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Bibliography on: Telomeres

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ESP: PubMed Auto Bibliography 14 Dec 2019 at 01:49 Created: 

Telomeres

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

Created with PubMed® Query: telomere[title] OR telomeres[title] NOT pmcbook NOT ispreviousversion

Citations The Papers (from PubMed®)

RevDate: 2019-12-13

Adamusová K, Khosravi S, Fujimoto S, et al (2019)

Two combinatorial patterns of telomere histone marks in plants with canonical and non-canonical telomere repeats.

The Plant journal : for cell and molecular biology [Epub ahead of print].

Telomeres, nucleoprotein structures at the ends of linear eukaryotic chromosomes, are crucial for the maintenance of genome integrity. In most plants, telomeres consist of conserved tandem repeat units comprising the TTTAGGG motif. Recently, non-canonical telomeres were described in several plants and plant taxons, including the carnivorous plant Genlisea hispidula (TTCAGG/TTTCAGG), the genus Cestrum (Solanaceae; TTTTTTAGGG), and plants from the Asparagales order with either a vertebrate-type telomere repeat TTAGGG or Allium genus-specific CTCGGTTATGGG repeat. We analyzed epigenetic modifications of telomeric histones in plants with canonical and non-canonical telomeres, and further in telomeric chromatin captured from leaves of Nicotiana benthamiana transiently transformed by telomere CRISPR-dCas9-eGFP, and of Arabidopsis thaliana stably transformed with TALE_telo C-3 × GFP. Two combinatorial patterns of telomeric histone modifications were identified: (i) an Arabidopsis-like pattern (A. thaliana, G. hispidula, Genlisea nigrocaulis, Allium cepa, Narcissus pseudonarcissus, Petunia hybrida, Solanum tuberosum, Solanum lycopersicum) with telomeric histones decorated predominantly by H3K9me2; (ii) a tobacco-like pattern (Nicotiana tabacum, N. benthamiana, C. elegans) with a strong H3K27me3 signal. Our data suggest that epigenetic modifications of plant telomere-associated histones are related neither to the sequence of the telomere motif nor to the lengths of the telomeres. Nor the phylogenetic position of the species plays the role; representatives of the Solanaceae family are included in both groups. Since both patterns of histone marks are compatible with fully functional telomeres in respective plants, we conclude that the described specific differences in histone marks are not critical for telomere functions.

RevDate: 2019-12-13

Karere GM, Mahaney MC, Newman DE, et al (2019)

Diet-induced leukocyte telomere shortening in a baboon model for early stage atherosclerosis.

Scientific reports, 9(1):19001 pii:10.1038/s41598-019-55348-8.

Reported associations between leukocyte telomere length (LTL) attrition, diet and cardiovascular disease (CVD) are inconsistent. This study explores effects of prolonged exposure to a high cholesterol high fat (HCHF) diet on LTL in a baboon model of atherosclerosis. We measured LTL by qPCR in pedigreed baboons fed a chow (n = 105) or HCHF (n = 106) diet for 2 years, tested for effects of diet on LTL, and association between CVD risk factors and atherosclerotic lesions with LTL. Though not different at baseline, after 2 years median LTL is shorter in HCHF fed baboons (P < 0.0001). Diet predicts sex- and age-adjusted LTL and LTL attrition (P = 0.0009 and 0.0156, respectively). Serum concentrations of CVD biomarkers are associated with LTL at the 2-year endpoint and LTL accounts approximately 6% of the variance in aortic lesions (P = 0.04). Although heritable at baseline (h2 = 0.27, P = 0.027) and after 2 years (h2 = 0.46, P = 0.0038), baseline LTL does not predict lesion extent after 2 years. Atherogenic diet influences LTL, and LTL is a potential biomarker for early atherosclerosis. Prolonged exposure to an atherogenic diet decreases LTL and increases LTL attrition, and shortened LTL is associated with early-stage atherosclerosis in pedigreed baboons.

RevDate: 2019-12-12

Everson F, Martens DS, Nawrot TS, et al (2019)

Personal exposure to NO2 and benzene in the Cape Town region of South Africa is associated with shorter leukocyte telomere length in women.

Environmental research, 182:108993 pii:S0013-9351(19)30790-X [Epub ahead of print].

Air pollution exposure is a major global health concern and has been associated with molecular aging. Unfortunately, the situation has not received much attention in the African region. The aim of this study was to investigate whether current personal ambient NO2 and benzene, toluene, ethyl-benzene and xylenes (ortho (o)-, meta (m)- and para (p)-xylene (BTEX) exposure is associated with leukocyte telomere length (LTL), a marker of molecular ageing, in apparently healthy women (mean ± SD age: 42.5 ± 13.4 years) residing in the Cape Town region of South Africa. The repeated measures study collected data from 61 women. Seven-day median (interquartile range (IQR)) personal NO2 and BTEX exposure levels were determined via compact passive diffusion samplers carried on the person prior to baseline (NO2: 14.2 (9.4-17.2) μg/m³; Benzene: 3.1 (2.1-5.3) μg/m³) and 6-month follow-up (NO2: 10.6 (6.6-13.6) μg/m³; Benzene: 2.2 (1.3-4.9) μg/m³) visits. LTL was measured at baseline and follow-up using a real-time PCR method. Multiple linear mixed model analyses (adjusting for age, body mass index, smoking, employment status, level of education and assessment visit) showed that each IQR increment increase in NO2 (7.0 μg/m³) and benzene (3.3 μg/m³) was associated with -7.30% (95% CI: -10.98 to -3.46%; p < 0.001) and -6.78% (95% CI: -11.88 to -1.39%; p = 0.015) difference in LTL, respectively. The magnitude of these effects of NO2 and benzene corresponds to the effect of an increase of 10.3- and 6.0-year in chronological age on LTL. Our study shows that personal exposures to NO2 and benzene are associated with molecular ageing as indicated by LTL in healthy women residing in the Cape Town region.

RevDate: 2019-12-12

Davé A, Pai CC, Durley SC, et al (2019)

Homologous recombination repair intermediates promote efficient de novo telomere addition at DNA double-strand breaks.

Nucleic acids research pii:5673631 [Epub ahead of print].

The healing of broken chromosomes by de novo telomere addition, while a normal developmental process in some organisms, has the potential to cause extensive loss of heterozygosity, genetic disease, or cell death. However, it is unclear how de novo telomere addition (dnTA) is regulated at DNA double-strand breaks (DSBs). Here, using a non-essential minichromosome in fission yeast, we identify roles for the HR factors Rqh1 helicase, in concert with Rad55, in suppressing dnTA at or near a DSB. We find the frequency of dnTA in rqh1Δ rad55Δ cells is reduced following loss of Exo1, Swi5 or Rad51. Strikingly, in the absence of the distal homologous chromosome arm dnTA is further increased, with nearly half of the breaks being healed in rqh1Δ rad55Δ or rqh1Δ exo1Δ cells. These findings provide new insights into the genetic context of highly efficient dnTA within HR intermediates, and how such events are normally suppressed to maintain genome stability.

RevDate: 2019-12-11

Rai R, Gu P, Broton C, et al (2019)

The Replisome Mediates A-NHEJ Repair of Telomeres Lacking POT1-TPP1 Independently of MRN Function.

Cell reports, 29(11):3708-3725.e5.

Telomeres use shelterin to protect chromosome ends from activating the DNA damage sensor MRE11-RAD50-NBS1 (MRN), repressing ataxia-telangiectasia, mutated (ATM) and ATM and Rad3-related (ATR) dependent DNA damage checkpoint responses. The MRE11 nuclease is thought to be essential for the resection of the 5' C-strand to generate the microhomologies necessary for alternative non-homologous end joining (A-NHEJ) repair. In the present study, we uncover DNA damage signaling and repair pathways engaged by components of the replisome complex to repair dysfunctional telomeres. In cells lacking MRN, single-stranded telomeric overhangs devoid of POT1-TPP1 do not recruit replication protein A (RPA), ATR-interacting protein (ATRIP), and RAD 51. Rather, components of the replisome complex, including Claspin, Proliferating cell nuclear antigen (PCNA), and Downstream neighbor of SON (DONSON), initiate DNA-PKcs-mediated p-CHK1 activation and A-NHEJ repair. In addition, Claspin directly interacts with TRF2 and recruits EXO1 to newly replicated telomeres to promote 5' end resection. Our data indicate that MRN is dispensable for the repair of dysfunctional telomeres lacking POT1-TPP1 and highlight the contributions of the replisome in telomere repair.

RevDate: 2019-12-11

Lincz LF, Scorgie FE, Garg MB, et al (2019)

A simplified method to calculate telomere length from Southern blot images of terminal restriction fragment lengths.

BioTechniques [Epub ahead of print].

Southern blotting of DNA terminal restriction fragment lengths is the gold standard for measuring mean telomere length. Analysis of the final image is a crucial step in this process, however, current techniques are cumbersome and prone to error. Here we present a simple and accurate method for analyzing telomere smears. Basic 2D gel imaging software was used to automatically subtract background, generate standard curves and calculate net intensity and MW at each position (i) along the telomere smear. Our method required no statistical software or major data manipulation and correctly classified >80% of 18 samples as having short, medium or long telomeres compared with 33-72% using other methods.

RevDate: 2019-12-11

Bateson M, Eisenberg DTA, D Nettle (2019)

Controlling for baseline telomere length biases estimates of the rate of telomere attrition.

Royal Society open science, 6(10):190937 pii:rsos190937.

Longitudinal studies have sought to establish whether environmental exposures such as smoking accelerate the attrition of individuals' telomeres over time. These studies typically control for baseline telomere length (TL) by including it as a covariate in statistical models. However, baseline TL also differs between smokers and non-smokers, and telomere attrition is spuriously linked to baseline TL via measurement error and regression to the mean. Using simulated datasets, we show that controlling for baseline TL overestimates the true effect of smoking on telomere attrition. This bias increases with increasing telomere measurement error and increasing difference in baseline TL between smokers and non-smokers. Using a meta-analysis of longitudinal datasets, we show that as predicted, the estimated difference in telomere attrition between smokers and non-smokers is greater when statistical models control for baseline TL than when they do not, and the size of the discrepancy is positively correlated with measurement error. The bias we describe is not specific to smoking and also applies to other exposures. We conclude that to avoid invalid inference, models of telomere attrition should not control for baseline TL by including it as a covariate. Many claims of accelerated telomere attrition in individuals exposed to adversity need to be re-assessed.

RevDate: 2019-12-11

Martínez-Ezquerro JD, Rodríguez-Castañeda A, Ortiz-Ramírez M, et al (2019)

OXIDATIVE STRESS, TELOMERE LENGTH, AND FRAILTY IN AN OLD AGE POPULATION.

Revista de investigacion clinica; organo del Hospital de Enfermedades de la Nutricion, 71(6):393-401.

Background: A global aging population requires focusing on the risk factors for unhealthy aging, preventive medicine, and chronic disease management. The identification of adverse health outcomes in older adults has been addressed by the characterization of frailty as a biological syndrome. In this field, oxidative stress and telomere length have been suggested as biomarkers of aging.

Objective: The objective of the study was to study the association of oxidative stress, telomere length, and frailty in an old age population.

Methods: We conducted a cross-sectional study based on 2015 data from 202 members of a cohort of older adults (n = 202; F/M gender ratio: 133/69; mean age: 69.89 ± 7.39 years). Reactive oxygen species were measured by dichlorofluorescein diacetate and lipid peroxidation by malondialdehyde. Telomere length was determined using quantitative polymerase chain reaction with SYBR Green Master Mix.

Results: Statistical analysis showed an association between telomere length and frailty but no association between oxidative stress and telomere length or frailty.

Conclusions: Telomere length could eventually be used as a marker to differentiate between healthy and unhealthy aging as expressed by frailty phenotype; oxidative stress seemed merely a biological process of aging.

RevDate: 2019-12-11

Clemente DBP, Maitre L, Bustamante M, et al (2019)

Obesity is associated with shorter telomeres in 8 year-old children.

Scientific reports, 9(1):18739 pii:10.1038/s41598-019-55283-8.

Telomere length is considered a biomarker of biological aging. Shorter telomeres and obesity have both been associated with age-related diseases. To evaluate the association between various indices of obesity with leukocyte telomere length (LTL) in childhood, data from 1,396 mother-child pairs of the multi-centre European birth cohort study HELIX were used. Maternal pre-pregnancy body mass index (BMI) and 4 adiposity markers in children at age 8 (6-11) years were assessed: BMI, fat mass, waist circumference, and skinfold thickness. Relative LTL was obtained. Associations of LTL with each adiposity marker were calculated using linear mixed models with a random cohort effect. For each 1 kg/m² increment in maternal pre-pregnancy BMI, the child's LTL was 0.23% shorter (95%CI: 0.01,0.46%). Each unit increase in child BMI z-score was associated with 1.21% (95%CI: 0.30,2.11%) shorter LTL. Inverse associations were observed between waist circumference and LTL (-0.96% per z-score unit; 95%CI: -2.06,0.16%), and skinfold thickness and LTL (-0.10% per z-score unit; 95%CI: -0.23,0.02%). In conclusion, this large multicentric study suggests that higher child adiposity indicators are associated with short telomeres in children, and that associations are stronger for child BMI than for maternal pre-pregnancy BMI.

RevDate: 2019-12-11

Nersisyan L, Nikoghosyan M, Arakelyan A, et al (2019)

WGS-based telomere length analysis in Dutch family trios implicates stronger maternal inheritance and a role for RRM1 gene.

Scientific reports, 9(1):18758 pii:10.1038/s41598-019-55109-7.

Telomere length (TL) regulation is an important factor in ageing, reproduction and cancer development. Genetic, hereditary and environmental factors regulating TL are currently widely investigated, however, their relative contribution to TL variability is still understudied. We have used whole genome sequencing data of 250 family trios from the Genome of the Netherlands project to perform computational measurement of TL and a series of regression and genome-wide association analyses to reveal TL inheritance patterns and associated genetic factors. Our results confirm that TL is a largely heritable trait, primarily with mother's, and, to a lesser extent, with father's TL having the strongest influence on the offspring. In this cohort, mother's, but not father's age at conception was positively linked to offspring TL. Age-related TL attrition of 40 bp/year had relatively small influence on TL variability. Finally, we have identified TL-associated variations in ribonuclease reductase catalytic subunit M1 (RRM1 gene), which is known to regulate telomere maintenance in yeast. We also highlight the importance of multivariate approach and the limitations of existing tools for the analysis of TL as a polygenic heritable quantitative trait.

RevDate: 2019-12-11

Tesmer VM, Smith EM, Danciu O, et al (2019)

Combining conservation and species-specific differences to determine how human telomerase binds telomeres.

Proceedings of the National Academy of Sciences of the United States of America pii:1911912116 [Epub ahead of print].

Telomerase catalyzes telomeric DNA synthesis at chromosome ends to allow for continued cell division. The telomeric protein TPP1 is essential for enhancing the processivity of telomerase and recruiting the enzyme to telomeres. The telomerase interaction surface on human TPP1 has been mapped to 2 regions of the N-terminal oligosaccharide/oligonucleotide-binding (OB) domain, namely the TPP1 glutamate (E) and leucine (L)-rich (TEL) patch and the N terminus of TPP1-oligosaccharide/oligonucleotide-binding (NOB) region. To map the telomerase side of the interface, we exploited the predicted structural similarities for human and Tetrahymena thermophila telomerase as well as the species specificity of human and mouse telomerase for their cognate TPP1 partners. We show that swapping in the telomerase essential N-terminal (TEN) and insertions in fingers domain (IFD)-TRAP regions of the human telomerase catalytic protein subunit TERT into the mouse TERT backbone is sufficient to bias the species specificity toward human TPP1. Employing a structural homology-based mutagenesis screen focused on surface residues of the TEN and IFD regions, we identified TERT residues that are critical for contacting TPP1 but dispensable for other aspects of telomerase structure or function. We present a functionally validated structural model for how human telomerase engages TPP1 at telomeres, setting the stage for a high-resolution structure of this interface.

RevDate: 2019-12-09

Markova DN, Christensen SM, E Betrán (2019)

Telomere-Specialized Retroelements in Drosophila: Adaptive Symbionts of the Genome, Neutral, or in Conflict?.

BioEssays : news and reviews in molecular, cellular and developmental biology [Epub ahead of print].

Linear chromosomes shorten in every round of replication. In Drosophila, telomere-specialized long interspersed retrotransposable elements (LINEs) belonging to the jockey clade offset this shortening by forming head-to-tail arrays at Drosophila telomere ends. As such, these telomeric LINEs have been considered adaptive symbionts of the genome, protecting it from premature decay, particularly as Drosophila lacks a conventional telomerase holoenzyme. However, as reviewed here, recent work reveals a high degree of variation and turnover in the telomere-specialized LINE lineages across Drosophila. There appears to be no absolute requirement for LINE activity to maintain telomeres in flies, hence the suggestion that the telomere-specialized LINEs may instead be neutral or in conflict with the host, rather than adaptive.

RevDate: 2019-12-09

Adam N, Degelman E, Briggs S, et al (2019)

Telomere analysis using 3D fluorescence microscopy suggests mammalian telomere clustering in hTERT-immortalized Hs68 fibroblasts.

Communications biology, 2:451 pii:692.

Telomere length and dynamics are central to understanding cell aging, genomic instability and cancer. Currently, there are limited guidelines for analyzing telomeric features in 3D using different cellular models. Image processing for telomere analysis is of increasing interest in many fields, however a lack of standardization can make comparisons and reproducibility an issue. Here we provide a user's guide for quantitative immunofluorescence microscopy of telomeres in interphase cells that covers image acquisition, processing and analysis. Strategies for determining telomere size and number are identified using normal human diploid Hs68 fibroblasts. We demonstrate how to accurately determine telomere number, length, volume, and degree of clustering using quantitative immunofluorescence. Using this workflow, we make the unexpected observation that hTERT-immortalized Hs68 cells with longer telomeres have fewer resolvable telomeres in interphase. Rigorous quantification indicates that this is due to telomeric clustering, leading to systematic underestimation of telomere number and overestimation of telomere size.

RevDate: 2019-12-09

Li Y, Li X, Cao M, et al (2019)

Seryl tRNA synthetase cooperates with POT1 to regulate telomere length and cellular senescence.

Signal transduction and targeted therapy, 4:50 pii:78.

Deregulated telomere length is a causative factor in many physiological and pathological processes, including aging and cancer. Many studies focusing on telomeres have revealed important roles for cooperation between the Shelterin protein complex and telomerase in maintaining telomere length. However, it remains largely unknown whether and how aging-related stresses, such as deregulated protein homeostasis, impact telomere length. Here, we explored the possible roles of aminoacyl tRNA synthetases (AARSs), key enzymes catalyzing the first reactions in protein synthesis, in regulating telomere length and aging. We selected seryl tRNA synthetase (SerRS) since our previous studies discovered expanded functions of SerRS in the nucleus in addition to its canonical cytoplasmic role in protein synthesis. In this study, we revealed that overexpression of SerRS promoted cellular senescence and inhibited the growth of cervical tumor xenografts in mice by triggering the senescence of tumor cells. In the nucleus, SerRS directly bound to telomeric DNA repeats and tethered more POT1 proteins to telomeres through a direct interaction between the UNE-S domain of SerRS and the OB1 domain of POT1. We further demonstrated that SerRS-induced enrichment of POT1 prevented the recruitment of telomerase to telomeres, resulting in progressive telomere shortening. Our data suggested a possible molecular link between protein synthesis and telomere length control, the deregulation of which may be associated with aging and cancer.

RevDate: 2019-12-09

Aref S, Al Saeed A, El Menshawy N, et al (2019)

Prognostic relevance of telomere length and telomerase reverse transcriptase variant (rs2242652) on the multiple myeloma patients.

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

BACKGROUND: The search for enhancement of multiple myeloma prognostic tools is an area of current research. This study aimed to assess the clinicopathological impact of telomere length and telomerase reverse transcriptase (TERT) polymorphic variant, rs2242652, on multiple myeloma (MM) patients.

METHODS: Fifty MM patients and 50 healthy controls were included. Relative telomere length (RTL) and rs2242652 genotype polymorphic variants of TERT were analyzed using real-time polymerase chain reaction (PCR). The MM patients' group was categorized into stage I (n = 16); stage II (n = 12), and stage III (n = 22).

RESULTS: The median telomere length was significantly longer in MM patients' group (0.78) as compared to controls (0.43) (P = .001). Multivariate regression analysis revealed that MM patients with RTL < 0.5 had significant poor response for induction remission therapy with odds ratio 26.45. On the other hand, TERT genotyping analysis of rs2242652 revealed insignificant difference between cases and controls (P = .234), regarding to induction remission response. Survival analysis using Kaplan-Meier curve revealed that patients with shorter telomere length and those with TERT genotype GA had shorter overall survival.

CONCLUSION: Telomere length and TERT rs2242652 genotype polymorphism could be used for refining risk stratification of MM patients.

RevDate: 2019-12-06

Zhang M, Hu ML, Huang JJ, et al (2019)

Association of leukocyte telomere length with non-alcoholic fatty liver disease in patients with type 2 diabetes.

Chinese medical journal [Epub ahead of print].

BACKGROUND: Leukocyte telomere has been shown to be related to insulin resistance-related diseases, such as type 2 diabetes mellitus (T2DM) and non-alcoholic fatty liver disease (NAFLD). This cross-sectional study investigated the association of leukocyte telomere length (LTL) with NAFLD in T2DM patients.

METHODS: Clinical features were collected and LTL was measured by Southern blot-based terminal restriction fragment length analysis in 120 T2DM patients without NAFLD and 120 age-matched T2DM patients with NAFLD. NAFLD was clinically defined by manifestations of ultrasonography. The correlation between LTL and clinical and biochemical parameters were analyzed by Pearson correlation or Spearman correlation analysis. Factors for NAFLD in T2DM patients were identified using multiple logistic regressions.

RESULTS: LTL in T2DM patients with NAFLD were significantly longer than those without NAFLD (6400.2 ± 71.8 base pairs [bp] vs. 6023.7 ± 49.5 bp, P < 0.001), especially when diabetes duration was less than 2 years. Meanwhile, the trend of shorter LTL was associated with the increased diabetes duration in T2DM patient with NAFLD, but not in T2DM patients without NAFLD. Finally, LTL (odds ratio [OR]: 1.001, 95% confidence interval [CI]: 1.000-1.002, P = 0.001), as well as body mass index (OR: 1.314, 95% CI: 1.169-1.477, P < 0.001) and triglycerides (OR: 1.984, 95% CI: 1.432-2.747, P < 0.001), had a significant association with NAFLD status in T2DM patients.

CONCLUSIONS: T2DM patients with NAFLD had a significantly longer LTL than those without NAFLD. The longer LTL was especially evident in the early stage of T2DM, indicating that longer LTL may be used as a biomarker for NAFLD in T2DM patients.

RevDate: 2019-12-06

Wang Y, Best A, Fernández-Torrón R, et al (2019)

Leukocyte telomere length in patients with myotonic dystrophy type I: a pilot study.

Annals of clinical and translational neurology [Epub ahead of print].

Myotonic dystrophy type I (DM1) is an autosomal dominant disease of which clinical manifestations resemble premature aging. We evaluated the contribution of telomere length in pathogenesis in 361 DM1 patients (12 with serial measurements) and 223 unaffected relative controls using qPCR assay. While no differences in baseline leukocyte relative telomere length (RTL) was noted, the data suggested an accelerated RTL attrition in DM1 (discovery cohort: T/S change/year = -0.013 in DM1 vs. -0.005 in controls, P = 0.04); similar trend was noted in validation cohort. Further investigations are needed to examine the role of TL in the pathophysiology of DM1.

RevDate: 2019-12-06

Opstad TB, Kalstad AA, Holte KB, et al (2019)

Shorter Leukocyte Telomere Lengths in Healthy Relatives of Patients with Coronary Heart Disease.

Rejuvenation research [Epub ahead of print].

Background and Aims Telomere length (TL), sirtuin (SIRT) 1, growth-differentiation-factor (GDF) 11 as well as inflammaging have been related to age-related diseases. In healthy subjects, we aimed to investigate whether leukocyte TL (LTL) associated with family history of coronary heart disease (CHD), age, sex and lifestyle, and further potential covariations between LTL, GDF11, SIRT1 and selected pro-inflammatory markers. Material and Methods In 118 healthy subjects (18-81years, 58% females), whole blood was collected for DNA and RNA isolation and PCR relative quantification of LTLs and gene-expression of SIRT1, GDF11, interleukin (IL)-18 and interferon (IFN)ƴ, respectively, and serum SIRT1 and IL-18 analyses. Results Shorter LTLs associated with a 7 fold higher frequency of hereditary CHD in subjects with LTLs in quartile (Q)1 compared to Q2-4 (OR=7.5, 95% CI 2.5-21.6, p<0.001, adjusted). We also observed that LTLs in Q4 compared to Q1-3 associated with higher leukocyte expression of SIRT1 and GDF11 (p=0.052 and p=0.058), lower IFNƴ expression (p=0.009) and lower circulating IL-18 levels (p=0.027). SIRT1 and GDF11 expression were strongly inter-correlated (Spearman rho=0.85, p<0.001). Overall, smoking, snus and alcohol consumption were not associated with LTLs. Conclusion The observed shorter LTLs in association with elevated expression of SIRT1 and GDF11 and dampened inflammation in hereditary-CHD-subjects, suggest impending risk of disease. More research are warranted to shed light on early lifestyle interventions targeting these mechanisms, to promote healthier ageing in individuals with hereditary burden.

RevDate: 2019-12-05

Gao K, Wei C, Zhu J, et al (2019)

Exploring the Causal Pathway From Telomere Length to Alzheimer's Disease: An Update Mendelian Randomization Study.

Frontiers in psychiatry, 10:843.

Increasing evidence shows that telomere length shortening is associated with the risk for Alzheimer's disease (AD), pointing to a potential modifiable target for prevention. However, the causality of this association is still not clear. To investigate the causal relationship between telomere length and AD, we use two-sample Mendelian randomization (MR) to assess potential causal inference. We used summary-level data for telomere length (9,190 participants) and AD (71,880 cases and 383,378 controls). We performed two-sample MR analysis with single nucleotide polymorphisms previously identified to be associated with telomere length. The MR analyses were conducted using the inverse-variance-weighted method and complemented with the maximum likelihood, weighted median, weighted mode approaches. MR evidence suggested that shorter telomere length was causally associated with a higher risk for AD (inverse-variance weighted estimate of odds ratio (OR): 1.03 per SD decrease of telomere length, P=1.21×10-2). The maximum likelihood, weighted median, weighted mode yielded a similar pattern of effects. The results were similar in sensitivity analyses. Using genetic instruments identified from large-scale genome-wide association study, robust evidence supports a causal role of telomere length shortening with increased risk of AD.

RevDate: 2019-12-04

Dantzer B, van Kesteren F, Westrick SE, et al (2019)

Maternal glucocorticoids promote offspring growth without inducing oxidative stress or shortening telomeres in wild red squirrels.

The Journal of experimental biology pii:jeb.212373 [Epub ahead of print].

Elevations in glucocorticoid levels (GCs) in breeding females may induce adaptive shifts in offspring life histories. Offspring produced by mothers with elevated GCs may be better prepared to face harsh environments where a faster pace of life is beneficial. We examined how experimentally elevated GCs in pregnant or lactating North American red squirrels (Tamiasciurus hudsonicus) affected offspring postnatal growth, structural size, oxidative stress levels (two antioxidants and oxidative protein damage) in three different tissues (blood, heart, liver), and liver telomere lengths. We predicted that offspring from mothers treated with GCs would grow faster but would also have higher levels of oxidative stress and shorter telomeres, which may predict reduced longevity. Offspring from mothers treated with GCs during pregnancy were 8.3% lighter around birth but grew (in body mass) 17.0% faster than those from controls, whereas offspring from mothers treated with GCs during lactation grew 34.8% slower than those from controls and did not differ in body mass around birth. Treating mothers with GCs during pregnancy or lactation did not alter the oxidative stress levels or telomere lengths of their offspring. Fast-growing offspring from any of the treatment groups did not have higher oxidative stress levels or shorter telomere lengths, indicating that offspring that grew faster early in life did not exhibit oxidative costs after this period of growth. Our results indicate that elevations in maternal GCs may induce plasticity in offspring growth without long-term oxidative costs to the offspring that might result in a shortened lifespan.

RevDate: 2019-12-04

Noguera JC, A Velando (2019)

Reduced telomere length in embryos exposed to predator cues.

The Journal of experimental biology pii:jeb.216176 [Epub ahead of print].

It is often assumed that embryos are isolated from external influences, but recent studies indicate that environmental stressors during prenatal stages can exert long-term negative effects on fitness. A potential mechanism by which predation risk may lastingly shape life-history traits and phenotypes is via effects on telomeres. However, whether prenatal exposition to environmental stressors, such as cues of predator presence, affects postnatal telomere length has not hitherto been investigated. Using an experimental design in which we modified the exposure of yellow-legged gull (Larus michahellis) embryos to social cues of predator presence (i.e. alarm calls), we show that prenatally exposed chicks had shorter telomeres after hatching. Since young birds with shorter telomere length have reduced fledging success, reproductive success and lifespan, the reduced telomere length in the exposed chicks is likely to have long-term fitness consequences. Moreover, our results provide a mechanistic link through which predators may negatively affect population dynamics.

RevDate: 2019-12-03

Abdulkina LR, Kobayashi C, Lovell JT, et al (2019)

Components of the ribosome biogenesis pathway underlie establishment of telomere length set point in Arabidopsis.

Nature communications, 10(1):5479 pii:10.1038/s41467-019-13448-z.

Telomeres cap the physical ends of eukaryotic chromosomes to ensure complete DNA replication and genome stability. Heritable natural variation in telomere length exists in yeast, mice, plants and humans at birth; however, major effect loci underlying such polymorphism remain elusive. Here, we employ quantitative trait locus (QTL) mapping and transgenic manipulations to identify genes controlling telomere length set point in a multi-parent Arabidopsis thaliana mapping population. We detect several QTL explaining 63.7% of the total telomere length variation in the Arabidopsis MAGIC population. Loss-of-function mutants of the NOP2A candidate gene located inside the largest effect QTL and of two other ribosomal genes RPL5A and RPL5B establish a shorter telomere length set point than wild type. These findings indicate that evolutionarily conserved components of ribosome biogenesis and cell proliferation pathways promote telomere elongation.

RevDate: 2019-12-02

de Souza MR, Rohr P, Kahl VFS, et al (2019)

The influence of polymorphisms of xenobiotic-metabolizing and DNA repair genes in DNA damage, telomere length and global DNA methylation evaluated in open-cast coal mining workers.

Ecotoxicology and environmental safety pii:S0147-6513(19)31306-5 [Epub ahead of print].

Coal plants represent one of the main sources of environmental pollution due to the combustion process of this mineral and the consequent release of gases and particles which, in significant quantities, can lead to a potential risk to health and the environment. The susceptibility of individuals to the genotoxic effects of coal mining can be modulated by genetic variations in the xenobiotic detoxification and DNA repair processes. The aim of this study was to evaluate if xenobiotic metabolism polymorphism, base excision repair polymorphisms and non-homologous end joining repair polymorphism, could modify individual susceptibility to genomic instability and epigenetic alterations induced in workers by occupational exposure to coal. In this study, polymerase chain reaction was used to examine the polymorphic sites. The sample population comprising 70 coal mine workers and 71 workers non-exposed to coal. Our results demonstrated the effect of individual genotypes on different biomarkers evaluated. Significant decrease in % of global DNA methylation were observed in CYP1A1 Val/- exposed individuals compared to CYP1A1 Ile/Ile individuals. Coal workers who carried the XRCC4 Ile/Ile genotype showed decrease NBUD frequencies, while the XRCC4 Thr/- genotype was associated with decrease in Buccal micronucleus cells for the group not exposed. No influence of GSTM1 null, GSTT1 null, GSTP1 Ile105Val, hOGG1 Ser326Cys, XRCC1 Arg194Trp polymorphisms was observed. Thus, the current study reinforces the importance of considering the effect of metabolizing and repair variant genotypes on the individual susceptibility to incorporate DNA damage, as these processes act in a coordinated manner to determine the final response to coal exposure.

RevDate: 2019-12-02

Navarro-Mateu F, Rubio-Aparicio M, Cayuela P, et al (2019)

The association of telomere length with substance use disorders: systematic review and meta-analysis protocol.

Systematic reviews, 8(1):298 pii:10.1186/s13643-019-1199-x.

BACKGROUND: The present protocol was designed for a systematic review and meta-analysis aimed at determining the association of telomere length with substance use disorders with the exclusion of nicotine addiction, and to identify potential moderators of the effect of telomere length. Such methodological information may provide guidance to improve the quality of future research on this important topic.

METHODS: Potential studies will be identified through electronic databases (PubMed/MEDLINE, EMBASE, PsycINFO, and Web of Science) up from inception onwards. The inclusion criteria will include published or unpublished observational studies (cohort, case-control, and cross-sectional studies) reporting telomere length in adult patients with substance use disorder compared with a control group. Non-human studies or other study designs such as reviews, case-only, family-based, and/or population studies with only healthy participants will be excluded, as well as those focused solely on nicotine addiction. The main outcome will be telomere length in adults with substance use disorder (primary) and, specifically, in those with alcohol use disorder (secondary). Two investigators will independently evaluate the preselected studies for possible inclusion and will extract data following a standardized protocol. Disagreements will be resolved by consensus. The risk of bias of all included studies will be assessed using the Newcastle-Ottawa Quality Assessment Scale for non-randomized studies. Data will be converted into standardized mean differences as effect size index, and random-effects models will be used for the meta-analysis. Cochran's Q statistic, I2 index, and visual inspection of the forest plot will be used to verify study heterogeneity. Subgroup analyses and meta-regressions will be conducted to ascertain heterogeneity. Several sensitivity analyses will be conducted to address the influence of potential confounding factors. Publication bias will be examined using the "funnel plot" method with Duval and Tweedie's trim-and-fill method and Egger test.

DISCUSSION: This systematic review will assess the association of telomere length with substance use disorders aside from nicotine addiction.

PROSPERO registration number CRD42019119785.

RevDate: 2019-11-30

Shahane AD, LeRoy AS, Denny BT, et al (2019)

Connecting cognition, cardiology, and chromosomes: Cognitive reappraisal impacts the relationship between heart rate variability and telomere length in CD8+CD28- cells.

Psychoneuroendocrinology, 112:104517 pii:S0306-4530(19)31258-2 [Epub ahead of print].

Individuals who poorly regulate emotion exhibit premature aging and worse general health. Telomere shortening, a prognostic biomarker of physical health, is related to aging, poor immunocompetence and autonomic nervous system functioning. Cognitive reappraisal is one type of emotion regulation strategy, which involves changing one's appraisal of an aversive situation to modify its emotional impact. Heart rate variability (HRV; i.e., oscillations in heart rate) relates to emotion regulatory processes, such that higher HRV typically reflects greater regulatory capacity. Previous research has identified a positive association between HRV and telomere length. Importantly, the association between HRV and telomere length may change depending on how often an individual uses cognitive reappraisal. One hundred and thirty-seven healthy participants completed measures of cognitive reappraisal frequency, HRV, and underwent blood draws to measure telomere length (computed with the relative ratio of telomere repeat copy number to single copy gene number) in the T cell effector population, CD8+CD28-. Cognitive reappraisal moderated the relationship between telomere length and HRV such that individuals with high cognitive reappraisal frequency had a significant positive association between HRV and telomere length, while individuals with average and less than average frequency did not exhibit this relationship. The results suggest that frequent usage of cognitive reappraisal enhances the already positive influence of HRV on chromosomal integrity in CD8+CD28- T lymphocytes. Although future research is needed to test these effects causally, these findings suggest that regularly using emotion regulation techniques may buffer the relationship between autonomic nervous system functioning and chromosomal integrity in immune cells.

RevDate: 2019-11-30

Hou J, Yin W, Li P, et al (2019)

Joint effect of polycyclic aromatic hydrocarbons and phthalates exposure on telomere length and lung function.

Journal of hazardous materials pii:S0304-3894(19)31617-6 [Epub ahead of print].

Exposure to polycyclic aromatic hydrocarbons and phthalates are linked to lung function decline and altered relative telomere length (RTL) accompanying with oxidative stress and inflammatory events in human body. However, limited data are available about impacts of co-exposure of PAHs and phthalates on lung function and RTL. We conducted a pilot study with repeated measures during the winter of 2014 and summer of 2015 in Wuhan city, China. Participants took part in the measures of lung function, RTL, urinary monohydroxylated-PAHs (OH-PAHs) and phthalate metabolites over three consecutive days in each season. Linear mixed-effect (LME) models and Bayesian kernel machine regression (BKMR) were used to analyze the relations of OH-PAHs or phthalate metabolites with lung function or RTL. LME models showed the negative associations of 3-day average of hydroxyphenanthrene (2 + 3-, 4-OHPhe) or 1-hydroxypyrene with FEV1, 3-day average of 2 + 3-OHPhe with FVC. BKMR models revealed the negative relation of eight OH-PAHs with FEV1, FVC or RTL; nine phthalate metabolites may counteract an overall effect of eight OH-PAHs on FEV1, FVC or RTL. The findings indicated that urinary phthalate metabolites may counteract the negative association of urinary OH-PAHs on FEV1 or FVC, which may be partially linked to shorter RTL regarding biological aging.

RevDate: 2019-11-29

Kim JH, Mo Nam C, Lee D, et al (2019)

Heritability of telomere length across three generations of Korean families.

Pediatric research pii:10.1038/s41390-019-0699-7 [Epub ahead of print].

AIM: Leukocyte telomere length (LTL), an indicator of aging, is influenced by both genetic and environmental factors; however, its heritability is unknown. We determined heritability and inheritance patterns of telomere length across three generations of families.

METHODS: We analyzed 287 individuals from three generations of 41 Korean families, including newborns, parents, and grandparents. LTL (the ratio of telomere repeat copy number to single gene copy number) was measured by quantitative real-time PCR. We estimated heritability using the SOLAR software maximum-likelihood variance component methods and a pedigree dataset. With adjustment for age and length of marriage, Pearson's partial correlation was performed for spousal pairs.

RESULTS: Heritability of LTL was high in all participants (h2 = 0.64). There were no significant differences in correlation coefficients of telomere length between paternal and maternal lines. There was a positive LTL correlation in grandfather-grandmother pairs (r = 0.25, p = 0.03) but not in father-mother pairs. After adjusting for age and length of marriage, the relationship between telomere lengths in grandfathers and grandmothers disappeared. There were inverse correlations between spousal rank differences of telomere length and length of marriage.

CONCLUSIONS: LTL is highly heritable without a sex-specific inheritance pattern and may be influenced by a shared environment.

RevDate: 2019-11-29

Zheng Q, Huang J, G Wang (2019)

Mitochondria, Telomeres and Telomerase Subunits.

Frontiers in cell and developmental biology, 7:274.

Mitochondrial functions and telomere functions have mostly been studied independently. In recent years, it, however, has become clear that there are intimate links between mitochondria, telomeres, and telomerase subunits. Mitochondrial dysfunctions cause telomere attrition, while telomere damage leads to reprogramming of mitochondrial biosynthesis and mitochondrial dysfunctions, which has important implications in aging and diseases. In addition, evidence has accumulated that telomere-independent functions of telomerase also exist and that the protein component of telomerase TERT shuttles between the nucleus and mitochondria under oxidative stress. Our previously published data show that the RNA component of telomerase TERC is also imported into mitochondria, processed, and exported back to the cytosol. These data show a complex regulation network where telomeres, nuclear genome, and mitochondria are co-regulated by multi-localization and multi-function proteins and RNAs. This review summarizes the connections between mitochondria and telomeres, the mitochondrion-related functions of telomerase subunits, and how they play a role in crosstalk between mitochondria and the nucleus.

RevDate: 2019-11-29

Zhao J, Nguyen LNT, Nguyen LN, et al (2019)

ATM Deficiency Accelerates DNA Damage, Telomere Erosion, and Premature T Cell Aging in HIV-Infected Individuals on Antiretroviral Therapy.

Frontiers in immunology, 10:2531.

HIV infection leads to a phenomenon of inflammaging, in which chronic inflammation induces an immune aged phenotype, even in individuals on combined antiretroviral therapy (cART) with undetectable viremia. In this study, we investigated T cell homeostasis and telomeric DNA damage and repair machineries in cART-controlled HIV patients at risk for inflammaging. We found a significant depletion of CD4 T cells, which was inversely correlated with the cell apoptosis in virus-suppressed HIV subjects compared to age-matched healthy subjects (HS). In addition, HIV CD4 T cells were prone to DNA damage that extended to chromosome ends-telomeres, leading to accelerated telomere erosion-a hallmark of cell senescence. Mechanistically, the DNA double-strand break (DSB) sensors MRE11, RAD50, and NBS1 (MRN complex) remained intact, but both expression and activity of the DNA damage checkpoint kinase ataxia-telangiectasia mutated (ATM) and its downstream checkpoint kinase 2 (CHK2) were significantly suppressed in HIV CD4 T cells. Consistently, ATM/CHK2 activation, DNA repair, and cellular functions were also impaired in healthy CD4 T cells following ATM knockdown or exposure to the ATM inhibitor KU60019 in vitro, recapitulating the biological effects observed in HIV-derived CD4 T cells in vivo. Importantly, ectopic expression of ATM was essential and sufficient to reduce the DNA damage, apoptosis, and cellular dysfunction in HIV-derived CD4 T cells. These results demonstrate that failure of DSB repair due to ATM deficiency leads to increased DNA damage and renders CD4 T cells prone to senescence and apoptotic death, contributing to CD4 T cell depletion or dysfunction in cART-controlled, latent HIV infection.

RevDate: 2019-11-27

Chatelain M, Drobniak SM, M Szulkin (2019)

The association between stressors and telomeres in non-human vertebrates: a meta-analysis.

Ecology letters [Epub ahead of print].

Animal response to stressors such as harsh environmental conditions and demanding biological processes requires energy generated through increased mitochondrial activity. This results in the production of reactive oxygen species (ROS). In vitro and some in vivo studies suggest that oxidative damage of DNA caused by ROS is responsible for telomere shortening. Since telomere length is correlated with survival in many vertebrates, telomere loss is hypothesised to trigger cellular ageing and/ or to reflect the harshness of the environment an individual has experienced. To improve our understanding of stress-induced telomere dynamics in non-human vertebrates, we analysed 109 relevant studies in a meta-analytical framework. Overall, the exposure to possible stressors was associated with shorter telomeres or higher telomere shortening rate (average effect size = -0.16 ± 0.03). This relationship was consistent for all phylogenetic classes and for all a priori-selected stressor categories. It was stronger in the case of pathogen infection, competition, reproductive effort and high activity level, which emphasises their importance in explaining intraspecific telomere length variability and, potentially, lifespan variability. Interestingly, the association between stressor exposure and telomeres in one hand, and oxidative stress in the other hand, covaried, suggesting the implication of oxidative stress in telomere dynamics.

RevDate: 2019-11-27

Tucker LA (2019)

Milk Fat Intake and Telomere Length in U.S. Women and Men: The Role of the Milk Fat Fraction.

Oxidative medicine and cellular longevity, 2019:1574021.

The associations between milk intake frequency and milk fat consumption and telomere length, an index of biological aging, were studied using an NHANES sample of 5,834 U.S. adults and a cross-sectional design. The milk consumption variables were assessed with the NHANES Diet Behavior and Nutrition questionnaire. The quantitative polymerase chain reaction method was used to measure leukocyte telomere length. Results showed that milk consumption frequency was not related to telomere length; however, there was a strong association between milk fat intake and telomere length. With the sample delimited to milk drinkers only, milk fat intake was linearly and inversely related to telomere length, after adjusting for the covariates (F = 8.6, P = 0.0066). For each 1 percentage point increase in milk fat consumed (e.g., 1% to 2%), adults had more than 4 years of additional biological aging. With milk fat intake divided into 5 categories (i.e., milk abstainers, nonfat, 1%, 2%, and full-fat milk), mean telomere lengths differed across the categories (F = 4.1, P = 0.0093). The mean telomere difference between the extremes of milk fat intake (nonfat vs. full-fat) was 145 base pairs, representing years of additional biological aging for full-fat milk consumers. Effect modification testing indicated that the milk fat and cellular aging association may be partly due to saturated fat intake differences across the milk fat groups. When the sample was delimited to adults reporting only high total saturated fat intake (tertile 3), the milk fat and telomere relationship was strong. However, when the sample was restricted to adults reporting only low saturated fat consumption (tertile 1), there was no relationship between milk fat intake and telomere length. Overall, the findings highlight an association of increased biological aging in U.S. adults who consumed high-fat milk. The results support the latest Dietary Guidelines for Americans (2015-2020), which recommend consumption of low-fat milk, but not high-fat milk, as part of a healthy diet.

RevDate: 2019-11-27

Boscolo-Rizzo P, Rampazzo E, Polesel J, et al (2019)

Predictive and prognostic significance of telomerase levels/telomere length in tissues and peripheral blood in head and neck squamous cell carcinoma.

Scientific reports, 9(1):17572 pii:10.1038/s41598-019-54028-x.

A growing body of evidence indicates that the expression of TERT, the catalytic subunit of telomerase, is a biological marker of progression in several cancers. We investigated the predictive and prognostic role of TERT levels and telomere length in tissues and peripheral blood in patients with head and neck squamous cell carcinoma (HNSCC). High TERT levels in cancer tissues were independently associated with worse response to therapy (odds ratio [OR]:6.26), regional failure (hazard ratio [HR]:5.75), progression (HR:2.12), and death (HR:3.53). Longer telomeres in the mucosa surrounding the tumor (SM) were independently associated with a lower risk of mucosal failure (HR:0.39). While telomere length in peripheral blood mononuclear cells (PBMC) significantly decreased with age, no correlation was found between age and telomere length in SM. No associations were found between TERT levels in plasma and telomere length in PBMC and the prognostic variables. High levels of TERT transcripts in cancer cells represent a reliable prognostic marker for identifying HNSCC patients with risk of progression. The altered relationship of telomere length to age in SM compared with PBMC suggests that in a subset of cases the phenotypically normal SM constitutes an acquired telomere-shortened epithelial field prone to genetic instability.

RevDate: 2019-11-26

Berneau SC, Shackleton J, Nevin C, et al (2019)

Associations of sperm telomere length with semen parameters, clinical outcomes and lifestyle factors in human normozoospermic samples.

Andrology [Epub ahead of print].

BACKGROUND: Many studies have demonstrated that lifestyle factors can affect sperm quality and fertility. Sperm Telomere Length (STL) has been reported as potential biomarker or sperm quality. However, no studies have investigated the how lifestyle factors can effect STL and associated clinical outcomes.

OBJECTIVES: The purpose of this manuscript is to investigate any association between STL with lifestyle factors, semen parameters and clinical outcomes.

MATERIALS AND METHODS: Sperm Telomere Length was measured using real-time PCR in normozoospermic male partners (n = 66) of couples undergoing ART treatment. Each participant also completed a detailed questionnaire about general lifestyle. Linear regression univariate and ANCOVA analyses were performed to respectively determine correlations between STL and study parameters or identify statistically significant differences in STL while controlling for age, BMI and other factors.

RESULTS: Using a linear regression model, STL is positively correlated with in vitro fertilisation success (n = 65, r = 0.37, P = .004) but not with embryo cleavage rates and post-implantation clinical outcomes including gestational age-adjusted birth weight. No associations were observed between STL and sperm count, concentration or progressive motility. We further found that STL did not associate age, BMI, health or lifestyle factors.

DISCUSSION: In somatic cells - The rate of telomere shortening is influenced by a number of lifestyle factors such as: smoking, diet and occupation. However, little is known about how lifestyle factors affect STL and subsequently reproductive outcome. Out data suggest that STL might have an important role mechanistically for fertilisation rate regardless of sperm parameters and lifestyle factors.

CONCLUSION: The results of this study demonstrate that STL is associated with in vitro fertilization rates, but not with semen parameters nor lifestyle factors. Further investigations are warranted to identify the potential variation of STL overtime to clarify its significance as a potential biomarker in ART.

RevDate: 2019-11-26

Duan X, Zhang D, Wang S, et al (2019)

Effects of polycyclic aromatic hydrocarbon exposure and miRNA variations on peripheral blood leukocyte DNA telomere length: A cross-sectional study in Henan Province, China.

The Science of the total environment pii:S0048-9697(19)35595-0 [Epub ahead of print].

Telomeres play a major role in human aging and disease, especially in most cancers. Telomere length was shortened in workers exposed to polycyclic aromatic hydrocarbons (PAHs) and influenced by individual genetic variations in telomere-binding proteins. MicroRNAs (miRNAs) can affect the progress of messenger RNA (mRNA) transcription; however, whether polymorphisms in miRNA can act on the telomere length is still unknown. Therefore, we aimed to explore the relationships between telomere damage and genetic polymorphisms in miRNA or environmental exposure. A total of 544 coke oven workers and 238 healthy controls were recruited. After collecting peripheral blood and extracting the genomic DNA of the study subjects, the telomere length (TL) in their leucocytes was detected by a real-time quantitative polymerase chain reaction (PCR), and polymorphisms in miRNAs were genotyped using the flight mass spectrometry technique. The concentrations of the four urine OH-PAHs were determined by high performance liquid chromatography (HPLC), and the Soxhlet extraction method was used to detect the concentration of coke oven emissions (COEs) in the air. We found that the peripheral blood leucocyte DNA TL was significantly shorter in the exposure group (0.75; 0.51, 1.08) than that in the control group (1.05; 0.76, 1.44) (Z = 7.692, P < 0.001). The total cumulative exposure dose (CED), 1-hydroxypyrene, 2-hydroxynaphthalene, and 3-hydroxyphenanthrene were significantly negatively correlated with TL (r = -0.307, P < 0.001; r = -0.212, P < 0.001; r = -0.110, P = 0.025; r = -0.251, P < 0.001, respectively). MiR-145 rs353291 GG, miR-30a rs2222722 CT/CC, and miR-197 rs1889470 AA could protect the telomere end in the exposed workers (P < 0.05). The interaction between miR-197 rs1889470 and the CED had an effect on TL (β = 0.066, P = 0.034). This is the first study to evaluate gene-environmental interactions for miRNA polymorphisms and PAH exposure in coke oven workers.

RevDate: 2019-11-26

Ojeda-Rodríguez A, Zazpe I, Alonso-Pedrero L, et al (2019)

Association between diet quality indexes and the risk of short telomeres in an elderly population of the SUN project.

Clinical nutrition (Edinburgh, Scotland) pii:S0261-5614(19)33130-9 [Epub ahead of print].

BACKGROUND: Shorter telomeres are associated with several age-related diseases, and lifestyle factors could influence this relationship. The aim of this study was to examine associations between salivary telomere length (TL) and diet quality using 5 evidence-based dietary indexes in an elderly (>55 years old) Spanish population of the SUN project (n = 886).

METHOD: TL was measured using the quantitative real-time polymerase chain reaction. Age-adjusted TL variable through residuals methods was used for all analysis. Diet quality was assessed by the Prime Diet Quality Score (PDQS), Fat Quality Index (FQI), Mediterranean Diet Adherence Screener (MEDAS), Dietary Approaches to Stop Hypertension (DASH) index and the Alternative Healthy Eating Index (AHEI-2010).

RESULTS: TL did differ according to sex, smoking status, and dyslipidemia in elderly subjects of the SUN study. In addition, subjects with dyslipidemia (compared to absence of dyslipidemia) had a significantly higher risk (27% vs. 18%, p = 0.015) of short telomeres (
CONCLUSION: Adherence to high quality diet is associated to longer salivary TL in our elderly Spanish population of the SUN study.

RevDate: 2019-11-25

Ravindranathan A, Diolaiti ME, Cimini BA, et al (2019)

In Situ Visualization of Telomere Length, Telomere Elongation, and TERT Expression in Single Cells.

Current protocols in cell biology, 85(1):e97.

Telomerase plays a critical role in cancer and aging by adding hexa-nucleotide repeats to the ends of telomeres and extending the cellular proliferative lifespan. The very low level of telomerase expression in most cell populations and the difficulty of detecting telomere elongation in single cells have limited the study of telomerase expression and function in individual cells of a heterogeneous population. The method described in this article combines single-molecule detection (RNAscope) of telomerase reverse transcriptase (TERT) with our previously described TSQ1 assay for in situ monitoring of telomere extension, thereby enabling detection of TERT expression, telomere length, and telomere elongation in single cells and providing a unique approach for studying the factors that regulate telomere elongation by telomerase. © 2019 by John Wiley & Sons, Inc. Basic Protocol 1: TSQ1 lentivirus production Basic Protocol 2: TSQ1 lentiviral infection and plating Basic Protocol 3: RNAscope analysis Basic Protocol 4: TSQ1 PNA-FISH detection.

RevDate: 2019-11-25

Gu CY, Jin SM, Qin XJ, et al (2019)

Genetic variants in RTEL1 influencing telomere length are associated with prostate cancer risk.

Journal of Cancer, 10(24):6170-6174 pii:jcav10p6170.

Telomere length measured in lymphocytes has been evaluated as a potential biomarker for prostate cancer (PCa) risk. Identifying genetic variants that affect telomere length and testing their association with disease could clarify any causal role. We therefore investigated associations between genetic variants in three telomere length-related genes and PCa risk in a case-control study. The influence of these variants on the leukocyte telomere lengths was then appraised by real-time PCR. RTEL1 rs2297441 [odds ratio (OR): 1.23; 95% confidence interval (CI): 1.03-1.46, P = 0.021] and rs3208008 (OR: 1.23; 95% CI: 1.03-1.46) were associated with PCa risk. These two risk single nucleotide polymorphisms (SNPs) (OR: 0.59; 95% CI: 0.39-0.89, P = 0.012 and OR: 0.58; 95% CI: 0.38-0.87, P = 0.009, respectively) and another SNP PARP1 rs1136410 (OR: 1.53; 95% CI: 1.01-2.31, P = 0.043) were also associated with leukocyte telomere length. These findings support that genetic determinants of telomere length may influence PCa risk.

RevDate: 2019-11-25

McLennan D, Recknagel H, Elmer KR, et al (2019)

Distinct telomere differences within a reproductively bimodal common lizard population.

Functional ecology, 33(10):1917-1927.

Different strategies of reproductive mode, either oviparity (egg-laying) or viviparity (live-bearing), will be associated with a range of other life-history differences that are expected to affect patterns of ageing and longevity. It is usually difficult to compare the effects of alternative reproductive modes because of evolutionary and ecological divergence. However, the very rare exemplars of reproductive bimodality, in which different modes exist within a single species, offer an opportunity for robust and controlled comparisons.One trait of interest that could be associated with life history, ageing and longevity is the length of the telomeres, which form protective caps at the chromosome ends and are generally considered a good indicator of cellular health. The shortening of these telomeres has been linked to stressful conditions; therefore, it is possible that differing reproductive costs will influence patterns of telomere loss. This is important because a number of studies have linked a shorter telomere length to reduced survival.Here, we have studied maternal and offspring telomere dynamics in the common lizard (Zootoca vivipara). Our study has focused on a population where oviparous and viviparous individuals co-occur in the same habitat and occasionally interbreed to form admixed individuals.While viviparity confers many advantages for offspring, it might also incur substantial costs for the mother, for example require more energy. Therefore, we predicted that viviparous mothers would have relatively shorter telomeres than oviparous mothers, with admixed mothers having intermediate telomere lengths. There is thought to be a heritable component to telomere length; therefore, we also hypothesized that offspring would follow the same pattern as the mothers.Contrary to our predictions, the viviparous mothers and offspring had the longest telomeres, and the oviparous mothers and offspring had the shortest telomeres. The differing telomere lengths may have evolved as an effect of the life-history divergence between the reproductive modes, for example due to the increased growth rate that viviparous individuals may undergo to reach a similar size at reproduction. A free http://onlinelibrary.wiley.com/doi/10.1111/1365-2435.13408/suppinfo can be found within the Supporting Information of this article.

RevDate: 2019-11-25

Khavinson VK, Pendina AA, Efimova OA, et al (2019)

Effect of Peptide AEDG on Telomere Length and Mitotic Index of PHA-Stimulated Human Blood Lymphocytes.

Bulletin of experimental biology and medicine pii:10.1007/s10517-019-04664-0 [Epub ahead of print].

We studied the effect of peptide AEDG on telomere length and mitotic index of PHA-stimulated blood lymphocytes from young (18-22 years, N=5) and middle-aged (49-54 years, N=6) men. In the younger age group, no significant changes in the mitotic index were detected, while in the middle-aged group, a decrease in this parameter was found in one case. The relative length of telomeric regions of metaphase chromosomes was evaluated by in situ fluorescence hybridization with DNA probes specific to telomeres. After incubation with peptide AEDG, significant changes in the relative telomere length were found in 7 of 11 individuals (3 cases in the younger age group and 4 cases in the middle age group). Significant increase in telomere length after exposure to peptide AEDG was revealed in 5 cases, including two individuals of the younger age group (by 41 and 55%) and three individuals of the middle age group (by 156, 18, and 76%). In one individual of the younger age group and in one of the middle-age group, a significant decrease in telomere length (by 37 and 15%, respectively) was found. A tendency to normalization of telomere lengths was noted: this parameter increased in individuals with initially lower telomere length relative to the group mean value and decreased in individuals with initially longer telomeres compared to the mean length in the group.

RevDate: 2019-11-24

PerezGrovas-Saltijeral A, Ochoa-Morales A, Miranda-Duarte A, et al (2019)

Telomere length analysis on leukocytes derived from patients with Huntington Disease.

Mechanisms of ageing and development pii:S0047-6374(19)30194-0 [Epub ahead of print].

INTRODUCTION: Huntington´s disease (HD) is a neurodegenerative disorder characterized by neuropsychiatric, motor and cognitive manifestations. It is caused by expansion of the trinucleotide CAG on HTT. The molecular bases are not completely understood, DNA damage, such as double and single strand breaks and oxidative stress (OS) have been implicated. At telomeres, DNA breaks are less efficiently repaired. Double strand breaks evoke the break induced replication (BIR) mechanism. BIR, plus inefficient repair can produce telomere shortening and cellular senescence. Our aim was to investigate the correlation between leukocyte relative telomeric length (RTL) and HD.

METHODS: 206 samples were analyzed, 71 patients with molecular diagnosis and symptomatology (HD), 29 individuals with positive molecular test but asymptomatic (PP) and 106 healthy individuals (NP).

RESULTS: We found a significant difference in RTL between HD patients compared with both, PP and NP, independently of subjects' age.

DISCUSSION: Here we present evidence supporting an association between telomere shortening and HD. Telomere shortening could be related to DNA damage caused by ROS and defective DNA repair mechanism. Both events have been probed to occur in the presence of a mutant Huntingtin. This study contributes with current evidence suggesting a potential role of telomere shortening as HD biomarker.

RevDate: 2019-11-24

Hu MH, Lin XT, Liu B, et al (2019)

Dimeric aryl-substituted imidazoles may inhibit ALT cancer by targeting the multimeric G-quadruplex in telomere.

European journal of medicinal chemistry pii:S0223-5234(19)31043-8 [Epub ahead of print].

In 10-15% of cancers, telomere maintenance is provided by a telomerase-independent mechanism known as alternative lengthening of telomere (ALT), making telomerase inhibitors ineffective on these cancers. Ligands that stabilize telomeric G-quadruplex (G4) are considered to be able to inhibit either the ALT process or disrupt the T-loop structure, which would be promising therapeutic agents for ALT cancers. Notably, the 3'-terminal overhang of telomeric DNA might fold into multimeric G4 containing consecutive G4 subunits, which offers an attractive target for selective ligands considering large numbers of G4s widespread in the genome. In this study, a dimeric aryl-substituted imidazole (DIZ-3) was developed as a selective multimeric G4 ligand based on a G4-ligand-dimerizing strategy. Biophysical experiments revealed that DIZ-3 intercalated into the G4-G4 interface, stabilizing the higher-order structure. Furthermore, this ligand was demonstrated to induce cell cycle arrest and apoptosis, and thus inhibited cell proliferation in an ALT cancer cell line. Cancer cells were more sensitive to DIZ-3, relative to normal cells. Notably, DIZ-3 had little effect on the transcription of several G4-dependent oncogenes. This study provides a nice example for discovering dimeric agents to potentially treat ALT cancers via targeting telomeric multimeric G4.

RevDate: 2019-11-23

Lv X, Wang X, Wang Y, et al (2019)

Folic acid delays age-related cognitive decline in senescence-accelerated mouse prone 8: alleviating telomere attrition as a potential mechanism.

Aging, 11: pii:102461 [Epub ahead of print].

The occurrence of telomere attrition in brain may cause senescence and death of neurons, leading to cognitive decline. Folic acid (FA) has been reported to improve cognitive performance in mild cognitive impairment; however, its association with telomere remains unclear. The study aimed to investigate if alleviation of telomere attrition by FA supplementation could act as a potential mechanism to delay age-related cognitive decline in senescence-accelerated mouse prone 8 (SAMP8). Aged SAMP8 mice were assigned to four treatment groups: FA-deficient diet (FA-D) group, FA-normal diet (FA-N) group, low FA-supplemented diet (FA-L) group and high FA-supplemented diet (FA-H) group. There was also an age-matched senescence-accelerated mouse resistant 1 (SAMR1) control group (Con-R), and a young SAMP8 control group (Con-Y). The results demonstrated that FA supplementation delayed age-related cognitive decline and neurodegeneration in SAMP8 mice. Importantly, this effect could be attributed to the alleviated telomere attrition, which might be interpreted by the decreased levels of reactive oxygen species. Additionally, improved telomere integrity stimulated mitochondrial function via telomere-p53-mithondria pathway, consequently delayed neuronal degeneration. In conclusion, we demonstrate that FA supplementation delays age-related neurodegeneration and cognitive decline in SAMP8 mice, in which alleviated telomere attrition could serve as one influential factor in the process.

RevDate: 2019-11-23

Anonymous (2019)

A Phosphoswitch in Shelterin Component TRF2 Mediates Telomere Dynamics.

Cancer discovery pii:2159-8290.CD-RW2019-177 [Epub ahead of print].

Phosphorylation of shelterin component TRF2 modulates telomere accessibility across the cell cycle.

RevDate: 2019-11-23

Ackermann S, M Fischer (2019)

Telomere Maintenance in Pediatric Cancer.

International journal of molecular sciences, 20(23): pii:ijms20235836.

Telomere length has been proposed as a biomarker of biological age and a risk factor for age-related diseases and cancer. Substantial progress has been made in recent decades in understanding the complex molecular relationships in this research field. However, the majority of telomere studies have been conducted in adults. The data on telomere dynamics in pediatric cancers is limited, and interpretation can be challenging, especially in cases where results are contrasting to those in adult entities. This review describes recent advances in the molecular characterization of structure and function of telomeres, regulation of telomerase activity in cancer pathogenesis in general, and highlights the key advances that have expanded our views on telomere biology in pediatric cancer, with special emphasis on the central role of telomere maintenance in neuroblastoma. Furthermore, open questions in the field of telomere maintenance research are discussed in the context of recently published literature.

RevDate: 2019-11-26

Giri N, Ravichandran S, Wang Y, et al (2019)

Prognostic significance of pulmonary function tests in dyskeratosis congenita, a telomere biology disorder.

ERJ open research, 5(4):.

Pulmonary fibrosis and pulmonary arteriovenous malformations are known manifestations of dyskeratosis congenita (DC), a telomere biology disorder (TBD) and inherited bone marrow failure syndrome caused by germline mutations in telomere maintenance genes resulting in very short telomeres. Baseline pulmonary function tests (PFTs) and long-term clinical outcomes have not been thoroughly studied in DC/TBDs. In this retrospective study, 43 patients with DC and 67 unaffected relatives underwent baseline PFTs and were followed for a median of 8 years (range 1-14). Logistic regression and competing risk models were used to compare PFT results in relation to clinical and genetic characteristics, and patient outcomes. Restrictive abnormalities on spirometry and moderate-to-severe reduction in diffusing capacity of the lung for carbon monoxide were significantly more frequent in patients with DC than relatives (42% versus 12%; p=0.008). The cumulative incidence of pulmonary disease by age 20 years was 55% in patients with DC with baseline PFT abnormalities compared with 17% in those with normal PFTs (p=0.02). None of the relatives developed pulmonary disease. X-linked recessive, autosomal recessive inheritance or heterozygous TINF2 variants were associated with early-onset pulmonary disease that mainly developed after haematopoietic cell transplantation (HCT). Overall, seven of 14 patients developed pulmonary disease post-HCT at a median of 4.7 years (range 0.7-12). The cumulative incidence of pulmonary fibrosis in patients with heterozygous non-TINF2 pathogenic variants was 70% by age 60 years. Baseline PFT abnormalities are common in patients with DC and associated with progression to significant pulmonary disease. Prospective studies are warranted to facilitate clinical trial development for patients with DC and related TBDs.

RevDate: 2019-11-26

Yu Y, Jia W, Lyu Y, et al (2019)

Pwp1 regulates telomere length by stabilizing shelterin complex and maintaining histone H4K20 trimethylation.

Cell discovery, 5:47.

Telomere maintenance is critical for chromosome stability. Here we report that periodic tryptophan protein 1 (PWP1) is involved in regulating telomere length homeostasis. Pwp1 appears to be essential for mouse development and embryonic stem cell (ESC) survival, as homozygous Pwp1-knockout mice and ESCs have never been obtained. Heterozygous Pwp1-knockout mice had shorter telomeres and decreased reproductive capacity. Pwp1 depletion induced rapid telomere shortening accompanied by reduced shelterin complex and increased DNA damage in telomeric regions. Mechanistically, PWP1 bound and stabilized the shelterin complex via its WD40 domains and regulated the overall level of H4K20me3. The rescue of telomere length in Pwp1-deficient cells by PWP1 overexpression depended on SUV4-20H2 co-expression and increased H4K20me3. Therefore, our study revealed a novel protein involved in telomere homeostasis in both mouse and human cells. This knowledge will improve our understanding of how chromatin structure and histone modifications are involved in maintaining telomere integrity.

RevDate: 2019-11-26

Nersisyan L, Hopp L, Loeffler-Wirth H, et al (2019)

Telomere Length Maintenance and Its Transcriptional Regulation in Lynch Syndrome and Sporadic Colorectal Carcinoma.

Frontiers in oncology, 9:1172.

Background: Activation of telomere maintenance mechanisms (TMMs) is a hallmark of most cancers, and is required to prevent genome instability and to establish cellular immortality through reconstitution of capping of chromosome ends. TMM depends on the cancer type. Comparative studies linking tumor biology and TMM have potential impact for evaluating cancer onset and development. Methods: We have studied alterations of telomere length, their sequence composition and transcriptional regulation in mismatch repair deficient colorectal cancers arising in Lynch syndrome (LS-CRC) and microsatellite instable (MSI) sporadic CRC (MSI s-CRC), and for comparison, in microsatellite stable (MSS) s-CRC and in benign colon mucosa. Our study applied bioinformatics analysis of whole genome DNA and RNA sequencing data and a pathway model to study telomere length alterations and the potential effect of the "classical" telomerase (TEL-) and alternative (ALT-) TMM using transcriptomic signatures. Results: We have found progressive decrease of mean telomere length in all cancer subtypes compared with reference systems. Our results support the view that telomere attrition is an early event in tumorigenesis. TMM gets activated in all tumors studied due to concerted overexpression of a large fraction of genes with direct relation to telomere function, where only a very small fraction of them showed recurrent mutations. TEL-related transcriptional state was dominating in all CRC subtypes, showing, however, subtype-specific activation patterns; while contribution of the ALT-TMM was slightly more prominent in the hypermutated MSI s-CRC and LS-CRC. TEL-TMM is mainly activated by over-expression of DKC1 and/or TERT genes and their interaction partners, where DKC1 is more prominent in MSS than in MSI s-CRC and can serve as a transcriptomic marker of TMM activity. Conclusions: Our results suggest that transcriptional patterns are indicative for TMM pathway activation with subtle differences between TEL and ALT mechanisms in a CRC subtype-specific fashion. Sequencing data potentially provide a suited measure to study alterations of telomere length and of underlying transcriptional regulation. Further studies are needed to improve this method.

RevDate: 2019-11-26

Ilska-Warner JJ, Psifidi A, Seeker LA, et al (2019)

The Genetic Architecture of Bovine Telomere Length in Early Life and Association With Animal Fitness.

Frontiers in genetics, 10:1048.

Health and survival are key goals for selective breeding in farm animals. Progress, however, is often limited by the low heritability of these animal fitness traits in addition to measurement difficulties. In this respect, relevant early-life biomarkers may be useful for breeding purposes. Telomere length (TL), measured in leukocytes, is a good candidate biomarker since TL has been associated with health, ageing, and stress in humans and other species. However, telomere studies are very limited in farm animals. Here, we examined the genetic background, genomic architecture, and factors affecting bovine TL measurements in early life, and the association of the latter with animal fitness traits expressed later in life associated with survival, longevity, health, and reproduction. We studied two TL measurements, one at birth (TLB) and another during the first lactation (TLFL) of a cow. We performed a genome-wide association study of dairy cattle TL, the first in a non-human species, and found that TLB and TLFL are complex, polygenic, moderately heritable, and highly correlated traits. However, genomic associations with distinct chromosomal regions were identified for the two traits suggesting that their genomic architecture is not identical. This is reflected in changes in TL throughout an individual's life. TLB had a significant association with survival, length of productive life and future health status of the animal, and could be potentially used as an early-life biomarker for disease predisposition and longevity in dairy cattle.

RevDate: 2019-11-20

Nonaka K, Aida J, Takubo K, et al (2019)

Correlation between Telomere Attrition of Zona Fasciculata and Adrenal Weight Reduction in Older Men.

The Journal of clinical endocrinology and metabolism pii:5634040 [Epub ahead of print].

CONTEXT: Although numerous theories are reported on sex differences in longevity, the underlying biological mechanisms remain unknown. We previously reported that telomere length in the zona reticularis (ZR) cells of the human adrenal cortex was significantly longer in older than that in younger subjects. However, we could not evaluate sex differences in the telomere lengths.

OBJECTIVE: To compare the telomere lengths of adrenocortical and adrenal medullar cells between men and women from infancy through older adulthood.

METHODS: Adrenal glands of 30 male (aged 0 to 100 years) and 25 female (aged 0 to 104 years) autopsied subjects were retrieved from autopsy files. Using quantitative fluorescence in situ hybridization, relative telomere lengths were determined in the parenchymal cells of the three adrenocortical zones and medulla. Age-related changes in the weight of adrenal glands were also investigated.

MAIN RESULTS: Older male subjects (aged 65 years or older) had significantly shorter telomere lengths in zona fasciculata (ZF) cells compared to the corresponding female subjects. In men, older subjects exhibited a significant age-related reduction in adrenal weight; however, no age-related changes in adrenal weight were detected in women.

CONCLUSION: Telomere attrition of ZF cells was correlated with adrenal weight reduction in older men but not in older women, suggesting a decreased number of ZF cells in older men. This may help us understand the possible biological mechanisms of sex difference in longevity of humans.

RevDate: 2019-11-26

Lu R, O'Rourke JJ, Sobinoff AP, et al (2019)

Author Correction: The FANCM-BLM-TOP3A-RMI complex suppresses alternative lengthening of telomeres (ALT).

Nature communications, 10(1):5345 pii:10.1038/s41467-019-13097-2.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

RevDate: 2019-11-21

Aguado J, Sola-Carvajal A, Cancila V, et al (2019)

Inhibition of DNA damage response at telomeres improves the detrimental phenotypes of Hutchinson-Gilford Progeria Syndrome.

Nature communications, 10(1):4990.

Hutchinson-Gilford progeria syndrome (HGPS) is a genetic disorder characterized by premature aging features. Cells from HGPS patients express progerin, a truncated form of Lamin A, which perturbs cellular homeostasis leading to nuclear shape alterations, genome instability, heterochromatin loss, telomere dysfunction and premature entry into cellular senescence. Recently, we reported that telomere dysfunction induces the transcription of telomeric non-coding RNAs (tncRNAs) which control the DNA damage response (DDR) at dysfunctional telomeres. Here we show that progerin-induced telomere dysfunction induces the transcription of tncRNAs. Their functional inhibition by sequence-specific telomeric antisense oligonucleotides (tASOs) prevents full DDR activation and premature cellular senescence in various HGPS cell systems, including HGPS patient fibroblasts. We also show in vivo that tASO treatment significantly enhances skin homeostasis and lifespan in a transgenic HGPS mouse model. In summary, our results demonstrate an important role for telomeric DDR activation in HGPS progeroid detrimental phenotypes in vitro and in vivo.

RevDate: 2019-11-20

Ling P, Qian C, Yu J, et al (2019)

Artificial nanozyme based on platinum nanoparticles anchored metal-organic frameworks with enhanced electrocatalytic activity for detection of telomeres activity.

Biosensors & bioelectronics, 149:111838 pii:S0956-5663(19)30917-0 [Epub ahead of print].

This study reports a new artificial nanozyme based on ultra-small Pt nanoparticles (Pt NPs) grown on nanoscale metalloporphyrin metal organic frameworks (P-MOF(Fe)) (termed as Pt@P-MOF(Fe)) as biomimetic catalysts and redox mediator to detect the telomerase activity. In this system, the P-MOF(Fe) were used as nanocarrier and signal media. The DNA functionalized Pt@P-MOF(Fe) was as signal probe and exhibited enhanced electrochemical signal in the presence of H2O2, owing to the synergistic effect between P-MOF(Fe) and Pt NPs. Upon the addition cell extract, the telomerase primer could extend and then hybridize with assistant DNA2 in the triple-helix, leading to the structure of triple-helix changes and release the hairpin DNA to hybridize with the capture DNA on the surface of Pt@P-MOF(Fe), resulting in the electrochemical signal readout of H2O2 reduction. With the aid of recycling amplification of Exonuclease III, the telomeres sensor exhibited the detection down to 20 Hela cell mL-1. This work supplies a new avenue to design artificial enzyme catalysts and serves as an ideal platform to use metalloporphyrin metal organic frameworks as signal media for detection of analytes.

RevDate: 2019-11-17

Beijers R, Daehn D, Shalev I, et al (2019)

Biological embedding of maternal postpartum depressive symptoms: The potential role of cortisol and telomere length.

Biological psychology pii:S0301-0511(19)30252-2 [Epub ahead of print].

Although maternal postpartum depressive symptoms (PDS) are associated with child behavior problems, the underlying biological mechanisms are poorly understood. Thus, the current study focused on 193 healthy mother-child dyads and investigated child cortisol and telomere length as potential mediating factors. At 3 and 6 months postpartum, mothers reported on PDS. At age 6, children provided saliva and buccal swab samples. At age 10, mothers and children reported on child behavior problems. Structural equation modelling revealed (a) no association between PDS and child behavior problems and thus no possibility of mediation, but that (b) lower cortisol forecast more child-reported internalizing problems, and (c) shorter telomere length predicted more child-reported internalizing and externalizing problems. These findings raise mediational questions about the determinants of these biomarkers.

RevDate: 2019-11-16

Nguyen MT, Lycett K, Olds T, et al (2019)

Objectively measured sleep and telomere length in a population-based cohort of children and midlife adults.

Sleep pii:5626508 [Epub ahead of print].

STUDY OBJECTIVES: Poor sleep patterns in older adults are associated with chromosomal telomere shortening, a marker of cellular senescence. However, studies have relied on self-reported sleep characteristics, with few data for younger individuals. We investigated whether sleep measured via actigraphy was cross-sectionally associated with telomere length in children and midlife adults.

METHODS: A population-based sample of 1874 11-12 year olds and midlife adults (mean age 44 years, SD 5.1) had biological and physical assessments at centers across Australia in 2015-2016. Sleep characteristics, including duration, onset, offset, day-to-day variability, and efficiency, were derived from actigraphy. Relative telomere length (T/S ratio) was measured by quantitative polymerase chain reaction on genomic DNA from peripheral blood. Multivariable regression models estimated associations, adjusting for prespecified confounders.

RESULTS: Both sleep and telomere data were available for 728 children and 1070 adults. Mean (SD) T/S ratio was 1.09 (0.55) in children and 0.81 (0.38) in adults. T/S ratio was not predicted by sleep duration (β 0.04, 95% confidence interval [CI] -0.02 to 0.09, p = .16, children; β -0.004, 95% CI -0.03 to 0.02, p = .70, adults) or most other sleep metrics. The only exception was a weak association between later sleep timing (the midpoint of sleep onset and offset) and longer telomeres in adults (β 0.03, 95% CI 0.01 to 0.06, p = .01).

CONCLUSIONS: Objective sleep characteristics show no convincing associations with telomere length in two largely healthy populations up to at least midlife. Sleep-telomere associations may be a late-life occurrence or may present only with a trigger such as presence of other morbidities.

RevDate: 2019-11-15

Wattis JAD, Qi Q, HM Byrne (2019)

Mathematical modelling of telomere length dynamics.

Journal of mathematical biology pii:10.1007/s00285-019-01448-y [Epub ahead of print].

Telomeres are repetitive DNA sequences located at the ends of chromosomes. During cell division, an incomplete copy of each chromosome's DNA is made, causing telomeres to shorten on successive generations. When a threshold length is reached replication ceases and the cell becomes 'senescent'. In this paper, we consider populations of telomeres and, from discrete models, we derive partial differential equations which describe how the distribution of telomere lengths evolves over many generations. We initially consider a population of cells each containing just a single telomere. We use continuum models to compare the effects of various mechanisms of telomere shortening and rates of cell division during normal ageing. For example, the rate (or probability) of cell replication may be fixed or it may decrease as the telomeres shorten. Furthermore, the length of telomere lost on each replication may be constant, or may decrease as the telomeres shorten. Where possible, explicit solutions for the evolution of the distribution of telomere lengths are presented. In other cases, expressions for the mean of the distribution are derived. We extend the models to describe cell populations in which each cell contains a distinct subpopulation of chromosomes. As for the simpler models, constant telomere shortening leads to a linear reduction in telomere length over time, whereas length-dependent shortening results in initially rapid telomere length reduction, slowing at later times. Our analysis also reveals that constant telomere loss leads to a Gaussian (normal) distribution of telomere lengths, whereas length-dependent loss leads to a log-normal distribution. We show that stochastic models, which include a replication probability, also lead to telomere length distributions which are skewed.

RevDate: 2019-11-15

Smith EM, Pendlebury DF, J Nandakumar (2019)

Structural biology of telomeres and telomerase.

Cellular and molecular life sciences : CMLS pii:10.1007/s00018-019-03369-x [Epub ahead of print].

Telomeres are protein-DNA complexes that protect chromosome ends from illicit ligation and resection. Telomerase is a ribonucleoprotein enzyme that synthesizes telomeric DNA to counter telomere shortening. Human telomeres are composed of complexes between telomeric DNA and a six-protein complex known as shelterin. The shelterin proteins TRF1 and TRF2 provide the binding affinity and specificity for double-stranded telomeric DNA, while the POT1-TPP1 shelterin subcomplex coats the single-stranded telomeric G-rich overhang that is characteristic of all our chromosome ends. By capping chromosome ends, shelterin protects telomeric DNA from unwanted degradation and end-to-end fusion events. Structures of the human shelterin proteins reveal a network of constitutive and context-specific interactions. The shelterin protein-DNA structures reveal the basis for both the high affinity and DNA sequence specificity of these interactions, and explain how shelterin efficiently protects chromosome ends from genome instability. Several protein-protein interactions, many provided by the shelterin component TIN2, are critical for upholding the end-protection function of shelterin. A survey of these protein-protein interfaces within shelterin reveals a series of "domain-peptide" interactions that allow for efficient binding and adaptability towards new functions. While the modular nature of shelterin has facilitated its part-by-part structural characterization, the interdependence of subunits within telomerase has made its structural solution more challenging. However, the exploitation of several homologs in combination with recent advancements in cryo-EM capabilities has led to an exponential increase in our knowledge of the structural biology underlying telomerase function. Telomerase homologs from a wide range of eukaryotes show a typical retroviral reverse transcriptase-like protein core reinforced with elements that deliver telomerase-specific functions including recruitment to telomeres and high telomere-repeat addition processivity. In addition to providing the template for reverse transcription, the RNA component of telomerase provides a scaffold for the catalytic and accessory protein subunits, defines the limits of the telomeric repeat sequence, and plays a critical role in RNP assembly, stability, and trafficking. While a high-resolution definition of the human telomerase structure is only beginning to emerge, the quick pace of technical progress forecasts imminent breakthroughs in this area. Here, we review the structural biology surrounding telomeres and telomerase to provide a molecular description of mammalian chromosome end protection and end replication.

RevDate: 2019-11-22

Crous-Bou M, Molinuevo JL, A Sala-Vila (2019)

Plant-Rich Dietary Patterns, Plant Foods and Nutrients, and Telomere Length.

Advances in nutrition (Bethesda, Md.), 10(Supplement_4):S296-S303.

The world's population is aging as a consequence of an increased global life expectancy. Identifying simple strategies to promote healthy aging (i.e., absence of major chronic diseases, preserved physical and cognitive functions, intact mental health, and good quality of life) have emerged as a major public health concern. Identifying biomarkers to better characterize the aging process is a research priority. Telomeres are repetitive DNA sequences at chromosome ends that prevent the loss of genomic DNA, protecting its physical integrity. Telomere length (TL) is considered a biomarker of aging: shorter telomeres are associated with a decreased life expectancy and increased rates of age-related chronic diseases. Telomere attrition has been shown to be accelerated by oxidative stress and inflammation. Since edible plants contain plenty of compounds with antioxidant and anti-inflammatory properties, it is plausible that their sustained consumption might help counteract telomere attrition. In this narrative review, we update evidence on the association between plant-rich dietary patterns and plant-based foods and TL. First, we summarize findings from observational studies on the association between TL and 1) adherence to plant-rich dietary patterns (mainly, but not only, focused on the Mediterranean diet); 2) consumption of seeds (mostly focused on nuts, grains, and coffee); and 3) intake of carotenoids, one of the plant-derived bioactives most studied in health and disease. Second, we summarize the main randomized controlled trials evaluating the effect on TL of dietary interventions involving either plant-rich dietary patterns or plant foods. Even though evidence from trials is very limited, several observational studies have reinforced the suggestive benefits of adherence to the Mediterranean diet (a plant-rich dietary pattern), consumption of seeds (and its derivatives), and dietary intake of carotenoids on TL, which further supports the research benefits of plant-rich dietary patterns and plant foods to promote health and longevity.

RevDate: 2019-11-15

Chen R, Zhan Y, Pedersen N, et al (2019)

Marital status, telomere length and cardiovascular disease risk in a Swedish prospective cohort.

Heart (British Cardiac Society) pii:heartjnl-2019-315629 [Epub ahead of print].

OBJECTIVE: To investigate if marital status is associated with risk of cardiovascular disease (CVD) and to explore the potential influence of leucocyte telomere length (LTL), a marker of biological ageing, on such association.

DESIGN: Population-based prospective cohort study SETTINGS: Swedish Twin Registry.

PARTICIPANTS: Based on the Screening Across the Lifespan Twin Study from the Swedish Twin Registry, we included 10 058 twins born between 1900 and 1958 who underwent an interview between 1998 and 2002 during which information about marital status was collected. Blood samples from these participants were subsequently collected between 2004 and 2008 and used for LTL assessment using quantitative PCR technique.

MAIN OUTCOME MEASURES: Incident cases of CVD were identified through the Swedish Patient Register and Causes of Death Register through December 31, 2016. Multivariable linear regression and Cox proportional hazards regression models were used to estimate the regression coefficients (βs) and HRs with 95% CIs respectively. Potential confounders included age, sex, educational attainment and body mass index.

RESULTS: A total of 2010 participants were diagnosed with CVD during a median follow-up of 9.8 years. LTL was shorter among individuals living singly, including those who were divorced or separated (β:-0.014, 95% CI: -0.035, 0.007), widowed (β:-0.035, 95% CI: -0.061, -0.010), or living alone (β:-0.033, 95% CI: -0.052, -0.014), than individuals who were married or cohabitating. One SD increase of LTL was associated with a lower risk of CVD (HR: 0.79, 95% CI: 0.66, 0.93). Individuals who were divorced or separated, widowed, or living alone had a higher risk of CVD than individuals who were married or cohabitating. The summary HR of CVD was 1.21 (95% CI: 1.08, 1.35) when comparing individuals who were living singly, regardless of reason, with the individuals who were married or cohabitating. LTL appeared to mediate little of the association between marital status and CVD (HR additionally adjusted for LTL: 1.20; 95% CI: 1.08, 1.34).

CONCLUSIONS: Living singly, regardless of reason, was associated with a shorter LTL and a higher risk of CVD. The association between marital status and CVD was however not greatly attributable to telomere shortening.

RevDate: 2019-11-14

Hua R, Wei H, Liu C, et al (2019)

FBXO47 regulates telomere-inner nuclear envelope integration by stabilizing TRF2 during meiosis.

Nucleic acids research pii:5625541 [Epub ahead of print].

During meiosis, telomere attachment to the inner nuclear envelope is required for proper pairing of homologous chromosomes and recombination. Here, we identified F-box protein 47 (FBXO47) as a regulator of the telomeric shelterin complex that is specifically expressed during meiotic prophase I. Knockout of Fbxo47 in mice leads to infertility in males. We found that the Fbxo47 deficient spermatocytes are unable to form a complete synaptonemal complex. FBXO47 interacts with TRF1/2, and the disruption of Fbxo47 destabilizes TRF2, leading to unstable telomere attachment and slow traversing through the bouquet stage. Our findings uncover a novel mechanism of FBXO47 in telomeric shelterin subunit stabilization during meiosis.

RevDate: 2019-11-17

Mickle AT, Brenner DR, Beattie T, et al (2019)

The Dietary Inflammatory Index® and Alternative Healthy Eating Index 2010 in relation to leucocyte telomere length in postmenopausal women: a cross-sectional study.

Journal of nutritional science, 8:e35.

Telomeres are nucleoprotein complexes that form the ends of eukaryotic chromosomes where they protect DNA from genomic instability, prevent end-to-end fusion and limit cellular replicative capabilities. Increased telomere attrition rates, and relatively shorter telomere length, is associated with genomic instability and has been linked with several chronic diseases, malignancies and reduced longevity. Telomeric DNA is highly susceptible to oxidative damage and dietary habits may make an impact on telomere attrition rates through the mediation of oxidative stress and chronic inflammation. The aim of this study was to examine the association between leucocyte telomere length (LTL) with both the Dietary Inflammatory Index® 2014 (DII®) and the Alternative Healthy Eating Index 2010 (AHEI-2010). This is a cross-sectional analysis using baseline data from 263 postmenopausal women from the Alberta Physical Activity and Breast Cancer Prevention (ALPHA) Trial, in Calgary and Edmonton, Alberta, Canada. No statistically significant association was detected between LTL z-score and the AHEI-2010 (P = 0·20) or DII® (P = 0·91) in multivariable adjusted models. An exploratory analysis of AHEI-2010 and DII® parameters and LTL revealed anthocyanidin intake was associated with LTL (P < 0·01); however, this association was non-significant after a Bonferroni correction was applied (P = 0·27). No effect modification by age, smoking history, or recreational physical activity was detected for either relationship. Increased dietary antioxidant and decreased oxidant intake were not associated with LTL in this analysis.

RevDate: 2019-11-15

Suh DI, Kang MJ, Park YM, et al (2019)

The risk of preschool asthma at 2-4 years is not associated with leukocyte telomere length at birth or at 1 year of age.

Asia Pacific allergy, 9(4):e33.

Background: Exposure to prenatal stress is associated with offspring allergic-disease development, and oxidative stress may mediate this relationship.

Objective: We aimed to evaluate whether leukocyte telomere length (LTL) shortening, a marker for exposure to oxidative stress, in early life is associated with increased risk of asthma development during the preschool period.

Methods: We assessed the follow-up clinical data of a subgroup from a birth cohort whose LTLs had been measured from cord-blood and 1-year peripheral-blood samples. We examined whether the LTLs would be associated with asthma development at the age of 2-4 years.

Results: The data of 84 subjects were analyzed. LTLs were measured from the cord-blood and 1-year peripheral blood of 75 and 79 subjects, respectively. Among them, 14 subjects (16.7%) developed bronchial asthma between 2-4 years old. Prenatally stressed subjects had marginally increased odds of developing asthma (p = 0.097). There was no significant difference in the odds of preschool-asthma development between the groups with shorter and longer cord-blood LTLs (odds ratio [OR], 0.651; 95% confidence interval [CI], 0.184-2.306) or in the odds between the groups with shorter and longer 1-year peripheral-blood LTLs (OR, 0.448; 95% CI, 0.135-1.483). Finally, subjects with both higher prenatal stress and shorter LTLs did not have significantly higher odds of preschool-asthma development (for cord-blood: OR, 1.242; 95% CI, 0.353-4.368; for 1-year peripheral-blood: OR, 1.451; 95% CI, 0.428-4.919).

Conclusion: There was no significant association between early life LTLs and higher risk of bronchial-asthma development during the preschool years.

RevDate: 2019-11-12

Shoeb M, Mustafa GM, Kodali VK, et al (2019)

A possible relationship between telomere length and markers of neurodegeneration in rat brain after welding fume inhalation exposure.

Environmental research pii:S0013-9351(19)30697-8 [Epub ahead of print].

Inhalation of welding fume (WF) can result in the deposition of toxic metals, such as manganese (Mn), in the brain and may cause neurological changes in exposed workers. Alterations in telomere length are indicative of cellular aging and, possibly, neurodegeneration. Here, we investigated the effect of WF inhalation on telomere length and markers of neurodegeneration in whole brain tissue in rats. Male Fischer-344 (F-344) rats were exposed by inhalation to stainless steel WF (20 mg/m3 x 3 h/d x 4 d/wk x 5 wk) or filtered air (control). Telomere length, DNA-methylation, gene expression of Trf1, Trf2, ATM, and APP, protein expression of p-Tau, α-synuclein, and presenilin 1 and 2 were assessed in whole brain tissue at 12 wk after WF exposure ended. Results suggest that WF inhalation increased telomere length without affecting telomerase in whole brain. Moreover, we observed that components of the shelterin complex, Trf1 and Trf2, play an important role in telomere end protection, and their regulation may be responsible for the increase in telomere length. In addition, expression of different neurodegeneration markers, such as p-Tau, presenilin 1-2 and α-synuclein proteins, were increased in brain tissue from the WF-exposed rats as compared to control. These findings suggest a possible correlation between epigenetic modifications, telomere length alteration, and neurodegeneration because of the presence of factors in serum after WF exposure that may cause extra-pulmonary effects as well as the translocation of potentially neurotoxic metals associated with WF to the central nervous system (CNS). Further studies are needed to investigate the brain region specificity and temporal response of these effects.

RevDate: 2019-11-23

Yun M, Li S, Yan Y, et al (2019)

Suppression effect of body weight on the association between cigarette smoking and telomere length: the Bogalusa Heart Study.

Aging, 11(21):9893-9900.

This study aimed to dissect the direct effect of smoking and its indirect effect through body mass index (BMI) on leukocyte telomere length (LTL) and to distinguish the mediation and suppression effects of BMI. The study cohort included 1,037 adults (729 Whites and 308 African Americans; 42.1% males; mean age: 40.3 years) with LTL measurements by Southern blotting. General third variable models were used to distinguish the mediation and suppression effects of BMI on the smoking-LTL association. After adjusting for age, race, sex and alcohol drinking, the total effect of smoking on LTL was significant (standardized regression coefficient, β= -0.061, p=0.034) without BMI included in the model. With additional adjustment for BMI, the indirect effect of smoking on LTL through BMI was estimated at β= 0.011 (p=0.023), and the direct effect of smoking on LTL was strengthened to β= -0.072 (p=0.012). The results were similar when pack-years of smoking was used. The effect parameters did not differ significantly between race and sex groups. These results suggest that BMI has a suppression effect, not a mediation effect, on the smoking-LTL association, which potentially contributes to previous inconsistencies in the effect of smoking on LTL.

RevDate: 2019-11-15

Grandin N, Pereira B, Cohen C, et al (2019)

The level of activity of the alternative lengthening of telomeres correlates with patient age in IDH-mutant ATRX-loss-of-expression anaplastic astrocytomas.

Acta neuropathologica communications, 7(1):175.

All cancer cells need to maintain functional telomeres to sustain continuous cell division and proliferation. In human diffuse gliomas, functional telomeres are maintained due either to reactivation of telomerase expression, the main pathway in most cancer types, or to activation of a mechanism called the alternative lengthening of telomeres (ALT). The presence of IDH1/2 mutations (IDH-mutant) together with loss of ATRX expression (ATRX-lost) are frequently associated with ALT in diffuse gliomas. However, detection of ALT, and a fortiori its quantification, are rarely, if ever, measured in neuropathology laboratories. We measured the level of ALT activity using the previously described quantitative "C-circle" assay and analyzed it in a well characterized cohort of 104 IDH-mutant and ATRX-lost adult diffuse gliomas. We report that in IDH-mutant ATRX-lost anaplastic astrocytomas, the intensity of ALT was inversely correlated with age (p < 0.001), the younger the patient, the higher the intensity of ALT. Strikingly, glioblastomas having progressed from anaplastic astrocytomas did not exhibit this correlation. ALT activity level in the tumor did not depend on telomere length in healthy tissue cells from the same patient. In summary, we have uncovered the existence, in anaplastic astrocytomas but not in glioblastomas with the same IDH and ATRX mutations, of a correlation between patient age and the level of activity of ALT, a telomerase-independent pathway of telomere maintenance.

RevDate: 2019-11-19

Rebello K, Moura LM, Xavier G, et al (2019)

Association between spontaneous activity of the default mode network hubs and leukocyte telomere length in late childhood and early adolescence.

Journal of psychosomatic research, 127:109864 pii:S0022-3999(19)30618-X [Epub ahead of print].

The impact of early life stress on mental health and telomere length shortening have been reported. Changes in brain default mode network (DMN) were found to be related to a myriad of psychiatric conditions in which stress may play a role. In this context, family environment and adverse childhood experiences (ACEs) are potential causes of stress. This is a hypothesis-driven study focused on testing two hypotheses: (i) there is an association between telomere length and the function of two main hubs of DMN: the posterior cingulate cortex (PCC) and the medial prefrontal cortex (mPFC); (ii) this association is modulated by family environment and/or ACEs. To the best of our knowledge, this is the first study investigating these hypotheses. Resting-state functional magnetic resonance imaging data and blood sample were collected from 389 subjects (6-15 age range). We assessed DMN fractional amplitude of low-frequency fluctuations (fALFF) and leukocyte telomere length (LTL). We fitted general linear models to test the main effects of LTL on DMN hubs and the interaction effects with Family Environment Scale (FES) and ACEs. The results did not survive a strict Bonferroni correction. However, uncorrected p-values suggest that LTL was positively correlated with fALFF in PCC and a FES interaction between FES and LTL at mPFC. Although marginal, our results encourage further research on the interaction between DMN hubs, telomere length and family environment, which may play a role on the biological embedding of stress.

RevDate: 2019-11-18
CmpDate: 2019-11-18

Muneer A (2019)

Interventions Addressing the Telomere-Telomerase System.

Advances in experimental medicine and biology, 1192:521-544.

Major psychiatric disorders are linked to early mortality and patients afflicted with these ailments demonstrate an increased risk of developing physical diseases that are characteristically seen in the elderly. Psychiatric conditions like major depressive disorder, bipolar disorder, and schizophrenia may be associated with accelerated cellular aging, indicated by shortened leukocyte telomere length (LTL), which could underlie this connection. Telomere shortening occurs with repeated cell division and is reflective of a cell's mitotic history. It is also influenced by cumulative exposure to inflammation and oxidative stress as well as the availability of telomerase, the telomere-lengthening enzyme. Precariously short telomeres can cause cells to undergo senescence, apoptosis, or genomic instability; shorter LTL correlates with compromised general health and foretells mortality. Important data specify that LTL may be reduced in principal psychiatric illnesses, possibly in proportion to exposure to the ailment. Telomerase, as measured in peripheral blood monocytes, has been less well characterized in psychiatric illnesses, but a role in mood disorder has been suggested by preclinical and clinical studies. In this manuscript, the most recent studies on LTL and telomerase activity in mood disorders are comprehensively reviewed, potential mediators are discussed, and future directions are suggested. An enhanced comprehension of cellular aging in psychiatric illnesses could lead to their re-conceptualizing as systemic ailments with manifestations both inside and outside the brain. At the same time, this paradigm shift could identify new treatment targets, helpful in bringing about lasting cures to innumerable sufferers across the globe.

RevDate: 2019-11-07

Zeng Z, Zhang W, Qian Y, et al (2019)

Association of telomere length with risk of rheumatoid arthritis: a meta-analysis and Mendelian randomization.

Rheumatology (Oxford, England) pii:5614334 [Epub ahead of print].

OBJECTIVE: To evaluate the telomere length (TL) in patients with RA relative to that in controls and to test whether TL is causally associated with risk of RA.

METHODS: Systematic review and meta-analysis of relevant literature was conducted to evaluate the association between TL and RA. Standardized mean differences with 95% CIs of TL in RA patients relative to controls were pooled using fixed or random-effects models. TL-related single-nucleotide polymorphisms were selected from a genome-wide association study of 37 684 individuals, and summary statistics of RA were obtained from a genome-wide association study meta-analysis including 14 361 RA patients and 43 923 controls. Mendelian randomization was performed using the inverse-variance weighted, weighted-median and likelihood-based methods. Sensitivity analyses were performed to test the robustness of the association.

RESULTS: In the meta-analysis of 911 RA patients and 2498 controls, we found that patients with RA had a significantly shorter TL compared with controls (standardized mean differences = -0.50; 95% CI -0.88, -0.11; P = 0.012). In the Mendelian randomization analysis, we found that genetically predicted longer TL was associated with a reduced risk of RA [odds ratio = 0.68; 95% CI 0.54, 0.86; P = 0.002 using the inverse-variance weighted method]. Sensitivity analyses using alternative Mendelian randomization approaches yielded similar findings, suggesting the robustness of the causal association.

CONCLUSION: Our study provides evidence for a negative causal association of TL with risk of RA. Further studies are warranted to elucidate the underlying mechanism for the role of telomeres in the development of RA.

RevDate: 2019-11-07

Vecoli C, Borghini A, Pulignani S, et al (2019)

Independent and Combined Effects of Telomere Shortening and mtDNA4977 Deletion on Long-term Outcomes of Patients with Coronary Artery Disease.

International journal of molecular sciences, 20(21): pii:ijms20215508.

Aging is one of the main risk factors for cardiovascular disease, resulting in a progressive organ and cell decline. This study evaluated a possible joint impact of two emerging hallmarks of aging, leucocyte telomere length (LTL) and common mitochondrial DNA deletion (mtDNA4977), on major adverse cardiovascular events (MACEs) and all-cause mortality in patients with coronary artery disease (CAD). We studied 770 patients (673 males, 64.8 ± 8.3 years) with known or suspected stable CAD. LTL and mtDNA4977 deletion were assessed in peripheral blood using qRT-PCR. During a median follow-up of 5.4 ± 1.2 years, MACEs were 140 while 86 deaths were recorded. After adjustments for confounding risk factors, short LTLs and high mtDNA4977 deletion levels acted independently as predictors of MACEs (HR: 2.2, 95% CI: 1.2-3.9, p = 0.01 and HR: 1.7, 95% CI: 1.1-2.9, p = 0.04; respectively) and all-cause mortality events (HR: 2.1, 95% CI: 1.1-4.6, p = 0.04 and HR: 2.3, 95% CI: 1.1-4.9, p = 0.02; respectively). Patients with both short LTLs and high mtDNA4977 deletion levels had an increased risk for MACEs (HR: 4.3; 95% CI: 1.9-9.6; p = 0.0006) and all-cause mortality (HR: 6.0; 95% CI: 2.0-18.4; p = 0.001). The addition of mtDNA4977 deletion to a clinical reference model was associated with a significant net reclassification improvement (NRI = 0.18, p = 0.01). Short LTL and high mtDNA4977 deletion showed independent and joint predictive value on adverse cardiovascular outcomes and all-cause mortality in patients with CAD. These findings strongly support the importance of evaluating biomarkers of physiological/biological age, which can predict disease risk and mortality more accurately than chronological age.

RevDate: 2019-11-08

Guha M, Srinivasan S, Sheehan MM, et al (2019)

Esophageal 3D organoids of MPV17-/- mouse model of mitochondrial DNA depletion show epithelial cell plasticity and telomere attrition.

Oncotarget, 10(58):6245-6259.

Esophageal squamous cell carcinoma (ESCC) is an aggressive cancer with late-stage detection and poor prognosis. This emphasizes the need to identify new markers for early diagnosis and treatment. Altered mitochondrial genome (mtDNA) content in primary tumors correlates with poor patient prognosis. Here we used three-dimensional (3D) organoids of esophageal epithelial cells (EECs) from the MPV17-/- mouse model of mtDNA depletion to investigate the contribution of reduced mtDNA content in ESCC oncogenicity. To test if mtDNA defects are a contributing factor in ESCC, we used oncogenic stimuli such as ESCC carcinogen 4-nitroquinoline oxide (4-NQO) treatment, or expressing p53R175H oncogenic driver mutation. We observed that EECs and 3D-organoids with mtDNA depletion had cellular, morphological and genetic alterations typical of an oncogenic transition. Furthermore, mitochondrial dysfunction induced cellular transformation is accompanied by elevated mitochondrial fission protein, DRP1 and pharmacologic inhibition of mitochondrial fission by mDivi-1 in the MPV17-/- organoids reversed the phenotype to that of normal EEC organoids. Our studies show that mtDNA copy number depletion, activates a mitochondrial retrograde response, potentiates telomere defects, and increases the oncogenic susceptibility towards ESCC. Furthermore, mtDNA depletion driven cellular plasticity is mediated via altered mitochondrial fission-fusion dynamics.

RevDate: 2019-11-08

Lirussi L, H Nilsen (2019)

Telomere maintenance: regulating hTERC fate through RNA modifications.

Molecular & cellular oncology, 6(6):e1670489.

Disturbances in telomere maintenance are common in cancer. We recently showed that Single-strand-selective monofunctional uracil-DNA glycosylase 1 (SMUG1) promotes telomere homeostasis by regulating the stability of the telomeric RNA component (hTERC). SMUG1-mediated recognition of base modifications may function in a regulated process serving to fine-tune the levels of hTERC.

RevDate: 2019-11-05

Galiè S, Canudas S, Muralidharan J, et al (2019)

Impact of Nutrition on Telomere Health: Systematic Review of Observational Cohort Studies and Randomized Clinical Trials.

Advances in nutrition (Bethesda, Md.) pii:5613358 [Epub ahead of print].

Diet, physical activity, and other lifestyle factors have been implicated in the pathophysiology of several chronic diseases, but also in a lower total mortality and longer life expectancy. One of the mechanisms in which diet can reduce the risk of disease is with regard to its impact on telomeres. Telomere length (TL) is highly correlated to chronological age and metabolic status. Individuals with shorter telomeres are at higher risk of chronic diseases and mortality. Diet may influence TL by several mechanisms such as regulating oxidative stress and inflammation or modulating epigenetic reactions. The present systematic review aims to examine the results from epidemiologic and clinical trials conducted in humans evaluating the role of nutrients, food groups, and dietary patterns on TL. We also discuss the possible mechanisms of action that influence this process, with the perspective that TL could be a novel biomarker indicating the risk of metabolic disturbances and age-related diseases. The available evidence suggests that some antioxidant nutrients, the consumption of fruits and vegetables, and Mediterranean diet are mainly associated with longer telomeres. However, most of the evidence is based on high heterogenic observational studies and very few randomized clinical trials (RCTs). Therefore, the associations summarized in the present review need to be confirmed with larger prospective cohort studies and better-designed RCTs.

RevDate: 2019-11-05

Kim ES, Tindle HA, Kubzansky LD, et al (2019)

The Relation of Optimism to Relative Telomere Length in Older Men and Women.

Psychosomatic medicine [Epub ahead of print].

OBJECTIVE: Mounting evidence suggests that higher optimism is associated with reduced risk of age-related morbidities and premature mortality. Yet, possible biological mechanisms underlying these associations remain understudied. One hypothesized mechanism is a slower rate of cellular aging, which in turn delays age-related declines in health.

METHODS: We used data from two large cohort studies to test the hypothesis that higher optimism is associated with longer leukocyte telomere length. Using cross-sectional data from the Health and Retirement Study (HRS; N=6,417; mean age=70 years) and the Women's Health Initiative (WHI; N=3,582; mean age=63 years), we used linear regression models to examine the association of optimism with relative telomere length (assessed in leukocytes from saliva [HRS] or plasma [WHI]). Models adjusted for sociodemographics, depression, health status, and health behaviors.

RESULTS: Considering both optimism and telomere length as continuous variables, we found consistently null associations in both cohorts, regardless of which covariates were included in the models. In models adjusting for demographics, depression, co-morbidities, and health behaviors, optimism was not associated with mean relative telomere length (HRS: β=-0.002; 95% CI:-0.014, 0.011; WHI: β=-0.004; 95% CI:-0.017, 0.009).

CONCLUSIONS: Findings do not support mean telomere length as a mechanism that explains observed relations of optimism with reduced risk of chronic disease in older adults. Future research is needed to evaluate other potential biological markers and pathways.

RevDate: 2019-11-08

Tucker LA (2019)

Serum and Dietary Folate and Vitamin B12 Levels Account for Differences in Cellular Aging: Evidence Based on Telomere Findings in 5581 U.S. Adults.

Oxidative medicine and cellular longevity, 2019:4358717.

Folate and vitamin B12 are essential for a variety of metabolic processes. Both micronutrients have been shown to reduce oxidative stress significantly. The present cross-sectional investigation evaluated the association between serum and dietary folate and vitamin B12 levels and leukocyte telomere length, an index of cellular aging influenced by oxidative stress. The study included 5581 adults from the National Health and Nutrition Examination Survey (NHANES). Because participants were randomly selected, results are generalizable to all civilian, noninstitutionalized U.S. adults. A blood draw provided DNA and serum folate and B12 information. The quantitative polymerase chain reaction method was used to measure telomere length. The Bio-Rad Quantaphase II folate and vitamin B12 radioassay kit was used to quantify levels of folate and vitamin B12. Dietary folate and vitamin B12 were assessed using a multipass 24 h recall. In some models, age, race, smoking pack-years, alcohol use, body mass index, total physical activity, hours fasted before the blood draw, and diabetes status were employed as covariates to minimize their influence. Findings showed that for each additional year of chronological age, telomeres were 15.6 base pairs shorter, on average (F = 378.8, p < 0.0001). Men had shorter telomeres than women after adjusting for all the covariates (F = 6.8, p = 0.0146). Serum (F = 10.5, p = 0.0030) and dietary (F = 5.0, p = 0.0325) folate concentrations were each linearly related to telomere length in women, but not in men, after controlling for age and race. Serum vitamin B12 and telomere length had a nonsignificant, inverse relationship in women, with age and race controlled (F = 2.8, p = 0.1056), but no relation in men. Dietary vitamin B12 was linearly related to telomere length in women, after adjusting for age and race (F = 4.3, p = 0.0468), but not in men. Overall, evidence indicates that folate and vitamin B12 levels, especially folate, account for meaningful differences in cell aging in women, but not in men.

RevDate: 2019-11-21

Xu M, Kiselar J, Whited TL, et al (2019)

POT1-TPP1 differentially regulates telomerase via POT1 His266 and as a function of single-stranded telomere DNA length.

Proceedings of the National Academy of Sciences of the United States of America, 116(47):23527-23533.

Telomeres cap the ends of linear chromosomes and terminate in a single-stranded DNA (ssDNA) overhang recognized by POT1-TPP1 heterodimers to help regulate telomere length homeostasis. Here hydroxyl radical footprinting coupled with mass spectrometry was employed to probe protein-protein interactions and conformational changes involved in the assembly of telomere ssDNA substrates of differing lengths bound by POT1-TPP1 heterodimers. Our data identified environmental changes surrounding residue histidine 266 of POT1 that were dependent on telomere ssDNA substrate length. We further determined that the chronic lymphocytic leukemia-associated H266L substitution significantly reduced POT1-TPP1 binding to short ssDNA substrates; however, it only moderately impaired the heterodimer binding to long ssDNA substrates containing multiple protein binding sites. Additionally, we identified a telomerase inhibitory role when several native POT1-TPP1 proteins coat physiologically relevant lengths of telomere ssDNA. This POT1-TPP1 complex-mediated inhibition of telomerase is abrogated in the context of the POT1 H266L mutation, which leads to telomere overextension in a malignant cellular environment.

RevDate: 2019-11-04

Saha A, Nanavaty VP, B Li (2019)

Telomere and Subtelomere R-loops and Antigenic Variation in Trypanosomes.

Journal of molecular biology pii:S0022-2836(19)30621-7 [Epub ahead of print].

Trypanosoma brucei is a kinetoplastid parasite that causes African trypanosomiasis, which is fatal if left untreated. T. brucei regularly switches its major surface antigen, VSG, to evade the host immune responses. VSGs are exclusively expressed from subtelomeric expression sites (ESs) where VSG genes are flanked by upstream 70 bp repeats and downstream telomeric repeats. The telomere downstream of the active VSG is transcribed into a long-noncoding RNA (TERRA), which forms RNA:DNA hybrids (R-loops) with the telomeric DNA. At an elevated level, telomere R-loops cause more telomeric and subtelomeric Double-Strand Breaks (DSBs) and increase VSG switching rate. In addition, stabilized R-loops are observed at the 70 bp repeats and immediately downstream of ES-linked VSGs in RNase H-defective cells, which also have an increased amount of subtelomeric DSBs and more frequent VSG switching. Although subtelomere plasticity is expected to be beneficial to antigenic variation, severe defects in subtelomere integrity and stability increase cell lethality. Therefore, regulation of the telomere and 70 bp repeat R-loop levels is important for the balance between antigenic variation and cell fitness in T. brucei. Additionally, the high level of the active ES transcription favors accumulation of R-loops at the telomere and 70 bp repeats, providing an intrinsic mechanism for local DSB formation, which is a strong inducer of VSG switching.

RevDate: 2019-11-22

Verhulst S (2019)

Improving comparability between qPCR-based telomere studies.

Comparability of findings from qPCR-based telomere studies is hampered by such measurement results being assay-specific, precluding a direct quantitative comparisons of observed differences and/or slopes of associations between studies. It is proposed that this can be partially alleviated by expressing qPCR-based telomere data as Z-scores.

RevDate: 2019-11-01

Pisanu C, Tsermpini EE, Skokou M, et al (2019)

Leukocyte telomere length is reduced in patients with major depressive disorder.

Drug development research [Epub ahead of print].

Major depressive disorder (MDD) is a chronic, severe psychiatric illness with an incidence of 3% worldwide. MDD patients have a significantly impaired quality of life and reduced life expectancy compared to unaffected individuals, the latter being largely accounted for by an increased incidence of suicide and cardiovascular disorders. The premature mortality observed in MDD has been considered a signature of accelerated aging, a hypothesis supported by data showing altered functioning and morphology of several brain regions that are typically present in the aging population. Telomere shortening is a hallmark of cellular aging, and as such several studies explored the involvement of disrupted telomere dynamics in MDD, reporting contrasting findings. In the current study, we measured leukocyte telomere length (LTL) in a sample of 54 MDD patients and 47 non-psychiatric controls characterized for response to antidepressant treatment. After correcting for age, sex, and body mass index, we showed significantly reduced LTL in affected individuals compared to controls (beta = -.22, p = .02). There was no difference in LTL between treatment resistant or responsive MDD patients. Moreover, we observed no correlation between lifetime exposure to antidepressants and LTL. Our study showed that MDD patients have shorter telomeres compared to controls, supporting the hypothesis of accelerated aging in this disorder. However, LTL seemed not to be influenced by antidepressant treatment or to correlate with clinical response to these antidepressants. Further investigations in larger samples and possibly with longitudinal design are warranted to elucidate the role of altered telomere dynamics in MDD.

RevDate: 2019-11-01

Grunst AS, Grunst ML, Bervoets L, et al (2019)

Proximity to roads, but not exposure to metal pollution, is associated with accelerated developmental telomere shortening in nestling great tits.

Environmental pollution (Barking, Essex : 1987) pii:S0269-7491(19)33270-1 [Epub ahead of print].

Comprehensively understanding the factors affecting physiology and fitness in urban wildlife requires concurrently considering multiple stressors. To this end, we simultaneously assessed how metal pollution and proximity to roads affect body condition and telomere shortening between days 8 and 15 of age in nestling great tits (Parus major), a common urban bird. We employed a repeated-measures sampling design to compare telomere shortening and body condition between nestlings from four urban study sites south of Antwerp, Belgium, which are located at different distances from a metal pollution point source. In addition, we explored associations between metal exposure and telomere dynamics on the individual level by measuring blood concentrations of five metals/metalloids, of which lead, copper and zinc were present at concentrations above the limit of detection. To assess whether roadway-associated stressors (e.g. noise and air pollution) might affect nestling condition and telomere shortening, we measured the proximity of nest boxes to roads. Metal exposure was not associated with nestling telomere length or body condition, despite elevated blood lead concentrations close to the metal pollution source (mean ± SE = 0.270 ± 0.095 μg/g wet weight at the most polluted study site), suggesting that nestlings may have some capacity to detoxify metals. However, nestlings from nest boxes near roads exhibited more telomere shortening between days 8 and 15 of age, and shorter telomeres at day 15. Nestlings in poorer condition also had shorter telomeres, but proximity to the road was unrelated to body condition. Thus, nutritional stress is unlikely to mediate the relationship between proximity to roads and telomere length. Rather, proximity to roads could have affected telomere shortening by exposing nestlings to air or noise pollution. Our study highlights that traffic-related pollution, which is implicated in human health problems, might also affect urban wildlife.

RevDate: 2019-10-30

Bizarro J, Bhardwaj A, Smith S, et al (2019)

Nopp140-mediated concentration of telomerase in Cajal bodies regulates telomere length.

Molecular biology of the cell [Epub ahead of print].

Cajal bodies (CBs) are nuclear organelles concentrating two kinds of RNA-protein complexes (RNPs), spliceosomal small nuclear (sn) and small CB-specific (sca)RNPs. Whereas the CB marker protein coilin is responsible for retaining snRNPs, the tether for scaRNPs is not known. Here we show that Nopp140, an intrinsically disordered CB phosphoprotein, is required to recruit and retain all scaRNPs in CBs. Knockdown of Nopp140 releases all scaRNPs leading to an unprecedented reduction in size of CB granules, hallmarks of CB ultrastructure. The CB-localizing protein WDR79 (aka TCAB1), which is mutated in the inherited bone marrow failure syndrome dyskeratosis congenita, is a specific component of all scaRNPs, including telomerase. Whereas mislocalization of telomerase by mutation of WDR79 leads to critically shortened telomeres, mislocalization of telomerase by Nopp140 knockdown leads to gradual extension of telomeres. Our studies suggest that the dynamic distribution of telomerase between CBs and nucleoplasm uniquely impacts telomere length maintenance and identify Nopp140 as a novel player in telomere biology.

RevDate: 2019-11-14

O'Rourke JJ, Bythell-Douglas R, Dunn EA, et al (2019)

ALT control, delete: FANCM as an anti-cancer target in Alternative Lengthening of Telomeres.

Nucleus (Austin, Tex.), 10(1):221-230.

Break-induced replication is a specific type of DNA repair that has a co-opted role in telomere extension by telomerase-negative cancer cells. This Alternative Lengthening of Telomeres (or 'ALT') is required for viability in approximately 10% of all carcinomas, but up to 50% of the soft-tissue derived sarcomas. In several recent studies, we and others demonstrate that expression and activity of FANCM, a DNA translocase protein, is essential for the viability of ALT-associated cancers. Here we provide a summary of how and why FANCM depletion leads to deletion of ALT-controlled cancers, predominantly through a hyper-activation of break-induced replication. We also discuss how FANCM can and has been targeted in cancer cell killing, including potential opportunities in ALT and other genetic backgrounds.

RevDate: 2019-11-12

Saha P, Kumar YP, Das T, et al (2019)

G-Quadruplex-Specific Cell-Permeable Guanosine-Anthracene Conjugate Inhibits Telomere Elongation and Induces Apoptosis by Repressing the c-MYC Gene.

Bioconjugate chemistry [Epub ahead of print].

We herein report a cell-membrane-permeable molecular probe ADG, prepared by conjugating guanosine with anthracene, selectively interacts with c-MYC G-quadruplex over other promoter and telomeric quadruplexes as well as duplex DNA. NMR spectroscopy suggests that ADG interacts with terminal G-quartets as well as with the nearby G-rich tract (G13-G14-G15 and G8-G9-G10) of c-MYC quadruplex. In vitro cellular studies indicate that ADG represses c-MYC expression by stabilizing its promoter G-quadruplex and alters c-MYC-related cellular events. ADG suppresses hTERT and BCL2 gene expressions in a promoter-independent manner, inhibits elongation of telomere length, and activates apoptotic cascades in cancer cells.

RevDate: 2019-11-26

Liu P, Zhang Y, L Ma (2019)

Telomere length and associated factors in older adults with hypertension.

The Journal of international medical research, 47(11):5465-5474.

RevDate: 2019-11-22

Yeap BB, Hui J, Knuiman M, et al (2019)

Associations of plasma IGF1, IGFBP3 and estradiol with leucocyte telomere length, a marker of biological age, in men.

European journal of endocrinology pii:EJE-19-0638.R1 [Epub ahead of print].

OBJECTIVE: Effects of insulin-like growth factor 1 (IGF1) and its binding proteins (IGFBPs) on ageing, and their interaction with sex hormones, remain uncertain. We examined associations of plasma IGF1, IGFBP1, IGFBP3, estradiol and testosterone, with leucocyte telomere length (LTL), a marker of biological age, in 2999 community-dwelling men aged 70-84 years.

METHODS: Plasma IGF1, IGFBP1 and IGFBP3 measured using immunoassay, sex hormones using mass spectrometry. LTL measured by PCR, expressed as ratio of telomeric to single-copy control gene DNA (T/S ratio). Linear regression models adjusted for age and cardiometabolic risk factors, median splits defined low/high groups.

RESULTS: Mean age was 76.7±3.2 years. IGF1 and IGFBP3 showed age-adjusted correlations with LTL (coefficient 0.59, p=0.001 and 0.45, p=0.013 respectively), IGFBP1 did not. In multivariable-adjusted models IGF1 and IGFBP3 (but not IGFBP1) were associated with LTL (T/S ratio 0.015 higher per 1SD increase in IGF1, p=0.007, and 0.011 per 1SD IGFBP3, p=0.049). IGF1 and estradiol were independently associated with longer telomeres (T/S ratio 0.012 higher per 1SD increase in estradiol, p=0.027, when included in model with IGF1). Testosterone was not associated with LTL. Men with both high IGF1 (>133 ug/L) and high estradiol (>70 pmol/L) had longer LTL compared to men with lower values (multivariable-adjusted T/S ratio 1.20 vs 1.16, p=0.018).

CONCLUSIONS: Higher IGF1 and IGFBP3 are independently associated with longer telomeres in older men. Additive associations of higher IGF1 and higher estradiol with telomere length are present. Further studies are needed to determine whether these hormonal exposures cooperate to slow biological ageing.

RevDate: 2019-10-28

Navarro-Ibarra MJ, Hernández J, G Caire-Juvera (2019)

Diet, physical activity and telomere length in adults.

Nutricion hospitalaria [Epub ahead of print].

Telomere length (TL) is a predictive biomarker of premature aging. Telomere shortening has been linked to age-related diseases and noncommunicable diseases (NCD), and may reflect the effects of behavioral, psychosocial and environmental factors on health status. Telomere attrition can be affected by lifestyle factors such as diet and physical activity. The search of studies included in this review was conducted on PubMed Central database. A majority of studies are cross-sectional, as there is a clear lack of prospective studies to evaluate the individual effect of dietary components, dietary patterns, and physical activity on TL in the long term. The current literature suggests that high adherence to Mediterranean diet (MD), with consumption of antioxidants, fiber and vegetables, as well as seeds and walnuts, is associated with longer TL. The dietary components of a healthy diet, such as carotenoids, vitamins A, C, D, E, polyphenols, fiber, and omega-3 fatty acids could help maintain TL. In contrast, a high consumption of sugary beverages, processed meat, and proinflammatory diets is associated with telomere shortening. In a majority of studies TL is positively associated with moderate physical activity. The predominant mechanisms through which a healthy diet and moderate physical exercise could mitigate telomere attrition include decreasing oxidative stress and inflammation. We shall not discuss the associations of possible risk or protective factors in terms of causality since the majority of studies are cross-sectional and randomized controlled trials are limited; accordingly, some results are inconclusive. For future research, we suggest evaluating the individual effects of dietary components, dietary patterns and physical activity, considering repeated measurements and exercise intensity, on TL. It is also advisable to include biomarkers of oxidative stress and inflammation proteins, and to measure telomerase activity.

RevDate: 2019-11-01

Wang H, Zhuang Y, Peng H, et al (2019)

The relationship between MUC5B promoter, TERT polymorphisms and telomere lengths with radiographic extent and survival in a Chinese IPF cohort.

Scientific reports, 9(1):15307.

Genetic factors were identified to be associated with the development of idiopathic pulmonary fibrosis (IPF). We aimed to investigate associations between mucin 5B (MUC5B) and telomerase reverse transcriptase (TERT) polymorphisms and telomere length (TL) with honeycombing extent and survival in a Chinese IPF cohort. Seventy-nine patients diagnosed with IPF were enrolled. The honeycombing extents in high resolution CT scan (HRCT) were quantitatively scored and defined as mild (<10%), moderate (10-50%), and severe (>50%) upon the honeycombing extents involving the total lung. We tested five single-nucleotide polymorphisms [rs35705950, rs868903 in MUC5B, rs2736100, rs2853676 in TERT and rs1881984 in Telomerase RNA Gene (TERC) and TLs in peripheral blood leucocytes, and evaluated their associations with radiographic extent and survival in IPF. The minor allele frequencies (MAF) were significantly greater for MUC5B rs868903 (P = 0.042) and TERT rs2853676 (P = 0.041) in IPF than those in healthy controls. CT/CC genotype of MUC5B rs868903 (p = 0.045) and short TLs (p = 0.035) were correlated with the more extensive honeycombing opacities in HRCT. After adjustment for age, sex, and smoking status, MUC5B rs868903 polymorphism was the significant gene risk factors for reduced survival (p = 0.044) in IPF. MUC5B promoter rs868903 polymorphism and TLs were associated with radiographic extent and survival in a Chinese IPF cohort. These findings suggested a genetic clue for exploring the underlying molecular basis and pathogenesis of IPF.

RevDate: 2019-10-25

Benetos A, Verhulst S, Labat C, et al (2019)

Telomere length tracking in children and their parents: implications for adult onset diseases.

FASEB journal : official publication of the Federation of American Societies for Experimental Biology [Epub ahead of print].

Adults with comparatively short or long leukocyte telomere length (LTL) typically continue to display comparatively short or long LTL throughout life. This LTL tracking stems from the inability of person-to-person variation in age-dependent LTL shortening during adulthood to offset the wide interindividual LTL variation established prior to adult life. However, LTL tracking in children is unstudied. This study aimed to examine LTL shortening rates and tracking in children and their parents. Longitudinal study in children (n = 67) and their parents (n = 99), whose ages at baseline were 11.4 ± 0.3 and 43.4 ± 0.4 yr, respectively. LTL was measured by Southern blotting at baseline and ∼14 yr thereafter. LTL displayed tracking in both children [intraclass correlation coefficient (ICC) = 0.905, P < 0.001] and their parents (ICC = 0.856, P < 0.001). The children's rate of LTL shortening was twice that of their parents (40.7 ± 2.5 bp/yr; 20.3 ± 2.1 bp/yr, respectively; P < 0.0001). LTL tracking applies not only to adulthood but also to the second decade of life. Coupled with previous work showing that the interindividual variation in LTL across newborns is as wide as in their parents, these findings support the thesis that the LTL-adult disease connection is principally determined before the second decade of life, perhaps mainly at birth.-Benetos, A., Verhulst, S., Labat, C., Lai, T.-P., Girerd, N., Toupance, S., Zannad, F., Rossignol, P., Aviv, A. Telomere length tracking in children and their parents: implications for adult onset diseases.

RevDate: 2019-11-26

Alrefaei GI, Alkarim SA, HS Abduljabbar (2019)

Impact of Mothers' Age on Telomere Length and Human Telomerase Reverse Transcriptase Expression in Human Fetal Membrane-Derived Mesenchymal Stem Cells.

Stem cells and development [Epub ahead of print].

Age-related cellular changes and limited replicative capacity of adult mesenchymal stem cells (MSCs) are few of the challenges confronting stem cell research. MSCs from human fetal membranes (hFM-MSCs), including placental, umbilical cord, and amniotic membrane, are considered an alternative to adult MSCs. However, the effect of mothers' age on hFM-MSC cellular properties is still not clearly established. This study aimed to evaluate the effect of mothers' age on hFM-MSC telomere length, telomerase activity, and proliferation ability in three different age groups: GI (20-29 years), GII (30-39 years), and GIII (≥40 years). hFM samples were collected from pregnant women ≤37 weeks after obtaining consent. hFM-MSCs were isolated and cultured to characterize them by flow cytometry and assess proliferation by MTT assay and doubling time. Telomere length and expression levels of human telomerase reverse transcriptase were assessed by quantitative real-time polymerase chain reaction (qRT-RCR). hFM-MSCs in the three age groups were spindle-shaped, plastic-adherent, and exhibited high proliferation rates and strong expression of hMSC markers. GI showed the longest telomere length in hMSCs in various FM regions, whereas GIII showed the highest level of telomerase expression. There was no difference in telomere length between GII and GIII, and both groups showed the same hMSC characteristics. In conclusion, although the hFM-MSCs derived from different fetal membranes maintained the MSC characteristics in all study groups, the hFM-MSCs of older mothers had shorter telomeres and higher telomerase activity and proliferation rate than did those derived from younger mothers. Thus, the hFM-MSCs of older mothers could be unsuitable for expansion in vitro or stem cell therapy. Determination of telomere length and telomerase expression level of hFM might help characterizing and understanding the biological differences of hFM-MSCs in different age groups.

RevDate: 2019-11-01

Ferreira MSV, Kirschner M, Halfmeyer I, et al (2019)

Comparison of flow-FISH and MM-qPCR telomere length assessment techniques for the screening of telomeropathies.

Annals of the New York Academy of Sciences [Epub ahead of print].

Assessment of telomere length (TL) in peripheral blood leukocytes is part of the diagnostic algorithm applied to patients with acquired bone marrow failure syndromes (BMFSs) and dyskeratosis congenita (DKC). Monochrome multiplex-quantitative polymerase chain reaction (MM-qPCR) and fluorescence in situ hybridization (flow-FISH) are methodologies available for TL screening. Dependent on TL expressed in relation to percentiles of healthy controls, further genetic testing for inherited mutations in telomere maintenance genes is recommended. However, the correct threshold to trigger this genetic workup is still under debate. Here, we prospectively compared MM-qPCR and flow-FISH regarding their capacity for accurate identification of DKC patients. All patients (n = 105) underwent genetic testing by next-generation sequencing and in 16 patients, mutations in DKC-relevant genes were identified. Whole leukocyte TL of patients measured by MM-qPCR was found to be moderately correlated with lymphocyte TL measured by flow-FISH (r² = 0.34; P < 0.0001). The sensitivity of both methods was high, but the specificity of MM-qPCR (29%) was significantly lower compared with flow-FISH (58%). These results suggest that MM-qPCR of peripheral blood cells is inferior to flow-FISH for clinical routine screening for suspected DKC in adult patients with BMFS due to lower specificity and a higher rate of false-positive results.

RevDate: 2019-11-16

Wang Z, Rice SV, Chang TC, et al (2019)

Molecular Mechanism of Telomere Length Dynamics and Its Prognostic Value in Pediatric Cancers.

Journal of the National Cancer Institute pii:5606722 [Epub ahead of print].

BACKGROUND: We aimed to systematically evaluate telomere dynamics across a spectrum of pediatric cancers, search for underlying molecular mechanisms, and assess potential prognostic value.

METHODS: The fraction of telomeric reads was determined from whole-genome sequencing data for paired tumor/normal samples from 653 patients with 23 cancer types from the Pediatric Cancer Genome Project (PCGP). Telomere dynamics were characterized as the ratio of telomere fractions between tumor and normal samples. Somatic mutations were gathered, RNA sequencing data for 330 patients were analyzed for gene expression, and Cox regression was used to assess the telomere dynamics on patient survival.

RESULTS: Telomere lengthening was observed in 28.7% of solid tumors, 10.5% of brain tumors, and 4.3% of hematological cancers. Among 81 samples with telomere lengthening, 26 had somatic mutations in ATRX, corroborated by a low level of ATRX expression in the subset of tumors with RNA sequencing. TERT amplification and/or activation was observed in 10 tumors with telomere lengthening, including 2 leukemias of the E2A-PBX1 subtype. Among hematological cancers, pathway analysis for genes with expressions most negatively correlated with telomere fractions suggest implication of a gene ontology process of antigen presentation by MHC class II. A higher ratio of telomere fractions was statistically significantly associated with poorer survival for patients with brain tumors (hazard ratio = 2.18, 95% confidence interval = 1.37 to 3.46).

CONCLUSION: Because telomerase inhibitors are currently being explored as potential agents to treat pediatric cancer, these data are valuable as they identify a subpopulation of patients with reactivation of telomerase who are most likely to benefit from this novel therapeutic option.

RevDate: 2019-11-08

Huang YQ, Lo K, Feng YQ, et al (2019)

The association of mean telomere length with all-cause, cerebrovascular and cardiovascular mortality.

Bioscience reports, 39(10):.

Mean telomere length (MLT) is a marker of cell aging and may associate with age-related diseases. However, the relationship between MLT and mortality risk remains unclear. We aimed to investigate the relationship between MLT and all-cause, cerebrovascular and cardiovascular mortality among adults in United States. We analyzed data were from National Health and Nutrition Examination Survey (NHANES, 1999-2002) with follow-up data through 31 December 2015. Based on MLT, participants were categorized into low, middle and high groups. Multivariate Cox proportional hazards regression, subgroup analysis and generalized additive model (GAM) were performed by using hazard ratios (HRs) and 95% confidence intervals (CIs). A total of 7827 participants were included in analysis (48.18% male). After 158.26 months of follow-up on average, there were 1876 (23.97%), 87 (1.11%) and 243 (3.10%) onset of all-cause, cerebrovascular and cardiovascular mortality. After adjustment for potential confounders, using the low group as the reference, HRs for all-cause (0.87 and 0.86), cerebrovascular (0.75 and 0.75) and cardiovascular mortality (1.01 and 0.69) for the middle to high groups were not statistically significant (all P>0.05 for trend). MLT was non-linearly related to all-cause mortality but not to cerebrovascular and cardiovascular mortality. It was the first study to demonstrate the non-linear relationship between MLT and all-cause mortality.

RevDate: 2019-10-24

Liu D, Zhu Z, Zhou L, et al (2019)

The joint effects of frailty and telomere length for predicting mortality in older adults: the National Health and Nutrition Examination Survey 1999-2002.

Aging clinical and experimental research pii:10.1007/s40520-019-01376-3 [Epub ahead of print].

BACKGROUND: Frailty and short telomere length, which address different aspects of biological aging, are separately associated with mortality in older adults.

AIMS: To evaluate whether the combination of these two biomarkers would be a better predictor of mortality than either alone.

METHODS: This present study included participants 60 years of age or older from the National Health and Nutrition Examination Survey in the 1999-2002 phase. The frailty phenotype was identified based on the Fried definition. Telomere length relative to standard reference DNA (T/S ratio) was assessed using quantitative polymerase chain reaction (PCR). Cox proportional hazards regression models were used to estimate the individual and combined effects of frailty phenotype and telomere length on all-cause and cardiovascular mortality.

RESULTS: Compared with participants with neither impairment, the mortality risks increased slightly among participants with short telomere length only (hazard ratio [HR] 1.19, 95% confidence interval [CI]: 1.00-1.42) or pre-frailty only (HR 2.16, 95% CI 1.80-2.60) and gradually elevated approximately 3 folds with both short telomere length and pre-frailty (HR 2.23, 95% CI 1.81-2.74) or frailty (HR 3.57, 95% CI 2.56-4.98). Moreover, participants with both short telomere length and frailty had the highest increased all-cause mortality (HR 5.16, 95% CI 3.38-7.85) and cardiovascular mortality (HR 4.67, 95% CI 2.02-10.82).

DISCUSSION AND CONCLUSIONS: The combined predictor had more capability of predicting mortality, which suggested that integrating both molecular biomarkers and physiological functional parameters would be a more informative measure of biological aging.

RevDate: 2019-10-24

Gedvilaite G, Vilkeviciute A, Kriauciuniene L, et al (2019)

The relationship between leukocyte telomere length and TERT, TRF1 single nucleotide polymorphisms in healthy people of different age groups.

Biogerontology pii:10.1007/s10522-019-09843-0 [Epub ahead of print].

Telomeres are nucleoprotein structures that cap the end of each chromosome and function to maintain genome stability. The length of telomeres is known to shorten with each cell division and it is well-established that telomere attrition is related to replicative capacity in vitro. Moreover, telomere loss is also correlated with the process of aging in vivo. That is why we aimed to find any associations of leukocyte telomere shortening with different age groups. We enrolled 291 healthy people in a study group. Samples of DNA from peripheral blood leukocytes were purified by the DNA salting-out method. The genotyping was carried out using the real-time polymerase chain reaction. The results were assessed using the statistical analysis software ''IBM SPSS Statistics 23.0". To determine the relationship between the leukocyte telomere length and single nucleotide polymorphisms of TERT and TRF1 and the age of healthy individuals. The relative leukocyte telomere length (T/S) measurement was performed in study subjects and compared between different age groups. We found that T/S in the first age group was statistically significantly higher than in the second group (p = 0.040), while in the second and the third age groups T/S was statistically significantly lower than in the fourth age group (p < 0.001 and p = 0.001 respectively). There was also a weak negative but statistically significant inverse correlation between the age of the subjects and the length of telomeres (p = 0.025). We found that TRF1 rs10107605 CC genotype was statistically significantly more frequent in subjects with long telomeres than in subjects with short telomeres (p = 0.009). The TRF1 rs10107605 CC genotype compared to AA genotype was associated with 75% decreased odds of telomere shortening (p = 0.017), and the CC genotype compared to AA + AC genotypes was associated with 75% decreased odds (p = 0.014). T/S correlates with age negatively. The frequencies of genotypes and alleles of TERT rs2736098, rs401681 and TRF1 rs1545827 did not differ between different age groups. The TRF1 rs10107605 polymorphism is associated with telomere shortening.

RevDate: 2019-11-02

Keener R, Connelly CJ, CW Greider (2019)

Tel1 Activation by the MRX Complex Is Sufficient for Telomere Length Regulation but Not for the DNA Damage Response in Saccharomyces cerevisiae.

Genetics pii:genetics.119.302713 [Epub ahead of print].

Previous models suggested that regulation of telomere length in S. cerevisiae by Tel1(ATM) and Mec1(ATR) would parallel the established pathways regulating the DNA damage response. Here we provide evidence that telomere length regulation differs from the DNA damage response in both the Tel1 and Mec1 pathways. We found that Rad53 mediates a Mec1 telomere length regulation pathway but is dispensable for T--el1 telomere length regulation, whereas in the DNA damage response Rad53 is regulated by both Mec1 and Tel1. Using epistasis analysis with a Tel1 hypermorphic allele, Tel1-hy909, we found that the MRX complex is not required downstream of Tel1 for telomere elongation but is required downstream of Tel1 for the DNA damage response. Our data suggest that nucleolytic telomere end processing is not a required step for telomerase to elongate telomeres.

RevDate: 2019-10-24

Yang L, Liu X, Song L, et al (2019)

Inhibiting repressive epigenetic modification promotes telomere rejuvenation in somatic cell reprogramming.

FASEB journal : official publication of the Federation of American Societies for Experimental Biology [Epub ahead of print].

The efficiency of somatic cell nuclear transfer (SCNT) reprogramming is extremely low in terms of production of cloned animals. Here, we found that telomere rejuvenation is a critical event for SCNT reprogramming. Through small-molecule screening, we identified that melatonin significantly improved the in vitro and in vivo developmental competence of SCNT-derived embryos. Through use of embryonic biopsy, single-cell RNA sequencing, and quantitative FISH experiments, we revealed that melatonin not only attenuated the zygotic genome activation defect but also facilitated telomere elongation in the SCNT embryos. Further investigation indicated that melatonin inhibited heterochromatic epigenetic modification related to gene silencing including DNA methylation and histone [3H] lysine 9 trimethylation. In addition, melatonin could increase the level of activation markers such as acetylated histone [3H]. This is the first study to characterize melatonin-treatment and telomere rejuvenation in SCNT-mediated reprogramming. Moreover, combinational use of melatonin-treated donor embryos and pseudo-pregnant recipients achieved synergistic enhancement of the production of cloned animals.-Yang, L., Liu, X., Song, L., Su, G., Di, A., Bai, C., Wei, Z., Li, G. Inhibiting repressive epigenetic modification promotes telomere rejuvenation in somatic cell reprogramming.

RevDate: 2019-10-23

Hailemariam S, De Bona P, Galletto R, et al (2019)

The telomere-binding protein Rif2 and ATP-bound Rad50 have opposing roles in the activation of yeast Tel1ATM kinase.

The Journal of biological chemistry pii:RA119.011077 [Epub ahead of print].

Saccharomyces cerevisiae Tel1 is the ortholog of human ATM kinase and initiates a cell cycle checkpoint in response to dsDNA breaks (DSBs). Tel1ATM kinase is activated synergistically by naked dsDNA and the Mre11-Rad50-Xrs2NBS1 complex (MRX). A multi-subunit protein complex, which is related to human shelterin, protects telomeres from being recognized as DSBs, thereby preventing a Tel1ATM checkpoint response. However, at very short telomeres, Tel1ATM can be recruited and activated by the MRX complex, resulting in telomere elongation. Conversely, at long telomeres, Rap1-interacting-factor 2 (Rif2) is instrumental in suppressing Tel1 activity. Here, using an in vitro reconstituted Tel1 kinase activation assay, we show that Rif2 inhibits MRX-dependent Tel1 kinase activity. Rif2 discharges the ATP-bound form of Rad50, which is essential for all MRX-dependent activities. This conclusion is further strengthened by experiments with a Rad50 allosteric ATPase mutant that maps outside of the conserved ATP binding pocket. We propose a model in which Rif2 attenuates Tel1 activity at telomeres by acting directly on Rad50 and discharging its activated ATP-bound state, thereby rendering the MRX complex incompetent for Tel1 activation. These findings expand our understanding of the mechanism by which Rif2 controls telomere length.

RevDate: 2019-10-22

Denham J (2019)

Telomere regulation: lessons learnt from mice and men, potential opportunities in horses.

Animal genetics [Epub ahead of print].

Telomeres are genetically conserved nucleoprotein complexes located at the ends of chromosomes that preserve genomic stability. In large mammals, somatic cell telomeres shorten with age, owing to the end replication problem and lack of telomere-lengthening events (e.g. telomerase and ALT activity). Therefore, telomere length reflects cellular replicative reserve and mitotic potential. Environmental insults can accelerate telomere attrition in response to cell division and DNA damage. As such, telomere shortening is considered one of the major hallmarks of ageing. Much effort has been dedicated to understanding the environmental perturbations that accelerate telomere attrition and therapeutic strategies to preserve or extend telomeres. As telomere dynamics seem to reflect cumulative cellular stress, telomere length could serve as a biomarker of animal welfare. The assessment of telomere dynamics (i.e. rate of shortening) in conjunction with telomere-regulating genes and telomerase activity in racehorses could monitor long-term animal health, yet it could also provide some unique opportunities to address particular limitations with the use of other animal models in telomere research. Considering the ongoing efforts to optimise the health and welfare of equine athletes, the purpose of this review is to discuss the potential utility of assessing telomere length in Thoroughbred racehorses. A brief review of telomere biology in large and small mammals will be provided, followed by discussion on the biological implications of telomere length and environmental (e.g. lifestyle) factors that accelerate or attenuate telomere attrition. Finally, the utility of quantifying telomere dynamics in horses will be offered with directions for future research.

RevDate: 2019-11-25

Germann CB (2019)

The Psilocybin-Telomere Hypothesis: An empirically falsifiable prediction concerning the beneficial neuropsychopharmacological effects of psilocybin on genetic aging.

Medical hypotheses, 134:109406 pii:S0306-9877(19)30822-9 [Epub ahead of print].

We introduce a novel hypothesis which states that the therapeutic utilisation of psilocybin has beneficial effects on genetic aging. Ex hypothesi, we predict a priori that controlled psilocybin interventions exert quantifiable positive impact on leucocyte telomere length (telomeres are a robust predictor of mortality and multifarious aging-related diseases). Our hypothesising follows the Popperian logic of scientific discovery, viz., bold (and refutable) conjectures form the very foundation of scientific progress. The 'psilocybin-telomere hypothesis' is formalised as a logically valid deductive (syllogistic) argument and we provide substantial evidence to support the underlying premises. Impetus for our theorising derives from a plurality of converging empirical sources indicating that psilocybin has persistent beneficial effects on various aspects of mental health (e.g., in the context of depression, anxiety, PTSD, OCD, addiction, etc.). Additional support is based on a large corpus of studies that establish reliable correlations between mental health and telomere attrition (improved mental health is generally correlated with longer telomeres). Another pertinent component of our argument is based on recent studies which demonstrate that "meditative states of consciousness" provide beneficial effects on genetic aging. Similarly, psilocybin can induce states of consciousness that are neurophysiologically and phenomenologically significantly congruent with meditative states. Furthermore, prior research has demonstrated that a single dose of psilocybin can occasion life-changing transformative experiences (≈ 70% of healthy volunteers rate their experience with psilocybin amongst the five personally most meaningful lifetime events, viz., ranked next to giving birth to a child or losing a loved one). We postulate that these profound psychological events leave quantifiable marks at the molecular genetic/epigenetic level. Given the ubiquitous availability and cost effectiveness of telomere length assays, we suggest that quantitative telomere analysis should be regularly included in future psilocybin studies as an adjunctive biological marker (i.e., to facilitate scientific consilience via methodological triangulation). In order to substantiate the 'psilocybin-telomere hypothesis' potential neuropsychopharmacological, endocrinological, and genetic mechanisms of action are discussed (e.g., HPA-axis reactivity, hippocampal neurogenesis, neurotropic growth factors such as BDNF, 5-HT2A receptor agonism, neuroplasticity/synaptoplasticity, brain-wide alterations in neuronal functional connectivity density, involvement of the SLC6A4 serotonin transporter gene, inter alia). The proposed research agenda is thus intrinsically highly interdisciplinary, and it has deep ramifications from a philosophy of science perspective as it connects the epistemic level (qualitative experiential phenomenology) with the ontic level (quantitative molecular genetics) of analysis. In the long term, multidisciplinary and innovative investigations of the 'psilocybin-telomere hypothesis' could contribute to the improvement of senotherapeutic psychological interventions and the identification of novel geroprotective and neuroprotective/restorative pharmaceutical targets to decelerate genetic aging and improve well-being and quality of life during the aging process.

RevDate: 2019-10-21

Victorelli S, Lagnado A, Halim J, et al (2019)

Senescent human melanocytes drive skin ageing via paracrine telomere dysfunction.

The EMBO journal [Epub ahead of print].

Cellular senescence has been shown to contribute to skin ageing. However, the role of melanocytes in the process is understudied. Our data show that melanocytes are the only epidermal cell type to express the senescence marker p16INK4A during human skin ageing. Aged melanocytes also display additional markers of senescence such as reduced HMGB1 and dysfunctional telomeres, without detectable telomere shortening. Additionally, senescent melanocyte SASP induces telomere dysfunction in paracrine manner and limits proliferation of surrounding cells via activation of CXCR3-dependent mitochondrial ROS. Finally, senescent melanocytes impair basal keratinocyte proliferation and contribute to epidermal atrophy in vitro using 3D human epidermal equivalents. Crucially, clearance of senescent melanocytes using the senolytic drug ABT737 or treatment with mitochondria-targeted antioxidant MitoQ suppressed this effect. In conclusion, our study provides proof-of-concept evidence that senescent melanocytes affect keratinocyte function and act as drivers of human skin ageing.

RevDate: 2019-10-24

Spindler MC, Redolfi J, Helmprobst F, et al (2019)

Electron tomography of mouse LINC complexes at meiotic telomere attachment sites with and without microtubules.

Communications biology, 2:376.

Telomere movements during meiotic prophase I facilitate synapsis and recombination of homologous chromosomes. Hereby, chromosome movements depend on the dynamic attachment of meiotic telomeres to the nuclear envelope and generation of forces that actively move the telomeres. In most eukaryotes, forces that move telomeres are generated in the cytoplasm by microtubule-associated motor proteins and transduced into the nucleus through the LINC complexes of the nuclear envelope. Meiotic LINC complexes, in mouse comprised of SUN1/2 and KASH5, selectively localize to the attachment sites of meiotic telomeres. For a better understanding of meiotic telomere dynamics, here we provide quantitative information of telomere attachment sites that we have generated with the aid of electron microscope tomography (EM tomography). Our data on the number, length, width, distribution and relation with microtubules of the reconstructed structures indicate that an average number of 76 LINC complexes would be required to move a telomere attachment site.

RevDate: 2019-11-02

Xu M, Qin J, Wang L, et al (2019)

Nuclear receptors regulate alternative lengthening of telomeres through a novel noncanonical FANCD2 pathway.

Science advances, 5(10):eaax6366.

Alternative lengthening of telomeres (ALT) is known to use homologous recombination (HR) to replicate telomeric DNA in a telomerase-independent manner. However, the detailed process remains largely undefined. It was reported that nuclear receptors COUP-TFII and TR4 are recruited to the enriched GGGTCA variant repeats embedded within ALT telomeres, implicating nuclear receptors in regulating ALT activity. Here, we identified a function of nuclear receptors in ALT telomere maintenance that involves a direct interaction between COUP-TFII/TR4 and FANCD2, the key protein in the Fanconi anemia (FA) DNA repair pathway. The COUP-TFII/TR4-FANCD2 complex actively induces the DNA damage response by recruiting endonuclease MUS81 and promoting the loading of the PCNA-POLD3 replication complex in ALT telomeres. Furthermore, the COUP-TFII/TR4-mediated ALT telomere pathway does not require the FA core complex or the monoubiquitylation of FANCD2, key steps in the canonical FA pathway. Thus, our findings reveal that COUP-TFII/TR4 regulates ALT telomere maintenance through a novel noncanonical FANCD2 pathway.

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

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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.

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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.

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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.

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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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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

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