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Bibliography on: Telomeres

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ESP: PubMed Auto Bibliography 25 Oct 2021 at 01:54 Created: 


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.

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Citations The Papers (from PubMed®)


RevDate: 2021-10-21

Wolf SE, Sanders TL, Beltran SE, et al (2021)

The telomere regulatory gene POT1 responds to stress and predicts performance in nature: implications for telomeres and life history evolution.

Molecular ecology [Epub ahead of print].

Telomeres are emerging as correlates of fitness-related traits and may be important mediators of ecologically relevant variation in life history strategies. Growing evidence suggests that telomere dynamics can be more predictive of performance than length itself, but very little work considers how telomere regulatory mechanisms respond to environmental challenges or influence performance in nature. Here, we combine observational and experimental datasets from free-living tree swallows (Tachycineta bicolor) to assess how performance is predicted by the telomere regulatory gene POT1, which encodes a shelterin protein that sterically blocks telomerase from repairing the telomere. First, we show that lower POT1 gene expression in the blood was associated with higher female quality, i.e. earlier breeding and heavier body mass. We next challenged mothers with an immune stressor (lipopolysaccharide injection) that led to 'sickness' in mothers and 24h of food restriction in their offspring. While POT1 did not respond to maternal injection, females with lower constitutive POT1 gene expression were better able to maintain feeding rates following treatment. Maternal injection also generated a one-day stressor for chicks, which responded with lower POT1 gene expression and elongated telomeres. Other putatively stress-responsive mechanisms (i.e. glucocorticoids, antioxidants) showed marginal responses in stress-exposed chicks. Model comparisons indicated that POT1 mRNA abundance was a largely better predictor of performance than telomere dynamics, indicating that telomere regulators may be powerful modulators of variation in life history strategies.

RevDate: 2021-10-21

Martinez-Verbo L, Estrada N, Cabezón M, et al (2021)

Mutational profile and relative telomere length in Chronic Myelomonocytic Leukemia subgroups according to the 2016 World Health Organization classification.

RevDate: 2021-10-21

Mizuno Y, Konishi S, Imai H, et al (2021)

Telomere length and urinary 8-hydroxy-2'-deoxyguanosine and essential trace element concentrations in female Japanese university students.

Journal of environmental science and health. Part A, Toxic/hazardous substances & environmental engineering [Epub ahead of print].

Telomere length is thought to be a biomarker of biological aging. This study examined whether telomere length was associated with urinary concentrations of 8-hydroxy-2'-deoxyguanosine (8-OHdG), a biomarker of oxidative stress, and antioxidative trace elements in 73 female Japanese university students (age: 19.2 ± 0.7 years). We quantified 8-OHdG and selenium in urine by liquid chromatography-mass spectrometry and inductively coupled plasma-mass spectrometry, respectively. Telomere length and urinary concentrations of other essential trace elements (molybdenum, cobalt, and chromium) that were previously measured in the same study participants, were used in this study. We used multiple linear regression analysis to examine the associations of telomere length with urinary 8-OHdG and essential trace element concentrations (covariates: urinary cotinine concentration, age, BMI, and drinking status). The geometric means (geometric standard deviation) of 8-OHdG and selenium were 3.4 (1.5) and 31 (1.3) µg/g creatinine, respectively. Telomere length was not associated with urinary 8-OHdG concentration, but was negatively associated with urinary selenium concentration. In conclusion, telomere length was not associated with urinary 8-OHdG concentration in the young women in this study. Longitudinal studies should be conducted to clarify the association between telomere shortening rate and oxidative stress level.

RevDate: 2021-10-22

Čapková Frydrychová R, Mason JM, V Peska (2021)

Editorial: Telomere Flexibility and Versatility: A Role of Telomeres in Adaptive Potential.

Frontiers in genetics, 12:771938.

RevDate: 2021-10-22

Yin X, Zhang Y, Chen Y, et al (2021)

Precise Characterization and Tracking of Stably Inherited Artificial Minichromosomes Made by Telomere-Mediated Chromosome Truncation in Brassica napus.

Frontiers in plant science, 12:743792.

Plant artificial minichromosomes are the next-generation technology for plant genetic engineering and represent an independent platform for expressing foreign genes and the tools for studying the structure and function of chromosomes. Minichromosomes have been successfully produced by telomere-mediated chromosome truncation in several plants. However, previous studies have primarily focused on the construction and rough characterization of minichromosomes, while the development of stably inherited minichromosomes and their precise characterization and tracking over different generations have rarely been demonstrated. In this study, a 0.35-kb direct repeat of the Arabidopsis telomeric sequence was transformed into Brassica napus to produce artificial minichromosomes, which were analyzed by multifluorescence in situ hybridization (multi-FISH), Southern hybridization, and primer extension telomere rapid amplification (PETRA). The stably inherited minichromosomes C2 and C4 were developed by crossing transgenic plants with wild-type plants and then selfing the hybrids. Notably, two truncation sites on chromosomes C2 and C4, respectively, were identified by resequencing; thus, the artificial minichromosomes were tracked over different generations with insertion site-specific PCR. This study provided two stably inherited minichromosomes in oilseed rape and describes approaches to precisely characterize the truncation position and track the minichromosomes in offspring through multi-FISH, genome resequencing, and insertion site-specific PCR.

RevDate: 2021-10-23

Spießberger M, Hoelzl F, Smith S, et al (2021)

The tarnished silver spoon? Trade-off between prenatal growth and telomere length in wild boar.

Journal of evolutionary biology [Epub ahead of print].

Life history theory predicts a trade-off between growth rates and lifespan, which is reflected by telomere length, a biomarker of somatic state. We investigated the correlation between telomere length and early life growth of wild boar piglets, Sus scrofa, kept under semi-natural conditions with high food availability to examine our hypothesis that increased pre-and post-natal growth will lead to telomere length attrition but that a high supply of nutrient may provide the possibility to compensate telomere loss via telomere repair mechanisms. As predicted, our data showed a clear negative correlation between birth body mass and initial telomere length: heavier neonates had shorter telomeres at birth, and we did not find an influence of the mother on initial telomere length. Body mass at birth correlated with body mass later in life and post-natal growth rate did not affect telomere length. We observed an increase in telomere length during postnatal development, suggesting that high food availability allowed piglets to invest into both, growth and telomere restoration. The increase in telomere length over the duration of the study was not accompanied by telomerase activity, thus telomere elongation was either caused by alternative mechanisms or by short pulses of telomerase activity, that we missed. Taken together, this study suggests a trade-off between investment into growth and telomere maintenance even before birth and the possibility to compensate telomere attrition during growth under high amounts of available energy.

RevDate: 2021-10-23

Gao X, Li S, Dong S, et al (2021)

Response to Letter to the Editor from Bin Zhou et al: "Association between Body Weight and Telomere Length Is Predominantly Mediated through C-Reactive Protein".

The Journal of clinical endocrinology and metabolism pii:6409246 [Epub ahead of print].

RevDate: 2021-10-23

Lahav Y, Avidor S, Levy D, et al (2021)

Shorter telomeres among individuals with physical disability: The moderating role of perceived stress.

The journals of gerontology. Series B, Psychological sciences and social sciences pii:6409398 [Epub ahead of print].

OBJECTIVES: Evidence suggests that individuals with physical disability may suffer from psychological distress and accelerated cellular aging, manifested by shortened telomere length (TL), compared with healthy individuals. Studies indicate that high levels of perceived stress and depression may increase the physiological susceptibility and thus, may contribute to a short TL. However, the moderating role of perceived stress and depression within the relationship between physical disability and TL remains unknown.

METHODS: The participants consisted of 119 male subjects (mean age 54.36 years, range 35-70). Of them, 30 were able-bodied and 86 had a physical disability: 34 were due to Poliomyelitis (polio) and 55 were due to spinal cord injury (SCI). Blood samples for TL analysis were collected; the participants completed questionnaires and underwent disability evaluation.

RESULTS: Participants with disability had a shorter TL as well as elevated levels of perceived stress and depression compared with able-bodied controls. Both the perceived stress and depression were correlated with a shorter TL. Nonetheless, perceived stress, rather than depression, moderated the relationship between disability and TL; among participants with higher perceived stress levels, in particular, individuals with physical disability had a shorter TL than the able-bodied controls.

DISCUSSION: The present findings suggest that individuals with physical disability and who exhibit high levels of perceived stress may be particularly vulnerable for accelerated cellular aging, suggesting that perceived stress can be used as a valuable target for intervention.

RevDate: 2021-10-23

Zhou B, Sun X, Yu N, et al (2021)

Letter to the Editor From Bin Zhou et al: "Association Between Body Weight and Telomere Length Is Predominantly Mediated Through C-Reactive Protein".

The Journal of clinical endocrinology and metabolism pii:6409244 [Epub ahead of print].

RevDate: 2021-10-23

Mangaonkar AA, Ferrer A, Vairo FPE, et al (2021)

Clinical and molecular correlates from a predominantly adult cohort of patients with short telomere lengths.

Blood cancer journal, 11(10):170.

RevDate: 2021-10-23

Kordowitzki P, Merle R, Hass PK, et al (2021)

Influence of Age and Breed on Bovine Ovarian Capillary Blood Supply, Ovarian Mitochondria and Telomere Length.

Cells, 10(10): pii:cells10102661.

Worldwide, dairy cows of the type of high-producing cattle (HPC) suffer from health and fertility problems at a young age and therefore lose productivity after an average of only three lactations. It is still contentious whether these problems are primarily due to genetics, management, feeding or other factors. Vascularization plays a fundamental role in the cyclic processes of reproductive organs, as well as in the regeneration of tissues. In a previous study, HPC were shown to have a greater ovarian corpus luteum vascularization compared to dual-purpose breeds. We hypothesize that this activated angiogenesis could likely lead to an early exhaustion of HPC's regenerative capacity and thus to premature reproductive senescence. The objective of this study was to investigate if a HPC breed (Holstein-Friesian, HF) exhibits higher ovarian angiogenesis than a dual-purpose breed (Polish Red cow, PR) and if this is related to early ovarian aging and finally reproductive failure. For this purpose, we assessed the degree of vascularization by means of ovarian blood vessel characterization using light microscopy. As indicators for aging, we measured ovarian mitochondrial size and telomere length in peripheral leukocytes. We report in this study that in both breeds the distance between capillaries became smaller with increasing age and that the mean telomere length decreased with increasing age. The only difference between the two breeds was that PR developed larger capillaries than HF. Neither a relationship between telomere length, nor the morphology of the mitochondrial apparatus and nor angiogenesis in HF was proven. Although the data trends indicated that the proportion of shortened telomeres in HF was higher than in the PR, no significant difference between the two breeds was detected.

RevDate: 2021-10-23

Zeid D, Mooney-Leber S, Seemiller LR, et al (2021)

Terc Gene Cluster Variants Predict Liver Telomere Length in Mice.

Cells, 10(10): pii:cells10102623.

Variants in a gene cluster upstream-adjacent to TERC on human chromosome 3, which includes genes APRM, LRRC31, LRRC34 and MYNN, have been associated with telomere length in several human populations. Currently, the mechanism by which variants in the TERC gene cluster influence telomere length in humans is unknown. Given the proximity between the TERC gene cluster and TERC (~0.05 Mb) in humans, it is speculated that cluster variants are in linkage disequilibrium with a TERC causal variant. In mice, the Terc gene/Terc gene cluster are also located on chromosome 3; however, the Terc gene cluster is located distantly downstream of Terc (~60 Mb). Here, we initially aim to investigate the interactions between genotype and nicotine exposure on absolute liver telomere length (aTL) in a panel of eight inbred mouse strains. Although we found no significant impact of nicotine on liver aTL, this first experiment identified candidate single nucleotide polymorphisms (SNPs) in the murine Terc gene cluster (within genes Lrrc31, Lrriq4 and Mynn) co-varying with aTL in our panel. In a second experiment, we tested the association of these Terc gene cluster variants with liver aTL in an independent panel of eight inbred mice selected based on candidate SNP genotype. This supported our initial finding that Terc gene cluster polymorphisms impact aTL in mice, consistent with data in human populations. This provides support for mice as a model for telomere dynamics, especially for studying mechanisms underlying the association between Terc cluster variants and telomere length. Finally, these data suggest that mechanisms independent of linkage disequilibrium between the Terc/TERC gene cluster and the Terc/TERC gene mediate the cluster's regulation of telomere length.

RevDate: 2021-10-23

Sung JY, JH Cheong (2021)

Pan-Cancer Analysis of Clinical Relevance via Telomere Maintenance Mechanism.

International journal of molecular sciences, 22(20): pii:ijms222011101.

Understanding the telomere maintenance mechanism (TMM) in immortal cancer cells is vital for TMM-targeted therapies in clinical settings. In this study, we classified four telomere maintenance mechanisms into telomerase, ALT, telomerase + ALT, and non-defined telomere maintenance mechanism (NDTMM) across 31 cancer types using 10,704 transcriptomic datasets from The Cancer Genome Atlas. Our results demonstrated that approximately 50% of the total cohort displayed ALT activity with high telomerase activity in most cancer types. We confirmed significant patient prognoses according to distinct TMMs in six cancer types: adrenocortical carcinoma (ACC), PAAD, HNSC, SARC, GBM, and metastatic cancer. Patients with metastasis had a poor prognosis in the ALT group (p < 0.006) subjected to RAS protein signal transduction. Glioblastoma patients had poor prognosis in NDTMM (p < 0.0043) and showed high levels of myeloid leukocyte activation. Pancreatic adenocarcinoma (p < 0.04) and head and neck squamous cell carcinoma (p < 0.046) patients had a good prognosis in the ALT group with high immune cell activation. Furthermore, we showed that master transcriptional regulators might affect the selection of the TMM pathway and explained why different telomere maintenance mechanisms exist. Furthermore, they can be used to segregate patients and predict responders to different TMM-targeted therapeutics.

RevDate: 2021-10-23

Gruber HJ, Semeraro MD, Renner W, et al (2021)

Telomeres and Age-Related Diseases.

Biomedicines, 9(10): pii:biomedicines9101335.

Telomeres are at the non-coding ends of linear chromosomes. Through a complex 3-dimensional structure, they protect the coding DNA and ensure appropriate separation of chromosomes. Aging is characterized by a progressive shortening of telomeres, which compromises their structure and function. Because of their protective function for genomic DNA, telomeres appear to play an important role in the development and progression of many age-related diseases, such as cardiovascular disease (CVD), malignancies, dementia, and osteoporosis. Despite substantial evidence that links telomere length with these conditions, the nature of these observations remains insufficiently understood. Therefore, future studies should address the question of causality. Furthermore, analytical methods should be further improved with the aim to provide informative and comparable results. This review summarize the actual knowledge of telomere biology and the possible implications of telomere dysfunction for the development and progression of age-related diseases. Furthermore, we provide an overview of analytical techniques for the measurement of telomere length and telomerase activity.

RevDate: 2021-10-23

Forsyth RG, Krenács T, Athanasou N, et al (2021)

Cell Biology of Giant Cell Tumour of Bone: Crosstalk between m/wt Nucleosome H3.3, Telomeres and Osteoclastogenesis.

Cancers, 13(20): pii:cancers13205119.

Giant cell tumour of bone (GCTB) is a rare and intriguing primary bone neoplasm. Worrisome clinical features are its local destructive behaviour, its high tendency to recur after surgical therapy and its ability to create so-called benign lung metastases (lung 'plugs'). GCTB displays a complex and difficult-to-understand cell biological behaviour because of its heterogenous morphology. Recently, a driver mutation in histone H3.3 was found. This mutation is highly conserved in GCTB but can also be detected in glioblastoma. Denosumab was recently introduced as an extra option of medical treatment next to traditional surgical and in rare cases, radiotherapy. Despite these new insights, many 'old' questions about the key features of GCTB remain unanswered, such as the presence of telomeric associations (TAs), the reactivation of hTERT, and its slight genomic instability. This review summarises the recent relevant literature of histone H3.3 in relation to the GCTB-specific G34W mutation and pays specific attention to the G34W mutation in relation to the development of TAs, genomic instability, and the characteristic morphology of GCTB. As pieces of an etiogenetic puzzle, this review tries fitting all these molecular features and the unique H3.3 G34W mutation together in GCTB.

RevDate: 2021-10-23

Hecker M, Bühring J, Fitzner B, et al (2021)

Genetic, Environmental and Lifestyle Determinants of Accelerated Telomere Attrition as Contributors to Risk and Severity of Multiple Sclerosis.

Biomolecules, 11(10): pii:biom11101510.

Telomeres are protective structures at the ends of linear chromosomes. Shortened telomere lengths (TL) are an indicator of premature biological aging and have been associated with a wide spectrum of disorders, including multiple sclerosis (MS). MS is a chronic inflammatory, demyelinating and neurodegenerative disease of the central nervous system. The exact cause of MS is still unclear. Here, we provide an overview of genetic, environmental and lifestyle factors that have been described to influence TL and to contribute to susceptibility to MS and possibly disease severity. We show that several early-life factors are linked to both reduced TL and higher risk of MS, e.g., adolescent obesity, lack of physical activity, smoking and vitamin D deficiency. This suggests that the mechanisms underlying the disease are connected to cellular aging and senescence promoted by increased inflammation and oxidative stress. Additional prospective research is needed to clearly define the extent to which lifestyle changes can slow down disease progression and prevent accelerated telomere loss in individual patients. It is also important to further elucidate the interactions between shared determinants of TL and MS. In future, cell type-specific studies and advanced TL measurement methods could help to better understand how telomeres may be causally involved in disease processes and to uncover novel opportunities for improved biomarkers and therapeutic interventions in MS.

RevDate: 2021-10-23

Badmus KA, Idrus Z, Meng GY, et al (2021)

Telomere Length and Regulatory Genes as Novel Stress Biomarkers and Their Diversities in Broiler Chickens (Gallus gallus domesticus) Subjected to Corticosterone Feeding.

Animals : an open access journal from MDPI, 11(10): pii:ani11102759.

This study was designed to characterize telomere length and its regulatory genes and to evaluate their potential as well-being biomarkers. Chickens were fed a diet containing corticosterone (CORT) for 4 weeks and performances, organ weight, plasma CORT levels, telomere lengths and regulatory genes were measured and recorded. Body weights of CORT-fed chickens were significantly suppressed (p < 0.05), and organ weights and circulating CORT plasma levels (p < 0.05) were altered. Interaction effect of CORT and duration was significant (p < 0.05) on heart and liver telomere length. CORT significantly (p < 0.05) shortened the telomere length of the whole blood, muscle, liver and heart. The TRF1, chTERT, TELO2 and HSF1 were significantly (p < 0.05) upregulated in the liver and heart at week 4 although these genes and TERRA were downregulated in the muscles at weeks 2 and 4. Therefore, telomere lengths and their regulators are associated and diverse, so they can be used as novel biomarkers of stress in broiler chickens fed with CORT.

RevDate: 2021-10-23

Fernández de la Puente M, Hernández-Alonso P, Canudas S, et al (2021)

Modulation of Telomere Length by Mediterranean Diet, Caloric Restriction, and Exercise: Results from PREDIMED-Plus Study.

Antioxidants (Basel, Switzerland), 10(10): pii:antiox10101596.

Telomere length (TL) has been associated with aging and is determined by lifestyle. However, the mechanisms by which a dietary pattern such as the Mediterranean diet (MedDiet) affects TL homeostasis are still unknown. Our aim was to analyse the effect of an energy-restricted MedDiet with physical activity promotion (intervention group) versus an unrestricted-caloric MedDiet with no weight-loss advice (control group) on TL and 8-hydroxydeoxyguanosine (8-OHdG) plasma levels. In total, 80 non-diabetic participants with metabolic syndrome were randomly selected from the PREDIMED (PREvención con DIeta MEDiterránea)-Plus-Reus study. TL was measured by a hybridisation method and 8-OHdG levels by ELISA at baseline and after one year of intervention. Linear mixed models (LMM)-raw and after adjusting for potential confounders-were used to examine the associations between TL or 8-OHdG plasma levels by intervention group and/or time. A total of 69 subjects with available DNA samples were included in the analyses. A significant β-coefficient was found for time towards increasing values through the year of follow-up for TL (unadjusted β of 0.740 (95% CI: 0.529 to 0.951), and multivariable model β of 0.700 (95% CI: 0.477 to 0.922)). No significant βs were found, neither for the intervention group nor for the interaction between the intervention group and time. Regarding 8-OHdG plasma levels, no significant βs were found for the intervention group, time, and its interaction. Our results suggest that MedDiet could have an important role in preventing telomere shortening, but calorie restriction and exercise promotion did not provide an additional advantage concerning telomere length after one year of MedDiet intervention.

RevDate: 2021-10-23

Yang J, Xu H, Cai B, et al (2021)

Genetically Predicted Longer Telomere Length May Reduce Risk of Hip Osteoarthritis.

Frontiers in genetics, 12:718890.

Objective: This two-sample Mendelian randomization (MR) study aimed to examine the potential causal association of telomere length (TL) with the risk of osteoarthritis (OA). Method: The summary-level data for OA was derived from the United Kingdom Biobank cohort, including 50,508 individuals of European descent. Eighteen single nucleotide polymorphisms associated with TL were identified as instrumental variables from the most up-to-date TL genome-wide association study (GWAS) involving over 78,592 individuals of European descent. Based on the GWASs data, MR was performed using established statistical analysis methods including the inverse variance weighted, weighted median, MR-Egger, and MR pleiotropy residual sum and outlier. Results: Genetically determined TL was not associated with the risk of total OA (IVW odds ratio [OR] = 1.00, 95% confidence interval [CI] = 0.83, 1.21). In subgroup analyses stratified by OA site, no evidence in favor of association between genetically determined TL and knee OA was found (IVW OR = 1.18, 95% CI = 0.89, 1.58). However, using WM method, we observed a limited protective effect of longer TL on the risk of hip OA (OR = 0.60, 95% CI = 0.36-0.99), whereas the results of the IVW (p = 0.931) and MR-PRESSO (p = 0.932) showed that TL had no effect on hip OA. Conclusions: This study does not support a causal association between TL and total OA. A potential protective association between longer TL and hip OA, though possible, remains less certain.

RevDate: 2021-10-20

Navarro PA, Wang F, Pimentel R, et al (2021)

Zidovudine inhibits telomere elongation, increases the transposable element LINE-1 copy number and compromises mouse embryo development.

Molecular biology reports [Epub ahead of print].

PURPOSE: Millions of pregnant, HIV-infected women take reverse transcriptase inhibitors, such as zidovudine (azidothymidine or AZT), during pregnancy. Reverse transcription plays important roles in early development, including regulation of telomere length (TL) and activity of transposable elements (TE). So we evaluated the effects of AZT on embryo development, TL, and copy number of an active TE, Long Interspersed Nuclear Element 1 (LINE-1), during early development in a murine model.

DESIGN: Experimental study.

METHODS: In vivo fertilized mouse zygotes from B6C3F1/B6D2F1 mice were cultured for 48 h in KSOM with no AZT (n = 45), AZT 1 μM (n = 46) or AZT 10 μM (n = 48). TL was measured by single-cell quantitative PCR (SC-pqPCR) and LINE-1 copy number by qPCR. The percentage of morulas at 48 h, TL and LINE-1 copy number were compared among groups.

RESULTS: Exposure to AZT 1 μM or 10 μM significantly impairs early embryo development. TL elongates from oocyte to control embryos. TL in AZT 1 μM embryos is shorter than in control embryos. LINE-1 copy number is significantly lower in oocytes than control embryos. AZT 1 μM increases LINE-1 copy number compared to oocytes controls, and AZT 10 μM embryos.

CONCLUSION: AZT at concentrations approaching those used to prevent perinatal HIV transmission compromises mouse embryo development, prevents telomere elongation and increases LINE-1 copy number after 48 h treatment. The impact of these effects on the trajectory of aging of children exposed to AZT early during development deserves further investigation.

RevDate: 2021-10-19

Brown AM, Wood EM, Capilla-Lasheras P, et al (2021)

Longitudinal evidence that older parents produce offspring with longer telomeres in a wild social bird.

Biology letters, 17(10):20210409.

As telomere length (TL) often predicts survival and lifespan, there is considerable interest in the origins of inter-individual variation in TL. Cross-generational effects of parental age on offspring TL are thought to be a key source of variation, but the rarity of longitudinal studies that examine the telomeres of successive offspring born throughout the lives of parents leaves such effects poorly understood. Here, we exploit TL measures of successive offspring produced throughout the long breeding tenures of parents in wild white-browed sparrow weaver (Plocepasser mahali) societies, to isolate the effects of within-parent changes in age on offspring TLs. Our analyses reveal the first evidence to date of a positive within-parent effect of advancing age on offspring TL: as individual parents age, they produce offspring with longer telomeres (a modest effect that persists into offspring adulthood). We consider the potential for pre- and post-natal mechanisms to explain our findings. As telomere attrition predicts offspring survival to adulthood in this species, this positive parental age effect could impact parent and offspring fitness if it arose via differential telomere attrition during offspring development. Our findings support the view that cross-generational effects of parental age can be a source of inter-individual variation in TL.

RevDate: 2021-10-18

Gorenjak V, Petrelis AM, Stathopoulou MG, et al (2021)

A genetic determinant of VEGF-A levels is associated with telomere attrition.

Aging, 13(undefined): pii:203636 [Epub ahead of print].

Telomere length (TL) is a hallmark of cellular aging and is associated with chronic diseases development. The vascular endothelial growth factor A (VEGF-A), a potent angiogenesis factor, is implicated in the pathophysiology of many chronic diseases. The aim of the present study was to investigate the associations between VEGF-A and TL. TL in leukocytes (LTL) and skeletal muscle (MTL) were measured, 10 VEGF-related polymorphisms genotyped, and VEGF-A plasma concentrations determined in 402 individuals from the TELARTA cohort. LTL/MTL ratio was calculated as an estimate of lifelong TL attrition. Associations between VEGF-A variants and levels, and TL parameters were investigated. We identified one significant association between the minor allele (T) of rs6993770 variant and LTL/MTL ratio (P=0.001143, β=0.0148, SE=0.004516). The rs6993770 is an intronic variant of the ZFPM2 gene, which is involved in haematopoiesis and the identified association with increased telomere attrition could be due to increased haematopoiesis. No significant epistatic interaction was identified, and no association was found between levels of VEGF-A and any of assessed phenotypes. We identified a potential common genetic regulation between VEGF-A and telomere length attrition that could be explained by mechanisms of increased hematopoiesis and production of platelets. VEGF-A and TL could play an important role in personalized medicine of chronic diseases and identification of molecular links between them can promote the understanding of their complex implications.

RevDate: 2021-10-19

Chakravarti D, RA DePinho (2021)

Telomere Dysfunction as an Initiator of Inflammation: Clues to an Age-Old Mystery.

Journal of inflammatory bowel diseases & disorders, 6(2):.

Inflammatory Bowel Disease (IBD) is a challenging medical condition that is driven by various genetic and environmental factors. Therapeutic opportunities for this disease remain limited due to the lack of in-depth understanding of the pathogenetic mechanisms and actionable targets driving the disease. Analysis of telomere dysfunctional mice and patients with genetic defects in telomere maintenance unexpectedly revealed phenotypes mirroring those observed in IBD. Molecular characterization of this model identified a pathway driven by telomere DNA damage-mediated activation of the ATM/cABL/YAP1 pathway, which directly regulates genes central to IBD pathogenesis and amenable to therapeutic intervention. This review summarizes the evidence correlating telomere dysfunction with IBD and colitis-associated cancer and proposes therapeutic opportunities for such inflammatory conditions targeting this newly identified pathway.

RevDate: 2021-10-19

Luttermann T, Rückert C, Wibberg D, et al (2021)

Establishment of a near-contiguous genome sequence of the citric acid producing yeast Yarrowia lipolytica DSM 3286 with resolution of rDNA clusters and telomeres.

NAR genomics and bioinformatics, 3(4):lqab085 pii:lqab085.

Yarrowia lipolytica is an oleaginous yeast that is particularly suitable for the sustainable production of secondary metabolites. The genome of this yeast is characterized by its relatively large size and its high number of different rDNA clusters located in its telomeric regions. However, due to the presence of long repetitive elements in the sub-telomeric regions, rDNA clusters and telomeres are missing in current genome assemblies of Y. lipolytica. Here, we present the near-contiguous genome sequence of the biotechnologically relevant strain DSM 3286. We employed a hybrid assembly strategy combining Illumina and nanopore sequencing reads to integrate all six rDNA clusters as well as telomeric repeats into the genome sequence. By fine-tuning of DNA isolation and library preparation protocols, we were able to create ultra-long reads that not only contained multiples of mitochondrial genomes but also shed light on the inter- and intra-chromosomal diversity of rDNA cluster types. We show that there are ten different rDNA units present in this strain that additionally appear in a predefined order in a cluster. Based on single reads, we also demonstrate that the number of rDNA repeats in a specific cluster varies from cell to cell within a population.

RevDate: 2021-10-18

Barakate A, Arrieta M, Macaulay M, et al (2021)

Downregulation of Barley Regulator of Telomere Elongation Helicase 1 Alters the Distribution of Meiotic Crossovers.

Frontiers in plant science, 12:745070.

Programmed meiotic DNA double-strand breaks (DSBs), necessary for proper chromosomal segregation and viable gamete formation, are repaired by homologous recombination (HR) as crossovers (COs) or non-crossovers (NCOs). The mechanisms regulating the number and distribution of COs are still poorly understood. The regulator of telomere elongation helicase 1 (RTEL1) DNA helicase was previously shown to enforce the number of meiotic COs in Caenorhabditis elegans but its function in plants has been studied only in the vegetative phase. Here, we characterised barley RTEL1 gene structure and expression using RNA-seq data previously obtained from vegetative and reproductive organs and tissues. Using RNAi, we downregulated RTEL1 expression specifically in reproductive tissues and analysed its impact on recombination using a barley 50k iSelect SNP Array. Unlike in C. elegans, in a population segregating for RTEL1 downregulated by RNAi, high resolution genome-wide genetic analysis revealed a significant increase of COs at distal chromosomal regions of barley without a change in their total number. Our data reveal the important role of RTEL1 helicase in plant meiosis and control of recombination.

RevDate: 2021-10-17

Ingold N, Dusingize JC, Neale RE, et al (2021)

Examining Evidence For A Causal Association Between Telomere Length & Nevus Count.

The Journal of investigative dermatology pii:S0022-202X(21)02332-0 [Epub ahead of print].

RevDate: 2021-10-15

Fu J, Ji X, Liu J, et al (2021)

Meta-analysis of the Connection Between Alzheimer Disease and Telomeres.

Alzheimer disease and associated disorders pii:00002093-900000000-99214 [Epub ahead of print].

BACKGROUND: Alzheimer disease (AD) is the most common neurodegenerative disease of the central nervous system. The stability of the telomere-telomerase system is closely related to AD. A previous meta-analysis indicated that AD patients had shorter telomere length (TL) than control subjects. However, there are no consistent telomerase activity findings in AD patients, and the published telomerase studies were not meta-analyzed yet.

METHODS: We searched all the related studies that probed into TL and/or telomerase activity in AD patients based on PubMed and Embase database from the establishment to September 2020. The Chinese National Knowledge Infrastructure, Wanfang and China Science and Technology Journal Database were also utilized. The quality of the included studies was evaluated by using Newcastle-Ottawa Scale. All the statistical analyses of this meta-analysis were performed using Stata version 15.0.

RESULTS: Analyzing 30 TL data from 2248 AD patients and 4865 controls, AD patients had a significantly shorter TL than the controls, with a standardized mean difference of -0.70 (confidence interval: -0.95 to -0.46; P<0.05). The meta-analysis included 3 primary studies and did not find a significant difference in the telomerase activity between 233 AD patients and 132 controls, but AD patients had a trend of increased telomerase activity compared with controls (standardized mean difference: 0.47; confidence interval: -0.29 to 1.23; P>0.05).

CONCLUSION: Our results showed that compared with the control group, the AD group had a shorter TL and may have higher telomerase activity.

RevDate: 2021-10-14

Criscuolo F, Dobson FS, Q Schull (2021)

The influence of phylogeny and life history on telomere lengths and telomere rate of change among bird species: A meta-analysis.

Ecology and evolution, 11(19):12908-12922 pii:ECE37931.

Longevity is highly variable among animal species and has coevolved with other life-history traits, such as body size and rates of reproduction. Telomeres, through their erosion over time, are one of the cell mechanisms that produce senescence at the cell level and might even have an influence on the rate of aging in whole organisms. However, uneroded telomeres are also risk factors of cell immortalization. The associations of telomere lengths, their rate of change, and life-history traits independent of body size are largely underexplored for birds. To test associations of life-history traits and telomere dynamics, we conducted a phylogenetic meta-analysis using studies of 53 species of birds. We restricted analyses to studies that applied the telomere restriction fragment length (TRF) method, and examined relationships between mean telomere length at the chick (Chick TL) and adult (Adult TL) stages, the mean rate of change in telomere length during life (TROC), and life-history traits. We examined 3 principal components of 12 life-history variables that represented: body size (PC1), the slow-fast continuum of pace of life (PC2), and postfledging parental care (PC3). Phylogeny had at best a small-to-medium influence on Adult and Chick TL (r 2 = .190 and .138, respectively), but a substantial influence on TROC (r 2 = .688). Phylogeny strongly influenced life histories: PC1 (r 2 = .828), PC2 (.838), and PC3 (.613). Adult TL and Chick TL were poorly associated with the life-history variables. TROC, however, was negatively and moderate-to-strongly associated with PC2 (unadjusted r = -.340; with phylogenetic correction, r = -.490). Independent of body size, long-lived species with smaller clutches, and slower embryonic rate of growth may exhibit less change in telomere length over their lifetimes. We suggest that telomere lengths may have diverged, even among closely avian-related species, yet telomere dynamics are strongly linked to the pace of life.

RevDate: 2021-10-13

Monteagudo M, Martínez P, Leandro-García LJ, et al (2021)

Analysis of Telomere Maintenance Related Genes Reveals NOP10 as a New Metastatic-Risk Marker in Pheochromocytoma/Paraganglioma.

Cancers, 13(19): pii:cancers13194758.

One of the main problems we face with PPGL is the lack of molecular markers capable of predicting the development of metastases in patients. Telomere-related genes, such as TERT and ATRX, have been recently described in PPGL, supporting the association between the activation of immortalization mechanisms and disease progression. However, the contribution of other genes involving telomere preservation machinery has not been previously investigated. In this work, we aimed to analyze the prognostic value of a comprehensive set of genes involved in telomere maintenance. For this study, we collected 165 PPGL samples (97 non-metastatic/63 metastatic), genetically characterized, in which the expression of 29 genes of interest was studied by NGS. Three of the 29 genes studied, TERT, ATRX and NOP10, showed differential expression between metastatic and non-metastatic cases, and alterations in these genes were associated with a shorter time to progression, independent of SDHB-status. We studied telomere length by Q-FISH in patient samples and in an in vitro model. NOP10 overexpressing tumors displayed an intermediate-length telomere phenotype without ALT, and in vitro results suggest that NOP10 has a role in telomerase-dependent telomere maintenance. We also propose the implementation of NOP10 IHC to better stratify PPGL patients.

RevDate: 2021-10-12

Velando A, Noguera JC, Aira M, et al (2021)

Gut microbiome and telomere length in gull hatchlings.

Biology letters, 17(10):20210398.

In many animals, recent evidence indicates that the gut microbiome may be acquired during early development, with possible consequences on newborns' health. Thus, it has been hypothesized that a healthy microbiome protects telomeres and genomic integrity against cellular stress. However, the link between the early acquired microbiome and telomere dynamics has not hitherto been investigated. In birds, this link may also be potentially modulated by the transfer of maternal glucocorticoids, since these substances dysregulate microbiome composition during postnatal development. Here, we examined the effect of the interplay between the microbiome and stress hormones on the telomere length of yellow-legged gull hatchlings by using a field experiment in which we manipulated the corticosterone content in eggs. We found that the hatchling telomere length was related to microbiome composition, but this relationship was not affected by the corticosterone treatment. Hatchlings with a microbiome dominated by potential commensal bacteria (i.e. Catellicoccus and Cetobacterium) had larger telomeres, suggesting that an early establishment of the species-specific microbiome during development may have important consequences on offspring health and survival.

RevDate: 2021-10-12

Stainczyk SA, F Westermann (2021)

Neuroblastoma - telomere maintenance, deregulated signalling transduction and beyond.

International journal of cancer [Epub ahead of print].

The childhood malignancy neuroblastoma belongs to the group of embryonal tumours and originates from progenitor cells of the sympathoadrenal lineage. Treatment options for children with high-risk and relapsed disease are still very limited. In recent years, an ever-growing molecular diversity was identified using (epi)-genetic profiling of neuroblastoma tumours, indicating that molecularly targeted therapies could be a promising therapeutic option. In this review article, we summarize the various molecular subtypes and genetic events associated with neuroblastoma and describe recent advances in targeted therapies. We lay a strong emphasis on the importance of telomere maintenance mechanisms for understanding tumour progression and risk classification of neuroblastoma. This article is protected by copyright. All rights reserved.

RevDate: 2021-10-11

van Batenburg AA, van Oosterhout MFM, Knoppert SN, et al (2021)

The Extent of Inflammatory Cell Infiltrate and Fibrosis in Lungs of Telomere- and Surfactant-Related Familial Pulmonary Fibrosis.

Frontiers in medicine, 8:736485.

Familial pulmonary fibrosis (FPF) is a monogenic disease most commonly involving telomere- (TERT) or surfactant- (SFTP) related mutations. These mutations have been shown to alter lymphocytic inflammatory responses, and FPF biopsies with histological lymphocytic infiltrates have been reported. Recently, a model of a surfactant mutation in mice showed that the disease initially started with an inflammatory response followed by fibrogenesis. Since inflammation and fibrogenesis are targeted by different drugs, we investigated whether the degree of these two features co-localize or occur independently in different entities of FPF, and whether they influence survival. We quantified the number of lymphocyte aggregates per surface area, the extent of diffuse lymphocyte cell infiltrate, the number of fibroblast foci per surface area, and the percentage of fibrotic lung surface area in digitally scanned hematoxylin and eosin (H&E) sections of diagnostic surgical biopsies of patients with TERT-related FPF (TERT-PF; n = 17), SFTP-related FPF (SFTP-PF; n = 7), and sporadic idiopathic pulmonary fibrosis (sIPF; n = 10). For comparison, we included biopsies of patients with cellular non-specific interstitial pneumonia (cNSIP; n = 10), an inflammatory interstitial lung disease with high lymphocyte influx and usually responsive to immunosuppressive therapy. The degree of inflammatory cell infiltrate and fibrosis in TERT-PF and SFTP-PF was not significantly different from that in sIPF. In comparison with cNSIP, the extent of lymphocyte infiltrates was significantly lower in sIPF and TERT-PF, but not in SFTP-PF. However, in contrast with cNSIP, in sIPF, TERT-PF, and SFTP-PF, diffuse lymphocyte cell infiltrates were predominantly present and lymphocyte aggregates were only present in fibrotic areas (p < 0.0001). Furthermore, fibroblast foci and percentage of fibrotic lung surface were associated with survival (p = 0.022 and p = 0.018, respectively), while this association was not observed for lymphocyte aggregates or diffuse lymphocytic infiltration. Inflammatory cells in diagnostic lung biopsies of TERT-PF, SFTP-PF, and sIPF were largely confined to fibrotic areas. However, based on inflammation and fibrosis, no differences were found between FPF and sIPF, substantiating the histological similarities between monogenic familial and sporadic disease. Furthermore, the degree of fibrosis, rather than inflammation, correlates with survival, supporting that fibrogenesis is the key feature for therapeutic targeting of FPF.

RevDate: 2021-10-11

Buddhachat K, Brown JL, Kaewkool M, et al (2021)

Life Expectancy in Marine Mammals Is Unrelated to Telomere Length but Is Associated With Body Size.

Frontiers in genetics, 12:737860.

Marine mammals vary greatly in size and lifespan across species. This study determined whether measures of adult body weight, length and relative telomere length were related to lifespan. Skin tissue samples (n = 338) were obtained from 23 marine mammal species, including four Mysticeti, 19 Odontoceti and one dugong species, and the DNA extracted to measure relative telomere length using real-time PCR. Life span, adult body weight, and adult body length of each species were retrieved from existing databases. The phylogenetic signal analysis revealed that body length might be a significant factor for shaping evolutionary processes of cetacean species through time, especially for genus Balaenoptera that have an enormous size. Further, our study found correlations between lifespan and adult body weight (R 2 = 0.6465, p < 0.001) and adult body length (R 2 = 0.6142, p ≤0.001), but no correlations with relative telomere length (R 2 = -0.0476, p = 0.9826). While data support our hypothesis that larger marine mammals live longer, relative telomere length is not a good predictor of species longevity.

RevDate: 2021-10-10

Lin YF, Chen PY, Liu HC, et al (2021)

Shortened leukocyte telomere length in young adults who use methamphetamine.

Translational psychiatry, 11(1):519.

Methamphetamine (METH) use, most prevalent in young adults, has been associated with high rates of morbidity and mortality. The relationship between METH use and accelerated biological aging, which can be measured using leukocyte telomere length (LTL), remains unclear. We examined whether young adult METH users have shorter LTL and explored the relationship between characteristics of METH use and LTL by using Mendelian randomization (MR) analysis. We compared the LTL for 187 METH users and 159 healthy individuals aged between 25 and 34 years and examined the relationship of LTL with METH use variables (onset age, duration, and maximum frequency of METH use) by using regression analyses. In addition, 2-stage-least-squares (2SLS) MR was also performed to possibly avoid uncontrolled confounding between characteristics of METH use and LTL. We found METH users had significantly shorter LTL compared to controls. Multivariate regression analysis showed METH use was negatively associated with LTL (β = -0.36, P < .001). Among METH users, duration of METH use was negatively associated with LTL after adjustment (β = -0.002, P = .01). We identified a single nucleotide polymorphism (SNP) rs6585206 genome-wide associated with duration of METH use. This SNP was used as an instrumental variable to avoid uncontrolled confounding for the relationship between the use duration and LTL shortening. In conclusion, we show that young adult METH users may have shorter LTL compared with controls and longer duration of METH use was significantly associated with telomere shortening. These observations suggest that METH use may accelerate biological senescence.

RevDate: 2021-10-10

Martin H, Doumic M, Teixeira MT, et al (2021)

Telomere shortening causes distinct cell division regimes during replicative senescence in Saccharomyces cerevisiae.

Cell & bioscience, 11(1):180.

BACKGROUND: Telomerase-negative cells have limited proliferation potential. In these cells, telomeres shorten until they reach a critical length and induce a permanently arrested state. This process called replicative senescence is associated with genomic instability and participates in tissue and organismal ageing. Experimental data using single-cell approaches in the budding yeast model organism show that telomerase-negative cells often experience abnormally long cell cycles, which can be followed by cell cycles of normal duration, before reaching the terminal senescent state. These series of non-terminal cell cycle arrests contribute to the heterogeneity of senescence and likely magnify its genomic instability. Due to their apparent stochastic nature, investigating the dynamics and the molecular origins of these arrests has been difficult. In particular, whether the non-terminal arrests series stem from a mechanism similar to the one that triggers terminal senescence is not known.

RESULTS: Here, we provide a mathematical description of sequences of non-terminal arrests to understand how they appear. We take advantage of an experimental data set of cell cycle duration measurements performed in individual telomerase-negative yeast cells that keep track of the number of generations since telomerase inactivation. Using numerical simulations, we show that the occurrence of non-terminal arrests is a generation-dependent process that can be explained by the shortest telomere reaching a probabilistic threshold length. While the onset of senescence is also triggered by telomere shortening, we highlight differences in the laws that describe the number of consecutive arrests in non-terminal arrests compared to senescence arrests, suggesting distinct underlying mechanisms and cellular states.

CONCLUSIONS: Replicative senescence is a complex process that affects cell divisions earlier than anticipated, as exemplified by the frequent occurrence of non-terminal arrests early after telomerase inactivation. The present work unravels two kinetically and mechanistically distinct generation-dependent processes underlying non-terminal and terminal senescence arrests. We suggest that these two processes are responsible for two consequences of senescence at the population level, the increase of genome instability on the one hand, and the limitation of proliferation capacity on the other hand.

RevDate: 2021-10-10

Ide S, Sasaki A, Kawamoto Y, et al (2021)

Telomere-specific chromatin capture using a pyrrole-imidazole polyamide probe for the identification of proteins and non-coding RNAs.

Epigenetics & chromatin, 14(1):46.

BACKGROUND: Knowing chromatin components at a DNA regulatory element at any given time is essential for understanding how the element works during cellular proliferation, differentiation and development. A region-specific chromatin purification is an invaluable approach to dissecting the comprehensive chromatin composition at a particular region. Several methods (e.g., PICh, enChIP, CAPTURE and CLASP) have been developed for isolating and analyzing chromatin components. However, all of them have some shortcomings in identifying non-coding RNA associated with DNA regulatory elements.

RESULTS: We have developed a new approach for affinity purification of specific chromatin segments employing an N-methyl pyrrole (P)-N-methylimidazole (I) (PI) polyamide probe, which binds to a specific sequence in double-stranded DNA via Watson-Crick base pairing as a minor groove binder. This new technique is called proteomics and RNA-omics of isolated chromatin segments (PI-PRICh). Using PI-PRICh to isolate mouse and human telomeric components, we found enrichments of shelterin proteins, the well-known telomerase RNA component (TERC) and telomeric repeat-containing RNA (TERRA). When PI-PRICh was performed for alternative lengthening of telomere (ALT) cells with highly recombinogenic telomeres, in addition to the conventional telomeric chromatin, we obtained chromatin regions containing telomeric repeat insertions scattered in the genome and their associated RNAs.

CONCLUSION: PI-PRICh reproducibly identified both the protein and RNA components of telomeric chromatin when targeting telomere repeats. PI polyamide is a promising alternative to simultaneously isolate associated proteins and RNAs of sequence-specific chromatin regions under native conditions, allowing better understanding of chromatin organization and functions within the cell.

RevDate: 2021-10-08

Cavalcante SG, Pereira BJA, Lerario AM, et al (2021)

The chromatin remodeler complex ATRX-DAXX-H3.3 and telomere length in meningiomas.

Clinical neurology and neurosurgery, 210:106962 pii:S0303-8467(21)00491-1 [Epub ahead of print].

ATRX-DAXX-H3.3 chromatin remodeler complex is a well known epigenetic factor responsible for the heterochromatin maintenance and control. ATRX is an important nucleosome controller, especially in tandem repeat regions, and DAXX is a multi-function protein with particular role in histone H3.3 deposition due to its chaperone characteristic. Abnormalities in this complex have been associated with telomere dysfunction and consequently with activation of alternative lengthening of telomeres mechanism, genomic instability, and tumor progression in different types of cancer. However, the characterization of this complex is still incomplete in meningioma. We analyzed ATRX, DAXX and H3.3 expressions and the telomere length in a cohort of meningioma of different malignant grades. We observed ATRX upregulation at gene and protein levels in grade II/III meningiomas. A low variability of telomere length was observed in meningiomas across different ages and malignant grades, in contrast to the shortening of telomere length with aging in normal controls.

RevDate: 2021-10-08

Morgunova V, Kordyukova M, Mikhaleva EA, et al (2021)

Loss of telomere silencing is accompanied by dysfunction of Polo kinase and centrosomes during Drosophila oogenesis and early development.

PloS one, 16(10):e0258156 pii:PONE-D-21-23668.

Telomeres are nucleoprotein complexes that protect the ends of eukaryotic linear chromosomes from degradation and fusions. Telomere dysfunction leads to cell growth arrest, oncogenesis, and premature aging. Telomeric RNAs have been found in all studied species; however, their functions and biogenesis are not clearly understood. We studied the mechanisms of development disorders observed upon overexpression of telomeric repeats in Drosophila. In somatic cells, overexpression of telomeric retrotransposon HeT-A is cytotoxic and leads to the accumulation of HeT-A Gag near centrosomes. We found that RNA and RNA-binding protein Gag encoded by the telomeric retrotransposon HeT-A interact with Polo and Cdk1 mitotic kinases, which are conserved regulators of centrosome biogenesis and cell cycle. The depletion of proteins Spindle E, Ccr4 or Ars2 resulting in HeT-A overexpression in the germline was accompanied by mislocalization of Polo as well as its abnormal stabilization during oogenesis and severe deregulation of centrosome biogenesis leading to maternal-effect embryonic lethality. These data suggest a mechanistic link between telomeric HeT-A ribonucleoproteins and cell cycle regulators that ensures the cell response to telomere dysfunction.

RevDate: 2021-10-07

Wang F, Chamani IJ, Luo D, et al (2021)

Inhibition of LINE-1 retrotransposition represses telomere reprogramming during mouse 2-cell embryo development.

Journal of assisted reproduction and genetics [Epub ahead of print].

PURPOSE: To investigate whether inhibition of LINE-1 affects telomere reprogramming during 2-cell embryo development.

METHODS: Mouse zygotes were cultured with or without 1 µM azidothymidine (AZT) for up to 15 h (early 2-cell, G1/S) or 24 h (late 2-cell, S/G2). Gene expression and DNA copy number were determined by RT-qPCR and qPCR respectively. Immunostaining and telomeric PNA-FISH were performed for co-localization between telomeres and ZSCAN4 or LINE-1-Orf1p.

RESULTS: LINE-1 copy number was remarkably reduced in later 2-cell embryos by exposure to 1 µM AZT, and telomere lengths in late 2-cell embryos with AZT were significantly shorter compared to control embryos (P = 0.0002). Additionally, in the absence of LINE-1 inhibition, Dux, Zscan4, and LINE-1 were highly transcribed in early 2-cell embryos, as compared to late 2-cell embryos (P < 0.0001), suggesting that these 2-cell genes are activated at the early 2-cell stage. However, in early 2-cell embryos with AZT treatment, mRNA levels of Dux, Zscan4, and LINE-1 were significantly decreased. Furthermore, both Zscan4 and LINE-1 encoded proteins localized to telomere regions in 2-cell embryos, but this co-localization was dramatically reduced after AZT treatment (P < 0.001).

CONCLUSIONS: Upon inhibition of LINE-1 retrotransposition in mouse 2-cell embryos, Dux, Zscan4, and LINE-1 were significantly downregulated, and telomere elongation was blocked. ZSCAN4 foci and their co-localization with telomeres were also significantly decreased, indicating that ZSCAN4 is an essential component of the telomere reprogramming that occurs in mice at the 2-cell stage. Our findings also suggest that LINE-1 may directly contribute to telomere reprogramming in addition to regulating gene expression.

RevDate: 2021-10-07

Borie R, E Renzoni (2021)

Pulmonary fibrosis associated with telomere-related gene mutations: A complex inheritance.

RevDate: 2021-10-07

Tung KTS, Hung CMW, Chan KL, et al (2021)

Influence of Maternal Infection and Pregnancy Complications on Cord Blood Telomere Length.

Oxidative medicine and cellular longevity, 2021:3339456.

Background: Exposure to suboptimal intrauterine environment might induce structural and functional changes that can affect neonatal health. Telomere length as an important indicator of cellular health has been associated with increased risk for disease development.

Objectives: This study was aimed to examine the independent and combined effects of maternal, obstetric, and foetal factors on cord blood telomere length (TL).

Methods: Pregnant women at the gestational age of 20th to 24th week who attended the antenatal clinic of a major local hospital in Hong Kong were recruited. Participants were asked to complete a questionnaire on demographics, health-related quality of life, and history of risk behaviors. Medical history including pregnancy complications and neonatal outcomes was obtained from electronic medical records of both mother and neonate. Umbilical cord blood was collected at delivery for TL determination.

Results: A total of 753 pregnant women (average age: 32.18 ± 4.51 years) were recruited. The prevalence of maternal infection, anaemia, and hypertension during pregnancy was 30.8%, 30.0%, and 6.0%, respectively. The adjusted regression model displayed that maternal infection was negatively associated with cord blood TL (β = -0.18, p = 0.026). This association became even stronger in the presence of antenatal anaemia, hypertension, delivery complications, or neonatal jaundice (β = -0.25 to -0.45).

Conclusions: This study consolidates evidence on the impact of adverse intrauterine environment at the cellular level. Maternal infection was significantly associated with shorter cord blood TL in a unique manner such that its presence may critically determine the susceptibility of telomere to other factors.

RevDate: 2021-10-06

Codd V, Wang Q, Allara E, et al (2021)

Polygenic basis and biomedical consequences of telomere length variation.

Nature genetics, 53(10):1425-1433.

Telomeres, the end fragments of chromosomes, play key roles in cellular proliferation and senescence. Here we characterize the genetic architecture of naturally occurring variation in leukocyte telomere length (LTL) and identify causal links between LTL and biomedical phenotypes in 472,174 well-characterized UK Biobank participants. We identified 197 independent sentinel variants associated with LTL at 138 genomic loci (108 new). Genetically determined differences in LTL were associated with multiple biological traits, ranging from height to bone marrow function, as well as several diseases spanning neoplastic, vascular and inflammatory pathologies. Finally, we estimated that, at the age of 40 years, people with an LTL >1 s.d. shorter than the population mean had a 2.5-year-lower life expectancy compared with the group with ≥1 s.d. longer LDL. Overall, we furnish new insights into the genetic regulation of LTL, reveal wide-ranging influences of LTL on physiological traits, diseases and longevity, and provide a powerful resource available to the global research community.

RevDate: 2021-10-06

Zhao H, Shen J, Chang D, et al (2021)

Land use mix and leukocyte telomere length in Mexican Americans.

Scientific reports, 11(1):19742.

It has been well-known that built environment features influence the risk of chronic diseases. However, the existing data of its relationship with telomere length, a biomarker of biological aging, is still limited, with no study available for Mexican Americans. This study investigates the relationship between several factors of the built environment with leukocyte telomere length among 5508 Mexican American adults enrolled in Mano-A-Mano, the Mexican American Cohort Study (MACS). Based on the quartile levels of telomere length, the study population was categorized into four groups, from the lowest (1st quartile) to the highest telomere length group (4th quartile). For individual built environment factors, their levels did not differ significantly across four groups. However, in the multinominal logistic regression analysis, increased Rundle's land use mixture (LUM) and Frank's LUM were found statistically significantly associated with increased odds of having high levels of telomere length (Rundle's LUM: 2nd quartile: Odds ratio (OR) 1.26, 95% Confidence interval (CI) 1.07, 1.48; 3rd quartile: OR 1.25, 95% CI 1.06, 1.46; 4th quartile: OR 1.19, 95% CI 1.01, 1.41; Frank's LUM: 2nd quartile: OR 1.34, 95% CI 1.02, 2.63; 3rd quartile: OR 1.55, 95% CI 1.04, 2.91; 4th quartile: OR 1.36, 95% CI 1.05, 2.72, respectively). The associations for Rundle's LUM remained significant after further adjusting other non-redundant built environment factors. Finally, in stratified analysis, we found the association between Rundle's LUM and telomere length was more evident among younger individuals (< 38 years old), women, and those with obesity, born in Mexico, having low levels of physical activity, and having low levels of acculturation than their relative counterparts. In summary, our results indicate that land use mixture may impact telomere length in leukocytes in Mexican Americans.

RevDate: 2021-10-04

Barade A, Aboobacker F, Korula A, et al (2021)

Impact of donor telomere length on survival in patients undergoing matched sibling donor transplantation for aplastic anaemia.

British journal of haematology [Epub ahead of print].

Although telomere shortening is seen frequently in patients with aplastic anaemia (AA), there are no data on its association in matched sibling donor (MSD) transplants. We evaluated the effect of pre-transplant telomere length of patients and donors, measured by quantitative real-time polymerase chain reaction in 163 recipients undergoing MSD transplants. The median age of patients and donors was 24 and 26 years, respectively. Fludarabine and cyclophosphamide was the main conditioning regimen used and all received peripheral blood stem cell grafts. Engraftment occurred in 89% with graft failure (primary and secondary) in 6%. Acute and chronic graft-versus-host disease (GVHD) occurred in 28% and 24%, respectively. At a median follow-up of 37 months, 117 patients (72%) were alive. All patients and donors were divided into short and long telomere length based on their median and quartile values. Patient telomere length was not associated with severity of AA, neutrophil recovery, graft failure, acute GVHD or chronic GVHD. Longer donor telomere length was associated with better overall survival [hazard ratio (HR) = 0·2, P = 0·006] but did not influence neutrophil recovery, graft failure, acute or chronic GVHD. The five-year overall survival was significantly better (94·9 ± 3·5% vs 65·4 ± 4·3%, P = 0·002) for donors with long (highest quartile, DTL-HQ) versus short (lower three quartiles, DTL-LQ) telomeres, respectively. On multivariate analysis, longer donor telomere length, recipient age and acute GVHD continued to remain significant. This is the first study demonstrating an association of donor telomere length on overall survival following MSD transplant for AA but it needs to be confirmed in larger studies.

RevDate: 2021-10-04

Jeon HJ, JS Oh (2021)

TRF1 Depletion Reveals Mutual Regulation Between Telomeres, Kinetochores, and Inner Centromeres in Mouse Oocytes.

Frontiers in cell and developmental biology, 9:749116.

In eukaryotic chromosomes, the centromere and telomere are two specialized structures that are essential for chromosome stability and segregation. Although centromeres and telomeres often are located in close proximity to form telocentric chromosomes in mice, it remained unclear whether these two structures influence each other. Here we show that TRF1 is required for inner centromere and kinetochore assembly in addition to its role in telomere protection in mouse oocytes. TRF1 depletion caused premature chromosome segregation by abrogating the spindle assembly checkpoint (SAC) and impairing kinetochore-microtubule (kMT) attachment, which increased the incidence of aneuploidy. Notably, TRF1 depletion disturbed the localization of Survivin and Ndc80/Hec1 at inner centromeres and kinetochores, respectively. Moreover, SMC3 and SMC4 levels significantly decreased after TRF1 depletion, suggesting that TRF1 is involved in chromosome cohesion and condensation. Importantly, inhibition of inner centromere or kinetochore function led to a significant decrease in TRF1 level and telomere shortening. Therefore, our results suggest that telomere integrity is required to preserve inner centromere and kinetochore architectures, and vice versa, suggesting mutual regulation between telomeres and centromeres.

RevDate: 2021-10-04

Hao L, Chen Q, Chen X, et al (2021)

Association of Serum Total Bilirubin Concentration with Telomere Length: The National Health and Nutrition Examination Survey.

Oxidative medicine and cellular longevity, 2021:4688900.

Introduction: Mildly increased bilirubin concentration has a protective effect on oxidative stress-related diseases. However, it remains unknown whether elevated circulating bilirubin is associated with longer telomere length. The aim of this cross-sectional study was to examine the association between total bilirubin concentration and telomere length.

Methods: We used the data from the National Health and Nutrition Examination Survey (NHANES) 1999-2002. The multivariable linear regression model was used to examine the association between total bilirubin concentration and telomere length. The nonlinear relationship was analyzed using a generalized additive model with the smoothing plot.

Results: A total of 7818 participants with a mean age of 49.20 ± 18.82 years were included. Compared with the lowest concentration of total bilirubin (Q1), the highest quartile of total bilirubin concentration was associated with longer telomere length in male (β = 0.04, 95 CI%: 0.00, 0.07, P = 0.024) and female (β = 0.04, 95 CI%: 0.02, 0.04, P = 0.002). Furthermore, an inverted U-shaped relationship between total bilirubin and telomere length was found. On the left of turning points (total bilirubin < 0.5 mg/dL), total bilirubin concentration was positively associated with telomere length (β = 0.23, 95 CI%: 0.14, 0.32, P < 0.001). However, the association between total bilirubin concentration and telomere length was not significant (β = 0.01, 95% CI: -0.01, 0.04, P = 0.346) above the turning point.

Conclusion: This is the first evidence based on a nationally representative survey demonstrating a positive and nonlinear association between total bilirubin concentration and telomere length. Future large-scale prospective studies are warranted to confirm our findings.

RevDate: 2021-10-04

Hastings WJ, Eisenberg DTA, I Shalev (2021)

Impact of Amplification Efficiency Approaches on Telomere Length Measurement via Quantitative-Polymerase Chain Reaction.

Frontiers in genetics, 12:728603.

Background: Precise determination of amplification efficiency is critical for reliable conversion of within-sample changes in fluorescence occurring on a logarithmic scale to between-sample differences in DNA content occurring on a linear scale. This endeavor is especially challenging for the telomere length (TL) quantitative-PCR (qPCR) assay, where amplification efficiency can vary between reactions targeting telomeric repeats (T) and those targeting a single-copy gene (S) to calculate TL as the T/S ratio. Methods: We compared seven different approaches toward estimating amplification efficiency, including the standard-curve method utilized by the qPCR instrument software, and alternative approaches which estimate efficiency on a reaction-by-reaction basis using the stand-alone program LinRegPCR. After calculating T/S ratios using efficiency estimates from each approach (N = 363), we tested their relative performance on metrics of assay precision and correlates of external validity including chronological age (age range = 1-72 years), across tissues within-person (leukocyte-buccal), and between parents and offspring. Results: Estimated amplification efficiency for telomere reactions was significantly lower than estimates for single-copy gene reactions. Efficiency estimates for both reaction sets were significantly higher when estimated with the standard-curve method utilized by the qPCR instrument relative to estimates reconstructed during the log-linear phase with LinRegPCR. While estimates of single-copy gene efficiency reconstructed using LinRegPCR measured within 90% of perfect exponential doubling (E = 1.92), estimates generated using the standard-curve method were inflated beyond 100% (E = 2.10-2.12), indicating poor fidelity. Despite differences in raw value, TL measurements calculated with LinRegPCR efficiency estimates exhibited similar relationships with external validity correlates to measurements generated using the qPCR instrument software. Conclusion: Since methods to estimate amplification efficiency can vary across qPCR instruments, we suggest that future analyses empirically consider external methods of efficiency calculations such as LinRegPCR, and that already generated data be re-analyzed to glean possible improvements.

RevDate: 2021-10-04

Bosquet Enlow M, Kane-Grade F, De Vivo I, et al (2021)

Corrigendum to "Patterns of change in telomere length over the first three years of life in healthy children" [Psychoneuroendocrinology 115 (2020) 104602].

RevDate: 2021-10-01

Zane L, Ensminger DC, JP Vázquez-Medina (2021)

Short-term elevations in glucocorticoids do not alter telomere lengths: A systematic review and meta-analysis of non-primate vertebrate studies.

PloS one, 16(10):e0257370 pii:PONE-D-21-13139.

BACKGROUND: The neuroendocrine stress response allows vertebrates to cope with stressors via the activation of the Hypothalamic-Pituitary-Adrenal (HPA) axis, which ultimately results in the secretion of glucocorticoids (GCs). Glucocorticoids have pleiotropic effects on behavior and physiology, and might influence telomere length dynamics. During a stress event, GCs mobilize energy towards survival mechanisms rather than to telomere maintenance. Additionally, reactive oxygen species produced in response to increased GC levels can damage telomeres, also leading to telomere shortening. In our systematic review and meta-analysis, we tested whether GC levels impact telomere length and if this relationship differs among time frame, life history stage, or stressor type. We hypothesized that elevated GC levels are linked to a decrease in telomere length.

METHODS: We conducted a literature search for studies investigating the relationship between telomere length and GCs in non-human vertebrates using four search engines: Web of Science, Google Scholar, Pubmed and Scopus, last searched on September 27th, 2020. This review identified 31 studies examining the relationship between GCs and telomere length. We pooled the data using Fisher's Z for 15 of these studies. All quantitative studies underwent a risk of bias assessment. This systematic review study was registered in the Open Science Framework Registry (

RESULTS: The pooled effect size from fifteen studies and 1066 study organisms shows no relationship between GCs and telomere length (Fisher's Z = 0.1042, 95% CI = 0.0235; 0.1836). Our meta-analysis synthesizes results from 15 different taxa from the mammalian, avian, amphibian groups. While these results support some previous findings, other studies have found a direct relationship between GCs and telomere dynamics, suggesting underlying mechanisms or concepts that were not taken into account in our analysis. The risk of bias assessment revealed an overall low risk of bias with occasional instances of bias from missing outcome data or bias in the reported result.

CONCLUSION: We highlight the need for more targeted experiments to understand how conditions, such as experimental timeframes, stressor(s), and stressor magnitudes can drive a relationship between the neuroendocrine stress response and telomere length.

RevDate: 2021-10-01

Gaydosh L, Mitchell C, Notterman D, et al (2021)

Demographic and developmental patterns in telomere length across adolescence.

Biodemography and social biology [Epub ahead of print].

Telomere length is often used in studies of adults as a biomarker of cellular aging and an indicator of stress exposure. However, we know little about how telomeres change over time, particularly over the course of the important developmental period of adolescence. We use data on telomere length collected at two points in time spanning adolescence (Years 9 and 15) from the Fragile Families and Child Wellbeing Study to examine longitudinal patterns (n = 1,654) in telomere length. We find a quantitatively small but significant average lengthening in telomere length across adolescence and little evidence of associations between telomere length and pubertal development.

RevDate: 2021-09-30

Peng Q, Zhou M, Zuo S, et al (2021)

Nuclear Factor Related to KappaB Binding Protein Is a Telomere-Associated Protein and Involved in Liver Cancer Development.

DNA and cell biology [Epub ahead of print].

Alternative lengthening of telomeres (ALT) is a homologous recombination-based telomere maintenance mechanism activated in 10-15% of human cancers. Although significant progress has been made, the key regulators of the ALT pathway and its role in cancer development remain elusive. Bioinformatics methods were used to predict novel telomere-associated proteins (TAPs) by analysis of large-scale ChIP-Seq data. Immunostaining and fluorescence in situ hybridization experiments were applied to detect the subcellular location of target genes and telomeres. Western blot and reverse transcription-polymerase chain reaction (RT-PCR) were used to examine the expression of targeting genes. Overall survival (OS) analyses were used to evaluate the relationship between gene expression and survival time; immunohistochemistry was used to detect the distribution of target genes in liver cancer tissues. We found that nuclear factor related to kappaB binding protein (NFRKB), a metazoan-specific subunit of the INO80 complex, can associate with telomeres in human ALT cells. Loss of NFRKB induces dysfunction of telomeres and less PML bodies in U2OS cells. In addition, NFRKB is low/moderately expressed in cytoplasm of normal hepatocytes but heavily accumulating in the nucleus of liver cancer cells. Finally, the high expression of NFRKB is associated with short OS time and poor prognosis. NFRKB is a TAP and protects telomeres from DNA damage in ALT cells. It is highly expressed in hepatocellular carcinoma (HCC) cells and predicts a poor prognosis. NFRKB may be a promising prognostic biomarker for the treatment of HCC in the future.

RevDate: 2021-09-30

Fritz MM, Walsh LC, Cole SW, et al (2021)

Kindness and cellular aging: A pre-registered experiment testing the effects of prosocial behavior on telomere length and well-being.

Brain, behavior, & immunity - health, 11:100187 pii:S2666-3546(20)30152-6.

Objective: Prosocial behavior can improve psychological well-being and physical health. However, the underlying biological mechanisms that mediate the relationship between prosociality and health remain unclear. In this pre-registered experiment, we tested whether a 4-week kindness intervention could slow leukocyte telomere shortening and increase well-being.

Methods: Community adults (N ​= ​230) were randomly assigned to complete 1 of 3 activities, each week for 4 weeks: to perform 3 kind acts for other people, to perform 3 kind acts for themselves, or to list daily activities. At baseline and post-intervention, participants came to the lab to provide a small dried blood spot (DBS) sample via finger prick for analysis of telomere length. Participants completed psychological measures (e.g., loneliness, life satisfaction) at baseline, post-intervention, and at the 2-week follow up.

Results: Participants who performed kind acts for others did not demonstrate hypothesized changes in well-being, nor in telomere length, relative to controls. Exploratory analyses revealed that, relative to controls, participants who did kind acts for others showed reductions in loneliness through the 2-week follow up.

Conclusions: The salubrious effects of prosocial behavior in the short term are not likely due to the inhibition of cellular aging (at least as indexed by telomere length). However, extending kindness to others holds promise as a future research direction for interventions to alleviate loneliness.

RevDate: 2021-09-30

Wang DX, Zhu XD, Ma XR, et al (2021)

Loss of Growth Differentiation Factor 11 Shortens Telomere Length by Downregulating Telomerase Activity.

Frontiers in physiology, 12:726345.

Maintenance of telomere length is essential to delay replicative cellular senescence. It is controversial on whether growth differentiation factor 11 (GDF11) can reverse cellular senescence, and this work aims to establish the causality between GDF11 and the telomere maintenance unequivocally. Using CRISPR/Cas9 technique and a long-term in vitro culture model of cellular senescence, we show here that in vitro genetic deletion of GDF11 causes shortening of telomere length, downregulation of telomeric reverse transcriptase (TERT) and telomeric RNA component (TERC), the key enzyme and the RNA component for extension of the telomere, and reduction of telomerase activity. In contrast, both recombinant and overexpressed GDF11 restore the transcription of TERT in GDF11KO cells to the wild-type level. Furthermore, loss of GDF11-induced telomere shortening is likely caused by enhancing the nuclear entry of SMAD2 which inhibits the transcription of TERT and TERC. Our results provide the first proof-of-cause-and-effect evidence that endogenous GDF11 plays a causal role for proliferative cells to maintain telomere length, paving the way for potential rejuvenation of the proliferative cells, tissues, and organs.

RevDate: 2021-09-29

Rouan A, Pousse M, Tambutté E, et al (2021)

Telomere dysfunction is associated with dark-induced bleaching in the reef coral Stylophora pistillata.

Molecular ecology [Epub ahead of print].

Telomere DNA length is a complex trait controlled both by multiple loci and environmental factors. A growing number of studies focus on the impact of stress and stress accumulation on telomere length and the link with survival and fitness in ecological contexts. Here, we investigated the telomere changes occurring in a symbiotic coral Stylophora pistillata that has experienced continuous darkness over six months. This stress condition led to the loss of its symbionts in a similar manner to that observed during large-scale bleaching events due to climate changes and anthropogenic activities, threatening reef ecosystems worldwide. We found that continuous darkness was associated with telomere length shortening. This result, together with a phylogenetic analysis of the telomere coral proteins and a transcriptome survey of the continuous darkness condition, pave the way for future studies on the role of telomeres in the coral stress response and the importance of environmentally induced telomere shortening in endangered coral species.

RevDate: 2021-09-29

Sung JY, JH Cheong (2021)

Alternative lengthening of telomeres is mechanistically linked to potential therapeutic vulnerability in the stem-like subtype of gastric cancer.

Clinical and translational medicine, 11(9):e561.

RevDate: 2021-09-29

Chandru S, Prabhu P, Balasubramanyam M, et al (2021)

Beneficial Primary Outcomes of Metabolic Surgery with Changes in Telomere Length and Mitochondrial DNA in Obese Asian Indians with Dysglycemia.

The Journal of the Association of Physicians of India, 69(9):11-12.

INTRODUCTION: Although metabolic surgery has been shown to offer beneficial primary outcome results in obese individuals / obese Type 2 diabetes mellitus (T2DM) patients, there is paucity of information on the underlying mechanisms. In the recent years, estimations of non-invasive molecular parameters viz., telomere length and mtDNA copy number (mtDNAcn) assume significance as robust biomarkers. However, there is lack of evidence about this especially, in the Indian context. To assess the changes in the telomere length and mtDNAcn levels after metabolic surgery in obese Asian Indians with dysglycemia along with routine measurements of anthropometry, glycemic/lipidimic parameters and inflammatory markers.

METHODS: This study is a prospective one-year follow-up study of 16 obese individuals with dysglycemia who underwent metabolic surgery at a tertiary diabetes centre in South India. Telomere length, mtDNAcn, serum adiponectin, glycated haemoglobin and high- sensitivity C-reactive protein (hs-CRP) levels were analysed before surgery and at 6 and 12 months after surgery.

RESULTS: There was a significant reduction in weight (p<0.001), BMI (p<0.001), waist circumference (p<0.001), fasting and postprandial glucose (p<0.05), HbA1c (p<0.001), triglycerides (p<0.05), hs CRP (p<0.05) and increase in serum adiponectin (p<0.05) at 6 and 12 months post-surgery compared to the preoperative status. There was a significant reduction in mtDNAcn (p<0.001) and a significant increase in telomere length (p<0.001) at 6 and 12 months post metabolic surgery.

CONCLUSION: We report an increase in telomere length and decrease in circulatory mtDNA copy number levels at 6 and 12 months post metabolic surgery in obese individuals with T2DM in India.

RevDate: 2021-09-29

Tichy ED, F Mourkioti (2021)

Telomere length assessments of muscle stem cells in rodent and human skeletal muscle sections.

STAR protocols, 2(4):100830 pii:S2666-1667(21)00536-0.

Measurements of telomere length in skeletal muscle stem cells (MuSCs), a rare cell population within muscles, provide insights into cellular dysfunction in diseased conditions. Here, we describe a protocol (cryosection muscle quantitative fluorescent in situhybridization) using skeletal muscle cryosections for assessments of telomere length in MuSCs, in their native environment. Using a free software, telomere length measurements are assessed on a single-cell level. We also provide methodology to perform data analyses in several ways. For complete details on the use and execution of this protocol, please refer to Tichy et al. (2021).

RevDate: 2021-09-29

Cuevas AG, Greatorex-Voith S, Abuelezam N, et al (2021)

Educational mobility and telomere length in middle-aged and older adults: testing three alternative hypotheses.

Biodemography and social biology [Epub ahead of print].

Critical period, social mobility, and social accumulation are three hypotheses that may explain how educational mobility impacts health. Thus far, there is little evidence on how these processes are associated with biological aging as measured by telomere length. Using cross-sectional data from the 2008 Health and Retirement Study, we examined the association between educational mobility (parental education and contemporaneous education) and telomere length. The final model is adjusted for sociodemographic factors and socioeconomic status, childhood adversity, and health behaviors/risk factors, as well as depressive symptoms. A total of 1,894 participants were included in the main analyses. High parental education was associated with longer telomere length in a fully adjusted model (B = 0.03, CI [0.002,0.07]). Downwardly mobile individuals (high parental education and low contemporaneous education) had longer telomere length compared to stably low individuals in a fully adjusted model (B = 0.05, CI [0.004,0.09]). There was support for the critical period hypothesis and partial support for the change hypothesis. There was no evidence to support the social accumulation hypothesis. Prospective studies are needed to understand the mechanism that can help further explain the association between educational mobility and telomere length.

RevDate: 2021-09-28

van der Vis JJ, van der Smagt JJ, van Batenburg AA, et al (2021)

Pulmonary fibrosis in non-mutation carriers of families with short telomere syndrome gene mutations.

Respirology (Carlton, Vic.) [Epub ahead of print].

BACKGROUND AND OBJECTIVE: Diagnostic and predictive genetic testing for disease cause and risk estimation is common in many countries. For genetic diseases, predictive test results are commonly straightforward: presence of the mutation involves increased risk for disease and absence of the mutation involves no inherit risk for disease. Germline mutations in telomere-related genes (TRGs) can lead to telomere shortening and are associated with short telomere syndrome (STS). Telomere length is heritable, and in families with STS due to a TRG mutation, progeny with and without the TRG mutation is known to have shorter than average telomeres. We hypothesize that progeny of TRG mutation carriers who did not inherit the TRG mutation may still develop pulmonary fibrosis.

METHODS: A genetic screen of 99 unrelated families with familial pulmonary fibrosis revealed five patients with features of pulmonary fibrosis but without carrying the familial disease-causing TRG mutation.

RESULTS: Features of STS were present in each family, including short telomeres in blood and tissue of the non-mutation carrying patients. Additional genetic, clinical or environmental risk factors for pulmonary fibrosis were present in each non-mutation carrying patient.

CONCLUSION: Our study shows that non-mutation carrying first-degree relatives in families with STS are at increased risk for pulmonary fibrosis. Disease development may be triggered by inherited short telomeres and additional risk factors for disease. This observation has profound consequences for genetic counselling. Unlike any other genetic syndrome, absence of the mutation does not imply absence of disease risk. Therefore, clinical follow-up is still urged for non-mutation carrying first-degree family members.

RevDate: 2021-09-28

Huang YC, CY Wang (2021)

Telomere Attrition and Clonal Hematopoiesis of Indeterminate Potential in Cardiovascular Disease.

International journal of molecular sciences, 22(18): pii:ijms22189867.

Clinical evidence suggests that conventional cardiovascular disease (CVD) risk factors cannot explain all CVD incidences. Recent studies have shown that telomere attrition, clonal hematopoiesis of indeterminate potential (CHIP), and atherosclerosis (telomere-CHIP-atherosclerosis, TCA) evolve to play a crucial role in CVD. Telomere dynamics and telomerase have an important relationship with age-related CVD. Telomere attrition is associated with CHIP. CHIP is commonly observed in elderly patients. It is characterized by an increase in blood cell clones with somatic mutations, resulting in an increased risk of hematological cancer and atherosclerotic CVD. The most common gene mutations are DNA methyltransferase 3 alpha (DNMT3A), Tet methylcytosine dioxygenase 2 (TET2), and additional sex combs-like 1 (ASXL1). Telomeres, CHIP, and atherosclerosis increase chronic inflammation and proinflammatory cytokine expression. Currently, their epidemiology and detailed mechanisms related to the TCA axis remain incompletely understood. In this article, we reviewed recent research results regarding the development of telomeres and CHIP and their relationship with atherosclerotic CVD.

RevDate: 2021-09-28

Monnin A, Vizeneux A, Nagot N, et al (2021)

Longitudinal Follow-Up of Blood Telomere Length in HIV-Exposed Uninfected Children Having Received One Year of Lopinavir/Ritonavir or Lamivudine as Prophylaxis.

Children (Basel, Switzerland), 8(9): pii:children8090796.

Telomere shortening can be enhanced upon human immunodeficiency virus (HIV) infection and by antiretroviral (ARV) exposures. The aim of this study was to evaluate the acute and long-term effect on telomere shortening of two ARV prophylaxes, lopinavir/ritonavir (LPV/r) and lamivudine (3TC), administered to children who are HIV-exposed uninfected (CHEU) to prevent HIV acquisition through breastfeeding during the first year of life, and to investigate the relationship between telomere shortening and health outcomes at six years of age. We included 198 CHEU and measured telomere length at seven days of life, at week-50 and at six years (year-6) using quantitative polymerase chain reaction. At week-50, telomere shortening was observed among 44.3% of CHEU, irrespective of the prophylactic treatment. Furthermore, this telomere shortening was neither associated with poor growth indicators nor neuropsychological outcomes at year-6, except for motor abilities (MABC test n = 127, β = -3.61, 95%CI: -7.08, -0.14; p = 0.04). Safety data on telomere shortening for infant HIV prophylaxis are scarce. Its association with reduced motor abilities deserves further attention among CHEU but also HIV-infected children receiving ARV treatment.

RevDate: 2021-09-27

Tometten M, Kirschner M, Isfort S, et al (2021)

Transient elastography in adult patients with cryptic dyskeratosis congenita reveals subclinical liver fibrosis: a retrospective analysis of the Aachen telomere biology disease registry.

Orphanet journal of rare diseases, 16(1):395.

BACKGROUND: Telomere biology disorders (TBD) such as dyskeratosis congenita (DKC) lead to progressive multi-organ failure as impaired telomere maintenance disturbs cellular proliferative capacity. A wide range of hepatic manifestations from asymptomatic liver enzyme elevation to overt liver fibrosis/cirrhosis can be observed in TBD patients. However, the incidence of hepatic involvement remains unknown. Non-invasive transient elastography (TE) predicts early fibrosis by measuring liver stiffness and may uncover subclinical liver damage in TBD patients.

METHODS: Liver screening procedures of nine TBD patients from the Aachen TBD Registry are being presented retrospectively. Following clinical suspicion, TBD was diagnosed using flow-FISH with telomere length (TL) below the 1% percentile and confirmed by next-generation sequencing (NGS) detecting pathogenic mutations in telomere maintenance genes TERC or TERT.

RESULTS: In all patients, TBD was first diagnosed in adulthood. Patients showed normal to slightly elevated liver function test parameters. Hepatic ultrasound revealed inhomogeneous parenchyma in seven (77.7%) and increased liver echogenicity in four patients (44.4%). Median liver stiffness was 10.7 kilopascal (kPa) (interquartile range 8.4, 15.7 kPa). Using 7.1 kPa as cut-off, 88.8% of patients were classified as moderate fibrosis to cirrhosis.

CONCLUSION: Subclinical chronic liver involvement is frequent in patients with adult-onset TBD. TE could have a valuable role in the routine work-up of patients with telomere disorders including DKC for early detection of patients at risk for liver function impairment.

RevDate: 2021-09-26

Nickels M, Mastana S, Codd V, et al (2021)

Comparison of Telomere Length in Young and Master Endurance Runners and Sprinters.

Journal of aging and physical activity pii:japa.2021-0236 [Epub ahead of print].

It is unclear how running modality influences telomere length (TL). This single laboratory visit study compared the TL of master sprinters and endurance runners with their young counterparts. The correlation between leukocyte and buccal cell TL in athletes was also explored. Participants consisted of 11 young controls, 11 young sprinters, 12 young endurance runners, 12 middle-aged controls, 11 master sprinters, and 12 master endurance runners. Blood and buccal samples were collected and randomized for analysis of TL by quantitative polymerase chain reaction. Young endurance runners displayed longer telomeres than master athletes (p < .05); however, these differences were not significant when controlled for covariates (p > .05). A positive correlation existed between leukocyte and buccal cell TL in athletes (r = .567, p < .001). In conclusion, young endurance runners possess longer telomeres than master endurance runners and sprinters, a consequence of lower body mass index and visceral fat.

RevDate: 2021-09-25

Lyu L, Yu J, Liu Y, et al (2021)

High Hemoglobin glycation index is associated with telomere attrition independent of HbA1c, mediating by TNFα.

The Journal of clinical endocrinology and metabolism pii:6375394 [Epub ahead of print].

CONTEXT: The hemoglobin glycation index(HGI) is correlated with metabolic diseases and inflammations. Whether the HGI is associated with the ageing process and how inflammation and oxidative stress affect the relationship remain unclear.

OBJECTIVE: We aim to analyze links between HGI and ageing biomarkers, and to explore a potential role of inflammation and oxidative stress in the correlations.

METHODS: A cross-sectional study of 434 subjects with different glucose intolerances in a rural community was enrolled. The HGI was calculated as the difference between the measured and predicted hemoglobin A1c(HbA1c). The population was categorized into tertiles of HGI. Telomere length(LTL) and mitochondrial DNA copy number(mtDNAcn) determined by PCR assay. Tumor necrosis factor α(TNFα) and interleukin 6(IL-6), 8-oxo-2'-deoxyguanosine(8-oxo-dG), superoxide dismutase(SOD) activities and glutathione reductase(GR) were measured.

RESULT: Participants in the high HGI group were older and reported a shorter LTL, higher levels of TNFα, SOD activities and HbA1c. Correlation analyses demonstrated that HGI was correlated with LTL(r=-0.25,p<0.001) and TNFα(r=0.19,p<0.001) regardless of HbA1c levels. No relationship was found between HGI and mtDNAcn. HGI(β=-0.238,95%CI(-0.430,-0.046),p=0.015) and TNFα(β=-0.02,95%CI(-0.030,-0.014),p<0.001) were proved to be correlated with LTL independently using multiple linear regression analysis. Ordinal logistic regression models showed that compared with subjects in High-HGI, the possibilities of a higher-level LTL was 5.29-fold in Low-HGI(OR5.29,95%CI(2.45,11.41),p<0.001), 2.41-fold in Moderate-HGI (OR2.41,95%CI(1.35,4.30),p=0.003) after controlling for confounding variables. Mediation analyses indicated that TNFα accounted for 30.39% effects of HGI on LTL.

CONCLUSION: HGI was negatively related to telomere attrition, independent of HbA1c. TNFα acted as a mediator of the relationship between HGI and LTL.

RevDate: 2021-09-24

Lee L, Perez Oliva AB, Martinez-Balsalobre E, et al (2021)

UFMylation of MRE11 is essential for telomere length maintenance and hematopoietic stem cell survival.

Science advances, 7(39):eabc7371.

[Figure: see text].

RevDate: 2021-09-24

Aida J, Takubo K, Vieth M, et al (2021)

Telomere lengths in Barrett's esophagus as a precancerous lesion.

Esophagus : official journal of the Japan Esophageal Society [Epub ahead of print].

BACKGROUND: We have reported that precancerous conditions and lesions invariably have shorter telomeres and associated chromosomal instability relative to normal tissue.

METHODS: Using the Q-FISH method and our original software, Tissue Telo, we estimated telomere lengths in cardiac- and intestinal-type mucosae in 48 cases of Barrett's esophagus (short-segment (SS) n = 18; long-segment (LS) n = 30).

RESULTS: There were no significant differences in telomere length between the cardiac and intestinal types in any of the 48 cases, suggesting that the presence or absence of goblet cells in the columnar segments is unrelated to telomere-dependent chromosomal instability in Barrett's esophagus. In LS Barrett's esophagus, telomeres were shorter in cardiac-type than in intestinal-type mucosa, suggesting that the former may play a more important role than the latter as a precancerous lesion in LS. Telomeres in cardiac-type mucosa were longer in SS than in LS, supporting the possibility that cardiac-type LS may pose a higher risk as a precancerous lesion than cardiac-type SS.

CONCLUSIONS: Although it has been considered that Barrett's carcinoma arises only from intestinal-type mucosa, our present findings support previous histogenetic studies suggesting that cardiac-type mucosa is more important as a precancerous condition in Barrett's esophagus than anticipated.

RevDate: 2021-09-24

Rattan P, Penrice DD, Ahn JC, et al (2021)

Inverse Association of Telomere Length With Liver Disease and Mortality in the US Population.

Hepatology communications [Epub ahead of print].

Physiologic aging leads to attrition of telomeres and replicative senescence. An acceleration of this process has been hypothesized in the progression of chronic liver disease. We sought to examine the association of telomere length (TL) with liver disease and its impact on mortality risk. A cohort of 7,072 adults with leukocyte TL measurements from the National Health and Nutrition Examination Survey 1999-2002 with mortality follow-up through 2015 was analyzed. Liver disease was defined by aminotransferase levels and classified into etiology-based and advanced fibrosis categories. Multivariable-adjusted linear regression models estimated effect sizes, with 95% confidence intervals (CIs), of the presence of liver disease on TL. Cox regression models evaluated associations between TL and all-cause mortality risk using adjusted hazard ratios (HRs). The cohort was representative of the US population with mean age 46.1 years and mean TL 5.79 kilobase pairs. No overall association between TL and liver disease was found; however, there was a significant negative association of TL and advanced liver fibrosis in individuals aged 65 and above. The liver disease cohort (HR 1.22, 95% CI 0.99-1.51) and those with metabolic syndrome (HR 1.26, 95% CI 0.96-1.67) had increased mortality risk with shorter TL. The relationship between TL and all-cause mortality was stronger in women (HR 1.51, 95% CI 1.02-2.23) and in non-Hispanic Whites (HR 1.37, 95% CI 1.02-1.84). Conclusion: Shortened leukocyte TL is independently associated with advanced liver disease at older ages, and with a higher risk of all-cause mortality in those with liver disease. These associations reaffirm the need to better understand the role of telomeres in the progression of liver disease.

RevDate: 2021-09-24

Polho GB, Cardillo GM, Kerr DS, et al (2022)

Antipsychotics preserve telomere length in peripheral blood mononuclear cells after acute oxidative stress injury.

Neural regeneration research, 17(5):1156-1160.

Antipsychotics may prolong or retain telomere length, affect mitochondrial function, and then affect the metabolism of nerve cells. To validate the hypothesis that antipsychotics can prolong telomere length after oxidative stress injury, leukocytes from healthy volunteers were extracted using Ficoll-Histopaque density gradient. The mononuclear cells layer was resuspended in cell culture medium. Oxidative stress was induced with hydrogen peroxide in cultured leukocytes. Four days later, leukocytes were treated with aripiprazole, haloperidol or clozapine for 7 days. Real-time PCR revealed that treatments with aripiprazole and haloperidol increased the telomere length by 23% and 20% in peripheral blood mononuclear cells after acute oxidative stress injury. These results suggest that haloperidol and aripiprazole can reduce the damage to telomeres induced by oxidative stress. The experiment procedure was approved by the Ethics Committee of Faculty of Medicine of the University of São Paulo (FMUSP/CAAE approval No. 52622616.8.0000.0065).

RevDate: 2021-09-24

Garus A, C Autexier (2021)


RNA (New York, N.Y.) pii:rna.078953.121 [Epub ahead of print].

Dyskerin and its homologues are ancient and conserved enzymes that catalyse the most common posttranscriptional modification found in cells, pseudouridylation. The resulting pseudouridines provide stability to RNA molecules and regulate ribosome biogenesis and splicing events. Dyskerin does not act independently - it is the core component of a protein heterotetramer, which associates with RNAs that contain the H/ACA motif. The variety of H/ACA RNAs that guide the function of this ribonucleoprotein (RNP) complex highlight the diversity of cellular processes in which dyskerin participates. When associated with small nucleolar (sno) RNAs, it regulates ribosomal (r) RNAs and ribosome biogenesis. By interacting with small Cajal Body (sca) RNAs, it targets small nuclear (sn) RNAs to regulate pre-mRNA splicing. As a component of the telomerase holoenzyme, dyskerin binds to the telomerase RNA to modulate telomere maintenance. In a disease context, dyskerin malfunction can result in multiple detrimental phenotypes. Mutations in DKC1, the gene that encodes dyskerin, cause the premature aging syndrome X-linked dyskeratosis congenita (X-DC), a still incurable disorder that typically leads to bone marrow failure. In this review, we present the classical and most recent findings on this essential protein, discussing the evolutionary, structural and functional aspects of dyskerin and the H/ACA RNP. The latest research underscores the role that dyskerin plays in the regulation of gene expression, translation efficiency and telomere maintenance, along with the impacts that defective dyskerin has on aging, cell proliferation, haematopoietic potential and cancer.

RevDate: 2021-09-23

Güneşliol BE, Karaca E, Ağagündüz D, et al (2021)

Association of physical activity and nutrition with telomere length, a marker of cellular aging: A comprehensive review.

Critical reviews in food science and nutrition [Epub ahead of print].

The aging of the population has great social and economic effects because it is characterized by a gradual loss in physiological integrity, resulting in functional decline, thereby loss of ability to move independently. Telomeres, the hallmarks of biological aging, play a protective role in both cell death and aging. Critically short telomeres give rise to a metabolically active cell that is unable to repair damage or divide, thereby leading to aging. Lifestyle factors such as physical activity (PA) and nutrition could be associated with telomere length (TL). Indeed, regular PA and healthy nutrition as integral parts of our lifestyle can slow down telomere shortening, thereby delaying aging. In this context, the present comprehensive review summarizes the data from recent literature on the association of PA and nutrition with TL.

RevDate: 2021-09-22

Sheldon EL, Ton R, Boner W, et al (2021)

Associations between DNA methylation and telomere length during early life: insight from wild zebra finches (Taeniopygia guttata).

Molecular ecology [Epub ahead of print].

Telomere length and DNA methylation (DNAm) are two promising biomarkers of biological age. Environmental factors and life history traits are known to affect variation in both these biomarkers, especially during early life, yet surprisingly little is known about their reciprocal association, especially in natural populations. Here, we explore how variation in DNAm, growth rate, and early-life conditions are associated with telomere length changes during development. We tested these associations by collecting data from wild, nestling zebra finches in the Australian desert. We found that increases in the level of DNAm were negatively correlated with telomere length changes across early life. We also confirm previously documented effects of post hatch growth rate and clutch size on telomere length in a natural ecological context for a species that has been extensively studied in the laboratory. However, we did not detect any effect of ambient temperature during developmental on telomere length dynamics. We also found that the absolute telomere length of wild zebra finches, measured using the in-gel TRF method, was similar to that of captive birds. Our findings highlight exciting new opportunities to link and disentangle potential relationships between DNA based biomarkers of aging, and of physiological reactions to environmental change.

RevDate: 2021-09-22

Nolte J (2021)

Lrrc34 interacts with Oct4 and has an impact on telomere length in mouse Embryonic Stem Cells.

Stem cells and development [Epub ahead of print].

Telomere length maintenance in pluripotent stem cells is a main characteristic and a major premise for their undifferentiated long term survival. However, little is known about the factors that control telomere length and elongation in these cells. Here, I describe Lrrc34 as a novel telomere length regulating gene in murine embryonic stem cells (mESCs). Downregulation of Lrrc34 results in significant reduction of telomerase activity and telomere length over time while also influencing the expression of known telomere length associated genes. Generating induced pluripotent stem cells (iPSCs) with Lrrc34 as a fifths factor in classical Yamanaka reprogramming increases the efficiency but did not have an impact on telomere length in the resulting iPSCs. Moreover, Lrrc34 was found to interact with Oct4, connecting the pluripotency network to telomere length regulation.

RevDate: 2021-09-22

Bazaz MR, Balasubramanian R, Monroy-Jaramillo N, et al (2021)

Linking the Triad of Telomere Length, Inflammation, and Gut Dysbiosis in the Manifestation of Depression.

ACS chemical neuroscience [Epub ahead of print].

Telomere length is an indispensable marker for cellular and biological aging, and it also represents an individual's physical and mental health status. Telomere shortening has been observed in chronic inflammatory conditions, which in turn accelerates aging and risk for psychiatric disorders, including depression. Considering the influence of inflammation and telomere shortening on the gut-brain axis, herein we describe a plausible interplay between telomere attrition, inflammation, and gut dysbiosis in the neurobiology of depression. Telomere shortening and hyperinflammation are well reported in depression. A negative impact of augmented inflammation has been noted on the intestinal permeability and microbial consortia and their byproducts in depressive patients. Moreover, gut dysbiosis provokes host-immune responses. As the gut microbiome is gaining importance in the manifestation and management of depression, herein we discuss whether telomere attrition is connected with the perturbation of commensal microflora. We also describe a pathological connection of cortisol with hyperinflammation, telomere shortening, and gut dysbiosis occurring in depression. This review summarizes how the triad of telomere attrition, inflammation, and gut dysbiosis is interconnected and modulates the risk for depression by regulating the systemic cortisol levels.

RevDate: 2021-09-21

Peña E, León-Mengíbar J, Powell TR, et al (2021)

Telomere length in patients with obesity submitted to bariatric surgery: A systematic review.

European eating disorders review : the journal of the Eating Disorders Association [Epub ahead of print].

BACKGROUND: Patients with obesity show evidence of increased levels of inflammation, oxidative stress and premature ageing. Telomere length (TL) is a key marker of cellular ageing, and patients with obesity often present shorter TL. Bariatric surgery (BS) is currently the most effective treatment for severe obesity. The aim of this systematic review was to explore whether the beneficial health effects observed after surgery in obese patients correspond to a restoration in TL or slower rates of shortening. As a secondary aim, we evaluated, at baseline and post-surgery, the relationship between TL and different factors that could play a role in TL changes along time.

METHODS: Searches for relevant articles were performed in MEDLINE, Web of Knowledge and SCOPUS. Prospective longitudinal studies that evaluated leukocyte TL in adult patients who had undergone BS were included. Data were extracted and evaluated by two independent researchers. The protocol was registered in PROSPERO with the number CRD42020197711.

RESULTS: Seven studies based on independent samples that fulfilled our inclusion criteria were included. Obese patients showed shorter telomeres compared to healthy individuals. Long-term studies (>2 years) seem to suggest an improvement in TL after surgery presumably due to the improvement of the inflammatory and oxidative levels of the patients induced by weight loss.

CONCLUSION: Studies seem to point towards a beneficial long-term effect of BS on TL recovery. However, the scarce number of studies and the heterogeneity in the variables analysed in the different cohorts make it difficult to draw a firm conclusion. More studies are needed to evaluate long-term changes to TL following BS.

RevDate: 2021-09-20

Gu P, Jia S, Takasugi T, et al (2021)

Distinct functions of POT1 proteins contribute to the regulation of telomerase recruitment to telomeres.

Nature communications, 12(1):5514.

Human shelterin components POT1 and TPP1 form a stable heterodimer that protects telomere ends from ATR-dependent DNA damage responses and regulates telomerase-dependent telomere extension. Mice possess two functionally distinct POT1 proteins. POT1a represses ATR/CHK1 DNA damage responses and the alternative non-homologous end-joining DNA repair pathway while POT1b regulates C-strand resection and recruits the CTC1-STN1-TEN1 (CST) complex to telomeres to mediate C-strand fill-in synthesis. Whether POT1a and POT1b are involved in regulating the length of the telomeric G-strand is unclear. Here we demonstrate that POT1b, independent of its CST function, enhances recruitment of telomerase to telomeres through three amino acids in its TPP1 interacting C-terminus. POT1b thus coordinates the synthesis of both telomeric G- and C-strands. In contrast, POT1a negatively regulates telomere length by inhibiting telomerase recruitment to telomeres. The identification of unique amino acids between POT1a and POT1b helps us understand mechanistically how human POT1 switches between end protective functions and promoting telomerase recruitment.

RevDate: 2021-09-25

Pignolo RJ, FB Johnson (2021)

Do the telomere ends justify the physical means?.

RevDate: 2021-09-17

Xiong F, WD Frasch (2021)

ΩqPCR measures telomere length from single-cells in base pair units.

Nucleic acids research pii:6371978 [Epub ahead of print].

ΩqPCR determines absolute telomere length in kb units from single cells. Accuracy and precision of ΩqPCR were assessed using 800 bp and 1600 bp synthetic telomeres inserted into plasmids, which were measured to be 819 ± 19.6 and 1590 ± 42.3 bp, respectively. This is the first telomere length measuring method verified in this way. The approach uses Ω-probes, a DNA strand containing sequence information that enables: (i) hybridization with the telomere via the 3' and 5' ends that become opposed; (ii) ligation of the hybridized probes to circularize the Ω-probes and (iii) circularized-dependent qPCR due to sequence information for a forward primer, and for a reverse primer binding site, and qPCR hydrolysis probe binding. Read through of the polymerase during qPCR occurs only in circularized Ω-probes, which quantifies their number that is directly proportional to telomere length. When used in concert with information about the cell cycle stage from a single-copy gene, and ploidy, the MTL of single cells measured by ΩqPCR was consistent with that obtained from large sample sizes by TRF.

RevDate: 2021-09-17

Bauch C, Boonekamp JJ, Korsten P, et al (2021)

High heritability of telomere length and low heritability of telomere shortening in wild birds.

Molecular ecology [Epub ahead of print].

Telomere length and telomere shortening predict survival in many organisms. This raises the question of the contribution of genetic and environmental effects to variation in these traits, which is still poorly known, particularly for telomere shortening. We used experimental (cross-fostering) and statistical (quantitative genetic 'animal' models) means to disentangle and estimate genetic and environmental contributions to telomere length variation in pedigreed free-living jackdaws (Corvus monedula). Telomere length was measured twice in nestlings, at ages 4 (n=715) and 29 days (n=474), using TRF-analysis, adapted to exclude interstitial telomeric sequences. Telomere length shortened significantly over the nestling period (10.4±0.3 bp/day) and was highly phenotypically (rP =0.95±0.01) and genetically (rG >0.99±0.01) correlated within individuals. Additive genetic effects explained a major part of telomere length variation among individuals, with its heritability estimated at h2 =0.74 on average. We note that TRF-based studies reported higher heritabilities than qPCR-based studies, and we discuss possible explanations. Parent-offspring regressions yielded similar heritability estimates for mothers and fathers when accounting for changes in paternal telomere length over life. Year effects explained a small but significant part of telomere length variation. Heritable variation for telomere shortening was low (h2 =0.09±0.11). The difference in heritability between telomere length (high) and telomere shortening (low) agrees with evolutionary theory, in that telomere shortening has stronger fitness consequences in this population. Despite the high heritability of telomere length, its evolvability, which scales the additive genetic variance by mean telomere length, was on average 0.48%. Hence evolutionary change of telomere length due to selection is likely to be slow.

RevDate: 2021-09-21

Nassour J, Schmidt TT, J Karlseder (2021)

Telomeres and Cancer: Resolving the Paradox.

Annual review of cancer biology, 5(1):59-77.

Decades of study on cell cycle regulation have provided great insight into human cellular life span barriers, as well as their dysregulation during tumorigenesis. Telomeres, the extremities of linear chromosomes, perform an essential role in implementing these proliferative boundaries and preventing the propagation of potentially cancerous cells. The tumor-suppressive function of telomeres relies on their ability to initiate DNA damage signaling pathways and downstream cellular events, ranging from cell cycle perturbation to inflammation and cell death. While the tumor-suppressor role of telomeres is undoubtable, recent advances have pointed to telomeres as a major source of many of the genomic aberrations found in both early- and late-stage cancers, including the most recently discovered mutational phenomenon of chromothripsis. Telomere shortening appears as a double-edged sword that can function in opposing directions in carcinogenesis. This review focuses on the current knowledge of the dual role of telomeres in cancer and suggests a new perspective to reconcile the paradox of telomeres and their implications in cancer etiology.

RevDate: 2021-09-17

Wang L, Song L, Liu B, et al (2021)

Association between maternal urinary selenium during pregnancy and newborn telomere length: results from a birth cohort study.

European journal of clinical nutrition [Epub ahead of print].

BACKGROUND: Newborn telomere length is considered as an effective predictor of lifespan and health outcomes in later life. Selenium is an essential trace element for human health, and its antioxidation is of great significance for the prevention of telomere erosion.

METHODS: We recruited 746 mother-newborn pairs in Wuhan Children's Hospital between 2013 and 2015. Urine samples were repeatedly collected at three time points during pregnancy, and umbilical cord blood samples were collected right after parturition. Urinary selenium concentration was detected using inductively coupled plasma mass spectrometry, and newborn telomere length was measured using quantitative real-time polymerase chain reaction. We applied general estimating equations to examine the trimester-specific association between maternal urinary selenium during pregnancy and newborn telomere length.

RESULTS: The median of creatinine-corrected selenium concentrations during pregnancy were 16.29, 18.08, and 18.35 μg/g·creatinine in the first, second, and third trimesters, respectively. Selenium concentrations in all the three trimesters were significantly associated with newborn telomere length. Per doubling of maternal urinary selenium concentrations was associated with 6.44% (95% CI: 0.92, 12.25), 6.54% (95% CI: 0.17, 13.31), and 6.02% (95% CI: 0.29, 12.09) longer newborn telomere length in the first, second, and third trimesters, respectively, after adjusting for potential confounders.

CONCLUSIONS: This is the first study to provide evidence for the effect of maternal selenium levels on fetal telomere erosion. Findings from our study suggested that maternal urinary selenium was positively associated with newborn telomere length, indicating that intrauterine selenium exposure might have effect on initial setting of human telomere length.

RevDate: 2021-09-15

García García C, Shin C, I Baik (2021)

Association between body temperature and leukocyte telomere length in middle-aged and older adults.

Epidemiology and health pii:epih.e2021063 [Epub ahead of print].

Objectives: Data on the association between body temperature (BT) and leukocyte telomere length (LTL), which has been widely used as a biomarker of cellular senescence in recent epidemiological studies, are limited. Aims: The present study aimed to explore the association between a normal BT range (35.0 to 37.5℃) and LTL in a 6-year longitudinal observation among 2004 male and female adults aged 50 or older.

Methods: BT was obtained by measuring a tympanic temperature and relative LTL was assayed using real-time polymerase chain reaction. Robust regression analysis was used to evaluate the association for baseline and follow-up values of LTL and their differences.

Results: A significant inverse association was found between baseline BT and LTL: regression coefficient estimate was -0.03 [95% confidence interval: -0.07, -0.001] (p<0.05). Such an association was stronger in participants with a body mass index >25 kg/m2 and in males (p<0.01). However, BT was not associated with the follow-up LTL and 6-year longitudinal differences in LTL.

Conclusion: These findings suggest that having a higher BT within a range between 35 and 37.5 ℃ (95 and 99 ℉) may be detrimental for obese persons in terms of biological aging.

RevDate: 2021-09-17

Roake CM, Juntilla M, Agarwal-Hashmi R, et al (2021)

Tissue-specific telomere shortening and degenerative changes in a patient with TINF2 mutation and dyskeratosis congenita.

Human pathology (New York), 25:.

Dyskeratosis congenita is a disease of impaired tissue maintenance downstream of telomere dysfunction. Characteristically, patients present with the clinical triad of nail dystrophy, oral leukoplakia, and skin pigmentation defects, but the disease involves degenerative changes in multiple organs. Mutations in telomere-binding proteins such as TINF2 (TRF1-interacting nuclear factor 2) or in telomerase, the enzyme that counteracts age related telomere shortening, are causative in dyskeratosis congenita. We present a patient who presented with severe hypoxemia at age 13. The patient had a history of myelodysplastic syndrome treated with bone marrow transplant at the age of 5. At age 18 she was hospitalized for an acute pneumonia progressing to respiratory failure, developed renal failure and ultimately, she and her family opted to withdraw support as she was not a candidate for a lung transplant. Sequencing of the patient's TINF2 locus revealed a heterozygous mutation (c.844C > T, Arg282Cys) which has previously been reported in a subset of dyskeratosis congenita patients. Tissue sections from multiple organs showed degenerative changes including disorganized bone remodeling, diffuse alveolar damage and small vessel proliferation in the lung, and hyperkeratosis with hyperpigmentation of the skin. Autopsy samples revealed a bimodal distribution of telomere length, with telomeres from donor hematopoietic tissues being an age-appropriate length and those from patient tissues showing pathogenic shortening, with the shortest telomeres in lung, liver, and kidney. We report for the first time a survey of degenerative changes and telomere lengths in multiple organs in a patient with dyskeratosis congenita.

RevDate: 2021-09-13

Ravindran S, Froy H, Underwood SL, et al (2021)

The association between female reproductive performance and leukocyte telomere length in wild Soay sheep.

Molecular ecology [Epub ahead of print].

Telomere length (TL), typically measured across a sample of blood cells, has emerged as an exciting potential marker of physiological state and of the costs of investment in growth and reproduction within evolutionary ecology. While there is mounting evidence from studies of wild vertebrates that short TL predicts raised subsequent mortality risk, the relationship between reproductive investment and TL is less clear cut, and previous studies report both negative and positive associations. In this study, we examined the relationship between TL and different aspects of maternal reproductive performance in a free-living population of Soay sheep. We find evidence for shorter TL in females that bred, and thus paid any costs of gestation, compared to females that did not breed. However, we found no evidence for any association between TL and litter size. Furthermore, females that invested in gestation and lactation actually had longer TL than females who only invested in gestation because their offspring died shortly after birth. We used multivariate models to decompose these associations into among- and within-individual effects, and discovered that within-individual effects were driving both the negative association between TL and gestation, and the positive association between TL and lactation. This suggests that telomere dynamics may reflect recent physiologically costly investment or variation in physiological condition, depending on the aspect of reproduction being investigated. Our results highlight the physiological complexity of vertebrate reproduction, and the need to better understand how and why different aspects of physiological variation underpinning life histories impact blood cell TL.

RevDate: 2021-09-11

Dhillon VS, Deo P, Chua A, et al (2021)

Sleep duration, Health Promotion Index (HPI), sRAGE and ApoE-ε4 genotype are associated with telomere length (TL) in healthy elderly Australians.

The journals of gerontology. Series A, Biological sciences and medical sciences pii:6368769 [Epub ahead of print].

Significant alterations in sleep duration and/or quality of sleep become more pronounced as people get older. Poor sleep in elderly people is associated with adverse health outcomes and cellular ageing. We examined the relationship between TL and sleep duration, Health Promotion Index (HPI), and tested whether the presence of ApoE-ε4 allele impacts both sleep and TL. The present study was carried out in 174 healthy elderly subjects (21% male; mean age 53.79 years) from South Australia. Lymphocyte telomere length (TL) was measured by real-time qPCR and ApoE genotype was determined by TaqMan assay. HPI was calculated from a questionnaire regarding 8 lifestyle habits, including sleeping hours. Multivariate regression analysis was used to establish these associations adjusted for specified confounders. TL was found to be inversely associated with age (r = - 0.199; p = 0.008) and BMI (r = - 0.121; p = 0.11), and was significantly shorter in participants who slept for <7 hours (p = 0.001) relative to those sleeping ≥7 hours. TL was positively correlated with HPI (r = 0.195; p = 0.009). ApoE-ε4 allele carriers who slept for less than 7 hours had shortest TL (p = 0.01) compared to non-carriers. Plasma sRAGE level was significantly (p = 0.001) lower in individuals who sleep <7 hours and ApoE-ϵ4 carriers. Our results suggest that inadequate sleep duration or poor HPI is associated with shorter TL in cognitively normal elderly people and that carriage of APOE-ε4 genotype may influence the extent of these effects.

RevDate: 2021-09-13

Shin HK, Park JH, Yu JH, et al (2021)

Association between telomere length and hepatic fibrosis in non-alcoholic fatty liver disease.

Scientific reports, 11(1):18004.

Telomere length has been linked to the prevalence and progression of metabolic disease. However, clinical implications of telomere length in biopsy-proven non-alcoholic fatty liver disease (NAFLD) patients remain unclear. Therefore, this study aimed to investigate the association of telomere length with the histological severity of NAFLD. The cross-sectional data derived from the prospectively enrolled Boramae NAFLD registry (n = 91) were analyzed. The liver tissues and clinical information were obtained from both NAFLD patients and non-NAFLD subjects. Binary logistic regression was performed to identify the independent association between telomere length and the histological severity of NAFLD. A total of 83 subjects with or without biopsy-proven NAFLD were included for analysis: non-NAFLD in 23 (27.7%), non-alcoholic fatty liver in 15 (18.1%), and non-alcoholic steatohepatitis (NASH) in 45 (54.2%). Telomere length measured from liver tissues showed a strong negative correlation (p < 0.001) with age, regardless of NAFLD status. Therefore, telomere length was corrected for age. Age-adjusted telomere length than decreased gradually with an increasing severity of fibrosis in patients with NAFLD (p < 0.028). In multivariate analysis, age-adjusted telomere length (odds ratio [OR] 0.59; 95% CI 0.37-0.92; p = 0.019) and high-density lipoprotein cholesterol (OR 0.94; 95% CI 0.80-0.99; p = 0.039) were independently associated with significant fibrosis. The age-adjusted telomere length tends to decrease along with the fibrosis stage of NAFLD. In particular, among the histological components of NAFLD, fibrosis severity seems to be related to telomere length in the liver.

RevDate: 2021-09-08

Lin A, Mertens AN, Arnold BF, et al (2021)

Telomere length is associated with growth in children in rural Bangladesh.

eLife, 10: pii:60389 [Epub ahead of print].

Background: Previously, we demonstrated that a water, sanitation, handwashing, and nutritional intervention improved linear growth and was unexpectedly associated with shortened childhood telomere length (TL) (Lin et al., 2017). Here, we assessed the association between TL and growth.

Methods: We measured relative TL in whole blood from 713 children. We reported differences between the 10th percentile and 90th percentile of TL or change in TL distribution using generalized additive models, adjusted for potential confounders.

Results: In cross-sectional analyses, long TL was associated with a higher length-for-age Z score at age 1 year (0.23 SD adjusted difference in length-for-age Z score (95% CI 0.05, 0.42; FDR-corrected p-value = 0.01)). TL was not associated with other outcomes.

Conclusions: Consistent with the metabolic telomere attrition hypothesis, our previous trial findings support an adaptive role for telomere attrition, whereby active TL regulation is employed as a strategy to address 'emergency states' with increased energy requirements such as rapid growth during the first year of life. Although short periods of active telomere attrition may be essential to promote growth, this study suggests that a longer overall initial TL setting in the first two years of life could signal increased resilience against future telomere erosion events and healthy growth trajectories.

Funding: Funded by the Bill and Melinda Gates Foundation.

RevDate: 2021-09-23

Belser C, Baurens FC, Noel B, et al (2021)

Telomere-to-telomere gapless chromosomes of banana using nanopore sequencing.

Communications biology, 4(1):1047.

Long-read technologies hold the promise to obtain more complete genome assemblies and to make them easier. Coupled with long-range technologies, they can reveal the architecture of complex regions, like centromeres or rDNA clusters. These technologies also make it possible to know the complete organization of chromosomes, which remained complicated before even when using genetic maps. However, generating a gapless and telomere-to-telomere assembly is still not trivial, and requires a combination of several technologies and the choice of suitable software. Here, we report a chromosome-scale assembly of a banana genome (Musa acuminata) generated using Oxford Nanopore long-reads. We generated a genome coverage of 177X from a single PromethION flowcell with near 17X with reads longer than 75 kbp. From the 11 chromosomes, 5 were entirely reconstructed in a single contig from telomere to telomere, revealing for the first time the content of complex regions like centromeres or clusters of paralogous genes.

RevDate: 2021-09-25

Shi S, Zhou Y, Lu Y, et al (2021)

Ccq1-Raf2 interaction mediates CLRC recruitment to establish heterochromatin at telomeres.

Life science alliance, 4(11):.

Telomeres, highly ordered DNA-protein complexes at eukaryotic linear chromosome ends, are specialized heterochromatin loci conserved among eukaryotes. In Schizosaccharomyces pombe, the shelterin complex is important for subtelomeric heterochromatin establishment. Despite shelterin has been demonstrated to mediate the recruitment of the Snf2/histone deacetylase-containing repressor complex (SHREC) and the Clr4 methyltransferase complex (CLRC) to telomeres, the mechanism involved in telomeric heterochromatin assembly remains elusive due to the multiple functions of the shelterin complex. Here, we found that CLRC plays a dominant role in heterochromatin establishment at telomeres. In addition, we identified a series of amino acids in the shelterin subunit Ccq1 that are important for the specific interaction between Ccq1 and the CLRC subunit Raf2. Finally, we demonstrated that the Ccq1-Raf2 interaction is essential for the recruitment of CLRC to telomeres, that contributes to histone H3 lysine 9 methylation, nucleosome stability and the shelterin-chromatin association, promoting a positive feedback mechanism for the nucleation and spreading of heterochromatin at subtelomeres. Together, our findings provide a mechanistic understanding of subtelomeric heterochromatin assembly by shelterin-dependent CLRC recruitment to chromosomal ends.

RevDate: 2021-09-08

Rolles B, Gorgulho J, Tometten M, et al (2021)

Telomere Shortening in Peripheral Leukocytes Is Associated With Poor Survival in Cancer Patients Treated With Immune Checkpoint Inhibitor Therapy.

Frontiers in oncology, 11:729207.

Background: Immune checkpoint inhibitor (ICI) therapy represents a new standard of care for an increasing number of malignancies. Nevertheless, response rates and outcome of ICI treatment vary between individuals and the identification of predictive markers or hints towards immune cell exhaustion during therapy has remained a major challenge. Leukocyte telomere length is an established predictive biomarker of replicative aging and cellular proliferative potential in various hematological diseases. However, its relevance in the context of ICI therapy has not been investigated to date. Here, we analyze the age-adapted delta telomere length (ΔTL) of peripheral leukocytes as a potential predictive and prognostic marker in patients undergoing ICI therapy.

Methods: Age-adapted delta telomere length (ΔTL) of 84 patients treated with ICIs for solid malignancies was measured via quantitative real-time PCR. ΔTL was correlated with outcome and clinical data.

Results: ΔTL was not significantly altered between patients with different tumor entities or tumor stages and did not predict tumor response to ICI therapy. However, ΔTLs at initiation of treatment were a prognostic marker for overall survival (OS). When using a calculated ideal cut-off value, the median OS in patients with shorter ΔTL was 5.7 months compared to 18.0 months in patients showing longer ΔTL. The prognostic role of age-adapted ΔTL was further confirmed by uni- and multivariate Cox-regression analyses.

Conclusion: In the present study, we demonstrate that shorter telomere lengths in peripheral blood leukocytes are associated with a significantly impaired outcome in patients receiving ICI therapy across different malignancies. We explain our findings by hypothesizing an older replicative age in peripheral leukocytes of patients with an impaired overall survival, reflected by a premature TL shortening. Whether this association is ICI-specific remains unknown. Further follow-up studies are needed to provide insights about the exact mechanism of how shortened telomeres eventually affect OS and could help guiding therapeutic decisions in future.

RevDate: 2021-09-10

Yang L, Wang B, Jiao X, et al (2021)

TAZ maintains telomere length in TNBC cells by mediating Rad51C expression.

Breast cancer research : BCR, 23(1):89.

BACKGROUND: Telomere maintenance is crucial for the unlimited proliferation of cancer cells and essential for the "stemness" of multiple cancer cells. TAZ is more extensively expressed in triple negative breast cancers (TNBC) than in other types of breast cancers, and promotes proliferation, transformation and EMT of cancer cells. It was reported that TAZ renders breast cancer cells with cancer stem cell features. However, whether TAZ regulates telomeres is still unclear. In this study, we explored the roles of TAZ in the regulation of telomere maintenance in TNBC cells.

METHODS: siRNA and shRNA was used to generate TAZ-depleted TNBC cell lines. qPCR and Southern analysis of terminal restriction fragments techniques were used to test telomere length. Co-immunoprecipitation, Western blotting, immunofluorescence, Luciferase reporter assay and Chromatin-IP were conducted to investigate the underlying mechanism.

RESULTS: By knocking down the expression of TAZ in TNBC cells, we found, for the first time, that TAZ is essential for the maintenance of telomeres in TNBC cells. Moreover, loss of TAZ causes senescence phenotype of TNBC cells. The observed extremely shortened telomeres in late passages of TAZ knocked down cells correlate with an elevated hTERT expression, reductions of shelterin proteins, and an activated DNA damage response pathway. Our data also showed that depletion of TAZ results in overexpression of TERRAs, which are a group of telomeric repeat-containing RNAs and regulate telomere length and integrity. Furthermore, we discovered that TAZ maintains telomere length of TNBC cells likely by facilitating the expression of Rad51C, a crucial element of homologous recombination pathway that promotes telomere replication.

CONCLUSIONS: This study supports the notion that TAZ is an oncogenic factor in TNBC, and further reveals a novel telomere-related pathway that is employed by TAZ to regulate TNBC.

RevDate: 2021-09-06

Dogan F, NR Forsyth (2021)

Epigenetic features in regulation of telomeres and telomerase in stem cells.

Emerging topics in life sciences pii:229723 [Epub ahead of print].

The epigenetic nature of telomeres is still controversial and different human cell lines might show diverse histone marks at telomeres. Epigenetic modifications regulate telomere length and telomerase activity that influence telomere structure and maintenance. Telomerase is responsible for telomere elongation and maintenance and is minimally composed of the catalytic protein component, telomerase reverse transcriptase (TERT) and template forming RNA component, telomerase RNA (TERC). TERT promoter mutations may underpin some telomerase activation but regulation of the gene is not completely understood due to the complex interplay of epigenetic, transcriptional, and posttranscriptional modifications. Pluripotent stem cells (PSCs) can maintain an indefinite, immortal, proliferation potential through their endogenous telomerase activity, maintenance of telomere length, and a bypass of replicative senescence in vitro. Differentiation of PSCs results in silencing of the TERT gene and an overall reversion to a mortal, somatic cell phenotype. The precise mechanisms for this controlled transcriptional silencing are complex. Promoter methylation has been suggested to be associated with epigenetic control of telomerase regulation which presents an important prospect for understanding cancer and stem cell biology. Control of down-regulation of telomerase during differentiation of PSCs provides a convenient model for the study of its endogenous regulation. Telomerase reactivation has the potential to reverse tissue degeneration, drive repair, and form a component of future tissue engineering strategies. Taken together it becomes clear that PSCs provide a unique system to understand telomerase regulation fully and drive this knowledge forward into aging and therapeutic application.

RevDate: 2021-09-06

Hu K, Ghandi M, FW Huang (2021)

Integrated evaluation of telomerase activation and telomere maintenance across cancer cell lines.

eLife, 10: pii:66198 [Epub ahead of print].

In cancer, telomere maintenance is critical for the development of replicative immortality. Using genome sequences from the Cancer Cell Line Encyclopedia and Genomics of Drug Sensitivity in Cancer Project, we calculated telomere content across 1,299 cancer cell lines. We find that telomerase reverse transcriptase (TERT) expression correlates with telomere content in lung, central nervous system, and leukemia cell lines. Using CRISPR/Cas9 screening data, we show that lower telomeric content is associated with dependency of CST telomere maintenance genes. Increased dependencies of shelterin members are associated with wild-type TP53 status. Investigating the epigenetic regulation of TERT, we find widespread allele-specific expression in promoter-wildtype contexts. TERT promoter-mutant cell lines exhibit hypomethylation at PRC2-repressed regions, suggesting a cooperative global epigenetic state in the reactivation of telomerase. By incorporating telomere content with genomic features across comprehensively characterized cell lines, we provide further insights into the role of telomere regulation in cancer immortality.

RevDate: 2021-09-07

Peng X, Huang J, Xia S, et al (2021)

Association of leukocyte telomere length with metabolic syndrome in type 2 diabetes mellitus.

Journal of research in medical sciences : the official journal of Isfahan University of Medical Sciences, 26:43.

Background: Leukocyte telomere length (LTL) has been revealed to be associated with aging-related diseases such as metabolic syndrome (MetS) and Type 2 diabetes mellitus (T2DM). We aimed to investigate the correlation of LTL with MetS and its components in T2DM patients in this cross-sectional study.

Materials and Methods: A total of 344 T2DM patients were enrolled into this study. LTL was measured by Southern blot-based terminal restriction fragment length analysis. MetS was clinically defined by 2007 Chinese Guidelines on Prevention and Treatment of Dyslipidemia in Adults.

Results: Of 344 T2DM patients, 53% had MetS. T2DM patients with MetS had significantly longer LTL than those without MetS (6451.95 ± 51.10 base pairs vs. 6076.13 ± 55.13 base pairs, P < 0.001), especially when T2DM patients had poor glycemic control (hemoglobin A1c ≥7%). Meanwhile, the trend of longer LTL was associated with the increased components of MetS in T2DM patient. Finally, LTL had a significant association with MetS (odds ratio [OR]: 2.096, 95% confidence interval [CI] 1.337-3.285, P = 0.001), low levels of high-density lipoprotein-cholesterol (HDL-C) (OR: 2.412, 95% CI 1.350-4.308, P = 0.003) in T2DM patients.

Conclusion: T2DM patients with MetS had a significantly longer LTL than those without MetS. The longer LTL was especially evident in T2DM patients with poor glycemic control. Longer LTL was positively associated with MetS, particularly low levels of HDL-C in T2DM patients.

RevDate: 2021-09-25

Darvishi FZ, M Saadat (2021)

Morphine treatment is associated with diminished telomere length together with down-regulated TERT and TERF2 mRNA levels.

Drug and alcohol dependence, 227:108982.

BACKGROUND: Drug dependence promotes accelerated aging and higher mortality compare with the general population. Telomere length is a biomarker of determination of cellular aging. Telomere attrition has been reported in heroin dependent patients. To investigate whether telomere length is affected by morphine or not, the expressions of hTERT and TERF2 in morphine treated human SH-SY5Y cells were determined and compared with untreated cells.

METHODS: The SH-SY5Y cells were treated with 1 and 5 μM concentrations of morphine for different exposure times (1d, 2d, 3d, 7d and 60 days). The mRNA levels of hTERT and TERF2 were determined using quantitative real-time RCR. The relative telomere length was measured as the ratio of telomere/36B4.

RESULTS: The hTERT and TERF2 mRNA levels were down regulated in morphine treated cells as a function of exposure duration. These alterations were reversible if morphine was removed from the culture medium. No reduction in the relative expression of hTERT and TERF2 in the cells exposed to N-acetyl cysteine (NAC) plus morphine was observed. In the SH-SY5Y cells treated by 5 μM morphine for 60 consecutive days, the hTERT and TERF2 mRNA levels and relative telomere lengths remarkably decreased.

CONCLUSIONS: Reversible alteration of mRNA levels by removing morphine from culture medium, and effect of NAC in co-treatment of morphine plus NAC, emphasize the role of reactive oxygen species in down-regulation of the expression of hTERT and TERF2 by morphine. Telomere attrition in morphine treated cells is a consequence of down-regulation of the expression of hTERT and TERF2.

RevDate: 2021-09-15

Atema E, van Noordwijk AJ, S Verhulst (2021)

Telomere dynamics in relation to experimentally increased locomotion costs and fitness in great tits.

Molecular ecology [Epub ahead of print].

Evidence that telomere length (TL) and dynamics can be interpreted as proxy for 'life stress' experienced by individuals stems largely from correlational studies. We tested for effects of an experimental increase of workload on telomere dynamics by equipping male great tits (Parus major) with a 0.9 g backpack for a full year. In addition, we analysed associations between natural life-history variation, TL and TL dynamics. Carrying 5% extra weight for a year did not significantly accelerate telomere attrition. This agrees with our earlier finding that this experiment did not affect survival or future reproduction. Apparently, great tit males were able to compensate behaviourally or physiologically for the increase in locomotion costs we imposed. We found no cross-sectional association between reproductive success and TL, but individuals with higher reproductive success (number of recruits) lost fewer telomere base pairs in the subsequent year. We used the TRF method to measure TL, which method yields a TL distribution for each sample, and the association between reproductive success and telomere loss was more pronounced in the higher percentiles of the telomere distribution, in agreement with the higher impact of ageing on longer telomeres within individuals. Individuals with longer telomeres and less telomere shortening were more likely to survive to the next breeding season, but these patterns did not reach statistical significance. Whether successful individuals are characterized by losing fewer or more base pairs from their telomeres varies between species, and we discuss aspects of ecology and social organisation that may explain this variation.

RevDate: 2021-09-03

Saunders CN, Kinnersley B, Culliford R, et al (2021)

Relationship between genetically determined telomere length and glioma risk.

Neuro-oncology pii:6363706 [Epub ahead of print].

BACKGROUND: Telomere maintenance is increasingly recognised as being fundamental to glioma oncogenesis with longer leucocyte telomere length (LTL) reported to increase risk of glioma. To gain further insight into the relationship between telomere genetics and risk of glioma we conducted several complementary analyses, using GWAS data on LTL (78,592 individuals) and glioma (12,488 cases and 18,169 controls).

METHODS: We performed both classical and Summary Mendelian Randomization (SMR), coupled with heterogeneity in dependent instruments tests, at genome-wide significant LTL loci to examine if an association was mediated by the same causal variant in glioma. To prioritize genes underscoring glioma-LTL associations we analysed gene expression and DNA methylation data.

RESULTS: Genetically increased LTL was significantly associated with increased glioma risk, IVW-RE ORSD 4.79 (95% CI: 2.11-10.85, P = 1.76 × 10 -4). SMR confirmed the previously reported LTL associations at 3q26.2 (TERC; PSMR = 1.33 × 10 -5), 5p15.33 (TERT; PSMR = 9.80 × 10 -27), 10q24.33 (STN1 alias OBFC1; PSMR = 4.31 × 10 -5) and 20q13.3 (STMN3/RTEL1; PSMR = 2.47 × 10 -4) glioma risk loci. Our analysis implicates variation at 1q42.12 (PSMR = 1.55 × 10 -2), 6p21.3 (PSMR = 9.76 × 10 -3), 6p22.2 (PSMR = 5.45 × 10 -3), 7q31.33 (PSMR = 6.52 × 10 -3) and 11q22.3 (PSMR = 8.89 × 10 -4) as risk factors for glioma risk. Whilst complicated by patterns of linkage disequilibrium, genetic variation involving PARP1, PRRC2A, CARMIL1, POT1 and ATM-NPAT1 was implicated in the aetiology of glioma.

CONCLUSIONS: These observations extend the role of telomere-related genes in the development of glioma.

RevDate: 2021-09-03

Purdue-Smithe AC, Kim K, Andriessen VC, et al (2021)

Preconception leukocyte telomere length and pregnancy outcomes among women with demonstrated fecundity.

Human reproduction (Oxford, England) pii:6363634 [Epub ahead of print].

STUDY QUESTION: Is preconception leukocyte telomere length associated with fecundability, pregnancy loss and live birth among women attempting natural conception with a history of 1-2 prior pregnancy losses?

SUMMARY ANSWER: Preconception leukocyte telomere length is not associated with fecundability, pregnancy loss or live birth.

WHAT IS KNOWN ALREADY: As women increasingly delay childbearing, accessible preconception biomarkers to predict pregnancy outcomes among women seeking natural conception could improve preconception counseling. Findings of small case-control or cross-sectional studies suggest that telomere attrition is associated with adverse pregnancy outcomes among women undergoing fertility treatment, but prospective studies in non-clinical populations are lacking.

STUDY DESIGN, SIZE, DURATION: Participants included 1228 women aged 18-40 years with a history of 1-2 prior pregnancy losses who were recruited at four university medical centers (2006-2012).

Preconception leukocyte telomere length was measured at baseline using PCR and reported as a ratio (T/S) in relation to population-specific standard reference DNA. Women were followed for up to six cycles while attempting to conceive. Associations of telomere length with fecundability, live birth and pregnancy loss were estimated using discrete Cox proportional hazards models and log-binomial models.

After adjustment for age, BMI, smoking and other factors, preconception telomere length was not associated with fecundability (Q4 vs Q1 FOR = 1.00; 95% CI = 0.79, 1.27), live birth (Q4 vs Q1 RR = 1.00; 95% CI = 0.85, 1.19), or pregnancy loss (Q4 vs Q1 RR = 1.12; 95% CI = 0.78, 1.62).

Telomere length was measured in leukocytes, which is an accessible tissue in women attempting natural conception but may not reflect telomere length in oocytes. Most women were younger than 35 years, limiting our ability to evaluate associations among older women. Participants had a history of 1-2 prior pregnancy losses; therefore, our findings may not be widely generalizable.

Despite prior research suggesting that telomere length may be associated with pregnancy outcomes among women seeking fertility treatment, our findings suggest that leukocyte telomere length is not a suitable biomarker of pregnancy establishment or maintenance among women attempting natural conception.

This research was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (National Institutes of Health, Bethesda, MD, USA; contract numbers HHSN267200603423, HHSN267200603424 and HHSN267200603426). The authors have no conflicts of interest to disclose.

TRIAL REGISTRATION NUMBER: The trial was registered with, number NCT00467363.

RevDate: 2021-09-25

Pennarun G, Picotto J, Etourneaud L, et al (2021)

Increase in lamin B1 promotes telomere instability by disrupting the shelterin complex in human cells.

Nucleic acids research, 49(17):9886-9905.

Telomere maintenance is essential to preserve genomic stability and involves telomere-specific proteins, DNA replication and repair proteins. Lamins are key components of the nuclear envelope and play numerous roles, including maintenance of the nuclear integrity, regulation of transcription, and DNA replication. Elevated levels of lamin B1, one of the major lamins, have been observed in some human pathologies and several cancers. Yet, the effect of lamin B1 dysregulation on telomere maintenance remains unknown. Here, we unveil that lamin B1 overexpression drives telomere instability through the disruption of the shelterin complex. Indeed, lamin B1 dysregulation leads to an increase in telomere dysfunction-induced foci, telomeric fusions and telomere losses in human cells. Telomere aberrations were preceded by mislocalizations of TRF2 and its binding partner RAP1. Interestingly, we identified new interactions between lamin B1 and these shelterin proteins, which are strongly enhanced at the nuclear periphery upon lamin B1 overexpression. Importantly, chromosomal fusions induced by lamin B1 in excess were rescued by TRF2 overexpression. These data indicated that lamin B1 overexpression triggers telomere instability through a mislocalization of TRF2. Altogether our results point to lamin B1 as a new interacting partner of TRF2, that is involved in telomere stability.

RevDate: 2021-09-01

Abbasalizad-Farhangi M (2021)

Central obesity accelerates leukocyte telomere length (LTL) shortening in apparently healthy adults: A systematic review and meta-analysis.

Critical reviews in food science and nutrition [Epub ahead of print].

Shorter telomere length is associated with numerous comorbidities; central obesity might trigger leukocyte telomere shortening; in the current meta-analysis we evaluated the association of central obesity with leukocyte telomere length among adults. A systematic search from Scopus, PubMed, Embase and Proquest electronic databases up to May 2021 was done. The final screening, provided five articles to be included in final meta-analysis. Those in the highest category of telomere length had 3.72 cm lower waist circumference (WC) compared with those in the lowest category (WMD=-3.718; CI=-7.180, -0.257 P = 0.035; I2 = 95.4%). Also, those in the highest LTL category had 0.02 lower waist to hip ratio (WHR) compared with those in the lowest category, although this association was not significant (WMD: -0.02; CI=-0.04, 0.01; P = 0.19; I2= 90.7%). In quality assessment of included studies, all of the studies had moderate or high quality score and there was no study with poor quality. Higher leukocyte telomere length was accompanied with lower WC among adults. This association was not significant for difference in WHR. Because of the high heterogeneity values and also because of the observational design of included studies, the inference of causality of these associations needs further investigations.Supplemental data for this article is available online at .

RevDate: 2021-08-30

Hailu EM, Lewis TT, Needham BL, et al (2021)

Longitudinal Associations Between Discrimination, Neighborhood Social Cohesion, and Telomere Length: The Multi-Ethnic Study of Atherosclerosis.

The journals of gerontology. Series A, Biological sciences and medical sciences pii:6324315 [Epub ahead of print].

BACKGROUND: We aimed to examine if neighborhood social cohesion moderated longitudinal associations between baseline reports of discrimination and 10-year changes in leukocyte telomere length (LTL).

METHODS: Data are from the Multi-Ethnic Study of Atherosclerosis (N = 1064; age range 45-84 years). Baseline discrimination was measured using the Major Experiences of Discrimination Scale (MDS; none, 1 domain, ≥2 domains) and the Experiences of Discrimination Scale (EDS; none, moderate, high). Neighborhood social cohesion at baseline was assessed via a community survey within census tract-defined neighborhoods. 10-year change in LTL was defined as regression to the mean-corrected 10-year difference in the ratio of telomeric DNA to a single-copy gene (T/S).

RESULTS: In linear mixed-effects models, we found that neighborhood social cohesion modified the effect of baseline reports of MDS on 10-year changes in LTL, independent of sociodemographic characteristics, health behaviors, and health conditions (p(χ 2) = .01). Among those residing in neighborhoods with low social cohesion, experiencing major discrimination in ≥2 domains was associated with faster LTL attrition over 10 years, compared to reporting no discrimination (β = -0.03; 95% confidence interval: -0.06, -0.003). We found no main associations for either discrimination measure and no interaction between EDS and neighborhood social cohesion.

CONCLUSIONS: Results indicate that neighborhood social cohesion is an important dimension of the neighborhood context that may moderate the impact of major experiences of discrimination on telomere length attrition. These findings help advance our understanding of the integral role that neighborhood environments play in attenuating the effect of discrimination on accelerated cell aging.


ESP Quick Facts

ESP Origins

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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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).


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


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 )