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Bibliography on: Telomeres

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ESP: PubMed Auto Bibliography 08 Feb 2023 at 01:55 Created: 

Telomeres

Wikipedia: A telomere is a region of repetitive nucleotide sequences at each end of a chromosome, which protects the end of the chromosome from deterioration or from fusion with neighboring chromosomes. Its name is derived from the Greek nouns telos (τέλος) "end" and merοs (μέρος, root: μερ-) "part". For vertebrates, the sequence of nucleotides in telomeres is TTAGGG, with the complementary DNA strand being AATCCC, with a single-stranded TTAGGG overhang. This sequence of TTAGGG is repeated approximately 2,500 times in humans. In humans, average telomere length declines from about 11 kilobases at birth to less than 4 kilobases in old age,[3] with average rate of decline being greater in men than in women. During chromosome replication, the enzymes that duplicate DNA cannot continue their duplication all the way to the end of a chromosome, so in each duplication the end of the chromosome is shortened (this is because the synthesis of Okazaki fragments requires RNA primers attaching ahead on the lagging strand). The telomeres are disposable buffers at the ends of chromosomes which are truncated during cell division; their presence protects the genes before them on the chromosome from being truncated instead. The telomeres themselves are protected by a complex of shelterin proteins, as well as by the RNA that telomeric DNA encodes.

Created with PubMed® Query: telomere.q.txt NOT pmcbook NOT ispreviousversion

Citations The Papers (from PubMed®)

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RevDate: 2023-02-07

Burraco P, Hernandez-Gonzalez M, Metcalfe NB, et al (2023)

Ageing across the great divide: tissue transformation, organismal growth and temperature shape telomere dynamics through the metamorphic transition.

Proceedings. Biological sciences, 290(1992):20222448.

Telomere attrition is considered a useful indicator of cellular and whole-organism ageing rate. While approximately 80% of animal species undergo metamorphosis that includes extensive tissue transformations (involving cell division, apoptosis, de-differentiation and de novo formation of stem cells), the effect on telomere dynamics is unknown. We measured telomeres in Xenopus laevis developing from larvae to adults under contrasting environmental temperatures. Telomere dynamics were linked to the degree of tissue transformation during development. Average telomere length in gut tissue increased dramatically during metamorphosis, when the gut shortens by 75% and epithelial cells de-differentiate into stem cells. In the liver (retained from larva) and hindlimb muscle (newly formed before metamorphosis), telomeres gradually shortened until adulthood, likely due to extensive cell division. Tail muscle telomere lengths were constant until tail resorption, and those in heart (retained from larva) showed no change over time. Telomere lengths negatively correlated with larval growth, but for a given growth rate, telomeres were shorter in cooler conditions, suggesting that growing in the cold is more costly. Telomere lengths were not related to post-metamorphic growth rate. Further research is now needed to understand whether telomere dynamics are a good indicator of ageing rate in species undergoing metamorphosis.

RevDate: 2023-02-07

Jones CY, Williams CL, Moreno SP, et al (2023)

Hyperextended telomeres promote C-circle formation in telomerase positive human cells.

bioRxiv : the preprint server for biology pii:2023.01.26.525615.

Telomere length maintenance is crucial to cancer cell immortality. Up to 15% of cancers utilize a telomerase-independent, recombination-based mechanism termed alternative lengthening of telomeres (ALT). The primary ALT biomarker is the C-circle, a type of circular DNA with extrachromosomal telomere repeats (cECTRs). How C-circles form is not well characterized. To investigate C-circle formation in telomerase+ cells, we studied the human cen3tel cell line, in which telomeres progressively hyper-elongated post TERT -immortalization. cECTR signal was observed in 2D gels and C-circle assays but not t-circle assays, which also detect cECTRs. Telomerase activity and C-circle signal were not separable in the analysis of clonal populations, consistent with C-circle production occurring within telomerase+ cells. Two other long telomere, telomerase+ (LTT+) cell lines, HeLa1.3 (~23 kb telomeres) and HeLaE1 (~50 kb telomeres), had similar cECTR properties. Telomerase activity did not directly impact C-circle signal in LTT+ cells; instead, C-circle signal correlated with telomere length. LTT+ lines were less sensitive to hydroxyurea than an ALT+ cell line, suggesting that ALT status is a stronger contributor to replication stress levels than telomere length. Additionally, FANCM did not suppress C-circles in LTT+ cells as it does in ALT+ cells. Thus, C-circle formation may be driven by telomere length, independently of telomerase and replication stress, highlighting limitations of C-circles as a stand-alone ALT biomarker.

RevDate: 2023-02-07

Landa I, Thornton CE, Xu B, et al (2023)

Telomerase reactivation induces progression of mouse Braf [V600E] -driven thyroid cancers without telomere lengthening.

bioRxiv : the preprint server for biology pii:2023.01.24.525280.

Mutations in the promoter of the telomerase reverse transcriptase (TERT) gene are the paradigm of a cross-cancer alteration in a non-coding region. TERT promoter mutations (TPMs) are biomarkers of poor prognosis in several tumors, including thyroid cancers. TPMs enhance TERT transcription, which is otherwise silenced in adult tissues, thus reactivating a bona fide oncoprotein. To study TERT deregulation and its downstream consequences, we generated a Tert mutant promoter mouse model via CRISPR/Cas9 engineering of the murine equivalent locus (Tert [-123C>T]) and crossed it with thyroid-specific Braf [V600E] -mutant mice. We also employed an alternative model of Tert overexpression (K5-Tert). Whereas all Braf [V600E] animals developed well-differentiated papillary thyroid tumors, 29% and 36% of Braf [V600E] +Tert [-123C>T] and Braf [V600E] +K5-Tert mice progressed to poorly differentiated thyroid cancers at week 20, respectively. Braf+Tert tumors showed increased mitosis and necrosis in areas of solid growth, and older animals from these cohorts displayed anaplastic-like features, i.e., spindle cells and macrophage infiltration. Murine Tert promoter mutation increased Tert transcription in vitro and in vivo , but temporal and intra-tumoral heterogeneity was observed. RNA-sequencing of thyroid tumor cells showed that processes other than the canonical Tert-mediated telomere maintenance role operate in these specimens. Pathway analysis showed that MAPK and PI3K/AKT signaling, as well as processes not previously associated with this tumor etiology, involving cytokine and chemokine signaling, were overactivated. Braf+Tert animals remained responsive to MAPK pathway inhibitors. These models constitute useful pre-clinical tools to understand the cell-autonomous and microenvironment-related consequences of Tert-mediated progression in advanced thyroid cancers and other aggressive tumors carrying TPMs.

RevDate: 2023-02-02

Pires VB, Lohner N, Wagner T, et al (2023)

RNA-DNA hybrids prevent resection at dysfunctional telomeres.

Cell reports, 42(2):112077 pii:S2211-1247(23)00088-8 [Epub ahead of print].

At critically short telomeres, stabilized TERRA RNA-DNA hybrids drive homology-directed repair (HDR) to delay replicative senescence. However, even at long- and intermediate-length telomeres, not subject to HDR, transient TERRA RNA-DNA hybrids form, suggestive of additional roles. We report that telomeric RNA-DNA hybrids prevent Exo1-mediated resection when telomeres become non-functional. We used the well-characterized cdc13-1 allele, where telomere resection can be induced in a temperature-dependent manner, to demonstrate that ssDNA generation at telomeres is either prevented or augmented when RNA-DNA hybrids are stabilized or destabilized, respectively. The viability of cdc13-1 cells is affected by the presence or absence of hybrids accordingly. Telomeric hybrids do not affect the shortening rate of bulk telomeres. We suggest that TERRA hybrids require dynamic regulation to drive HDR at short telomeres; hybrid presence may initiate HDR through replication stress, whereby their removal allows strand resection.

RevDate: 2023-02-02

Van Ommen CE, Hsieh AYY, Albert AY, et al (2023)

Lower anti-mullerian hormone levels are associated with HIV in reproductive age women and shorter leukocyte telomere length among late reproductive age women.

AIDS (London, England) pii:00002030-990000000-00186 [Epub ahead of print].

OBJECTIVES: We sought to better understand factors associated with ovarian aging in women living with HIV (WLWH).

DESIGN: HIV has been associated with diminished fertility, younger age at menopause, and shorter leukocyte telomere length (LTL), a marker of cellular aging. We herein examine cross-sectional and longitudinal associations between LTL, Anti-Mullerian hormone (AMH), and HIV.

METHODS: We included WLWH and HIV-negative women 12-50 years of age in the CARMA cohort with ≥ 1 study visit(s). LTL and AMH were measured by qPCR and ELISA, respectively. Women were analysed in peak reproductive (<35 years) vs. late reproductive (≥35 years) life phases. Using multivariable mixed-effect linear or logistic regressions, we assessed factors associated with AMH and ΔAMH/year while adjusting for relevant confounders.

RESULTS: WLWH had shorter LTL and lower AMH levels compared to HIV-negative controls despite being of similar age. After adjusting for relevant factors, HIV was associated with 20% lower AMH levels in women <35 years and shorter LTL was associated with AMH levels below 2 ng/ml among women ≥35 years. Longitudinally, ΔAMH/year was largely related to initial AMH level among older women, and to age in younger women.

CONCLUSIONS: Factors associated with AMH change across women's reproductive lifespan. Lower AMH among peak reproductive aged WLWH suggests that HIV may have an initial detrimental effect on ovarian reserve, an observation that may warrant counselling around pregnancy planning. In women ≥35, the association between shorter LTL and lower AMH suggests that the immune and reproductive aging connections are more important in this age group.

RevDate: 2023-01-31

Eguchi A, Gonzalez AFGS, Torres-Bigio SI, et al (2023)

TRF2 rescues telomere attrition and prolongs cell survival in Duchenne muscular dystrophy cardiomyocytes derived from human iPSCs.

Proceedings of the National Academy of Sciences of the United States of America, 120(6):e2209967120.

Duchenne muscular dystrophy (DMD) is a severe muscle wasting disease caused by the lack of dystrophin. Heart failure, driven by cardiomyocyte death, fibrosis, and the development of dilated cardiomyopathy, is the leading cause of death in DMD patients. Current treatments decrease the mechanical load on the heart but do not address the root cause of dilated cardiomyopathy: cardiomyocyte death. Previously, we showed that telomere shortening is a hallmark of DMD cardiomyocytes. Here, we test whether prevention of telomere attrition is possible in cardiomyocytes differentiated from patient-derived induced pluripotent stem cells (iPSC-CMs) and if preventing telomere shortening impacts cardiomyocyte function. We observe reduced cell size, nuclear size, and sarcomere density in DMD iPSC-CMs compared with healthy isogenic controls. We find that expression of just one telomere-binding protein, telomeric repeat-binding factor 2 (TRF2), a core component of the shelterin complex, prevents telomere attrition and rescues deficiencies in cell size as well as sarcomere density. We employ a bioengineered platform to micropattern cardiomyocytes for calcium imaging and perform Southern blots of telomere restriction fragments, the gold standard for telomere length assessments. Importantly, preservation of telomere lengths in DMD cardiomyocytes improves their viability. These data provide evidence that preventing telomere attrition ameliorates deficits in cell morphology, activation of the DNA damage response, and premature cell death, suggesting that TRF2 is a key player in DMD-associated cardiac failure.

RevDate: 2023-01-30

Morgunova VV, Sokolova OA, Sizova TV, et al (2022)

Dysfunction of Lamin B and Physiological Aging Cause Telomere Instability in Drosophila Germline.

Biochemistry. Biokhimiia, 87(12):1600-1610.

Chromatin spatial organization in the nucleus is essential for the genome functioning and regulation of gene activity. The nuclear lamina and lamina-associated proteins, lamins, play a key role in this process. Lamin dysfunction leads to the decompaction and transcriptional activation of heterochromatin, which is associated with the premature aging syndrome. In many cell types, telomeres are located at the nuclear periphery, where their replication and stability are ensured by the nuclear lamina. Moreover, diseases associated with defects in lamins and telomeres have similar manifestations and resemble physiological aging. Understanding molecular changes associated with aging at the organismal level is especially important. In this study, we compared the effects caused by the mutation in lamin B and physiological aging in the germline of the model organism Drosophila melanogaster. We have shown that the impaired localization of lamin B leads to the heterochromatin decompaction and transcriptional activation of some transposable elements and telomeric repeats. Both DNA damage and activation of homologous recombination in the telomeres were observed in the germ cells of lamin B mutants. The instability of repeat-enriched heterochromatin can be directly related to the genome destabilization, germ cell death, and sterility observed in lamin B mutants. Similar processes were observed in Drosophila germline in the course of physiological aging, which indicates a close link between the maintenance of the heterochromatin stability at the nuclear periphery and mechanisms of aging.

RevDate: 2023-01-30

Hsu BY, Cossin-Sevrin N, Stier A, et al (2023)

Prenatal thyroid hormones accelerate postnatal growth and telomere shortening in wild great tits.

The Journal of experimental biology pii:286797 [Epub ahead of print].

Early-life environment is known to affect later-life health and disease, which could be mediated by the early-life programming of telomere length, a key hallmark of ageing. According to the fetal programming of telomere biology hypothesis, variation in prenatal exposure to hormones is likely to influence telomere length. Yet the contribution of key metabolic hormones, i.e. thyroid hormones (THs), has been largely ignored. We recently showed that in contrast to predictions, exposure to elevated prenatal THs increased postnatal telomere length in wild collared flycatchers, but the generality of such effect, its underlying proximate mechanisms and consequences on survival have not been investigated. We therefore conducted a comprehensive study evaluating the impact of THs on potential drivers of telomere dynamics (growth, post-natal THs, mitochondria and oxidative stress), telomere length and medium-term survival using wild great tits as a model system. While prenatal THs did not significantly affect telomere length a week after hatching (i.e. day 7), they influenced postnatal telomere shortening (i.e. shorter telomeres at day 14 and the following winter) but not apparent survival. Circulating THs, mitochondrial density or oxidative stress biomarkers were not significantly influenced, whereas TH-supplemented group showed accelerated growth, which may explain the observed delayed effect on telomeres. We discuss several alternative hypotheses that may explain the contrast with our previous findings in flycatchers. Given that shorter telomeres in early life tend to be carried until adulthood and are often associated with decreased survival prospects, the effects of prenatal THs on telomeres may have long-lasting effects on senescence.

RevDate: 2023-01-30

Yuan Y, Tan Y, Qiu X, et al (2022)

Sperm telomere length as a novel biomarker of male infertility and embryonic development: A systematic review and meta-analysis.

Frontiers in endocrinology, 13:1079966.

BACKGROUND: Telomeres have an essential role in maintaining the integrity and stability of the human chromosomal genome and preserving essential DNA biological functions. Several articles have been published on the association of STL with male semen parameters and clinical pregnancy. The results, however, are either inconclusive or inconsistent. Therefore, this meta-analysis aimed to systematically assess the accuracy and clinical value of sperm telomere length (STL) as a new marker for diagnosing male infertility and predicting the quality of embryonic development.

METHODS: We performed a comprehensive systematic search for relevant publications in PubMed, the Cochrane Library, Web of Science, Embase, Scopus, and Ovid, from database build to August 2022. All experimental studies exploring the association of STL with male semen quality, male infertility, or embryonic development were included.

RESULTS: Overall, Twelve prospective observational cohort studies (1700 patients) were eligible for inclusion in the meta-analysis. The meta-analysis showed a positive linear correlation between STL and semen parameters. The optimal cut-off value for STL diagnosing male infertility was 1.0, with a sensitivity and specificity of 80%. Regarding STL and embryonic development, the clinical pregnancy rate was associated with longer STL, and there was no significant difference between the two groups regarding fertilization rate.

CONCLUSION: Our study showed that STL has good diagnostic and predictive value for male fertility and clinical pregnancy and could be used as a new biomarker for diagnosing male infertility and predicting embryonic development.

https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42022303333.

RevDate: 2023-01-27

Valdiani A, H Ofoghi (2023)

Enzymatic approaches against SARS-CoV-2 infection with an emphasis on the telomere-associated enzymes.

Biotechnology letters [Epub ahead of print].

The pandemic phase of coronavirus disease 2019 (COVID-19) appears to be over in most countries. However, the unexpected behaviour and unstable nature of coronaviruses, including temporary hiatuses, re-emergence, emergence of new variants, and changing outbreak epicentres during the COVID-19 pandemic, have been frequently reported. The mentioned trend shows the fact that in addition to vaccine development, different strategies should be considered to deal effectively with this disease, in long term. In this regard, the role of enzymes in regulating immune responses to Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has recently attracted much attention. Moreover, several reports confirm the association of short telomeres with sever COVID-19 symptoms. This review highlights the role of several enzymes involved in telomere length (TL) regulation and explains their relevance to SARS-CoV-2 infection. Apparently, inhibition of telomere shortening (TS) through inhibition and/or activation of these enzymes could be a potential target in the treatment of COVID-19, which may also lead to a reduction in disease severity.

RevDate: 2023-01-27

Szeltner Z, Ferenc G, Juhász T, et al (2023)

Probing telomereric-like G4 structures with full or partial 2'-deoxy-5-hydroxyuridine substitutions.

Biochimie pii:S0300-9084(23)00009-3 [Epub ahead of print].

Guanine quadruplexes (G4s) are stable four-stranded secondary DNA structures held together by noncanonical G-G base tetrads. We synthesised the nucleoside analogue 2'-deoxy-5-hydroxyuridine (H) and inserted its phosphoramidite into telomeric repeat-type model oligonucleotides. Full and partial substitutions were made, replacing all guanines in all the three tetrads of a three-tier G4 structure, or only in the putative upper, central, or lower tetrads. We characterised these modified structures using CD, UV absorbance spectroscopy, native gel studies, and a capture oligo-based G4 disruption kinetic assay. The strand separation activity of BLM helicase on these substituted structures was also investigated. Two of the partially H-substituted constructs adopted G4-like structures, but displayed lower thermal stabilities compared to unsubstituted G4. The construct modified in its central tetrad remained mostly denatured, but the possibility of a special structure for the fully replaced variant remained open. H substitutions did not interfere with the G4-resolving activity of BLM helicase, but its efficiency was highly influenced by construct topology and even more by the G4 ligand PhenDC3. Our results suggest that the H modification can be incorporated into G quadruplexes, but only at certain positions to maintain G4 stability. The destabilizing effect observed for 2'-deoxy-5-hydroxyuridine indicates that the cytosine deamination product 5-hydroxyuracil and its nucleoside counterpart in RNA (5-hydroxyuridine), might also be destabilizing in cellular DNA and RNA quadruplexes. The kinetic assay employed in this study can be generally employed for a fast comparison of the stabilities of various G4s either in their free or ligand-bound states.

RevDate: 2023-01-27

Anonymous (2023)

Heritable Defects in Mitotic and Telomere Function Confer Sarcoma Risk.

Cancer discovery pii:716234 [Epub ahead of print].

Mitotic and telomere function pathways were identified to play a role in sarcoma susceptibility.

RevDate: 2023-01-27

Wai KM, Swe T, Myar MT, et al (2022)

Telomeres susceptibility to environmental arsenic exposure: Shortening or lengthening?.

Frontiers in public health, 10:1059248.

Maintaining telomere length plays a crucial role in regulating cellular life span. Telomere lengthening or shortening is one of the important biomarkers which could predict the preceding or present diseases. Meanwhile, the impact of environmental arsenic exposure on telomere length has increasingly concerned. Although previous studies demonstrated the effects of arsenic on telomere length, the findings were unclear on whether telomere shortens or lengthens by arsenic exposure. Thus, this manuscript summarized and discussed the telomere length alteration following arsenic exposure and the possible does-response effect of arsenic on telomere length. The present review suggested that different age groups may respond differently to arsenic exposure, and the dose-response effect of arsenic could be a critical factor in its effect on telomere length. Moreover, speciation analysis of arsenic could be more informative in identifying the effect of arsenic on telomere length.

RevDate: 2023-01-26

Hoerr RE, Eng A, Payen C, et al (2023)

Hotspot of de novo telomere addition stabilizes linear amplicons in yeast grown in sulfate-limiting conditions.

Genetics pii:7005643 [Epub ahead of print].

Evolution is driven by the accumulation of competing mutations that influence survival. A broad form of genetic variation is the amplification or deletion of DNA (≥50 bp) referred to as copy number variation. In humans, copy number variation may be inconsequential, contribute to minor phenotypic differences, or cause conditions such as birth defects, neurodevelopmental disorders, and cancers. To identify mechanisms that drive copy number variation, we monitored the experimental evolution of Saccharomyces cerevisiae populations grown under sulfate-limiting conditions. Cells with increased copy number of the gene SUL1, which encodes a primary sulfate transporter, exhibit a fitness advantage. Previously, we reported interstitial inverted triplications of SUL1 as the dominant rearrangement in a haploid population. Here, in a diploid population, we find instead that small linear fragments containing SUL1 form and are sustained over several generations. Many of the linear fragments are stabilized by de novo telomere addition within a telomere-like sequence near SUL1 (within the SNF5 gene). Using an assay that monitors telomerase action following an induced chromosome break, we show that this region acts as a hotspot of de novo telomere addition and that required sequences map to a region of <250 base pairs. Consistent with previous work showing that association of the telomere-binding protein Cdc13 with internal sequences stimulates telomerase recruitment, mutation of a four-nucleotide motif predicted to associate with Cdc13 abolishes de novo telomere addition. Our study suggests that internal telomere-like sequences that stimulate de novo telomere addition can contribute to adaptation by promoting genomic plasticity.

RevDate: 2023-01-26

Heaphy CM, AD Singhi (2023)

Reprint of: The Diagnostic and Prognostic Utility of Incorporating DAXX, ATRX, and Alternative Lengthening of Telomeres (ALT) to the Evaluation of Pancreatic Neuroendocrine Tumors (PanNETs).

Pancreatic neuroendocrine tumors (PanNETs) are a heterogeneous group of neoplasms with increasing incidence and an ill-defined pathobiology. Although many PanNETs are indolent and remain stable for years, a subset may behave aggressively and metastasize widely. Thus, the increasing and frequent detection of PanNETs presents a treatment dilemma. Current prognostic systems are susceptible to interpretation errors, sampling issues, and do not accurately reflect the clinical behavior of these neoplasms. Hence, additional biomarkers are needed to improve the prognostic stratification of patients diagnosed with a PanNET. Recent studies have identified alterations in death domain-associated protein 6 (DAXX) and alpha-thalassemia/mental retardation X-linked (ATRX), as well as alternative lengthening of telomeres (ALT), as promising prognostic biomarkers. This review summarizes the identification, clinical utility, and specific nuances in testing for DAXX/ATRX by immunohistochemistry and ALT by telomere-specific fluorescence in situ hybridization in PanNETs. Furthermore, a discussion on diagnostic indications for DAXX, ATRX, and ALT status is provided to include the distinction between PanNETs and pancreatic neuroendocrine carcinomas (PanNECs), and determining pancreatic origin for metastatic neuroendocrine tumors in the setting of an unknown primary.

RevDate: 2023-01-26

Uzuncakmak SK, Dirican E, Ozcan H, et al (2023)

Relation of ATPase6 Mutations and Telomere Length in Schizophrenia Patients.

Clinical psychopharmacology and neuroscience : the official scientific journal of the Korean College of Neuropsychopharmacology, 21(1):162-170.

OBJECTIVE: Schizophrenia is a serious mental disorder. Mutations in mitochondrial genes can change energy metabolism. Telomere is a tandem sequence at the end of chromosomes. Shorter telomere length has been shown in schizophrenia. The aim of this study was to determine the relationship between ATPase6 gene mutations and telomere length in schizophrenia patients.

METHODS: Blood samples of 34 patients and 34 healthy controls were used. In this study conventional PCR, Sanger sequencing technic and real-time PCR were utilized.

RESULTS: Five different mutations (A8860G, A8836, G8697A, C8676T, and A8701G) in the ATPase6 gene were identified in schizophrenia patients. The most seen mutation was A8860G (94%). Telomere length analysis indicated the relation of ATPase6 gene mutations and telomere length variations (p = 0.001). Patients carrying the A8860G mutation had shorter telomere lengths than patients carrying other mutations. Comparing telomere length between schizophrenia patients and healthy controls revealed that the mean telomere length of schizophrenia patients was shorter than healthy controls (p = 0.006). The demographic analysis demonstrated a significant relationship between marital status and telomere length (p = 0.011). Besides that, the duration of the illness is another factor that impacts telomere length (p = 0.044). There is no significant relation between telomere length and other clinical and demographic characteristics including education status, age, gender, etc.

CONCLUSION: In conclusion, telomere length and ATPase6 gene mutations have a significant relation. Studies with larger patient populations and investigation of other mitochondrial gene mutations will make the clearer link between telomere length and mitochondrial mutations.

RevDate: 2023-01-26

Holmes O, Nones K, Tang YH, et al (2022)

qmotif: determination of telomere content from whole-genome sequence data.

Bioinformatics advances, 2(1):vbac005.

MOTIVATION: Changes in telomere length have been observed in cancer and can be indicative of mechanisms involved in carcinogenesis. Most methods used to estimate telomere length require laboratory analysis of DNA samples. Here, we present qmotif, a fast and easy tool that determines telomeric repeat sequences content as an estimate of telomere length directly from whole-genome sequencing.

RESULTS: qmotif shows similar results to quantitative PCR, the standard method for high-throughput clinical telomere length quantification. qmotif output correlates strongly with the output of other tools for determining telomere sequence content, TelSeq and TelomereHunter, but can run in a fraction of the time-usually under a minute.

qmotif is implemented in Java and source code is available at https://github.com/AdamaJava/adamajava, with instructions on how to build and use the application available from https://adamajava.readthedocs.io/en/latest/.

SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics Advances online.

RevDate: 2023-01-25

Park S, Kim SG, Lee S, et al (2023)

Causal linkage of tobacco smoking with ageing: Mendelian randomization analysis towards telomere attrition and sarcopenia.

Journal of cachexia, sarcopenia and muscle [Epub ahead of print].

BACKGROUND: Ageing traits and frailty are important health issues in modern medicine. Evidence supporting the causal effects of tobacco smoking on various ageing traits is required.

METHODS: This study performed Mendelian randomization (MR) analysis instrumenting 377 genetic variants associated with being an ever-smoker at a genome-wide significance level to test the causal estimates from tobacco smoking. The outcome data were obtained from 337 138 white British ancestry participants from the UK Biobank. Leucocyte telomere length, appendicular lean mass index, subjective walking pace, handgrip strength, and wristband accelerometry-determined physical activity degree were collected as ageing-related outcomes. Summary-level MR analysis was performed using the inverse variance-weighted method and pleiotropy-robust MR methods, including weighted median and MR-Egger. Observational association between the outcome traits and phenotypically being an ever-smoker was also investigated.

RESULTS: Summary-level MR analysis indicated that a higher genetic predisposition for tobacco smoking was significantly associated with shorter leucocyte telomere length (twofold increase in prevalence of smoking towards standardized Z-score, -0.041 [-0.054, -0.028]), lower appendicular lean mass index (-0.007 [-0.010, -0.005]), slower walking pace (ordinal category, -0.047 [-0.054, -0.033]) and lower time spent on moderate-to-vigorous physical activity (hours per week, -0.39 [-0.56, -0.23]). The causal estimates were non-significant towards handgrip strength phenotype (kg, 0.074 [-0.055, 0.204]). Pleiotropy-robust MR results generally supported the main causal estimates. The observational findings also showed significant association between being an ever-smoker and the ageing traits.

CONCLUSIONS: Genetically predicted and observational tobacco smoking status are significantly associated with poor ageing phenotypes. Healthcare providers may continue to reduce tobacco use, which may be helpful in reducing the burden of ageing and frailty.

RevDate: 2023-01-24

Sabot D, Lovegrove R, P Stapleton (2023)

The association between sleep quality and telomere length: A systematic literature review.

Brain, behavior, & immunity - health, 28:100577.

Several sleep parameters present an elevated risk for processes that contribute to cellular aging. Short sleep duration, sleep apnoea, and insomnia are significantly associated with shorter telomeres, a biological marker of cellular aging. However, there has been no review or analysis of studies that have examined the association between the psychological construct of sleep quality and telomere length. The present study aimed to provide a systematic review of the association between sleep quality and telomere length. A systematic review of English articles was conducted using MEDLINE/PubMed, PsycINFO, Google Scholar, and Web of Science electronic databases, with the final search conducted on 3rd September 2021. Search terms included sleep quality, poor sleep, insomnia, sleep difficulties, sleep issue*, non-restorative sleep, telomere*, cellular aging, and immune cell telomere length. Study eligibility criteria included human participants aged 18 years or older and a reproducible methodology. Study appraisal and synthesis were completed using a systematic search in line with a PICOS approach (P = Patient, problem, or population; I = Intervention, prognostic factor, exposure; C = Comparison, control, or comparator; O = Outcomes; S = Study designs). Twenty-two studies met review inclusion criteria. Qualitative synthesis of the literature indicated insufficient evidence overall to support a significant association between sleep quality and telomere length. Limitations across studies were addressed, such as the assessment of examined constructs. Findings highlight important targets for future research, including the standardised operationalisation of the sleep quality construct and experimental study designs. Research in this area has clinical significance by identifying possible mechanisms that increase the risk for age-related disease and mortality. PROSPERO Registration No.: CRD 42021233139.

RevDate: 2023-01-23

Kim JS, Manichaikul AW, Hoffman EA, et al (2022)

MUC5B, telomere length and longitudinal quantitative interstitial lung changes: the MESA Lung Study.

Thorax pii:thorax-2021-218139 [Epub ahead of print].

BACKGROUND: The MUC5B promoter variant (rs35705950) and telomere length are linked to pulmonary fibrosis and CT-based qualitative assessments of interstitial abnormalities, but their associations with longitudinal quantitative changes of the lung interstitium among community-dwelling adults are unknown.

METHODS: We used data from participants in the Multi-Ethnic Study of Atherosclerosis with high-attenuation areas (HAAs, Examinations 1-6 (2000-2018)) and MUC5B genotype (n=4552) and telomere length (n=4488) assessments. HAA was defined as the per cent of imaged lung with attenuation of -600 to -250 Hounsfield units. We used linear mixed-effects models to examine associations of MUC5B risk allele (T) and telomere length with longitudinal changes in HAAs. Joint models were used to examine associations of longitudinal changes in HAAs with death and interstitial lung disease (ILD).

RESULTS: The MUC5B risk allele (T) was associated with an absolute change in HAAs of 2.60% (95% CI 0.36% to 4.86%) per 10 years overall. This association was stronger among those with a telomere length below an age-adjusted percentile of 5% (p value for interaction=0.008). A 1% increase in HAAs per year was associated with 7% increase in mortality risk (rate ratio (RR)=1.07, 95% CI 1.02 to 1.12) for overall death and 34% increase in ILD (RR=1.34, 95% CI 1.20 to 1.50). Longer baseline telomere length was cross-sectionally associated with less HAAs from baseline scans, but not with longitudinal changes in HAAs.

CONCLUSIONS: Longitudinal increases in HAAs were associated with the MUC5B risk allele and a higher risk of death and ILD.

RevDate: 2023-01-23

Liu H, Xu C, Diplas BH, et al (2023)

Cancer-associated SMARCAL1 loss-of-function mutations promote alternative lengthening of telomeres and tumorigenesis in telomerase-negative glioblastoma cells.

Neuro-oncology pii:6998515 [Epub ahead of print].

BACKGROUND: Telomere maintenance mechanisms are required to enable the replicative immortality of malignant cells. While most cancers activate the enzyme telomerase, a subset of cancers use telomerase-independent mechanisms termed alternative lengthening of telomeres (ALT). ALT occurs via homology directed-repair mechanisms and is frequently associated with ATRX mutations. We previously showed that a subset of adult GBM patients with ATRX-expressing ALT-positive tumors harbored loss-of-function mutations in the SMARCAL1 gene, which encodes an annealing helicase involved in replication fork remodeling and the resolution of replication stress. However, the causative relationship between SMARCAL1 deficiency, tumorigenesis, and de novo telomere synthesis is not understood.

METHODS: We used a patient-derived ALT-positive GBM cell line with native SMARCAL1 deficiency to investigate the role of SMARCAL1 in ALT-mediated de novo telomere synthesis, replication stress, and gliomagenesis in vivo.

RESULTS: Inducible rescue of SMARCAL1 expression suppresses ALT indicators and inhibits de novo telomere synthesis in GBM and osteosarcoma cells, suggesting that SMARCAL1 deficiency plays a functional role in ALT induction in cancers that natively lack SMARCAL1 function. SMARCAL1-deficient ALT-positive cells can be serially propagated in vivo in the absence of detectable telomerase activity, demonstrating that the SMARCAL1-deficient ALT phenotype maintains telomeres in a manner that promotes tumorigenesis.

CONCLUSIONS: SMARCAL1 deficiency is permissive to ALT and promote gliomagenesis. Inducible rescue of SMARCAL1 in ALT-positive cell lines permits the dynamic modulation of ALT activity, which will be valuable for future studies aimed at understanding the mechanisms of ALT and identifying novel anti-cancer therapeutics that target the ALT phenotype.

RevDate: 2023-01-23

Yin H, JG Pickering (2023)

Telomere Length: Implications for Atherogenesis.

Current atherosclerosis reports [Epub ahead of print].

PURPOSE OF REVIEW: The purpose of the study is to explore the evidence linking telomere length with atherosclerotic ischemic disease.

RECENT FINDINGS: There has been a recent expansion in strategies for measuring telomere length, including analyzing genome sequence data and capitalizing on genomic loci that associate with telomere length. These, together with more established approaches, have been used to generate a more complete picture of telomere length relationships with ischemic disease. Whereas earlier meta-analyses suggested an association between short leukocyte telomeres and ischemic disease, several recent large population studies now provide particularly compelling data, including an association with cardiovascular mortality. In addition, whether short leukocyte telomeres might be causally related to ischemic disease has been interrogated using Mendelian randomization strategies, which point to shorter leukocyte telomeres as a determining risk factor. Importantly however, the wide, interindividual variability in telomere length still means that a single assessment of leukocyte telomere length in an individual does not reliably report on a biological aging process. In this regard, recent multi-tissue analyses of telomere length dynamics are providing both new mechanistic insights into how telomere length and shortening rates may participate in atherogenesis and risk prediction opportunities. The balance of evidence indicates that short leukocyte telomeres confer a risk for atherosclerotic cardiovascular disease. Moreover, an integrated analysis of telomere lengths in leukocytes and other tissues may provide a window into individualized telomere dynamics, raising new prospects for risk management.

RevDate: 2023-01-23

Xiao Y, Xu D, Jiang C, et al (2022)

Telomere maintenance-related genes are important for survival prediction and subtype identification in bladder cancer.

Frontiers in genetics, 13:1087246.

Background: Bladder cancer ranks among the top three in the urology field for both morbidity and mortality. Telomere maintenance-related genes are closely related to the development and progression of bladder cancer, and approximately 60%-80% of mutated telomere maintenance genes can usually be found in patients with bladder cancer. Methods: Telomere maintenance-related gene expression profiles were obtained through limma R packages. Of the 359 differential genes screened, 17 prognostically relevant ones were obtained by univariate independent prognostic analysis, and then analysed by LASSO regression. The best result was selected to output the model formula, and 11 model-related genes were obtained. The TCGA cohort was used as the internal group and the GEO dataset as the external group, to externally validate the model. Then, the HPA database was used to query the immunohistochemistry of the 11 model genes. Integrating model scoring with clinical information, we drew a nomogram. Concomitantly, we conducted an in-depth analysis of the immune profile and drug sensitivity of the bladder cancer. Referring to the matrix heatmap, delta area plot, consistency cumulative distribution function plot, and tracking plot, we further divided the sample into two subtypes and delved into both. Results: Using bioinformatics, we obtained a prognostic model of telomere maintenance-related genes. Through verification with the internal and the external groups, we believe that the model can steadily predict the survival of patients with bladder cancer. Through the HPA database, we found that three genes, namely ABCC9, AHNAK, and DIP2C, had low expression in patients with tumours, and eight other genes-PLOD1, SLC3A2, RUNX2, RAD9A, CHMP4C, DARS2, CLIC3, and POU5F1-were highly expressed in patients with tumours. The model had accurate predictive power for populations with different clinicopathological features. Through the nomogram, we could easily assess the survival rate of patients. Clinicians can formulate targeted diagnosis and treatment plans for patients based on the prediction results of patient survival, immunoassays, and drug susceptibility analysis. Different subtypes help to further subdivide patients for better treatment purposes. Conclusion: According to the results obtained by the nomogram in this study, combined with the results of patient immune-analysis and drug susceptibility analysis, clinicians can formulate diagnosis and personalized treatment plans for patients. Different subtypes can be used to further subdivide the patient for a more precise treatment plan.

RevDate: 2023-01-23

Semeraro MD, Beltrami AP, Kharrat F, et al (2022)

The impact of moderate endurance exercise on cardiac telomeres and cardiovascular remodeling in obese rats.

Frontiers in cardiovascular medicine, 9:1080077.

INTRODUCTION: Hypercaloric nutrition and physical inactivity cause obesity, a potential driver of myocardial apoptosis and senescence that may accelerate cardiac aging. Although physical activity reduces mortality, its impact on myocardial aging is insufficiently understood. Here we investigated the effects of a hypercaloric high-fat diet (HFD) and regular exercise training on cardiac cells telomeres and histomorphometric indices of cardiac aging.

METHODS: Ninety-six 4-months old female Sprague-Dawley rats were fed for 10 months normal (ND) or a HFD diet. Half of the animals in each group performed 30 min treadmill-running sessions on 5 consecutive days per week. At study end, cardiomyocyte cross-sectional area (CSA), interstitial collagen content, vascular density, apoptotic and senescent cells, relative telomere length (RTL), and expression of telomerase-reverse transcriptase (Tert) as marker of telomere-related senescence and apoptosis were analyzed.

RESULTS: Compared to ND, the HFD group developed obesity, higher CSA, lower capillary density and tended to have more apoptotic cardiomyocytes and interstitials cells. Myocardial RTL and the expression of Terf-1 and Terf-2 were comparable in sedentary HFD and ND animals. In the HFD group, regular moderate endurance exercise improved myocardial vascularization, but had no effect on CSA or apoptosis. Notably, the combination of exercise and HFD increased senescence when compared to sedentary ND or HFD, and reduced RTL when compared to exercise ND animals. Exercising HFD animals also showed a trend toward higher Tert expression compared to all other groups. In addition, exercise reduced Terf-1 expression regardless of diet.

CONCLUSION: HFD-induced obesity showed no effects on myocardial telomeres and induced only mild morphologic alterations. Summarized, long-term moderate endurance exercise partially reverses HFD-induced effects but may even trigger cardiac remodeling in the context of obesity.

RevDate: 2023-01-21

Dhillon VS, Deo P, Thomas P, et al (2023)

Low Magnesium in Conjunction with High Homocysteine and Less Sleep Accelerates Telomere Attrition in Healthy Elderly Australian.

International journal of molecular sciences, 24(2): pii:ijms24020982.

The relationship between sleep and micronutrients, including magnesium, is implicated in its regulation. The effects of low magnesium and other micronutrients on sleep disruption and telomere loss are not well understood. The present study was carried out in 172 healthy elderly subjects from South Australia. Plasma micronutrients including magnesium were measured. Each participant provided information about their sleep hours (<7 h or ≥7 h). Lymphocyte telomere length (TL) was measured by real-time qPCR assay. Plasma magnesium level was significantly low in subjects who sleep less than 7 h (p = 0.0002). TL was significantly shorter in people who are low in magnesium and sleep less than 7 h (p = 0.01). Plasma homocysteine (Hcy) is negatively associated with magnesium (r = -0.299; p < 0.0001). There is a significant interaction effect of magnesium and Hcy on sleep duration (p = 0.04) and TL (p = 0.003). Our results suggest that inadequate magnesium levels have an adverse impact on sleep and telomere attrition rate in cognitively normal elderly people, and this may be exacerbated by low levels of vitamin B12 and folate that elevate Hcy concentration.

RevDate: 2023-01-21

López-Armas GDC, Ramos-Márquez ME, Navarro-Meza M, et al (2023)

Leukocyte Telomere Length Predicts Severe Disability in Relapsing-Remitting Multiple Sclerosis and Correlates with Mitochondrial DNA Copy Number.

International journal of molecular sciences, 24(2): pii:ijms24020916.

Multiple sclerosis (MS) is a chronic autoimmune inflammatory disease that affects the nervous system. Peripheral blood leukocyte telomere length (LTL) and mitochondrial DNA copy number (mtDNA-CN) are potential biomarkers of neurological disability and neural damage. Our objective was to assess the LTL and mtDNA-CN in relapsing-remitting MS (RRMS). We included 10 healthy controls, 75 patients with RRMS, 50 of whom had an Expanded Disability Status Scale (EDSS) from 0 to 3 (mild to moderate disability), and 25 had an EDSS of 3.5 to 7 (severe disability). We use the Real-Time Polymerase Chain Reaction (qPCR) technique to quantify absolute LTL and absolute mtDNA-CN. ANOVA test show differences between healthy control vs. severe disability RRMS and mild-moderate RRMS vs. severe disability RRMS (p = 0.0130). LTL and mtDNA-CN showed a linear correlation in mild-moderate disability RRMS (r = 0.378, p = 0.007). Furthermore, we analyzed LTL between RRMS groups with a ROC curve, and LTL can predict severe disability (AUC = 0.702, p = 0.0018, cut-off < 3.0875 Kb, sensitivity = 75%, specificity = 62%), whereas the prediction is improved with a logistic regression model including LTL plus age (AUC = 0.762, p = 0.0001, sensitivity = 79.17%, specificity = 80%). These results show that LTL is a biomarker of disability in RRMS and is correlated with mtDNA-CN in mild-moderate RRMS patients.

RevDate: 2023-01-20

Bountziouka V, Nelson CP, Wang Q, et al (2023)

Dietary patterns and practices and leucocyte telomere length: Findings from the UK Biobank.

Journal of the Academy of Nutrition and Dietetics pii:S2212-2672(23)00017-5 [Epub ahead of print].

BACKGROUND: Shorter telomere length (TL) is associated with risk of several age-related diseases and decreased lifespan, but the extent to which dietary patterns and practices associate with TL is uncertain.

OBJECTIVE: This study aimed to investigate the association of dietary patterns and practices and leucocyte TL (LTL).

DESIGN: This was a cross-sectional study.

PARTICIPANTS: / setting: Data collected voluntarily from up to 422,797 UK Biobank participants, during 2006-2010.

MAIN OUTCOME MEASURES: LTL was measured as a ratio of the telomere repeat number to a single-copy gene and was loge-transformed and standardised (z-LTL).

STATISTICAL ANALYSIS: A-priori adherence to the Mediterranean diet was assessed through the MedDietScore. Principal component analysis was used to a-posteriori extract the "Meat" and "Prudent" dietary patterns. Additional dietary practices considered were the self-reported adherence to "Vegetarian" diet, "Eating 5-a-day of fruit and vegetables" and "Abstaining from eggs/dairy/wheat/sugar". Associations between quintiles of dietary patterns or adherence to dietary practices with z-LTL were investigated through multivariable linear regression models (adjusted for demographic, lifestyle and clinical characteristics).

RESULTS: Adherence to the "Mediterranean" and the "Prudent" patterns, was positively associated with LTL, with an effect magnitude in z-LTL of 0.020SD and 0.014SD, respectively, for the highest vs the lowest quintile of adherence to the pattern (both P<0.05). Conversely, a reversed association between quintile of the "Meat" pattern and LTL was observed, with z-LTL being on average shorter by 0.025SD (P=6.12x10[-05]) for participants in the highest quintile of the pattern compared to the lowest quintile. For adherents to "5-a-day" z-LTL was on average longer by 0.027SD (P=5.36x10[-09]), and for "abstainers", LTL was shorter by 0.016SD (P=2.51x10[-04]). The association of LTL with a vegetarian diet was non-significant after adjustment for demographic, lifestyle and clinical characteristics.

CONCLUSION: Several dietary patterns and practices, associated with beneficial health effects, are significantly associated with longer LTL. However, the magnitude of the association was small, and any clinical relevance is uncertain.

RevDate: 2023-01-20

Park HS, Im K, Shin DY, et al (2023)

Telomere integrated scoring system of myelodysplastic syndrome.

Journal of clinical laboratory analysis [Epub ahead of print].

INTRODUCTION: Recently, multigene target sequencing is widely performed for the purpose of prognostic prediction and application of targeted therapy. Here, we proposed a new scoring system that encompasses gene variations, telomere length, and Revised International Prognostic Scoring System (IPSS-R) together in Asian myelodysplastic syndrome.

METHODS: We developed a new scoring model of these variables: age ≥ 65 years + IPSS-R score + ASXL1 mutation + TP53 mutation + Telomere length (<5.37). According to this new scoring system, patients were divided into four groups: very good score cutoff (≤3.0), good (3.0-4.5), poor (4.5-7.0), and very poor (>7.0).

RESULTS: The median OS was 170.1, 100.4, 46.0, and 12.0 months for very good, good, poor, and very poor, retrospectively (p < 0.001). Meanwhile, according to the conventional IPSS-R scoring system, the median OS was 141.3, 50.2, 93.0, 36.0, and 16.2 months for very low, low, intermediate, high, and very high, retrospectively (p < 0.001).

CONCLUSIONS: The newly developed model incorporating molecular variations and TL yielded more clear separations of the survival curves. By adding the presence of gene mutation and telomere length to the existing IPSS-R, its predictive ability can be further improved in myelodysplastic syndrome.

RevDate: 2023-01-19

Armstrong E, J Boonekamp (2023)

Does oxidative stress shorten telomeres in vivo? A meta-analysis.

Ageing research reviews pii:S1568-1637(23)00013-2 [Epub ahead of print].

Telomere attrition is considered a hallmark of ageing. Untangling the proximate causes of telomere attrition may therefore reveal important aspects about the ageing process. In a landmark paper in 2002 Thomas von Zglinicki demonstrated that oxidative stress accelerates telomere attrition in cell culture. In the next 20 years, oxidative stress became firmly embedded into modern theories of ageing and telomere attrition. However, a recent surge of in vivo studies reveals an inconsistent pattern questioning the unequivocal role of oxidative stress in telomere length and telomere attrition (henceforth referred to as telomere dynamics), in living organisms. Here we report the results of the first formal meta-analysis on the association between oxidative stress and telomere dynamics in vivo, representing 37 studies, 4,969 individuals, and 18,677 correlational measurements. The overall correlation between oxidative stress markers and telomere dynamics was indistinguishable from zero (r=0.027). This result was independent of the type of oxidative stress marker, telomere dynamic, or taxonomic group. However, telomere measurement method affected the analysis and the subset of TRF-based studies showed a significant overall correlation (r=0.09), supporting the prediction that oxidative stress accelerates telomere attrition. The correlation was more pronounced in short-lived species and during the adult life phase, when ageing becomes apparent. We then performed an additional meta-analysis of interventional studies (n=7) manipulating oxidative stress. This revealed a significant effect of treatment on telomere dynamics (d=0.36). Our findings provide new support for the hypothesis that oxidative stress causes telomere attrition in living organisms.

RevDate: 2023-01-19

Ballinger ML, Pattnaik S, Mundra PA, et al (2023)

Heritable defects in telomere and mitotic function selectively predispose to sarcomas.

Science (New York, N.Y.), 379(6629):253-260.

Cancer genetics has to date focused on epithelial malignancies, identifying multiple histotype-specific pathways underlying cancer susceptibility. Sarcomas are rare malignancies predominantly derived from embryonic mesoderm. To identify pathways specific to mesenchymal cancers, we performed whole-genome germline sequencing on 1644 sporadic cases and 3205 matched healthy elderly controls. Using an extreme phenotype design, a combined rare-variant burden and ontologic analysis identified two sarcoma-specific pathways involved in mitotic and telomere functions. Variants in centrosome genes are linked to malignant peripheral nerve sheath and gastrointestinal stromal tumors, whereas heritable defects in the shelterin complex link susceptibility to sarcoma, melanoma, and thyroid cancers. These studies indicate a specific role for heritable defects in mitotic and telomere biology in risk of sarcomas.

RevDate: 2023-01-18

Lv BB, Yang CL, Tan ZX, et al (2023)

Association between cadmium exposure and pulmonary function reduction: Potential mediating role of telomere attrition in chronic obstructive pulmonary disease patients.

Ecotoxicology and environmental safety, 251:114548 pii:S0147-6513(23)00052-0 [Epub ahead of print].

BACKGROUND: Environmental cadmium (Cd) exposure is linked to pulmonary function injury in the general population. But, the association between blood Cd concentration and pulmonary function has not been investigated thoroughly in chronic obstructive pulmonary disease (COPD) patients, and the potential mechanisms are unclear.

METHODS: All eligible 789 COPD patients were enrolled from Anhui COPD cohort. Blood specimens and clinical information were collected. Pulmonary function test was conducted. The subunit of telomerase, telomerase reverse transcriptase (TERT), was determined through enzyme linked immunosorbent assay (ELISA). Blood Cd was measured via inductively coupled-mass spectrometer (ICP-MS).

RESULTS: Blood Cd was negatively and dose-dependently associated with pulmonary function. Each 1-unit increase of blood Cd was associated with 0.861 L decline in FVC, 0.648 L decline in FEV1, 5.938 % decline in FEV1/FVC %, and 22.098 % decline in FEV1 % among COPD patients, respectively. Age, current-smoking, self-cooking and higher smoking amount aggravated Cd-evoked pulmonary function decrease. Additionally, there was an inversely dose-response association between Cd concentration and TERT in COPD patients. Elevated TERT obviously mediated 29.53 %, 37.50 % and 19.48 % of Cd-evoked FVC, FEV1, and FEV1 % declines in COPD patients, respectively.

CONCLUSION: Blood Cd concentration is strongly associated with the decline of pulmonary function and telomerase activity among COPD patients. Telomere attrition partially mediates Cd-induced pulmonary function decline, suggesting an underlying mechanistic role of telomere attrition in pulmonary function decline from Cd exposure in COPD patients.

RevDate: 2023-01-18

James EN, Sagi-Kiss V, Bennett M, et al (2023)

Dyskeratosis Congenita links telomere attrition to age-related systemic energetics.

The journals of gerontology. Series A, Biological sciences and medical sciences pii:6991261 [Epub ahead of print].

Underlying mechanisms of plasma metabolite signatures of human ageing and age-related diseases are not clear but telomere attrition and dysfunction are central to both. Dyskeratosis Congenita (DC) is associated with mutations in the telomerase enzyme complex (TERT, TERC, and DKC1) and progressive telomere attrition. We analyzed the effect of telomere attrition on senescence associated metabolites in fibroblast conditioned media and DC patient plasma. Samples were analyzed by gas chromatography/ mass spectrometry and liquid chromatography/ mass spectrometry. We showed extracellular citrate was repressed by canonical telomerase function in vitro and associated with DC leukocyte telomere attrition in vivo; leading to the hypothesis that altered citrate metabolism detects telomere dysfunction. However, elevated citrate and senescence factors only weakly distinguished DC patients from controls, whereas elevated levels of other tricarboxylic acid cycle metabolites, lactate and especially pyruvate distinguished them with high significance. The DC plasma signature most resembled that of patients with loss of function pyruvate dehydrogenase complex mutations and that of older subjects but significantly not those of type 2 diabetes, lactic acidosis, or elevated mitochondrial reactive oxygen species (1-3). Additionally, our data are consistent with further metabolism of citrate and lactate in the liver and kidneys. Citrate uptake in certain organs modulates age-related disease in mice and our data has similarities with age-related disease signatures in humans. Our results have implications for the role of telomere dysfunction in human ageing in addition to its early diagnosis and the monitoring of anti-senescence therapeutics, especially those designed to improve telomere function.

RevDate: 2023-01-18

Storchova R, Palek M, Palkova N, et al (2023)

Phosphorylation of TRF2 promotes its interaction with TIN2 and regulates DNA damage response at telomeres.

Nucleic acids research pii:6991041 [Epub ahead of print].

Protein phosphatase magnesium-dependent 1 delta (PPM1D) terminates the cell cycle checkpoint by dephosphorylating the tumour suppressor protein p53. By targeting additional substrates at chromatin, PPM1D contributes to the control of DNA damage response and DNA repair. Using proximity biotinylation followed by proteomic analysis, we identified a novel interaction between PPM1D and the shelterin complex that protects telomeric DNA. In addition, confocal microscopy revealed that endogenous PPM1D localises at telomeres. Further, we found that ATR phosphorylated TRF2 at S410 after induction of DNA double strand breaks at telomeres and this modification increased after inhibition or loss of PPM1D. TRF2 phosphorylation stimulated its interaction with TIN2 both in vitro and at telomeres. Conversely, induced expression of PPM1D impaired localisation of TIN2 and TPP1 at telomeres. Finally, recruitment of the DNA repair factor 53BP1 to the telomeric breaks was strongly reduced after inhibition of PPM1D and was rescued by the expression of TRF2-S410A mutant. Our results suggest that TRF2 phosphorylation promotes the association of TIN2 within the shelterin complex and regulates DNA repair at telomeres.

RevDate: 2023-01-17

Tham CY, Poon L, Yan T, et al (2023)

High-throughput telomere length measurement at nucleotide resolution using the PacBio high fidelity sequencing platform.

Nature communications, 14(1):281.

Telomeres are specialized nucleoprotein structures at the ends of linear chromosomes. The progressive shortening of steady-state telomere length in normal human somatic cells is a promising biomarker for age-associated diseases. However, there remain substantial challenges in quantifying telomere length due to the lack of high-throughput method with nucleotide resolution for individual telomere. Here, we describe a workflow to capture telomeres using newly designed telobaits in human culture cell lines as well as clinical patient samples and measure their length accurately at nucleotide resolution using single-molecule real-time (SMRT) sequencing. Our results also reveal the extreme heterogeneity of telomeric variant sequences (TVSs) that are dispersed throughout the telomere repeat region. The presence of TVSs disrupts the continuity of the canonical (5'-TTAGGG-3')n telomere repeats, which affects the binding of shelterin complexes at the chromosomal ends and telomere protection. These findings may have profound implications in human aging and diseases.

RevDate: 2023-01-17

Lambert-Lanteigne P, Young A, C Autexier (2023)

Complex interaction network revealed by mutation of human telomerase 'Insertion in Fingers' and essential N-terminal domains, and the telomere protein TPP1.

The Journal of biological chemistry pii:S0021-9258(23)00048-0 [Epub ahead of print].

In the majority of human cancer cells, cellular immortalization depends on the maintenance of telomere length by telomerase. An essential step required for telomerase function is its recruitment to telomeres, which is regulated by the interaction of the telomere protein, TPP1, with the telomerase essential N-terminal (TEN) domain of the human telomerase reverse transcriptase, hTERT. We previously reported that the hTERT 'insertion in fingers domain' (IFD) recruits telomerase to telomeres in a TPP1-dependent manner. Here we use hTERT truncations and the IFD domain containing mutations in conserved residues or premature aging disease-associated mutations to map the interactions between the IFD and TPP1. We find that the hTERT-IFD domain can interact with TPP1. However, deletion of the IFD motif in hTERT lacking the N-terminus and the C-terminal extension does not abolish interaction with TPP1, suggesting the IFD is not essential for hTERT interaction with TPP1. Several conserved residues in the central IFD-TRAP region that we reported regulate telomerase recruitment to telomeres and cell immortalization compromise interaction of the hTERT-IFD domain with TPP1 when mutated. Using a similar approach, we find that the IFD domain interacts with the TEN domain, but is not essential for intramolecular hTERT interactions with the TEN domain. IFD-TEN interactions are not disrupted by multiple amino acid changes in the IFD or TEN, thus highlighting a complex regulation of IFD-TEN interactions as suggested by recent cryo-EM structures of human telomerase.

RevDate: 2023-01-17

Schneper LM, Drake AJ, Dunstan T, et al (2023)

Characteristics of salivary telomere length shortening in preterm infants.

PloS one, 18(1):e0280184 pii:PONE-D-22-20483.

OBJECTIVE: To examine the association between gestational age, telomere length (TL) and rate of shortening in newborns.

STUDY DESIGN: Genomic DNA was isolated from buccal samples of 39 term infants at birth and one year and 32 preterm infants at birth, term-adjusted age (40 weeks post-conception) and age one-year corrected for gestational duration. Telomere length was measured by quantitative real-time PCR. Demographic and clinical data were collected during clinic or research visits and from hospital records. Socioeconomic status was estimated using the deprivation category (DEPCAT) scores derived from the Carstairs score of the subject's postal code.

RESULTS: At birth, preterm infants had longer telomeres than infants born at term. However, there was no difference in telomere length between preterm infants and term infants at one year of age, implying that the rate of telomere shortening was greater in pre-term than term infants. Interestingly, TL at age 40 weeks post-conception in preterm infants was significantly longer than term infant TL at birth, suggesting that time since conception is not the only factor that affects rate of shortening. Several factors, including sex, fetal growth restriction, maternal age, maternal booking body mass index (BMI), mother education level and DEPCAT score, also differed between the preterm and term groups.

CONCLUSIONS: Preterm infants have longer telomeres than term infants at birth. In the studied cohort, the rate of telomere shortening was greater in the premature group compared with the term infants. This finding agrees with previous studies using cord blood, suggesting that the longer TL in premature infants detected at birth do not persist and demonstrating that use of saliva DNA is acceptable for studies of telomere dynamics in infants. However, that the TL at age 40 weeks post-conception in preterm is longer than term infants at birth suggests that biological factors other than time since conception also affect rate of shortening.

RevDate: 2023-01-16

Fu A, Zheng Y, Guo J, et al (2023)

Telomere-to-telomere genome assembly of bitter melon (Momordica charantia L. var. abbreviata Ser.) reveals fruit development, composition and ripening genetic characteristics.

Horticulture research, 10(1):uhac228.

Momordica charantia L. var. abbreviata Ser. (Mca), known as bitter gourd or bitter melon, is a Momordica variety with medicinal value and belongs to the Cucurbitaceae family. In view of the lack of genomic information on bitter gourd and other Momordica species and to promote Mca genomic research, we assembled a 295.6-Mb telomere-to-telomere (T2T) high-quality Mca genome with six gap-free chromosomes after Hi-C correction. This genome is anchored to 11 chromosomes, which is consistent with the karyotype information, and comprises 98 contigs (N50 of 25.4 Mb) and 95 scaffolds (N50 of 25.4 Mb). The Mca genome harbors 19 895 protein-coding genes, of which 45.59% constitute predicted repeat sequences. Synteny analysis revealed variations involved in fruit quality during the divergence of bitter gourd. In addition, assay for transposase-accessible chromatin by high-throughput sequencing and metabolic analysis showed that momordicosides and other substances are characteristic of Mca fruit pulp. A combined transcriptomic and metabolomic analysis revealed the mechanisms of pigment accumulation and cucurbitacin biosynthesis in Mca fruit peels, providing fundamental molecular information for further research on Mca fruit ripening. This report provides a new genetic resource for Momordica genomic studies and contributes additional insights into Cucurbitaceae phylogeny.

RevDate: 2023-01-15

Zong ZQ, Chen SW, Wu Y, et al (2023)

Ambient air pollution exposure and telomere length: a systematic review and meta-analysis.

Public health, 215:42-55 pii:S0033-3506(22)00344-4 [Epub ahead of print].

OBJECTIVE: This study aimed to provide evidence of the associations between pre- and post-birth and adulthood air pollution exposure with telomere length.

STUDY DESIGN: The databases of PubMed, Embase, and Web of Science were searched up to June 1st, 2022 in order to include relevant observational studies and perform a systematic review and meta-analysis.

METHODS: The random-effects meta-analysis was grouped by air pollutant and exposure window (pre- and post-birth and adulthood) to evaluate the summary effect estimate. Cochran's Q and I[2] statistics were used to evaluate the heterogeneity among the included studies. The quality of individual studies was evaluated using the national toxicology program/office of health assessment and translation risk of bias rating tool.

RESULTS: We identified 18 studies, covering 8506 children and 2263 adults from multiple countries. We found moderate evidence that particulate matter less than 2.5 μm (PM2.5) exposure during the entire pregnancy (-0.043, 95% CI: -0.067, -0.018), nitrogen dioxide (NO2) exposure during the first trimester (-0.016, 95% confidence interval [CI]: -0.027, -0.005), long-term adulthood PM2.5 exposure were associated with shortening telomere length. Mild to high between-study heterogeneity was observed for the most tested air pollutant-telomere length combinations in different exposure windows.

CONCLUSIONS: This systematic review and meta-analysis provides the evidence which strongly supports that prenatal PM2.5 and NO2 exposures were related to reduced telomere length, while prenatal sulfur dioxide (SO2) and carbon monoxide (CO) exposures, childhood PM2.5, particulate matter less than 10 μm (PM10), NO2 exposures and short-term adulthood PM2.5 and PM10 exposures were not associated with telomere length. Further high-quality studies are needed to elaborate our suggestive associations.

RevDate: 2023-01-14

Rutherford Siegel S, Ulrich M, SF Logue (2023)

Comparison qPCR study for selecting a valid single copy gene for measuring absolute telomere length.

Gene pii:S0378-1119(23)00033-1 [Epub ahead of print].

Telomere shortening is a well-known biomarker for biological aging. A previous review of the methods used to measure telomere length (TL) noted how challenging it is to compare results from different studies using diverse methodological techniques. The most commonly used high throughput method for measuring average TL is the quantitative PCR (qPCR) method, where there are two protocols available; the relative telomere length and the absolute telomere length (aTL) method. All qPCR methods have similarities in that they use two different primer sets to measure the telomere repeat sequence (TTAGGG)n and a single copy gene region to calculate the average telomere length (T/S) ratio. The difference between the relative and the aTL assay lies with the introduction of a duplex oligomer standards to identify telomere length in kilobase pairs rather than using the traditional relative telomere length T/S ratio method. Problems were noted using 36B4 (RPLP0) which was originally used as a suitable single copy gene with the qPCR assays. A previous aTL publication attempted to replace the 36B4 (RPLP0) single copy gene using the IFNB1 gene but results showed a lack of agreement in TL results when compared to the DNAmTL assay. Here, we compare the two single copy gene assays previously used for the aTL assay and offer an alternative IFNB1 single copy gene assay without non-specific priming amplification to provide more consistent diploid copy number determination and a more robust and reproducible assay for measuring absolute telomere length.

RevDate: 2023-01-13

Guo YZ, Zhang Y, Wang Q, et al (2023)

Alternative telomere maintenance mechanism in Alligator sinensis provides insights into aging evolution.

iScience, 26(1):105850.

Lifespan is a life-history trait that undergoes natural selection. Telomeres are hallmarks of aging, and shortening rate predicts species lifespan, making telomere maintenance mechanisms throughout different lifespans a worthy topic for study. Alligators are suitable for the exploration of anti-aging molecular mechanisms, because they exhibit low or even negligible mortality in adults and no significant telomere shortening. Telomerase reverse transcriptase (TERT) expression is absent in the adult Alligator sinensis, as in humans. Selection analyses on telomere maintenance genes indicated that ATM, FANCE, SAMHD1, HMBOX1, NAT10, and MAP3K4 experienced positive selection on A. sinensis. Repressed pleiotropic ATM kinase in A. sinensis suggests their fitness optimum shift. In ATM downstream, Alternative Lengthening of Telomeres (ALT)-related genes were clustered in a higher expression pattern in A. sinensis, which covers 10-15% of human cancers showing no telomerase activities. In summary, we demonstrated how telomere shortening, telomerase activities, and ALT contributed to anti-aging strategies.

RevDate: 2023-01-12

Romero-Zamora D, MT Hayashi (2023)

A non-catalytic N-terminus domain of WRN prevents mitotic telomere deprotection.

Scientific reports, 13(1):645.

Telomeric ends form a loop structure (T-loop) necessary for the repression of ATM kinase activation throughout the normal cell cycle. However, cells undergoing a prolonged mitotic arrest are prone to lose the T-loop, resulting in Aurora B kinase-dependent mitotic telomere deprotection, which was proposed as an anti-tumor mechanism that eliminates precancerous cells from the population. The mechanism of mitotic telomere deprotection has not been elucidated. Here, we show that WRN, a RECQ helicase family member, can suppress mitotic telomere deprotection independently of its exonuclease and helicase activities. Truncation of WRN revealed that N-terminus amino acids 168-333, a region that contains a coiled-coil motif, is sufficient to suppress mitotic telomere deprotection without affecting both mitotic Aurora B-dependent spindle checkpoint and ATM kinase activity. The suppressive activity of the WRN[168-333] fragment is diminished in cells partially depleted of TRF2, while WRN is required for complete suppression of mitotic telomere deprotection by TRF2 overexpression. Finally, we found that phosphomimetic but not alanine mutations of putative Aurora B target sites in the WRN[168-333] fragment abolished its suppressive effect. Our findings reveal a non-enzymatic function of WRN, which may be regulated by phosphorylation in cells undergoing mitotic arrest. We propose that WRN enhances the protective function of TRF2 to counteract the hypothetical pathway that resolves the mitotic T-loop.

RevDate: 2023-01-12

Vulsteke JB, Smith V, Bonroy C, et al (2023)

Identification of new telomere- and telomerase-associated autoantigens in systemic sclerosis.

Journal of autoimmunity, 135:102988 pii:S0896-8411(22)00196-2 [Epub ahead of print].

PURPOSE: In up to 20% of patients with systemic sclerosis (SSc) no known autoantibody specificity can be identified. Recently discovered autoantigens, such as telomeric repeat binding factor 1 (TERF1), as well as established autoantigens, like RuvBL1/2, are associated with telomere and telomerase biology. We aimed to identify new telomere- and telomerase-associated autoantigens in patients with SSc without known autoantibody specificity.

METHODS: Unlabelled protein immunoprecipitation combined with gel-free liquid chromatography-tandem mass spectrometry (IP-MS) was performed with sera of 106 patients with SSc from two tertiary referral centres that had a nuclear pattern on HEp-2 indirect immunofluorescence without previously identified autoantibody. Telomere- or telomerase-associated proteins or protein complexes precipitated by individual sera were identified. Candidate autoantigens were confirmed through immunoprecipitation-western blot (IP-WB). A custom Luminex xMAP assay for 5 proteins was evaluated with sera from persons with SSc (n = 467), other systemic autoimmune rheumatic diseases (n = 923), non-rheumatic disease controls (n = 187) and healthy controls (n = 199).

RESULTS: Eight telomere- and telomerase-associated autoantigens were identified in a total of 11 index patients, including the THO complex (n = 3, all with interstitial lung disease and two with cardiac involvement), telomeric repeat-binding factor 2 (TERF2, n = 1), homeobox-containing protein 1 (HMBOX1, n = 2), regulator of chromosome condensation 1 (RCC1, n = 1), nucleolar and coiled-body phosphoprotein 1 (NOLC1, n = 1), dyskerin (DKC1, n = 1), probable 28S rRNA (cytosine(4447)-C(5))-methyltransferase (NOP2, n = 1) and nuclear valosin-containing protein-like (NVL, n = 2). A Luminex xMAP assay for THO complex subunit 1 (THOC1), TERF2, NOLC1, NOP2 and NVL revealed high reactivity in all index patients, but also in other patients with SSc and disease controls. However, the reactivity by xMAP assay in these other patients was not confirmed by IP-WB.

CONCLUSION: IP-MS revealed key telomere- and telomerase-associated proteins and protein complexes as autoantigens in patients with SSc.

RevDate: 2023-01-10

Sohn I, Shin C, I Baik (2023)

Associations of green tea, coffee, and soft drink consumption with longitudinal changes in leukocyte telomere length.

Scientific reports, 13(1):492.

Whether beverage consumption is associated with longitudinal observation of telomere length remains unclear. We evaluated the association of green tea, coffee, and soft drink consumption with 6-year changes in leukocyte telomere length (LTL). The study included 1952 participants who provided whole blood samples for LTL assays during the baseline (year 2011-2012) and follow-up (year 2017-2018) periods and reported baseline information on consumption of green tea, coffee, and soft drinks. Robust regression analysis was used to analyze the association adjusted for potential confounding variables. In the results, an inverse association between green tea consumption and LTL changes from baseline, which indicate telomere shortening, was found; regression coefficient [95% confidence interval] was - 0.097 [- 0.164, - 0.029] for participants who daily consumed at least 1 cup of green tea compared with non-consumers (p value = 0.006). This association was stronger among women (versus men) and younger participants aged 50-64 years (versus older). However, a positive association between soft drink consumption and LTL shortening was observed among women (p value < 0.05). Coffee consumption was not associated with LTL changes. These findings suggested that green tea consumption may be protective against telomere shortening reflecting biological aging whereas coffee and soft drink consumption may not.

RevDate: 2023-01-08

Montoya M, BN Uchino (2023)

Social support and telomere length: a meta-analysis.

Journal of behavioral medicine [Epub ahead of print].

Previous studies have shown that lower social support is associated with higher all-cause mortality (Holt-Lunstad et al. in PLoS ONE Medicine 7:e1000316, 2010). While social support has been associated with system-specific biological measures (e.g., cardiovascular), there is the need to elucidate more general biological mechanisms linking social support to health risk across a number of diseases. In this meta-analytic review, the link between social support and telomere length (Cawthon et al. in Lancet 361:393-395, 2003) was conducted based on the updated PRISMA guidelines (Page et al., 2021). Across 17 studies, higher social support was not significantly related to longer telomere length (Zr = 0.010, 95% CI [- 0.028, 0.047], p > 0.05). The confidence interval indicated that the bulk of plausible values were small to null associations. Little evidence for bias was found as shown by funnel plots and Kendall's Tau. Moderator analyses focusing on the measure of support, health of sample, age, type of assay specimen, and gender were not significant. In conclusion, this review showed no significant relationship between social support and telomere length and highlights important future directions.

RevDate: 2023-01-08

Faugeras E, Véronèse L, Jeannin G, et al (2022)

Telomere Status of Advanced Non-Small-Cell Lung Cancer Offers a Novel Promising Prognostic and Predictive Biomarker.

Cancers, 15(1): pii:cancers15010290.

Telomere length appears to correlate with survival in early non-small-cell lung cancer (NSCLC), but the prognostic impact of telomere status in advanced NSCLC remains undetermined. Our purpose was to evaluate telomere parameters as prognostic and predictive biomarkers in advanced NSCLC. In 79 biopsies obtained before treatment, we analyzed the telomere length and expression of TERT and shelterin complex genes (TRF1, TRF2, POT1, TPP1, RAP1, and TIN2), using quantitative PCR. Non-responders to first-line chemotherapy were characterized by shorter telomeres and low RAP1 expression (p = 0.0035 and p = 0.0069), and tended to show higher TERT levels (p = 0.058). In multivariate analysis, short telomeres were associated with reduced event-free (EFS, p = 0.0023) and overall survival (OS, p = 0.00041). TERT and TRF2 overexpression correlated with poor EFS (p = 0.0069 and p = 0.00041) and OS (p = 0.0051 and p = 0.007). Low RAP1 and TIN2 expression-levels were linked to reduced EFS (p = 0.00032 and p = 0.0069) and OS (p = 0.000051 and p = 0.02). Short telomeres were also associated with decreased survival after nivolumab therapy (p = 0.097). Evaluation of telomere status in advanced NSCLC emerges as a useful biomarker that allows for the selection of patient groups with different clinical evolutions, to establish personalized treatment.

RevDate: 2023-01-08

García-Martínez S, González-Gamo D, Tesolato SE, et al (2022)

Telomere Length and Telomerase Activity in Subcutaneous and Visceral Adipose Tissues from Obese and Non-Obese Patients with and without Colorectal Cancer.

Cancers, 15(1): pii:cancers15010273.

To investigate the molecular mechanisms that link obesity and colorectal cancer (CRC), we analyzed parameters related to telomere function in subcutaneous and visceral adipose tissues (SAT and VAT), including subjects with and without CRC, who were classified according to their body mass index (BMI). Adipose tissues were obtained from 147 patients who had undergone surgery. A total of 66 cases corresponded to CRC patients, and 81 subjects were not affected by cancer. Relative telomere length was established by qPCR, and telomerase activity was determined by a method based on the telomeric repeat amplification protocol. Our results indicated longer telomeres in patients affected by CRC, both in SAT and VAT, when compared to the group of subjects without CRC. Tumor local invasion was associated with telomere length (TL) in SAT. Considering the BMI values, significant differences were found in the TL of both adipose tissues between subjects affected by CRC and those without cancer. Overweight subjects showed the greatest differences, with longer telomeres in the group of CRC patients, and a higher number of cases with telomerase reactivation in the VAT of subjects without cancer. In conclusion, parameters related to telomere function in adipose tissue could be considered as potential biomarkers in the evaluation of CRC and obesity.

RevDate: 2023-01-07

Rolles B, Ferreira MSV, Vieri M, et al (2023)

Telomere length dynamics measured by flow-FISH in patients with obesity undergoing bariatric surgery.

Scientific reports, 13(1):304.

Obesity has negative effects on comorbidities, health-related quality of life and survival. Telomere length (TL) changes after bariatric surgery have been reported, but the studies are contradictory, and analyses using state-of-the art techniques for TL measurement, such as flow-FISH, are sparse. We measured TL dynamics via flow-FISH in patients undergoing bariatric surgery and compared their TL with 105 healthy individuals. Patients with obesity who underwent bariatric surgery were included. Lymphocyte and granulocyte absolute and age-adjusted (aa) TL were analyzed by flow-FISH before (preoperative cohort, n = 45) and after surgery (follow-up cohort, n = 35) at month 5.5 ± 3.9 (mean ± standard deviation [SD]). The initial lymphocyte aaTL was significantly shorter (-0.37 kb ± 0.18 kb, P = 0.045) in patients with obesity, while the granulocyte aaTL was not different from that in the healthy comparison population (0.28 kb ± 0.17 kb, P = 0.11). The telomere dynamics after surgery showed an increase in mean TL in both lymphocytes and granulocytes of patients with a pronounced BMI loss of ≥ 10 kg/m[2]. We did not find any association between TL increase after surgery and age, sex or the type of procedure selected for bariatric surgery. We confirmed that patients suffering from obesity have significantly shorter lymphocyte TL using flow-FISH. Along with and dependent on the degree of weight reduction after bariatric surgery, TL significantly increased in both lymphocytes and granulocytes after a mean of 5.5 months. Our results show that bariatric surgery affects not only body weight but also biomarkers of aging, such as TL.

RevDate: 2023-01-06

Troxel WM, Madrigano J, Haas AC, et al (2023)

Examining the Cross-sectional Association Between Neighborhood Conditions, Discrimination, and Telomere Length in a Predominantly African American Sample.

Journal of racial and ethnic health disparities [Epub ahead of print].

Disproportionate exposure to adverse neighborhood conditions and greater discrimination may contribute to health disparities among African Americans (AAs). We examined whether adverse neighborhood conditions, alone or in conjunction with discrimination, associate with shorter leukocyte telomere length among a predominantly AA cohort. The sample included 200 residents from two low-income neighborhoods (96% AA; mean age = 67 years). Perceived neighborhood conditions and discrimination were surveyed in 2018, and objective neighborhood conditions (total crime rate, neighborhood walkability, ambient air pollution (PM2.5, black carbon)) were collected in 2017/2018. Relative telomere length (T/S; ratio of telomeric DNA to a single-gene copy) was assessed from blood samples. Linear regression models estimated the main effects of each neighborhood condition and discrimination and their interactions on the T/S ratio. Less walkable neighborhoods were associated with shorter telomeres. Higher air pollution (PM2.5) was associated with shorter telomeres among those experiencing greater discrimination. Findings highlight the importance of understanding the intersecting influences of historic and contemporary sources of systemic racism and how they contribute to accelerated aging among adults.

RevDate: 2023-01-06

Hassanpour H, Farhadi N, Bahadoran S, et al (2023)

Cardiac telomere attrition following changes in the expression of shelterin genes in pulmonary hypertensive chickens.

British poultry science [Epub ahead of print].

1. The alterations of relative telomere length and expression of shelterin genes (TRF1, TRF2, RAP1, POT1, and TPP1) were evaluated from the chickens' right heart ventricle in the early and last stages of cold-induced pulmonary hypertension (PHS) at 21 and 42 d of age.2. The relative telomere length in the right ventricular tissues was significantly shorter in the PHS group of broilers than in the control group at 42 d, but did not statistically change at 21 d of age. There was a significant negative correlation between relative telomere length and RV:TV ratio in the broilers at 42 d of age.3. The relative expression of POT1, RAP1 and TPP1 genes in the right ventricular tissues was significantly lower in the PHS group than in the control group at 21 d. The relative expression of the TRF2 gene was only higher in the PHS group of broilers than control at 42 d. The mRNA level of the TRF2 gene exhibited a significant positive correlation with RV:TV ratio at 42 d.4. It was concluded that most shelterin genes are dysregulated in the early stage of PHS (right ventricular hypertrophy) while telomere attrition occurs only at the last stage (heart dilation/failure).

RevDate: 2023-01-06

Ask TF, S Sütterlin (2022)

Prefrontally modulated vagal neuroimmunomodulation is associated with telomere length.

Frontiers in neuroscience, 16:1063162.

BACKGROUND: Accumulated senescent cells are proposed to be one of the main drivers of age-related pathology such as dementia and cancer through disruption of tissue structure and function. We recently proposed the Neuro-Immuno-Senescence Integrative Model (NISIM), which relates prefrontally modulated vagal tone and subsequent balance between vagal and sympathetic input to the spleen to inflammatory responses leading to generation of reactive oxygen species and oxidative telomere damage.

AIM: In this study, we assess inflammation as a mediator in the relationship between prefrontally modulated vagal tone and leukocyte telomere length (LTL). We also assess the relationship between a recently proposed index of vagal neuroimmunomodulation (vagal tone/inflammation ratio; NIM index) and telomere length.

METHODS: This study uses participant data from a large nationally representative longitudinal study since 1974 with a total of 45,000 Norwegian residents so far. A sub-sample of 131 participants from which ultrashort recordings (30 s) of vagal tone, c reactive protein, and LTL could be obtained were included in the study. Relationships were analyzed with Pearson's correlations and hierarchical multiple linear regression using either vagal tone and CRP or the NIM index to predict telomere length.

RESULTS: Vagal tone was a significant positive predictor of telomere length but this was not mediated by c reactive protein, even after controlling for confounders. The NIM index was a significant positive predictor of telomere length, also when controlling for confounders. In a follow-up analysis simultaneously comparing telomere length between groups with high and low values of vagal tone, and between groups with high and low NIM index values, telomere length was only significantly different between NIM index groups.

CONCLUSION: This is the first study suggesting that prefrontally modulated vagal neuroimmunomodulation is associated with telomere length thus supporting the NISIM. Results indicate that the NIM index is a more sensitive indicator of vagal neuroimmunomodulation than vagal tone and CRP in isolation.

RevDate: 2023-01-05

Liu Q, Li Z, Huang L, et al (2023)

Telomere and mitochondria mediated the association between dietary inflammatory index and mild cognitive impairment: A prospective cohort study.

Immunity & ageing : I & A, 20(1):1.

BACKGROUND: Diet and chronic inflammation might play a major role in the pathogenesis of mild cognitive impairment (MCI). In addition, peripheral blood leukocyte telomere length (LTL) and mitochondrial DNA copy number (mtDNAcn) might mediate the relationship between inflammation and MCI risk. The purpose of the present study is to evaluate whether inflammatory potential of diet assessed by dietary inflammatory index (DII), chronic inflammation, peripheral blood LTL, and mtDNAcn were associated with the risk of MCI.

RESULTS: A population-based cohort study was conducted with a total of 2944 participants. During a median follow-up of 2 years, 438 (14.90%) individuals were new-onset MCI. After adjustment, a higher score of DII (hazard ratio [HR]: 1.056, 95% CI: 1.005, 1.109), a higher log systemic immune inflammation index (SII) (HR: 1.333, 95% CI: 1.089, 1.633) and log system inflammation response index (SIRI) (HR: 1.487, 95% CI: 1.024, 2.161) predicted elevated risk of MCI. An increased mtDNAcn (HR: 0.843, 95% CI: 0.712, 0.997), but not LTL, predicted a decreased risk of MCI. Negative associations of log SII with LTL (β:-0.359, 95% CI: -0.445, -0.273) and mtDNAcn (β:-0.048, 95% CI: -0.090, -0.006) were found. Additionally, negative associations of log SIRI with LTL (β: -0.035, 95% CI: -0.052, -0.017) and mtDNAcn (β:-0.136, 95% CI: -0.216, -0.056) were also found. Path analysis suggested that SIRI, LTL, and mtDNAcn, in series, have mediation roles in the association between DII score and MCI risk.

CONCLUSIONS: Higher DII, SII, and SIRI might predict a greater risk of MCI, while a longer LTL and an increased mtDNAcn were linked to a reduced risk of MCI among the older population. LTL and mtDNAcn could play mediation roles in the association between DII and MCI risk.

RevDate: 2023-01-05

Duan X, Huang T, Zhang D, et al (2023)

Effect and interaction of TNKS genetic polymorphisms and environmental factors on telomere damage in COEs-exposure workers.

Ecotoxicology and environmental safety, 250:114489 pii:S0147-6513(22)01329-X [Epub ahead of print].

Coke oven emissions (COEs) contain many carcinogenic polycyclic aromatic hydrocarbons (PAHs). Telomere damage is an early biological marker reflecting long-term COEs-exposure. Whereas, whether the genetic variations of telomere-regulated gene TNKS have an effect on the COEs-induced telomere damage is unknown. So we detected the environmental exposure levels, relative telomere length (RTL), and TNKS genetic polymorphisms among 544 COEs-exposure workers and 238 healthy participants. We found that the RTL of the wild homozygous GG genotype in rs1055328 locus was statistically shorter compared with the CG+CC genotype for the healthy participants using covariance analysis(P = 0.008). In the Generalized linear model (GLM) analysis, TNKS rs1055328 GG could accelerate telomere shortening (P = 0.011); and the interaction between TNKS rs1055328 GG and COEs-exposure had an effect on RTL (P = 0.002). In conclusion, this study was the first to discover the role of TNKS rs1055328 locus in COEs-induced telomere damage, and proved that chromosomal damage was a combined consequence of environmental and genetic factors.

RevDate: 2023-01-05

Hu J, Song J, Chen Z, et al (2022)

Reverse causal relationship between periodontitis and shortened telomere length: Bidirectional two-sample Mendelian random analysis.

Frontiers in immunology, 13:1057602.

BACKGROUND: Observational studies have demonstrated a link between shortened telomere lengths(TL) and chronic periodontitis. However, whether the shortened TL is the cause or the result of periodontitis is unknown.Therefore, our objective was to investigate a bidirectional causal relationship between periodontitis and TL using a two-sample Mendel randomized (MR) study.

METHODS: A two-sample bidirectional MR analysis using publicly available genome-wide association study (GWAS) data was used. As the primary analysis, inverse variance weighting (IVW) was employed. To identify pleiotropy, we used leave-one-out analysis, MR-Egger, Weighted median, Simple mode, Weighted mode, and MR pleiotropy residual sum and outlier (MR-PRESSO).

RESULTS: In reverse MR results, a genetic prediction of short TL was causally associated with a higher risk of periodontitis (IVW: odds ratio [OR]: 1.0601, 95% confidence interval [CI]: 1.0213 to 1.1002; P =0.0021) and other complementary MR methods. In the forward MR analysis, periodontitis was shown to have no significant effect on TL (IVW: p = 0.7242), with consistent results for the remaining complementary MR. No pleiotropy was detected in sensitivity analysis (all P>0.05).

CONCLUSION: Our MR studies showed a reverse causal relationship, with shorten TL being linked to a higher risk of periodontitis, rather than periodontitis shorten that TL. Future research is needed to investigate the relationship between cell senescence and the disease.

RevDate: 2023-01-02

Seki Y, Aczel D, Torma F, et al (2023)

No strong association among epigenetic modifications by DNA methylation, telomere length, and physical fitness in biological aging.

Biogerontology [Epub ahead of print].

Cellular senescence is greatly accelerated by telomere shortening, and the steps forward in human aging are strongly influenced by environmental and lifestyle factors, whether DNA methylation (DNAm) is affected by exercise training, remains unclear. In the present study, we investigated the relationships between physiological functions, maximal oxygen uptake (VO2max), vertical jump, working memory, telomere length (TL) assessed by RT-PCR, DNA methylation-based estimation of TL (DNAmTL), and DNA methylation-based biomarkers of aging of master rowers (N = 146) and sedentary subjects (N = 95), aged between 37 and 85 years. It was found that the TL inversely correlated with chronological age. We could not detect an association between telomere length and VO2max, vertical jump, and working memory by RT-PCR method, while these physiological test results showed a correlation with DNAmTL. DNAmGrimAge and DNAmPhenoAge acceleration were inversely associated with telomere length assessed by both methods. It appears that there are no strong beneficial effects of exercise or physiological fitness on telomere shortening, however, the degree of DNA methylation is associated with telomere length.

RevDate: 2023-01-02

Lv Z, Cui J, J Zhang (2022)

Associations between serum urate and telomere length and inflammation markers: Evidence from UK Biobank cohort.

Frontiers in immunology, 13:1065739.

OBJECTIVE: Hyperuricemia and gout have become gradually more common. The effect of serum urate on organism aging and systematic inflammation is not determined. This study aims to evaluate whether serum urate is causally associated with cellular aging markers and serum inflammation markers.

METHODS: A Mendelian randomization study was performed on summary-level data from the largest published genome-wide association studies. Single nucleotide polymorphisms with a genome-wide significance level were selected as instrumental variables for leukocyte telomere length (LTL), and serum soluble makers of inflammation (CRP, IL-6, TNF-α, and IGF-1). Standard inverse variance weighted (IVW) method was used as the primary statistical method. The weighted median, MR-Egger regression, and MR-PRESSO methods were used for sensitivity analysis.

RESULTS: An inverse causal association of genetically predicted serum urate levels and LTL was found using IVW method (OR: 0.96, 95%CI 0.95, 0.97; β=-0.040; SE=0.0072; P=4.37×10[-8]). The association was also supported by MR results using MR-Egger method and weighted median method. The MR-PRESSO analysis and leave-one-out sensitivity analysis supported the robustness of the combined results. In terms of other aging-related serum biomarkers, there was no evidence supporting a causal effect of serum urate on CRP, IL-6, TNF-α, or IGF-1 levels.

CONCLUSIONS: Serum urate levels are negatively associated with telomere length but are not associated with serum soluble indicators of inflammation. Telomere length may be a critical marker that reflects urate-related organismal aging and may be a mechanism in the age-related pathologies and mortality caused by hyperuricemia.

RevDate: 2023-01-02

Al Khleifat A, Iacoangeli A, Jones AR, et al (2022)

Telomere length analysis in amyotrophic lateral sclerosis using large-scale whole genome sequence data.

Frontiers in cellular neuroscience, 16:1050596.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the loss of upper and lower motor neurons, leading to progressive weakness of voluntary muscles, with death following from neuromuscular respiratory failure, typically within 3 to 5 years. There is a strong genetic contribution to ALS risk. In 10% or more, a family history of ALS or frontotemporal dementia is obtained, and the Mendelian genes responsible for ALS in such families have now been identified in about 50% of cases. Only about 14% of apparently sporadic ALS is explained by known genetic variation, suggesting that other forms of genetic variation are important. Telomeres maintain DNA integrity during cellular replication, differ between sexes, and shorten naturally with age. Sex and age are risk factors for ALS and we therefore investigated telomere length in ALS.

METHODS: Samples were from Project MinE, an international ALS whole genome sequencing consortium that includes phenotype data. For validation we used donated brain samples from motor cortex from people with ALS and controls. Ancestry and relatedness were evaluated by principal components analysis and relationship matrices of DNA microarray data. Whole genome sequence data were from Illumina HiSeq platforms and aligned using the Isaac pipeline. TelSeq was used to quantify telomere length using whole genome sequence data. We tested the association of telomere length with ALS and ALS survival using Cox regression.

RESULTS: There were 6,580 whole genome sequences, reducing to 6,195 samples (4,315 from people with ALS and 1,880 controls) after quality control, and 159 brain samples (106 ALS, 53 controls). Accounting for age and sex, there was a 20% (95% CI 14%, 25%) increase of telomere length in people with ALS compared to controls (p = 1.1 × 10[-12]), validated in the brain samples (p = 0.03). Those with shorter telomeres had a 10% increase in median survival (p = 5.0×10[-7]). Although there was no difference in telomere length between sporadic ALS and familial ALS (p=0.64), telomere length in 334 people with ALS due to expanded C9orf72 repeats was shorter than in those without expanded C9orf72 repeats (p = 5.0×10[-4]).

DISCUSSION: Although telomeres shorten with age, longer telomeres are a risk factor for ALS and worsen prognosis. Longer telomeres are associated with ALS.

RevDate: 2022-12-31

Liu Y, Song L, Wu M, et al (2022)

Association between rare earth element exposure during pregnancy and newborn telomere length.

Environmental science and pollution research international [Epub ahead of print].

Telomere length (TL) is considered a marker of biological aging and lifetime health, and some epidemiological studies report that the environmental exposures may influence TL at birth. We aimed to investigate the associations between prenatal rare earth elements (REE) exposure and newborn TL. A total of 587 mother-newborn pairs were recruited during 2013 to 2015 in Wuhan, China. Maternal urinary concentrations of REE collected during three trimesters were measured by inductively coupled plasma mass spectrometry. Quantitative real-time polymerase chain reaction was used to measure relative cord blood TL. The trimester-specific associations between prenatal REE exposure and cord blood TL were evaluated using multiple informant models. Weighted quantile sum regression was used to estimate the mixture effect of urinary REE on cord blood TL. After adjustment for potential confounders, per doubling of urinary REE (Dy, Yb, Pr, Nd, and Tm) concentrations (μg/g creatinine) during the second trimester was respectively associated with 1.94% (95% CI 0.19%, 3.72%), 2.10% (95% CI 0.31%, 3.92%), 2.11% (95% CI 0.35%, 3.89%), 2.08% (95% CI 0.01%, 4.20%), and 1.38% (95% CI 0.09%, 2.70%) increase in cord blood TL. Furthermore, exposure to the mixture of REE during the second trimester was also significantly associated with increased cord blood TL (percent change 1.20%, 95% CI 0.30%, 2.11%). However, these associations were not statistically significant in the first and third trimesters. This study provides new evidence on the potential effect of prenatal REE exposure on the initial (newborn) setting of offspring's telomere biology. Further epidemiological studies are warranted to confirm our findings.

RevDate: 2022-12-30

Mei Q, Yu Q, Li X, et al (2023)

Regulation of telomere silencing by the core histones-autophagy-Sir2 axis.

Life science alliance, 6(3): pii:6/3/e202201614.

Telomeres contain compacted heterochromatin, and genes adjacent to telomeres are subjected to transcription silencing. Maintaining telomere structure integrity and transcription silencing is important to prevent the occurrence of premature aging and aging-related diseases. How telomere silencing is regulated during aging is not well understood. Here, we find that the four core histones are reduced during yeast chronological aging, leading to compromised telomere silencing. Mechanistically, histone loss promotes the nuclear export of Sir2 and its degradation by autophagy. Meanwhile, reducing core histones enhances the autophagy pathway, which further accelerates autophagy-mediated Sir2 degradation. By screening the histone mutant library, we identify eight histone mutants and one histone modification (histone methyltransferase Set1-catalyzed H3K4 trimethylation) that regulate telomere silencing by modulating the core histones-autophagy-Sir2 axis. Overall, our findings reveal core histones and autophagy as causes of aging-coupled loss of telomere silencing and shed light on dynamic regulation of telomere structure during aging.

RevDate: 2022-12-30

Dondoladze K, Nikolaishvili M, Museliani T, et al (2022)

EFFECT OF RADIATION ON AGING PROCESSES AND TELOMERE LENGTH.

Problemy radiatsiinoi medytsyny ta radiobiolohii, 27:107-119.

Telomeres are the ending areas of chromosomes - protective «caps» that ensure the stability of chromosomes. Telomere shortening is one of the most important biological signs of aging and is involved in cellular aging and the «mitotic clock» mechanism. One of the known mechanisms of the impact of radiation on the aging process is damage to telomeres by free radicals. Oxidative stress has a toxic effect on telomere length. The increase in free radicals occurs under the action of both ionizing and nonionizing radiation, although antioxidant mechanisms are often able to neutralize harmful free radicals. Low doses of nonionizing and ionizing radiation even cause the activation of antioxidant systems, however, when the body is exposed to radiation at a high dose or for a long time, or if pathological processes with oxidative stress occur in the body, damage to cells becomes more noticeable, and aging processes accelerate. Maintaining telomere length and a normal rate of aging is important for health. In this review, we want to discuss the role of ionizing and nonionizing radiation in cellular aging, in particular, in the shortening of telomere length.

RevDate: 2022-12-29

Clé DV, Catto LFB, Gutierrez-Rodrigues F, et al (2022)

Effects of nandrolone decanoate on telomere length and clinical outcome in patients with telomeropathies: a prospective trial.

Haematologica [Epub ahead of print].

Androgens have been reported to elongate telomeres in retrospective and prospective trials with patients with telomeropathies, mainly with bone marrow failure. In our single-arm prospective clinical trial, 17 patients with short telomeres and/or germline pathogenic variants in telomere-biology genes associated with at least one cytopenia and/or radiologic diagnosis of ILD were treated with 5 mg/kg of intramuscular nandrolone decanoate every 15 days for 2 years. Ten of 13 evaluable patients (77%) showed telomere elongation at 12 months by flow-FISH (average increase, 0.87 kb; 95% CI, 0.20-1.55 kb; p=0.01). At 24 months, all 10 evaluable patients showed telomere elongation (average increase, 0.49 kb; 95% CI, 0.24-1.23 kb; p=0.18). Hematologic response was achieved in 8/16 patients (50%) with marrow failure at 12 months, and in 10/16 patients (63%) at 24 months. Seven patients had ILD at baseline, and two and three had pulmonary response at 12 and 24 months, respectively. Two patients died due to pulmonary failure during treatment. In the remaining evaluable patients, the pulmonary function remained stable or improved, but showed consistent decline after cessation of treatment. Somatic mutations in myeloid neoplasm-related genes were present in a minority of patients and were mostly stable during drug treatment. The most common adverse events (AE) were elevations in liver function test levels in 88%, acne in 59%, and virilization in 59%. No AE grade ≥ 4 was observed. Our findings indicate that nandrolone decanoate elongates telomeres in patients with telomeropathies, which correlated with clinical improvement in some cases and tolerable adverse events. ClinicalTrials.gov Identifier: NCT02055456.

RevDate: 2022-12-29

Wang J, Hao Y, Zhu Z, et al (2022)

Causality of telomere length associated with calcific aortic valvular stenosis: A Mendelian randomization study.

Frontiers in medicine, 9:1077686.

BACKGROUND: Observational studies have shown that calcific aortic valve stenosis (CAVS) is associated with a shorter telomere length (TL). However, the results of observational studies are often influenced by confounding factors and reverse causal associations; it is unclear whether there is a causal relationship between TL and CAVS. This study aimed to investigate the causal relationship between TL and CAVS.

MATERIALS AND METHODS: Genome-wide association study (GWAS) data on TL (n = 472,174) and CAVS (n = 311,437) were used to assess the effect of TL on CAVS. All the participants were of European ancestry. Three Mendelian randomization (MR) methods, namely, MR-Egger, weighted median, and inverse variance weighted (IVW), were used to assess the potential causal effect of TL on CAVS. Heterogeneity was assessed using Cochran's Q statistic. Leave-one-out and MR-Egger regression methods were used for sensitivity and pleiotropy analyses. Forward and reverse MR analyses were performed.

RESULTS: In total, 118 valid and independent TL genetic instrumental variants were extracted from the GWAS dataset. MR analysis showed that TL was negatively associated with CAVS (odds ratios [OR] = 0.727, 95% confidence interval [CI]: 0.565-0.936, and P = 0.013 by weighted median; OR = 0.763, 95% CI: 0.634-0.920, and P = 0.005 by IVW; OR = 0.757, 95% CI: 0.549-1.044, and P = 0.055 by MR-Egger). Sensitivity and pleiotropy analyses showed that the results of this study were relatively stable and that there was no significant pleiotropy. Reverse MR analyses consistently suggested the absence of causal effects of CAVS liability on TL levels.

CONCLUSION: A causal relationship between the shortening of TL and the development of CAVS in the European population was suggested in this study, and a theoretical basis was provided to investigate the pathogenesis of CAVS.

RevDate: 2022-12-27

Yang X, Benny PA, Cervera-Marzal E, et al (2022)

Placental telomere length shortening is not associated with severe preeclampsia but the gestational age.

Aging, 14: pii:204445 [Epub ahead of print].

Variations in telomere length (TL) have been associated with aging, stress, and many diseases. Placenta TL is an essential molecular component influencing the outcome of birth. Previous investigations into the relationship between placenta TL and preeclampsia (PE) have produced conflicting findings. We conducted a retrospective case-control analysis in this study to address the disparity. We used placenta samples from 224 births received from Hawaii Biorepository (HiBR) between 2006 and 2013, comprising 129 healthy full-term controls and 95 severe PE samples. The average absolute placental TL was calculated using the quantitative polymerase chain reaction (qPCR) technique. We utilized multiple linear regressions to associate placental TL with severe PE and other demographic, clinical and physiological data. The outcome demonstrates that the placental TL of severe PE cases did not significantly differ from that of healthy controls. Instead, there is a strong correlation between gestational age and placenta TL shortening. Placental TL also exhibits racial differences: (1) Latino moms' TL is significantly longer than non-Latino mothers' (p=0.009). (2) Caucasian patients with severe PE have shorter TL than non-Caucasian patients (p=0.0037). This work puts the long-standing question of whether severe PE influences placental TL to rest. Placental TL is not related to severe PE but is negatively associated with gestational age and is also affected by race.

RevDate: 2022-12-27

Van Der Stukken C, Nawrot TS, Wang C, et al (2022)

The association between ambient particulate matter exposure and the telomere-mitochondrial axis of aging in newborns.

Environment international, 171:107695 pii:S0160-4120(22)00622-5 [Epub ahead of print].

BACKGROUND: Particulate matter (PM) is associated with aging markers at birth, including telomeres and mitochondria. It is unclear whether markers of the core-axis of aging, i.e. tumor suppressor p53 (p53) and peroxisome proliferator-activated receptor gamma co-activator 1 alpha (PGC-1α), are associated with prenatal air pollution and whether there are underlying mechanisms.

METHODS: 556 mother-newborn pairs from the ENVIRONAGE birth cohort were recruited at the East Limburg Hospital in Genk (Belgium). In placenta and cord blood, telomere length (TL) and mitochondrial DNA content (mtDNAc) were measured using quantitative real-time polymerase chain reaction (qPCR). In cord plasma, p53 and PGC-1α protein levels were measured using ELISA. Daily ambient PM2.5 concentrations during gestation were calculated using a spatial temporal interpolation model. Distributed lag models (DLMs) were applied to assess the association between prenatal PM2.5 exposure and each molecular marker. Mediation analysis was performed to test for underlying mechanisms.

RESULTS: A 5 µg/m[3] increment in PM2.5 exposure was associated with -11.23 % (95 % CI: -17.36 % to -4.65 %, p = 0.0012) and -7.34 % (95 % CI: -11.56 % to -2.92 %, p = 0.0014) lower placental TL during the entire pregnancy and second trimester respectively, and with -12.96 % (95 % CI: -18.84 % to -6.64 %, p < 0.001) lower placental mtDNAc during the third trimester. Furthermore, PM2.5 exposure was associated with a 12.42 % (95 % CI: -1.07 % to 27.74 %, p = 0.059) higher cord plasma p53 protein level and a -3.69 % (95 % CI: -6.97 % to -0.31 %, p = 0.033) lower cord plasma PGC-1α protein level during the third trimester. Placental TL mediated 65 % of the negative and 17 % of the positive association between PM2.5 and placental mtDNAc and cord plasma p53 protein levels, respectively.

CONCLUSION: Ambient PM2.5 exposure during pregnancy is associated with markers of the core-axis of aging, with TL as a mediating factor. This study strengthens the hypothesis of the air pollution induced core-axis of aging, and may unravel a possible underlying mediating mechanism in an early-life epidemiological context.

RevDate: 2022-12-27

Ardestani SK, Jamali T, Taravati A, et al (2022)

Changes in hormones, Leukocyte Telomere Length (LTL), and p16[INK4a] expression in SM-exposed individuals in favor of the cellular senescence.

Drug and chemical toxicology [Epub ahead of print].

Sulfur mustard (SM) is a chemical warfare agent with well-known severe toxic effects and may cause long-term debilitating injuries. We aimed to evaluate aging and longevity in Iranian SM-exposed survivors using some endocrine and molecular biomarkers for the first time. Dehydroepiandrosterone (DHEA), prolactin (PRL), cortisol, testosterone, and luteinizing hormone (LH) were measured in 289 male SM-veterans and 66 age-matched males using the ELISA method. Leukocyte Telomere Length (LTL) measurement and p16[INK4a] expression were measured in the peripheral blood leukocytes of 55 males who were exposed to SM. We found a significantly lower serum DHEAS level and higher serum PRL level in SM-exposed groups (without any related to the severity of lung injuries) compared to healthy controls, but no significant difference in serum levels of cortisol, testosterone, and LH. The molar ratio of DHEAS/cortisol was significantly higher in controls compared to the SM-exposed individuals especially those with severe lung damage. Some biological parameters of allostatic load score such as DHEAS and DHEAS/cortisol ratio significantly decreased long-term after the SM exposure. Additionally, we found that LTL was shorter in SM-exposed veterans rather than unexposed controls while p16[INK4a] gene expression significantly increased in these groups. It seems that DHEAS, DHEAS/cortisol ratio, LTL, and p16[INK4a] gene expression have changed significantly in favor of cellular senescence in SM-exposed patients. Therefore, it seems that SM exposure increases biological age compared to chronological age in SM-exposed survivors.

RevDate: 2022-12-26

Matsuda Y, Ye J, Yamakawa K, et al (2022)

Association of longer telomere length in cancer cells and cancer-associated fibroblasts with worth prognosis.

Journal of the National Cancer Institute pii:6958556 [Epub ahead of print].

BACKGROUND: Telomere dysfunction has been reported to be directly involved in carcinogenesis owing to chromosomal instability and immortalization; however, the clinicopathological significance of telomeres remains controversial. We have shown that telomere shortening occurs in normal-appeared duct cells at the initiation and then progresses during the progression of pancreatic cancer. In this study, we determined the clinicopathological and prognostic value of telomere length (TL) in cancer progression.

METHODS: TL in both cancer cells and cancer-associated fibroblasts (CAFs) was analyzed by high throughput quantitative fluorescence in situ hybridization (FISH) using a previously reported cohort comprising 1,434 cases of adenocarcinoma (ADC), squamous cell carcinoma (SCC), adenosquamous carcinoma (ASC), hepatocellular carcinoma (HCC), and renal cell carcinoma (RCC), which are known cancers with a significantly low incidence of alternative lengthening of telomeres. Cases were divided into two groups as follows: longer and shorter telomeres, according to the median TL of cancer cells and CAFs. The statistical significance of TL in cancer cells and CAFs on clinicopathological characteristics and prognosis were analyzed.

RESULTS: There was a close association between TL in cancer cells and CAFs. Longer telomeres in cancer cells and CAFs were associated with aggressive features such as advanced stage, high mitosis score and nuclear score, poorly differentiated cancer, and desmoplastic stroma in ADC. Furthermore, a longer TL was an independent prognostic factor for ADC, SCC and RCC.

CONCLUSION: Longer telomeres are associated with worse prognosis in ADC, SCC and RCC. Thus, TL is a novel biomarker for the diagnosis of aggressive cancers with poor prognoses.

RevDate: 2022-12-23

D'Angiolo M, Yue JX, De Chiara M, et al (2022)

Telomeres are shorter in wild Saccharomyces cerevisiae isolates than in domesticated ones.

Genetics pii:6958701 [Epub ahead of print].

Telomeres are ribonucleoproteins that cap chromosome-ends and their DNA length is controlled by counteracting elongation and shortening processes. The budding yeast Saccharomyces cerevisiae has been a leading model to study telomere DNA length control and dynamics. Its telomeric DNA is maintained at a length that slightly varies between laboratory strains, but little is known about its variation at the species level. The recent publication of the genomes of over 1000 S. cerevisiae strains enabled us to explore telomere DNA length variation at an unprecedented scale. Here, we developed a bioinformatic pipeline (YeaISTY) to estimate telomere DNA length from whole-genome-sequences and applied it to the sequenced S. cerevisiae collection. Our results revealed broad natural telomere DNA length variation among the isolates. Notably, telomere DNA length is shorter in those derived from wild rather than domesticated environments. Moreover, telomere DNA length variation is associated with mitochondrial metabolism, and this association is driven by wild strains. Overall, these findings reveal broad variation in budding yeast's telomere DNA length regulation, which might be shaped by its different ecological life-styles.

RevDate: 2022-12-23

Sagris M, Theofilis P, Antonopoulos AS, et al (2022)

Telomere Length: A Cardiovascular Biomarker and a Novel Therapeutic Target.

International journal of molecular sciences, 23(24):.

Coronary artery disease (CAD) is a multifactorial disease with a high prevalence, particularly in developing countries. Currently, the investigation of telomeres as a potential tool for the early detection of the atherosclerotic disease seems to be a promising method. Telomeres are repetitive DNA sequences located at the extremities of chromosomes that maintain genetic stability. Telomere length (TL) has been associated with several human disorders and diseases while its attrition rate varies significantly in the population. The rate of TL shortening ranges between 20 and 50 bp and is affected by factors such as the end-replication phenomenon, oxidative stress, and other DNA-damaging agents. In this review, we delve not only into the pathophysiology of TL shortening but also into its association with cardiovascular disease and the progression of atherosclerosis. We also provide current and future treatment options based on TL and telomerase function, trying to highlight the importance of these cutting-edge developments and their clinical relevance.

RevDate: 2022-12-19

Wong KK, Cheng F, Lim CKP, et al (2022)

Early emergence of sexual dimorphism in offspring leukocyte telomere length was associated with maternal and children's glucose metabolism-a longitudinal study.

BMC medicine, 20(1):490.

BACKGROUND: Leukocyte telomere length (LTL) is suggested to be a biomarker of biological age and reported to be associated with metabolic diseases such as type 2 diabetes. Glucose metabolic traits including glucose and insulin levels have been reported to be associated with LTL in adulthood. However, there is relatively little research focusing on children's LTL and the association with prenatal exposures. This study investigates the relationship between maternal and offspring glucose metabolism with offspring LTL in early life.

METHODS: This study included 882 mother-child pairs from the HAPO Hong Kong Field Centre, with children evaluated at age 7.0 ± 0.4 (mean ± SD) years. Glucose metabolic traits including maternal post-load glucose during pregnancy, children's glucose and insulin levels, and their derived indices at follow-up were measured or calculated. Offspring LTL was assessed using real-time polymerase chain reaction.

RESULTS: Sex- and age-adjusted children's LTL was found to be associated with children's HOMA-IR (β=-0.046 ± 0.016, p=0.005). Interestingly, both children's and maternal post-load glucose levels were positively associated with children's LTL. However, negative associations were observed between children's LTL and children's OGTT insulin levels. In addition, the LTL in females was more strongly associated with pancreatic beta-cell function whilst LTL in males was more strongly associated with OGTT glucose levels.

CONCLUSIONS: Our findings suggest a close association between maternal and offspring glucose metabolic traits with early life LTL, with the offspring sex as an important modifier of the disparate relationships in insulin production and response.

RevDate: 2022-12-19

Derenzini E, Gueli A, Risso A, et al (2022)

Long telomeres at baseline and male sex are main determinants of telomere loss following chemotherapy exposure in lymphoma patients.

Hematological oncology [Epub ahead of print].

Although chemotherapy (CHT) exposure is an established cause of telomere attrition, determinants of telomere length (TL) dynamics after chemotherapy are poorly defined. In this study, we analyzed granulocyte telomere dynamics in 34 adult lymphoma patients undergoing first-line CHT. TL was measured by southern blot at each CHT cycle and after 1 year from CHT completion. Median age was 59 yrs (range 22-77). Median number of CHT cycles was 6 (range 3-6). The majority of patients (79%, n=27) experienced TL shortening following CHT exposure. Mean telomere loss was 673 base pairs (bp) by cycle 6. Telomere shortening was an early event as 87% of the total telomere loss (mean 586 bp) occurred by the end of cycle 3, with no significant recovery after 1 year. A significant correlation was observed between baseline TL and total or fractional telomere loss (p<0.001), with telomere shortening by cycle 3 observed predominantly in male patients with long telomeres at pre-treatment evaluation. Stratifying the analysis by gender and age only young women (<51 years of age) did not show significant telomere shortening following chemotherapy exposure. These findings indicate that gender and baseline TL are major determinants of TL dynamics following chemotherapy exposure in lymphoma patients. This article is protected by copyright. All rights reserved.

RevDate: 2022-12-16

Zamora-Camacho FJ, Burraco P, Zambrano-Fernández S, et al (2022)

Ammonium effects on oxidative stress, telomere length, and locomotion across life stages of an anuran from habitats with contrasting land-use histories.

The Science of the total environment pii:S0048-9697(22)08027-5 [Epub ahead of print].

Understanding the mechanistic implications behind wildlife responses to global changes is a central topic in eco-evolutionary research. In particular, anthropic pollution is known to impact wild populations across the globe, which may have even stronger consequences for species with complex life cycles. Among vertebrates, amphibians represent a paradigmatic example of metamorphosis, and their characteristics make them highly vulnerable to pollution. Here, we tested for differences in the redox status, telomere length, and locomotor performance across life stages of green frogs (Pelophylax perezi) from agrosystem and natural habitats, both constitutively and in response to an experimental ammonium exposure (10 mg/L). We found that larvae from the agrosystem constitutively showed an enhanced redox status (better antioxidant balance against H2O2, lower lipid peroxidation) but shorter telomeres as compared to larvae from the natural environment. The larval redox response to ammonium was, overall, similar in both habitats. In contrast, after metamorphosis, the redox status of individuals from the natural habitat seemed to cope better with ammonium exposure (denoted by lower lipid peroxidation), and differences between habitats in telomere length were no longer present. Intriguingly, while the swimming performance of larvae did not correlate with individual's physiology, metamorphs with lower glutathione reductase activity and longer telomeres had a better jumping performance. This may suggest that locomotor performance is both traded off with the production of reactive oxygen species and potentiated directly by longer telomeres or indirectly by the mechanisms that buffer their shortening. Overall, our study suggests that contrasting land-use histories can drive divergence in physiological pathways linked to individual health and lifespan. Since this pattern was life-stage dependent, divergent habitat conditions can have contrasting implications across the ontogenetic development of species with complex life cycles.

RevDate: 2022-12-16

Warecki B, Bast I, Tajima M, et al (2022)

Connections between sister and non-sister telomeres of segregating chromatids maintain euploidy.

Current biology : CB pii:S0960-9822(22)01828-0 [Epub ahead of print].

The complete separation of sister chromatids during anaphase is a fundamental requirement for successful mitosis. Therefore, divisions with either persistent DNA-based connections or lagging chromosome fragments threaten aneuploidy if unresolved. Here, we demonstrate the existence of an anaphase mechanism in normally dividing cells in which pervasive connections between telomeres of segregating chromosomes aid in rescuing lagging chromosome fragments. We observe that in a large proportion of Drosophila melanogaster neuronal stem cell divisions, early anaphase sister and non-sister chromatids remain connected by thin telomeric DNA threads. Normally, these threads are resolved in mid-to-late anaphase via a spatial mechanism. However, we find that the presence of a nearby unrepaired DNA break recruits histones, BubR1 kinase, Polo kinase, Aurora B kinase, and BAF to the telomeric thread of the broken chromosome, stabilizing it. Stabilized connections then aid lagging chromosome rescue. These results suggest a model in which pervasive anaphase telomere-telomere connections that are normally resolved quickly can instead be stabilized to retain wayward chromosome fragments. Thus, the liability of persistent anaphase inter-chromosomal connections in normal divisions may be offset by their ability to maintain euploidy in the face of chromosome damage and genome loss.

RevDate: 2022-12-15

Wang C, Gu Y, Zhou J, et al (2022)

Leukocyte telomere length in children born following blastocyst-stage embryo transfer.

Nature medicine [Epub ahead of print].

Perinatal and childhood adverse outcomes associated with assisted reproductive technology (ART) has been reported, but it remains unknown whether the initial leukocyte telomere length (LTL), which is an indicator of age-related phenotypes in later life, is affected. Here, we estimated the LTLs of 1,137 individuals from 365 families, including 202 children conceived by ART and 205 children conceived spontaneously from two centers of the China National Birth Cohort, using whole-genome sequencing (WGS) data. One-year-old children conceived by ART had shorter LTLs than those conceived spontaneously (beta, -0.36; P = 1.29 × 10[-3]) after adjusting for plurality, sex and other potential confounding factors. In particular, blastocyst-stage embryo transfer was associated with shorter LTL (beta, -0.54, P = 2.69 × 10[-3]) in children conceived by ART. The association was validated in 586 children conceived by ART from five centers using different LTL quantification methods (that is, WGS or qPCR). Blastocyst-stage embryo transfer resulted in shorter telomere lengths in mice at postnatal day 1 (P = 2.10 × 10[-4]) and mice at 6 months (P = 0.042). In vitro culturing of mice embryos did not result in shorter telomere lengths in the late cleavage stage, but it did suppress telomerase activity in the early blastocyst stage. Our findings demonstrate the need to evaluate the long-term consequences of ART, particularly for aging-related phenotypes, in children conceived by ART.

RevDate: 2022-12-14

Akay GG (2022)

Telomeres and Psychological Stress: Perspective on Psychopathologies.

Noro psikiyatri arsivi, 59(4):330-337 pii:archneuro-59-330.

INTRODUCTION: Telomeres are specialized DNA-protein complexes located at the ends of all chromosomes and act as a "molecular clock" to determine the replicative lifespan of the cells. Recent studies indicate that life-long exposure to stress, starting from the prenatal period, causes many diseases to emerge at an early age, and telomeres may be possible mediators in this process. This article aims to review the relationship between the stress-telomere-disease triad and the potential role of telomere dysfunction in psychopathologies in the light of current literature.

METHODS: A literature search was conducted along the lines of a narrative review. PubMed and Web of Science databases were used to identify all types of articles published from inception to January 2022. After the title/abstract search, articles available in full text and English were selected based on key findings, the applicability of the method used to test the hypothesis, limitations, interpretation of the results, and impact of the results in the field. A total of 73 records were included in this narrative review.

RESULTS: The fact that some age-related chronic diseases, such as cardiovascular diseases and type 2 diabetes, are seen more frequently and at an earlier age in certain psychopathologies including depression, bipolar disorder, and schizophrenia suggests that these disorders are premature ageing syndromes. Although there are some conflicting results in the literature, in line with this hypothesis, the presence of shortened telomeres reported in these psychopathologies and the impact of lifelong exposure to stress on this process are remarkable.

CONCLUSION: Many of the studies point to an association and do not tell much about the causality. Hence, the elucidation of the biological processes underlying the relationship between psychological stress, dysfunctional telomeres and complex, common age-related diseases, as well as psychiatric disorders is important and further studies are needed at the cellular level.

RevDate: 2022-12-15

Ito J, Kageyama M, Hara S, et al (2022)

Paternal aging impacts mitochondrial DNA content and telomere length in mouse embryos.

Mitochondrion, 68:105-113 pii:S1567-7249(22)00106-4 [Epub ahead of print].

Mitochondrial DNA (mtDNA) copy number and telomere length (TL) in blastocysts derived from the same male mice at young (10-19-week-old) and aged (40-49-week-old) time points and mtDNA and TL in the hearts of offspring derived from young and aged male mice were examined. Paternal aging correlated with reduced mtDNA and TL in blastocysts. mtDNA and TL were significantly correlated, which was also observed in bovine blastocysts. Moreover, mtDNA in the heart of offspring was reduced in male mice with paternal aging. In conclusion, paternal aging affects embryonic mtDNA and TL, potentially impacting their offspring.

RevDate: 2022-12-13

Misino S, Busch A, Wagner CB, et al (2022)

TERRA increases at short telomeres in yeast survivors and regulates survivor associated senescence (SAS).

Nucleic acids research pii:6885047 [Epub ahead of print].

Cancer cells achieve immortality by employing either homology-directed repair (HDR) or the telomerase enzyme to maintain telomeres. ALT (alternative lengthening of telomeres) refers to the subset of cancer cells that employ HDR. Many ALT features are conserved from yeast to human cells, with the yeast equivalent being referred to as survivors. The non-coding RNA TERRA, and its ability to form RNA-DNA hybrids, has been implicated in ALT/survivor maintenance by promoting HDR. It is not understood which telomeres in ALT/survivors engage in HDR, nor is it clear which telomeres upregulate TERRA. Using yeast survivors as a model for ALT, we demonstrate that HDR only occurs at telomeres when they become critically short. Moreover, TERRA levels steadily increase as telomeres shorten and decrease again following HDR-mediated recombination. We observe that survivors undergo cycles of senescence, in a similar manner to non-survivors following telomerase loss, which we refer to as survivor associated senescence (SAS). Similar to 'normal' senescence, we report that RNA-DNA hybrids slow the rate of SAS, likely through the elongation of critically short telomeres, however decreasing the rate of telomere shortening may contribute to this effect. In summary, TERRA RNA-DNA hybrids regulate telomere dysfunction-induced senescence before and after survivor formation.

RevDate: 2022-12-12

Nasiri L, Vaez-Mahdavi MR, Hassanpour H, et al (2022)

Increased serum lipofuscin associated with leukocyte telomere shortening in veterans: a possible role for sulfur mustard exposure in delayed-onset accelerated cellular senescence.

International immunopharmacology, 114:109549 pii:S1567-5769(22)01034-7 [Epub ahead of print].

BACKGROUND: Sulfur mustard (SM) is a toxic gas that causes chronic inflammation and oxidative stress leading to cell senescence. This study aimed to evaluate two indicators of biological aging (i.e., serum lipofuscin level and leukocyte telomere length) and assess their relationship based on the severity of SM exposure in the long term.

METHODS: The study was performed on two groups of male participants. 1) SM-exposed group (exposed to SM once in 1987), 73 volunteers. 2) Non-exposed group, 16 healthy volunteers. The SM-exposed group was categorized into three subgroups based on the severity of SM exposure and body damage (asymptom, mild, and severe). The blood sample was prepared from members of each group. The serum lipofuscin, TGF-β, malondialdehyde (MDA), c-reactive protein (CRP), and leukocyte telomere length (TL) were measured in all participants.

RESULTS: The MDA level was increased in the SM-exposed group (mean = 39.6 µM, SD = 16.5) compared to the non-exposed group (mean = 21.1 µM, SD = 10.3) (P < 0.05). The CRP level was also increased in the SM-exposed group (mean = 5.12 mg/l, SD = 3.36) compared to the non-exposed group (mean = 3.51 mg/l, SD = 1.21), while the TGF-β level was decreased (P < 0.05) in the SM-exposed group (mean = 52.6 pg/ml, SD = 18.7) compared to the non-exposed group (mean = 68.9 pg/ml, SD = 13.8). The relative TL was shorter in the SM-exposed group (mean = 0.40, SD = 0.28) than in the non-exposed group (mean = 2.25, SD = 1.41) (P < 0.05). The lipofuscin level was higher in the total SM-exposed group (mean = 1.44 ng/ml, SD = 0.685) than in the non-exposed group (mean = 0.88 ng/ml, SD = 0.449) (P < 0.05). The MDA and CRP levels were increased in the SM-exposed subgroups of asymptom, mild, and severe than the non-exposed group, while TGF-β level and TL were decreased in those subgroups. The lipofuscin level was higher in the SM-exposed subgroups of mild and severe than in the non-exposed group. The regression analysis determined a negative correlation between lipofuscin level and TL. The lipofuscin/TL ratio was higher in the total SM-exposed group (mean = 6.36, SD = 5.342) than in the non-exposed group (mean = 0.51, SD=0.389). This ratio was also higher in the SM-exposed subgroups of asymptom, mild, and severe than in the non-exposed group. The lipofuscin/TL ratio did not differ between mild and severe subgroups.

CONCLUSION: The delayed toxicity of SM is associated with chronic oxidative stress, continuous inflammatory stimulation, increased lipofuscin, and telomere shortening. Future studies are needed to verify the suitability of serum lipofuscin to telomere length ratio in determining the severity of SM toxicity.

RevDate: 2022-12-12

Zhang Y, Liu J, Li X, et al (2022)

Dietary selenium excess affected spermatogenesis via DNA damage and telomere-related cell senescence and apoptosis in mice.

Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association pii:S0278-6915(22)00754-2 [Epub ahead of print].

Selenium (Se) is a vital microelement for spermatogenesis and male fertility. The aim of this study was to investigate the effects of Se on the male reproductive function and possible mechanisms. Fourty male mice were randomly divided into 0, 0.1, 0.3 and 0.9 mg/kg Se supplementation groups and given with Se dietary intervention for 12 weeks. Our data showed that excessive Se intake damaged the tissue structure of testes and epididymides of the mice, resulting in decreased sperm quality and quantity. Moreover, excessive Se induced oxidative stress, causing DNA damage and activated DNA damage repair factors (Mre11/Rad50/Nbs1), and also disrupted telomere function by shortening telomere length and decreasing TERT expression. Se excess activated the senescence pathway p53/p21/p16, leading to germ cell senescence, and inhibited cell proliferation by suppressing the Sirt1/Foxo1/c-Myc pathway. All of this led to spermatogenic cell apoptosis, thereby causing a decrease of sperm quantity and quality. In conclusion, excessive Se caused reproductive toxicity via inducing telomere dysfunction due to DNA damage, leading to germ cellular senescence and apoptosis in the testes of male mice. Our research provide new proof to explain the underlying mechanism of male reproductive toxicity triggered by excessive Se intake.

RevDate: 2022-12-11

Toupance S, Karampatsou SI, Labat C, et al (2022)

Longitudinal Association of Telomere Dynamics with Obesity and Metabolic Disorders in Young Children.

Nutrients, 14(23): pii:nu14235191.

In adults, short leukocyte telomere length (LTL) is associated with metabolic disorders, such as obesity and diabetes mellitus type 2. These associations could stem from early life interactions between LTL and metabolic disorders. To test this hypothesis, we explored the associations between LTL and metabolic parameters as well as their evolution over time in children with or without obesity at baseline. Seventy-three (n = 73) children attending our Outpatient Clinic for the Prevention and Management of Overweight and Obesity in Childhood and Adolescence, aged 2-10 years (mean ± SD: 7.6 ± 2.0 years), were followed for 2 to 4 years. Anthropometric, clinical, and biological (including LTL by Southern blot) measurements were performed annually. Baseline LTL correlated negatively with BMI (p = 0.02), fat percentage (p = 0.01), and blood glucose (p = 0.0007). These associations persisted after adjustments for age and sex. No associations were found between LTL attrition during the follow-up period and any of the metabolic parameters. In young children, obesity and metabolic disturbances were associated with shorter telomeres but were not associated with more pronounced LTL attrition. These results suggest that short telomeres contribute to the development of obesity and metabolic disorders very early in life, which can have a major impact on health.

RevDate: 2022-12-11

Mulet A, J Signes-Costa (2022)

Idiopathic Pulmonary Fibrosis and Telomeres.

Journal of clinical medicine, 11(23): pii:jcm11236893.

Idiopathic pulmonary fibrosis is an interstitial lung disease of unknown etiology with a highly compromised prognosis and a significant mortality rate within a few years of diagnosis. Despite being idiopathic, it has been shown that telomeric shortening could play an important role in its etiopathogenesis. Mutations in telomere-related genes have been identified, but they are not always present despite telomere shortening. On the other hand, this telomeric shortening has been linked to a worse prognosis of the disease independently of other clinical factors, implying it may serve as a biomarker.

RevDate: 2022-12-11

Vilkeviciute A, Gedvilaite G, Banevicius M, et al (2022)

Relative Leukocyte Telomere Length and Genetic Variants in Telomere-Related Genes and Serum Levels Role in Age-Related Macular Degeneration.

Cells, 11(23): pii:cells11233847.

UNLABELLED: Telomere shortening is well known to be associated with ageing. Age is the most decisive risk factor for age-related macular degeneration (AMD) development. The older the individual, the higher the AMD risk. For this reason, we aimed to find any associations between telomere length, distribution of genetic variants in telomere-related genes (TERT, TERT-CLPTM1, TRF1, TRF2, and TNKS2), and serum TERF-1 and TERF2 levels on AMD development.

METHODS: Our study enrolled 342 patients with AMD and 177 healthy controls. Samples of DNA from peripheral blood leukocytes were extracted by DNA salting-out method. The genotyping of TERT rs2736098, rs401681 in TERT-CLPTM1 locus, TRF1 rs1545827, rs10107605, TNKS2 rs10509637, rs10509639, and TRF2 rs251796 and relative leukocyte telomere length (T/S) measurement were carried out using the real-time polymerase chain reaction method. Serum TERF-1 and TERF2 levels were measured by enzymatic immunoassay (ELISA).

RESULTS: We found longer telomeres in early AMD patients compared to the control group. Additionally, we revealed that minor allele C at TRF1 rs10107605 was associated with decreases the odds of both early and exudative AMD. Each minor allele G at TRF2 rs251796 and TRF1 rs1545827 C/T genotype and C/T+T/T genotypes, compared to the C/C genotype, increases the odds of having shorter telomeres. Furthermore, we found elevated TERF1 serum levels in the early AMD group compared to the control group.

CONCLUSIONS: In conclusion, these results suggest that relative leukocyte telomere length and genetic variants of TRF1 and TRF2 play a role in AMD development. Additionally, TERF1 is likely to be associated with early AMD.

RevDate: 2022-12-11

Farrukh S, Baig S, Hussain R, et al (2022)

Parental Genetics Communicate with Intrauterine Environment to Reprogram Newborn Telomeres and Immunity.

Cells, 11(23): pii:cells11233777.

Telomeres, markers for cellular senescence, have been found substantially influenced by parental inheritance. It is well known that genomic stability is preserved by the DNA repair mechanism through telomerase. This study aimed to determine the association between parents-newborn telomere length (TL) and telomerase gene (TERT), highlighting DNA repair combined with TL/TERT polymorphism and immunosenescence of the triad. The mother-father-newborn triad blood samples (n = 312) were collected from Ziauddin Hospitals, Pakistan, between September 2021 and June 2022. The telomere length (T/S ratio) was quantified by qPCR, polymorphism was identified by Sanger sequencing, and immunosenescence by flow cytometry. The linear regression was applied to TL and gene association. The newborns had longest TL (2.51 ± 2.87) and strong positive association (R = 0.25, p&nbsp;≤ 0.0001) (transgenerational health effects) with mothers' TL (1.6 ± 2.00). Maternal demographics-socioeconomic status, education, and occupation-showed significant effects on TL of newborns (p < 0.015, 0.034, 0.04, respectively). The TERT risk genotype CC (rs2736100) was predominant in the triad (0.6, 0.5, 0.65, respectively) with a strong positive association with newborn TL (β = 2.91, <0.0011). Further analysis highlighted the expression of KLRG 1+ in T-cells with shorter TL but less frequent among newborns. The study concludes that TERT, parental TL, antenatal maternal health, and immunity have a significantly positive effect on the repair of newborn TL.

RevDate: 2022-12-10

Nelson N, Feurstein S, Niaz A, et al (2022)

Functional genomics for curation of variants in telomere biology disorder associated genes, a systematic review.

Genetics in medicine : official journal of the American College of Medical Genetics pii:S1098-3600(22)01059-0 [Epub ahead of print].

PURPOSE: Patients with an underlying telomere biology disorder (TBD) have variable clinical presentations and can be challenging to diagnose clinically. A genomic diagnosis for patients presenting with TBD is vital for optimal treatments. Unfortunately, many variants identified during diagnostic testing are variants of uncertain significance (VUS). This complicates management decisions, delays treatment and risks non-uptake of a potentially curative therapies. Improved application of functional genomic evidence may reduce VUS classifications.

METHODS: We systematically searched the literature for published functional assays interrogating TBD gene variants. Where possible, established likely benign/benign and likely pathogenic/pathogenic variants were used to estimate the assay sensitivity, specificity, positive predictive value, negative predictive value and odds of pathogenicity.

RESULTS: 3131 articles were screened and 151 met inclusion criteria. Sufficient data to enable a PS3/BS3 recommendation was available for TERT variants only. We recommend PS3 and BS3 can be applied at a moderate and supportive level respectively. PS3/BS3 application was limited by a lack of assay standardisation and limited inclusion of benign variants.

CONCLUSION: Further assay standardisation and assessment of benign variants is required for optimal use of the PS3/BS3 criterion for TBD gene variant classification.

RevDate: 2022-12-09

Savage SA (2022)

Dyskeratosis congenita and telomere biology disorders.

Hematology. American Society of Hematology. Education Program, 2022(1):637-648.

Numerous genetic discoveries and the advent of clinical telomere length testing have led to the recognition of a spectrum of telomere biology disorders (TBDs) beyond the classic dyskeratosis congenita (DC) triad of nail dysplasia, abnormal skin pigmentation, and oral leukoplakia occurring with pediatric bone marrow failure. Patients with DC/TBDs have very short telomeres for their age and are at high risk of bone marrow failure, cancer, pulmonary fibrosis (PF), pulmonary arteriovenous malformations, liver disease, stenosis of the urethra, esophagus, and/or lacrimal ducts, avascular necrosis of the hips and/or shoulders, and other medical problems. However, many patients with TBDs do not develop classic DC features; they may present in middle age and/or with just 1 feature, such as PF or aplastic anemia. TBD-associated clinical manifestations are progressive and attributed to aberrant telomere biology caused by the X-linked recessive, autosomal dominant, autosomal recessive, or de novo occurrence of pathogenic germline variants in at least 18 different genes. This review describes the genetics and clinical manifestations of TBDs and highlights areas in need of additional clinical and basic science research.

RevDate: 2022-12-09

Picos-Cárdenas VJ, Beltrán-Ontiveros SA, Cruz-Ramos JA, et al (2022)

Novel TINF2 gene mutation in dyskeratosis congenita with extremely short telomeres: A case report.

World journal of clinical cases, 10(33):12440-12446.

BACKGROUND: Dyskeratosis congenita is a rare disease characterized by bone marrow failure and a clinical triad of oral leukoplakia, nail dystrophy, and abnormal skin pigmentation. The genetics of dyskeratosis congenita include mutations in genes involved in telomere maintenance, including TINF2.

CASE SUMMARY: Here, we report a female patient who presented thrombocytopenia, anemia, reticulate hyperpigmentation, dystrophy in fingernails and toenails, and leukoplakia on the tongue. A histopathological study of the skin showed dyskeratocytes; however, a bone marrow biopsy revealed normal cell morphology. The patient was diagnosed with dyskeratosis congenita, but her family history did not reveal significant antecedents. Whole-exome sequencing showed a novel heterozygous punctual mutation in exon 6 from the TINF2 gene, namely, NM_001099274.1:c.854delp.(Val285Alafs*32). An analysis of telomere length showed short telomeres relative to the patient's age.

CONCLUSION: The disease in this patient was caused by a germline novel mutation of TINF2 in one of her parents.

RevDate: 2022-12-09

Sieverling L, Hong C, Koser SD, et al (2022)

Author Correction: Genomic footprints of activated telomere maintenance mechanisms in cancer.

Nature communications, 13(1):7574 pii:10.1038/s41467-022-32328-7.

RevDate: 2022-12-06

He F, Yu Q, Wang M, et al (2022)

SESAME-catalyzed H3T11 phosphorylation inhibits Dot1-catalyzed H3K79me3 to regulate autophagy and telomere silencing.

Nature communications, 13(1):7526.

The glycolytic enzyme, pyruvate kinase Pyk1 maintains telomere heterochromatin by phosphorylating histone H3T11 (H3pT11), which promotes SIR (silent information regulator) complex binding at telomeres and prevents autophagy-mediated Sir2 degradation. However, the exact mechanism of action for H3pT11 is poorly understood. Here, we report that H3pT11 directly inhibits Dot1-catalyzed H3K79 tri-methylation (H3K79me3) and uncover how this histone crosstalk regulates autophagy and telomere silencing. Mechanistically, Pyk1-catalyzed H3pT11 directly reduces the binding of Dot1 to chromatin and inhibits Dot1-catalyzed H3K79me3, which leads to transcriptional repression of autophagy genes and reduced autophagy. Despite the antagonism between H3pT11 and H3K79me3, they work together to promote the binding of SIR complex at telomeres to maintain telomere silencing. Furthermore, we identify Reb1 as a telomere-associated factor that recruits Pyk1-containing SESAME (Serine-responsive SAM-containing Metabolic Enzyme) complex to telomere regions to phosphorylate H3T11 and prevent the invasion of H3K79me3 from euchromatin into heterochromatin to maintain telomere silencing. Together, these results uncover a histone crosstalk and provide insights into dynamic regulation of silent heterochromatin and autophagy in response to cell metabolism.

RevDate: 2022-12-07
CmpDate: 2022-12-07

Martinez D, Lavebratt C, Millischer V, et al (2022)

Shorter telomere length and suicidal ideation in familial bipolar disorder.

PloS one, 17(12):e0275999 pii:PONE-D-22-12118.

Bipolar Disorder (BD) has recently been related to a process of accelerated aging, with shortened leukocyte telomere length (LTL) in this population. It has also been observed that the suicide rate in BD patients is higher than in the general population, and more recently the telomere length variation has been described as shorter in suicide completers compared with control subjects. Objectives The aim of the present study was to investigate if there is an association between LTL and BD in families where two or more members have BD including clinical symptomatology variables, along with suicide behavior. Methods Telomere length and single copy gene ratio (T/S ratio) was measured using quantitative polymerase chain reaction in a sample of 143 relatives from 22 families, of which 60 had BD. The statistical analysis was performed with a polygenic mixed model. Results LTL was associated with suicidal ideation (p = 0.02) as that there is an interaction between suicidal ideation and course of the disorder (p = 0.02). The estimated heritability for LTL in these families was 0.68. In addition, covariates that relate to severity of disease, i.e. suicidal ideation and course of the disorder, showed an association with shorter LTL in BD patients. No difference in LTL between BD patients and healthy relatives was observed. Conclusion LTL are shorter in subjects with familial BD suggesting that stress related sub-phenotypes possibly accelerate the process of cellular aging and correlate with disease severity and suicidal ideation.

RevDate: 2022-12-06

Shi H, Li X, Yu H, et al (2022)

Potential effect of dietary zinc intake on telomere length: A cross-sectional study of US adults.

Frontiers in nutrition, 9:993425.

BACKGROUND: Telomere length, which is related to chronic diseases and premature mortality, is influenced by dietary factors. Zinc is known as a dietary antioxidant micronutrient, however, its impact on telomere length remains unclear.

OBJECTIVE: We aimed to examine the potential effect of dietary zinc intake on telomere length among middle-aged and older individuals in the US.

MATERIALS AND METHODS: Our study included 3,793 US participants aged 45 years and older from the 1999 to 2002 National Health and Nutrition Examination Survey (NHANES). 24-h dietary recall interviews were employed to evaluate zinc consumption. Leukocyte telomere length was assessed by real-time quantitative polymerase chain reaction (qPCR). We adopted generalized linear models to investigate the effect of dietary zinc intake on telomere length, and subgroup analyses were further applied. We further evaluated the dose-response relationship using restricted cubic spline analysis.

RESULTS: Among the 3,793 participants, the average telomere length was 0.926 ± 0.205 (T/S ratio) or 5509.5 ± 494.9 (bp). After adjusting for major confounders, every 5 mg increment in dietary zinc consumption was related to 0.64% (95% CI: 0.17%, 1.10%) longer telomere length. In the subgroup analyses, significant relationships were found in females (Percentage change: 1.11%; 95% CI: 0.48%, 1.75%), obese (Percentage change: 0.88%; 95% CI: 0.26%, 1.50%), and low energy intake individuals (Percentage change: 0.99%; 95% CI: 0.51%, 1.46%). Additionally, we revealed a positive linear relationship between dietary zinc intake and telomere length (P for non-linearity = 0.636).

CONCLUSION: Our study revealed that elevated dietary zinc intake was significantly related to longer telomere length among adults aged 45 years and older in the US. And the association was more pronounced in females, obese, and low energy intake individuals.

RevDate: 2022-12-06

Krasnienkov DS, Gorodna OV, Kaminska TM, et al (2022)

Analysis of Relative Average Length of Telomeres in Leukocytes of Women with COVID-19.

Cytology and genetics, 56(6):526-529.

Coronavirus disease (COVID-19) is an acute infectious disease of the respiratory tract caused by a new SARS-CoV-2 coronavirus. A global vaccination program against SARS-CoV-2 continues, and the incidence of COVID-19 worldwide is significantly decreasing. However, among millions of those who survived COVID-19, numerous groups will need assistance due to increased clinical consequences after COVID-19. Currently, there is a need to search for molecular biomarkers for monitoring the onset and progression of post-COVID syndrome. For this purpose, the relative average length of chromosome regions was studied in the groups of women of reproductive age: in the group of patients (n = 64) recovered from COVID-19 and in the control group (n = 42) of women of the same age. The analysis was carried out using a method of multiplex monochrome quantitative real-time PCR on DNA samples isolated from the peripheral blood leukocytes. According to the results of the study, it was established that the relative average length of chromosomes in the peripheral blood leukocytes was statistically significantly lower in the group of patients with COVID-19 than in the control group (p < 0.05). The results obtained allow one to state that the observed shortening of the relative average length of telomeres in the group of patients that recovered from COVID-19 can indicate that SARS-CoV-2 infection can directly cause the erosion of telomeres in the blood cells, particularly, in leukocytes. Thus, the determination of the relative average length of telomeres can be an informative prognostic marker for estimating the risk of the severity of COVID-19 disease and the development of post-COVID syndrome.

RevDate: 2022-12-06
CmpDate: 2022-12-06

Zizza A, Panico A, Grassi T, et al (2022)

Is telomere length in buccal or salivary cells a useful biomarker of exposure to air pollution? A review.

Mutation research. Genetic toxicology and environmental mutagenesis, 883-884:503561.

Telomeres are repetitive DNA-protein sequences located at the end of chromosomes and play an essential role in preserving information in our genome by protecting against end-to-end fusion, nucleolytic degradation, breakage, and inappropriate recombination. The telomeres shorten with aging and this process can be affected by oxidative stress and inflammation. Environmental and occupational factors may contribute to telomere length (TL) shortening, as demonstrated by an increasing number of studies. In particular, air pollution was associated with aging-related health outcomes and molecular alterations, such as telomeric shortening. Leukocytes are widely used for TL measurement. However, buccal and salivary cells have more intimate contact with airborne pollutants and are easier to sample. The objective of this review was to identify whether salivary or buccal TL represents a valid marker for evaluating the effects of pollution on health. The reviewed studies investigated the association between TL and occupational exposure (genotoxic substances in mechanical workers, and pesticides in pesticides applicators), residential traffic exposure (NOx, NO2, PM2.5, PM10, and black carbon), and household air pollution (PM2.5 and black carbon from biomass stoves). The studies involved adults and children. Although few studies have yet been carried out, almost all reported a negative association between salivary or buccal TL and exposure to air pollutants stating that it could be a good indicator of occupational or airborne pollution exposure. However, further research is needed to evaluate the effect of acute versus long-term exposure on salivary or buccal TL as well as the role of confounding factors. Moreover, most of the reviewed studies were conducted on healthy adults, so it is important to deeply investigate how TL is associated with all-cause mortality such as cancer, diabetes, cardiovascular disease, and respiratory disease, how it can be affected during childhood, and which changes over time can be associated with diseases' onset in adulthood.

RevDate: 2022-12-03

Safaee MM, Lin J, Smith DL, et al (2022)

Association of telomere length with risk of complications in adult spinal deformity surgery: a pilot study of 43 patients.

Journal of neurosurgery. Spine [Epub ahead of print].

OBJECTIVE: Risk stratification is a critical element of surgical planning. Early tools were fairly crude, while newer instruments incorporate disease-specific elements and markers of frailty. It is unknown if discrepancies between chronological and cellular age can guide surgical planning or treatment. Telomeres are DNA-protein complexes that serve an important role in protecting genomic DNA. Their shortening is a consequence of aging and environmental exposures, with well-established associations with diseases of aging and mortality. There are compelling data to suggest that telomere length can provide insight toward overall health. The authors sought to determine potential associations between telomere length and postoperative complications.

METHODS: Adults undergoing elective surgery for spinal deformity were prospectively enrolled. Telomere length was measured from preoperative whole blood using quantitative polymerase chain reaction and expressed as the ratio of telomere (T) to single-copy gene (S) abundance (T/S ratio), with higher T/S ratios indicating longer telomere length. Demographic and patient data included age, BMI, and results for the following rating scales: the Adult Spinal Deformity Frailty Index (ASD-FI), Oswestry Disability Index (ODI), Scoliosis Research Society-22r (SRS-22r), American Society of Anesthesiology (ASA) classification, and Charlson Comorbidity Index (CCI). Operative and postoperative complication data (medical or surgical within 90 days) were also collected.

RESULTS: Forty-three patients were enrolled, including 31 women (53%), with a mean age of 66 years and a mean BMI of 28.5. The mean number of levels fused was 11, with 21 (48.8%) combined anterior-posterior approaches. Twenty-two patients (51.2%) had a medical or surgical complication. Patients with a postoperative complication had a significantly lower T/S ratio (0.712 vs 0.813, p = 0.008), indicating shorter telomere length, despite a mild difference in age compared with patients without a postoperative complication (68 vs 63 years, p = 0.069). Patients with complications also had higher CCI scores than patients without complications (2.3 vs 3.8, p = 0.004). There were no significant differences in sex, BMI, ASD-FI score, ASA class, preoperative ODI and SRS-22r scores, number of levels fused, or use of three-column osteotomies. In a multivariate model including age, frailty, ASA class, use of an anterior-posterior approach, CCI score, and telomere length, the authors found that short telomere length was significantly associated with postoperative complications. Patients whose telomere length fell in the shortest quartile had the highest risk (OR 18.184, p = 0.030).

CONCLUSIONS: Short telomere length was associated with an increased risk of postoperative complications despite only a mild difference in chronological age. Increasing comorbidity scores also trended toward significance. Larger prospective studies are needed; however, these data provide a compelling impetus to investigate the role of biological aging as a component of surgical risk stratification.

RevDate: 2022-12-02

Virseda-Berdices A, Concostrina-Martinez L, Martínez-González O, et al (2022)

RELATIVE TELOMERE LENGTH IMPACT ON MORTALITY OF COVID-19: SEX DIFFERENCES.

Journal of medical virology [Epub ahead of print].

INTRODUCTION: Increasing age is associated with severity and higher mortality of COVID-19. Telomere shortening is associated with higher risk of infections and may be used to identify those patients who are more likely to die. We evaluated the association between relative telomere length (RTL) and COVID-19 mortality.

METHODS: RTL was measured in patients hospitalized because of COVID-19. We used Kaplan-Meier method to analyze survival probabilities, and Cox regression to investigate the association between RTL and mortality (30 and 90 days).

RESULTS: 608 patients were included in the analysis (mean age =72.5 years, 41.1% women, and 53.8% Caucasic). During the study period, 75 people died from COVID-19 and 533 survived. Lower RTL was associated with a higher risk of death in women either at 30 (adjusted HR (aHR)=3.33; 95%CI=1.05-10.00; p=0.040) and at 90 days (aHR=3.57; 95%CI=1.23-11.11; p=0.019).

CONCLUSION: Lower RTL was associated with a higher risk of dying of COVID-19 in women. This finding suggests that RTL has an essential role in the prognosis of this subset of the population. This article is protected by copyright. All rights reserved.

RevDate: 2022-12-02

Mayer SE, Guan J, Lin J, et al (2022)

Intergenerational effects of maternal lifetime stressor exposure on offspring telomere length in Black and White women.

Psychological medicine pii:S0033291722003397 [Epub ahead of print].

BACKGROUND: Although maternal stressor exposure has been associated with shorter telomere length (TL) in offspring, this literature is based largely on White samples. Furthermore, timing of maternal stressors has rarely been examined. Here, we examined how maternal stressors occurring during adolescence, pregnancy, and across the lifespan related to child TL in Black and White mothers.

METHOD: Mothers (112 Black; 110 White; Mage = 39) and their youngest offspring (n = 222; Mage = 8) were part of a larger prospective cohort study, wherein mothers reported their stressors during adolescence (assessed twice during adolescence for the past year), pregnancy (assessed in midlife for most recent pregnancy), and across their lifespan (assessed in midlife). Mother and child provided saliva for TL measurement. Multiple linear regression models examined the interaction of maternal stressor exposure and race in relation to child TL, controlling for maternal TL and child gender and age. Race-stratified analyses were also conducted.

RESULTS: Neither maternal adolescence nor lifespan stressors interacted with race in relation to child TL. In contrast, greater maternal pregnancy stressors were associated with shorter child TL, but this effect was present for children of White but not Black mothers. Moreover, this effect was significant for financial but not social pregnancy stressors. Race-stratified models revealed that greater financial pregnancy stressors predicted shorter telomeres in offspring of White, but not Black mothers.

CONCLUSIONS: Race and maternal stressors interact and are related to biological aging across generations, but these effects are specific to certain races, stressors, and exposure time periods.

RevDate: 2022-12-02

Aiello A, Accardi G, Alì S, et al (2021)

Possible Association of Telomere Length With Sleep Duration. A Preliminary Pilot Study in a Sicilian Cohort with Centenarians.

Translational medicine @ UniSa, 24(1):24-29.

Telomere length (TL) is considered a biomarker of ageing although this topic is still debated. Also, sleep pattern changes are physiological part of the normal ageing process. In fact, it is widely recognized that sleep duration declines with age, leading to dysregulation of circadian rhythms. The aim of our study was to analyse the possible association of sleep duration with TL in a sample of 135 subjects with ages ranging from 20 to 111 years, recruited from Palermo and neighbouring municipalities in Sicily (Italy). Preliminary data suggest that relative TL (RTL) decreases with age in both men and women. However, at older ages, the difference between men and women tends to narrow. Nonagenarian and centenarian women do not show RTL values significantly different from those observed in adult and old women (40-89 years aged). Moreover, to analyse the relationship between TL and sleep, we stratified sleep duration into greater or lesser than 8-h periods. We found that centenarians, who daily sleep 8 hours or more, have longer RTL than centenarians who sleep fewer than 8 hours. Although the relatively small sample size of centenarians, we provide preliminary evidence that sleep duration may affect the RTL of centenarians. To the best of our knowledge, this is the first study to examine the relationship between centenarians, RTL and sleep duration. Further studies with greater sample size of centenarians are required to replicate and extend these data.

RevDate: 2022-11-28

Ni W, Wolf K, Breitner S, et al (2022)

Higher Daily Air Temperature Is Associated with Shorter Leukocyte Telomere Length: KORA F3 and KORA F4.

Environmental science & technology [Epub ahead of print].

Higher air temperature is associated with increased age-related morbidity and mortality. To date, short-term effects of air temperature on leukocyte telomere length have not been investigated in an adult population. We aimed to examine the short-term associations between air temperature and leukocyte telomere length in an adult population-based setting, including two independent cohorts. This population-based study involved 5864 participants from the KORA F3 (2004-2005) and F4 (2006-2008) cohort studies conducted in Augsburg, Germany. Leukocyte telomere length was assessed by a quantitative PCR-based method. We estimated air temperature at each participant's residential address through a highly resolved spatiotemporal model. We conducted cohort-specific generalized additive models to explore the short-term effects of air temperature on leukocyte telomere length at lags 0-1, 2-6, 0-6, and 0-13 days separately and pooled the estimates by fixed-effects meta-analysis. Our study found that between individuals, an interquartile range (IQR) increase in daily air temperature was associated with shorter leukocyte telomere length at lags 0-1, 2-6, 0-6, and 0-13 days (%change: -2.96 [-4.46; -1.43], -2.79 [-4.49; -1.07], -4.18 [-6.08; -2.25], and -6.69 [-9.04; -4.27], respectively). This meta-analysis of two cohort studies showed that between individuals, higher daily air temperature was associated with shorter leukocyte telomere length.

RevDate: 2022-11-30
CmpDate: 2022-11-29

Lan B, Bai Y, Chang X, et al (2022)

Independent and joint effect of relative telomere length and type 2 diabetes on all-cause mortality in American adults.

Frontiers in endocrinology, 13:1035017.

OBJECTIVE: The joint effect of leukocyte telomere length (LTL) and type 2 diabetes (T2D) on the risk of all-cause death has been sparsely explored. The study designed to examine the joint effect of T2D and LTL on the probability of death in American adults.

METHODS: A cohort of 6862 adults with LTL measurements and with or without T2D from the NHANES 1999-2002 with follow-up information until 2015 was studied. Quantitative PCR was used to measure the length of telomeres relative to standard reference DNA (T/S ratio). Individuals were grouped into three tertiles according to the LTL levels, with the first tertile demonstrating the lowest one and used as the reference group. The effects of LTL and T2D status on death were evaluated using Kaplan-Meier curves along with log-rank test. Three Cox proportional hazards models with adjustment for various confounders were used to examine the links between TL and all-cause death possibility using adjusted hazard ratios (HRs).

RESULTS: Adults in the sample averaged 45.54 years of age, with 49.51% being male. After a median follow-up period of 14.4 years, 1543 (22.5%) individuals died from all cause. The probability of all-cause mortality was higher among individuals with LTL in the highest tertile than individuals in the lowest tertile (aHR = 0.89; 95%CI: 0.77-1.03); however, the difference did not reach the level of statistical significance (P = 0.11). Conversely, the individuals with T2D had a higher probability of death than individuals without (aHR = 1.26; 95%CI: 1.06-1.50; P = 0.0092). When LTL and T2D status were investigated jointly, subjects in the highest TLT tertile and with T2D had the highest probability of mortality compared with their counterparts (aHR = 1.34; 95%CI: 1.07-1.68; P = 0.0101). However, there was no independent effect of low TLT on mortality as demonstrated among individuals with diabetes (aHR = 1.14; 95%CI: 0.95-1.38; P = 0.1662).

CONCLUSION: The joint effect of TLT and T2D was larger than the sum of the independent effects on the risk of all-cause death. Participants with high TLT and diabetes showed the highest possibility of death compared with other groups.

RevDate: 2022-11-29
CmpDate: 2022-11-29

Zhao G, Guo D, Li L, et al (2022)

The Association between Dietary Magnesium Intake and Telomere Length in Adults with Hypertension.

The journal of nutrition, health & aging, 26(11):1010-1015.

BACKGROUND: Dietary micronutrients are significantly associated with telomere length, as shown in multiple studies. However, no study has investigated the association between magnesium intake and telomere length in adults with hypertension.

METHODS: Participants were included from the National Health and Nutrition Examination Survey (NHANES) in 1999-2000 and 2001-2002. Dietary magnesium intake was assessed using the 24 - hour recall method and the telomere length of leukocytes was measured using polymerase chain reaction (PCR). A multivariate regression model was then used to assess the association between dietary magnesium intake and telomere length in adults with hypertension.

RESULTS: Our final analysis included 2199 hypertensive adults (46.79% males) with a mean dietary magnesium intake of 254.82±133.47 mg/day. Linear regression, adjusted for race, sex, age, smoking, uric acid, and other variables, showed that every 1 mg increase in dietary magnesium intake was associated with a 0.20 (95% CI: 0.01, 0.39, p = 0.043) longer telomere length in all participants. In the ≥45 years age group, there was a statistically significant association between the telomere length and dietary magnesium (95% CI: 0.16, 0.63, p <0.001).

CONCLUSIONS: This study suggests that increased magnesium intake is associated with a longer telomere length in hypertensive adults, especially in those ≥45 years of age. However, further research is needed to determine a causal relationship.

RevDate: 2022-11-30
CmpDate: 2022-11-29

Maciejewska N, Olszewski M, Jurasz J, et al (2022)

Teloxantron inhibits the processivity of telomerase with preferential DNA damage on telomeres.

Cell death & disease, 13(11):1005.

Telomerase reactivation is one of the hallmarks of cancer, which plays an important role in cellular immortalization and the development and progression of the tumor. Chemical telomerase inhibitors have been shown to trigger replicative senescence and apoptotic cell death both in vitro and in vivo. Due to its upregulation in various cancers, telomerase is considered a potential target in cancer therapy. In this study, we identified potent, small-molecule telomerase inhibitors using a telomerase repeat amplification protocol assay. The results of the assay are the first evidence of telomerase inhibition by anthraquinone derivatives that do not exhibit G-quadruplex-stabilizing properties. The stability of telomerase in the presence of its inhibitor was evaluated under nearly physiological conditions using a cellular thermal shift assay. Our data showed that the compound induced aggregation of the catalytic subunit (hTERT) of human telomerase, and molecular studies confirmed the binding of the hit compound with the active site of the enzyme. The ability of new derivatives to activate DNA double-strand breaks (DSBs) was determined by high-resolution microscopy and flow cytometry in tumor cell lines differing in telomere elongation mechanism. The compounds triggered DSBs in TERT-positive A549 and H460 lung cancer cell lines, but not in TERT-negative NHBE normal human bronchial epithelial and ALT-positive U2OS osteosarcoma cell lines, which indicates that the induction of DSBs was dependent on telomerase inhibition. The observed DNA damage activated DNA damage response pathways involving ATM/Chk2 and ATR/Chk1 cascades. Additionally, the compounds induced apoptotic cell death through extrinsic and intrinsic pathways in lung cancer cells. Taken together, our study demonstrated that anthraquinone derivatives can be further developed into novel telomerase-related anticancer agents.

RevDate: 2022-11-26

Tao HY, He SM, Zhao CY, et al (2022)

Antitumor efficacy of a recombinant EGFR-targeted fusion protein conjugate that induces telomere shortening and telomerase downregulation.

International journal of biological macromolecules pii:S0141-8130(22)02784-2 [Epub ahead of print].

OBJECTIVE: To prepare a recombinant EGFR-targeted fusion protein drug conjugate acting on telomere and telomerase; and evaluate its antitumor efficacy.

METHODS: We prepared a recombinant fusion protein Fv-LDP-D3 which consists of the Fv fragment of an anti-EGFR monoclonal antibody (MAb), the apoprotein of lidamycin (LDP), and the third domain (D3) of human serum albumin (HSA); then generated the conjugate Fv-LDP-D3 ~ AE by integrating the active enediyne chomophore (AE) of lidamycin. Accordingly, in vitro and in vivo experiments were performed.

RESULTS: As shown, Fv-LDP-D3 specifically bound to EGFR highly-expressing cancer cells and intensely entered K-Ras mutant cells via enhanced macropinocytosis. By in vivo imaging, Fv-LDP-D3 displayed intense accumulation and persistent retention in tumor-site. Furthermore, the conjugate Fv-LDP-D3 ~ AE displayed highly potent cytotoxicity to cancer cells with IC50 at 0.1 nM level. The conjugate induced telomere shortening and downregulation of telomerase and EGFR pathway related proteins. Fv-LDP-D3 ~ AE exhibited prominent antitumor efficacy against human colorectal cancer xenograft accompanying with significant increase of serum IFN-β in athymic mice.

CONCLUSION: The recombinant fusion protein conjugate that exhibits the capability of tumor-targeting drug delivery can induce telomere shortening and telomerase downregulation. The investigation may lay the foundation for the development of MAb-HSA domain-based fusion protein drug conjugates.

RevDate: 2022-12-06

Jenkins AJ, Syreeni A, Mutter S, et al (2022)

Telomeres in clinical diabetes research - Moving towards precision medicine in diabetes care?.

Diabetes research and clinical practice, 194:110178 pii:S0168-8227(22)00992-5 [Epub ahead of print].

The early prediction of health outcomes for people with diabetes mellitus is desirable, as are adjunct therapies to reduce the related chronic complications and risk of premature death. The length of telomeres, protective caps on chromosome ends, is influenced by genetic and acquired factors, and shorter telomeres have been associated with and predictive of adverse cardiometabolic outcomes. Many studies have shown associations between telomere length in white blood cells (WBC) and diabetes per se and its chronic complications, and some studies show that telomeres do not always progressively shorten in people with diabetes. With the pandemic of diabetes and taking into consideration the calculations of residual risk using existent risk equations, additional tests to stratify subject risk are desirable. In this evolving era of precision medicine for people with diabetes, this 'global biomarker' of WBC telomere length may be useful to help predict health outcomes, to monitor health status, and may be a therapeutic target. We comment on the field of telomere investigations in diabetes, including recommending areas for further clinical research.

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In the early 1990's, Robert Robbins was a faculty member at Johns Hopkins, where he directed the informatics core of GDB — the human gene-mapping database of the international human genome project. To share papers with colleagues around the world, he set up a small paper-sharing section on his personal web page. This small project evolved into The Electronic Scholarly Publishing Project.

ESP Support

In 1995, Robbins became the VP/IT of the Fred Hutchinson Cancer Research Center in Seattle, WA. Soon after arriving in Seattle, Robbins secured funding, through the ELSI component of the US Human Genome Project, to create the original ESP.ORG web site, with the formal goal of providing free, world-wide access to the literature of classical genetics.

ESP Rationale

Although the methods of molecular biology can seem almost magical to the uninitiated, the original techniques of classical genetics are readily appreciated by one and all: cross individuals that differ in some inherited trait, collect all of the progeny, score their attributes, and propose mechanisms to explain the patterns of inheritance observed.

ESP Goal

In reading the early works of classical genetics, one is drawn, almost inexorably, into ever more complex models, until molecular explanations begin to seem both necessary and natural. At that point, the tools for understanding genome research are at hand. Assisting readers reach this point was the original goal of The Electronic Scholarly Publishing Project.

ESP Usage

Usage of the site grew rapidly and has remained high. Faculty began to use the site for their assigned readings. Other on-line publishers, ranging from The New York Times to Nature referenced ESP materials in their own publications. Nobel laureates (e.g., Joshua Lederberg) regularly used the site and even wrote to suggest changes and improvements.

ESP Content

When the site began, no journals were making their early content available in digital format. As a result, ESP was obliged to digitize classic literature before it could be made available. For many important papers — such as Mendel's original paper or the first genetic map — ESP had to produce entirely new typeset versions of the works, if they were to be available in a high-quality format.

ESP Help

Early support from the DOE component of the Human Genome Project was critically important for getting the ESP project on a firm foundation. Since that funding ended (nearly 20 years ago), the project has been operated as a purely volunteer effort. Anyone wishing to assist in these efforts should send an email to Robbins.

ESP Plans

With the development of methods for adding typeset side notes to PDF files, the ESP project now plans to add annotated versions of some classical papers to its holdings. We also plan to add new reference and pedagogical material. We have already started providing regularly updated, comprehensive bibliographies to the ESP.ORG site.

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Good Beginner's Books

Although multicellular eukaryotes (MCEs) are the most visible component of the biosphere, they represent a highly derived and constrained evolutionary subset of the biosphere, unrepresentative of the vast, mostly unseen, microbial world of prokaryotic life that comprises at least half of the planet's biomass and most of its genetic diversity. The existence of telomeres is one component of the specialized biology of eukaryotes. R. Robbins

Electronic Scholarly Publishing
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E-mail: RJR8222 @ gmail.com

Papers in Classical Genetics

The ESP began as an effort to share a handful of key papers from the early days of classical genetics. Now the collection has grown to include hundreds of papers, in full-text format.

Digital Books

Along with papers on classical genetics, ESP offers a collection of full-text digital books, including many works by Darwin (and even a collection of poetry — Chicago Poems by Carl Sandburg).

Timelines

ESP now offers a much improved and expanded collection of timelines, designed to give the user choice over subject matter and dates.

Biographies

Biographical information about many key scientists.

Selected Bibliographies

Bibliographies on several topics of potential interest to the ESP community are now being automatically maintained and generated on the ESP site.

ESP Picks from Around the Web (updated 07 JUL 2018 )