p < 0.001).
CONCLUSIONS: This MR study indicates that an increase in genetically predicted circulating LA levels is associated with longer LTL. Additionally, it appears that circulating LA levels play a role in mediating some of the impact that BMI has on LTL.}, }
@article {pmid39639031, year = {2024}, author = {Dai, M and Li, K and Sacirovic, M and Zemmrich, C and Ritter, O and Bramlage, P and Persson, AB and Buschmann, E and Buschmann, I and Hillmeister, P}, title = {Cell-free plasma telomere length correlated with the risk of cardiovascular events using machine learning classifiers.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {30390}, pmid = {39639031}, issn = {2045-2322}, mesh = {Humans ; *Machine Learning ; Male ; Female ; Middle Aged ; *Coronary Artery Disease/blood/diagnosis ; Retrospective Studies ; Aged ; *Heart Failure/blood/diagnosis ; Telomere ; Biomarkers/blood ; Telomere Homeostasis ; Risk Factors ; }, abstract = {This retrospective study explored the association between circulating cell-free plasma telomere length (cf-TL) and coronary artery disease (CAD) and heart failure (HF). Data from 518 participants were collected, including clinical and laboratory data. cf-TL was measured in plasma samples and machine learning (ML) classification models were developed to differentiate between CAD, HF and control conditions. Our results showed that cf-TL was significantly prolonged in HF patients compared to controls, but no significant difference was observed between CAD patients and controls. Additionally, cf-TL was significantly correlated with nitric oxide metabolites (NOx) and flow-mediated dilation (FMD), suggesting a potential link with endothelial function. To avoid data leakage and ensure the model captured only relationships relevant to the research question, we utilized a temporal data split, holding out the last year's data for testing (n = 81) and using the remaining data for training (n = 324) and validation (n = 109). The ML models using four variables achieved an area under the curve (AUC) of 0.795 in the validation dataset and 0.717 in the test dataset for CAD classification, and 0.829 in the validation dataset and 0.806 in the test dataset for HF classification. SHAP analysis revealed that cf-TL had minimal impact on the predictions of the CAD model, as indicated by consistently low SHAP values, whereas in the HF model, cf-TL exhibited a broader range of SHAP values, indicating a greater contribution to the model's classification. These findings suggest that cf-TL may play a more prominent role in HF pathophysiology and could serve as a valuable biomarker for predicting HF risk. Further studies are warranted to explore cf-TL's diagnostic and prognostic potential across different cardiovascular diseases.}, }
@article {pmid39638969, year = {2024}, author = {Sadr, Z and Ghasemi, M and Jafarpour, S and Seyfi, R and Ghasemi, A and Boustanipour, E and Khorshid, HRK and Ehtesham, N}, title = {Beginning at the ends: telomere and telomere-based cancer therapeutics.}, journal = {Molecular genetics and genomics : MGG}, volume = {300}, number = {1}, pages = {1}, pmid = {39638969}, issn = {1617-4623}, mesh = {Humans ; *Neoplasms/genetics/therapy/drug therapy ; *Telomere/genetics/metabolism ; *Telomerase/genetics/metabolism ; *Telomere Homeostasis ; Animals ; }, abstract = {Telomeres, which are situated at the terminal ends of chromosomes, undergo a reduction in length with each cellular division, ultimately reaching a critical threshold that triggers cellular senescence. Cancer cells circumvent this senescence by utilizing telomere maintenance mechanisms (TMMs) that grant them a form of immortality. These mechanisms can be categorized into two primary processes: the reactivation of telomerase reverse transcriptase and the alternative lengthening of telomeres (ALT) pathway, which is dependent on homologous recombination (HR). Various strategies have been developed to inhibit telomerase activation in 85-95% of cancers, including the use of antisense oligonucleotides such as small interfering RNAs and endogenous microRNAs, agents that simulate telomere uncapping, expression modulators, immunotherapeutic vaccines targeting telomerase, reverse transcriptase inhibitors, stabilization of G-quadruplex structures, and gene therapy approaches. Conversely, in the remaining 5-15% of human cancers that rely on ALT, mechanisms involve modifications in the chromatin environment surrounding telomeres, upregulation of TERRA long non-coding RNA, enhanced activation of the ataxia telangiectasia and Rad-3-related protein kinase signaling pathway, increased interactions with nuclear receptors, telomere repositioning driven by HR, and recombination events between non-sister chromatids, all of which present potential targets for therapeutic intervention. Additionally, combinatorial therapy has emerged as a strategy that employs selective agents to simultaneously target both telomerase and ALT, aiming for optimal clinical outcomes. Given the critical role of anti-TMM strategies in cancer treatment, this review provides an overview of the latest insights into the structure and function of telomeres, their involvement in tumorigenesis, and the advancements in TMM-based cancer therapies.}, }
@article {pmid39638831, year = {2024}, author = {Zhu, N and Wang, X and Zhu, H and Zheng, Y}, title = {Exploring the role of alternative lengthening of telomere-related genes in diagnostic modeling for non-alcoholic fatty liver disease.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {30309}, pmid = {39638831}, issn = {2045-2322}, mesh = {*Non-alcoholic Fatty Liver Disease/genetics/pathology/diagnosis/metabolism ; Animals ; Mice ; Humans ; Telomere Homeostasis/genetics ; Disease Models, Animal ; Gene Regulatory Networks ; Gene Expression Profiling ; Telomere/genetics/metabolism ; Prognosis ; }, abstract = {Previous studies have reported an association between telomere length and non-alcoholic fatty liver disease (NAFLD). This study aimed to explore the involvement of alternative lengthening of telomere-related genes (ALTRGs) in the pathology of NAFLD, construct a risk signature, and evaluate both treatment and prognosis. Three NAFLD datasets (GSE48452, GSE89632, and GSE63067) were collected from the GEO database and merged into combined GEO datasets. ALTRGs were collected from GeneCards and PubMed databases. Differentially expressed genes (DEGs) were identified, and functional enrichment analysis was performed. This study employed a support vector machine algorithm and least absolute shrinkage and selection operator regression analysis to identify key genes for constructing a diagnostic model. High- and low-risk groups were identified from the combined GEO datasets using the diagnostic model. Gene set enrichment analysis, regulatory network analysis, and intergroup immune infiltration analysis were performed. This study identified the key genes using receiver operating characteristic and Friends analysis. Expression of these genes was validated in a mouse model of NAFLD. Twenty-five genes were differentially expressed, with a positive correlation between FOS and EGR1 and a negative correlation between MYC and CEBPA. A diagnostic model was constructed using 12 genes, and high- and low-risk groups were identified. CAMK2G, ERBB2, FOSB, WT1, and CEBPA showed certain accuracy, and their expression levels were significantly different in the model. Immune infiltration analysis between the risk groups revealed that six immune cells were statistically significant. This includes a strong negative interaction between type 2 T helper cells and SPHK2 in the high-risk group. These findings suggest that ALTRDEGs are potential therapeutic targets and prognostic indicators for NAFLD. However, further investigations are required to elucidate the specific underlying mechanisms.}, }
@article {pmid39636971, year = {2024}, author = {Liu, J and Li, Q and Hu, Y and Yu, Y and Zheng, K and Li, D and Qin, L and Yu, X}, title = {The complete telomere-to-telomere sequence of a mouse genome.}, journal = {Science (New York, N.Y.)}, volume = {386}, number = {6726}, pages = {1141-1146}, doi = {10.1126/science.adq8191}, pmid = {39636971}, issn = {1095-9203}, mesh = {Animals ; Mice ; *Telomere/genetics ; *Genome ; Repetitive Sequences, Nucleic Acid ; Sequence Analysis, DNA ; Mouse Embryonic Stem Cells ; Haploidy ; }, abstract = {The current reference genome of Mus musculus, GRCm39, has major gaps in both euchromatic and heterochromatic regions associated with repetitive sequences. In this work, we have sequenced and assembled the telomere-to-telomere genome of mouse haploid embryonic stem cells. The results reveal more than 7.7% of previously uncovered sequences of the mouse genome, including ribosomal DNA arrays and pericentromeric and subtelomeric regions, as well as an additional 140 genes predicted to be protein-coding. This study helps to address knowledge gaps in the mouse genome.}, }
@article {pmid39636650, year = {2024}, author = {Myllymäki, M and Reilly, CR}, title = {Somatic symphony: telomeres and CH.}, journal = {Blood}, volume = {144}, number = {23}, pages = {2369-2371}, doi = {10.1182/blood.2024026841}, pmid = {39636650}, issn = {1528-0020}, }
@article {pmid39635126, year = {2024}, author = {Burkert, M and Blanc, E and Thiessen, N and Weber, C and Toedling, J and Monti, R and Dombrowe, VM and Stella de Biase, M and Kaufmann, TL and Haase, K and Waszak, SM and Eggert, A and Beule, D and Schulte, JH and Ohler, U and Schwarz, RF}, title = {Copy-number dosage regulates telomere maintenance and disease-associated pathways in neuroblastoma.}, journal = {iScience}, volume = {27}, number = {10}, pages = {110918}, pmid = {39635126}, issn = {2589-0042}, abstract = {Telomere maintenance in neuroblastoma is linked to poor outcome and caused by either telomerase reverse transcriptase (TERT) activation or through alternative lengthening of telomeres (ALT). In contrast to TERT activation, commonly caused by genomic rearrangements or MYCN amplification, ALT is less well understood. Alterations at the ATRX locus are key drivers of ALT but only present in ∼50% of ALT tumors. To identify potential new pathways to telomere maintenance, we investigate allele-specific gene dosage effects from whole genomes and transcriptomes in 115 primary neuroblastomas. We show that copy-number dosage deregulates telomere maintenance, genomic stability, and neuronal pathways and identify upregulation of variants of histone H3 and H2A as a potential alternative pathway to ALT. We investigate the interplay between TERT activation, overexpression and copy-number dosage and reveal loss of imprinting at the RTL1 gene associated with poor clinical outcome. These results highlight the importance of gene dosage in key oncogenic mechanisms in neuroblastoma.}, }
@article {pmid39633874, year = {2024}, author = {Almuraikhy, S and Naja, K and Anwardeen, N and Sellami, M and Al-Amri, HS and Al-Sulaiti, H and Bashraheel, SS and Aden, AA and Elrayess, MA}, title = {Metabolic signatures of combined exercise and fasting: an expanded perspective on previous telomere length findings.}, journal = {Frontiers in aging}, volume = {5}, number = {}, pages = {1494095}, pmid = {39633874}, issn = {2673-6217}, abstract = {INTRODUCTION: Aging is a complex process marked by a gradual decline in physiological function and increased susceptibility to diseases. Telomere length is frequently regarded as one of the primary biomarkers of aging. Metabolic profiles are key features in longevity and have been associated with both age and age-related diseases. We previously reported an increase in the telomere length in healthy female subjects when Ramadan fasting was combined with physical training. This study aims to characterize the metabolic signature differentiating the combined effects of exercise and fasting from exercise alone and explore the correlations with the previously reported telomere length changes.
METHODS: Twenty-nine young, non-obese, and healthy female subjects were previously randomized into two groups: one group followed a 4-week exercise program, while the other group followed the same 4-week exercise program but also fasted during Ramadan. Metabolic profiles were assessed pre- and post-intervention using untargeted metabolomics.
RESULTS AND DISCUSSION: Our results showed a significant decrease in many lipid metabolites in the exercise-while-fasting group, particularly ceramides. Our study sheds light on the dynamic changes in lipid metabolism and its potential role in inflammation and age-related diseases, and contributes to the broader understanding of how lifestyle factors can influence cellular aging and metabolic health.}, }
@article {pmid39633416, year = {2024}, author = {Wang, Q and Gao, Y and Song, J and Taiwaikuli, D and Ding, H and Yang, X and Tang, B and Zhou, X}, title = {DNA methylation-based telomere length is more strongly associated with cardiovascular disease and long-term mortality than quantitative polymerase chain reaction-based telomere length: evidence from the NHANES 1999-2002.}, journal = {Clinical epigenetics}, volume = {16}, number = {1}, pages = {177}, pmid = {39633416}, issn = {1868-7083}, support = {82260064//National Natural Science Foundation of China/ ; }, mesh = {Humans ; *Cardiovascular Diseases/genetics/mortality ; Female ; Male ; Middle Aged ; Aged ; *DNA Methylation/genetics ; *Nutrition Surveys ; *Telomere/genetics ; Telomere Homeostasis/genetics ; Polymerase Chain Reaction/methods ; Proportional Hazards Models ; Cohort Studies ; }, abstract = {BACKGROUND: Telomere length (TL) serves as a pivotal gauge of cellular aging, with shorter TL linked to various age-related ailments. Recently, a DNA methylation-based TL estimator, known as DNAmTL, has emerged as a novel TL measurement tool. Our current investigation scrutinized the correlation between DNAmTL and the risks of cardiovascular disease (CVD) and enduring mortality among middle-aged and elderly individuals.
METHODS: We enrolled a nationwide, population-based cohort of subjects from the National Health and Nutrition Examination Survey spanning 1999 to 2002, possessing data on both DNAmTL and quantitative polymerase chain reaction-based TL (qPCRTL). Logistic regression models and Cox proportional hazards models were employed to evaluate the associations of DNAmTL with CVD risk and mortality, respectively.
RESULTS: The cohort comprised 2532 participants, with a weighted CVD prevalence of 19.06%. Notably, each one-kilobase increase in DNAmTL was linked to a 53% diminished CVD risk [odds ratio (OR): 0.47, 95% confidence interval (CI): 0.23-0.95, P = 0.035]. Over a median follow-up period of 206 months, 1361 deaths were recorded (53.75%), with 590 (23.30%) ascribable to CVD. Individuals with the lengthiest DNAmTL exhibited a 36% lower risk of all-cause mortality (hazard ratio (HR): 0.64, 95% CI: 0.49-0.85, P = 0.002) and a 35% decrease in CVD mortality (HR: 0.65, 95% CI: 0.43-0.98, P = 0.044) compared to those with shortest DNAmTL. Notably, a stronger association with age was observed for DNAmTL compared to qPCRTL (r = -0.58 vs. r = - 0.25). Analysis of receiver operating characteristic (ROC) curves suggested superior predictive performance of DNAmTL over qPCRTL for CVD (area under curve (AUC): 0.63 vs. 0.55, P < 0.001), all-cause (AUC: 0.74 vs. 0.62, P < 0.001), and CVD mortality (AUC: 0.75 vs. 0.64, P < 0.001).
CONCLUSION: Longer DNAmTL was positively correlated with reduced CVD risk and long-term mortality in middle-aged and elderly cohorts. Notably, DNAmTL outperformed qPCRTL as an aging biomarker in the stratification of CVD risks and mortality.}, }
@article {pmid39633034, year = {2024}, author = {Saraswati, S and Martínez, P and Serrano, R and Mejías, D and Graña-Castro, O and Álvarez Díaz, R and Blasco, MA}, title = {Author Correction: Renal fibroblasts are involved in fibrogenic changes in kidney fibrosis associated with dysfunctional telomeres.}, journal = {Experimental & molecular medicine}, volume = {}, number = {}, pages = {}, doi = {10.1038/s12276-024-01370-4}, pmid = {39633034}, issn = {2092-6413}, }
@article {pmid39628055, year = {2024}, author = {Wang, X and Sun, Z and Qi, F and Zhou, Z and Du, P and Shi, L and Dong, W and Huang, B and Han, S and Pavan, S and Zhang, M and Cui, M and Xu, J and Liu, H and Qin, L and Zhang, Z and Dai, X and Gao, W and Miao, L and Zhao, R and Wang, J and Wang, M and Zhi, C and Hu, Y and Zhao, H and Chen, L and Jin, X and Sun, Y and Zheng, Z and Zhang, X}, title = {A telomere-to-telomere genome assembly of the cultivated peanut.}, journal = {Molecular plant}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.molp.2024.12.001}, pmid = {39628055}, issn = {1752-9867}, }
@article {pmid39624822, year = {2024}, author = {Saretzki, G}, title = {Editorial: Chronic stress, telomeres and aging.}, journal = {Frontiers in endocrinology}, volume = {15}, number = {}, pages = {1504405}, pmid = {39624822}, issn = {1664-2392}, }
@article {pmid39623492, year = {2024}, author = {Sumesh, D and Lin, J and Wojcicki, JM}, title = {High school diploma is associated with longer postpartum leukocyte telomere length in a cohort of primarily Latina women.}, journal = {Maternal health, neonatology and perinatology}, volume = {10}, number = {1}, pages = {25}, pmid = {39623492}, issn = {2054-958X}, abstract = {OBJECTIVE: This study investigates correlates of maternal leukocyte telomere length (LTL) in the immediate postpartum period using a cross-sectional study design from an existing prospective longitudinal birth cohort of primarily Latina women. The study focuses on the role of maternal health and dietary habits in pregnancy and maternal education level and LTL at delivery.
STUDY DESIGN: Latina mothers were recruited during the immediate postpartum period prior to 24 h at two San Francisco hospitals and dried blood spots were collected for LTL analysis via quantitative polymerase chain reaction (qPCR). We used multivariable linear regression models to determine independent predictors of maternal LTL during the postpartum period.
RESULTS: In multivariable regression models, increasing maternal age was associated with shorter LTL during the immediate postpartum period (Coeff - 0.015; p < 0.01) whereas having a high school diploma was associated with longer LTL versus not having graduated from high school (Coeff 0.12; p < 0.01).
CONCLUSION: Maternal education level as a potential marker of exposure to life stressors and socioeconomic status was associated with maternal LTL after adjusting for age and other potential confounders in women of reproductive age.}, }
@article {pmid39618119, year = {2024}, author = {Chen, J and Liu, H and Pang, Y and Wang, Y and Ren, Z and Liu, J and Nan, Y and Liu, D}, title = {Genetic Association of Chronic Pains and Analgesics With Telomere Length: A Mendelian Randomization Study.}, journal = {Biological research for nursing}, volume = {}, number = {}, pages = {10998004241303536}, doi = {10.1177/10998004241303536}, pmid = {39618119}, issn = {1552-4175}, abstract = {Objective: The aim of this study was to explore the causal relationships between chronic pains (back pain, facial pain, general pain, headaches, knee pain, hip pain, neck/shoulder pain, stomach/abdominal pain) and analgesics (codeine, diclofenac, ibuprofen, morphine, paracetamol, tramadol) with telomere length using Mendelian randomization methods. Methods: In the study, various statistical methods including inverse variance weighted (IVW), Mendelian Randomization-Egger, weighted median, simple mode, and weighted mode were used to investigate the relationships between chronic pains, analgesics, and telomere length. Heterogeneity and pleiotropy tests were conducted to ensure the accuracy of the results. Results: The results of the IVW analysis revealed positive causal relationships between hip pain (odds ratio (OR): 1.145; 95% confidence interval (CI): 1.021-1.285; p = .020), and stomach/abdominal pain (OR: 1.100; 95% CI: 1.008-1.200; p = 0.033) with telomere length. Use of tramadol (OR: 0.074; 95% CI: 0.009-0.605; p = 0.015) had a negative causal relationships with telomere length. Conclusion: This study found positive associations between hip pain and stomach/abdominal pain with telomere length, and a negative association between tramadol and telomere length. However, no significant causal relationships were found with other types of chronic pains and analgesics. This could help develop healthier chronic pain treatments, avoiding the abuse of analgesics.}, }
@article {pmid39616267, year = {2024}, author = {Kvarnung, M and Pettersson, M and Chun-On, P and Rafati, M and McReynolds, LJ and Norberg, A and Moura, PL and Pesonen, I and Chaireti, R and Grönros Söderholm, B and Burlin, J and Rydén, J and Lindberg, EH and Giri, N and Savage, SA and Agarwal, S and Nordgren, A and Tesi, B}, title = {Identification of biallelic POLA2 variants in two families with an autosomal recessive telomere biology disorder.}, journal = {European journal of human genetics : EJHG}, volume = {}, number = {}, pages = {}, pmid = {39616267}, issn = {1476-5438}, support = {SLS-973171//Svenska Läkaresällskapet (Swedish Society of Medicine)/ ; FoUI-985957//Stockholms Läns Landsting (Stockholm County Council)/ ; FoUI-972766//Stockholms Läns Landsting (Stockholm County Council)/ ; }, abstract = {POLA2 encodes the accessory subunit of DNA polymerase α (polα)/primase, which is crucial for telomere C-strand fill-in. Incomplete fill-in of the C-rich telomeric strand after DNA replication has been proposed as a mechanism for Coats plus syndrome, a phenotype within the broader spectrum of telomere biology disorders (TBD). Coats plus syndrome has so far been associated with pathogenic variants in POT1, CTC1, and STN1. Here we report the findings of biallelic deleterious rare variants in POLA2 gene detected by whole genome sequencing and segregation analysis in five young adults from two unrelated families. All five individuals displayed abnormally short telomeres and a clinical phenotype suggesting a TBD disorder with Coats plus features including retinal and gastrointestinal telangiectasias. Our results suggest POLA2 as a novel autosomal recessive gene for a TBD with Coats plus features.}, }
@article {pmid39616073, year = {2024}, author = {Modi, P and Pennington, K and Shah, S and Mangaonkar, A and Goswami, U}, title = {Clinical Outcomes of Lung Transplant Recipients with Myelodysplastic Syndrome and Short Telomere Syndrome-Case Series.}, journal = {Transplantation proceedings}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.transproceed.2024.10.038}, pmid = {39616073}, issn = {1873-2623}, abstract = {Limited data exists concerning the postlung transplantation outcomes of patients diagnosed with myelodysplastic syndrome (MDS). We delineate the clinical trajectories and outcomes for 3 patients with MDS and Short Telomere Syndrome (STS) who underwent lung transplantation. Our findings suggest that patients with STS and low-risk MDS, especially those harboring the SF3B1 mutation, tolerated standard immunosuppression and antimicrobial prophylaxis well without significant deviation from a typical post-transplant course. Therefore, individuals with low-risk MDS should not be automatically excluded from lung transplantation consideration. Post-transplant monitoring is crucial to promptly detect and manage cytopenias. Conversely, our patient, diagnosed with high-risk MDS post-transplantation faced a poor prognosis, with severe cytopenias limiting immunosuppression treatment and resulting in rejection. Thus, abundance of caution is warranted when contemplating lung transplantation for individuals with high-risk MDS and STS. Further research is necessary to validate these findings.}, }
@article {pmid39615158, year = {2024}, author = {Tilekli, MM and Yılmaz, AK and Yasul, Y and Çon, N and Mercan, S and Tek, N}, title = {Influence of diet and exercise on leukocyte telomere length, markers of oxidative stress and inflammation in rats.}, journal = {Experimental and molecular pathology}, volume = {140}, number = {}, pages = {104947}, doi = {10.1016/j.yexmp.2024.104947}, pmid = {39615158}, issn = {1096-0945}, abstract = {Telomere length is an important biomarker of biological aging and is affected by nutrition and physical activity. This study investigated the effects of diets with different fat contents and increased physical activity on certain pro/anti-inflammatory and oxidative stress markers and aging. The study is performed in a randomized, experimental, and controlled design with 48 rats, 8 weeks old, divided into 6 different groups (Control (C), exercise (E), unsaturated fat diet (USF), saturated fat diet (SF), unsaturated fat diet + exercise (USF + E), and saturated fat diet + exercise (SF + E)). The rats performed aerobic swimming exercise for 50 days and were fed a diet with different fat content. TAS, TOS, and MDA levels were determined by colorimetric analysis while 8-OHdG, IL-10, and TNF-α were determined by ELISA. Additionally, leukocyte telomere length is determined by the PCR method. Weight changes were also recorded. Plasma TOS, OSI, and TNF-α were lowest in the USF group and highest in the SF and SF + E groups. MDA, 8-OHdG and TG levels were highest in the SF group. The lowest IL-10 level was detected in group C. TL level was the highest in the USF group. There was also a moderate, negative, and significant correlation between telomeres and TOS, OSI, and TNF-α. The groups with the highest body weight gain were C, SF, and SF + E. Diets low in saturated fat or high in unsaturated fat, and physical activity were associated with leukocyte telomere length and alteration of oxidative and pro/anti-inflammatory markers.}, }
@article {pmid39614920, year = {2024}, author = {Taseva, T and Koycheva, Y and Racheva, R and Raycheva, T and Hodzhev, Y and Nikolova, E and Ilieva, M and Krasteva, M}, title = {Altered Mitochondrial DNA Copy Number and Telomere Length in Patients with Substance Use Disorder: Correlation with Age, Sex, and Chronic Diseases.}, journal = {Biochemical genetics}, volume = {}, number = {}, pages = {}, pmid = {39614920}, issn = {1573-4927}, support = {Grant number KP-06-H25/5//Bulgarian National Science Fund (BNSF), Ministry of Education and Science, Bulgaria/ ; Grant number KP-06-H25/5//Bulgarian National Science Fund (BNSF), Ministry of Education and Science, Bulgaria/ ; Grant number KP-06-H25/5//Bulgarian National Science Fund (BNSF), Ministry of Education and Science, Bulgaria/ ; Grant number KP-06-H25/5//Bulgarian National Science Fund (BNSF), Ministry of Education and Science, Bulgaria/ ; Grant number KP-06-H25/5//Bulgarian National Science Fund (BNSF), Ministry of Education and Science, Bulgaria/ ; Grant number KP-06-H25/5//Bulgarian National Science Fund (BNSF), Ministry of Education and Science, Bulgaria/ ; }, abstract = {Substance use disorder (SUD) is a complex condition involving psychological, sociocultural, and genetic factors. In this study, we examined the alternations in mitochondrial DNA copy number (mtDNAcn) and telomere length (TL) and their relationship to demographic, medical, heredity, and substance use characteristics in patients with SUD and healthy controls. We investigated a total cohort of 54 participants: 21 healthy individuals, 17 patients with alcohol dependence (AD), and 16 patients with drug dependence (DD). TL and mtDNAcn were measured using quantitative real-time PCR, with statistical methods used to assess the association between variables. We observed a significant decrease in mtDNAcn in both SUD groups, particularly associated with chronic diseases in the AD group. No significant differences in TL were found among the three groups. Sex-associated analysis revealed a significant mtDNAcn reduction in the DD males and elevated TL in AD males compared to control males. Correlation analyses showed associations between the two biomarkers and age, sex, and chronic diseases. Our findings suggest that leukocyte mtDNAcn is a more sensitive marker than TL in patients with SUD, indicating sex-specific patterns of alterations. These findings require confirmation through larger cohort recruitment.}, }
@article {pmid39614014, year = {2024}, author = {Jones-Weinert, C and Mainz, L and Karlseder, J}, title = {Telomere function and regulation from mouse models to human ageing and disease.}, journal = {Nature reviews. Molecular cell biology}, volume = {}, number = {}, pages = {}, pmid = {39614014}, issn = {1471-0080}, abstract = {Telomeres protect the ends of chromosomes but shorten following cell division in the absence of telomerase activity. When telomeres become critically short or damaged, a DNA damage response is activated. Telomeres then become dysfunctional and trigger cellular senescence or death. Telomere shortening occurs with ageing and may contribute to associated maladies such as infertility, neurodegeneration, cancer, lung dysfunction and haematopoiesis disorders. Telomere dysfunction (sometimes without shortening) is associated with various diseases, known as telomere biology disorders (also known as telomeropathies). Telomere biology disorders include dyskeratosis congenita, Høyeraal-Hreidarsson syndrome, Coats plus syndrome and Revesz syndrome. Although mouse models have been invaluable in advancing telomere research, full recapitulation of human telomere-related diseases in mice has been challenging, owing to key differences between the species. In this Review, we discuss telomere protection, maintenance and damage. We highlight the differences between human and mouse telomere biology that may contribute to discrepancies between human diseases and mouse models. Finally, we discuss recent efforts to generate new 'humanized' mouse models to better model human telomere biology. A better understanding of the limitations of mouse telomere models will pave the road for more human-like models and further our understanding of telomere biology disorders, which will contribute towards the development of new therapies.}, }
@article {pmid39613012, year = {2024}, author = {Liu, Q and Fan, G and Bi, J and Fang, Q and Luo, F and Huang, X and Li, H and Liu, B and Yan, L and Guo, W and Hu, L and Mei, S and Wang, Y and Song, L}, title = {Exposure to multiple metals and leukocyte telomere length in children and adolescents: The mediating effect of thyroid hormones.}, journal = {Environmental research}, volume = {}, number = {}, pages = {120483}, doi = {10.1016/j.envres.2024.120483}, pmid = {39613012}, issn = {1096-0953}, abstract = {Exposure to metals has been related to alterations in leukocyte telomere length (LTL), an aging marker. However, the evidence regarding this relationship in children and adolescents, as well as the underlying mechanisms, remains unclear. Therefore, we aimed to explore the individual and mixture effects of metals on LTL in children and adolescents and to assess the mediating role of thyroid hormones and the modifying effect of a healthy lifestyle. In a cross-sectional study performed in Liuzhou, China, we assessed 5 serum thyroid hormones, 18 urinary metals, and LTL among 1050 children and adolescents aged 6-18 years. We employed multivariate linear regression and weighted quantile sum (WQS) regression to assess the associations of urinary metals with LTL in children and adolescents. Mediation analyses were conducted to explore the effects of thyroid hormones on these relationships. Urinary cobalt (Co), nickel (Ni), strontium (Sr), mercury (Hg), cadmium (Cd), and thallium (Tl) were related to a shorter LTL in children and adolescents. The WQS regression showed a 6.31% (95% CI: -8.76%, -3.79%) decrease in LTL per quartile increase in the WQS index, and identified Ni (23.3%), Sr (21.7%), and Tl (18.0%) as the major contributors. Mediation analyses showed that triiodothyronine (T3) mediated 14.8% and 8.1% of the associations of urinary Sr and Hg with LTL, respectively, and suppressed 9.3% of the association with urinary Co. Furthermore, the inverse associations of Sr, Cd, and Tl with LTL were attenuated among participants who adopted a healthy lifestyle. Our findings suggested that exposure to Co, Ni, Sr, Cd, Hg, Tl, and their mixture were related to a shorter LTL in children and adolescents, potentially mediated by thyroid hormones. Additionally, adopting a healthy lifestyle may alleviate these adverse effects.}, }
@article {pmid39608550, year = {2024}, author = {Fang, H and Wu, J and Xie, L and Li, Y and Huang, J and Yan, X and He, X and Deng, W and Chen, J and Ji, Y and Li, R and Wen, C and Yu, W and Wang, P}, title = {Telomere-to-telomere genome assembly of eggplant (Solanum melongena L.) promotes gene fine localization of the green stripe (GS) in pericarp.}, journal = {International journal of biological macromolecules}, volume = {}, number = {}, pages = {138094}, doi = {10.1016/j.ijbiomac.2024.138094}, pmid = {39608550}, issn = {1879-0003}, abstract = {Fruit appearance of eggplant is a key commercial trait, and the precise selection of new varieties with diverse aesthetics aligns with current breeding objectives. However, functional genomics research in eggplant remains underdeveloped. Here, we assembled the first telomere-to-telomere (T2T) eggplant genome, as well as chloroplast and mitochondrial genomes for the inbred line 'NO211'. The 1.06-Gb SmT2T genome is anchored to 12 chromosomes, nine of which are gap-free, totaling three gaps. This assembly harbors 36,505 genes and 64.08 % repetitive sequences, identifying 12 centromeres and 22 telomeres. Utilizing the SmT2T genome for bulked segregant analysis (BSA) and forward genetic approach with green-striped 'NO211' and pure green 'P13' as parents, the green stripe (GS) locus was finely mapped to a 9-Kb region on Chr4, containing a single gene, eggplant.04G07850 (GLK protein). Sequence analysis and qRT-PCR revealed that a single-base deletion in the exon of SmGLK in 'P13' led to premature stop codon, and SmGLK expression was significantly higher in the pericarp of 'NO211' compared to 'P13'. A marker was developed and validated in 36 germplasms, demonstrating co-segregation with green-striped rind trait. This study provides an ideal reference genome for eggplant functional genomics studies, facilitating mechanistic research on peel stripe formation and molecular-assisted selection for fruit appearance.}, }
@article {pmid39608081, year = {2024}, author = {Tan, MY and Zhang, P and Gao, M}, title = {Letter to the editor - "Association of healthy and unhealthy plant-based diets with telomere length".}, journal = {Clinical nutrition (Edinburgh, Scotland)}, volume = {44}, number = {}, pages = {12-13}, doi = {10.1016/j.clnu.2024.11.030}, pmid = {39608081}, issn = {1532-1983}, }
@article {pmid39605578, year = {2024}, author = {Lin, SY and Futeran, H and Levine, MT}, title = {Adaptive protein coevolution preserves telomere integrity.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2024.11.11.623029}, pmid = {39605578}, issn = {2692-8205}, abstract = {Many essential conserved functions depend, paradoxically, on proteins that evolve rapidly under positive selection. How such adaptively evolving proteins promote biological innovation while preserving conserved, essential functions remains unclear. Here, we experimentally test the hypothesis that adaptive protein-protein coevolution within an essential multi-protein complex mitigates the deleterious incidental byproducts of innovation under pressure from selfish genetic elements. We swapped a single, adaptively evolving subunit of a telomere protection complex from Drosophila yakuba into its close relative, D. melanogaster . The heterologous subunit uncovered a catastrophic interspecies incompatibility that caused lethal telomere fusions. Restoring six adaptively evolving sites on the protein-protein interaction surface, or introducing the D. yakuba interaction partner, rescued telomere integrity and viability. Our in vivo , evolution-guided manipulations illuminate how adaptive protein-protein coevolution preserves essential functions threatened by an evolutionary pressure to innovate.}, }
@article {pmid39603404, year = {2024}, author = {Teng, Y and Gao, Y and Liu, L and Zhang, W and Li, C and Lian, B and Sun, H and Sun, L}, title = {Sex differential effects of early maternal separation on PTSD susceptibility in adult rats accompanied by telomere shortening in the hippocampus.}, journal = {Neuroscience}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.neuroscience.2024.11.058}, pmid = {39603404}, issn = {1873-7544}, abstract = {Early life stress (ELS) is thought to be a leading cause of mental disorders in adulthood, including PTSD. Recent studies have found that such stress has a gender and resilient specific effect on adult PTSD. This study aimed to assess emotion, and cognitive behavior, and to examine the sex differences and resilience of ELS on adult PTSD. At the same time, the expression of hippocampal telomere length and telomere repeat binding factors (TRF1 and TRF2) were detected to explore the mechanism of telomere length change. Rat offspring were separated from their dams (3 h/day or 6 h/day from PND2 ∼ PND14). Then, pups were treated with a single prolonged stress (SPS) procedure when they reached adulthood (PND80). Rats exposed early to MS and SPS showed anxiety-like and depression-like behaviors as well as impaired learning and memory. The rats exposed to MS3h showed reduced anxiety-like and depression-like behavior upon re-experiencing "secondary stress" compared to the SPS and MS6h groups. Behavioral results showed no significant gender difference. However, gender and SPS factors significantly affected telomere length and TRF1 and TRF2 gene expression in hippocampus. The SPS effect and MS*SPS interaction significantly impacted TRF1 and TRF2 protein expression. In conclusion, this study shows that MS has different effects on anxiety, depression, and cognitive memory deficits in rats experiencing "secondary stress" in adulthood and is accompanied by telomere shortening in the hippocampus. This reveals the potential impact of early MS on PTSD and provides a new perspective for further research in the field of psychological stress.}, }
@article {pmid39603108, year = {2024}, author = {Li, X and Li, M and Cheng, J and Guan, S and Hou, L and Zu, S and Yang, L and Wu, H and Li, H and Fan, Y and Zhang, B}, title = {"Reply - Letter to the editor" - "Association of healthy and unhealthy plant-based diets with telomere length".}, journal = {Clinical nutrition (Edinburgh, Scotland)}, volume = {44}, number = {}, pages = {9-11}, doi = {10.1016/j.clnu.2024.11.032}, pmid = {39603108}, issn = {1532-1983}, }
@article {pmid39596838, year = {2024}, author = {Tucker, LA and Bates, CJ}, title = {Telomere Length and Biological Aging: The Role of Strength Training in 4814 US Men and Women.}, journal = {Biology}, volume = {13}, number = {11}, pages = {}, doi = {10.3390/biology13110883}, pmid = {39596838}, issn = {2079-7737}, abstract = {Telomere length is an index of cellular aging. Healthy lifestyles are associated with reduced oxidative stress and longer telomeres, whereas unhealthy behaviors are related to shorter telomeres and greater biological aging. This investigation was designed to determine if strength training accounted for differences in telomere length in a random sample of 4814 US adults. Data from the National Health and Nutrition Examination Survey (NHANES) were employed to answer the research questions using a cross-sectional design. Time spent strength training was calculated by multiplying days of strength training per week by minutes per session. Participation in other forms of physical activity was also calculated based on reported involvement in 47 other activities. Weighted multiple regression and partial correlation were used to calculate the mean differences in telomere length across levels of strength training, adjusting for differences in potential confounders. With the demographic covariates controlled, strength training and telomere length were linearly related (F = 14.7, p = 0.0006). Likewise, after adjusting for all the covariates, the linear association remained strong and significant (F = 14.7, p = 0.0006). In this national sample, 90 min per week of strength training was associated with 3.9 years less biological aging, on average. Regular strength training was strongly related to longer telomeres and less biological aging in 4814 US adults.}, }
@article {pmid39596019, year = {2024}, author = {Zhao, L and Li, Z and Jiang, S and Xia, C and Deng, K and Liu, B and Wang, Z and Liu, Q and He, M and Zou, M and Xia, Z}, title = {The Telomere-to-Telomere Genome of Jaboticaba Reveals the Genetic Basis of Fruit Color and Citric Acid Content.}, journal = {International journal of molecular sciences}, volume = {25}, number = {22}, pages = {}, doi = {10.3390/ijms252211951}, pmid = {39596019}, issn = {1422-0067}, support = {ZDYF2022XDNY149//Hainan Province Science and Technology Special Fund/ ; }, mesh = {*Fruit/genetics/metabolism ; *Citric Acid/metabolism ; *Genome, Plant ; Telomere/genetics/metabolism ; Myrtaceae/genetics/metabolism ; Gene Expression Regulation, Plant ; Pigmentation/genetics ; Phylogeny ; }, abstract = {Jaboticaba is a typical tropical plant that blossoms and bears fruit on the tree trunks and branches. The fruits resemble grapes in appearance and texture and are also known as "treegrapes". Currently, research on the genomics of jaboticaba is lacking. In this study, we constructed an integrated, telomere-to-telomere (T2T) gap-free reference genome and two nearly complete haploid genomes, thereby providing a high-quality genomic resource. Furthermore, we unveiled the evolutionary history of several species within the Myrtaceae family, highlighting significant expansions in metabolic pathways such as the citric acid cycle, glycolysis/gluconeogenesis, and phenylpropanoid biosynthesis throughout their evolutionary process. Transcriptome analysis of jaboticaba fruits of different colors revealed that the development of fruit skin color in jaboticaba is associated with the phenylpropanoid and flavonoid biosynthesis pathways, with the flavanone 3-hydroxylase (F3H) gene potentially regulating fruit skin color. Additionally, by constructing the regulatory pathway of the citric acid cycle, we found that low citric acid content is correlated with high expression levels of genes such as thiamin diphosphate (ThDP) and low expression of phosphoenolpyruvate carboxykinase (PEPCK), indicating that PEPCK positively regulates citric acid content. These T2T genomic resources will accelerate jaboticaba pepper genetic improvement and help to understand jaboticaba genome evolution.}, }
@article {pmid39595175, year = {2024}, author = {Lv, J and Zhao, X and Zhao, L and Gong, C and Zheng, W and Guo, L and Wang, J and Liang, T}, title = {The Notable Role of Telomere Length Maintenance in Complex Diseases.}, journal = {Biomedicines}, volume = {12}, number = {11}, pages = {}, pmid = {39595175}, issn = {2227-9059}, support = {62171236//National Natural Science Foundation of China/ ; BE2022799//the Key Project of Social Development in Jiangsu Province, China/ ; 22KJA180006//the Key Projects of Natural Science Research in Universities of Jiangsu Province, China/ ; NA//the Priority Academic Program Development of Jiangsu Higher Education Institution (PAPD)/ ; }, abstract = {Telomere length function serves as a critical biomarker for biological aging and overall health. Its maintenance is linked to cancer, neurodegenerative conditions, and reproductive health. This review mainly examines genetic variations and environmental influences on telomere dynamics, highlighting key regulatory genes and mechanisms. Advances in telomere measurement methodologies are also reviewed, underscoring the importance of precise telomere assessment for disease prevention and treatment. Telomerase activation offers potential for cellular lifespan extension and anti-aging effects, whereas its inhibition emerges as a promising therapeutic approach for cancer. Regulatory mechanisms of tumor suppressor genes on telomerase activity are analyzed, with a comprehensive overview of the current state and future potential of telomerase inhibitors. In addition, the association between telomeres and neurodegenerative diseases is discussed, detailing how telomere attrition heightens disease risk and outlining multiple pathways by which telomerase protects neurons from damage and apoptosis.}, }
@article {pmid39590949, year = {2024}, author = {Jiang, Y and Xu, Z and Wang, M and Liu, H and Li, Y and Xu, S}, title = {Association Between Prenatal Exposure to Organochlorine Pesticides and Telomere Length in Neonatal Cord Blood.}, journal = {Toxics}, volume = {12}, number = {11}, pages = {}, doi = {10.3390/toxics12110769}, pmid = {39590949}, issn = {2305-6304}, support = {(91643207, 81273083)//National Natural Science Foundation of China/ ; (2017YFC0212003)//National Key R&D Program of China/ ; (JCYJ20210324131213037)//Shenzhen Science and Technology Innovation Committee/ ; (SZSM202103008)//High-Level Project of Medicine in Nanshan, Shenzhen; Sanming Project of Medicine in Shenzhen/ ; }, abstract = {Objectives: Environmental exposure may affect the telomere length (TL) of newborns, which is considered as an early biomarker indicating susceptibility for later life diseases. However, the effects of prenatal organochlorine pesticide (OCP) exposure on newborn TL remain unclear. This study aimed to investigate the association between prenatal exposure levels of OCPs during pregnancy and TL in neonatal cord blood. Methods: A total of 168 mother-infant pairs from a birth cohort in Wuhan, China, were included this study. The concentrations of hexachlorocyclohexanes (HCHs, including β-HCH, α-HCH, and γ-HCH), p,p'-dichlorodiphenyltrichloroethane (p,p'-DDT) and its metabolites (p,p'-dichlorodiphenyldichloroethane, p,p'-DDD; p,p'-dichlorodiphenyldichloroethylene, p,p'-DDE) were measured in cord blood. The associations between the OCPs and the TL in newborns were analyzed by a generalized linear regression model. Stratified analyses by newborn sex, maternal gestational weight gain, and pregnancy body mass index (BMI) were performed to evaluate if the associations were modified by these factors. Results: The detection rates of various OCPs ranged from 50.9% to 100.0%. The median concentration of p,p'-DDE was the highest (33.90 ng/g lipid), followed by β-HCH (8.67 ng/g lipid), and the median concentrations of the other OCPs were between 0.12 and 0.33 ng/g lipid. Among the all newborns, a two-fold increase in the γ-HCH concentration in the cord blood was significantly associated with a 0.024 (95% CI: -0.041, -0.007) decrease in the TL. After stratification by newborn sex, the inverse association between γ-HCH and the TL was only statistically significant in boys, but not in girls (P for interaction <0.05). In addition, after stratification by pre-pregnancy BMI, β-HCH and p,p'-DDT concentrations were significantly associated with a decreased TL in the overweight pre-pregnancy BMI group [-0.111 (95% CI: -0.203, -0.018) and -0.036 (95% CI: -0.049, -0.023), respectively]. Conclusions: Prenatal exposure to OCPs during pregnancy was associated with a decreased neonatal telomere length, which may be affected by the newborn sex and pre-pregnancy BMI. These findings may provide new insights into the mechanisms underlying OCP-induced adverse health effects.}, }
@article {pmid39589440, year = {2024}, author = {Hong, L and Xu, XD and Yang, L and Wang, M and Li, S and Yang, H and Ye, SY and Chen, LL and Song, JM}, title = {Construction and analysis of telomere-to-telomere genomes for 2 sweet oranges: Longhuihong and Newhall (Citrus sinensis).}, journal = {GigaScience}, volume = {13}, number = {}, pages = {}, doi = {10.1093/gigascience/giae084}, pmid = {39589440}, issn = {2047-217X}, support = {KYLX20240900007//Chongqing Municipal Financial Science and Technology Innovation Project/ ; NKY-2022AB005//Ministry of Agriculture/ ; }, mesh = {*Citrus sinensis/genetics ; *Genome, Plant ; *Telomere/genetics ; Genomics/methods ; }, abstract = {BACKGROUND: Sweet orange (Citrus sinensis Osbeck) is a fruit crop of high nutritional value that is widely consumed around the world. However, its susceptibility to low-temperature stress limits its cultivation and production in regions prone to frost damage, severely impacting the sustainable development of the sweet orange industry. Therefore, developing cold-resistant sweet orange varieties is of great necessity. Traditional hybrid breeding methods are not feasible due to the polyembryonic phenomenon in sweet oranges, necessitating the enhancement of its germplasm through molecular breeding. High-quality reference genomes are valuable for studying crop resistance to biotic and abiotic stresses. However, the lack of genomic resources for cold-resistant sweet orange varieties has hindered the progress in developing such varieties and researching their molecular mechanisms of cold resistance.
FINDINGS: This study integrated PacBio HiFi, ONT, Hi-C, and Illumina sequencing data to assemble telomere-to-telomere (T2T) reference genomes for the cold-resistant sweet orange mutant "Longhuihong" (Citrus sinensis [L.] Osb. cv. LHH) and its wild-type counterpart "Newhall" (C. sinensis [L.] Osb. cv. Newhall). Comprehensive evaluations based on multiple criteria revealed that both genomes exhibit high continuity, completeness, and accuracy. The genome sizes were 340.28 Mb and 346.33 Mb, with contig N50 of 39.31 Mb and 36.77 Mb, respectively. In total, 31,456 and 30,021 gene models were annotated in the respective genomes. Leveraging these assembled genomes, comparative genomics analyses were performed, elucidating the evolutionary history of the sweet orange genome. Moreover, the study identified 2,886 structural variants between the 2 genomes, with several SVs located in the upstream, downstream, or intronic regions of homologous genes known to be associated with cold resistance.
CONCLUSIONS: The study de novo assembled 2 T2T reference genomes of sweet orange varieties exhibiting different levels of cold tolerance. These genomes serve as valuable foundational resources for genomic research and molecular breeding aimed at enhancing cold tolerance in sweet oranges. Additionally, they expand the existing repository of reference genomes and sequencing data resources for C. sinensis. Moreover, these genomes provide a critical data foundation for comparative genomics analyses across different plant species.}, }
@article {pmid39587573, year = {2024}, author = {Hassan, R and Bhat, GR and Mir, FA and Ganie, HA and Mushtaq, I and Bhat, MA and Asimi, RP and Afroze, D}, title = {Concomitant telomere attrition is associated with spinal muscular atrophy in highly inbred region of North India: unraveling the thread in Kashmir region.}, journal = {BMC medical genomics}, volume = {17}, number = {1}, pages = {275}, pmid = {39587573}, issn = {1755-8794}, mesh = {Humans ; *Muscular Atrophy, Spinal/genetics ; India ; Male ; Female ; *Telomere Shortening ; *Telomere/genetics ; Child, Preschool ; Child ; Case-Control Studies ; Adolescent ; Infant ; Survival of Motor Neuron 1 Protein/genetics ; Adult ; }, abstract = {Spinal muscular atrophy (SMA) is a rare genetic disorder that unequivocally results in the degeneration of motor neurons, leading to muscle weakness and atrophy. This condition is caused by a mutation in the survival motor neuron 1 (SMN1) gene, which inevitably results in a deficiency of the SMN protein. In present study, we investigated the potential role of telomere attrition in SMA patients. Relative telomere length in peripheral blood lymphocytes was measured by Monochrome Multiplex Quantitative Polymerase Chain Reaction (MMQPCR) in 98 subjects and we conclusively found that SMA cases exhibit telomere attrition compared to healthy controls (P = 4 × 10[- 2]). Moreover, significant attrition was also observed in severe form of SMA, i.e. SMA type 0 (P = 0.04) as well.Although, the exact mechanism through which telomere shortening contributes to the pathogenesis of SMA is not fully understood and is yet to be delineated. However, one possibility is that telomere shortening leads to genomic instability and DNA damage, which can contribute to motor neuron degeneration. Another possibility is that telomere shortening leads to cellular senescence, which can impair the ability of motor neurons to regenerate and repair themselves. Recent studies have suggested that telomere shortening may be a potential therapeutic target in SMA. Thus, understanding the role of SMN1 gene in disease pathogenesis & its effect on telomere length will aid in estimating the risk & prognosis of SMA in genetically less explored & highly inbred region of Kashmir, Northern India.}, }
@article {pmid39586626, year = {2024}, author = {Baird, DM}, title = {Telomere Dynamics in Human Health and Disease.}, journal = {Cold Spring Harbor perspectives in biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/cshperspect.a041701}, pmid = {39586626}, issn = {1943-0264}, abstract = {Telomere function is critical for genomic stability; in the context of a functional TP53 response, telomere erosion leads to a G1/S cell-cycle arrest and the induction of replicative senescence, a process that is considered to underpin the ageing process in long-lived species. Abrogation of the TP53 pathway allows for continued cell division, telomere erosion, and the complete loss of telomere function; the ensuing genomic instability facilitates clonal evolution and malignant progression. Telomeres display extensive length heterogeneity in the population that is established at birth, and this affects the individual risk of a broad range of diseases, including cardiovascular disease and cancer. In this perspective, I discuss telomere length heterogeneity at the levels of the population, individual, and cell, and consider how the dynamics of these essential chromosomal structures contribute to human disease.}, }
@article {pmid39582797, year = {2025}, author = {Kaliman, P and Álvarez-López, MJ and Lehodey, A and Fernández, D and Chocat, A and Schlosser, M and de La Sayette, V and Vivien, D and Marchant, NL and Chételat, G and Lutz, A and Poisnel, G and , }, title = {Effect of an 18-Month Meditation Training on Telomeres in Older Adults: A Secondary Analysis of the Age-Well Randomized Controlled Trial.}, journal = {Biological psychiatry global open science}, volume = {5}, number = {1}, pages = {100398}, pmid = {39582797}, issn = {2667-1743}, abstract = {BACKGROUND: Shorter telomeres are associated with increased risk of cognitive decline and age-related diseases. Developing interventions to promote healthy aging by preserving telomere integrity is of paramount importance. Here, we investigated the effect of an 18-month meditation intervention on telomere length (TL) measures in older people without cognitive impairment.
METHODS: A total of 137 adults age ≥65 years were randomized to one of the 3 groups (meditation training, non-native language training, or passive control). We evaluated the 50th and 20th percentile TL and the percentage of critically short telomeres (<3 kbp) in peripheral blood mononuclear cells.
RESULTS: Mixed model analysis showed a time effect indicating a general decrease on the 50th percentile TL (F = 80.72, p adjusted < .001), without a significant group effect or time × group interaction. No significant effect was detected in the 20th percentile TL or the percentage of critically short telomeres. Secondary analysis showed that only in the meditation training group 1) the 50th percentile TL positively correlated with class attendance time (r = 0.45, p adjusted < .011), 2) the 50th and 20th percentile TL positively correlated with responsiveness to the intervention, evaluated through a composite score (r = 0.46, p adjusted < .010 and r = 0.41, p adjusted = .029, respectively), and 3) lower scores on a measure of the personality trait "openness to experience" correlated with a lower percentage of critically short telomeres after the intervention (r = 0.44, p adjusted = .015).
CONCLUSIONS: In older adults, we found no evidence for a main effect of an 18-month meditation training program on TL compared with the control groups. Our findings highlight the importance of considering the impact of moderating factors when measuring the effectiveness of meditation-based trainings.}, }
@article {pmid39580387, year = {2024}, author = {Li, P and Meng, L and Tu, H and Luo, S and Gong, X}, title = {The impact of Radioresistant-Related Telomere Genes in the prognosis and immune infiltration in lung adenocarcinoma.}, journal = {Cancer cell international}, volume = {24}, number = {1}, pages = {387}, pmid = {39580387}, issn = {1475-2867}, support = {82473378//National Natural Science Foundation of China/ ; 2021071//Shanghai Talents Development Fund Project/ ; SKPY2021006//Clinical Research fundation of Shanghai Pulmonary Hospital/ ; fkzr2436//National Natural Science Foundation Cultivation Project of Shanghai Pulmonary Hospital/ ; }, abstract = {INTRODUCTION: Lung adenocarcinoma (LUAD), a common subtype of NSCLC, has a high mortality rate. Telomere genes are influenced by radiation therapy, affecting treatment response. Additionally, immune cell presence in the tumor microenvironment plays a crucial role in cancer prognosis. However, the role of Radioresistant-Related Telomere Genes (RRTGs) in LUAD prognosis and immune infiltration remains unclear.
METHODS: In this research, we utilized diverse bioinformatics techniques to examine our personally tested information along with publicly accessible datasets. We conducted a comprehensive study on the genetic and transcriptional differences, predictive significance, and expression profiles of RRTGs. Afterwards, a RRTGs score was developed to forecast the overall survival (OS) and ascertain its reliable predictive capacity for patients with LUAD. Following this, dependable nomograms were developed to enhance the practicality of RRTGs scoring in a clinical setting. Furthermore, the investigation delved into the associations among RRTGs, infiltration of immune cells, prognosis, and clinical treatments of patients. Gene Set Enrichment Analysis (GSEA) was conducted to explore the potential mechanisms by which RRTGs influence the regulation of LUAD. Then, Western blot, qRT-PCR and Immunohistochemistry were used to detect the expression levels of RRTGs in cell lines and LUAD tumor tissues.
RESULTS: Our research indicates that certain genes related to telomeres have a notable correlation with the prognosis of patients diagnosed with LUAD. The RRTGs score, which includes three key genes (ARRB1, PLK1, and DSG2), was developed to forecast the OS and its dependable predictive capability for individuals diagnosed with LUAD was ascertained. Afterwards, extremely reliable nomograms were developed to improve the practicality of the RRTGs score. Moreover, as illustrated, genetic characteristics can be utilized to assess the infiltration of immune cells in tumors, as well as clinical attributes and prognosis. RRTGs score characterizes tumor mutational burden, immune activity, and notable survival probabilities in addition. Furthermore, GSEA results revealed that RRTGs may influence LUAD by modulating immune-related pathways in high-risk groups and regulating cell cycle and DNA repair processes in low-risk groups. The RRTGs (ARRB1 and PLK1) were upregulated in A549 cells and radiosensitive NSCLC tissues compared to radioresistant A549 cells and NSCLC tissues.
CONCLUSION: In conclusion, this research emphasizes the significance of RRTGs in the outlook of LUAD. The findings contributed to a better understanding of the link between radiotherapy, telomere-related genes, and prognosis in LUAD, and identified potential therapeutic targets for patients with LUAD.}, }
@article {pmid39578472, year = {2024}, author = {Lu, S and Liu, Y and Li, M and Ge, Q and Wang, C and Song, Y and Zhou, B and Chen, S}, title = {Gap-free telomere-to-telomere haplotype assembly of the tomato hind (Cephalopholis sonnerati).}, journal = {Scientific data}, volume = {11}, number = {1}, pages = {1268}, pmid = {39578472}, issn = {2052-4463}, mesh = {*Haplotypes ; *Telomere/genetics ; *Solanum lycopersicum/genetics ; Animals ; High-Throughput Nucleotide Sequencing ; Genome, Plant ; Bees/genetics ; }, abstract = {The tomato hind (Cephalopholis sonnerati) is an emerging economically important grouper in recent years. With the increasing maturity of sequencing technologies and assembly methodologies, a higher quality reference genome has become both accessible and necessary. In this study, we present two telomere-to-telomere (T2T) gap-free haplotype assemblies of the tomato hind with lengths of 1039.53 Mb (YSFRI_Csonn_HA_1.0, N50 43.83 Mb) and 1039.91 Mb (YSFRI_Csonn_HB_1.0, N50 44.09 Mb). Reads from next-generation sequencing, ONT ultra-long sequencing, and PacBio HiFi sequencing exhibited mapping rates exceeding 99.8% when aligned to these two assemblies. Evaluation using Merqury indicated high accuracy for both assemblies, with average quality values of 51.80 and 51.83, respectively. Percentages of 97.9% and 97.8% of complete BUSCOs were achieved, and a total of 23,270 and 23,184 protein-code genes were inferred in each assembly. Moreover, telomere identification, centromere prediction, and repetitive sequence annotation were also successfully performed. These two assemblies provide robust foundation for the genetic analysis and development of molecular genetic breeding technologies in C. sonnerati.}, }
@article {pmid39574740, year = {2024}, author = {Mohanty, SK and Chiaromonte, F and Makova, KD}, title = {Evolutionary Dynamics of G-Quadruplexes in Human and Other Great Ape Telomere-to-Telomere Genomes.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2024.11.05.621973}, pmid = {39574740}, issn = {2692-8205}, abstract = {G-quadruplexes (G4s) are non-canonical DNA structures that can form at approximately 1% of the human genome. G4s contribute to point mutations and structural variation and thus facilitate genomic instability. They play important roles in regulating replication, transcription, and telomere maintenance, and some of them evolve under purifying selection. Nevertheless, the evolutionary dynamics of G4s has remained underexplored. Here we conducted a comprehensive analysis of predicted G4s (pG4s) in the recently released, telomere-to-telomere (T2T) genomes of human and other great apes-bonobo, chimpanzee, gorilla, Bornean orangutan, and Sumatran orangutan. We annotated tens of thousands of new pG4s in T2T compared to previous ape genome assemblies, including 41,236 in the human genome. Analyzing species alignments, we found approximately one-third of pG4s shared by all apes studied and identified thousands of species- and genus-specific pG4s. pG4s accumulated and diverged at rates consistent with divergence times between the studied species. We observed a significant enrichment and hypomethylation of pG4 shared across species at regulatory regions, including promoters, 5' and 3'UTRs, and origins of replication, strongly suggesting their formation and functional role in these regions. pG4s shared among great apes displayed lower methylation levels compared to species-specific pG4s, suggesting evolutionary conservation of functional roles of the former. Many species-specific pG4s were located in the repetitive and satellite regions deciphered in the T2T genomes. Our findings illuminate the evolutionary dynamics of G4s, their role in gene regulation, and their potential contribution to species-specific adaptations in great apes, emphasizing the utility of high-resolution T2T genomes in uncovering previously elusive genomic features.}, }
@article {pmid39574517, year = {2024}, author = {Peker Eyüboğlu, İ and Koca, S and Çelik, B and Güllü Amuran, G and Uğurlu, MÜ and Alan, Ö and Akın Telli, T and Yumuk, PF and Akkiprik, M}, title = {Neoadjuvant Chemotherapy Shortens the cfDNA Telomere Length in Breast Cancer Patients.}, journal = {International journal of breast cancer}, volume = {2024}, number = {}, pages = {6117394}, pmid = {39574517}, issn = {2090-3170}, abstract = {Introduction: Cancer is a genetic disease that affects people worldwide, and breast cancer is the most common cancer in women. Studies have been conducted on molecular parameters to predict tumor behavior and develop therapeutic strategies. Telomeres, which are at the end of chromosomes, have been studied for their relationship with breast cancer, but more research is needed to understand their role in the disease. Circulating-free DNA (cfDNA) is DNA that is free in the bloodstream and is considered a promising target for early cancer detection, treatment response monitoring, and prognosis assessment. This study is aimed at comparing cfDNA telomere length of breast cancer patients and healthy individuals and analyzing the impact of neoadjuvant chemotherapy on telomere length in cfDNA. Materials and Methods: Blood samples were collected from 33 breast cancer patients undergoing neoadjuvant chemotherapy before and after treatment. The quantitative PCR method is used to measure the average telomere lengths. Results: This study found that the telomere length of cfDNA in breast cancer patients before and after treatment is significantly shorter than in the control group. Neoadjuvant chemotherapy is found to shorten the cfDNA telomere length, especially in the treatment-responsive group. Conclusion: Our study suggests that telomere length in cfDNA may be a useful biomarker for predicting therapy response and possible reoccurrence of the disease in breast cancer patients.}, }
@article {pmid39574146, year = {2024}, author = {Wang, L and Zhang, J and Liu, F and Shi, Q and Gao, F and Li, J and Liu, Y and Kong, F and Xu, D}, title = {Maternal infection of SARS-CoV-2 during the first and second trimesters leads to newborn telomere shortening.}, journal = {Journal of translational medicine}, volume = {22}, number = {1}, pages = {1049}, pmid = {39574146}, issn = {1479-5876}, mesh = {Humans ; Female ; Infant, Newborn ; *COVID-19/virology ; Pregnancy ; *Telomere Shortening ; Adult ; *Pregnancy Complications, Infectious/virology ; *SARS-CoV-2/physiology ; Pregnancy Trimester, Second ; Placenta/virology/metabolism ; Fetal Blood/virology ; Telomere/metabolism ; Cytokines/metabolism/blood ; Male ; }, abstract = {BACKGROUND: Initial telomere length (TL) in newborns is the major determinant for TL in later life while TL in newborn/early-life predicts long-term health and lifespan. It is important to identify key factors that affect telomere homeostasis throughout embryonic development for precision interventions to maintain optimal TL in fetus/prenatal infants. SARS-CoV-2 has caused a widespread global pandemic of COVID-19, but it remains unclear whether maternal SARS-CoV-2 infection impairs prenatal telomere homeostasis.
METHODS: We recruited 413 normally delivered newborns whose mothers were either non-infected or infected with SARS-CoV-2 during different trimesters of pregnancy (otherwise healthy). Telomere length (TL) in cord blood (CB) was assessed using qPCR. CB and maternal blood were analyzed for cytokine levels. Placental senescence was determined using senescence-associated β-galactosidase staining.
RESULTS: Control (non-infected maternal) newborn TL was significantly longer than that from maternal infection (1.568 ± 0.340 vs 1.390 ± 0.350, P = 0.005). Such shorter TL was observed only if maternal infection of SARS-CoV-2 occurred in the first and second trimesters of pregnancy (1.261 ± 0.340 and 1.346 ± 0.353, P < 0.0001 and 0.001, respectively). There were no differences in TL between controls and infection at the third trimester (1.568 ± 0.340 vs 1.565 ± 0.329, P > 0.05). Across the first trimester, there was a positive correlation between newborn TL and gestational weeks with maternal infection, suggesting that the earlier maternal infection occurs, the worse effect is taken on fetal telomere homeostasis. Placental senescence coupled with the downregulated expression of telomerase reverse transcriptase was significantly more frequent from the maternal infection at the first trimester. There were no differences in IL-6, C reactive protein and other cytokine levels in CB and maternal serum or placentas.
CONCLUSIONS: Maternal SARS-CoV-2 infection at the first and second trimesters leads to significantly shorter TL and earlier infection causes much more severe TL damage. The infection-mediated cell senescence and other histopathological abnormalities result in defective placental function through which fetal telomere homeostasis is impaired. Thus, vaccination against COVID-19 should be done in advance for women who plan pregnancy.}, }
@article {pmid39568075, year = {2024}, author = {Di Pietro, E and Burla, R and La Torre, M and González-García, MP and Dello Ioio, R and Saggio, I}, title = {Telomeres: an organized string linking plants and mammals.}, journal = {Biology direct}, volume = {19}, number = {1}, pages = {119}, pmid = {39568075}, issn = {1745-6150}, support = {A0375E0189-2020-36640//POR FESR Lazio 2014-2020/ ; 20229LHY5L//Ministero dell'Università e della Ricerca/ ; IG-24614//Fondazione AIRC per la ricerca sul cancro ETS/ ; }, abstract = {Telomeres are pivotal determinants of cell stemness, organismal aging, and lifespan. Herein, we examined similarities in telomeres of Arabidopsis thaliana, mice, and humans. We report the common traits, which include their composition in multimers of TTAGGG sequences and their protection by specialized proteins. Moreover, given the link between telomeres, on the one hand, and cell proliferation and stemness on the other, we discuss the counterintuitive convergence between plants and mammals in this regard, focusing on the impact of niches on cell stemness. Finally, we suggest that tackling the study of telomere function and cell stemness by taking into consideration both plants and mammals can aid in the understanding of interconnections and contribute to research focusing on aging and organismal lifespan determinants.}, }
@article {pmid39567477, year = {2024}, author = {Wu, H and Luo, LY and Zhang, YH and Zhang, CY and Huang, JH and Mo, DX and Zhao, LM and Wang, ZX and Wang, YC and He-Hua, E and Bai, WL and Han, D and Dou, XT and Ren, YL and Dingkao, R and Chen, HL and Ye, Y and Du, HD and Zhao, ZQ and Wang, XJ and Jia, SG and Liu, ZH and Li, MH}, title = {Telomere-to-telomere genome assembly of a male goat reveals variants associated with cashmere traits.}, journal = {Nature communications}, volume = {15}, number = {1}, pages = {10041}, pmid = {39567477}, issn = {2041-1723}, support = {2021YFD1200900//Ministry of Science and Technology of the People's Republic of China (Chinese Ministry of Science and Technology)/ ; }, mesh = {Animals ; *Goats/genetics ; *Telomere/genetics ; Male ; *Polymorphism, Single Nucleotide ; *Genome/genetics ; Breeding ; Genetic Variation ; Y Chromosome/genetics ; Genomic Structural Variation ; }, abstract = {A complete goat (Capra hircus) reference genome enhances analyses of genetic variation, thus providing insights into domestication and selection in goats and related species. Here, we assemble a telomere-to-telomere (T2T) gap-free genome (2.86 Gb) from a cashmere goat (T2T-goat1.0), including a Y chromosome of 20.96 Mb. With a base accuracy of >99.999%, T2T-goat1.0 corrects numerous genome-wide structural and base errors in previous assemblies and adds 288.5 Mb of previously unresolved regions and 446 newly assembled genes to the reference genome. We sequence the genomes of five representative goat breeds for PacBio reads, and use T2T-goat1.0 as a reference to identify a total of 63,417 structural variations (SVs) with up to 4711 (7.42%) in the previously unresolved regions. T2T-goat1.0 was applied in population analyses of global wild and domestic goats, which revealed 32,419 SVs and 25,397,794 SNPs, including 870 SVs and 545,026 SNPs in the previously unresolved regions. Also, our analyses reveal a set of selective variants and genes associated with domestication (e.g., NKG2D and ABCC4) and cashmere traits (e.g., ABCC4 and ASIP).}, }
@article {pmid39563242, year = {2024}, author = {Ferguson, S and Bar-Ness, YD and Borevitz, J and Jones, A}, title = {Correction: A telomere-to-telomere Eucalyptus regnans genome: unveiling haplotype variance in structure and genes within one of the world's tallest trees.}, journal = {BMC genomics}, volume = {25}, number = {1}, pages = {1107}, doi = {10.1186/s12864-024-10952-5}, pmid = {39563242}, issn = {1471-2164}, }
@article {pmid39561615, year = {2024}, author = {Panelli, DM and Mayo, JA and Wong, RJ and Becker, M and Feyaerts, D and Marić, I and Wu, E and Gotlib, IH and Gaudillière, B and Aghaeepour, N and Druzin, ML and Stevenson, DK and Shaw, GM and Bianco, K}, title = {Corrigendum to "Mode of delivery predicts postpartum maternal leukocyte telomere length" [Eur. J. Obstetr. Gynecol. Reprod. Biol. 300 (2024) 224-229].}, journal = {European journal of obstetrics, gynecology, and reproductive biology}, volume = {304}, number = {}, pages = {35}, doi = {10.1016/j.ejogrb.2024.11.017}, pmid = {39561615}, issn = {1872-7654}, }
@article {pmid39561502, year = {2024}, author = {Pedklang, N and Navasumrit, P and Chompoobut, C and Promvijit, J and Hunsonti, P and Ruchirawat, M}, title = {Effects of particulate air pollution on BPDE-DNA adducts, telomere length, and mitochondrial DNA copy number in human exhaled breath condensate and BEAS-2B cells.}, journal = {International journal of hygiene and environmental health}, volume = {263}, number = {}, pages = {114488}, doi = {10.1016/j.ijheh.2024.114488}, pmid = {39561502}, issn = {1618-131X}, abstract = {Traffic-related particulate matter (PM) and polycyclic aromatic hydrocarbons (PAHs) have been linked to respiratory diseases and cancer risk in humans. Genomic damage, including benzo[a]pyrene diolepoxide (BPDE)-DNA adducts as well as alterations in telomere length (TL) and mitochondrial DNA copy number (mtDNA-CN) are associated with respiratory diseases. This study aimed to investigate the association between exposure to traffic-related particulate pollutants and genomic damage in exhaled breath condensate (EBC) in human subjects and a bronchial epithelial cell line (BEAS-2B). Among the 60 healthy recruited subjects, residents living in high-traffic-congested areas were exposed to higher concentrations of PM2.5 (1.66-fold, p < 0.01), UFPs (1.79-fold, p < 0.01), PM2.5-PAHs (1.50-fold, p < 0.01), and UFPs-PAHs (1.35-fold, p < 0.05), than those in low-traffic-congested areas. In line with increased exposure to particulate air pollution, the high-traffic-exposed group had significantly increased BPDE-DNA adducts (1.40-fold, p < 0.05), TL shortening (1.24-fold, p < 0.05), and lower mtDNA-CN (1.38-fold, p < 0.05) in EBC. The observations in the human study linking exposure to PM2.5, UFPs, PM2.5-PAHs, and UFPs-PAHs with the aforementioned biological effects were confirmed by an in vitro cell-based study, in which BEAS-2B cells were treated with diesel exhaust particulate matter (DEP) containing fine and ultrafine PM and PAHs. Increased BPDE-DNA adducts levels, shortened TL, and decreased mtDNA-CN were also found in treated BEAS-2B cells. The shortened TL and decreased mtDNA-CN were in part mediated by decreased transcript levels of hTERT, and SIRT1, which are involved in telomerase activity and mitochondrial biogenesis, respectively. These results suggest that exposure to traffic-related particulate pollutants can cause genomic instability in respiratory cells, which may increase the health risk of respiratory diseases and the development of cancer.}, }
@article {pmid39556024, year = {2024}, author = {Laemmerer, A and Lehmann, C and Mayr, L and Bruckner, K and Gabler, L and Senfter, D and Meyer, P and Balber, T and Pirker, C and Jaunecker, CN and Kirchhofer, D and Vician, P and Griesser, M and Spiegl-Kreinecker, S and Schmook, MT and Traub-Weidinger, T and Kuess, P and Eckert, F and Federico, A and Madlener, S and Stepien, N and Robl, B and Baumgartner, A and Hainfellner, JA and Dieckmann, K and Dorfer, C and Roessler, K and Corsini, NS and Holzmann, K and Schmidt, WM and Peyrl, A and Azizi, AA and Haberler, C and Beck, A and Pfister, SM and Schueler, J and Loetsch-Gojo, D and Knoblich, JA and Berger, W and Gojo, J}, title = {Alternative lengthening of telomere-based immortalization renders H3G34R -mutant diffuse hemispheric glioma hypersensitive to PARP inhibitor combination regimens.}, journal = {Neuro-oncology}, volume = {}, number = {}, pages = {}, doi = {10.1093/neuonc/noae228}, pmid = {39556024}, issn = {1523-5866}, abstract = {BACKGROUND: Diffuse hemispheric glioma, H3G34R/V-mutant (DHG-H3G34) is characterized by poor prognosis and lack of effective treatment options. DHG-H3G34R further harbor deactivation of Alpha-Thalassemia/Mental Retardation Syndrome X-linked protein (ATRX; DHG-H3G34R_ATRX) suggesting a unique interaction of these two oncogenic alterations. In this study, we dissect their cell biological interplay, investigate the impact on telomere stabilization and, consequently, validate a targeted therapy approach.
METHODS: We characterized patient-derived primary pediatric high-grade glioma (pHGG) models for telomere-maintenance mechanisms, DNA damage stress (including protein expression, pH2AX/Rad51 foci, cell-cycle arrest) and their sensitivity towards poly-ADP polymerase inhibitor (PARPi) combinations. Human induced pluripotent stem cells (iPSCs) were used for modelling the disease. The anticancer activity of PARPi combinations in vivo was studied in Chorioallantoic Membrane (CAM) and orthotopic in vivo experiments. Finally, we treated a DHG-H3G34R_ATRX patient with a PARPi combination therapy.
RESULTS: We elaborate that alternative lengthening of telomeres (ALT) is a key characteristic of DHG-H3G34R_ATRX. A dominant cooperative effect between H3G34R and ATRX loss in ALT activation also became apparent in iPSCs, which endogenously exert telomerase activity. In both, patient-derived DHG-H3G34R_ATRX models and H3G34R+/ATRX- iPSCs, the ALT phenotype was associated with increased basal DNA damage stress, mediating synergistic susceptibility towards PARPi (talazoparib, niraparib) combinations with topoisomerase-I inhibitors (topotecan, irinotecan). In a first-of-its-kind case, treatment of a DHG-H3G34R_ATRX patient with the brain-penetrant PARP inhibitor niraparib and topotecan resulted in a significant tumor reduction.
CONCLUSION: Our preclinical and clinical data strongly support the further development of PARPis together with DNA damage stress-inducing treatment regimens for DHG-H3G34R_ATRX.}, }
@article {pmid39554689, year = {2024}, author = {Pearce, E and Majid, A and Brown, T and Wilsnack, C and Rising, C and Thompson, AS and Shepherd, RF and Niknafs, A and Werner-Lin, A and Gilkey, MB and Ribisl, KM and Hutson, SP and Han, PKJ and Savage, SA}, title = {A "rotating menu" of medical uncertainty for families affected by telomere biology disorders: A qualitative interview study.}, journal = {SSM. Qualitative research in health}, volume = {6}, number = {}, pages = {}, pmid = {39554689}, issn = {2667-3215}, abstract = {BACKGROUND: Medical uncertainty may cause distress and challenge medical decision-making for patients with rare diseases and their caregivers. Few studies have examined the experience and management of medical uncertainty in rare disease and the dynamics of multiple medical uncertainty sources, issues, and management strategies.
OBJECTIVE: We explored the experience and management of uncertainty in individuals with telomere biology disorders (TBDs), a set of rare cancer-prone bone marrow failure syndromes, and their caregivers.
DESIGN: Participants (N=32) in this qualitative-descriptive study were individuals with a TBD (n=17) and/or their caregivers (n=15). We thematically analyzed transcripts to describe the presence and dynamics of medical uncertainty in TBDs using categories from a previously published taxonomy.
RESULTS: Individuals with TBDs and caregivers described medical uncertainty as a chronic burden embodied amidst a range of interrelated sources and issues. Scientific uncertainty included diagnostic and prognostic ambiguity. Practical uncertainty focused on logistical challenges of building and maintaining medical care teams. Personal uncertainty included difficulty realigning self-identity, goals, and relationship expectations post-diagnosis. Scientific, practical, and personal uncertainty issues were entangled. The rarity of TBDs resulted in limited scientific knowledge, which gave rise to practical and personal uncertainties affecting medical decision-making and relationship formation (e.g., creating trusted care teams where patient knowledge of TBDs may exceed that of clinicians). Participants used multiple strategies for uncertainty management, particularly information-seeking and community-building. However, these management strategies could intensify, rather than resolve, participants' medical uncertainty.
CONCLUSION: In TBDs, medical uncertainty manifests as a network of multiple, interrelated, sources and issues, which require evolving management strategies. Researchers must be mindful that complex, synergistic uncertainty networks contribute to psychosocial challenges in TBDs. Additional research is warranted to address scientific uncertainty in TBDs, including clinical manifestations and underlying biology, and to develop psychosocial interventions that recognize and anticipate evolving uncertainty.}, }
@article {pmid39554068, year = {2024}, author = {Chung, G and Piano, F and Gunsalus, KC}, title = {TeloSearchLR: an algorithm to detect novel telomere repeat motifs using long sequencing reads.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2024.10.29.617943}, pmid = {39554068}, issn = {2692-8205}, abstract = {Telomeres are eukaryotic chromosome end structures that guard against sequence loss and aberrant chromosome fusions. Telomeric repeat motifs (TRMs), the minimal repeating unit of a telomere, vary from species to species, with some evolutionary clades experiencing a rapid sequence divergence. To explore the full scope of this evolutionary divergence, many bioinformatic tools have been developed to infer novel TRMs using repetitive sequence search on short sequencing reads. However, novel telomeric motifs remain unidentified in up to half of the sequencing libraries assayed with these tools. A possible reason may be that short reads, derived from extensively sheared DNA, preserve little to no positional context of the repetitive sequences assayed. On the other hand, if a sequencing read is sufficiently long, telomeric sequences must appear at either end rather than in the middle. The TeloSearchLR algorithm relies on this to help identify novel TRMs on long reads, in many cases where short-read search tools have failed. In addition, we demonstrate that TeloSearchLR can reveal unusually long telomeric motifs not maintained by telomerase, and it can also be used to anchor terminal scaffolds in new genome assemblies.}, }
@article {pmid39553389, year = {2024}, author = {Packer, A and Habiballa, L and Tato-Barcia, E and Breen, G and Brooker, H and Corbett, A and Arathimos, R and Ballard, C and Hampshire, A and Palmer, A and Dima, D and Aarsland, D and Creese, B and Malanchini, M and Powell, TR}, title = {Telomere length and cognitive changes in 7,877 older UK adults of European ancestry.}, journal = {Frontiers in aging}, volume = {5}, number = {}, pages = {1480326}, pmid = {39553389}, issn = {2673-6217}, abstract = {BACKGROUND: Telomere length (TL) has been linked to cognitive function, decline and dementia. This study aimed to explore whether both measured TL and genetic disposition for TL predict dimensions of cognitive performance in a longitudinal sample of older UK adults.
METHODS: We analysed data from PROTECT study participants aged ≥50 years without a dementia diagnosis, who had completed longitudinal cognitive testing. We calculated polygenic scores for telomere length (PGS-TL) for 7,877 participants and measured relative telomere length (RTL) in a subgroup of 846 participants using DNA extracted from saliva samples collected within 6 months either side of their baseline cognitive testing. Latent growth models were used to examine whether RTL and PGS-TL predict both baseline and longitudinal changes in cognitive performance (4 time-points, annually).
RESULTS: In the whole sample, we did not observe significant associations between either measure of telomere length and initial or longitudinal changes in cognitive performance. Stratifying by median age, in older adults (≥ ∼62 years), longer baseline RTL showed a nominal association with poorer baseline verbal reasoning performance (n = 423, M intercept = 47.58, B = -1.05, p = .011) and PGS-TL was associated with performance over time (n = 3,939; slope factor, M slope = 3.23, B = -0.45, p = .001; slope [2] factor, M slope [2] = 0.21, B = 0.13, p = .002).
CONCLUSION: Our findings suggest either the absence of a significant relationship between telomere length (RTL and PGS-TL) and cognitive performance (baseline and change over time), or possibly a weak age-dependent and domain-specific relationship, in older adults of European ancestry. More research is needed in representative and ancestrally diverse samples over a longer assessment period. Alternative biological ageing indicators may still provide utility in the early detection of individuals at risk for cognitive decline (e.g., pace-of ageing epigenetic clocks).}, }
@article {pmid39553152, year = {2024}, author = {Xie, S and Xiao, H and Zhang, F and Lan, Y and Luo, M}, title = {Identification and Validation of Telomere-Related Gene Signature in Intervertebral Disc Degeneration.}, journal = {Cureus}, volume = {16}, number = {10}, pages = {e71735}, pmid = {39553152}, issn = {2168-8184}, abstract = {This study investigates the role of telomere-related differentially expressed genes (TRDEGs) in intervertebral disc degeneration (IVDD) through comprehensive bioinformatics analyses. Data were sourced from the Gene Expression Omnibus (GEO) with datasets GSE245147 and GSE124272 used for initial identification and validation, respectively. The GSE245147 dataset comprised transcriptional profiles from nucleus pulposus cells of both degenerated and non-degenerated human nucleus pulposus (NP) tissues. Using the limma package, 198TRDEGs were identified by intersecting differentially expressed genes (DEGs) with telomere-related genes (TRGs) from the TelNet database. Functional enrichment analyses using the Database for Annotation, Visualization and Integrated Discovery (DAVID) revealed that TRDEGs are significantly involved in cell division, chromosome segregation, and other mitotic processes. Protein-protein interaction (PPI) networks constructed using the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) database and visualized with Cytoscape (Cytoscape Consortium, San Diego, CA, USA) identified key hub genes such as CDK1, CCNA2, and AURKB. Pearson correlation and receiver operating characteristic (ROC) analyses highlighted five hub genes (ASPM, BUB1B, CDC20, KIF2C, TTK) with significant predictive value for IVDD. Additionally, mRNA-microRNA (miRNA) interaction analysis using NetworkAnalyst identified key miRNAs interacting with these hub genes. This study provides insights into the molecular mechanisms of IVDD and identifies potential targets for therapeutic intervention.}, }
@article {pmid39548087, year = {2024}, author = {Piras, M and Lin, J and Sadler, MC and Ranjbar, S and Grosu, C and Laaboub, N and Preisig, M and Gamma, F and Plessen, KJ and von Gunten, A and Conus, P and Kutalik, Z and Eap, CB}, title = {Psychotropic-induced weight gain and telomere length: results from a one-year longitudinal study and a large population-based cohort.}, journal = {Translational psychiatry}, volume = {14}, number = {1}, pages = {471}, pmid = {39548087}, issn = {2158-3188}, mesh = {Humans ; *Weight Gain/drug effects/genetics ; Male ; Female ; Longitudinal Studies ; *Psychotropic Drugs/adverse effects ; Middle Aged ; *Telomere Shortening/drug effects ; Adult ; *C-Reactive Protein ; Body Mass Index ; Telomere/drug effects/genetics ; Aged ; }, abstract = {Weight-inducing psychotropic treatments are risk factors for age-related diseases such as cardiovascular disorders, which are associated with both inflammation and telomere length shortening. With a longitudinal design, the present study evaluates telomere length trajectories after 1 year of weight-inducing psychotropic medication, accounting for weight changes and the inflammatory biomarker high-sensitivity C-Reactive Protein (CRP). Among 200 patients, an overall median telomere shortening of -41.2 bp was observed (p = 0.014), which is comparable with the general population's yearly telomere attrition. Linear regression showed on average -93.1 and -58.9 bp of further telomere shortening per five units of BMI for BMI values < or ≥30 kg/m[2], respectively (p = 0.003 and p = 0.009, respectively). Importantly, the overall telomere shortening was predicted to be increased four-fold among patients with low baseline weight (i.e., 50 kg) and with clinically relevant weight gain (≥ 7%) after 1 year of treatment (interaction term between relevant weight gain and baseline weight: +6.3 bp, p = 0.016). Patients with relevant weight gain showed greater CRP levels (+ 49%; p = 0.016), and a telomere shortening of -36.2 bp (p = 0.010) was estimated whenever CRP level doubled. Mendelian randomization using UKBiobank data showed a causal effect of BMI on telomere shortening, notably stronger among patients receiving weight-inducing psychotropic treatments (n = 9798) than among psychiatric patients without such drugs (n = 16228) and non-psychiatric controls (n = 252932) (beta: -0.37, -0.12, -0.06, respectively; p = 0.004, p < 0.001, p < 0.001, respectively). Ultimately, telomere trajectories were associated with 1 year weight gain and increases in CRP levels, with telomere shortening strongly enhanced by BMI increments among patients receiving weight-inducing psychotropic treatments.}, }
@article {pmid39543404, year = {2024}, author = {Muñoz-Pardeza, J and López-Gil, JF and Huerta-Uribe, N and Hormazábal-Aguayo, I and Ojeda-Rodríguez, A and Del Moral, AM and Izquierdo, M and García-Hermoso, A}, title = {Is physical fitness associated with leucocyte telomere length in youth with type 1 diabetes?.}, journal = {Pediatric research}, volume = {}, number = {}, pages = {}, pmid = {39543404}, issn = {1530-0447}, abstract = {BACKGROUND: In type 1 diabetes, telomere length (TL) may predict complications and could be influenced by glycaemic control and physical activity, but its relationship with physical fitness in youths remains unexplored. The aim of the study was to assess the association between physical fitness and TL in youth with type 1 diabetes, both at baseline and one year later.
METHODS: Eighty-three children and adolescents (aged 6-18 years; 44.6% girls) with type 1 diabetes from the Diactive-1 Cohort Study were involved in this study. Physical fitness was assessed using spirometry on a cycloergometer (i.e., peak oxygen consumption), dynamometry, and maximal isometric strength (one-repetition maximum [1RM]), and muscle power. Leucocyte TL was assessed using multiplex monochrome real-time quantitative polymerase chain reaction.
RESULTS: Positive cross-sectional associations were identified between 1RM (unstandardized beta coefficient [B] = 0.042, 95% bias corrected and accelerated [BCa] confidence interval [CI] 0.012-0.069), muscle power (B = 0.056, 95% BCa CI 0.02-0.250), and overall physical fitness (B = 0.043, 95% BCa CI 0.015-0.071) with TL independent of maturation, glycated haemoglobin, and diabetes duration. However, no associations were observed one year later.
CONCLUSION: Higher levels of fitness, particularly muscle strength, may play a role in telomere dynamics in youth with type 1 diabetes, suggesting that strength training exercise could be beneficial.
IMPACT: This is the first study to examine cross-sectional and longitudinal perspectives on the correlation among muscle strength, peak oxygen consumption [VO2peak] and telomere length in youths with type 1 diabetes. Higher physical fitness levels, as assessed by measures such as one-repetition maximum, muscle power, and overall physical fitness, are positively associated with telomere length in youths with type 1 diabetes. Understanding this link could improve management strategies, prioritizing muscle strength training for better long-term health in type 1 diabetes.}, }
@article {pmid39538053, year = {2024}, author = {da Cunha Agostini, L and da Silva, GN}, title = {Telomere length as a biomarker for cerebrovascular diseases: current evidence.}, journal = {Molecular biology reports}, volume = {51}, number = {1}, pages = {1150}, pmid = {39538053}, issn = {1573-4978}, support = {001//Coordenação de Aperfeiçoamento de Pessoal de Nível Superior/ ; 314486/2023-2//Conselho Nacional de Desenvolvimento Científico e Tecnológico , Brasil/ ; APQ-03555-22//Fundação de Amparo à Pesquisa do Estado de Minas Gerais , Brasil/ ; 23109.016819/2023-81//Pró-Reitoria de Pesquisa e Pós-Graduação, Universidade Federal de Ouro Preto/ ; 23109.009436/2023-56//Pró-Reitoria de Pesquisa e Pós-Graduação, Universidade Federal de Ouro Preto/ ; }, mesh = {Humans ; *Cerebrovascular Disorders/genetics/diagnosis ; *Biomarkers ; *Telomere/genetics/metabolism ; Risk Factors ; Telomere Homeostasis ; Telomere Shortening/genetics ; Stroke/genetics ; }, abstract = {Cerebrovascular disease (CVD) includes a range of conditions affecting the brain's blood vessels, which can result in reduced blood flow to brain tissue. The most common manifestation of CVD is stroke, the second leading cause of death and the third leading cause of disability worldwide. Major risk factors for CVD encompass gender, age, smoking, hypertension, diabetes, physical inactivity, obesity, alcohol consumption, and metabolic syndrome. Research suggests a link between telomere length and an increased risk of CVD, particularly in ischemic stroke cases. This review highlights key findings on the relationship between telomere length and CVD, underscoring its clinical importance. The analysis utilizes scientific literature from PubMed, Scopus, and SciELO up to 2024. Results show that shorter telomere length is associated with various types of CVD, including stroke, ischemic stroke, hemorrhagic stroke, and cardioembolic stroke. Some studies propose that telomere length measurement could be a valuable biomarker for CVD, potentially improving prevention, diagnosis, and management strategies.}, }
@article {pmid39537670, year = {2024}, author = {Katneni, VK and Krishnan, K and Prabhudas, SK and Jayaraman, R and Quraishi, N and Vasagam, K and Jangam, AK and Angel, JRJ and Kaikkolante, N and Jayaraman, K and Mudagandur, SS}, title = {Genome assembly at chromosome scale with telomere ends for Pearlspot, Etroplus suratensis.}, journal = {Scientific data}, volume = {11}, number = {1}, pages = {1226}, pmid = {39537670}, issn = {2052-4463}, support = {BT/PR34518/AAQ/3/965/2019//Department of Biotechnology, Ministry of Science and Technology (DBT)/ ; }, mesh = {Animals ; *Cichlids/genetics ; *Genome ; *Telomere/genetics ; Chromosomes ; Salinity ; }, abstract = {The pearlspot, Etroplus suratensis is a climate resilient cichlid fish that exhibits unusual adaptation to salinity. The fish is able to complete full life cycle in diverse salinity habitats ranging from fresh water to marine environments. High-quality primary and phased genome assemblies were generated for pearlspot fish using PacBio HiFi and Arima HiC sequencing technologies, for the first time. The primary assembly is highly contiguous with contig N50 length of 36 Mb. The final assembly is of 1.247 Gb with N50 length of 51.57 Mb and 98% of the genome length anchored to 24 chromosomes. The genome was assessed to be 99.9% complete based on BUSCO evaluation and was predicted to contain 52.96% repeat elements. We have predicted 27,192 protein encoding genes, of which 21,580 were functionally annotated. The genome offers an invaluable resource to understand adaptation of pearlspot fish to diverse salinity habitats.}, }
@article {pmid39533571, year = {2024}, author = {Li, J and Hu, L and Huang, X}, title = {Causal relationship between leukocyte telomere length and two cardiomyopathies based on a bidirectional Mendelian randomization approach.}, journal = {Medicine}, volume = {103}, number = {45}, pages = {e40308}, doi = {10.1097/MD.0000000000040308}, pmid = {39533571}, issn = {1536-5964}, support = {No. 2022YFC3500102//National Key Research and Development Program of China/ ; }, mesh = {Humans ; *Mendelian Randomization Analysis ; *Leukocytes ; Telomere/genetics ; Cardiomyopathy, Dilated/genetics ; Cardiomyopathies/genetics ; Cardiomyopathy, Hypertrophic/genetics ; Genetic Predisposition to Disease ; }, abstract = {This study aims to employ the Mendelian randomization (MR) approach to investigate the relationship between leukocyte telomere length (TL) and 2 prevalent forms of cardiomyopathies. Using R software (4.3.1) for MR study, independent genetic variants associated with leukocyte TL were extracted from the Integrative Epidemiology Unit database, while cardiomyopathies data were pooled from FinnGen and European Bioinformatics Institute databases. Analytical methodologies included inverse-variance weighting, MR-Egger regression, and weighted median methods. Further analyses involved MR-Egger intercept and MR-PRESSO for handling horizontal pleiotropy and Cochran Q test for study heterogeneity. Our forward Mendelian randomization study indicates a positive correlation between longer leukocyte TL and the risk of 2 forms of cardiomyopathies: the longer the leukocyte telomere, the higher is the risk of cardiomyopathies. Specifically, for hypertrophic obstructive cardiomyopathy the OR is 2.23 (95% CI: 1.19-4.14, P = .01), for hypertrophic cardiomyopathy the OR is 1.80 (95% CI: 1.14-2.85, P = .01), and for dilated cardiomyopathy the OR is 1.32 (95% CI: 1.01-1.71, P = .04). In contrast, our reverse Mendelian randomization showed that cardiomyopathies were not directly associated with TL, and the inverse-variance-weighted test was not statistically significant for any of the 3 (P > .05). The reliability tests for the forward Mendelian randomization, including both MR-Egger intercept and MR-PRESSO tests, show no evidence of horizontal pleiotropy, and Cochran Q test indicates no heterogeneity. The "leave-one-out" sensitivity analysis revealed no outlier genes. The reliability tests for the reverse Mendelian randomization, including both MR-Egger intercept and MR-PRESSO tests, also indicate no genetic pleiotropy. Despite the heterogeneity shown in our study between hypertrophic cardiomyopathy and leukocyte TL, the sensitivity analysis did not identify any anomalies. Our Mendelian randomization study suggests that longer leukocyte TL is associated with an increased risk of hypertrophic obstructive cardiomyopathy, hypertrophic cardiomyopathy, and dilated cardiomyopathy. However, the onset of these 2 kinds of disease does not directly lead to changes in leukocyte TL.}, }
@article {pmid39531590, year = {2024}, author = {Zhang, B and Zhao, Y}, title = {Association Analysis of Telomere Length and Vision in a Large Community-Based Survey.}, journal = {Ophthalmic epidemiology}, volume = {}, number = {}, pages = {1-7}, doi = {10.1080/09286586.2024.2422349}, pmid = {39531590}, issn = {1744-5086}, abstract = {PURPOSE: To investigate whether there is a direct, age-independent association between telomere length and visual acuity decline in a large community-based cohort study.
METHODS: Participants older than 40 with linked leukocyte telomere length (LTL) were enrolled in NHANES. LTL was assayed using qPCR from the participants' blood samples. Best corrected visual acuity (BCVA) of the better-seeing eye was analyzed, with visual impairment (VI) defined as BCVA ≥ 20/40. LTL was grouped into quartiles, and its association with BCVA and VI was evaluated after adjusting for covariates.
RESULTS: Among the 4,480 enrolled participants, the weighted means of age, BCVA, and telomere length were 56.1 ± 11.9 years, 0.05 ± 0.08 logMAR, and 5,662 ± 36 base pairs, respectively. The proportion of VI was 2.6%. After adjusting for covariates including sex, ethnicity, education, family poverty income ratio, general health status, hypertension, diabetes, smoking, and body mass index, BCVA was significantly worse in participants with shorter LTL, with a significant trend (p = 0.002). However, after further adjusting for age, the association between LTL and BCVA was no longer significant, without a trend (p = 0.640). No significant association or trend between LTL and VI was found in the stepwise logistic model.
CONCLUSIONS: No age-independent association between LTL and BCVA was found. Our study indicates LTL may not serve as a biomarker for age-related visual acuity decline.}, }
@article {pmid39529015, year = {2024}, author = {Zeng, F and Chen, Y and Lin, J}, title = {Identification of alternative lengthening of telomeres-related genes prognosis model in hepatocellular carcinoma.}, journal = {BMC cancer}, volume = {24}, number = {1}, pages = {1386}, pmid = {39529015}, issn = {1471-2407}, mesh = {Humans ; *Carcinoma, Hepatocellular/genetics/pathology/mortality ; *Liver Neoplasms/genetics/pathology/mortality ; Prognosis ; *Biomarkers, Tumor/genetics ; *Gene Expression Regulation, Neoplastic ; Telomere Homeostasis/genetics ; Cell Proliferation/genetics ; Nomograms ; Cell Line, Tumor ; Female ; Male ; Gene Expression Profiling ; Kaplan-Meier Estimate ; }, abstract = {BACKGROUND: Hepatocellular carcinoma (HCC) is a common malignant tumor worldwide, characterized by high mortality. This study aimed to explore the prognostic value and function of alternative lengthening of telomeres (ALT)-related genes in HCC.
METHODS: Differentially expressed genes (DEGs) were identified based on The Cancer Genome Atlas (TCGA) and then intersected with ALT-related genes to obtain ALTDEGs. Risk score model was constructed using the least absolute shrinkage and selection operator (LASSO) algorithm and Cox regression and validated with Gene Expression Omnibus (GEO) datasets. The predictive efficacy of the risk score and ALTs-score was evaluated by Kaplan-Meier curves, time-ROC curves, and the nomogram analyses. The impacts of SMG5 silencing on the HCC cell behaviors were assessed by CCK-8, wound healing, and Transwell assays.
RESULTS: A total of 500 ALTDEGs were screened and 13 genes (CDCA8, SMG5, RAD54B, FOXD2, NOL10, RRP12, CCT5, CCT4, HDAC1, DDX1, HRG, HDAC2, and PPP1CB) were identified for constructing a prognostic model. The overall survival (OS) curves, time-ROC curves, and nomograms based on the risk score or ALTs-score were developed to optimally predict the survival of HCC patients. ALTs-score was correlated with immune infiltration and confirmed its value in predicting immunotherapy outcomes. Furthermore, RT-qPCR demonstrated that eight risk signature genes were up-regulated in HCC cells. SMG5 silencing suppressed the proliferation, migration, and invasion of HCC cells. It was also found that SMG5 silencing reduced C-circle level in SNU-387 cells.
CONCLUSION: We identified new ALT-related prognostic biomarkers for HCC. SMG5 knockdown inhibited the HCC progression, which might be a promising target for HCC therapy.}, }
@article {pmid39528945, year = {2024}, author = {Kezer, CA and Kusztos, V and Kassmeyer, B and Lennon, R and Rattan, P and Kamath, PS and Shah, VH and Simonetto, DA}, title = {Impact of sociodemographic disparities on sarcopenia, telomere length, and mortality in patients with liver disease in the US population.}, journal = {BMC gastroenterology}, volume = {24}, number = {1}, pages = {404}, pmid = {39528945}, issn = {1471-230X}, mesh = {Humans ; *Sarcopenia/mortality ; Male ; Female ; Middle Aged ; *Liver Diseases/mortality ; United States/epidemiology ; Aged ; Adult ; *Nutrition Surveys ; Age Factors ; Telomere/genetics ; Proportional Hazards Models ; Telomere Shortening ; Sociodemographic Factors ; Socioeconomic Factors ; Comorbidity ; }, abstract = {BACKGROUND & AIMS: Sarcopenia is common in patients with liver disease and both sarcopenia and short telomeres are associated with mortality, however their relationship in patients with liver disease remains unknown.
METHODS: A cohort of 16,072 adults from the National Health and Nutrition Examination Survey from 1999 to 2006 was analyzed. Liver disease was defined by aminotransferases and classified into etiology-based categories. Sarcopenia was defined by dual-energy x-ray absorptiometry. All analyses were conducted separately on each multiple imputation data set and combined via Rubin's rules. P-values for group comparisons were calculated by testing logistic regression parameter estimates. Cox proportional hazards regression was used for mortality analysis with mortality data available until 2015.
RESULTS: Sarcopenia was present in 9.5% of patients with liver disease. Age, race, income, education, physical inactivity, and certain medical comorbidities were associated with sarcopenia. Patients with liver disease and sarcopenia had significantly shorter telomeres than patients with liver disease without sarcopenia when unadjusted for age. The interaction between telomere length and sarcopenia was significantly associated with all-cause mortality.
CONCLUSIONS: The implications of telomere length on all-cause mortality in patients with liver disease varied by age and sarcopenia status. Shorter telomeres appear to be more highly associated with increased mortality in older patients without sarcopenia.}, }
@article {pmid39528488, year = {2024}, author = {Giaccherini, M and Clay-Gilmour, AI and Liotti, R and Macauda, A and Gentiluomo, M and Brown, EE and Machiela, MJ and Chanock, SJ and Hildebrandt, MAT and Norman, AD and Manasanch, E and Rajkumar, SV and Hofmann, JN and Berndt, SI and Bhatti, P and Giles, GG and Ziv, E and Kumar, SK and Camp, NJ and Cozen, W and Slager, SL and Canzian, F and Gemignani, F and Vachon, CM and Campa, D}, title = {Genetically determined telomere length in monoclonal gammopathy of undetermined significance, multiple myeloma risk and outcome.}, journal = {Blood cancer journal}, volume = {14}, number = {1}, pages = {200}, pmid = {39528488}, issn = {2044-5385}, }
@article {pmid39527203, year = {2025}, author = {Zhang, H and Kerr, C and Audry, J and Runge, KW}, title = {A Rapidly Inducible DNA Double-Strand Break to Monitor Telomere Formation, DNA Repair, and Checkpoint Activation.}, journal = {Methods in molecular biology (Clifton, N.J.)}, volume = {2862}, number = {}, pages = {209-221}, pmid = {39527203}, issn = {1940-6029}, mesh = {*DNA Breaks, Double-Stranded ; *Schizosaccharomyces/genetics/metabolism ; *DNA Repair ; *Telomere/metabolism/genetics ; Cell Cycle Checkpoints ; Deoxyribonucleases, Type II Site-Specific/metabolism ; DNA, Fungal/genetics/metabolism ; Schizosaccharomyces pombe Proteins/metabolism/genetics ; }, abstract = {The study of processes that govern genome integrity has been augmented by the ability to create a precise DNA double-strand break (DSB) in a short period of time that allows the kinetics of DNA metabolism and protein recruitment to be followed. Defined DSBs are made by expressing endonucleases with long recognition sites that are rare or absent in the genome, and require that the endonuclease is only active when induced. Research in this area in Schizosaccharomyces pombe was limited because rapidly inducible promoters were not available until around 2005, and several rapidly inducible DSB systems are now available. Here, we describe a system to rapidly induce a modified I-SceI endonuclease that can generate a DSB 20 min after induction. I-SceI has no recognition sites in the S. pombe genome, allowing the introduction of complex substrates to monitor the effects of a new DSB in real time. This chapter describes how I-SceI can be most efficiently induced and a simple cell length measurement assay to monitor cell cycle checkpoint activation from a single DSB.}, }
@article {pmid39526375, year = {2024}, author = {Blanchard, M and Lin, J and Hurley, S and Goldberg, D and Von Behren, J and Wang, SS and Reynolds, P and Clague DeHart, J}, title = {Telomere length and chronotype among women in the California Teachers Study (CTS).}, journal = {Chronobiology international}, volume = {}, number = {}, pages = {1-12}, doi = {10.1080/07420528.2024.2422865}, pmid = {39526375}, issn = {1525-6073}, abstract = {While links between certain chronotypes and poorer health outcomes have been well established in previous studies, few studies have examined the relationship between chronotype and cellular aging. Using data from the California Teachers Study (CTS), the present study evaluates the relationship between cellular aging and chronobiology through an analysis of leukocyte telomere length (LTL) and chronotype among 817 predominantly postmenopausal women with no history of cancer and occupations not associated with night-shift work. Unconditional logistic regression models were run to estimate odds ratios (ORs) for each chronotype category, adjusted for age, ethnicity, and smoking status. Analyses were then stratified by potential modifiers to assess whether results varied among specific subgroups within the sample. Women who reported being current evening types and evening types from teen years to now were significantly less likely to have short LTL compared to women who reported being current morning types or morning types from teen years to now (OR = 0.72; 95% CI = 0.53-0.98; OR = 0.57; 95% CI = 0.39-0.84). Our results suggest that women with no history of cancer who identify as evening chronotypes may undergo decreased cellular aging compared to women in the same population who identify as morning types. Further studies on populations of postmenopausal women are warranted.}, }
@article {pmid39525171, year = {2024}, author = {Mazumdar, J and Chowdhury, P and Mondal, BC and Das, AK and Ghosh, U}, title = {Elevated Telomeric Repeat-Containing RNA (TERRA) Levels Linked to Telomere Dysfunction and Telomerase Inactivity in Blood Cells of Children With Aplastic Anemia.}, journal = {Cureus}, volume = {16}, number = {10}, pages = {e71241}, doi = {10.7759/cureus.71241}, pmid = {39525171}, issn = {2168-8184}, abstract = {Background Aplastic anemia (AA) is characterized by pancytopenia and hypocellularity of the bone marrow. Certain inherited or genetic forms of AA have also been associated with telomere dysfunction. Here, we report the clinical manifestations of eleven AA patients aged between one and 12 years, along with the expression of a few candidate genes involved in the telomere length (TL) maintenance pathway. Methods The clinical manifestations were recorded for all the patients. The average telomere length of peripheral blood mononuclear cells (PBMC), the expression of telomerase subunits, telomere-associated proteins, and chromosome-specific telomeric repeat-containing RNA (TERRA) in whole blood cells of each patient was compared with an age-matched control group consisting of five clinically confirmed normal individuals. Results Out of 11 AA patients, four were found to have upper limb anomalies, and two showed short stature along with other defects. All the patients showed significantly shorter telomere length compared with the age-matched control group. The essential subunits of telomerase (hTERT and hTERC) were significantly low, and the shelterin protein is abnormally expressed in all patients implicating a compromised TL maintenance pathway. Notably, AA with combined androgen and prednisolone treatment showed a marked reduction of TERRA level than that of AA without androgen/prednisolone therapy. Conclusion Based on the findings and observations made, it appears that there might be an association between telomere dysfunction and elevated levels of TERRA in patients diagnosed with aplastic anemia who are 12 years of age or younger.}, }
@article {pmid39523870, year = {2024}, author = {Qi, X and Gao, L and Qi, L}, title = {Genetic Determinants of Telomere Length and Risk of Aneurysmal Subarachnoid Hemorrhage: A Bidirectional Two-Sample Mendelian Randomization Study.}, journal = {The International journal of neuroscience}, volume = {}, number = {}, pages = {1-22}, doi = {10.1080/00207454.2024.2414285}, pmid = {39523870}, issn = {1563-5279}, abstract = {BACKGROUND: Our objective is to investigate the potential causal relationship between telomere length (TL) and aneurysmal subarachnoid hemorrhage (aSAH) and intracranial aneurysms (IAs) by conducting a bidirectional two-sample Mendelian Randomization (MR) study.
METHODS: We utilized publicly available summary data from genome-wide association studies (GWAS) for comprehensive analysis. Telomere length-associated data were sourced from the Epidemiology Unit (IEU) GWAS database (n = 472,174), while data pertaining to intracranial aneurysms were derived from a GWAS meta-analysis conducted by Bakker et al, encompassing aneurysmal subtypes including aSAH (n = 77,074), IAs (n = 79,429), and unruptured intracranial aneurysms (uIA) (n = 74,004), all sampled from European populations. The primary method for MR analysis employed was the Inverse Variance Weighted (IVW) method. Additionally, we conducted various sensitivity analyses to assess the heterogeneity and pleiotropy of study findings. Reverse MR analysis was employed to explore potential reverse causality.
RESULTS: In the forward MR analysis, the IVW method indicated a negative association between TL and aSAH (OR = 0.636, 95% CI: 0.459-0.883, p = 0.006) as well as IAs (OR = 0.670, 95% CI: 0.499-0.900, p = 0.0079). There was no evidence of heterogeneity or horizontal pleiotropy in the forward MR analysis. Reverse MR analysis did not reveal any causal relationship between aSAH, IAs, uIA and TL.
CONCLUSIONS: In European populations, there exists a causal relationship between longer TL and reduced risks of aSAH and IAs Further research is warranted to elucidate the underlying mechanisms and the potential of TL as an intervention target for lowering the incidence of aSAH and IAs.}, }
@article {pmid39522643, year = {2024}, author = {Heaphy, CM and Patel, S and Smith, K and Wondisford, AR and Lynskey, ML and O'Sullivan, RJ and Fuhrer, K and Han, X and Seethala, RR and Liu, TC and Cao, D and Ertunc, O and Zheng, Q and Stojanova, M and Zureikat, AH and Paniccia, A and Lee, K and Ongchin, MC and Pingpank, JF and Zeh, HJ and Hogg, ME and Geller, D and Marsh, JW and Brand, RE and Chennat, JS and Das, R and Fasanella, KE and Gabbert, C and Khalid, A and McGrath, K and Lennon, AM and Sarkaria, S and Singh, H and Slivka, A and Hsu, D and Zhang, JY and Nacev, BA and Nikiforova, MN and Wald, AI and Vaddi, N and De Marzo, AM and Singhi, AH and Bell, PD and Singhi, AD}, title = {Detection of Alternative Lengthening of Telomeres via Chromogenic in situ Hybridization (ALT-CISH) for the Prognostication of PanNETs and Other Neoplasms.}, journal = {Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc}, volume = {}, number = {}, pages = {100651}, doi = {10.1016/j.modpat.2024.100651}, pmid = {39522643}, issn = {1530-0285}, abstract = {Molecular studies have shown ALT to be an important prognostic biomarker of shorter relapse-free survival (RFS) for patients with pancreatic neuroendocrine tumors (PanNETs) and other neoplasms. However, the preferred method of detecting ALT in tissue is by fluorescence in situ hybridization (FISH), which has several clinical limitations. These issues necessitate the creation of a chromogenic ALT assay that can be easily implemented into routine practice. A CISH assay was developed using genetically modified osteosarcoma cell lines, 20 normal pancreata, 20 ALT-positive PanNETs, and 20 ALT-negative PanNETs. Thereafter, it was validated on a multi-institutional cohort of 360 surgically resected PanNETs and correlated with multiple clinicopathologic features, RFS, and FISH results. Separately, 109 leiomyosarcomas (LMS) were evaluated by both CISH and FISH, and, similarly, the prognostic significance of ALT status was assessed. Upon optimization, ALT-CISH was identified in 112 of 360 (31%) primary PanNETs and was 100% concordant with FISH testing. ALT correlated with several adverse prognostic findings and distant metastasis (all p<0.004). The 5-year RFS for patients with ALT-positive PanNETs was 35% as compared to 94% for ALT-negative PanNETs. By multivariate analysis, ALT was an independent prognostic factor for shorter RFS. Similarly, ALT was associated with shorter RFS in LMS patients and, analogous to PanNETs, a negative, independent prognostic factor. ALT-CISH was developed and validated in not only PanNETs, but also sarcomas, specifically LMS. CISH testing has multiple advantages over FISH that facilitate its widespread clinical use in the detection of ALT and prognostication of patients with diverse neoplasms.}, }
@article {pmid39520989, year = {2024}, author = {Mostovoy, Y and Boone, PM and Huang, Y and Garimella, KV and Tan, KT and Russell, BE and Salani, M and de Esch, CEF and Lemanski, J and Curall, B and Hauenstein, J and Lucente, D and Bowers, T and DeSmet, T and Gabriel, S and Morton, CC and Meyerson, M and Hastie, AR and Gusella, J and Quintero-Rivera, F and Brand, H and Talkowski, ME}, title = {Resolution of ring chromosomes, Robertsonian translocations, and complex structural variants from long-read sequencing and telomere-to-telomere assembly.}, journal = {American journal of human genetics}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.ajhg.2024.10.006}, pmid = {39520989}, issn = {1537-6605}, abstract = {Delineation of structural variants (SVs) at sequence resolution in highly repetitive genomic regions has long been intractable. The sequence properties, origins, and functional effects of classes of genomic rearrangements such as ring chromosomes and Robertsonian translocations thus remain unknown. To resolve these complex structures, we leveraged several recent milestones in the field, including (1) the emergence of long-read sequencing, (2) the gapless telomere-to-telomere (T2T) assembly, and (3) a tool (BigClipper) to discover chromosomal rearrangements from long reads. We applied these technologies across 13 cases with ring chromosomes, Robertsonian translocations, and complex SVs that were unresolved by short reads, followed by validation using optical genome mapping (OGM). Our analyses resolved 10 of 13 cases, including a Robertsonian translocation and all ring chromosomes. Multiple breakpoints were localized to genomic regions previously recalcitrant to sequencing such as acrocentric p-arms, ribosomal DNA arrays, and telomeric repeats, and involved complex structures such as a deletion-inversion and interchromosomal dispersed duplications. We further performed methylation profiling from long-read data to discover phased differential methylation in a gene promoter proximal to a ring fusion, suggesting a long-range position effect (LRPE) with heterochromatin spreading. Breakpoint sequences suggested mechanisms of SV formation such as microhomology-mediated and non-homologous end-joining, as well as non-allelic homologous recombination. These methods provide some of the first glimpses into the sequence resolution of Robertsonian translocations and illuminate the structural diversity of ring chromosomes and complex chromosomal rearrangements with implications for genome biology, prediction of LRPEs from integrated multi-omics technologies, and molecular diagnostics in rare disease cases.}, }
@article {pmid39514990, year = {2024}, author = {Amatya, S and Bhatia, P and Raina, S and Sreedharanunni, S and Singh, M and Rahman, E and Archana, MV and Trehan, A}, title = {Corrigendum to "Clinical utility of relative telomere length analysis in pediatric bone marrow failure" [Blood Cells Mol. Dis. 109 (2024) 102882].}, journal = {Blood cells, molecules & diseases}, volume = {110}, number = {}, pages = {102899}, doi = {10.1016/j.bcmd.2024.102899}, pmid = {39514990}, issn = {1096-0961}, }
@article {pmid39513855, year = {2024}, author = {Knecht, H and Petrogiannis-Haliotis, T and Louis, S and Mai, S}, title = {3D-Q-FISH/Telomere/TRF2 Nanotechnology Identifies a Progressively Disturbed Telomere/Shelterin/Lamin AC Complex as the Common Pathogenic, Molecular/Spatial Denominator of Classical Hodgkin Lymphoma.}, journal = {Cells}, volume = {13}, number = {21}, pages = {}, doi = {10.3390/cells13211748}, pmid = {39513855}, issn = {2073-4409}, mesh = {*Hodgkin Disease/genetics/pathology/virology/metabolism/diagnosis ; Humans ; *Telomere/metabolism ; Cell Line, Tumor ; In Situ Hybridization, Fluorescence ; Nanotechnology/methods ; Reed-Sternberg Cells/metabolism/pathology ; Shelterin Complex/metabolism ; }, abstract = {The bi- or multinucleated Reed-Sternberg cell (RS) is the diagnostic cornerstone of Epstein-Barr Virus (EBV)-positive and EBV-negative classical Hodgkin lymphoma (cHL). cHL is a germinal center (GC)-derived B-cell disease. Hodgkin cells (H) are the mononuclear precursors of RS. An experimental model has to fulfill three conditions to qualify as common pathogenic denominator: (i) to be of GC-derived B-cell origin, (ii) to be EBV-negative to avoid EBV latency III expression and (iii) to support permanent EBV-encoded oncogenic latent membrane protein (LMP1) expression upon induction. These conditions are unified in the EBV-, diffuse large B-Cell lymphoma (DLBCL) cell line BJAB-tTA-LMP1. 3D reconstructive nanotechnology revealed spatial, quantitative and qualitative disturbance of telomere/shelterin interactions in mononuclear H-like cells, with further progression during transition to RS-like cells, including progressive complexity of the karyotype with every mitotic cycle, due to BBF (breakage/bridge/fusion) events. The findings of this model were confirmed in diagnostic patient samples and correlate with clinical outcomes. Moreover, in vitro, significant disturbance of the lamin AC/telomere interaction progressively occurred. In summary, our research over the past three decades identified cHL as the first lymphoid malignancy driven by a disturbed telomere/shelterin/lamin AC interaction, generating the diagnostic RS. Our findings may act as trailblazer for tailored therapies in refractory cHL.}, }
@article {pmid39512472, year = {2024}, author = {Zhu, S and Zheng, W and Rao, D and Tang, Z and Liao, X}, title = {Leukocyte telomere length and lung function: a mendelian randomization study in European population.}, journal = {Frontiers in physiology}, volume = {15}, number = {}, pages = {1373064}, doi = {10.3389/fphys.2024.1373064}, pmid = {39512472}, issn = {1664-042X}, abstract = {BACKGROUND: The telomere has long been regarded as a dependable biomarker for cellular senescence. The lung function can reflect the function and status of the lungs. As individuals age beyond adulthood, there is a gradual decline in lung function. However, the existence of a associated between leukocyte telomere length (LTL) and lung function remains uncertain.
METHODS: A two-sample Mendelian randomization (MR) analysis was used. The Single-nucleotide polymorphisms (SNPs) of LTL from the genome-wide association (GWAS) study were used as exposure instruments variable, and the lung function indicator including Forced expiratory volume in 1-s (FEV1), FEV1 Best measure, FEV1 predicted and Forced vital capacity (FVC) from the Neale Lab and MRC-IEU were used as outcomes. The associated between the exposures and outcomes was assessed using inverse-variance weighted (IVW), MR-Egger, and weighted median methods. Sensitivity analysis was conducted using Cochran's Q-test, MR-Egger intercept test, MR-PRESSO, leave-one-out analysis, and Steriger test.
RESULTS: Using the IVW method, a significant association was identified between genetically determined telomere length extension and enhanced lung function in FEV1, with ukb-a-336 (P = 0.127, OR = 1.028,95CI% = 1.003-1.042) and ukb-b-19657 (P = 7.26E-05, OR = 1.051,95CI% = 1.025-1.077),in FEV1 predicted, ukb-a-234 (P = 0.013, OR = 1.029,95CI% = 1.003-1.042), ukb-b-8428 (P = 0.001, OR = 1.032,95CI% = 1.012-1.052), in FEV1 best measure, ukb-a-231 (P = 7.24E-05, OR = 1.050,95CI% = 1.025-1.075), ukb-b-11141 (P = 1.40E-09, OR = 1.067,95CI% = 1.045-1.090).The sensitivity analysis did not reveal heterogeneity or horizontal pleiotropy.Meanwhile, the Steriger test results also indicate that the directionality between exposure and outcome is correct. Therefore, the results indicated robustness.
CONCLUSION: There is a correlation between longer LTL and better lung function in the European dataset.}, }
@article {pmid39511975, year = {2024}, author = {Hu, T and Duan, L and Shangguan, L and Zhao, Q and Hang, Y and Wang, X and Li, X and Yang, N and Yan, F and Lv, Q and Tang, L and Liu, M and Qiang, W and Wang, X and Wang, X and Zhang, M}, title = {Haploid-Phased Chromosomal Telomere-to-Telomere Genome Assembly of Medicinal Plant Uncaria rhynchophylla Dissects Genetic Controls on the Biosynthesis of Bioactive Alkaloids.}, journal = {Plant, cell & environment}, volume = {}, number = {}, pages = {}, doi = {10.1111/pce.15257}, pmid = {39511975}, issn = {1365-3040}, support = {//This work was supported by the Key Core Technology Research Project for Mountainous Agriculture in Guizhou (GZNYGJHX-2023011); the Major Special Project of Science and Technology Programme in Guizhou (2017-5411-06); the Construction Project of State Engineering Technology Institute for Karst Desertification Control of China (2012FU125X13); the Construction Project of Modern Industry Technology system of traditional Chinese Medicinal Materials in Guizhou (GZCYTX-02); Guizhou Provincial Basic Research Programme (Natural Science) (Qian Ke He Ji Chu-ZK [2022] General 096) and the Scientific Research Project of Ordinary Undergraduate Colleges and Universities of Guizhou Provincial Department of Education (Qian Jiao Ji [2022] No. 145)./ ; }, abstract = {Natural indole alkaloids provide important medicinal resources and defences to environmental stresses. The Uncaria genus is a recorded traditional medicinal woody plant with high alkaloids. Genomic insights into alkaloid variation remain elusive. Here, we have dissected the haploid-resolved chromosomal T2T genome assembly of Uncaria rhynchophylla with a size of ~634 Mb and contig N50 of 27 Mb using PacBio HiFi long-reads plus Hi-C reads and anchored the contigs on 22 pairs of confirmed chromosomes. This genome contains 56% repeat sequences and ~29 000 protein-encoding genes. U. rhynchophylla diverged from a common ancestor shared with Coffea around 20 million years ago and contains expanded and contracted gene families associated with secondary metabolites and defences/resistance to stresses. We constructed the pathway and mined genes for rhynchophylline alkaloid biosynthesis. Fifty-three alkaloids in this pathway and eight differentially expressed genes are the keys to alkaloid accumulation. Elevated alkaloid levels are driven by high copy numbers of critical genes STRs and SGRs involved in strictosidine synthesis and hydrolysis as evidenced by phylogenetic, expression and RNA interference analyses. These results advance our genetic understanding and guide further breeding improvements, stress adaptation studies and pharmaceutical development.}, }
@article {pmid39509271, year = {2024}, author = {Lynskey, ML and Brown, EE and Bhargava, R and Wondisford, AR and Ouriou, JB and Freund, O and Bowman, RW and Smith, BA and Lardo, SM and Schamus-Hayes, S and Hainer, SJ and O'Sullivan, RJ}, title = {HIRA protects telomeres against R-loop-induced instability in ALT cancer cells.}, journal = {Cell reports}, volume = {43}, number = {11}, pages = {114964}, doi = {10.1016/j.celrep.2024.114964}, pmid = {39509271}, issn = {2211-1247}, abstract = {Inactivating mutations in chromatin modifiers, like the α-thalassemia/mental retardation, X-linked (ATRX)-death domain-associated protein (DAXX) chromatin remodeling/histone H3.3 deposition complex, drive the cancer-specific alternative lengthening of telomeres (ALT) pathway. Prior studies revealed that HIRA, another histone H3.3 chaperone, compensates for ATRX-DAXX loss at telomeres to sustain ALT cancer cell survival. How HIRA rescues telomeres from the consequences of ATRX-DAXX deficiency remains unclear. Here, using an assay for transposase-accessible chromatin using sequencing (ATAC-seq) and cleavage under targets and release using nuclease (CUT&RUN), we establish that HIRA-mediated deposition of new H3.3 maintains telomeric chromatin accessibility to prevent the detrimental accumulation of nucleosome-free single-stranded DNA (ssDNA) in ATRX-DAXX-deficient ALT cells. We show that the HIRA-UBN1/UBN2 complex deposits new H3.3 to prevent TERRA R-loop buildup and transcription-replication conflicts (TRCs) at telomeres. Furthermore, HIRA-mediated H3.3 incorporation into telomeric chromatin links productive ALT to the phosphorylation of serine 31, an H3.3-specific amino acid, by Chk1. Therefore, we identify a critical role for HIRA-mediated H3.3 deposition that ensures the survival of ATRX-DAXX-deficient ALT cancer cells.}, }
@article {pmid39506437, year = {2024}, author = {Song, B and Lou, J and Mu, L and Lu, X and Sun, J and Tang, B}, title = {An Innovative Telomere-associated Prognosis Model in AML: Predicting Immune Infiltration and Treatment Responsiveness.}, journal = {Current medicinal chemistry}, volume = {}, number = {}, pages = {}, doi = {10.2174/0109298673334218241021044800}, pmid = {39506437}, issn = {1875-533X}, abstract = {AIMS: To build an innovative telomere-associated scoring model to predict prognosis and treatment responsiveness in acute myeloid leukemia (AML).
BACKGROUND: AML is a highly heterogeneous malignant hematologic disorder with a poor prognosis. While telomere maintenance is frequently observed in tumors, investigations into telomere-related genes (TRGs) in AML remain limited.
OBJECTIVES: This study aimed to identify prognostic TRGs using the least absolute shrinkage and selection operator (LASSO) Cox regression and multivariate Cox regression, evaluate their predictive value, explore the association between TRG scores and immune cell infiltration, and assess the sensitivity of high-scoring AML patients to chemotherapeutic agents.
METHOD: Univariate Cox regression analysis was conducted on the TCGA cohort to identify prognostic TRGs and to develop the TRG scoring model using LASSO-Cox and multivariate Cox regression. Validation was performed on the GSE37642 cohort. Immune cell infiltration patterns were assessed through computational analysis, and the sensitivity to chemotherapeutic agents was evaluated.
RESULTS: Thirteen prognostic TRGs were identified, and a seven-TRG scoring model (including NOP10, OBFC1, PINX1, RPA2, SMG5, MAPKAPK5, and SMN1) was developed. Higher TRG scores were associated with a poorer prognosis, as confirmed in the GSE37642 cohort, and remained an independent prognostic factor even after adjusting for other clinical characteristics. The high-score group was characterized by elevated infiltration of B cells, T helper cells, natural killer cells, tumor-infiltrating lymphocytes, regulatory T (Treg) cells, M2 macrophages, neutrophils, and monocytes, along with reduced infiltration of gamma delta T cells, CD4- T cells, and resting mast cells. Moreover, high infiltration of M2 macrophages and Tregs was associated with poor overall survival compared to low infiltration. Notably, high-risk AML patients were resistant to Erlotinib, Parthenolide, and Nutlin-3a, but sensitive to AC220, Midostaurin, and Tipifarnib. Additionally, using RT-qPCR, we observed significantly higher expression of two model genes, OBFC1 and SMN1, in AML tissues compared to control tissues.
CONCLUSION: This innovative TRG scoring model demonstrates considerable predictive value for AML patient prognosis, offering valuable insights for optimizing treatment strategies and personalized medicine approaches. The identified TRGs and associated scoring models could aid in risk stratification and guide tailored therapeutic interventions in AML patients.}, }
@article {pmid39506036, year = {2024}, author = {Allsopp, RC and Hernández, LM and Taylor, MK}, title = {The Val66Met variant of brain-derived neurotrophic factor is linked to reduced telomere length in a military population: a pilot study.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {27013}, pmid = {39506036}, issn = {2045-2322}, abstract = {In military populations, gene-environment interactions can influence performance and health outcomes. Brain-derived neurotrophic factor (BDNF) is a central nervous system protein that is important for neuronal function and synaptic plasticity. A BDNF single nucleotide polymorphism, rs6265, leads to an amino acid substitution of valine (Val) with methionine (Met) at codon 66 (Val66Met), which may influence an individual's response to occupational stress, and predispose military members to psychological disorders. Telomere length (TL), a novel measure of biological aging, can be used as a biomarker of stress. Accordingly, telomere shortening may be a surrogate indicator of physiological weathering due to chronic disease and stressful life events. To increase our understanding about the potential effect of the Val66Met mutation on the human stress response, we evaluated the relationships between Val66Met, TL, and mental health symptoms in a military population. In this pilot study (N = 164), we observed an association between Val66Met and reduced TL (p = 0.048). There was no relationship between Val66Met and mental health symptoms. These results support the investigation of gene-environment interactions, and their potential influence on TL due to occupational stress such as military service.}, }
@article {pmid39503976, year = {2024}, author = {Yılmaz, ŞG and Bozkurt, H}, title = {The expression of shelterin genes and telomere repeat analysis and their effect on Alzheimer's disease.}, journal = {Molecular biology reports}, volume = {51}, number = {1}, pages = {1124}, pmid = {39503976}, issn = {1573-4978}, support = {RM.21.01, RM.19.01, RM.16.01, SBF.14.01//Gaziantep Üniversitesi/ ; }, mesh = {Humans ; *Alzheimer Disease/genetics ; *Telomere-Binding Proteins/genetics/metabolism ; Male ; Female ; *Shelterin Complex/metabolism ; *Telomere/genetics/metabolism ; Middle Aged ; Telomeric Repeat Binding Protein 2/genetics/metabolism ; Telomere Shortening/genetics ; Adult ; Case-Control Studies ; Telomere Homeostasis/genetics ; Gene Expression Regulation ; Tripeptidyl-Peptidase 1 ; }, abstract = {BACKGROUND: Alzheimer's disease (AD) is an age-related dementia disorder characterized by memory loss and behavioral changes. Maintaining the integrity of telomere shortening in AD is important for cellular survival and homeostasis in all cells, especially glial cells. The shelterin protein complex provides telomere integrity. Measuring the expression levels of shelterin genes and determining the telomere lengths regulated by this complex will reveal their effects on AD progression and adult neurogenesis and will allow the detection of the disease or the determination of the progression process from an accessible tissue.
METHODS AND RESULTS: The study population included 111 patients and 91 healthy controls (male and female, < 50 age). The clinical histories (age, gender, hypertension, diabetes mellitus, obesity, cardiovascular disease, MMSE, medication use, family history, sleep disorders, seizure), covariates (HGB, ESR, Na, P, Cl, BUN, CRP, B12, TSH, Glucose, and MRI findings) and the expressional changes of shelterin genes (TERF1, TERF2, TINF2, POT1, TPP1, and RAP1) between the patient and control groups were evaluated relatively. ROC analyses determined the diagnostic power of telomere repeats and gene expressions.
CONCLUSIONS: In conclusion, upregulation of expression of shleterin complex genes was detected in AD, where telomeres are significantly shorter than in controls (P < 0.05). However, only TERF2 and RAP1 were significant (P < 0.05). A positive relationship was detected between telomere repeats and these genes (P < 0.05). Telomere repeats may be a strong diagnostic criterion to distinguish AD individuals from healthy individuals (AUC = 1.000). The upregulation of TERF2 and RAP1 core genes required for telomere integrity results in the instability of excessively shortened telomeres. Expression silencing of these genes may increase telomerase activity and maintain cellular survival. Also, the detection of telomere repeats has potential in the early diagnosis of AD patients.}, }
@article {pmid39501561, year = {2024}, author = {Gao, B and Sun, PC and Song, YC and Chen, MX and Zhang, DY and Liu, YG and Dai, T and Zhu, FY}, title = {A telomere-to-telomere genome assembly of Salix cheilophila reveals its evolutionary signatures for environmental adaptation.}, journal = {Plant communications}, volume = {}, number = {}, pages = {101182}, doi = {10.1016/j.xplc.2024.101182}, pmid = {39501561}, issn = {2590-3462}, }
@article {pmid39500624, year = {2024}, author = {Billing, D and Sfeir, A}, title = {The Role of Microhomology-Mediated End Joining (MMEJ) at Dysfunctional Telomeres.}, journal = {Cold Spring Harbor perspectives in biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/cshperspect.a041687}, pmid = {39500624}, issn = {1943-0264}, abstract = {DNA double-strand break (DSB) repair pathways are crucial for maintaining genome stability and cell viability. However, these pathways can mistakenly recognize chromosome ends as DNA breaks, leading to adverse outcomes such as telomere fusions and malignant transformation. The shelterin complex protects telomeres from activation of DNA repair pathways by inhibiting nonhomologous end joining (NHEJ), homologous recombination (HR), and microhomology-mediated end joining (MMEJ). The focus of this paper is on MMEJ, an error-prone DSB repair pathway characterized by short insertions and deletions flanked by sequence homology. MMEJ is critical in mediating telomere fusions in cells lacking the shelterin complex and at critically short telomeres. Furthermore, studies suggest that MMEJ is the preferred pathway for repairing intratelomeric DSBs and facilitates escape from telomere crisis. Targeting MMEJ to prevent telomere fusions in hematologic malignancies is of potential therapeutic value.}, }
@article {pmid39500623, year = {2024}, author = {O'Sullivan, RJ and Greenberg, RA}, title = {Mechanisms of Alternative Lengthening of Telomeres.}, journal = {Cold Spring Harbor perspectives in biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/cshperspect.a041690}, pmid = {39500623}, issn = {1943-0264}, abstract = {In recent years, significant advances have been made in understanding the intricate details of the mechanisms underlying alternative lengthening of telomeres (ALT). Studies of a specialized DNA strand break repair mechanism, known as break-induced replication, and the advent of telomere-specific DNA damaging strategies and proteomic methodologies to profile the ribonucleoprotein composition of telomeres enabled the discovery of networks of proteins that coordinate the stepwise homology-directed DNA repair and DNA synthesis processes of ALT. These networks couple mediators of homologous recombination, DNA template-switching, long-range template-directed DNA synthesis, and DNA strand resolution with SUMO-dependent liquid condensate formation to create discrete nuclear bodies where telomere extension occurs. This review will discuss the recent findings of how these networks may cooperate to mediate telomere extension by the ALT mechanism and their impact on telomere function and integrity in ALT cancer cells.}, }
@article {pmid39500371, year = {2024}, author = {Burraco, P and Gabor, C and Bryant, A and Gardette, V and Lengagne, T and Bonzom, JM and Orizaola, G}, title = {Ionizing radiation has negligible effects on the age, telomere length and corticosterone levels of Chornobyl tree frogs.}, journal = {Biology letters}, volume = {20}, number = {11}, pages = {20240287}, doi = {10.1098/rsbl.2024.0287}, pmid = {39500371}, issn = {1744-957X}, support = {//Carl Tryggers Foundation/ ; //Helga Ax:son Johnsons Stiftelse/ ; //Ministerio de Ciencia e Innovación/ ; //Uppsala University Zoological Foundation/ ; //French Institute for Radiological Protection and Nuclear Safety-IRSN/ ; //Spanish Association of Terrestrial Ecology-AEET/ ; //Swedish Radiation Protection Agency-SSM/ ; //Spanish Ministry of Science, Innovation and Universities/ ; }, mesh = {Animals ; *Corticosterone/blood ; *Chernobyl Nuclear Accident ; *Anura/genetics ; Ukraine ; Telomere/radiation effects ; Radiation, Ionizing ; Aging/radiation effects ; Male ; }, abstract = {The accident that occurred at the Chornobyl nuclear power plant (Ukraine, 1986) contaminated a large extension of territory after the deposition of radioactive material. It is still under debate whether the chronic exposure to the radiation levels currently present in the area has long-term effects on organisms, such as decreases in longevity. Here, we investigate whether current levels of radiation in Chornobyl negatively impact the age of the Eastern tree frog Hyla orientalis. We also explore whether radiation induces changes in an ageing marker, telomere length or the stress hormone corticosterone. We found no effect of total individual absorbed radiation (including both external and internal exposure) on frog age (n = 197 individuals sampled in 3 consecutive years). We also did not find any relationship between individual absorbed radiation and telomere length, nor between individual absorbed radiation and corticosterone levels. Our results suggest that radiation levels currently experienced by Chornobyl tree frogs may not be high enough to cause severe chronic damage to semi-aquatic vertebrates such as this species. This is the first study addressing age and stress hormones in Chornobyl wildlife, and thus future research will confirm if these results can be extended to other taxa.}, }
@article {pmid39499700, year = {2024}, author = {Rodrigues, P and Furtado, G and Martins, M and Vieira, R and Orlandi, A and Brito-Costa, S and Moisão, A and Corona, L and Lima, D and Brito, T}, title = {Exposing telomere length's impact on malnutrition risk among older adults residing in the community: Insights from cross-sectional data analysis.}, journal = {PloS one}, volume = {19}, number = {11}, pages = {e0308612}, doi = {10.1371/journal.pone.0308612}, pmid = {39499700}, issn = {1932-6203}, mesh = {Humans ; *Malnutrition/epidemiology ; Aged ; Female ; Male ; Cross-Sectional Studies ; Middle Aged ; Risk Factors ; *Telomere/genetics ; Aged, 80 and over ; Brazil/epidemiology ; Independent Living ; Nutritional Status ; Telomere Shortening ; Nutrition Assessment ; Geriatric Assessment/methods ; }, abstract = {BACKGROUND: Successful aging is associated with an increase in life expectancy. For a better understanding of the aging process, recognize the relationship between telomere length and nutritional status is a novel approach in geriatric science. Telomers shortening coincides with a decrease in life expectancy, and an increased risk of malnutrition-related diseases.
GOALS: The goal of this study was to investigate whether a shorter telomere length is associated with a greater likelihood of malnutrition in community-dwelling older adults.
METHODS: A cross-sectional study with a probabilistic sample of 448 older people aged 60 years old or over, and living in the urban area of an inland Brazilian municipality was conducted. The information was gathered in two stages: a) a personal interview was conducted to obtain sociodemographic, cognitive, and functional autonomy data. The Mini Nutritional Assessment was used to assess the risk of malnutrition. b) a blood sample was taken to proceed with the relative quantitative study of telomere length using real-time qPCR method. The differences between the groups were estimated using Pearson's v2 and Fisher's exact tests. In the data analysis, descriptive statistics and multiple logistic regression were applied.
RESULTS: In 34.15% of the total sample, malnutrition was recognized as a risk factor. Older people with the shortest telomere length had more chances of getting malnutrition (OR = 1.63; IC:95% = 1.04-2.55) compared to those with longer telomeres, independent of age groups, family income, multimorbidity, cognitive decline, and depressive symptoms.
CONCLUSION: The creation of clinical trials and the implementation of therapies to reduce the risk of malnutrition will be aided using the telomere length as an aging innovative biomarker, connected with nutritional status.}, }
@article {pmid39497037, year = {2024}, author = {Mao, H and Lin, T and Huang, S and Xie, Z and Chen, J and Shen, X and Ding, Y and Xu, G and Chen, Z}, title = {Association between monocyte to high-density lipoprotein cholesterol ratio and telomere length: based on NHANES 1999-2002.}, journal = {BMC cardiovascular disorders}, volume = {24}, number = {1}, pages = {616}, pmid = {39497037}, issn = {1471-2261}, support = {2023KY244//Medical Science and Technology Project of Zhejiang Province/ ; }, abstract = {BACKGROUND: Telomere length is closely associated with the occurrence and development of cardiovascular and other diseases. Monocyte to high-density lipoprotein cholesterol ratio (MHR) is a novel indicator of inflammation, oxidative stress, and metabolic syndrome, with some predictive ability for related disease risks in clinical practice. However, there is no research on the correlation between these two factors.
METHODS: Using data from the National Health and Nutrition Examination Survey (NHANES) from 1999 to 2002, we conducted analysis and research on the correlation between MHR and telomere length using the Kruskal-Wallis H test, Spearman rank correlation analysis, and partial correlation analysis. Weighted linear regression analysis assessed the strength of the association between the two variables, while restricted cubic spline regression (RCS) explored potential nonlinear relationships between them.
RESULTS: The results of correlation analysis showed that MHR levels were negatively correlated with telomere length (ρ=-0.083, P < 0.001), and this relationship remained statistically significant after controlling for other covariates (P all < 0.001). Weighted linear regression analysis showed that after adjusting for all covariates, MHR remained negatively associated with telomere length (β = -0.020; 95% CI: -0.039 to -0.002; P = 0.037). Subgroup analysis shows that the negative association between MHR and telomere length appeared more striking among females (𝛽 = -0.024; 95%CI: -0.050 to 0.001; P = 0.058), the Non-Hispanic White (𝛽 = -0.022; 95%CI: -0.045 to 0.002; P = 0.066), and other race (𝛽 = -0.067; 95%CI: -0.134 to -0.000; P = 0.049). Using RCS explored potential nonlinear relationships between MHR and telomere length, revealing no nonlinear relationship between the two (P = 0.102).
CONCLUSIONS: This study suggests a negative correlation between MHR levels and telomere length in American adults. More comprehensive research is needed to confirm these findings in the future.}, }
@article {pmid39493885, year = {2024}, author = {Herrera-Moyano, E and Porreca, RM and Ranjha, L and Skourti, E and Gonzalez-Franco, R and Stylianakis, E and Sun, Y and Li, R and Saleh, A and Montoya, A and Kramer, H and Vannier, JB}, title = {Human SKI component SKIV2L regulates telomeric DNA-RNA hybrids and prevents telomere fragility.}, journal = {iScience}, volume = {27}, number = {11}, pages = {111096}, pmid = {39493885}, issn = {2589-0042}, abstract = {Super killer (SKI) complex is a well-known cytoplasmic 3'-5' mRNA decay complex that functions with the exosome to degrade excessive and aberrant mRNAs, is implicated with the extraction of mRNA at stalled ribosomes, tackling aberrant translation. Here, we show that SKIV2L and TTC37 of the hSKI complex are present within the nucleus, localize on chromatin and at some telomeres during the G2 cell cycle phase. In cells, SKIV2L prevents telomere replication stress, independently of its helicase domain, and increases the stability of telomere DNA-RNA hybrids in G2. We further demonstrate that purified hSKI complex binds telomeric DNA and RNA substrates in vitro and SKIV2L association with telomeres is dependent on DNA-RNA hybrids. Taken together, our results provide a nuclear function for SKIV2L of the hSKI complex in overcoming replication stress at telomeres mediated by its recruitment to DNA-RNA hybrid structures in G2 and thus maintaining telomere stability.}, }
@article {pmid39493361, year = {2024}, author = {Zhao, W and Wu, J and Tian, M and Xu, S and Hu, S and Wei, Z and Lin, G and Tang, L and Wang, R and Feng, B and Wang, B and Lyu, H and Paetz, C and Feng, X and Xue, JY and Li, P and Chen, Y}, title = {Characterization of O-methyltransferases in the biosynthesis of phenylphenalenone phytoalexins based on the telomere-to-telomere gapless genome of Musella lasiocarpa.}, journal = {Horticulture research}, volume = {11}, number = {4}, pages = {uhae042}, pmid = {39493361}, issn = {2662-6810}, abstract = {Phenylphenalenones (PhPNs), phytoalexins in wild bananas (Musaceae), are known to act against various pathogens. However, the abundance of PhPNs in many Musaceae plants of economic importance is low. Knowledge of the biosynthesis of PhPNs and the application of biosynthetic approaches to improve their yield is vital for fighting banana diseases. However, the processes of PhPN biosynthesis, especially those involved in methylation modification, remain unclear. Musella lasiocarpa is a herbaceous plant belonging to Musaceae, and due to the abundant PhPNs, their biosynthesis in M. lasiocarpa has been the subject of much attention. In this study, we assembled a telomere-to-telomere gapless genome of M. lasiocarpa as the reference, and further integrated transcriptomic and metabolomic data to mine the candidate genes involved in PhPN biosynthesis. To elucidate the diversity of PhPNs in M. lasiocarpa, three screened O-methyltransferases (Ml01G0494, Ml04G2958, and Ml08G0855) by phylogenetic and expressional clues were subjected to in vitro enzymatic assays. The results show that the three were all novel O-methyltransferases involved in the biosynthesis of PhPN phytoalexins, among which Ml08G0855 was proved to function as a multifunctional enzyme targeting multiple hydroxyl groups in PhPN structure. Moreover, we tested the antifungal activity of PhPNs against Fusarium oxysporum and found that the methylated modification of PhPNs enhanced their antifungal activity. These findings provide valuable genetic resources in banana breeding and lay a foundation for improving disease resistance through molecular breeding.}, }
@article {pmid39491652, year = {2024}, author = {Zhou, F and Sun, Z and Cheng, L and Dong, Y}, title = {Leptin modulates ovarian granulosa cell apoptosis by regulating telomerase activity and telomere length in polycystic ovary syndrome.}, journal = {Laboratory investigation; a journal of technical methods and pathology}, volume = {}, number = {}, pages = {102169}, doi = {10.1016/j.labinv.2024.102169}, pmid = {39491652}, issn = {1530-0307}, abstract = {Leptin (LEP) is implicated in the pathogenesis of polycystic ovary syndrome (PCOS). This study investigates the mechanism of LEP in PCOS. The baseline information of 80 PCOS patients and matched controls was analyzed, with serum and follicular fluid (FF) LEP and LEP receptor (LEPR) levels, telomerase activity, and relative telomere length (TL) measured. The correlation of FF LEP with telomerase activity and TL was analyzed. The viability and apoptosis of KGN cells (the ovarian granulosa cells) treated with gradient LEP were assessed. LEP-LEPR interaction was examined. LEPR, c-MYC, and TERT levels and c-MYC protein expression in the TERT promoter region were determined. Nuclear c-MYC translocation was detected. LEP was upregulated in sera and FF of PCOS patients. FF LEP positively-correlated with telomerase activity and TL. Low-concentration LEP facilitated KGN cell proliferation and high-concentration LEP dose-dependently suppressed cell proliferation, promoted apoptosis, upregulated LEPR and increased telomerase activity and relative TL. LEP-LEPR interaction upregulated c-MYC and facilitated its nuclear accumulation. c-MYC enrichment in the TERT promoter region upregulated TERT, altering telomerase activity and TL and inducing cell apoptosis. Briefly, LEP/LEPR activate c-MYC, modulate TERT expression, and increase telomerase activity and TL, thus inducing ovarian granulosa cell apoptosis and participating in PCOS.}, }
@article {pmid39489788, year = {2024}, author = {Trachu, N and Reungwetwattana, T and Meanwatthana, J and Sukasem, C and Majam, T and Saengsiwaritt, W and Jittikoon, J and Udomsinprasert, W}, title = {Leukocytes telomere length as a biomarker of adverse drug reactions induced by Osimertinib in advanced non-small cell lung cancer.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {26543}, pmid = {39489788}, issn = {2045-2322}, mesh = {Humans ; *Carcinoma, Non-Small-Cell Lung/drug therapy/genetics ; Female ; *Acrylamides/adverse effects ; Male ; *Leukocytes/drug effects/metabolism ; *Lung Neoplasms/drug therapy/genetics ; *Aniline Compounds/adverse effects ; Middle Aged ; Aged ; *Telomere/drug effects ; Antineoplastic Agents/adverse effects/therapeutic use ; Telomere Homeostasis/drug effects ; Biomarkers/blood ; Drug-Related Side Effects and Adverse Reactions/diagnosis ; Biomarkers, Tumor/blood/genetics ; Case-Control Studies ; Indoles ; Pyrimidines ; }, abstract = {This study aimed to measure relative telomere length (RTL) in blood leukocytes of advanced-stage NSCLC patients either with or without Osimertinib-induced ADRs and determine whether RTL could serve as a biomarker of Osimertinib-induced ADRs. Blood leukocytes RTL were measured in 63 advanced-stage NSCLC patients and 62 age-matched healthy controls using real-time polymerase chain reaction. In patients with advanced-stage NSCLC, RTL was significantly shorter than that in healthy controls (P < 0.001). Compared to patients without ADRs and those with mild/moderate ADRs, patients with severe ADRs exhibited significantly decreased RTL (P < 0.001, P < 0.001, respectively). ROC curve analysis uncovered a diagnostic value of RTL as a biomarker of Osimertinib-induced ADRs (AUC = 1.000, P < 0.001). Kaplan-Meier analysis revealed a significant association between shorter RTL and increased cumulative incidence of Osimertinib-induced ADRs in patients with advanced-stage NSCLC (P < 0.001). Shorter RTL in blood leukocytes would reflect the occurrence of Osimertinib-induced ADRs and might emerge as a promising biomarker for identifying advanced-stage NSCLC patients who are at risk of experiencing Osimertinib-induced ADRs, particularly those with severe ADRs.}, }
@article {pmid39482583, year = {2024}, author = {Hu, J and Zhang, J and Liu, Y and Qin, J and Bai, H and Qin, X}, title = {Causal linkage of Graves' disease with aging: Mendelian randomization analysis of telomere length and age-related phenotypes.}, journal = {BMC geriatrics}, volume = {24}, number = {1}, pages = {901}, pmid = {39482583}, issn = {1471-2318}, support = {2018YFE0207300//National Key Research and Development Program of China/ ; 345 Talent Project//Shengjing Hospital of China Medical University/ ; }, mesh = {Humans ; *Mendelian Randomization Analysis/methods ; *Graves Disease/genetics/epidemiology ; *Aging/genetics ; *Genome-Wide Association Study/methods ; *Phenotype ; Telomere ; Telomere Homeostasis/physiology ; Female ; Male ; Aged ; Polymorphism, Single Nucleotide ; }, abstract = {BACKGROUND: Aging is an irreversible progressive decline in physical function. Graves' disease (GD) is a common cause of hyperthyroidism and is characterized by elevated levels of the thyroid hormone (TH). High TH levels are associated with aging and a shortened lifespan. The causal relationship between GD and aging has yet to be investigated.
METHODS: We used genome-wide association study (GWAS) datasets and Mendelian randomization (MR) analysis to explore the causal link between GD and aging. To assess the statistical power of instrumental variables (IVs), F-statistics and R[2] were used. MR analysis was conducted using inverse-variance weighting (IVW), MR-Egger, weighted median, and weighted mode. The odds ratio (OR) and 95% CI were calculated to estimate the relative risk of GD to the outcomes. The Cochran Q test, I[2], MR-PRESSO test, and MR-Egger regression intercept were calculated using statistical and leave-one-out analyses to test the heterogeneity, horizontal pleiotropy, and stability of the IVs on the outcomes.
RESULTS: F-statistics of the five IVs were greater than 10, and the R[2] values ranged from 0.033 to 0.156 (R[2] > 0.01). According to the results of the IVW analysis, GD had no causal effect on facial aging (p = 0.189), age-related macular degeneration (p = 0.346), and Alzheimer's disease (p = 0.479). There was a causal effect of GD on the remaining outcomes: telomere length (TL) (OR = 0.982; 95%CI:0.969-0.994; p = 0.004), senile cataract (OR = 1.031; 95%CI:1.002-1.060; p = 0.033), age-related hearing impairment (OR = 1.009; 95%CI:1.004-1.014; p = 0.001), chronic obstructive pulmonary disease (COPD) (OR = 1.055; 95%CI:1.008-1.103; p = 0.020), and sarcopenia (OR = 1.027; 95%CI:1.009-1.046; p = 0.004).
CONCLUSIONS: GD accelerates the occurrence of age-related phenotypes including TL, senile cataracts, age-related hearing impairment, COPD, and sarcopenia. In contrast, there are no causal linkages between GD and facial aging, age-related macular degeneration, or Alzheimer's disease. Further experimental studies could be conducted to elucidate the mechanisms by which GD facilitates aging, which could help slow down the progress of aging.}, }
@article {pmid39483338, year = {2024}, author = {Harman, A and Bryan, TM}, title = {Telomere maintenance and the DNA damage response: a paradoxical alliance.}, journal = {Frontiers in cell and developmental biology}, volume = {12}, number = {}, pages = {1472906}, pmid = {39483338}, issn = {2296-634X}, abstract = {Telomeres are the protective caps at the ends of linear chromosomes of eukaryotic organisms. Telomere binding proteins, including the six components of the complex known as shelterin, mediate the protective function of telomeres. They do this by suppressing many arms of the canonical DNA damage response, thereby preventing inappropriate fusion, resection and recombination of telomeres. One way this is achieved is by facilitation of DNA replication through telomeres, thus protecting against a "replication stress" response and activation of the master kinase ATR. On the other hand, DNA damage responses, including replication stress and ATR, serve a positive role at telomeres, acting as a trigger for recruitment of the telomere-elongating enzyme telomerase to counteract telomere loss. We postulate that repression of telomeric replication stress is a shared mechanism of control of telomerase recruitment and telomere length, common to several core telomere binding proteins including TRF1, POT1 and CTC1. The mechanisms by which replication stress and ATR cause recruitment of telomerase are not fully elucidated, but involve formation of nuclear actin filaments that serve as anchors for stressed telomeres. Perturbed control of telomeric replication stress by mutations in core telomere binding proteins can therefore cause the deregulation of telomere length control characteristic of diseases such as cancer and telomere biology disorders.}, }
@article {pmid39484296, year = {2023}, author = {Themoteo, RM and De Paula, VJR and Rocha, NKR and Brentani, H and Forlenza, OV}, title = {Lithium Prevents Telomere Shortening in Cortical Neurons in Amyloid-Beta Induced Toxicity.}, journal = {NeuroSci}, volume = {4}, number = {1}, pages = {1-8}, pmid = {39484296}, issn = {2673-4087}, abstract = {BACKGROUND: There is consistent evidence of the potential benefits of lithium attenuating mechanisms of neurodegeneration, including those related to the pathophysiology of Alzheimer's disease (AD), and facilitating neurotrophic and protective responses, including maintenance of telomere length. The aim was to investigate the protective effect of the pre-treatment with lithium on amyloid-beta (Aβ)-induced toxicity and telomere length in neurons.
METHODS: Cortical neurons were treated with lithium chloride at therapeutic and subtherapeutic concentrations (2 mM, 0.2 mM and 0.02 mM) for seven days. Amyloid toxicity was induced 24 h before the end of lithium treatment.
RESULTS: Lithium resulted in 120% (2 mM), 180% (0.2 mM) and 140% (0.02 mM) increments in telomere length as compared to untreated controls. Incubation with Aβ1-42 was associated with significant reductions in MTT uptake (33%) and telomere length (83%) as compared to controls.
CONCLUSIONS: Lithium prevented loss of culture viability and telomere shortening in neuronal cultures challenged with Aβ fibrils.}, }
@article {pmid39482017, year = {2024}, author = {Chuang, LC}, title = {Which one occurs first?Telomere length (TL) shortening or PCOS?.}, journal = {Taiwanese journal of obstetrics & gynecology}, volume = {63}, number = {6}, pages = {967}, doi = {10.1016/j.tjog.2024.05.028}, pmid = {39482017}, issn = {1875-6263}, }
@article {pmid39474987, year = {2024}, author = {Ye, Q and Apsley, AT and Hastings, WJ and Etzel, L and Newschaffer, C and Shalev, I}, title = {Parental age at birth, telomere length, and autism spectrum disorders in the UK Biobank cohort.}, journal = {Autism research : official journal of the International Society for Autism Research}, volume = {}, number = {}, pages = {}, doi = {10.1002/aur.3258}, pmid = {39474987}, issn = {1939-3806}, abstract = {Older parental age at birth is associated with increased risk of autism spectrum disorders (ASD) in offspring. Independently, shorter telomere length (TL) has also been shown to be associated with ASD in children. However, older paternal age at birth, with or without controlling for maternal age, has been associated with longer TL, a seemingly contradictory finding. Here, we conducted a retrospective cohort study among participants in the UK Biobank to disentangle associations between leukocyte TL and ASD status in adults, and the potential moderation by parental age on adult offspring's TL. Participants with ASD diagnosis (N = 87) with a mean age of 46.0 (SD 4.4) years were matched to participants without ASD diagnosis (N = 870) based on age, sex, ethnicity, education, household income, and assessment center. No statistically significant differences were seen in TL between participants with and without ASD when parental age at birth was not considered. However, there was a significant interaction between ASD diagnostic status and parental age on participants' TL, such that older paternal or maternal age at birth was more strongly associated with longer TL in participants with ASD. This study suggests that the shortened TL observed in children with ASD in previous research may partially depend on parental age at birth. Future studies tracking TL attrition before ASD diagnosis are warranted to depict temporal associations and the interacting effects of parental age at birth and ASD status on TL across the lifespan.}, }
@article {pmid39474905, year = {2024}, author = {Bianco-Miotto, T and Phillips, AL and Heinze, DR and Pennell, CE and Maganga, RK and Beilin, LJ and Mori, TA and Grieger, JA}, title = {Adverse pregnancy outcomes are associated with shorter telomere length in the 17-year-old child.}, journal = {Journal of developmental origins of health and disease}, volume = {15}, number = {}, pages = {e26}, doi = {10.1017/S2040174424000291}, pmid = {39474905}, issn = {2040-1752}, mesh = {Humans ; Female ; Pregnancy ; Adolescent ; Male ; *Pregnancy Outcome/epidemiology ; *Telomere ; Prospective Studies ; Adult ; Pregnancy Complications/genetics/epidemiology ; Infant, Newborn ; Telomere Shortening ; Western Australia/epidemiology ; }, abstract = {This study examined associations between pregnancy and infant birth outcomes with child telomere length at age 17 years; and investigated if there are sex differences between pregnancy complications and telomere length. We utilised the population-based prospective Raine cohort study in Western Australia, Australia. 2900 pregnant women were recruited at 16-20 weeks' gestation (Gen 1), and their children (Gen 2) were followed up over several years. Generalised linear models were used to examine relationships between pregnancy or birth outcomes (gestational diabetes, pre-eclampsia, preterm birth, low birth weight, macrosomia), and as a composite, with telomere length, measured via a DNA sample from blood at 17 years of age. Analyses were adjusted for a range of confounders. Among the 1202 included children, there were no differences in child telomere length for any of the individual maternal or birth weight pregnancy outcomes nor were there any significant interactions between each of the complications (individual or composite) and the sex of the child. However, females born from any of the 5 adverse outcomes had shorter telomeres (estimated mean (SE) = -0.159 (0.061), p = 0.010) than females born in the absence of these complications. Specifically, females born from a pre-eclamptic pregnancy had shorter telomeres than females not born from a pre-eclamptic pregnancy (estimated mean (SE) = -0.166 (0.072), p = 0.022). No relationships were observed in males. Further longitudinal studies are needed to understand mediating factors that are important in predicting offspring telomere length and the necessity to investigate females and males independently.}, }
@article {pmid39474122, year = {2024}, author = {Fernández de la Puente, M and Valle-Hita, C and Salas-Huetos, A and Martínez, MÁ and Sánchez-Resino, E and Canudas, S and Torres-Oteros, D and Relat, J and Babio, N and Salas-Salvadó, J}, title = {Sperm and leukocyte telomere length are related to sperm quality parameters in healthy men from the Led-Fertyl study.}, journal = {Human reproduction open}, volume = {2024}, number = {4}, pages = {hoae062}, pmid = {39474122}, issn = {2399-3529}, abstract = {STUDY QUESTION: Could sperm and leukocyte telomere length (TL) be associated with sperm quality parameters and reproductive health in men from the general population?
SUMMARY ANSWER: A positive association between sperm and leukocyte TL with sperm concentration and total count has been demonstrated.
WHAT IS KNOWN ALREADY: Male factors account for almost half of cases of couple infertility, and shorter TLs have been observed in sperm from men with impaired sperm parameters. However, evidence in men from the general population is limited.
STUDY DESIGN SIZE DURATION: A total of 200 volunteers of reproductive age were recruited between February 2021 and April 2023 to participate in the Lifestyle and Environmental Determinants of Seminogram and Other Male Fertility-Related Parameters (Led-Fertyl) cross-sectional study.
TLs in sperm and leukocytes were measured using quantitative polymerase chain reaction (qPCR) in 168 and 194 participants, respectively. Sperm parameters, including concentration, total count, motility, vitality, and morphology, were analyzed using a computer-assisted sperm analysis (CASA) SCA[®] system according to the World Health Organization (WHO) 2010 guidelines. Multivariable regression models were performed to assess the associations between sperm and leukocyte TL, either in tertiles or as continuous variables, and sperm quality parameters while adjusting for potential confounders.
Participants in tertiles 2 (T2) and 3 (T3) of sperm TL showed a higher sperm concentration (β: 1.09; 95% CI: 0.09-2.09 and β: 2.06; 95% CI: 1.04-3.09 for T2 and T3, respectively; P-trend < 0.001), compared to those in the reference tertile (T1). Participants in the highest tertile of sperm TL showed higher total sperm count (β: 3.83; 95% CI: 2.08-5.58 for T3 vs T1; P-trend < 0.001). Participants in the top tertile of leukocyte TL showed higher sperm concentration (β: 1.49; 95% CI: 0.44-2.54 for T3 vs T1; P-trend = 0.004), and total count (β: 3.49; 95% CI: 1.62-5.35 for T3 vs T1; P-trend < 0.001) compared with participants in T1. These results remained consistent when sperm and leukocyte TL were modelled as continuous variables.
One limitation is the impossibility of establishing a cause-effect relationship due to the cross-sectional study design. Additionally, the sample size of the study cannot be considered large.
Sperm and leukocyte TLs are associated with sperm quality parameters in the general population. Additional determinations and further studies with larger sample sizes are needed to clarify the mechanisms underlying these associations and to investigate the further implications.
The Led-Fertyl study was supported by the Spanish government's official funding agency for biomedical research, Instituto de Salud Carlos III (ISCIII), through the Fondo de Investigación para la Salud (FIS) and co-funded by the European Union ERDF/ESF, 'A way to make Europe'/'Investing in your future' (PI21/01447), and the Diputació de Tarragona (2021/11-No.Exp. 8004330008-2021-0022642). J.S.-S., senior author of the present study, is partially supported by ICREA under the ICREA Academia program. M.F.d.l.P. was supported by a predoctoral grant from the Rovira i Virgili University and Diputació de Tarragona (2020-PMF-PIPF-8). C.V.-H. received a predoctoral grant from the Generalitat de Catalunya (2022 FI_B100108). M.Á.M. was supported by the Sara Borrell postdoctoral fellowship (CD21/00045-Instituto de Salud Carlos III (ISCIII)). All authors declare that they have no conflicts of interest.
TRIAL REGISTRATION NUMBER: N/A.}, }
@article {pmid39468654, year = {2024}, author = {Lyu, Y and Zhao, H and Zeng, G and Yang, J and Shao, Q and Wu, H}, title = {Mapping the evolving trend of research on leukocyte telomere length: a text-mining study.}, journal = {Human genomics}, volume = {18}, number = {1}, pages = {117}, pmid = {39468654}, issn = {1479-7364}, support = {LHGJ20210294//2021 joint construction project of Henan Medical Science and Technology Breakthrough Plan/ ; }, mesh = {Humans ; *Leukocytes ; *Telomere/genetics ; *Data Mining ; *Bibliometrics ; *Telomere Homeostasis/genetics ; Aging/genetics ; }, abstract = {BACKGROUND: Substantial evidence indicates that measuring leukocyte telomere length (LTL) is a useful tool that may be considered as a valuable biomarker of individual biological age, correlating with numerous chronic disorders. However, to date, there has been a lack of in-depth understanding regarding the current landscape and forthcoming developments in the LTL field. Therefore, this study aimed to utilize bibliometric methods to summarize the knowledge structure, current focus, and emerging directions in this field.
METHOD: Scientific publications on LTL spanning the period from 2000 to 2022 were acquired from the Web of Science Core Collection database. Several bibliometric tools including CiteSpace, VOSviewer, and an online website were utilized for bibliometric analysis. The primary evaluations encompassed investigating the major contributors and their collaborative relationships among countries/regions, institutions, and authors, conducting co-citation analyses of authors, journals, as well as reference, examining reference bursts, as well as performing co-occurrence analyses of keywords.
RESULTS: There are 1818 papers with 66,668 citations identified. Both the annual publication and citation counts on LTL exhibited significant upward trends. The United States emerged as the most prominent contributor, as evidenced by the greatest volume of papers and the highest H-index value. University of California San Francisco and Aviv A were identified as the most productive institution and author in this domain, respectively. Reference analysis revealed that longitudinal study and mendelian randomization study are the most concerned research method in this field recently. Keywords analysis showed that the most concerned diseases in LTL fields were aging, inflammation, cardiovascular diseases, endocrine diseases, neurological and psychiatric diseases, and cancers. In addition, the following research directions such as "COPD", "mendelian randomization", "adiposity", "colorectal cancer", "National Health and Nutrition Examination Survey (NHNES)", "telomerase reverse transcriptase", "pregnancy" have garnered increasing attention in recent times and hold the potential to evolve into research foci in the foreseeable future.
CONCLUSION: This is the first bibliometric study that provides comprehensive overview of LTL research. The findings of this study could become valuable references for investigators to explore and address the current and emerging challenges in LTL research.}, }
@article {pmid39468351, year = {2024}, author = {Salgado, S and Abreu, PL and Moleirinho, B and Guedes, DS and Larcombe, L and Azzalin, CM}, title = {Human PC4 supports telomere stability and viability in cells utilizing the alternative lengthening of telomeres mechanism.}, journal = {EMBO reports}, volume = {}, number = {}, pages = {}, pmid = {39468351}, issn = {1469-3178}, support = {2021.00143.CEECIND//Fundação para a Ciência e a Tecnologia (FCT)/ ; PTDC/MED-ONC/7864/2020//Fundação para a Ciência e a Tecnologia (FCT)/ ; 2022.11369.BD//Fundação para a Ciência e a Tecnologia (FCT)/ ; LCF/PR/HP21/52310016//LaCaixa Foundation/ ; LCF/PR/HP21/52310016//TessellateBio/ ; }, abstract = {Cancer cells with an activated Alternative Lengthening of Telomeres (ALT) mechanism elongate telomeres via homology-directed repair. Sustained telomeric replication stress is an essential trigger of ALT activity; however, it can lead to cell death if not properly restricted. By analyzing publicly available data from genome-wide CRISPR KO screenings, we have identified the multifunctional protein PC4 as a novel factor essential for ALT cell viability. Depletion of PC4 results in rapid ALT cell death, while telomerase-positive cells show minimal effects. PC4 depletion induces replication stress and telomere fragility primarily in ALT cells, and increases ALT activity. PC4 binds to telomeric DNA in cells, and its binding can be enhanced by telomeric replication stress. Finally, a mutant PC4 with partly impaired single stranded DNA binding activity is capable to localize to telomeres and suppress ALT activity and telomeric replication stress. We propose that PC4 supports ALT cell viability, at least partly, by averting telomere dysfunction. Further studies of PC4 interactions at ALT telomeres may hold promise for innovative therapies to eradicate ALT cancers.}, }
@article {pmid39467523, year = {2024}, author = {Alwehaidah, MS and Bakhiet, M}, title = {Association of leukocyte telomere length and the risk of disease severity and metabolic comorbidities in Arab patients with psoriasis.}, journal = {Cytogenetic and genome research}, volume = {}, number = {}, pages = {1-13}, doi = {10.1159/000542323}, pmid = {39467523}, issn = {1424-859X}, abstract = {INTRODUCTION: Several studies have related shortened leukocyte telomere length (LTL) with age-related diseases and worse prognosis. Telomere length attrition has recently been associated with inflammatory diseases, including psoriasis. However, no study has demonstrated an association between LTL and the risk of disease severity and metabolic comorbidities in Arab patients with psoriasis (Ps).
METHODS: 68 Ps and 42 normal controls (NC) were included. LTL and oxidative damage were determined by quantitative (q) PCR. Odds ratios (OR) and 95% confidence intervals (CI) were calculated using logistic regression. Statistical differences between the groups were determined using 2 and t-tests.
RESULTS: Patients with psoriasis had significantly shorter LTL (P= 0.032) and higher oxidative damage (P= 0.015) than those without psoriasis. Patients with moderate-to-severe index (P= 0.03) and metabolic comorbidity showed significantly shorter LTL (P= 0.003) compared to patients with mild index and without metabolic comorbidity, respectively. Patients with short LTL (≤ 0.9) were correlated with higher risk of moderate-to-severe conditions (OR= 6.98, 95% CI= 2.3-20.8, P= 0.001) and metabolic comorbidities (OR= 2.89, 95% CI= 1.02- 8.2, P= 0.04).
CONCLUSION: LTL shortening may be a consequence of increased oxidative damage, and is related to the risk of severe psoriasis and metabolic comorbidities. Therefore, LTL may be a good candidate biomarker for predicting the risk of poor prognosis in patients with psoriasis.}, }
@article {pmid39464117, year = {2024}, author = {McLester-Davis, LWY and Norton, D and Papale, LA and James, TT and Salazar, H and Asthana, S and Johnson, SC and Gooding, DC and Roy, TR and Alisch, RS and Drury, SS and Gleason, CE and Zuelsdorff, M}, title = {Telomere length and cognitive function among middle-aged and older participants from communities underrepresented in aging research: A preliminary study.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2024.10.14.618331}, pmid = {39464117}, issn = {2692-8205}, abstract = {OBJECTIVE: Accelerated biological aging is a plausible and modifiable determinant of dementia burden facing minoritized communities, but is not well-studied in these historically underrepresented populations. Our objective was to preliminarily characterize relationships between telomere length and cognitive health among American Indian/Alaska Native (AI/AN) and Black/African American (B/AA) middle-aged and older adults.
METHODS: This study included data on telomere length and cognitive test performance from 187 participants, enrolled in one of two community-based cognitive aging cohorts and who identified their primary race as AI/AN or B/AA.
RESULTS: Nested multivariable regression models revealed preliminary evidence for associations between telomere length and cognitive performance, and these associations were partially independent of chronological age.
DISCUSSION: Small sample size limited estimate precision, however, findings suggest future work on telomere length and cognitive health in underrepresented populations at high risk for dementia is feasible and valuable as a foundation for social and behavioral intervention research.}, }
@article {pmid39463989, year = {2024}, author = {Kim, D and Bhargava, R and Wang, SC and Lee, D and Patel, R and Oh, S and Bowman, RW and Na, CH and O'Sullivan, RJ and Miller, KM}, title = {TRIM24 directs replicative stress responses to maintain ALT telomeres via chromatin signaling.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2024.10.18.618947}, pmid = {39463989}, issn = {2692-8205}, abstract = {An inability to replicate the genome can cause replication stress and genome instability. Here, we develop BLOCK-ID, a proteomic method to identify and visualize proteins at stressed replication forks. This approach successfully identified novel mediators of the replication stress response, including the chromatin acetylation reader protein TRIM24. In validating TRIM24 function, we uncovered its crucial role in coordinating Alternative Lengthening of Telomeres (ALT), a cancer-specific telomere extension pathway involving replication stress. Our data reveal that TRIM24 is directed to telomeres via a p300/CBP-dependent acetylation chromatin signaling cascade, where it organizes ALT-associated PML bodies (APBs) to promote telomere DNA synthesis. Strikingly, we demonstrate that when artificially tethered at telomeres, TRIM24 can stimulate new telomere DNA synthesis in a SUMO-dependent manner, independently of p300/CBP or PML-dependent APBs. Thus, this study identifies a TRIM24 chromatin signaling pathway required for ALT telomere maintenance.}, }
@article {pmid39463735, year = {2024}, author = {Rodriguez, MD and Bailey, SM and Doherty, PF and Huyvaert, KP}, title = {Increased Reproductive Output and Telomere Shortening Following Calcium Supplementation in a Wild Songbird.}, journal = {Ecology and evolution}, volume = {14}, number = {10}, pages = {e70483}, pmid = {39463735}, issn = {2045-7758}, abstract = {Life history theory predicts increased parental investment comes with fitness costs, often expressed as negative effects on survival and future reproduction. To better understand the costs of reproduction and life history trade-offs, we evaluated calcium supplementation at a high-elevation site in Colorado as a novel approach to experimentally alter reproductive investment in nesting female Tachycineta bicolor (tree swallow). Calcium is a nutrient critical to avian reproduction as the intake of natural calcium is essential for egg production, embryo development, and nestling growth. Altering calcium availability exclusively during the breeding season allowed examination of individual biological responses to experimental modification of reproduction, as well as the reproductive costs associated with egg production and laying an entire clutch. As a functional endpoint and proxy for fitness and longevity, telomere length was measured at the beginning and end of each breeding season. Telomeres-protective "caps" at the ends of chromosomes-have been shown to shorten with aging and a variety of stressors, including higher reproductive output. Results demonstrate that tree swallow mothers supplemented with calcium during the breeding season experience higher reproductive output and produce offspring with longer telomeres, which came at the cost of relatively shorter telomeres during the reproductive season. These findings provide additional support for reproductive trade-offs, and also challenge previous calcium supplementation studies that suggest excess calcium reduces the cost of reproduction.}, }
@article {pmid39462986, year = {2024}, author = {Savage, SA and Bertuch, AA and , }, title = {Different phenotypes with different endings-Telomere biology disorders and cancer predisposition with long telomeres.}, journal = {British journal of haematology}, volume = {}, number = {}, pages = {}, doi = {10.1111/bjh.19851}, pmid = {39462986}, issn = {1365-2141}, support = {/CP/NCI NIH HHS/United States ; R01 HL131744/GF/NIH HHS/United States ; }, abstract = {Rare germline pathogenic variants (GPVs) in genes essential in telomere length maintenance and function have been implicated in two broad classes of human disease. The telomere biology disorders (TBDs) are a spectrum of life-threatening conditions, including bone marrow failure, liver and lung disease, cancer and other complications caused by GPVs in telomere maintenance genes that result in short and/or dysfunctional telomeres and reduced cellular replicative capacity. In contrast, cancer predisposition with long telomeres (CPLT) is a disorder associated with elevated risk of a variety of cancers, primarily melanoma, thyroid cancer, sarcoma, glioma and lymphoproliferative neoplasms caused by GPVs in shelterin complex genes that lead to excessive telomere elongation and increased cellular replicative capacity. While telomeres are at the root of both disorders, the term TBD is used to convey the clinical phenotypes driven by critically short or otherwise dysfunctional telomeres and their biological consequences.}, }
@article {pmid39461942, year = {2024}, author = {Qi, Y and Shan, D and Cao, Y and Ma, N and Lu, L and Tian, L and Feng, Z and Ke, F and Jian, J and Gao, Z and Xu, Y}, title = {Telomere-to-telomere Genome Assembly of two representative Asian and European pear cultivars.}, journal = {Scientific data}, volume = {11}, number = {1}, pages = {1170}, pmid = {39461942}, issn = {2052-4463}, support = {CARS-28//Earmarked Fund for China Agriculture Research System/ ; CARS-28//Earmarked Fund for China Agriculture Research System/ ; }, mesh = {*Pyrus/genetics ; *Genome, Plant ; *Telomere/genetics ; Genetic Variation ; Chromosomes, Plant ; }, abstract = {As the third most important temperate fruit, Pear (Pyrus spp.) exhibits a remarkable genetic diversity and is classified into two mainly categories known as Asian pear and European pear. Although several pear genomes are available, most of the released versions are fragmented and not chromosome-level high-quality. In this study, we report two high-quality genomes for Pyrus bretschneideri Rhed. cv. 'Danshansuli' (DS) and Pyrus communis L. cv. 'Conference' (KFL), which represent the predominant Asian and European cultivars, respectively, with nearly telomere-to-telomere (T2T) gap-free level. The finally assembled genome sizes for DS and KFL were 510.98 Mb and 510.71 Mb, respectively, with Contig N50 of 29.47 Mb and 30.47 Mb, where each chromosome was represented by a single contig. The DS and KFL genomes yielded a total of 46,394 and 44,702 protein-coding genes, respectively. Among these genes, the functional annotation accounted for 96.47% and 96.46% in the DS and KFL genomes. The two novels nearly T2T genomic information offers an invaluable resource for comparative genomics, genetic diversity analysis, molecular breeding strategies, and functional exploration.}, }
@article {pmid39461596, year = {2024}, author = {Rattan, P and Nguyen, K and Penrice, DD and Povero, D and Simonetto, DA}, title = {Underrecognized Association of Porto-Sinusoidal Vascular Disorder and Telomere Biology Disorders.}, journal = {Journal of hepatology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jhep.2024.10.029}, pmid = {39461596}, issn = {1600-0641}, }
@article {pmid39459444, year = {2024}, author = {Lee, SH and Kim, TK and Yoo, JH and Park, HJ and Kim, JH and Lee, JH}, title = {Analysis of the Association between Telomere Length and Neurological Disability in Stroke Types.}, journal = {Medicina (Kaunas, Lithuania)}, volume = {60}, number = {10}, pages = {}, doi = {10.3390/medicina60101657}, pmid = {39459444}, issn = {1648-9144}, support = {2022R1G1A100745513//National Research Foundation of Korea/ ; }, mesh = {Humans ; Female ; Male ; Prospective Studies ; Aged ; Middle Aged ; *Stroke/complications/physiopathology/genetics ; Telomere ; Ischemic Stroke/complications/genetics/physiopathology ; Disability Evaluation ; Prognosis ; Disabled Persons/statistics & numerical data ; Aged, 80 and over ; }, abstract = {Background and Objectives: The association between neurological disability, prognosis, and telomere length (TL) in patients with stroke has been investigated in various ways. However, analysis of the type of stroke and ischemic stroke subgroups is limited. In this study, we aimed to determine the association between TL and neurological disability according to stroke type. Materials and Methods: This prospective study included patients with stroke who visited a single-center emergency department (ED) between January 2022 and December 2023. The association between TL and neurological disabilities, using the Modified Rankin Scale (mRS) and National Institutes of Health Stroke Scale (NIHSS), was evaluated according to the patient's stroke type and subgroup of ischemic stroke. Multivariate analysis was performed to determine the association between neurological disabilities in patients with ischemic stroke and the subgroups. Results: A total of 271 patients with stroke were enrolled. The NIHSS score was found to be higher at the time of ED visit (adjusted odds ratio [OR], 5.23; 95% confidence interval [CI], 1.59-17.2, p < 0.01) and 1 day later (adjusted OR, 7.78; 95% CI, 1.97-30.70, p < 0.01) in the ischemic stroke group with a short TL. In the other determined etiology (OD) or undetermined etiology (UD) group, the NIHSS was higher in the short TL group at the ED visit (adjusted OR, 7.89; 95% CI, 1.32-47.25, p = 0.02) and 1 day after (adjusted OR, 7.02; 95% CI, 1.14-43.47, p = 0.04). Conclusions: TL is associated with neurological disability in early ischemic stroke and is prominent in the UD and OD subgroups.}, }
@article {pmid39457663, year = {2024}, author = {Zole, E and Baumanis, E and Freimane, L and Dāle, R and Leiše, A and Lietuvietis, V and Ranka, R}, title = {Changes in TP53 Gene, Telomere Length, and Mitochondrial DNA in Benign Prostatic Hyperplasia Patients.}, journal = {Biomedicines}, volume = {12}, number = {10}, pages = {}, doi = {10.3390/biomedicines12102349}, pmid = {39457663}, issn = {2227-9059}, abstract = {BACKGROUND: Benign prostatic hyperplasia (BPH) is a growing issue due to an ageing population. Our study investigated the possible associations between BPH and ageing hallmarks, including the telomere length (TL) and mitochondrial genome copy number (mtDNA CN), along with genetic variations in the TP53 gene and mtDNA.
METHODS: Prostate tissue samples were obtained from 32 patients with BPH, together with 30 blood samples. As a healthy control group, age-matching blood DNA samples were used. For the comparison of mtDNA sequence data, 50 DNA samples of the general Latvian population were used. The full mtDNA genome was analyzed by using Next-Generation Sequencing (NGS), the TP53 gene by Sanger sequencing, and the mtDNA copy number (mtDNA CN) and telomere length (TL) byqPCR assay.
RESULTS: The results showed that in BPH patients, telomeres in the prostate tissue were significantly longer than in blood cells, while the TL in blood cells of the healthy controls was the shortest. Also, the mtDNA amount in the prostate tissue of BPH patients was significantly greater in comparison with blood cells, and controls had the smallest mtDNA CN. We did not find any mutations in the TP53 gene that could be linked to BPH; however, in mtDNA, we found several unique mutations and heteroplasmic changes, as well as genetic changes that have been previously associated with prostate cancer.
CONCLUSIONS: In conclusion, prolonged telomeres and changes in the mtDNA amount might be involved in the molecular mechanisms of BPH. Some of the heteroplasmic or homoplasmic mtDNA variants might also contribute to the development of BPH. Additional studies are needed to substantiate these findings.}, }
@article {pmid39457609, year = {2024}, author = {Villar-Juárez, GE and Genis-Mendoza, AD and Martínez-López, JNI and Fresan, A and Tovilla-Zaráte, CA and Nolasco-Rosales, GA and Juárez-De la Cruz, GI and Ramos, DR and Villar-Soto, M and Mejía-Ortiz, P and Gómez Mendiola, M and Juárez-Rojop, IE and Nicolini, H}, title = {Exploring the Relationship between Telomere Length and Cognitive Changes in Post-COVID-19 Subjects.}, journal = {Biomedicines}, volume = {12}, number = {10}, pages = {}, doi = {10.3390/biomedicines12102296}, pmid = {39457609}, issn = {2227-9059}, abstract = {BACKGROUND/OBJECTIVES: Emerging evidence suggests that patients suffering from COVID-19 may experience neurocognitive symptoms. Furthermore, other studies indicate a probable association between leukocyte telomere length (LTL) and neurocognitive changes in subjects with post-COVID-19 condition. Our study was designed to determine the correlation between telomere length and cognitive changes in post-COVID-19 subjects.
METHODS: This study included 256 subjects, categorized based on SARS-CoV-2 infection from 2020 to 2023. In addition, subjects with a psychiatric diagnosis were considered. Moreover, the MoCA and MMSE scales were applied. Telomere length was determined using a polymerase chain reaction, and statistical analysis was employed using ANOVA and X[2] tests.
RESULTS: We identified a decrease in LTL in individuals with post-COVID-19 conditions compared to those without SARS-CoV-2 infection (p ≤ 0.05). However, no association was found between LTL and cognitive impairment in the subjects post-COVID-19.
CONCLUSIONS: The findings suggest that LTL is affected by SARS-CoV-2 infection. Nonetheless, this important finding requires further research by monitoring neurological changes in subjects with post-COVID condition.}, }
@article {pmid39456511, year = {2024}, author = {Kapetanou, M and Athanasopoulou, S and Goutas, A and Makatsori, D and Trachana, V and Gonos, E}, title = {α-Terpineol Induces Shelterin Components TRF1 and TRF2 to Mitigate Senescence and Telomere Integrity Loss via A Telomerase-Independent Pathway.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {13}, number = {10}, pages = {}, doi = {10.3390/antiox13101258}, pmid = {39456511}, issn = {2076-3921}, support = {Biomage project//Private/ ; Postdoctoral Fellowship//Hellenic Pasteur Institute/ ; }, abstract = {Cellular senescence is a hallmark of aging characterized by irreversible growth arrest and functional decline. Progressive telomeric DNA shortening in dividing somatic cells, programmed during development, leads to critically short telomeres that trigger replicative senescence and thereby contribute to aging. Therefore, protecting telomeres from DNA damage is essential in order to avoid entry into senescence and organismal aging. In several organisms, including mammals, telomeres are protected by a protein complex named shelterin that prevents DNA damage at the chromosome ends through the specific function of its subunits. Here, we reveal that the nuclear protein levels of shelterin components TRF1 and TRF2 decline in fibroblasts reaching senescence. Notably, we identify α-terpineol as an activator that effectively enhances TRF1 and TRF2 levels in a telomerase-independent manner, counteracting the senescence-associated decline in these crucial proteins. Moreover, α-terpineol ameliorates the cells' response to oxidative DNA damage, particularly at the telomeric regions, thus preserving telomere length and delaying senescence. More importantly, our findings reveal the significance of the PI3K/AKT pathway in the regulation of shelterin components responsible for preserving telomere integrity. In conclusion, this study deepens our understanding of the molecular pathways involved in senescence-associated telomere dysfunction and highlights the potential of shelterin components to serve as targets of therapeutic interventions, aimed at promoting healthy aging and combating age-related diseases.}, }
@article {pmid39456194, year = {2024}, author = {Han, F and Riaz, F and Pu, J and Gao, R and Yang, L and Wang, Y and Song, J and Liang, Y and Wu, Z and Li, C and Tang, J and Xu, X and Wang, X}, title = {Connecting the Dots: Telomere Shortening and Rheumatic Diseases.}, journal = {Biomolecules}, volume = {14}, number = {10}, pages = {}, doi = {10.3390/biom14101261}, pmid = {39456194}, issn = {2218-273X}, mesh = {Humans ; *Rheumatic Diseases/genetics/metabolism ; *Telomere Shortening/genetics ; *Telomerase/metabolism/genetics ; *Telomere/metabolism/genetics ; Oxidative Stress/genetics ; Animals ; }, abstract = {Telomeres, repetitive sequences located at the extremities of chromosomes, play a pivotal role in sustaining chromosomal stability. Telomerase is a complex enzyme that can elongate telomeres by appending telomeric repeats to chromosome ends and acts as a critical factor in telomere dynamics. The gradual shortening of telomeres over time is a hallmark of cellular senescence and cellular death. Notably, telomere shortening appears to result from the complex interplay of two primary mechanisms: telomere shelterin complexes and telomerase activity. The intricate interplay of genetic, environmental, and lifestyle influences can perturb telomere replication, incite oxidative stress damage, and modulate telomerase activity, collectively resulting in shifts in telomere length. This age-related process of telomere shortening plays a considerable role in various chronic inflammatory and oxidative stress conditions, including cancer, cardiovascular disease, and rheumatic disease. Existing evidence has shown that abnormal telomere shortening or telomerase activity abnormalities are present in the pathophysiological processes of most rheumatic diseases, including different disease stages and cell types. The impact of telomere shortening on rheumatic diseases is multifaceted. This review summarizes the current understanding of the link between telomere length and rheumatic diseases in clinical patients and examines probable telomere shortening in peripheral blood mononuclear cells and histiocytes. Therefore, understanding the intricate interaction between telomere shortening and various rheumatic diseases will help in designing personalized treatment and control measures for rheumatic disease.}, }
@article {pmid39448973, year = {2024}, author = {Hassanpour, H and Javdani, M and Changaniyan-Khorasgani, Z and Rezazadeh, E and Jalali, R and Mojtahed, M}, title = {Is castration leading to biological aging in dogs? Assessment of lipid peroxidation, inflammation, telomere length, mitochondrial DNA copy number, and expression of telomerase and age-related genes.}, journal = {BMC veterinary research}, volume = {20}, number = {1}, pages = {485}, pmid = {39448973}, issn = {1746-6148}, mesh = {Animals ; Dogs ; Male ; *Lipid Peroxidation ; *Aging ; *Telomerase/genetics/metabolism ; *Inflammation/veterinary/genetics/metabolism ; *DNA, Mitochondrial/genetics ; Telomere ; Orchiectomy/veterinary ; Malondialdehyde/blood/metabolism ; C-Reactive Protein/metabolism/genetics/analysis ; DNA Copy Number Variations ; }, abstract = {BACKGROUND: Biological aging is a complex process influenced by various factors, including reproductive status and castration. This study aimed to evaluate the impact of castration on biological aging in dogs.
METHOD: Fifteen male crossbred dogs were randomly divided into a sham-operation control group (n = 5) and a castrated group (n = 10). Blood samples were collected at weeks 0, 4, 8, 12, 16, and 18 post-surgery. Malondialdehyde (MDA as indicator of Lipid peroxidation), C-reactive protein (as an indicator of inflammation), telomere length, mitochondrial DNA (mtDNA) copy number, and the expression of age-related (P16, P21, TBX2) and telomerase-related (TERT) genes were assessed in blood samples.
RESULTS: Plasma MDA levels were higher in the control group at weeks 16 and 18, while CRP levels were higher only at week 18. Telomere length and mtDNA copy number were lower in the control group at week 18. Gene expression analysis showed that P16 was lower in the control group at weeks 8 and 12, P21 and TERT were lower at weeks 16 and 18, and TBX2 was lower at weeks 16 and 18. The TBX2/P16 ratio was lower in the control group at weeks 16 and 18 but higher at week 12, while the TBX2/P21 ratio did not differ between groups.
CONCLUSION: Castration appears to have a protective effect against biological aging in dogs, as evidenced by lower lipid peroxidation, inflammation, and age-related changes in telomere length, mtDNA copy number, and gene expression.}, }
@article {pmid39448517, year = {2024}, author = {Domínguez-de-Barros, A and Sifaoui, I and Dorta-Guerra, R and Lorenzo-Morales, J and Castro-Fuentes, R and Córdoba-Lanús, E}, title = {Telomere- and oxidative stress dynamics in Psittacidae species with different longevity trajectories.}, journal = {GeroScience}, volume = {}, number = {}, pages = {}, pmid = {39448517}, issn = {2509-2723}, support = {PP-167-2019-19//Loro Parque Fundación/ ; CB21/13/00100//Instituto de Salud Carlos III/ ; 2023-2028 - PI-CC202302222//Cabildo de Tenerife/ ; Cabildo.23//Cabildo de Tenerife/ ; }, abstract = {Telomeres, conserved DNA sequences at chromosome ends, naturally shorten with age, exacerbated by external factors like environmental challenges and reproduction. Birds, particularly psittacine, are gaining prominence as new aging models over the years because of their unique characteristics. This study explores erythrocyte telomere length (TL) and oxidative stress markers in plasma of long- and short-lived captive birds of the order Psittaciformes over four years. Long-lived birds consistently exhibited longer TL than short-lived ones (p = 0.012) but experienced a more pronounced TL shortening rate (p < 0.001) than short-lived ones. Breeding individuals experienced increased TL shortening compared to non-reproductive counterparts in long-lived birds (p = 0.008). Interestingly, long-lived birds showed a higher total antioxidant capacity than short-lived ones (p < 0.001), which was also increased during breeding (p = 0.026). A significant correlation was found between the telomere length shortening rate within the 4 years of study and the accumulated oxidative stress (r = 0.426, p = 0.069) in short-lived birds. These findings shed light on TL and oxidative stress dynamics over time, revealing distinct patterns influenced by life-traits among longevity groups.}, }
@article {pmid39443618, year = {2024}, author = {Kandemir, I and Sahin, AY and Oyaci, Y and Khudiyeva, S and Sahin, M and Aksakal, MT and Pehlivan, M and Bas, F and Pehlivan, S}, title = {Effect of obesity and NAFLD on leukocyte telomere length and hTERT gene MNS16A VNTR variant.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {25055}, pmid = {39443618}, issn = {2045-2322}, mesh = {Humans ; Adolescent ; *Telomerase/genetics ; Female ; Male ; *Non-alcoholic Fatty Liver Disease/genetics/pathology ; *Obesity/genetics/complications ; Child ; *Minisatellite Repeats/genetics ; *Telomere/genetics ; Young Adult ; Leukocytes/metabolism ; Case-Control Studies ; }, abstract = {It is known that telomere length (TL) (evaluated with T/S ratio) is shortened in the presence of obesity. In this study, we aimed to investigate how obesity in adolescents and non-alcoholic liver disease (NAFLD) within the obese group affect TL and the clinical significance of the human telomerase reverse transcriptase (hTERT) gene MNS16A VNTR variant in terms of NAFLD. Adolescents with exogenous obesity and healthy controls (aged 10-19 years) who applied to our adolescent outpatient clinic between May-October 2023 were included in this study. We performed upper abdominal ultrasonography to investigate the presence of NAFLD in adolescents with obesity and divided into two groups: those without hepatosteatosis (obese NAFLD (-)) and those with hepatosteatosis (obese NAFLD (+)). We recorded body weight, height, waist circumference, and blood pressure measurements and measured the T/S ratio (telomere sequence copy number/gene single copy number) by the Quantitative Polymerase Chain Reaction method. The groups were compared using frequentist and Bayesian methods. Eighty-three obese adolescents [63 NAFLD(+) 20 NAFLD(-)] and 69 lean controls were included in the study. Pairwise comparisons revealed that T/S ratio was significantly lower in the obese NAFLD (-) group than the obese NAFLD (+) and the control group (p = 0.025, p = 0.007, respectively). T/S ratio was lower in the LL allele group than in the other alleles (p = 0.022) and slightly higher in the obese group with metabolic syndrome compared to the obese group without metabolic syndrome (p = 0.072). hTERT-MNS16A-VNTR gene variant LL allele had a negative correlation with T/S ratio among the obese adolescent group. Patients with LL alleles had higher ALT, GGT, HOMA-IR, and ALT/AST. Diastolic blood pressure had a significant correlation with the T/S ratio. The T/S ratio was shorter in the obese adolescent group compared to healthy ones but was higher in the NAFLD (+) obese compared to the NAFLD (-) obese. ALT level and ALT/AST ratio were higher, T/S ratio was lower in the hTERT MNS16A VNTR variant LL allele group among obese adolescents. In addition, there was a significant correlation between the T/S ratio and diastolic blood pressure in obese adolescents.}, }
@article {pmid39441032, year = {2024}, author = {Gao, Q and Yu, J and Liu, Y and Xing, B and Ping, F and Xu, L and Li, W and Zhang, H and Li, Y}, title = {Elevated 1-Hour Post Load Glucose as a Predictor for Telomere Attrition: a study based on a Chinese Community population.}, journal = {The Journal of clinical endocrinology and metabolism}, volume = {}, number = {}, pages = {}, doi = {10.1210/clinem/dgae748}, pmid = {39441032}, issn = {1945-7197}, abstract = {CONTEXT: 1-hour post-load glucose (1h-PG) detects dysglycemia-related disorders more effectively than traditional glycemic parameters. Hyperglycemia accelerates aging, whether 1h-PG outperforms in predicting aging remains unclear.
OBJECTIVE: To Compare the effectiveness of 1h-PG with other glycemic parameters in identifying and predicting telomere attrition.
METHODS: We conducted a cross-sectional and longitudinal study based on a Chinese community cohort. Multivariate linear regression and logistic regression were used to analyze the associations between glycemic parameters and telomere length. The area under the receiver operating characteristic (AUROC) curve were used to compare the differentiating and predictive ability. Populations were regrouped by glucose tolerance status and 1h-PG to compare telomere length. Analyses were separately conducted in non-diabetic and diabetic populations.
RESULTS: The cross-sectional study included 715 participants. Only 1h-PG was significantly negatively associated with RTL in both non-diabetic (β = -0.106, 95%CI -0.068 to -0.007, P = 0.017) (odds ratio [OR] = 1.151, 95% CI 1.069 to 1.239, P = 0.005) and diabetic (β = -0.222, 95%CI -0.032 to -0.007, P = 0.002) (OR = 1.144, 95% CI 1.041 to 1.258, P = 0.035) populations. The longitudinal study recruited 437 populations and 112 remained in 7-years follow-up. 1h-PG was associated with telomere shortening in the non-diabetic group (β = -0.314, 95%CI -0.276 to -0.032, P = 0.016) (OR = 2.659, 95% CI 1.158 to 6.274, P = 0.021). AUROC analysis showed that 1h-PG outperformed other glycemic parameters in identifying and predicting telomere attrition. Reclassification revealed that normal glucose tolerance and prediabetic individuals with elevated 1h-PG had telomere lengths comparable to prediabetic and diabetic populations, respectively.
CONCLUSIONS: 1h-PG outperforms other glycemic parameters in predicting telomere attrition and can be a valuable marker for early aging detection.}, }
@article {pmid39438947, year = {2024}, author = {Coulter, T and Hill, C and McKnight, AJ}, title = {Insights into the length and breadth of methodologies harnessed to study human telomeres.}, journal = {Biomarker research}, volume = {12}, number = {1}, pages = {127}, pmid = {39438947}, issn = {2050-7771}, abstract = {Telomeres are protective structures at the end of eukaryotic chromosomes that are strongly implicated in ageing and ill health. They attrition upon every cellular reproductive cycle. Evidence suggests that short telomeres trigger DNA damage responses that lead to cellular senescence. Accurate methods for measuring telomeres are required to fully investigate the roles that shortening telomeres play in the biology of disease and human ageing. The last two decades have brought forth several techniques that are used for measuring telomeres. This editorial highlights strengths and limitations of traditional and emerging techniques, guiding researchers to choose the most appropriate methodology for their research needs. These methods include Quantitative Polymerase Chain Reaction (qPCR), Omega qPCR (Ω-qPCR), Terminal Restriction Fragment analysis (TRF), Single Telomere Absolute-length Rapid (STAR) assays, Single TElomere Length Analysis (STELA), TElomere Shortest Length Assays (TESLA), Telomere Combing Assays (TCA), and Long-Read Telomere Sequencing. Challenges include replicating telomere measurement within and across cohorts, measuring the length of telomeres on individual chromosomes, and standardised reporting for publications. Areas of current and future focus have been highlighted, with recent methodical advancements, such as long-read sequencing, providing significant scope to study telomeres at an individual chromosome level.}, }
@article {pmid39438690, year = {2024}, author = {Tyer, C}, title = {High-resolution measurement of individual telomere lengths with Telo-seq.}, journal = {Nature reviews. Cancer}, volume = {}, number = {}, pages = {}, pmid = {39438690}, issn = {1474-1768}, }
@article {pmid39435041, year = {2024}, author = {}, title = {Erratum: Targeting Telomere Dynamics as an Effective Approach for the Development of Cancer Therapeutics [Corrigendum].}, journal = {International journal of nanomedicine}, volume = {19}, number = {}, pages = {10367-10368}, doi = {10.2147/IJN.S500182}, pmid = {39435041}, issn = {1178-2013}, abstract = {[This corrects the article DOI: 10.2147/IJN.S448556.].}, }
@article {pmid39432594, year = {2024}, author = {Dai, H and Chen, Z}, title = {Association between dietary vitamin K and telomere length: Based on NHANES 2001 to 2002.}, journal = {Medicine}, volume = {103}, number = {42}, pages = {e40157}, doi = {10.1097/MD.0000000000040157}, pmid = {39432594}, issn = {1536-5964}, mesh = {Humans ; Male ; Female ; *Nutrition Surveys ; Middle Aged ; *Telomere/drug effects ; *Vitamin K/administration & dosage ; *Diet/statistics & numerical data ; Adult ; Aged ; Cross-Sectional Studies ; Body Mass Index ; }, abstract = {As an anti-inflammatory and antioxidant, vitamin K has the potential to reduce telomere attrition. However, the correlation between dietary vitamin K and telomere length (TL) has not been reported. We aimed to investigate the association between these 2 variables. This study included 3754 participants from the National Health and Nutrition Examination Survey 2001-2002 database. We used multivariate linear regression and restricted cubic splines to assess the relationship between dietary vitamin K intake and TL. Subgroup analyses and interaction tests were utilized to examine the stability of the results. After adjusting for all variables, each unit increase in daily dietary intake of vitamin K lengthened telomeres by 0.22 base pairs (β = 0.22, 95% CI: 0.09-0.36, P = .001). Individuals with the highest dietary vitamin K intake had significantly longer TL (β = 80.27, 95% CI: 20.83-139.71, P = .008). Subgroup analyses suggested that this association persisted in populations stratified by gender, age, diabetes, cardiovascular disease (CVD), body mass index and total energy intake (P for interaction > .05). A linear relationship between dietary vitamin K intake and TL was observed in restricted cubic splines (P for nonlinear = .554). In conclusion, our findings suggest that dietary vitamin K intake is positively associated with TL, providing recent evidence to guide the management of healthy diets.}, }
@article {pmid39430825, year = {2024}, author = {Ding, X and Zhang, Y and You, S}, title = {A novel prognostic model based on telomere-related lncRNAs in gastric cancer.}, journal = {Translational cancer research}, volume = {13}, number = {9}, pages = {4608-4624}, pmid = {39430825}, issn = {2219-6803}, abstract = {BACKGROUND: Telomeres are specialized structures at the ends of chromosomes that are important for their protection. Over time, long non-coding RNAs (lncRNAs) have gradually come into the spotlight as essential biomarkers of proliferation, migration, and invasion of human malignant tumors. Nevertheless, the impact of telomere-related lncRNAs (TRLs) in gastric cancer is currently unknown. In the present study, we screen the TRLs and identify a prognostic TRLs signature in gastric cancer.
METHODS: First, telomere-related genes (TRGs) were retrieved from the website, and RNA sequencing (RNA-seq) data and clinical data of stomach adenocarcinoma (STAD) patients were gathered from The Cancer Genome Atlas (TCGA) database. Gastric cancer patients' lncRNAs and overall survival (OS) were found to be related using univariate Cox regression analysis. Next, least absolute shrinkage and selection operator (LASSO) regression analysis and multifactorial Cox regression analysis were used to further screen telomere-related differentially expressed lncRNAs (TRDELs), and finally six lncRNAs were obtained, including LINC01537, CFAP61-AS1, DIRC1, RABGAP1L-IT1, DBH-AS1, and REPIN1-AS1. According to these six TRDELs, a prognostic model for gastric cancer was constructed. The samples were divided into the training group and the testing group at random, and the reliability of prognostic model was validated in both groups and overall samples. In addition, we performed Kaplan-Meier (K-M) survival curve analysis, independent prognostic analysis, and functional enrichment analysis to validate the predictive value and independence of the model, as well as immune cell correlation analysis, clustering analysis, and principal component analysis (PCA) to further explore the relationship between this model and the tumor cells. Finally, we performed the drug sensitivity analysis to identify a few small molecules that may have a therapeutic effect on gastric cancer.
RESULTS: Finally, we constructed a prognostic model for gastric cancer consisting of six TRDELs. According to the K-M curve, the prognosis of the low-risk group was noticeably superior than that of the high-risk group. Multivariate Cox regression analysis suggested that risk score was an independent prognostic element. Receiver operating characteristic (ROC) curves, nomogram, and calibration curve indicated that the prognostic model had good predictive ability. Functional enrichment analysis demonstrated major pathways with high- and low-risk groups. Next, both tumor microenvironment (TME) and immune correlation analysis showed discrepancy in the high- and low-risk groups. Through drug sensitivity analysis, we screened four small molecules that might be beneficial for gastric cancer treatment.
CONCLUSIONS: A prognostic model consisting of these six TRDELs was capable to predict the prognosis of gastric cancer patients.}, }
@article {pmid39430816, year = {2024}, author = {Lin, H and Yin, W}, title = {Telomere-related prognostic signature for survival assessments in lung adenocarcinoma.}, journal = {Translational cancer research}, volume = {13}, number = {9}, pages = {4520-4533}, pmid = {39430816}, issn = {2219-6803}, abstract = {BACKGROUND: Telomere-related genes (TRGs) are important in many different types of cancers. However, there is a lack of research on the relationship between their expression and prognosis in lung adenocarcinoma (LUAD) patients. This study is to investigate the prognostic value of TRGs in LUAD and to develop a TRG signature that can predict patient survival.
METHODS: A total of 2,086 TRGs were obtained from a database of genes involved in telomere maintenance (TelNet), while the clinical information and tumor RNA expression profiles of 513 LUAD patients were acquired from The Cancer Genome Atlas (TCGA) database. Statistical methodologies, such as least absolute shrinkage and selection operator (LASSO)-Cox, were employed to construct a prognostic model with predictive capabilities.
RESULTS: We analyzed 1,339 telomere-associated differentially expressed genes and identified a ten-gene predictive signature for LUAD. This signature exhibited effective prognostic classification capabilities across multiple datasets, including GSE3141 (58 samples), GSE8894 (63 samples), GSE50081 (127 samples), and GSE72094 (398 samples). Furthermore, we screened tumor-sensitive drugs targeting this signature. High telomere levels were associated with reduced survival in lung cancer patients who underwent surgery. Compared to the traditional TNM (tumor node metastasis classification) grading method, our telomere-associated gene panel demonstrated superior prediction accuracy. Notably, patients in the high-risk group, defined by the telomere-associated signature, exhibited improved responses to immunotherapy, suggesting potential benefits for this subgroup of patients.
CONCLUSIONS: This study presents a comprehensive molecular signature comprising TRGs, which holds potential for functional and therapeutic investigations. Additionally, it serves as an integrated tool to identify crucial molecules for immunotherapy in lung cancer.}, }
@article {pmid39429092, year = {2024}, author = {Rubio-Carrasco, K and de la Torre, PG and Martínez-Ezquerro, JD and Sánchez-García, S and García-Vences, E and Camacho-Arroyo, I and Rodríguez-Dorantes, M and González-Covarrubias, V}, title = {Hypertension Control Is Associated with Telomere Length in Older Adults.}, journal = {DNA and cell biology}, volume = {}, number = {}, pages = {}, doi = {10.1089/dna.2024.0173}, pmid = {39429092}, issn = {1557-7430}, abstract = {Hypertension is the leading risk for cardiovascular disease and worldwide mortality. Uncontrolled blood pressure worsens with age and its control is part of public health strategies especially for older adults. Telomere length (TL) has been associated with hypertension, with age and sex as relevant confounding factors, but it is not clear whether hypertension control in older adults impacts on TL and if this relationship is consistently age and sex dependent. TL was assessed in leukocytes of 369 hypertensive patients. Individuals were >60 years male (169) and female (200) and have been diagnosed and treated for hypertension for at least four years. TL was measured by RT-PCR using a commercial probe. Regression models were developed considering systolic and diastolic blood pressure control as dependent variables and age, sex, glucose, and lipid levels as confounding factors. TL showed a mean of 7.5 ± 5.1 Kb, and no difference between males and females was observed. We identified a significant association between systolic blood pressure control and TL (p value = 0.039) and a trend for diastolic blood pressure (p value = 0.061). These observations confirm and expand previous reports showing that hypertension control can have an impact on TL and consequently on other factors of healthy aging.}, }
@article {pmid39426946, year = {2024}, author = {Wang, B and Kou, H and Wang, Y and Zhang, Q and Jiang, D and Wang, J and Zhao, Z and Zhou, Y and Zhang, M and Sui, L and Zhao, M and Liu, Y and Liu, Y and Shi, L and Wang, F}, title = {LAP2α orchestrates alternative lengthening of telomeres suppression through telomeric heterochromatin regulation with HDAC1: unveiling a potential therapeutic target.}, journal = {Cell death & disease}, volume = {15}, number = {10}, pages = {761}, pmid = {39426946}, issn = {2041-4889}, support = {32170762//National Natural Science Foundation of China (National Science Foundation of China)/ ; }, mesh = {Humans ; Animals ; *Telomere Homeostasis/drug effects ; *Telomere/metabolism ; *Heterochromatin/metabolism ; Mice ; Cell Line, Tumor ; Osteosarcoma/genetics/pathology/metabolism/drug therapy ; Sister Chromatid Exchange ; DNA-Binding Proteins/metabolism/genetics ; Methotrexate/pharmacology/therapeutic use ; Cell Proliferation/drug effects ; Membrane Proteins ; }, abstract = {In response to the challenge of telomere attrition during DNA replication, cancer cells predominantly employ telomerase or, in 10-15% of cases, the alternative lengthening of telomeres (ALT). The intricate details of ALT, however, remain elusive. In this study, we unveil that the knockdown of lamina-associated polypeptide 2 alpha (LAP2α) in ALT cells results in telomere dysfunction, triggering a notable increase in ALT-associated hallmarks, including high frequencies of PML bodies (APBs), C-rich extrachromosomal circles (C-circles), and telomere sister chromatid exchange (T-SCE). Furthermore, LAP2α emerges as a crucial player in break-induced telomere replication for telomerase-positive cells following telomeric double-strand breaks. Mechanistically, our investigation suggests that LAP2α may influence the regulation of the heterochromatic state of telomeres, thereby affecting telomeric accessibility. In line with our findings, LAP2α expression is markedly reduced in ALT-positive osteosarcoma. And the use of methotrexate (MTX) can restore the heterochromatin state altered by LAP2α depletion. This is evidenced by a significant inhibition of tumor proliferation in ALT-positive patient-derived xenograft (PDX) mouse models. These results indicate the important role of LAP2α in regulating ALT activity and offer insights into the interplay between lamina-associated proteins and telomeres in maintaining telomere length. Importantly, our findings may help identify a more appropriate target population for the osteosarcoma therapeutic drug, MTX.}, }
@article {pmid39426311, year = {2024}, author = {Douglas, ME}, title = {How to write an ending: Telomere replication as a multistep process.}, journal = {DNA repair}, volume = {144}, number = {}, pages = {103774}, doi = {10.1016/j.dnarep.2024.103774}, pmid = {39426311}, issn = {1568-7856}, abstract = {Telomeres are protective nucleoprotein caps found at the natural ends of eukaryotic chromosomes and are crucial for the preservation of stable chromosomal structure. In cycling cells, telomeres are maintained by a multi-step process called telomere replication, which involves the eukaryotic replisome navigating a complex repetitive template tightly bound by specific proteins, before terminating at the chromosome end prior to a 5' resection step that generates a protective 3' overhang. In this review, we examine mechanistic aspects of the telomere replication process and consider how individual parts of this multistep event are integrated and coordinated with one-another.}, }
@article {pmid39422841, year = {2024}, author = {Fu, H and Zhu, Y and Lin, L and Jiang, P and Cai, G and Zeng, L and Li, X and Zhang, Y and Li, C and Zhan, H and Zhang, B and Yang, Z}, title = {Shorter Leukocyte Telomere Length Is Associated with Increased Major Adverse Cardiovascular Events or Mortality in Patients with Essential Hypertension.}, journal = {Journal of cardiovascular translational research}, volume = {}, number = {}, pages = {}, pmid = {39422841}, issn = {1937-5395}, support = {82171578//National Natural Science Foundation of China/ ; 2023B03J0121//Science and Technology Project of Guangzhou City/ ; 20221800906192//Dongguan Science and Technology of Social Development Program/ ; }, abstract = {The association between leukocyte telomere length (LTL) alteration and major adverse cardiovascular events (MACE) or mortality in patients with hypertension is still unclear. 20,034 patients with essential hypertension were enrolled from UK biobank. Multivariable COX regression models were performed to assess the association. LTL was shorter in hypertensive patients with MACE compared to those without MACE. Hypertensive patients in the lowest LTL quartile were at higher risk to develop MACE (adjusted HR 1.15 [95% CI 1.02-1.29], vs top LTL quartile, p-trend = 0.03). Similarly, shorter LTL was related with increased mortality (adjusted HR 1.18[95% CI 1.06-1.3], lowest vs top LTL quartile, p-trend < 0.001). This investigation demonstrated that shorter LTL is associated with increased risk of MACE or mortality in patients with essential hypertension, which indicates that LTL may be a potential predictor of prognosis or underlying therapeutic target for hypertension.}, }
@article {pmid39420560, year = {2024}, author = {Lu, D and Liu, C and Ji, W and Xia, R and Li, S and Liu, Y and Liu, N and Liu, Y and Deng, XW and Li, B}, title = {Nanopore Ultra-long Sequencing and Adaptive Sampling Spur Plant Complete Telomere-to-Telomere Genome Assembly.}, journal = {Molecular plant}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.molp.2024.10.008}, pmid = {39420560}, issn = {1752-9867}, abstract = {The pursuit of complete telomere-to-telomere (T2T) genome assembly in plants, challenged by genomic complexity, has been advanced by Oxford Nanopore Technologies (ONT), which offers ultra-long, real-time sequencing. Despite its promise, sequencing length and gap filling remain significant challenges. This study optimized DNA extraction and library preparation, achieving DNA lengths exceeding 485 Kb, average N50 read lengths of 80.57 Kb, with reaching up to 440 Kb, and maximum reads of 5.83 Mb. Importantly, it demonstrated that combining ultra-long sequencing and adaptive sampling can effectively fill gaps during assembly, evidenced by successfully achieving the Arabidopsis genome remaining gaps and an unknown telomeric region in watermelon. Our methodologies improve the feasibility of complete T2T genomic assemblies across plants, enhancing genome-based research in diverse fields.}, }
@article {pmid39420004, year = {2024}, author = {Lam, SY and van der Lugt, R and Cerutti, A and Yalçin, Z and Thouin, AM and Simonetta, M and Jacobs, JJL}, title = {OTUD5 promotes end-joining of deprotected telomeres by promoting ATM-dependent phosphorylation of KAP1[S824].}, journal = {Nature communications}, volume = {15}, number = {1}, pages = {8960}, pmid = {39420004}, issn = {2041-1723}, support = {812829//EC | EU Framework Programme for Research and Innovation H2020 | H2020 Priority Excellent Science | H2020 Marie Skłodowska-Curie Actions (H2020 Excellent Science - Marie Skłodowska-Curie Actions)/ ; 2019-2/12826//KWF Kankerbestrijding (Dutch Cancer Society)/ ; institutional grant to the Netherlands Cancer Institute//KWF Kankerbestrijding (Dutch Cancer Society)/ ; Institutional grant to the Netherlands Cancer Institute//Dutch Ministry of Health, Welfare and Sport | Rijksinstituut voor Volksgezondheid en Milieu (Netherlands National Institute for Public Health and the Environment)/ ; }, mesh = {Phosphorylation ; *Tripartite Motif-Containing Protein 28/metabolism/genetics ; *Ataxia Telangiectasia Mutated Proteins/metabolism/genetics ; *Telomere/metabolism ; Humans ; *DNA End-Joining Repair ; DNA Damage ; Ubiquitin-Protein Ligases/metabolism/genetics ; Heterochromatin/metabolism ; Endopeptidases/metabolism/genetics ; HEK293 Cells ; Ubiquitination ; }, abstract = {Appropriate repair of damaged DNA and the suppression of DNA damage responses at telomeres are essential to preserve genome stability. DNA damage response (DDR) signaling consists of cascades of kinase-driven phosphorylation events, fine-tuned by proteolytic and regulatory ubiquitination. It is not fully understood how crosstalk between these two major classes of post-translational modifications impact DNA repair at deprotected telomeres. Hence, we performed a functional genetic screen to search for ubiquitin system factors that promote KAP1[S824] phosphorylation, a robust DDR marker at deprotected telomeres. We identified that the OTU family deubiquitinase (DUB) OTUD5 promotes KAP1[S824] phosphorylation by facilitating ATM activation, through stabilization of the ubiquitin ligase UBR5 that is required for DNA damage-induced ATM activity. Loss of OTUD5 impairs KAP1[S824] phosphorylation, which suppresses end-joining mediated DNA repair at deprotected telomeres and at DNA breaks in heterochromatin. Moreover, we identified an unexpected role for the heterochromatin factor KAP1 in suppressing DNA repair at telomeres. Altogether our work reveals an important role for OTUD5 and KAP1 in relaying DDR-dependent kinase signaling to the control of DNA repair at telomeres and heterochromatin.}, }
@article {pmid39416992, year = {2024}, author = {Cadiñanos, J and Rodríguez-Centeno, J and Montejano, R and Esteban-Cantos, A and Mena-Garay, B and Jiménez-González, M and Saiz-Medrano, G and de Miguel, R and Rodríguez-Artalejo, F and Bernardino, JI and Marcelo-Calvo, C and Gutierrez-García, L and Martínez-Martín, P and Díez Vidal, A and de Gea Grela, A and Ortolá, R and Rodés, B and Arribas, JR}, title = {Partial Recovery of Telomere Length After Long-term Virologic Suppression in Persons With HIV-1.}, journal = {Open forum infectious diseases}, volume = {11}, number = {10}, pages = {ofae550}, pmid = {39416992}, issn = {2328-8957}, abstract = {BACKGROUND: People with HIV-1 (PWH) age differently than the general population. Blood telomere length (BTL) attrition is a surrogate biomarker of immunosenescence and aging in PWH. BTL is reduced immediately after HIV-1 infection and recovers in PWH with long-term virologic suppression, but the extent of this recovery is unknown.
METHODS: This prospective 6-year observational study assessed the evolution of BTL in PWH who were virologically suppressed. A cross-sectional analysis additionally compared BTL with age- and sex-matched blood donors and sex-matched persons older than 60 years from a general population cohort. DNA from whole blood was isolated, and relative BTL was determined by monochrome quantitative multiplex polymerase chain reaction assay and expressed as the ratio of telomere to single-copy gene (T/S).
RESULTS: A total of 128 PWH were included in the prospective 6-year observational study. These same 128 PWH (median age, 55 years; 27.3% women) were compared cross-sectionally at 6-year follow-up with 128 age- and gender-matched blood donors (median age, 55 years) and 128 gender-matched individuals older than 60 years from a general population cohort (median age, 70 years). An inverse correlation between age and BTL was observed. The median BTL of PWH was shorter than their matched blood donors (T/S, 1.07 [IQR, 0.95-1.17] vs 1.28 [IQR, 1.12-1.48]; P < .001) but longer than the elderly population (T/S, 0.89 [IQR, 0.77-0.98], P < .001). PWH experienced a BTL increase at 6 years of 2.9% (T/S, 1.04 vs 1.07; P = .002). In PWH, age was associated with a shorter BTL (coefficient, -0.007 45, SE = 0.002 04, P = .002) and baseline lower CD4 count with a gain in BTL (coefficient, -0.000 06, SE = 0.000 02, P = .004). Shorter baseline BTL (odds ratio, 0.91 [95% CI, .87-.94]; P < .001) and higher glucose levels (odds ratio, 1.04 [95% CI, 1.02-1.07]; P = .003) were associated with a greater similarity of BTL to the elderly population.
CONCLUSIONS: PWH with long-term virologic suppression experience a trend toward an increased BTL after 6 years of follow-up. Middle-aged people with long-term controlled HIV-1 have a shorter BTL than expected for their chronologic age but longer than that of people 15 years older in the general population.}, }
@article {pmid39413125, year = {2024}, author = {Zhang, Y and Ma, Z and Kang, L and Yang, L}, title = {Effect of telomere shortening on disease progression in patients with inflammatory bowel disease: A systematic review and meta-analysis protocol.}, journal = {PloS one}, volume = {19}, number = {10}, pages = {e0311662}, doi = {10.1371/journal.pone.0311662}, pmid = {39413125}, issn = {1932-6203}, mesh = {Humans ; *Inflammatory Bowel Diseases/genetics/pathology ; *Systematic Reviews as Topic ; *Disease Progression ; *Telomere Shortening ; *Meta-Analysis as Topic ; Telomere/genetics ; }, abstract = {INTRODUCTION: Inflammatory bowel disease (IBD) remains a major public health challenge worldwide. In recent years, it has been discovered that a link between telomere shortening and disease progression in IBD patients has been present. However, there is controversy as to whether telomere shortening precipitates disease progression or disease progression causes telomere shortening. There is also a shortage of systematic reviews and data synthesis to explain the association between telomere shortening and disease progression in individuals with IBD. We aimed to systematically review the association between telomere shortening and disease advancement in individuals with IBD to inform future studies.
METHODS AND ANALYSIS: We will undertake a thorough search of the electronic database from the beginning until December 31, 2023. We will search the databases: MEDLINE/PubMed, Embase, Web of Science, China National Knowledge Infrastructure (CNKI), VIP, Wanfang Database (Wanfang), CMB, Cochrane Library, Cochran Clinical Trials Registry, and the World Health Organization International Clinical Trials Registry Platform. Two reviewers will assess the discovered citations for eligibility based on the title and abstract before proceeding to the full-text and data extraction phases. These reviewers will debate and settle any conflicts that arise during the inclusion process; a third reviewer will settle any issues that remain. The validated data extraction form will be used to collect data for eligible research. The included studies will undergo a quality and bias check and will proceed meta-analysis.
DISCUSSION: This systematic review and meta-analysis will reveal a positive correlation between illness progression and telomere shortening in individuals with IBD, perhaps demonstrating three causal links between them. This study will conduct the first systematic review and meta-analysis examining the correlation between telomere shortening and illness advancement in individuals with IBD. Exploring the connection between these two situations can enhance the comprehension of the development and advancement of IBD.
PROSPERO registration number: CRD42024501171.}, }
@article {pmid39410901, year = {2024}, author = {Polo, CM and Pereira de Brito, TR and Roberto Silva, W and Lima, DB and Nunes, DP and Colombo, FA and Orlandi, AADS and Corona, LP}, title = {Shorter Telomere Length is Associated with Food Insecurity in Older People: A Cross-Sectional Study.}, journal = {Current aging science}, volume = {}, number = {}, pages = {}, doi = {10.2174/0118746098320942240924074044}, pmid = {39410901}, issn = {1874-6128}, abstract = {BACKGROUND: Telomere length has been investigated as a biomarker of biological aging and is associated with several diseases, lifestyle, and socioeconomic factors.
OBJECTIVE: This study aimed to verify whether food insecurity is associated with shorter telomere length in older people.
METHODS: This is a cross-sectional study carried out in a municipality in the interior of Brazil, with a sample of 440 older people from the community. For telomere length analysis, a blood sample was obtained from each participant, followed by real-time qPCR, and sociodemographic and health information was collected through interviews. Food security/insecurity was measured using the reduced version of the Brazilian Food Insecurity Scale. Descriptive analysis and multiple logistic regression were performed to analyze the factors associated with shorter telomere length, adopting a significance level of 5%.
RESULTS: We found that food insecurity was significantly associated with shorter telomere length, regardless of age group, skin color, tabagism, physical activity, milk and dairy consumption, living arrangement, and basic activities of daily life.
CONCLUSION: The findings show the importance of ensuring full access to adequate nutrition for the older population, who are physiologically and socially vulnerable.}, }
@article {pmid39409990, year = {2024}, author = {Loukopoulou, C and Nikolouzakis, T and Koliarakis, I and Vakonaki, E and Tsiaoussis, J}, title = {Telomere Length and Telomerase Activity as Potential Biomarkers for Gastrointestinal Cancer.}, journal = {Cancers}, volume = {16}, number = {19}, pages = {}, doi = {10.3390/cancers16193370}, pmid = {39409990}, issn = {2072-6694}, abstract = {Gastrointestinal (GI) cancers, such as colorectal and gastric cancers, pose significant global health challenges due to their high rates of incidence and mortality. Even with advancements in treatment and early detection, many patients still face poor outcomes, highlighting the critical need for new biomarkers and therapeutic targets. Telomere length (TL) and telomerase activity (TA) have gained attention in this context. Telomeres, protective nucleotide sequences at chromosome ends, shorten with each cell division, leading to cellular aging. Telomerase, a ribonucleoprotein enzyme, counteracts this shortening by adding telomeric repeats, a process tightly regulated in normal cells but often dysregulated in cancer. This review critically evaluates the role of TL and TA in the pathogenesis of GI cancers, examining their potential as diagnostic, prognostic, and predictive biomarkers. It explores how alterations in telomere biology contribute to the initiation and progression of GI tumors and assesses the therapeutic implications of targeting telomerase. By integrating findings from diverse studies, this review aims to elucidate the intricate relationship between telomere dynamics and gastrointestinal carcinogenesis, offering insights into how TL and TA could be leveraged to enhance the early detection, treatment, and prognosis of GI cancers.}, }
@article {pmid39408829, year = {2024}, author = {Rubtsova, MP and Nikishin, DA and Vyssokikh, MY and Koriagina, MS and Vasiliev, AV and Dontsova, OA}, title = {Telomere Reprogramming and Cellular Metabolism: Is There a Link?.}, journal = {International journal of molecular sciences}, volume = {25}, number = {19}, pages = {}, doi = {10.3390/ijms251910500}, pmid = {39408829}, issn = {1422-0067}, support = {23-SH04-20//Development Program of the MSU Interdisciplinary Scientific and Educational School "Molecular technologies of living systems and synthetic biology" at the Lomonosov Moscow State University/ ; }, mesh = {Humans ; *Telomere/metabolism/genetics ; Animals ; *Telomere Homeostasis ; Cell Proliferation ; Cellular Reprogramming/genetics ; Germ Cells/metabolism ; }, abstract = {Telomeres-special DNA-protein structures at the ends of linear eukaryotic chromosomes-define the proliferation potential of cells. Extremely short telomeres promote a DNA damage response and cell death to eliminate cells that may have accumulated mutations after multiple divisions. However, telomere elongation is associated with the increased proliferative potential of specific cell types, such as stem and germ cells. This elongation can be permanent in these cells and is activated temporally during immune response activation and regeneration processes. The activation of telomere lengthening mechanisms is coupled with increased proliferation and the cells' need for energy and building resources. To obtain the necessary nutrients, cells are capable of finely regulating energy production and consumption, switching between catabolic and anabolic processes. In this review, we focused on the interconnection between metabolism programs and telomere lengthening mechanisms during programmed activation of proliferation, such as in germ cell maturation, early embryonic development, neoplastic lesion growth, and immune response activation. It is generally accepted that telomere disturbance influences biological processes and promotes dysfunctionality. Here, we propose that metabolic conditions within proliferating cells should be involved in regulating telomere lengthening mechanisms, and telomere length may serve as a marker of defects in cellular functionality. We propose that it is possible to reprogram metabolism in order to regulate the telomere length and proliferative activity of cells, which may be important for the development of approaches to regeneration, immune response modulation, and cancer therapy. However, further investigations in this area are necessary to improve the understanding and manipulation of the molecular mechanisms involved in the regulation of proliferation, metabolism, and aging.}, }
@article {pmid39408588, year = {2024}, author = {Kim, M and Kang, D and Kim, HS and Lee, JM and Park, S and Kwag, D and Lee, C and Hong, Y and Na, D and Koh, Y and Sun, CH and An, H and Kim, YJ and Kim, Y}, title = {Influence of the Bone Marrow Microenvironment on Hematopoietic Stem Cell Behavior Post-Allogeneic Transplantation: Development of Clonal Hematopoiesis and Telomere Dynamics.}, journal = {International journal of molecular sciences}, volume = {25}, number = {19}, pages = {}, doi = {10.3390/ijms251910258}, pmid = {39408588}, issn = {1422-0067}, support = {NRF-2022R1A2C2006746//National Research Foundation of Korea/ ; }, mesh = {Humans ; *Hematopoietic Stem Cell Transplantation/methods ; Male ; Middle Aged ; Female ; *Clonal Hematopoiesis/genetics ; Adult ; *Hematopoietic Stem Cells/metabolism ; *Telomere/genetics ; Aged ; Transplantation, Homologous ; Mutation ; Myelodysplastic Syndromes/genetics/therapy/etiology ; Bone Marrow/metabolism ; }, abstract = {Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potential cure for myelodysplastic neoplasms (MDSs) and other hematologic malignancies. This study investigates post-transplantation genetic evolution and telomere dynamics in hematopoietic cells, with a focus on clonal hematopoiesis (CH). We conducted a longitudinal analysis of 21 MDS patients who underwent allo-HSCT between September 2009 and February 2015. Genetic profiles of hematopoietic cells from both recipients and donors were compared at equivalent pre- and post-transplantation time points. Targeted sequencing identified CH-associated mutations, and real-time quantitative PCR measured telomere length. Furthermore, we compared CH incidence between recipients and age-matched controls from the GENIE cohort from routine health checkups. Post-allo-HSCT, 38% of recipients developed somatic mutations not detected before transplantation, indicating de novo CH originating from donor cells. Compared to age-matched healthy controls, recipients showed a significantly higher incidence of CH, suggesting increased susceptibility to genetic changes post-transplant. Telomere length analysis also revealed accelerated shortening in transplanted cells, highlighting the heightened stress and proliferation demands in the new microenvironment. Our findings reveal a notable incidence of donor-derived CH in allo-HSCT recipients, alongside significant telomere attrition. This suggests the potential influence of the marrow microenvironment on genetic and molecular changes in hematopoietic cells.}, }
@article {pmid39406502, year = {2024}, author = {Kamath, SS and Bindra, M and Pal, D and Jain, C}, title = {Telomere-to-telomere assembly by preserving contained reads.}, journal = {Genome research}, volume = {}, number = {}, pages = {}, doi = {10.1101/gr.279311.124}, pmid = {39406502}, issn = {1549-5469}, abstract = {Automated telomere-to-telomere (T2T) de novo assembly of diploid and polyploid genomes remains a formidable task. A string graph is a commonly used assembly graph representation in the assembly algorithms. The string graph formulation employs graph simplification heuristics, which drastically reduce the count of vertices and edges. One of these heuristics involves removing the reads contained in longer reads. In practice, this heuristic occasionally introduces gaps in the assembly by removing all reads that cover one or more genome intervals. The factors contributing to such gaps remain poorly understood. In this work, we mathematically derived the frequency of observing a gap near a germline and a somatic heterozygous variant locus. Our analysis shows that (i) an assembly gap due to contained read deletion is an order of magnitude more frequent in Oxford Nanopore reads than PacBio HiFi reads due to differences in their read-length distributions, and (ii) this frequency decreases with an increase in the sequencing depth. Drawing cues from these observations, we addressed the weakness of the string graph formulation by developing the RAFT assembly algorithm. RAFT addresses the issue of contained reads by fragmenting reads and producing a more uniform read-length distribution. The algorithm retains spanned repeats in the reads during the fragmentation. We empirically demonstrate that RAFT significantly reduces the number of gaps using simulated datasets. Using real Oxford Nanopore and PacBio HiFi datasets of the HG002 human genome, we achieved a twofold increase in the contig NG50 and the number of haplotype-resolved T2T contigs compared to Hifiasm.}, }
@article {pmid39401753, year = {2023}, author = {Baser, E and Inandiklioglu, N and Aydogan Kırmızı, D and Ercan, F and Caniklioğlu, A and Kara, M and Onat, T and Yalvac, ES}, title = {Correction: Placental and Umbilical Cord Blood Oxidative Stress Level and Telomere Homeostasis in Early Onset Severe Preeclampsia.}, journal = {Zeitschrift fur Geburtshilfe und Neonatologie}, volume = {227}, number = {2}, pages = {e267}, doi = {10.1055/a-2416-9430}, pmid = {39401753}, issn = {1439-1651}, }
@article {pmid39400911, year = {2024}, author = {Machelová, A and Dadejová, MN and Franek, M and Mougeot, G and Simon, L and Le Goff, S and Duc, C and Bassler, J and Demko, M and Schwarzerová, J and Desset, S and Probst, AV and Dvořáčková, M}, title = {The histone chaperones ASF1 and HIRA are required for telomere length and 45S rDNA copy number homeostasis.}, journal = {The Plant journal : for cell and molecular biology}, volume = {}, number = {}, pages = {}, doi = {10.1111/tpj.17041}, pmid = {39400911}, issn = {1365-313X}, support = {23-06643S//Grantová Agentura České Republiky/ ; MUNI/R/1364/2023//Grant Agency of Masaryk University/ ; ANR-11 JSV2 009 01//French National Research Agency/ ; ANR-12 ISV6 0001//French National Research Agency/ ; CZ.02.01.01/00/22_008/0004581//European Regional Development Fund Programme Johannes Amos Comenius/ ; }, abstract = {Genome stability is significantly influenced by the precise coordination of chromatin complexes that facilitate the loading and eviction of histones from chromatin during replication, transcription, and DNA repair processes. In this study, we investigate the role of the Arabidopsis H3 histone chaperones ANTI-SILENCING FUNCTION 1 (ASF1) and HISTONE REGULATOR A (HIRA) in the maintenance of telomeres and 45S rDNA loci, genomic sites that are particularly susceptible to changes in the chromatin structure. We find that both ASF1 and HIRA are essential for telomere length regulation, as telomeres are significantly shorter in asf1a1b and hira mutants. However, these shorter telomeres remain localized around the nucleolus and exhibit a comparable relative H3 occupancy to the wild type. In addition to regulating telomere length, ASF1 and HIRA contribute to silencing 45S rRNA genes and affect their copy number. Besides, ASF1 supports global heterochromatin maintenance. Our findings also indicate that ASF1 transiently binds to the TELOMERE REPEAT BINDING 1 protein and the N terminus of telomerase in vivo, suggesting a physical link between the ASF1 histone chaperone and the telomere maintenance machinery.}, }
@article {pmid39399813, year = {2024}, author = {Yerukala Sathipati, S and Jeong, S and Sharma, P and Mayer, J and Sharma, R and Ho, SY and Hebbring, S}, title = {Exploring prognostic implications of miRNA signatures and telomere maintenance genes in kidney cancer.}, journal = {Molecular therapy. Oncology}, volume = {32}, number = {4}, pages = {200874}, pmid = {39399813}, issn = {2950-3299}, abstract = {Kidney cancer, particularly clear cell renal cell carcinoma (KIRC), presents significant challenges in disease-specific survival. This study investigates the prognostic potential of microRNAs (miRNAs) in kidney cancers, including KIRC and kidney papillary cell carcinoma (KIRP), focusing on their interplay with telomere maintenance genes. Utilizing data from The Cancer Genome Atlas, miRNA expression profiles of 166 KIRC and 168 KIRP patients were analyzed. An evolutionary learning-based kidney survival estimator identified robust miRNA signatures predictive of 5-year survival for both cancer types. For KIRC, a 37-miRNA signature showed a correlation coefficient (R) of 0.82 and mean absolute error (MAE) of 0.65 years. Similarly, for KIRP, a 23-miRNA signature exhibited an R of 0.82 and MAE of 0.64 years, demonstrating comparable predictive accuracy. These signatures also displayed diagnostic potential with receiver operating characteristic curve values between 0.70 and 0.94. Bioinformatics analysis revealed targeting of key telomere-associated genes such as TERT, DKC1, CTC1, and RTEL1 by these miRNAs, implicating crucial pathways such as cellular senescence and proteoglycans in cancer. This study highlights the significant link between miRNAs and telomere genes in kidney cancer survival, offering insights for therapeutic targets and improved prognostic markers.}, }
@article {pmid39388510, year = {2024}, author = {Song, X and Lin, D and Wang, D and Weng, S and Qiu, S and Zhou, W and Xiao, A and Zhang, N}, title = {Association of lymphocyte count and serum albumin concentration with telomere length in Chinese sanitation workers.}, journal = {PloS one}, volume = {19}, number = {10}, pages = {e0311736}, doi = {10.1371/journal.pone.0311736}, pmid = {39388510}, issn = {1932-6203}, mesh = {Humans ; Male ; Lymphocyte Count ; Adult ; China ; Female ; Case-Control Studies ; Middle Aged ; *Sanitation ; *Serum Albumin/analysis ; Telomere/metabolism ; Lymphocytes/metabolism ; Inflammation/blood ; Telomere Homeostasis ; East Asian People ; }, abstract = {OBJECTIVE: This study aimed to examine the association between inflammation-related indicators (IRIs) and telomere length (TL) in Chinese sanitation workers.
METHODS: This study adopted a case-control design, conducted from January to December 2022 in Shenzhen, a city in eastern China. A total of 80 sanitation workers, as well as 80 matched controls, were randomly recruited from the Luohu district of Shenzhen city in China. Their blood samples were collected and analyzed for the IRIs and TL in the Medical Laboratory of Shenzhen Prevention and Treatment Center for Occupational Diseases. The relationship between IRIs and TL was analyzed using multivariate linear regression, and their dose-response relationship was explored using restricted cubic spline analysis.
RESULTS: The systemic inflammatory index (SII), platelet-to-lymphocyte ratio (PLR), and neutrophil-to-lymphocyte ratio (NLR) were significantly elevated in the sanitation workers in comparison to the controls. Moreover, the lymphocyte count (LYM), serum albumin concentration (ALB), and TL were found to be lower in the sanitation workers compared to the controls (P < 0.05). After adjusting for potential confounding variables, LYM was negatively correlated with TL in the sanitation workers (β = -0.31, 95% CI: -0.57, -0.05), whereas no correlation was observed in the controls. Furthermore, ALB demonstrated a non-linear relationship with TL in sanitation workers.
CONCLUSION: We found higher novel inflammatory markers (SII, PLR, and NLR) in the sanitation workers, and identified a correlation between LYM and ALB with shortened TL in them, providing new evidence for the effect of elevated inflammation on accelerated aging in Chinese sanitation workers.}, }
@article {pmid39385582, year = {2024}, author = {Fernández de la Puente, M and Marti, A and Canudas, S and Zalba, G and Razquin, C and Boccardi, V and Mecocci, P and Babio, N and Castañer-Niño, O and Toledo, E and Buil-Cosiales, P and Salas-Salvadó, J and García-Calzón, S}, title = {Telomere length and 4-year changes in cognitive function in an older Mediterranean population at high risk of cardiovascular disease.}, journal = {Age and ageing}, volume = {53}, number = {10}, pages = {}, doi = {10.1093/ageing/afae216}, pmid = {39385582}, issn = {1468-2834}, support = {021/CB07/03/2004//CIBEROBN/ ; //Instituto de Salud Carlos III/ ; //Fondo de Investigación para la Salud/ ; PI13/00462//European Regional Development Fund/ ; //Institución Catalana de Investigación y Estudios Avanzados/ ; IJC2019-040796-I//Juan de la Cierva-Incorporación/ ; 2020-PMF-PIPF-8//Rovira i Virgili University and Diputació de Tarragona/ ; }, mesh = {Humans ; Male ; Aged ; Female ; *Cognition ; *Cardiovascular Diseases/epidemiology/prevention & control ; *Cognitive Dysfunction/epidemiology/diagnosis/psychology/prevention & control ; Middle Aged ; Spain/epidemiology ; Time Factors ; Telomere ; Cognitive Aging/psychology ; Age Factors ; Risk Factors ; Telomere Homeostasis ; Diet, Mediterranean ; Risk Assessment ; Executive Function ; Aging/psychology ; Heart Disease Risk Factors ; Telomere Shortening ; }, abstract = {BACKGROUND: Cognitive decline, a common process of brain ageing, has been associated with telomere length (TL). Delving into the identification of reliable biomarkers of brain ageing is essential to prevent accelerated cognitive impairment.
METHODS: We selected 317 non-smoking 'Prevención con Dieta Mediterránea-Plus' (PREDIMED-Plus) participants (mean age, 65.8 ± 5.0 years) with metabolic syndrome from two trial centres who were following a lifestyle intervention. We measured TL and cognitive function at baseline and after 3 and 4 years of follow-up, respectively. Associations between baseline or 3-year changes in TL and baseline or 4-year changes in cognitive function were analysed using multivariable regression models.
RESULTS: Baseline TL was not associated with baseline cognitive performance. Nevertheless, longer baseline TL was associated with improved 4-year changes in the Executive Function domain (β: 0.29; 95%CI: 0.12 to 0.44; P < 0.001) and the Global Cognitive Function domain (β: 0.19; 95%CI: 0.05 to 0.34; P = 0.010). Besides, a positive association was found between longer baseline TL and improved 4-year changes in the animal version of the Verbal Fluency Test (β: 0.33; 95%CI: 0.12 to 0.52; P = 0.002). By contrast, 3-year changes in TL were not associated with changes in cognitive function after 4 years.
CONCLUSIONS: Longer baseline TL could protect from cognitive decline and be used as a useful biomarker of brain ageing function in an older Mediterranean population at risk of cardiovascular disease and cognitive impairment.}, }
@article {pmid39379870, year = {2024}, author = {Vrettou, M and Lager, S and Toffoletto, S and Iliadis, SI and Kallak, TK and Agnafors, S and Nieratschker, V and Skalkidou, A and Comasco, E}, title = {Peripartum depression symptom trajectories, telomere length and genotype, and adverse childhood experiences.}, journal = {BMC psychiatry}, volume = {24}, number = {1}, pages = {661}, pmid = {39379870}, issn = {1471-244X}, abstract = {BACKGROUND: As a biological marker for cellular senescence, telomere length (TL) has been linked to a variety of psychiatric disorders and adverse childhood experiences (ACE), though only preliminarily to peripartum depression (PPD). The present study sought to examine the association between TL and PPD, assessing the moderating role of ACE and genetic polymorphic variations related with the telomere machinery.
METHODS: Adversity was self-reported, likewise were depressive symptoms evaluated at pregnancy week 17 and 32, as well as six-weeks and six-months postpartum. TL was assessed by use of qPCR in blood samples collected during delivery from females with antenatal depression resolving postpartum, females with depression persisting to postpartum, and healthy controls. Twenty haplotype-tagging Single Nucleotide Polymorphisms in the Telomerase Reverse Transcriptase (TERT) and three in the Telomerase RNA Component (TERC) genes were genotyped.
RESULTS: TL was negatively correlated with severity of PPD symptoms at pregnancy week 32 and postpartum week 6. PPD was associated with shorter TL. Lastly, ACE, but not the TERT/TERC genotype, moderated the TL-trajectory association; with increasing ACE, individuals with persistent PPD symptoms had shorter TL, whereas the opposite pattern (longer TL) was observed in the controls.
CONCLUSIONS: The findings contribute to further understanding of PPD underpinnings, suggesting a negative relationship with TL.}, }
@article {pmid39379607, year = {2024}, author = {Barchitta, M and Maugeri, A and La Mastra, C and Favara, G and La Rosa, MC and Magnano San Lio, R and Gholizade Atani, Y and Gallo, G and Agodi, A}, title = {Pre-pregnancy BMI, gestational weight gain, and telomere length in amniotic fluid: a causal graph analysis.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {23396}, pmid = {39379607}, issn = {2045-2322}, support = {"La coorte Mamma and Bambino: un approccio Multisettoriale Alla salute Materno-Infantile Mediante valutazione dell'Esposoma nelle Donne, MAMI-MED"//University of Catania, Italy, Department of Medical and Surgical Science and Advanced Technologies "GF Ingrassia" Programma ricerca di ateneo UNICT 2020-22 linea 2, PIAno di inCEntivi per la RIcerca di Ateneo 2020/2022/ ; }, mesh = {Humans ; Female ; Pregnancy ; *Body Mass Index ; *Amniotic Fluid/metabolism ; *Gestational Weight Gain ; Adult ; Telomere/genetics ; Telomere Homeostasis ; Overweight/genetics ; Infant, Newborn ; }, abstract = {Previous investigations have suggested a potential association between pre-pregnancy body mass index (BMI) and gestational weight gain (GWG) with telomere length (TL) in various tissues of pregnant women and newborns. Nonetheless, as association does not imply causation, our objective was to investigate the causal connections among pre-pregnancy BMI, GWG, and TL in amniotic fluid. The analysis included 136 mother-child pairs from the Mamma & Bambino cohort, and three causal graph models were developed to depict the interconnections between pre-pregnancy BMI, GWG, and TL. Causal graph analysis was conducted utilizing the do-operator to estimate the causal effect of GWG and the controlled direct effect of pregestational BMI. We revealed that transitioning from non-adequate to adequate GWG had a positive impact on the probability of having "long" TL (i.e., a value greater than the population median) in all three models. When considering the effect of pre-pregnancy BMI, the highest probability of "long" TL was observed in normal weight women with adequate GWG. In contrast, the effect of adequate GWG became minimal among overweight women. These results shed light on the potential causality between pre-pregnancy BMI, GWG, and TL in amniotic fluid, emphasizing the importance of appropriate weight management before and during pregnancy for optimal TL outcomes.}, }
@article {pmid39377032, year = {2024}, author = {Assari, S and Dezfuli, M and Peyrovinasab, A and Zare, H}, title = {Does Adulthood Socioeconomic Status Predict Subsequent Telomere Length in Racially and Ethnically Diverse Women?.}, journal = {Journal of biomedical and life sciences}, volume = {4}, number = {1}, pages = {47-59}, pmid = {39377032}, issn = {2771-2303}, abstract = {BACKGROUND: Telomere length is a critical biomarker of cellular aging and overall health. While childhood socioeconomic status (SES) indicators such as education and poverty can have long-lasting effects on biological aging, research has shown contradictory results regarding the impact of adulthood SES on future telomere length, particularly in racially and ethnically diverse individuals. This study investigates the effects of baseline adulthood SES indicators such as education and poverty on telomere length nine years later in women, using data from the Future of Families and Child Wellbeing Study (FFCWS).
METHODS: We analyzed data from the FFCWS, a longitudinal cohort study. The sample included baseline adulthood SES and follow-up telomere length measure of women (n = 2,421) with varying socioeconomic conditions. Telomere length was measured from saliva samples nine years after the baseline measure of adulthood SES. Education, poverty, and marital status at baseline were assessed. Multivariate linear regression models were used to examine the association between adulthood SES indicators at baseline and future telomere length, controlling for potential confounders.
RESULTS: From the total 2,421 women, 675 were Latino White, 1,158 were non-Latino Black, and 588 were non-Latino White. Our findings indicate that for non-Latino White women poverty at certain level, and childbirth weight, and for non-Latino Black maternal age were predictors of telomere lengths nine years later.
CONCLUSION: Poverty at a specific level, maternal age and childbirth weight serve as predictors of telomere lengths nine years later in some women. These findings underscore the importance of socioeconomic factors and early-life influences in understanding telomere dynamics and aging processes among women from varied racial and ethnic backgrounds.}, }
@article {pmid39373625, year = {2024}, author = {Jiang, G and Cao, L and Wang, Y and Li, L and Wang, Z and Zhao, H and Qiu, Y and Feng, B}, title = {Causality between telomere length and the risk of hematologic malignancies: A bidirectional Mendelian randomization study.}, journal = {Cancer research communications}, volume = {}, number = {}, pages = {}, doi = {10.1158/2767-9764.CRC-24-0402}, pmid = {39373625}, issn = {2767-9764}, abstract = {Growing evidence indicates a relationship between telomere length (TL) and the stage, prognosis, and treatment responsiveness of hematopoietic malignancies. However, the relationship between TL and the risk of hematologic malignancies remains unclear, considering the vulnerability of observational studies to potential confounding and reverse causation. Two-sample bidirectional mendelian randomization (MR) analysis was conducted utilizing publicly available genome-wide association study data to assess whether TL was causally associated with the risk of hematologic malignancies. The inverse variance-weighted approach was used as the primary assessment approach to evaluate the effects of the causes, augmented by the weighted median and MR-Egger methods. Cochran's Q test, MR Egger intercept test, MR-PRESSO, and leave-one-out analysis were performed to evaluate sensitivity, heterogeneity, and pleiotropy. According to forward MR estimations, longer TL was related to an increased risk of acute lymphocytic leukemia (OR=2.690, p=0.041), chronic lymphocytic leukemia (OR=2.155, p=0.005), multiple myeloma (OR=1.845, p=0.024), Hodgkin lymphoma (OR=1.697, p=0.014), and non-Hodgkin lymphoma (OR=1.737, p=0.009). Specific types of non-Hodgkin lymphoma were also associated with TL. The reverse MR results revealed that hematological malignancies had no effect on TL. This MR analysis revealed an association between longer TL and an increased risk of specific hematologic malignancies, indicating a potential role of TL in the risk evaluation and management in hematologic malignancies.}, }
@article {pmid39371255, year = {2024}, author = {Rolles, B and Tometten, M and Meyer, R and Kirschner, M and Beier, F and Brümmendorf, TH}, title = {Inherited Telomere Biology Disorders: Pathophysiology, Clinical Presentation, Diagnostics, and Treatment.}, journal = {Transfusion medicine and hemotherapy : offizielles Organ der Deutschen Gesellschaft fur Transfusionsmedizin und Immunhamatologie}, volume = {51}, number = {5}, pages = {292-309}, pmid = {39371255}, issn = {1660-3796}, abstract = {BACKGROUND: Telomeres are the end-capping structures of all eukaryotic chromosomes thereby protecting the genome from damage and degradation. During the aging process, telomeres shorten continuously with each cell division until critically short telomeres prevent further proliferation whereby cells undergo terminal differentiation, senescence, or apoptosis. Premature aging due to critically short telomere length (TL) can also result from pathogenic germline variants in the telomerase complex or related genes that typically counteract replicative telomere shortening in germline and certain somatic cell populations, e.g., hematopoetic stem cells. Inherited diseases that result in altered telomere maintenance are summarized under the term telomere biology disorder (TBD).
SUMMARY: Since TL both reflects but more importantly restricts the replicative capacity of various human tissues, a sufficient telomere reserve is particularly important in cells with high proliferative activity (e.g., hematopoiesis, immune cells, intestinal cells, liver, lung, and skin). Consequently, altered telomere maintenance as observed in TBDs typically results in premature replicative cellular exhaustion in the respective organ systems eventually leading to life-threatening complications such as bone marrow failure (BMF), pulmonary fibrosis, and liver cirrhosis.
KEY MESSAGES: The recognition of a potential congenital origin in approximately 10% of adult patients with clinical BMF is of utmost importance for the proper diagnosis, appropriate patient and family counseling, to prevent the use of inefficient treatment and to avoid therapy-related toxicities including appropriate donor selection when patients have to undergo stem cell transplantation from related donors. This review summarizes the current state of knowledge about TBDs with particular focus on the clinical manifestation patterns in children (termed early onset TBD) compared to adults (late-onset TBD) including typical treatment- and disease course-related complications as well as their prognosis and adequate therapy. Thereby, it aims to raise awareness for a disease group that is currently still highly underdiagnosed particularly when it first manifests itself in adulthood.}, }
@article {pmid39370492, year = {2024}, author = {Farias, TG and Santos, MSD and Mencalha, AL and da Fonseca, AS}, title = {Low-power red laser and blue LED modulate telomere maintenance and length in human breast cancer cells.}, journal = {Lasers in medical science}, volume = {39}, number = {1}, pages = {248}, pmid = {39370492}, issn = {1435-604X}, support = {88887.636295/2021-00//Coordenação de Aperfeiçoamento de Pessoal de Nível Superior/ ; E26/019.001958/2019//Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro/ ; }, mesh = {Humans ; *Breast Neoplasms/radiotherapy/genetics/pathology ; Female ; *Telomeric Repeat Binding Protein 2/metabolism/genetics ; *Telomere/radiation effects ; *Low-Level Light Therapy/methods ; *Telomeric Repeat Binding Protein 1/metabolism/genetics ; Cell Line, Tumor ; RNA, Messenger/metabolism/genetics ; MCF-7 Cells ; Telomere Homeostasis/radiation effects ; Shelterin Complex ; Telomere-Binding Proteins ; }, abstract = {Cancer cells have the ability to undergo an unlimited number of cell divisions, which gives them immortality. Thus, the cancer cell can extend the length of its telomeres, allowing these cells to divide unlimitedly and avoid entering the state of senescence or cellular apoptosis. One of the main effects of photobiomodulation (PBM) is the increase in the production of adenosine triphosphate (ATP) and free radicals, mainly reactive oxygen species (ROS). Existent data indicates that high levels of ROS can cause shortening and dysfunctional telomeres. Therefore, a better understanding of the effects induced by PBM on cancer cell telomere maintenance is needed. This work aimed to evaluate the effects of low-power red laser (658 nm) and blue LED (470 nm) on the TRF1 and TRF2 mRNA levels and telomere length in human breast cancer cells. MCF-7 and MDA-MB-231 cells were irradiated with a low-power red laser (69 J cm[-2], 0.77 W/cm[-2]) and blue LED (482 J cm[-2], 5.35 W/cm[-2]), alone or in combination, and the relative mRNA levels of the genes and telomere length were assessed by quantitative reverse transcription polymerase chain reaction. The results suggested that exposure to certain red laser and blue LED fluences decreased the TRF1 and TRF2 mRNA levels in both human breast cancer cells. Telomere length was increased in MCF-7 cells after exposure to red laser and blue LED. However, telomere length in MDA-MB-231 was shortened after exposure to red laser and blue LED at fluences evaluated. Our research suggests that photobiomodulation induced by red laser and low-power blue LED could alter telomere maintenance and length.}, }
@article {pmid39368029, year = {2024}, author = {Xing, B and Yu, J and Liu, Y and He, S and Gao, Q and Chen, X and Ping, F and Xu, L and Li, W and Zhang, H and Li, Y}, title = {The negative association between sodium-driven nutrient pattern and telomere length: the chain mediating role of diastolic pressure and waist circumference.}, journal = {Aging clinical and experimental research}, volume = {36}, number = {1}, pages = {201}, pmid = {39368029}, issn = {1720-8319}, support = {2022YFC2010102//National Key R&D Program of China/ ; CIFMS,2021-I2M-1-002//the CAMS Innovation Fund for Medical Sciences/ ; }, mesh = {Humans ; Male ; Female ; Middle Aged ; *Waist Circumference ; Cross-Sectional Studies ; *Blood Pressure/physiology ; *Telomere ; Adult ; China ; Sodium, Dietary ; Diet ; Aged ; Leukocytes/metabolism/physiology ; Telomere Homeostasis/physiology ; }, abstract = {BACKGROUND: Numerous single nutrients have been suggested to be linked with leukocyte telomere length (LTL). However, data on nutrient patterns (NPs), particularly in Chinese population, are scarce. This study aimed to examine the relationship between nutrient-based dietary patterns and LTL, and the potential role of metabolic factors.
METHODS: Dietary data was obtained via 24-hour food recalls, and principal component analysis (PCA) was used to identify NPs. LTL was assessed using a real-time PCR assay. Multiple linear regression was conducted to determine the association between NPs and LTL. The potential role of metabolism among them was analyzed using mediation models.
RESULTS: A total of 779 individuals from northern China were included in this cross-sectional analysis. Five main nutrient patterns were identified. Adjusted linear regression showed that the "high sodium" pattern was inversely associated with LTL (B=-0.481(-0.549, -0.413), P < 0.05). The "high vitamin E-fat" pattern exhibited a positive correlation (B = 0.099(0.029, 0.170), P < 0.05), whereas the "high vitamin A-vitamin B2" pattern was negatively correlated with LTL (B=-0.120(-0.183, -0.057), P < 0.05), respectively. No significant associations were observed for the remaining nutrient patterns. The mediation model demonstrated that diastolic blood pressure and waist circumference could individually and collectively mediate the negative impact of the "high sodium" pattern on LTL (BDBP=-0.0173(-0.0333, -0.0041), BWC=-0.0075(-0.0186, -0.0004), Bjoint=-0.0033 (-0.0072, -0.0006), all P < 0.05). Moreover, glycosylated hemoglobin and non-high-density lipoprotein cholesterol mediate the relationship between the "high vitamin E-fat" pattern and LTL (BHbA1c=0.0170(0.0010,0.0347), Bnon-HDL-C= 0.0335 (0.0067, 0.0626), all P < 0.05), respectively.
CONCLUSIONS: The "high sodium" and "high vitamin E-fat" nutrient patterns demonstrated negative and positive associations with LTL and metabolic indicators may play complex mediating roles in these relationships.}, }
@article {pmid39367328, year = {2024}, author = {Félix, NQ and Tornquist, L and Sehn, AP and D'avila, HF and Todendi, PF and de Moura Valim, AR and Reuter, CP}, title = {The association of telomere length with body mass index and immunological factors differs according to physical activity practice among children and adolescents.}, journal = {BMC pediatrics}, volume = {24}, number = {1}, pages = {633}, pmid = {39367328}, issn = {1471-2431}, support = {001//Coordenação de Aperfeiçoamento de Pessoal de Nível Superior , Brasil/ ; 001//Coordenação de Aperfeiçoamento de Pessoal de Nível Superior , Brasil/ ; 001//Coordenação de Aperfeiçoamento de Pessoal de Nível Superior , Brasil/ ; }, mesh = {Humans ; Male ; Female ; Cross-Sectional Studies ; *Body Mass Index ; Child ; Adolescent ; *Exercise ; *Sleep ; *Telomere ; Brazil ; Screen Time ; Leisure Activities ; Immunologic Factors ; Linear Models ; }, abstract = {BACKGROUND: This study aims to verify the relationship between screen and sleep time, body mass index (BMI) and immunological factors with telomere length according to leisure-time physical activity (PA) in children and adolescents.
METHODS: A cross-sectional study involving a sample of 476 schoolchildren of both sexes, aged seven to 17 years, from a community in southern Brazil. Behavioral variables (PA, sleep time, and screen time) were self-reported using a questionnaire. PA was classified as inactive and any PA (doing some physical activity). The associations of screen time, sleep time, BMI, and immunologic factors with telomere length were tested using multiple linear regression models, with the sample divided according to the schoolchildren's leisure-time physical activity practices.
RESULTS: An inverse association between BMI and telomere length (β: -0.239; 95% CI: -0.468; -0.010) and a direct association of leukocytes (β: 0.151; 95% CI: 0.029; 0.278) and neutrophils (β: 0.131; 95% CI: 0.008; 0.254) with telomeres were found in the inactive students. No association was found between screen time and sleep time and telomeres. No association was found among students who engaged in any PA.
CONCLUSION: The associations between telomeres, BMI, and immunologic factors were found only in inactive students. These results suggest that the association between BMI and immunological factors and telomere length may be influenced by physical activity.}, }
@article {pmid39353511, year = {2024}, author = {Wu, Y and Huang, C and Fan, B and Wu, H and Mei, Y and Cheng, F}, title = {The relationship between leukocyte telomere length and risk of depression and anxiety: Evidence from UK Biobank.}, journal = {Journal of affective disorders}, volume = {369}, number = {}, pages = {195-201}, doi = {10.1016/j.jad.2024.09.138}, pmid = {39353511}, issn = {1573-2517}, abstract = {BACKGROUND: Telomere length is a cellular aging marker implicated in various health outcomes. A growing body of evidence suggests a link between leukocyte telomere length (LTL) and mental health outcomes. However, there have been no studies focused on the relationship between LTL and the future risk of depression and anxiety. This study aimed to investigate the associations between LTL and depression/anxiety, examining both cross-sectional prevalence and prospective incidence.
METHODS: Data from 364,331 UK Biobank participants were analyzed. LTL was measured at baseline, and mental health status was assessed through hospital records and online surveys. Logistic regression and Cox proportional hazards models were employed for cross-sectional and prospective analyses with appropriate adjustment, respectively.
RESULTS: The mean (SD) age of the subjects was 57.03 (13.34) years and follow-up duration was 8.80 (5.39) years. Cross-sectionally, shorter LTL was associated with increased odds of depression (OR: 1.401, 95 % CI: 1.291-1.521) and anxiety (1.347 (1.198-1.515)) at baseline, which remained significant after adjustment. Among those free of depression/anxiety at baseline, baseline shorter LTL was associated with a higher risk of incident depression (HR: 1.615, 95 % CI: 1.447-1.803) and anxiety (1.430 (1.293-1.581)) during follow-up period. These associations remained robust after adjusting for various covariates.
CONCLUSIONS: Our findings indicated an association between shorter telomeres and an increased risk of prevalent depression/anxiety and shorter telomeres precede the onset of these mental health conditions. Considering the potential clinical implications, our study underscores the relevance of LTL as a predictive tool for identifying individuals at risk of developing depression and anxiety.}, }
@article {pmid39356569, year = {2024}, author = {Premužić, V and Toupance, S and Hollander, A and Stipančić, Ž and Bukal, N and Jelaković, A and Brzić, I and Čulig, B and Slade, N and Benetos, A and Jelaković, B}, title = {Longer Telomere Length in Balkan Endemic Nephropathy Patients Undergoing Chronic Hemodialysis is Associated with Lower Cardiovascular Mortality.}, journal = {Kidney360}, volume = {}, number = {}, pages = {}, doi = {10.34067/KID.0000000603}, pmid = {39356569}, issn = {2641-7650}, abstract = {BACKGROUND: Balkan endemic nephropathy (BEN) is characterized with later onset and milder forms of hypertension, and with lower pulse wave velocity (PWV) than other end-stage kidney disease (ESKD). Longer telomeres are associated with better cardiovascular (CV) prognosis. Therefore, we hypothesized that telomere length (TL) could be longer in BEN patients compared to other ESKD patients.
METHODS: A total of 124 patients undergoing hemodialysis (HD) (68 BEN, 56 non-BEN) were enrolled and followed-up for 72 months. TL was measured in leukocytes by Southern blot at inclusion.
RESULTS: Age and sex-adjusted TL was significantly longer in the BEN group (p<0.001). TL was negatively associated with carotid-femoral PWV in BEN patients. BEN patients had significantly lower CV mortality than non-BEN ESKD patients (p<0.001). In the BEN group shorter TL (1kb change) was the only determinant of shorter survival (HR 0.11). Using the TL threshold defined by ROC analysis (TL < 6.21 kb), we showed in both groups significantly higher CV mortality in the presence of short telomeres (Log-rank (Mantel-p<0.001).
CONCLUSIONS: Longer telomeres are associated with less CV mortality in patients undergoing chronic HD. BEN patients had longer TL and longer survival than other ESKD patients. In BEN patients, TL was negatively associated with arterial stiffness and positively associated with survival. This study confirmed our hypothesis that BEN is associated with slower vascular aging and that longer TL may partially explain this phenomenon.}, }
@article {pmid39355591, year = {2024}, author = {Sun, JY and Xu, Q and Shen, H and Huang, W and Qu, Q and Sun, W and Kong, XQ}, title = {The Association between Leucocyte Telomere Length and Survival Outcomes in Patients with Cardiovascular Disease.}, journal = {Reviews in cardiovascular medicine}, volume = {25}, number = {9}, pages = {333}, pmid = {39355591}, issn = {2153-8174}, abstract = {BACKGROUND: We explore the association between leucocyte telomere length (LTL) and all-cause and cardiovascular disease (CVD)-specific death in CVD patients.
METHODS: We acquired 1599 CVD patients from a nationally representative US population survey for this study. We applied Kaplan-Meier curves, adjusted weighted Cox regression models, and restricted cubic spline to investigate the association between LTL and all-cause death. Additionally, we employed competing risk regression to assess the impact of LTL on cardiovascular-specific death, setting non-cardiovascular death as a competing event.
RESULTS: The overall mortality rate was 31.0% after a median follow-up of 13.9 years. Patients with shorter LTL exhibited a higher risk of all-cause death, with an adjusted hazard ratio (HR) of 1.25 (95% confidence interval (CI): 1.05-1.48). Restricted cubic spline illustrated a linear dose-response relationship. In gender-specific analyses, female patients with shorter LTL showed a higher risk of death (weighted HR, 1.79; 95% CI, 1.29-2.48), whereas this association was not observed in males (weighted HR, 0.90; 95% CI, 0.61-1.32). The Fine-Gray competing risk model revealed no significant relationship between LTL and cardiovascular-specific mortality but a significant association with non-cardiovascular death (adjusted HR, 1.24; 95% CI, 1.02-1.51).
CONCLUSIONS: LTL is inversely associated with all-cause death in female CVD patients. The significant correlation between reduced LTL and increased all-cause mortality emphasizes LTL as a potential marker for tertiary prevention against cardiovascular disease.}, }
@article {pmid39355254, year = {2024}, author = {Xu, W and Sang, S and Wang, J and Guo, S and Zhang, X and Zhou, H and Chen, Y}, title = {Identification of telomere-related lncRNAs and immunological analysis in ovarian cancer.}, journal = {Frontiers in immunology}, volume = {15}, number = {}, pages = {1452946}, pmid = {39355254}, issn = {1664-3224}, mesh = {Humans ; *RNA, Long Noncoding/genetics ; Female ; *Ovarian Neoplasms/genetics/immunology/mortality ; Prognosis ; *Biomarkers, Tumor/genetics ; *Gene Expression Regulation, Neoplastic ; *Telomere/genetics ; Cell Line, Tumor ; Nomograms ; Middle Aged ; Lymphocytes, Tumor-Infiltrating/immunology/metabolism ; }, abstract = {BACKGROUND: Ovarian cancer (OC) is a global malignancy characterized by metastatic invasiveness and recurrence. Long non-coding RNAs (lncRNAs) and Telomeres are closely connected with several cancers, but their potential as practical prognostic markers in OC is less well-defined.
METHODS: Relevant mRNA and clinical data for OC were sourced from The Cancer Genome Atlas (TCGA) database. The telomere-related lncRNAs (TRLs) prognostic model was established by univariate/LASSO/multivariate regression analyses. The effectiveness of the TRLs model was evaluated and measured via the nomogram. Additionally, immune infiltration, tumor mutational load (TMB), and drug sensitivity were evaluated. We validated the expression levels of prognostic genes. Subsequently, PTPRD-AS1 knockdown was utilized to perform the CCK8 assay, colony formation assay, transwell assay, and wound healing assay of CAOV3 cells.
RESULTS: A six-TRLs prognostic model (PTPRD-AS1, SPAG5-AS1, CHRM3-AS2, AC074286.1, FAM27E3, and AC018647.3) was established, which can effectively predict patient survival rates and was successfully validated using external datasets. According to the nomogram, the model could effectively predict prognosis. Furthermore, we detected the levels of regulatory T cells and M2 macrophages were comparatively higher in the high-risk TRLs group, but the levels of activated CD8 T cells and monocytes were the opposite. Finally, the low-risk group was more sensitive to anti-cancer drugs. The mRNA levels of PTPRD-AS1, SPAG5-AS1, FAM27E3, and AC018647.3 were significantly over-expressed in OC cell lines (SKOV3, A2780, CAOV3) in comparison to normal IOSE-80 cells. AC074286.1 were over-expressed in A2780 and CAOV3 cells and CHRM3-AS2 only in A2780 cells. PTPRD-AS1 knockdown decreased the proliferation, cloning, and migration of CAOV3 cells.
CONCLUSION: Our study identified potential biomarkers for the six-TRLs model related to the prognosis of OC.}, }
@article {pmid39354183, year = {2024}, author = {Wilsnack, C and Rising, CJ and Pearce, EE and Forbes Shepherd, R and Thompson, AS and Majid, A and Werner-Lin, A and Savage, SA and Hutson, SP}, title = {Defining the complex needs of families with rare diseases-the example of telomere biology disorders.}, journal = {European journal of human genetics : EJHG}, volume = {}, number = {}, pages = {}, pmid = {39354183}, issn = {1476-5438}, abstract = {Families with rare diseases, such as telomere biology disorders (TBDs), may have extensive unmet needs given the heterogeneity, chronicity, and potential severity of illness. TBDs are rare inherited syndromes associated with high risk of bone marrow failure, cancer, pulmonary fibrosis, and other severe, chronic complications. To identify gaps in clinical care, we aimed to ascertain the perceived unmet needs of adults and family caregivers, current or bereaved, of individuals with TBDs. Participants were aged ≥18 years with a self-reported TBD diagnosis and/or ever caregivers to one or more family members with a TBD. Participants completed an online survey (N = 35) and/or an audio-recorded telephone interview (N = 32). We calculated descriptive statistics in SPSS and thematically analyzed interview transcripts. Quantitative and qualitative data were analyzed concurrently. Most participants were aged ≥35 years, female, highly educated, and medically insured. Survey respondents reported numerous unmet needs in psychosocial, medical, financial, and daily activity domains. In interviews, participant descriptions validated and contextualized the salience of these unmet needs. Both qualitative and quantitative data identified critical shortfalls in addressing chronic family distress and specialty care coordination. Adults and caregivers of individuals with TBDs have a high risk of adverse psychosocial sequelae given extensive unmet needs. These findings provide a foundation for understanding the range and extent of gaps in care for families with rare diseases, especially TBDs but that are likely applicable to others. Tailored multi-disciplinary interventions involving patients, families, clinicians, researchers, and patient advocacy communities are required to appropriately address care needs for all rare diseases.}, }
@article {pmid39351882, year = {2024}, author = {Lee, H and Niida, H and Sung, S and Lee, J}, title = {Haplotype-resolved de novo assembly revealed unique characteristics of alternative lengthening of telomeres in mouse embryonic stem cells.}, journal = {Nucleic acids research}, volume = {}, number = {}, pages = {}, doi = {10.1093/nar/gkae842}, pmid = {39351882}, issn = {1362-4962}, support = {NRF-2020R1A2C3003352//National Research Foundation of Korea/ ; SSTF-BA1501-52//Samsung Science and Technology Foundation/ ; }, abstract = {Telomeres protect chromosome ends from DNA damage responses, and their dysfunction triggers genomic alterations like chromosome fusion and rearrangement, which can lead to cellular death. Certain cells, including specific cancer cells, adopt alternative lengthening of telomere (ALT) to counteract dysfunctional telomeres and proliferate indefinitely. While telomere instability and ALT activity are likely major sources of genomic alteration, the patterns and consequences of such changes at the nucleotide level in ALT cells remain unexplored. Here we generated haplotype-resolved genome assemblies for type I ALT mouse embryonic stem cells, facilitated by highly accurate or ultra-long reads and Hi-C reads. High-quality genome revealed ALT-specific complex chromosome end structures and various genomic alterations including over 1000 structural variants (SVs). The unique sequence (mTALT) used as a template for type I ALT telomeres showed traces of being recruited into the genome, with mTALT being replicated with remarkably high accuracy. Subtelomeric regions exhibited distinct characteristics: resistance to the accumulation of SVs and small variants. We genotyped SVs at allele resolution, identifying genes (Rgs6, Dpf3 and Tacc2) crucial for maintaining ALT telomere stability. Our genome assembly-based approach elucidated the unique characteristics of ALT genome, offering insights into the genome evolution of cells surviving telomere-derived crisis.}, }
@article {pmid39350941, year = {2024}, author = {Lin, F and Luo, J and Zhu, Y and Liang, H and Li, D and Han, D and Chang, Q and Pan, P and Zhang, Y}, title = {Association Between Adverse Early Life Factors and Telomere Length in Middle and Late Life.}, journal = {Innovation in aging}, volume = {8}, number = {9}, pages = {igae070}, pmid = {39350941}, issn = {2399-5300}, abstract = {BACKGROUND AND OBJECTIVES: Telomere length (TL) has been acknowledged as biomarker of biological aging. Numerous investigations have examined associations between individual early life factors and leukocyte TL; however, the findings were far from consistent.
RESEARCH DESIGN AND METHODS: We evaluated the relationship between individual and combined early life factors and leukocytes TL in middle and late life using data from the UK Biobank. The early life factors (eg, maternal smoking, breastfeeding, birth weight, and comparative body size and height to peers at age 10) were measured. The regression coefficients (β) and 95% confidence interval (CI) were applied to assess the link of the early life factors and TL in adulthood. Flexible parametric survival models incorporated age to calculate the relationship between early life factors and life expectancy.
RESULTS: Exposure to maternal smoking, lack of breastfeeding, low birth weight, and shorter height compared to peers at age 10 were identified to be associated with shorter TL in middle and older age according to the large population-based study with 197 504 participants. Individuals who experienced more than 3 adverse early life factors had the shortest TL in middle and late life (β = -0.053; 95% CI = -0.069 to -0.038; p < .0001), as well as an average of 0.54 years of life loss at the age of 45 and 0.49 years of life loss at the age of 60, compared to those who were not exposed to any early life risk factors.
DISCUSSION AND IMPLICATIONS: Early life factors including maternal smoking, non-breastfed, low birth weight, and shorter height compared to peers at age 10 were associated with shorter TL in later life. In addition, an increased number of the aforementioned factors was associated with a greater likelihood of shorter TL in adulthood, as well as a reduced life expectancy.}, }
@article {pmid39350032, year = {2024}, author = {Ferguson, S and Bar-Ness, YD and Borevitz, J and Jones, A}, title = {A telomere-to-telomere Eucalyptus regnans genome: unveiling haplotype variance in structure and genes within one of the world's tallest trees.}, journal = {BMC genomics}, volume = {25}, number = {1}, pages = {913}, pmid = {39350032}, issn = {1471-2164}, abstract = {BACKGROUND: Eucalyptus regnans (Mountain Ash) is an Australian native giant tree species which form forests that are among the highest known carbon-dense biomasses in the world. To enhance genomic studies in this ecologically important species, we assembled a high-quality, mostly telomere-to-telomere complete, chromosome-level, haplotype-resolved reference genome. We sampled a single tree, the Centurion, which is currently a contender for the world's tallest flowering plant.
RESULTS: Using long-read sequencing data (PacBio HiFi, Oxford Nanopore ultra-long reads) and chromosome conformation capture data (Hi-C), we assembled the most contiguous and complete Eucalyptus reference genome to date. For each haplotype, we observed contig N50s exceeding 36 Mbp, scaffold N50s exceeding 43 Mbp, and genome BUSCO completeness exceeding 99%. The assembled genome revealed extensive structural variations between the two haplotypes, consisting mostly of insertions, deletions, duplications and translocations. Analysis of gene content revealed haplotype-specific genes, which were enriched in functional categories related to transcription, energy production and conservation. Additionally, many genes reside within structurally rearranged regions, particularly duplications, suggesting that haplotype-specific variation may contribute to environmental adaptation in the species.
CONCLUSIONS: Our study provides a foundation for future research into E. regnans environmental adaptation, and the high-quality genome will be a powerful resource for conservation of carbon-dense giant tree forests.}, }
@article {pmid39349834, year = {2024}, author = {Saraswati, S and Martínez, P and Serrano, R and Mejías, D and Graña-Castro, O and Álvarez Díaz, R and Blasco, MA}, title = {Renal fibroblasts are involved in fibrogenic changes in kidney fibrosis associated with dysfunctional telomeres.}, journal = {Experimental & molecular medicine}, volume = {}, number = {}, pages = {}, pmid = {39349834}, issn = {2092-6413}, abstract = {Tubulointerstitial fibrosis associated with chronic kidney disease (CKD) represents a global health care problem. We previously reported that short and dysfunctional telomeres lead to interstitial renal fibrosis; however, the cell-of-origin of kidney fibrosis associated with telomere dysfunction is currently unknown. We induced telomere dysfunction by deleting the Trf1 gene encoding a telomere-binding factor specifically in renal fibroblasts in both short-term and long-term life-long experiments in mice to identify the role of fibroblasts in renal fibrosis. Short-term Trf1 deletion in renal fibroblasts was not sufficient to trigger kidney fibrosis but was sufficient to induce inflammatory responses, ECM deposition, cell cycle arrest, fibrogenesis, and vascular rarefaction. However, long-term persistent deletion of Trf1 in fibroblasts resulted in kidney fibrosis accompanied by an elevated urinary albumin-to-creatinine ratio (uACR) and a decrease in mouse survival. These cellular responses lead to the macrophage-to-myofibroblast transition (MMT), endothelial-to-mesenchymal transition (EndMT), and partial epithelial-to-mesenchymal transition (EMT), ultimately causing kidney fibrosis at the humane endpoint (HEP) when the deletion of Trf1 in fibroblasts is maintained throughout the lifespan of mice. Our findings contribute to a better understanding of the role of dysfunctional telomeres in the onset of the profibrotic alterations that lead to kidney fibrosis.}, }
@article {pmid39349547, year = {2024}, author = {Geng, D and Liu, H and Wang, H and Wang, H}, title = {Telomere length exhibits inverse association with migraine among Americans aged 20-50 years, without implications beyond age 50: a cross-sectional study.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {22597}, pmid = {39349547}, issn = {2045-2322}, support = {H2020307041//the Natural Science Foundation of Hebei Province/ ; 236Z7745G//the Central Government Guides Local Funds for Science and Technology Development/ ; }, mesh = {Humans ; *Migraine Disorders/genetics ; Middle Aged ; Adult ; Cross-Sectional Studies ; Male ; Female ; Young Adult ; *Telomere/genetics ; United States/epidemiology ; Nutrition Surveys ; Telomere Shortening ; Age Factors ; Telomere Homeostasis ; Aged ; Leukocytes/metabolism ; }, abstract = {Migraine, common in individuals under 50 years, is linked to oxidative stress. The association between telomere length shortening and migraine, along with potential age-related influences, has not been comprehensively studied. This cross-sectional study included data from 6169 participants in the National Health and Nutrition Survey (NHANES) from 1999 to 2002, encompassing information on peripheral blood leukocyte telomere length, severe headache or migraine, and potential confounders. Stratifying by age (20-50 years, > 50 years), we employed multivariable logistic regression, restricted cubic splines and interaction test to investigate age-influenced telomere length in relation to migraine. In participants aged 20-50 years, the odds ratio (OR) for migraine in the shortest telomere length group T1 (0.39-0.89) was 1.35 (95% confidence interval [95% CI] 1.01, 1.79) compared to the longest group T3 (1.10-9.42), whereas in those aged > 50 years, the OR of T1 was 0.93 (95% CI 0.60, 1.43). Additionally, telomere length and age interacted in the development of migraine (p for interaction: 0.010). In individuals aged 20-50, an L-shaped relationship was found between telomere length and migraine, with an inflection point at 1.02T/S ratio. The OR was 9.34 (95% CI 1.56, 55.99) for telomere lengths < 1.02T/S ratio. These findings suggest age influences the association between telomere length and migraine in U.S. adults.}, }
@article {pmid39348051, year = {2025}, author = {Nonaka, K and Aida, J and Hasegawa, Y and Arai, T and Ishiwata, T and Takubo, K}, title = {Telomere Length Measurement in Human Tissue Sections by Quantitative Fluorescence In Situ Hybridization (Q-FISH).}, journal = {Methods in molecular biology (Clifton, N.J.)}, volume = {2857}, number = {}, pages = {9-14}, pmid = {39348051}, issn = {1940-6029}, mesh = {Humans ; *In Situ Hybridization, Fluorescence/methods ; *Telomere/genetics/metabolism ; *Peptide Nucleic Acids/metabolism/genetics ; *Paraffin Embedding/methods ; Tissue Fixation/methods ; Telomere Homeostasis ; Centromere/metabolism/genetics ; }, abstract = {Telomeres in most somatic cells shorten with each cell division, and critically short telomeres lead to cellular dysfunction, cell cycle arrest, and senescence. Thus, telomere shortening is an important hallmark of human cellular senescence. Quantitative fluorescence in situ hybridization (Q-FISH) using formalin-fixed paraffin-embedded (FFPE) tissue sections allows the estimation of telomere lengths in individual cells in histological sections. In our Q-FISH method, fluorescently labelled peptide nucleic acid (PNA) probes are hybridized to telomeric and centromeric sequences in FFPE human tissue sections, and relative telomere lengths (telomere signal intensities relative to centromere signal intensities) are measured. This chapter describes our Q-FISH protocols for assessing relative telomere lengths in FFPE human tissue sections.}, }
@article {pmid39346776, year = {2024}, author = {Fu, C and Tian, X and Wu, S and Chu, X and Cheng, Y and Wu, X and Yang, W}, title = {Role of telomere dysfunction and immune infiltration in idiopathic pulmonary fibrosis: new insights from bioinformatics analysis.}, journal = {Frontiers in genetics}, volume = {15}, number = {}, pages = {1447296}, pmid = {39346776}, issn = {1664-8021}, abstract = {BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic progressive interstitial lung disease characterized by unexplained irreversible pulmonary fibrosis. Although the etiology of IPF is unclear, studies have shown that it is related to telomere length shortening. However, the prognostic value of telomere-related genes in IPF has not been investigated.
METHODS: We utilized the GSE10667 and GSE110147 datasets as the training set, employing differential expression analysis and weighted gene co-expression network analysis (WGCNA) to screen for disease candidate genes. Then, we used consensus clustering analysis to identify different telomere patterns. Next, we used summary data-based mendelian randomization (SMR) analysis to screen core genes. We further evaluated the relationship between core genes and overall survival and lung function in IPF patients. Finally, we performed immune infiltration analysis to reveal the changes in the immune microenvironment of IPF.
RESULTS: Through differential expression analysis and WGCNA, we identified 35 significant telomere regulatory factors. Consensus clustering analysis revealed two distinct telomere patterns, consisting of cluster A (n = 26) and cluster B (n = 19). Immune infiltration analysis revealed that cluster B had a more active immune microenvironment, suggesting its potential association with IPF. Using GTEx eQTL data, our SMR analysis identified two genes with potential causal associations with IPF, including GPA33 (PSMR = 0.0013; PHEIDI = 0.0741) and MICA (PSMR = 0.0112; PHEIDI = 0.9712). We further revealed that the expression of core genes is associated with survival time and lung function in IPF patients. Finally, immune infiltration analysis revealed that NK cells were downregulated and plasma cells and memory B cells were upregulated in IPF. Further correlation analysis showed that GPA33 expression was positively correlated with NK cells and negatively correlated with plasma cells and memory B cells.
CONCLUSION: Our study provides a new perspective for the role of telomere dysfunction and immune infiltration in IPF and identifies potential therapeutic targets. Further research may reveal how core genes affect cell function and disease progression, providing new insights into the complex mechanisms of IPF.}, }
@article {pmid39344239, year = {2024}, author = {Li, J and Liu, PP and Wang, Y and Ren, CY and Zhang, M}, title = {Lectin YKL-40 Level and Telomere Length are Indicators of Insomnia Disorder.}, journal = {Journal of integrative neuroscience}, volume = {23}, number = {9}, pages = {180}, doi = {10.31083/j.jin2309180}, pmid = {39344239}, issn = {0219-6352}, support = {QN2019124//Anhui University of Science and Technology university-level project/ ; YZ2023H1A002//Anhui University of Science and Technology medical special cultivation project/ ; }, mesh = {Humans ; *Chitinase-3-Like Protein 1/blood ; Male ; Female ; *Sleep Initiation and Maintenance Disorders/blood/metabolism ; Adult ; Middle Aged ; *Telomere/metabolism ; Biomarkers/blood ; Leukocytes/metabolism ; }, abstract = {OBJECTIVE: To explore the relationship between YKL-40 level, telomere length, and different subtypes of insomnia disorder.
METHODS: A total of 145 individuals suffering from insomnia were enrolled and divided into four groups according to the insomniac subtypes: difficulty initiating sleep, early morning awakening, difficulty maintaining sleep, and mixed symptoms. Eighty healthy controls were also collected at the same time. Peripheral leukocyte genomic DNA was extracted, relative telomere lengths were measured using the real-time quantitative polymerase chain reaction method, and YKL-40 levels were determined using enzyme-linked immunoassay. Logistic regression modeling was used to analyze the correlation between different insomnia subtypes, YKL-40 level, and telomere length.
RESULTS: People with telomere lengths in the lowest tertile were more likely to have trouble falling asleep (odds ratio (OR) 2.13, 95% confidence interval (CI) 1.22-3.63; p = 0.03) and had a higher frequency of mixed symptoms (OR 1.49, 95% CI 1.30-2.81; p = 0.04). People in the highest tertile of YKL-40 level had an increased chance of waking up early (OR 2.98, 95% CI 1.54-5.33; p = 0.01) and more mixed symptoms (OR 1.47, 95% CI 1.22-2.79; p = 0.02). Furthermore, using receiver operating characteristic curve analysis, the area under the curve of YKL-40 level and telomere length was 0.806 and 0.746, respectively.
CONCLUSIONS: Telomere length in patients with difficulty initiating sleep and mixed symptoms was significantly shortened and the level of YKL-40 in people who have early morning awakening and mixed symptoms was significantly increased. Our findings provide the first evidence that leukocyte telomere length and YKL-40 level are individually linked to mixed symptoms.}, }
@article {pmid39344121, year = {2024}, author = {Li, Z and Wang, M and Zeng, S and Wang, Z and Ying, Y and Chen, Q and Zhang, C and He, W and Sheng, C and Wang, Y and Zhang, Z and Xu, C and Wang, H}, title = {Investigating the Shared Genetic Architecture Between Leukocyte Telomere Length and Prostate Cancer.}, journal = {The world journal of men's health}, volume = {}, number = {}, pages = {}, doi = {10.5534/wjmh.240062}, pmid = {39344121}, issn = {2287-4208}, support = {81772720/NNSFC/National Natural Science Foundation of China/China ; 81972391/NNSFC/National Natural Science Foundation of China/China ; 82172871/NNSFC/National Natural Science Foundation of China/China ; 2021008149//Naval Medical University/China ; 2020YXK019//Naval Medical University/China ; }, abstract = {PURPOSE: Evidence of an association between leukocyte telomere length (LTL) and prostate cancer (PCa) is accumulating; however, their shared genetic basis remains unclear.
MATERIALS AND METHODS: Using summary statistics obtained from the genome-wide association study (GWAS), we quantified the global and local genetic correlations between two traits. Subsequently, we identified potential pleiotropic loci, common tissue-enriched regions, and risk gene loci while inferring assumed causal relationships.
RESULTS: Our study demonstrated a global genetic correlation between LTL and PCa (genetic correlation=0.066, p=0.017), which was further confirmed in local genomic regions. Cross-trait GWAS meta-analysis revealed 44 shared loci, including 10 novel pleiotropic single nucleotide polymorphisms appearing concurrently in significant local genetic correlation regions. Notably, two new loci (rs9419958; rs3730668) were additionally validated to co-localize. For the first time, we identified a significant shared genetic enrichment of both traits in the small intestine tissue at the terminal ileum, with functional genes in this region affecting both LTL and PCa. Concurrently, Mendelian randomization analysis indicated a positive causal relationship between LTL and PCa.
CONCLUSIONS: In conclusion, our study makes a significant contribution to the ongoing debate concerning the potential association between longer LTL and a higher risk of PCa. Additionally, we provide new evidence for the development of therapeutic targets for PCa and propose new directions for future risk prediction in this regard.}, }
@article {pmid39342869, year = {2024}, author = {Kyriacou, E and Lingner, J}, title = {TERRA long noncoding RNA: At the interphase of telomere damage, rescue and signaling.}, journal = {Current opinion in cell biology}, volume = {91}, number = {}, pages = {102437}, doi = {10.1016/j.ceb.2024.102437}, pmid = {39342869}, issn = {1879-0410}, abstract = {TERRA long noncoding RNAs play key roles in telomere function and maintenance. They can orchestrate telomeric chromatin remodeling, regulate telomere maintenance by telomerase and homology-directed repair, and they participate in the telomeric DNA damage response. TERRA associates with chromosome ends through base-pairing forming R-loops, which are mediated by the RAD51 DNA recombinase and its partner RAD51AP1. Telomeric R-loops interfere with replication fork progression, stimulating a switch of telomere maintenance from semiconservative DNA replication to homology-directed repair (HDR). The latter mechanism is exploited by a subset of cancer cells that lack telomerase, referred to as ALT. In addition, TERRA stimulates HDR at short telomeres during aging, delaying cellular senescence. During carcinogenesis, when cells with eroded telomeres enter replicative crisis, TERRA acts as a signaling molecule to mediate autophagic cell death.}, }
@article {pmid39339711, year = {2024}, author = {Boccardi, V and Polom, J}, title = {Searching for Beauty and Health: Aging in Women, Nutrition, and the Secret in Telomeres.}, journal = {Nutrients}, volume = {16}, number = {18}, pages = {}, doi = {10.3390/nu16183111}, pmid = {39339711}, issn = {2072-6643}, mesh = {Humans ; Female ; *Telomere ; *Aging/physiology ; *Nutritional Status ; *Beauty ; Women's Health ; Quality of Life ; Longevity ; Healthy Aging ; Life Style ; Diet ; }, abstract = {Women typically outlive men, yet they often experience greater frailty and a higher incidence of chronic diseases as they age. By exploring the biological foundations of aging, with a particular focus on telomere dynamics, this manuscript aims to describe how dietary and lifestyle choices can significantly influence the aging process. The review comprehensively examines current research, underscoring the power of nutrition to counteract age-related changes, support healthy aging, and maintain vitality and beauty in women. The exploration of telomeres-the protective caps at the ends of chromosomes-reveals how they serve as markers of cellular aging and are potential targets for interventions aimed at enhancing women's longevity and quality of life. This study also emphasizes the importance of sex-specific approaches and precision medicine in understanding the unique health challenges women face as they age. By proposing targeted strategies, the review seeks to address these challenges, offering insights into preventive measures that can foster resilience, promote well-being, and extend healthy life expectancy in women. Ultimately, this work provides a sophisticated understanding of the aging process in women, highlighting the pivotal role of tailored interventions in preserving both health and beauty.}, }
@article {pmid39338301, year = {2024}, author = {Mantadaki, AE and Baliou, S and Linardakis, M and Vakonaki, E and Tzatzarakis, MN and Tsatsakis, A and Symvoulakis, EK}, title = {Quercetin Intake and Absolute Telomere Length in Patients with Type 2 Diabetes Mellitus: Novel Findings from a Randomized Controlled Before-and-After Study.}, journal = {Pharmaceuticals (Basel, Switzerland)}, volume = {17}, number = {9}, pages = {}, doi = {10.3390/ph17091136}, pmid = {39338301}, issn = {1424-8247}, abstract = {Telomeres, the protective chromosomal ends, progressively shorten and potentially are implicated in the pathogenesis of age-related diseases. In type 2 diabetes (T2DM), telomere shortening may play an important role, but the whole 'picture' remains limited. From a therapeutic perspective, the phytonutrient quercetin appears to be clinically effective and safe for patients with T2DM. Considering the above, we aimed to examine whether quercetin could interfere with telomere length (TL) dynamics. One hundred patients with T2DM on non-insulin medications registered within a primary healthcare facility were stratified by age and sex and randomly assigned to either standard care or standard care plus quercetin (500 mg/day) for 12 weeks, succeeded by an 8-week washout period and another 12 weeks of supplementation. Of the 88 patients completing the trial, 82 consented to blood sampling for TL measurements. Health assessments and whole blood absolute TL measurements using quantitative polymerase chain reaction (qPCR) were conducted at baseline and study end, and the findings of this subcohort are presented. Quercetin supplementation was associated with a significant increase in mean TL (odds ratio ≥ 2.44; p < 0.05) with a strengthened association after full adjustment for potential confounders through multiple logistic regression analysis (odds ratio = 3.48; p = 0.026), suggesting it as a potentially promising supplementation option. Further studies are needed to confirm this finding, elucidating the underlying molecular mechanisms of quercetin.}, }
@article {pmid39335189, year = {2024}, author = {Fabiani, R and Chiavarini, M and Rosignoli, P and Giacchetta, I}, title = {Leucocyte Telomere Length and Lung Cancer Risk: A Systematic Review and Meta-Analysis of Prospective Studies.}, journal = {Cancers}, volume = {16}, number = {18}, pages = {}, doi = {10.3390/cancers16183218}, pmid = {39335189}, issn = {2072-6694}, abstract = {Although numerous epidemiological studies are available, the relationship between leukocyte telomere length (LTL) and lung cancer risk is still controversial. This systematic review and meta-analysis, performed according to the PRISMA statement and MOOSE guidelines, aims to summarize the evidence and calculate the risk of lung cancer associated with LTL. The literature search was performed on PubMed, Web of Science, and Scopus databases through May 2024. A random-effects model was used to calculate the pooled risk. Heterogeneity was assessed using I[2] and Cochran's Q statistic. Begg's and Egger's tests were used to detect publication bias. Based on 8055 lung cancer cases and 854,653 controls (nine prospective studies), longer LTL was associated with a significant 42% increment in all types of lung cancer risk (OR 1.42, 95% CI 1.24-1.63). The effect was even more evident for adenocarcinomas (OR 1.98, 95% CI 1.69-2.31), while no association was observed for squamous cell carcinoma (OR 0.87, 95% CI 0.72-1.06). Significantly, no association was found for current smokers (OR 1.08, 95% CI 0.90-1.30), while it remained high for both never-smokers (OR 1.92, 95% CI 1.62-2.28) and former smokers (OR 1.34, 95% CI 1.11-1.62). No significant publication bias was evidenced. Longer LTL is associated with an increment in lung cancer risk particularly in never-smoker subjects.}, }
@article {pmid39333471, year = {2024}, author = {Olagunju, TA and Rosen, BD and Neibergs, HL and Becker, GM and Davenport, KM and Elsik, CG and Hadfield, TS and Koren, S and Kuhn, KL and Rhie, A and Shira, KA and Skibiel, AL and Stegemiller, MR and Thorne, JW and Villamediana, P and Cockett, NE and Murdoch, BM and Smith, TPL}, title = {Telomere-to-telomere assemblies of cattle and sheep Y-chromosomes uncover divergent structure and gene content.}, journal = {Nature communications}, volume = {15}, number = {1}, pages = {8277}, pmid = {39333471}, issn = {2041-1723}, support = {USDA-NIFA-2021-67016-33416//United States Department of Agriculture | National Institute of Food and Agriculture (NIFA)/ ; IDA01566//United States Department of Agriculture | National Institute of Food and Agriculture (NIFA)/ ; 3040-31000-104-000-D//United States Department of Agriculture | Agricultural Research Service (USDA Agricultural Research Service)/ ; 8042-31000-112-000-D//United States Department of Agriculture | Agricultural Research Service (USDA Agricultural Research Service)/ ; }, mesh = {Animals ; *Telomere/genetics ; Cattle/genetics ; Sheep/genetics ; *Y Chromosome/genetics ; Male ; Centromere/genetics ; Evolution, Molecular ; Genome/genetics ; Female ; }, abstract = {Reference genomes of cattle and sheep have lacked contiguous assemblies of the sex-determining Y chromosome. Here, we assemble complete and gapless telomere to telomere (T2T) Y chromosomes for these species. We find that the pseudo-autosomal regions are similar in length, but the total chromosome size is substantially different, with the cattle Y more than twice the length of the sheep Y. The length disparity is accounted for by expanded ampliconic region in cattle. The genic amplification in cattle contrasts with pseudogenization in sheep suggesting opposite evolutionary mechanisms since their divergence 19MYA. The centromeres also differ dramatically despite the close relationship between these species at the overall genome sequence level. These Y chromosomes have been added to the current reference assemblies in GenBank opening new opportunities for the study of evolution and variation while supporting efforts to improve sustainability in these important livestock species that generally use sire-driven genetic improvement strategies.}, }
@article {pmid39332705, year = {2024}, author = {da Cruz, NFS and Sengillo, JD and Shah, SM and López-Font, FJ and Negron, CI and Berrocal, AM}, title = {Telomere Biology Disorders: Report on Clinical and Angiographic Findings.}, journal = {Ophthalmology. Retina}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.oret.2024.09.011}, pmid = {39332705}, issn = {2468-6530}, abstract = {PURPOSE: To evaluate the retinal vasculature in pediatric patients with telomere biology disorders (TBD).
DESIGN: Retrospective consecutive case series.
SUBJECTS: Pediatric patients with a diagnosis of TBD who underwent widefield fluorescein angiography (FA).
METHODS: Electronic medical records of pediatric patients with TBD at a tertiary referral eye center were reviewed from January 2019 to July 2023. Vascular phenotype was assessed by reviewing FA images.
MAIN OUTCOMES MEASURES: Incomplete peripheral vascularization, aneurysmal dilatation, terminal arborization, anastomotic loops, capillary dropout, neovascularization, tortuosity, leakage from tractional membranes, and blockage from hemorrhage.
RESULTS: Fourteen eyes from 7 patients were included. All patients were genetically confirmed for TBD. The most common genetic variants were in CTC1 (5 patients; 71.4%), ACD (1 patient; 14.3%), and RTEL1 (1 patient; 14.3%). On FA, the most common findings were incomplete peripheral vascularization (14 eyes, 100%), aneurysmal dilatation (12 eyes, 85.7%), terminal arborization (12 eyes, 85.7%), anastomotic loops (12 eyes, 85.7%), capillary dropout (10 eyes, 71.4%), and neovascularization (9 eyes, 64.3%). Regarding treatment, laser photocoagulation (14 eyes, 100%), intravitreal bevacizumab injection (13 eyes, 92.6%), and sub-tenon's Kenalog (11 eyes, 78.6%) were utilized. All patients managed with laser photocoagulation and/or bevacizumab required multiple treatments.
CONCLUSION: Our study describes a spectrum of vascular changes evidenced by widefield FA in pediatric patients with genetically confirmed TBD. Although further research is warranted to fully understand the etiology of these subtle vascular anomalies, widefield FA should be conducted in patients with genetically confirmed or suspected TBD.}, }
@article {pmid39331358, year = {2024}, author = {Mattiolo, P and Bevere, M and Mafficini, A and Verschuur, AVD and Calicchia, M and Hackeng, WM and Simbolo, M and Paiella, S and Dreijerink, KMA and Landoni, L and Pedron, S and Cingarlini, S and Salvia, R and Milella, M and Lawlor, RT and Valk, GD and Vriens, MR and Scarpa, A and Brosens, LA and Luchini, C}, title = {Glucagon-Producing Pancreatic Neuroendocrine Tumors (Glucagonomas) are Enriched in Aggressive Neoplasms with ARX and PDX1 Co-expression, DAXX/ATRX Mutations, and ALT (Alternative Lengthening of Telomeres).}, journal = {Endocrine pathology}, volume = {}, number = {}, pages = {}, pmid = {39331358}, issn = {1559-0097}, support = {26343, 28054, 29829//Associazione Italiana per la Ricerca sul Cancro/ ; 26343, 28054, 29829//Associazione Italiana per la Ricerca sul Cancro/ ; 2020-1 12978//KWF Kankerbestrijding/ ; 2020-1 12978//KWF Kankerbestrijding/ ; J38D19000690001//Fondazione Italiana per la ricerca sulle Malattie del Pancreas/ ; J38D19000690001//Fondazione Italiana per la ricerca sulle Malattie del Pancreas/ ; (RF CO-2019-12369662: CUP: B39C21000370001//Ministero della Salute/ ; }, abstract = {Glucagonomas are functioning pancreatic neuroendocrine tumors (PanNETs) responsible for glucagonoma syndrome. This study aims to shed light on the clinicopathological and molecular features of these neoplasms. Six patients with glucagonomas were identified. All neoplasms were investigated with immunohistochemistry for neuroendocrine markers (Synaptophysin, Chromogranin-A), ATRX, DAXX, ARX, and PDX1 transcription factors. Fluorescent in situ hybridization (FISH) for assessing alternative lengthening of telomeres (ALT), and next-generation sequencing (NGS) for molecular profiling were performed. All cases were large single masses (mean size of 8.2 cm), with necrolytic migratory erythema as the most common symptom (6/6 cases, 100%). All neoplasms were well-differentiated G1 tumors, except one case that was G2. The tumors consistently showed classic/conventional histomorphology, with solid-trabecular and nested architecture. Lymphatic and vascular invasion (6/6, 100%), perineural infiltration (4/6, 66.6%), and nodal metastasis (4/6, 66.6%) were frequently observed. Transcription factors expression showed strong ARX expression in all tumors, and PDX1 expression in 5/6 cases (83.3%), indicating co-occurring alpha- and beta-cell differentiation. NGS showed recurrent somatic MEN1 and ATRX/DAXX biallelic inactivation. Cases with ATRX or DAXX mutations also showed matched loss of ATRX or DAXX protein expression and ALT. One case harbored somatic MUTYH inactivation and showed a high tumor mutational burden (TMB, 41.0 mut/Mb). During follow-up, one patient died of the disease, and four patients developed distant metastasis. Pancreatic glucagonomas are distinct PanNETs with specific clinicopathological and molecular features, including histological aspects of biological aggressiveness, co-occurring alpha- and beta-cell differentiation, MEN1 and DAXX/ATRX mutations enrichment, and the possible presence of high-TMB as an actionable marker.}, }
@article {pmid39330362, year = {2024}, author = {Chen, X and Wei, Y and Meng, G and Wang, M and Peng, X and Dai, J and Dong, C and Huo, G}, title = {Telomere-to-Telomere Haplotype-Resolved Genomes of Agrocybe chaxingu Reveals Unique Genetic Features and Developmental Insights.}, journal = {Journal of fungi (Basel, Switzerland)}, volume = {10}, number = {9}, pages = {}, doi = {10.3390/jof10090602}, pmid = {39330362}, issn = {2309-608X}, support = {JXXTCX202409//Collaborative Innovation Project of Modern Agricultural Research of Jiangxi Province/ ; 20212BBF61002, 20212BBF63013//Project of Science and Technology Department of Jiangxi Province/ ; JXXTCXBSJJ202213//Collaborative Innovation Project of Modern Agricultural Research of Jiangxi Province/ ; none//Crop Seeds Joint Research of Jiangxi Province/ ; CARS20//China Agriculture Research System/ ; }, abstract = {Agrocybe chaxingu is a widely cultivated edible fungus in China, which is rich in nutrients and medicinal compounds. However, the lack of a high-quality genome hinders further research. In this study, we assembled the telomere-to-telomere genomes of two sexually compatible monokaryons (CchA and CchB) derived from a primarily cultivated strain AS-5. The genomes of CchA and CchB were 50.60 Mb and 51.66 Mb with contig N50 values of 3.95 Mb and 3.97 Mb, respectively. Each contained 13 complete chromosomes with telomeres at both ends. The high mapping rate, uniform genome coverage, high LAI score, all BUSCOs with 98.5%, and all base accuracy exceeding 99.999% indicated the high level of integrity and quality of these two assembled genomes. Comparison of the two genomes revealed that approximately 30% of the nucleotide sequences between homologous chromosomes were non-syntenic, including 19 translocations, 36 inversions, and 15 duplications. An additional gene CchA_000467 was identified at the Mat A locus of CchA, which was observed exclusively in the Cyclocybe cylindracea species complex. A total of 613 (4.26%) and 483 (3.4%) unique genes were identified in CchA and CchB, respectively, with over 80% of these being hypothetical proteins. Transcriptomic analysis revealed that the expression levels of unique genes in CchB were significantly higher than those in CchA, and both CchA and CchB had unique genes specifically expressed at stages of mycelium and fruiting body. It was indicated that the growth and development of the A. chaxingu strain AS-5 required the coordinated action of two different nuclei, with CchB potentially playing a more significant role. These findings contributed to a more profound comprehension of the growth and developmental processes of basidiomycetes.}, }
@article {pmid39329317, year = {2024}, author = {Naish, M}, title = {Bridging the gap: unravelling plant centromeres in the telomere-to-telomere era.}, journal = {The New phytologist}, volume = {}, number = {}, pages = {}, doi = {10.1111/nph.20149}, pmid = {39329317}, issn = {1469-8137}, support = {//School of the Biological Sciences, University of Cambridge/ ; }, abstract = {Centromeres are specific regions of the chromosomes that play a pivotal role in the segregation of chromosomes, by facilitating the loading of the kinetochore, which forms the link between the chromosomes to the spindle fibres during cell division. In plants and animals, these regions often form megabase-scale loci of tandemly repeated DNA sequences, which have presented a challenge to genomic studies even in model species. The functional designation of centromeres is determined epigenetically by the incorporation of a centromere-specific variant of histone H3. Recent developments in long-read sequencing technology have allowed the assembly of these regions for the first time and have prompted a reassessment of fidelity of centromere function and the evolutionary dynamics of these regions.}, }
@article {pmid39329264, year = {2024}, author = {Granger, SL and Sharma, R and Kaushik, V and Razzaghi, M and Honda, M and Gaur, P and Bhat, DS and Labenz, SM and Heinen, JE and Williams, BA and Tabei, SMA and Wlodarski, MW and Antony, E and Spies, M}, title = {Human hnRNPA1 reorganizes telomere-bound replication protein A.}, journal = {Nucleic acids research}, volume = {}, number = {}, pages = {}, doi = {10.1093/nar/gkae834}, pmid = {39329264}, issn = {1362-4962}, support = {R35GM131704/NH/NIH HHS/United States ; K08 DK134873/DK/NIDDK NIH HHS/United States ; CA078586/BC/NCI NIH HHS/United States ; }, abstract = {Human replication protein A (RPA) is a heterotrimeric ssDNA binding protein responsible for many aspects of cellular DNA metabolism. Dynamic interactions of the four RPA DNA binding domains (DBDs) with DNA control replacement of RPA by downstream proteins in various cellular metabolic pathways. RPA plays several important functions at telomeres where it binds to and melts telomeric G-quadruplexes, non-canonical DNA structures formed at the G-rich telomeric ssDNA overhangs. Here, we combine single-molecule total internal reflection fluorescence microscopy (smTIRFM) and mass photometry (MP) with biophysical and biochemical analyses to demonstrate that heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1) specifically remodels RPA bound to telomeric ssDNA by dampening the RPA configurational dynamics and forming a ternary complex. Uniquely, among hnRNPA1 target RNAs, telomeric repeat-containing RNA (TERRA) is selectively capable of releasing hnRNPA1 from the RPA-telomeric DNA complex. We speculate that this telomere specific RPA-DNA-hnRNPA1 complex is an important structure in telomere protection.}, }
@article {pmid39324245, year = {2024}, author = {Sánchez-González, JL and Juárez-Vela, R and Dutil Muñoz de la Torre, V and Andrés-Olivera, MDP and Martín-Vallejo, J and Morán-Bayón, Á and Gonçalves-Cerejeira, JI and Gestoso-Uzal, N and González-Sarmiento, R and Pérez, J}, title = {Effect of strength-based physical exercise on telomere length as a marker of premature ageing in patients with schizophrenia: study protocol for a pilot randomised controlled trial.}, journal = {BJPsych open}, volume = {10}, number = {5}, pages = {e162}, doi = {10.1192/bjo.2024.753}, pmid = {39324245}, issn = {2056-4724}, abstract = {BACKGROUND: Patients with schizophrenia die decades earlier than the general population. Among the factors involved in this mortality gap, evidence suggests a telomere length shortening in this clinical population, which is associated with premature ageing. Recent studies support the use of strength-based training exercise programmes to maintain, or even elongate, telomere length in healthy elderly populations. However, studies aiming at modifying telomere length in severe mental illnesses, such as schizophrenia, are still very scarce.
AIMS: To investigate the effect of a strength-based physical exercise programme on the telomere length of individuals with schizophrenia.
METHOD: We propose a pragmatic, randomised controlled trial including 40 patients aged ≥18 years, with a stable diagnosis of schizophrenia, attending the Complejo de Rehabilitación Psicosocial (CRPS, Psychosocial Rehabilitation Centre) in Salamanca, Spain. These patients will be randomly assigned (1:1) to either receive the usual treatment and rehabilitation programmes offered by CRPS (treatment-as-usual group) or these plus twice weekly sessions of an evidence-based, strength-based training exercise programme for 12 weeks (intervention group). The primary outcome will be effect on telomere length. Secondary outcomes will include impact on cognitive function, frailty and quality of life.
RESULTS: We expect to show the importance of implementing strength-based physical exercise programmes for patients with schizophrenia. We could find that such programmes induce biological and genetic changes that may lengthen life expectancy and decrease physical fragility.
CONCLUSIONS: We anticipate that our trial findings could contribute to parity of esteem for mental health, reducing premature ageing in patients with severe mental illnesses, such as schizophrenia.}, }
@article {pmid39317127, year = {2024}, author = {Katerina, S}, title = {Telomeres and immunodeficiencies.}, journal = {Human immunology}, volume = {85}, number = {6}, pages = {111146}, doi = {10.1016/j.humimm.2024.111146}, pmid = {39317127}, issn = {1879-1166}, abstract = {The function of the immune system is highly dependent on cellular differentiation and clonal expansion of antigen-specific lymphocytes. Telomeres are conserved DNA-protein structures of linear chromosome termini. Telomere length has been investigated to be different in various lymphocyte subpopulations depending on their function and to change with aging. Association of accelerated telomere loss compared to matched controls has already been confirmed in many syndromes with immune dysregulation. Immunodeficiencies connected with dysfunction of telomere termini are dyskeratosis congenita, ICF syndrome (Immunodeficiency, centromeric instability and facial anomalies syndrome) genetic disorders involving DNA repair and disorders involving the VDJ recombination.}, }
@article {pmid39316766, year = {2024}, author = {Gutierrez-Rodrigues, F and Groarke, EM and Thongon, N and Rodriguez-Sevilla, JJ and Bazzo Catto, LF and Niewisch, MR and Shalhoub, RN and McReynolds, LJ and Clé, DV and Patel, BA and Ma, X and Hironaka, D and Donaires, FS and Spitofsky, NR and Santana, BA and Lai, TP and Alemu, L and Kajigaya, S and Darden, I and Zhou, W and Browne, PV and Paul, S and Lack, J and Young, DJ and DiNardo, CD and Aviv, A and Ma, F and Michels de Oliveira, M and Azambuja, AP and Dunbar, CE and Olszewska, M and Olivier, E and Papapetrou, EP and Giri, N and Alter, BP and Bonfim, CMS and Wu, CO and Garcia-Manero, G and Savage, SA and Young, NS and Colla, S and Calado, RT}, title = {Clonal landscape and clinical outcomes of telomere biology disorders: somatic rescuing and cancer mutations.}, journal = {Blood}, volume = {}, number = {}, pages = {}, doi = {10.1182/blood.2024025023}, pmid = {39316766}, issn = {1528-0020}, abstract = {Telomere biology disorders (TBD), caused by pathogenic germline variants in telomere-related genes, present with multi-organ disease and a predisposition to cancer. Clonal hematopoiesis (CH) as a marker of cancer development and survival in TBD is poorly understood. Here, we characterized the clonal landscape of a large cohort of 207 TBD patients with a broad range of age and phenotype. CH occurred predominantly in symptomatic patients and in signature genes typically associated with cancers: PPM1D, POT1, TERT promoter (TERTp), U2AF1S34, and/or TP53. Chromosome 1q gain (Chr1q+) was the commonest karyotypic abnormality. Clinically, multiorgan involvement and CH in TERTp, TP53, and splicing factor genes associated with poorer overall survival. Chr1q+, and splicing factor or TP53 mutations significantly increased the risk of hematologic malignancies, regardless of the clonal burden. Chr1q+ and U2AF1S34 mutated clones were pre-malignant events associated with the secondary acquisition of mutations in genes related to hematologic malignancies. Like known effects of Chr1q+ and TP53-CH, functional studies demonstrated that U2AF1S34 mutations primarily compensated for aberrant upregulation of TP53 and interferon pathways in telomere-dysfunctional hematopoietic stem cells, highlighting the TP53 pathway as a canonical route of malignancy in TBD. In contrast, somatic POT1/PPM1D/TERTp-CH had distinct trajectories unrelated to cancer development. With implications beyond TBD, our data show that telomere dysfunction is a strong selective pressure for CH. In TBD, CH is a poor prognostic marker associated with worse overall survival. The identification of key regulatory pathways that drive clonal transformation in TBD allows the identification of patients at a higher risk of cancer development.}, }
@article {pmid39312382, year = {2024}, author = {Song, T and Liu, J and Zhao, K and Li, S and Qiu, M and Zhang, M and Wang, H}, title = {The causal effect of telomere length on the risk of malignant lymphoma: A Mendelian randomization study.}, journal = {Medicine}, volume = {103}, number = {38}, pages = {e39584}, doi = {10.1097/MD.0000000000039584}, pmid = {39312382}, issn = {1536-5964}, mesh = {*Mendelian Randomization Analysis/methods ; Humans ; *Genome-Wide Association Study ; Lymphoma/genetics/epidemiology ; Hodgkin Disease/genetics/epidemiology ; Telomere/genetics ; Risk Factors ; Lymphoma, Follicular/genetics/epidemiology ; Genetic Predisposition to Disease ; Polymorphism, Single Nucleotide ; }, abstract = {Telomere length (TL) has been implicated in the risk assessment of numerous cancers in observational studies. Nevertheless, the relationship between TL and malignant lymphoma remains unclear, displaying inconsistent patterns across different studies. A summary dataset for genome-wide association study of TL and malignant lymphoma was acquired from the OpenGWAS website. An extensive 2-sample Mendelian randomization (MR) analysis was performed, encompassing various methodologies such as MR-Egger, weighted median, weighted mode, simple mode, and the primary method of inverse-variance weighting (IVW). Sensitivity evaluations were performed using the Cochran Q test, MR-Egger regression, and leave-one-out analysis. The main method IVW revealed that TL substantially increased the risk of Hodgkin lymphoma (HL; odds ratio [OR] = 2.135; 95% confidence interval [CI] = 1.181-3.859; P = .012). Both the IVW and weighted median methods indicated statistical associations between genetically predicted TL and other types of non-HL (OR = 1.671, 95% CI = 1.009-2.768, P = .045; OR = 2.310, 95% CI = 1.033-5.169, P = .042). However, there was no association between TL and diffuse large B-cell lymphoma, follicular lymphoma, or mature T/natural Killer-cell lymphoma, and sensitivity analysis revealed no heterogeneity or horizontal pleiotropy, indicating that the causal effect was robust. Our study shows that TL plays different roles in different types of lymphomas. A longer TL significantly increases the risk of HL and other types of non-HL.}, }
@article {pmid39307671, year = {2024}, author = {Lan, L and Zhang, R and Liang, Y and Chen, H and Zhao, H and Zhuo, X}, title = {Evaluating the Effect of Telomere Length on Oral and Oropharyngeal Cancer Risk Using Mendelian Randomization.}, journal = {International dental journal}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.identj.2024.07.1218}, pmid = {39307671}, issn = {1875-595X}, abstract = {INTRODUCTION: The aim of this study was to explore the causal relationship between telomere length and Oral and oropharyngeal cancers by using Mendelian randomization (MR) analysis.
METHODS: We carried out a 2-sample MR to examine the causal association between telomere length and Oral and oropharyngeal cancers. Two large genome-wide association studies (GWAS) were employed to identify single nucleotide polymorphisms (SNPs) as instrumental variables through statistical and biological approaches. The data on SNP-oral and oropharyngeal cancer risk factor associations were sourced from various consortia/UK Biobank. The inverse variance weighted (IVW) method was employed as the primary approach for overall causal estimation in MR, with sensitivity analyses conducted to assess potential confounding by pleiotropy, heterogeneity, and the leave-one-out analysis.
RESULTS: The statistically driven approach indicates limited evidence of a genetically causal effect of telomere length on the risk of oral cavity cancer (OR = 0.999, 95% CI 0.998-1.000, P = .100), oropharyngeal cancer (OR = 0.999, 95% CI 0.998-1.001, P = .650), combined oral and oropharyngeal cancer (OR = 0.999, 95% CI 0.998-1.000, P = .119) in Europeans. The biologically driven approach demonstrated consistent causal effects across all MR methods, thereby further strengthening the reliability of the results. Moreover, the MR-Egger (Q [df] 170.816 [130], P = .009) and inverse variance weighted methods (Q [df] 171.656 [131], P = .010) identified considerable heterogeneity among instrumental variable estimates in Oral cavity cancer, and no evidence of horizontal pleiotropy was detected.
CONCLUSIONS: No significant causal associations between telomere length and Oral and oropharyngeal cancers were found in this study.}, }
@article {pmid39297884, year = {2024}, author = {Chen, Z and Vallega, KA and Wang, D and Quan, Z and Fan, S and Wang, Q and Leal, T and Ramalingam, SS and Sun, SY}, title = {Inhibition of hTERT/telomerase/telomere mediates therapeutic efficacy of osimertinib in EGFR mutant lung cancer.}, journal = {The Journal of experimental medicine}, volume = {221}, number = {11}, pages = {}, doi = {10.1084/jem.20240435}, pmid = {39297884}, issn = {1540-9538}, support = {UG1 CA233259/NH/NIH HHS/United States ; /CA/NCI NIH HHS/United States ; }, mesh = {*Acrylamides/pharmacology/therapeutic use ; *Telomerase/genetics/metabolism/antagonists & inhibitors ; *Aniline Compounds/pharmacology/therapeutic use ; Humans ; *ErbB Receptors/genetics/antagonists & inhibitors/metabolism ; *Lung Neoplasms/drug therapy/genetics/pathology ; Animals ; *Telomere/metabolism/drug effects ; *Carcinoma, Non-Small-Cell Lung/drug therapy/genetics/pathology ; *Mutation ; Cell Line, Tumor ; *Drug Resistance, Neoplasm/genetics/drug effects ; Mice ; Xenograft Model Antitumor Assays ; Protein Kinase Inhibitors/pharmacology/therapeutic use ; Antineoplastic Agents/pharmacology/therapeutic use ; Indoles ; Pyrimidines ; }, abstract = {The inevitable acquired resistance to osimertinib (AZD9291), an FDA-approved third-generation EGFR tyrosine kinase inhibitor (EGFR-TKI) for the treatment of patients with advanced non-small cell lung cancer (NSCLC) harboring EGFR activating or T790M resistant mutations, limits its long-term clinical benefit. Telomere maintenance via telomerase reactivation is linked to uncontrolled cell growth and is a cancer hallmark and an attractive cancer therapeutic target. Our effort toward understanding the action mechanisms, including resistance mechanisms, of osimertinib has led to the identification of a novel and critical role in maintaining c-Myc-dependent downregulation of hTERT, a catalytic subunit of telomerase, and subsequent inhibition of telomerase/telomere and induction of telomere dysfunction in mediating therapeutic efficacy of osimertinib. Consequently, osimertinib combined with the telomere inhibitor, 6-Thio-dG, which is currently tested in a phase II trial, effectively inhibited the growth of osimertinib-resistant tumors, regressed EGFRm NSCLC patient-derived xenografts, and delayed the emergence of acquired resistance to osimertinib, warranting clinical validation of this strategy to manage osimertinib acquired resistance.}, }
@article {pmid39303890, year = {2024}, author = {Ma, K and Zhu, M and Zhang, A and Zuo, M and Huang, Y and Wan, Y and Tao, F and Sun, Y}, title = {Intergenerational continuation of parent-child separation and 1-year telomere length attrition among mother-offspring dyads in rural China: The moderating effects of resilience.}, journal = {Journal of affective disorders}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jad.2024.09.098}, pmid = {39303890}, issn = {1573-2517}, abstract = {BACKGROUND: Although stressor exposure early in life was known risk factor for telomere length (TL) attrition, limited literature explored it across generations. Furthermore, the effects of resilience have rarely been examined. Here, we examined whether the effects of intergenerational parent-child separation on offspring 1-year TL attrition vary by the levels of resilience.
METHOD: In a sample of 342 mother-child dyads living in rural China, the intergenerational continuation of parent-child separation was defined as the two generations both experiencing parent-child separation from both parents for >6 months a year early in life assessed by the parent-reported questionnaire, whereas intergenerational discontinuity refers to parent-child separation exposed in one generation only. TL was measured at baseline (from June to November 2021) and 1-year later with children's buccal mucosa swabs, with resilience polygenic risk scores (PRS) evaluated based on 4 single-nucleotide variations in 4 resilience-related genes (OXTR, FKBP5, NPY, and TNF-α).
RESULTS: Among 342 mother-offspring dyads, 35 (10.2 %) experienced intergenerational continuation of parent-child separation, and 139 (40.6 %) were identified as discontinuous. Remarkably, a 0.12-point reduction in TL attrition was only associated with intergenerational continuation of parent-child separation (95 % CI: 0.04, 0.21, P < 0.01) but not discontinuity. Importantly, the association between intergenerational continuation of parent-child separation with accelerated TL attrition disappeared in offspring with high resilience PRS (β = 0.07, 95%CI: -0.06, 0.21).
CONCLUSION: Our findings highlight the importance of breaking the intergenerational cycle of parent-child separation and the moderating effects of resilience on TL attrition for children exposed to adversity.}, }
@article {pmid39303531, year = {2024}, author = {Hailu, EM and Gao, X and Needham, BL and Seeman, T and Lewis, TT and Mujahid, MS}, title = {Associations between historical and contemporary measures of structural racism and leukocyte telomere length: The Multi-Ethnic Study of Atherosclerosis (MESA).}, journal = {Social science & medicine (1982)}, volume = {360}, number = {}, pages = {117229}, doi = {10.1016/j.socscimed.2024.117229}, pmid = {39303531}, issn = {1873-5347}, abstract = {BACKGROUND: We assessed the link between two manifestations of structural racism-historical redlining and contemporary racial residential segregation-and baseline and 10-year changes in leukocyte telomere length (LTL).
METHODS: We used data on Black and Hispanic/Latinx participants from Exams I and V of the Multi-Ethnic Study of Atherosclerosis Stress Ancillary Study (N = 741, age range = 45-84 years). LTL was defined as the ratio of telomeric DNA to a single copy gene (T/S), and 10-year changes were adjusted for regression to the mean. We used 1930s Home Owners' Loan Corporation maps to assign three historical redlining grades (A&B: best/still desirable, C: declining, D: hazardous/redlined) to participants' neighborhoods (census-tracts) at baseline. The Getis-Ord Gi∗ statistic was used to evaluate census-tract level baseline residential segregation (low/moderate/high).
RESULTS: In mixed-effects regression models accounting for neighborhood clustering, individual characteristics, and current neighborhood environments, those living in highly segregated Black neighborhoods had 0.08 shorter baseline LTL (95% CI: -0.13, -0.04), than those residing in the least segregated neighborhoods. We did not find a relationship between residing in segregated neighborhoods and 10-year LTL changes, and associations between residing in historically redlined neighborhoods and both baseline LTL and 10-year changes in LTL were null. Across discriminatory disinvestment trajectories examined, individuals residing in highly segregated but non-redlined neighborhoods had 0.6 shorter baseline LTL than individuals residing in non-redlined neighborhoods with low/moderate segregation (95% CI: -0.12, -0.01).
CONCLUSIONS: Our results highlight the impact of racial segregation on cellular aging and underscore the need to ameliorate structural inequities within segregated neighborhoods.}, }
@article {pmid39303078, year = {2024}, author = {Zhang, J and Liu, S and Zhao, S and Nie, Y and Zhang, Z}, title = {A telomere-to-telomere haplotype-resolved genome of white-fruited strawberry reveals the complexity of fruit colour formation of cultivated strawberry.}, journal = {Plant biotechnology journal}, volume = {}, number = {}, pages = {}, doi = {10.1111/pbi.14479}, pmid = {39303078}, issn = {1467-7652}, support = {RC220306//Shenyang Young and Middle-aged Science and Technology Innovation Talents Support Plan/ ; 2023020525-JH1/102-02//sub-project of Liaoning Province Germplasm Innovation Grain Storage and Technology Special Program/ ; 32130092//National Natural Science Foundation of China/ ; 32272681//National Natural Science Foundation of China/ ; }, }
@article {pmid39296266, year = {2024}, author = {Froney, MM and Cook, CR and Cadiz, AM and Flinter, KA and Ledeboer, ST and Chan, B and Burris, LE and Hardy, BP and Pearce, KH and Wardell, AC and Golitz, BT and Jarstfer, MB and Pattenden, SG}, title = {A First-in-Class High-Throughput Screen to Discover Modulators of the Alternative Lengthening of Telomeres (ALT) Pathway.}, journal = {ACS pharmacology & translational science}, volume = {7}, number = {9}, pages = {2799-2819}, pmid = {39296266}, issn = {2575-9108}, abstract = {Telomeres are a protective cap that prevents chromosome ends from being recognized as double-stranded breaks. In somatic cells, telomeres shorten with each cell division due to the end replication problem, which eventually leads to senescence, a checkpoint proposed to prevent uncontrolled cell growth. Tumor cells avoid telomere shortening by activating one of two telomere maintenance mechanisms (TMMs): telomerase reactivation or alternative lengthening of telomeres (ALT). TMMs are a viable target for cancer treatment as they are not active in normal, differentiated cells. Whereas there is a telomerase inhibitor currently undergoing clinical trials, there are no known ALT inhibitors in development, partially because the complex ALT pathway is still poorly understood. For cancers such as neuroblastoma and osteosarcoma, the ALT-positive status is associated with an aggressive phenotype and few therapeutic options. Thus, methods that characterize the key biological pathways driving ALT will provide important mechanistic insight. We have developed a first-in-class phenotypic high-throughput screen to identify small-molecule inhibitors of ALT. Our screen measures relative C-circle level, an ALT-specific biomarker, to detect changes in ALT activity induced by compound treatment. To investigate epigenetic mechanisms that contribute to ALT, we screened osteosarcoma and neuroblastoma cells against an epigenetic-targeted compound library. Hits included compounds that target chromatin-regulating proteins and DNA damage repair pathways. Overall, the high-throughput C-circle assay will help expand the repertoire of potential ALT-specific therapeutic targets and increase our understanding of ALT biology.}, }
@article {pmid39292074, year = {2024}, author = {Pérez-López, FR and Fernández-Alonso, AM and Ulloque-Badaracco, JR and Benites-Zapata, VA and Varikasuvu, SR}, title = {Telomere length in subjects with and without SARS-CoV-2 infection: a systematic review and meta-analysis.}, journal = {Revista da Associacao Medica Brasileira (1992)}, volume = {70}, number = {9}, pages = {e20240387}, doi = {10.1590/1806-9282.20240387}, pmid = {39292074}, issn = {1806-9282}, mesh = {Humans ; *COVID-19 ; *SARS-CoV-2 ; Telomere/genetics ; Telomere Shortening ; }, }
@article {pmid39291738, year = {2024}, author = {Zheng, YL and Wu, X and Williams, M and Verhulst, S and Lin, J and Takahashi, Y and Ma, JX and Wang, Y}, title = {High-throughput single telomere analysis using DNA microarray and fluorescent in situ hybridization.}, journal = {Nucleic acids research}, volume = {}, number = {}, pages = {}, doi = {10.1093/nar/gkae812}, pmid = {39291738}, issn = {1362-4962}, support = {U01ES011786//National Institute of Health/ ; //Georgetown University/ ; }, abstract = {The human telomere system is highly dynamic. Both short and long leucocyte average telomere lengths (aTL) are associated with an increased risk of cancer and early death, illustrating the complex relationship between TL and human health and the importance of assessing TL distributions with single TL analysis. A DNA microarray and telomere fluorescent in situ hybridization (DNA-array-FISH) approach was developed to measure the base-pair (bp) lengths of single telomeres. On average 32000 telomeres were measured per DNA sample with one microarray chip assaying 96 test DNA samples. Various telomere parameters, i.e. aTL and the frequency of short/long telomeres, were computed to delineate TL distribution. The intra-assay and inter-assay coefficient of variations of aTL ranged from 1.37% to 3.98%. The correlation coefficient (r) of aTL in repeated measurements ranged from 0.91 to 1.00, demonstrating high measurement precision. aTLs measured by DNA-array-FISH predicted aTLs measured by terminal restriction fragment (TRF) analysis with r ranging 0.87-0.99. A new accurate and high-throughput method has been developed to measure the bp lengths of single telomeres. The large number of single TL data provides an opportunity for an in-depth analysis of telomere dynamics and the complex relationship between telomere and age-related diseases.}, }
@article {pmid39291733, year = {2024}, author = {Kim, S and Park, SH and Kang, N and Ra, JS and Myung, K and Lee, KY}, title = {Polyubiquitinated PCNA triggers SLX4-mediated break-induced replication in alternative lengthening of telomeres (ALT) cancer cells.}, journal = {Nucleic acids research}, volume = {}, number = {}, pages = {}, doi = {10.1093/nar/gkae785}, pmid = {39291733}, issn = {1362-4962}, support = {IBS-R022-D1//Institute for Basic Science/ ; //National Research Foundation of Korea/ ; RS-2023-00251939//MSIT/ ; //National Research Foundation of Korea/ ; }, abstract = {Replication stresses are the major source of break-induced replication (BIR). Here, we show that in alternative lengthening of telomeres (ALT) cells, replication stress-induced polyubiquitinated proliferating cell nuclear antigen (PCNA) (polyUb-PCNA) triggers BIR at telomeres and the common fragile site (CFS). Consistently, depleting RAD18, a PCNA ubiquitinating enzyme, reduces the occurrence of ALT-associated promyelocytic leukemia (PML) bodies (APBs) and mitotic DNA synthesis at telomeres and CFS, both of which are mediated by BIR. In contrast, inhibiting ubiquitin-specific protease 1 (USP1), an Ub-PCNA deubiquitinating enzyme, results in an increase in the above phenotypes in a RAD18- and UBE2N (the PCNA polyubiquitinating enzyme)-dependent manner. Furthermore, deficiency of ATAD5, which facilitates USP1 activity and unloads PCNAs, augments recombination-associated phenotypes. Mechanistically, telomeric polyUb-PCNA accumulates SLX4, a nuclease scaffold, at telomeres through its ubiquitin-binding domain and increases telomere damage. Consistently, APB increase induced by Ub-PCNA depends on SLX4 and structure-specific endonucleases. Taken together, our results identified the polyUb-PCNA-SLX4 axis as a trigger for directing BIR.}, }
@article {pmid39287993, year = {2024}, author = {Li, W and Chen, H and Yuan, X and Yao, Q and Zhang, M}, title = {Study of the role of leukocyte telomere length-related lncRNA NBR2 in Alzheimer's disease.}, journal = {Aging}, volume = {16}, number = {}, pages = {}, doi = {10.18632/aging.206107}, pmid = {39287993}, issn = {1945-4589}, abstract = {Alzheimer's Syndrome (AD) is a neurodegenerative disease that is prevalent in middle-aged and elderly people. As the disease progresses, patients gradually lose the ability to take care of themselves, which brings a heavy burden to the family. There is a link between leukocyte telomere length (LTL) and cognitive ability. To search for possible pathogenic mechanisms and potential therapeutic agents, we demonstrated a causal link between LTL and AD using Mendelian randomization analysis (MR). The expression of the target gene NBR2 and the downstream mRNA GJA1 and GJA1-related genes, pathway enrichment, and association with immune cells were further explored. Using the gene cluster-drug target interaction network, we obtained potential therapeutic drugs. Our study provides evidence for a causal link between AD and LTL, suggesting medicines that may treat and alleviate AD symptoms.}, }
@article {pmid39284832, year = {2024}, author = {Zhao, J and Yang, K and Lu, Y and Zhou, L and Fu, H and Feng, J and Wu, J}, title = {Proteomic Mendelian randomization to identify protein biomarkers of telomere length.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {21594}, pmid = {39284832}, issn = {2045-2322}, mesh = {Humans ; *Mendelian Randomization Analysis ; *Biomarkers/blood ; *Genome-Wide Association Study ; *Quantitative Trait Loci ; *Proteomics/methods ; Telomere Homeostasis ; Telomere/metabolism/genetics ; Proteome/metabolism ; Blood Proteins/genetics/metabolism ; Telomere Shortening ; }, abstract = {Shortening of telomere length (TL) is correlated with many age-related disorders and is a hallmark of biological aging. This study used proteome-wide Mendelian randomization to identify the protein biomarkers associated with telomere length. Protein quantitative trait loci (pQTL) were derived from two studies, the deCODE Health study (4907 plasma proteins) and the UK Biobank Pharma Proteomics Project (2923 plasma proteins). Summary data from genome-wide association studies (GWAS) for TL were obtained from the UK Biobank (472,174 cases) and GWAS Catalog (418,401 cases). The association between proteins and TL was further assessed using colocalization and summary data-based Mendelian randomization (SMR) analyses. The protein-protein network, druggability assessment, and phenome-wide MR were used to further evaluate the potential biological effects, druggability, and safety of the target proteins. Proteome-wide MR analysis identified 22 plasma proteins that were causally associated with telomere length. Five of these proteins (APOE, SPRED2, MAX, RALY, and PSMB1) had the highest evidence of association with TL and should be prioritized. This study revealed telomere length-related protein biomarkers, providing new insights into the development of new treatment targets for chronic diseases and anti-aging intervention strategies.}, }
@article {pmid39283687, year = {2024}, author = {Yin, D and Chen, C and Lin, D and Hua, Z and Ying, C and Zhang, J and Zhao, C and Liu, Y and Cao, Z and Zhang, H and Wang, C and Liang, L and Xu, P and Jian, J and Liu, K}, title = {Telomere-to-telomere gap-free genome assembly of the endangered Yangtze finless porpoise and East Asian finless porpoise.}, journal = {GigaScience}, volume = {13}, number = {}, pages = {}, doi = {10.1093/gigascience/giae067}, pmid = {39283687}, issn = {2047-217X}, support = {2021YFD1200304//National Key Research and Development of China/ ; }, mesh = {*Porpoises/genetics ; *Telomere/genetics ; Animals ; *Genome ; Endangered Species ; Phylogeny ; Genomics/methods ; East Asian People ; }, abstract = {BACKGROUND: The Yangtze finless porpoise (Neophocaena asiaeorientalis asiaeorientalis, YFP) and the East Asian finless porpoise (Neophocaena asiaeorientalis sunameri, EFP) are 2 subspecies of the narrow-ridged finless porpoise that live in freshwater and saltwater, respectively. The main objective of this study was to provide contiguous chromosome-level genome assemblies for YFP and EFP.
RESULTS: Here, we generated and upgraded the genomes of YFP and EFP at the telomere-to-telomere level through the integration of PacBio HiFi long reads, ultra-long ONT reads, and Hi-C sequencing data with a total size of 2.48 Gb and 2.50 Gb, respectively. The scaffold N50 of 2 genomes was 125.12 Mb (YFP) and 128 Mb (EFP) with 1 contig for 1 chromosome. The telomere repeat and centromere position were clearly identified in both YFP and EFP genomes. In total, 5,480 newfound genes were detected in the YFP genome, including 56 genes located in the newly identified centromere regions. Additionally, synteny blocks, structural similarities, phylogenetic relationships, gene family expansion, and inference of selection were studied in connection with the genomes of other related mammals.
CONCLUSIONS: Our research findings provide evidence for the gradual adaptation of EFP in a marine environment and the potential sensitivity of YFP to genetic damage. Compared to the 34 cetacean genomes sourced from public databases, the 2 new assemblies demonstrate superior continuity with the longest contig N50 and scaffold N50 values, as well as the lowest number of contigs. The improvement of telomere-to-telomere gap-free reference genome resources supports conservation genetics and population management for finless porpoises.}, }
@article {pmid39279436, year = {2024}, author = {Thompson, AS and Niewisch, MR and Giri, N and McReynolds, LJ and Savage, SA}, title = {Germline RTEL1 Variants in Telomere Biology Disorders.}, journal = {American journal of medical genetics. Part A}, volume = {}, number = {}, pages = {e63882}, doi = {10.1002/ajmg.a.63882}, pmid = {39279436}, issn = {1552-4833}, support = {//Division of Cancer Epidemiology and Genetics, National Cancer Institute/ ; }, abstract = {Rare germline variation in regulator of telomere elongation helicase 1 (RTEL1) is associated with telomere biology disorders (TBDs). Biallelic RTEL1 variants result in childhood onset dyskeratosis congenita and Hoyeraal-Hreidarsson syndrome whereas heterozygous individuals usually present later in life with pulmonary fibrosis or bone marrow failure. We compiled all TBD-associated RTEL1 variants in the literature and assessed phenotypes and outcomes of 44 individuals from 14 families with mono- or biallelic RTEL1 variants enrolled in clinical trial NCT00027274. Variants were classified by adapting ACMG-AMP guidelines using clinical information, telomere length, and variant allele frequency data. Compared with heterozygotes, individuals with biallelic RTEL1 variants had an earlier age at diagnosis (median age 35.5 vs. 5.1 years, p < 0.01) and worse overall survival (median age 66.5 vs. 22.9 years, p < 0.001). There were 257 unique RTEL1 variants reported in 47 publications, and 209 had a gnomAD minor allele frequency <1%. Only 38.3% (80/209) met pathogenic/likely pathogenic criteria. Notably, 8 of 209 reported disease-associated variants were benign or likely benign and the rest were variants of uncertain significance. Given the considerable differences in outcomes of TBDs associated with RTEL1 germline variants and the extent of variation in the gene, systematic functional studies and standardization of variant curation are urgently needed to inform clinical management.}, }
@article {pmid39279213, year = {2024}, author = {Maillet, F and Galimard, JE and Borie, R and Lainey, E and Larcher, L and Passet, M and Plessier, A and Leblanc, T and Terriou, L and Lebon, D and Alcazer, V and Cathebras, P and Loschi, M and Wadih, AC and Marcais, A and Marceau-Renaut, A and Couque, N and Lioure, B and Soulier, J and Ba, I and Socié, G and Peffault de Latour, R and Kannengiesser, C and Sicre de Fontbrune, F}, title = {Haematological features of telomere biology disorders diagnosed in adulthood: A French nationwide study of 127 patients.}, journal = {British journal of haematology}, volume = {}, number = {}, pages = {}, doi = {10.1111/bjh.19767}, pmid = {39279213}, issn = {1365-2141}, abstract = {Data on haematological features of telomere biology disorders (TBD) remain scarce. We describe haematological, extra-haematological characteristics and prognosis of 127 genetically confirmed TBD patients diagnosed after the age of 15. Ninety-three index cases and 34 affected relatives were included. At diagnosis of TBD, 76.3% of index cases had haematological features, half pulmonary features and a third liver features. At diagnosis, bone marrow failure (BMF) was present in 59 (46.5%), myelodysplastic syndrome (MDS) in 22 (17.3%) and acute myeloid leukaemia (AML) in 2 (1.6%) while 13 (10.2%) developed or worsened bone marrow involvement during follow-up. At diagnosis, compared to MDS/AML patients, BMF patients were younger (median 23.1 years vs. 43.8, p = 0.007), and had a better outcome (4-year overall survival 76.3% vs. 31.8%, p < 0.001). While frequencies and burden of cytogenetical and somatic mutations increased significantly in myeloid malignancies, some abnormalities were also observed in patients with normal blood counts and BMF, notably somatic spliceosome variants. Solid cancers developed in 8.7% patients, mainly human papillomavirus-related cancers and hepatocellular carcinomas. TBD is a multiorgan progressive disease. While BMF is the main haematological disorder, high-risk myeloid malignancies are common, and are, together with age, the only factors associated with a worse outcome.}, }
@article {pmid39267212, year = {2024}, author = {Rivera, AS and Chao, CR and Hechter, RC}, title = {Disparities in Telomere length by Sexual Orientation in Adults from the Genetic Epidemiology Research on Aging Cohort.}, journal = {American journal of epidemiology}, volume = {}, number = {}, pages = {}, doi = {10.1093/aje/kwae352}, pmid = {39267212}, issn = {1476-6256}, abstract = {The weathering hypothesis proposes that marginalized people experience faster biologic aging due to cumulative stress which translates to chronic disease disparities. We assessed telomere length (TL) differences, an aging biomarker, by sexual orientation (bisexual, gay/lesbian, straight) among 102,258 individuals enrolled in the Resource for Genetic Epidemiology Research on Aging Cohort during 2008 through 2011 (mean age of 60.6 years, 58% female, and 7.6% bisexual/gay/lesbian). We used linear models to estimate differences in telomere length, stratified by sex/gender and adjusted for age (at salivary sample) and socio-demographic variables and Kitagawa-Blinder-Oaxaca decomposition to quantify contributions of participant factors on TL differences. Among females, there was no significant difference in age-adjusted telomere length by sexual orientation after adjustment for socio-demographics (ref: straight; bisexual 0.007, 95%CI: -0.03 to 0.04; lesbian: 0.005, 95%CI: -0.02 to 0.03). Among males, only gay (-0.04, 95%CI: -0.06 to -0.02) but not bisexual (-0.02, 95%CI: -0.06 to 0.02) men had significantly shorter age-adjusted telomere length compared to straight men after adjusting for socio-demographic variables. Decomposition analysis identified ever smoking and marital status as significant drivers of the gay-straight disparity. Studies confirming our findings are needed and the implications of shorter telomeres on gay men's health requires further investigation.}, }
@article {pmid39275278, year = {2024}, author = {de Jaeger, C and Kruiskamp, S and Voronska, E and Lamberti, C and Baramki, H and Beaudeux, JL and Cherin, P}, title = {A Natural Astragalus-Based Nutritional Supplement Lengthens Telomeres in a Middle-Aged Population: A Randomized, Double-Blind, Placebo-Controlled Study.}, journal = {Nutrients}, volume = {16}, number = {17}, pages = {}, doi = {10.3390/nu16172963}, pmid = {39275278}, issn = {2072-6643}, mesh = {Humans ; Double-Blind Method ; Middle Aged ; *Dietary Supplements ; Male ; Female ; *Astragalus Plant/chemistry ; *Telomere/drug effects ; *Telomerase/metabolism ; Telomere Homeostasis/drug effects ; Telomere Shortening/drug effects ; }, abstract = {Telomeres are ribonucleoprotein structures that form a protective buffer at the ends of chromosomes, maintaining genomic integrity during the cell cycle. A decrease in average telomere length is associated with with age and with aging-related diseases such as cancer and cardiovascular disease. In this study, we conducted a randomized, double-blind, placebo-controlled trial over six months to compare the effects of the Astragalus-based supplement versus a placebo on telomere length (TL) in 40 healthy volunteers (mean age 56.1 ± 6.0 years). Twenty subjects received the supplement, and 20 received placebo capsules. All participants completed the study, and no adverse side effects were reported at six months. Subjects taking the Astragalus-based supplement exhibited significantly longer median TL (p = 0.01) and short TL (p = 0.004), along with a lower percentage of short telomeres, over the six-month period, while the placebo group showed no change in TL. This trial confirmed that the supplement significantly lengthens both median and short telomeres by increasing telomerase activity and reducing the percentage of short telomeres (<3 Kbp) in a statistically and possibly clinically significant manner. These results align with a previous open prospective trial, which found no toxicity associated with the supplement's intake. These findings suggest that this Astragalus-based supplement warrants further investigation for its potential benefits in promoting health, extending life expectancy, and supporting healthy aging.}, }
@article {pmid39273401, year = {2024}, author = {Dratwa-Kuzmin, M and Hadra, BA and Oguz, F and Ogret, Y and Constantinescu, I and Apostol, D and Talangescu, A and Constantinescu, AE and Maruntelu, I and Kościńska, K and Lukanov, T and Naumova, E and Bogunia-Kubik, K}, title = {Telomere Length, HLA, and Longevity-Results from a Multicenter Study.}, journal = {International journal of molecular sciences}, volume = {25}, number = {17}, pages = {}, doi = {10.3390/ijms25179457}, pmid = {39273401}, issn = {1422-0067}, mesh = {Humans ; *Longevity/genetics ; Aged ; Middle Aged ; Male ; Adult ; Female ; Aged, 80 and over ; Adolescent ; *HLA Antigens/genetics ; Young Adult ; Telomere/genetics ; Alleles ; Telomere Homeostasis ; Aging/genetics/immunology ; Haplotypes ; }, abstract = {Aging is an exceptionally complex process that depends on genetic, environmental, and lifestyle factors. Previous studies within the International HLA and Immunogenetics Workshop (IHIWS) component "Immunogenetics of Ageing" showed that longevity is associated with positive selection of HLA-DRB1*11- and DRB1*16-associated haplotypes, shown to be protective against diseases. Within the 18th IHIWS, we aimed to investigate the relevance of telomere length for successful aging and its association with classical HLAs. In total 957 individuals from Bulgaria, Turkey, Romania, and Poland in two age groups, elderly individuals (age 65-99 years) and ethnically matched young group (age 18-64 years), were investigated. The obtained results confirmed interpopulation differences in the distribution of HLA alleles, documented the lengths of telomeres in analyzed populations, and demonstrated significant associations of telomere length with aging as well as with the presence of some HLA class I or class II alleles. They suggest that telomere length assessment combined with HLA genotyping may help identify immunogenetic profiles associated with longevity. The associations between HLA and telomeres support the theory that HLA genes influence the aging process. However, further research is needed to clarify the biological basis of the observed relationships.}, }
@article {pmid39265426, year = {2024}, author = {Edzie, J and Alcala, C and Bloomquist, TR and Gutierrez-Avila, I and Just, AC and Midya, V and Téllez Rojo, MM and Estrada-Gutierrez, G and Wright, RJ and Wright, RO and Baccarelli, AA and Rosa, MJ}, title = {Prenatal and early life exposure to fine particulate matter and telomere length in early childhood.}, journal = {International journal of hygiene and environmental health}, volume = {263}, number = {}, pages = {114447}, doi = {10.1016/j.ijheh.2024.114447}, pmid = {39265426}, issn = {1618-131X}, abstract = {BACKGROUND: Telomere length is a biomarker of molecular aging that may be impacted by air pollution exposure starting in utero. We aimed to examine the association between prenatal and early life exposure to fine particulate matter (PM2.5) and leukocyte telomere length (LTL) in children and explore sex differences.
METHODS: Analyses included 384 mother-child pairs enrolled in the Programming Research in Obesity, Growth, and Environmental Stressors (PROGRESS) birth cohort in Mexico City. Exposure to PM2.5 was estimated at the residential level using a satellite based spatio-temporally resolved prediction model. Average relative LTL was measured in DNA isolated from blood collected at age 4-6 years using quantitative real-time polymerase chain reaction. Linear regression models were used to examine the association between average PM2.5 across pregnancy, individual trimesters, first postnatal year, and LTL. Models were adjusted for maternal age and education at enrollment, prenatal environmental tobacco smoke exposure, child sex, age, and body mass index z-score at LTL measurement. Effect modification by sex was investigated with interaction terms and stratification.
RESULTS: In trimester specific models, we found an association between 2nd trimester PM2.5 and elongated LTL (β: 4.34, 95%CI [0.42, 8.42], per 5 μg/m[3] increase). There was suggestive effect modification by sex on average 2nd trimester PM2.5 with stronger associations seen in females compared to males (β: 7.12, [95%CI: 0.98, 13.6] and β: 1.43 [95%CI: -3.46, 6.57]) per 5 μg/m[3] increase respectively.
CONCLUSION: Second trimester PM2.5 levels were associated with changes in LTL in early childhood. Understanding temporal and sex differences in PM2.5 exposure may provide insights into telomere dynamics over early life.}, }
@article {pmid39261898, year = {2024}, author = {Zhao, W and Li, B and Zhang, M and Zhou, P and Zhu, Y}, title = {As a novel prognostic model for breast cancer, the identification and validation of telomere-related long noncoding RNA signatures.}, journal = {World journal of surgical oncology}, volume = {22}, number = {1}, pages = {245}, pmid = {39261898}, issn = {1477-7819}, support = {PW2023A-18//Pudong New Area Health Research General Project/ ; PWRd2023-10//Pudong New District Health Committee Discipline Leader Program/ ; }, abstract = {BACKGROUND: Telomeres are a critical component of chromosome integrity and are essential to the development of cancer and cellular senescence. The regulation of breast cancer by telomere-associated lncRNAs is not fully known, though. The goals of this study were to describe predictive telomere-related LncRNAs (TRL) in breast cancer and look into any possible biological roles for these RNAs.
METHODS: We obtained RNA-seq data, pertinent clinical data, and a list of telomere-associated genes from the cancer genome atlas and telomere gene database, respectively. We subjected differentially expressed TRLs to co-expression analysis and univariate Cox analysis to identify a prognostic TRL. Using LASSO regression analysis, we built a prognostic model with 14 TRLs. The accuracy of the model's prognostic predictions was evaluated through the utilization of Kaplan-Meier (K-M) analysis as well as receiver operating characteristic (ROC) curve analysis. Additionally, immunological infiltration and immune drug prediction were done using this model. Patients with breast cancer were divided into two subgroups using cluster analysis, with the latter analyzed further for variations in response to immunotherapy, immune infiltration, and overall survival, and finally, the expression of 14-LncRNAs was validated by RT-PCR.
RESULTS: We developed a risk model for the 14-TRL, and we used ROC curves to demonstrate how accurate the model is. The model may be a standalone prognostic predictor for patients with breast cancer, according to COX regression analysis. The immune infiltration and immunotherapy results indicated that the high-risk group had a low level of PD-1 sensitivity and a high number of macrophages infiltrating. In addition, we've discovered a number of small-molecule medicines with considerable for use in treating high-risk groups. The cluster 2 subtype showed the highest immune infiltration, the highest immune checkpoint expression, and the worst prognosis among the two subtypes defined by cluster analysis, which requires more attention and treatment.
CONCLUSION: As a possible biomarker, the proposed 14-TRL signature could be utilized to evaluate clinical outcomes and treatment efficacy in breast cancer patients.}, }
@article {pmid39256983, year = {2024}, author = {Musa, I and Yang, N and Breslin, J and Paulden, O and Geliebter, J and Tiwari, R and Li, XM}, title = {Inhibition of Myeloma Cell Function by Cannabinoid-Enriched Product Associated With Regulation of Telomere and TP53.}, journal = {Integrative cancer therapies}, volume = {23}, number = {}, pages = {15347354241267979}, doi = {10.1177/15347354241267979}, pmid = {39256983}, issn = {1552-695X}, mesh = {Humans ; *Multiple Myeloma/drug therapy ; Cell Line, Tumor ; *Telomere/drug effects/metabolism ; *Tumor Suppressor Protein p53/metabolism ; *Cannabinoids/pharmacology ; *Telomerase/metabolism ; Cell Survival/drug effects ; NF-kappa B/metabolism ; Immunoglobulin E ; Immunoglobulin G ; Cell Proliferation/drug effects ; Gene Expression Regulation, Neoplastic/drug effects ; }, abstract = {Multiple myeloma is a hematological cancer caused by the uncontrolled proliferation of abnormal plasma cells in the bone marrow, leading to excessive immunoglobulin production. Our study aimed to examine the anticancer properties of BRF1A, a cannabinoid (CBD)-enriched product, on 2 myeloma cell lines: U266 and ARH-7. We treated U266 and ARH-77 myeloma cells with varying doses of BRF1A and measured the production of IgE and IgG antibodies using ELISA. Cell viability was assessed using trypan blue and CCK-8 assays. We measured the expression of genes related to the production of IgE and IgG antibodies, IgEH, and IgGH. We determined its effect on the expression of telomerase and its phosphorylated form as an indicator of telomere stabilization. Furthermore, we determined its effect on other cancer-related targets such as NF-ĸB, c-Myc, and TP53 in U266 cells using reverse transcription polymerase chain reaction (RT-PCR) and western blotting. BRF1A reduced myeloma cell IgE and IgG production in a time and dose-dependent manner. It also suppressed the expression of p-IκBα, p-NFκB (p65), and total NFκB protein, as well as XBP1u and XBP1s. It increased the gene and protein expression of telomere and hTERT and significantly increased cancer suppressor TP53 gene and p53 protein expression. Additionally, BRF1A decreased the c-Myc gene and protein expression. Our study has shown that a CBD-enriched product can reduce the growth of myeloma cells by suppressing the critical functions of IgE- and IgG-producing cells. This study could help bridge the gap in understanding how cannabinoid-containing products affect cancer, aging, telomere, and cancer-suppressor gene activity.}, }
@article {pmid39256139, year = {2024}, author = {Pepke, ML and Hansen, SB and Limborg, MT}, title = {Telomere dynamics as mediators of gut microbiota-host interactions.}, journal = {Trends in cell biology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.tcb.2024.08.003}, pmid = {39256139}, issn = {1879-3088}, abstract = {The highly proliferative gut tissue exhibits rapid telomere shortening with systemic effects on the host organism. Recent studies have demonstrated a bidirectionality in interactions between intestinal telomere length dynamics and the composition and activity of the gut microbiome thus linking processes of inflammation, dysbiosis and aging across different vertebrate species.}, }
@article {pmid39253978, year = {2024}, author = {Carr, L and Norris, K and Parker, H and Nilsson-Takeuchi, A and Bryant, D and Amarasinghe, H and Kadalayil, L and Else, M and Pettitt, A and Hillmen, P and Schuh, A and Walewska, R and Baird, DM and Oscier, DG and Oakes, CC and Gibson, J and Pepper, C and Strefford, JC}, title = {Telomere length and DNA methylation epitype both provide independent prognostic information in CLL patients; data from the UK CLL4, ARCTIC and ADMIRE clinical trials.}, journal = {British journal of haematology}, volume = {}, number = {}, pages = {}, doi = {10.1111/bjh.19765}, pmid = {39253978}, issn = {1365-2141}, support = {Cancer Research UK Southampton Centre grant C34999/CRUK_/Cancer Research UK/United Kingdom ; ECRIN-M3 accelerator award C42023/A29370/CRUK_/Cancer Research UK/United Kingdom ; programme C2750/A23669/CRUK_/Cancer Research UK/United Kingdom ; }, }
@article {pmid39253325, year = {2024}, author = {Liu, J and Pan, R}, title = {Genetic liability to human serum metabolites is causally linked to telomere length: insights from genome-wide Mendelian randomization and metabolic pathways analysis.}, journal = {Frontiers in nutrition}, volume = {11}, number = {}, pages = {1458442}, doi = {10.3389/fnut.2024.1458442}, pmid = {39253325}, issn = {2296-861X}, abstract = {BACKGROUND: Telomere has been recognized as a biomarker of accelerating aging, and telomere length (TL) shortening is closely related to diverse chronic illnesses. Human serum metabolites have demonstrated close correlations with TL maintenance or shortening in observational studies. Nevertheless, little is known about the underlying pathological mechanisms, and Mendelian randomization (MR) analysis of serum metabolites may provide a more comprehensive understanding of the potential biological process.
METHODS: We employed a two-sample MR analysis method to assess the causal links between 486 serum metabolites and TL. We applied the inverse-variance weighted (IVW) approach as our primary analysis, and to assure the stability and robustness of our results, additional analysis methods including the weighted median, MR-Egger, and weighted mode were conducted. MR-Egger intercept test was utilized to detect the pleiotropy. Cochran's Q test was implemented to quantify the extent of heterogeneity. Furthermore, the pathway analysis was conducted to identify potential metabolic pathways.
RESULTS: We identified 11 known blood metabolites associated with TL. Among these metabolites, four were lipid (taurocholate, dodecanedioate, 5,8-tetradecadienoate, and 15-methylpalmitate), one amino acid (levulinate (4-oxovaleate)), one carbohydrate (lactate), one nucleotide (pseudouridine), one energy (phosphate), and three xenobiotics (2-hydroxyacetaminophen sulfate, paraxanthine, and ergothioneine). The known protective metabolites included levulinate (4-oxovaleate), dodecanedioate, 5,8-tetradecadienoate, lactate, phosphate, paraxanthine, and ergothioneine. Multiple metabolic pathways have been identified as being implicated in the maintenance of telomere length.
CONCLUSION: Our MR analysis provided suggestive evidence supporting the causal relationships between 11 identified blood metabolites and TL, necessitating further exploration to clarify the mechanisms by which these serum metabolites and metabolic pathways may affect the progression of telomeres.}, }
@article {pmid39252519, year = {2024}, author = {Furui, Y and Saito, S and Maruyama, Y and Okura, E and Hirabayashi, K and Tanaka, M and Nakazawa, Y}, title = {Successful ibrutinib treatment for pulmonary involvement in a post-transplant patient with inherited bone marrow failure syndrome and very short telomeres.}, journal = {Pediatric blood & cancer}, volume = {}, number = {}, pages = {e31314}, doi = {10.1002/pbc.31314}, pmid = {39252519}, issn = {1545-5017}, }
@article {pmid39250995, year = {2024}, author = {Feng, Y and Guo, X and Luo, M and Sun, Y and Sun, L and Zhang, H and Zou, Y and Liu, D and Lu, H}, title = {GbHSP90 act as a dual functional role regulated in telomere stability in Ginkgo biloba.}, journal = {International journal of biological macromolecules}, volume = {}, number = {}, pages = {135240}, doi = {10.1016/j.ijbiomac.2024.135240}, pmid = {39250995}, issn = {1879-0003}, abstract = {The heat shock protein 90 (HSP90) family members are not only widely involved in animal cellular immune response and signal transduction pathway regulation, but also play an important role in plant development and environmental stress response. Here,we identified a HSP90 family member in Ginkgo biloba, designated as GbHSP90, which performs a dual functional role to regulate telomere stability. GbHSP90 was screened by a yeast one-hybrid library using the Ginkgo biloba telomeric DNA (TTTAGGG)5. Fluorescence polarization, surface plasmon resonance(SPR) and EMSA technologyies revealed a specific interaction between GbHSP90 and the double-stranded telomeric DNA via its N-CR region, with no affinity for the single-stranded telomeric DNA or human double-stranded telomeric DNA. Furthermore, yeast two-hybrid system and Split-LUC assay demonstrated that GbHSP90 can interacts with two telomere end-binding proteins:the ginkgo telomerase reverse transcriptase (GbTERT) and the ginkgo Structural Maintenance of Chromosomes protein 1 (GbSMC1). Overexpression of GbHSP90 in human 293 T and HeLa cells increased cell growth rate, the content of telomerase reverse transcriptase (TERT), and promote cell division and inhibit cell apoptosis. Our results indicated GbHSP90 have dually functions: as a telomere-binding protein that binds specifically to double-stranded telomeric DNA and as a molecular chaperone that modulates cell differentiation and apoptosis by binding to telomere protein complexes in Ginkgo biloba. This study contributes to a significantly understanding of the unique telomere complex structure and regulatory mechanisms in Ginkgo biloba, a long-lived tree species.}, }
@article {pmid39250900, year = {2024}, author = {Vostatek, R and Hohensinner, P and Schmaldienst, S and Lorenz, M and Klauser-Braun, R and Pabinger, I and Säemann, M and Ay, C and Königsbrügge, O}, title = {Telomere length is associated with increased risk of cardiovascular events in patients with end-stage kidney disease on hemodialysis.}, journal = {Cardiorenal medicine}, volume = {}, number = {}, pages = {1-16}, doi = {10.1159/000541112}, pmid = {39250900}, issn = {1664-5502}, abstract = {INTRODUCTION: Patients with chronic kidney disease (CKD), especially those with end-stage kidney disease (ESKD) on hemodialysis (HD), are at increased risk for cardiovascular disease (CVD), including myocardial infarction and ischemic stroke. A shortening in telomere length, as a parameter for accelerated vascular aging, is an established biomarker for CVD in the general population. We aimed to elucidate the role of telomere length in ESKD patient on HD and its association with cardiovascular outcomes.
METHODS: Telomere length was measured in a prospective population-based cohort study of prevalent HD patients. DNA was isolated from whole blood, sampled at baseline, and analyzed for telomere length via a qPCR-based approach. The risk for the occurrence of the independently adjudicated 3P-MACE outcome (myocardial infarction, ischemic stroke, and cardiovascular death) was statistically analyzed considering the competing risk of non-cardiovascular death.
RESULTS: In the cohort of 308 patients with ESKD (115 (37.3%) women, median (25th-75th percentile) age: 67.0 (56.8 - 76.0), the median telomere length was 1.51 kb (25th-75th percentile 0.6-3.2 kb). The 3P-MACE outcome occurred with an incidence rate of 9.4 per 100 patient-years. Patients with longer telomere length more frequently had vascular nephropathy compared to patients with shorter telomere length. Interestingly, patients in the highest quartile of telomere length had a 1.8-fold increased risk for 3P-MACE (95%CI 1.051-3.201, p=0.033), after multivariable adjustment for age, history of stroke, myocardial infarction, venous thromboembolism, presence of heart valve replacement, atrial fibrillation, smoking, anticoagulation, or immunosuppressive use.
CONCLUSION: Surprisingly, in this high-risk cohort of patients with ESKD on HD, longer telomere lengths were associated with increased risk of cardiovascular events.}, }
@article {pmid39248546, year = {2024}, author = {Nayır Büyükşahin, H and Emiralioğlu, N and Yalçın, E and Ozcan, HN and Oğuz, B and Utine, GE and Kiper, PÖ and Karaosmanoğlu, B and Orhan, D and Unal, S and Güzelkaş, İ and Alboğa, D and Doğru, D and Özçelik, U and Kiper, N}, title = {Two cases with undefined childhood interstitial lung disease: Can it be related to telomere variants?.}, journal = {Journal of paediatrics and child health}, volume = {}, number = {}, pages = {}, doi = {10.1111/jpc.16666}, pmid = {39248546}, issn = {1440-1754}, }
@article {pmid39246285, year = {2024}, author = {Piedrabuena, MA and Correale, J and Farez, MF and Rodríguez Murúa, S and Martínez Canyazo, C and Fiol, M and Marrodan, M and Ysrraelit, MC}, title = {Telomere length as a biomarker in multiple sclerosis.}, journal = {Multiple sclerosis (Houndmills, Basingstoke, England)}, volume = {}, number = {}, pages = {13524585241273054}, doi = {10.1177/13524585241273054}, pmid = {39246285}, issn = {1477-0970}, abstract = {BACKGROUND: Leukocyte telomere length (LTL) shortens with age and may be related to multiple sclerosis (MS).
OBJECTIVE: We hypothesize that chronologically young people with MS (pwMS) with short LTL behave similarly to older MS subjects.
METHODS: Prospective 2-year study including two cohorts of young (18-35 years) and elderly (⩾50 years) pwMS with similar disease duration. Physical and cognitive evaluation, 3 T brain magnetic resonance imaging (MRI) and retinal nerve fiber layer (RNFL) measurement by optical coherence tomography were performed. LTL was measured by quantitative polymerase chain reaction assay.
RESULTS: Around 105 patients were included, 57 young and 48 elderly. LTL was shorter in older patients (0.61 versus 0.57, p = 0.0081) and in males (female, 0.60; male, 0.59; p = 0.01335). For every 10-year increase in age, LTL was 0.02 U shorter. In elderly, LTL correlated with disease duration (p = 0.05), smoking (p = 0.03), Expanded Disability Status Scale (EDSS; p = 0.004), 9HPT (p = 0.00007), high-efficacy therapies (p = 0.001), brain lesion volume (BLV) (p = 0.011), and number of T2 lesions (p = 0.01). In young patients, LTL did not correlate with clinical or radiological variables. For every 0.1 U shorter LTL, gray matter volume decreased 1.75 cm[3] and white matter volume 1.78 cm[3].
CONCLUSION: LTL correlated with disability and BLV in elderly. Besides LTL shortening, other variables should be considered as mechanisms of neurodegeneration that might be involved in aging pwMS.}, }
@article {pmid39239547, year = {2024}, author = {Huang, J and Feng, Y and Shi, Y and Shao, W and Li, G and Chen, G and Li, Y and Yang, Z and Yao, Z}, title = {Telomeres and telomerase in Sarcoma disease and therapy.}, journal = {International journal of medical sciences}, volume = {21}, number = {11}, pages = {2065-2080}, pmid = {39239547}, issn = {1449-1907}, mesh = {Humans ; *Telomerase/genetics/metabolism ; *Sarcoma/genetics/therapy/pathology ; *Telomere/genetics/metabolism ; *Telomere Homeostasis/genetics ; Prognosis ; Mutation ; }, abstract = {Sarcoma is a rare tumor derived from the mesenchymal tissue and mainly found in children and adolescents. The outcome for patients with sarcoma is relatively poor compared with that for many other solid malignant tumors. Sarcomas have a highly heterogeneous pathogenesis, histopathology and biological behavior. Dysregulated signaling pathways and various gene mutations are frequently observed in sarcomas. The telomere maintenance mechanism (TMM) has recently been considered as a prognostic factor for patients with sarcomas, and alternative lengthening of telomeres (ALT) positivity has been correlated with poor outcomes in patients with several types of sarcomas. Therefore, telomeres and telomerases may be useful targets for treating sarcomas. This review aims to provide an overview of telomere and telomerase biology in sarcomas.}, }
@article {pmid39237122, year = {2024}, author = {Cao, Z and Li, Y and Wu, J}, title = {Causal linkage of psoriasis with ageing: Mendelian randomization and enrichment analysis towards telomere length and psoriasis.}, journal = {Postgraduate medical journal}, volume = {}, number = {}, pages = {}, doi = {10.1093/postmj/qgae115}, pmid = {39237122}, issn = {1469-0756}, support = {2019YFA0112100//National Key Research and Development Program of China/ ; }, abstract = {OBJECTIVE: Several studies demonstrated potential associations between the telomere length (TL) in leukocytes and psoriasis or psoriatic arthritis (PsA). This study aimed to investigate whether there was the causal genetic relationship between TL and psoriatic diseases bidirectionally.
METHODS: Two-sample univariable MR (UVMR) analysis was applied to explore the bidirectional causal association of TL with overall psoriasis, psoriasis vulgaris (PV) and PsA. Multivariable MR (MVMR) and the mediation effects analysis were applied to test whether the bidirectional associations between TLs and psoriasis were mediated by body mass index (BMI), alcohol, and smoking status.
RESULTS: According to the UVMR results, a negative causal impact of TL on the risk of overall psoriasis was found (OR = 0.775; 95% CI: 0.646-0.931; P = 6.36 × 10-3), and a similar trend was observed in the reversed direction for psoriasis-TL (IVW-β = -0.0097; 95% CI: -0.0170 to -0.0024; P = 9.12 × 10-3). There were also negative genetic associations between TL and PV bidirectionally. The independent association of genetically predicted TL and overall psoriasis persisted in the MVMR results controlled for BMI, smoking, and alcohol consumption (ORMVMR = 0.736; 95% CI: 0.597 to 0.907; P = 0.004). An independent significant association of genetic predisposition to PsA with TL was also found (βMVMR = 0.006; 95% CI: 0.001 to 0.012; P = 0.033). The mediation analysis showed that BMI partially mediated the reverse association between PSO and TL.
CONCLUSION: This MR study revealed an association between genetic indicators of shortened TL and risk of overall psoriasis and PV, and genetic predisposition to PsA was associated with longer TL. Key message What is already known on this topic? Telomere length (TL) is acknowledged to reflect an individual's biological age but is also associated with dysregulated immune function and immunosenescence. The impact of aging on psoriasis is controversial. Existing evidence suggests that aging may influence pathological changes and clinical course but whether aging is an independent risk factor remains unclear. What this study adds? The current study found an association between genetic indicators of shortened TL and the risk of overall psoriasis and psoriasis vulgaris (PV). There was a bidirectional link between genetically indicated overall psoriasis and shortened TL. A possible positive genetic association between PsA and TL was also found. How this study might affect research, practice, or policy? Our study may provide evidence for TL as new diagnostic and therapeutic strategies in clinical practices for psoriasis. Greater efforts to psoriasis management may substantially reduce the aging attributable to TL shortening. Future large-scale GWAS and experimental studies are warranted to examine the mechanistic basis for links between TL and psoriasis to improve understanding and illuminate possible therapeutic targets for psoriatic disease.}, }
@article {pmid39235665, year = {2024}, author = {Scarabino, D and Veneziano, L and Nethisinghe, S and Mantuano, E and Fiore, A and Granata, G and Solanky, N and Zanni, G and Cavalcanti, F and Corbo, RM and Giunti, P}, title = {Unusual Age-Dependent Behavior of Leukocytes Telomere Length in Friedreich's Ataxia.}, journal = {Movement disorders : official journal of the Movement Disorder Society}, volume = {}, number = {}, pages = {}, doi = {10.1002/mds.29976}, pmid = {39235665}, issn = {1531-8257}, support = {//Department of Health's National Institute for Health Research Biomedical Research Centre's/ ; //National Institute for Health Research University College London/ ; project 739510//European Reference Network for Rare Neurological Diseases/ ; MR/N028767/1//Medical Research Council Centre for Neurodevelopmental Disorders/ ; 2018/2019 grants//Sapienza University of Rome/ ; }, abstract = {BACKGROUND: Friedreich ataxia (FRDA) is an autosomal recessive neurodegenerative disorder caused by an expanded GAA repeat in the first intron of the FXN gene.
OBJECTIVE: The aim of this study was to analyze leukocyte telomeres length (LTL) in FRDA to verify the possible relationships between LTL and disease progression. We investigated LTL in a cohort of FRDA biallelic patients (n = 61), heterozygous (n = 29), and age-matched healthy subjects (n = 87).
METHODS: LTL was measured by real-time polymerase chain reaction quantitative analysis (qPCR).
RESULTS: The results showed that before 35 years of age, leukocyte telomeres were longer in patients than in controls, whereas the reverse applies in patients above 36 years of age. Interestingly, LTL was greater than controls at any age in heterozygous subjects. This picture mirrors what has been previously observed in vitro in FRDA cultured fibroblasts, showing significantly longer telomeres at early passages because of activation of an alternative lengthening of telomeres (ALT)-like mechanism, but showing accelerated telomere shortening as population doubling increases. GAA1 repeat length is positively correlated with the LTL and negatively correlated with the age at blood sampling. The relationship of LTL with clinical parameters (cardiomyopathy, diabetes, dependence on a wheelchair) was also analyzed. Significantly shorter leukocyte telomeres were associated with the presence of cardiomyopathy, but not with diabetes and the dependence on a wheelchair.
CONCLUSIONS: Overall, the present study indicates that telomere length analysis in FRDA may be a relevant biomarker for following the stages of the disease. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.}, }
@article {pmid39234237, year = {2024}, author = {Zhang, J and Xia, X and He, S}, title = {Deciphering the causal association and underlying transcriptional mechanisms between telomere length and abdominal aortic aneurysm.}, journal = {Frontiers in immunology}, volume = {15}, number = {}, pages = {1438838}, pmid = {39234237}, issn = {1664-3224}, mesh = {*Aortic Aneurysm, Abdominal/genetics/immunology ; Animals ; Mice ; Humans ; *Genome-Wide Association Study ; *Telomere Homeostasis ; *Telomere/genetics ; Mendelian Randomization Analysis ; Biomarkers ; Male ; Disease Models, Animal ; Mice, Inbred C57BL ; Transcriptome ; Genetic Predisposition to Disease ; }, abstract = {BACKGROUND: The purpose of this study is to investigate the causal effect and potential mechanisms between telomere length and abdominal aortic aneurysm (AAA).
METHODS: Summary statistics of telomere length and AAA were derived from IEU open genome-wide association studies and FinnGen R9, respectively. Bi-directional Mendelian randomization (MR) analysis was conducted to reveal the causal relationship between AAA and telomere length. Three transcriptome datasets were retrieved from the Gene Expression Omnibus database and telomere related genes was down-loaded from TelNet. The overlapping genes of AAA related differentially expressed genes (DEGs), module genes, and telomere related genes were used for further investigation. Telomere related diagnostic biomarkers of AAA were selected with machine learning algorisms and validated in datasets and murine AAA model. The correlation between biomarkers and immune infiltration landscape was established.
RESULTS: Telomere length was found to have a suggestive negative associations with AAA [IVW, OR 95%CI = 0.558 (0.317-0.701), P < 0.0001], while AAA showed no suggestive effect on telomere length [IVW, OR 95%CI = 0.997 (0.990-1.004), P = 0.4061]. A total of 40 genes was considered as telomere related DEGs of AAA. PLCH2, PRKCQ, and SMG1 were selected as biomarkers after multiple algorithms and validation. Immune infiltration analysis and single cell mRNA analysis revealed that PLCH2 and PRKCQ were mainly expressed on T cells, while SMG1 predominantly expressed on T cells, B cells, and monocytes. Murine AAA model experiments further validated the elevated expression of biomarkers.
CONCLUSION: We found a suggestive effect of telomere length on AAA and revealed the potential biomarkers and immune mechanism of telomere length on AAA. This may shed new light for diagnosis and therapeutics on AAA.}, }
@article {pmid39231615, year = {2024}, author = {Kochman, R and Ba, I and Yates, M and Pirabakaran, V and Gourmelon, F and Churikov, D and Lafaille, M and Kermasson, L and Hamelin, C and Marois, I and Jourquin, F and Braud, L and Bechara, M and Lainey, E and Nunes, H and Breton, P and Penhouet, M and David, P and Géli, V and Lachaud, C and Maréchal, A and Revy, P and Kannengiesser, C and Saintomé, C and Coulon, S}, title = {Heterozygous RPA2 variant as a novel genetic cause of telomere biology disorders.}, journal = {Genes & development}, volume = {}, number = {}, pages = {}, doi = {10.1101/gad.352032.124}, pmid = {39231615}, issn = {1549-5477}, abstract = {Premature telomere shortening or telomere instability is associated with a group of rare and heterogeneous diseases collectively known as telomere biology disorders (TBDs). Here we identified two unrelated individuals with clinical manifestations of TBDs and short telomeres associated with the identical monoallelic variant c.767A>G; Y256C in RPA2 Although the replication protein A2 (RPA2) mutant did not affect ssDNA binding and G-quadruplex-unfolding properties of RPA, the mutation reduced the affinity of RPA2 with the ubiquitin ligase RFWD3 and reduced RPA ubiquitination. Using engineered knock-in cell lines, we found an accumulation of RPA at telomeres that did not trigger ATR activation but caused short and dysfunctional telomeres. Finally, both patients acquired, in a subset of blood cells, somatic genetic rescue events in either POT1 genes or TERT promoters known to counteract the accelerated telomere shortening. Collectively, our study indicates that variants in RPA2 represent a novel genetic cause of TBDs. Our results further support the fundamental role of the RPA complex in regulating telomere length and stability in humans.}, }
@article {pmid39232410, year = {2024}, author = {Konishi, K and Jacobs, EG and Aroner, S and De Vivo, I and Smith, B and Scribner-Weiss, B and Makris, N and Seitz-Holland, J and Remington, A and Aizley, H and Kubicki, M and Goldstein, JM}, title = {Leukocyte telomere length and memory circuitry and cognition in early aging: Impact of sex and menopausal status.}, journal = {Hormones and behavior}, volume = {165}, number = {}, pages = {105631}, doi = {10.1016/j.yhbeh.2024.105631}, pmid = {39232410}, issn = {1095-6867}, abstract = {Telomere length (TL) is an important cellular marker of biological aging impacting the brain and heart. However, how it is related to the brain (e.g., cognitive function and neuroanatomic architecture), and how these relationships may vary by sex and reproductive status, is not well established. Here we assessed the association between leukocyte TL and memory circuitry regional brain volumes and memory performance in early midlife, in relation to sex and reproductive status. Participants (N = 198; 95 females, 103 males; ages 45-55) underwent structural MRI and neuropsychological assessments of verbal, associative, and working memory. Overall, shorter TL was associated with smaller white matter volume in the parahippocampal gyrus and dorsolateral prefrontal cortex. In males, shorter TL was associated with worse working memory performance and corresponding smaller white matter volumes in the parahippocampal gyrus, anterior cingulate cortex, and dorsolateral prefrontal cortex. In females, the impact of cellular aging was revealed over the menopausal transition. In postmenopausal females, shorter TL was associated with poor associative memory performance and smaller grey matter volume in the right hippocampus. In contrast, TL was not related to memory performance or grey and white matter volumes in any memory circuitry region in pre/perimenopausal females. Results demonstrated that shorter TL is associated with worse memory function and smaller volume in memory circuitry regions in early midlife, an association that differs by sex and reproductive status. Taken together, TL may serve as an early indicator of sex-dependent brain abnormalities in early midlife.}, }
@article {pmid39231146, year = {2024}, author = {Rönne-Petersén, L and Niemi, M and Walach, H and Lavebratt, C and Yang, LL and Gerdle, B and Ghafouri, B and Falkenberg, T}, title = {Exploring emotional well-being, spiritual, religious and personal beliefs and telomere length in chronic pain patients-A pilot study with cross-sectional design.}, journal = {PloS one}, volume = {19}, number = {9}, pages = {e0308924}, doi = {10.1371/journal.pone.0308924}, pmid = {39231146}, issn = {1932-6203}, mesh = {Humans ; Male ; Female ; Pilot Projects ; Cross-Sectional Studies ; Middle Aged ; *Chronic Pain/psychology ; Aged ; *Quality of Life ; *Spirituality ; Adult ; Emotions ; Telomere/genetics ; Surveys and Questionnaires ; Sweden ; Patient Reported Outcome Measures ; Depression/psychology ; Telomerase/metabolism/genetics ; Religion ; }, abstract = {Living with chronic pain is associated with substantial suffering and high societal costs. Patient reported outcomes (PROM's) and cellular ageing should be considered in pain management. The aim of this study was to explore correlations of PROM's and cellular ageing (telomere length [TL] and telomerase activity [TA]) amongst patients with chronic non-malignant pain. This was an explorative pilot study with cross-sectional design and recruitment was done at two pain rehabilitation facilities in Sweden, with inpatient setting/integrative care and outpatient setting/multimodal care, respectively. Eighty-four patients were enrolled by referral to pain rehabilitation in Sweden. The main outcome measures collected after admission in addition to TL and TA were the following PROMs: Numerical Rating Scale (NRS), Chronic Pain Acceptance Questionnaire (CPAQ), Hospital Anxiety and Depression Scale (HADS), Five Facets Mindfulness Questionnaire (FFMQ), WHO Quality of Life-Spiritual, Religious and Personal Beliefs (WHOQoL-SRPB) and EuroQol 5 Dimensions (EQ-5D). All the PROM's showed evidence of poor overall health status among the participants. TL correlated negatively with HADS score (r = -.219, p = .047) and positively with WHOQoL-SRPB (r = .224, p = .052). TL did not correlate with any of the pain measures. TA correlated positively with pain spread (r = .222, p = .049). A mediation of the direct effect of spiritual well-being on TL by anxiety and depression could be shown (b = 0.008; p = .045). The correlations between TL and SRPB and anxiety and depression suggest some importance of emotional and SRPB dimensions in pain management, with implications for cellular aging, which may warrant further study. Trial registration: ClinicalTrials.gov Identifier: NCT02459639.}, }
@article {pmid39225247, year = {2024}, author = {Noveir, SD and Galamgam, J and Pithadia, D and Truong, A and Hogeling, M and Cheng, CE}, title = {Reticulated pigmentary changes and Terry's nails in a patient with a TERT variant-associated telomere biology disorder.}, journal = {Pediatric dermatology}, volume = {}, number = {}, pages = {}, doi = {10.1111/pde.15735}, pmid = {39225247}, issn = {1525-1470}, abstract = {Telomere biology disorders (TBD) are a complex set of inherited illnesses characterized by short telomeres. Dyskeratosis congenita (DC), which is now considered a severe TBD phenotype, is characterized by reticulated pigmentary changes, nail dystrophy, premalignant oral leukoplakia, and systemic involvement. This case describes a 2-year-old female with reticulated pigmentary changes and Terry's nails who was found to have a TERT variant and short telomeres; she lacked other mucocutaneous and systemic features of TBD. This report describes a unique clinical presentation of TBD and highlights the importance of upholding suspicion for TBD in individuals with limited or subtle features of classic DC.}, }
@article {pmid39224814, year = {2024}, author = {Burrow, TA and Koneru, B and Macha, SJ and Sun, W and Barr, FG and Triche, TJ and Reynolds, CP}, title = {Prevalence of alternative lengthening of telomeres in pediatric sarcomas determined by the telomeric DNA C-circle assay.}, journal = {Frontiers in oncology}, volume = {14}, number = {}, pages = {1399442}, pmid = {39224814}, issn = {2234-943X}, abstract = {INTRODUCTION: Alternative lengthening of telomeres (ALT) occurs in sarcomas and ALT cancers share common mechanisms of therapy resistance or sensitivity. Telomeric DNA C-circles are self-primed circular telomeric repeats detected with a PCR assay that provide a sensitive and specific biomarker exclusive to ALT cancers. We have previously shown that 23% of high-risk neuroblastomas are of the ALT phenotype. Here, we investigate the frequency of ALT in Ewing's family sarcoma (EFS), rhabdomyosarcoma (RMS), and osteosarcoma (OS) by analyzing DNA from fresh frozen primary tumor samples utilizing the real-time PCR C-circle Assay (CCA).
METHODS: We reviewed prior publications on ALT detection in pediatric sarcomas. DNA was extracted from fresh frozen primary tumors, fluorometrically quantified, C-circles were selectively enriched by isothermal rolling cycle amplification and detected by real-time PCR.
RESULTS: The sample cohort consisted of DNA from 95 EFS, 191 RMS, and 87 OS primary tumors. One EFS and 4 RMS samples were inevaluable. Using C-circle positive (CC+) cutoffs previously defined for high-risk neuroblastoma, we observed 0 of 94 EFS, 5 of 187 RMS, and 62 of 87 OS CC+ tumors.
CONCLUSIONS: Utilizing the ALT-specific CCA we observed ALT in 0% of EFS, 2.7% of RMS, and 71% of OS. These data are comparable to prior studies in EFS and OS using less specific ALT markers. The CCA can provide a robust and sensitive means of identifying ALT in sarcomas and has potential as a companion diagnostic for ALT targeted therapeutics.}, }
@article {pmid39223261, year = {2024}, author = {Sung, JY and Kim, SG and Park, SY and Kim, JR and Choi, HC}, title = {Telomere stabilization by metformin mitigates the progression of atherosclerosis via the AMPK-dependent p-PGC-1α pathway.}, journal = {Experimental & molecular medicine}, volume = {}, number = {}, pages = {}, pmid = {39223261}, issn = {2092-6413}, support = {2022R1A5A2018865//National Research Foundation of Korea (NRF)/ ; 2022R1I1A1A01055818//National Research Foundation of Korea (NRF)/ ; }, abstract = {Telomere dysfunction is a well-known molecular trigger of senescence and has been associated with various age-related diseases, including atherosclerosis. However, the mechanisms involved have not yet been elucidated, and the extent to which telomeres contribute to atherosclerosis is unknown. Therefore, we investigated the mechanism of metformin-induced telomere stabilization and the ability of metformin to inhibit vascular smooth muscle cell (VSMC) senescence caused by advanced atherosclerosis. The present study revealed that metformin inhibited the phenotypes of atherosclerosis and senescence in VSMCs. Metformin increased the phosphorylation of AMPK-dependent PGC-1α and thus increased telomerase activity and the protein level of TERT in OA-treated VSMCs. Mechanistically, the phosphorylation of AMPK and PGC-1α by metformin not only enhanced telomere function but also increased the protein level of TERT, whereas TERT knockdown accelerated the development of atherosclerosis and senescent phenotypes in OA-treated VSMCs regardless of metformin treatment. Furthermore, the in vivo results showed that metformin attenuated the formation of atherosclerotic plaque markers in the aortas of HFD-fed ApoE KO mice. Although metformin did not reduce plaque size, it inhibited the phosphorylation of the AMPK/PGC-1α/TERT signaling cascade, which is associated with the maintenance and progression of plaque formation, in HFD-fed ApoE KO mice. Accordingly, metformin inhibited atherosclerosis-associated phenotypes in vitro and in vivo. These observations show that the enhancement of telomere function by metformin is involved in specific signaling pathways during the progression of atherosclerosis. These findings suggest that telomere stabilization by metformin via the AMPK/p-PGC-1α pathway might provide a strategy for developing therapeutics against vascular diseases such as atherosclerosis.}, }
@article {pmid39222545, year = {2024}, author = {Cao, X and Fang, L and Jiang, Y and Zeng, T and Bai, S and Li, S and Liu, Y and Zhong, W and Lu, C and Yang, H}, title = {Nanoscale octopus guiding telomere entanglement: An innovative strategy for inducing apoptosis in cancer cells.}, journal = {Biomaterials}, volume = {313}, number = {}, pages = {122777}, doi = {10.1016/j.biomaterials.2024.122777}, pmid = {39222545}, issn = {1878-5905}, abstract = {Telomere length plays a crucial role in cellular aging and the risk of diseases. Unlike normal cells, cancer cells can extend their own survival by maintaining telomere stability through telomere maintenance mechanism. Therefore, regulating the lengths of telomeres have emerged as a promising approach for anti-cancer treatment. In this study, we introduce a nanoscale octopus-like structure designed to induce physical entangling of telomere, thereby efficiently triggering telomere dysfunction. The nanoscale octopus, composed of eight-armed PEG (8-arm-PEG), are functionalized with cell penetrating peptide (TAT) to facilitate nuclear entry and are covalently bound to N-Methyl Mesoporphyrin IX (NMM) to target G-quadruplexes (G4s) present in telomeres. The multi-armed configuration of the nanoscale octopus enables targeted binding to multiple G4s, physically disrupting and entangling numerous telomeres, thereby triggering telomere dysfunction. Both in vitro and in vivo experiments indicate that the nanoscale octopus significantly inhibits cancer cell proliferation, induces apoptosis through telomere entanglement, and ultimately suppresses tumor growth. This research offers a novel perspective for the development of innovative anti-cancer interventions and provides potential therapeutic options for targeting telomeres.}, }
@article {pmid39222177, year = {2024}, author = {Kienzl, P and Deloria, AJ and Hunjadi, M and Hadolt, JM and Haering, MF and Bothien, A and Mejri, D and Korkut-Demirbaş, M and Sampl, S and Weber, G and Pirker, C and Laengle, S and Braunschmid, T and Dragona, E and Marian, B and Gagos, S and Lu, L and Henson, JD and Lau, LMS and Reddel, RR and Mikulits, W and Stättner, S and Holzmann, K}, title = {Telomere transcripts act as tumor suppressor and are associated with favorable prognosis in colorectal cancer with low proliferating cell nuclear antigen expression.}, journal = {Cellular oncology (Dordrecht, Netherlands)}, volume = {}, number = {}, pages = {}, doi = {10.1007/s13402-024-00986-y}, pmid = {39222177}, issn = {2211-3436}, abstract = {Telomeric repeat-containing RNAs (TERRA) and telomerase RNA component (TERC) regulate telomerase activity (TA) and thereby contribute to telomere homeostasis by influencing telomere length (TL) and the cell immortality hallmark of cancer cells. Additionally, the non-canonical functions of telomerase reverse transcriptase (TERT) and TERRA appear to be involved in the epithelial-mesenchymal transition (EMT), which is important for cancer progression. However, the relationship between TERRA and patient prognosis has not been fully characterized. In this small-scale study, 68 patients with colorectal cancer (CRC) were evaluated for correlations between telomere biology, proliferation, and EMT gene transcripts and disease outcome. The proliferating cell nuclear antigen (PCNA) and the epithelial splicing regulatory proteins 1 and 2 (ESRP1 and ESRP2) showed a positive correlation with TERRA, while TA and TERRA exhibited an inverse correlation. Consistent with previous findings, the present study revealed higher expression levels of TERT and TERC, and increased TA and TL in CRC tumor tissue compared to adjacent non-tumor tissue. In contrast, lower expression levels of TERRA were observed in tumor tissue. Patients with high TERRA expression and low PCNA levels exhibited favorable overall survival rates compared to individuals with the inverse pattern. Furthermore, TERRA suppressed CRC tumor growth in severe combined immunodeficiency disease (SCID) mice. In conclusion, our study extends previously published research on TERRA suggesting its potential therapeutic role in telomerase-positive CRC.}, }
@article {pmid39216403, year = {2024}, author = {Yun, Z and Liu, Z and Shen, Y and Sun, Z and Zhao, H and Du, X and Lv, L and Zhang, Y and Hou, L}, title = {Genetic analysis from multiple cohorts implies causality between 2200 druggable genes, telomere length, and leukemia.}, journal = {Computers in biology and medicine}, volume = {181}, number = {}, pages = {109064}, doi = {10.1016/j.compbiomed.2024.109064}, pmid = {39216403}, issn = {1879-0534}, abstract = {BACKGROUND: Clinical therapeutic targets for leukemia remain to be identified and the causality between leukemia and telomere length is unclear.
METHODS: This work employed cis expression quantitative trait locus (eQTL) for 2,200 druggable genes from the eQTLGen Consortium and genome-wide association studies (GWAS) summary data for telomere length in seven blood cell types from the UK Biobank, Netherlands Cohort as exposures. GWAS data for lymphoid leukemia (LL) and myeloid leukemia (ML) from FinnGen and Lee Lab were used as outcomes for discovery and replication cohorts, respectively. Robust Mendelian randomization (MR) findings were generated from seven MR models and a series of sensitivity analyses. Summary-data-based MR (SMR) analysis and transcriptome-wide association studies (TWAS) were further implemented to verify the association between identified druggable genes and leukemia. Single-cell type expression analysis was employed to identify the specific expression of leukemia casual genes on human bone marrow and peripheral blood immune cells. Multivariable MR analysis, linkage disequilibrium score regression (LDSC), and Bayesian colocalization analysis were performed to further validate the relationship between telomere length and leukemia. Mediation analysis was used to assess the effects of identified druggable genes affecting leukemia via telomere length. Phenome-wide MR (Phe-MR) analysis for assessing the effect of leukemia causal genes and telomere length on 1,403 disease phenotypes.
RESULTS: Combining the results of the meta-analysis for MR estimates from two cohorts, SMR and TWAS analysis, we identified five LL causal genes (TYMP, DSTYK, PPIF, GDF15, FAM20A) and three ML causal genes (LY75, ADA, ABCA2) as promising drug targets for leukemia. Univariable MR analysis showed genetically predicted higher leukocyte telomere length increased the risk of LL (odds ratio [OR] = 2.33, 95 % confidence interval [95 % CI] 1.70-3.18; P = 1.33E-07), and there was no heterogeneity and horizontal pleiotropy. Evidence from the meta-analysis of two cohorts strengthened this finding (OR = 1.88, 95 % CI 1.06-3.05; P = 0.01). Multivariable MR analysis showed the causality between leukocyte telomere length and LL without interference from the other six blood cell telomere length (OR = 2.72, 95 % CI 1.88-3.93; P = 1.23E-07). Evidence from LDSC supported the positive genetic correlation between leukocyte telomere length and LL (rg = 0.309, P = 0.0001). Colocalization analysis revealed that the causality from leukocyte telomere length on LL was driven by the genetic variant rs770526 in the TERT region. The mediation analysis via two-step MR showed that the causal effect from TYMP on LL was partly mediated by leukocyte telomere length, with a mediated proportion of 12 %.
CONCLUSION: Our study identified several druggable genes associated with leukemia risk and provided new insights into the etiology and drug development of leukemia. We also found that genetically predicted higher leukocyte telomere length increased LL risk and its potential mechanism of action.}, }
@article {pmid39214240, year = {2024}, author = {Sung, YN and Stojanova, M and Shin, S and Cho, H and Heaphy, CM and Hong, SM}, title = {Gradual Telomere Shortening in the Tumorigenesis of Pancreatic and Hepatic Mucinous Cystic Neoplasms.}, journal = {Human pathology}, volume = {}, number = {}, pages = {105653}, doi = {10.1016/j.humpath.2024.105653}, pmid = {39214240}, issn = {1532-8392}, abstract = {Mucinous cystic neoplasm (MCN) is one of the precursor lesions of pancreatic ductal adenocarcinoma and intrahepatic cholangiocarcinoma. The aim of this study is to examine the presence of short telomeres in promoting the tumorigenesis of MCN by measuring telomere lengths in distinct components of MCN, including the mucinous lining epithelium, non-mucinous lining epithelium, and ovarian-type stroma. A total of 45 patients with MCN (30 pancreatic and 15 hepatic cases) were obtained. Quantitative telomere-specific fluorescent in situ hybridization was performed to measure the telomere length of specific cell types within MCNs, including mucinous lining epithelium, non-mucinous lining epithelium, and ovarian-type stroma, as well as normal ductal epithelium and adenocarcinoma. Relative telomere lengths tended to decrease between normal ductal epithelium, ovarian-type stroma, non-mucinous lining epithelium, mucinous lining epithelium, and adenocarcinoma regardless of the involved organs. Among the analyzed cell types, relative telomere lengths were significantly different between normal ductal epithelium (3.31 ± 0.78), ovarian-type stroma (2.90 ± 0.93), non-mucinous lining epithelium (2.84 ± 0.79), mucinous lining epithelium (2.49 ± 0.93), and adenocarcinoma (1.19 ± 0.59), respectively (P < 0.001, mixed-effects model). As expected, no difference in relative telomere lengths was observed between normal ductal epithelium and ovarian-type stroma; however, significant differences were observed in pair-wise comparisons between ovarian-type stroma vs. non-mucinous lining epithelium (P = 0.001), non-mucinous lining epithelium vs. mucinous lining epithelium (P = 0.005), and mucinous lining epithelium vs. adenocarcinoma (P < 0.001). These findings suggest gradual telomere shortening occurs in the tumorigenesis of MCN, which may have important implications for the progression of this disease.}, }
@article {pmid39213174, year = {2024}, author = {Martens, DS and Lammertyn, EJ and Goeminne, PC and Colpaert, K and Proesmans, M and Vanaudenaerde, BM and Nawrot, TS and Dupont, LJ}, title = {Leukocyte telomere length and attrition in association with disease severity in cystic fibrosis patients.}, journal = {Aging}, volume = {16}, number = {}, pages = {}, doi = {10.18632/aging.206093}, pmid = {39213174}, issn = {1945-4589}, abstract = {Cystic fibrosis (CF) is characterized by chronic airway inflammation and premature aging. The link with leukocyte telomere length (LTL) as a marker of biological aging is unclear. We studied disease severity and LTL in 168 CF patients of which 85 patients had a second retrospective LTL assessment. A higher FEV1 was associated with longer LTL, with a stronger effect in men (5.08% longer LTL) compared to women (0.41% longer LTL). A higher FEV1/FVC ratio was associated with 7.05% (P=0.017) longer LTL in men. CF asthma, as defined by the treatment with inhaled corticosteroids, was associated with -6.65% shorter LTL (P=0.028). Men homozygous for the ΔF508 genotype showed a -10.48% (P=0.026) shorter LTL compared to heterozygotes. A genotype-specific non-linear association between LTL shortening and chronological age was observed. Stronger age-related LTL shortening was observed in patients homozygous for the ΔF508 genotype (P-interaction= 0.044). This work showed that disease severity in CF patients negatively influences LTL, with slightly more pronounced effects in men. The homozygous genotype for ΔF508 may play a role in LTL attrition in CF patients. Understanding factors in CF patients that accelerate biological aging provides insights into mechanisms that can extend the overall life quality in CF-diseased.}, }
@article {pmid39208769, year = {2024}, author = {Mlakar, V and Akkouh, I and Halff, EF and Srivastava, DP and Birkenæs, V and Ueland, T and Quintana, DS and Ormerod, MBEG and Steen, NE and Djurovic, S and Andreassen, OA and Aas, M}, title = {Telomere biology and its maintenance in schizophrenia spectrum disorders: Exploring links to cognition.}, journal = {Schizophrenia research}, volume = {272}, number = {}, pages = {89-95}, doi = {10.1016/j.schres.2024.08.011}, pmid = {39208769}, issn = {1573-2509}, abstract = {OBJECTIVE: Contemporary research suggests reduced telomere length in schizophrenia spectrum disorders (SZ) compared to age-adjusted non-affected individuals. However, the role of telomere maintenance and telomere repair in SZ is poorly understood as well as the involvement of telomere biology in cognitive abnormalities in SZ.
METHODS: The study consisted of 758 participants (SZ [n = 357] and healthy controls, HC [n = 401]) collected as part of the Norwegian TOP study. Participants were assessed with standardized neuropsychological tests measuring five cognitive domains. Leucocyte telomere length (TL) was measured via blood and determined by quantitative real-time Polymerase Chain Reaction (qPCR) providing a telomere to single copy ratio (T/S ratio), used to estimate the mean telomere length. Telomerase activity was assessed by the expression levels of the Telomerase Reverse Transcriptase (TERT) and Telomerase RNA Component (TERC) genes. To assess telomere maintenance and telomere repair we calculated the telomerase expression to TL ratio (TERT/TL and TERC/TL respectively).
RESULTS: Patients had reduced TERT (F = 5.03, p = 0.03), but not TERC expression (F = 1.04, p = 0.31), and higher TERT/TL (F = 6.68, p = 0.01) and TERC/TL (F = 6.71, p = 0.01), adjusted for age, sex, and ethnicity. No statistically significant association was observed between any of the telomere biology markers and the cognitive domains (p > 0.05).
CONCLUSION: Our study shows changes in TERT expression and telomere maintenance and telomere repair in SZ compared HC. However, the role of telomere biology in the mechanism underlying cognitive impairment in psychosis seems limited.}, }
@article {pmid39201686, year = {2024}, author = {Andreikos, D and Kyrodimos, E and Kotsinas, A and Chrysovergis, A and Papacharalampous, GX}, title = {The Association between Telomere Length and Head and Neck Cancer Risk: A Systematic Review and Meta-Analysis.}, journal = {International journal of molecular sciences}, volume = {25}, number = {16}, pages = {}, doi = {10.3390/ijms25169000}, pmid = {39201686}, issn = {1422-0067}, mesh = {Humans ; *Head and Neck Neoplasms/genetics/pathology ; *Telomere Homeostasis ; *Telomere/genetics/metabolism ; Risk Factors ; Odds Ratio ; }, abstract = {Telomeres play a crucial role in maintaining chromosomal integrity and regulating the number of cell divisions and have been associated with cellular aging. Telomere length (TL) has been widely studied in manifold cancer types; however, the results have been inconsistent. This systematic review and meta-analysis aims to analyze the evidence on the association between TL and head and neck cancer (HNC) risk. We comprehensively searched the literature in PubMed, Cochrane Library, and Scopus and identified nine eligible studies, which yielded 11 datasets. The odds ratios (ORs) and 95% confidence intervals (CIs) were used to ascertain the strength of the association. On the basis of the median TL, we defined two groups, short TL and long TL, with the latter being the reference group. Our analysis found a significant relationship between short TL and increased HNC risk (OR 1.38, 95% CI: 1.10-1.73, p = 0.005), while significant heterogeneity among the studies was noted. The subgroup analysis on HNC subtypes revealed a significant association between short TL and oral cancers (OR 2.08, 95% CI: 1.23-3.53, p = 0.007). Additionally, subgroup analysis indicates that adjustments for age, sex, and smoking did not affect the significance of our findings. In conclusion, our meta-analysis found evidence for an association between short TL and HNC risk, which could indicate that TL might act as a potential biomarker for HNC risk, but high-quality prospective studies are imperative to validate our findings.}, }
@article {pmid39201341, year = {2024}, author = {Pańczyszyn, A and Boniewska-Bernacka, E and Wertel, I and Sadakierska-Chudy, A and Goc, A}, title = {Telomeres and SIRT1 as Biomarkers of Gamete Oxidative Stress, Fertility, and Potential IVF Outcome.}, journal = {International journal of molecular sciences}, volume = {25}, number = {16}, pages = {}, doi = {10.3390/ijms25168652}, pmid = {39201341}, issn = {1422-0067}, mesh = {Humans ; *Oxidative Stress ; *Biomarkers ; *Fertilization in Vitro/methods ; *Telomere/metabolism/genetics ; *Sirtuin 1/metabolism/genetics ; Germ Cells/metabolism ; Fertility/genetics ; Female ; Male ; }, abstract = {The number of infertile couples undergoing in vitro fertilisation (IVF) has increased significantly. The efficacy of this procedure is contingent upon a multitude of factors, including gamete quality. One factor influencing gamete quality is oxidative stress, which leads to telomere damage and accelerates cellular ageing. Identifying new biomarkers that can predict the success of assisted reproduction techniques is a current relevant area of research. In this review, we discuss the potential role of SIRT1, a protein known to protect against oxidative stress and telomeres, which are responsible for genome stability, as biomarkers of gamete quality and assisted reproduction technique outcomes.}, }
@article {pmid39200358, year = {2024}, author = {Khalatyan, AS and Shishparenok, AN and Avetisov, KS and Gladilina, YA and Blinova, VG and Zhdanov, DD}, title = {Association of Telomere Length in T Lymphocytes, B Lymphocytes, NK Cells and Monocytes with Different Forms of Age-Related Macular Degeneration.}, journal = {Biomedicines}, volume = {12}, number = {8}, pages = {}, doi = {10.3390/biomedicines12081893}, pmid = {39200358}, issn = {2227-9059}, abstract = {BACKGROUND: Age plays a primary role in the development of age-related macular degeneration (AMD). Telomere length (TL) is one of the most relevant biomarkers of aging. In our study, we aimed to determine the association of TL with T lymphocytes, B lymphocytes, NK cells or monocytes with different forms of AMD.
METHODS: Our study included 62 patients with AMD: geographic atrophy (GA), neovascular AMD (NVAMD) with and without macular atrophy and 22 healthy controls. Each leukocyte subtype was isolated from peripheral blood by immunomagnetic separation, and the DNA was purified. The TL in the genomic DNA was determined using qPCR by amplifying the telomere region with specific oligonucleotide primers and normalizing to the control gene. Statistical analysis was performed using R version 4.5.1.
RESULTS: We observed a statistically significant increase in TL in the T cells between the control and NVAMD groups but not for the GA group. The B cells and monocytes showed a significant decrease in TL in all AMD groups. The TL in the NK cells did not decrease in any of the AMD groups.
CONCLUSIONS: The TL in the monocytes had the strongest association with AMD. It reflects a person's "telomeric status" and may become a diagnostic hallmark of these degenerative processes.}, }
@article {pmid39200189, year = {2024}, author = {Levstek, T and Breznik, N and Vujkovac, B and Nowak, A and Trebušak Podkrajšek, K}, title = {Dynamics of Leukocyte Telomere Length in Patients with Fabry Disease.}, journal = {Biomedicines}, volume = {12}, number = {8}, pages = {}, doi = {10.3390/biomedicines12081724}, pmid = {39200189}, issn = {2227-9059}, support = {P1-0170//Slovenian Research Agency/ ; NA//Takeda Pharmaceuticals/ ; }, abstract = {Fabry disease (FD) leads to significant morbidity and mortality, which may indicate accelerated ageing. However, it is still unclear whether there is a relationship between telomere length (TL), a marker of biological ageing, and disease outcome. We aimed to examine the relationship between leukocyte TL (LTL) dynamics and the presence of advanced disease stages and/or late complications of FD, including hypertrophic cardiomyopathy, nephropathy and stroke, both cross-sectionally and longitudinally. DNA was extracted from peripheral blood leukocytes and quantitative PCR was utilized to determine relative LTL in 99 Fabry patients. In the longitudinal analysis, we included 50 patients in whom at least three measurements were performed over a period of 5-10 years. The results showed a significant inverse correlation between LTL and age (ρ = -0.20, p = 0.05). No significant differences in LTL were found between females and males (p = 0.79) or between patients receiving disease-specific therapy and those without (p = 0.34). In a cross-sectional analysis, no association was found between the presence (p = 0.15) or number (p = 0.28) of advanced stages of the disease and/or late complications and LTL. Similarly, in a longitudinal analysis, no difference in LTL dynamics was found regarding the presence (p = 0.16) of advanced stage organ involvement and/or late complications or their number. These findings indicate that LTL dynamics in adulthood may not be a reliable indicator of disease outcomes in Fabry patients. Therefore, LTL may more accurately reflect the disease burden in early life, when TL is primarily determined.}, }
@article {pmid39198715, year = {2024}, author = {Tummala, H and Walne, AJ and Badat, M and Patel, M and Walne, AM and Alnajar, J and Chow, CC and Albursan, I and Frost, JM and Ballard, D and Killick, S and Szitányi, P and Kelly, AM and Raghavan, M and Powell, C and Raymakers, R and Todd, T and Mantadakis, E and Polychronopoulou, S and Pontikos, N and Liao, T and Madapura, P and Hossain, U and Vulliamy, T and Dokal, I}, title = {The evolving genetic landscape of telomere biology disorder dyskeratosis congenita.}, journal = {EMBO molecular medicine}, volume = {}, number = {}, pages = {}, pmid = {39198715}, issn = {1757-4684}, support = {MR/P018440/1//UKRI | Medical Research Council (MRC)/ ; MR/P018440/1//UKRI | Medical Research Council (MRC)/ ; MR/P018440/1//UKRI | Medical Research Council (MRC)/ ; 14032/LLR_/Blood Cancer UK/United Kingdom ; 14032/LLR_/Blood Cancer UK/United Kingdom ; }, abstract = {Dyskeratosis congenita (DC) is a rare inherited bone marrow failure syndrome, caused by genetic mutations that principally affect telomere biology. Approximately 35% of cases remain uncharacterised at the genetic level. To explore the genetic landscape, we conducted genetic studies on a large collection of clinically diagnosed cases of DC as well as cases exhibiting features resembling DC, referred to as 'DC-like' (DCL). This led us to identify several novel pathogenic variants within known genetic loci and in the novel X-linked gene, POLA1. In addition, we have also identified several novel variants in POT1 and ZCCHC8 in multiple cases from different families expanding the allelic series of DC and DCL phenotypes. Functional characterisation of novel POLA1 and POT1 variants, revealed pathogenic effects on protein-protein interactions with primase, CTC1-STN1-TEN1 (CST) and shelterin subunit complexes, that are critical for telomere maintenance. ZCCHC8 variants demonstrated ZCCHC8 deficiency and signs of pervasive transcription, triggering inflammation in patients' blood. In conclusion, our studies expand the current genetic architecture and broaden our understanding of disease mechanisms underlying DC and DCL disorders.}, }
@article {pmid39198664, year = {2024}, author = {Qiu, YD and Yan, Q and Wang, Y and Ye, YF and Wang, Y and Wang, MY and Wang, PP and Zhang, SY and Wang, DL and Yan, H and Ruan, J and Zhao, YJ and Huang, LH and Cho, N and Wang, K and Zheng, XH and Liu, ZG}, title = {Author Correction: Discovery of a selective TRF2 inhibitor FKB04 induced telomere shortening and senescence in liver cancer cells.}, journal = {Acta pharmacologica Sinica}, volume = {}, number = {}, pages = {}, doi = {10.1038/s41401-024-01370-0}, pmid = {39198664}, issn = {1745-7254}, }
@article {pmid39197728, year = {2024}, author = {Neto, IVS and Pinto, AP and de Andrade, RV and de Souza, FHV and de Souza, PEN and Assis, V and Tibana, RA and Neves, RVP and Rosa, TDS and Prestes, J and da Silva, ASR and Marqueti, RC}, title = {Paternal exercise induces antioxidant defenses by α-Klotho/Keap1 pathways in the skeletal muscle of offspring exposed to a high fat-diet without changing telomere length.}, journal = {The Journal of nutritional biochemistry}, volume = {}, number = {}, pages = {109747}, doi = {10.1016/j.jnutbio.2024.109747}, pmid = {39197728}, issn = {1873-4847}, abstract = {Although previous studies demonstrated that the ancestral lifestyle can enhance the metabolic health of offspring exposed to an obesogenic diet, the specific connections between these positive effects in redox state and telomere length are unknown. We investigated the impact of paternal resistance training (RT) on stress-responsive signaling and the pathways involved in telomere homeostasis in skeletal muscle. This investigation encompassed both the fathers and first-generation litter exposed to a long-term standard diet (24 weeks) and high fat diet (HFD). Wistar rats were randomized into sedentary or trained fathers (8 weeks of resistance training). The offspring were obtained by mating with sedentary females. Upon weaning, male offspring were divided into four groups: offspring of sedentary or trained fathers exposed to either a control diet or HFD. The gastrocnemius was prepared for reverse transcription-quantitative polymerase chain reaction, immunoblotting, ELISA, and electron paramagnetic resonance spectroscopy. RT upregulated shelterin mRNA levels and antioxidant protein, preserving muscle telomere in fathers. Conversely, HFD induced a disturbance in the redox balance, which may have contributed to the offspring telomere shortening from sedentary fathers. Pre-conceptional paternal RT downregulates Kelch-like ECH-associated protein 1 (Keap1) mRNA levels in the skeletal muscle of progeny exposed to HFD, driving an increase in Glutathione reductase mRNA levels, Sod1 and Catalase protein levels to mitigate ROS production. Also, paternal exercise upregulates α-Klotho protein levels, mediating antioxidative responses without altering shelterin mRNA levels and telomere length. We provide the first in-depth analysis that the offspring's redox state seems to be directly associated with the beneficial effects of paternal exercise.}, }
@article {pmid39197110, year = {2024}, author = {Roka, K and Solomou, E and Kattamis, A and Stiakaki, E}, title = {Telomere biology disorders: from dyskeratosis congenita and beyond.}, journal = {Postgraduate medical journal}, volume = {}, number = {}, pages = {}, doi = {10.1093/postmj/qgae102}, pmid = {39197110}, issn = {1469-0756}, abstract = {Defective telomerase function or telomere maintenance causes genomic instability. Alterations in telomere length and/or attrition are the primary features of rare diseases known as telomere biology disorders or telomeropathies. Recent advances in the molecular basis of these disorders and cutting-edge methods assessing telomere length have increased our understanding of this topic. Multiorgan manifestations and different phenotypes have been reported even in carriers within the same family. In this context, apart from dyskeratosis congenita, disorders formerly considered idiopathic (i.e. pulmonary fibrosis, liver cirrhosis) frequently correlate with underlying defective telomere maintenance mechanisms. Moreover, these patients are prone to developing specific cancer types and exhibit exceptional sensitivity and toxicity in standard chemotherapy regimens. The current review describes the diverse spectrum of clinical manifestations of telomere biology disorders in pediatric and adult patients, their correlation with pathogenic variants, and considerations during their management to increase awareness and improve a multidisciplinary approach.}, }
@article {pmid39195250, year = {2024}, author = {Ghilain, C and Vidal-Cruchez, O and Joly, A and Debatisse, M and Gilson, E and Giraud-Panis, MJ}, title = {Innovative Tools for DNA Topology Probing in Human Cells Reveal a Build-Up of Positive Supercoils Following Replication Stress at Telomeres and at the FRA3B Fragile Site.}, journal = {Cells}, volume = {13}, number = {16}, pages = {}, doi = {10.3390/cells13161361}, pmid = {39195250}, issn = {2073-4409}, support = {TELOCHROM//Agence Nationale de la Recherche/ ; REPLITOP//French National Cancer Institute/ ; Equipe labellisée//Fondation ARC pour la Recherche sur le Cancer/ ; }, mesh = {Humans ; *Telomere/metabolism ; *DNA, Superhelical/metabolism ; *DNA Replication ; Chromosome Fragile Sites ; Telomeric Repeat Binding Protein 2/metabolism/genetics ; Nucleic Acid Conformation ; DNA/metabolism ; DNA Topoisomerases, Type II/metabolism ; }, abstract = {Linear unconstrained DNA cannot harbor supercoils since these supercoils can diffuse and be eliminated by free rotation of the DNA strands at the end of the molecule. Mammalian telomeres, despite constituting the ends of linear chromosomes, can hold supercoils and be subjected to topological stress. While negative supercoiling was previously observed, thus proving the existence of telomeric topological constraints, positive supercoils were never probed due to the lack of an appropriate tool. Indeed, the few tools available currently could only investigate unwound (Trioxsalen) or overwound (GapR) DNA topology (variations in twist) but not the variations in writhe (supercoils and plectonemes). To address this question, we have designed innovative tools aimed at analyzing both positive and negative DNA writhe in cells. Using them, we could observe the build-up of positive supercoils following replication stress and inhibition of Topoisomerase 2 on telomeres. TRF2 depletion caused both telomere relaxation and an increase in positive supercoils while the inhibition of Histone Deacetylase I and II by TSA only caused telomere relaxation. Moving outside telomeres, we also observed a build-up of positive supercoils on the FRA3B fragile site following replication stress, suggesting a topological model of DNA fragility for this site.}, }
@article {pmid39192622, year = {2024}, author = {Aali, R and Asli Gharehbagh, H and Gholampour, A and Sorooshian, A and Panahi, Y}, title = {Children exposed to salt-dust emission from Urmia Lake have short telomere length: a case-control pilot study.}, journal = {International journal of environmental health research}, volume = {}, number = {}, pages = {1-8}, doi = {10.1080/09603123.2024.2394136}, pmid = {39192622}, issn = {1369-1619}, abstract = {This study aimed to measure telomere length in healthy children living next to Urmia Lake, Iran, which is exposed to salt dust from a drying lakebed. In this case-control pilot study, we recruited 39 sex- and age-matched healthy children from two different geographic regions to study the relative telomere lengths using qPCR. We categorized the study samples into high-impact and low-impact areas based on wind direction, aerosol particle level, and distance from the lake. Our main results revealed that children living in high-impact areas have shorter telomeres than those living in low-impact areas. Furthermore, according to our statistical model, parental age significantly affected telomere length in children, but inversely. When the father's age impact was positive, the mother had a negative effect. Based on our results, to prevent Urmia Lake from dying out completely, national and international organizations should implement comprehensive visions and strategies for its restoration.}, }
@article {pmid39192284, year = {2024}, author = {Zhuang, X and Chen, P and Yang, R and Man, X and Wang, R and Shi, Y}, title = {Mendelian randomization analysis reveals the combined effects of epigenetics and telomere biology in hematologic cancers.}, journal = {Clinical epigenetics}, volume = {16}, number = {1}, pages = {120}, pmid = {39192284}, issn = {1868-7083}, support = {Y20240077//the Public Welfare Science and Technology Project of Wenzhou/ ; Y20240077//the Public Welfare Science and Technology Project of Wenzhou/ ; Y20240077//the Public Welfare Science and Technology Project of Wenzhou/ ; Y20240077//the Public Welfare Science and Technology Project of Wenzhou/ ; Y20240077//the Public Welfare Science and Technology Project of Wenzhou/ ; Y20240077//the Public Welfare Science and Technology Project of Wenzhou/ ; No. LQ19H080002//Natural Science Foundation of Zhejiang Province/ ; }, abstract = {BACKGROUND: Telomere shortening and epigenetic modifications are key factors in aging and hematologic diseases. This study investigates the relationship of telomere length and epigenetic age acceleration (EAA) with hematologic cancers, blood cells, and biochemical markers through the epigenetic clocks.
METHODS: This study primarily utilizes genome-wide association studies of populations of European descent as instrumental variables, exploring the causal relationships between exposures and outcomes through a bidirectional two-sample Mendelian randomization (MR) approach. MR techniques include inverse variance weighted (IVW), MR Egger, and weighted median modes. Heterogeneity and pleiotropy in MR are assessed using Cochran's Q test and the MR Egger intercept, with the robustness of the conclusions further validated by multivariable MR (MVMR).
RESULTS: Our research shows that longer telomere lengths significantly increase the risk of multiple myeloma, leukemia, and lymphoma (OR > 1, P < 0.05) and establish a causal relationship between telomere length and red blood cell indices such as RBC (OR = 1.121, PIVW = 0.034), MCH (OR = 0.801, PIVW = 2.046e-06), MCV (OR = 0.801, PIVW = 0.001), and MCHC (OR = 0.813, PIVW = 0.002). Additionally, MVMR analysis revealed an association between DNA methylation PhenoAge acceleration and alkaline phosphatase (OR = 1.026, PIVW = 0.007).
CONCLUSION: The study clarifies the relationships between telomere length, EAA, and hematological malignancies, further emphasizing the prognostic significance of telomere length and EAA. This deepens our understanding of the pathogenesis of hematological diseases, which can inform risk assessment and therapeutic strategies.}, }
@article {pmid39192095, year = {2024}, author = {Burren, OS and Dhindsa, RS and Deevi, SVV and Wen, S and Nag, A and Mitchell, J and Hu, F and Loesch, DP and Smith, KR and Razdan, N and Olsson, H and Platt, A and Vitsios, D and Wu, Q and , and Codd, V and Nelson, CP and Samani, NJ and March, RE and Wasilewski, S and Carss, K and Fabre, M and Wang, Q and Pangalos, MN and Petrovski, S}, title = {Genetic architecture of telomere length in 462,666 UK Biobank whole-genome sequences.}, journal = {Nature genetics}, volume = {}, number = {}, pages = {}, pmid = {39192095}, issn = {1546-1718}, support = {MR/M012816/1//RCUK | Medical Research Council (MRC)/ ; MR/M012816/1//RCUK | Medical Research Council (MRC)/ ; MR/M012816/1//RCUK | Medical Research Council (MRC)/ ; BRC-1215-20010//DH | National Institute for Health Research (NIHR)/ ; BRC-1215-20010//DH | National Institute for Health Research (NIHR)/ ; BRC-1215-20010//DH | National Institute for Health Research (NIHR)/ ; MR/M012816/1//British Heart Foundation (BHF)/ ; }, abstract = {Telomeres protect chromosome ends from damage and their length is linked with human disease and aging. We developed a joint telomere length metric, combining quantitative PCR and whole-genome sequencing measurements from 462,666 UK Biobank participants. This metric increased SNP heritability, suggesting that it better captures genetic regulation of telomere length. Exome-wide rare-variant and gene-level collapsing association studies identified 64 variants and 30 genes significantly associated with telomere length, including allelic series in ACD and RTEL1. Notably, 16% of these genes are known drivers of clonal hematopoiesis-an age-related somatic mosaicism associated with myeloid cancers and several nonmalignant diseases. Somatic variant analyses revealed gene-specific associations with telomere length, including lengthened telomeres in individuals with large SRSF2-mutant clones, compared with shortened telomeres in individuals with clonal expansions driven by other genes. Collectively, our findings demonstrate the impact of rare variants on telomere length, with larger effects observed among genes also associated with clonal hematopoiesis.}, }
@article {pmid39190187, year = {2024}, author = {Milosevic, T and Naumovic, R and Sopic, M and Vekic, J and Guzonjic, A and Pesic, S and Miljkovic-Trailovic, M and Kotur-Stevuljevic, J}, title = {COVID-19 increases mortality in hemodialysis patients: exploring links with inflammation and telomere attrition.}, journal = {Molecular biology reports}, volume = {51}, number = {1}, pages = {938}, pmid = {39190187}, issn = {1573-4978}, support = {451-03-47/2023 01/ 200161//Ministry of Education, Science, and Technological Development, Republic of Serbia, through Grant Agreement with the University of Belgrade-Faculty of Pharmacy/ ; 451-03-47/2023 01/ 200161//Ministry of Education, Science, and Technological Development, Republic of Serbia, through Grant Agreement with the University of Belgrade-Faculty of Pharmacy/ ; 451-03-47/2023 01/ 200161//Ministry of Education, Science, and Technological Development, Republic of Serbia, through Grant Agreement with the University of Belgrade-Faculty of Pharmacy/ ; 451-03-47/2023 01/ 200161//Ministry of Education, Science, and Technological Development, Republic of Serbia, through Grant Agreement with the University of Belgrade-Faculty of Pharmacy/ ; 451-03-47/2023 01/ 200161//Ministry of Education, Science, and Technological Development, Republic of Serbia, through Grant Agreement with the University of Belgrade-Faculty of Pharmacy/ ; }, mesh = {Humans ; *COVID-19/mortality/virology ; Male ; Female ; *Renal Dialysis ; Middle Aged ; Aged ; *C-Reactive Protein/metabolism ; *Inflammation ; Lymphocytes/metabolism ; Neutrophils/metabolism ; Telomere/genetics/metabolism ; SARS-CoV-2 ; L-Lactate Dehydrogenase/blood ; Kaplan-Meier Estimate ; Kidney Failure, Chronic/therapy/mortality/blood ; }, abstract = {BACKGROUND AND OBJECTIVE: An increased risk of mortality and hospitalization was consistently demonstrated in hemodialysis (HD) patients affected by pandemic coronavirus infection (COVID-19). In this study, we analyzed parameters that may impact mortality in COVID-19 HD patients, including neutrophil-to-lymphocyte ratio (NLR), lactate dehydrogenase (LDH), C-reactive protein (CRP), COVID-19 disease status and telomere length in peripheral blood cells (TL).
MATERIALS AND METHODS: A total of 130 chronic hemodialysis patients were enrolled and followed up for 18 months. Patients were categorized into groups based on their COVID-19 disease history and subsequent data about their survival status at the end of the study. Routine laboratory parameters were assessed using standard automated methods and TL was determined using the modified Cawthon method. Survival predictors were analyzed using Kaplan-Meier analysis.
RESULTS: Deceased patients (30%) were older with higher body mass index (BMI), higher levels of LDH, NLR index, CRP and lower TL and lymphocytes count compared to survivors. Kaplan-Meier survival analysis showed six parameters were significant mortality predictors in the following order of significance: COVID-19 history, 2-years cardiovascular mortality risk score, NLR, TL, CRP, LDH. Using binary logistic regression analysis Summary risk score, a combination of these six parameters revealed as the best predictor of patient's survival in this group of parameters (log rank 25.4, p < 0.001).
CONCLUSION: Compared to the general population, the mortality rate among HD patients persists at a higher level despite advancements in HD technology and patient care. The situation has been exacerbated by COVID-19, by significant increase in mortality rate among these patients.}, }
@article {pmid39189448, year = {2024}, author = {Wondimagegnhu, B and Ma, W and Paul, T and Liao, TW and Lee, CY and Sanford, S and Opresko, PL and Myong, S}, title = {The molecular mechanism for TERRA recruitment and annealing to telomeres.}, journal = {Nucleic acids research}, volume = {}, number = {}, pages = {}, doi = {10.1093/nar/gkae732}, pmid = {39189448}, issn = {1362-4962}, support = {F31CA268939/GF/NIH HHS/United States ; }, abstract = {Telomeric repeat containing RNA (TERRA) is a noncoding RNA that is transcribed from telomeres. Previous study showed that TERRA trans anneals by invading into the telomeric duplex to form an R-loop in mammalian cells. Here, we elucidate the molecular mechanism underlying TERRA recruitment and invasion into telomeres in the context of shelterin proteins, RAD51 and RNase H using single molecule (sm) assays. We demonstrate that TERRA trans annealing into telomeric DNA exhibits dynamic movement that is stabilized by TRF2. TERRA annealing to the telomeric duplex results in the formation of a stable triplex structure which differs from a conventional R-loop. We identified that the presence of a sub-telomeric DNA and a telomeric overhang in the form of a G-quadruplex significantly enhances TERRA annealing to telomeric duplex. We also demonstrate that RAD51-TERRA complex invades telomere duplex more efficiently than TERRA alone. Additionally, TRF2 increases TERRA affinity to telomeric duplex and protects it from RNase H digestion. In contrast, TRF1 represses TERRA annealing to telomeric duplex and fails to provide protection against RNase H digestion. Our findings provide an in-depth molecular mechanism underpinning TERRA recruitment and annealing to the telomere.}, }
@article {pmid39188883, year = {2024}, author = {Murillo-Ortiz, BO and García-Corrales, K and Martínez-Garza, S and Romero-Vázquez, MJ and Agustín-Godínez, E and Escareño-Gómez, A and Silva-Guerrero, DG and Mendoza-Ramírez, S and Murguia-Perez, M}, title = {Association of hTERT expression, Her2Neu, estrogen receptors, progesterone receptors, with telomere length before and at the end of treatment in breast cancer patients.}, journal = {Frontiers in medicine}, volume = {11}, number = {}, pages = {1450147}, pmid = {39188883}, issn = {2296-858X}, abstract = {BACKGROUND: Breast cancer shows significant clinical, morphologic, and molecular variation. Telomeres are nucleoprotein complexes composed of hexanucleotide repeat DNA sequence, TTAGGG, and numerous telomere-associated proteins. The maintenance of telomere length is carried out by a ribonucleoprotein called telomerase, which consists of two main components: a catalytic subunit called hTERT (human telomerase reverse transcriptase) and an RNA template called hTR (human telomerase RNA). The importance of evaluating hTERT expression lies in its potential therapeutic application, being an attractive target due to its almost non-existent expression in normal somatic cells. It is also expected that the anti-neoplastic effect would appear earlier in neoplastic cells with shorter telomeres. Additionally, a significant relationship has been observed between Her2-Neu overexpression and Her2-Neu positivity, which could suggest new combined therapies.The aim of this study was to detect the expression of hTERT, estrogen receptor (ER), progesterone receptor (PR), and HER2-Neu in neoplastic breast tissue embedded in paraffin before treatment and to investigate the relationship between them and with baseline and post-treatment telomere length, as well as with various clinicopathological parameters.
MATERIALS AND METHODS: A cross-sectional-correlational, 21 women diagnosed with breast cancer at the Oncology Service of the High Specialty Medical Unit No. 1 of Bajio of the Mexican Institute of Social Security. The study complies with the Helsinki Declaration and was approved by the Institutional Ethical Committee of the Mexican Institute of Social Security (R-2019-1001-127). A peripheral blood sample was obtained before oncological treatment and at the end of oncological treatment for the measurement of telomere length by extracting DNA from leukocytes, was performed by the quantitative polymerase chain reaction (PCR) method described by Cawthon. Tumor samples were collected from each patient at the oncology department for immunohistochemical determination of biomarker expression (ER, PR, Her2/neu) and hTERT.
RESULTS: Of the 21 cases included in the study, the median age was 57.57 years. Eighteen cases were classified as invasive ductal carcinoma NOS (85.71%), 10 were histologic grade 2 (47.61%), 16 cases were hormone receptor positive (76.19%), 7 were Her2Neu positive (33.33%), and only 2 cases were triple negative (9.52%). Positive hTERT expression was detected in 11 cases (52.38%) and was negative in the remaining cases. A significant association was identified between hTERT-positive cases and Her2-Neu positive cases (p = 0.04). Baseline and post-treatment telomere lengths showed a significant difference using the non-parametric Wilcoxon t-test (p = 0.002). In hTERT-positive cases, there was significant telomere shortening at the end of oncological treatment (6.14 ± 1.54 vs. 4.75 ± 1.96 Kb, p = 0.007).
CONCLUSION: Positive hTERT immunostaining cases were associated with poor prognostic factors, such as Her2-Neu overexpression and post-treatment telomere shortening. In the future, hTERT immunostaining could be used to select patients for therapies with antagonistic effects on hTERT, as well as in the selection of more appropriate chemotherapy regimens for patients who express it.}, }
@article {pmid39188229, year = {2024}, author = {Kim, D and Danpanichkul, P and Wijarnpreecha, K and Cholankeril, G and Ahmed, A}, title = {Leukocyte Telomere Shortening in MASLD and All-cause/Cause-specific Mortality.}, journal = {Clinical and molecular hepatology}, volume = {}, number = {}, pages = {}, doi = {10.3350/cmh.2024.0691}, pmid = {39188229}, issn = {2287-285X}, }
@article {pmid39180127, year = {2024}, author = {Song, Y and Xu, J and Geng, W and Yin, L and Wang, J and Zhao, J}, title = {Association and causal impact of TERT genetic variants on peripheral blood leukocyte telomere length and cerebral small vessel disease risk in a Chinese Han population: a mendelian randomization analysis.}, journal = {Orphanet journal of rare diseases}, volume = {19}, number = {1}, pages = {309}, pmid = {39180127}, issn = {1750-1172}, support = {no. 19-1124-038//Shenyang Science and Technology Bureau, China/ ; }, mesh = {Humans ; *Telomerase/genetics ; *Mendelian Randomization Analysis ; *Cerebral Small Vessel Diseases/genetics ; *Polymorphism, Single Nucleotide/genetics ; Female ; *Leukocytes/metabolism ; Male ; Middle Aged ; Asian People/genetics ; Aged ; Telomere/genetics ; Genetic Predisposition to Disease ; Genotype ; China ; Risk Factors ; East Asian People ; }, abstract = {BACKGROUND: Previous observational studies have highlighted potential relationships between the telomerase reverse transcriptase (TERT) gene, short leukocyte telomere length (LTL), and cerebrovascular disease. However, it remains to be established as to whether TERT gene variants are associated with an elevated risk of cerebral small vessel disease (CSVD), and whether there is a causal relationship between LTL and CSVD.
METHODS: Five TERT single nucleotide polymorphisms (SNPs) were analyzed in 307 CSVD patients and 320 healthy controls in whom LTL values were quantified. Allele models and four genetic models were used to explore the relationship between these SNP genotypes and CSVD risk. A Mendelian randomization analysis of CSVD risk was then performed using LTL-related SNPs and the polygenic risk score (PRS) constructed from these SNPs as genetic instrumental variables to predict the causal relationship between LTL and CSVD risk.
RESULTS: Model association analyses identified two SNPs that were significantly associated with CSVD risk. LTL was significantly correlated with age (P < 0.001), and the MR analysis revealed an association between short LTL and an elevated risk of CSVD. PRS-based genetic prediction of short LTLs was also significantly related to an elevated CSVD risk.
CONCLUSION: Multiple genetic models and MR results indicate that TERT gene SNPs may be related to an elevated risk of CSVD, and that shorter LTL may be causally linked to such CSVD risk.}, }
@article {pmid39179728, year = {2024}, author = {Jin, Z and Liu, X and Guo, H and Chen, S and Zhu, X and Pan, S and Wu, Y}, title = {Sex-specific modulating role of social support in the associations between oxidative stress, inflammation, and telomere length in older adults.}, journal = {Journal of behavioral medicine}, volume = {}, number = {}, pages = {}, pmid = {39179728}, issn = {1573-3521}, support = {81971019//National Natural Science Foundation of China/ ; 82271482//National Natural Science Foundation of China/ ; }, abstract = {Telomere length, a biomarker of human aging, is related to adverse health outcomes. Growing evidence indicates that oxidative stress and inflammation contributes to telomere shortening, whereas social support may protect from telomere shortening. Despite sex differences in telomere length and social support, little is known about whether there are sex differences in the relationship between oxidative stress/inflammation and telomere length, and sex-specific moderating roles of social support in older adults. Using data from the National Health and Nutrition Examination Survey (NHANES) 1999-2002, this study assessed whether the associations between oxidative stress/inflammation and telomere length vary with sex and explored social support as a moderator in these associations among 2289 older adults. Oxidative stress was measured based on serum Gamma-glutamyl transferase (GGT), and inflammation was measured based on C-reactive protein (CRP). After adjusting for the covariates, GGT was significantly associated with telomere length in females only (β = - 0.037, 95% CI = - 0.070, - 0.005), while CRP was associated with telomere length in males only (β = - 0.019, 95% CI = - 0.035, - 0.002). Moreover, high social support mitigated the negative association between GGT and telomere length, which was more evident in females. Furthermore, social support moderated the association between CRP and telomere length in males aged 70 and above. Our findings indicated that biological mechanisms related to telomere length may vary with sex, while social support plays a sex-specific moderating role.}, }
@article {pmid39178054, year = {2024}, author = {Squassina, A and Pisanu, C and Menesello, V and Meloni, A and Congiu, D and Manchia, M and Paribello, P and Abate, M and Bortolomasi, M and Baune, BT and Gennarelli, M and Minelli, A}, title = {Leukocyte Telomere Length and Mitochondrial DNA Copy Number in Treatment-Resistant Depression and Response to Electroconvulsive Therapy: A Pilot Longitudinal Study.}, journal = {The journal of ECT}, volume = {}, number = {}, pages = {}, doi = {10.1097/YCT.0000000000001060}, pmid = {39178054}, issn = {1533-4112}, abstract = {OBJECTIVES: In this study, we investigated if changes in leukocyte telomere length (LTL) and mitochondrial DNA copy number (mtDNA-cn), 2 markers of cellular aging, are associated with treatment-resistant depression (TRD) and with response to electroconvulsive therapy (ECT).
METHODS: LTL and mtDNA-cn were measured in 31 TRD patients before (T0), 1 week (T1), and 4 weeks (T2) after the ECT course, as well as in a sample of 65 healthy controls.
RESULTS: TRD patients had significantly shorter LTL and higher mtDNA-cn compared with healthy controls at baseline. In the TRD sample, LTL was inversely correlated with Montgomery-Åsberg Depression Rating Scale scores at baseline. Baseline levels of LTL or mtDNA-cn were not correlated with response to ECT. Similarly, changes in LTL or mtDNA-cn were not associated with response to ECT either when considered as a dichotomous trait (responders vs nonresponders) or as a percentage change in symptoms improvements.
CONCLUSIONS: Ours is the first longitudinal study exploring the role of LTL and mtDNA-cn in response to ECT. Findings of this pilot investigation suggest that LTL and mtDNA-cn may constitute disease biomarkers for TRD but are not involved in response to ECT.}, }
@article {pmid39177475, year = {2024}, author = {He, Z and Wu, J and Li, W and Du, Y and Lu, L}, title = {Investigation of G-Quadruplex DNA-Mediated Charge Transport for Exploring DNA Oxidative Damage in Telomeres.}, journal = {Langmuir : the ACS journal of surfaces and colloids}, volume = {}, number = {}, pages = {}, doi = {10.1021/acs.langmuir.4c01604}, pmid = {39177475}, issn = {1520-5827}, abstract = {The human telomeric DNA 3' single-stranded overhang comprises tandem repeats of the sequence d(TTAGGG), which can fold into the stable secondary structure G-quadruplex (G4) and is susceptible to oxidative damage due to the enrichment of G bases. 8-Oxoguanine (8-oxoG) formed in telomeric DNA destabilizes G4 secondary structures and then inhibits telomere functions such as the binding of G4 proteins and the regulation of the length of telomeres. In this work, we developed a G4-DNA self-assembled monolayer electrochemical sensing interface using copper-free click chemistry based on the reaction of dibenzocyclooctyl with azide, resulting in a high yield of DNA tethers with order and homogeneity surfaces, that is more suitable for G-quadruplex DNA charge transport (CT) research. At high DNA coverage density surfaces, G-quadruplex DNA is 4 times more conductive than double-stranded DNA owing to the well-stacked aromatic rings of G-quartets acting as good charge transfer channels. The effect of telomeric oxidative damage on G-quadruplex-mediated CT is investigated. The accommodation of 8-oxoG at G sites originally in the syn or anti conformation around the glycosyl bond in the nonsubstituted hTel G-quadruplex causes structural perturbation and a conformational shift, which disrupts the π-stack, affecting the charge transfer and attenuating the electrochemical signal. The current intensity was found to correlate with the amount of 8-oxodG, and the detection limit was estimated to be approximately one lesion in 286 DNA bases, which can be converted into 64.7 fmol on the basis of the total surface DNA coverage. The improved G4-DNA order and homogeneity sensing interface represent a major step forward in this regard, providing a reliable and controlled electrochemical platform for the accurate measurement and diagnosis of G4-DNA oxidative damage.}, }
@article {pmid39173315, year = {2024}, author = {Vaz, D and Vasconcelos, S and Caniçais, C and Costa, B and Ramalho, C and Marques, J and Dória, S}, title = {X-chromosome inactivation pattern and telomere length in recurrent pregnancy loss.}, journal = {Reproductive biology}, volume = {24}, number = {4}, pages = {100933}, doi = {10.1016/j.repbio.2024.100933}, pmid = {39173315}, issn = {2300-732X}, abstract = {Recurrent pregnancy loss is a reproductive disorder affecting about 1 to 5 % of pregnant women worldwide that requires our attention, especially considering that about 50 % of cases are idiopathic. The present study is focused on testing a possible association between extreme skewed X-chromosome inactivation patterns and/or shortened telomeres with idiopathic cases since both are considered non-consensual potential causes underlying recurrent pregnancy loss in the scientific community. For this purpose, two groups of women were analyzed and compared: a group of women with idiopathic recurrent pregnancy loss and a second group of age-matched women with proven fertility, and both X-chromosome inactivation patterns and telomere length were measured and compared from maternal DNA extracted from peripheral blood. Our data showed no statistically significant differences between groups, suggesting no association between extreme skewed X-chromosome inactivation or shortened telomeres with recurrent pregnancy losses. Additionally, the effect of maternal age on both X-chromosome inactivation pattern and telomere length was tested, but no significant correlation was observed between advanced maternal age and extreme skewed X-chromosome inactivation or telomere shortening. This study represents one more valid contribution to the investigation of causes underlying recurrent pregnancy loss suggesting that, new variables may be considered since the pattern of X-chromosome inactivation and telomere length do not seem to be related to this reproductive disorder. Briefly, considering its clinical relevance, it is mandatory a continuous effort in the scientific community to cover new potential recurrent pregnancy loss-related causes.}, }
@article {pmid39174689, year = {2024}, author = {Spinou, M and Naska, A and Nelson, CP and Codd, V and Samani, NJ and Bountziouka, V}, title = {Micronutrient intake and telomere length: findings from the UK Biobank.}, journal = {European journal of nutrition}, volume = {}, number = {}, pages = {}, pmid = {39174689}, issn = {1436-6215}, support = {MR/M012816/1/MRC_/Medical Research Council/United Kingdom ; }, abstract = {PURPOSE: To investigate whether micronutrient intake from food as well as the regular uptake of specific vitamins and/or minerals are associated with leucocyte telomere length (LTL).
METHODS: This is a cross-sectional study using data from 422,693 UK Biobank participants aged from 40 to 69 years old, during 2006-2010. LTL was measured as the ratio of telomere repeat number to a single-copy gene and was loge-transformed and z-standardized (z-LTL). Information concerning supplement use was collected at baseline through the touchscreen assessment, while micronutrient intake from food were self-reported through multiple web-based 24 h recall diaries. The association between micronutrient intake or supplement use and z-LTL was assessed using multivariable linear regression models adjusting for demographic, lifestyle and clinical characteristics.
RESULTS: About 50% (n = 131,810) of the participants, with complete data on all covariates, self-reported regular supplement intake. Whilst overall supplement intake was not associated with z-LTL, trends toward shorter z-LTL with regular vitamin B (-0.019 (95% CI: -0.041; 0.002)) and vitamin B9 (-0.027 (-0.054; 0.000)) supplement intake were observed. z-LTL was associated with food intake of pantothenic acid (-0.020 (-0.033; -0.007)), vitamin B6 (-0.015 (-0.027; -0.003)), biotin (0.010 (0.002; 0.018)) and folate (0.016 (0.003; 0.030)). Associations of z-LTL with these micronutrients were differentiated according to supplement intake.
CONCLUSION: Negative associations equivalent to a year or less of age-related change in LTL between micronutrient intake and LTL were observed. Due to this small effect, the clinical importance of the associations and any relevance to the effects of vitamin and micronutrient intake toward chronic disease prevention remains uncertain.}, }
@article {pmid39170634, year = {2024}, author = {Domínguez-de-Barros, A and Sifaoui, I and Dorta-Guerra, R and Lorenzo-Morales, J and Castro-Fuentes, R and Córdoba-Lanús, E}, title = {DNA damage (8-OHdG) and telomere length in captive Psittacidae birds with different longevity.}, journal = {Frontiers in veterinary science}, volume = {11}, number = {}, pages = {1430861}, pmid = {39170634}, issn = {2297-1769}, abstract = {Aging is a complex process influenced by internal and external factors. Oxidative stress damages DNA, leading to 8-hydroxy-2' deoxyguanosine formation (8-OHdG). Telomere shortening is considered a biomarker of aging and oxidative stress may enhance its attrition. The ability to manage and repair oxidative stress varies among species and life histories. Avian species, such as Psittacidae birds, exhibit exceptional lifespans despite their physiological characteristics that might suggest otherwise. This study investigates 8-OHdG levels in serum samples from long- and short-lived birds of the order Psittaciformes, examining their relationship with telomere length and antioxidant capacity based on lifespan strategies. Among 43 individuals analyzed 26 belonged to the "long-lived species" group and 17 belonged to the "short-lived species" one. Relative telomere length (rTL) was measured in DNA isolated from whole blood by qPCR, and oxidative stress markers, such as Total Antioxidant Capacity (TAC) and 8-OHdG, were determined by spectrophotometry in serum samples. Long-lived birds had longer rTL than short-lived ones [1.308 ± 0.11 vs. 0.565 ± 0.13, (p < 0.001)]. On the contrary, short-lived birds showed more DNA damage than their counterparts [3.847 ± 0.351 vs. 2.012 ± 0.308, respectively, (p < 0.001)]. Old birds had shorter rTL than young ones, for both longevity groups (p < 0.001). Although no correlation was found between 8-OHdG levels and age, nor 8-OHdG and telomere length, long-lived birds exhibited 75.42-unit increased TAC levels when increased 8-OHdG concentrations (p = 0.046). These findings highlight distinct patterns of telomere length and oxidative stress influenced by lifespan strategies among avian longevity groups.}, }
@article {pmid39164231, year = {2024}, author = {Ghosh, S and Nguyen, MT and Choi, HE and Stahl, M and Kühn, AL and Van der Auwera, S and Grabe, HJ and Völzke, H and Homuth, G and Myers, SA and Hogaboam, CM and Noth, I and Martinez, FJ and Petsko, GA and Glimcher, LH}, title = {RIOK2 transcriptionally regulates TRiC and dyskerin complexes to prevent telomere shortening.}, journal = {Nature communications}, volume = {15}, number = {1}, pages = {7138}, pmid = {39164231}, issn = {2041-1723}, mesh = {Humans ; *Idiopathic Pulmonary Fibrosis/genetics/metabolism/pathology ; *Telomere Shortening ; *Telomerase/metabolism/genetics ; *Nuclear Proteins/metabolism/genetics ; *Cell Cycle Proteins/metabolism/genetics ; Fibroblasts/metabolism ; Myelodysplastic Syndromes/genetics/metabolism ; Telomere/metabolism/genetics ; Gene Expression Regulation ; Lung/metabolism/pathology ; }, abstract = {Telomere shortening is a prominent hallmark of aging and is emerging as a characteristic feature of Myelodysplastic Syndromes (MDS) and Idiopathic Pulmonary Fibrosis (IPF). Optimal telomerase activity prevents progressive shortening of telomeres that triggers DNA damage responses. However, the upstream regulation of telomerase holoenzyme components remains poorly defined. Here, we identify RIOK2, a master regulator of human blood cell development, as a critical transcription factor for telomere maintenance. Mechanistically, loss of RIOK2 or its DNA-binding/transactivation properties downregulates mRNA expression of both TRiC and dyskerin complex subunits that impairs telomerase activity, thereby causing telomere shortening. We further show that RIOK2 expression is diminished in aged individuals and IPF patients, and it strongly correlates with shortened telomeres in MDS patient-derived bone marrow cells. Importantly, ectopic expression of RIOK2 alleviates telomere shortening in IPF patient-derived primary lung fibroblasts. Hence, increasing RIOK2 levels prevents telomere shortening, thus offering therapeutic strategies for telomere biology disorders.}, }
@article {pmid39159130, year = {2024}, author = {Maimaiti, A and Ma, J and Hao, C and Han, D and Wang, Y and Wang, Z and Abudusalamu, R}, title = {DNA methylation-estimated phenotypes, telomere length and risk of ischemic stroke: epigenetic age acceleration of screening and a Mendelian randomization study.}, journal = {Aging}, volume = {16}, number = {}, pages = {}, doi = {10.18632/aging.206072}, pmid = {39159130}, issn = {1945-4589}, abstract = {BACKGROUND: Aging is a complex biological process that may be accelerated in certain pathological conditions. DNA methylation age (DNAmAge) has emerged as a biomarker for biological age, which can differ from chronological age. This research peels back the layers of the relationship between fast-forward aging and ischemic stroke, poking and prodding the potential two-way causal influences between stroke and biological aging indicators.
METHODS: We analyzed a cohort of ischemic stroke patients, comparing DNAmAge with chronological age to measure age acceleration. We assessed variations in age acceleration among stroke subtypes and between sexes. Using Mendelian randomization, we examined the causal links between stroke, aging biomarkers like telomere length, and age acceleration's effect on stroke risk.
RESULTS: Our investigation reveals a pronounced association between ischemic stroke and age acceleration, most notably in patients with cardioembolic strokes, who exhibited a striking median difference of 9 years between DNAmAge and chronological age. Furthermore, age acceleration differed significantly across stroke subtypes and was higher in women than in men. In terms of causality, MR analysis indicated a modest negative effect of stroke on telomere length, but no causal effect of age phenotypes on stroke or its subtypes. However, some indication of a potential causal effect of ischemic stroke on PhenoAge acceleration was observed.
CONCLUSION: The study provides insight into the relationship between DNAmAge and ischemic stroke, particularly cardioembolic stroke, and suggests possible gender differences. These insights carry profound clinical significance and set stage for future investigations into the entwined pathways of stroke and accelerated aging.}, }
@article {pmid39153550, year = {2024}, author = {Wang, SM and Chang, HH and Chang, YH and Tsai, TY and Chen, PS and Lu, RB and Wang, TY}, title = {Shortening of telomere length may be associated with inflammatory cytokine levels in patients with bipolar disorder.}, journal = {Journal of affective disorders}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jad.2024.08.084}, pmid = {39153550}, issn = {1573-2517}, abstract = {BACKGROUND: Bipolar disorder (BD) is hypothesized to be associated with accelerated biological aging. Telomere length (TL) is a biomarker of aging, and although TL decreases with each cell division, the rate of telomere shortening may be affected by inflammation. We aimed to investigate whether TL is decreased in BD patients and to determine the association between TL and inflammatory markers in such patients.
METHODS: 137 BD patients and 118 healthy controls (HCs) were recruited. Leukocyte TL and plasma levels of cytokines [tumor necrosis factor (TNF)-α, interleukin (IL)-8, IL-6, IL-10, transforming growth factor (TGF)-β1], C-reactive protein (CRP), and brain-derived neurotrophic factor (BDNF) were assessed.
RESULTS: TL did not differ significantly between the BD patients and HCs after adjustment for potential confounding factors (P = 0.79). TL was significantly negatively associated with age (β = -0.006, P < 0.001). In addition, log TNF-α levels were significantly negatively associated with TL (P = 0.009), in both the BD patients (P = 0.02) and HCs (P = 0.05).
CONCLUSION: We found a significant association between TNF-α levels and TL shortening in both BD patients and HCs. However, BD patients did not display increased TL shortening relative to HCs. Studies that involve larger sample sizes and control for the heterogeneity of BD participants will be needed.}, }
@article {pmid39151532, year = {2024}, author = {Liu, H and Yan, W and Li, J and Luo, D and Yan, D}, title = {Causal relationship between telomere length and osteonecrosis: Bidirectional two-sample Mendelian randomization analysis.}, journal = {Medicine}, volume = {103}, number = {33}, pages = {e39324}, doi = {10.1097/MD.0000000000039324}, pmid = {39151532}, issn = {1536-5964}, mesh = {*Mendelian Randomization Analysis ; Humans ; *Genome-Wide Association Study ; *Osteonecrosis/genetics ; Telomere Shortening/genetics ; Telomere/genetics ; Genetic Predisposition to Disease ; }, abstract = {Recent mounting evidence suggests that shortening of telomere length (TL) is associated with impaired bone health; yet, a genetic causal relationship between TL and osteonecrosis remains uncertain. This study aimed to investigate the potential causal relationship between TL and osteonecrosis using bidirectional two-sample Mendelian randomization (MR). Genome-wide association study summary statistics for TL were sourced from the IEU Open genome-wide association study project, while osteonecrosis data were obtained from the FinnGen Biobank database. A range of MR methodologies-including inverse variance weighting, MR-Egger, weighted median, simple mode, and weighted mode-were utilized for analysis, along with the MR-Egger intercept method for horizontal pleiotropy assessment, and Cochran Q and leave-one-out methods for heterogeneity testing. The forward MR analysis indicated a significant causal relationship between TL and osteonecrosis, suggesting that genetically predicted shorter TL is associated with an elevated risk of developing osteonecrosis (OR = 0.611, 95% confidence interval 0.394-0.948, P = .028). The reverse MR analysis revealed no significant influence of osteonecrosis on TL (OR = 0.999, 95% confidence interval 0.994-1.005, P = .802). Analyses for heterogeneity and horizontal pleiotropy yielded robust results. Our study demonstrates that individuals with shorter TL have an increased risk of developing osteonecrosis, whereas osteonecrosis has no effect on TL.}, }
@article {pmid39149261, year = {2024}, author = {Porubsky, D and Dashnow, H and Sasani, TA and Logsdon, GA and Hallast, P and Noyes, MD and Kronenberg, ZN and Mokveld, T and Koundinya, N and Nolan, C and Steely, CJ and Guarracino, A and Dolzhenko, E and Harvey, WT and Rowell, WJ and Grigorev, K and Nicholas, TJ and Oshima, KK and Lin, J and Ebert, P and Watkins, WS and Leung, TY and Hanlon, VCT and McGee, S and Pedersen, BS and Goldberg, ME and Happ, HC and Jeong, H and Munson, KM and Hoekzema, K and Chan, DD and Wang, Y and Knuth, J and Garcia, GH and Fanslow, C and Lambert, C and Lee, C and Smith, JD and Levy, S and Mason, CE and Garrison, E and Lansdorp, PM and Neklason, DW and Jorde, LB and Quinlan, AR and Eberle, MA and Eichler, EE}, title = {A familial, telomere-to-telomere reference for human de novo mutation and recombination from a four-generation pedigree.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2024.08.05.606142}, pmid = {39149261}, issn = {2692-8205}, abstract = {Using five complementary short- and long-read sequencing technologies, we phased and assembled >95% of each diploid human genome in a four-generation, 28-member family (CEPH 1463) allowing us to systematically assess de novo mutations (DNMs) and recombination. From this family, we estimate an average of 192 DNMs per generation, including 75.5 de novo single-nucleotide variants (SNVs), 7.4 non-tandem repeat indels, 79.6 de novo indels or structural variants (SVs) originating from tandem repeats, 7.7 centromeric de novo SVs and SNVs, and 12.4 de novo Y chromosome events per generation. STRs and VNTRs are the most mutable with 32 loci exhibiting recurrent mutation through the generations. We accurately assemble 288 centromeres and six Y chromosomes across the generations, documenting de novo SVs, and demonstrate that the DNM rate varies by an order of magnitude depending on repeat content, length, and sequence identity. We show a strong paternal bias (75-81%) for all forms of germline DNM, yet we estimate that 17% of de novo SNVs are postzygotic in origin with no paternal bias. We place all this variation in the context of a high-resolution recombination map (∼3.5 kbp breakpoint resolution). We observe a strong maternal recombination bias (1.36 maternal:paternal ratio) with a consistent reduction in the number of crossovers with increasing paternal (r=0.85) and maternal (r=0.65) age. However, we observe no correlation between meiotic crossover locations and de novo SVs, arguing against non-allelic homologous recombination as a predominant mechanism. The use of multiple orthogonal technologies, near-telomere-to-telomere phased genome assemblies, and a multi-generation family to assess transmission has created the most comprehensive, publicly available "truth set" of all classes of genomic variants. The resource can be used to test and benchmark new algorithms and technologies to understand the most fundamental processes underlying human genetic variation.}, }
@article {pmid39147445, year = {2024}, author = {Souza, MR and Garcia, ALH and Dalberto, D and Picinini, J and Touguinha, LBA and Salvador, M and da Silva, J}, title = {Multiple factors influence telomere length and DNA damage in individuals environmentally exposed to a coal-burning power plant.}, journal = {Mutation research. Genetic toxicology and environmental mutagenesis}, volume = {898}, number = {}, pages = {503793}, doi = {10.1016/j.mrgentox.2024.503793}, pmid = {39147445}, issn = {1879-3592}, mesh = {Humans ; Male ; *DNA Damage ; *Coal/adverse effects ; *Power Plants ; Middle Aged ; Adult ; *Environmental Exposure/adverse effects ; *Telomere/drug effects/genetics ; *Oxidative Stress/drug effects ; Telomere Shortening/drug effects ; Comet Assay ; Micronucleus Tests ; Coal Mining ; Occupational Exposure/adverse effects ; Aged ; Telomere Homeostasis/drug effects ; }, abstract = {Coal is a mixture of several chemicals, many of which have mutagenic and carcinogenic effects and are a key contributor to the global burden of mortality and disease. Previous studies suggest that coal is related to telomeric shortening in individuals occupationally exposed, however little is known about the effects of mining and burning coal on the telomeres of individuals living nearby. Therefore, the primary objective of this investigation was to assess the impact of proximity to coal power plants and coal mines on the genomic instability of individuals environmentally exposed, while also exploring potential associations with individual characteristics, oxidative stress, inflammatory responses, and the presence of inorganic elements. This study involved 80 men participants from three cities around a thermoelectric power plant and one city unexposed to coal and byproducts. DNA was extracted from peripheral blood samples obtained from each participant, and the telomeres length (TL) was assessed using quantitative real-time polymerase chain reaction (qPCR) methodology. No significant difference was observed between exposed individuals (6227 ± 2884 bp) when compared to the unexposed group (5638 ± 2452 bp). Nevertheless, TL decrease was associated with age and risk for cardiovascular disease; and longer TL was found to be linked with increased concentrations of silicon and phosphorus in blood samples. No correlations were observed between TL with comet assay (visual score), micronucleus test, oxidative stress, and inflammatory results. Additional research is required to ascertain the potential correlation between these changes and the onset of diseases and premature mortality.}, }
@article {pmid39147922, year = {2024}, author = {Huang, G and Bao, Z and Feng, L and Zhai, J and Wendel, JF and Cao, X and Zhu, Y}, title = {A telomere-to-telomere cotton genome assembly reveals centromere evolution and a Mutator transposon-linked module regulating embryo development.}, journal = {Nature genetics}, volume = {}, number = {}, pages = {}, pmid = {39147922}, issn = {1546-1718}, support = {32388101//National Natural Science Foundation of China (National Science Foundation of China)/ ; 32201747//National Natural Science Foundation of China (National Science Foundation of China)/ ; }, abstract = {Assembly of complete genomes can reveal functional genetic elements missing from draft sequences. Here we present the near-complete telomere-to-telomere and contiguous genome of the cotton species Gossypium raimondii. Our assembly identified gaps and misoriented or misassembled regions in previous assemblies and produced 13 centromeres, with 25 chromosomal ends having telomeres. In contrast to satellite-rich Arabidopsis and rice centromeres, cotton centromeres lack phased CENH3 nucleosome positioning patterns and probably evolved by invasion from long terminal repeat retrotransposons. In-depth expression profiling of transposable elements revealed a previously unannotated DNA transposon (MuTC01) that interacts with miR2947 to produce trans-acting small interfering RNAs (siRNAs), one of which targets the newly evolved LEC2 (LEC2b) to produce phased siRNAs. Systematic genome editing experiments revealed that this tripartite module, miR2947-MuTC01-LEC2b, controls the morphogenesis of complex folded embryos characteristic of Gossypium and its close relatives in the cotton tribe. Our study reveals a trans-acting siRNA-based tripartite regulatory pathway for embryo development in higher plants.}, }
@article {pmid39145950, year = {2024}, author = {da Cruz, NFS and Berrocal, AM}, title = {Genetic Testing for Rare Retinal Diseases in Telomere Biology Disorders.}, journal = {JAMA ophthalmology}, volume = {}, number = {}, pages = {}, doi = {10.1001/jamaophthalmol.2024.2947}, pmid = {39145950}, issn = {2168-6173}, }
@article {pmid39145097, year = {2024}, author = {Liu, X and Wang, J and Su, D and Wang, Q and Li, M and Zuo, Z and Han, Q and Li, X and Zhen, F and Fan, M and Chen, T}, title = {Development and validation of a glioma prognostic model based on telomere-related genes and immune infiltration analysis.}, journal = {Translational cancer research}, volume = {13}, number = {7}, pages = {3182-3199}, pmid = {39145097}, issn = {2219-6803}, abstract = {BACKGROUND: Gliomas are the most prevalent primary brain tumors, and patients typically exhibit poor prognoses. Increasing evidence suggests that telomere maintenance mechanisms play a crucial role in glioma development. However, the prognostic value of telomere-related genes in glioma remains uncertain. This study aimed to construct a prognostic model of telomere-related genes and further elucidate the potential association between the two.
METHODS: We acquired RNA-seq data for low-grade glioma (LGG) and glioblastoma (GBM), along with corresponding clinical information from The Cancer Genome Atlas (TCGA) database, and normal brain tissue data from the Genotype-Tissue Expression (GTEX) database for differential analysis. Telomere-related genes were obtained from TelNet. Initially, we conducted a differential analysis on TCGA and GTEX data to identify differentially expressed telomere-related genes, followed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses on these genes. Subsequently, univariate Cox analysis and log-rank tests were employed to obtain prognosis-related genes. Least absolute shrinkage and selection operator (LASSO) regression analysis and multivariate Cox regression analysis were sequentially utilized to construct prognostic models. The model's robustness was demonstrated using receiver operating characteristic (ROC) curve analysis, and multivariate Cox regression of risk scores for clinical characteristics and prognostic models were calculated to assess independent prognostic factors. The aforementioned results were validated using the Chinese Glioma Genome Atlas (CGGA) dataset. Finally, the CIBERSORT algorithm analyzed differences in immune cell infiltration levels between high- and low-risk groups, and candidate genes were validated in the Human Protein Atlas (HPA) database.
RESULTS: Differential analysis yielded 496 differentially expressed telomere-related genes. GO and KEGG pathway analyses indicated that these genes were primarily involved in telomere-related biological processes and pathways. Subsequently, a prognostic model comprising ten telomere-related genes was constructed through univariate Cox regression analysis, log-rank test, LASSO regression analysis, and multivariate Cox regression analysis. Patients were stratified into high-risk and low-risk groups based on risk scores. Kaplan-Meier (K-M) survival analysis revealed worse outcomes in the high-risk group compared to the low-risk group, and establishing that this prognostic model was a significant independent prognostic factor for glioma patients. Lastly, immune infiltration analysis was conducted, uncovering notable differences in the proportion of multiple immune cell infiltrations between high- and low-risk groups, and eight candidate genes were verified in the HPA database.
CONCLUSIONS: This study successfully constructed a prognostic model of telomere-related genes, which can more accurately predict glioma patient prognosis, offer potential targets and a theoretical basis for glioma treatment, and serve as a reference for immunotherapy through immune infiltration analysis.}, }
@article {pmid39145075, year = {2024}, author = {Chen, H and Pan, Y and Lv, C and He, W and Wu, D and Xuan, Q}, title = {Telomere-related gene risk model for prognosis prediction in colorectal cancer.}, journal = {Translational cancer research}, volume = {13}, number = {7}, pages = {3495-3521}, pmid = {39145075}, issn = {2219-6803}, abstract = {BACKGROUND: Colorectal cancer (CRC) is the third-most prevalent cancer globally. The biological significance of telomeres in CRC carcinogenesis and progression is underscored by accumulating data. Nevertheless, not much is known about how telomere-related genes (TRGs) affect CRC prognosis. Therefore, the aim of this study was to investigate the role of TRGs in CRC prognosis.
METHODS: We retrospectively obtained the expression profiles and clinical data of CRC patients from public databases. Utilizing least absolute shrinkage and selection operator (LASSO) regression analysis, we created a telomere-related risk model to predict survival outcomes, identifying ten telomere-related differentially expressed genes (TRDEGs). Based on TRDEGs, we stratified patients from The Cancer Genome Atlas (TCGA) into low- and high-risk subsets. Subsequently, we conducted comprehensive analyses, including survival assessment, immune cell infiltration, drug sensitivity, and prediction of molecular interactions using Kaplan-Meier curves, ESTIMATE, CIBERSORT, OncoPredict, and other approaches.
RESULTS: The model showed exceptional predictive accuracy for survival. Significant differences in survival were observed between the two groups of participants grouped according to the model (P<0.001), and this difference was further confirmed in the external validation set (GSE39582) (P=0.004). Additionally, compared to the low-risk group, the high-risk group exhibited significantly advanced tumor node metastasis (TNM) stages, lower proportions of activated CD4[+] T cells, effector memory CD4[+] T cells, and memory B cells, but increased ratios of M2 macrophages and regulatory T cells (Tregs), elevated tumor immune dysfunction and exclusion (TIDE) scores, and diminished sensitivity to dabrafenib, lapatinib, camptothecin, docetaxel, and telomerase inhibitor IX, reflecting the signature's capacity to distinguish clinical pathological characteristics, immune environment, and drug efficacy. Finally, we validated the expression of the ten TRDEGs (ACACB, TPX2, SRPX, PPARGC1A, CD36, MMP3, NAT2, MMP10, HIGD1A, and MMP1) through quantitative real-time polymerase chain reaction (qRT-PCR) and found that compared to normal cells, the expression levels of ACACB, HIGD1A, NAT2, PPARGC1A, and TPX2 in CRC cells were elevated, whereas those of CD36, SRPX, MMP1, MMP3, and MMP10 were reduced.
CONCLUSIONS: Overall, we constructed a telomere-related biomarker capable of predicting prognosis and treatment response in CRC individuals, offering potential guidance for drug therapy selection and prognosis prediction.}, }
@article {pmid39141123, year = {2024}, author = {Huang, W and Han, G and Taylor, BD and Neal, G and Kochan, K and Page, RL}, title = {Maternal peripheral blood telomere length and preterm birth in African American women: a pilot study.}, journal = {Archives of gynecology and obstetrics}, volume = {}, number = {}, pages = {}, pmid = {39141123}, issn = {1432-0711}, abstract = {PURPOSE: This study aimed to explore the association between preterm birth and telomere length of maternal peripheral blood in African American women.
METHODS: 78 African American women were recruited for this study between 2018 and 2023 from 2 prenatal clinics in central and east Texas. Participants provided blood samples and completed clinic questionnaires, with clinical data collected from their post-delivery medical records. Telomere length was measured using monochrome multiplex quantitative real-time polymerase chain reaction. Linear regression and multinomial logistic regression were used to analyze the association between telomere length and gestational length. Kruskal-Wallis's test and Fisher's exact test were used to compare preterm birth, early-term birth and full-term birth by telomere length, social-demographic characteristics, stress and discrimination.
RESULTS: The rates of preterm birth was higher in pregnant women with shorter telomeres. After adjusting for confounders, for every 10-units increase in the relative telomere-to-single-copy gene (T/S) ratio, gestational days increased by 1.090 days (90% CI 0.182, 1.997), and for every 10-units decrease in the T/S ratio, the odds of preterm birth was 2.664 (90% CI 1.064, 6.673) times greater than the odds of full-term birth. No statistically significant associations were observed between stress, discrimination, and either preterm birth or telomere length.
CONCLUSIONS: Maternal peripheral blood telomere shortening is associated with preterm birth, providing support to further explore the clinical utility of maternal telomere testing for prediction and early intervention of preterm birth and the study of biological mechanisms of spontaneous preterm birth.}, }
@article {pmid39137932, year = {2024}, author = {Xerfan, EMS and Tempaku, PF and Tufik, S and Andersen, ML}, title = {The effects of the space environment on circadian rhythm and sleep in astronauts: An emphasis on the telomere length dynamics associated with sleep.}, journal = {Journal of sleep research}, volume = {}, number = {}, pages = {e14312}, doi = {10.1111/jsr.14312}, pmid = {39137932}, issn = {1365-2869}, support = {//Conselho Nacional de Desenvolvimento Científico e Tecnológico/ ; //Associação Fundo de Incentivo à Pesquisa/ ; #2020/13467-8//Fundação de Amparo à Pesquisa do Estado de São Paulo/ ; }, }
@article {pmid39127691, year = {2024}, author = {Chen, Y and Zhang, X and Wang, L and Fang, M and Lu, R and Ma, Y and Huang, Y and Chen, X and Sheng, W and Shi, L and Zheng, Z and Qiu, Y}, title = {Telomere-to-telomere genome assembly of Eleocharis dulcis and expression profiles during corm development.}, journal = {Scientific data}, volume = {11}, number = {1}, pages = {869}, pmid = {39127691}, issn = {2052-4463}, mesh = {*Telomere/genetics ; *Genome, Plant ; *Eleocharis/genetics/growth & development ; Transcriptome ; }, abstract = {Eleocharis dulcis (Burm. f.) Trin. ex Hensch., commonly known as Chinese water chestnut, is a traditional aquatic vegetable in China, and now is widely cultivated throughout the world because of its high nutritional value and unique tastes. Here, we report the assembly of a 493.24 Mb telomere-to-telomere (T2T) genome of E. dulcis accomplished by integrating ONT ultra-long reads, PacBio long reads and Hi-C data. The reference genome was anchored onto 111 gap-free chromosomes, containing 48.31% repeat elements and 33,493 predicted protein-coding genes. Whole genome duplication (WGD) and inter-genomic synteny analyses indicated that chromosome breakage and genome duplication in E. dulcis possibly occurred multiple times during genome evolution after its divergence from a common ancestor with Rhynchospora breviuscula at ca. 35.6 Mya. A comparative time-course transcriptome analysis of corm development revealed different patterns of gene expression between cultivated and wild accessions with the highest number of differentially expressed genes (DEGs, 15,870) at the middle swelling stage and some of the DEGs were significantly enriched for starch metabolic process.}, }
@article {pmid39125728, year = {2024}, author = {Boniewska-Bernacka, E and Pańczyszyn, A and Głąb, G and Goc, A}, title = {Telomere Length, Telomerase Activity, and Vaginal Microbiome in Patients with HPV-Related Precancerous Lesions.}, journal = {International journal of molecular sciences}, volume = {25}, number = {15}, pages = {}, doi = {10.3390/ijms25158158}, pmid = {39125728}, issn = {1422-0067}, support = {P-2023-007//Institute of Medical Sciences, University of Opole, Opole, Poland./ ; }, mesh = {Humans ; Female ; *Telomerase/metabolism/genetics ; *Vagina/microbiology/virology ; *Microbiota/genetics ; *Papillomavirus Infections/virology/complications/genetics ; Adult ; *Telomere/metabolism/genetics ; Middle Aged ; *Precancerous Conditions/virology/microbiology/genetics/pathology ; *Uterine Cervical Neoplasms/virology/microbiology/genetics/pathology ; Telomere Homeostasis ; Papillomaviridae/genetics ; }, abstract = {Persistent high-risk human papillomaviruses (HR HPVs) infection leads to the development of squamous intraepithelial lesions in cervical cells that may lead to cancer. The telomere length, telomerase activity, and species composition of the vaginal microbiome may influence the dynamic of changes and the process of carcinogenesis. In the present study, we analyze relative telomere length (RTL), relative hTERT expression (gene for the telomerase component-reverse transcriptase) in cervical smear cells and vaginal microbiomes. Total RNA and DNA were isolated from tissue samples of 109 patients from the following groups: control, carrier, low-grade or high-grade squamous intraepithelial lesion (L SIL and H SIL, respectively), and cancer. The quantitative PCR method was used to measure telomere length and telomerase expression. Vaginal microbiome bacteria were divided into community state types using morphotype criteria. Significant differences between histopathology groups were confirmed for both relative telomere length and relative hTERT expression (p < 0.001 and p = 0.001, respectively). A significant difference in RTL was identified between carriers and H SIL (p adj < 0.001) groups, as well as between carriers and L SIL groups (p adj = 0.048). In both cases, RTL was lower among carriers. The highest relative hTERT expression level was recorded in the H SIL group, and the highest relative hTERT expression level was recorded between carriers and the H SIL group (p adj < 0.001). A correlation between genotype and biocenosis was identified for genotype 16+A (p < 0.001). The results suggest that identification of HPV infection, telomere length assessment, and hTERT expression measurement together may be more predictive than each of these analyses performed separately.}, }
@article {pmid39125404, year = {2024}, author = {Baliou, S and Ioannou, P and Apetroaei, MM and Vakonaki, E and Fragkiadaki, P and Kirithras, E and Tzatzarakis, MN and Arsene, AL and Docea, AO and Tsatsakis, A}, title = {The Impact of the Mediterranean Diet on Telomere Biology: Implications for Disease Management-A Narrative Review.}, journal = {Nutrients}, volume = {16}, number = {15}, pages = {}, doi = {10.3390/nu16152525}, pmid = {39125404}, issn = {2072-6643}, mesh = {Humans ; *Diet, Mediterranean ; *Telomere ; Telomere Homeostasis ; Telomere Shortening ; Aging ; Telomerase/metabolism ; Disease Management ; Oxidative Stress ; Polyphenols ; Autoimmune Diseases ; }, abstract = {INTRODUCTION: Telomeres are nucleoprotein complexes at the ends of chromosomes that are under the control of genetic and environmental triggers. Accelerated telomere shortening is causally implicated in the increasing incidence of diseases. The Mediterranean diet has recently been identified as one that confers protection against diseases. This review aimed to identify the effect of each component of the Mediterranean diet on telomere length dynamics, highlighting the underlying molecular mechanisms.
METHODS: PubMed was searched to identify relevant studies to extract data for conducting a narrative review.
RESULTS: The Mediterranean diet alleviates clinical manifestations in many diseases. Focusing on autoimmune diseases, the Mediterranean diet can be protective by preventing inflammation, mitochondrial malfunction, and abnormal telomerase activity. Also, each Mediterranean diet constituent seems to attenuate aging through the sustenance or elongation of telomere length, providing insights into the underlying molecular mechanisms. Polyphenols, vitamins, minerals, and fatty acids seem to be essential in telomere homeostasis, since they inhibit inflammatory responses, DNA damage, oxidative stress, mitochondrial malfunction, and cell death and induce telomerase activation.
CONCLUSIONS: The Mediterranean diet is beneficial for maintaining telomere dynamics and alleviating age-related illnesses. This review provides a comprehensive overview of cross-sectional, observational, and randomized controlled trials regarding the beneficial impact of every constituent in the Mediterranean diet on telomere length and chronic disease management.}, }
@article {pmid39118803, year = {2024}, author = {Samadi, FM and Suhail, S and Sonam, M and Ahmad, MK and Kumar, V and Chandra, S and Mohammad, S}, title = {Comparing Length and Telomere Expression at Oral Precancerous and Cancerous Stages.}, journal = {Iranian journal of pathology}, volume = {19}, number = {2}, pages = {146-151}, doi = {10.30699/IJP.2024.1996330.3081}, pmid = {39118803}, issn = {1735-5303}, abstract = {BACKGROUND & OBJECTIVE: Telomeres consist of repetitive G-rich nucleotides located at the end of each chromosome, acting as protein binding sites. The aim of this study was to examine the differences in telomere length in blood, saliva, and tissue samples at various stages of oral precancerous and cancerous lesions.
METHODS: Samples of blood, tissue, and saliva were collected from patients with oral precancerous and cancerous lesions. DNA extraction was performed. Then, a TRAP assay was conducted to assess and compare the telomere length and telomerase expression.
RESULTS: The levels of telomerase activity (TA) in the DNA samples ranged from 0.19 to 6.91 (2.05+1.37) among oral squamous cell carcinoma (OSCC) patients and from 0.17 to 4.5 (0.28+4.25) among precancerous patients. A significant difference was observed in TA levels between OSCC and precancerous samples (t=3.9691, P= 0.0000).
CONCLUSION: Assessing the telomerase activity is crucial for studying the behavior of carcinoma in the clinical setting. The augmented telomerase expression and the length of telomere contribute to OSCC progression. Hence, this study adds a diagnostic tool that can serve as a biomarker for the early detection and prognosis of OSCC.}, }
@article {pmid39116978, year = {2024}, author = {Sun, S and Ma, W and Mi, C and Mao, P}, title = {Telomerase reverse transcriptase, a telomere length maintenance protein in alfalfa (Medicago sativa), confers Arabidopsis thaliana seeds aging tolerance via modulation of telomere length.}, journal = {International journal of biological macromolecules}, volume = {}, number = {}, pages = {134388}, doi = {10.1016/j.ijbiomac.2024.134388}, pmid = {39116978}, issn = {1879-0003}, abstract = {Numerous studies have investigated seed aging, with a particular emphasis on the involvement of reactive oxygen species. Reactive oxygen species diffuse into the nucleus and damage telomeres, resulting in loss of genetic integrity. Telomerase reverse transcriptase (TERT) plays an essential role in maintaining plant genomic stability. Genome-wide analyses of TERT genes in alfalfa (Medicago sativa) have not yet been conducted, leaving a gap in our understanding of the mechanisms underlying seed aging associated with TERT genes. In this study, four MsTERT genes were identified in the alfalfa genome. The expression profiles of the four MsTERT genes during seed germination indicated that MS. gene79077 was significantly upregulated by seed aging. Transgenic seeds overexpressing MS. gene79077 in Arabidopsis exhibited enhanced tolerance to seed aging by reducing the levels of H2O2 and increasing telomere length and telomerase activity. Furthermore, transcript profiling of aging-treated Arabidopsis wild-type and overexpressing seeds showed an aging response in genes related to glutathione-dependent detoxification and antioxidant defense pathways. These results revealed that MS. gene79077 conferred Arabidopsis seed-aging tolerance via modulation of antioxidant defense and telomere homeostasis. This study provides a new way to understand stress-responsive MsTERT genes for the potential genetic improvement of seed vigor.}, }
@article {pmid39113664, year = {2024}, author = {Li, Y and Sági-Kiss, V and James, ELN and Dokal, I and Parkinson, KE and Bundy, JG}, title = {Nucleotide sugars correlate with leukocyte telomere length as part of a dyskeratosis congenita metabolomic plasma signature.}, journal = {Haematologica}, volume = {}, number = {}, pages = {}, doi = {10.3324/haematol.2023.284721}, pmid = {39113664}, issn = {1592-8721}, abstract = {Not available.}, }
@article {pmid39113075, year = {2024}, author = {Virseda-Berdices, A and Behar-Lagares, R and Martínez-González, O and Blancas, R and Bueno-Bustos, S and Brochado-Kith, O and Manteiga, E and Mallol Poyato, MJ and López Matamala, B and Martín Parra, C and Resino, S and Jiménez-Sousa, MÁ and Fernández-Rodríguez, A}, title = {Longer ICU stay and invasive mechanical ventilation accelerate telomere shortening in COVID-19 patients 1 year after recovery.}, journal = {Critical care (London, England)}, volume = {28}, number = {1}, pages = {267}, pmid = {39113075}, issn = {1466-609X}, support = {1.013.005//Fundación Universidad Alfonso X el Sabio/ ; CB21/13/00044//CIBER - Consorcio Centro de Investigación Biomédica en Red-(CB 2021), Instituo de Salud Carlos III, Ministerio de Ciencia e Innovación and Unión Europea - NextGenerationEU/ ; COV20/1144//Instituto de Salud Carlos III/ ; }, abstract = {Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes virus-induced-senescence. There is an association between shorter telomere length (TL) in coronavirus disease 2019 (COVID-19) patients and hospitalization, severity, or even death. However, it remains unknown whether virus-induced-senescence is reversible. We aim to evaluate the dynamics of TL in COVID-19 patients 1 year after recovery from intensive care units (ICU). Longitudinal study enrolling 49 patients admitted to ICU due to COVID-19 (August 2020 to April 2021). Relative telomere length (RTL) quantification was carried out in whole blood by monochromatic multiplex real-time quantitative PCR (MMqPCR) assay at hospitalization (baseline) and 1 year after discharge (1-year visit). The association between RTL and ICU length of stay (LOS), invasive mechanical ventilation (IMV), prone position, and pulmonary fibrosis development at 1-year visit was evaluated. The median age was 60 years, 71.4% were males, median ICU-LOS was 12 days, 73.5% required IMV, and 38.8% required a prone position. Patients with longer ICU-LOS or who required IMV showed greater RTL shortening during follow-up. Patients who required pronation had a greater RTL shortening during follow-up. IMV patients who developed pulmonary fibrosis showed greater RTL reduction and shorter RTL at the 1-year visit. Patients with longer ICU-LOS and those who required IMV had a shorter RTL in peripheral blood, as observed 1 year after hospital discharge. Additionally, patients who required IMV and developed pulmonary fibrosis had greater telomere shortening, showing shorter telomeres at the 1-year visit. These patients may be more prone to develop cellular senescence and lung-related complications; therefore, closer monitoring may be needed.}, }
@article {pmid39110381, year = {2024}, author = {Vazquez-Moreno, M and Perales-Herrera, A and Ramírez-Silva, I and Martínez-Gómez, LE and García-Cerón, A and Paredes-Barrientos, JC and Hernández-Mendoza, H and Martinez-Garza, S and Murillo-Ortiz, B and Cruz, M}, title = {Dietary Zinc Intake and the Association of Insulin Level and HOMA-IR with Telomere Shortening in Mexican Children.}, journal = {Biological trace element research}, volume = {}, number = {}, pages = {}, pmid = {39110381}, issn = {1559-0720}, support = {FIS/IMSS/PROT/PRIO/ 18/079//Instituto Mexicano del Seguro Social/ ; }, abstract = {PURPOSE: The relationship between dietary zinc (Zn) intake, metabolic diseases, and telomere length has been little explored in the children population. This observational cross-sectional study assesses the association between obesity (OB), cardiometabolic traits, telomere length, and dietary Zn intake in children with normal weight (NW) and OB from Mexico City.
METHODS: Anthropometric data, blood pressure, biochemical measurements, the homeostatic model assessment of insulin resistance (HOMA-IR) and leucocyte telomere length (determined by quantitative-PCR) were analyzed in 171 children with NW and 172 with OB. Furthermore, dietary Zn intake was evaluated in 117 children NW and 120 with OB.
RESULTS: Telomere shortening was associated with fasting plasma insulin (FPI) and HOMA-IR in NW (beta coefficient [β]FPI = -0.022 ± 0.008, p = 0.009; βHOMA-IR = -0.096 ± 0.040, p = 0.020) and OB (βFPI = -0.007 ± 0.002, p = 0.003; βHOMA-IR = -0.034 ± 0.012, p = 0.005) children. Dietary Zn intake resulted negatively associated with FPI (β = -2.418 ± 0.764, p = 0.002) and HOMA-IR (β = -0.399 ± 0.014, p = 0.009) in children with OB. Then, in children with OB, the association between FPI, HOMA-IR, and telomere shortening was evaluated separately in groups of low, medium, and high dietary Zn intake (according to tertiles). The association between FPI, HOMA-IR, and telomere shortening was not significant in the high Zn intake group (PFPI = 0.633; PHOMA-IR = 0.567).
CONCLUSION: Our results suggest that a high Zn intake may ameliorate the telomere shortening related to high FPI and HOMA-IR.}, }
@article {pmid39109967, year = {2024}, author = {Feng, J and Zhang, W and Chen, C and Liang, Y and Li, T and Wu, Y and Liu, H and Wu, J and Lin, W and Li, J and He, Y and He, J and Luan, A}, title = {The pineapple reference genome: Telomere-to-telomere assembly, manually curated annotation, and comparative analysis.}, journal = {Journal of integrative plant biology}, volume = {}, number = {}, pages = {}, doi = {10.1111/jipb.13748}, pmid = {39109967}, issn = {1744-7909}, support = {32272677//National Natural Science Foundation of China/ ; 2019YFD1001104//National Key R&D Program of China/ ; 1630032024026//Central Public-interest Scientific Institution Basal Research Fund for Chinese Academy of Tropical Agricultural Sciences/ ; 1630032024001//Central Public-interest Scientific Institution Basal Research Fund for Chinese Academy of Tropical Agricultural Sciences/ ; 1630052023011//Central Public-interest Scientific Institution Basal Research Fund for Chinese Academy of Tropical Agricultural Sciences/ ; 323QN279//Hainan Provincial Natural Science Foundation of China/ ; }, abstract = {Pineapple is the third most crucial tropical fruit worldwide and available in five varieties. Genomes of different pineapple varieties have been released to date; however, none of them are complete, with all exhibiting substantial gaps and representing only two of the five pineapple varieties. This significantly hinders the advancement of pineapple breeding efforts. In this study, we sequenced the genomes of three varieties: a wild pineapple variety, a fiber pineapple variety, and a globally cultivated edible pineapple variety. We constructed the first gap-free reference genome (Ref) for pineapple. By consolidating multiple sources of evidence and manually revising each gene structure annotation, we identified 26,656 protein-coding genes. The BUSCO evaluation indicated a completeness of 99.2%, demonstrating the high quality of the gene structure annotations in this genome. Utilizing these resources, we identified 7,209 structural variations across the three varieties. Approximately 30.8% of pineapple genes were located within ±5 kb of structural variations, including 30 genes associated with anthocyanin synthesis. Further analysis and functional experiments demonstrated that the high expression of AcMYB528 aligns with the accumulation of anthocyanins in the leaves, both of which may be affected by a 1.9-kb insertion fragment. In addition, we developed the Ananas Genome Database, which offers data browsing, retrieval, analysis, and download functions. The construction of this database addresses the lack of pineapple genome resource databases. In summary, we acquired a seamless pineapple reference genome with high-quality gene structure annotations, providing a solid foundation for pineapple genomics and a valuable reference for pineapple breeding.}, }
@article {pmid39108072, year = {2024}, author = {Biswas, A and Bhattacharya, M and Ghosh, P and Dey, SK}, title = {Role of Telomere Length in Radiation Response of Hematopoietic Stem & Progenitor Cells in Newborns.}, journal = {Fetal and pediatric pathology}, volume = {}, number = {}, pages = {1-15}, doi = {10.1080/15513815.2024.2381752}, pmid = {39108072}, issn = {1551-3823}, abstract = {OBJECTIVE: Wide inter-individual variations in ionizing radiation (IR) responses of neonatal hematopoietic system calls for identifying reliable biomarkers to effectively estimate radiation exposure damages in neonates.
METHODS: Association between telomere length (TL) at birth and radiation sensitivity of cord blood hematopoietic stem cells (HSC) from 166 healthy newborns were investigated by assessing their clonogenic differentiation. TL was determined as terminal restriction fragment (TRF) by Southern blot method.
RESULTS: TL correlated with surviving fractions of total progenitor colony forming cell (CFC) content at 0.75 Gy (p < 0.05), granulo-macrophagic lineage colony forming units (CFU-GM) at 0.75 Gy (p < 0.05) and erythroid burst forming unit (BFU-E) at 0.75 Gy (p < 0.05) & at 3 Gy (p < 0.05) of newborns.
CONCLUSION: Our results indicate risks for HSC clonogenic survival in neonates with shorter telomeres after IR exposure. These observations might aid in considering TL at birth as an assessment factor for radiation related hematopoietic challenges in children.}, }
@article {pmid39107495, year = {2024}, author = {Nai, S and Wang, M and Yang, J and Ling, B and Dong, Q and Yang, X and Du, X and Lu, M and Liu, L and Yu, Z and Chen, L}, title = {Novel role for Ddx39 in differentiation and telomere length regulation of embryonic stem cells.}, journal = {Cell death and differentiation}, volume = {}, number = {}, pages = {}, pmid = {39107495}, issn = {1476-5403}, abstract = {Erk signaling is indispensable for the self-renewal and differentiation of mouse embryonic stem cells (ESCs), as well as telomere homeostasis. But how Erk regulates these biological processes remains unclear. We identified 132 Erk2 interacting proteins by co-immunoprecipitation and mass spectrometric analysis, and focused on Ddx39 as a potential Erk2 substrate. We demonstrated that Erk2 phosphorylates Ddx39 on Y132 and Y138. Ddx39 knockout (KO) ESCs are defective in differentiation, due to reduced H3K27ac level upon differentiation. Phosphorylation of Ddx39 promotes the recruitment of Hat1 to acetylate H3K27 and activate differentiation genes. In addition, Ddx39 KO leads to telomere elongation in ESCs. Ddx39 is recruited to telomeres by the telomere-binding protein Trf1, consequently disrupting the DNA loop formed by Trf1 and suppressing the alternative lengthening of telomeres (ALT). Phosphorylation of Ddx39 weakens its interaction with Trf1, releasing it from telomeres. Thus, ALT activity is enhanced, and telomeres are elongated. Altogether, our studies reveal an essential role of Ddx39 in the differentiation and telomere homeostasis of ESCs.}, }
@article {pmid39103182, year = {2024}, author = {Strauss, JD and Brown, DW and Zhou, W and Dagnall, C and Yuan, JM and Im, A and Savage, SA and Wang, Y and Rafati, M and Spellman, SR and Gadalla, SM}, title = {Telomere length and clonal chromosomal alterations in peripheral blood of patients with severe aplastic anaemia.}, journal = {British journal of haematology}, volume = {}, number = {}, pages = {}, doi = {10.1111/bjh.19681}, pmid = {39103182}, issn = {1365-2141}, support = {75N910D00024/CA/NCI NIH HHS/United States ; U24CA076518/CA/NCI NIH HHS/United States ; N00014-21-1-2954//Office of Naval Research/ ; N00014-23-1-2057//Office of Naval Research/ ; HHSH250201700006C/HRSA/HRSA HHS/United States ; //National Marrow Donor Program/ ; }, abstract = {Severe aplastic anaemia (SAA) is a rare and life-threatening bone marrow failure disorder. We used data from the transplant outcomes in aplastic anaemia study to characterize mosaic chromosomal alterations (mCAs) in the peripheral blood of 738 patients with acquired SAA and evaluate their associations with telomere length (TL) and survival post-haematopoietic cell transplant (HCT). The median age at HCT was 20.4 years (range = 0.2-77.4). Patients with SAA had shorter TL than expected for their age (median TL percentile for age: 35.7th; range <1-99.99). mCAs were detected in 211 patients (28.6%), with chr6p copy-neutral loss of heterozygosity (6p-CNLOH) in 15.9% and chr7 loss in 3.0% of the patients; chrX loss was detected in 4.1% of female patients. Negative correlations between mCA cell fraction and measured TL (r = -0.14, p = 0.0002), and possibly genetically predicted TL (r = -0.07, p = 0.06) were noted. The post-HCT 3-year survival probability was low in patients with chr7 loss (39% vs. 72% in patients with chr6-CNLOH, 60% in patients with other mCAs and 70% in patients with no mCAs; p-log rank = 0.001). In multivariable analysis, short TL (p = 0.01), but not chr7 loss (p = 0.29), was associated with worse post-HCT survival. TL may guide clinical decisions in patients with SAA.}, }
@article {pmid39103649, year = {2024}, author = {Kalbfleisch, TS and McKay, SD and Murdoch, BM and Adelson, DL and Almansa-Villa, D and Becker, G and Beckett, LM and Benítez-Galeano, MJ and Biase, F and Casey, T and Chuong, E and Clark, E and Clarke, S and Cockett, N and Couldrey, C and Davis, BW and Elsik, CG and Faraut, T and Gao, Y and Genet, C and Grady, P and Green, J and Green, R and Guan, D and Hagen, D and Hartley, GA and Heaton, M and Hoyt, SJ and Huang, W and Jarvis, E and Kalleberg, J and Khatib, H and Koepfi, KP and Koltes, J and Koren, S and Kuehn, C and Leeb, T and Leonard, A and Liu, GE and Low, WY and McConnell, H and McRae, K and Miga, K and Mousel, M and Neibergs, H and Olagunju, T and Pennell, M and Petry, B and Pewsner, M and Phillippy, AM and Pickett, BD and Pineda, P and Potapova, T and Rachagani, S and Rhie, A and Rijnkels, M and Robic, A and Rodriguez Osorio, N and Safonova, Y and Schettini, G and Schnabel, RD and Sirpu Natesh, N and Stegemiller, M and Storer, J and Stothard, P and Stull, C and Tosser-Klopp, G and Traglia, GM and Tuggle, CK and Van Tassell, CP and Watson, C and Weikard, R and Wimmers, K and Xie, S and Yang, L and Smith, TPL and O'Neill, RJ and Rosen, BD}, title = {The Ruminant Telomere-to-Telomere (RT2T) Consortium.}, journal = {Nature genetics}, volume = {}, number = {}, pages = {}, pmid = {39103649}, issn = {1546-1718}, support = {Grant Number 2023-67015-39000//United States Department of Agriculture | Agricultural Research Service (USDA Agricultural Research Service)/ ; }, abstract = {Telomere-to-telomere (T2T) assemblies reveal new insights into the structure and function of the previously 'invisible' parts of the genome and allow comparative analyses of complete genomes across entire clades. We present here an open collaborative effort, termed the 'Ruminant T2T Consortium' (RT2T), that aims to generate complete diploid assemblies for numerous species of the Artiodactyla suborder Ruminantia to examine chromosomal evolution in the context of natural selection and domestication of species used as livestock.}, }
@article {pmid39100478, year = {2024}, author = {Wang, Y and Sun, F and Yue, C and Man, Q}, title = {Peripheral blood leukocyte Telomere length and endometriosis: A Mendelian randomization study.}, journal = {Heliyon}, volume = {10}, number = {14}, pages = {e33854}, pmid = {39100478}, issn = {2405-8440}, abstract = {BACKGROUND: The link between peripheral blood leukocyte telomere length (LTL) and endometriosis has remained uncertain. In order to investigate this association, a two-sample Mendelian randomization(MR) analysis was performed.
METHODS: We extracted Single-nucleotide polymorphisms (SNPs) associated with LTL from a published genome-wide association study (GWAS) comprising 472,174 individuals. Data on endometriosis, including its seven subtypes, were sourced from the iue open gwas project. Four methods were employed for MR: Inverse-variance weighted analysis (IVW), Mendelian randomization-Egger regression (MR Egger), weighted-median analysis, and Weighted Mode.
RESULTS: Genetically determined LTL was identified as a factor that can promote the occurrence of endometriosis. With every 1-SD increase in LTL, the risk of endometriosis increased by 26 % (OR = 1.260, 95 % CI = 1.073 to 1.479; P = 0.005). Genetically determined LTL also contributed to endometriosis subtypes: intestine (OR = 3.584, 95 % CI = 1.597 to 8.041; P = 0.002), ovary (OR = 1.308, 95 % CI = 1.033 to 1.655; P = 0.026), rectovaginal septum and vagina (OR = 1.360, 95 % CI = 1.000 to 1.851; P = 0.049). There was no observed causal relationship between LTL and the other four subtypes.
CONCLUSION: This study, utilizing genetic data, offers evidence that longer LTL may cause increased risks of endometriosis, specifically endometriosis of the intestine, ovary, rectovaginal septum and vagina. These findings not only suggest that LTL may serve as a predictive factor for assessing the prevalence of three endometriosis subtypes but also provide new insights into the study of endometriosis pathogenesis.}, }
@article {pmid39097069, year = {2024}, author = {Sun, S and Ma, W and Mao, P}, title = {Overexpression of protection of telomeres 1 (POT1), a single-stranded DNA-binding proteins in alfalfa (Medicago sativa), enhances seed vigor.}, journal = {International journal of biological macromolecules}, volume = {277}, number = {Pt 3}, pages = {134300}, doi = {10.1016/j.ijbiomac.2024.134300}, pmid = {39097069}, issn = {1879-0003}, abstract = {Extensive bodies of research are dedicated to the study of seed aging with a particular focus on the roles of reactive oxygen species (ROS), and the ensuing oxidative damage during storage, as a primary cause of seed vigor decreasing. ROS diffuse to the nucleus and damage the telomeres, resulting in a loss of genetic integrity. Protection of telomeres 1 (POT1) is a telomeric protein that binds to the telomere region, and plays an essential role in maintaining genomic stability in plants. In this study, there were totally four MsPOT1 genes obtained from alfalfa genome. Expression analysis of four MsPOT1 genes in germinated seed presented the different expressions. Four MsPOT1 genes displayed high expression levels at the early stage of seed germination, Among the four POT1 genes, it was found that MS. gene040108 was significantly up-regulated in the early germination stage of CK seeds, but down-regulated in aged seeds. RT-qPCR assays and RNA-seq data revealed that MsPOT1-X gene was significantly induced by seed aging treatment. Transgenic seeds overexpressing MsPOT1-X gene in Arabidopsis thaliana and Medicago trunctula exhibited enhanced seed vigor, telomere length, telomerase activity associated with reduced H2O2 content. These results would provide a new way to understand aging stress-responsive MsPOT1 genes for genetic improvement of seed vigor. Although a key gene regulating seed vigor was identified in this study, the specific mechanism of MsPOT1-X gene regulating seed vigor needs to be further explored.}, }
@article {pmid39096784, year = {2024}, author = {Amatya, S and Bhatia, P and Raina, S and Sreedharanunni, S and Singh, M and Rahman, E and Archana, MV and Trehan, A}, title = {Clinical utility of relative telomere length analysis in pediatric bone marrow failure.}, journal = {Blood cells, molecules & diseases}, volume = {109}, number = {}, pages = {102882}, doi = {10.1016/j.bcmd.2024.102882}, pmid = {39096784}, issn = {1096-0961}, abstract = {INTRODUCTION: Telomere length related studies are limited in pediatric marrow failure cases due to difficulty in establishing population specific age related normograms. Moreover, there is paucity of data related to clinical relevance of telomere length in idiopathic aplastic anemia (IAA) and non telomere biology inherited bone marrow failure syndrome (IBMFS) cases.
METHODOLOGY: Hence, in current study we investigated Relative telomere length (RTL) by RQ-PCR in 83 samples as: healthy controls (n = 44), IAA (n = 15) and IBMFS (n = 24). In addition, we performed chromosomal breakage studies and targeted NGS to screen for pathogenic variants.
RESULTS & CONCLUSION: Median RTL was significantly different between control vs. IBMFS (p-0.002), IAA vs. IBMFS (p-0.0075) and DC vs. non-DC IBMFS (p-0.011) but not between control vs. IAA (p-0.46). RTL analysis had clinical utility in differentiating BMF cases as 75 % (9/12) of DC had short/very short telomeres compared to only 17 % (2/12) of non-DC IBMFS, 7 % (1/15) of IAA and 7 % (3/44) of controls (p < 0.001).}, }
@article {pmid39095379, year = {2024}, author = {Li, M and Chen, C and Wang, H and Qin, H and Hou, S and Yang, X and Jian, J and Gao, P and Liu, M and Mu, Z}, title = {Telomere-to-telomere genome assembly of sorghum.}, journal = {Scientific data}, volume = {11}, number = {1}, pages = {835}, pmid = {39095379}, issn = {2052-4463}, mesh = {*Sorghum/genetics ; *Genome, Plant ; *Telomere/genetics ; }, abstract = {"Cuohu Bazi" (CHBZ) is an ancient sorghum variety collected from the fields of China, known for its agronomic traits like dwarf stature, early maturation. In this study, we present the first telomere-to-telomere (T2T) and gap-free genome assembly of CHBZ using PacBio HiFi reads, Oxford Nanopore Technologies, and Hi-C data. The assembled genome comprises 724.85 Mb, effectively resolving all 3,913 gaps that were present in the previous sorghum BTx623 reference genome. Notably, the T2T assembly captures 10 centromeres and all 20 telomeres, providing strong support for their integrity. This assembly is of high quality in terms of contiguity (contig N50: 71.1 Mb), completeness (BUSCO score: 99.01%, k-mer completeness: 98.88%), and correctness (QV: 61.60). Repetitive sequences accounted for 70.41% of the genome and a total of 32,855 protein-coding genes have been annotated. Furthermore, 161 CHBZ-specific presence/absence variants genes have been identified when comparing to BTx623 genome. This study provides valuable insights for future research on sorghum genetics, genomics, and evolutionary history.}, }
@article {pmid39093267, year = {2024}, author = {McCullough, KB and Vege, SS and Mangaonkar, AA and Ferrer, A and Patnaik, MM}, title = {Pancreatitis as a Potential Consequence of Danazol Therapy for Telomere Biology Disorders.}, journal = {Mayo Clinic proceedings}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.mayocp.2024.03.019}, pmid = {39093267}, issn = {1942-5546}, }
@article {pmid39087945, year = {2024}, author = {He, X and Cao, L and Fu, X and Wu, Y and Wen, H and Gao, Y and Huo, W and Wang, M and Liu, M and Su, Y and Liu, G and Zhang, M and Hu, F and Hu, D and Zhao, Y}, title = {The association between telomere length and diabetes mellitus: accumulated evidence from observational studies.}, journal = {The Journal of clinical endocrinology and metabolism}, volume = {}, number = {}, pages = {}, doi = {10.1210/clinem/dgae536}, pmid = {39087945}, issn = {1945-7197}, abstract = {OBJECTIVE: In order to assess the associations between telomere length (TL) and diabetes mellitus (DM), especially type 2 diabetes (T2DM), we performed this systematic review and meta-analysis.
METHODS: PubMed, Embase, and Web of Science were thoroughly searched up to July 11, 2023. The pooled standardized mean difference (SMD) and the 95% confidence interval (CI) were evaluated using the random-effects model. Age, sex, study design, duration of diabetes, region, sample size, and body mass index (BMI) were used to stratify subgroup analyses.
RESULTS: A total of 37 observational studies involving 18,181 participants from 14 countries were included in the quantitative meta-analysis. In this study, patients with diabetes had shorter TL than the non-diabetic, whether those patients had T1DM (-2.70; 95% CI: -4.47, -0.93; P<0.001), T2DM (-3.70; 95% CI: -4.20, -3.20; P<0.001), or other types of diabetes (-0.71; 95% CI: -1.10, -0.31; P<0.001). Additionally, subgroup analysis of T2DM showed that TL was significantly correlated with age, sex, study design, diabetes duration, sample size, detection method, region, and BMI.
CONCLUSION: A negative correlation was observed between TL and DM. To validate this association in the interim, more extensive, superior prospective investigations and clinical trials are required.}, }
@article {pmid39086950, year = {2024}, author = {Zhu, S and Hao, Z and Chen, Q and Liu, X and Wu, W and Luo, Y and Zhang, F}, title = {Casual effects of telomere length on sarcoidosis: a bidirectional Mendelian randomization analysis.}, journal = {Frontiers in medicine}, volume = {11}, number = {}, pages = {1408980}, pmid = {39086950}, issn = {2296-858X}, abstract = {BACKGROUND: Telomere length, crucial for genomic stability, have been implicated in various inflamm-aging diseases, but their role in sarcoidosis remains unexplored.
OBJECTIVE: This study aims to explore the casual effects between TL and sarcoidosis via a bidirectional Mendelian Randomization (MR) study.
METHODS: We examined single nucleotide polymorphisms (SNPs) associated with TL and sarcoidosis, utilizing available open-access genome-wide association study (GWAS) databases from the UK Biobank and FinnGen. We employed five MR techniques, including Inverse Variance Weighted (IVW), MR Egger, weighted median (WM), Robust adjusted profile score (RAPS), and Maximum likelihood, to assess causal relationships and explore pleiotropy.
RESULTS: Summary data extracted from GWAS datasets of TL (n = 472,174) and (n = 217,758) of European ancestry. Employing 130 SNPs with genome-wide significance as instrumental factors for TL, we detect a significant negative correlation between TL and sarcoidosis (OR: 0.682, 95% confidence interval: 0.524-0.888, p : 0.0045). Similarly, utilizing 6 SNPs with genome-wide significance as instrumental factors for sarcoidosis, we fail to identify a noteworthy association between sarcoidosis and TL (OR: 0.992, 95% confidence interval: 0.979-1.005, p : 0.2424).
CONCLUSION: Our results suggest that longer telomeres may reduce the risk of sarcoidosis, highlighting TL as a potential biomarker for diagnosis and long-term monitoring. Understanding the critical role of telomere shortening enables more effective focus on diagnosing, treating, and curing sarcoidosis linked to telomeres. Clinical investigations into treatments that enhance TL are warranted.}, }
@article {pmid39086030, year = {2024}, author = {Liu, Q and Fan, G and Bi, J and Fang, Q and Luo, F and Huang, X and Li, H and Liu, B and Yan, L and Guo, W and Wang, Y and Song, L}, title = {Associations of childhood and adulthood body size, and child-to-adult body size change with adult telomere length.}, journal = {Diabetes, obesity & metabolism}, volume = {}, number = {}, pages = {}, doi = {10.1111/dom.15825}, pmid = {39086030}, issn = {1463-1326}, support = {2023AFB663//Hubei Provincial Natural Science Foundation of China/ ; 82003479//National Natural Science Foundation of China/ ; 82073660//National Natural Science Foundation of China/ ; 2019M662646//China Postdoctoral Science Foundation/ ; 2020T130220//China Postdoctoral Science Foundation/ ; }, abstract = {AIM: To comprehensively examine the associations of childhood and adulthood body size, and child-to-adult body size change with adult leucocyte telomere length (LTL).
METHODS: We included 453 602 participants from the UK Biobank. Childhood body size at the age of 10 years was collected through a questionnaire. Adulthood body size was assessed using body mass index (BMI), waist circumference (WC), waist-to-hip ratio (WHR), fat mass index (FMI), and fat-free mass index (FFMI).
RESULTS: Individuals with plumper body size in childhood exhibited shorter LTL in adulthood (-0.0086 [-0.0017, -0.0004]). Adulthood BMI (-0.0286 [-0.0315, -0.0258]), WC (-0.0271 [-0.0303, -0.0238]), WHR (-0.0269 [-0.0308, -0.0230]) and FMI (-0.0396 [-0.0438, -0.0351]) were negatively associated with LTL, whereas FFMI (0.0095 [0.0039, 0.0152]) was positively associated with LTL. Compared to individuals consistently having an average/normal weight in both childhood and adulthood, those who maintained or developed overweight/obesity from childhood to adulthood had a shorter adult LTL, regardless of childhood body size. Notably, the LTL shortening effect was not observed in individuals with plumper body size in childhood but normal weight in adulthood.
CONCLUSIONS: Childhood and adulthood obesity are both associated with LTL shortening in adulthood. Transitioning to or maintaining overweight/obese status from childhood to adulthood is associated with shorter adult LTL, whereas this effect can be reversed if plumper children become normal weight.}, }
@article {pmid39082280, year = {2024}, author = {Prince, S and Maguemoun, K and Ferdebouh, M and Querido, E and Derumier, A and Tremblay, S and Chartrand, P}, title = {CoPixie, a novel algorithm for single-particle track colocalization, enables efficient quantification of telomerase dynamics at telomeres.}, journal = {Nucleic acids research}, volume = {}, number = {}, pages = {}, doi = {10.1093/nar/gkae669}, pmid = {39082280}, issn = {1362-4962}, support = {PJT-162156/CAPMC/CIHR/Canada ; //Natural Sciences and Engineering Research Council of Canada/ ; //Fonds de recherche du Québec-Nature et technologies/ ; }, abstract = {Single-particle imaging and tracking can be combined with colocalization analysis to study the dynamic interactions between macromolecules in living cells. Indeed, single-particle tracking has been extensively used to study protein-DNA interactions and dynamics. Still, unbiased identification and quantification of binding events at specific genomic loci remains challenging. Herein, we describe CoPixie, a new software that identifies colocalization events between a theoretically unlimited number of imaging channels, including single-particle movies. CoPixie is an object-based colocalization algorithm that relies on both pixel and trajectory overlap to determine colocalization between molecules. We employed CoPixie with live-cell single-molecule imaging of telomerase and telomeres, to test the model that cancer-associated POT1 mutations facilitate telomere accessibility. We show that POT1 mutants Y223C, D224N or K90E increase telomere accessibility for telomerase interaction. However, unlike the POT1-D224N mutant, the POT1-Y223C and POT1-K90E mutations also increase the duration of long-lasting telomerase interactions at telomeres. Our data reveal that telomere elongation in cells expressing cancer-associated POT1 mutants arises from the dual impact of these mutations on telomere accessibility and telomerase retention at telomeres. CoPixie can be used to explore a variety of questions involving macromolecular interactions in living cells, including between proteins and nucleic acids, from multicolor single-particle tracks.}, }
@article {pmid39082275, year = {2024}, author = {Liang, F and Rai, R and Sodeinde, T and Chang, S}, title = {TRF2-RAP1 represses RAD51-dependent homology-directed telomere repair by promoting BLM-mediated D-loop unwinding and inhibiting BLM-DNA2-dependent 5'-end resection.}, journal = {Nucleic acids research}, volume = {}, number = {}, pages = {}, doi = {10.1093/nar/gkae642}, pmid = {39082275}, issn = {1362-4962}, support = {W81XWH-22-1-0099//Department of Defense/ ; RO1GM141350/NH/NIH HHS/United States ; }, abstract = {Inappropriate homology-directed repair (HDR) of telomeres results in catastrophic telomere loss and aberrant chromosome fusions, leading to genome instability. We have previously shown that the TRF2-RAP1 heterodimer protects telomeres from engaging in aberrant telomere HDR. Cells lacking the basic domain of TRF2 and functional RAP1 display HDR-mediated telomere clustering, resulting in the formation of ultrabright telomeres (UTs) and massive chromosome fusions. Using purified proteins, we uncover three distinct molecular pathways that the TRF2-RAP1 heterodimer utilizes to protect telomeres from engaging in aberrant HDR. We show mechanistically that TRF2-RAP1 inhibits RAD51-initiated telomeric D-loop formation. Both the TRF2 basic domain and RAP1-binding to TRF2 are required to block RAD51-mediated homology search. TRF2 recruits the BLM helicase to telomeres through its TRFH domain to promote BLM-mediated unwinding of telomere D-loops. In addition, TRF2-RAP1 inhibits BLM-DNA2-mediated 5' telomere end resection, preventing the generation of 3' single-stranded telomere overhangs necessary for RAD51-dependent HDR. Importantly, cells expressing BLM mutants unable to interact with TRF2 accumulate telomere D-loops and UTs. Our findings uncover distinct molecular mechanisms coordinated by TRF2-RAP1 to protect telomeres from engaging in aberrant HDR.}, }
@article {pmid39081620, year = {2024}, author = {Obeagu, EI and Obeagu, GU}, title = {Telomere Dynamics in Sickle Cell Anemia: Unraveling Molecular Aging and Disease Progression.}, journal = {Journal of blood medicine}, volume = {15}, number = {}, pages = {313-323}, doi = {10.2147/JBM.S462758}, pmid = {39081620}, issn = {1179-2736}, abstract = {Sickle Cell Anemia (SCA) is a hereditary blood disorder characterized by the presence of abnormal hemoglobin, leading to the formation of sickle-shaped red blood cells. While extensive research has unraveled many aspects of the genetic and molecular basis of SCA, the role of telomere dynamics in disease progression remains a relatively unexplored frontier. This review seeks to provide a comprehensive examination of telomere biology within the context of SCA, aiming to elucidate its potential impact on molecular aging and the progression of the disease. The impact of oxidative stress on telomere dynamics in SCA is explored, with a particular focus on how increased reactive oxygen species (ROS) may contribute to accelerated telomere shortening and genomic instability. Furthermore, the potential relationship between telomere dysfunction and cellular senescence in SCA is investigated, shedding light on how telomere dynamics may contribute to the premature aging of cells in this population. The review concludes by summarizing key findings and proposing potential therapeutic strategies targeting telomere dynamics to mitigate disease progression in SCA. It also identifies gaps in current understanding and suggests avenues for future research, emphasizing the importance of further investigating telomere biology to advance our understanding of molecular aging and disease progression in Sickle Cell Anemia. This comprehensive exploration of telomere dynamics in SCA offers insights into potential mechanisms of molecular aging and disease progression, paving the way for targeted therapeutic interventions and improved disease management.}, }
@article {pmid39080469, year = {2024}, author = {Hussein-Agha, R and Kannengiesser, C and Lainey, E and Marcais, A and Srour, M and Sterin, A and Buchbinder, N and Borie, R and Plessier, A and Socié, G and Peffault de Latour, R and Sicre de Fontbrune, F}, title = {Alemtuzumab-based conditioning regimen before hematopoietic stem cell transplantation in patients with short telomere syndromes: a retrospective study of the SFGM-TC.}, journal = {Bone marrow transplantation}, volume = {}, number = {}, pages = {}, pmid = {39080469}, issn = {1476-5365}, abstract = {While HSCT is the only curative option for patients with short telomere syndromes (STSs) and severe bone marrow failure (BMF) or myeloid malignancies (MM), their increase sensitivity to conditioning regimen strongly affect outcomes. To minimize HSCT related mortality, alemtuzumab-based conditioning regimens have been proposed, but the number of patients transplanted with those regimens reported in the literature remains very low. We retrospectively analyzed outcome of adults and adolescents with STSs transplanted after an alemtuzumab, fludarabine and cyclophosphamide based regimen registered by the SFGM-TC. Seven patients were transplanted for a BMF and 5 for a MM (median age 34 years, (IQR [22-45])). The 2-year GRFS for patients with MM was 20% (95% CI [3;100]), and 57% (95% CI [30;100]) in others. In univariate (hazard ratio, HR = 6, 95% CI [1;31]) and multivariate analysis (HR = 26, 95% CI [2;414]) stem cell source was a predictive factor for GRFS. Three of the 5 patients with pre-transplant MM relapsed and 2 of them died at last follow up. The 2-year OS was 66% (95% CI [43;99]) in the whole cohort with a median follow up of 32 months (IQR [13-56]). In conclusion, Alemtuzumab-based conditioning regimen with bone marrow is an option for patients with STSs and BMF, but others modalities have to be explored for patients with MM.}, }
@article {pmid39074257, year = {2024}, author = {Han, MH and Kwon, HS and Hwang, M and Park, HH and Jeong, JH and Park, KW and Kim, EJ and Yoon, SJ and Yoon, B and Jang, JW and Hong, JY and Choi, SH and Koh, SH}, title = {Association between osteoporosis and the rate of telomere shortening.}, journal = {Aging}, volume = {16}, number = {}, pages = {}, doi = {10.18632/aging.206034}, pmid = {39074257}, issn = {1945-4589}, abstract = {A shorter leukocyte telomere length (LTL) is reported to be associated with age-related diseases, including osteoporosis. Many studies have tried identifying the association between LTL and osteoporosis, although it remains controversial. This study aimed to determine whether osteoporosis is independently associated with LTL shortening in a prospective longitudinal cohort. The KBASE study is an independent multicenter prospective cohort in South Korea, which began in 2014. We compared the LTL values for each participant at baseline and over a 2-year follow-up period. Boxplots were used to demonstrate the differences in the change in LTL over a 2-year follow-up according to osteoporosis. Multivariable linear regression was conducted to identify whether osteoporosis is independently associated with the rate of telomere shortening. A total of 233 subjects (from 55 to 88 years) from the KBASE cohort were finally enrolled in the study. We observed that the LTL decreased by approximately 1.2 kbp over 2 years. While the LTL decreased as age increased, the rate of LTL shortening did not increase with age. Multivariable linear regression analysis indicated that only osteoporosis was independently associated with rapid LTL shortening over 2 years (B, -8.08; p = 0.038). We sought to identify an association between osteoporosis and LTL shortening in an independent prospective cohort. We found that participants with osteoporosis had significantly faster LTL shortening over 2 years than those without osteoporosis. We hope this study will help elucidate the underlying mechanisms in the relationship between LTL and osteoporosis in the future.}, }
@article {pmid39068742, year = {2024}, author = {Chen, X and Ren, Q and Wu, F and Zhu, K and Tao, J and Zhang, A}, title = {Exposure to four typical heavy metals induced telomere shortening of peripheral blood mononuclear cells in relevant with declined urinary aMT6s in rats.}, journal = {Ecotoxicology and environmental safety}, volume = {283}, number = {}, pages = {116791}, doi = {10.1016/j.ecoenv.2024.116791}, pmid = {39068742}, issn = {1090-2414}, abstract = {Environmental heavy metals pollution have seriously threatened the health of human beings. An increasing number of researches have demonstrated that environmental heavy metals can influence the telomere length of Peripheral Blood Mononuclear Cells (PBMCs), which implicate biological aging as well as predicts diseases. Our previous study has shown that methylmercury (MeHg)-induced telomere shortening in rat brain tissue was associated with urinary melatonin metabolite 6-sulfatoxymelatonin (aMT6s) levels. Here, we aimed to further elucidate the impact of 4 typical heavy metals (As, Hg, Cd and Pb) on telomere length of PBMCs and their association with urinary aMT6s in rats. In this study, eighty-eight male Sprague-Dawley rats were randomized grouped into eleven groups. Among them, forty 3-month-old (young) and forty 12-month-old (middle-aged) rats were divided into young or middle-aged control groups as well as typical heavy metals exposed groups, respectively. Eight 24-month-old rats (old) was divided into aging control group. The results showed that MeHg exposure in young rats while sodium arsenite (iAs), MeHg, cadmium chloride (CdCl2), lead acetate (PbAc) exposure in middle-aged rats for 3 months significantly reduced the levels of and urinary aMT6s, as well as telomere length of PBMCs. In addition, they also induced abnormalities in serum oxidative stress (SOD, MDA and GPx) and inflammatory (IL-1β, IL-6 and TNF-α) indicators. Notably, there was a significant positive correlation between declined level of urinary aMT6s and the shortening of telomere length in PBMCs in rats exposed to 4 typical heavy metals. These results suggested that 4 typical heavy metals exposure could accelerate the reduction of telomere length of PBMCs partially by inducing oxidative stress and inflammatory in rats, while ageing may be an important synergistic factor. Urinary aMT6s detection may be a alternative method to reflect telomere toxic effects induced by heavy metal exposure.}, }
@article {pmid39062937, year = {2024}, author = {Apetroaei, MM and Fragkiadaki, P and Velescu, BȘ and Baliou, S and Renieri, E and Dinu-Pirvu, CE and Drăgănescu, D and Vlăsceanu, AM and Nedea, MII and Udeanu, DI and Docea, AO and Tsatsakis, A and Arsene, AL}, title = {Pharmacotherapeutic Considerations on Telomere Biology: The Positive Effect of Pharmacologically Active Substances on Telomere Length.}, journal = {International journal of molecular sciences}, volume = {25}, number = {14}, pages = {}, doi = {10.3390/ijms25147694}, pmid = {39062937}, issn = {1422-0067}, abstract = {Telomeres are part of chromatin structures containing repeated DNA sequences, which function as protective caps at the ends of chromosomes and prevent DNA degradation and recombination, thus ensuring the integrity of the genome. While telomere length (TL) can be genetically inherited, TL shortening has been associated with ageing and multiple xenobiotics and bioactive substances. TL has been characterised as a reliable biomarker for the predisposition to developing chronic pathologies and their progression. This narrative review aims to provide arguments in favour of including TL measurements in a complex prognostic and diagnostic panel of chronic pathologies and the importance of assessing the effect of different pharmacologically active molecules on the biology of telomeres. Medicines used in the management of cardiovascular diseases, diabetes, schizophrenia, hormone replacement therapy at menopause, danazol, melatonin, and probiotics have been studied for their positive protective effects against TL shortening. All these classes of drugs are analysed in the present review, with a particular focus on the molecular mechanisms involved.}, }
@article {pmid39059352, year = {2024}, author = {Al-Dulaimi, S and Matta, S and Slijepcevic, P and Roberts, T}, title = {5-aza-2'-deoxycytidine induces telomere dysfunction in breast cancer cells.}, journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie}, volume = {178}, number = {}, pages = {117173}, doi = {10.1016/j.biopha.2024.117173}, pmid = {39059352}, issn = {1950-6007}, abstract = {AIMS: Azacitidine, a drug that epigenetically modifies DNA, is widely used to treat haematological malignancies. However, at low doses, it demethylates DNA, and as a result, can alter gene expression. In our previous publication, we showed that low doses of azacitidine induce telomere length elongation in breast cancer cells. In this study, we aim to identify the mechanisms which lead to telomere length increases.
METHODS: Breast cancer cell lines representing different molecular sub-types were exposed to 5-aza-2'-deoxycytidine (5-aza) in 2 and 3D cultures, followed by DNA, RNA, and protein extractions. Samples were then analysed for telomere length, DNA damage, telomerase, and ALT activity.
RESULTS: We show that treatment of the cell lines with 5-aza for 72 h induced DNA damage at the telomeres and increased ALT activity 3-fold. We also identified a gene, POLD3, which may be involved in the ALT activity seen after treatment.
CONCLUSION: Our results indicate that while 5-aza is a useful drug for treating haematological cancers, surviving cancer cells that have been exposed to lower doses of the drug may activate mechanisms such as ALT. This could lead to cancer cell survival and possible resistance to 5-aza clinically.}, }
@article {pmid39057072, year = {2024}, author = {Macamo, ED and Mkhize-Kwitshana, ZL and Mthombeni, J and Naidoo, P}, title = {The Impact of HIV and Parasite Single Infection and Coinfection on Telomere Length: A Systematic Review.}, journal = {Current issues in molecular biology}, volume = {46}, number = {7}, pages = {7258-7290}, doi = {10.3390/cimb46070431}, pmid = {39057072}, issn = {1467-3045}, support = {HDID5149/KR/2021//SAMRC/ ; }, abstract = {HIV and parasite infections accelerate biological aging, resulting in immune senescence, apoptosis and cellular damage. Telomere length is considered to be one of the most effective biomarkers of biological aging. HIV and parasite infection have been reported to shorten telomere length in the host. This systematic review aimed to highlight work that explored the influence of HIV and parasite single infections and coinfection on telomere length. Using specific keywords related to the topic of interest, an electronic search of several online databases (Google Scholar, Web of Science, Scopus, Science Direct and PubMed) was conducted to extract eligible articles. The association between HIV infection or parasite infection and telomere length and the association between HIV and parasite coinfection and telomere length were assessed independently. The studies reported were mostly conducted in the European countries. Of the 42 eligible research articles reviewed, HIV and parasite single infections were independently associated with telomere length shortening. Some studies found no association between antiretroviral therapy (ART) and telomere length shortening, while others found an association between ART and telomere length shortening. No studies reported on the association between HIV and parasite coinfection and telomere length. HIV and parasite infections independently accelerate telomere length shortening and biological aging. It is possible that coinfection with HIV and parasites may further accelerate telomere length shortening; however, this is a neglected field of research with no reported studies to date.}, }
@article {pmid39057051, year = {2024}, author = {Macamo, ED and Mkhize-Kwitshana, ZL and Duma, Z and Mthombeni, J and Naidoo, P}, title = {Telomere Length in a South African Population Co-Infected with HIV and Helminths.}, journal = {Current issues in molecular biology}, volume = {46}, number = {7}, pages = {6853-6867}, doi = {10.3390/cimb46070409}, pmid = {39057051}, issn = {1467-3045}, support = {HDID5149/KR/202//SAMRC/ ; }, abstract = {Biological ageing refers to the gradual decrease in physiological functions, resulting in immune senescence, cellular damage and apoptosis. Telomere length is a biomarker of biological ageing. Limited studies have associated shorter telomere length with HIV and parasite single infections, with no studies reporting the association of HIV and parasite co-infection with telomere length. The study aimed to investigate whether telomere length shortening is accelerated in a South African population co-infected with HIV and helminths compared to participants singly infected with either HIV or helminths. Additionally, telomere length data were compared with participants' biochemical and full blood count parameters. A total of 200 participants were in groups of uninfected control, HIV single infection, helminth single infection and HIV and helminth co-infection groups. Relative telomere length (RTL) was determined using Real-Time PCR and associated with biochemical and full blood count parameters using multivariate regression analysis models that were adjusted for confounders. The uninfected control group was used as a reference group. The uninfected control group had the highest mean RTL (1.21 ± 0.53) while the HIV-infected (0.96 ± 0.42) and co-infected (0.93 ± 0.41) groups had similar RTLs, and lastly, the helminth-infected group (0.83 ± 0.33) had the lowest RTL (p = 0.0002). When compared to the uninfected control group, a significant association between RTL and biochemical parameters, including blood iron (β = -0.48), ferritin (β = -0.48), transferrin saturation (β = -0.57), transferrin (β = -0.57), phosphate (β = -0.47), vitamin A (β = -0.49) and C-reactive protein (β = -0.52) were noted in the co-infected group (p < 0.05). In addition, a significant association between RTL and full blood count, including (β = -0.47), haematocrit (β = -0.46), mean corpuscular volume (β = -0.47), lymphocytes (β = -0.45), mean corpuscular haemoglobin concentration (β = -0.45), red cell distribution width (β = -0.47), monocytes (β = -0.45), eosinophils (β = -0.45), basophils (β = -0.44) and transferrin saturation (β = -0.57) were also noted in the co-infected group (p < 0.05). Accelerated biological ageing, as indicated by telomere length shortening, is associated with HIV and helminth co-infections.}, }
@article {pmid39055058, year = {2024}, author = {Chen, X and Liu, B and Zhou, J and Lin, J and Jiang, W and Xie, R}, title = {Association between telomere length and erectile dysfunction: a cross-sectional study.}, journal = {Frontiers in endocrinology}, volume = {15}, number = {}, pages = {1391013}, doi = {10.3389/fendo.2024.1391013}, pmid = {39055058}, issn = {1664-2392}, mesh = {Humans ; Male ; *Erectile Dysfunction ; Cross-Sectional Studies ; Middle Aged ; *Telomere ; Leukocytes/metabolism/pathology ; Aged ; Adult ; Nutrition Surveys ; Telomere Homeostasis ; Telomere Shortening ; Risk Factors ; }, abstract = {BACKGROUND: Leukocyte telomere length (LTL) serves as a significant biomarker of aging. Erectile dysfunction (ED) is a commonly observed condition among middle-aged and older men. The objective of this study is to explore the potential association between LTL and ED.
METHODS: We utilized data from the National Health and Nutrition Examination Survey (NHANES) to examine the association between LTL and ED. Weighted multivariate regression analyses were performed as the primary statistical method. Subgroup analyses were conducted to investigate specific population subsets, and restricted cubic spline (RCS) analyses were employed to assess the non-linear relationship between LTL and ED.
RESULTS: The results of weighted multivariate regression analyses revealed a negative correlation between LTL and the risk of ED. Individuals with ED exhibited shorter LTL compared to those without ED. For each unit increase in LTL, there was a 54% reduction in the risk of ED (odds ratios[OR] 0.46, 95% confidence intervals[CI] 0.25-0.85). When LTL was considered as a categorical variable, the group with the longest LTL (Q5) had a 44% lower risk of ED compared to the group with the shortest LTL(Q1) (OR 0.56, 95% CI 0.39-0.81). A non-linear relationship was observed between TL and ED. Various sensitivity analyses were conducted to validate the stability of the results, and consistent findings were obtained.
CONCLUSION: The negative association between leukocyte LTL and ED suggests that delaying the shortening of LTL may decrease the risk of ED.}, }
@article {pmid39054789, year = {2024}, author = {Tempaku, PF and D'Almeida, V and Andersen, ML and Tufik, S}, title = {Sleep is associated with telomere shortening: A population-based longitudinal study.}, journal = {Journal of sleep research}, volume = {}, number = {}, pages = {e14274}, doi = {10.1111/jsr.14274}, pmid = {39054789}, issn = {1365-2869}, support = {#23/08657-0 to VDA//Fundação de Amparo à Pesquisa do Estado de São Paulo/ ; #20/13467-8 to MLA//Fundação de Amparo à Pesquisa do Estado de São Paulo/ ; }, abstract = {As the chronological age increases, there is a decrease in the telomere length (TL). Associations between TL and age-related diseases have been described. Since the major pathophysiological factors related to inadequate sleep (including sleep complaints and sleep disorders) contribute to the exacerbation of inflammation and oxidative stress, an association of sleep and TL has been proposed. The aim of this study was to evaluate the association between sleep-related variables with TL in a longitudinal framework. We used data derived from the EPISONO cohort, which was followed over 8 years. All individuals answered sleep-related questionnaires, underwent a full-night polysomnography (PSG), and had their blood collected for DNA extraction. The TL was measured through a quantitative real time polymerase chain reaction. Age, sex, body mass index (BMI), smoking, physical activity status, and the 10 principal components (ancestry estimate) were considered covariables. Of the 1042 individuals in the EPISONO cohort, 68.3% agreed to participate in the follow-up study (n = 712). Baseline SpO2 (ß = 0.008, p = 0.007), medium SpO2 (ß = 0.013, p = 0.013), and total sleep time <90% (ß = -0.122, p = 0.012) had an effect on TL from the follow-up. The 8 year TL attrition was inversely associated with total sleep time, sleep efficiency, sleep architecture variables, wake after sleep onset, arousal index, oxygen-related variables baseline, and the presence of obstructive sleep apnea (OSA). We conclude that individuals with worse sleep quality, alterations in sleep architecture, and OSA had greater TL attrition over the 8 years. Using a longitudinal approach, these findings confirm previous cross-sectional evidence linking sleep with accelerated biological ageing.}, }
@article {pmid39054004, year = {2024}, author = {Ng, GYQ and Hande, MP}, title = {Use of peptide nucleic acid probe to determine telomere dynamics in improving chromosome analysis in genetic toxicology studies.}, journal = {Mutation research. Genetic toxicology and environmental mutagenesis}, volume = {897}, number = {}, pages = {503773}, doi = {10.1016/j.mrgentox.2024.503773}, pmid = {39054004}, issn = {1879-3592}, mesh = {*Peptide Nucleic Acids ; *Telomere/drug effects/genetics ; Humans ; *In Situ Hybridization, Fluorescence/methods ; Animals ; Mutagens/toxicity ; Karyotyping/methods ; }, abstract = {Genetic toxicology, strategically located at the intersection of genetics and toxicology, aims to demystify the complex interplay between exogenous agents and our genetic blueprint. Telomeres, the protective termini of chromosomes, play instrumental roles in cellular longevity and genetic stability. Traditionally karyotyping and fluorescence in situ hybridisation (FISH), have been indispensable tools for chromosomal analysis following exposure to genotoxic agents. However, their scope in discerning nuanced molecular dynamics is limited. Peptide Nucleic Acids (PNAs) are synthetic entities that embody characteristics of both proteins and nucleic acids and have emerged as potential game-changers. This perspective report comprehensively examines the vast potential of PNAs in genetic toxicology, with a specific emphasis on telomere research. PNAs' superior resolution and precision make them a favourable choice for genetic toxicological assessments. The integration of PNAs in contemporary analytical workflows heralds a promising evolution in genetic toxicology, potentially revolutionizing diagnostics, prognostics, and therapeutic avenues. In this timely review, we attempted to assess the limitations of current PNA-FISH methodology and recommend refinements.}, }
@article {pmid39052566, year = {2024}, author = {Huang, SH and Abrametz, K and McGrath, SL and Kobryn, K}, title = {Design and characterization of hyperactive mutants of the Agrobacterium tumefaciens telomere resolvase, TelA.}, journal = {PloS one}, volume = {19}, number = {7}, pages = {e0307590}, doi = {10.1371/journal.pone.0307590}, pmid = {39052566}, issn = {1932-6203}, mesh = {*Agrobacterium tumefaciens/genetics/enzymology ; *Telomere/metabolism/genetics ; *Bacterial Proteins/genetics/metabolism/chemistry ; Mutation ; Models, Molecular ; }, abstract = {Telomere resolvases are a family of DNA cleavage and rejoining enzymes that produce linear DNAs terminated by hairpin telomeres from replicated intermediates in bacteria that possess linear replicons. The telomere resolvase of Agrobacterium tumefaciens, TelA, has been examined at the structural and biochemical level. The N-terminal domain of TelA, while not required for telomere resolution, has been demonstrated to play an autoinhibitory role in telomere resolution, conferring divalent metal responsiveness on the reaction. The N-terminal domain also inhibits the competing reactions of hp telomere fusion and recombination between replicated telomere junctions. Due to the absence of the N-terminal domain from TelA/DNA co-crystal structures we produced an AlphaFold model of a TelA monomer. The AlphaFold model suggested the presence of two inhibitory interfaces; one between the N-terminal domain and the catalytic domain and a second interface between the C-terminal helix and the N-core domain of the protein. We produced mutant TelA's designed to weaken these putative interfaces to test the validity of the modeled interfaces. While our analysis did not bear out the details of the predicted interfaces the model was, nonetheless, extremely useful in guiding design of mutations that, when combined, demonstrated an additive activation of TelA exceeding 250-fold. For some of these hyperactive mutants stimulation of telomere resolution has also been accompanied by activation of competing reactions. However, we have also characterized hyperactive TelA mutants that retain enough autoinhibition to suppress the competing reactions.}, }
@article {pmid39050459, year = {2024}, author = {Tomasova, K and Seborova, K and Kroupa, M and Horak, J and Kavec, M and Vodickova, L and Rob, L and Hruda, M and Mrhalova, M and Bartakova, A and Bouda, J and Fleischer, T and Kristensen, VN and Vodicka, P and Vaclavikova, R}, title = {Telomere length as a predictor of therapy response and survival in patients diagnosed with ovarian carcinoma.}, journal = {Heliyon}, volume = {10}, number = {13}, pages = {e33525}, pmid = {39050459}, issn = {2405-8440}, abstract = {Impaired telomere length (TL) maintenance in ovarian tissue may play a pivotal role in the onset of epithelial ovarian cancer (OvC). TL in either target or surrogate tissue (blood) is currently being investigated for use as a predictor in anti-OvC therapy or as a biomarker of the disease progression, respectively. There is currently an urgent need for an appropriate approach to chemotherapy response prediction. We performed a monochrome multiplex qPCR measurement of TL in peripheral blood leukocytes (PBL) and tumor tissues of 209 OvC patients. The methylation status and gene expression of the shelterin complex and telomerase catalytic subunit (hTERT) were determined within tumor tissues by High-Throughput DNA methylation profiling and RNA sequencing (RNA-Seq) analysis, respectively. The patients sensitive to cancer treatment (n = 46) had shorter telomeres in PBL compared to treatment-resistant patients (n = 93; P = 0.037). In the patients with a different therapy response, transcriptomic analysis showed alterations in the peroxisome proliferator-activated receptor (PPAR) signaling pathway (q = 0.001). Moreover, tumor TL shorter than the median corresponded to better overall survival (OS) (P = 0.006). TPP1 gene expression was positively associated with TL in tumor tissue (P = 0.026). TL measured in PBL could serve as a marker of platinum therapy response in OvC patients. Additionally, TL determined in tumor tissue provides information on OvC patients' OS.}, }
@article {pmid39048791, year = {2024}, author = {Garg, V and Bohra, A and Mascher, M and Spannagl, M and Xu, X and Bevan, MW and Bennetzen, JL and Varshney, RK}, title = {Unlocking plant genetics with telomere-to-telomere genome assemblies.}, journal = {Nature genetics}, volume = {}, number = {}, pages = {}, pmid = {39048791}, issn = {1546-1718}, abstract = {Contiguous genome sequence assemblies will help us to realize the full potential of crop translational genomics. Recent advances in sequencing technologies, especially long-read sequencing strategies, have made it possible to construct gapless telomere-to-telomere (T2T) assemblies, thus offering novel insights into genome organization and function. Plant genomes pose unique challenges, such as a continuum of ancient to recent polyploidy and abundant highly similar and long repetitive elements. Owing to progress in sequencing approaches, for most crop plants, chromosome-scale reference genome assemblies are available, but T2T assembly construction remains challenging. Here we describe methods for haplotype-resolved, gapless T2T assembly construction in plants, including various crop species. We outline the impact of T2T assemblies in elucidating the roles of repetitive elements in gene regulation, as well as in pangenomics, functional genomics, genome-assisted breeding and targeted genome manipulation. In conjunction with sequence-enriched germplasm repositories, T2T assemblies thus hold great promise for basic and applied plant sciences.}, }
@article {pmid39045889, year = {2024}, author = {Yang, C and Zhang, Y and Li, J and Liu, X and Qiu, J and Zhang, J and Liu, X and Zhang, Y and Zhao, Y}, title = {Short leukocyte telomere length and high plasma phospholipid fatty acids increase the risk of type 2 diabetes.}, journal = {Endocrine connections}, volume = {}, number = {}, pages = {}, doi = {10.1530/EC-24-0033}, pmid = {39045889}, issn = {2049-3614}, abstract = {In the last forty years, there has been a notable rise in the occurrence of diabetes within China, leading to the country now having the highest number of individuals affected by this condition globally. This prospective observational study examined the effect of different baseline relative leukocyte telomere length (RTL) and the combined effect of baseline RTL and plasma phospholipid fatty acid (PPFA) on the risk of developing diabetes. Adults from Ningxia Province who underwent baseline and follow-up surveys were included in the study. The correlation between the baseline RTL and PPFA was investigated using a multiple linear regression model. The combined effect of baseline RTL and PPFA levels on the risk of developing type 2 diabetes mellitus (T2DM) were investigated using a cox regression model with time as the covariate. A total of 1461 study subjects were included in this study. 141 subjects developed T2DM during the follow-up period. The baseline age was negatively correlated with RTL.Multiple linear regression analysis showed that C16:0 and MUFA concentrations influenced RTL. Subjects with shorter RTL at baseline had a higher risk of developing diabetes than those with longer RTL. Subjects with shorter RTL and higher C16:0 and MUFA concentrations at baseline had a higher risk of developing T2DM than those with longer RTL and lower C16:0 and MUFA concentrations. Our findings indicated that PPFA affects changes in RTL. In addition, RTL and PPFA are associated with the occurrence of T2DM.}, }
@article {pmid39045323, year = {2024}, author = {Ibraheem Shelash Al-Hawary, S and Ali Alzahrani, A and Ghaleb Maabreh, H and Abed Jawad, M and Alsaadi, SB and Kareem Jabber, N and Alawadi, A and Alsalamy, A and Alizadeh, F}, title = {The association of metabolic syndrome with telomere length as a marker of cellular aging: a systematic review and meta-analysis.}, journal = {Frontiers in genetics}, volume = {15}, number = {}, pages = {1390198}, pmid = {39045323}, issn = {1664-8021}, abstract = {BACKGROUND: It has been suggested that metabolic syndrome (MetS) accelerates the aging process, potentially contributing to the development of age-related complications. Available studies examining the relation of MetS to telomere length (TL), a putative biological marker of aging, have yielded inconclusive findings. This meta-analysis was performed to investigate the association between MetS and TL.
METHODS: A comprehensive systematic search was conducted in PubMed and Scopus databases to identify relevant literature published up to February 2024. Standard mean difference (SMD) and standardized beta coefficient (β) with their 95% confidence intervals (CI) were used as effect sizes to measure the associations using the random effects model.
RESULTS: A total of nine studies, comprising a total sample size of 8,606 participants, were eligible for the meta-analysis. No significant difference in mean TL was found between patients with and without MetS (SMD = -0.03, 95%CI = -0.17 to 0.10), with a significant heterogeneity across the studies (I [2] = 89.7.0%, p ≤ 0.001). In contrast, it was revealed that MetS is negatively related to TL (β = -0.08, 95%CI = -0.15 to -0.004). In the subgroup analysis, this finding was supported by the International Diabetes Federation (IDF) definition of MetS.
CONCLUSION: This meta-analysis highlighted that MetS may be linked to a shorter TL. Additional studies are required to confirm this finding.}, }
@article {pmid39045115, year = {2022}, author = {Zakharova, N and Bravve, L and Mamedova, G and Kaydan, M and Ershova, E and Martynov, A and Veiko, N and Kostyuk, S}, title = {Telomere Length as a Marker of Suicidal Risk in Schizophrenia.}, journal = {Consortium psychiatricum}, volume = {3}, number = {2}, pages = {37-47}, pmid = {39045115}, issn = {2713-2919}, abstract = {BACKGROUND: Schizophrenia and suicidal behavior are associated with shortening in the length of telomeres. The aim of the study was to compare the content (pg/mcg) of telomeric repeat in DNA isolated from peripheral blood cells in three groups of subjects: patients with schizophrenia and a history of suicide attempts, patients with schizophrenia without suicidal tendencies, and healthy control volunteers.
METHODS: Relapses according to gender and age were examined in 47 patients with schizophrenia with suicidal behavior, 47 patients without self-destructive conditions, and 47 volunteers with healthy control and maintenance for the content of telomeric and the number of copies of mitochondrial DNA (mtDNA) in peripheral blood leukocytes.
RESULTS: Analysis of determining the content of telomeric repeat (TR) in the DNA of massive weight gain in the series: patients with schizophrenia and suicidal attempts - patients with schizophrenia without suicidal observations - healthy controls (225±28.4 (227 [190; 250]) vs. 243±21 (245 [228; 260]) vs. 255±17.9 (255 [242; 266]), p <0.005. The same trend is observed for the number of mtDNA copies (257±101.5 (250 [194; 297])) vs. 262.3±59.3 (254 [217; 312]) vs. 272±79.9 (274 [213; 304]); p=0.012), but no significant differences were recorded.
CONCLUSIONS: For the first time, the phenomenon of telomere shortening was discovered in schizophrenics with suicidal risk. The length of the telomere corresponds to the parameter of a biological marker - an objectively measured indicator of normal or pathological processes, but gaining an idea of its reliability is still necessary for verification with an assessment of its sensitivity, specificity, and positive and negative predictive value. The telomere may be considered a putative predictive indicator of suicidal risk.}, }
@article {pmid39042999, year = {2024}, author = {L Rocha, J and Lou, RN and Sudmant, PH}, title = {Structural variation in humans and our primate kin in the era of telomere-to-telomere genomes and pangenomics.}, journal = {Current opinion in genetics & development}, volume = {87}, number = {}, pages = {102233}, doi = {10.1016/j.gde.2024.102233}, pmid = {39042999}, issn = {1879-0380}, abstract = {Structural variants (SVs) account for the majority of base pair differences both within and between primate species. However, our understanding of inter- and intra-species SV has been historically hampered by the quality of draft primate genomes and the absence of genome resources for key taxa. Recently, advances in long-read sequencing and genome assembly have begun to radically reshape our understanding of SVs. Two landmark achievements include the publication of a human telomere-to-telomere (T2T) genome as well as the development of the first human pangenome reference. In this review, we first look back to the major works laying the foundation for these projects. We then examine the ways in which T2T genome assemblies and pangenomes are transforming our understanding of and approach to primate SV. Finally, we discuss what the future of primate SV research may look like in the era of T2T genomes and pangenomics.}, }
@article {pmid39043540, year = {2024}, author = {Goncalves da Silva, D and Graciano da Silva, N and Amato, AA}, title = {Leukocyte telomere length in subjects with metabolic dysfunction-associated steatotic liver disease.}, journal = {Arab journal of gastroenterology : the official publication of the Pan-Arab Association of Gastroenterology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.ajg.2024.06.005}, pmid = {39043540}, issn = {2090-2387}, abstract = {BACKGROUND AND STUDY AIMS: This study aimed to examine the association between peripheral leukocyte telomere length and indicators of metabolic abnormalities in subjects with metabolic dysfunction-associated steatotic liver disease (MASLD) assessed by magnetic resonance imaging (MRI).
PATIENTS AND METHODS: This cross-sectional study included adults over 20 years with body mass index (BMI) of over >25 kg/m[2] and sonographic evidence of hepatic steatosis. The subjects were evaluated by clinical and biochemical variables, determination of hepatic fat fraction by MRI and relative peripheral leukocyte telomere length by quantitative real-time polymerase chain reaction.
RESULTS: Thirty-two subjects (22 men and 10 women) with MASLD were included, with a median age of 40 years, median BMI of 33.75 kg/m[2], median HFF 19 %, and median relative T/S ratio of 0.64. Subjects with relative T/S ratio below the median had significantly higher age, lower BMI, higher AST serum levels, higher GGT serum levels, lower serum ferritin levels, and higher FIB4 score. In a multivariable logistic regression model considering relative T/S ratio below or above the median only age was significantly associated with relative T/S ratio. Our findings suggest that age is the most important factor associated with telomere length among subjects with MASLD.
CONCLUSION: Our findings suggest that age is the most important factor associated with telomere length among subjects with MASLD.}, }
@article {pmid39042290, year = {2024}, author = {Bortoletto, S and Nunes-Souza, E and Marchi, R and Ruthes, MO and Okano, LM and Tofolo, MV and Centa, A and Fonseca, AS and Rosolen, D and Cavalli, LR}, title = {MicroRNAs role in telomere length maintenance and telomerase activity in tumor cells.}, journal = {Journal of molecular medicine (Berlin, Germany)}, volume = {}, number = {}, pages = {}, pmid = {39042290}, issn = {1432-1440}, abstract = {MiRNAs, a class of non-coding RNA molecules, have emerged as critical modulators of telomere length and telomerase activity by finely tuning the expression of target genes (and not gene targets) within signaling pathways involved in telomere homeostasis. The primary objective of this systematic review was to compile and synthesize the existing body of knowledge on the role, association, and involvement of miRNAs in telomere length. Additionally, the review explored the regulation, function, and activation mechanism of the human telomerase reverse transcriptase (hTERT) gene and telomerase activity in tumor cells. A comprehensive analysis of 47 selected articles revealed 40 distinct miRNAs involved in these processes. These miRNAs were shown to exert their function, in both clinical cases and cell line models, either directly or indirectly, regulating hTERT and telomerase activity through distinct molecular mechanisms. The regulatory roles of these miRNAs significantly affected major cancer phenotypes, with outcomes largely dependent on the tissue type and the cellular actions within the tumor cells, whereby they functioned as oncogenes or tumor suppressors. These findings strongly support the pivotal role of miRNAs in modulating telomere length and telomerase activity, thereby contributing to the intricate and complex regulation of telomere homeostasis in tumor cells. Moreover, they emphasize the potential of targeting miRNAs and key regulatory genes as therapeutic strategies to disrupt cancer cell growth and promote senescence, offering promising avenues for novel cancer treatments.}, }
@article {pmid39038850, year = {2024}, author = {Zhao, R and Xu, M and Yu, X and Wondisford, AR and Lackner, RM and Salsman, J and Dellaire, G and Chenoweth, DM and O'Sullivan, RJ and Zhao, X and Zhang, H}, title = {SUMO promotes DNA repair protein collaboration to support alternative telomere lengthening in the absence of PML.}, journal = {Genes & development}, volume = {}, number = {}, pages = {}, doi = {10.1101/gad.351667.124}, pmid = {39038850}, issn = {1549-5477}, abstract = {The alternative lengthening of telomeres (ALT) pathway maintains telomere length in a significant fraction of cancers that are associated with poor clinical outcomes. A better understanding of ALT mechanisms is therefore necessary for developing new treatment strategies for ALT cancers. SUMO modification of telomere proteins contributes to the formation of ALT telomere-associated PML bodies (APBs), in which telomeres are clustered and DNA repair proteins are enriched to promote homology-directed telomere DNA synthesis in ALT. However, it is still unknown whether-and if so, how-SUMO supports ALT beyond APB formation. Here, we show that SUMO condensates that contain DNA repair proteins enable telomere maintenance in the absence of APBs. In PML knockout ALT cell lines that lack APBs, we found that SUMOylation is required for manifesting ALT features independent of PML and APBs. Chemically induced telomere targeting of SUMO produces condensate formation and ALT features in PML-null cells. This effect requires both SUMOylation and interactions between SUMO and SUMO interaction motifs (SIMs). Mechanistically, SUMO-induced effects are associated with the accumulation of DNA repair proteins, including Rad52, Rad51AP1, RPA, and BLM, at telomeres. Furthermore, Rad52 can undergo phase separation, enrich SUMO at telomeres, and promote telomere DNA synthesis in collaboration with the BLM helicase in a SUMO-dependent manner. Collectively, our findings suggest that SUMO condensate formation promotes collaboration among DNA repair factors to support ALT telomere maintenance without PML. Given the promising effects of SUMOylation inhibitors in cancer treatment, our findings suggest their potential use in perturbing telomere maintenance in ALT cancer cells.}, }
@article {pmid39037376, year = {2024}, author = {Coukos, A and Saglietti, C and Sempoux, C and Haubitz, M and Greuter, T and Mittaz-Crettol, L and Maurer, F and Mdawar-Bailly, E and Moradpour, D and Alberio, L and Good, JM and Baerlocher, GM and Fraga, M}, title = {High prevalence of short telomeres in idiopathic porto-sinusoidal vascular disorder.}, journal = {Hepatology communications}, volume = {8}, number = {8}, pages = {}, doi = {10.1097/HC9.0000000000000500}, pmid = {39037376}, issn = {2471-254X}, mesh = {Humans ; Male ; Female ; Cross-Sectional Studies ; Middle Aged ; *Telomere Shortening/genetics ; Aged ; Adult ; Prevalence ; Telomere/genetics ; Hypertension, Portal/genetics ; In Situ Hybridization, Fluorescence ; Telomere-Binding Proteins/genetics ; Telomerase/genetics ; }, abstract = {BACKGROUND: Telomeres prevent damage to coding DNA as end-nucleotides are lost during mitosis. Mutations in telomere maintenance genes cause excessive telomere shortening, a condition known as short telomere syndrome (STS). One hepatic manifestation documented in STS is porto-sinusoidal vascular disorder (PSVD).
METHODS: As the etiology of many cases of PSVD remains unknown, this study explored the extent to which short telomeres are present in patients with idiopathic PSVD.
RESULTS: This monocentric cross-sectional study included patients with histologically defined idiopathic PSVD. Telomere length in 6 peripheral blood leukocyte subpopulations was assessed using fluorescent in situ hybridization and flow cytometry. Variants of telomere-related genes were identified using high-throughput exome sequencing. In total, 22 patients were included, of whom 16 (73%) had short (9/22) or very short (7/22) telomeres according to age-adjusted reference ranges. Fourteen patients (64%) had clinically significant portal hypertension. Shorter telomeres were more frequent in males (p = 0.005) and patients with concomitant interstitial lung disease (p < 0.001), chronic kidney disease (p < 0.001), and erythrocyte macrocytosis (p = 0.007). Portal hypertension (p = 0.021), low serum albumin level (p < 0.001), low platelet count (p = 0.007), and hyperbilirubinemia (p = 0.053) were also associated with shorter telomeres. Variants in known STS-related genes were identified in 4 patients with VSTel and 1 with STel.
CONCLUSIONS: Short and very short telomeres were highly prevalent in patients with idiopathic PSVD, with 31% presenting with variants in telomere-related genes. Telomere biology may play an important role in vascular liver disease development. Clinicians should consider measuring telomeres in any patient presenting with PSVD.}, }
@article {pmid39033276, year = {2024}, author = {Panelli, DM and Wang, X and Mayo, J and Wong, RJ and Hong, X and Becker, M and Aghaeepour, N and Druzin, ML and Zuckerman, BS and Stevenson, DK and Shaw DrPH, GM and Bianco, K}, title = {Association of pregnancy complications and postpartum maternal leukocyte telomeres in two diverse cohorts: a nested case-control study.}, journal = {BMC pregnancy and childbirth}, volume = {24}, number = {1}, pages = {490}, pmid = {39033276}, issn = {1471-2393}, support = {NIH K12HD103084/NH/NIH HHS/United States ; R35GM138353/GF/NIH HHS/United States ; }, mesh = {Humans ; Female ; Pregnancy ; Case-Control Studies ; Adult ; *Leukocytes ; *Postpartum Period ; *Pre-Eclampsia/blood ; *Premature Birth/epidemiology ; Pilot Projects ; Pregnancy Complications/blood ; Telomere ; Cohort Studies ; Urban Population/statistics & numerical data ; Telomere Shortening ; Young Adult ; }, abstract = {BACKGROUND: Biologic strain such as oxidative stress has been associated with short leukocyte telomere length (LTL), as well as with preeclampsia and spontaneous preterm birth, yet little is known about their relationships with each other. We investigated associations of postpartum maternal LTL with preeclampsia and spontaneous preterm birth.
METHODS: This pilot nested case control study included independent cohorts of pregnant people with singleton gestations from two academic institutions: Cohort 1 (hereafter referred to as Suburban) were enrolled prior to 20 weeks' gestation between 2012 and 2018; and Cohort 2 (hereafter referred to as Urban) were enrolled at delivery between 2000 and 2012. Spontaneous preterm birth or preeclampsia were the selected pregnancy complications and served as cases. Cases were compared with controls from each study cohort of uncomplicated term births. Blood was collected between postpartum day 1 and up to 6 months postpartum and samples were frozen, then simultaneously thawed for analysis. Postpartum LTL was the primary outcome, measured using quantitative polymerase chain reaction (PCR) and compared using linear multivariable regression models adjusting for maternal age. Secondary analyses were done stratified by mode of delivery and self-reported level of stress during pregnancy.
RESULTS: 156 people were included; 66 from the Suburban Cohort and 90 from the Urban Cohort. The Suburban Cohort was predominantly White, Hispanic, higher income and the Urban Cohort was predominantly Black, Haitian, and lower income. We found a trend towards shorter LTLs among people with preeclampsia in the Urban Cohort (6517 versus 6913 bp, p = 0.07), but not in the Suburban Cohort. There were no significant differences in LTLs among people with spontaneous preterm birth compared to term controls in the Suburban Cohort (6044 versus 6144 bp, p = 0.64) or in the Urban Cohort (6717 versus 6913, p = 0.37). No differences were noted by mode of delivery. When stratifying by stress levels in the Urban Cohort, preeclampsia was associated with shorter postpartum LTLs in people with moderate stress levels (p = 0.02).
CONCLUSION: Our exploratory results compare postpartum maternal LTLs between cases with preeclampsia or spontaneous preterm birth and controls in two distinct cohorts. These pilot data contribute to emerging literature on LTLs in pregnancy.}, }
@article {pmid39032311, year = {2024}, author = {Panelli, DM and Mayo, JA and Wong, RJ and Becker, M and Feyaerts, D and Marić, I and Wu, E and Gotlib, IH and Gaudillière, B and Aghaeepour, N and Druzin, ML and Stevenson, DK and Shaw, GM and Bianco, K}, title = {Mode of delivery predicts postpartum maternal leukocyte telomere length.}, journal = {European journal of obstetrics, gynecology, and reproductive biology}, volume = {300}, number = {}, pages = {224-229}, doi = {10.1016/j.ejogrb.2024.07.026}, pmid = {39032311}, issn = {1872-7654}, abstract = {BACKGROUND: Recent studies have suggested that pregnancy accelerates biologic aging, yet little is known about how biomarkers of aging are affected by events during the peripartum period. Given that immune shifts are known to occur following surgery, we explored the relation between mode of delivery and postpartum maternal leukocyte telomere length (LTL), a marker of biologic aging.
STUDY DESIGN: Postpartum maternal blood samples were obtained from a prospective cohort of term, singleton livebirths without hypertensive disorders or peripartum infections between 2012 and 2018. The primary outcome was postpartum LTLs from one blood sample drawn between postpartum week 1 and up to 6 months postpartum, measured from thawed frozen peripheral blood mononuclear cells using quantitative PCR in basepairs (bp). Multivariable linear regression models compared LTLs between vaginal versus cesarean births, adjusting for age, body mass index, and nulliparity as potential confounders. Analyses were conducted in two mutually exclusive groups: those with LTL measured postpartum week 1 and those measured up to 6 months postpartum. Secondarily, we compared multiomics by mode of delivery using machine-learning methods to evaluate whether other biologic changes occurred following cesarean. These included transcriptomics, metabolomics, microbiomics, immunomics, and proteomics (serum and plasma).
RESULTS: Of 67 included people, 50 (74.6 %) had vaginal and 17 (25.4 %) had cesarean births. LTLs were significantly shorter after cesarean in postpartum week 1 (5755.2 bp cesarean versus 6267.8 bp vaginal, p = 0.01) as well as in the later draws (5586.6 versus 5945.6 bp, p = 0.04). After adjusting for confounders, these differences persisted in both week 1 (adjusted beta -496.1, 95 % confidence interval [CI] -891.1, -101.1, p = 0.01) and beyond (adjusted beta -396.8; 95 % CI -727.2, -66.4. p = 0.02). Among the 15 participants who also had complete postpartum multiomics data available, there were predictive signatures of vaginal versus cesarean births in transcriptomics (cell-free [cf]RNA), metabolomics, microbiomics, and proteomics that did not persist after false discovery correction.
CONCLUSION: Maternal LTLs in postpartum week 1 were nearly 500 bp shorter following cesarean. This difference persisted several weeks postpartum, even though other markers of inflammation had normalized. Mode of delivery should be considered in any analyses of postpartum LTLs and further investigation into this phenomenon is warranted.}, }
@article {pmid39031441, year = {2024}, author = {Djos, A and Svensson, J and Gaarder, J and Umapathy, G and Nilsson, S and Ek, T and Vogt, H and Georgantzi, K and Öra, I and Träger, C and Kogner, P and Martinsson, T and Fransson, S}, title = {Loss of Chromosome Y in Neuroblastoma Is Associated With High-Risk Disease, 11q-Deletion, and Telomere Maintenance.}, journal = {Genes, chromosomes & cancer}, volume = {63}, number = {7}, pages = {e23260}, doi = {10.1002/gcc.23260}, pmid = {39031441}, issn = {1098-2264}, support = {TM 22-156; SF 18-99 18-099//Swedish Childhood Cancer Foundation/ ; PK PR2023-007//Swedish Childhood Cancer Foundation/ ; KP2020-0021//Swedish Childhood Cancer Foundation/ ; PROF2019-0001//Swedish Childhood Cancer Foundation/ ; TM 22-2359//Swedish Cancer Foundation/ ; PK 22-2492 Pj//Swedish Cancer Foundation/ ; ALFGBG-447171//Swedish state under the LUA/ALF agreement/ ; TM 521-2014-3031//Swedish Research Council/ ; TM/PK-RB13-0204//Swedish Foundation for Strategic Research/ ; }, mesh = {Humans ; *Neuroblastoma/genetics/pathology ; Male ; *Chromosomes, Human, Y/genetics ; *Chromosome Deletion ; *Chromosomes, Human, Pair 11/genetics ; Infant ; Child, Preschool ; Female ; Telomere Homeostasis/genetics ; Child ; Histone Demethylases/genetics ; Telomere/genetics ; N-Myc Proto-Oncogene Protein/genetics ; Sweden/epidemiology ; }, abstract = {Neuroblastoma (NB) is a heterogeneous childhood cancer with a slightly higher incidence in boys than girls, with the reason for this gender disparity unknown. Given the growing evidence for the involvement of loss of the Y chromosome (LoY) in male diseases including cancer, we investigated Y chromosome status in NB. Male NB tumor samples from a Swedish cohort, analyzed using Cytoscan HD SNP-microarray, were selected. Seventy NB tumors were analyzed for aneuploidy of the Y chromosome, and these data were correlated with other genetic, biological, and clinical parameters. LoY was found in 21% of the male NB tumors and it was almost exclusively found in those with high-risk genomic profiles. Furthermore, LoY was associated with increased age at diagnosis and enriched in tumors with 11q-deletion and activated telomere maintenance mechanisms. In contrast, tumors with an MYCN-amplified genomic profile retained their Y chromosome. The understanding of LoY in cancer is limited, making it difficult to conclude whether LoY is a driving event in NB or function of increased genomic instability. Gene expression analysis of Y chromosome genes in male NB tumors showed low expression of certain genes correlating with worse overall survival. KDM5D, encoding a histone demethylase stands out as an interesting candidate for further studies. LoY has been shown to impact the epigenomic layer of autosomal loci in nonreproductive tissues, and KDM5D has been reported as downregulated and/or associated with poor survival in different malignancies. Further studies are needed to explore the mechanisms and functional consequences of LoY in NB.}, }
@article {pmid39030357, year = {2024}, author = {Jeon, HJ and Levine, MT and Lampson, MA}, title = {Telomere Elongation During Pre-Implantation Embryo Development.}, journal = {Advances in anatomy, embryology, and cell biology}, volume = {238}, number = {}, pages = {121-129}, pmid = {39030357}, issn = {0301-5556}, mesh = {Animals ; *Embryonic Development/genetics ; *Telomere/metabolism ; Humans ; Telomere Homeostasis ; Telomerase/metabolism/genetics ; }, abstract = {The primary mechanism of telomere elongation in mammals is reverse transcription by telomerase. An alternative (ALT) pathway elongates telomeres by homologous recombination in some cancer cells and during pre-implantation embryo development, when telomere length increases rapidly within a few cell cycles. The maternal and paternal telomeres in the zygote are genetically and epigenetically distinct, with differences in telomere length and in chromatin packaging. We discuss models for how these asymmetries may contribute to telomere regulation during the earliest embryonic cell cycles and suggest directions for future research.}, }
@article {pmid39023108, year = {2024}, author = {Bem, MMS and Paraizo-Horvath, CMS and Freitas, PS and Brito, TRP}, title = {Is it possible that menopause is associated with telomere length? Findings of an integrative review.}, journal = {Climacteric : the journal of the International Menopause Society}, volume = {}, number = {}, pages = {1-5}, doi = {10.1080/13697137.2024.2376193}, pmid = {39023108}, issn = {1473-0804}, abstract = {OBJECTIVE: Knowing the important repercussions of menopause for women's health and that female longevity can be better understood through studies based on aging biomarkers, studies on the relationship between menopause and telomere shortening may help to better understand this stage of life. This study aimed to analyze what research has been produced regarding the relationship between menopause and telomere length.
METHODS: This integrative literature review included searches in PubMed, CINAHL, LILACS, Web of Science and Scopus databases. Four studies were selected for the final sample.
RESULTS: The findings of these studies indicate that older age for menopause and longer reproductive life (difference between age at menopause and menarche) are associated with longer telomeres, that is, with longevity.
CONCLUSION: The relationship between menopause and telomere length is uncertain. The small number of studies included in this review, and the fact that the results indicate that the relationship between menopause and telomere length may be dependent on the stage of the menopause and race/ethnicity, suggest that additional research focusing on these variables should be carried out.}, }
@article {pmid39021990, year = {2024}, author = {Nila, NN and Mahmud, Z and Paul, A and Rahman, T and Hossain Howlader, MZ and Hosen, MI}, title = {Investigating the structural and functional consequences of germline single nucleotide polymorphisms located in the genes of the alternative lengthening of telomere (ALT) pathway.}, journal = {Heliyon}, volume = {10}, number = {12}, pages = {e33110}, pmid = {39021990}, issn = {2405-8440}, abstract = {BACKGROUND: The Alternative Lengthening of Telomeres (ALT) pathway represents a non-canonical mechanism of telomere maintenance that operates independently of the conventional telomerase activity. The three biologically significant proteins, designated as SMARCAL1 (SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A-like protein 1), DAXX (Death domain-associated protein 6) and ATRX (alpha-thalassemia/mental retardation, X-linked) are associated with ALT in certain cancer types. The purpose of this study was to identify the most high-risk nsSNPs (non-synonymous Single Nucleotide Polymorphisms) within these three genes and assess their impacts on the structure and function of the proteins they encode.
METHODS: The reported genetic polymorphisms of SMARCAL1, DAXX and ATRX genes were retrieved from the Ensembl database. Later, various computational tools like PROVEAN, PolyPhen2, SNPs and GO, SNAP2, Predict-SNP, Panther and PMut were used to predict the most deleterious nsSNPs. MutPred was used to understand the underlying molecular reasons of those nsSNPs being deleterious, followed by prediction of Post Translational Modification Sites (PTMs) using ModPred. I-Mutant and MUpro were used to predict the effect of SNP on energy stability. Later, 3D clustering analysis was done using Mutation 3D server. Moreover, ConSurf was utilized to identify the conservation scores of wild-type amino acids. Additionally, the NCBI conserved domain search tool was employed to pinpoint conserved domains within these three proteins. Project-Hope helped for biophysical validation, followed by prediction of these genes' interaction and function by using GeneMANIA.
RESULT: Analysis on SMARCAL1 protein revealed that among 665 nsSNPs, four were identified as the most deleterious: L578S, T581S, P582A, and P582S. Similarly, within the DAXX protein, among a pool of 480 nsSNPs, P284S, R230C, and R230S were found out to be the most deleterious variants. In case of ATRX protein, V178D, R246C, and V277G, from the total of 1009 nsSNPs, were predicted to be the most deleterious. All these nsSNPs were found to occur at residue positions that are 100 % conserved within protein domains and were predicted to be most damaging from both structural and functional perspectives and highly destabilizing to their corresponding proteins.
CONCLUSION: Computational investigation on the 3 proteins-SMARCAL1, DAXX and ATRX through different bioinformatics analysis tools concludes that the identified high risk nsSNPs of these proteins are pathogenic SNPs. These variants potentially exert functional and structural influences, thus making them valuable candidates for future genetic studies.}, }
@article {pmid39019487, year = {2024}, author = {Salberg, S and Smith, MJ and Lamont, R and Chen, Z and Beauchamp, MH and Craig, W and Doan, Q and Gravel, J and Zemek, R and Lannin, NA and Yeates, KO and Mychasiuk, R}, title = {Shorter Telomere Length Is Associated With Older Age, Poor Sleep Hygiene, and Orthopedic Injury, but Not Mild Traumatic Brain Injury, in a Cohort of Canadian Children.}, journal = {The Journal of head trauma rehabilitation}, volume = {}, number = {}, pages = {}, pmid = {39019487}, issn = {1550-509X}, abstract = {BACKGROUND: Predicting recovery following pediatric mild traumatic brain injury (mTBI) remains challenging. The identification of objective biomarkers for prognostic purposes could improve clinical outcomes. Telomere length (TL) has previously been used as a prognostic marker of cellular health in the context of mTBI and other neurobiological conditions. While psychosocial and environmental factors are associated with recovery outcomes following pediatric mTBI, the relationship between these factors and TL has not been investigated. This study sought to examine the relationships between TL and psychosocial and environmental factors, in a cohort of Canadian children with mTBI or orthopedic injury (OI).
METHODS: Saliva was collected at a postacute (median 7 days) timepoint following injury to assess TL from a prospective longitudinal cohort of children aged 8 to 17 years with either mTBI (n = 202) or OI (n = 90), recruited from 3 Canadian sites. Questionnaires regarding psychosocial and environmental factors were obtained at a postacute follow-up visit and injury outcomes were assessed at a 3-month visit. Univariable associations between TL and psychosocial, environmental, and outcome variables were assessed using Spearman's correlation. Further adjusted analyses of these associations were performed by including injury group, age, sex, and site as covariates in multivariable generalized linear models with a Poisson family, log link function, and robust variance estimates.
RESULTS: After adjusting for age, sex, and site, TL in participants with OI was 7% shorter than those with mTBI (adjusted mean ratio = 0.93; 95% confidence interval, 0.89-0.98; P = .003). As expected, increasing age was negatively associated with TL (Spearman's r = -0.14, P = .016). Sleep hygiene at 3 months was positively associated with TL (adjusted mean ratio = 1.010; 95% confidence interval, 1.001-1.020; P = .039).
CONCLUSION: The relationships between TL and psychosocial and environmental factors in pediatric mTBI and OI are complex. TL may provide information regarding sleep quality in children recovering from mTBI or OI; however, further investigation into TL biomarker validity should employ a noninjured comparison group.}, }
@article {pmid39013263, year = {2024}, author = {Martínez-Ezquerro, JD and Ortiz-Ramírez, M and García-delaTorre, P and González-Covarrubias, V and Sánchez-García, S}, title = {Physical Performance and Telomere Length in Older Adults.}, journal = {Archives of medical research}, volume = {55}, number = {6}, pages = {103046}, doi = {10.1016/j.arcmed.2024.103046}, pmid = {39013263}, issn = {1873-5487}, abstract = {BACKGROUND: The aging population prompts studying risk factors and markers to predict healthy aging. Telomere length is a promising candidate for assessing various age-related traits.
AIM OF THE STUDY: To investigate the association between physical performance and telomere length.
METHODS: We enrolled 323 older Mexican adults from the "Cohort of Obesity, Sarcopenia, and Frailty of Older Mexican Adults" affiliated with the Instituto Mexicano del Seguro Social and assessed their physical performance using the Short Physical Performance Battery, dividing participants into low (≤7) and high (>7) groups. Absolute telomere length was determined by qPCR, and individuals were classified into short (≤4.22 kb) and long (>4.22 kb) groups. We calculated the mean and adjusted mean, considering sex and age, among others, with 95% CI. We estimated the effect size between physical performance and telomere length using Cohen's d for unequal group sizes and calculated the odds ratio for physical performance based on telomere length.
RESULTS: Participants with low physical performance had significantly shorter telomeres (mean 4.14.44.7 kb, adjusted mean 3.54.04.5 kb, p <0.001), while those with high physical performance exhibited longer telomeres (mean 5.55.75.9 kb, adjusted mean 4.75.35.8 kb, p <0.001), with a medium-to-high telomere length effect size (d = 0.762). The odds of low physical activity increased 2.13.66.1-fold per kb of telomere attrition (adjOR 1.73.36.3, p <0.001).
CONCLUSION: Decreased physical function is associated with shorter telomere length. Absolute telomere length presents a promising biomarker for distinguishing between healthy and unhealthy aging, warranting further investigation.}, }
@article {pmid39013662, year = {2024}, author = {Band, G and Leffler, EM}, title = {Malaria endemicity linked to shorter telomeres in leukocytes.}, journal = {Trends in parasitology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.pt.2024.06.017}, pmid = {39013662}, issn = {1471-5007}, abstract = {Leukocyte telomere length is a highly polygenic trait that has been associated with a complex range of lifestyle factors and disease risk. McQuillan et al.'s results comparing telomere length to malaria incidence rates suggest that infections may be another important factor, possibly through permanent shortening of telomeres in hematopoietic progenitor cells.}, }
@article {pmid39012375, year = {2024}, author = {Kallingal, A and Krzemieniecki, R and Maciejewska, N and Brankiewicz-Kopcińska, W and Baginski, M}, title = {TRF1 and TRF2: pioneering targets in telomere-based cancer therapy.}, journal = {Journal of cancer research and clinical oncology}, volume = {150}, number = {7}, pages = {353}, pmid = {39012375}, issn = {1432-1335}, mesh = {Humans ; *Neoplasms/genetics/drug therapy/metabolism/therapy ; *Telomeric Repeat Binding Protein 2/metabolism/genetics ; *Telomeric Repeat Binding Protein 1/metabolism/genetics ; *Telomere/metabolism ; Molecular Targeted Therapy/methods ; Antineoplastic Agents/therapeutic use/pharmacology ; Shelterin Complex ; Telomere-Binding Proteins ; }, abstract = {This article presents an in-depth exploration of the roles of Telomere Repeat-binding Factors 1 and 2 (TRF1 and TRF2), and the shelterin complex, in the context of cancer biology. It emphasizes their emerging significance as potential biomarkers and targets for therapeutic intervention. Central to the shelterin complex, TRF1 and TRF2 are crucial in maintaining telomere integrity and genomic stability, their dysregulation often being a hallmark of cancerous cells. The article delves into the diagnostic and prognostic capabilities of TRF1 and TRF2 across various cancer types, highlighting their sensitivity and specificity. Furthermore, it reviews current strides in drug discovery targeting the shelterin complex, detailing specific compounds and their modes of action. The review candidly addresses the challenges in developing therapies aimed at the shelterin complex, including drug resistance, off-target effects, and issues in drug delivery. By synthesizing recent research findings, the article sheds light on the intricate relationship between telomere biology and cancer development. It underscores the urgency for continued research to navigate the existing challenges and fully leverage the therapeutic potential of TRF1, TRF2, and the shelterin complex in the realm of cancer treatment.}, }
@article {pmid39010148, year = {2024}, author = {Yang, Q and Zhang, J and Fan, Z}, title = {Causal association between telomere length and female reproductive endocrine diseases: a univariable and multivariable Mendelian randomization analysis.}, journal = {Journal of ovarian research}, volume = {17}, number = {1}, pages = {146}, pmid = {39010148}, issn = {1757-2215}, abstract = {BACKGROUND: The relationship between leukocyte telomere length (LTL) and female reproductive endocrine diseases has gained significant attention and research interest in recent years. However, there is still limited understanding of the exact impacts of LTL on these diseases. Therefore, the primary objective of this study was to investigate the genetic causal association between LTL and female reproductive endocrine diseases by employing Mendelian randomization (MR) analysis.
METHODS: Instruments for assessing genetic variation associated with exposure and outcome were derived from summary data of published genome-wide association studies (GWAS). Inverse-variance weighted (IVW) was utilized as the main analysis method to investigate the causal relationship between LTL and female reproductive endocrine diseases. The exposure data were obtained from the UK Biobanks GWAS dataset, comprising 472,174 participants of European ancestry. The outcome data were acquired from the FinnGen consortium, including abnormal uterine bleeding (menorrhagia and oligomenorrhea), endometriosis (ovarian endometrioma and adenomyosis), infertility, polycystic ovary syndrome (PCOS), premature ovarian insufficiency (POI) and premenstrual syndrome (PMS). Furthermore, to account for potential confounding factors such as smoking, alcohol consumption, insomnia, body mass index (BMI) and a history of pelvic inflammatory disease (PID), multivariable MR (MVMR) analysis was also conducted. Lastly, a series of pleiotropy tests and sensitivity analyses were performed to ensure the reliability and robustness of our findings. P < 0.0063 was considered to indicate statistically significant causality following Bonferroni correction.
RESULTS: Our univariable MR analysis demonstrated that longer LTL was causally associated with an increased risk of menorrhagia (IVW: odds ratio [OR]: 1.1803; 95% confidence interval [CI]: 1.0880-1.2804; P = 0.0001) and ovarian endometrioma (IVW: OR: 1.2946; 95%CI: 1.0970-1.5278; P = 0.0022) at the Bonferroni significance level. However, no significant correlation was observed between LTL and oligomenorrhea (IVW: OR: 1.0124; 95%CI: 0.7350-1.3946; P = 0.9398), adenomyosis (IVW: OR: 1.1978; 95%CI: 0.9983-1.4372; P = 0.0522), infertility (IVW: OR: 1.0735; 95%CI: 0.9671-1.1915; P = 0.1828), PCOS (IVW: OR: 1.0633; 95%CI: 0.7919-1.4278; P = 0.6829), POI (IVW: OR: 0.8971; 95%CI: 0.5644-1.4257; P = 0.6459) or PMS (IVW: OR: 0.7749; 95%CI: 0.4137-1.4513; P = 0.4256). Reverse MR analysis indicated that female reproductive endocrine diseases have no causal effect on LTL. MVMR analysis suggested that the causal effect of LTL on menorrhagia and ovarian endometrioma remained significant after accounting for smoking, alcohol consumption, insomnia, BMI and a history of PID. Pleiotropic and sensitivity analyses also showed robustness of our results.
CONCLUSION: The results of our bidirectional two-sample MR analysis revealed that genetically predicted longer LTL significantly increased the risk of menorrhagia and ovarian endometrioma, which is consistent with the findings from MVMR studies. However, we did not notice any significant effects of LTL on oligomenorrhea, adenomyosis, infertility, PCOS, POI or PMS. Additionally, reproductive endocrine disorders were found to have no impact on LTL. To enhance our understanding of the effect and underlying mechanism of LTL on female reproductive endocrine diseases, further large-scale studies are warranted in the future.}, }
@article {pmid39005478, year = {2024}, author = {Comstock, W and Sanford, E and Navarro, M and Smolka, MB}, title = {Profiling Tel1 Signaling Reveals a Non-Canonical Motif Targeting DNA Repair and Telomere Control Machineries.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2024.07.03.601872}, pmid = {39005478}, issn = {2692-8205}, abstract = {The stability of the genome relies on Phosphatidyl Inositol 3-Kinase-related Kinases (PIKKs) that sense DNA damage and trigger elaborate downstream signaling responses. In S. cerevisiae , the Tel1 kinase (ortholog of human ATM) is activated at DNA double strand breaks (DSBs) and short telomeres. Despite the well-established roles of Tel1 in the control of telomere maintenance, suppression of chromosomal rearrangements, activation of cell cycle checkpoints, and repair of DSBs, the substrates through which Tel1 controls these processes remain incompletely understood. Here we performed an in depth phosphoproteomic screen for Tel1-dependent phosphorylation events. To achieve maximal coverage of the phosphoproteome, we developed a scaled-up approach that accommodates large amounts of protein extracts and chromatographic fractions. Compared to previous reports, we expanded the number of detected Tel1-dependent phosphorylation events by over 10-fold. Surprisingly, in addition to the identification of phosphorylation sites featuring the canonical motif for Tel1 phosphorylation (S/T-Q), the results revealed a novel motif (D/E-S/T) highly prevalent and enriched in the set of Tel1-dependent events. This motif is unique to Tel1 signaling and not shared with the Mec1 kinase, providing clues to how Tel1 plays specialized roles in DNA repair and telomere length control. Overall, these findings define a Tel1-signaling network targeting numerous proteins involved in DNA repair, chromatin regulation, and telomere maintenance that represents a framework for dissecting the molecular mechanisms of Tel1 action.}, }
@article {pmid39002862, year = {2024}, author = {Dimitrov, M and Merkle, S and Cao, Q and Tryon, RK and Vercellotti, GM and Holtan, SG and Kao, RL and Srikanthan, M and Terezakis, SA and Tolar, J and Ebens, CL}, title = {Allogeneic hematopoietic cell transplant for bone marrow failure or myelodysplastic syndrome in dyskeratosis congenita/telomere biology disorders: Single-center single-arm open-label trial of reduced intensity conditioning without radiation.}, journal = {Transplantation and cellular therapy}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jtct.2024.07.007}, pmid = {39002862}, issn = {2666-6367}, abstract = {BACKGROUND: Dyskeratosis congenita/Telomere biology disorders (DC/TBD) often manifest as bone marrow failure (BMF) or myelodysplastic syndrome (MDS). Allogeneic hematopoietic cell transplant (alloHCT) rescues hematologic complications, but radiation and alkylator-based conditioning regimens cause diffuse whole-body toxicity and may expedite DC/TBD-specific non-hematopoietic complications. Optimization of conditioning intensity in DC/TBD to allow for donor hematopoietic cell engraftment with the least amount of toxicity remains a critical goal of the alloHCT field.
OBJECTIVES/STUDY DESIGN: We report prospectively collected standard alloHCT outcomes from a single-center single-arm open-label clinical trial of bone marrow or peripheral blood stem cell alloHCT for DC/TBD-associated BMF or MDS. Conditioning was reduced intensity (RIC) including alemtuzumab 1mg/kg, fludarabine 200 mg/m[2], and cyclophosphamide 50 mg/kg. A previous single-arm open-label phase II clinical trial for the same patient population conducted at the same center, differing only by inclusion of 200 centigray of total body irradiation (TBI), served as a control cohort.
RESULTS: The Non-TBI cohort included 10 patients (ages 1.7-65.9 years, median follow-up of 3.9 years) compared to the control TBI cohort which included 12 patients (ages 2.2-52.2 years, median follow-up of 10.5 years). Baseline characteristics differed only in total CD34+ cells received, with a median of 5.6 (Non-TBI) compared to 2.6 (TBI) x 10[6]/kg (p=0.02; no difference in total nucleated cells). The cumulative incidence of day +100 grade II-IV acute and 4-year chronic graft-versus-host disease (GvHD) were low at 0 and 10% (Non-TBI) and 8 and 17% (TBI), respectively (acute, p=0.36; chronic, p=0.72). Primary graft failure was absent. Secondary non-neutropenic graft failure occurred in one (Non-TBI cohort). The Non-TBI cohort demonstrated delayed achievement of full donor chimerism but superior lymphocyte recovery. There was no difference in 4-year overall survival at 80% (Non-TBI) and 75% (TBI; p=0.78). MDS as an indication for alloHCT was uncommon, but overall associated with poor outcomes. There were 3 MDS patients in the Non-TBI cohort: 1 relapsed and died at day+387; 1 relapsed at day+500 and is alive 5.5 years later following salvage with a 2[nd] alloHCT; 1 relapsed at day+1093 and is alive at day +100 after a 2[nd] alloHCT. There was 1 MDS patient in the TBI cohort who achieved 100% donor myeloid engraftment without relapse but died at day+827 from a bacterial infection in the setting of immune mediated cytopenia.
CONCLUSION: Elimination of TBI from the RIC regimen for DC/TBD was not associated with significant changes in rates of graft failure, GvHD, and overall survival, but was associated with delayed achievement of full donor chimerism and improved lymphocyte reconstitution. For DC/TBD-associated BMF, TBI appears to be dispensable. Optimal approaches to DC/TBD-associated MDS remain unclear. Larger cohorts are needed to better assess the unique contribution of TBI and donor CD34+ cell dose. Longer follow-up is required to assess differences in DC/TBD complications and late effects.}, }
@article {pmid39002254, year = {2024}, author = {Redon, L and Constant, T and Smith, S and Habold, C and Giroud, S}, title = {Understanding seasonal telomere length dynamics in hibernating species.}, journal = {Journal of thermal biology}, volume = {123}, number = {}, pages = {103913}, doi = {10.1016/j.jtherbio.2024.103913}, pmid = {39002254}, issn = {0306-4565}, abstract = {Oxidative stress is thought to be one of the main causes of ageing as it progressively damages cell components throughout life, eventually causing cellular failure and apoptosis. In many organisms, telomeres shorten throughout life under the effect of, amongst other factors, oxidative stress, and are therefore commonly used as marker of biological ageing. However, hibernators, which are regularly exposed to acute oxidative stress when rewarming from torpor, are unexpectedly long-lived. In this review, we explore the causes of oxidative stress associated with hibernation and its impact on telomere dynamics in different taxa, focussing on hibernating rodents. We then speculate on the adaptive mechanisms of hibernators to compensate for the effects of oxidative stress, which may explain their increased longevity. Because winter hibernation appears to be associated with high oxidative stress, hibernators, particularly rodents, may periodically invest in repair mechanisms and antioxidant defences, resulting in seasonal variations in telomere lengths. This research shows how species with a slow life-history strategy deal with large changes in oxidative stress, unifying evolutionary and physiological theories of ageing. Because of the marked seasonal variation in telomere length, we also draw attention when using telomeres as markers for biological aging in seasonal heterotherms and possibly in other highly seasonal species.}, }
@article {pmid39001954, year = {2024}, author = {Boccardi, V and Cari, L and Bastiani, P and Scamosci, M and Cecchetti, R and Nocentini, G and Mecocci, P}, title = {Aberrant telomeric structures and serum markers of telomere dysfunction in healthy aging: a preliminary study.}, journal = {Biogerontology}, volume = {}, number = {}, pages = {}, pmid = {39001954}, issn = {1573-6768}, abstract = {Telomeres undergo a progressive shortening process as individuals age, and it has been proposed that severely shortened and dysfunctional telomeres play a role in the aging process and the onset of age-related diseases in human beings. An emerging body of evidence indicates that the shortening of telomeres in cultured human cells is also influenced by other replication defects occurring within telomeric repeats. These abnormalities can be detected on metaphase chromosomes. Recent studies have also identified a set of serological markers for telomere dysfunction and DNA damage (elongation factor 1α [EF-1α], stathmin, and N-acetyl-glucosaminidase). With this study, the correlation between telomere abnormalities (by FISH) and these biomarkers as measured in blood serum (by ELISA) from a cohort of 22 healthy subjects at different ages (range 26-101 years) was analyzed. A strong positive correlation between aging and the presence of aberrant telomere structures, sister telomere loss (STL), and sister telomere chromatid fusions (STCF) was detected. When serum markers of telomere dysfunction were correlated with telomere abnormalities, we found that stathmin correlated with total aberrant telomeres structures (r = 0.431, p = 0.0453) and STCF (r = 0.533, p = 0.0107). These findings suggest that serum stathmin can be considered an easy-to-get marker of telomere dysfunction and may serve as valuable indicators of aging.}, }
@article {pmid39001406, year = {2024}, author = {Park, M and Lee, DE and Hong, Y and Suh, JK and Lee, JA and Kim, M and Park, HJ}, title = {Telomere Length in Adolescent and Young Adult Survivors of Childhood Cancer.}, journal = {Cancers}, volume = {16}, number = {13}, pages = {}, doi = {10.3390/cancers16132344}, pmid = {39001406}, issn = {2072-6694}, support = {2022-0195//National Cancer Center/Republic of Korea ; }, abstract = {We examined the leukocyte relative telomere length (RTL) in Korean adolescent and young adult (AYA) survivors of childhood cancer and evaluated the association of leukocyte RTL with multiple factors, including malignancy type, cancer treatment, age, and chronic health conditions (CHCs). Eighty-eight AYA survivors of childhood cancer with a median follow-up period of 73 months were recruited. RTL in pediatric cancer survivors was not significantly shorter than the predicted value for age-matched references. Neither age at diagnosis nor duration of therapy influenced the RTL. Among the 43 patients with hematologic malignancies, those who underwent allogeneic hematopoietic stem cell transplantation (HSCT) showed a significant shortening of the RTL compared with those who did not (p = 0.039). Among the 15 patients who underwent allogeneic HSCT, those who developed acute graft-versus-host disease (GVHD) of grade II or higher had significantly shorter RTL than those who did not (p = 0.012). Patients with grade II CHCs had significantly shorter RTL than those without CHCs or with grade I CHCs (p = 0.001). Survivors with ≥2 CHCs also exhibited shorter RTL (p = 0.027). Overall, pediatric cancer survivors had similar telomere lengths compared to age-matched references. HSCT recipients and patients with severe or multiple CHCs had shorter telomeres. GVHD augmented telomere attrition in HSCT recipients.}, }
@article {pmid38993011, year = {2024}, author = {Chik, HYJ and Mannarelli, ME and Dos Remedios, N and Simons, MJP and Burke, T and Schroeder, J and Dugdale, HL}, title = {Adult telomere length is positively correlated with survival and lifetime reproductive success in a wild passerine.}, journal = {Molecular ecology}, volume = {}, number = {}, pages = {e17455}, doi = {10.1111/mec.17455}, pmid = {38993011}, issn = {1365-294X}, support = {PCIG12-GA-2012-333096/ERC_/European Research Council/International ; NE/J024567/1//Natural Environment Research Council/ ; }, abstract = {Explaining variation in individual fitness is a key goal in evolutionary biology. Recently, telomeres, repeating DNA sequences capping chromosome ends, have gained attention as a biomarker for body state, physiological costs, and senescence. Existing research has provided mixed evidence for whether telomere length correlates with fitness, including survival and reproductive output. Moreover, few studies have examined how the rate of change in telomere length correlates with fitness in wild populations. Here, we intensively monitored an insular population of house sparrows, and collected longitudinal telomere and life history data (16 years, 1225 individuals). We tested whether telomere length and its rate of change predict fitness measures, namely survival, lifespan and annual and lifetime reproductive effort and success. Telomere length positively predicted short-term survival, independent of age, but did not predict lifespan, suggesting either a diminishing telomere length-survival correlation with age or other extrinsic factors of mortality. The positive association of telomere length with survival translated into reproductive benefits, as birds with longer telomeres produced more genetic recruits, hatchlings and reared more fledglings over their lifetime. In contrast, there was no association between telomere dynamics and annual reproductive output, suggesting telomere dynamics might not reflect the costs of reproduction in this population, potentially masked by variation in individual quality. The rate of change of telomere length did not correlate with neither lifespan nor lifetime reproductive success. Our results provide further evidence that telomere length correlates with fitness, and contribute to our understanding of the selection on, and evolution of, telomere dynamics.}, }
@article {pmid38987851, year = {2024}, author = {Yin, Q and Tang, TT and Lu, XY and Ni, WJ and Yin, D and Zhang, YL and Jiang, W and Zhang, Y and Li, ZL and Wen, Y and Gan, WH and Zhang, AQ and Lv, LL and Wang, B and Liu, BC}, title = {Macrophage-derived exosomes promote telomere fragility and senescence in tubular epithelial cells by delivering miR-155.}, journal = {Cell communication and signaling : CCS}, volume = {22}, number = {1}, pages = {357}, pmid = {38987851}, issn = {1478-811X}, support = {82070735;82030024;81720108007//National Natural Science Foundation of China/ ; 82070735;82030024;81720108007//National Natural Science Foundation of China/ ; 2018YFC130046, 2018YFC1314000//National Key Research Programme of Ministry of Science and Technology/ ; }, abstract = {BACKGROUND: Chronic kidney disease (CKD) is highly prevalent worldwide, and its global burden is substantial and growing. CKD displays a number of features of accelerated senescence. Tubular cell senescence is a common biological process that contributes to CKD progression. Tubulointerstitial inflammation is a driver of tubular cell senescence and a common characteristic of CKD. However, the mechanism by which the interstitial inflammation drives tubular cell senescence remains unclear. This paper aims to explore the role of exosomal miRNAs derived from macrophages in the development of tubular cell senescence.
METHODS: Among the identified inflammation-related miRNAs, miR-155 is considered to be one of the most important miRNAs involved in the inflammatory response. Macrophages, the primary immune cells that mediate inflammatory processes, contain a high abundance of miR-155 in their released exosomes. We assessed the potential role of miR-155 in tubular cell senescence and renal fibrosis. We subjected miR-155[-/-] mice and wild-type controls, as well as tubular epithelial cells (TECs), to angiotensin II (AngII)-induced kidney injury. We assessed kidney function and injury using standard techniques. TECs were evaluated for cell senescence and telomere dysfunction in vivo and in vitro. Telomeres were measured by the fluorescence in situ hybridization.
RESULTS: Compared with normal controls, miR-155 was up-regulated in proximal renal tubule cells in CKD patients and mouse models of CKD. Moreover, the expression of miR-155 was positively correlated with the extent of renal fibrosis, eGFR decline and p16[INK4A] expression. The overexpression of miR-155 exacerbated tubular senescence, evidenced by increased detection of p16[INK4A]/p21expression and senescence-associated β-galactosidase activity. Notably, miR-155 knockout attenuates renal fibrosis and tubule cell senescence in vivo. Interestingly, once released, macrophages-derived exosomal miR-155 was internalized by TECs, leading to telomere shortening and dysfunction through targeting TRF1. A dual-luciferase reporter assay confirmed that TRF1 was the direct target of miR-155. Thus, our study clearly demonstrates that exosomal miR-155 may mediate communication between macrophages and TECs, subsequently inducing telomere dysfunction and senescence in TECs.
CONCLUSIONS: Our work suggests a new mechanism by which macrophage exosomes are involved in the development of tubule senescence and renal fibrosis, in part by delivering miR-155 to target TRF1 to promote telomere dysfunction. Our study may provide novel strategies for the treatment of AngII-induced kidney injury.}, }
@article {pmid38979576, year = {2024}, author = {Semper, C and Watanabe, N and Karimullina, E and Patel, DT and Di Leo, R and Castellanos, M and Patel, DH and Chaconas, G and Savchenko, A}, title = {Structure analysis of the telomere resolvase from the Lyme disease spirochete Borrelia garinii reveals functional divergence of its C-terminal domain.}, journal = {Nucleic acids research}, volume = {}, number = {}, pages = {}, doi = {10.1093/nar/gkae580}, pmid = {38979576}, issn = {1362-4962}, support = {//National Institute of Allergy and Infectious Diseases/ ; HHSN272201700060C/NH/NIH HHS/United States ; /HH/HHS/United States ; PJT-153336/CAPMC/CIHR/Canada ; }, abstract = {Borrelia spirochetes are the causative agents of Lyme disease and relapsing fever, two of the most common tick-borne illnesses. A characteristic feature of these spirochetes is their highly segmented genomes which consists of a linear chromosome and a mixture of up to approximately 24 linear and circular extrachromosomal plasmids. The complexity of this genomic arrangement requires multiple strategies for efficient replication and partitioning during cell division, including the generation of hairpin ends found on linear replicons mediated by the essential enzyme ResT, a telomere resolvase. Using an integrative structural biology approach employing advanced modelling, circular dichroism, X-ray crystallography and small-angle X-ray scattering, we have generated high resolution structural data on ResT from B. garinii. Our data provides the first high-resolution structures of ResT from Borrelia spirochetes and revealed active site positioning in the catalytic domain. We also demonstrate that the C-terminal domain of ResT is required for both transesterification steps of telomere resolution, and is a requirement for DNA binding, distinguishing ResT from other telomere resolvases from phage and bacteria. These results advance our understanding of the molecular function of this essential enzyme involved in genome maintenance in Borrelia pathogens.}, }
@article {pmid38977857, year = {2024}, author = {Zhang, Y and Zhao, M and Tan, J and Huang, M and Chu, X and Li, Y and Han, X and Fang, T and Tian, Y and Jarret, R and Lu, D and Chen, Y and Xue, L and Li, X and Qin, G and Li, B and Sun, Y and Deng, XW and Deng, Y and Zhang, X and He, H}, title = {Telomere-to-telomere Citrullus super-pangenome provides direction for watermelon breeding.}, journal = {Nature genetics}, volume = {}, number = {}, pages = {}, pmid = {38977857}, issn = {1546-1718}, abstract = {To decipher the genetic diversity within the cucurbit genus Citrullus, we generated telomere-to-telomere (T2T) assemblies of 27 distinct genotypes, encompassing all seven Citrullus species. This T2T super-pangenome has expanded the previously published reference genome, T2T-G42, by adding 399.2 Mb and 11,225 genes. Comparative analysis has unveiled gene variants and structural variations (SVs), shedding light on watermelon evolution and domestication processes that enhanced attributes such as bitterness and sugar content while compromising disease resistance. Multidisease-resistant loci from Citrullus amarus and Citrullus mucosospermus were successfully introduced into cultivated Citrullus lanatus. The SVs identified in C. lanatus have not only been inherited from cordophanus but also from C. mucosospermus, suggesting additional ancestors beyond cordophanus in the lineage of cultivated watermelon. Our investigation substantially improves the comprehension of watermelon genome diversity, furnishing comprehensive reference genomes for all Citrullus species. This advancement aids in the exploration and genetic enhancement of watermelon using its wild relatives.}, }
@article {pmid38974386, year = {2024}, author = {Zhang, Z and Zhang, J and Zhang, K and Ge, X and Zhai, X}, title = {Robust evidence supports a causal link between higher birthweight and longer telomere length: a mendelian randomization study.}, journal = {Frontiers in genetics}, volume = {15}, number = {}, pages = {1264028}, pmid = {38974386}, issn = {1664-8021}, abstract = {BACKGROUND: Observational studies have suggested a potential relationship between birthweight and telomere length. However, the causal link between these two parameters remains undefined. In this study, we use Mendelian Randomization (MR). This method employs genetic variants as instrumental variables, to explore the existence of causal associations and elucidate the causal relationship between birth weight and telomere length.
METHODS: We used 35 single nucleotide polymorphisms (SNPs) as instrumental variables for birth weight. These SNPs were identified from a meta-analysis involving 153,781 individuals. Furthermore, we obtained summary statistics for telomere length from a study conducted on 472,174 United Kingdom Biobank participants. To evaluate the causal estimates, we applied the random effect inverse variance weighted method (IVW) and several other MR methods, such as MR-Egger, weighted median, and MR-PRESSO, to verify the reliability of our findings.
RESULTS: Our analysis supports a significant causal relationship between genetically predicted birth weight and telomer3e length. The inverse variance weighted analysis results for birth weight (Beta = 0.048; 95%CI = 0.023 to 0.073; p < 0.001) corroborate this association.
CONCLUSION: Our study provides robust evidence supporting a causal link between higher birth weight and longer telomere length.}, }
@article {pmid38973734, year = {2024}, author = {Farzan, SF and Niu, Z and Guo, F and Shahriar, M and Kibriya, MG and Jasmine, F and Sarwar, G and Jackson, BP and Ahsan, H and Argos, M}, title = {Exposure to metal mixtures and telomere length in Bangladeshi children.}, journal = {American journal of epidemiology}, volume = {}, number = {}, pages = {}, doi = {10.1093/aje/kwae181}, pmid = {38973734}, issn = {1476-6256}, abstract = {Telomere length is associated with chronic diseases and in younger populations, may represent a biomarker of disease susceptibility. As growing evidence suggests that environmental factors, including metals, may impact telomere length, we investigated the association between 17 metals measured in toenail samples and leukocyte relative telomere length (RTL), among 472 five- to seven-year-old children enrolled in the Bangladesh Environmental Research in Children's Health (BiRCH) cohort. In single exposure linear regression models, a doubling of arsenic (As) and mercury (Hg) (μg/g) were associated with a -0.21 (95%CI: -0.032, -0.010; p=0.0005) and -0.017 (95%CI: -0.029, -0.004; p=0.006) difference in RTL, respectively. In Bayesian Kernel Machine Regression (BKMR) mixture models, the overall metal mixture was inversely associated with RTL (P-for-trend <0.001). Negative associations with RTL were observed with both log2-As and log2-Hg, while an inverted U-shaped association was observed for log2-zinc (Zn) with RTL. We found little evidence of interaction among metals. Sex-stratification identified stronger associations of the overall mixture and log2-As with RTL among females, compared to males. Our study suggests that As and Hg may independently influence RTL in mid-childhood. Further studies are needed to investigate potential long-term impacts of metal-associated telomere shortening in childhood on health outcomes in adult life.}, }
@article {pmid38972874, year = {2024}, author = {Zhao, H and Zhou, H and Sun, G and Dong, B and Zhu, W and Mu, X and Li, X and Wang, J and Zhao, M and Yang, W and Zhang, G and Ji, R and Geng, T and Gong, D and Meng, H and Wang, J}, title = {Telomere-to-telomere genome assembly of the goose Anser cygnoides.}, journal = {Scientific data}, volume = {11}, number = {1}, pages = {741}, pmid = {38972874}, issn = {2052-4463}, mesh = {Animals ; *Geese/genetics ; *Telomere/genetics ; *Genome ; Molecular Sequence Annotation ; }, abstract = {Our study presents the assembly of a high-quality Taihu goose genome at the Telomere-to-Telomere (T2T) level. By employing advanced sequencing technologies, including Pacific Biosciences HiFi reads, Oxford Nanopore long reads, Illumina short reads, and chromatin conformation capture (Hi-C), we achieved an exceptional assembly. The T2T assembly encompasses a total length of 1,197,991,206 bp, with contigs N50 reaching 33,928,929 bp and scaffold N50 attaining 81,007,908 bp. It consists of 73 scaffolds, including 38 autosomes and one pair of Z/W sex chromosomes. Importantly, 33 autosomes were assembled without any gap, resulting in a contiguous representation. Furthermore, gene annotation efforts identified 34,898 genes, including 436,162 RNA transcripts, encompassing 806,158 exons, 743,910 introns, 651,148 coding sequences (CDS), and 135,622 untranslated regions (UTR). The T2T-level chromosome-scale goose genome assembly provides a vital foundation for future genetic improvement and understanding the genetic mechanisms underlying important traits in geese.}, }
@article {pmid38967394, year = {2024}, author = {Liang, C and Zhao, R and Du, J and Zhao, G and Zhang, Y}, title = {The association between dietary selenium intake and telomere length in hypertension.}, journal = {Journal of clinical hypertension (Greenwich, Conn.)}, volume = {}, number = {}, pages = {}, doi = {10.1111/jch.14861}, pmid = {38967394}, issn = {1751-7176}, support = {82100283//National Natural Science Foundation of China/ ; 82270407//National Natural Science Foundation of China/ ; 232102310181//The Scientific and Technological Project of Henan Province/ ; }, abstract = {Telomere length is closely linked to biological aging, oxidative stress, and the development of cardiovascular diseases. This study aimed to assess the association between dietary selenium intake and telomere length in individuals with hypertension. Data on dietary selenium intake were captured through the National Health and Nutrition Examination Survey (NHANES) computer-assisted dietary interview system (CADI). Telomere length determination entailed selecting blood samples from all participants in the NHANES database. The analysis was performed using Analysis System software, with Empower stats utilized for data analysis. Results showed that there was a significant association between dietary selenium intake and telomere length in hypertension, particularly within the female group. In female hypertension cases, a 1 mcg increase in dietary selenium intake corresponded to a telomere length increase of 1.19 bp, even after adjusting for age, race, BMI, marital status, physical activity, energy intake, and stroke history. The relationship between dietary selenium intake and telomere length exhibited a linear pattern in female hypertension patients. This study identified a positive association between dietary selenium intake and telomere length in hypertension, particularly within the female group.}, }
@article {pmid38966866, year = {2024}, author = {Yang, T and Cai, Y and Huang, T and Yang, D and Yang, X and Yin, X and Zhang, C and Yang, Y and Yang, Y}, title = {A telomere-to-telomere gap-free reference genome assembly of avocado provides useful resources for identifying genes related to fatty acid biosynthesis and disease resistance.}, journal = {Horticulture research}, volume = {11}, number = {7}, pages = {uhae119}, doi = {10.1093/hr/uhae119}, pmid = {38966866}, issn = {2662-6810}, abstract = {Avocado (Persea americana Mill.) is an economically valuable plant because of the high fatty acid content and unique flavor of its fruits. Its fatty acid content, especially the relatively high unsaturated fatty acid content, provides significant health benefits. We herein present a telomere-to-telomere gapless genome assembly (841.6 Mb) of West Indian avocado. The genome contains 40 629 predicted protein-coding genes. Repeat sequences account for 57.9% of the genome. Notably, all telomeres, centromeres, and a nucleolar organizing region are included in this genome. Fragments from these three regions were observed via fluorescence in situ hybridization. We identified 376 potential disease resistance-related nucleotide-binding leucine-rich repeat genes. These genes, which are typically clustered on chromosomes, may be derived from gene duplication events. Five NLR genes (Pa11g0262, Pa02g4855, Pa07g3139, Pa07g0383, and Pa02g3196) were highly expressed in leaves, stems, and fruits, indicating they may be involved in avocado disease responses in multiple tissues. We also identified 128 genes associated with fatty acid biosynthesis and analyzed their expression patterns in leaves, stems, and fruits. Pa02g0113, which encodes one of 11 stearoyl-acyl carrier protein desaturases mediating C18 unsaturated fatty acid synthesis, was more highly expressed in the leaves than in the stems and fruits. These findings provide valuable insights that enhance our understanding of fatty acid biosynthesis in avocado.}, }
@article {pmid38964064, year = {2024}, author = {Chang-Chien, J and Kuo, ML and Tseng, YL and Huang, HY and Tsai, HJ and Yao, TC}, title = {Differential effects of long- and short-term exposure to PM2.5 on accelerating telomere shortening: from in vitro to epidemiological studies.}, journal = {Ecotoxicology and environmental safety}, volume = {281}, number = {}, pages = {116650}, doi = {10.1016/j.ecoenv.2024.116650}, pmid = {38964064}, issn = {1090-2414}, abstract = {Exposure to air pollutants has been associated with DNA damage and increases the risks of respiratory diseases, such as asthma and COPD; however short- and long-term effects of air pollutants on telomere dysfunction remain unclear. We investigated the impact of short- and long-term exposure to fine particulate matter with an aerodynamic diameter below 2.5 μm (PM2.5) on telomere length in human bronchial epithelial BEAS-2B cells, and assessed the potential correlation between PM2.5 exposure and telomere length in the LIGHTS childhood cohort study. We observed that long-term, but not short-term, PM2.5 exposure was significantly associated with telomere shortening, along with the downregulation of human telomerase reverse transcriptase (hTERT) mRNA and protein levels. Moreover, long-term exposure to PM2.5 induced proinflammatory cytokine secretion, notably interleukin 6 (IL-6) and IL-8, triggered subG1 cell cycle arrest, and ultimately caused cell death. Long-term exposure to PM2.5 upregulated the LC3-II/ LC3-I ratio but led to p62 protein accumulation in BEAS-2B cells, suggesting a blockade of autophagic flux. Moreover, consistent with our in vitro findings, our epidemiological study found significant association between annual average exposure to higher PM2.5 and shortening of leukocyte telomere length in children. However, no significant association between 7-day short-term exposure to PM2.5 and leukocyte telomere length was observed in children. By combining in vitro experimental and epidemiological studies, our findings provide supportive evidence linking potential regulatory mechanisms to population level with respect to long-term PM2.5 exposure to telomere shortening in humans.}, }
@article {pmid38963484, year = {2024}, author = {Lim, CJ}, title = {Telomere C-Strand Fill-In Machinery: New Insights into the Human CST-DNA Polymerase Alpha-Primase Structures and Functions.}, journal = {Sub-cellular biochemistry}, volume = {104}, number = {}, pages = {73-100}, pmid = {38963484}, issn = {0306-0225}, mesh = {Humans ; *Telomere/metabolism/genetics ; *DNA Polymerase I/metabolism/genetics/chemistry ; *DNA Primase/metabolism/genetics/chemistry ; *Telomere-Binding Proteins/metabolism/genetics ; *DNA Replication ; Telomerase/metabolism/genetics ; }, abstract = {Telomeres at the end of eukaryotic chromosomes are extended by a specialized set of enzymes and telomere-associated proteins, collectively termed here the telomere "replisome." The telomere replisome acts on a unique replicon at each chromosomal end of the telomeres, the 3' DNA overhang. This telomere replication process is distinct from the replisome mechanism deployed to duplicate the human genome. The G-rich overhang is first extended before the complementary C-strand is filled in. This overhang is extended by telomerase, a specialized ribonucleoprotein and reverse transcriptase. The overhang extension process is terminated when telomerase is displaced by CTC1-STN1-TEN1 (CST), a single-stranded DNA-binding protein complex. CST then recruits DNA polymerase α-primase to complete the telomere replication process by filling in the complementary C-strand. In this chapter, the recent structure-function insights into the human telomere C-strand fill-in machinery (DNA polymerase α-primase and CST) will be discussed.}, }
@article {pmid38960007, year = {2024}, author = {Alehagen, U and Aaseth, J and Schomburg, L and Larsson, A and Opstad, T and Alexander, J}, title = {Selenoprotein P increases upon Selenium and Coenzyme Q10 Supplementation and is Associated with Telomere Length, Quality of Life and Reduced Inflammation and Mortality.}, journal = {Free radical biology & medicine}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.freeradbiomed.2024.06.027}, pmid = {38960007}, issn = {1873-4596}, abstract = {BACKGROUND: Selenoprotein P (SELENOP) transports selenium to extrahepatic tissues and is a biomarker of selenium status. Low soil selenium leads to low dietary selenium intake. A consequence is an increased risk of cardiovascular disease.
OBJECTIVE: To investigate clinical aspects associated with SELENOP deficiency, including biomarkers of inflammation, quality of life, and mortality within 12 years, and the effect of dietary selenium and coenzyme Q10 supplementation on SELENOP.
METHODS: SELENOP was determined at inclusion and after four years of supplementation in 403 elderly community-living participants low in selenium receiving selenium yeast (200 μg/day) and coenzyme Q10 (200 mg/ day), or placebo. Pre-intervention, the average serum selenium level was 67μg/L. T-tests, repeated measures of variance, Cox proportional regressions analyses, Kaplan-Meier graphs and ANCOVA analyses were applied. Associations with biomarkers of inflammation, telomere length, quality of life and mortality were investigated. Benchmark modelling was used to determine the serum selenium concentration at which the saturation levels of SELENOP and GPx3 was achieved. Comparison with GPx3 and serum selenium to identify increased mortality risk was performed, and the effect of supplementation on SELENOP levels were evaluated.
RESULTS: Inverse associations were observed between the level of SELENOP at inclusion and biomarkers for inflammation. At follow-up, shorter telomere lengths were seen in those with low levels of SELENOP at inclusion, whereas high levels of SELENOP were associated with better quality of life and decreased mortality. SELENOP had increased prognostic power compared to GPx3 and selenium. Saturation of SELENOP was achieved at a serum selenium level of 146 μg/L, and for GPx3 at 99 μg/L. Supplementation induced higher levels of SELENOP.
CONCLUSION: Significant associations between SELENOP and inflammation, length of telomeres, quality of life, and mortality were observed. Thus, selenium supplementation improved SELENOP expression, thereby facilitating systemic selenium bioavailability and resulting in the observed positive health effects.}, }
@article {pmid38959478, year = {2024}, author = {Panda, S and Roychowdhury, T and Dutta, A and Chakraborty, S and Das, T and Chatterjee, S}, title = {ALTering Cancer by Triggering Telomere Replication Stress through the Stabilization of Promoter G-Quadruplex in SMARCAL1.}, journal = {ACS chemical biology}, volume = {}, number = {}, pages = {}, doi = {10.1021/acschembio.4c00285}, pmid = {38959478}, issn = {1554-8937}, abstract = {Most of the human cancers are dependent on telomerase to extend the telomeres. But ∼10% of all cancers use a telomerase-independent, homologous recombination mediated pathway called alternative lengthening of telomeres (ALT). Due to the poor prognosis, ALT status is not being considered yet in the diagnosis of cancer. No such specific treatment is available to date for ALT positive cancers. ALT positive cancers are dependent on replication stress to deploy DNA repair pathways to the telomeres to execute homologous recombination mediated telomere extension. SMARCAL1 (SWI/SNF related, matrix-associated, actin-dependent regulator of chromatin, subfamily A-like 1) is associated with the ALT telomeres to resolve replication stress thus providing telomere stability. Thus, the dependency on replication stress regulatory factors like SMARCAL1 made it a suitable therapeutic target for the treatment of ALT positive cancers. In this study, we found a significant downregulation of SMARCAL1 expression by stabilizing the G-quadruplex (G4) motif found in the promoter of SMARCAL1 by potent G4 stabilizers, like TMPyP4 and BRACO-19. SMARCAL1 downregulation led toward the increased localization of PML (promyelocytic leukemia) bodies in ALT telomeres and triggered the formation of APBs (ALT-associated promyelocytic leukemia bodies) in ALT positive cell lines, increasing telomere replication stress and DNA damage at a genomic level. Induction of replication stress and hyper-recombinogenic phenotype in ALT positive cells mediated by G4 stabilizing molecules already highlighted their possible application as a new therapeutic window to target ALT positive tumors. In accordance with this, our study will also provide a valuable insight toward the development of G4-based ALT therapeutics targeting SMARCAL1.}, }
@article {pmid38953168, year = {2024}, author = {Estrem, B and Davis, RE and Wang, J}, title = {End resection and telomere healing of DNA double-strand breaks during nematode programmed DNA elimination.}, journal = {Nucleic acids research}, volume = {}, number = {}, pages = {}, doi = {10.1093/nar/gkae579}, pmid = {38953168}, issn = {1362-4962}, support = {AI155588/NH/NIH HHS/United States ; //University of Tennessee, Knoxville/ ; }, abstract = {Most DNA double-strand breaks (DSBs) are harmful to genome integrity. However, some forms of DSBs are essential to biological processes, such as meiotic recombination and V(D)J recombination. DSBs are also required for programmed DNA elimination (PDE) in ciliates and nematodes. In nematodes, the DSBs are healed with telomere addition. While telomere addition sites have been well characterized, little is known regarding the DSBs that fragment nematode chromosomes. Here, we used embryos from the human and pig parasitic nematode Ascaris to characterize the DSBs. Using END-seq, we demonstrate that DSBs are introduced before mitosis, followed by extensive end resection. The resection profile is unique for each break site, and the resection generates 3'-overhangs before the addition of neotelomeres. Interestingly, telomere healing occurs much more frequently on retained DSB ends than on eliminated ends. This biased repair of the DSB ends may be due to the sequestration of the eliminated DNA into micronuclei, preventing neotelomere formation at their ends. Additional DNA breaks occur within the eliminated DNA in both Ascaris and Parascaris, ensuring chromosomal breakage and providing a fail-safe mechanism for PDE. Overall, our data indicate that telomere healing of DSBs is specific to the break sites responsible for nematode PDE.}, }
@article {pmid38950694, year = {2024}, author = {Zhang, D and Eckhardt, CM and McGroder, C and Benesh, S and Porcelli, J and Depender, C and Bogyo, K and Westrich, J and Thomas-Wilson, A and Jobanputra, V and Garcia, CK}, title = {Clinical Impact of Telomere Length Testing for Interstitial Lung Disease.}, journal = {Chest}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.chest.2024.06.006}, pmid = {38950694}, issn = {1931-3543}, abstract = {BACKGROUND: Shortened telomere length (TL) is a genomic risk factor for fibrotic interstitial lung disease (ILD), but its role in clinical management is unknown.
RESEARCH QUESTION: What is the clinical impact of TL testing on the management of ILD?
STUDY DESIGN AND METHODS: Patients were evaluated in the Columbia University ILD clinic and underwent CLIA-certified TL testing by flow cytometry and fluorescence in-situ hybridization (FlowFISH) as part of clinical management. Short TL was defined as below the 10[th] age-adjusted percentile for either granulocytes or lymphocytes by FlowFISH. Patients were offered genetic counseling and testing if they had short TL or a family history of ILD. FlowFISH TL was compared against research qPCR TL measurement.
RESULTS: A total of 108 patients underwent TL testing, including those with clinical features of short telomere syndrome such as familial pulmonary fibrosis (50%) or extrapulmonary manifestations in the patient (25%) or a relative (41%). The overall prevalence of short TL was 46% and was similar across clinical ILD diagnoses. The number of short telomere clinical features was independently associated with detecting short TL (OR 2.00, 95% CI [1.27, 3.32]). TL testing led to clinical management changes for 35 (32%) patients, most commonly resulting in reduction or avoidance of immunosuppression. Of the patients who underwent genetic testing (n=34), a positive or candidate diagnostic finding in telomere-related genes was identified in 10 (29%) patients. Inclusion of TL testing below the 1[st] percentile helped reclassify 8 of 9 variants of uncertain significance (VUS) into actionable findings. The qPCR test correlated with FlowFISH, but age-adjusted percentile cutoffs may not be equivalent between the two assays.
INTERPRETATION: Incorporating TL testing in ILD impacted clinical management and led to the discovery of new actionable genetic variants.}, }
@article {pmid38951712, year = {2024}, author = {Lechel, A and Ande, S and Ju, Z and Plentz, RR and Schaetzlein, S and Rudolph, C and Wilkens, L and Wiemann, SU and Saretzki, G and Malek, NP and Manns, MP and Buer, J and Rudolph, KL}, title = {Author Correction: The cellular level of telomere dysfunction determines induction of senescence or apoptosis in vivo.}, journal = {EMBO reports}, volume = {}, number = {}, pages = {}, doi = {10.1038/s44319-024-00192-9}, pmid = {38951712}, issn = {1469-3178}, }
@article {pmid38946430, year = {2024}, author = {Longo, M and Greco, E and Listorti, I and Varricchio, MT and Litwicka, K and Arrivi, C and Mencacci, C and Greco, P}, title = {Telomerase activity, telomere length, and the euploidy rate of human embryos.}, journal = {Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology}, volume = {40}, number = {1}, pages = {2373742}, doi = {10.1080/09513590.2024.2373742}, pmid = {38946430}, issn = {1473-0766}, mesh = {Humans ; Female ; Adult ; *Telomerase/genetics/metabolism ; *Telomere ; Prospective Studies ; Pregnancy ; Aneuploidy ; Fertilization in Vitro ; Granulosa Cells/metabolism ; Infertility, Female/genetics/therapy ; Ovulation Induction ; Blastocyst ; Telomere Homeostasis/physiology ; Sperm Injections, Intracytoplasmic ; }, abstract = {BACKGROUND: Telomeres maintain chromosome stability, while telomerase counteracts their progressive shortening. Telomere length varies between cell types, with leukocyte telomere length (LTL) decreasing with age. Reduced telomerase activity has been linked to reproductive issues in females, such as low pregnancy rates and premature ovarian failure, with recent studies indicating correlations between telomere length in granulosa cells and IVF outcomes.
OBJECTIVES: The study aims to explore the relationship between telomere length, telomerase activity, and euploid blastocyst rate in infertile women undergoing IVF/ICSI PGT-A cycles.
METHODS: This prospective study involves 108 patients undergoing controlled ovarian stimulation and PGT-A. Telomere length and telomerase activity were measured in peripheral mononuclear cells and granulosa cells (GC), respectively.
RESULTS: The telomere repeat copy number to single gene copy number ratio (T/S) results respectively 0.6 ± 0.8 in leukocytes and 0.7 ± 0.9 in GC. An inverse relationship was found between LTL and the patient's age (p < .01). A higher aneuploid rate was noticed in patients with short LTL, with no differences in ovarian reserve markers (p = .15), number of oocytes retrieved (p = .33), and number of MII (p = 0.42). No significant association was noticed between telomere length in GC and patients' age (p = 0.95), in ovarian reserve markers (p = 0.32), number of oocytes retrieved (p = .58), number of MII (p = .74) and aneuploidy rate (p = .65).
CONCLUSION: LTL shows a significant inverse correlation with patient age and higher aneuploidy rates. Telomere length in GCs does not correlate with patient age or reproductive outcomes, indicating differential telomere dynamics between leukocytes and granulosa cells.}, }
@article {pmid38945863, year = {2024}, author = {Teramoto, N and Okada, Y and Aburada, N and Hayashi, M and Ito, J and Shirasuna, K and Iwata, H}, title = {Resveratrol intake by males increased the mitochondrial DNA copy number and telomere length of blastocysts derived from aged mice.}, journal = {The Journal of reproduction and development}, volume = {}, number = {}, pages = {}, doi = {10.1262/jrd.2024-043}, pmid = {38945863}, issn = {1348-4400}, abstract = {The present study examined whether male resveratrol intake affected mitochondrial DNA copy number (mt-cn) and telomere length (TL) in blastocysts fathered by young and aged male mice. C57BL/6N male mice supplied with water or water containing 0.1 mM resveratrol were used for embryo production at 14-23 and 48-58 weeks of age. Two-cell-stage embryos were collected from the oviducts of superovulated female mice (8-15 weeks old) and cultured for 3 days until the blastocyst stage. Mt-cn and TL levels were measured by real-time polymerase chain reaction. Resveratrol intake did not affect body weight or water consumption. Resveratrol intake increased the expression levels of SIRT1 in the liver, the antioxidative ability of serum, and extended TL in the heart, whereas there was no significant difference in mt-cn in the heart or TL in sperm. The rate of blastocyst development was significantly lower in aged male mice than in younger mice, and resveratrol intake increased the total number of blastocysts derived from both young and aged males. Resveratrol intake did not affect mt-cn or TL in blastomeres of blastocyst-stage embryos derived from young mice, but significantly increased both mt-cn and TL in blastomeres of blastocysts derived from aged fathers. In conclusion, resveratrol intake increased mt-cn and TL levels in blastocysts derived from aged male mice.}, }
@article {pmid38943658, year = {2024}, author = {Moeckel, C and Gaydosh, L and Schneper, L and Mitchell, C and Notterman, DA}, title = {Material hardship and telomere length in children.}, journal = {Child development}, volume = {}, number = {}, pages = {}, doi = {10.1111/cdev.14126}, pmid = {38943658}, issn = {1467-8624}, support = {P2CHD047879//Eunice Kennedy Shriver National Institute of Child Health and Human Development/ ; R01HD036916//Eunice Kennedy Shriver National Institute of Child Health and Human Development/ ; R01HD076592//Eunice Kennedy Shriver National Institute of Child Health and Human Development/ ; R01HD36916//Eunice Kennedy Shriver National Institute of Child Health and Human Development/ ; R01HD39135//Eunice Kennedy Shriver National Institute of Child Health and Human Development/ ; R01HD40421//Eunice Kennedy Shriver National Institute of Child Health and Human Development/ ; }, abstract = {Telomere length (TL) serves as a biomarker of exposure to stressors, including material hardship. Data from the Future of Families and Child Wellbeing Study (1998-2015) were utilized to determine whether prior material hardship was associated with shorter salivary TL at years 9 and 15. 49% of the year 9 study population were female, 49% were Black, and 25% were Hispanic. At year 9 (N = 1990), regression analyses found a significant association between prior material hardship and shorter TL (β = -.005, p < .01). Additionally, at year 15 (N = 1874), material hardship experienced during infancy and toddlerhood was associated with shorter TL (β = -.009, p < .01), pointing toward infancy and toddlerhood as a sensitive period.}, }
@article {pmid38943263, year = {2024}, author = {Lee, Y and Jugessur, A and Gjessing, HK and Harris, JR and Susser, E and Magnus, P and Aviv, A}, title = {Effect of polygenic scores of telomere length alleles on telomere length in newborns and parents.}, journal = {Aging cell}, volume = {}, number = {}, pages = {e14241}, doi = {10.1111/acel.14241}, pmid = {38943263}, issn = {1474-9726}, support = {R01 HL134840/NH/NIH HHS/United States ; 223273//Norges Forskningsråd/ ; 229624//Norges Forskningsråd/ ; 262043//Norges Forskningsråd/ ; 262700//Norges Forskningsråd/ ; }, abstract = {In adults, polygenic scores (PGSs) of telomere length (TL) alleles explain about 4.5% of the variance in TL, as measured by quantitative polymerase chain reaction (qPCR). Yet, these PGSs strongly infer a causal role of telomeres in aging-related diseases. To better understand the determinants of TL through the lifespan, it is essential to examine to what extent these PGSs explain TL in newborns. This study investigates the effect of PGSs on TL in both newborns and their parents, with TL measured by Southern blotting and expressed in base-pairs (bp). Additionally, the study explores the impact of PGSs related to transmitted or non-transmitted alleles on TL in newborns. For parents and newborns, the PGS effects on TL were 172 bp (p = 2.03 × 10[-15]) and 161 bp (p = 3.06 × 10[-8]), explaining 6.6% and 5.2% of the TL variance, respectively. The strongest PGS effect was shown for maternally transmitted alleles in newborn girls, amounting to 214 bp (p = 3.77 × 10[-6]) and explaining 7.8% of the TL variance. The PGS effect of non-transmitted alleles was 56 bp (p = 0.0593) and explained 0.6% of the TL variance. Our findings highlight the importance of TL genetics in understanding early-life determinants of TL. They point to the potential utility of PGSs composed of TL alleles in identifying susceptibility to aging-related diseases from birth and reveal the presence of sexual dimorphism in the effect of TL alleles on TL in newborns. Finally, we attribute the higher TL variance explained by PGSs in our study to TL measurement by Southern blotting.}, }
@article {pmid38937972, year = {2024}, author = {Wang, K and Jin, J and Wang, J and Wang, X and Sun, J and Meng, D and Wang, X and Guo, L}, title = {The complete telomere-to-telomere genome assembly of lettuce.}, journal = {Plant communications}, volume = {}, number = {}, pages = {101011}, doi = {10.1016/j.xplc.2024.101011}, pmid = {38937972}, issn = {2590-3462}, }
@article {pmid38936230, year = {2024}, author = {Rodríguez-Fernández, B and Sánchez-Benavides, G and Genius, P and Minguillon, C and Fauria, K and De Vivo, I and Navarro, A and Molinuevo, JL and Gispert, JD and Sala-Vila, A and Vilor-Tejedor, N and Crous-Bou, M and , }, title = {Association between telomere length and cognitive function among cognitively unimpaired individuals at risk of Alzheimer's disease.}, journal = {Neurobiology of aging}, volume = {141}, number = {}, pages = {140-150}, doi = {10.1016/j.neurobiolaging.2024.05.015}, pmid = {38936230}, issn = {1558-1497}, abstract = {INTRODUCTION: Leukocyte telomere length (LTL) is an objective biomarker of biological aging, and it is proposed to play a crucial role in Alzheimer's disease (AD) risk. We aimed at evaluating the cross-sectional association between LTL and cognitive performance in middle-aged cognitively unimpaired individuals at increased risk of AD.
METHODS: A total of 1520 participants from the ALFA cohort were included. Relative telomere length was measured in leukocytes through qPCR. LTL was residualized against age and sex, and associations with cognitive performance were assessed in short and long groups based on residualized LTL (rLTL). Interactions with sex and genetic risk of AD were tested.
RESULTS: Non-linear associations were found between LTL and episodic memory (EM). Better EM was associated with longer rLTL among women in the short rLTL group.
DISCUSSION: Results suggest a potential role of telomeres in the cognitive aging process with sex-specific patterns.}, }
@article {pmid38935034, year = {2024}, author = {Vaghefi, E and An, S and Corbett, R and Squirrell, D}, title = {Association of retinal image-based, deep learning cardiac BioAge with telomere length and cardiovascular biomarkers.}, journal = {Optometry and vision science : official publication of the American Academy of Optometry}, volume = {}, number = {}, pages = {}, doi = {10.1097/OPX.0000000000002158}, pmid = {38935034}, issn = {1538-9235}, abstract = {SIGNIFICANCE: Our retinal image-based deep learning (DL) cardiac biological age (BioAge) model could facilitate fast, accurate, noninvasive screening for cardiovascular disease (CVD) in novel community settings and thus improve outcome with those with limited access to health care services.
PURPOSE: This study aimed to determine whether the results issued by our DL cardiac BioAge model are consistent with the known trends of CVD risk and the biomarker leukocyte telomere length (LTL), in a cohort of individuals from the UK Biobank.
METHODS: A cross-sectional cohort study was conducted using those individuals in the UK Biobank who had LTL data. These individuals were divided by sex, ranked by LTL, and then grouped into deciles. The retinal images were then presented to the DL model, and individual's cardiac BioAge was determined. Individuals within each LTL decile were then ranked by cardiac BioAge, and the mean of the CVD risk biomarkers in the top and bottom quartiles was compared. The relationship between an individual's cardiac BioAge, the CVD biomarkers, and LTL was determined using traditional correlation statistics.
RESULTS: The DL cardiac BioAge model was able to accurately stratify individuals by the traditional CVD risk biomarkers, and for both males and females, those issued with a cardiac BioAge in the top quartile of their chronological peer group had a significantly higher mean systolic blood pressure, hemoglobin A1c, and 10-year Pooled Cohort Equation CVD risk scores compared with those individuals in the bottom quartile (p<0.001). Cardiac BioAge was associated with LTL shortening for both males and females (males: -0.22, r2 = 0.04; females: -0.18, r2 = 0.03).
CONCLUSIONS: In this cross-sectional cohort study, increasing CVD risk whether assessed by traditional biomarkers, CVD risk scoring, or our DL cardiac BioAge, CVD risk model, was inversely related to LTL. At a population level, our data support the growing body of evidence that suggests LTL shortening is a surrogate marker for increasing CVD risk and that this risk can be captured by our novel DL cardiac BioAge model.}, }
@article {pmid38929154, year = {2024}, author = {Shan, J and Mo, J and An, C and Xiang, L and Qi, J}, title = {β-Cyclocitral from Lavandula angustifolia Mill. Exerts Anti-Aging Effects on Yeasts and Mammalian Cells via Telomere Protection, Antioxidative Stress, and Autophagy Activation.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {13}, number = {6}, pages = {}, doi = {10.3390/antiox13060715}, pmid = {38929154}, issn = {2076-3921}, support = {2022YFE0104000//the National Key R&D Program of China/ ; 22177102//NSFC/ ; }, abstract = {We used a replicative lifespan (RLS) experiment of K6001 yeast to screen for anti-aging compounds within lavender extract (Lavandula angustifolia Mill.), leading to the discovery of β-cyclocitral (CYC) as a potential anti-aging compound. Concurrently, the chronological lifespan (CLS) of YOM36 yeast and mammalian cells confirmed the anti-aging effect of CYC. This molecule extended the yeast lifespan and inhibited etoposide (ETO)-induced cell senescence. To understand the mechanism of CYC, we analyzed its effects on telomeres, oxidative stress, and autophagy. CYC administration resulted in notable increases in the telomerase content, telomere length, and the expression of the telomeric shelterin protein components telomeric-repeat binding factor 2 (TRF2) and repressor activator protein 1 (RAP1). More interestingly, CYC reversed H2O2-induced telomere damage and exhibited strong antioxidant capacity. Moreover, CYC improved the survival rate of BY4741 yeast under oxidative stress induced by 6.2 mM H2O2, increasing the antioxidant enzyme activity while reducing the reactive oxygen species (ROS), reactive nitrogen species (RNS), and malondialdehyde (MDA) levels. Additionally, CYC enhanced autophagic flux and free green fluorescent protein (GFP) expression in the YOM38-GFP-ATG8 yeast strain. However, CYC did not extend the RLS of K6001 yeast mutants, such as Δsod1, Δsod2, Δcat, Δgpx, Δatg2, and Δatg32, which lack antioxidant enzymes or autophagy-related genes. These findings reveal that CYC acts as an anti-aging agent by modifying telomeres, oxidative stress, and autophagy. It is a promising compound with potential anti-aging effects and warrants further study.}, }
@article {pmid38928414, year = {2024}, author = {Harutyunyan, T and Sargsyan, A and Kalashyan, L and Igityan, H and Grigoryan, B and Davtyan, H and Aroutiounian, R and Liehr, T and Hovhannisyan, G}, title = {Changes in Telomere Length in Leukocytes and Leukemic Cells after Ultrashort Electron Beam Radiation.}, journal = {International journal of molecular sciences}, volume = {25}, number = {12}, pages = {}, doi = {10.3390/ijms25126709}, pmid = {38928414}, issn = {1422-0067}, support = {22SC-BMBF-1C001//RA MESCS Science Committee and German Federal Ministry of Education and Research/ ; 21AG-1F068//RA MESCS Science Committee/ ; 01DK24003//German Aerospace Center (= Deutsches Forschungszentrum für Luft- und Raumfahrt, DLR)/ ; }, mesh = {Humans ; K562 Cells ; *Leukocytes/radiation effects/metabolism ; *Electrons ; *Telomere/radiation effects/genetics/metabolism ; Leukemia/genetics/pathology/radiotherapy ; Telomere Homeostasis/radiation effects ; In Situ Hybridization, Fluorescence ; Telomere Shortening/radiation effects ; DNA Damage/radiation effects ; Dose-Response Relationship, Radiation ; }, abstract = {Application of laser-generated electron beams in radiotherapy is a recent development. Accordingly, mechanisms of biological response to radiation damage need to be investigated. In this study, telomere length (TL) as endpoint of genetic damage was analyzed in human blood cells (leukocytes) and K562 leukemic cells irradiated with laser-generated ultrashort electron beam. Metaphases and interphases were analyzed in quantitative fluorescence in situ hybridization (Q-FISH) to assess TL. TLs were shortened compared to non-irradiated controls in both settings (metaphase and interphase) after irradiation with 0.5, 1.5, and 3.0 Gy in blood leukocytes. Radiation also caused a significant TL shortening detectable in the interphase of K562 cells. Overall, a negative correlation between TL and radiation doses was observed in normal and leukemic cells in a dose-dependent manner. K562 cells were more sensitive than normal blood cells to increasing doses of ultrashort electron beam radiation. As telomere shortening leads to genome instability and cell death, the results obtained confirm the suitability of this biomarker for assessing genotoxic effects of accelerated electrons for their further use in radiation therapy. Observed differences in TL shortening between normal and K562 cells provide an opportunity for further development of optimal radiation parameters to reduce side effects in normal cells during radiotherapy.}, }
@article {pmid38927760, year = {2024}, author = {Arellano, MYG and VanHeest, M and Emmadi, S and Abdul-Hafez, A and Ibrahim, SA and Thiruvenkataramani, RP and Teleb, RS and Omar, H and Kesaraju, T and Mohamed, T and Madhukar, BV and Omar, SA}, title = {Role of Mesenchymal Stem/Stromal Cells (MSCs) and MSC-Derived Extracellular Vesicles (EVs) in Prevention of Telomere Length Shortening, Cellular Senescence, and Accelerated Biological Aging.}, journal = {Bioengineering (Basel, Switzerland)}, volume = {11}, number = {6}, pages = {}, doi = {10.3390/bioengineering11060524}, pmid = {38927760}, issn = {2306-5354}, abstract = {Biological aging is defined as a progressive decline in tissue function that eventually results in cell death. Accelerated biologic aging results when the telomere length is shortened prematurely secondary to damage from biological or environmental stressors, leading to a defective reparative mechanism. Stem cells therapy may have a potential role in influencing (counteract/ameliorate) biological aging and maintaining the function of the organism. Mesenchymal stem cells, also called mesenchymal stromal cells (MSCs) are multipotent stem cells of mesodermal origin that can differentiate into other types of cells, such as adipocytes, chondrocytes, and osteocytes. MSCs influence resident cells through the secretion of paracrine bioactive components such as cytokines and extracellular vesicles (EVs). This review examines the changes in telomere length, cellular senescence, and normal biological age, as well as the factors contributing to telomere shortening and accelerated biological aging. The role of MSCs-especially those derived from gestational tissues-in prevention of telomere shortening (TS) and accelerated biological aging is explored. In addition, the strategies to prevent MSC senescence and improve the antiaging therapeutic application of MSCs and MSC-derived EVs in influencing telomere length and cellular senescence are reviewed.}, }
@article {pmid38927389, year = {2024}, author = {Almuraikhy, S and Sellami, M and Naja, K and Al-Amri, HS and Anwardeen, N and Aden, A and Dömling, A and Elrayess, MA}, title = {Joint Effects of Exercise and Ramadan Fasting on Telomere Length: Implications for Cellular Aging.}, journal = {Biomedicines}, volume = {12}, number = {6}, pages = {}, doi = {10.3390/biomedicines12061182}, pmid = {38927389}, issn = {2227-9059}, support = {IRCC-2022-467//Qatar University/ ; }, abstract = {Aging is a fundamental biological process that progressively impairs the functionality of the bodily systems, leading to an increased risk of diseases. Telomere length is one of the most often used biomarkers of aging. Recent research has focused on developing interventions to mitigate the effects of aging and improve the quality of life. The objective of this study was to investigate the combined effect of exercise and Ramadan fasting on telomere length. Twenty-nine young, non-obese, healthy females were randomized into two groups: the control group underwent a 4-week exercise training program, and the second group underwent a 4-week exercise training program while fasting during Ramadan. Blood samples were collected, and measurements of clinical traits, cytokines, oxidative stress, and telomere length were performed before and after intervention. Telomere length increased significantly from baseline in the exercise-while-fasting group, but showed no significant change in the exercise control group. This increase was accompanied by a reduction in TNF-α, among other cytokines. Additionally, a significant positive correlation was observed between the mean change in telomere length and HDL in the exercise-while-fasting group only. This study is the first to report an increase in telomere length after combining Ramadan fasting with training, suggesting that exercising while fasting may be an effective tool for slowing down the aging rate. Further studies using larger and more diverse cohorts are warranted.}, }
@article {pmid38926996, year = {2024}, author = {Li, DN and Wen, XH}, title = {[Role of Telomere in Clonal Evolution of Acquired Aplastic Anemia--Review].}, journal = {Zhongguo shi yan xue ye xue za zhi}, volume = {32}, number = {3}, pages = {962-964}, doi = {10.19746/j.cnki.issn.1009-2137.2024.03.048}, pmid = {38926996}, issn = {1009-2137}, mesh = {*Anemia, Aplastic/genetics ; Humans ; *Telomere/genetics ; *Clonal Evolution ; *Telomerase/genetics ; Telomere Shortening ; }, abstract = {Studies have found that 1/3 patients with acquired aplastic anemia have shortened telomere length, and the shorter the telomere, the longer the disease course, the more prone to relapse, the lower the overall survival rate, and the higher the probability of clonal evolution. The regulation of telomere length is affected by many factors, including telomerase activity, telomerase-related genes, telomere regulatory proteins and other related factors. Telomere shortening can lead to genetic instability and increases the probability of clonal evolution in patients with acquired aplastic anemia. This article reviews the role of telomere in the clonal evolution of acquired aplastic anemia and factors affecting telomere length.}, }
@article {pmid38933758, year = {2023}, author = {Zhang, Y and Pang, N and Huang, X and Meng, W and Meng, L and Zhang, B and Jiang, Z and Zhang, J and Yi, Z and Luo, Z and Wang, Z and Niu, L}, title = {Ultrasound deep brain stimulation decelerates telomere shortening in Alzheimer's disease and aging mice.}, journal = {Fundamental research}, volume = {3}, number = {3}, pages = {469-478}, doi = {10.1016/j.fmre.2022.02.010}, pmid = {38933758}, issn = {2667-3258}, abstract = {Telomere length is a reliable biomarker for health and longevity prediction in both humans and animals. The common neuromodulation techniques, including deep brain stimulation (DBS) and optogenetics, have excellent spatial resolution and depth penetration but require implementation of electrodes or optical fibers. Therefore, it is important to develop methods for noninvasive modulation of telomere length. Herein, we reported on a new method for decelerating telomere shortening using noninvasive ultrasound deep brain stimulation (UDBS). Firstly, we found that UDBS could activate the telomerase-associated proteins in normal mice. Then, in the Alzheimer's disease mice, UDBS was observed to decelerate telomere shortening of the cortex and myocardial tissue and to effectively improve spatial learning and memory abilities. Similarly, UDBS was found to significantly slow down telomere shortening of the cortex and peripheral blood, and improve motor and cognitive functions in aging mice. Finally, transcriptome analysis revealed that UDBS upregulated the neuroactive ligand-receptor interaction pathway. Overall, the present findings established the critical role of UDBS in delaying telomere shortening and indicated that ultrasound modulation of telomere length may constitute an effective therapeutic strategy for aging and aging-related diseases.}, }
@article {pmid38926610, year = {2024}, author = {Wang, Z and Zuo, M and Li, W and Chen, S and Yuan, Y and He, Y and Yang, Y and Mao, Q and Liu, Y}, title = {The impact of telomere length on the risk of idiopathic normal pressure hydrocephalus: a bidirectional Mendelian randomization study.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {14713}, pmid = {38926610}, issn = {2045-2322}, support = {2023YFG0127//the Sichuan Science and Technology Program/ ; 2023YFQ0002//the Sichuan Science and Technology Program/ ; }, abstract = {Idiopathic normal pressure hydrocephalus (iNPH) affects mainly aged populations. The gradual shortening of telomere length (TL) is one of the hallmarks of aging. Whereas the genetic contribution of TL to the iNPH is incompletely understood. We aimed to investigate the causal relationship between TL and iNPH through the Mendelian randomization (MR) analysis. We respectively obtained 186 qualified single nucleotide polymorphisms (SNPs) of TL and 20 eligible SNPs of iNPH for MR analysis. The result of MR analysis showed that genetically predicted longer TL was significantly associated with a reduced odd of iNPH (odds ratio [OR] = 0.634 95% Confidence interval [CI] 0.447-0.899, p = 0.011). The causal association remained consistent in multivariable MR (OR = 0.530 95% CI 0.327-0.860, p = 0.010). However, there was no evidence that the iNPH was causally associated with the TL (OR = 1.000 95% CI 0.996-1.004, p = 0.955). Our study reveals a potential genetic contribution of TL to the etiology of iNPH, that is a genetically predicted increased TL might be associated with a reduced risk of iNPH.}, }
@article {pmid38922965, year = {2024}, author = {Joo, SY and Sung, K and Lee, H}, title = {Balancing act: BRCA2's elaborate management of telomere replication through control of G-quadruplex dynamicity.}, journal = {BioEssays : news and reviews in molecular, cellular and developmental biology}, volume = {}, number = {}, pages = {e2300229}, doi = {10.1002/bies.202300229}, pmid = {38922965}, issn = {1521-1878}, support = {2020R1A5A1018081//National Research Foundation of Korea (NRF)/ ; 2021R1A2C1006191//National Research Foundation of Korea (NRF)/ ; }, abstract = {In billion years of evolution, eukaryotes preserved the chromosome ends with arrays of guanine repeats surrounded by thymines and adenines, which can form stacks of four-stranded planar structure known as G-quadruplex (G4). The rationale behind the evolutionary conservation of the G4 structure at the telomere remained elusive. Our recent study has shed light on this matter by revealing that telomere G4 undergoes oscillation between at least two distinct folded conformations. Additionally, tumor suppressor BRCA2 exhibits a unique mode of interaction with telomere G4. To elaborate, BRCA2 directly interacts with G-triplex (G3)-derived intermediates that form during the interconversion of the two different G4 states. In doing so, BRCA2 remodels the G4, facilitating the restart of stalled replication forks. In this review, we succinctly summarize the findings regarding the dynamicity of telomeric G4, emphasize its importance in maintaining telomere replication homeostasis, and the physiological consequences of losing G4 dynamicity at the telomere.}, }
@article {pmid38922089, year = {2024}, author = {Ouyang, C and Yang, Y and Pan, J and Liu, H and Wang, X and Zhou, S and Shi, X and Zhang, Y and Wang, D and Hu, X}, title = {Leukocyte Telomere Length Mediates the Associations between Blood Lead and Cadmium with Hypertension among Adults in the United States: A Cross-Sectional Study.}, journal = {Toxics}, volume = {12}, number = {6}, pages = {}, doi = {10.3390/toxics12060409}, pmid = {38922089}, issn = {2305-6304}, support = {No. 23JRRA0969//Gansu Provincial Natural Science Foundation/ ; }, abstract = {There is evidence to support the links between lead and cadmium exposure with hypertension and also with leukocyte telomere length (LTL). The objective of this study is to investigate the role that LTL may play in the relationship between lead and cadmium exposure and hypertension. This study consisted of 3718 participants from the National Health and Nutrition Examination Survey (NHANES) 1999-2002. Logistic regression was used to analyze the relationship between blood metals with hypertension, and the mediating model was used to evaluate the mediating effect of LTL. In the fully adjusted model, both blood lead and cadmium ln-transformed concentrations were significantly positively associated with hypertension risk, as were all quartiles of blood lead. Additionally, we observed positive linear dose-response relationships with hypertension by restricted cubic spline analysis (both p overall < 0.001, p non-linear = 0.3008 for lead and p non-linear = 0.7611 for cadmium). The ln-transformed blood lead and cadmium concentrations were associated with shorter LTL. LTL was inversely related to hypertension and the OR was 0.65 (95% CI: 0.47 to 0.89). Furthermore, LTL had mediating effects on the associations of blood lead and cadmium with hypertension risk, and the mediation proportions were 2.25% and 4.20%, respectively. Our findings suggested that exposure to lead and cadmium raised the risk of hypertension, while LTL played as a mediating factor.}, }
@article {pmid38919841, year = {2024}, author = {Croons, H and Martens, DS and Vanderstukken, C and Sleurs, H and Rasking, L and Peusens, M and Renaers, E and Plusquin, M and Nawrot, TS}, title = {Telomere length in early childhood and its association with attention: a study in 4-6 year old children.}, journal = {Frontiers in pediatrics}, volume = {12}, number = {}, pages = {1358272}, pmid = {38919841}, issn = {2296-2360}, abstract = {Telomere length (TL), a marker of cellular aging, has been studied in adults with regard to its connection to cognitive function. However, little is known about the association between TL and cognitive development in children. This study investigated the interplay between TL and cognitive functioning in 283 Belgian children aged four to six years of the Environmental Influence on Aging in Early Life (ENVIRONAGE) birth cohort. Child leukocyte TL was measured using qPCR, while cognitive functioning, including attention and memory, was assessed using the Cambridge Neuropsychological Test Automated Battery (CANTAB). Linear regression models were employed to examine the association between TL and cognitive outcomes, adjusting for potential confounders. We found an inverse association between TL and the spatial errors made during the Motor Screening task (p = 0.017), indicating a higher motor accuracy in children with longer telomeres. No significant associations were found between TL and other cognitive outcomes. Our results suggest a specific link between TL and motor accuracy but not with the other cognitive domains.}, }
@article {pmid38917803, year = {2024}, author = {Tan, KT and Slevin, MK and Leibowitz, ML and Garrity-Janger, M and Shan, J and Li, H and Meyerson, M}, title = {Neotelomeres and telomere-spanning chromosomal arm fusions in cancer genomes revealed by long-read sequencing.}, journal = {Cell genomics}, volume = {}, number = {}, pages = {100588}, doi = {10.1016/j.xgen.2024.100588}, pmid = {38917803}, issn = {2666-979X}, abstract = {Alterations in the structure and location of telomeres are pivotal in cancer genome evolution. Here, we applied both long-read and short-read genome sequencing to assess telomere repeat-containing structures in cancers and cancer cell lines. Using long-read genome sequences that span telomeric repeats, we defined four types of telomere repeat variations in cancer cells: neotelomeres where telomere addition heals chromosome breaks, chromosomal arm fusions spanning telomere repeats, fusions of neotelomeres, and peri-centromeric fusions with adjoined telomere and centromere repeats. These results provide a framework for the systematic study of telomeric repeats in cancer genomes, which could serve as a model for understanding the somatic evolution of other repetitive genomic elements.}, }
@article {pmid38916238, year = {2024}, author = {Zhang, J and Yang, XY and Chen, J and Zhou, Q and Pan, G and Wang, Y and Luo, W and Hou, J and Bao, H and Xu, G and Tang, G and Bai, H and Yu, R}, title = {A Poly(amino acid)-Based Nanomedicine Strategy: Telomere-Telomerase Axis Targeting and Magnetic Resonance Imaging in Hepatocellular Carcinoma Treatment.}, journal = {Nano letters}, volume = {}, number = {}, pages = {}, doi = {10.1021/acs.nanolett.4c01767}, pmid = {38916238}, issn = {1530-6992}, abstract = {Targeting telomere maintenance has emerged as a promising strategy for hepatocellular carcinoma (HCC) treatment. However, given the duality of the telomere-telomerase axis in telomere maintenance, a comprehensive strategy is urgently needed. Herein, we develop a poly(amino acid) (D-PAAs)-based strategy for spatiotemporal codelivery of telomerase inhibitor, BIBR1523, and AKT inhibitor, isobavachalcone. By leveraging D-PAAs' modifiability, we synthesize polymer-inhibitor conjugates (PB and PI) and a folic acid-decorated tumor-targeting vector (PF). These building blocks undergo micellization to fabricate a codelivery nanomedicine (P-BI@P-FA) by exploiting D-PAAs' noncovalent assembly. P-BI@P-FA improves the pharmacokinetics, tumor selectivity, and bioavailability of small molecule inhibitors and initiates a dual telomere-specific inhibition by combining telomerase deactivation with telomere disruption. Furthermore, a hybrid tumor-targeting magnetic nanosystem is designed using D-PAAs and manganese dioxide to showcase magnetic resonance imaging capacities. Our D-PAAs-based strategy addresses the pressing need for telomere-specific HCC treatment while allowing for diagnostic application, presenting a promising avenue for nanomedicine design.}, }
@article {pmid38915611, year = {2024}, author = {Teplitz, GM and Pasquier, E and Bonnell, E and Laurentiis, E and Bartle, L and Lucier, JF and Sholes, S and Greider, CW and Wellinger, RJ}, title = {A mechanism for telomere-specific telomere length regulation.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2024.06.12.598646}, pmid = {38915611}, abstract = {Telomeric DNA, composed of short, direct repeats, is of crucial importance for chromosome stability. Due to intrinsic problems with replicating this DNA, the repeat tracts shorten at each cell division. Once repeat tracts become critically short, a telomeric stress signal induces cellular senescence and division arrest, which eventually may lead to devastating age-related degenerative diseases associated with dysfunctional telomers. Conversely, maintenance of telomere length by telomerase upregulation is a hallmark of cancer. Therefore, telomere length is a critical determinant of telomere function. How telomere length is established and molecular mechanisms for telomere-specific length regulation remained unknown. Here we show that subtelomeric chromatin is a determinant for how telomere equilibrium set-length is established in cis . The results demonstrate that telomerase recruitment mediated by the telomere-associated Sir4 protein is modulated on chromosome 3L in a telomere-specific way. Increased Sir4 abundance on subtelomeric heterochromatin of this specific telomere leads to telomere lengthening of only that telomere in cis , but not at other telomeres. Therefore, this work describes a mechanism for a how telomere-specific repeat tract length can be established. Further, our results will force the evaluation of telomere length away from a generalized view to a more telomere-specific consideration.}, }
@article {pmid38914514, year = {2024}, author = {Yang, SH and Liu, HT and Wang, TF and Liou, YS and Sun, DS and Wang, JH and Chen, LY}, title = {Shorter donor leukocyte telomere length is associated with poor peripheral blood stem cell mobilization induced by granulocyte colony-stimulating factor.}, journal = {Journal of the Formosan Medical Association = Taiwan yi zhi}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jfma.2024.06.017}, pmid = {38914514}, issn = {0929-6646}, abstract = {BACKGROUND/PURPOSE: Insufficient numbers of peripheral blood stem cells (PBSC) after granulocyte colony-stimulating factor (G-CSF) mobilization occurs in a significant proportion of PBSC collections, often from older age donors. Telomere length (TL) is often used as an indicator of an individual's biological age. This study aimed to investigate the relationship between donors' leukocyte TL and the outcome of G-CSF-induced PBSC mobilization in healthy unrelated donors.
METHODS: Donors' leukocyte TLs and the outcome of G-CSF-induced PBSC mobilization, as assessed by pre-harvest CD34[+] cell counts, were analyzed in 39 healthy PBSC donors. TL in a non-mobilized general population (n = 90) was included as a control group. G-CSF mobilization effect was categorized into three groups according to pre-harvest CD34[+] cell count: poor (≤25/μL, PMD), intermediate (between 25 and 180/μL), and good (≥180/μl, GMD).
RESULTS: Leukocyte TL of PBSC donors correlated well with pre-harvest CD34[+] cell counts (r = 0.645, p < 0.001). Leukocyte TLs of PMDs (n = 8) were significantly shorter than those of GMDs (n = 9) and non-mobilization controls (p < 0.05). Moreover, all PMD TLs were below the 50th percentile, and 62.5% of PMDs had TLs below the 10th percentile of age-matched control participants. In contrast, no GMD TLs were below the 10th percentile; in fact, 33.3% (3/9) of them were above the 90th percentile.
CONCLUSION: Our results indicate that shorter donor leukocyte TL is associated with poor G-CSF-induced PBSC mobilization. TL, which represents a donor's biological age, could be a potential predictor for mobilization outcome.}, }
@article {pmid38910895, year = {2024}, author = {Gu, L and Liu, M and Zhang, Y and Zhou, H and Wang, Y and Xu, ZX}, title = {Telomere-related DNA damage response pathways in cancer therapy: prospective targets.}, journal = {Frontiers in pharmacology}, volume = {15}, number = {}, pages = {1379166}, pmid = {38910895}, issn = {1663-9812}, abstract = {Maintaining the structural integrity of genomic chromosomal DNA is an essential role of cellular life and requires two important biological mechanisms: the DNA damage response (DDR) mechanism and telomere protection mechanism at chromosome ends. Because abnormalities in telomeres and cellular DDR regulation are strongly associated with human aging and cancer, there is a reciprocal regulation of telomeres and cellular DDR. Moreover, several drug treatments for DDR are currently available. This paper reviews the progress in research on the interaction between telomeres and cellular DNA damage repair pathways. The research on the crosstalk between telomere damage and DDR is important for improving the efficacy of tumor treatment. However, further studies are required to confirm this hypothesis.}, }
@article {pmid38902824, year = {2024}, author = {Zhao, S and Li, J and Duan, S and Liu, C and Wang, H and Lu, J and Zhao, N and Sheng, X and Wu, Y and Li, Y and Sun, B and Liu, L}, title = {UBQLN1 links proteostasis and mitochondria function to telomere maintenance in human embryonic stem cells.}, journal = {Stem cell research & therapy}, volume = {15}, number = {1}, pages = {180}, pmid = {38902824}, issn = {1757-6512}, support = {32030033//National Natural Science Foundation of China/ ; 82230052//National Natural Science Foundation of China/ ; 32261160571//National Natural Science Foundation of China/ ; 20JCZDJC00550//Tianjin Science and Technology Plan Key Project/ ; }, abstract = {BACKGROUND: Telomeres consist of repetitive DNA sequences at the chromosome ends to protect chromosomal stability, and primarily maintained by telomerase or occasionally by alternative telomere lengthening of telomeres (ALT) through recombination-based mechanisms. Additional mechanisms that may regulate telomere maintenance remain to be explored. Simultaneous measurement of telomere length and transcriptome in the same human embryonic stem cell (hESC) revealed that mRNA expression levels of UBQLN1 exhibit linear relationship with telomere length.
METHODS: In this study, we first generated UBQLN1-deficient hESCs and compared with the wild-type (WT) hESCs the telomere length and molecular change at RNA and protein level by RNA-seq and proteomics. Then we identified the potential interacting proteins with UBQLN1 using immunoprecipitation-mass spectrometry (IP-MS). Furthermore, the potential mechanisms underlying the shortened telomeres in UBQLN1-deficient hESCs were analyzed.
RESULTS: We show that Ubiquilin1 (UBQLN1) is critical for telomere maintenance in human embryonic stem cells (hESCs) via promoting mitochondrial function. UBQLN1 deficiency leads to oxidative stress, loss of proteostasis, mitochondria dysfunction, DNA damage, and telomere attrition. Reducing oxidative damage and promoting mitochondria function by culture under hypoxia condition or supplementation with N-acetylcysteine partly attenuate the telomere attrition induced by UBQLN1 deficiency. Moreover, UBQLN1 deficiency/telomere shortening downregulates genes for neuro-ectoderm lineage differentiation.
CONCLUSIONS: Altogether, UBQLN1 functions to scavenge ubiquitinated proteins, preventing their overloading mitochondria and elevated mitophagy. UBQLN1 maintains mitochondria and telomeres by regulating proteostasis and plays critical role in neuro-ectoderm differentiation.}, }
@article {pmid38900410, year = {2024}, author = {Alarabi, M and Pan, Z and Romero-Gómez, M and George, J and Eslam, M}, title = {Telomere length and mortality in lean MAFLD: the other face of metabolic adaptation.}, journal = {Hepatology international}, volume = {}, number = {}, pages = {}, pmid = {38900410}, issn = {1936-0541}, support = {APP1053206//National Health and Medical Research Council/ ; APP2001692//National Health and Medical Research Council/ ; APP1107178//National Health and Medical Research Council/ ; APP1108422//National Health and Medical Research Council/ ; }, abstract = {BACKGROUND AND AIMS: Healthy weight (lean) patients with metabolic dysfunction-associated fatty liver disease (MAFLD) have a more favorable metabolic and histological profile in cross-sectional studies compared with their non-lean counterparts. Paradoxically, they also have higher overall mortality. The underpinning pathophysiology of this paradox is not understood. Telomere attrition is associated with increased mortality in various diseases.
METHODS: We investigated the role of telomere length in the pathogenesis of lean MAFLD in cohorts with biopsy-proven MAFLD (n = 303). We measured serum malondialdehyde (MDA) levels and hepatic 8-hydroxydeoxyguanosine (8-OHdG) and 4-hydroxy-2-nonenal (4-HNE) expression (reactive oxygen species (ROS) markers), growth/differentiation factor-15 (GDF-15) and tested the effect of H2O2 on telomere length and activity in hepatocyte cell lines. The association between leukocyte telomere length and mortality was examined.
RESULTS: Telomere length was significantly lower in patients with lean MAFLD (p < 0.001). They also demonstrated an increase in ROS levels and decreases in GDF-15. H2O2 induced telomere shortening and reducing telomere activity in hepatocyte cell lines. We subsequently confirmed that telomere length shortening at baseline is associated with increased hazards of all-cause mortality; the deleterious effect was more profound in lean people.
CONCLUSION: Differences in telomere length in part explain the increased mortality of lean compared to non-lean patients with MAFLD. The effect is in part mediated through ROS activation and provide opportunities for therapy.}, }
@article {pmid38899963, year = {2024}, author = {Sheng, Y and Liang, S and Wu, S and Shao, Y and Qiu, X and Liu, S and Huang, D and Pan, D and Wang, L and Juan, JTH and Zeng, X}, title = {Sex-specific effects of maternal blood pressure on newborn telomere length: A prospective study.}, journal = {International journal of gynaecology and obstetrics: the official organ of the International Federation of Gynaecology and Obstetrics}, volume = {}, number = {}, pages = {}, doi = {10.1002/ijgo.15721}, pmid = {38899963}, issn = {1879-3479}, support = {AB17195012//Guangxi Science and Technology Program/ ; 81860587//National Natural Science Foundation of China/ ; GXMUYSF202203//Youth Science Foundation of Guangxi Medical University/ ; }, abstract = {OBJECTIVE: To investigate the relationship between maternal blood pressure (BP) and neonatal cord blood telomere length (TL) during pregnancy, and to clarify the sensitive period.
METHODS: We conducted a prospective cohort study with 621 mother-newborn pairs from the Guangxi Zhuang Birth Cohort (GZBC) in China. Multiple informant models, restricted cubic spline regression (RCS) models, and quantile regression models were conducted to analyze the correlation between maternal BP and neonatal TL.
RESULTS: Maternal diastolic blood pressure (DBP) was inversely related to neonatal cord blood TL in the second trimester (P = 0.015) and the third trimester (P = 0.011). There was a male-specific relationship between maternal BP and neonatal TL. A 1 mmHg increment in maternal systolic blood pressure (SBP) and DBP during the second trimester was related with 0.42% (95% CI: -0.80%, -0.04%) and 0.61% (95% CI: -1.13%, -0.09%) shorter TL in male newborns, respectively. Per unit increase of maternal DBP during the third trimester was related with 0.54% (95% CI: -1.03%, -0.05%) shorter TL in male newborns. Pregnant women with hypertensive disease of pregnancy (HDP) had male offspring with shorter TL (P = 0.003). However, no significant relationships were found in female newborns (P = 0.570).
CONCLUSION: Maternal BP during pregnancy is inversely correlated with male neonatal TL and the second and third trimesters are sensitive windows.}, }
@article {pmid38896081, year = {2024}, author = {Wang, YM and Kaj-Carbaidwala, B and Lane, A and Agarwal, S and Beier, F and Bertuch, A and Borovsky, KA and Brennan, SK and Calado, RT and Catto, LFB and Dufour, C and Ebens, CL and Fioredda, F and Giri, N and Gloude, N and Goldman, F and Hertel, PM and Himes, R and Keel, SB and Koura, DT and Kratz, CP and Kulkarni, S and Liou, I and Nakano, TA and Nastasio, S and Niewisch, MR and Penrice, DD and Sasa, GS and Savage, SA and Simonetto, DA and Ziegler, DS and Miethke, AG and Myers, KC and , }, title = {Liver disease and transplantation in telomere biology disorders: An international multicenter cohort.}, journal = {Hepatology communications}, volume = {8}, number = {7}, pages = {}, doi = {10.1097/HC9.0000000000000462}, pmid = {38896081}, issn = {2471-254X}, mesh = {Humans ; *Liver Transplantation ; Female ; Male ; Retrospective Studies ; Adult ; Middle Aged ; Telomere ; Adolescent ; Liver Diseases/surgery/genetics ; Young Adult ; Child ; Treatment Outcome ; Child, Preschool ; }, abstract = {BACKGROUND: Patients with telomere biology disorders (TBD) develop hepatic disease, including hepatitis, cirrhosis, and hepatopulmonary syndrome. No specific treatment exists for TBD-related liver disease, and the role of liver transplantation (LT) remains controversial. Our study objectives were to describe the clinical characteristics, management, and outcomes in patients with TBD-related liver disease, and their LT outcomes.
METHODS: Data from 83 patients with TBD-associated liver disease were obtained from 17 participating centers in the Clinical Care Consortium of Telomere-Associated Ailments and by self-report for our retrospective, multicenter, international cohort study.
RESULTS: Group A ("Advanced") included 40 patients with advanced liver disease. Of these, 20 underwent LT (Group AT). Group M ("Mild") included 43 patients not warranting LT evaluation, none of whom were felt to be medically unfit for liver transplantation. Supplemental oxygen requirement, pulmonary arteriovenous malformation, hepatopulmonary syndrome, and higher bilirubin and international normalized ratio values were associated with Group A. Other demographics, clinical manifestations, and laboratory findings were similar between groups. Six group A patients were declined for LT; 3 died on the waitlist. Median follow-up post-LT was 2.9 years (range 0.6-13.2 y). One-year survival post-LT was 73%. Median survival post-LT has not been reached. Group AT patients had improved survival by age compared to all nontransplant patients (log-rank test p = 0.02). Of 14 patients with pretransplant hypoxemia, 8 (57%) had improved oxygenation after transplant.
CONCLUSIONS: LT recipients with TBD do not exhibit excessive posttransplant mortality, and LT improved respiratory status in 57%. A TBD diagnosis should not exclude LT consideration.}, }
@article {pmid38896046, year = {2024}, author = {Cianciosi, D and Forbes-Hernandez, T and Armas Diaz, Y and Elexpuru-Zabaleta, M and Quiles, JL and Battino, M and Giampieri, F}, title = {Manuka honey's anti-metastatic impact on colon cancer stem-like cells: unveiling its effects on epithelial-mesenchymal transition, angiogenesis and telomere length.}, journal = {Food & function}, volume = {}, number = {}, pages = {}, doi = {10.1039/d4fo00943f}, pmid = {38896046}, issn = {2042-650X}, abstract = {Colorectal cancer often leads to metastasis, with cancer stem cells (CSCs) playing a pivotal role in this process. Two closely linked mechanisms, epithelial-mesenchymal transition and angiogenesis, contribute to metastasis and recent research has also highlighted the impact of telomere replication on this harmful tumor progression. Standard chemotherapy alone can inadvertently promote drug-resistant CSCs, posing a challenge. Combining chemotherapy with other compounds, including natural ones, shows promise in enhancing effectiveness while minimizing side effects. This study investigated the anti-metastatic potential of Manuka honey, both alone and in combination with 5-fluorouracil, using a 3D model of colonospheres enriched with CSC-like cells. In summary, it was observed that the treatment reduced migration ability by downregulating the transcription factors Slug, Snail, and Twist, which are key players in epithelial-mesenchymal transition. Additionally, Manuka honey downregulated pro-angiogenic factors and shortened CSC telomeres by downregulating c-Myc - demonstrating an effective anti-metastatic potential. This study suggests new research opportunities for studying the impact of natural compounds when combined with pharmaceuticals, with the potential to enhance effectiveness and reduce side effects.}, }
@article {pmid38895181, year = {2024}, author = {Mori, JO and Platz, EA and Lu, J and Brame, A and Han, M and Joshu, CE and De Marzo, AM and Meeker, AK and Heaphy, CM}, title = {Longer prostate stromal cell telomere length is associated with increased risk of death from other cancers.}, journal = {Frontiers in medicine}, volume = {11}, number = {}, pages = {1390769}, pmid = {38895181}, issn = {2296-858X}, abstract = {BACKGROUND: Telomeres are located at chromosomal termini and function to maintain genomic integrity. Telomere dysfunction is a well-recognized contributor to aging and age-related diseases, such as prostate cancer. Since telomere length is highly heritable, we postulate that stromal cell telomere length in the tissue of a particular solid organ may generally reflect constitutive stromal cell telomere length in other solid organs throughout the body. Even with telomere loss occurring with each round of cell replication, in general, telomere length in prostate stromal cells in mid-life would still be correlated with the telomere length in stromal cells in other organs. Thus, we hypothesize that prostate stromal cell telomere length and/or telomere length variability is a potential indicator of the likelihood of developing future solid cancers, beyond prostate cancer, and especially lethal cancer.
METHODS: To explore this hypothesis, we conducted a cohort study analysis of 1,175 men who were surgically treated for prostate cancer and were followed for death, including from causes other than their prostate cancer.
RESULTS: In this cohort study with a median follow-up of 19 years, we observed that longer prostate stromal cell telomere length measured in tissue microarray spots containing prostate cancer was associated with an increased risk of death from other solid cancers. Variability in telomere length among these prostate stromal cells was possibly positively associated with risk of death from other solid cancers.
CONCLUSION: Studying the link between stromal cell telomere length and cancer mortality may be important for guiding the development of cancer interception and prevention strategies.}, }
@article {pmid38892366, year = {2024}, author = {Lohberger, B and Barna, S and Glänzer, D and Eck, N and Leithner, A and Georg, D}, title = {DNA-PKcs Inhibition Sensitizes Human Chondrosarcoma Cells to Carbon Ion Irradiation via Cell Cycle Arrest and Telomere Capping Disruption.}, journal = {International journal of molecular sciences}, volume = {25}, number = {11}, pages = {}, pmid = {38892366}, issn = {1422-0067}, support = {P32103-B//Austrian Science Foundation/ ; }, mesh = {Humans ; *DNA-Activated Protein Kinase/antagonists & inhibitors/metabolism/genetics ; Cell Line, Tumor ; *Chondrosarcoma/metabolism/genetics/radiotherapy/drug therapy ; *Heavy Ion Radiotherapy ; *Telomere/drug effects/metabolism ; Cell Cycle Checkpoints/drug effects/radiation effects ; DNA Repair/drug effects ; Radiation Tolerance/drug effects ; Pyrazoles/pharmacology ; Cell Proliferation/drug effects ; Bone Neoplasms/metabolism/genetics/pathology/drug therapy ; G2 Phase Cell Cycle Checkpoints/drug effects/radiation effects ; }, abstract = {In order to overcome the resistance to radiotherapy in human chondrosarcoma cells, the prevention from efficient DNA repair with a combined treatment with the DNA-dependent protein kinase catalytic subunit (DNA-PKcs) inhibitor AZD7648 was explored for carbon ion (C-ion) as well as reference photon (X-ray) irradiation (IR) using gene expression analysis, flow cytometry, protein phosphorylation, and telomere length shortening. Proliferation markers and cell cycle distribution changed significantly after combined treatment, revealing a prominent G2/M arrest. The expression of the G2/M checkpoint genes cyclin B, CDK1, and WEE1 was significantly reduced by IR alone and the combined treatment. While IR alone showed no effects, additional AZD7648 treatment resulted in a dose-dependent reduction in AKT phosphorylation and an increase in Chk2 phosphorylation. Twenty-four hours after IR, the key genes of DNA repair mechanisms were reduced by the combined treatment, which led to impaired DNA repair and increased radiosensitivity. A time-dependent shortening of telomere length was observed in both cell lines after combined treatment with AZD7648 and 8 Gy X-ray/C-ion IR. Our data suggest that the inhibition of DNA-PKcs may increase sensitivity to X-rays and C-ion IR by impairing its functional role in DNA repair mechanisms and telomere end protection.}, }
@article {pmid38891017, year = {2024}, author = {Deb, S and Berei, J and Miliavski, E and Khan, MJ and Broder, TJ and Akurugo, TA and Lund, C and Fleming, SE and Hillwig, R and Ross, J and Puri, N}, title = {The Effects of Smoking on Telomere Length, Induction of Oncogenic Stress, and Chronic Inflammatory Responses Leading to Aging.}, journal = {Cells}, volume = {13}, number = {11}, pages = {}, pmid = {38891017}, issn = {2073-4409}, support = {Bridge Grant//University of Illinois Chicago, Rockford campus/ ; }, mesh = {Humans ; *Inflammation/genetics/pathology ; *Aging/genetics ; *Telomeric Repeat Binding Protein 2/metabolism/genetics ; *Shelterin Complex ; *Cytokines/metabolism ; *Telomere/metabolism ; *Telomerase/metabolism/genetics ; *Smoking/adverse effects ; Ubiquitins/metabolism/genetics ; Telomere-Binding Proteins/metabolism/genetics ; Interferon-gamma/metabolism ; Telomere Homeostasis ; Male ; Telomere Shortening ; Female ; Middle Aged ; }, abstract = {Telomeres, potential biomarkers of aging, are known to shorten with continued cigarette smoke exposure. In order to further investigate this process and its impact on cellular stress and inflammation, we used an in vitro model with cigarette smoke extract (CSE) and observed the downregulation of telomere stabilizing TRF2 and POT1 genes after CSE treatment. hTERT is a subunit of telomerase and a well-known oncogenic marker, which is overexpressed in over 85% of cancers and may contribute to lung cancer development in smokers. We also observed an increase in hTERT and ISG15 expression levels after CSE treatment, as well as increased protein levels revealed by immunohistochemical staining in smokers' lung tissue samples compared to non-smokers. The effects of ISG15 overexpression were further studied by quantifying IFN-γ, an inflammatory protein induced by ISG15, which showed greater upregulation in smokers compared to non-smokers. Similar changes in gene expression patterns for TRF2, POT1, hTERT, and ISG15 were observed in blood and buccal swab samples from smokers compared to non-smokers. The results from this study provide insight into the mechanisms behind smoking causing telomere shortening and how this may contribute to the induction of inflammation and/or tumorigenesis, which may lead to comorbidities in smokers.}, }
@article {pmid38890299, year = {2024}, author = {Schmidt, TT and Tyer, C and Rughani, P and Haggblom, C and Jones, JR and Dai, X and Frazer, KA and Gage, FH and Juul, S and Hickey, S and Karlseder, J}, title = {High resolution long-read telomere sequencing reveals dynamic mechanisms in aging and cancer.}, journal = {Nature communications}, volume = {15}, number = {1}, pages = {5149}, pmid = {38890299}, issn = {2041-1723}, support = {CA227934//U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/ ; P30CA014195//U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/ ; CA234047//U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/ ; GM142173//U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS)/ ; AG0773424//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; 19PABH134610000//American Heart Association (American Heart Association, Inc.)/ ; ALTF 668-2019//European Molecular Biology Organization (EMBO)/ ; }, mesh = {Humans ; *Telomere/genetics/metabolism ; *Neoplasms/genetics/metabolism ; *Aging/genetics ; Telomerase/genetics/metabolism ; Cell Line, Tumor ; Telomere Shortening/genetics ; Sequence Analysis, DNA/methods ; High-Throughput Nucleotide Sequencing/methods ; Alleles ; }, abstract = {Telomeres are the protective nucleoprotein structures at the end of linear eukaryotic chromosomes. Telomeres' repetitive nature and length have traditionally challenged the precise assessment of the composition and length of individual human telomeres. Here, we present Telo-seq to resolve bulk, chromosome arm-specific and allele-specific human telomere lengths using Oxford Nanopore Technologies' native long-read sequencing. Telo-seq resolves telomere shortening in five population doubling increments and reveals intrasample, chromosome arm-specific, allele-specific telomere length heterogeneity. Telo-seq can reliably discriminate between telomerase- and ALT-positive cancer cell lines. Thus, Telo-seq is a tool to study telomere biology during development, aging, and cancer at unprecedented resolution.}, }
@article {pmid38890274, year = {2024}, author = {Sanchez, SE and Gu, Y and Wang, Y and Golla, A and Martin, A and Shomali, W and Hockemeyer, D and Savage, SA and Artandi, SE}, title = {Digital telomere measurement by long-read sequencing distinguishes healthy aging from disease.}, journal = {Nature communications}, volume = {15}, number = {1}, pages = {5148}, pmid = {38890274}, issn = {2041-1723}, mesh = {Humans ; *Telomere/genetics/metabolism ; *Telomere Homeostasis/genetics ; *Machine Learning ; Adult ; Healthy Aging/genetics ; Middle Aged ; Male ; Aged ; Female ; Telomere Shortening/genetics ; Aging/genetics ; Nanopore Sequencing/methods ; Young Adult ; }, abstract = {Telomere length is an important biomarker of organismal aging and cellular replicative potential, but existing measurement methods are limited in resolution and accuracy. Here, we deploy digital telomere measurement (DTM) by nanopore sequencing to understand how distributions of human telomere length change with age and disease. We measure telomere attrition and de novo elongation with up to 30 bp resolution in genetically defined populations of human cells, in blood cells from healthy donors and in blood cells from patients with genetic defects in telomere maintenance. We find that human aging is accompanied by a progressive loss of long telomeres and an accumulation of shorter telomeres. In patients with defects in telomere maintenance, the accumulation of short telomeres is more pronounced and correlates with phenotypic severity. We apply machine learning to train a binary classification model that distinguishes healthy individuals from those with telomere biology disorders. This sequencing and bioinformatic pipeline will advance our understanding of telomere maintenance mechanisms and the use of telomere length as a clinical biomarker of aging and disease.}, }
@article {pmid38886039, year = {2024}, author = {Alcock, LJ and Sudhakar, HK and Young, R and Lau, YH}, title = {Fluorescence polarization assay for screening FANCM-RMI inhibitors to target the alternative lengthening of telomeres.}, journal = {Methods in enzymology}, volume = {698}, number = {}, pages = {361-378}, doi = {10.1016/bs.mie.2024.04.014}, pmid = {38886039}, issn = {1557-7988}, mesh = {Humans ; *Fluorescence Polarization/methods ; *Telomere Homeostasis/drug effects ; Protein Binding ; Telomere/metabolism/genetics ; DNA Helicases ; }, abstract = {Alternative Lengthening of Telomeres (ALT) is a mechanism used by 10-15% of all cancers to achieve replicative immortality, bypassing the DNA damage checkpoint associated with short telomeres that leads to cellular senescence or apoptosis. ALT does not occur in non-cancerous cells, presenting a potential therapeutic window for cancers where this mechanism is active. Disrupting the FANCM-RMI interaction has emerged as a promising therapeutic strategy that induces synthetic ALT lethality in genetic studies on cancer cell lines. There are currently no chemical inhibitors reported in the literature, in part due to the lack of reliable biophysical or biochemical assays to screen for FANCM-RMI disruption. Here we describe the development of a robust competitive fluorescence polarization (FP) assay that quantifies target binding at the FANCM-RMI interface. The assay employs a labeled peptide tracer TMR-RaMM2 derived from the native MM2 binding motif, which binds to recombinant RMI1-RMI2 and can be displaced by competitive inhibitors. We report the methods for recombinant production of RMI1-RMI2, design and evaluation of the tracer TMR-RaMM2, along with unlabeled peptide inhibitor controls to enable ALT-targeted drug discovery.}, }
@article {pmid38886520, year = {2024}, author = {Chung, HG and Yang, PS and Cho, S and Jang, E and Kim, D and Yu, HT and Kim, TH and Uhm, JS and Sung, JH and Pak, HN and Lee, MH and Joung, B}, title = {The associations of leukocyte telomere length and intermediary cardiovascular phenotype with adverse cardiovascular outcomes in the white population.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {13975}, pmid = {38886520}, issn = {2045-2322}, abstract = {The evidence about the associations of leukocyte telomere length (LTL) and intermediary cardiovascular phenotypes with adverse cardiovascular outcomes is inconclusive. This study assessed these relationships with cardiovascular imaging, electrocardiography, and the risks of sudden cardiac death (SCD), coronary events, and heart failure (HF) admission. We conducted a cross-sectional analysis of UK Biobank participants enrolled between 2006 and 2010. LTL was measured using quantitative polymerase chain reactions. Electronic health records were used to determine the incidence of SCD, coronary events, and HF admission. Cardiovascular measurements were made using cardiovascular magnetic resonance imaging and machine learning. The associations of LTL with SCD, coronary events, and HF admission and cardiac magnetic resonance imaging, electrocardiogram parameters of 33,043 and 19,554 participants were evaluated by multivariate regression. The median (interquartile range) follow-up period was 11.9 (11.2-12.6) years. Data was analyzed from January to May 2023. Among the 403,382 white participants without coronary artery disease or HF, 181,637 (45.0%) were male with a mean age of 57.1 years old. LTL was independently negatively associated with a risk of SCD (LTL third quartile vs first quartile: hazard ratio [HR]: 0.81, 95% confidence interval [CI]: 0.72-0.92), coronary events (LTL third quartile vs first quartile: HR: 0.88, 95% CI: 0.84-0.92), and HF admission (LTL fourth quartile vs first quartile: HR: 0.84, 95% CI: 0.74-0.95). LTL was also independently positively associated with cardiac remodeling, specifically left ventricular mass index, left-ventricular-end systolic and diastolic volumes, mean left ventricular myocardial wall thickness, left ventricular stroke volume, and with electrocardiogram changes along the negative degree of T-axis. Cross-sectional study results showed that LTL was positively associated with heart size and cardiac function in middle age, but electrocardiography results did not show these associations, which could explain the negative association between LTL and risk of SCD, coronary events, and HF admission in UK Biobank participants.}, }
@article {pmid38884214, year = {2024}, author = {Khayat, F and Alshmery, M and Pal, M and Oliver, AW and Bianchi, A}, title = {Binding of the TRF2 iDDR motif to RAD50 highlights a convergent evolutionary strategy to inactivate MRN at telomeres.}, journal = {Nucleic acids research}, volume = {}, number = {}, pages = {}, doi = {10.1093/nar/gkae509}, pmid = {38884214}, issn = {1362-4962}, support = {C302/A24386/CRUK_/Cancer Research UK/United Kingdom ; //University of Sussex/ ; }, abstract = {Telomeres protect chromosome ends from unscheduled DNA repair, including from the MRN (MRE11, RAD50, NBS1) complex, which processes double-stranded DNA breaks (DSBs) via activation of the ATM kinase, promotes DNA end-tethering aiding the non-homologous end-joining (NHEJ) pathway, and initiates DSB resection through the MRE11 nuclease. A protein motif (MIN, for MRN inhibitor) inhibits MRN at budding yeast telomeres by binding to RAD50 and evolved at least twice, in unrelated telomeric proteins Rif2 and Taz1. We identify the iDDR motif of human shelterin protein TRF2 as a third example of convergent evolution for this telomeric mechanism for binding MRN, despite the iDDR lacking sequence homology to the MIN motif. CtIP is required for activation of MRE11 nuclease action, and we provide evidence for binding of a short C-terminal region of CtIP to a RAD50 interface that partly overlaps with the iDDR binding site, indicating that the interaction is mutually exclusive. In addition, we show that the iDDR impairs the DNA binding activity of RAD50. These results highlight direct inhibition of MRN action as a crucial role of telomeric proteins across organisms and point to multiple mechanisms enforced by the iDDR to disable the many activities of the MRN complex.}, }
@article {pmid38883734, year = {2024}, author = {Skåra, KH and Lee, Y and Jugessur, A and Gjessing, HK and Aviv, A and Brumpton, B and Naess, Ø and Hernáez, Á and Hanevik, HI and Magnus, P and Magnus, MC}, title = {Telomere length in relation to fecundability and use of assisted reproductive technologies: the Norwegian Mother, Father, and Child Cohort Study.}, journal = {Research square}, volume = {}, number = {}, pages = {}, doi = {10.21203/rs.3.rs-4430021/v1}, pmid = {38883734}, abstract = {In women, shorter telomeres have been reported to be associated with conditions such as endometriosis and polycystic ovary syndrome, whereas other studies have reported the opposite. In men, studies mostly report associations between shorter telomeres and sperm quality. To our knowledge, no studies have thus far investigated the associations between TL and fecundability or the use of ART. This study is based on the Norwegian Mother, Father, and Child Cohort (MoBa) Study and uses data from the Medical Birth Registry of Norway (MBRN). We included women (24,645 with genotype data and 1,054 with TL measurements) and men (18,339 with genotype data and 965 with TL measurements) participating between 1998 and 2008. We investigated the associations between leukocyte TL and fecundability, infertility, and the use of ART. We also repeated the analyses using instrumental variables for TL, including genetic risk scores for TL and genetically predicted TL. Approximately 11% of couples had experienced infertility and 4% had used ART. TL was not associated with fecundability among women (fecundability ratio [FR], 0.98; 95% confidence interval [CI], 0.92-1.04) or men (FR, 0.99; CI, 0.93-1.06), nor with infertility among women (odds ratio [OR], 1.03; CI, 0.85-1.24) or men (OR, 1.05; CI, 0.87-1.28). We observed an increased likelihood of using ART with increasing TL among men (OR, 1.22; CI, 1.03-1.46), but not among women (OR, 1.10; CI, 0.92-1.31). No significant associations were observed using the instrumental variables. Our results indicate that TL is a poor biomarker of fecundability, infertility and use of ART in MoBa. Additional studies are required to replicate the association observed between TL and ART in men.}, }
@article {pmid38883396, year = {2024}, author = {Castro, A and Lardone, MC and Giraudo, F and López, P and Ortiz, E and Iñiguez, G and Cassorla, F and Codner, E}, title = {Differential Effect of 2 Hormonal Contraceptives on the Relative Telomere Length of Youth With Type 1 Diabetes.}, journal = {Journal of the Endocrine Society}, volume = {8}, number = {7}, pages = {bvae091}, pmid = {38883396}, issn = {2472-1972}, abstract = {CONTEXT: Adolescents and young women (AYA) with type 1 diabetes (T1D) may require hormonal contraception for an extended period. However, it is unclear what effect hormonal contraception has on telomere length, a marker of the risk for complications.
OBJECTIVE: To investigate the relative telomere length (RTL) in AYA with T1D (AYA-T1D) and healthy young women (AYA-C) after 18 months of combined oral contraception use (COC) with ethinyl estradiol/desogestrel, or a subdermal etonogestrel implant (IM).
METHODS: A nonrandomized prospective study was performed in which 39 AYA-T1D and 40 AYA-C chose the COC or the IM. RTL was measured by monochrome multiplex-quantitative PCR in DNA from peripheral blood mononuclear cells (PBMC). The impact of contraceptives and clinical variables on RTL was assessed using lineal regression analysis.
RESULTS: Longer RTL compared to baseline was observed in AYA-T1D (P < .05) and AYA-C (P < .01) after using the IM. However, the total of AYA and the AYA-C group treated with COC decreased RTL after 18 months of treatment compared to baseline (P < .05). The type of contraceptive used was determinant for the changes in RTL compared to baseline in all subjects and controls (P ≤ .006). For AYA-T1D, HbA1c levels were not associated with RTL, but the high-sensitivity C-reactive protein was negatively related with the changes in RTL at 18 months compared to baseline (standardized R[2] : 0.230, P = .003).
CONCLUSION: IM was associated with longer RTL in AYA-T1D and AYA-C. In contrast, a shortening of telomere length in PBMC was observed after using COC.}, }
@article {pmid38883331, year = {2024}, author = {Song, Y and Zhang, Y and Wang, X and Yu, X and Liao, Y and Zhang, H and Li, L and Wang, Y and Liu, B and Li, W}, title = {Telomere-to-telomere reference genome for Panax ginseng highlights the evolution of saponin biosynthesis.}, journal = {Horticulture research}, volume = {11}, number = {6}, pages = {uhae107}, pmid = {38883331}, issn = {2662-6810}, abstract = {Ginseng (Panax ginseng) is a representative of Chinese traditional medicine, also used worldwide, while the triterpene saponin ginsenoside is the most important effective compound within it. Ginseng is an allotetraploid, with complex genetic background, making the study of its metabolic evolution challenging. In this study, we assembled a telomere-to-telomere ginseng reference genome, constructed of 3.45 Gb with 24 chromosomes and 77 266 protein-coding genes. Additionally, the reference genome was divided into two subgenomes, designated as subgenome A and B. Subgenome A contains a larger number of genes, whereas subgenome B has a general expression advantage, suggesting that ginseng subgenomes experienced asymmetric gene loss with biased gene expression. The two subgenomes separated approximately 6.07 million years ago, and subgenome B shows the closest relation to Panax vietnamensis var. fuscidiscus. Comparative genomics revealed an expansion of gene families associated with ginsenoside biosynthesis in both ginseng subgenomes. Furthermore, both tandem duplications and proximal duplications play crucial roles in ginsenoside biosynthesis. We also screened functional genes identified in previous research and found that some of these genes located in colinear regions between subgenomes have divergence functions, revealing an unbalanced evolution in both subgenomes and the saponin biosynthesis pathway in ginseng. Our work provides important resources for future genetic studies and breeding programs of ginseng, as well as the biosynthesis of ginsenosides.}, }
@article {pmid38882679, year = {2024}, author = {Zhang, J and Wen, J and Dai, Z and Zhang, H and Zhang, N and Lei, R and Liu, Z and Peng, L and Cheng, Q}, title = {Causal association and shared genetics between telomere length and COVID-19 outcomes: New evidence from the latest large-scale summary statistics.}, journal = {Computational and structural biotechnology journal}, volume = {23}, number = {}, pages = {2429-2441}, pmid = {38882679}, issn = {2001-0370}, abstract = {BACKGROUND: Observational studies suggested that leukocyte telomere length (LTL) is shortened in COVID-19 patients. However, the genetic association and causality remained unknown.
METHODS: Based on the genome-wide association of LTL (N = 472,174) and COVID-19 phenotypes (N = 1086,211-2597,856), LDSC and SUPERGNOVA were used to estimate the genetic correlation. Cross-trait GWAS meta-analysis, colocalization, fine-mapping analysis, and transcriptome-wide association study were conducted to explore the shared genetic etiology. Mendelian randomization (MR) was utilized to infer the causality. Upstream and downstream two-step MR was performed to investigate the potential mediating effects.
RESULTS: LDSC identified a significant genetic association between LTL and all COVID-19 phenotypes (rG < 0, p < 0.05). Six significant regions were observed for LTL and COVID-19 susceptibility and hospitalization, respectively. Colocalization analysis found rs144204502, rs34517439, and rs56255908 were shared causal variants between LTL and COVID-19 phenotypes. Numerous biological pathways associated with LTL and COVID-19 outcomes were identified, mainly involved in -immune-related pathways. MR showed that longer LTL was significantly associated with a lower risk of COVID-19 severity (OR [95% CI] = 0.81 [0.71-0.92], p = 1.24 ×10[-3]) and suggestively associated with lower risks of COVID-19 susceptibility (OR [95% CI] = 0.96 [0.92-1.00], p = 3.44 ×10[-2]) and COVID-19 hospitalization (OR [95% CI] = 0.89 [0.80-0.98], p = 1.89 ×10[-2]). LTL partially mediated the effects of BMI, smoking, and education on COVID-19 outcomes. Furthermore, six proteins partially mediated the causality of LTL on COVID-19 outcomes, including BNDF, QPCT, FAS, MPO, SFTPB, and APOF.
CONCLUSIONS: Our findings suggested that shorter LTL was genetically associated with a higher risk of COVID-19 phenotypes, with shared genetic etiology and potential causality.}, }
@article {pmid38882488, year = {2024}, author = {Wei, C and Gao, L and Xiao, R and Wang, Y and Chen, B and Zou, W and Li, J and Mace, E and Jordan, D and Tao, Y}, title = {Complete telomere-to-telomere assemblies of two sorghum genomes to guide biological discovery.}, journal = {iMeta}, volume = {3}, number = {2}, pages = {e193}, pmid = {38882488}, issn = {2770-596X}, abstract = {The assembly of two sorghum T2T genomes corrected the assembly errors in the current reference, uncovered centromere variation, boosted functional genomics research, and accelerated sorghum improvement.}, }
@article {pmid38879916, year = {2024}, author = {Li, X and Li, M and Cheng, J and Guan, S and Hou, L and Zu, S and Yang, L and Wu, H and Li, H and Fan, Y and Zhang, B}, title = {Association of healthy and unhealthy plant-based diets with telomere length.}, journal = {Clinical nutrition (Edinburgh, Scotland)}, volume = {43}, number = {8}, pages = {1694-1701}, doi = {10.1016/j.clnu.2024.06.004}, pmid = {38879916}, issn = {1532-1983}, abstract = {BACKGROUND & AIMS: Previous studies have shown that plant-rich dietary patterns, such as the Mediterranean diet, are associated with longer telomeres. However, no association has been found between vegetarian diet and telomere length. We hypothesized that the quality of plant-based diets plays an important role in telomere length.
METHODS: Data were obtained from the National Health and Nutrition Examination Survey 1999-2002. Diet was assessed using a 24-h recall method. Plant-based diet quality was assessed using the overall plant-based diet index (PDI), healthy PDI (hPDI), and unhealthy PDI (uPDI). Telomere length was measured using quantitative PCR. Linear and ordinal logistic regression models were used to assess the association of PDIs with log-transformed telomere length and ordinal quintiles of telomere length in descending order, respectively.
RESULTS: In both regression models, the overall PDI was not associated with telomere length. The hPDI was associated with longer telomere length [percentage change = 2.34%, 95% confidence interval (CI): 0.42%, 4.31%, Ptrend = 0.016; odds ratio (OR) = 0.81, 95% CI: 0.69, 0.95, Ptrend = 0.013]. However, uPDI was associated with shorter telomere length (percentage change = -3.17%, 95% CI: -5.65%, -0.62%, Ptrend = 0.017; OR = 1.25, 95% CI:1.03, 1.53, Ptrend = 0.014) and this inverse association was stronger in the non-Hispanic white population (Pinteraction = 0.001 in both regression models).
CONCLUSIONS: A plant-based dietary pattern rich in healthy plant foods is associated with longer telomeres. However, plant-based dietary patterns rich in unhealthy plant-based foods are associated with shorter telomere lengths, especially in non-Hispanic white populations.}, }
@article {pmid38875394, year = {2024}, author = {Fu, Y and Lou, H and Chen, Q and Wu, S and Chen, H and Liang, K and Ge, Y and Zhao, C}, title = {Objective assessment of the association between telomere length, a biomarker of aging, and health screening indicators: A cross-sectional study.}, journal = {Medicine}, volume = {103}, number = {24}, pages = {e38533}, doi = {10.1097/MD.0000000000038533}, pmid = {38875394}, issn = {1536-5964}, mesh = {Humans ; Cross-Sectional Studies ; Male ; Female ; Middle Aged ; *Aging/genetics/physiology ; Adult ; Aged ; *Telomere ; *Biomarkers/blood ; Young Adult ; Physical Examination/methods ; Aged, 80 and over ; Health Status ; Health Status Indicators ; }, abstract = {Physical examination data are used to indicate individual health status and organ health, and understanding which physical examination data are indicative of physiological aging is critical for health management and early intervention. There is a lack of research on physical examination data and telomere length. Therefore, the present study analyzed the association between blood telomere length and physical examination indices in healthy people of different ages to investigate the role and association of various organs/systems with physiological aging in the human body. The present study was a cross-sectional study. Sixteen physical examination indicators of different tissue and organ health status were selected and analyzed for trends in relation to actual age and telomere length (TL). The study included 632 individuals with a total of 11,766 data for 16 physical examination indicators. Age was linearly correlated with 11 indicators. Interestingly, telomere length was strongly correlated only with the renal indicators eGFR (P < .001), CYS-C (P < .001), and SCR (P < .001). The study established that renal aging or injury is a risk factor for Physical aging of the human body. Early identification and management are essential to healthcare.}, }
@article {pmid38875139, year = {2024}, author = {Gillooly, JF and Khazan, ES}, title = {Telomeres and the Rate of Living: Linking Biological Clocks of Senescence.}, journal = {Ecological and evolutionary physiology}, volume = {97}, number = {3}, pages = {157-163}, doi = {10.1086/730588}, pmid = {38875139}, issn = {2993-7973}, mesh = {Animals ; *Telomere/metabolism ; *Aging/genetics/physiology ; *Biological Clocks/physiology/genetics ; Telomere Shortening ; Longevity/genetics/physiology ; Energy Metabolism/physiology ; Vertebrates/genetics/physiology ; }, abstract = {AbstractTwo prominent theories of aging, one based on telomere dynamics and the other on mass-specific energy flux, propose biological time clocks of senescence. The relationship between these two theories, and the biological clocks proposed by each, remains unclear. Here, we examine the relationships between telomere shortening rate, mass-specific metabolic rate, and lifespan among vertebrates (mammals, birds, fishes). Results show that telomere shortening rate increases linearly with mass-specific metabolic rate and decreases nonlinearly with increasing body mass in the same way as mass-specific metabolic rate. Results also show that both telomere shortening rate and mass-specific metabolic rate are similarly related to lifespan and that both strongly predict differences in lifespan, although the slopes of the relationships are less than linear. On average, then, telomeres shorten a fixed amount per unit of mass-specific energy flux. So the mitotic clock of telomere shortening and the energetics-based clock described by metabolic rate can be viewed as alternative measures of the same biological clock. These two processes may be linked, we speculate, through the process of cell division.}, }
@article {pmid38869742, year = {2024}, author = {Wang, Q and Xi, L and Yang, N and Song, J and Taiwaikul, D and Zhang, X and Bo, Y and Tang, B and Zhou, X}, title = {Association of leukocyte telomere length with risk of all-cause and cardiovascular mortality in middle-aged and older individuals without cardiovascular disease: a prospective cohort study of NHANES 1999-2002.}, journal = {Aging clinical and experimental research}, volume = {36}, number = {1}, pages = {131}, pmid = {38869742}, issn = {1720-8319}, support = {82060069//National Natural Science Foundation of China/ ; }, mesh = {Humans ; *Cardiovascular Diseases/mortality/genetics ; Male ; Middle Aged ; *Leukocytes/metabolism ; Female ; *Nutrition Surveys ; Prospective Studies ; *Telomere/genetics ; Aged ; Risk Factors ; }, abstract = {BACKGROUND: Leukocyte telomere length (LTL) shorting was significantly associated with mortality. This study aimed to investigate the potential association between LTL and all-cause mortality as well as cardiovascular disease (CVD) mortality in middle-aged or older individuals without a history of CVD.
METHODS: A total of 4174 participants from the National Health and Nutrition Examination Survey (NHANES) conducted between 1999 and 2002 were included in this analysis. Cox proportional hazards regression models were utilized to estimate the association between LTL and mortality outcomes. Restricted cubic spline (RCS) curves were employed to evaluate the potential non-linear association.
RESULTS: Over a median follow-up period of 217 months, the weighted rates of all-cause mortality and CVD mortality were 28.58% and 8.32% respectively. Participants in the highest LTL group exhibited a significantly decreased risk of both all-cause mortality (HR: 0.65, 95% CI: 0.54-0.78, P < 0.001) and CVD mortality (HR: 0.64, 95% CI: 0.45-0.93, P < 0.001) compared to those in the lowest group. Kaplan-Meier survival curves further supported a significant association between shorter telomere length and increased risks of both all-cause and CVD mortality (log-rank test P < 0.001). RCS curves demonstrated a linear dose-response relationship between LTL and all-cause mortality as well as CVD mortality. Subgroup and sensitivity analyses confirmed the robustness of the results.
CONCLUSION: Shorter leukocyte telomere length could serve as a potential biomarker for risk stratification of all-cause and CVD mortality among middle-aged and older individuals without a history of CVD.}, }
@article {pmid38865824, year = {2024}, author = {Du, B and Liu, B and Fang, YK and Zheng, JZ and Wu, J and Tao, FZ and Zhang, MY and Zhang, TJ}, title = {Shugan Tongluo Qiangjing recipe protects against varicocele of EVC rats through modulating sperm DNA damage, telomere expression and oxidative stress.}, journal = {Tissue & cell}, volume = {89}, number = {}, pages = {102414}, doi = {10.1016/j.tice.2024.102414}, pmid = {38865824}, issn = {1532-3072}, abstract = {Varicocele (VC) refers to expansion and tortuosity of spreading venous plexus in spermatic cord due to poor blood flow. This study aimed to investigate effects of Shugan Tongluo Qiangjing recipe (SGTL) on sperm DNA damage and oxidative stress in experimental VC (EVC) rats. EVC model was established by partial ligation of left renal vein. Spermatic vein diameter, testicular weight, sperm DNA fragmentation index (DFI) were evaluated. Telomere reverse transcriptase (TERT) expression, telomere gene transcription, and testicular tissue morphology were determined·H2O2, catalase, SOD, T-AOC were measured with colorimetry. SGTL significantly decreased spermatic vein diameter (P=0.000) and increased testicular weight (P=0.013) of rats compared those of EVC rats. SGTL maintained testicular tissue morphology in EVC rats. SGTL markedly reduced sperm DFI value in sperm of rats compared to EVC rats (P=0.000). SGTL significantly enhanced TERT expression and telomere gene transcription (P=0.028) in testis of rats compared to EVC rats. SGTL reduced H2O2 levels (P=0.001) and promoted CAT activity (P=0.016), SOD activity (P=0.049), and T-AOC activity (P=0.047) of rats, compared to EVC rats. In conclusion, SGTL could reduce pathogenic process of EVC by reducing sperm DNA damage and regulating telomere length in EVC rats, which may be related to oxidative stress regulation.}, }
@article {pmid38865460, year = {2024}, author = {Bettin, N and Querido, E and Gialdini, I and Grupelli, GP and Goretti, E and Cantarelli, M and Andolfato, M and Soror, E and Sontacchi, A and Jurikova, K and Chartrand, P and Cusanelli, E}, title = {TERRA transcripts localize at long telomeres to regulate telomerase access to chromosome ends.}, journal = {Science advances}, volume = {10}, number = {24}, pages = {eadk4387}, doi = {10.1126/sciadv.adk4387}, pmid = {38865460}, issn = {2375-2548}, mesh = {*Telomerase/metabolism/genetics ; Humans ; *Telomere/metabolism/genetics ; Telomere Homeostasis ; HeLa Cells ; RNA/metabolism/genetics ; Transcription, Genetic ; Telomere-Binding Proteins/metabolism/genetics ; Cell Cycle/genetics ; Chromosomes, Human/metabolism/genetics ; DNA-Binding Proteins ; Transcription Factors ; }, abstract = {The function of TERRA in the regulation of telomerase in human cells is still debated. While TERRA interacts with telomerase, how it regulates telomerase function remains unknown. Here, we show that TERRA colocalizes with the telomerase RNA subunit hTR in the nucleoplasm and at telomeres during different phases of the cell cycle. We report that TERRA transcripts relocate away from chromosome ends during telomere lengthening, leading to a reduced number of telomeric TERRA-hTR molecules and consequent increase in "TERRA-free" telomerase molecules at telomeres. Using live-cell imaging and super-resolution microscopy, we show that upon transcription, TERRA relocates from its telomere of origin to long chromosome ends. Furthermore, TERRA depletion by antisense oligonucleotides promoted hTR localization to telomeres, leading to increased residence time and extended half-life of hTR molecules at telomeres. Overall, our findings indicate that telomeric TERRA transcripts inhibit telomere elongation by telomerase acting in trans, impairing telomerase access to telomeres that are different from their chromosome end of origin.}, }
@article {pmid38863926, year = {2024}, author = {Yang, S and Wang, X and Li, Y and Zhou, L and Guo, G and Wu, M}, title = {The association between telomere length and blood lipids: a bidirectional two-sample Mendelian randomization study.}, journal = {Frontiers in endocrinology}, volume = {15}, number = {}, pages = {1338698}, pmid = {38863926}, issn = {1664-2392}, mesh = {Humans ; *Mendelian Randomization Analysis ; *Genome-Wide Association Study ; *Lipids/blood ; Cholesterol, LDL/blood ; Triglycerides/blood ; Telomere/genetics ; Cholesterol, HDL/blood ; Polymorphism, Single Nucleotide ; Telomere Homeostasis ; Apolipoprotein A-I/blood/genetics ; }, abstract = {BACKGROUND: Observational studies suggest an association between telomere length (TL) and blood lipid (BL) levels. Nevertheless, the causal connections between these two traits remain unclear. We aimed to elucidate whether genetically predicted TL is associated with BL levels via Mendelian randomization (MR) and vice versa.
METHODS: We obtained genetic instruments associated with TL, triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), apolipoprotein A-1 (ApoA-1) and apolipoprotein B (ApoB) from large-scale genome-wide association studies (GWASs). The causal relationships between TL and BL were investigated via bidirectional MR, multivariable MR and mediation analysis methods. The inverse variance weighted (IVW) method was employed as the principal methodology, complemented by several other estimators to enhance the robustness of the analysis.
RESULTS: In the forward MR analyses, we identified significant positive correlation between genetically predicted TL and the levels of TG (β=0.04, 95% confidence interval [CI]: 0.01 to 0.06, p = 0.003). In the reverse MR analysis, TG (β=0.02, 95% CI: 0.01 to 0.03, p = 0.004), LDL-C (β=0.03, 95% CI: 0.01 to 0.04, p = 0.001) and ApoB (β=0.03, 95% CI: 0.01 to 0.04, p = 9.71×10[-5]) were significantly positively associated with TL, although this relationship was not observed in the multivariate MR analysis. The mediation analysis via two-step MR showed no significant mediation effects acting through obesity-related phenotypes in analysis of TL with TG, while the effect of LDL-C on TL was partially mediated by body mass index (BMI) in the reverse direction, with mediated proportion of 12.83% (95% CI: 0.62% to 25.04%).
CONCLUSIONS: Our study indicated that longer TL were associated with higher TG levels, while conversely, higher TG, LDL-C, and ApoB levels predicted longer TL, with BMI partially mediating these effects. Our findings present valuable insights into the development of preventive strategies and interventions that specifically target TL-related aging and age-related diseases.}, }
@article {pmid38857178, year = {2024}, author = {Asim Javed, M and Mukhopadhyay, S and Normandeau, E and Brochu, AS and Pérez-López, E}, title = {Telomere-to-telomere genome assembly of the clubroot pathogen Plasmodiophora brassicae.}, journal = {Genome biology and evolution}, volume = {}, number = {}, pages = {}, doi = {10.1093/gbe/evae122}, pmid = {38857178}, issn = {1759-6653}, abstract = {Plasmodiophora brassicae (Woronin, 1877), a biotrophic, obligate parasite, is the causal agent of clubroot disease in brassicas. The clubroot pathogen has been reported in more than 80 countries worldwide, causing economic losses of hundreds of millions every year. Despite its widespread impact, very little is known about the molecular strategies it employs to induce the characteristic clubs in the roots of susceptible hosts during infection, nor about the mechanisms it uses to overcome genetic resistance. Here, we provide the first telomere-to-telomere complete genome of Plasmodiophora brassicae. We generated ∼ 27 Gb of Illumina, Oxford Nanopore, and PacBio HiFi data from resting spores of strain Pb3A and produced a 25.3 Mb assembly comprising 20 chromosomes, with an N50 of 1.37 Mb. The BUSCO score, the highest reported for any member of the group Rhizaria (Eukaryota: 88.2%), highlights the limitations within the Eukaryota database for members of this lineage. Using available transcriptomic data and protein evidence, we annotated the Pb3A genome, identifying 10,521 protein-coding gene models. This high-quality, complete genome of Plasmodiophora brassicae will serve as a crucial resource for the plant pathology community to advance the much-needed understanding of the evolution of the clubroot pathogen.}, }
@article {pmid38856709, year = {2024}, author = {Vieira, RA and Nunes, DP and Lima, DB and Rocha, GDS and Corona, LP and Santos-Orlandi, AAD and Sampaio, ES and Rodrigues, PCOG and de Brito, TRP}, title = {Association between telomere length and anorexia of ageing: a cross-sectional study conducted with community-dwelling older people.}, journal = {Journal of human nutrition and dietetics : the official journal of the British Dietetic Association}, volume = {}, number = {}, pages = {}, doi = {10.1111/jhn.13338}, pmid = {38856709}, issn = {1365-277X}, support = {//Fundação de Amparo à Pesquisa do Estado de Minas Gerais - FAPEMIG/ ; //Conselho Nacional de Desenvolvimento Científico e Tecnológico/ ; }, abstract = {BACKGROUND: To verify whether shorter telomere length is associated with anorexia of ageing in community-dwelling older people.
METHODS: Conducted as a cross-sectional investigation, the study enrolled 448 participants residing in an urban area of a municipality in Brazil. Relative telomere length in blood samples was measured using quantitative polymerase chain reaction (qPCR), whereas the presence of anorexia of ageing was determined using the Simplified Appetite Nutritional Questionnaire. Data analysis employed multiple logistic regression.
RESULTS: Among the 448 older individuals surveyed, 70.69% were female, and the predominant age bracket ranged from 60 to 69 years (45.08%). Approximately 25% exhibited the shortest telomeric length, with a corresponding anorexia of ageing prevalence of 41.16%. Older individuals with diminished telomere lengths displayed an increased likelihood of experiencing anorexia of ageing (odds ratio [OR] = 1.92; 95% confidence interval [CI] = 1.12-3.29), independent of factors such as gender, age group, depressive symptoms, pain and performance in basic daily life activities.
CONCLUSIONS: The observed association between anorexia of ageing and a telomeric biomarker underscores the imperative to meticulously evaluate the nutritional dimensions of older people, with a view to implementing interventions that may enhance their overall health status.}, }
@article {pmid38851349, year = {2024}, author = {Colominas-Ciuró, R and Gray, FE and Arikan, K and Zahn, S and Meier, C and Criscuolo, F and Bize, P}, title = {Effects of persistent organic pollutants on telomere dynamics are sex and age-specific in a wild long-lived bird.}, journal = {The Science of the total environment}, volume = {}, number = {}, pages = {173785}, doi = {10.1016/j.scitotenv.2024.173785}, pmid = {38851349}, issn = {1879-1026}, abstract = {Chemical pollution is a major man-made environmental threat to ecosystems and natural animal populations. Of concern are persistent organic pollutants (POPs), which can persist in the environment for many years. While bioaccumulating throughout the lives of wild animals, POPs can affect their health, reproduction, and survival. However, measuring long-term effects of POPs in wild populations is challenging, and therefore appropriate biomarkers are required in wildlife ecotoxicology. One potential target is telomere length, since telomere preservation has been associated to survival and longevity, and stressors as chemical pollution can disrupt its maintenance. Here, we investigated the effects of different classes of POPs on relative telomere length (RTL) and its rate of change (TROC) in wild long-lived Alpine swifts (Tachymarptis melba). As both RTL and TROC are often reported to differ between sexes and with chronological age, we tested for sex- and age-specific (pre-senescent vs. senescent, ≥ 9 age of years, individuals) effects of POPs. Our results showed that senescent females presented longer RTL and elongated telomeres over time compared to pre-senescent females and males. These sex- and age-related differences in RTL and TROC were influenced by POPs, but differently depending on whether they were organochlorine pesticides (OCPs) or industrial polychlorinated biphenyls (PCBs). OCPs (particularly drins) were negatively associated with RTL, with the strongest negative effects being found in senescent females. Conversely, PCBs led to slower rates of telomere shortening, especially in females. Our study indicates diametrically opposed effects of OCPs on RTL and PCBs on TROC, and these effects were more pronounced in females and senescent individuals. The mechanisms behind these effects (e.g., increased oxidative stress by OCPs; upregulation of telomerase activity by PCBs) remain unknown. Our results highlight the importance in wildlife ecotoxicology to account for sex- and age-related effects when investigating the health effects of pollutants on biomarkers such as telomeres.}, }
@article {pmid38849401, year = {2024}, author = {Sánchez-Ortí, JV and Correa-Ghisays, P and Balanzá-Martínez, V and Macías Saint-Gerons, D and Berenguer-Pascual, E and Romá-Mateo, C and Victor, VM and Forés-Martos, J and San-Martin, C and Selva-Vera, G and Tabarés-Seisdedos, R}, title = {Systemic inflammation, oxidative damage and neurocognition predict telomere length in a transdiagnostic sample stratified by global DNA methylation levels.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {13159}, pmid = {38849401}, issn = {2045-2322}, support = {UGP-14-184 Project//Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunitat Valenciana/ ; PI22/1009//Instituto de Salud Carlos III/ ; PI22/00424//Instituto de Salud Carlos III/ ; PROMETEO/2019/027//European Regional Development Fund/ ; CIPROM/2022/32//European Regional Development Fund/ ; CB06/04/0071//Ministerio de Ciencia e Innovación/ ; 0456-03-40//Grand Challenges Canada/ ; }, mesh = {Humans ; *DNA Methylation ; Male ; Female ; *Oxidative Stress ; *Inflammation/blood/genetics ; Adult ; Middle Aged ; *Telomere/genetics/metabolism ; *Schizophrenia/genetics/blood ; Diabetes Mellitus, Type 2/genetics ; Biomarkers/blood ; Bipolar Disorder/genetics/blood ; Depressive Disorder, Major/genetics/blood ; Leukocytes/metabolism ; Epigenesis, Genetic ; Telomere Homeostasis ; Cognition ; Case-Control Studies ; }, abstract = {Epigenetic mechanisms contribute to the maintenance of both type 2 diabetes mellitus (T2DM) and psychiatric disorders. Emerging evidence suggests that molecular pathways and neurocognitive performance regulate epigenetic dynamics in these disorders. The current combined and transdiagnostic study investigated whether inflammatory, oxidative stress, adhesion molecule, neurocognitive and functional performance are significant predictors of telomere dynamics in a sample stratified by global DNA methylation levels. Peripheral blood inflammation, oxidative stress and adhesion molecule biomarkers and neurocognitive function were assessed twice over a 1-year period in 80 individuals, including 16 with schizophrenia (SZ), 16 with bipolar disorder (BD), 16 with major depressive disorder (MDD), 15 with T2DM, and 17 healthy controls (HCs). Leukocyte telomere length (LTL) was measured by qRT-PCR using deoxyribonucleic acid (DNA) extracted from peripheral blood samples. A posteriori, individuals were classified based on their global methylation score (GMS) at baseline into two groups: the below-average methylation (BM) and above-average methylation (AM) groups. Hierarchical and k-means clustering methods, mixed one-way analysis of variance and linear regression analyses were performed. Overall, the BM group showed a significantly higher leukocyte telomere length (LTL) than the AM group at both time points (p = 0.02; η[2]p = 0.06). Moreover, the BM group had significantly lower levels of tumor necrosis factor alpha (TNF-α) (p = 0.03; η[2]p = 0.06) and C-reactive protein (CRP) (p = 0.03; η[2]p = 0.06) than the AM group at the 1-year follow-up. Across all participants, the regression models showed that oxidative stress (reactive oxygen species [ROS]) (p = 0.04) and global cognitive score [GCS] (p = 0.02) were significantly negatively associated with LTL, whereas inflammatory (TNF-α) (p = 0.04), adhesion molecule biomarkers (inter cellular adhesion molecule [ICAM]) (p = 0.009), and intelligence quotient [IQ] (p = 0.03) were significantly positively associated with LTL. Moreover, the model predictive power was increased when tested in both groups separately, explaining 15.8% and 28.1% of the LTL variance at the 1-year follow-up for the AM and BM groups, respectively. Heterogeneous DNA methylation in individuals with T2DM and severe mental disorders seems to support the hypothesis that epigenetic dysregulation occurs in a transdiagnostic manner. Our results may help to elucidate the interplay between epigenetics, molecular processes and neurocognitive function in these disorders. DNA methylation and LTL are potential therapeutic targets for transdiagnostic interventions to decrease the risk of comorbidities.}, }
@article {pmid38849156, year = {2024}, author = {Murphy, WJ and Harris, AJ}, title = {Toward telomere-to-telomere cat genomes for precision medicine and conservation biology.}, journal = {Genome research}, volume = {}, number = {}, pages = {}, doi = {10.1101/gr.278546.123}, pmid = {38849156}, issn = {1549-5469}, abstract = {Genomic data from species of the cat family Felidae promise to stimulate veterinary and human medical advances, and clarify the coherence of genome organization. We describe how interspecies hybrids have been instrumental in the genetic analysis of cats, from the first genetic maps to propelling cat genomes toward the T2T standard set by the human genome project. Genotype-to-phenotype mapping in cat models has revealed dozens of health-related genetic variants, the molecular basis for mammalian pigmentation and patterning, and species-specific adaptations. Improved genomic surveillance of natural and captive populations across the cat family tree will increase our understanding of the genetic architecture of traits, population dynamics, and guide a future of genome-enabled biodiversity conservation.}, }
@article {pmid38845982, year = {2024}, author = {Shi, HZ and Wang, MW and Huang, YS and Liu, Z and Li, L and Wan, LP}, title = {A telomere-related gene risk model for predicting prognosis and treatment response in acute myeloid leukemia.}, journal = {Heliyon}, volume = {10}, number = {11}, pages = {e31705}, doi = {10.1016/j.heliyon.2024.e31705}, pmid = {38845982}, issn = {2405-8440}, abstract = {Acute myeloid leukemia (AML) is a prevalent hematological malignancy among adults. Recent studies suggest that the length of telomeres could significantly affect both the risk of developing AML and the overall survival (OS). Despite the limited focus on the prognostic value of telomere-related genes (TRGs) in AML, our study aims at addressing this gap by compiling a list of TRGs from TelNet, as well as collecting clinical information and TRGs expression data through the Gene Expression Omnibus (GEO) database. The GSE37642 dataset, sourced from GEO and based on the GPL96 platform, was divided into training and validation sets at a 6:4 ratio. Additionally, the GSE71014 dataset (based on the GPL10558 platform), GSE12417 dataset (based on the GPL96 and GPL570 platforms), and another portion of the GSE37642 dataset (based on the GPL570 platform) were designated as external testing sets. Univariate Cox regression analysis identified 96 TRGs significantly associated with OS. Subsequent Lasso-Cox stepwise regression analysis pinpointed eight TRGs (MCPH1, SLC25A6, STK19, PSAT1, KCTD15, DNMT3B, PSMD5, and TAF2) exhibiting robust predictive potential for patient survival. Both univariate and multivariate survival analyses unveiled TRG risk scores and age as independent prognostic variables. To refine the accuracy of survival prognosis, we developed both a nomogram integrating clinical parameters and a predictive risk score model based on TRGs. In subsequent investigations, associations were emphasized not solely regarding the TRG risk score and immune infiltration patterns but also concerning the response to immune-checkpoint inhibitor (ICI) therapy. In summary, the establishment of a telomere-associated genetic risk model offers a valuable tool for prognosticating AML outcomes, thereby facilitating informed treatment decisions.}, }
@article {pmid38843356, year = {2024}, author = {Yeo, D and Zars Fisher, EL and Khosla, S and Farr, JN and Westendorf, JJ}, title = {Hdac3-deficiency increases senescence-associated distention of satellite DNA and telomere-associated foci in osteoprogenitor cells.}, journal = {Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research}, volume = {}, number = {}, pages = {}, doi = {10.1093/jbmr/zjae085}, pmid = {38843356}, issn = {1523-4681}, abstract = {Histone deacetylase 3 (Hdac3) is an epigenetic regulator of gene expression and interacts with skeletal transcription factors such as Runx2. We previously reported that conditional deletion of Hdac3 in Osterix-Cre recombinase-expressing osteoprogenitor cells (Hdac3 CKOOsx) caused osteopenia and increased marrow adiposity, both hallmarks of skeletal aging. We also showed that Runx2+ cells within osteogenic cultures of Hdac3-depleted bone marrow stromal cells (BMSCs) contain lipid droplets (LDs). Cellular senescence, a non-proliferative metabolically active state, is associated with increased marrow adiposity, bone loss and aging. In this study, we sought to determine if Hdac3 depleted Runx2+ pre-osteoblasts from young mice exhibit chromatin changes associated with early cellular senescence and how these events correlate with the appearance of LDs. We first confirmed that BMSCs from Hdac3 CKOOsx mice have more Runx2 + LD+ cells compared to controls under osteogenic conditions. We then measured senescence-associated distention of satellite DNA (SADS) and telomere-associated foci (TAFs) in Hdac3 CKOOsx and control BMSCs. In situ, Runx2+ cells contained more SADs per nuclei in Hdac3 CKOOsx femora than in controls. Runx2+ BMSCs from Hdac3 CKOOsx mice also contained more SADS and TAFs per nuclei than Runx2+ cells from age-matched control mice in vitro. SADs and TAFs were present at similar levels in Runx2 + LD+ cells and Runx2 + LD- cells from Hdac3 CKOOsx mice. Hdac inhibitors also increased the number of SADS in Runx2 + LD+ and Runx2 + LD- wildtype BMSCs. Senolytics reduced viable cell numbers in Hdac3 CKOOsx BMSC cultures. These data demonstrate that depletion of Hdac3 in osteochondral progenitor cells triggers LD formation and early events in cellular senescence in Runx2+ BMSCs through mutually exclusive mechanisms.}, }
@article {pmid38838667, year = {2024}, author = {Cai, SW and Takai, H and Zaug, AJ and Dilgen, TC and Cech, TR and Walz, T and de Lange, T}, title = {POT1 recruits and regulates CST-Polα/primase at human telomeres.}, journal = {Cell}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.cell.2024.05.002}, pmid = {38838667}, issn = {1097-4172}, abstract = {Telomere maintenance requires the extension of the G-rich telomeric repeat strand by telomerase and the fill-in synthesis of the C-rich strand by Polα/primase. At telomeres, Polα/primase is bound to Ctc1/Stn1/Ten1 (CST), a single-stranded DNA-binding complex. Like mutations in telomerase, mutations affecting CST-Polα/primase result in pathological telomere shortening and cause a telomere biology disorder, Coats plus (CP). We determined cryogenic electron microscopy structures of human CST bound to the shelterin heterodimer POT1/TPP1 that reveal how CST is recruited to telomeres by POT1. Our findings suggest that POT1 hinge phosphorylation is required for CST recruitment, and the complex is formed through conserved interactions involving several residues mutated in CP. Our structural and biochemical data suggest that phosphorylated POT1 holds CST-Polα/primase in an inactive, autoinhibited state until telomerase has extended the telomere ends. We propose that dephosphorylation of POT1 releases CST-Polα/primase into an active state that completes telomere replication through fill-in synthesis.}, }
@article {pmid38837945, year = {2024}, author = {Bai, M and Jiang, S and Chu, S and Yu, Y and Shan, D and Liu, C and Zong, L and Liu, Q and Liu, N and Xu, W and Mei, Z and Jian, J and Zhang, C and Zhao, S and Chiu, TY and Simonsen, HT}, title = {The telomere-to-telomere (T2T) genome of Peucedanum praeruptorum Dunn provides insights into the genome evolution and coumarin biosynthesis.}, journal = {GigaScience}, volume = {13}, number = {}, pages = {}, doi = {10.1093/gigascience/giae025}, pmid = {38837945}, issn = {2047-217X}, support = {2022YFD1201600//National Key Research and Development Program of China/ ; }, mesh = {*Coumarins/metabolism ; *Genome, Plant ; *Apiaceae/genetics/metabolism ; *Telomere/genetics/metabolism ; Evolution, Molecular ; Phylogeny ; Genomics/methods ; Biosynthetic Pathways/genetics ; }, abstract = {BACKGROUND: Traditional Chinese medicine has used Peucedanum praeruptorum Dunn (Apiaceae) for a long time. Various coumarins, including the significant constituents praeruptorin (A-E), are the active constituents in the dried roots of P. praeruptorum. Previous transcriptomic and metabolomic studies have attempted to elucidate the distribution and biosynthetic network of these medicinal-valuable compounds. However, the lack of a high-quality reference genome impedes an in-depth understanding of genetic traits and thus the development of better breeding strategies.
RESULTS: A telomere-to-telomere (T2T) genome was assembled for P. praeruptorum by combining PacBio HiFi, ONT ultra-long, and Hi-C data. The final genome assembly was approximately 1.798 Gb, assigned to 11 chromosomes with genome completeness >98%. Comparative genomic analysis suggested that P. praeruptorum experienced 2 whole-genome duplication events. By the transcriptomic and metabolomic analysis of the coumarin metabolic pathway, we presented coumarins' spatial and temporal distribution and the expression patterns of critical genes for its biosynthesis. Notably, the COSY and cytochrome P450 genes showed tandem duplications on several chromosomes, which may be responsible for the high accumulation of coumarins.
CONCLUSIONS: A T2T genome for P. praeruptorum was obtained, providing molecular insights into the chromosomal distribution of the coumarin biosynthetic genes. This high-quality genome is an essential resource for designing engineering strategies for improving the production of these valuable compounds.}, }
@article {pmid38837897, year = {2024}, author = {Graham, MK and Xu, B and Davis, C and Meeker, AK and Heaphy, CM and Yegnasubramanian, S and Dyer, MA and Zeineldin, M}, title = {The TERT promoter is polycomb-repressed in neuroblastoma cells with long telomeres.}, journal = {Cancer research communications}, volume = {}, number = {}, pages = {}, doi = {10.1158/2767-9764.CRC-22-0287}, pmid = {38837897}, issn = {2767-9764}, abstract = {Acquiring a telomere maintenance mechanism is a hallmark of high-risk neuroblastoma and commonly occurs by expressing telomerase (TERT). Telomerase-negative neuroblastoma has long telomeres and utilize the telomerase-independent alternative lengthening of telomeres (ALT) mechanism. Conversely, no discernable telomere maintenance mechanism is detected in a fraction of neuroblastoma with long telomeres. Here, we show, unlike most cancers, DNA of the TERT promoter is broadly hypomethylated in neuroblastoma. In telomerase-positive neuroblastoma cells, the hypomethylated DNA promoter is approximately 1.5-kb. The TERT locus shows active chromatin marks with low enrichment for the repressive mark, H3K27me3. MYCN, a commonly amplified oncogene in neuroblstoma, binds to the promoter and induces TERT expression. Strikingly, in neuroblastoma with long telomeres, the hypomethylated region spans the entire TERT locus, including multiple nearby genes with enrichment for the repressive H3K27me3 chromatin mark. Furthermore, subtelomeric regions showed enrichment of repressive chromatin marks in neuroblastomas with long telomeres relative to those with short telomeres. These repressive marks were even more evident at the genic loci, suggesting a telomere position effect. Inhibiting H3K27 methylation by three different EZH2 inhibitors induced the expression of TERT in cell lines with long telomeres and H3K27me3 marks in the promoter region. EZH2 inhibition facilitated MYCN binding to the TERT promoter in neuroblastoma cells with long telomeres. Taken together, these data suggest that epigenetic regulation of TERT expression differs in neuroblastoma depending on the telomere maintenance status, and H3K27 methylation is important in repressing TERT expression in neuroblastoma with long telomeres.}, }
@article {pmid38837510, year = {2024}, author = {Sun, P and Gu, KJ and Zheng, G and Sikora, AG and Li, C and Zafereo, M and Wei, P and Wu, J and Shete, S and Liu, J and Li, G}, title = {Genetic variations associated with telomere length predict the risk of recurrence of non-oropharyngeal head and neck squamous cell carcinoma.}, journal = {Molecular carcinogenesis}, volume = {}, number = {}, pages = {}, doi = {10.1002/mc.23768}, pmid = {38837510}, issn = {1098-2744}, abstract = {Genetic factors underlying lymphocyte telomere length (LTL) may provide insights into genomic stability and integrity, with direct links to susceptibility to cancer recurrence. Polymorphisms in telomere-associated genes are strongly associated with LTL and cancer risk, while few large studies have explored the associations between LTL-related polymorphisms and recurrence risk of non-oropharyngeal head and neck squamous cell carcinoma (non-OPHNSCC). Totally 1403 non-OPHNSCC patients were recruited and genotyped for 16 LTL-related polymorphisms identified by genome-wide association studies. Univariate and multivariate analyzes were performed to evaluate associations between the polymorphisms and non-OPHNSCC recurrence risk. Patients carrying rs755017 GA/GG, rs2487999 TC/TT, rs2736108 TC/TT, or rs6772228 AT/AA genotypes exhibited shorter DFS than those with the rs755017 AA, rs2487999 CC, rs2736108 CC, or s6772228 TT genotypes, respectively (all log-rank p < 0.05). Multivariable analysis confirmed an increased risk of recurrence for patients carrying rs755017 GA/GG, rs2487999 TC/TT, rs2736108 TC/TT, or rs6772228 AT/AA genotypes (adjusted hazard ratio [aHR]: 1.66, 95% confidence interval [CI]: 1.32-2.07; aHR: 1.77, 95% CI: 1.41-2.23; aHR: 1.56, 95% CI: 1.22-1.99; aHR: 1.52, 95% CI: 1.20-1.93, respectively). Further stratified analysis revealed stronger associations between these genotypes and recurrence risk in ever-smokers and patients undergoing chemoradiotherapy. The similar but particularly pronounced results were observed for the combined risk genotypes of the four significant polymorphisms. This is the first large study on non-OPHNSCC patients showing that LTL-related polymorphisms may modify risk of non-OPHNSCC recurrence individually and jointly, particularly when analyzed in the context of smoking status and personized treatment. Larger studies are needed to validate these results.}, }
@article {pmid38837026, year = {2024}, author = {Liu, WS and Wu, BS and Yang, L and Chen, SD and Zhang, YR and Deng, YT and Wu, XR and He, XY and Yang, J and Feng, JF and Cheng, W and Xu, YM and Yu, JT}, title = {Whole exome sequencing analyses reveal novel genes in telomere length and their biomedical implications.}, journal = {GeroScience}, volume = {}, number = {}, pages = {}, pmid = {38837026}, issn = {2509-2723}, support = {2022ZD0211600//Science and Technology Innovation 2030 Major Projects/ ; 92249305//National Natural Science Foundation of China/ ; 82271471//National Natural Science Foundation of China/ ; 82071201//National Natural Science Foundation of China/ ; 2018SHZDZX01//Shanghai Municipal Science and Technology Major Project/ ; }, abstract = {Telomere length is a putative biomarker of aging and is associated with multiple age-related diseases. There are limited data on the landscape of rare genetic variations in telomere length. Here, we systematically characterize the rare variant associations with leukocyte telomere length (LTL) through exome-wide association study (ExWAS) among 390,231 individuals in the UK Biobank. We identified 18 robust rare-variant genes for LTL, most of which estimated effects on LTL were significant (> 0.2 standard deviation per allele). The biological functions of the rare-variant genes were associated with telomere maintenance and capping and several genes were specifically expressed in the testis. Three novel genes (ASXL1, CFAP58, and TET2) associated with LTL were identified. Phenotypic association analyses indicated significant associations of ASXL1 and TET2 with cancers, age-related diseases, blood assays, and cardiovascular traits. Survival analyses suggested that carriers of ASXL1 or TET2 variants were at increased risk for cancers; diseases of the circulatory, respiratory, and genitourinary systems; and all-cause and cause-specific deaths. The CFAP58 carriers were at elevated risk of deaths due to cancers. Collectively, the present whole exome sequencing study provides novel insights into the genetic landscape of LTL, identifying novel genes associated with LTL and their implications on human health and facilitating a better understanding of aging, thus pinpointing the genetic relevance of LTL with clonal hematopoiesis, biomedical traits, and health-related outcomes.}, }
@article {pmid38831447, year = {2024}, author = {Wu, X and Hu, C and Wu, T and Du, X and Peng, Z and Xue, W and Chen, Y and Dong, L}, title = {Mendelian randomization evidence based on European ancestry for the causal effects of leukocyte telomere length on prostate cancer.}, journal = {Human genomics}, volume = {18}, number = {1}, pages = {56}, pmid = {38831447}, issn = {1479-7364}, support = {82103485//National Natural Science Foundation of China/ ; 2022YQ014//Shanghai Municipal Health Commission Talent Plan/ ; }, abstract = {BACKGROUND: Several lines of evidence suggest that leukocyte telomere length (LTL) can affect the development of prostate cancer (PC).
METHODS: Here, we employed single nucleoside polymorphisms (SNPs) as instrumental variables (IVs) for LTL (n = 472,174) and conducted Mendelian randomization analysis to estimate their causal impact on PCs (79,148 patients/61,106 controls and 6311 patients/88,902 controls).
RESULTS: Every 1-s.d extension of LTL increased the risk of PCs by 34%. Additionally, the analysis of candidate mediators between LTL and PCs via two-step Mendelian randomization revealed that among the 23 candidates, Alzheimer's disease, liver iron content, sex hormone binding global levels, naive CD4-CD8-T cell% T cell, and circulating leptin levels played substantial mediating roles. There is no robust evidence to support the reverse causal relationship between LTL and the selected mediators of PCs. Adjusting for the former four mediators, rather than adjusting for circulating leptin levels, decreased the impact of LTL on PCs.
CONCLUSION: This study provides potential intervention measures for preventing LTL-induced PCs.}, }
@article {pmid38830842, year = {2024}, author = {Nageshan, RK and Ortega, R and Krogan, N and Cooper, JP}, title = {Fate of telomere entanglements is dictated by the timing of anaphase midregion nuclear envelope breakdown.}, journal = {Nature communications}, volume = {15}, number = {1}, pages = {4707}, pmid = {38830842}, issn = {2041-1723}, support = {GM145820-01//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; }, mesh = {*Nuclear Envelope/metabolism ; *Schizosaccharomyces/genetics/metabolism ; *Telomere/metabolism ; *Schizosaccharomyces pombe Proteins/metabolism/genetics ; *Telomere-Binding Proteins/metabolism/genetics ; *Anaphase ; DNA Replication ; }, abstract = {Persisting replication intermediates can confer mitotic catastrophe. Loss of the fission yeast telomere protein Taz1 (ortholog of mammalian TRF1/TRF2) causes telomeric replication fork (RF) stalling and consequently, telomere entanglements that stretch between segregating mitotic chromosomes. At ≤20 °C, these entanglements fail to resolve, resulting in lethality. Rif1, a conserved DNA replication/repair protein, hinders the resolution of telomere entanglements without affecting their formation. At mitosis, local nuclear envelope (NE) breakdown occurs in the cell's midregion. Here we demonstrate that entanglement resolution occurs in the cytoplasm following this NE breakdown. However, in response to taz1Δ telomeric entanglements, Rif1 delays midregion NE breakdown at ≤20 °C, in turn disfavoring entanglement resolution. Moreover, Rif1 overexpression in an otherwise wild-type setting causes cold-specific NE defects and lethality, which are rescued by membrane fluidization. Hence, NE properties confer the cold-specificity of taz1Δ lethality, which stems from postponement of NE breakdown. We propose that such postponement promotes clearance of simple stalled RFs, but resolution of complex entanglements (involving strand invasion between nonsister telomeres) requires rapid exposure to the cytoplasm.}, }
@article {pmid38830229, year = {2024}, author = {Koyuncu, H and Kara, N and Dabak, Ş}, title = {Investigation of the possible effects of night shift on telomere length and mtDNA copy number in nurses.}, journal = {Nucleosides, nucleotides & nucleic acids}, volume = {}, number = {}, pages = {1-14}, doi = {10.1080/15257770.2024.2348089}, pmid = {38830229}, issn = {1532-2335}, abstract = {In this study, we aimed to investigate the impacts of altered circadian rhythm on telomere length and mtDNA copy number (mtDNA-CN) in nurses working night shifts. In our study, 52 healthy nurses working in shifts at Ondokuz Mayıs University Hospital and 45 healthy control subjects working during the day were included. qRT-PCR technique was used for the determination of telomere length and mtDNA-CN. It was observed that the shift-work group had poor sleep quality (p = 0.004), feeling tired (p < 0.01) and stressed (p = 0.02) more than control group working during the day. Nurses working in shifts were found to have 1.18 times longer telomeres with respect to the control group working during the day (p = 0.005). When compared among shift workers, poor sleep quality and insufficient sleep duration shortened telomeres (r = 0.32; p = 0.02). There was no statistically significantdisparity regarding mtDNA-CN among the nurses working in shifts and the control group working during the day (p = 0.07). Insufficient sleep was associated with decreased mtDNA-CN when shift-working nurses were compared according to sleep quality (p = 0.006). Furthermore, mtDNA-CN of nurses with poor sleep quality was correlated with lower mtDNA-CN in comparison to nurses with good sleep quality (r = 0.284; p = 0.04). The mtDNA-CN of the nurses was positively associated with the sleep duration the night sleep before the night shift (r = 0.32; p = 0.02). Inadequate sleep duration and quality were observed to cause a reduction in mtDNA-CN of nurses. In conclusion, it has been observed that poor sleep quality and duration are related to shortened telomere length and decreased mtDNA-CN in night shift nurses.}, }
@article {pmid38825615, year = {2024}, author = {Zheng, J and Chen, J and Li, H and Li, Y and Dong, W and Jiang, X}, title = {Predicting prostate adenocarcinoma patients' survival and immune signature: a novel risk model based on telomere-related genes.}, journal = {Discover oncology}, volume = {15}, number = {1}, pages = {203}, pmid = {38825615}, issn = {2730-6011}, support = {82072808//the National Natural Science Foundation of China/ ; 2023QNYXYB016//Youth Medical Innovation and Practice Research Program of Guangzhou/ ; }, abstract = {Alterations in telomeres constitute some of the earliest occurrences in the tumourigenesis of prostate adenocarcinoma (PRAD) and persist throughout the progression of the tumour. While the activity of telomerase and the length of telomeres have been demonstrated to correlate with the prognosis of PRAD, the prognostic potential of telomere-related genes (TRGs) in this disease remains unexplored. Utilising mRNA expression data from the Cancer Genome Atlas (TCGA), we devised a risk model and a nomogram to predict the survival outcomes of patients with PRAD. Subsequently, our investigations extended to the relationship between the risk model and immune cell infiltration, sensitivity to chemotherapeutic drugs, and specific signalling pathways. The risk model we developed is predicated on seven key TRGs, and immunohistochemistry results revealed significant differential expression of three TRGs in tumours and paracancerous tissues. Based on the risk scores, PRAD patients were stratified into high-risk and low-risk cohorts. The Receiver operating characteristics (ROC) and Kaplan-Meier survival analyses corroborated the exceptional predictive performance of our novel risk model. Multivariate Cox regression analysis indicated that the risk score was an independent risk factor associated with Overall Survival (OS) and was significantly associated with T and N stages of PRAD patients. Notably, the high-risk group exhibited a greater response to chemotherapy and immunosuppression compared to the low-risk group, offering potential guidance for treatment strategies for high-risk patients. In conclusion, our new risk model, based on TRGs, serves as a reliable prognostic indicator for PRAD. The model holds significant value in guiding the selection of immunotherapy and chemotherapy in the clinical management of PRAD patients.}, }
@article {pmid38824190, year = {2024}, author = {Hinchie, AM and Sanford, SL and Loughridge, KE and Sutton, RM and Parikh, AH and Gil Silva, AA and Sullivan, DI and Chun-On, P and Morrell, MR and McDyer, JF and Opresko, PL and Alder, JK}, title = {A persistent variant telomere sequence in a human pedigree.}, journal = {Nature communications}, volume = {15}, number = {1}, pages = {4681}, pmid = {38824190}, issn = {2041-1723}, support = {R01HL135062//U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; }, mesh = {Humans ; *Telomere/metabolism/genetics ; *Telomere-Binding Proteins/metabolism/genetics ; *Shelterin Complex/metabolism ; *Pedigree ; *Telomerase/genetics/metabolism ; Male ; Female ; Telomere Homeostasis/genetics ; Base Sequence ; Adult ; }, abstract = {The telomere sequence, TTAGGG, is conserved across all vertebrates and plays an essential role in suppressing the DNA damage response by binding a set of proteins termed shelterin. Changes in the telomere sequence impair shelterin binding, initiate a DNA damage response, and are toxic to cells. Here we identify a family with a variant in the telomere template sequence of telomerase, the enzyme responsible for telomere elongation, that led to a non-canonical telomere sequence. The variant is inherited across at least one generation and one family member reports no significant medical concerns despite ~9% of their telomeres converting to the novel sequence. The variant template disrupts telomerase repeat addition processivity and decreased the binding of the telomere-binding protein POT1. Despite these disruptions, the sequence is readily incorporated into cellular chromosomes. Incorporation of a variant sequence prevents POT1-mediated inhibition of telomerase suggesting that incorporation of a variant sequence may influence telomere addition. These findings demonstrate that telomeres can tolerate substantial degeneracy while remaining functional and provide insights as to how incorporation of a non-canonical telomere sequence might alter telomere length dynamics.}, }
@article {pmid38816532, year = {2024}, author = {Agabekian, IA and Abdulkina, LR and Lushnenko, AY and Young, PG and Valeeva, LR and Boskovic, O and Lilly, EG and Sharipova, MR and Shippen, DE and Juenger, TE and Shakirov, EV}, title = {Arabidopsis AN3 and OLIGOCELLULA genes link telomere maintenance mechanisms with cell division and expansion control.}, journal = {Plant molecular biology}, volume = {114}, number = {3}, pages = {65}, pmid = {38816532}, issn = {1573-5028}, support = {GM127402/GM/NIGMS NIH HHS/United States ; GM065383/GM/NIGMS NIH HHS/United States ; 21-14-00147//Russian Science Foundation/ ; }, mesh = {*Arabidopsis/genetics/metabolism ; *Arabidopsis Proteins/genetics/metabolism ; *Telomere/genetics/metabolism ; *Cell Division/genetics ; *Telomerase/genetics/metabolism ; Telomere Homeostasis/genetics ; Gene Expression Regulation, Plant ; Mutation ; Transcription Factors/metabolism/genetics ; Cell Proliferation/genetics ; Meristem/genetics/metabolism ; }, abstract = {Telomeres are conserved chromosomal structures necessary for continued cell division and proliferation. In addition to the classical telomerase pathway, multiple other genes including those involved in ribosome metabolism and chromatin modification contribute to telomere length maintenance. We previously reported that Arabidopsis thaliana ribosome biogenesis genes OLI2/NOP2A, OLI5/RPL5A and OLI7/RPL5B have critical roles in telomere length regulation. These three OLIGOCELLULA genes were also shown to function in cell proliferation and expansion control and to genetically interact with the transcriptional co-activator ANGUSTIFOLIA3 (AN3). Here we show that AN3-deficient plants progressively lose telomeric DNA in early homozygous mutant generations, but ultimately establish a new shorter telomere length setpoint by the fifth mutant generation with a telomere length similar to oli2/nop2a -deficient plants. Analysis of double an3 oli2 mutants indicates that the two genes are epistatic for telomere length control. Telomere shortening in an3 and oli mutants is not caused by telomerase inhibition; wild type levels of telomerase activity are detected in all analyzed mutants in vitro. Late generations of an3 and oli mutants are prone to stem cell damage in the root apical meristem, implying that genes regulating telomere length may have conserved functional roles in stem cell maintenance mechanisms. Multiple instances of anaphase fusions in late generations of oli5 and oli7 mutants were observed, highlighting an unexpected effect of ribosome biogenesis factors on chromosome integrity. Overall, our data implicate AN3 transcription coactivator and OLIGOCELLULA proteins in the establishment of telomere length set point in plants and further suggest that multiple regulators with pleiotropic functions can connect telomere biology with cell proliferation and cell expansion pathways.}, }
@article {pmid38816389, year = {2024}, author = {Zhang, Z and Zhang, X and Tian, Y and Wang, L and Cao, J and Feng, H and Li, K and Wang, Y and Dong, S and Ye, W and Wang, Y}, title = {Complete telomere-to-telomere genomes uncover virulence evolution conferred by chromosome fusion in oomycete plant pathogens.}, journal = {Nature communications}, volume = {15}, number = {1}, pages = {4624}, pmid = {38816389}, issn = {2041-1723}, support = {32172374//National Natural Science Foundation of China (National Science Foundation of China)/ ; }, mesh = {*Telomere/genetics ; *Oomycetes/genetics/pathogenicity ; *Phylogeny ; Virulence/genetics ; *Evolution, Molecular ; Plant Diseases/microbiology/genetics ; Pythium/genetics/pathogenicity ; Phytophthora/genetics/pathogenicity ; Chromosomes/genetics ; Plants/microbiology/genetics ; Genome/genetics ; }, abstract = {Variations in chromosome number are occasionally observed among oomycetes, a group that includes many plant pathogens, but the emergence of such variations and their effects on genome and virulence evolution remain ambiguous. We generated complete telomere-to-telomere genome assemblies for Phytophthora sojae, Globisporangium ultimum, Pythium oligandrum, and G. spinosum. Reconstructing the karyotype of the most recent common ancestor in Peronosporales revealed that frequent chromosome fusion and fission drove changes in chromosome number. Centromeres enriched with Copia-like transposons may contribute to chromosome fusion and fission events. Chromosome fusion facilitated the emergence of pathogenicity genes and their adaptive evolution. Effectors tended to duplicate in the sub-telomere regions of fused chromosomes, which exhibited evolutionary features distinct to the non-fused chromosomes. By integrating ancestral genomic dynamics and structural predictions, we have identified secreted Ankyrin repeat-containing proteins (ANKs) as a novel class of effectors in P. sojae. Phylogenetic analysis and experiments further revealed that ANK is a specifically expanded effector family in oomycetes. These results revealed chromosome dynamics in oomycete plant pathogens, and provided novel insights into karyotype and effector evolution.}, }
@article {pmid38808110, year = {2024}, author = {McCollum, SE and Canter, O and Fasanello, VJ and Gronsky, S and Haussmann, MF}, title = {Birds of a feather age together: telomere dynamics and social behavior predict life span in female Japanese quail (Coturnix japonica).}, journal = {Frontiers in endocrinology}, volume = {15}, number = {}, pages = {1363468}, doi = {10.3389/fendo.2024.1363468}, pmid = {38808110}, issn = {1664-2392}, mesh = {Animals ; *Coturnix/physiology ; Female ; *Longevity ; *Telomere ; *Social Behavior ; *Aging/physiology ; Behavior, Animal ; Feathers ; Telomere Shortening ; Aggression/physiology ; Corticosterone/blood ; }, abstract = {Social support is vital for mental and physical health and is linked to lower rates of disease and early mortality. Conversely, anti-social behavior can increase mortality risks, both for the initiator and target of the behavior. Chronic stress, which also can increase mortality, may serve as an important link between social behavior and healthy lifespan. There is a growing body of literature in both humans, and model organisms, that chronic social stress can result in more rapid telomere shortening, a measure of biological aging. Here we examine the role of anti-social behavior and social support on physiological markers of stress and aging in the social Japanese quail, Coturnix Japonica. Birds were maintained in groups for their entire lifespan, and longitudinal measures of antisocial behavior (aggressive agonistic behavior), social support (affiliative behavior), baseline corticosterone, change in telomere length, and lifespan were measured. We found quail in affiliative relationships both committed less and were the targets of less aggression compared to birds who were not in these relationships. In addition, birds displaying affiliative behavior had longer telomeres, and longer lifespans. Our work suggests a novel pathway by which social support may buffer against damage at the cellular level resulting in telomere protection and subsequent longer lifespans.}, }
@article {pmid38805768, year = {2024}, author = {Salinas-Rodriguez, A and Manrique-Espinoza, B and Rivera-Almaraz, A and Sánchez-López, JM and Rosas-Vargas, H}, title = {Telomere Length is Associated with the Prevalence, Persistence, and Incidence of Sarcopenia.}, journal = {Archives of medical research}, volume = {55}, number = {4}, pages = {103007}, doi = {10.1016/j.arcmed.2024.103007}, pmid = {38805768}, issn = {1873-5487}, abstract = {BACKGROUND: Telomere length (TL) shortening has been identified as a marker of aging and associated with adverse health outcomes, but evidence of its association with sarcopenia is inconclusive.
AIMS: Estimate the cross-sectional and prospective associations between TL and sarcopenia.
METHODS: We used data from Waves 3 and 4 (2017, 2021) of the Study on Global Aging and Adult Health in Mexico (SAGE-Mexico). The cross-sectional sample consisted of 1,738 adults aged 50 and older, and the longitudinal sample consisted of 1,437. Relative TL was determined by real-time quantitative polymerase chain reaction (qPCR) on DNA extracted from saliva samples and quantified as the telomere/single-copy gene (T/S) ratio. Sarcopenia was defined according to the European Working Group on Sarcopenia in Older People (EWGSOP2).
RESULTS: The mean salivary TL was 1.50 T/S units (95% CI: 1.49-1.52). The baseline prevalence of sarcopenia was 13.3% (95% CI: 9.8-16.8%). The incidence and persistence of sarcopenia were 6.8% (95% CI: 5.0-9.5%) and 7.0% (95% CI: 5.1-9.6%), respectively. The results showed that a one standard deviation decrease in TL was cross-sectionally associated with higher odds of sarcopenia (OR = 1.31; 95% CI: 1.03-1.67) and prospectively with a higher incidence (RRR = 1.55; 95% CI: 1.06-2.25) and persistence (RRR = 1.50; 95% CI: 1.01-2.24) of sarcopenia.
CONCLUSIONS: Older adults with shorter TL had higher rates of incident and persistent sarcopenia. Implementation of interventions to delay the decline of TL in older adults is warranted. Further translational studies are needed to elucidate the effects of exercise or diet on DNA repair in the telomeric region and their associations with sarcopenia.}, }
@article {pmid38802448, year = {2024}, author = {Sadler, DE and Watts, PC and Uusi-Heikkilä, S}, title = {Directional selection, not the direction of selection, affects telomere length and copy number at ribosomal RNA loci.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {12162}, pmid = {38802448}, issn = {2045-2322}, support = {325107//Research Council of Finland/ ; 324602//Research Council of Finland/ ; 325107//Research Council of Finland/ ; }, mesh = {Animals ; *Telomere/genetics ; *Zebrafish/genetics ; *DNA Copy Number Variations ; *DNA, Mitochondrial/genetics ; *Selection, Genetic ; *RNA, Ribosomal/genetics ; Temperature ; Telomere Homeostasis ; Body Size/genetics ; }, abstract = {Many fisheries exert directional selection on traits such as body size and growth rate. Whether directional selection impacts regions of the genome associated with traits related to growth is unknown. To address this issue, we characterised copy number variation in three regions of the genome associated with cell division, (1) telomeric DNA, (2) loci transcribed as ribosomal RNA (rDNA), and (3) mitochondrial DNA (mtDNA), in three selection lines of zebrafish reared at three temperatures (22 °C, 28 °C, and 34 °C). Selection lines differed in (1) the direction of selection (two lines experienced directional selection for large or small body size) and (2) whether they experienced any directional selection itself. Lines that had experienced directional selection were smaller, had lower growth rate, shorter telomeres, and lower rDNA copy number than the line that experiencing no directional selection. Neither telomere length nor rDNA copy number were affected by temperature. In contrast, mtDNA content increased at elevated temperature but did not differ among selection lines. Though directional selection impacts rDNA and telomere length, direction of such selection did not matter, whereas mtDNA acts as a stress marker for temperature. Future work should examine the consequences of these genomic changes in natural fish stocks.}, }
@article {pmid38802042, year = {2024}, author = {Bolzán, AD}, title = {CONSIDERATIONS ON THE SCORING OF TELOMERE ABERRATIONS IN VERTEBRATE CELLS DETECTED BY TELOMERE OR TELOMERE PLUS CENTROMERE PNA-FISH.}, journal = {Mutation research. Reviews in mutation research}, volume = {}, number = {}, pages = {108507}, doi = {10.1016/j.mrrev.2024.108507}, pmid = {38802042}, issn = {1388-2139}, abstract = {Given that telomeres play a fundamental role in maintaining genomic stability, the study of the chromosomal aberrations involving telomeric sequences is a topic of considerable research interest. In recent years, the scoring of these types of aberrations has been used in vertebrate cells, particularly human cells, to evaluate the effects of genotoxic agents on telomeres and the involvement of telomeric sequences on chromosomal aberrations. Currently, chromosomal aberrations involving telomeric sequences are evaluated in peripheral blood lymphocytes or immortalized cell lines, using telomere or telomere plus centromere fluorescence in situ hybridization (FISH) with Peptide Nucleic Acid (PNA) probes (PNA-FISH). The telomere PNA probe is more efficient in the detection of telomeric sequences than conventional FISH with a telomere DNA probe. In addition, the intensity of the telomeric PNA-FISH probe signal is directly correlated with the number of telomeric repeats. Therefore, use of this type of probe can identify chromosomal aberrations involving telomeres as well as determine the telomere length of the sample. There are several mistakes and inconsistencies in the literature regarding the identification of telomere aberrations, which prevent accurate scoring and data comparison between different publications concerning these types of aberrations. The aim of this review is to clarify these issues, and provide proper terminology and criteria for the identification, scoring, and analysis of telomere aberrations.}, }
@article {pmid38794655, year = {2024}, author = {Feng, Z and Wang, Y and Fu, Z and Liao, J and Liu, H and Zhou, M}, title = {Exploring the Causal Effects of Mineral Metabolism Disorders on Telomere and Mitochondrial DNA: A Bidirectional Two-Sample Mendelian Randomization Analysis.}, journal = {Nutrients}, volume = {16}, number = {10}, pages = {}, doi = {10.3390/nu16101417}, pmid = {38794655}, issn = {2072-6643}, support = {2022A1515012593//Guangdong Basic and Applied Basic Research Foundation/ ; 82273582 and 82103785//National Natural Science Foundation of China/ ; }, mesh = {*Mendelian Randomization Analysis ; Humans ; *DNA, Mitochondrial/genetics ; *Telomere/metabolism ; Minerals/metabolism ; Aging/genetics ; DNA Copy Number Variations ; Trace Elements/blood ; Iron/metabolism/blood ; Biomarkers/blood ; }, abstract = {The aim of this study was to assess the causal relationships between mineral metabolism disorders, representative of trace elements, and key aging biomarkers: telomere length (TL) and mitochondrial DNA copy number (mtDNA-CN). Utilizing bidirectional Mendelian randomization (MR) analysis in combination with the two-stage least squares (2SLS) method, we explored the causal relationships between mineral metabolism disorders and these aging indicators. Sensitivity analysis can be used to determine the reliability and robustness of the research results. The results confirmed that a positive causal relationship was observed between mineral metabolism disorders and TL (p < 0.05), while the causal relationship with mtDNA-CN was not significant (p > 0.05). Focusing on subgroup analyses of specific minerals, our findings indicated a distinct positive causal relationship between iron metabolism disorders and both TL and mtDNA-CN (p < 0.05). In contrast, disorders in magnesium and phosphorus metabolism did not exhibit significant causal effects on either aging biomarker (p > 0.05). Moreover, reverse MR analysis did not reveal any significant causal effects of TL and mtDNA-CN on mineral metabolism disorders (p > 0.05). The combination of 2SLS with MR analysis further reinforced the positive causal relationship between iron levels and both TL and mtDNA-CN (p < 0.05). Notably, the sensitivity analysis did not indicate significant pleiotropy or heterogeneity within these causal relationships (p > 0.05). These findings highlight the pivotal role of iron metabolism in cellular aging, particularly in regulating TL and sustaining mtDNA-CN, offering new insights into how mineral metabolism disorders influence aging biomarkers. Our research underscores the importance of trace element balance, especially regarding iron intake, in combating the aging process. This provides a potential strategy for slowing aging through the adjustment of trace element intake, laying the groundwork for future research into the relationship between trace elements and healthy aging.}, }
@article {pmid38793637, year = {2024}, author = {Yang, NY and Hsieh, AYY and Chen, Z and Campbell, AR and Gadawska, I and Kakkar, F and Sauve, L and Bitnun, A and Brophy, J and Murray, MCM and Pick, N and Krajden, M and Côté, HCF and Cihr Team On Cellular Aging And Hiv Comorbidities In Women And Children Carma, }, title = {Chronic and Latent Viral Infections and Leukocyte Telomere Length across the Lifespan of Female and Male Individuals Living with or without HIV.}, journal = {Viruses}, volume = {16}, number = {5}, pages = {}, doi = {10.3390/v16050755}, pmid = {38793637}, issn = {1999-4915}, support = {HET-85515/CAPMC/CIHR/Canada ; TCO-125269//Canadian Institutes of Health Researc/ ; GER-163053/CAPMC/CIHR/Canada ; }, mesh = {Humans ; Female ; *HIV Infections/virology/immunology ; Male ; *Leukocytes/virology ; Middle Aged ; Adult ; Aged ; Young Adult ; Adolescent ; Child ; Telomere/genetics ; Infant ; Child, Preschool ; Latent Infection/virology ; Virus Diseases/virology/immunology ; Chronic Disease ; Cohort Studies ; Infant, Newborn ; }, abstract = {BACKGROUND: Chronic/latent viral infections may accelerate immunological aging, particularly among people living with HIV (PLWH). We characterized chronic/latent virus infections across their lifespan and investigated their associations with leukocyte telomere length (LTL).
METHODS: Participants enrolled in the CARMA cohort study were randomly selected to include n = 15 for each decade of age between 0 and >60 y, for each sex, and each HIV status. Cytomegalovirus (CMV), Epstein-Barr virus (EBV), human herpesvirus 8 (HHV-8), herpes simplex virus 1 (HSV-1), and HSV-2 infection were determined serologically; HIV, hepatitis C (HCV), and hepatitis B (HBV) were self-reported. LTLs were measured using monochrome multiplex qPCR. Associations between the number of viruses, LTL, and sociodemographic factors were assessed using ordinal logistic and linear regression modeling.
RESULTS: The study included 187 PLWH (105 female/82 male) and 190 HIV-negative participants (105 female/84 male), ranging in age from 0.7 to 76.1 years. Living with HIV, being older, and being female were associated with harbouring a greater number of chronic/latent non-HIV viruses. Having more infections was in turn bivariately associated with a shorter LTL. In multivariable analyses, older age, living with HIV, and the female sex remained independently associated with having more infections, while having 3-4 viruses (vs. 0-2) was associated with a shorter LTL.
CONCLUSIONS: Our results suggest that persistent viral infections are more prevalent in PLWH and females, and that these may contribute to immunological aging. Whether this is associated with comorbidities later in life remains an important question.}, }
@article {pmid38792881, year = {2024}, author = {Tariq, JA and Mandokhail, K and Sajjad, N and Hussain, A and Javaid, H and Rasool, A and Sadaf, H and Javaid, S and Durrani, AR}, title = {Effects of Age and Biological Age-Determining Factors on Telomere Length in Type 2 Diabetes Mellitus Patients.}, journal = {Medicina (Kaunas, Lithuania)}, volume = {60}, number = {5}, pages = {}, doi = {10.3390/medicina60050698}, pmid = {38792881}, issn = {1648-9144}, mesh = {Humans ; *Diabetes Mellitus, Type 2/genetics ; Male ; Female ; Middle Aged ; *Telomere ; Adult ; Aged ; *Aging/physiology ; Age Factors ; Pakistan/epidemiology ; Telomere Shortening ; Leukocytes/metabolism ; }, abstract = {Background and Objectives: Telomere length (TL) undergoes attrition over time, indicating the process of aging, and is linked to a higher risk of diabetes mellitus type 2 (DM-2). This molecular epidemiological study investigated the correlation between leukocyte TL variations and determinants of molecular aging in 121 Pakistani DM-2 patients. Materials and Methods: The ratio of telomere repeats to the SCG copy number was calculated to estimate the TL in each sample through qPCR assays. Results: In this study, smaller mean TLs were observed in 48.8% of males (6.35 ± 0.82 kb), 3.3% of underweight patients (5.77 ± 1.14 kb), 61.2% of patients on regular medication (6.50 ± 0.79 kb), 9.1% with very high stress levels (5.94 ± 0.99 kb), 31.4% of smokers (5.83 ± 0.73 kb), 40.5% of patients with low physical activity (6.47 ± 0.69 kb), 47.9% of hypertensive patients (5.93 ± 0.64 kb), 10.7% of patients with DM-2 for more than 15 years, and 3.3% of patients with a delayed onset of DM-2 (6.00 ± 0.93 kb). Conclusion: This research indicated a significant negative correlation (R[2] = 0.143) between TL and the age of DM-2 patients. This study demonstrated that the correlation of telomere length with age in DM-2 patients was also influenced by various age-determining factors, including hypertension and smoking habits, with significant strong (R[2] = 0.526) and moderate (R[2] = 0.299) correlations, respectively; sex, obesity, the stress level and age at the onset of diabetes with significant weak correlations (R[2] = 0.043, 0.041, 0.037, and 0.065, respectively), and no significant correlations of medication routine, rate of physical activity, and the durations of DM-2 with age-adjusted telomere length. These results challenge TL as the sole marker of aging, thus highlighting the need for further research to understand underlying factors and mitigate the effect of aging or premature aging on diabetic patients.}, }
@article {pmid38789417, year = {2024}, author = {Keener, R and Chhetri, SB and Connelly, CJ and Taub, MA and Conomos, MP and Weinstock, J and Ni, B and Strober, B and Aslibekyan, S and Auer, PL and Barwick, L and Becker, LC and Blangero, J and Bleecker, ER and Brody, JA and Cade, BE and Celedon, JC and Chang, YC and Cupples, LA and Custer, B and Freedman, BI and Gladwin, MT and Heckbert, SR and Hou, L and Irvin, MR and Isasi, CR and Johnsen, JM and Kenny, EE and Kooperberg, C and Minster, RL and Naseri, T and Viali, S and Nekhai, S and Pankratz, N and Peyser, PA and Taylor, KD and Telen, MJ and Wu, B and Yanek, LR and Yang, IV and Albert, C and Arnett, DK and Ashley-Koch, AE and Barnes, KC and Bis, JC and Blackwell, TW and Boerwinkle, E and Burchard, EG and Carson, AP and Chen, Z and Chen, YI and Darbar, D and de Andrade, M and Ellinor, PT and Fornage, M and Gelb, BD and Gilliland, FD and He, J and Islam, T and Kaab, S and Kardia, SLR and Kelly, S and Konkle, BA and Kumar, R and Loos, RJF and Martinez, FD and McGarvey, ST and Meyers, DA and Mitchell, BD and Montgomery, CG and North, KE and Palmer, ND and Peralta, JM and Raby, BA and Redline, S and Rich, SS and Roden, D and Rotter, JI and Ruczinski, I and Schwartz, D and Sciurba, F and Shoemaker, MB and Silverman, EK and Sinner, MF and Smith, NL and Smith, AV and Tiwari, HK and Vasan, RS and Weiss, ST and Williams, LK and Zhang, Y and Ziv, E and Raffield, LM and Reiner, AP and , and , and , and Arvanitis, M and Greider, CW and Mathias, RA and Battle, A}, title = {Validation of human telomere length multi-ancestry meta-analysis association signals identifies POP5 and KBTBD6 as human telomere length regulation genes.}, journal = {Nature communications}, volume = {15}, number = {1}, pages = {4417}, pmid = {38789417}, issn = {2041-1723}, support = {R35GM139580//U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS)/ ; 5K12GM123914//U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS)/ ; R01HL-120393//U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS)/ ; R01HL153805//U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS)/ ; R01 DK071891/DK/NIDDK NIH HHS/United States ; R01AG081244//U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS)/ ; R01AG069120//U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS)/ ; R35CA209974//U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS)/ ; R01HL68959//U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; R01HL68959//U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; R01HL87681//U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; R01HL079915//U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; R01HL105756//U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; }, mesh = {Humans ; *Genome-Wide Association Study ; *Telomere/genetics/metabolism ; K562 Cells ; *Telomere Homeostasis/genetics ; Polymorphism, Single Nucleotide ; Gene Expression Regulation ; CRISPR-Cas Systems ; }, abstract = {Genome-wide association studies (GWAS) have become well-powered to detect loci associated with telomere length. However, no prior work has validated genes nominated by GWAS to examine their role in telomere length regulation. We conducted a multi-ancestry meta-analysis of 211,369 individuals and identified five novel association signals. Enrichment analyses of chromatin state and cell-type heritability suggested that blood/immune cells are the most relevant cell type to examine telomere length association signals. We validated specific GWAS associations by overexpressing KBTBD6 or POP5 and demonstrated that both lengthened telomeres. CRISPR/Cas9 deletion of the predicted causal regions in K562 blood cells reduced expression of these genes, demonstrating that these loci are related to transcriptional regulation of KBTBD6 and POP5. Our results demonstrate the utility of telomere length GWAS in the identification of telomere length regulation mechanisms and validate KBTBD6 and POP5 as genes affecting telomere length regulation.}, }
@article {pmid38781848, year = {2024}, author = {Bao, L and Zhou, Y and Shu, J and Li, H and Xi, S and Xu, M and Cai, Q and Dai, X and Zeng, Y and Zeng, F}, title = {Impact of telomere length and mitochondrial DNA copy number variants on survival of newborn cloned calves.}, journal = {Theriogenology}, volume = {225}, number = {}, pages = {1-8}, doi = {10.1016/j.theriogenology.2024.05.019}, pmid = {38781848}, issn = {1879-3231}, abstract = {An established technology to create cloned animals is through the use of somatic cell nuclear transfer (SCNT), in which reprogramming the somatic cell nucleus to a totipotent state by enucleated oocyte cytoplasm is a necessary process, including telomere length reprogramming. The limitation of this technology; however, is that the live birth rate of offspring produced through SCNT is significantly lower than that of IVF. Whether and how telomere length play a role in the development of cloned animals is not well understood. Only a few studies have evaluated this association in cloned mice, and fewer still in cloned cows. In this study, we investigated the difference in telomere length as well as the abundance of some selected molecules between newborn deceased cloned calves and normal cows of different ages either produced by SCNT or via natural conception, in order to evaluate the association between telomere length and abnormal development of cloned cows. The absolute telomere length and relative mitochondrial DNA (mtDNA) copy number were determined by real-time quantitative PCR (qPCR), telomere related gene abundance by reverse-transcription quantitative PCR (RT-qPCR), and senescence-associated β-galactosidase (SA-β-gal) expression by SA-β-gal staining. The results demonstrate that the newborn deceased SCNT calves had significantly shortened telomere lengths compared to newborn naturally conceived calves and newborn normal SCNT calves. Significantly lower mtDNA copy number, and significantly lower relative abundance of LMNB1 and TERT, higher relative abundance of CDKN1A, and aberrant SA-β-gal expression were observed in the newborn deceased SCNT calves, consistent with the change in telomere length. These results demonstrate that abnormal telomere shortening, lower mtDNA copy number and abnormal abundance of related genes were specific to newborn deceased SCNT calves, suggesting that abnormally short telomere length may be associated with abnormal development in the cloned calves.}, }
@article {pmid38777848, year = {2024}, author = {Dhawan, V and Malhotra, N and Singh, N and Dadhwal, V and Dada, R}, title = {Yoga and its effect on sperm genomic integrity, gene expression, telomere length and perceived quality of life in early pregnancy loss.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {11711}, pmid = {38777848}, issn = {2045-2322}, mesh = {*Yoga ; Humans ; *Quality of Life ; Male ; Female ; Pregnancy ; *Spermatozoa/metabolism ; Adult ; Abortion, Habitual/genetics/psychology/therapy ; Telomere/genetics/metabolism ; Prospective Studies ; Telomere Homeostasis ; Sperm Motility/genetics ; }, abstract = {Achieving successful pregnancy outcomes is a delicate interplay between the maternal and the fetal counterparts. Paternal factors play a critical role in health and disease of offspring. Early pregnancy loss (EPL) is a psychologically devastating condition affecting the quality of life (QOL). Thus, it needs to be managed by a mind body integrated approach like yoga.The prospective single arm exploratory studyincluded male partners of couples experiencing recurrent pregnancy loss (RPL, n = 30), and recurrent implantation failure (RIF, n = 30) and semen samples wereassessed at the beginning and completion of yoga (6 weeks) (WHO 2010).A significant increase in the sperm concentration, motility, decrease in seminal ROS, DFI and increase in relative sperm telomere length was found at the end of yoga. The relative expression of genes critical for early embryonic developmentnormalized towards the levels of controls. WHOQOL-BREF questionnaire scores to assess QOL also showed improvement.Integration of regular practice yoga into our lifestyle may help in improving seminal redox status, genomic integrity, telomere length, normalizing gene expression and QOL, highlighting the need to use an integrated, holistic approach in management of such cases. This is pertinent for decreasing the transmission of mutation and epimutation load to the developing embryo, improving pregnancy outcomes and decreasing genetic and epigenetic disease burden in the next generation.}, }
@article {pmid38775978, year = {2024}, author = {Jeremian, R and Lytvyn, Y and Fotovati, R and Li, K and Sachdeva, M and Tarafdar, N and Georgakopoulos, JR and Piguet, V and Litvinov, IV and Yeung, J}, title = {Signatures of epigenetic, biological and mitotic age acceleration and telomere shortening are associated with arsenic-induced skin lesions.}, journal = {Archives of dermatological research}, volume = {316}, number = {5}, pages = {195}, pmid = {38775978}, issn = {1432-069X}, mesh = {Humans ; *Epigenesis, Genetic ; Adult ; *Arsenic/adverse effects/toxicity ; Female ; *DNA Methylation/drug effects ; *Telomere Shortening/drug effects ; Male ; Child ; Adolescent ; Young Adult ; Middle Aged ; Mitosis/drug effects/genetics ; Skin/pathology/drug effects ; Skin Diseases/chemically induced/genetics/pathology ; Skin Neoplasms/genetics/chemically induced/pathology ; }, abstract = {Chronic arsenic exposure is a global health hazard significantly associated with the development of deleterious cutaneous changes and increased keratinocyte cancer risk. Although arsenic exposure is associated with broad-scale cellular and molecular changes, gaps exist in understanding how these changes impact the skin and facilitate malignant transformation. Recently developed epigenetic "clocks" can accurately predict chronological, biological and mitotic age, as well as telomere length, on the basis of tissue DNA methylation state. Deviations of predicted from expected age (epigenetic age dysregulation) have been associated with numerous complex diseases, increased all-cause mortality and higher cancer risk. We investigated the ability of these algorithms to detect molecular changes associated with chronic arsenic exposure in the context of associated skin lesions. To accomplish this, we utilized a multi-algorithmic approach incorporating seven "clocks" (Horvath, Skin&Blood, PhenoAge, PCPhenoAge, GrimAge, DNAmTL and epiTOC2) to analyze peripheral blood of pediatric and adult cohorts of arsenic-exposed (n = 84) and arsenic-naïve (n = 33) individuals, among whom n = 18 were affected by skin lesions. Arsenic-exposed adults with skin lesions exhibited accelerated epigenetic (Skin&Blood: + 7.0 years [95% CI 3.7; 10.2], q = 6.8 × 10[-4]), biological (PhenoAge: + 5.8 years [95% CI 0.7; 11.0], q = 7.4 × 10[-2], p = 2.8 × 10[-2]) and mitotic age (epiTOC2: + 19.7 annual cell divisions [95% CI 1.8; 37.7], q = 7.4 × 10[-2], p = 3.2 × 10[-2]) compared to healthy arsenic-naïve individuals; and accelerated epigenetic age (Skin&Blood: + 2.8 years [95% CI 0.2; 5.3], q = 2.4 × 10[-1], p = 3.4 × 10[-2]) compared to lesion-free arsenic-exposed individuals. Moreover, lesion-free exposed adults exhibited accelerated Skin&Blood age (+ 4.2 [95% CI 1.3; 7.1], q = 3.8 × 10[-2]) compared to their arsenic-naïve counterparts. Compared to the pediatric group, arsenic-exposed adults exhibited accelerated epigenetic (+ 3.1 to 4.4 years (95% CI 1.2; 6.4], q = 2.4 × 10[-4]-3.1 × 10[-3]), biological (+ 7.4 to 7.8 years [95% CI 3.0; 12.1] q = 1.6 × 10[-3]-2.8 × 10[-3]) and mitotic age (+ 50.0 annual cell divisions [95% CI 15.6; 84.5], q = 7.8 × 10[-3]), as well as shortened telomere length (- 0.23 kilobases [95% CI - 0.13; - 0.33], q = 2.4 × 10[-4]), across all seven algorithms. We demonstrate that lifetime arsenic exposure and presence of arsenic-associated skin lesions are associated with accelerated epigenetic, biological and mitotic age, and shortened telomere length, reflecting altered immune signaling and genomic regulation. Our findings highlight the usefulness of DNA methylation-based algorithms in identifying deleterious molecular changes associated with chronic exposure to the heavy metal, serving as potential prognosticators of arsenic-induced cutaneous malignancy.}, }
@article {pmid38773655, year = {2024}, author = {Carlund, O and Thörn, E and Osterman, P and Fors, M and Dernstedt, A and Forsell, MNE and Erlanson, M and Landfors, M and Degerman, S and Hultdin, M}, title = {Semimethylation is a feature of diffuse large B-cell lymphoma, and subgroups with poor prognosis are characterized by global hypomethylation and short telomere length.}, journal = {Clinical epigenetics}, volume = {16}, number = {1}, pages = {68}, pmid = {38773655}, issn = {1868-7083}, mesh = {Humans ; *Lymphoma, Large B-Cell, Diffuse/genetics/mortality ; *DNA Methylation/genetics ; Female ; Male ; Prognosis ; Middle Aged ; Aged ; Adult ; Rituximab/therapeutic use ; Aged, 80 and over ; Cyclophosphamide/therapeutic use ; Doxorubicin/therapeutic use ; Vincristine/therapeutic use ; Prednisone/therapeutic use ; Telomere/genetics ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use ; Telomere Shortening/genetics ; Epigenesis, Genetic/genetics ; CpG Islands/genetics ; }, abstract = {BACKGROUND: Large B-cell lymphoma (LBCL) is the most common lymphoma and is known to be a biologically heterogeneous disease regarding genetic, phenotypic, and clinical features. Although the prognosis is good, one-third has a primary refractory or relapsing disease which underscores the importance of developing predictive biological markers capable of identifying high- and low-risk patients. DNA methylation (DNAm) and telomere maintenance alterations are hallmarks of cancer and aging. Both these alterations may contribute to the heterogeneity of the disease, and potentially influence the prognosis of LBCL.
RESULTS: We studied the DNAm profiles (Infinium MethylationEPIC BeadChip) and relative telomere lengths (RTL) with qPCR of 93 LBCL cases: Diffuse large B-cell lymphoma not otherwise specified (DLBCL, n = 66), High-grade B-cell lymphoma (n = 7), Primary CNS lymphoma (n = 8), and transformation of indolent B-cell lymphoma (n = 12). There was a substantial methylation heterogeneity in DLBCL and other LBCL entities compared to normal cells and other B-cell neoplasms. LBCL cases had a particularly aberrant semimethylated pattern (0.15 ≤ β ≤ 0.8) with large intertumor variation and overall low hypermethylation (β > 0.8). DNAm patterns could not be used to distinguish between germinal center B-cell-like (GC) and non-GC DLBCL cases. In cases treated with R-CHOP-like regimens, a high percentage of global hypomethylation (β < 0.15) was in multivariable analysis associated with worse disease-specific survival (DSS) (HR 6.920, 95% CI 1.499-31.943) and progression-free survival (PFS) (HR 4.923, 95% CI 1.286-18.849) in DLBCL and with worse DSS (HR 5.147, 95% CI 1.239-21.388) in LBCL. These cases with a high percentage of global hypomethylation also had a higher degree of CpG island methylation, including islands in promoter-associated regions, than the cases with less hypomethylation. Additionally, telomere length was heterogenous in LBCL, with a subset of the DLBCL-GC cases accounting for the longest RTL. Short RTL was independently associated with worse DSS (HR 6.011, 95% CI 1.319-27.397) and PFS (HR 4.689, 95% CI 1.102-19.963) in LBCL treated with R-CHOP-like regimens.
CONCLUSION: We hypothesize that subclones with high global hypomethylation and hypermethylated CpG islands could have advantages in tumor progression, e.g. by inactivating tumor suppressor genes or promoting treatment resistance. Our findings suggest that cases with high global hypomethylation and thus poor prognosis could be candidates for alternative treatment regimens including hypomethylating drugs.}, }
@article {pmid38771124, year = {2024}, author = {Brown, LM and Elbon, MC and Bharadwaj, A and Damle, G and Lachance, J}, title = {Does effective population size govern evolutionary differences in telomere length?.}, journal = {Genome biology and evolution}, volume = {}, number = {}, pages = {}, doi = {10.1093/gbe/evae111}, pmid = {38771124}, issn = {1759-6653}, abstract = {Lengths of telomeres vary by an order of magnitude across mammalian species. Similarly, age- and sex-standardized telomere lengths differ by up to 1 kb (14%) across human populations. How to explain these differences? Telomeres play a central role in senescence and aging, and genes that affect telomere length are likely under weak selection (i.e., telomere length is a trait that is subject to nearly neutral evolution). Importantly, natural selection is more effective in large populations than small populations. Here, we propose that observed differences in telomere length across species and populations are largely due to differences in effective population sizes. In this perspective, we present preliminary evolutionary genetic evidence supporting this hypothesis and highlight the need for more data.}, }
@article {pmid38769327, year = {2024}, author = {Chen, W and Wang, X and Sun, J and Wang, X and Zhu, Z and Ayhan, DH and Yi, S and Yan, M and Zhang, L and Meng, T and Mu, Y and Li, J and Meng, D and Bian, J and Wang, K and Wang, L and Chen, S and Chen, R and Jin, J and Li, B and Zhang, X and Deng, XW and He, H and Guo, L}, title = {Two telomere-to-telomere gapless genomes reveal insights into Capsicum evolution and capsaicinoid biosynthesis.}, journal = {Nature communications}, volume = {15}, number = {1}, pages = {4295}, pmid = {38769327}, issn = {2041-1723}, mesh = {*Capsicum/genetics/metabolism ; *Capsaicin/metabolism ; *Genome, Plant ; *Telomere/genetics/metabolism ; *Phylogeny ; *Evolution, Molecular ; Fruit/genetics/metabolism ; Retroelements/genetics ; Gene Expression Regulation, Plant ; }, abstract = {Chili pepper (Capsicum) is known for its unique fruit pungency due to the presence of capsaicinoids. The evolutionary history of capsaicinoid biosynthesis and the mechanism of their tissue specificity remain obscure due to the lack of high-quality Capsicum genomes. Here, we report two telomere-to-telomere (T2T) gap-free genomes of C. annuum and its wild nonpungent relative C. rhomboideum to investigate the evolution of fruit pungency in chili peppers. We precisely delineate Capsicum centromeres, which lack high-copy tandem repeats but are extensively invaded by CRM retrotransposons. Through phylogenomic analyses, we estimate the evolutionary timing of capsaicinoid biosynthesis. We reveal disrupted coding and regulatory regions of key biosynthesis genes in nonpungent species. We also find conserved placenta-specific accessible chromatin regions, which likely allow for tissue-specific biosynthetic gene coregulation and capsaicinoid accumulation. These T2T genomic resources will accelerate chili pepper genetic improvement and help to understand Capsicum genome evolution.}, }
@article {pmid38763334, year = {2024}, author = {Hakobyan, M and Binder, H and Arakelyan, A}, title = {Pan-cancer analysis of telomere maintenance mechanisms.}, journal = {The Journal of biological chemistry}, volume = {}, number = {}, pages = {107392}, doi = {10.1016/j.jbc.2024.107392}, pmid = {38763334}, issn = {1083-351X}, abstract = {Telomeres, protective caps at chromosome ends, maintain genomic stability and control cell lifespan. Dysregulated telomere maintenance mechanisms (TMM) are cancer hallmarks, enabling unchecked cell proliferation. We conducted a pan-cancer evaluation of TMM using RNA sequencing data from The Cancer Genome Atlas (TCGA) for 33 different cancer types and analyzed the activities of telomerase-dependent (TEL) and alternative lengthening of telomeres (ALT) TMM pathways in detail. To further characterize the TMM profiles, we categorized the tumors based on their ALT and TEL TMM pathway activities into five major phenotypes: ALT [high] TEL [low], ALT [low] TEL [low], ALT [middle] TEL [middle], ALT [high] TEL [high], and ALT [low] TEL [high]. These phenotypes refer to variations in telomere maintenance strategies, shedding light on the heterogeneous nature of telomere regulation in cancer. Moreover, we investigated the clinical implications of TMM phenotypes by examining their associations with clinical characteristics and patient outcomes. Specific TMM profiles were linked to specific survival patterns, emphasizing the potential of TMM profiling as a prognostic indicator and aiding in personalized cancer treatment strategies. Gene ontology analysis of the TMM phenotypes unveiled enriched biological processes associated with cell cycle regulation (both TEL and ALT), DNA replication (TEL), and chromosome dynamics (ALT) showing that telomere maintenance is tightly intertwined with cellular processes governing proliferation and genomic stability. Overall, our study provides an overview of the complexity of transcriptional regulation of telomere maintenance mechanisms in cancer.}, }
@article {pmid38760657, year = {2024}, author = {Moix, S and Sadler, MC and Kutalik, Z and Auwerx, C}, title = {Breaking down causes, consequences, and mediating effects of telomere length variation on human health.}, journal = {Genome biology}, volume = {25}, number = {1}, pages = {125}, pmid = {38760657}, issn = {1474-760X}, support = {310030_189147//Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung/ ; }, mesh = {Humans ; Male ; Female ; *Telomere/metabolism/genetics ; *Mendelian Randomization Analysis ; Telomere Shortening ; Middle Aged ; Leukocytes/metabolism ; Aged ; Telomere Homeostasis ; Life Style ; Adult ; Body Mass Index ; }, abstract = {BACKGROUND: Telomeres form repeated DNA sequences at the ends of chromosomes, which shorten with each cell division. Yet, factors modulating telomere attrition and the health consequences thereof are not fully understood. To address this, we leveraged data from 326,363 unrelated UK Biobank participants of European ancestry.
RESULTS: Using linear regression and bidirectional univariable and multivariable Mendelian randomization (MR), we elucidate the relationships between leukocyte telomere length (LTL) and 142 complex traits, including diseases, biomarkers, and lifestyle factors. We confirm that telomeres shorten with age and show a stronger decline in males than in females, with these factors contributing to the majority of the 5.4% of LTL variance explained by the phenome. MR reveals 23 traits modulating LTL. Smoking cessation and high educational attainment associate with longer LTL, while weekly alcohol intake, body mass index, urate levels, and female reproductive events, such as childbirth, associate with shorter LTL. We also identify 24 traits affected by LTL, with risk for cardiovascular, pulmonary, and some autoimmune diseases being increased by short LTL, while longer LTL increased risk for other autoimmune conditions and cancers. Through multivariable MR, we show that LTL may partially mediate the impact of educational attainment, body mass index, and female age at childbirth on proxied lifespan.
CONCLUSIONS: Our study sheds light on the modulators, consequences, and the mediatory role of telomeres, portraying an intricate relationship between LTL, diseases, lifestyle, and socio-economic factors.}, }
@article {pmid38757009, year = {2024}, author = {Pańczyszyn, A and Boniewska-Bernacka, E and Włodarczyk, K and Wertel, I and Goc, A}, title = {Telomeres and telomerase in endometrial cancer and hyperplasia.}, journal = {Archives of medical science : AMS}, volume = {20}, number = {2}, pages = {682-685}, doi = {10.5114/aoms/186189}, pmid = {38757009}, issn = {1734-1922}, abstract = {INTRODUCTION: The study aimed to measure telomeres length (TL) and telomerase expression in normal endometrium and endometrial hyperplasia and cancer.
METHODS: Total RNA and DNA were isolated from endometrium samples of 117 patients. The RT-PCR method was used to determine telomerase expression and relative telomere length.
RESULTS: The control group had the longest telomeres in comparison to the hyperplasia and endometrial cancer groups. Only in the endometrial cancer group was telomerase expressed and positively correlated with telomere length.
CONCLUSIONS: Telomere extension in endometrial cancer is mediated by telomerase, but telomere length may not be an indicator of endometrioid cancer development.}, }
@article {pmid38755561, year = {2024}, author = {Stephens, Z and Kocher, JP}, title = {Characterization of telomere variant repeats using long reads enables allele-specific telomere length estimation.}, journal = {BMC bioinformatics}, volume = {25}, number = {1}, pages = {194}, pmid = {38755561}, issn = {1471-2105}, abstract = {Telomeres are regions of repetitive DNA at the ends of linear chromosomes which protect chromosome ends from degradation. Telomere lengths have been extensively studied in the context of aging and disease, though most studies use average telomere lengths which are of limited utility. We present a method for identifying all 92 telomere alleles from long read sequencing data. Individual telomeres are identified using variant repeats proximal to telomere regions, which are unique across alleles. This high-throughput and high-resolution characterization of telomeres could be foundational to future studies investigating the roles of specific telomeres in aging and disease.}, }
@article {pmid38755232, year = {2024}, author = {Grula, CC and Rinehart, JD and Anacleto, A and Kittilson, JD and Heidinger, BJ and Greenlee, KJ and Rinehart, JP and Bowsher, JH}, title = {Telomere length is longer following diapause in two solitary bee species.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {11208}, pmid = {38755232}, issn = {2045-2322}, support = {3060-21220-032-00D.//USDA-ARS/ ; 1557940//NSF-IOS/ ; FEC 1826834//NSF RII Track-2/ ; }, mesh = {Animals ; Bees/genetics/physiology ; *Telomere/genetics/metabolism ; Pupa/growth & development/genetics ; Female ; Male ; Telomere Homeostasis ; Larva/genetics/growth & development/physiology ; Diapause/genetics ; }, abstract = {The mechanisms that underlie senescence are not well understood in insects. Telomeres are conserved repetitive sequences at chromosome ends that protect DNA during replication. In many vertebrates, telomeres shorten during cell division and in response to stress and are often used as a cellular marker of senescence. However, little is known about telomere dynamics across the lifespan in invertebrates. We measured telomere length in larvae, prepupae, pupae, and adults of two species of solitary bees, Osmia lignaria and Megachile rotundata. Contrary to our predictions, telomere length was longer in later developmental stages in both O. lignaria and M. rotundata. Longer telomeres occurred after emergence from diapause, which is a physiological state with increased tolerance to stress. In O. lignaria, telomeres were longer in adults when they emerged following diapause. In M. rotundata, telomeres were longer in the pupal stage and subsequent adult stage, which occurs after prepupal diapause. In both species, telomere length did not change during the 8 months of diapause. Telomere length did not differ by mass similarly across species or sex. We also did not see a difference in telomere length after adult O. lignaria were exposed to a nutritional stress, nor did length change during their adult lifespan. Taken together, these results suggest that telomere dynamics in solitary bees differ from what is commonly reported in vertebrates and suggest that insect diapause may influence telomere dynamics.}, }
@article {pmid38755031, year = {2024}, author = {Giri, P and Thakor, F and Dwivedi, M}, title = {Implication of regulatory T cells' telomere shortening in pathogenesis of generalized vitiligo.}, journal = {Human immunology}, volume = {}, number = {}, pages = {110812}, doi = {10.1016/j.humimm.2024.110812}, pmid = {38755031}, issn = {1879-1166}, abstract = {Generalized vitiligo(GV) is a skin depigmenting condition due to loss of melanocytes. Regulatory T cells(Tregs), responsible for peripheral tolerance, show altered numbers and functions in GV patients, likely influenced by the aging process. Therefore, the present study was focused on measuring the relative telomere length of Tregs in 96 GV patients and 90 controls by qPCR, along with correlation of relative telomere length with in vitro Treg suppressive capacity. Interestingly, we found significantly decreased relative telomere length in Tregs of GV patients as compared to controls(p = 0.0001). Additionally, age based-analysis suggested significant decrease in relative telomere length in elderly GV patients(>40 years) in comparison to young GV patients(0-20 years; p = 0.0027). Furthermore, age of onset analysis suggested for reduced relative telomere length in early onset GV patients (0-20 years) in comparison to late onset GV patients(>40 years; p = 0.0036). The correlation analysis suggested positive correlation for relative telomere length with in vitro Tregs suppressive capacity(r = 0.68 & r = 0.45; p < 0.0001). Additionally, the in vitro Tregs suppressive capacity was significantly reduced in elderly GV patients(p = 0.003) and early onset GV patients(p = 0.0074). Overall, our study for the first time demonstrated that, the Tregs ageing due to telomere shortening may be responsible for altered Treg functions and number.}, }
@article {pmid38747543, year = {2024}, author = {Kumar, S and Rajkumar, SV and Jevremovic, D and Kyle, RA and Shifrin, Y and Nguyen, M and Husain, Z and Alikhah, A and Jafari, A and Mai, S and Anderson, K and Louis, S}, title = {Three-dimensional telomere profiling predicts risk of progression in smoldering multiple myeloma.}, journal = {American journal of hematology}, volume = {}, number = {}, pages = {}, doi = {10.1002/ajh.27364}, pmid = {38747543}, issn = {1096-8652}, support = {//Telo Genomics Corp./ ; }, abstract = {Smoldering multiple myeloma (SMM) is a precursor stage that precedes multiple myeloma (MM). SMM is heterogenous with nearly 40% of patients progressing to MM in the first 5 years. The high rate of progression of SMM patients highlights the need for early intervention, which underscores the importance of identifying SMM patients with the highest risk of progression. Several risk stratification models showed utility in identifying high-risk SMM patients; however, these systems showed limited sensitivity. To date, identifying high-risk SMM patients remains an important clinical need. In this study, we present the 3-dimensional telomere profiling as a structural biomarker capable of stratifying SMM patients as a function of genomic instability. Quantifying telomere dysfunction using the TeloView technology showed utility in risk stratification of cancer patients, particularly hematological malignancies. In this study, we analyzed 168 SMM patients. We report an AUC in ROC analysis of 0.8 using a subset of the patients as a training dataset. We then conducted a blind validation on a different cohort and demonstrated a positive predictive value of 85% and negative predictive value of 73%, with sensitivity and specificity of 83% and 76%, respectively. We examined the correlation between the TeloView prediction and the 20-2-20 scoring system, and cytogenetic abnormalities. We report a correlation of 53% with the 20-2-20 scores and over 60% correlation with cytogenetic abnormalities. The result of this study presents the telomere profiling as an effective biomarker able to stratify SMM patients to their respective risk groups with high sensitivity and specificity.}, }
@article {pmid38747360, year = {2024}, author = {Nanda, A and Logan, A and Tennyson, RL}, title = {The influence of perceived stress and motivation on telomere length among NCAA swimmers.}, journal = {American journal of human biology : the official journal of the Human Biology Council}, volume = {}, number = {}, pages = {e24091}, doi = {10.1002/ajhb.24091}, pmid = {38747360}, issn = {1520-6300}, support = {//The Center for Leadership in Athletics at the University of Washington/ ; //Shanahan Endowment Fellowship/ ; T32 HD101442-01//Eunice Kennedy Shriver National Institute of Child Health and Human Development/ ; //Center for Studies in Demography & Ecology/ ; //University of Washington (UW)/ ; NIH/NIA5T32AG66574-2//Biological Mechanisms for Healthy Aging Training Grant/ ; //Mary Gates Endowment Fund for Research/ ; }, abstract = {INTRODUCTION: Telomere length (TL) shortening is associated with increased cellular senescence and functional decline with age. Regular physical activity is posited to safeguard against TL shortening, but there is disagreement on how concurrent psychosocial stress may influence this relationship. The current analysis explored whether psychosocial stress is associated with TL differences in highly physically active individuals.
METHODS: TL was measured from capillary dried blood spots collected from Division-I (D-1) and Division-III (D-3) National Collegiate Athletics Association (NCAA) swimmers (N = 28) and non-athlete students from the same schools (N = 15). All participants completed Cohen's Perceived Stress Scale (PSS) and student-athletes completed an additional questionnaire to assess psychosocial factors associated with their lifestyle; The Student Athletes' Motivation towards Sports and Academics Questionnaire (SAMSAQ). Semi-structured interviews further contextualized how student-athletes internalize their stress.
RESULTS: There was no significant difference in TL or PSS scores between swimmers and controls. D-1 swimmers reported significantly higher career and student-athlete motivation scores compared to D-3, but non-significantly higher PSS and similar academic motivation scores. Themes from interviews with collegiate swimmers included COVID-19 stress, fear of injury, pressure from academics, expectations to perform, and financial pressures.
CONCLUSIONS: These themes may have contributed to higher PSS scores in D-1 swimmers compared to D-3 but did not appear to impact their TL. Given differences in perceived stress, sources of stress, and SAMSAQ scores, further analyses with larger sample sizes are needed to better understand how these factors influence human biology and health while engaged in intense physical activity.}, }
@article {pmid38744897, year = {2024}, author = {Siametis, A and Stratigi, K and Giamaki, D and Chatzinikolaou, G and Akalestou-Clocher, A and Goulielmaki, E and Luke, B and Schumacher, B and Garinis, GA}, title = {Transcription stress at telomeres leads to cytosolic DNA release and paracrine senescence.}, journal = {Nature communications}, volume = {15}, number = {1}, pages = {4061}, pmid = {38744897}, issn = {2041-1723}, support = {GA 64663//EC | Horizon 2020 Framework Programme (EU Framework Programme for Research and Innovation H2020)/ ; }, mesh = {*Cellular Senescence/genetics ; Animals ; *Telomere/metabolism/genetics ; Mice ; *Cytosol/metabolism ; *DNA Damage ; *Paracrine Communication ; DNA/metabolism ; Transcription, Genetic ; Mice, Knockout ; Humans ; Extracellular Vesicles/metabolism ; Genomic Instability ; Aging/genetics/metabolism ; Oxidative Stress ; Mice, Inbred C57BL ; }, abstract = {Transcription stress has been linked to DNA damage -driven aging, yet the underlying mechanism remains unclear. Here, we demonstrate that Tcea1[-/-] cells, which harbor a TFIIS defect in transcription elongation, exhibit RNAPII stalling at oxidative DNA damage sites, impaired transcription, accumulation of R-loops, telomere uncapping, chromatin bridges, and genome instability, ultimately resulting in cellular senescence. We found that R-loops at telomeres causally contribute to the release of telomeric DNA fragments in the cytoplasm of Tcea1[-/-] cells and primary cells derived from naturally aged animals triggering a viral-like immune response. TFIIS-defective cells release extracellular vesicles laden with telomeric DNA fragments that target neighboring cells, which consequently undergo cellular senescence. Thus, transcription stress elicits paracrine signals leading to cellular senescence, promoting aging.}, }
@article {pmid38743757, year = {2024}, author = {Tannemann, N and Erbel, R and Nöthen, MM and Jöckel, KH and Pechlivanis, S}, title = {Genetic polymorphisms affecting telomere length and their association with cardiovascular disease in the Heinz-Nixdorf-Recall study.}, journal = {PloS one}, volume = {19}, number = {5}, pages = {e0303357}, doi = {10.1371/journal.pone.0303357}, pmid = {38743757}, issn = {1932-6203}, mesh = {Humans ; *Polymorphism, Single Nucleotide ; *Cardiovascular Diseases/genetics ; Male ; Female ; Middle Aged ; Aged ; *Telomere/genetics ; *Genetic Predisposition to Disease ; Risk Factors ; Telomere Homeostasis/genetics ; }, abstract = {Short telomeres are associated with cardiovascular disease (CVD). We aimed to investigate, if genetically determined telomere-length effects CVD-risk in the Heinz-Nixdorf-Recall study (HNRS) population. We selected 14 single-nucleotide polymorphisms (SNPs) associated with telomere-length (p<10-8) from the literature and after exclusion 9 SNPs were included in the analyses. Additionally, a genetic risk score (GRS) using these 9 SNPs was calculated. Incident CVD was defined as fatal and non-fatal myocardial infarction, stroke, and coronary death. We included 3874 HNRS participants with available genetic data and had no known history of CVD at baseline. Cox proportional-hazards regression was used to test the association between the SNPs/GRS and incident CVD-risk adjusting for common CVD risk-factors. The analyses were further stratified by CVD risk-factors. During follow-up (12.1±4.31 years), 466 participants experienced CVD-events. No association between SNPs/GRS and CVD was observed in the adjusted analyses. However, the GRS, rs10936599, rs2487999 and rs8105767 increase the CVD-risk in current smoker. Few SNPs (rs10936599, rs2487999, and rs7675998) showed an increased CVD-risk, whereas rs10936599, rs677228 and rs4387287 a decreased CVD-risk, in further strata. The results of our study suggest different effects of SNPs/GRS on CVD-risk depending on the CVD risk-factor strata, highlighting the importance of stratified analyses in CVD risk-factors.}, }
@article {pmid38743633, year = {2024}, author = {Su, Y and Yang, X and Wang, Y and Li, J and Long, Q and Cao, S and Wang, X and Liu, Z and Huang, S and Chen, Z and Peng, Y and Zhang, F and Xue, H and Cao, X and Zhang, M and Yisilam, G and Chu, Z and Gao, Y and Zhou, Y and Liu, Z and Xiao, H and Tian, X}, title = {Phased Telomere-to-Telomere Reference Genome and Pangenome Reveal an Expansion of Resistance Genes during Apple Domestication.}, journal = {Plant physiology}, volume = {}, number = {}, pages = {}, doi = {10.1093/plphys/kiae258}, pmid = {38743633}, issn = {1532-2548}, abstract = {The cultivated apple (Malus domestica Borkh.) is a cross-pollinated perennial fruit tree of great economic importance. Previous versions of apple reference genomes were unphased, fragmented, and lacked comprehensive insights into the highly heterozygous genome, which impeded genetic studies and breeding programs in apple. In this study, we assembled a haplotype-resolved telomere-to-telomere reference genome for the diploid apple cultivar Golden Delicious. Subsequently, we constructed a pangenome based on twelve assemblies from wild and cultivated apples to investigate different types of resistance gene analogs (RGAs). Our results revealed the dynamics of the gene gain and loss events during apple domestication. Compared with cultivated species, more gene families in wild species were significantly enriched in oxidative phosphorylation, pentose metabolic process, responses to salt, and abscisic acid biosynthesis process. Interestingly, our analyses demonstrated a higher prevalence of RGAs in cultivated apples than their wild relatives, partially attributed to segmental and tandem duplication events in certain RGAs classes. Other types of structural variations, mainly deletions and insertions, have affected the presence and absence of TIR-NB-ARC-LRR (TNL), NB-ARC-LRR (NL), and CC-NB-ARC-LRR (CNL) genes. Additionally, hybridization/introgression from wild species has also contributed to the expansion of resistance genes in domesticated apples. Our haplotype-resolved T2T genome and pangenome provide important resources for genetic studies of apples, emphasizing the need to study the evolutionary mechanisms of resistance genes in apple breeding programs.}, }
@article {pmid38738582, year = {2024}, author = {Rasouli, S and Dakic, A and Wang, QE and Mitchell, D and Blakaj, DM and Putluri, N and Li, J and Liu, X}, title = {Noncanonical functions of telomerase and telomeres in viruses-associated cancer.}, journal = {Journal of medical virology}, volume = {96}, number = {5}, pages = {e29665}, doi = {10.1002/jmv.29665}, pmid = {38738582}, issn = {1096-9071}, support = {R01CA222148/NH/NIH HHS/United States ; R33CA258016/NH/NIH HHS/United States ; R01CA276474/NH/NIH HHS/United States ; U01CA278927/NH/NIH HHS/United States ; R33CA258016/NH/NIH HHS/United States ; R01CA276474/NH/NIH HHS/United States ; U01CA278927/NH/NIH HHS/United States ; }, mesh = {*Telomerase/metabolism/genetics ; Humans ; *Neoplasms/virology/genetics ; *Telomere/metabolism ; Herpesvirus 4, Human/genetics/pathogenicity/physiology ; RNA/metabolism/genetics ; }, abstract = {The cause of cancer is attributed to the uncontrolled growth and proliferation of cells resulting from genetic changes and alterations in cell behavior, a phenomenon known as epigenetics. Telomeres, protective caps on the ends of chromosomes, regulate both cellular aging and cancer formation. In most cancers, telomerase is upregulated, with the telomerase reverse transcriptase (TERT) enzyme and telomerase RNA component (TERC) RNA element contributing to the maintenance of telomere length. Additionally, it is noteworthy that two viruses, human papillomavirus (HPV) and Epstein-Barr virus (EBV), utilize telomerase for their replication or persistence in infected cells. Also, TERT and TERC may play major roles in cancer not related to telomere biology. They are involved in the regulation of gene expression, signal transduction pathways, cellular metabolism, or even immune response modulation. Furthermore, the crosstalk between TERT, TERC, RNA-binding proteins, and microRNAs contributes to a greater extent to cancer biology. To understand the multifaceted roles played by TERT and TERC in cancer and viral life cycles, and then to develop effective therapeutic strategies against these diseases, are fundamental for this goal. By investigating deeply, the complicated mechanisms and relationships between TERT and TERC, scientists will open the doors to new therapies. In its analysis, the review emphasizes the significance of gaining insight into the multifaceted roles that TERT and TERC play in cancer pathogenesis, as well as their involvement in the viral life cycle for designing effective anticancer therapy approaches.}, }
@article {pmid38735573, year = {2024}, author = {Li, C and Zhang, Y and Zhang, K and Fu, H and Lin, L and Cai, G and Zhang, X and Yang, X and Zhang, Z and Yang, Z and Zhang, B}, title = {Association Between Ultra-Processed Foods Consumption and Leucocyte Telomere Length: A cross-sectional study of UK Biobank.}, journal = {The Journal of nutrition}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.tjnut.2024.05.001}, pmid = {38735573}, issn = {1541-6100}, abstract = {OBJECTIVE: This study investigates the association between consumption of ultra-processed foods and leucocyte telomere length.
METHODS: This cross-sectional study utilized data from the UK Biobank, including a total of 64,690 participants. LTL was measured using Q-PCR with natural logarithmic conversion and Z-score normalization. Dietary data were collected through a 24-hour recall questionnaire from 2009 to 2010. UPFs were identified using the Nova food classification as either a continuous or a categorical variable respectively. Multiple linear regression models were employed to analyze the association between UPF consumption and LTL.
RESULTS: The included participants had an average age of 56.26 years, of whom 55.2% were female. After adjusting for demographic and health-related variables, LTL exhibited a decrease of 0.005 (95% CI:-0.007,-0.002) with one UPF serving increase. Compared to participants consuming ≤3.5 servings/day, those consuming 3.5 to <6 servings showed a shortening of LTL by 0.025 (95% CI: -0.046, -0.003). Participants consuming 6 to ≤8 servings/day and >8 servings/day had LTL shortening of 0.032 (95% CI: -0.054, -0.011) and 0.037 (95% CI: -0.060, -0.014), respectively (P for trend=0.002). Subgroup analyses by UPF subclasses revealed that the consumption of ready-to-eat/heated food (β=-0.010, 95% CI:-0.016,-0.004), beans and potatoes (β=-0.027, 95% CI:-0.043,-0.012), animal-based products (β=-0.012, 95% CI:-0.020,-0.005), artificial sugar (β=-0.014, 95% CI:-0.025,-0.003), and beverages (β=-0.005, 95% CI:-0.009,-0.001) showed negative associations with LTL. Conversely, breakfast cereals (β=0.022, 95% CI:0.006,0.038) and vegetarian alternatives (β=0.056, 95% CI:0.026,0.085) showed positive correlations with LTL.
CONCLUSIONS: Our study found that a higher consumption of total UPF was associated with a shorter LTL. However, some UPFs may be associated with longer LTL, depending on their nutritional composition.}, }
@article {pmid38731223, year = {2024}, author = {Duseikaite, M and Gedvilaite, G and Mikuzis, P and Andrulionyte, J and Kriauciuniene, L and Liutkeviciene, R}, title = {Investigating the Relationship between Telomere-Related Gene Variants and Leukocyte Telomere Length in Optic Neuritis Patients.}, journal = {Journal of clinical medicine}, volume = {13}, number = {9}, pages = {}, doi = {10.3390/jcm13092694}, pmid = {38731223}, issn = {2077-0383}, abstract = {Optic neuritis (ON) is a condition marked by optic nerve inflammation due to various potential triggers. Research indicates a link between telomeres and inflammation, as studies demonstrate that inflammation can lead to increased telomere shortening. Aim: We aimed to determine the associations of telomere-related telomeric repeat binding factor 1 (TERF1) rs1545827, rs10107605, and telomeric repeat binding factor 2 (TERF2) rs251796 polymorphisms and relative leukocyte telomere length (LTL) with the occurrence of ON. Methods: In this research, a total of 73 individuals diagnosed with optic neuritis (ON) were studied and the control group included 170 individuals without any health issues. The DNA samples were obtained from peripheral blood leukocytes, which were purified using the DNA salting-out technique. Real-time polymerase chain reaction (RT-PCR) assessed single-nucleotide polymorphisms (SNPs) and relative leukocyte telomere lengths (LTL). The data obtained were processed and analyzed using the "IBM SPSS Statistics 29.0" program. Results: Our study revealed the following results: in the male group, TERF2 rs251796 (AA, AG, and TT) statistically significantly differed between the long and short telomere group, with frequencies of 65.7%, 22.9%, and 2.0% in long telomeres, compared to 35.1%, 56.8%, and 8.1% in the short telomere group (p = 0.013). The TERF2 rs251796 CT genotype, compared to CC, under the codominant genetic model, was associated with 4.7-fold decreased odds of telomere shortening (p = 0.005). Meanwhile, CT+TT genotypes, compared to CC under the dominant genetic model, were associated with 3.5-fold decreased odds of telomere shortening (p = 0.011). Also, the CT genotype, compared to CC+TT, under the overdominant genetic model, was associated with 4.4-fold decreased odds of telomere shortening (p = 0.004). Conclusions: The current evidence may suggest a protective role of TERF2 rs251796 in the occurrence of ON in men.}, }
@article {pmid38730258, year = {2024}, author = {Cheng, H and Asri, M and Lucas, J and Koren, S and Li, H}, title = {Scalable telomere-to-telomere assembly for diploid and polyploid genomes with double graph.}, journal = {Nature methods}, volume = {}, number = {}, pages = {}, pmid = {38730258}, issn = {1548-7105}, support = {R01HG010040//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; U01HG010971//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; U41HG010972//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; K99HG012798//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; }, abstract = {Despite advances in long-read sequencing technologies, constructing a near telomere-to-telomere assembly is still computationally demanding. Here we present hifiasm (UL), an efficient de novo assembly algorithm combining multiple sequencing technologies to scale up population-wide near telomere-to-telomere assemblies. Applied to 22 human and two plant genomes, our algorithm produces better diploid assemblies at a cost of an order of magnitude lower than existing methods, and it also works with polyploid genomes.}, }
@article {pmid38729362, year = {2024}, author = {Lozano, M and McEachan, RRC and Wright, J and Yang, TC and Dow, C and Kadawathagedara, M and Lepeule, J and Bustamante, M and Maitre, L and Vrijheid, M and Brantsæter, AL and Meltzer, HM and Bempi, V and Roumeliotaki, T and Thomsen, C and Nawrot, T and Broberg, K and Llop, S}, title = {Early life exposure to mercury and relationships with telomere length and mitochondrial DNA content in European children.}, journal = {The Science of the total environment}, volume = {}, number = {}, pages = {173014}, doi = {10.1016/j.scitotenv.2024.173014}, pmid = {38729362}, issn = {1879-1026}, abstract = {BACKGROUND: Telomere length (TL) and mitochondrial function expressed as mitochondrial DNA copy number (mtDNAcn) are biomarkers of aging and oxidative stress and inflammation, respectively. Methylmercury (MeHg), a common pollutant in fish, induces oxidative stress. We hypothesized that elevated oxidative stress from exposure to MeHg decreases mtDNAcn and shortens TL.
METHODS: Study participants are 6-11-year-old children from the HELIX multi-center birth cohort study, comprising six European countries. Prenatal and postnatal total mercury (THg) concentrations were measured in blood samples, TL and mtDNAcn were determined in child DNA. Covariates and confounders were obtained by questionnaires. Robust regression models were run, considering sociodemographic and lifestyle covariates, as well as fish consumption. Sex, ethnicity, and fish consumption interaction models were also run.
RESULTS: We found longer TL with higher pre- and postnatal THg blood concentrations, even at low-level THg exposure according to the RfD proposed by the US EPA. The prenatal association showed a significant linear relationship with a 3.46 % increase in TL for each unit increased THg. The postnatal association followed an inverted U-shaped marginal non-linear relationship with 1.38 % an increase in TL for each unit increased THg until reaching a cut-point at 0.96 μg/L blood THg, from which TL attrition was observed. Higher pre- and postnatal blood THg concentrations were consistently related to longer TL among cohorts and no modification effect of fish consumption nor children's sex was observed. No association between THg exposure and mtDNAcn was found.
DISCUSSION: We found evidence that THg is associated with TL but the associations seem to be time- and concentration-dependent. Further studies are needed to clarify the mechanism behind the telomere changes of THg and related health effects.}, }
@article {pmid38718720, year = {2024}, author = {Ogłuszka, M and Chen, CY and Poławska, E and Starzyński, RR and Liput, K and Siekierko, U and Pareek, CS and Pierzchała, M and Kang, JX}, title = {Elevated tissue status of omega-3 fatty acids protects against age-related telomere attrition in fat-1 transgenic mice.}, journal = {Clinical nutrition (Edinburgh, Scotland)}, volume = {43}, number = {6}, pages = {1488-1494}, doi = {10.1016/j.clnu.2024.05.001}, pmid = {38718720}, issn = {1532-1983}, abstract = {BACKGROUND & AIMS: Leukocyte telomere length (LTL) is a biomarker of aging that may be influenced by dietary factors. Omega-3 fatty acids (n-3 FA) have been suggested to affect LTL. However, research on this effect has been inconclusive. The aim of the study was to test the hypothesis about the positive effect of n-3 FA on LTL.
METHODS: Fat-1 transgenic mice, which can convert omega-6 fatty acids (n-6 FA) to n-3 FA and have elevated levels of endogenous n-3 FA in their tissues, were used to study the effects of n-3 FA on LTL at different ages. Blood samples from 10-month-old wild-type (WT) mice (n = 10) and fat-1 mice (n = 10) and 3-month-old WT mice (n = 5) and fat-1 mice (n = 5) were used to measure relative and absolute LTL. The levels of proteins critical for telomere maintenance were examined by Western blot analysis.
RESULTS: Fat-1 transgenic mice had longer leukocyte telomeres than their WT siblings, suggesting a slower rate of age-related telomere shortening in fat-1 mice. In animals aged 10 months, the LTL was significantly longer in fat-1 than in WT mice (mean ± SEM; relative LTL: WT = 1.00 ± 0.09 vs. fat-1: 1.25 ± 0.05, P = 0.031; absolute LTL: WT = 64.41 ± 6.50 vs. fat-1: 78.53 ± 3.86, P = 0.048). The difference in LTL observed in three-month-old mice was insignificant, however the mean LTL was still longer in fat-1 mice than in the WT mice. Fat-1 mice also had abundant levels of two shelterin proteins: TRF1 (27%, P = 0.028) and TRF2 (47%, P = 0.040) (telomeric repeat binding factor 1 and 2) compared to WT animals.
CONCLUSION: This study, for the first time in a unique animal model free of dietary confounders, has demonstrated that increased levels of n-3 FA in tissues can reduce telomere attrition. The data presented indicate the possibility of using omega-3 fatty acids to reduce accelerated telomere attrition and, consequently, counteract premature aging and reduce the risk of age-related diseases.}, }
@article {pmid38714889, year = {2024}, author = {Wondisford, AR and Lee, J and Lu, R and Schuller, M and Groslambert, J and Bhargava, R and Schamus-Haynes, S and Cespedes, LC and Opresko, PL and Pickett, HA and Min, J and Ahel, I and O'Sullivan, RJ}, title = {Deregulated DNA ADP-ribosylation impairs telomere replication.}, journal = {Nature structural & molecular biology}, volume = {}, number = {}, pages = {}, pmid = {38714889}, issn = {1545-9985}, abstract = {The recognition that DNA can be ADP ribosylated provides an unexpected regulatory level of how ADP-ribosylation contributes to genome stability, epigenetics and immunity. Yet, it remains unknown whether DNA ADP-ribosylation (DNA-ADPr) promotes genome stability and how it is regulated. Here, we show that telomeres are subject to DNA-ADPr catalyzed by PARP1 and removed by TARG1. Mechanistically, we show that DNA-ADPr is coupled to lagging telomere DNA strand synthesis, forming at single-stranded DNA present at unligated Okazaki fragments and on the 3' single-stranded telomere overhang. Persistent DNA-linked ADPr, due to TARG1 deficiency, eventually leads to telomere shortening. Furthermore, using the bacterial DNA ADP-ribosyl-transferase toxin to modify DNA at telomeres directly, we demonstrate that unhydrolyzed DNA-linked ADP-ribose compromises telomere replication and telomere integrity. Thus, by identifying telomeres as chromosomal targets of PARP1 and TARG1-regulated DNA-ADPr, whose deregulation compromises telomere replication and integrity, our study highlights and establishes the critical importance of controlling DNA-ADPr turnover for sustained genome stability.}, }
@article {pmid38708177, year = {2024}, author = {Tao, HY and Zhao, CY and Wang, Y and Sheng, WJ and Zhen, YS}, title = {Targeting Telomere Dynamics as an Effective Approach for the Development of Cancer Therapeutics.}, journal = {International journal of nanomedicine}, volume = {19}, number = {}, pages = {3805-3825}, pmid = {38708177}, issn = {1178-2013}, mesh = {Humans ; *Neoplasms/drug therapy/therapy ; *Telomere/drug effects ; *Antineoplastic Agents/pharmacology/chemistry ; *Telomerase/antagonists & inhibitors ; Animals ; Drug Delivery Systems/methods ; Nanoparticles/chemistry ; Immunotherapy/methods ; Neoplastic Stem Cells/drug effects ; }, abstract = {Telomere is a protective structure located at the end of chromosomes of eukaryotes, involved in maintaining the integrity and stability of the genome. Telomeres play an essential role in cancer progression; accordingly, targeting telomere dynamics emerges as an effective approach for the development of cancer therapeutics. Targeting telomere dynamics may work through multifaceted molecular mechanisms; those include the activation of anti-telomerase immune responses, shortening of telomere lengths, induction of telomere dysfunction and constitution of telomerase-responsive drug release systems. In this review, we summarize a wide variety of telomere dynamics-targeted agents in preclinical studies and clinical trials, and reveal their promising therapeutic potential in cancer therapy. As shown, telomere dynamics-active agents are effective as anti-cancer chemotherapeutics and immunotherapeutics. Notably, these agents may display efficacy against cancer stem cells, reducing cancer stem levels. Furthermore, these agents can be integrated with the capability of tumor-specific drug delivery by the constitution of related nanoparticles, antibody drug conjugates and HSA-based drugs.}, }
@article {pmid38706908, year = {2024}, author = {Yan, M and Zhang, Z and Wang, L and Huang, H and Wang, J and Zhu, C and Li, Z and Xu, Z}, title = {Cross-talk of Three Molecular Subtypes of Telomere Maintenance Defines Clinical Characteristics and Tumor Microenvironment in Gastric Cancer.}, journal = {Journal of Cancer}, volume = {15}, number = {10}, pages = {3227-3241}, pmid = {38706908}, issn = {1837-9664}, abstract = {Background: Telomere maintenance takes part in the regulation of gastric cancer (GC) pathogenesis and is essential for patients' clinical features. Though the correlation between a single telomere maintenance-related gene and GC has previously been published, comprehensive exploration and systematic analysis remain to be studied. Our study is aimed at determining telomere maintenance-related molecular subtypes and examining their role in GC. Methods: By analyzing the transcriptome data, we identified three telomere maintenance-associated clusters (TMCs) with heterogeneity in clinical features and tumor microenvironment (TME). Then, we screened five prognostic telomere maintenance-related genes and established corresponding TM scores. Additionally, the expression level and biological function of tubulin beta 6 class V (TUBB6) were validated in GC tissues and cells. Results: TMC1 was correlated with EMT and TGF-beta pathway and predicted low tumor mutation burden (TMB) as well as bad prognostic outcomes. TMC3 was associated with cell cycle and DNA repair. In terms of TMB and overall survival, TMC3 exhibited opposite results against TMC1. Significant heterogeneity was observed between TMCs. TUBB6 was upregulated and could promote GC proliferation, migration, and invasion. Conclusion: Altogether, combining bioinformatics and functional experiments, we identified three molecular subtypes based on telomere maintenance-associated genes in GC, which could bring new ideas and novel biomarkers to the clinic.}, }
@article {pmid38701745, year = {2024}, author = {McQuillan, MA and Verhulst, S and Hansen, MEB and Beggs, W and Meskel, DW and Belay, G and Nyambo, T and Mpoloka, SW and Mokone, GG and Fokunang, C and Njamnshi, AK and Chanock, SJ and Aviv, A and Tishkoff, SA}, title = {Association between telomere length and Plasmodium falciparum malaria endemicity in sub-Saharan Africans.}, journal = {American journal of human genetics}, volume = {111}, number = {5}, pages = {927-938}, doi = {10.1016/j.ajhg.2024.04.003}, pmid = {38701745}, issn = {1537-6605}, mesh = {Humans ; *Malaria, Falciparum/genetics/epidemiology/parasitology ; Male ; Female ; Adult ; Africa South of the Sahara/epidemiology ; *Telomere/genetics ; Endemic Diseases ; Plasmodium falciparum/genetics/pathogenicity ; Black People/genetics ; Middle Aged ; Leukocytes/metabolism ; Telomere Homeostasis/genetics ; Young Adult ; Sub-Saharan African People ; }, abstract = {Leukocyte telomere length (LTL) varies significantly across human populations, with individuals of African ancestry having longer LTL than non-Africans. However, the genetic and environmental drivers of LTL variation in Africans remain largely unknown. We report here on the relationship between LTL, genetics, and a variety of environmental and climatic factors in ethnically diverse African adults (n = 1,818) originating from Botswana, Tanzania, Ethiopia, and Cameroon. We observe significant variation in LTL among populations, finding that the San hunter-gatherers from Botswana have the longest leukocyte telomeres and that the Fulani pastoralists from Cameroon have the shortest telomeres. Genetic factors explain ∼50% of LTL variation among individuals. Moreover, we observe a significant negative association between Plasmodium falciparum malaria endemicity and LTL while adjusting for age, sex, and genetics. Within Africa, adults from populations indigenous to areas with high malaria exposure have shorter LTL than those in populations indigenous to areas with low malaria exposure. Finally, we explore to what degree the genetic architecture underlying LTL in Africa covaries with malaria exposure.}, }
@article {pmid38696464, year = {2024}, author = {Lee, J and Lee, J and Sohn, EJ and Taglialatela, A and O'Sullivan, RJ and Ciccia, A and Min, J}, title = {Extrachromosomal telomere DNA derived from excessive strand displacements.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {121}, number = {19}, pages = {e2318438121}, doi = {10.1073/pnas.2318438121}, pmid = {38696464}, issn = {1091-6490}, support = {CA207209//HHS | NIH | National Cancer Institute (NCI)/ ; CA262316//HHS | NIH | National Cancer Institute (NCI)/ ; CA197774//HHS | NIH | National Cancer Institute (NCI)/ ; CA245259//HHS | NIH | National Cancer Institute (NCI)/ ; }, mesh = {*Telomere/genetics/metabolism ; Humans ; *DNA, Single-Stranded/metabolism/genetics ; *Telomere Homeostasis ; DNA Replication ; DNA/genetics/metabolism ; DNA, Circular/genetics/metabolism ; Blotting, Southern ; DNA Polymerase III/metabolism/genetics ; }, abstract = {Alternative lengthening of telomeres (ALT) is a telomere maintenance mechanism mediated by break-induced replication, evident in approximately 15% of human cancers. A characteristic feature of ALT cancers is the presence of C-circles, circular single-stranded telomeric DNAs composed of C-rich sequences. Despite the fact that extrachromosomal C-rich single-stranded DNAs (ssDNAs), including C-circles, are unique to ALT cells, their generation process remains undefined. Here, we introduce a method to detect single-stranded telomeric DNA, called 4SET (Strand-Specific Southern-blot for Single-stranded Extrachromosomal Telomeres) assay. Utilizing 4SET, we are able to capture C-rich single-stranded DNAs that are near 200 to 1500 nucleotides in size. Both linear C-rich ssDNAs and C-circles are abundant in the fractions of cytoplasm and nucleoplasm, which supports the idea that linear and circular C-rich ssDNAs are generated concurrently. We also found that C-rich ssDNAs originate during Okazaki fragment processing during lagging strand DNA synthesis. The generation of C-rich ssDNA requires CST-PP (CTC1/STN1/TEN1-PRIMASE-Polymerase alpha) complex-mediated priming of the C-strand DNA synthesis and subsequent excessive strand displacement of the C-rich strand mediated by the DNA Polymerase delta and the BLM helicase. Our work proposes a model for the generation of C-rich ssDNAs and C-circles during ALT-mediated telomere elongation.}, }
@article {pmid38695985, year = {2024}, author = {Fragkiadaki, P and Kouvidi, E and Angelaki, A and Nikolopoulou, D and Vakonaki, E and Tsatsakis, A}, title = {Evaluation of telomere length and telomerase activity on predicting in vitro fertilization treatment outcomes.}, journal = {Journal of assisted reproduction and genetics}, volume = {}, number = {}, pages = {}, pmid = {38695985}, issn = {1573-7330}, abstract = {The current article is a literature review aiming to provide an overview of the existing knowledge on the association between telomere length and telomerase activity and in vitro fertilization. Recently, telomeres have been used as an effective biomarker to determine biological age, which may differ from chronological age due to genetic, lifestyle, and environmental factors. Cellular senescence, along with other exogenous and mainly environmental factors, can enhance telomere wear, further shortening their ends and may also affect reproductive aging. IVF is a common fertility treatment caused by female reasons (age, ovulation disorders, damaged or blocked fallopian tubes, endometriosis), male reasons (low sperm quantity or quality), or unexplained infertility. A growing number of studies have proposed a relationship between telomere length and telomerase activity and IVF success and have suggested their use as candidate biomarkers for IVF outcome. Nevertheless, additional studies are necessary to be conducted, in order to clarify the possible implication of telomeres in IVF and to evaluate their possible role as valuable predictors of IVF result.}, }
@article {pmid38695626, year = {2024}, author = {Wirtz, L and Casanova, F and Schaffrath, U and Wegner, A}, title = {Development of a telomere vector-based approach to overcome limitations caused by lethal phenotypes in the study of essential genes in Magnaporthe oryzae.}, journal = {Molecular plant pathology}, volume = {25}, number = {5}, pages = {e13460}, doi = {10.1111/mpp.13460}, pmid = {38695626}, issn = {1364-3703}, support = {//RWTH Aachen University scholarships for Doctoral Students/ ; SCHA 631/11-1//Deutsche Forschungsgemeinschaft/ ; }, mesh = {*Telomere/genetics ; *Phenotype ; *Genes, Essential ; *Genetic Vectors/genetics ; CRISPR-Cas Systems/genetics ; Genes, Fungal/genetics ; Gene Deletion ; Magnaporthe/genetics/pathogenicity ; *Ascomycota ; }, abstract = {Reverse genetic approaches are common tools in genomics for elucidating gene functions, involving techniques such as gene deletion followed by screening for aberrant phenotypes. If the generation of gene deletion mutants fails, the question arises whether the failure stems from technical issues or because the gene of interest (GOI) is essential, meaning that the deletion causes lethality. In this report, we introduce a novel method for assessing gene essentiality using the phytopathogenic ascomycete Magnaporthe oryzae. The method is based on the observation that telomere vectors are lost in transformants during cultivation without selection pressure. We tested the hypothesis that essential genes can be identified in deletion mutants co-transformed with a telomere vector. The M. oryzae gene MoPKC, described in literature as essential, was chosen as GOI. Using CRISPR/Cas9 technology transformants with deleted GOI were generated and backed up by a telomere vector carrying a copy of the GOI and conferring fenhexamid resistance. Transformants in which the GOI deletion in the genome was not successful lost the telomere vector on media without fenhexamid. In contrast, transformants with confirmed GOI deletion retained the telomere vector even in absence of fenhexamid selection. In the latter case, the maintenance of the telomere indicates that the GOI is essential for the surveillance of the fungi, as it would have been lost otherwise. The method presented here allows to test for essentiality of genes when no mutants can be obtained from gene deletion approaches, thereby expanding the toolbox for studying gene function in ascomycetes.}, }
@article {pmid38690161, year = {2024}, author = {Khattar, E and Salvati, E}, title = {Editorial: Novel insights connecting telomere biology to cancer development and progression.}, journal = {Frontiers in oncology}, volume = {14}, number = {}, pages = {1405618}, doi = {10.3389/fonc.2024.1405618}, pmid = {38690161}, issn = {2234-943X}, }
@article {pmid38689496, year = {2024}, author = {Yun, L and Zhang, C and Liang, T and Tian, Y and Ma, G and Courdavault, V and Sun, S and Ma, B and Li, Z and Li, R and Cao, F and Shen, X and Wei, J and Li, Y and Guo, B and Sun, C}, title = {Insights into the dammarane-type triterpenoid spaonin biosynthesis from the telomere-to-telomere genome of Gynostemma pentaphyllum.}, journal = {Plant communications}, volume = {}, number = {}, pages = {100932}, doi = {10.1016/j.xplc.2024.100932}, pmid = {38689496}, issn = {2590-3462}, }
@article {pmid38689492, year = {2024}, author = {Bao, J and Zhang, H and Wang, F and Li, L and Zhu, X and Xu, J and Wang, Y and Liu, Z and Zhai, G and Xu, H and Lin, F and Zhu, Y}, title = {Telomere-to-telomere genome assemblies of two Chinese Baijiu-brewing sorghum landraces.}, journal = {Plant communications}, volume = {}, number = {}, pages = {100933}, doi = {10.1016/j.xplc.2024.100933}, pmid = {38689492}, issn = {2590-3462}, }
@article {pmid38688277, year = {2024}, author = {DeBoy, EA and Nicosia, AM and Liyanarachchi, S and Iyer, SS and Shah, MH and Ringel, MD and Brock, P and Armanios, M}, title = {Telomere-lengthening germline variants predispose to a syndromic papillary thyroid cancer subtype.}, journal = {American journal of human genetics}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.ajhg.2024.04.006}, pmid = {38688277}, issn = {1537-6605}, abstract = {Papillary thyroid cancer (PTC) is the most common endocrine malignancy. 10% to 15% of individuals show familial clustering with three or more affected members, but the factors underlying this risk are unknown. In a group of recently studied individuals with POT1 pathogenic variants and ultra-long telomere length, PTC was the second most common solid tumor. We tested whether variants in POT1 and four other telomere-maintenance genes associated with familial cancer underlie PTC susceptibility. Among 470 individuals, we identified pathogenic or likely pathogenic variants in three genes encoding telomere-binding proteins: POT1, TINF2, and ACD. They were found in 4.5% and 1.5% of familial and unselected cases, respectively. Individuals harboring these variants had ultra-long telomere length, and 15 of 18 (83%) developed other cancers, of which melanoma, lymphoma, and sarcoma were most common. Among individuals with PTC and melanoma, 22% carried a deleterious germline variant, suggesting that a long-telomere syndrome might be clinically recognizable. Successive generations had longer telomere length than their parents and, at times, developed more cancers at younger ages. Tumor sequencing identified a single oncogenic driver, BRAF p.Val600Glu, in 10 of 10 tumors studied, but no telomere-maintenance mechanism, including at the TERT promoter. These data identify a syndromic subset of PTCs with locus heterogeneity and telomere lengthening as a convergent mechanism. They suggest these germline variants lower the threshold to cancer by obviating the need for an acquired telomere-maintenance mechanism in addition to sustaining the longevity of oncogenic mutations.}, }
@article {pmid38685189, year = {2024}, author = {Walker, CG and Thayer, ZM and Marks, EJ and Ly, KN and Pillai, A and Waldie, K and Underwood, L and Snell, RG and Knowles, SD and Cha, JE and Morton, SMB}, title = {Association between maternal depression symptoms and child telomere length.}, journal = {Journal of psychiatric research}, volume = {174}, number = {}, pages = {319-325}, doi = {10.1016/j.jpsychires.2024.04.037}, pmid = {38685189}, issn = {1879-1379}, abstract = {The biological mechanisms that explain how adverse early life events influence adult disease risk are poorly understood. One proposed mechanism is via the induction of accelerated biological aging, for which telomere length is considered a biomarker. We aimed to determine if maternal depression pre- and post-partum was associated with telomere length in children at 4 years of age (n = 4299). Mothers completed structured questionnaires assessing depression during pregnancy (Edinburgh Depression Scale), at 9 months (Edinburgh Depression Scale), and at 54 months postpartum (Patient Health Questionnaire 9). Regression methods were used to investigate the relationship between telomere length (DNA from saliva) and maternal depression score recorded at each stage. Significant covariates included in the final model were: maternal age at pregnancy; child sex; child ethnicity; gestational age group, and rurality group. Child telomere length was found to be longer if their mother had a higher depression score at both postpartum time points tested (9 months of age; coefficient 0.003, SE = 0.001, P = 0.01, 54 months of age; coefficient 0.003, SE = 0.002, P = 0.02). Although these findings seem paradoxical, increased telomere length may be an adaptive response to early life stressors. We propose several testable hypotheses for these results and to determine if the positive association between depression and telomere length is a developmental adaptation or an indirect consequence of environmental factors.}, }
@article {pmid38680187, year = {2024}, author = {Yudin, NS and Igoshin, AV and Romashov, GA and Martynov, AA and Larkin, DM}, title = {Influence of breed and environment on leukocyte telomere length in cattle.}, journal = {Vavilovskii zhurnal genetiki i selektsii}, volume = {28}, number = {2}, pages = {190-197}, doi = {10.18699/vjgb-24-23}, pmid = {38680187}, issn = {2500-0462}, abstract = {High milk yield is associated with reduced longevity in high-producing dairy cattle breeds. Pre-term culling leads to high replacement heifer demand and economic losses for the dairy industry. Selection for this trait is limited because of low heritability and difficulties in phenotype measurement. Telomeres are elements found at the ends of chromosomes, consisting of repetitive DNA sequences, several thousand base pairs in length, coupled with nucleoprotein complexes. Eventually, in humans and most other animals, telomere length reduces with age. When telomeric DNA is truncated to a critical length, cell ageing, cell cycle arrest, and apoptosis are induced. As a result, telomere length can be considered as a predictor of health risks and an individual's lifespan. The leukocyte telomere length may be used as a proxy phenotype of productive lifespan to improve cattle selection. Our objectives were to assess the effects of breed and breed group (dairy vs. beef) on the leukocyte telomere length and to estimate the effect of cold climate on this trait in Kalmyk cattle populations from the South (Rostov Oblast) and Far North (Republic of Sakha) regions of Russia. The leukocyte telomere lengths were estimated computationally from whole-genome resequencing data. We leveraged data on leukocyte telomere length, sex, and age of 239 animals from 17 cattle breeds. The breed factor had a significant effect on leukocyte telomere length across our sample. There was no difference in leukocyte telomere length between dairy and beef groups. The population factor had a significant effect on leukocyte telomere length in Kalmyk animals. In conclusion, we found that breed, but not breed group (dairy vs. beef), was significantly associated with leukocyte telomere length in cattle. Residence in colder climates was associated with longer leukocyte telomere length in Kalmyk breed cattle.}, }
@article {pmid38679744, year = {2024}, author = {Limardi, PC and Panigoro, SS and Siregar, NC and Sutandyo, N and Witjaksono, F and Priliani, L and Oktavianthi, S and Malik, SG}, title = {Higher peripheral blood mitochondrial DNA copy number and relative telomere length in under 48 years Indonesian breast cancer patients.}, journal = {BMC research notes}, volume = {17}, number = {1}, pages = {120}, pmid = {38679744}, issn = {1756-0500}, mesh = {Humans ; *Breast Neoplasms/genetics/blood ; Female ; *DNA, Mitochondrial/blood/genetics ; Indonesia ; Middle Aged ; Case-Control Studies ; Adult ; *DNA Copy Number Variations/genetics ; *Telomere/genetics ; Telomere Homeostasis ; Biomarkers, Tumor/blood/genetics ; Aged ; }, abstract = {OBJECTIVE: Breast cancer is the leading cause of cancer incidence and mortality among Indonesian women. A comprehensive investigation is required to enhance the early detection of this disease. Mitochondrial DNA copy number (mtDNA-CN) and relative telomere length (RTL) have been proposed as potential biomarkers for several cancer risks, as they are linked through oxidative stress mechanisms. We conducted a case-control study to examine peripheral blood mtDNA-CN and RTL patterns in Indonesian breast cancer patients (n = 175) and healthy individuals (n = 181). The relative ratios of mtDNA-CN and RTL were determined using quantitative real-time PCR (qPCR).
RESULTS: Median values of mtDNA-CN and RTL were 1.62 and 0.70 in healthy subjects and 1.79 and 0.73 in breast cancer patients, respectively. We found a positive association between peripheral blood mtDNA-CN and RTL (p < 0.001). In under 48 years old breast cancer patients, higher peripheral blood mtDNA-CN (mtDNA-CN ≥ 1.73 (median), p = 0.009) and RTL (continuous variable, p = 0.010) were observed, compared to the corresponding healthy subjects. We also found a significantly higher 'High-High' pattern of mtDNA-CN and RTL in breast cancer patients under 48 years old (p = 0.011). Our findings suggest that peripheral blood mtDNA-CN and RTL could serve as additional minimally invasive biomarkers for breast cancer risk evaluation.}, }
@article {pmid38676403, year = {2024}, author = {Wong, JYY and Blechter, B and Liu, Z and Shi, J and Roger, VL}, title = {Genetic susceptibility to chronic diseases leads to heart failure among Europeans: the influence of leukocyte telomere length.}, journal = {Human molecular genetics}, volume = {}, number = {}, pages = {}, doi = {10.1093/hmg/ddae063}, pmid = {38676403}, issn = {1460-2083}, support = {1ZIACP010120-28/CA/NCI NIH HHS/United States ; 1ZIAHL006285-01/HL/NHLBI NIH HHS/United States ; }, abstract = {BACKGROUND: Genetic susceptibility to various chronic diseases has been shown to influence heart failure (HF) risk. However, the underlying biological pathways, particularly the role of leukocyte telomere length (LTL), are largely unknown. We investigated the impact of genetic susceptibility to chronic diseases and various traits on HF risk, and whether LTL mediates or modifies the pathways.
METHODS: We conducted prospective cohort analyses on 404 883 European participants from the UK Biobank, including 9989 incident HF cases. Multivariable Cox regression was used to estimate associations between HF risk and 24 polygenic risk scores (PRSs) for various diseases or traits previously generated using a Bayesian approach. We assessed multiplicative interactions between the PRSs and LTL previously measured in the UK Biobank using quantitative PCR. Causal mediation analyses were conducted to estimate the proportion of the total effect of PRSs acting indirectly through LTL, an integrative marker of biological aging.
RESULTS: We identified 9 PRSs associated with HF risk, including those for various cardiovascular diseases or traits, rheumatoid arthritis (P = 1.3E-04), and asthma (P = 1.8E-08). Additionally, longer LTL was strongly associated with decreased HF risk (P-trend = 1.7E-08). Notably, LTL strengthened the asthma-HF relationship significantly (P-interaction = 2.8E-03). However, LTL mediated only 1.13% (P < 0.001) of the total effect of the asthma PRS on HF risk.
CONCLUSIONS: Our findings shed light onto the shared genetic susceptibility between HF risk, asthma, rheumatoid arthritis, and other traits. Longer LTL strengthened the genetic effect of asthma in the pathway to HF. These results support consideration of LTL and PRSs in HF risk prediction.}, }
@article {pmid38669426, year = {2024}, author = {Xia, J and Xu, L and Yu, Y and Wu, M and Wang, X and Wang, Y and Li, C and Sun, J and Lv, X and Zhao, J and Zhang, Y}, title = {Associations between weight-adjusted-waist index and telomere length: Results from NHANES: An observational study.}, journal = {Medicine}, volume = {103}, number = {17}, pages = {e37905}, doi = {10.1097/MD.0000000000037905}, pmid = {38669426}, issn = {1536-5964}, mesh = {Humans ; Male ; Female ; *Nutrition Surveys ; Cross-Sectional Studies ; Middle Aged ; Adult ; *Telomere/genetics ; Obesity/genetics ; Waist Circumference ; Aged ; Body Weight ; Body Mass Index ; }, abstract = {Previous studies have demonstrated the connection between obesity and telomere length. A recently devised metric for determining obesity, the weight-adjusted-waist index (WWI), offers a distinct advantage in predicting fat and lean mass by depicting weight-independent abdominal adiposity. This article presents the results of the inaugural study on the relationship between WWI and telomere length in adult populations. The cross-sectional investigation analyzed data from 3479 participants from the National Health and Nutrition Examination Survey (NHANES) conducted from 1999 to 2000. To inspect linear and nonlinear correlations, we adopted weighted multiple logistic regression analysis and smooth curve fit, respectively. In addition, threshold effects and subgroup analyses were accomplished. In the fully adapted model, a significant adverse association of WWI with telomere length was detected [β = -0.02, 95% CI: (-0.03, -0.00), P value = 0.01]. The adverse correlation remained consistent across all subcategories. We also discovered an inverted U-shaped curve linking WWI and telomere length, with a conspicuous inflection point of 10.07 cm/√kg. For the first time, our research demonstrated strong links between WWI and telomere length. The inflection point suggests that controlling WWI within an optimum range might be essential for aging and health.}, }
@article {pmid38663933, year = {2024}, author = {Yan, X and Yang, P and Li, Y and Liu, T and Zha, Y and Wang, T and Zhang, J and Feng, Z and Li, M}, title = {New insights from bidirectional Mendelian randomization: causal relationships between telomere length and mitochondrial DNA copy number in aging biomarkers.}, journal = {Aging}, volume = {16}, number = {}, pages = {}, doi = {10.18632/aging.205765}, pmid = {38663933}, issn = {1945-4589}, abstract = {Mitochondrial DNA (mtDNA) copy number and telomere length (TL) are dynamic factors that have been linked to the aging process in organisms. However, the causal relationship between these variables remains uncertain. In this research, instrumental variables (IVs) related to mtDNA copy number and TL were obtained from publicly available genome-wide association studies (GWAS). Through bidirectional Mendelian randomization (MR) analysis, we examined the potential causal relationship between these factors. The forward analysis, with mtDNA copy number as the exposure and TL as the outcome, did not reveal a significant effect (B=-0.004, P>0.05). On the contrary, upon conducting a reverse analysis, it was found that there exists a positive causal relationship (B=0.054, P<0.05). Sensitivity analyses further confirmed the reliability of these results. The outcomes of this study indicate a one-way positive causal relationship, indicating that telomere shortening in the aging process may lead to a decrease in mtDNA copy number, providing new perspectives on their biological mechanisms.}, }
@article {pmid38663837, year = {2024}, author = {Inoue, Y and Aoki, S and Ito, J and Hara, S and Shirasuna, K and Iwata, H}, title = {Telomere length determines the mitochondrial copy number in blastocyst-stage embryos.}, journal = {Mitochondrion}, volume = {}, number = {}, pages = {101887}, doi = {10.1016/j.mito.2024.101887}, pmid = {38663837}, issn = {1872-8278}, abstract = {Telomere length (TL) and mitochondrial DNA copy number (mt-cn) are associated with embryonic development. Here, we investigated the correlation between TL and mt-cn in bovine embryos to determine whether TL regulates mt-cn. TL and mt-cn were closely correlated in embryos derived from six bulls. Treatment of embryos with a telomerase inhibitor (TMPyP) and siTERT shortened the TL and reduced mt-cn in blastocysts. RNA-sequencing of blastocysts developed with TMPyP revealed differentially expressed genes associated with transforming growth factor-β1 signaling and inflammation. In conclusion, TL regulates mt-cn in embryos.}, }
@article {pmid38658004, year = {2024}, author = {Tunnicliffe, L and Muzambi, R and Bartlett, JW and Howe, L and Abdul Basit, K and Warren-Gash, C}, title = {Infection and telomere length: a systematic review protocol.}, journal = {BMJ open}, volume = {14}, number = {4}, pages = {e081881}, doi = {10.1136/bmjopen-2023-081881}, pmid = {38658004}, issn = {2044-6055}, mesh = {Humans ; *Systematic Reviews as Topic ; *Research Design ; Telomere Shortening ; Telomere/genetics ; Infections ; }, abstract = {INTRODUCTION: Telomeres are a measure of cellular ageing with potential links to diseases such as cardiovascular diseases and cancer. Studies have shown that some infections may be associated with telomere shortening, but whether an association exists across all types and severities of infections and in which populations is unclear. Therefore we aim to collate available evidence to enable comparison and to inform future research in this field.
METHODS AND ANALYSIS: We will search for studies involving telomere length and infection in various databases including MEDLINE (Ovid interface), EMBASE (Ovid interface), Web of Science, Scopus, Global Health and the Cochrane Library. For grey literature, the British Library of electronic theses databases (ETHOS) will be explored. We will not limit by study type, geographical location, infection type or method of outcome measurement. Two researchers will independently carry out study selection, data extraction and risk of bias assessment using the ROB2 and ROBINS-E tools. The overall quality of the studies will be determined using the Grading of Recommendations Assessment, Development and Evaluation criteria. We will also evaluate study heterogeneity with respect to study design, exposure and outcome measurement and if there is sufficient homogeneity, a meta-analysis will be conducted. Otherwise, we will provide a narrative synthesis with results grouped by exposure category and study design.
ETHICS AND DISSEMINATION: The present study does not require ethical approval. Results will be disseminated via publishing in a peer-reviewed journal and conference presentations.
PROSPERO REGISTRATION NUMBER: CRD42023444854.}, }
@article {pmid38657142, year = {2024}, author = {Nageshan, RK and Krogan, N and Cooper, JP}, title = {Parallel genetic screens identify nuclear envelope homeostasis as a key determinant of telomere entanglement resolution in fission yeast.}, journal = {G3 (Bethesda, Md.)}, volume = {}, number = {}, pages = {}, doi = {10.1093/g3journal/jkae078}, pmid = {38657142}, issn = {2160-1836}, abstract = {In fission yeast lacking the telomere binding protein, Taz1, replication forks stall at telomeres, triggering deleterious downstream events. Strand invasion from one taz1Δ telomeric stalled fork to another on a separate (non-sister) chromosome leads to telomere entanglements, which are resolved in mitosis at 32°C; however, entanglement resolution fails at ≤20°C, leading to cold-specific lethality. Previously, we found that loss of the mitotic function of Rif1, a conserved DNA replication and repair factor, suppresses cold sensitivity by promoting resolution of entanglements without affecting entanglement formation. To understand the underlying pathways of mitotic entanglement resolution, we performed a series of genomewide synthetic genetic array screens to generate a comprehensive list of genetic interactors of taz1Δ and rif1Δ. We modified a previously described screening method to ensure that the queried cells were kept in log phase growth. In addition to recapitulating previously identified genetic interactions, we find that loss of genes encoding components of the nuclear pore complex (NPC) promotes telomere disentanglement and suppresses taz1Δ cold sensitivity. We attribute this to more rapid anaphase midregion nuclear envelope (NE) breakdown in the absence of these NPC components. Loss of genes involved in lipid metabolism reverses the ability of rif1+ deletion to suppress taz1Δ cold sensitivity, again pinpointing NE modulation. A rif1+ separation-of-function mutant that specifically loses Rif1's mitotic functions yields similar genetic interactions. Genes promoting membrane fluidity were enriched in a parallel taz1+ synthetic lethal screen at permissive temperature, cementing the idea that the cold specificity of taz1Δ lethality stems from altered NE homeostasis.}, }
@article {pmid38656297, year = {2024}, author = {Hu, C and Zhu, XT and He, MH and Shao, Y and Qin, Z and Wu, ZJ and Zhou, JQ}, title = {Elimination of subtelomeric repeat sequences exerts little effect on telomere essential functions in Saccharomyces cerevisiae.}, journal = {eLife}, volume = {12}, number = {}, pages = {}, doi = {10.7554/eLife.91223}, pmid = {38656297}, issn = {2050-084X}, support = {2023YFA0913400//National Key Research and Development Program of China/ ; 32150004//The National Natural Science Foundation of China/ ; }, mesh = {*Saccharomyces cerevisiae/genetics ; *Telomere/metabolism/genetics ; *Repetitive Sequences, Nucleic Acid/genetics ; *Telomerase/genetics/metabolism ; Telomere Homeostasis ; Saccharomyces cerevisiae Proteins/genetics/metabolism ; Sequence Deletion ; }, abstract = {Telomeres, which are chromosomal end structures, play a crucial role in maintaining genome stability and integrity in eukaryotes. In the baker's yeast Saccharomyces cerevisiae, the X- and Y'-elements are subtelomeric repetitive sequences found in all 32 and 17 telomeres, respectively. While the Y'-elements serve as a backup for telomere functions in cells lacking telomerase, the function of the X-elements remains unclear. This study utilized the S. cerevisiae strain SY12, which has three chromosomes and six telomeres, to investigate the role of X-elements (as well as Y'-elements) in telomere maintenance. Deletion of Y'-elements (SY12[YΔ]), X-elements (SY12[XYΔ+Y]), or both X- and Y'-elements (SY12[XYΔ]) did not impact the length of the terminal TG1-3 tracks or telomere silencing. However, inactivation of telomerase in SY12[YΔ], SY12[XYΔ+Y], and SY12[XYΔ] cells resulted in cellular senescence and the generation of survivors. These survivors either maintained their telomeres through homologous recombination-dependent TG1-3 track elongation or underwent microhomology-mediated intra-chromosomal end-to-end joining. Our findings indicate the non-essential role of subtelomeric X- and Y'-elements in telomere regulation in both telomerase-proficient and telomerase-null cells and suggest that these elements may represent remnants of S. cerevisiae genome evolution. Furthermore, strains with fewer or no subtelomeric elements exhibit more concise telomere structures and offer potential models for future studies in telomere biology.}, }
@article {pmid38649458, year = {2024}, author = {Li, H and Durbin, R}, title = {Genome assembly in the telomere-to-telomere era.}, journal = {Nature reviews. Genetics}, volume = {}, number = {}, pages = {}, pmid = {38649458}, issn = {1471-0064}, abstract = {Genome sequences largely determine the biology and encode the history of an organism, and de novo assembly - the process of reconstructing the genome sequence of an organism from sequencing reads - has been a central problem in bioinformatics for four decades. Until recently, genomes were typically assembled into fragments of a few megabases at best, but now technological advances in long-read sequencing enable the near-complete assembly of each chromosome - also known as telomere-to-telomere assembly - for many organisms. Here, we review recent progress on assembly algorithms and protocols, with a focus on how to derive near-telomere-to-telomere assemblies. We also discuss the additional developments that will be required to resolve remaining assembly gaps and to assemble non-diploid genomes.}, }
@article {pmid38643009, year = {2024}, author = {Dilixiati, D and Kadier, K and Laihaiti, D and Lu, JD and Azhati, B and Rexiati, M}, title = {Association between leucocyte telomere length and erectile dysfunction in US adults: a secondary study based on 2001-2002 NHANES data.}, journal = {BMJ open}, volume = {14}, number = {4}, pages = {e077808}, doi = {10.1136/bmjopen-2023-077808}, pmid = {38643009}, issn = {2044-6055}, abstract = {OBJECTIVE: We aimed to explore the association between the leucocyte telomere length (LTL) and erectile dysfunction (ED) among a nationally representative sample of US adults.
DESIGN: Secondary population-based study.
SETTING: The National Health and Nutrition Examination Survey (NHANES) (2001-2002).
PARTICIPANTS: A total of 1694 male participants were extracted from the NHANES database for 2001-2002.
The primary focus of the study was to determine the association between the LTL and ED, using multivariate logistic regression and restricted cubic spline models for examination. The secondary outcome measures involved conducting stratified subgroup analyses to exclude interactions of different variables with the LTL.
RESULTS: Participants with ED had shorter LTLs than those without ED (p<0.05). After adjusting for confounding factors, compared with the reference lowest LTL quartile, the ORs and 95% CIs for the second, third and fourth LTL quartiles were (OR 1.51; 95% CI 1.01 to 2.26), (OR 1.79; 95% CI 1.24 to 2.58) and (OR 1.25; 95% CI 0.74 to 2.11), respectively. In addition, restricted cubic splines showed an inverted J-curve relationship between the LTL and ED. At an LTL of 1.037, the curve showed an inflection point. The ORs (95% CI) of ED on the left and right sides of the inflection point were (OR 1.99; 95% CI 0.39 to 10.20; p=0.385) and (OR 0.17; 95% CI 0.03 to 0.90; p=0.039).
CONCLUSION: Our results demonstrated an inverted J-curve relationship between the LTL and ED. When the LTL was ≥1.037, the incidence of ED decreased with increasing LTL.}, }
@article {pmid38641551, year = {2024}, author = {Fernández-Varas, B and Manguan-García, C and Rodriguez-Centeno, J and Mendoza-Lupiáñez, L and Calatayud, J and Perona, R and Martín-Martínez, M and Gutierrez-Rodriguez, M and Benítez-Buelga, C and Sastre, L}, title = {Clinical mutations in the TERT and TERC genes coding for telomerase components induced oxidative stress, DNA damage at telomeres and cell apoptosis besides decreased telomerase activity.}, journal = {Human molecular genetics}, volume = {33}, number = {9}, pages = {818-834}, doi = {10.1093/hmg/ddae015}, pmid = {38641551}, issn = {1460-2083}, support = {//Fondo de Investigaciones Sanitarias, Instituto de Salud Carlos III/ ; PI20-00335//European Regional Development/ ; PIE-202180E073//Consejo Superior de Investigaciones Cientificas, Spain/ ; POSTD20042BENI//Fundación Científica Asociación Española Contra el Cancer/ ; }, abstract = {Telomeres are nucleoprotein structures at the end of chromosomes that maintain their integrity. Mutations in genes coding for proteins involved in telomere protection and elongation produce diseases such as dyskeratosis congenita or idiopathic pulmonary fibrosis known as telomeropathies. These diseases are characterized by premature telomere shortening, increased DNA damage and oxidative stress. Genetic diagnosis of telomeropathy patients has identified mutations in the genes TERT and TERC coding for telomerase components but the functional consequences of many of these mutations still have to be experimentally demonstrated. The activity of twelve TERT and five TERC mutants, five of them identified in Spanish patients, has been analyzed. TERT and TERC mutants were expressed in VA-13 human cells that express low telomerase levels and the activity induced was analyzed. The production of reactive oxygen species, DNA oxidation and TRF2 association at telomeres, DNA damage response and cell apoptosis were determined. Most mutations presented decreased telomerase activity, as compared to wild-type TERT and TERC. In addition, the expression of several TERT and TERC mutants induced oxidative stress, DNA oxidation, DNA damage, decreased recruitment of the shelterin component TRF2 to telomeres and increased apoptosis. These observations might indicate that the increase in DNA damage and oxidative stress observed in cells from telomeropathy patients is dependent on their TERT or TERC mutations. Therefore, analysis of the effect of TERT and TERC mutations of unknown function on DNA damage and oxidative stress could be of great utility to determine the possible pathogenicity of these variants.}, }
@article {pmid38634789, year = {2024}, author = {Li, B and Xiong, W and Zuo, W and Shi, Y and Wang, T and Chang, L and Wu, Y and Ma, H and Bian, Q and Chang, ACY}, title = {Proximal telomeric decompaction due to telomere shortening drives FOXC1-dependent myocardial senescence.}, journal = {Nucleic acids research}, volume = {}, number = {}, pages = {}, doi = {10.1093/nar/gkae274}, pmid = {38634789}, issn = {1362-4962}, support = {82070248//National Natural Science Foundation of China/ ; 0900000024//Shanghai Institutions of Higher Learning/ ; }, abstract = {Telomeres, TTAGGGn DNA repeat sequences located at the ends of eukaryotic chromosomes, play a pivotal role in aging and are targets of DNA damage response. Although we and others have demonstrated presence of short telomeres in genetic cardiomyopathic and heart failure cardiomyocytes, little is known about the role of telomere lengths in cardiomyocyte. Here, we demonstrate that in heart failure patient cardiomyocytes, telomeres are shortened compared to healthy controls. We generated isogenic human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMs) with short telomeres (sTL-CMs) and normal telomeres (nTL-CMs) as model. Compared to nTL-CMs, short telomeres result in cardiac dysfunction and expression of senescent markers. Using Hi-C and RNASeq, we observe that short telomeres induced TAD insulation decrease near telomeric ends and this correlated with a transcription upregulation in sTL-CMs. FOXC1, a key transcription factor involved in early cardiogenesis, was upregulated in sTL-CMs and its protein levels were negatively correlated with telomere lengths in heart failure patients. Overexpression of FOXC1 induced hiPSC-CM aging, mitochondrial and contractile dysfunction; knockdown of FOXC1 rescued these phenotypes. Overall, the work presented demonstrate that increased chromatin accessibility due to telomere shortening resulted in the induction of FOXC1-dependent expression network responsible for contractile dysfunction and myocardial senescence.}, }
@article {pmid38634106, year = {2024}, author = {Garcia-Medina, JS and Sienkiewicz, K and Narayanan, SA and Overbey, EG and Grigorev, K and Ryon, KA and Burke, M and Proszynski, J and Tierney, B and Schmidt, CM and Mencia-Trinchant, N and Klotz, R and Ortiz, V and Foox, J and Chin, C and Najjar, D and Matei, I and Chan, I and Cruchaga, C and Kleinman, A and Kim, J and Lucaci, A and Loy, C and Mzava, O and De Vlaminck, I and Singaraju, A and Taylor, LE and Schmidt, JC and Schmidt, MA and Blease, K and Moreno, J and Boddicker, A and Zhao, J and Lajoie, B and Altomare, A and Kruglyak, S and Levy, S and Yu, M and Hassane, DC and Bailey, SM and Bolton, K and Mateus, J and Mason, CE}, title = {Genome and clonal hematopoiesis stability contrasts with immune, cfDNA, mitochondrial, and telomere length changes during short duration spaceflight.}, journal = {Precision clinical medicine}, volume = {7}, number = {1}, pages = {pbae007}, pmid = {38634106}, issn = {2516-1571}, abstract = {BACKGROUND: The Inspiration4 (I4) mission, the first all-civilian orbital flight mission, investigated the physiological effects of short-duration spaceflight through a multi-omic approach. Despite advances, there remains much to learn about human adaptation to spaceflight's unique challenges, including microgravity, immune system perturbations, and radiation exposure.
METHODS: To provide a detailed genetics analysis of the mission, we collected dried blood spots pre-, during, and post-flight for DNA extraction. Telomere length was measured by quantitative PCR, while whole genome and cfDNA sequencing provided insight into genomic stability and immune adaptations. A robust bioinformatic pipeline was used for data analysis, including variant calling to assess mutational burden.
RESULT: Telomere elongation occurred during spaceflight and shortened after return to Earth. Cell-free DNA analysis revealed increased immune cell signatures post-flight. No significant clonal hematopoiesis of indeterminate potential (CHIP) or whole-genome instability was observed. The long-term gene expression changes across immune cells suggested cellular adaptations to the space environment persisting months post-flight.
CONCLUSION: Our findings provide valuable insights into the physiological consequences of short-duration spaceflight, with telomere dynamics and immune cell gene expression adapting to spaceflight and persisting after return to Earth. CHIP sequencing data will serve as a reference point for studying the early development of CHIP in astronauts, an understudied phenomenon as previous studies have focused on career astronauts. This study will serve as a reference point for future commercial and non-commercial spaceflight, low Earth orbit (LEO) missions, and deep-space exploration.}, }
@article {pmid38633384, year = {2024}, author = {Yu, HJ and Byun, YH and Park, CK}, title = {Techniques for assessing telomere length: A methodological review.}, journal = {Computational and structural biotechnology journal}, volume = {23}, number = {}, pages = {1489-1498}, pmid = {38633384}, issn = {2001-0370}, abstract = {Telomeres are located at the ends of chromosomes and have specific sequences with a distinctive structure that safeguards genes. They possess capping structures that protect chromosome ends from fusion events and ensure chromosome stability. Telomeres shorten in length during each cycle of cell division. When this length reaches a certain threshold, it can lead to genomic instability, thus being implicated in various diseases, including cancer and neurodegenerative disorders. The possibility of telomeres serving as a biomarker for aging and age-related disease is being explored, and their significance is still under study. This is because post-mitotic cells, which are mature cells that do not undergo mitosis, do not experience telomere shortening due to age. Instead, other causes, for example, exposure to oxidative stress, can directly damage the telomeres, causing genomic instability. Nonetheless, a general agreement has been established that measuring telomere length offers valuable insights and forms a crucial foundation for analyzing gene expression and epigenetic data. Numerous approaches have been developed to accurately measure telomere lengths. In this review, we summarize various methods and their advantages and limitations for assessing telomere length.}, }
@article {pmid38631323, year = {2024}, author = {de Punder, K and Salinas-Manrique, J and Dietrich, DE and Karabatsiakis, A}, title = {Serum levels of the steroid hormone dehydroepiandrosterone (DHEA) are associated with psychological trauma and lymphocyte telomere integrity in women suffering from depression.}, journal = {Neuroimmunomodulation}, volume = {}, number = {}, pages = {}, doi = {10.1159/000538893}, pmid = {38631323}, issn = {1423-0216}, abstract = {INTRODUCTION: Emerging studies highlight the telomere system as an aging mechanism underlying the association between exposure to psychological trauma and the development of a wide range of physical and mental disorders, including major depressive disorder (MDD). Here, we investigated associations of circulating levels of the steroid hormone dehydroepiandrosterone (DHEA) with immune cell telomere length (TL) in the context of lifetime trauma exposure and MDD.
METHODS: Lifetime traumatic events (trauma load) were assessed using the Essener Trauma Inventory (ETI) in n=22 postmenopausal female inpatients with MDD and n=22 non-depressed controls. All women completed the Beck's Depression Inventory-II to assess the severity of current depressive symptoms. DHEA concentration in serum was measured by immunoassay and TL was quantified in kilobase units using quantitative fluorescent in situ hybridization (qFISH) in total peripheral blood mononuclear cells (PBMC) and in selected T cell subpopulations isolated by FACS separation.
RESULTS: Higher trauma load was significantly associated with lower DHEA concentration, which in turn was linked to more depression-related fatigue. Furthermore, DHEA concentration was positively and significantly associated with TL in memory CD4+ T cells as well as in naïve and memory CD8+ T cells, but not in naïve CD4+ T cells and total PBMC. Mediational analysis suggested that DHEA concentration is a mediator in the relationship between trauma load and memory CD8+ T cell TL.
CONCLUSION: The current findings suggest a potential role of DHEA as a biological resilience factor that may exert beneficial effects on telomere integrity, especially in conditions related to distress.}, }
@article {pmid38631073, year = {2024}, author = {Zhong, M and Salberg, S and Sampangi, S and van der Walt, A and Butzkueven, H and Mychasiuk, R and Jokubaitis, V}, title = {Leukocyte telomere length in multiple sclerosis: relationship between disability severity and pregnancy history.}, journal = {Multiple sclerosis and related disorders}, volume = {86}, number = {}, pages = {105607}, doi = {10.1016/j.msard.2024.105607}, pmid = {38631073}, issn = {2211-0356}, abstract = {BACKGROUND: Aging-related processes contribute to neurodegeneration and disability in multiple sclerosis (MS). Biomarkers of biological aging such as leukocyte telomere length (LTL) could help personalise prognosis. Pregnancy has been shown to be protective against disability accumulation in women with MS, though it is unclear if this effect relates to aging mechanisms or LTL.
OBJECTIVES: This study aimed to cross-sectionally characterise LTL in a cohort of individuals with MS, and to correlate LTL with disability severity and pregnancy history.
METHODS: We extracted DNA from the whole blood of 501 people with MS in Melbourne, Australia. Expanded Disability Status Scale (EDSS) score and demographic data, as well as pregnancy history for 197 females, were obtained at sample collection. Additional data were extracted from the MSBase Registry. LTL was determined in base pairs (bp) using real-time quantitative polymerase chain reaction.
RESULTS: A relationship between EDSS score and shorter LTL was robust to multivariable adjustment for demographic and clinical factors including chronological age, with an adjusted LTL reduction per 1.0 increase in EDSS of 97.1 bp (95 % CI = 9.7-184.5 bp, p = 0.030). Adjusted mediation analysis found chronological age accounted for 33.6 % of the relationship between LTL and EDSS score (p = 0.018). In females with pregnancy data, history of pregnancy was associated with older age (median 49.7 vs 33.0 years, p < 0.001). There were no significant relationships between adjusted LTL and any history of pregnancy (LTL increase of 65.3 bp, 95 % CI = -471.0-601.5 bp, p = 0.81) or number of completed pregnancies (LTL increase of 14.6 bp per pregnancy, 95 % CI = -170.3-199.6 bp, p = 0.87).
CONCLUSIONS: The correlation between LTL and disability independent of chronological age and other factors points to a link between neurological reserve in MS and biological aging, and a potential research target for pathophysiological and therapeutic mechanisms. Although LTL did not significantly differ by pregnancy history, longitudinal analyses could help identify interactions with prospectively captured pregnancy effects.}, }
@article {pmid38629454, year = {2024}, author = {Liang, X and Aouizerat, BE and So-Armah, K and Cohen, MH and Marconi, VC and Xu, K and Justice, AC}, title = {DNA methylation-based telomere length is associated with HIV infection, physical frailty, cancer, and all-cause mortality.}, journal = {Aging cell}, volume = {}, number = {}, pages = {e14174}, doi = {10.1111/acel.14174}, pmid = {38629454}, issn = {1474-9726}, support = {R01-DA035616/DA/NIDA NIH HHS/United States ; R01-DA038632/DA/NIDA NIH HHS/United States ; R01-DA047063/DA/NIDA NIH HHS/United States ; R01-DA047820/DA/NIDA NIH HHS/United States ; R03-DA039745/DA/NIDA NIH HHS/United States ; U01-AA020790/AA/NIAAA NIH HHS/United States ; U01-AA020795/AA/NIAAA NIH HHS/United States ; U01-AA020799/AA/NIAAA NIH HHS/United States ; U10-AA013566/AA/NIAAA NIH HHS/United States ; U24-AA020794/AA/NIAAA NIH HHS/United States ; }, abstract = {Telomere length (TL) is an important indicator of cellular aging. Shorter TL is associated with several age-related diseases including coronary heart disease, heart failure, diabetes, osteoporosis, and cancer. Recently, a DNA methylation-based TL (DNAmTL) estimator has been developed as an alternative method for directly measuring TL. In this study, we examined the association of DNAmTL with cancer prevalence and mortality risk among people with and without HIV in the Veterans Aging Cohort Study Biomarker Cohort (VACS, N = 1917) and Women's Interagency HIV Study Cohort (WIHS, N = 481). We profiled DNAm in whole blood (VACS) or in peripheral blood mononuclear cells (WIHS) using an array-based method. Cancer prevalence was estimated from electronic medical records and cancer registry data. The VACS Index was used as a measure of physiologic frailty. Models were adjusted for self-reported race and ethnicity, batch, smoking status, alcohol consumption, and five cell types (CD4, CD8, NK, B cell, and monocyte). We found that people with HIV had shorter average DNAmTL than those without HIV infection [beta = -0.25, 95% confidence interval (-0.32, -0.18), p = 1.48E-12]. Greater value of VACS Index [beta = -0.002 (-0.003, -0.001), p = 2.82E-05] and higher cancer prevalence [beta = -0.07 (-0.10, -0.03), p = 1.37E-04 without adjusting age] were associated with shortened DNAmTL. In addition, one kilobase decrease in DNAmTL was associated with a 40% increase in mortality risk [hazard ratio: 0.60 (0.44, 0.82), p = 1.42E-03]. In summary, HIV infection, physiologic frailty, and cancer are associated with shortening DNAmTL, contributing to an increased risk of all-cause mortality.}, }
@article {pmid38621495, year = {2024}, author = {Moura, HF and Schuch, JB and Ornell, F and Bandeira, CE and Massuda, R and Dotto Bau, CH and Grevet, EH and Kessler, FHP and von Diemen, L}, title = {Association between telomere length with alcohol use disorder and internalizing/externalizing comorbidities in a Brazilian male sample.}, journal = {Alcohol (Fayetteville, N.Y.)}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.alcohol.2024.04.004}, pmid = {38621495}, issn = {1873-6823}, abstract = {BACKGROUND: Shortening telomere length (TL) is an important ageing marker associated with substance use disorder (SUD). However, the influence of psychiatric and clinical comorbidities and alcohol-related outcomes has not been much explored in the context of TL in individuals with alcohol use disorder (AUD) and may be a source of heterogeneity in AUD studies. Therefore, our aim was to investigate the influence of AUD, alcohol-related outcomes, and common psychiatric comorbidities on TL in men with AUD and healthy controls (HC).
METHODS: Men with AUD (n=108, mean age=52.4, SD=8.6) were recruited in a detoxification unit, and HC (n=80, mean age=50.04, SD=9.1) from the blood bank, both located in Brazil. HC had no current or lifetime diagnosis of any substance use disorder. Psychiatric comorbidities were assessed using SCID-I. TL ratio was measured in triplicates using quantitative multiplex PCR.
RESULTS: Telomere length did not differ between individuals with AUD and HC (p=0.073) or was associated with AUD-related outcomes, trauma, or clinical comorbidities. Individuals with externalizing disorders had longer TL when comparing with those with internalizing disorders (p=0.018) or without comorbidity (p=0.018).
CONCLUSION: Our findings indicate that TL was influenced by the presence of psychiatric comorbidity rather than case or control status. These results were adjusted for potential confounders, such as age.}, }
@article {pmid38617276, year = {2024}, author = {Greshnova, A and Pál, K and Martinez, JFI and Canzar, S and Makova, KD}, title = {Transcript Isoform Diversity of Y Chromosome Ampliconic Genes of Great Apes Uncovered Using Long Reads and Telomere-to-Telomere Reference Genome Assemblies.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2024.04.02.587783}, pmid = {38617276}, abstract = {Y chromosomes of great apes harbor A mpliconic G enes (YAGs)-multi-copy gene families (BPY2 , CDY , DAZ , HSFY , PRY , RBMY , TSPY , VCY , and XKRY) that encode proteins important for spermatogenesis. Previous work assembled YAG transcripts based on their targeted sequencing but not using reference genome assemblies, potentially resulting in an incomplete transcript repertoire. Here we used the recently produced gapless telomere-to-telomere (T2T) Y chromosome assemblies of great ape species (bonobo, chimpanzee, human, gorilla, Bornean orangutan, and Sumatran orangutan) and analyzed RNA data from whole-testis samples for the same species. We generated hybrid transcriptome assemblies by combining targeted long reads (Pacific Biosciences), untargeted long reads (Pacific Biosciences) and untargeted short reads (Illumina)and mapping them to the T2T reference genomes. Compared to the results from the reference-free approach, average transcript length was more than two times higher, and the total number of transcripts decreased three times, improving the quality of the assembled transcriptome. The reference-based transcriptome assemblies allowed us to differentiate transcripts originating from different Y chromosome gene copies and from their non-Y chromosome homologs. We identified two sources of transcriptome diversity-alternative splicing and gene duplication with subsequent diversification of gene copies. For each gene family, we detected transcribed pseudogenes along with protein-coding gene copies. We revealed previously unannotated gene copies of YAGs as compared to currently available NCBI annotations, as well as novel isoforms for annotated gene copies. This analysis paves the way for better understanding Y chromosome gene functions, which is important given their role in spermatogenesis.}, }
@article {pmid38615081, year = {2024}, author = {Li, Z and Yang, J and Ji, X and Liu, J and Yin, C and Bhadauria, V and Zhao, W and Peng, YL}, title = {First telomere-to-telomere gapless assembly of the rice blast fungus Pyricularia oryzae.}, journal = {Scientific data}, volume = {11}, number = {1}, pages = {380}, pmid = {38615081}, issn = {2052-4463}, abstract = {Rice blast caused by Pyricularia oryzae (syn., Magnaporthe oryzae) was one of the most destructive diseases of rice throughout the world. Genome assembly was fundamental to genetic variation identification and critically impacted the understanding of its ability to overcome host resistance. Here, we report a gapless genome assembly of rice blast fungus P. oryzae strain P131 using PacBio, Illumina and high throughput chromatin conformation capture (Hi-C) sequencing data. This assembly contained seven complete chromosomes (43,237,743 bp) and a circular mitochondrial genome (34,866 bp). Approximately 14.31% of this assembly carried repeat sequences, significantly greater than its previous assembled version. This assembly had a 99.9% complement in BUSCO evaluation. A total of 14,982 genes protein-coding genes were predicted. In summary, we assembled the first telomere-to-telomere gapless genome of P. oryzae, which would be a valuable genome resource for future research on the genome evolution and host adaptation.}, }
@article {pmid38615017, year = {2024}, author = {Li, J and Yang, C and Zhang, Y and Li, Q and Liu, X and Zhang, Y and Zhao, Y}, title = {Study of association of leptin with leukocyte telomere length in a Chinese rural population.}, journal = {Lipids in health and disease}, volume = {23}, number = {1}, pages = {103}, pmid = {38615017}, issn = {1476-511X}, support = {U22A20360//National Natural Science Foundation of China/ ; 82060592//National Natural Science Foundation of China/ ; 2021BEG02026//key R&D projects in Ningxia Hui Autonomous Region/ ; }, abstract = {BACKGROUND: Previous studies have demonstrated the relationship between adipocyte factors, insulin resistance, and other indicators with telomere length. However, these studies did not consider the influence of changes in different indicators on telomere length over time. Therefore, the aim of this study is to elucidate the impact of changes in adipocyte factors, HOMA-IR, and other indicators on the dynamic variation of telomere length.
METHODS: The data were from a cohort study conducted in Ningxia, China. A total of 1624 subjects were analyzed. Adipokines and relative leukocyte telomere length (RLTL) were measured, and changes in Homeostatic Model Assessment for Insulin Resistance (HOMA-IR), Homeostatic Model Assessment for β-Cell Function (HOMA-β), and Quantitative Insulin Sensitivity Check Index (QUICKI) were calculated. Generalized linear models evaluated associations between changes in adipokines and RLTL changes. Furthermore, univariate analyses examined the effects of changes in adipokines and insulin resistance indicators on ΔRLTL.
RESULTS: The research findings indicate that females generally have shorter telomeres compared to males. In comparison to the low-level group of Δleptin (LEP), the high-level group of ΔLEP shows a negative correlation with ΔRLTL (B=-1.32, 95% CI (-2.38, -0.27)). Even after multivariable adjustments, this relationship persists (B=-1.31, 95% CI (-2.24, -0.23)). Further analysis reveals that after adjusting for ΔHOMA-IR, ΔHOMA-β, and ΔQUICKI, the high-level group of ΔLEP still exhibits a significant negative correlation with ΔRLTL (B=-1.37, 95% CI (-2.43, -0.31)). However, the interaction effects between ΔHOMA-IR, ΔHOMA-β, ΔQUICKI, and ΔLEP do not affect ΔRLTL.
CONCLUSIONS: Elevated levels of leptin were significantly correlated with shortened telomere length. This suggests that increased leptin levels may impact overall individual health by affecting telomere length, underscoring the importance of measures to reduce leptin levels to mitigate the onset and progression of related diseases.}, }
@article {pmid38611064, year = {2024}, author = {Wakita, H and Lu, Y and Li, X and Kobayashi, T and Hachiya, T and Ide, H and Horie, S}, title = {Evaluating Leukocyte Telomere Length and Myeloid-Derived Suppressor Cells as Biomarkers for Prostate Cancer.}, journal = {Cancers}, volume = {16}, number = {7}, pages = {}, doi = {10.3390/cancers16071386}, pmid = {38611064}, issn = {2072-6694}, abstract = {BACKGROUND: Leukocyte telomere length (LTL) and myeloid-derived suppressor cells (MDSC) are associated with aging and the development and progression of cancer. However, the exact nature of this relationship remains unclear. Our study aimed to investigate the potential of LTL and MDSC as diagnostic biomarkers for prostate cancer while also seeking to deepen our understanding of the relationship of these potential biomarkers to each other.
METHODS: Our study involved patients undergoing a prostate biopsy. We analyzed the relative LTL in genomic DNA obtained from peripheral blood leukocytes as well as the percentage of MDSC and their subtypes in peripheral blood mononuclear cells (PBMC). Our evaluation focused on examining the relationship between LTL and MDSC and pathological diagnoses as well as investigating the correlation between LTL and MDSC levels.
RESULTS: In our study of 102 participants, 56 were pathologically diagnosed with localized prostate cancer (cancer group), while 46 tested negative (control group). The cancer group exhibited significantly shorter LTL in comparison to the control group (p = 0.024). Additionally, the cancer group showed a tendency towards a higher percentage of monocytic MDSC (M-MDSC), although this difference did not reach statistical significance (p = 0.056). Our multivariate logistic regression analysis revealed that patients with shorter LTL and higher percentages of M-MDSC had a 2.98-fold (95% CI = 1.001-8.869, p = 0.049) and 3.03-fold (95% CI = 1.152-7.977, p = 0.025) increased risk of prostate cancer diagnosis, respectively. There was also a significant negative correlation between LTL and M-MDSC. (r = -0.347, p < 0.001).
CONCLUSIONS: Our research has established a correlation between LTL and MDSC in patients undergoing biopsy for prostate cancer. Notably, we observed that individuals with localized prostate cancer tend to have shorter LTL and a higher percentage of M-MDSC prior to their diagnosis. These findings suggest that LTL and M-MDSC could potentially serve as adjunctive biomarkers for the early diagnosis of prostate cancer.}, }
@article {pmid38610915, year = {2024}, author = {Moustakli, E and Zikopoulos, A and Skentou, C and Dafopoulos, S and Stavros, S and Dafopoulos, K and Drakakis, P and Georgiou, I and Zachariou, A}, title = {Association of Obesity with Telomere Length in Human Sperm.}, journal = {Journal of clinical medicine}, volume = {13}, number = {7}, pages = {}, doi = {10.3390/jcm13072150}, pmid = {38610915}, issn = {2077-0383}, abstract = {Background: Telomere attrition and mitochondrial dysfunction are two fundamental aspects of aging. Calorie restriction (CR) is the best strategy to postpone aging since it can enhance telomere attrition, boost antioxidant capacity, and lower the generation of reactive oxygen species (ROS). Since ROS is produced by mitochondria and can readily travel to cell nuclei, it is thought to be a crucial molecule for information transfer between mitochondria and cell nuclei. Important variables that affect the quality and functionality of sperm and may affect male reproductive health and fertility include telomere length, mitochondrial content, and the ratio of mitochondrial DNA (mtDNA) to nuclear DNA (nDNA). Telomere damage results from mitochondrial failure, whereas nuclear DNA remains unaffected. This research aims to investigate potential associations between these three variables and how they might relate to body mass index. Methods: Data were collected from 82 men who underwent IVF/ICSI at the University Hospital of Ioannina's IVF Unit in the Obstetrics and Gynecology Department. Evaluations included sperm morphology, sperm count, sperm motility, and participant history. To address this, male participants who were categorized into three body mass index (ΒΜΙ) groups-normal, overweight, and obese-had their sperm samples tested. Results: For both the normal and overweight groups, our results show a negative connection between relative telomere length and ΒΜI. As an illustration of a potential connection between mitochondrial health and telomere maintenance, a positive correlation was found for the obese group. Only the obese group's results were statistically significant (p < 0.05). More evidence that longer telomeres are associated with lower mitochondrial content can be found in the negative connection between telomere length and mitochondrial content in both the normal and overweight groups. However, the obese group showed a positive association. The data did not reach statistical significance for any of the three groups. These associations may affect sperm quality since telomere length and mitochondrial concentration are indicators of cellular integrity and health. Moreover, the ratio of mtDNA to nDNA was positively correlated with the relative telomere lengths of the obese group, but negatively correlated with the normal and overweight groups. In every group that was studied, the results were not statistically significant. According to this, male fertility may be negatively impacted by an imbalance in the copy number of the mitochondrial genome compared to the nuclear DNA in sperm. Conclusions: Essentially, the goal of our work is to determine whether mitochondria and telomere length in human sperm interact. Understanding these connections may aid in the explanation of some male infertility causes and possibly contribute to the creation of new treatment modalities for problems pertaining to reproductive health. The functional implications of these connections and their applications in therapeutic settings require further investigation.}, }
@article {pmid38607251, year = {2024}, author = {Wang, B and Xiong, Y and Li, R and Zhang, J and Zhang, S}, title = {Shorter telomere length increases the risk of lymphocyte immunodeficiency: A Mendelian randomization study.}, journal = {Immunity, inflammation and disease}, volume = {12}, number = {4}, pages = {e1251}, doi = {10.1002/iid3.1251}, pmid = {38607251}, issn = {2050-4527}, support = {2020SF-072//Key project of Research and development program of Shaanxi Province/ ; YXJLRH2022062//Innovation project for medical Integration in Xi'an Jiaotong University/ ; 2020YJ(ZYTS)018//Free exploration project of the second affiliated hospital of Xi'an Jiaotong University/ ; }, abstract = {BACKGROUND: For a long time, the prevailing viewpoint suggests that shorter telomere contribute to chromosomal instability, which is a shared characteristic of both aging and cancer. The newest research presented that T cell immune deficiency rather than chromosome instability predisposes patients with short telomere syndromes to some cancers. However, the relationship between genetically determined telomere length (TL) and immune cells remains unclear.
METHODS: The two-sample Mendelian randomization analysis was conducted to elucidate the potential causal relationship. The genetic data of TL and immune cells were obtained from the Genome-Wide Association Study. The inverse variance weighted (IVW) method was used to estimate the effects primarily and another four methods were as a supplement. Sensitivity analysis was used to test the results.
RESULTS: The IVW method showed a significant correlation between TL and the percentage of T cells in lymphocytes (odds ratio [OR]: 1.222, 95% confidence interval [CI]: 1.014-1.472, p = .035), indicating that shorter TL significantly increases the risk of low T cell percentage. Further analysis of T cell subsets indicated that shorter TL may primarily lead to a lower percentage of Natural Killer T cells (OR: 1.574, 95% CI: 1.281-1.935, p < .001). Analysis of B cell subsets revealed that shorter TL may be associated with a higher percentage of Naive-mature B cells, and a lower percentage of Memory B cells. And the sensitivity analysis indicated the validity and robustness of our findings.
CONCLUSION: In summary, our findings suggest that shorter TL may be associated with a decline in the percentage of T cell, as well as impediments in the differentiation of B cell, consequently leading to the onset of immunosenescence and immunodeficiency. The relevant mechanisms and potential therapeutic avenues still need further investigation.}, }
@article {pmid38606545, year = {2024}, author = {Nitschke, NJ and Jelsig, AM and Lautrup, C and Lundsgaard, M and Severinsen, MT and Cowland, JB and Maroun, LL and Andersen, MK and Grønbæk, K}, title = {Expanding the understanding of telomere biology disorder with reports from two families harboring variants in ZCCHC8 and TERC.}, journal = {Clinical genetics}, volume = {}, number = {}, pages = {}, doi = {10.1111/cge.14534}, pmid = {38606545}, issn = {1399-0004}, support = {//Rigshospitalet/ ; R302-A17259//Kræftens Bekæmpelse/ ; R223-A13071//Kræftens Bekæmpelse/ ; }, abstract = {Telomere biology disorder (TBD) can present within a wide spectrum of symptoms ranging from severe congenital malformations to isolated organ dysfunction in adulthood. Diagnosing TBD can be challenging given the substantial variation in symptoms and age of onset across generations. In this report, we present two families, one with a pathogenic variant in ZCCHC8 and another with a novel variant in TERC. In the literature, only one family has previously been reported with a ZCCHC8 variant and TBD symptoms. This family had multiple occurrences of pulmonary fibrosis and one case of bone marrow failure. In this paper, we present a second family with the same ZCCHC8 variant (p.Pro186Leu) and symptoms of TBD including pulmonary fibrosis, hematological disease, and elevated liver enzymes. The suspicion of TBD was confirmed with the measurement of short telomeres in the proband. In another family, we report a novel likely pathogenic variant in TERC. Our comprehensive description encompasses hematological manifestations, as well as pulmonary and hepatic fibrosis. Notably, there are no other reports which associate this variant to disease. The families expand our understanding of the clinical implications and genetic causes of TBD.}, }
@article {pmid38605518, year = {2024}, author = {Jia, KH and Zhang, X and Li, LL and Shi, TL and Liu, D and Yang, Y and Cong, Y and Li, R and Pu, Y and Gong, Y and Chen, X and Si, YJ and Tian, R and Qian, Z and Ding, H and Li, N}, title = {Telomere-to-telomere cultivated and wild soybean genome assembly provides insights into evolution and domestication under structural variation.}, journal = {Plant communications}, volume = {}, number = {}, pages = {100919}, doi = {10.1016/j.xplc.2024.100919}, pmid = {38605518}, issn = {2590-3462}, }
@article {pmid38603928, year = {2024}, author = {Chang, CH and Hwang, PA}, title = {Low-molecular-weight fucoidan increases telomere length and immunostimulatory effects on NK-92 cells following inhaled anesthetic injury.}, journal = {Mutation research}, volume = {828}, number = {}, pages = {111857}, doi = {10.1016/j.mrfmmm.2024.111857}, pmid = {38603928}, issn = {1873-135X}, abstract = {Inhaled anesthetics, such as isoflurane, may cause side effects, including short-term immunosuppression and DNA damage. In contrast, low molecular weight fucoidan (LMF), derived from brown seaweed, exhibits promising immunomodulatory effects. In this study, we determined the effect of isoflurane on telomeres and examined the potential of LMF to ameliorate the harmful effects of isoflurane. Male Lewis rats, the mouse lymphoma cell line YAC-1, and the human nature killer cell line NK-92 MI were exposed to isoflurane. The relative telomere length (T/S) ratio and mRNA expression were determined by quantitative PCR. The viability assay was used to assess cell viability. In vivo, 2% isoflurane exposure, which is a clinically relevant concentration, reduced telomere length, and correlated with exposure frequency and duration. Isoflurane concentrations above 2% shortened YAC-1 telomeres, with minimal impact on cell viability. LMF pre-treatment enhanced NK-92 MI cell survival resulting from isoflurane exposure and exerted superior telomere protection compared with LMF post-treatment. Furthermore, adding LMF during isoflurane exposure resulted in a significant increase in IFN-γ, TNF-α, and IL-10 mRNA compared with the untreated group. LMF protected against isoflurane-induced telomere shortening, enhanced NK cell viability, and modulated cytokine expression, thus mitigating postoperative immune suppression and risk of tumor metastasis.}, }
@article {pmid38603523, year = {2024}, author = {Karimian, K and Groot, A and Huso, V and Kahidi, R and Tan, KT and Sholes, S and Keener, R and McDyer, JF and Alder, JK and Li, H and Rechtsteiner, A and Greider, CW}, title = {Human telomere length is chromosome end-specific and conserved across individuals.}, journal = {Science (New York, N.Y.)}, volume = {}, number = {}, pages = {eado0431}, doi = {10.1126/science.ado0431}, pmid = {38603523}, issn = {1095-9203}, abstract = {Short telomeres cause age-related disease and long telomeres predispose to cancer; however, the mechanisms regulating telomere length are unclear. We developed a nanopore-based method, Telomere Profiling, to determine telomere length at nearly single nucleotide resolution. Mapping telomere reads to chromosome ends showed chromosome end-specific length distributions that could differ by more than six kilobases. Telomere lengths in 147 individuals showed certain chromosome ends were consistently longer or shorter. The same rank order was found in newborn cord blood, suggesting that telomere length is determined at birth and chromosome end-specific telomere length differences are maintained as telomeres shorten with age. Telomere Profiling makes precision investigation of telomere length widely accessible for laboratory, clinical, and drug discovery efforts and will allow deeper insights into telomere biology.}, }
@article {pmid38600880, year = {2024}, author = {Gao, Y and Xu, DD and Hu, Z}, title = {Telomere-to-telomere genome assembly of Oldenlandia diffusa.}, journal = {DNA research : an international journal for rapid publication of reports on genes and genomes}, volume = {}, number = {}, pages = {}, doi = {10.1093/dnares/dsae012}, pmid = {38600880}, issn = {1756-1663}, abstract = {We report the complete telomere-to-telomere genome assembly of Oldenlandia diffusa which renowned in traditional Chinese medicine, comprising 16 chromosomes and spanning 499.7 Mb. The assembly showcases 28 telomeres and minimal gaps, with a total of only five. Repeat sequences constitute 46.41% of the genome, and 49,701 potential protein-coding genes have been predicted. Compared with O. corymbosa, O. diffusa exhibits chromosome duplication and fusion events, diverging 20.34 million years ago. Additionally, a total of 11 clusters of terpene synthase have been identified. The comprehensive genome sequence, gene catalog, and terpene synthase clusters of O. diffusa detailed in this study will significantly contribute to advancing research in this species' genetic, genomic, and pharmacological aspects.}, }
@article {pmid38600443, year = {2024}, author = {Wang, B and Jia, Y and Dang, N and Yu, J and Bush, SJ and Gao, S and He, W and Wang, S and Guo, H and Yang, X and Ma, W and Ye, K}, title = {Near telomere-to-telomere genome assemblies of two Chlorella species unveil the composition and evolution of centromeres in green algae.}, journal = {BMC genomics}, volume = {25}, number = {1}, pages = {356}, pmid = {38600443}, issn = {1471-2164}, support = {32200510//National Natural Science Foundation of China/ ; 2022YFC3400300//National Key Research and Development Program of China/ ; }, abstract = {BACKGROUND: Centromeres play a crucial and conserved role in cell division, although their composition and evolutionary history in green algae, the evolutionary ancestors of land plants, remains largely unknown.
RESULTS: We constructed near telomere-to-telomere (T2T) assemblies for two Trebouxiophyceae species, Chlorella sorokiniana NS4-2 and Chlorella pyrenoidosa DBH, with chromosome numbers of 12 and 13, and genome sizes of 58.11 Mb and 53.41 Mb, respectively. We identified and validated their centromere sequences using CENH3 ChIP-seq and found that, similar to humans and higher plants, the centromeric CENH3 signals of green algae display a pattern of hypomethylation. Interestingly, the centromeres of both species largely comprised transposable elements, although they differed significantly in their composition. Species within the Chlorella genus display a more diverse centromere composition, with major constituents including members of the LTR/Copia, LINE/L1, and LINE/RTEX families. This is in contrast to green algae including Chlamydomonas reinhardtii, Coccomyxa subellipsoidea, and Chromochloris zofingiensis, in which centromere composition instead has a pronounced single-element composition. Moreover, we observed significant differences in the composition and structure of centromeres among chromosomes with strong collinearity within the Chlorella genus, suggesting that centromeric sequence evolves more rapidly than sequence in non-centromeric regions.
CONCLUSIONS: This study not only provides high-quality genome data for comparative genomics of green algae but gives insight into the composition and evolutionary history of centromeres in early plants, laying an important foundation for further research on their evolution.}, }
@article {pmid38593805, year = {2024}, author = {Jiang, H and Zhang, T and Kaur, H and Shi, T and Krishnan, A and Kwon, Y and Sung, P and Greenberg, RA}, title = {BLM helicase unwinds lagging strand substrates to assemble the ALT telomere damage response.}, journal = {Molecular cell}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.molcel.2024.03.011}, pmid = {38593805}, issn = {1097-4164}, abstract = {The Bloom syndrome (BLM) helicase is critical for alternative lengthening of telomeres (ALT), a homology-directed repair (HDR)-mediated telomere maintenance mechanism that is prevalent in cancers of mesenchymal origin. The DNA substrates that BLM engages to direct telomere recombination during ALT remain unknown. Here, we determine that BLM helicase acts on lagging strand telomere intermediates that occur specifically in ALT-positive cells to assemble a replication-associated DNA damage response. Loss of ATRX was permissive for BLM localization to ALT telomeres in S and G2, commensurate with the appearance of telomere C-strand-specific single-stranded DNA (ssDNA). DNA2 nuclease deficiency increased 5'-flap formation in a BLM-dependent manner, while telomere C-strand, but not G-strand, nicks promoted ALT. These findings define the seminal events in the ALT DNA damage response, linking aberrant telomeric lagging strand DNA replication with a BLM-directed HDR mechanism that sustains telomere length in a subset of human cancers.}, }
@article {pmid38594465, year = {2024}, author = {Shou, S and Li, Y and Chen, J and Zhang, X and Zhang, C and Jiang, X and Liu, F and Yi, L and Zhang, X and Geer, E and Pu, Z and Pang, B}, title = {Understanding, diagnosing, and treating pancreatic cancer from the perspective of telomeres and telomerase.}, journal = {Cancer gene therapy}, volume = {}, number = {}, pages = {}, pmid = {38594465}, issn = {1476-5500}, abstract = {Telomerase is associated with cellular aging, and its presence limits cellular lifespan. Telomerase by preventing telomere shortening can extend the number of cell divisions for cancer cells. In adult pancreatic cells, telomeres gradually shorten, while in precancerous lesions of cancer, telomeres in cells are usually significantly shortened. At this time, telomerase is still in an inactive state, and it is not until before and after the onset of cancer that telomerase is reactivated, causing cancer cells to proliferate. Methylation of the telomerase reverse transcriptase (TERT) promoter and regulation of telomerase by lactate dehydrogenase B (LDHB) is the mechanism of telomerase reactivation in pancreatic cancer. Understanding the role of telomeres and telomerase in pancreatic cancer will help to diagnose and initiate targeted therapy as early as possible. This article reviews the role of telomeres and telomerase as biomarkers in the development of pancreatic cancer and the progress of research on telomeres and telomerase as targets for therapeutic intervention.}, }
@article {pmid38593475, year = {2024}, author = {Teixeira, GA and Travenzoli, NM and Tavares, MG}, title = {Chromosomal organization of different repetitive sequences in four wasp species of the genus Trypoxylon Latreille (Hymenoptera: Crabronidae) and insights into the composition of wasp telomeres.}, journal = {Genome}, volume = {}, number = {}, pages = {}, doi = {10.1139/gen-2023-0132}, pmid = {38593475}, issn = {1480-3321}, abstract = {This study characterizes the chromosomal organization of DNA repetitive sequences and the karyotypic evolution in four representatives of the solitary wasp genus Trypoxylon using conventional and molecular cytogenetic techniques. Our findings present the first cytogenetic data for T. rogenhoferi (2n=30) and T. albonigrum (2n=32) while the karyotypes of T. nitidum (2n=30) and T. lactitarse (2n=30) were similar to those described previously. Fluorochrome staining and microsatellite distribution data revealed differences in the constitutive heterochromatin composition among species. Trypoxylon nitidum and T. albonigrum exhibited a single rRNA gene site, potentially representing an ancestral pattern for aculeate Hymenoptera, while T. rogenhoferi and T. lactitarse showed two pericentromeric rRNA gene sites, suggesting amplification events in their ancestral clade. The (TCAGG)n motif hybridized in the terminal regions of the chromosomes in all four Trypoxylon species, which may suggest that this sequence is part of their telomeres. Notably, the presence of this repetitive sequence in the centromeric regions of certain chromosome pairs in two species supports the hypothesis of chromosomal fusions or inversions in the ancestral karyotype of Trypoxylon. The study expands the chromosomal mapping data of repetitive sequences in wasps and offers insights into the dynamic evolutionary landscape of karyotypes in these insects.}, }
@article {pmid38593055, year = {2024}, author = {Karadağ, A and Dirican, E and Özmerdiven, ÇG and Özen, A and Ayan, S and Kabadere, S}, title = {Evaluation of miR-130b-3p and miR-375 levels and telomere length with telomerase activity in prostate cancer.}, journal = {Nucleosides, nucleotides & nucleic acids}, volume = {}, number = {}, pages = {1-12}, doi = {10.1080/15257770.2024.2334896}, pmid = {38593055}, issn = {1532-2335}, abstract = {Prostate cancer (PC) is the most frequent cancer in males, as well as the second highest cause of cancer-related deaths in men. Differences in expression levels of miRNAs were linked with prostat cancer pathogenesis. qPCR was used to evaluate the expression of miR-130b-3p and miR-375 in Benign Prostate Hyperplasia (BPH (n = 20) and PC (n = 22, pre- and post-operative) patients plasma. Relative telomere lengths (RLTs) in genomic DNA isolated from plasma were measured with qPCR, and telomerase activity analyzed by the ELISA method. PSA levels of PC patients were greater than of BPH patients (p = 0.0473). miR-130b-3p and miR-375 levels were significantly lower in pre-operative specimens of PC patients according to BPH (p = 0,0362, p = 0.0168, respectively). Similarly, post-operative miR-375 levels were lower in PC patients than in BPH patients (p = 0.1866). BPH patients had shorter RTLs than PC patients in both pre- (p=0.0438) and post-operative (p=0.0297) specimens. Telomerase activity was higher in PC patients than BPH(p = 0.0129). Interestingly, telomerase activity was further increased after surgery (p = 0.0003). We aim to identify the levels of miR-130b-3p and miR-375 expression and their relationship with telomerase activity in PC patients. Our data suggest that miRNAs and telomere length (TL) with telomerase activity may play a role in regulating prostate tumorgenesis and may be used as biomarkers for PC diagnosis.}, }
@article {pmid38588482, year = {2024}, author = {de la Rosa, R and Le, A and Holm, S and Ye, M and Bush, NR and Hessler, D and Koita, K and Bucci, M and Long, D and Thakur, N}, title = {Associations Between Early-Life Adversity, Ambient Air Pollution, and Telomere Length in Children.}, journal = {Psychosomatic medicine}, volume = {}, number = {}, pages = {}, doi = {10.1097/PSY.0000000000001276}, pmid = {38588482}, issn = {1534-7796}, abstract = {OBJECTIVE: Examine the independent associations and interaction between early-life adversity and residential ambient air pollution exposure on relative buccal telomere length (rBTL).
METHODS: Experiences of abuse, neglect, household challenges, and related life events were identified in a cross-sectional sample of children ages 1-11 years (n = 197) using the 17-item Pediatric ACEs and Related Life Event Screener (PEARLS) tool. The PEARLS tool was analyzed both as a total score and across established domains (Maltreatment, Household Challenges, and Social Context). Ground-level fine particulate matter (PM2.5) concentrations were matched to residential locations for the one and twelve months prior to biospecimen collection. We used multivariable linear regression models to examine for independent associations between continuous PM2.5 exposure and PEARLS score/domains with rBTL. Additionally, effect modification by PEARLS scores and domains on associations between PM2.5 exposure and rBTL was examined.
RESULTS: Study participants were 47% girls, with mean age = 5.9 years [standard deviation: 3.4] median reported PEARLS score of 2 [interquartile range (IQR): 4], median 12-month prior PM2.5 concentrations of 11.8 μg/m3 [IQR: 2.7], median 1-month prior PM2.5 concentrations of 10.9 μg/m3 [IQR: 5.8], and rBTL of 0.1 [IQR: 0.03]. Mean 12-month prior PM2.5 exposure was inversely associated with rBTL (ß = -0.02, 95% CI: -0.04, -0.01). While reported PEARLS scores and domains were not independently associated with rBTL, we observed a greater decrement in rBTL with increment of average annual PM2.5 as reported Social Context domain items increased (p-interaction<0.05).
CONCLUSION: Our results suggest that adverse Social Context factors may accelerate the association between chronic PM2.5 exposure on telomere shortening during childhood.}, }
@article {pmid38588418, year = {2024}, author = {Padmanaban, S and Lambacher, NJ and Tesmer, VM and Zhang, J and Shibuya, H and Nandakumar, J}, title = {Caenorhabditis elegans telomere-binding proteins TEBP-1 and TEBP-2 adapt the Myb module to dimerize and bind telomeric DNA.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {121}, number = {16}, pages = {e2316651121}, doi = {10.1073/pnas.2316651121}, pmid = {38588418}, issn = {1091-6490}, support = {R01HD108809//HHS | NIH | Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)/ ; R35GM148276//HHS | NIH | National Institute of General Medical Sciences (NIGMS)/ ; 211377Pj//Cancerfonden (Swedish Cancer Society)/ ; }, abstract = {Protecting chromosome ends from misrecognition as double-stranded (ds) DNA breaks is fundamental to eukaryotic viability. The protein complex shelterin prevents a DNA damage response at mammalian telomeres. Mammalian shelterin proteins TRF1 and TRF2 and their homologs in yeast and protozoa protect telomeric dsDNA. N-terminal homodimerization and C-terminal Myb-domain-mediated dsDNA binding are two structural hallmarks of end protection by TRF homologs. Yet our understanding of how Caenorhabditis elegans protects its telomeric dsDNA is limited. Recently identified C. elegans proteins TEBP-1 (also called DTN-1) and TEBP-2 (also called DTN-2) are functional homologs of TRF proteins, but how they bind DNA and whether or how they dimerize is not known. TEBP-1 and TEBP-2 harbor three Myb-containing domains (MCDs) and no obvious dimerization domain. We demonstrate biochemically that only the third MCD binds DNA. We solve the X-ray crystal structure of TEBP-2 MCD3 with telomeric dsDNA to reveal the structural mechanism of telomeric dsDNA protection in C. elegans. Mutagenesis of the DNA-binding site of TEBP-1 and TEBP-2 compromises DNA binding in vitro, and increases DNA damage signaling, lengthens telomeres, and decreases brood size in vivo. Via an X-ray crystal structure, biochemical validation of the dimerization interface, and SEC-MALS analysis, we demonstrate that MCD1 and MCD2 form a composite dimerization module that facilitates not only TEBP-1 and TEBP-2 homodimerization but also heterodimerization. These findings provide fundamental insights into C. elegans telomeric dsDNA protection and highlight how different eukaryotes have evolved distinct strategies to solve the chromosome end protection problem.}, }
@article {pmid38587381, year = {2024}, author = {Martin, NA and McLester-Davis, LWY and Roy, TR and Magruder, MG and Hastings, WJ and Drury, SS}, title = {Monochrome Multiplex Quantitative PCR Telomere Length Measurement.}, journal = {Journal of visualized experiments : JoVE}, volume = {}, number = {205}, pages = {}, doi = {10.3791/66545}, pmid = {38587381}, issn = {1940-087X}, abstract = {Telomeres are ribonucleoprotein structures at the end of all eukaryotic chromosomes that protect DNA from damage and preserve chromosome stability. Telomere length (TL) has been associated with various exposures, biological processes, and health outcomes. This article describes the monochrome multiplex quantitative polymerase chain reaction (MMqPCR) assay protocol routinely conducted in our laboratory for measuring relative mean TL from human DNA. There are several different PCR-based TL measurement methods, but the specific protocol for the MMqPCR method presented in this publication is repeatable, efficient, cost-effective, and suitable for population-based studies. This detailed protocol outlines all information necessary for investigators to establish this assay in their laboratory. In addition, this protocol provides specific steps to increase the reproducibility of TL measurement by this assay, defined by the intraclass correlation coefficient (ICC) across repeated measurements of the same sample. The ICC is a critical factor in evaluating expected power for a specific study population; as such, reporting cohort-specific ICCs for any TL assay is a necessary step to enhance the overall rigor of population-based studies of TL. Example results utilizing DNA samples extracted from peripheral blood mononuclear cells demonstrate the feasibility of generating highly repeatable TL data using this MMqPCR protocol.}, }
@article {pmid38587189, year = {2024}, author = {Lee, JJ and Kim, H and Park, H and Lee, U and Kim, C and Lee, M and Shin, Y and Jung, JJ and Lee, HB and Han, W and Lee, H}, title = {Disruption of G-quadruplex dynamicity by BRCA2 abrogation instigates phase separation and break-induced replication at telomeres.}, journal = {Nucleic acids research}, volume = {}, number = {}, pages = {}, doi = {10.1093/nar/gkae251}, pmid = {38587189}, issn = {1362-4962}, support = {2020R1A5A1018081//National Research Foundation of Korea/ ; //Hyundai Motor Chung Mong-Koo Foundation/ ; }, abstract = {Dynamic interaction between BRCA2 and telomeric G-quadruplexes (G4) is crucial for maintaining telomere replication homeostasis. Cells lacking BRCA2 display telomeric damage with a subset of these cells bypassing senescence to initiate break-induced replication (BIR) for telomere synthesis. Here we show that the abnormal stabilization of telomeric G4 following BRCA2 depletion leads to telomeric repeat-containing RNA (TERRA)-R-loop accumulation, triggering liquid-liquid phase separation (LLPS) and the assembly of Alternative Lengthening of Telomeres (ALT)-associated promyelocytic leukemia (PML) bodies (APBs). Disruption of R-loops abolishes LLPS and impairs telomere synthesis. Artificial engineering of telomeric LLPS restores telomere synthesis, underscoring the critical role of LLPS in ALT. TERRA-R-loops also recruit Polycomb Repressive Complex 2 (PRC2), leading to tri-methylation of Lys27 on histone H3 (H3K27me3) at telomeres. Half of paraffin-embedded tissue sections from human breast cancers exhibit APBs and telomere length heterogeneity, suggesting that BRCA2 mutations can predispose individuals to ALT-type tumorigenesis. Overall, BRCA2 abrogation disrupts the dynamicity of telomeric G4, producing TERRA-R-loops, finally leading to the assembly of telomeric liquid condensates crucial for ALT. We propose that modulating the dynamicity of telomeric G4 and targeting TERRA-R-loops in telomeric LLPS maintenance may represent effective therapeutic strategies for treating ALT-like cancers with APBs, including those with BRCA2 disruptions.}, }
@article {pmid38584235, year = {2024}, author = {Lagunas-Rangel, FA}, title = {Giardia telomeres and telomerase.}, journal = {Parasitology research}, volume = {123}, number = {4}, pages = {179}, pmid = {38584235}, issn = {1432-1955}, abstract = {Giardia duodenalis, the protozoan responsible for giardiasis, is a significant contributor to millions of diarrheal diseases worldwide. Despite the availability of treatments for this parasitic infection, therapeutic failures are alarmingly frequent. Thus, there is a clear need to identify new therapeutic targets. Giardia telomeres were previously identified, but our understanding of these structures and the critical role played by Giardia telomerase in maintaining genomic stability and its influence on cellular processes remains limited. In this regard, it is known that all Giardia chromosomes are capped by small telomeres, organized and protected by specific proteins that regulate their functions. To counteract natural telomere shortening and maintain high proliferation, Giardia exhibits constant telomerase activity and employs additional mechanisms, such as the formation of G-quadruplex structures and the involvement of transposable elements linked to telomeric repeats. Thus, this study aims to address the existing knowledge gap by compiling the available information (until 2023) about Giardia telomeres and telomerase, focusing on highlighting the distinctive features within this parasite. Furthermore, the potential feasibility of targeting Giardia telomeres and/or telomerase as an innovative therapeutic strategy is discussed.}, }
@article {pmid38581556, year = {2024}, author = {Mason, CE and Sierra, MA and Feng, HJ and Bailey, SM}, title = {Telomeres and aging: on and off the planet!.}, journal = {Biogerontology}, volume = {25}, number = {2}, pages = {313-327}, pmid = {38581556}, issn = {1573-6768}, abstract = {Improving human healthspan in our rapidly aging population has never been more imperative. Telomeres, protective "caps" at the ends of linear chromosomes, are essential for maintaining genome stability of eukaryotic genomes. Due to their physical location and the "end-replication problem" first envisioned by Dr. Alexey Olovnikov, telomeres shorten with cell division, the implications of which are remarkably profound. Telomeres are hallmarks and molecular drivers of aging, as well as fundamental integrating components of the cumulative effects of genetic, lifestyle, and environmental factors that erode telomere length over time. Ongoing telomere attrition and the resulting limit to replicative potential imposed by cellular senescence serves a powerful tumor suppressor function, and also underlies aging and a spectrum of age-related degenerative pathologies, including reduced fertility, dementias, cardiovascular disease and cancer. However, very little data exists regarding the extraordinary stressors and exposures associated with long-duration space exploration and eventual habitation of other planets, nor how such missions will influence telomeres, reproduction, health, disease risk, and aging. Here, we briefly review our current understanding, which has advanced significantly in recent years as a result of the NASA Twins Study, the most comprehensive evaluation of human health effects associated with spaceflight ever conducted. Thus, the Twins Study is at the forefront of personalized space medicine approaches for astronauts and sets the stage for subsequent missions. We also extrapolate from current understanding to future missions, highlighting potential biological and biochemical strategies that may enable human survival, and consider the prospect of longevity in the extreme environment of space.}, }
@article {pmid38580193, year = {2024}, author = {Yun, JJ and Unai, S and Budev, MM and Anandamurthy, B and Almeida, F and Turowski, J and McCurry, KR and Pettersson, G}, title = {Salvage Lung Retransplantation: En-Bloc Double Lung with Bronchial Artery Revascularization For Bronchial Dehiscence Related to Short Telomeres.}, journal = {The Journal of thoracic and cardiovascular surgery}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jtcvs.2024.03.026}, pmid = {38580193}, issn = {1097-685X}, }
@article {pmid38577209, year = {2024}, author = {Rodseth, E and Sumasgutner, P and Tate, G and Nilsson, JF and Watson, H and Maritz, MF and Ingle, RA and Amar, A}, title = {Pleiotropic effects of melanin pigmentation: haemoparasite infection intensity but not telomere length is associated with plumage morph in black sparrowhawks.}, journal = {Royal Society open science}, volume = {11}, number = {4}, pages = {230370}, pmid = {38577209}, issn = {2054-5703}, abstract = {There is increasing recognition of the potential pleiotropic effects of melanin pigmentation, particularly on immunity, with reports of variation in haemoparasite infection intensity and immune responses between the morphs of colour-polymorphic bird species. In a population of the black sparrowhawk (Accipiter melanoleucus) in western South Africa, light morphs have a higher haemoparasite infection intensity, but no physiological effects of this are apparent. Here, we investigate the possible effects of haemoparasite infection on telomere length in this species and explore whether relative telomere length is associated with either plumage morph or sex. Using quantitative polymerase chain reaction analysis, we confirmed that dark morphs had a lower haemoparasite infection intensity than light morphs. However, we found no differences in telomere length associated with either the haemoparasite infection status or morph in adults, although males have longer telomeres than females. While differences in haemoparasite intensity between morphs are consistent with pleiotropic effects of melanin pigmentation in the black sparrowhawk, we found no evidence that telomere length was associated with haemoparasite infection. Further work is needed to investigate the implications of possible pleiotropic effects of plumage morph and their potential role in the maintenance of colour polymorphism in this species.}, }
@article {pmid38577142, year = {2024}, author = {Prasad, R and Kaur, G}, title = {Recent Domains in Telomere and Telomerase Targeting for Accomplished Cancer Therapy.}, journal = {Indian journal of clinical biochemistry : IJCB}, volume = {39}, number = {2}, pages = {151-153}, pmid = {38577142}, issn = {0970-1915}, }
@article {pmid38574731, year = {2024}, author = {LaBella, KA and Hsu, WH and Li, J and Qi, Y and Liu, Y and Liu, J and Wu, CC and Liu, Y and Song, Z and Lin, Y and Blecher, JM and Jiang, S and Shang, X and Han, J and Spring, DJ and Zhang, J and Xia, Y and DePinho, RA}, title = {Telomere dysfunction alters intestinal stem cell dynamics to promote cancer.}, journal = {Developmental cell}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.devcel.2024.03.020}, pmid = {38574731}, issn = {1878-1551}, abstract = {Telomere dynamics are linked to aging hallmarks, and age-associated telomere loss fuels the development of epithelial cancers. In Apc-mutant mice, the onset of DNA damage associated with telomere dysfunction has been shown to accelerate adenoma initiation via unknown mechanisms. Here, we observed that Apc-mutant mice engineered to experience telomere dysfunction show accelerated adenoma formation resulting from augmented cell competition and clonal expansion. Mechanistically, telomere dysfunction induces the repression of EZH2, resulting in the derepression of Wnt antagonists, which causes the differentiation of adjacent stem cells and a relative growth advantage to Apc-deficient telomere dysfunctional cells. Correspondingly, in this mouse model, GSK3β inhibition countered the actions of Wnt antagonists on intestinal stem cells, resulting in impaired adenoma formation of telomere dysfunctional Apc-mutant cells. Thus, telomere dysfunction contributes to cancer initiation through altered stem cell dynamics, identifying an interception strategy for human APC-mutant cancers with shortened telomeres.}, }
@article {pmid38566416, year = {2024}, author = {Amiard, S and Feit, L and Vanrobays, E and Simon, L and Le Goff, S and Loizeau, L and Wolff, L and Butter, F and Bourbousse, C and Barneche, F and Tatout, C and Probst, AV}, title = {The TELOMERE REPEAT BINDING proteins TRB4 and TRB5 function as transcriptional activators of PRC2-controlled genes to regulate plant development.}, journal = {Plant communications}, volume = {}, number = {}, pages = {100890}, doi = {10.1016/j.xplc.2024.100890}, pmid = {38566416}, issn = {2590-3462}, abstract = {Plant-specific transcriptional regulators called TELOMERE REPEAT BINDING proteins (TRBs) combine two DNA-binding domains, the GH1 domain, which binds to linker DNA and is shared with H1 histones, and the Myb/SANT domain, which specifically recognizes the telobox DNA-binding site motif. TRB1, TRB2, and TRB3 proteins recruit Polycomb group complex 2 (PRC2) to deposit H3K27me3 and JMJ14 to remove H3K4me3 at gene promoters containing telobox motifs to repress transcription. Here, we demonstrate that TRB4 and TRB5, two related paralogs belonging to a separate TRB clade conserved in spermatophytes, regulate the transcription of several hundred genes involved in developmental responses to environmental cues. Indeed, TRB4 binds to several thousand sites in the genome, mainly at TSS and promoter regions of transcriptionally active and H3K4me3-marked genes, but unlike TRB1 it is not enriched at H3K27me3-marked gene bodies. Yet, TRB4 can physically interact with the catalytic components of PRC2, SWINGER and CURLY LEAF (CLF). Unexpectedly, we show that TRB4 and TRB5 are required for distinctive phenotypic traits observed in clf mutant plants and accordingly function as transcriptional activators of several hundred of CLF-controlled genes, including key flowering genes. We further demonstrate that TRB4 shares multiple target genes with TRB1 and physically and genetically interacts with members of both TRB clades. Collectively, this study uncovers that TRB proteins engage in both positive and negative interactions with other members of the family to regulate plant development through both PRC2-dependent and independent mechanisms.}, }
@article {pmid38565156, year = {2024}, author = {Ravindran, S and Underwood, SL and Dorrens, J and Seeker, LA and Watt, K and Wilbourn, RV and Sparks, AM and Sinclair, R and Chen, Z and Pilkington, JG and McNeilly, TN and Harrington, L and Pemberton, JM and Nussey, DH and Froy, H}, title = {No correlative evidence of costs of infection or immunity on leucocyte telomere length in a wild population of Soay sheep.}, journal = {Proceedings. Biological sciences}, volume = {291}, number = {2020}, pages = {20232946}, doi = {10.1098/rspb.2023.2946}, pmid = {38565156}, issn = {1471-2954}, abstract = {Telomere length (TL) is a biomarker hypothesized to capture evolutionarily and ecologically important physiological costs of reproduction, infection and immunity. Few studies have estimated the relationships among infection status, immunity, TL and fitness in natural systems. The hypothesis that short telomeres predict reduced survival because they reflect costly consequences of infection and immune investment remains largely untested. Using longitudinal data from a free-living Soay sheep population, we tested whether leucocyte TL was predicted by infection with nematode parasites and antibody levels against those parasites. Helminth parasite burdens were positively associated with leucocyte TL in both lambs and adults, which is not consistent with TL reflecting infection costs. We found no association between TL and helminth-specific IgG levels in either young or old individuals which suggests TL does not reflect costs of an activated immune response or immunosenescence. Furthermore, we found no support for TL acting as a mediator of trade-offs between infection, immunity and subsequent survival in the wild. Our results suggest that while variation in TL could reflect short-term variation in resource investment or environmental conditions, it does not capture costs of infection and immunity, nor does it behave like a marker of an individual's helminth-specific antibody immune response.}, }
@article {pmid38565848, year = {2024}, author = {Muoio, D and Laspata, N and Dannenberg, RL and Curry, C and Darkoa-Larbi, S and Hedglin, M and Uttam, S and Fouquerel, E}, title = {PARP2 promotes Break Induced Replication-mediated telomere fragility in response to replication stress.}, journal = {Nature communications}, volume = {15}, number = {1}, pages = {2857}, pmid = {38565848}, issn = {2041-1723}, support = {R35GM142982//U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS)/ ; }, abstract = {PARP2 is a DNA-dependent ADP-ribosyl transferase (ARTs) enzyme with Poly(ADP-ribosyl)ation activity that is triggered by DNA breaks. It plays a role in the Base Excision Repair pathway, where it has overlapping functions with PARP1. However, additional roles for PARP2 have emerged in the response of cells to replication stress. In this study, we demonstrate that PARP2 promotes replication stress-induced telomere fragility and prevents telomere loss following chronic induction of oxidative DNA lesions and BLM helicase depletion. Telomere fragility results from the activity of the break-induced replication pathway (BIR). During this process, PARP2 promotes DNA end resection, strand invasion and BIR-dependent mitotic DNA synthesis by orchestrating POLD3 recruitment and activity. Our study has identified a role for PARP2 in the response to replication stress. This finding may lead to the development of therapeutic approaches that target DNA-dependent ART enzymes, particularly in cancer cells with high levels of replication stress.}, }
@article {pmid38565642, year = {2024}, author = {Huang, R and Bornman, MSR and Stricker, PD and Simoni Brum, I and Mutambirwa, SBA and Jaratlerdsiri, W and Hayes, VM}, title = {The impact of telomere length on prostate cancer aggressiveness, genomic instability and health disparities.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {7706}, pmid = {38565642}, issn = {2045-2322}, support = {International Research Training Program Scholarship//Australian Government/ ; APP2001098//National Health and Medical Research Council/ ; APP2001098//National Health and Medical Research Council/ ; PC210168//Congressionally Directed Medical Research Programs/ ; PC210168//Congressionally Directed Medical Research Programs/ ; Petre Chair//Petre Foundation/ ; }, abstract = {The telomere repetitive TTAGGG motif at the ends of chromosomes, serves to preserve genomic integrity and chromosomal stability. In turn, genomic instability is a hallmark of cancer-implicating telomere disturbance. Prostate cancer (PCa) shows significant ancestral disparities, with men of African ancestry at the greatest risk for aggressive disease and associated genomic instability. Yet, no study has explored the role of telomere length (TL) with respect to ancestrally driven PCa health disparities. Patient- and technically-matched tumour-blood whole genome sequencing data for 179 ancestrally defined treatment naïve PCa patients (117 African, 62 European), we assessed for TL (blood and tumour) associations. We found shortened tumour TL to be associated with aggressive PCa presentation and elevated genomic instabilities, including percentage of genome alteration and copy number gains, in men of African ancestry. For European patients, tumour TL showed significant associations with PCa driver genes PTEN, TP53, MSH2, SETBP1 and DDX11L1, while shorter blood TL (< 3200 base pairs) and tumour TL (< 2861 base pairs) were correlated with higher risk for biochemical recurrence. Concurring with previous studies linking TL to PCa diagnosis and/or prognosis, for the first time we correlated TL differences with patient ancestry with important implications for future treatments targeting telomere dysfunction.}, }
@article {pmid38559121, year = {2024}, author = {Estrem, B and Davis, RE and Wang, J}, title = {End resection and telomere healing of DNA double-strand breaks during nematode programmed DNA elimination.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2024.03.15.585292}, pmid = {38559121}, abstract = {Most DNA double-strand breaks (DSBs) are harmful to genome integrity. However, some forms of DSBs are essential to biological processes, such as meiotic recombination and V(D)J recombination. DSBs are also required for programmed DNA elimination (PDE) in ciliates and nematodes. In nematodes, the DSBs are healed with telomere addition. While telomere addition sites have been well-characterized, little is known regarding the DSBs that fragment nematode chromosomes. Here, we used embryos from the nematode Ascaris to study the timing of PDE breaks and examine the DSBs and their end processing. Using END-seq, we characterize the DSB ends and demonstrate that DNA breaks are introduced before mitosis, followed by extensive end resection. The resection profile is unique for each break site, and the resection generates 3' overhangs before the addition of telomeres. Interestingly, telomere healing occurs much more frequently on retained DSB ends than on eliminated ends. This biased repair of the DSB ends in Ascaris may be due to the sequestration of the eliminated DNA into micronuclei, preventing their ends from telomere healing. Additional DNA breaks occur within the eliminated DNA in both Ascaris and Parascaris , ensuring chromosomal breakage and providing a fail-safe mechanism for nematode PDE.}, }
@article {pmid38553835, year = {2024}, author = {Kirk, B and Kuo, CL and Liu, P and Xiang, M and Earp, JE and Kositsawat, J and Kuchel, GA and Duque, G}, title = {Leukocyte telomere length is associated with MRI-thigh fat-free muscle volume: data from 16 356 UK Biobank adults.}, journal = {Journal of cachexia, sarcopenia and muscle}, volume = {}, number = {}, pages = {}, doi = {10.1002/jcsm.13461}, pmid = {38553835}, issn = {2190-6009}, support = {NR018963-01A1//National Institute of Nursing Research, National Institute of Health, USA/ ; P30AG067988//National Institute on Aging, National Institute of Health, USA./ ; //TSI Pharmaceuticals/ ; ICG001874//Australian Government (Department of Industry, Science and Resources)/ ; }, abstract = {BACKGROUND: Telomere attrition may share common biological mechanisms with bone and muscle loss with aging. Here, we investigated the association between these hallmarks of aging using data from UK Biobank, a large observational study.
METHODS: Leukocyte telomere length (LTL as T/S ratio) was measured using a multiplex qPCR assay at baseline (2006-2010). Bone mineral density (whole body and regional; via dual-energy X-ray absorptiometry), trabecular bone score (via lumbar-spine dual-energy X-ray absorptiometry images), fat-free muscle volume (thighs; via magnetic resonance imaging), and muscle fat infiltration (thighs; via magnetic resonance imaging) were measured during the imaging visit (2014-2018). Regression models were used to model LTL against a muscle or bone outcome, unadjusted and adjusted for covariates.
RESULTS: A total of 16 356 adults (mean age: 62.8 ± 7.5 years, 50.5% women) were included. In the fully adjusted model, thigh fat-free muscle volume was associated with LTL in the overall sample (adjusted standardized β (aβ) = 0.017, 95% CI 0.009 to 0.026, P < 0.001, per SD increase in LTL), with stronger associations in men (aβ = 0.022, 95% CI 0.010 to 0.034, P < 0.001) than in women (aβ = 0.013, 95% CI 0.000 to 0.025, P = 0.041) (sex-LTL P = 0.028). The adjusted odds ratio (aOR) for low thigh fat-free muscle volume (body mass index-adjusted, sex-specific bottom 20%) was 0.93 per SD increase in LTL (95% CI 0.89 to 0.96, P < 0.001) in the overall sample, with stronger associations in men (aOR = 0.92, 95% CI 0.87 to 0.99, P = 0.008) than women (aOR = 0.93, 95% CI 0.88 to 0.98, P = 0.009), although the sex difference was not statistically significant in this model (sex-LTL P = 0.37). LTL was not associated with bone mineral density, trabecular bone score, or muscle fat infiltration in the overall or subgroup analyses (P > 0.05).
CONCLUSIONS: LTL was consistently associated with thigh fat-free muscle volume in men and women. Future research should investigate moderating effects of lifestyle factors (e.g., physical activity, nutrition, or chronic diseases) in the association between LTL and muscle volume.}, }
@article {pmid38552826, year = {2024}, author = {Dehdashti, B and Miri, M and Khanahmad, H and Feizi, A and Mohammadi, F and Rouholamin, S and Amin, MM}, title = {In-Utero exposure to potential sources of indoor air pollution and umbilical cord blood leukocyte telomere length.}, journal = {Environmental research}, volume = {}, number = {}, pages = {118791}, doi = {10.1016/j.envres.2024.118791}, pmid = {38552826}, issn = {1096-0953}, abstract = {Indoor air pollution (IAP) has been associated with various adverse health effects. However, the evidence regarding such an association with leukocyte telomere length (LTL) in cord blood samples is still scarce. Therefore, the present study aimed to assess the relationship between exposure to indicators of IAP and LTL in umbilical cord blood samples. This cross-sectional study was based on 188 mother-newborn pairs who participated in our study between 2020 and 2022 in Isfahan, Iran. Umbilical LTL was measured by quantitative real-time polymerase chain reaction (qRT-PCR) technique. Linear mixed-effect models were used to assess the relationship between IAP indicators and umbilical LTL, adjusted for relevant covariates. The median (interquartile range (IQR)) of umbilical LTL was 0.92 (0.47). In fully adjusted models, frequency of using degreasing spray during pregnancy (times per month) (β = -0.047, 95% CI:0.09, -0.05, P-value = 0.02), using air freshener spray during pregnancy (β = -0.26, 95% CI: -0.5, -0.02, P-value = 0.03) and frequency of using insecticides during pregnancy (times per month) (β = -0.025, 95% CI: -0.047, -0.003, P-value = 0.02) were significantly associated with shorter umbilical LTL. There was a positive significant relationship between the frequency of using cleaning spray during pregnancy (times per month) with umbilical LTL (β = 0.019, 95% CI: 0.005, 0.033, P-value = 0.01). Furthermore, the direct connection of the parking with home and the frequency of using barbecue (times per week) were marginally associated with shorter umbilical LTL. For other indicators of IAP, we did not observe any statistically significant associations. Overall, this study suggested a negative association between prenatal exposure to IAP during pregnancy and umbilical LTL.}, }
@article {pmid38550590, year = {2024}, author = {Kraft, BD and Verhulst, S and Lai, TP and Sullenger, BA and Wang, Y and Rountree, W and Chen, L and Woods, CW and Denny, TN and Aviv, A}, title = {T-cell count and T-cell telomere length in patients with severe COVID-19.}, journal = {Frontiers in immunology}, volume = {15}, number = {}, pages = {1356638}, doi = {10.3389/fimmu.2024.1356638}, pmid = {38550590}, issn = {1664-3224}, abstract = {Lymphocyte telomere length (TL) is highly variable and shortens with age. Short telomeres may impede TL-dependent T-cell clonal expansion with viral infection. As SARS-CoV-2 infection can induce prolonged and severe T-cell lymphopenia, infected adults, and particularly older adults with short telomeres, may display severe T-cell lymphopenia. To examine the relationship between T-cell TL parameters and T-cell counts, we studied 40 patients hospitalized with severe COVID-19. T-cells were isolated from lymphocytes, counted using flow cytometry, and their TL parameters were measured using the Telomere Shortest Length Assay. The cohort (median age = 62 years, 27% female) was racially and ethnically diverse (33% White, 35% Black, and 33% Other). On intensive care unit study day 1, T-cell count (mean=1.03 x10[9]/L) was inversely related to age (p=0.007) and higher in females than males (p=0.025). Mean TL was 3.88 kilobases (kb), and 45.3% of telomeres were shorter than 3 kb. Using multiple regression analysis and adjusting for age and sex, T-cell count decreased with increased proportion of T-cell telomeres shorter than 3 kb (p=0.033) and increased with mean TL (p=0.052). Our findings suggest an association between the buildup of short telomeres within T-cells and explain in part reduced peripheral blood T-cell counts in patients with severe COVID-19. Shortened T-cell telomeres may be a risk factor for COVID-19-associated T-cell lymphopenia.}, }
@article {pmid38542157, year = {2024}, author = {Pochechueva, TV and Schwenzer, N and Kohl, T and Brandenburg, S and Kaltenecker, G and Wollnik, B and Lehnart, SE}, title = {3D Super-Resolution Nuclear Q-FISH Imaging Reveals Cell-Cycle-Related Telomere Changes.}, journal = {International journal of molecular sciences}, volume = {25}, number = {6}, pages = {}, doi = {10.3390/ijms25063183}, pmid = {38542157}, issn = {1422-0067}, support = {EXC 2067//Deutsche Forschungsgemeinschaft/ ; }, abstract = {We present novel workflows for Q-FISH nanoscopy with the potential for prognostic applications and resolving novel chromatin compaction changes. DNA-fluorescence in situ hybridization (DNA-FISH) is a routine application to visualize telomeres, repetitive terminal DNA sequences, in cells and tissues. Telomere attrition is associated with inherited and acquired diseases, including cancer and cardiomyopathies, and is frequently analyzed by quantitative (Q)-FISH microscopy. Recently, nanoscopic imaging techniques have resolved individual telomere dimensions and their compaction as a prognostic marker, in part leading to conflicting conclusions still unresolved to date. Here, we developed a comprehensive Q-FISH nanoscopy workflow to assess telomeres with PNA telomere probes and 3D-Stimulated Emission Depletion (STED) microscopy combined with Dynamic Intensity Minimum (DyMIN) scanning. We achieved single-telomere resolution at high, unprecedented telomere coverage. Importantly, our approach revealed a decrease in telomere signal density during mitotic cell division compared to interphase. Innovatively expanding FISH-STED applications, we conducted double FISH targeting of both telomere- and chromosome-specific sub-telomeric regions and accomplished FISH-STED in human cardiac biopsies. In summary, this work further advanced Q-FISH nanoscopy, detected a new aspect of telomere compaction related to the cell cycle, and laid the groundwork for future applications in complex cell types such as post-mitotic neurons and muscle cells.}, }
@article {pmid38540683, year = {2024}, author = {Olson, CL and Wuttke, DS}, title = {Guardians of the Genome: How the Single-Stranded DNA-Binding Proteins RPA and CST Facilitate Telomere Replication.}, journal = {Biomolecules}, volume = {14}, number = {3}, pages = {}, doi = {10.3390/biom14030263}, pmid = {38540683}, issn = {2218-273X}, support = {R01 GM139274/NH/NIH HHS/United States ; }, abstract = {Telomeres act as the protective caps of eukaryotic linear chromosomes; thus, proper telomere maintenance is crucial for genome stability. Successful telomere replication is a cornerstone of telomere length regulation, but this process can be fraught due to the many intrinsic challenges telomeres pose to the replication machinery. In addition to the famous "end replication" problem due to the discontinuous nature of lagging strand synthesis, telomeres require various telomere-specific steps for maintaining the proper 3' overhang length. Bulk telomere replication also encounters its own difficulties as telomeres are prone to various forms of replication roadblocks. These roadblocks can result in an increase in replication stress that can cause replication forks to slow, stall, or become reversed. Ultimately, this leads to excess single-stranded DNA (ssDNA) that needs to be managed and protected for replication to continue and to prevent DNA damage and genome instability. RPA and CST are single-stranded DNA-binding protein complexes that play key roles in performing this task and help stabilize stalled forks for continued replication. The interplay between RPA and CST, their functions at telomeres during replication, and their specialized features for helping overcome replication stress at telomeres are the focus of this review.}, }
@article {pmid38540177, year = {2024}, author = {Younoussa, H and Gadji, M and Soumboundou, M and Colicchio, B and Said, A and Ndoye, NA and Junker, S and Plesch, A and Heidingsfelder, L and Diagne, NR and Dieterlen, A and Voisin, P and Carde, P and Jeandidier, E and M'kacher, R}, title = {Telomere Dysfunction in Pediatric Patients with Differences/Disorders of Sexual Development.}, journal = {Biomedicines}, volume = {12}, number = {3}, pages = {}, doi = {10.3390/biomedicines12030565}, pmid = {38540177}, issn = {2227-9059}, abstract = {UNLABELLED: Differences/Disorders of sex development (DSDs) are conditions in which the development of chromosomal, gonadal, and anatomical sexes is atypical. DSDs are relatively rare, but their incidence is becoming alarmingly common in sub-Saharan Africa (SSA). Their etiologies and mechanisms are poorly understood. Therefore, we have investigated cytogenetic profiles, including telomere dysfunction, in a retrospective cohort of Senegalese DSD patients.
MATERIALS AND METHODS: Peripheral blood lymphocytes were sampled from 35 DSD patients (mean age: 3.3 years; range 0-18 years) admitted to two hospital centers in Dakar. Peripheral blood lymphocytes from 150 healthy donors were used as a control. Conventional cytogenetics, telomere, and centromere staining followed by multiplex FISH, as well as FISH with SRY-specific probes, were employed.
RESULTS: Cytogenetic analysis identified 19 male and 13 female patients with apparently normal karyotypes, two patients with Turner syndrome, and one patient with Klinefelter syndrome. Additional structural chromosome aberrations were detected in 22% of the patients (8/35). Telomere analysis revealed a reduction in mean telomere lengths of DSD patients compared to those of healthy donors of similar age. This reduction in telomere length was associated with an increased rate of telomere aberrations (telomere loss and the formation of telomere doublets) and the presence of additional chromosomal aberrations.
CONCLUSIONS: To the best of our knowledge, this study is the first to demonstrate a correlation between telomere dysfunction and DSDs. Further studies may reveal the link between telomere dysfunction and possible mechanisms involved in the disease itself, such as DNA repair deficiency or specific gene mutations. The present study demonstrates the relevance of implementing telomere analysis in prenatal tests as well as in diagnosed genetic DSD disorders.}, }
@article {pmid38540151, year = {2024}, author = {Duseikaite, M and Vilkeviciute, A and Kunceviciene, E and Gedvilaite, G and Kriauciuniene, L and Liutkeviciene, R}, title = {Associations between ZNF676, CTC1 Gene Polymorphisms and Relative Leukocyte Telomere Length with Myopia and Its Degree.}, journal = {Biomedicines}, volume = {12}, number = {3}, pages = {}, doi = {10.3390/biomedicines12030538}, pmid = {38540151}, issn = {2227-9059}, abstract = {BACKGROUND: The interaction between environmental and genetic factors that influence eye growth, regulated by vision, contributes to the development and progression of myopia. This dynamic interaction significantly contributes to the multifaceted development and progression of myopia, a prevalent ocular condition. Our study delves into the associations between ZNF676 and CTC1 gene polymorphisms and their impact on the relative leukocyte telomere length (relative LTL) in myopia, as well as its degree. By unravelling these underpinnings in conjunction with environmental influences, we aim to enhance our understanding of the complex mechanisms that drive the onset and severity of myopia.
METHODS: This study included patients with myopia and ophthalmologically healthy subjects. DNA was extracted from peripheral venous blood by the salting out method. Genotyping of ZNF676 rs412658 and CTC1 rs3027234, as well as the measurement of relative LTL, were conducted using a real-time polymerase chain reaction method (RT-PCR). The data obtained were statistically analyzed using the "IBM SPSS Statistics 29.0" software program.
RESULTS: The results show that myopic patients who are homozygous for the rs3027234 rare allele genotype of the CTC1 gene have statistically significantly shorter relative LTL compared to patients with the CC and CT genotypes. Also, men with the CTC1 rs3027234 TT genotype have statistically significantly longer leukocyte telomeres than women with the same genotype. The respective median (IQR) of the relative LTL for women and men is 0.280 (0.463) vs. 0.696 (0.440), with a p-value of 0.027. The myopia group with the ZNF676 rs412658 CC genotype has statistically significantly shorter leukocyte telomeres than the control group with the same genotype (age ≤ 29), and the p-value is 0.011. Also, the myopia group with the ZNF676 rs412658 CT and CTC1 rs3027234 CT genotypes have statistically significantly longer leukocyte telomeres than the control group with the same genotypes (age > 29), with p-values that are, respectively, 0.016 and 0.012. The evaluation of the genotype distributions of the polymorphisms in the myopia patients showed that ZNF676 rs412658 CT genotype carriers have 4-fold decreased odds of high myopia occurrence (OR = 0.250; CI: 0.076-0.826; p = 0.023). Also, the evaluation of the allele distributions of the polymorphism under the additive genetic model in the myopia group showed that the ZNF676 rs412658 T allele was associated with similar odds of high myopia (OR = 0.269; 95% CI: 0.090-0.807; p = 0.019). The comprehensive p-value, assessing the relative LTL of subjects across the different levels of myopia, signifies a statistical difference in the relative LTL among individuals with varying degrees of myopia. There was a statistically significant difference in relative LTL between mild and moderate myopia degrees (0.819 (1.983) vs. 0.083 (0.930), p = 0.007).
CONCLUSIONS: CTC1 rs3027234 TT may be considered a protective genotype for telomere shortening in men, while the overall telomere shortening might be linked to the worse myopia degree. The ZNF676 rs412658 T allele may protect against a high myopia occurrence.}, }
@article {pmid38539016, year = {2024}, author = {Mutz, J and Wong, WLE and Powell, TR and Young, AH and Dawe, GS and Lewis, CM}, title = {The duration of lithium use and biological ageing: telomere length, frailty, metabolomic age and all-cause mortality.}, journal = {GeroScience}, volume = {}, number = {}, pages = {}, pmid = {38539016}, issn = {2509-2723}, abstract = {Lithium is an established first-line treatment for bipolar disorder. Beyond its therapeutic effect as a mood stabiliser, lithium exhibits potential anti-ageing effects. This study aimed to examine the relationship between the duration of lithium use, biological ageing and mortality. The UK Biobank is an observational study of middle-aged and older adults. We tested associations between the duration of lithium use (number of prescriptions, total duration of use and duration of the first prescription period) and telomere length, frailty, metabolomic age (MileAge) delta, pulse rate and all-cause mortality. Five hundred ninety-one individuals (mean age = 57.49 years; 55% females) had been prescribed lithium. There was no evidence that the number of prescriptions (β = - 0.022, 95% CI - 0.081 to 0.037, p = 0.47), the total duration of use (β = - 0.005, 95% CI - 0.023 to 0.013, p = 0.57) or the duration of the first prescription period (β = - 0.018, 95% CI - 0.051 to 0.015, p = 0.29) correlated with telomere length. There was also no evidence that the duration of lithium use correlated with frailty or MileAge delta. However, a higher prescription count and a longer duration of use was associated with a lower pulse rate. The duration of lithium use did not predict all-cause mortality. We observed no evidence of associations between the duration of lithium use and biological ageing markers, including telomere length. Our findings suggest that the potential anti-ageing effects of lithium do not differ by the duration of use.}, }
@article {pmid38533417, year = {2024}, author = {Xu, B and Ren, J and Zhu, S and Ding, Y and Zhou, W and Guo, Q and Fang, Y and Zheng, J}, title = {Causal relationship between telomere length and risk of intracranial aneurysm: a bidirectional Mendelian randomization study.}, journal = {Frontiers in neurology}, volume = {15}, number = {}, pages = {1355895}, pmid = {38533417}, issn = {1664-2295}, abstract = {BACKGROUND: Telomere length is closely linked to the aging phenotype, where cellular aging results in the production of a cascade of cell factors and the senescence-associated secretory phenotype (SASP), leading to an inflammatory response. The presence of inflammation plays a crucial role in the formation of intracranial aneurysms. Nevertheless, the relationship between telomere length and intracranial aneurysms remains unclear. This study aims to explore the causal connection between telomere length and intracranial aneurysms through the utilization of Mendelian randomization (MR) analysis.
METHODS: Data on telomere length were obtained from the genome-wide association studies conducted on the UK Biobank, comprising a total of 472,174 participants. Data on intracranial aneurysms were obtained from the summary dataset of the Global Genome-wide Association Study (GWAS) conducted by the International Stroke Genetics Consortium. The dataset consisted of 7,495 cases and 71,934 controls, all of European descent. Initially, the linkage disequilibrium score was used to investigate the connection between telomere length and intracranial aneurysms. Subsequently, a bidirectional MR was conducted using two-sample analysis to assess whether there is a causal connection between telomere length and intracranial aneurysm risk. The results were analyzed utilizing five MR methods, with the inverse variance weighted method serving as the main methodology. In addition, we did various analyses to evaluate the presence of heterogeneity, pleiotropy, and sensitivity in the study results. A reverse MR analysis was conducted to investigate potential reverse causal links.
RESULTS: In the forward MR analysis, it was observed that both the inverse variance-weighted and weighted median analyses implied a potential causal relationship between longer telomere length and a decreased incidence of intracranial aneurysms (IVW: OR = 0.66, 95% CI: 0.47-0.92, p = 1.49 × 10[-2]). There was no heterogeneity or horizontal pleiotropy. The findings were verified to be robust through the utilization of leave-one-out analysis. The use of reverse MR analysis did not establish a potential causal link between the occurrence of intracranial aneurysms and telomere length.
CONCLUSION: There may exist a potential correlation between longer telomere length and a decreased likelihood of intracranial aneurysms within the European population. The present study offers novel insights into the correlation between telomere length and intracranial aneurysms. Additional research is required to clarify the underlying mechanisms and validate our discoveries in diverse populations.}, }
@article {pmid38525449, year = {2024}, author = {Chauhan, VS and Sibin, MK and Yadav, P and Sharma, M}, title = {To study childhood trauma in patients with bipolar affective disorder and its association with leucocyte telomere length.}, journal = {Medical journal, Armed Forces India}, volume = {80}, number = {2}, pages = {184-191}, pmid = {38525449}, issn = {0377-1237}, abstract = {BACKGROUND: Childhood traumatic (CT) events are more frequent in Bipolar Affective Disorder (BD) than in healthy individuals. As per existing studies, telomere shortening might be associated with psychiatric illnesses and aging-related disorders. One basis could be CT in BD aiding in telomere shortening.
METHODS: 100 BD patients and 100 healthy controls (HC) were matched for age and sex. All the participants were administered Childhood Trauma Questionnaire (CTQ). Subsequently, Quantitative Polymerase Chain Reaction (q-PCR) was performed in order to verify leukocyte telomere length (LTL) for both cases and controls.
RESULTS: Presence of subtypes of moderate to severe CT among cases revealed emotional abuse in 35%, physical abuse in 16%, and sexual abuse in 15%. BD patients had significantly shorter telomeres in comparison to HC. BD patients with CT had significantly shorter LTL as compared to healthy controls with CT. The association between CT and LTL was not statistically significant in cases as well as in controls.
CONCLUSIONS: Our study revealed presence of CT (moderate to severe) in 46% of BD patients and 12% in age and sex-matched healthy controls. All CT subtypes except sexual abuse were significantly higher among cases than in healthy controls. Mean score of LTL among cases including that with CT was significantly lower than the healthy controls.}, }
@article {pmid38519061, year = {2024}, author = {Lieber, SB and Lipschultz, RA and Syed, S and Rajan, M and Venkatraman, S and Lin, M and Reid, MC and Lue, NF and Mandl, LA}, title = {Association of phenotypic frailty and hand grip strength with telomere length in SLE.}, journal = {Lupus science & medicine}, volume = {11}, number = {1}, pages = {}, doi = {10.1136/lupus-2023-001008}, pmid = {38519061}, issn = {2053-8790}, abstract = {OBJECTIVE: Frailty and objective hand grip strength (one of the components of the frailty phenotype) are both risk factors for worse health outcomes in SLE. Whether telomere length, an established cellular senescence marker, is a biologic correlate of the frailty phenotype and hand grip strength in patients with SLE is not clear. First, we aimed to evaluate differences in telomere length between frail and non-frail women with SLE and then assessed whether frailty or hand grip strength is differentially associated with telomere length after adjusting for relevant confounders.
METHODS: Women ≥18 years of age with validated SLE enrolled at a single medical centre. Fried frailty status (which includes hand grip strength), clinical characteristics and telomere length were assessed cross-sectionally. Differences between frail and non-frail participants were evaluated using Fisher's exact or Wilcoxon rank-sum tests. The associations between frailty and hand grip strength and telomere length were determined using linear regression.
RESULTS: Of the 150 enrolled participants, 131 had sufficient data for determination of frailty classification; 26% were frail with a median age of 45 years. There was a non-significant trend towards shorter telomere length in frail versus non-frail participants (p=0.07). Hand grip strength was significantly associated with telomere length (beta coefficient 0.02, 95% CI 0.004, 0.04), including after adjustment for age, SLE disease activity and organ damage, and comorbidity (beta coefficient 0.02, 95% CI 0.002, 0.04).
CONCLUSIONS: Decreased hand grip strength, but not frailty, was independently associated with shortened telomere length in a cohort of non-elderly women with SLE. Frailty in this middle-aged cohort may be multifactorial rather than strictly a manifestation of accelerated ageing.}, }
@article {pmid38518608, year = {2024}, author = {Wei, B and Zhou, Y and Li, Q and Zhen, S and Wu, Q and Xiao, Z and Liao, J and Zhu, B and Duan, J and Yang, X and Liang, F}, title = {Outdoor fine particulate matter exposure and telomere length in humans: A systematic review and meta-analysis.}, journal = {Ecotoxicology and environmental safety}, volume = {275}, number = {}, pages = {116206}, doi = {10.1016/j.ecoenv.2024.116206}, pmid = {38518608}, issn = {1090-2414}, abstract = {Although the association between changes in human telomere length (TL) and ambient fine particulate matter (PM2.5) has been documented, there remains disagreement among the related literature. Our study conducted a systematic review and meta-analysis of epidemiological studies to investigate the health effects of outdoor PM2.5 exposure on human TL after a thorough database search. To quantify the overall effect estimates of TL changes associated with every 10 μg/m[3] increase in PM2.5 exposure, we focused on two main topics, which were outdoor long-term exposure and prenatal exposure of PM2.5. Additionally, we included a summary of short-term PM2.5 exposure and its impact on TL due to limited data availability. Our qualitative analysis included 20 studies with 483,600 participants. The meta-analysis showed a statistically significant association between outdoor PM2.5 exposure and shorter human TL, with pooled impact estimates (β) of -0.12 (95% CI: -0.20, -0.03, I[2]= 95.4%) for general long-term exposure and -0.07 (95% CI: -0.15, 0.00, I[2]= 74.3%) for prenatal exposure. In conclusion, our findings suggest that outdoor PM2.5 exposure may contribute to TL shortening, and noteworthy associations were observed in specific subgroups, suggesting the impact of various research variables. Larger, high-quality studies using standardized methodologies are necessary to strengthen these conclusions further.}, }
@article {pmid38516039, year = {2024}, author = {Carver, AJ and Hing, B and Elser, BA and Lussier, SJ and Yamanashi, T and Howard, MA and Kawasaki, H and Shinozaki, G and Stevens, HE}, title = {Correlation of telomere length in brain tissue with peripheral tissues in living human subjects.}, journal = {Frontiers in molecular neuroscience}, volume = {17}, number = {}, pages = {1303974}, doi = {10.3389/fnmol.2024.1303974}, pmid = {38516039}, issn = {1662-5099}, abstract = {Telomeres are important to chromosomal stability, and changes in their length correlate with disease, potentially relevant to brain disorders. Assessing telomere length in human brain is invasive, but whether peripheral tissue telomere length correlates with that in brain is not known. Saliva, buccal, blood, and brain samples were collected at time points before, during, and after subjects undergoing neurosurgery (n = 35) for intractable epilepsy. DNA was isolated from samples and average telomere length assessed by qPCR. Correlations of telomere length between tissue samples were calculated across subjects. When data were stratified by sex, saliva telomere length correlated with brain telomere length in males only. Buccal telomere length correlated with brain telomere length when males and females were combined. These findings indicate that in living subjects, telomere length in peripheral tissues variably correlates with that in brain and may be dependent on sex. Peripheral tissue telomere length may provide insight into brain telomere length, relevant to assessment of brain disorder pathophysiology.}, }
@article {pmid38515829, year = {2024}, author = {Chien, CW and Tang, YA and Jeng, SL and Pan, HA and Sun, HS}, title = {Blastocyst telomere length predicts successful implantation after frozen-thawed embryo transfer.}, journal = {Human reproduction open}, volume = {2024}, number = {2}, pages = {hoae012}, doi = {10.1093/hropen/hoae012}, pmid = {38515829}, issn = {2399-3529}, abstract = {STUDY QUESTION: Do embryos with longer telomere length (TL) at the blastocyst stage have a higher capacity to survive after frozen-thawed embryo transfer (FET)?
SUMMARY ANSWER: Digitally estimated TL using low-pass whole genome sequencing (WGS) data from the preimplantation genetic testing for aneuploidy (PGT-A) process demonstrates that blastocyst TL is the most essential factor associated with likelihood of implantation.
WHAT IS KNOWN ALREADY: The lifetime TL is established in the early cleavage cycles following fertilization through a recombination-based lengthening mechanism and starts erosion beyond the blastocyst stage. In addition, a telomerase-mediated slow erosion of TL in human fetuses has been observed from a gestational age of 6-11 weeks. Finally, an abnormal shortening of telomeres is likely involved in embryo loss during early development.
STUDY DESIGN SIZE DURATION: Blastocyst samples were obtained from patients who underwent PGT-A and FET in an IVF center from March 2015 to May 2018. Digitally estimated mitochondrial copy number (mtCN) and TL were used to study associations with the implantation potential of each embryo.
In total, 965 blastocysts from 232 cycles (164 patients) were available to investigate the biological and clinical relevance of TL. A WGS-based workflow was applied to determine the ploidy of each embryo. Data from low-pass WGS-PGT-A were used to estimate the mtCN and TL for each embryo. Single-variant and multi-variant logistic regression, decision tree, and random forest models were applied to study various factors in association with the implantation potential of each embryo.
Of the 965 blastocysts originally available, only 216 underwent FET. While mtCN from the transferred embryos is significantly associated with the ploidy call of each embryo, mtCN has no role in impacting IVF outcomes after an embryo transfer in these women. The results indicate that mtCN is a marker of embryo aneuploidy. On the other hand, digitally estimated TL is the most prominent univariant factor and showed a significant positive association with pregnancy outcomes (P < 0.01, odds ratio 79.1). We combined several maternal and embryo parameters to study the joint effects on successful implantation. The machine learning models, namely decision tree and random forest, were trained and yielded classification accuracy of 0.82 and 0.91, respectively. Taken together, these results support the vital role of TL in governing implantation potential, perhaps through the ability to control embryo survival after transfer.
The small sample size limits our study as only 216 blastocysts were transferred. The number was further reduced to 153 blastocysts, where pregnancy outcomes could be accurately traced. The other limitation of this study is that all data were collected from a single IVF center. The uniform and controlled operation of IVF cycles in a single center may cause selection bias.
We present novel findings to show that digitally estimated TL at the blastocyst stage is a predictor of pregnancy capacity after a FET cycle. As elective single-embryo transfer has become the mainstream direction in reproductive medicine, prioritizing embryos based on their implantation potential is crucial for clinical infertility treatment in order to reduce twin pregnancy rate and the time to pregnancy in an IVF center. The AI-powered, random forest prediction model established in this study thus provides a way to improve clinical practice and optimize the chances for people with fertility problems to achieve parenthood.
This study was supported by a grant from the National Science and Technology Council, Taiwan (MOST 108-2321-B-006-013 -). There were no competing interests.
TRIAL REGISTRATION NUMBER: N/A.}, }
@article {pmid38512957, year = {2024}, author = {An, G and Zhao, X and Zhao, C}, title = {Unraveling the causal association between leukocyte telomere length and infertility: A two-sample Mendelian randomization study.}, journal = {PloS one}, volume = {19}, number = {3}, pages = {e0298997}, doi = {10.1371/journal.pone.0298997}, pmid = {38512957}, issn = {1932-6203}, abstract = {Infertility is a significant challenge in modern society, and observed studies have reported the association between telomere length and infertility. Whether this relationship is causal remains controversial.We employed two-sample mendelian randomization (MR) to investigate the causal relationship between leukocyte telomere length (LTL) and major causes of infertility, including male and female infertility, sperm abnormalities, and endometriosis. MR analyses were mainly performed using the inverse variance weighted (IVW) method and complemented with other MR methods.Our findings demonstrate a causal association between LTL and endometriosis (OR1.304, 95% CI (1.122,1.517), p = 0.001), suggesting its potential as a biomarker for this condition. However, we did not observe a significant causal relationship between LTL and other infertility causes.Our study presents compelling evidence on the relationship between LTL and endometriosis. Meanwhile, our study demonstrates that there is no causal relationship between LTL and infertility. This research contributes to the field by shedding light on the importance of LTL in the early diagnosis and intervention of endometriosis.}, }
@article {pmid38510147, year = {2024}, author = {Keller, D and Stinus, S and Umlauf, D and Gourbeyre, E and Biot, E and Olivier, N and Mahou, P and Beaurepaire, E and Andrey, P and Crabbe, L}, title = {Non-random spatial organization of telomeres varies during the cell cycle and requires LAP2 and BAF.}, journal = {iScience}, volume = {27}, number = {4}, pages = {109343}, pmid = {38510147}, issn = {2589-0042}, abstract = {Spatial genome organization within the nucleus influences major biological processes and is impacted by the configuration of linear chromosomes. Here, we applied 3D spatial statistics and modeling on high-resolution telomere and centromere 3D-structured illumination microscopy images in cancer cells. We found a multi-scale organization of telomeres that dynamically evolved from a mixed clustered-and-regular distribution in early G1 to a purely regular distribution as cells progressed through the cell cycle. In parallel, our analysis revealed two pools of peripheral and internal telomeres, the proportions of which were inverted during the cell cycle. We then conducted a targeted screen using MadID to identify the molecular pathways driving or maintaining telomere anchoring to the nuclear envelope observed in early G1. Lamina-associated polypeptide (LAP) proteins were found transiently localized to telomeres in anaphase, a stage where LAP2α initiates the reformation of the nuclear envelope, and impacted telomere redistribution in the next interphase together with their partner barrier-to-autointegration factor (BAF).}, }
@article {pmid38509838, year = {2024}, author = {Wolf, SE and Woodruff, MJ and Chang van Oordt, DA and Clotfelter, ED and Cristol, DA and Derryberry, EP and Ferguson, SM and Stanback, MT and Taff, CC and Vitousek, MN and Westneat, DF and Rosvall, KA}, title = {Among-population variation in telomere regulatory proteins and their potential role as hidden drivers of intraspecific variation in life history.}, journal = {The Journal of animal ecology}, volume = {}, number = {}, pages = {}, doi = {10.1111/1365-2656.14071}, pmid = {38509838}, issn = {1365-2656}, support = {T32 HD049336/NH/NIH HHS/United States ; }, abstract = {Biologists aim to explain patterns of growth, reproduction and ageing that characterize life histories, yet we are just beginning to understand the proximate mechanisms that generate this diversity. Existing research in this area has focused on telomeres but has generally overlooked the telomere's most direct mediator, the shelterin protein complex. Shelterin proteins physically interact with the telomere to shape its shortening and repair. They also regulate metabolism and immune function, suggesting a potential role in life history variation in the wild. However, research on shelterin proteins is uncommon outside of biomolecular work. Intraspecific analyses can play an important role in resolving these unknowns because they reveal subtle variation in life history within and among populations. Here, we assessed ecogeographic variation in shelterin protein abundance across eight populations of tree swallow (Tachycineta bicolor) with previously documented variation in environmental and life history traits. Using the blood gene expression of four shelterin proteins in 12-day-old nestlings, we tested the hypothesis that shelterin protein gene expression varies latitudinally and in relation to both telomere length and life history. Shelterin protein gene expression differed among populations and tracked non-linear variation in latitude: nestlings from mid-latitudes expressed nearly double the shelterin mRNA on average than those at more northern and southern sites. However, telomere length was not significantly related to latitude. We next assessed whether telomere length and shelterin protein gene expression correlate with 12-day-old body mass and wing length, two proxies of nestling growth linked to future fecundity and survival. We found that body mass and wing length correlated more strongly (and significantly) with shelterin protein gene expression than with telomere length. These results highlight telomere regulatory shelterin proteins as potential mediators of life history variation among populations. Together with existing research linking shelterin proteins and life history variation within populations, these ecogeographic patterns underscore the need for continued integration of ecology, evolution and telomere biology, which together will advance understanding of the drivers of life history variation in nature.}, }
@article {pmid38504468, year = {2024}, author = {Hastings, WJ and Ye, Q and Wolf, SE and Ryan, CP and Das, SK and Huffman, KM and Kobor, MS and Kraus, WE and MacIsaac, JL and Martin, CK and Racette, SB and Redman, LM and Belsky, DW and Shalev, I}, ti