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Bibliography on: Telomeres

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ESP: PubMed Auto Bibliography 09 Apr 2020 at 01:51 Created: 


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

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Citations The Papers (from PubMed®)

RevDate: 2020-04-08

Chalouni M, Rodriguez-Centeno J, Samri A, et al (2020)

Correlation between blood telomere length and CD4+ CD8+ T-cell subsets changes 96 weeks after initiation of antiretroviral therapy in HIV-1-positive individuals.

PloS one, 15(4):e0230772 pii:PONE-D-19-29458.

In 31 participants who started first-line antiretroviral therapy in the NEAT 001/ANRS 143 clinical trial, we found after 96 weeks a statistically significant increase in blood telomere length (TL) of 0.04 (T/S Ratio) (p = 0.03). This increase was positively correlated with both the change in the percentage of CD4+ T-cells and with the decrease of CD38+ molecules on Central Memory CD8+ and negatively correlated with the change in the percentage of CD4+ Effector Memory cells. Increase in TL could be an expression of immune reconstitution and the associated decrease in immune activation. We acknowledge for the low statistical power due to the small sample size and the potential for false positive results due to multiple testing. Hence, further studies are needed to confirm these observations.

RevDate: 2020-04-08

Utyro O, Perła-Kaján J, H Jakubowski (2020)

The Cbs Locus Affects the Expression of Senescence Markers and mtDNA Copy Number, but not Telomere Dynamics in Mice.

International journal of molecular sciences, 21(7): pii:ijms21072520.

Cystathionine β-synthase (CBS) is a housekeeping enzyme that catalyzes the first step of the homocysteine to cysteine transsulfuration pathway. Homozygous deletion of the Cbs gene in mice causes severe hyperhomocysteinemia and reduces life span. Here, we examined a possible involvement of senescence, mitochondrial DNA, and telomeres in the reduced life span of Cbs-/- mice. We found that senescence-related p21, Pai-1, Mcp1, and Il-6 mRNAs were significantly upregulated (2-10-fold) in liver, while p21 was upregulated in the brain of Cbs-/- mice (n = 20) compared with control Cbs+/- siblings (n = 20) in a sex- and age-dependent manner. Telomere length in blood (n = 80), liver (n = 40), and brain (n = 40) was not affected by the Cbs-/- genotype, but varied with sex and/or age. Levels of mitochondrial DNA tended to be reduced in livers, but not brains and blood, of Cbs-/- females (n = 20-40). The Cbs-/- genotype significantly reduced Tert mRNA expression in brain, but not liver, in a sex- and age-dependent manner. Multiple regression analysis showed that the senescence-related liver (but not brain) mRNAs and liver (but not brain or blood) mitochondrial DNA were associated with the Cbs genotype. In contrast, telomere length in blood, brain, and liver was not associated with the Cbs genotype or hyperhomocysteinemia, but was associated with sex (in brain and liver) and age (in brain and blood). Taken together, these findings suggest that the changes in senescence marker expression and mtDNA levels, but not telomere shortening, could account for the reduced life span of Cbs-/- mice.

RevDate: 2020-04-08

Joglekar MV, Satoor SN, Wong WKM, et al (2020)

An Optimised Step-by-Step Protocol for Measuring Relative Telomere Length.

Methods and protocols, 3(2): pii:mps3020027.

Telomeres represent the nucleotide repeat sequences at the ends of chromosomes and are essential for chromosome stability. They can shorten at each round of DNA replication mainly because of incomplete DNA synthesis of the lagging strand. Reduced relative telomere length is associated with aging and a range of disease states. Different methods such as terminal restriction fragment analysis, real-time quantitative PCR (qPCR) and fluorescence in situ hybridization are available to measure telomere length; however, the qPCR-based method is commonly used for large population-based studies. There are multiple variations across qPCR-based methods, including the choice of the single-copy gene, primer sequences, reagents, and data analysis methods in the different reported studies so far. Here, we provide a detailed step-by-step protocol that we have optimized and successfully tested in the hands of other users. This protocol will help researchers interested in measuring relative telomere lengths in cells or across larger clinical cohort/study samples to determine associations of telomere length with health and disease.

RevDate: 2020-04-07

Tan J, L Lan (2020)

The DNA secondary structures at telomeres and genome instability.

Cell & bioscience, 10:47 pii:409.

Telomeric DNA are TTAGGG tandem repeats, which are susceptible for oxidative DNA damage and hotspot regions for formation of DNA secondary structures such as t-loop, D-loop, G-quadruplexes (G4), and R-loop. In the past two decades, unique DNA or RNA secondary structures at telomeres or some specific regions of genome have become promising therapeutic targets. G-quadruplex and R-loops at telomeres or transcribed regions of genome have been considered as the potential targets for cancer therapy. Here we discuss the potentials to target the secondary structures (G4s and R-loops) in genome as therapy approaches.

RevDate: 2020-04-06

Koi Y, Tsutani Y, Nishiyama Y, et al (2020)

Diagnostic performance of peripheral leukocyte telomere G-tail length for detecting breast cancer.

The telomere G-tail (G-tail) plays an essential role in maintaining chromosome stability. In this study, we assessed the leukocyte G-tail length of breast cancer (BC) patients and cancer-free individuals and evaluated the association between the G-tail length and the presence of BC. A significant shortening of the median G-tail length was observed in BC patients compared with cancer-free individuals and was found in the early phase of BC. Our study indicated that the leukocyte G-tail length might be a potential biomarker for BC detection.

RevDate: 2020-04-05

Zaguia N, Laplagne E, Colicchio B, et al (2020)

A new tool for genotoxic risk assessment: Reevaluation of the cytokinesis-block micronucleus assay using semi-automated scoring following telomere and centromere staining.

Mutation research, 850-851:503143.

BACKGROUND: The cytokinesis-block micronucleus (CBMN) assay is an internationally recognized method for measuring DNA damage after exposure to genotoxic agents, as well as a biomarker for DNA repair and chromosomal instability. The high baseline level of micronuclei (MN) in the healthy population has limited the sensitivity and application of the CBMN assay for the follow-up of exposed populations. We reevaluated the sensitivity of the CBNM assay using semi-automated MN scoring following telomere and centromere (TC) staining after in vitro exposure to genotoxic agents (mitomycin or radiation) or aneugenic agents (vinblastine).

MATERIALS AND METHODS: Blood samples from 12 healthy donors were exposed to 137Cs at seven doses from 0.1-4 Gy and cultured for 72 h. Cytochalasin B was added at 46 h of culture. The exposure of chemical agents (mitomycin or vinblastine) was performed after 48 h of culture for 3 h. Cytochalasin B was added after treatment and slides were prepared 24 h after. MN was semi-automatically scored following TC staining. Nucleoplasmic bridges (NPBs) and nuclear buds (NBUDs) were assessed in a human cell line after TC staining.

RESULTS: The introduction TC staining to the scoring of MN not only renders MN scoring more efficient and robust, but also permits discrimination between exposure to clastogenic (MN with only telomere signals) and aneugenic agents (MN with both TC signals). The resulting improvement of MN detection led to an increase in the sensitivity of the CBMN assay following low-dose radiation exposure (0.3 versus 0.1 Gy). Hyperradiosensitivity phenomenon was observed after low dose exposure. A dose-response curve was obtained for up to 4 Gy. In addition, TC staining permits assessment of the nature of NPBs and NBUDs as biomarkers for genotoxicity and chromosomal instability.

CONCLUSION: These approaches can be potentially used to follow-up populations exposed to genotoxic agents and assess cancer risk.

RevDate: 2020-04-02

Ghosh M, Janssen L, Martens DS, et al (2020)

Increased telomere length and mtDNA copy number induced by multi-walled carbon nanotube exposure in the workplace.

Journal of hazardous materials, 394:122569 pii:S0304-3894(20)30558-6 [Epub ahead of print].

Carbon nanotubes (CNTs) except MWCNT-7 have been classified as Group 3 ["Not classifiable as to its carcinogenicity to humans"] by the IARC. Despite considerable mechanistic evidence in vitro/in vivo, the classification highlights a general lack of data, especially among humans. In our previous study, we reported epigenetic changes in the MWCNT exposed workers. Here, we evaluated whether MWCNT can also cause alterations in aging related features including relative telomere length (TL) and/or mitochondrial copy number (mtDNAcn). Relative TL and mtDNAcn were measured on extracted DNA from peripheral blood from MWCNT exposed workers (N = 24) and non-exposed controls (N = 43) using a qPCR method. A higher mtDNAcn and longer TL were observed in MWCNT exposed workers when compared to controls. Independent of age, sex, smoking behavior, alcohol consumption and BMI, MWCNT-exposure was associated with an 18.30 % increase in blood TL (95 % CI: 7.15-30.62 %; p = 0.001) and 35.21 % increase in mtDNAcn (95 % CI: 19.12-53.46 %). Our results suggest that exposure to MWCNT can induce an increase in the mtDNAcn and TL; however, the mechanistic basis or consequence of such change requires further experimental studies.

RevDate: 2020-04-02

Kim C, Sung S, Kim J, et al (2020)

Repair and Reconstruction of Telomeric and Subtelomeric Regions and Genesis of New Telomeres: Implications for Chromosome Evolution.

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

DNA damage repair within telomeres are suppressed to maintain the integrity of linear chromosomes, but the accidental activation of repairs can lead to genome instability. This review develops the concept that mechanisms to repair DNA damage in telomeres contribute to genetic variability and karyotype evolution, rather than catastrophe. Spontaneous breaks in telomeres can be repaired by telomerase, but in some cases DNA repair pathways are activated, and can cause chromosomal rearrangements or fusions. The resultant changes can also affect subtelomeric regions that are adjacent to telomeres. Subtelomeres are actively involved in such chromosomal changes, and are therefore the most variable regions in the genome. The case of Caenorhabditis elegans in the context of changes of subtelomeric structures revealed by long-read sequencing is also discussed. Theoretical and methodological issues covered in this review will help to explore the mechanism of chromosome evolution by reconstruction of chromosomal ends in nature.

RevDate: 2020-04-01

Mendez-Bermudez A, Giraud-Panis MJ, Ye J, et al (2020)

Heterochromatin replication goes hand in hand with telomere protection.

Nature structural & molecular biology pii:10.1038/s41594-020-0400-1 [Epub ahead of print].

Telomeres arose from the need to stabilize natural chromosome ends, resulting in terminal chromatin structures with specific protective functions. Their constituent proteins also execute general functions within heterochromatin, mediating late replication and facilitating fork progression. Emerging insights into the mechanisms governing heterochromatin replication suggest telomeres and heterochromatin act in concert during development and aging. They also suggest a common evolutionary origin for these two chromosome regions that arose during eukaryogenesis.

RevDate: 2020-04-01

Iloabuchi C, Innes KE, U Sambamoorthi (2020)

Association of sleep quality with telomere length, a marker of cellular aging: A retrospective cohort study of older adults in the United States.

Sleep health pii:S2352-7218(19)30265-7 [Epub ahead of print].

BACKGROUND: Sleep quality is a risk factor for age-related diseases, and although the underlying mechanisms remain unclear, the effects of poor sleep quality on telomere length (TL) may play a role.

OBJECTIVE: The objective of the study was to evaluate the independent association between sleep quality and salivary TL in a large sample of older adults.

DESIGN: We adopted a retrospective cohort design, and participants comprised 5,268 adults drawn from the Health and Retirement Study. We used the 2006 (baseline) and 2008 (follow-up) waves. Baseline sleep quality was assessed using 4 Likert scale questions (trouble falling asleep, waking up during the night, waking up too early and not being able to fall sleep again, and feeling well rested in the morning). The TL was assessed using the T/S ratio, a continuous variable. The associations between sleep quality and T/S were assessed using multivariable ordinary least squares regressions. All analyses were adjusted for demographics, lifestyle characteristics, psychosocial, and other factors.

RESULTS: Overall, 16% reported never feeling well rested in the morning; 25.7% of respondents always had trouble waking during the night; and 12.8% always had trouble waking up too early in the morning. Respondents who never felt rested in the morning had significantly shorter TL than those who always felt rested in the morning (adjusted beta = -0.08, standard error = 0.03, p < 0.01). The composite sleep measure was not significantly associated with shorter TL.

CONCLUSIONS: In this cohort of older adults, not feeling well rested in the morning was significantly and inversely associated with TL; however, the composite measure of sleep quality was not significantly associated with TL. These findings suggest a potential connection between one of the measures of impaired sleep and reduction in TL, a marker of cellular aging that has been linked to multiple chronic conditions.

RevDate: 2020-03-31

Prasad R, Pal D, W Mohammad (2020)

Therapeutic Targets in Telomerase and Telomere Biology of Cancers.

Indian journal of clinical biochemistry : IJCB, 35(2):135-146.

Telomeres play an important role to conserve genomic integrity by protecting the ends of chromosomes in normal cells. Since, their progressive shortening during successive cell division which lead to chromosomal instability. Notably, telomere length is perpetuated by telomerase in large majority of cancers, thereby ensure indefinite cell proliferation-a hallmark of cancer-and this unique feature has provided telomerase as the preferred target for drug development in cancer therapeutics. Cancer cells have acquired the potential to have telomere length maintenance by telomerase activation- up-regulation of hTERT gene expression in tumor cells is synchronized by multiple genetic and epigenetic modification mechanisms viz hTERT structural variants, hTERT promoter mutation and epigenetic modifications through hTERT promoter methylation which have been implicated in various cancers initiation and progression. In view of these facts, strategies have been made to target the underlining molecular mechanisms involved in telomerase reactivation as well as of telomere structure with special reference to distortion of sheltrin proteins. This review is focussed on extensive understanding of telomere and telomerase biology. which will provide indispensable informations for enhancing the efficiency of rational anticancer drug design. However, there is also an urgent need for better understanding of cell signalling pathways for alternative lengthening of telomere which is present in telomerase negative cancer for therapeutic targets.

RevDate: 2020-03-31

Aghaee S, Allen A, Ramirez J, et al (2020)

Everyday discrimination and telomere length in a multiethnic cohort of breast cancer survivors.

Ethnicity & health [Epub ahead of print].

Objectives: Racial/ethnic minority women have disproportionately lower breast cancer survival rates compared to white women. As minorities in the US are exposed to higher levels of discrimination, and exposure to discrimination has been associated with shorter telomere lengths (TLs), we investigated the association between perceived everyday discrimination and TL in a multiethnic sample of breast cancer survivors.Design: We examined a cohort of 58 breast cancer survivors who participated in a pilot study to investigate biological stress. Participants were drawn from the Equality in Breast Cancer Care (EBCC) study and were asked to provide saliva samples for DNA extraction. Ordinary least squares linear regression was used to derive regression coefficients (β) and 95% confidence intervals (CI).Results: Higher levels of everyday discrimination were associated with longer TLs (eβ = 1.04, CI: 1.01-1.07), adjusting for age, race/ethnicity, breast cancer stage, and breast cancer subtype. Luminal B subtypes were associated with longer telomeres relative to luminal A, while African Americans were less likely than Whites to have longer telomeres.Conclusions: Further research, particularly longitudinal studies, is needed to understand how discrimination, and other social stressors, impact biological stress and health outcomes.

RevDate: 2020-03-30

Fernandes CAH, Morea EGO, Dos Santos GA, et al (2020)

A multi-approach analysis highlights the relevance of RPA-1 as a telomere end-binding protein (TEBP) in Leishmania amazonensis.

Biochimica et biophysica acta. General subjects pii:S0304-4165(20)30119-7 [Epub ahead of print].

BACKGROUND: Telomeres are chromosome end structures important in the maintenance of genome homeostasis. They are replenished by the action of telomerase and associated proteins, such as the OB (oligonucleotide/oligosaccharide-binding)-fold containing telomere-end binding proteins (TEBP) which plays an essential role in telomere maintenance and protection. The nature of TEBPs is well known in higher and some primitive eukaryotes, but it remains undetermined in trypanosomatids. Previous in silico searches have shown that there are no homologs of the classical TEPBs in trypanosomatids, including Leishmania sp. However, Replication Protein A subunit 1 (RPA-1), an OB-fold containing DNA-binding protein, was found co-localized with trypanosomatids telomeres and showed a high preference for the telomeric G-rich strand.

METHODS AND RESULTS: We predicted the absence of structural homologs of OB-fold containing TEBPs in the Leishmania sp. genome using structural comparisons. We demonstrated by molecular docking that the ssDNA binding mode of LaRPA-1 shares features with the higher eukaryotes POT1 and RPA-1 crystal structures ssDNA binding mode. Using fluorescence spectroscopy, protein-DNA interaction assays, and FRET, we respectively show that LaRPA-1 shares some telomeric functions with the classical TEBPs since it can bind at least one telomeric repeat, protect the telomeric G-rich DNA from 3'-5' Exonuclease I digestion, and unfold telomeric G-quadruplex.

CONCLUSIONS: Our results suggest that RPA-1 emerges as a TEBP in trypanosomatids, and in this context, we present two possible evolutionary landscapes of trypanosomatids RPA-1 that could reflect upon the evolution of OB-fold containing TEBPs from all eukaryotes.

RevDate: 2020-03-29

Udomsinprasert W, Chanhom N, Suvichapanich S, et al (2020)

Leukocyte telomere length as a diagnostic biomarker for anti-tuberculosis drug-induced liver injury.

Scientific reports, 10(1):5628 pii:10.1038/s41598-020-62635-2.

Despite being relatively rare, anti-tuberculosis drug-induced liver injury (ATDILI) is a leading cause of acute liver failure and a major reason for treatment discontinuation, because of no specific and selective markers for ATDILI. Herein, this study aimed to investigate whether telomere length, a biological indicator of age-related diseases, is associated with ATDILI outcomes and could serve as an early ATDILI biomarker. Relative telomere length (RTL) in blood leukocyte of 100 age- and gender-matched healthy controls, 49 tuberculosis patients with ATDILI, and 53 tuberculosis patients with non-ATDILI was quantified using real-time polymerase chain reaction. Both tuberculosis patients with and without ATDILI had significantly shorter RTL than healthy controls. Compared with tuberculosis patients with non-ATDILI, RTL in those with ATDILI was significantly increased. Longer RTL was found to be significantly associated with increased susceptibility to ATDILI. Multivariate linear regression analysis showed that an increment in RTL was independently correlated with elevated values of aspartate aminotransferase and alanine aminotransferase assessed within 60 days after anti-tuberculosis treatment. Kaplan-Meier curve analysis demonstrated that longer RTL was associated with elevated rates of hepatotoxicity in tuberculosis patients. Receiver-operating characteristic curve analysis unveiled a diagnostic accuracy of RTL as a novel indicator for ATDILI progression (AUC = 0.73), which yielded more sensitive and specific values than traditional liver biomarkers including serum enzyme activities of aminotransferases measured within 7 days after treatment with anti-tuberculosis regimens. Collectively, aberrant RTL in blood leukocyte would reflect hepatotoxicity induced by anti-tuberculosis agents and might have a potential biomarker for early ATDILI progression.

RevDate: 2020-03-29

Pepper C, Norris K, C Fegan (2020)

Clinical utility of telomere length measurements in cancer.

Current opinion in genetics & development, 60:107-111 pii:S0959-437X(20)30017-4 [Epub ahead of print].

Cancer remains one of the leading causes of death in the developed world and despite impressive advances in therapeutic modalities, only a small subset of patients are currently cured. The underlying genetic heterogeneity of cancers clearly plays a crucial role in determining both the clinical course of individual pathologies and their responses to standard treatments. Although every tumour is to some extent distinct, there are recurrent features of cancers that can be exploited as therapeutic targets and as prognostic and predictive biomarkers; one such attribute is telomere length. Here we discuss the utility of telomere length evaluation in cancer and describe some of the promise and challenges of bringing this into clinical practice.

RevDate: 2020-03-28

Loe TK, Li JSZ, Zhang Y, et al (2020)

Telomere length heterogeneity in ALT cells is maintained by PML-dependent localization of the BTR complex to telomeres.

Genes & development pii:gad.333963.119 [Epub ahead of print].

Telomeres consist of TTAGGG repeats bound by protein complexes that serve to protect the natural end of linear chromosomes. Most cells maintain telomere repeat lengths by using the enzyme telomerase, although there are some cancer cells that use a telomerase-independent mechanism of telomere extension, termed alternative lengthening of telomeres (ALT). Cells that use ALT are characterized, in part, by the presence of specialized PML nuclear bodies called ALT-associated PML bodies (APBs). APBs localize to and cluster telomeric ends together with telomeric and DNA damage factors, which led to the proposal that these bodies act as a platform on which ALT can occur. However, the necessity of APBs and their function in the ALT pathway has remained unclear. Here, we used CRISPR/Cas9 to delete PML and APB components from ALT-positive cells to cleanly define the function of APBs in ALT. We found that PML is required for the ALT mechanism, and that this necessity stems from APBs' role in localizing the BLM-TOP3A-RMI (BTR) complex to ALT telomere ends. Strikingly, recruitment of the BTR complex to telomeres in a PML-independent manner bypasses the need for PML in the ALT pathway, suggesting that BTR localization to telomeres is sufficient to sustain ALT activity.

RevDate: 2020-03-27

Liu Y, Ma C, Li P, et al (2020)

Leukocyte Telomere Length Independently Predicts 3-Year Diabetes Risk in a Longitudinal Study of Chinese Population.

Oxidative medicine and cellular longevity, 2020:9256107.

Cellular aging markers, including telomere length and mitochondrial function, as well as oxidative stress and inflammation markers influence each other and form a complex network, which is affected in diabetes. However, it remains unknown whether these markers could independently predict future diabetes after adjustment for their mutual effects. We conducted a 3-year longitudinal study in a Chinese cohort that comprised 108 nondiabetic individuals at baseline. The 2-hour 75 g oral glucose tolerance tests were performed at baseline and at 3-year follow-up. At baseline, leukocyte telomere length (LTL) and mitochondrial DNA copy number (mtDNAcn) in leukocytes were determined using the polymerase chain reaction method. Tumor necrosis factor (TNF-α), interleukin-6, 8-hydroxy-2-deoxyguanosine levels, and superoxide dismutase (SOD) activity were measured by the enzyme-linked immunosorbent assay. Participants who developed diabetes at the 3-year follow-up (n = 28) had shorter LTL and higher levels of TNF-α and SOD activity at baseline. Baseline LTL was found to be independently associated with the development of diabetes at the 3-year follow-up after the adjustment for mtDNAcn, markers of oxidative stress and inflammation, and conventional diabetes risk factors. Our findings suggest that LTL is an independent predictor for 3-year diabetes risk, which might inform timely prevention and treatment of diabetes. Telomere shortening might be involved in the pathogenesis of diabetes independently of conventional diabetes risk factors, mtDNAcn, or oxidative stress and inflammation pathways.

RevDate: 2020-03-27

Yang ZY, Kao TW, Peng TC, et al (2020)

Examining the association between serum phosphate levels and leukocyte telomere length.

Scientific reports, 10(1):5438 pii:10.1038/s41598-020-62359-3.

Accelerated telomere attrition is related to various diseases, and multiple factors have been reported to influence telomere length. However, little attention has focused on the relationship between serum phosphate levels and mean telomere length. The purpose of this study was to explore the relationship between serum phosphate levels and mean telomere length in the US general population. A total of 7,817 participants from the 1999-2002 NHANES were included. The association between serum phosphate levels and mean telomere length was investigated using regression models. A remarkably positive relationship between serum phosphate levels and mean telomere length emerged after adjustments were made for covariates. The adjusted β coefficient of serum phosphate levels for mean telomere length was 0.038 (95% confidence intervals (CIs), 0.022 to 0.095, p = 0.002). A longer telomere length was observed in participants with serum phosphate levels in the highest quartiles, and a dose-dependent association was observed. Our study demonstrated that higher quartiles of phosphate had a remarkable correlation with longer telomere length.

RevDate: 2020-03-27

Moslem A, Rad A, de Prado Bert P, et al (2020)

Association of exposure to air pollution and telomere length in preschool children.

The Science of the total environment, 722:137933 pii:S0048-9697(20)31446-7 [Epub ahead of print].

Exposure to air pollution is associated with adverse health effects; however, the available evidence of its association with telomere length (TL), an early marker of ageing, in children is still scarce with no study available for preschool children. This study aimed to investigate the association of exposure to air pollution and traffic indicators at home and kindergarten with relative leukocyte TL (LTL) in preschool children. This cross-sectional study included 200 preschool children (5-7 years old) recruited from 27 kindergartens in Sabzevar, Iran (2017). Outdoor annual average levels PM1, PM2.5, and PM10 at residential address and kindergartens were estimated applying land use regression (LUR) models. Moreover, indoor levels of PMs at kindergartens were measured for four days in each season resulting in a total of 16 days of measurements for each kindergarten. Total streets length in different buffers and distance to major road were calculated as traffic indicators at residential address and kindergartens. We applied quantitative real-time polymerase chain reaction (qRT-PCR) to measure relative LTL in blood samples obtained from children. Mixed linear regression models were developed with qPCR plate and kindergarten as random effects, to estimate association of each pollutant and traffic indicator with LTL, controlled for relevant covariates. Higher concentrations of outdoor PM1, PM2.5, and PM10, at home and kindergartens were associated with shorter relative LTL. Similarly, increase in indoor PM2.5 concentrations at kindergartens was associated with shorter relative LTL (β = -0.18, 95% CI: -0.36, -0.01, P-value < 0.01). Moreover, higher total street length in 100 m buffer around residence and lower residential distance to major roads were associated with shorter relative LTL (β = -0.25, 95% CI: -0.37, -0.13, P-value < 0.01, and 0.32, 95% CI: 0.20, 0.44, P-value < 0.01, respectively). Overall, our study suggested that higher exposure to air pollution and traffic at kindergarten and residential home were associated with shorter relative LTL in preschool children.

RevDate: 2020-03-27

Arimura-Omori M, Kiyohara C, Yanagihara T, et al (2020)

Association between Telomere-Related Polymorphisms and the Risk of IPF and COPD as a Precursor Lesion of Lung Cancer: Findings from the Fukuoka Tobacco-Related Lung Disease (FOLD) Registry.

Asian Pacific journal of cancer prevention : APJCP, 21(3):667-673.

BACKGROUND: Lung cancer coexisting with idiopathic pulmonary fibrosis (IPF) or chronic obstructive pulmonary disease (COPD) can lead to poor prognosis. Telomere-related polymorphisms may be implicated in the pathogenesis of these three lung diseases. As to elucidate the mechanism of lung cancer via IPF or COPD may enable early detection and early treatment of the disease, we firstly examined the association between telomere-related polymorphisms and the risk of IPF and COPD in a case-control study.

MATERIALS AND METHODS: A total of 572 patients with IPF (n = 155) or COPD (n = 417), who were derived from our on-going cohort study, and controls (n = 379), who were derived from our previous case-control study, were included in this study. Telomerase reverse transcriptase (TERT) rs2736100, telomere RNA component (TERC) rs1881984, and oligonucleotide/oligosaccharide-binding fold containing1 (OBFC1) rs11191865 were genotyped with real-time PCR using TaqMan fluorescent probes. Unconditional logistic regression was used to assess the adjusted odds ratios and 95% confidence intervals.

RESULTS: TERT rs2736100 was significantly associated with the risk of IPF; increases in the number of this risk allele increased the risk of IPF (Ptrend = 0.008). Similarly, TERT rs2736100 was associated with the risk of COPD. In regard to the combined action of the three loci, increasing numbers of "at-risk" genotypes increased the risk of IPF in a dose-dependent manner (P trend=0.003).

CONCLUSIONS: TERT rs2736100 was associated with the risks of both IPF and COPD in a Japanese population. A combination of the "at-risk" genotypes might be important to identify the population at risk for IPF more clearly.

RevDate: 2020-03-26

Wang L, Song L, Liu B, et al (2020)

Earlier maternal menarche is associated with shorter newborn telomere length.

European journal of pediatrics pii:10.1007/s00431-020-03621-8 [Epub ahead of print].

The aim of our study was to investigate the relationship between maternal age at menarche and newborn telomere length which has been linked to lifespan and many age-related diseases. There were 734 mother-newborn pairs recruited from Wuhan Children's Hospital Wuhan, Hubei Province, China. Age at menarche was self-reported and categorized into three groups (≤ 12 years, 13 years, and ≥ 14 years). Telomere length in cord blood was measured using quantitative real-time polymerase chain reaction and expressed as the ratio of telomere copy number to single-copy gene number (T/S). The mean age at menarche of 734 mothers was 13.1 (± 1.1) years and the adjusted geometric means in the T/S of newborn telomeres in the three groups were 0.693, 0.721, and 0.748 respectively. Earlier age at menarche (≤ 12 years), compared with later age at menarche ≥ 14 years, was significantly associated with 7.32% (95% CI - 13.70%, - 0.23%) shorter telomere length in offspring after adjusting for potential confounders.Conclusion: Mothers with earlier age at menarche were more likely to give birth newborn with shorter telomere length. Our study provides evidences for the effect of earlier menarche on fetal telomere programming in offspring.What is Known:• Newborn telomere length is considered an indicator of lifespan and health outcomes in later life.• The adverse effects of earlier menarche age to their offspring have been found, but its relationship with newborn telomere length has not been assessed before.What is New:• This is the first study to explore the relationship of maternal menarche age with newborn telomere length.• We provided primary evidence that earlier maternal age at menarche was associated with shorter newborn telomere length.

RevDate: 2020-03-23

Heaphy CM, Bi WL, Coy S, et al (2020)

Telomere length alterations and ATRX/DAXX loss in pituitary adenomas.

Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc pii:10.1038/s41379-020-0523-2 [Epub ahead of print].

Telomeres are nucleoprotein complexes located at the termini of eukaryotic chromosomes that prevent exonucleolytic degradation and end-to-end chromosomal fusions. Cancers often have critically shortened, dysfunctional telomeres contributing to genomic instability. Telomere shortening has been reported in a wide range of precancerous lesions and invasive carcinomas. However, the role of telomere alterations, including the presence of alternative lengthening of telomeres (ALT), has not been studied in pituitary adenomas. Telomere length and the presence of ALT were assessed directly at the single cell level using a telomere-specific fluorescence in situ hybridization assay in tissue microarrays. Tumors were characterized as either ALT-positive or having short, normal, or long telomere lengths and then these categories were compared with clinicopathological characteristics. ATRX and DAXX expression was studied through immunohistochemistry. We characterized a discovery set of 106 pituitary adenomas including both functional and nonfunctional subsets (88 primary, 18 recurrent). Telomere lengths were estimated and we observed 64 (59.4%) cases with short, 39 (36.8%) cases with normal, and 0 (0%) cases with long telomeres. We did not observe significant differences in the clinicopathological characteristics of the group with abnormally shortened telomeres compared to the group with normal telomeres. However, three pituitary adenomas were identified as ALT-positive of which two were recurrent tumors. Two of these three ALT-positive cases had alterations in either of the chromatin remodeling proteins, ATRX and DAXX, which are routinely altered in other ALT-positive tumor subtypes. In a second cohort of 32 recurrent pituitary adenomas from 22 patients, we found that the tumors from 36% of patients (n = 8) were ALT-positive. This study demonstrates that short telomere lengths are prevalent in pituitary adenomas and that ALT-positive pituitary adenomas are enriched in recurrent disease.

RevDate: 2020-03-21

Henninger E, MT Teixeira (2020)

Telomere-driven mutational processes in yeast.

Current opinion in genetics & development, 60:99-106 pii:S0959-437X(20)30023-X [Epub ahead of print].

Telomeres are part of the system that guards genome integrity in eukaryotes, protecting linear chromosomes from fusions and degradations. The protective functions of telomeres are put at risk in physiological situations where telomeres shorten and trigger replicative senescence. Current models suggest that when telomeres shorten, combined actions of the DNA damage signalling network, DNA repair pathways, and the mechanics of mitosis result in translocations, gene losses, and aneuploidy. In yeasts, many of these processes (signalling, repair, mitosis) can be molecularly dissected because telomerase can be experimentally removed to enable detection of early and rare events. Here we review recent findings on telomere-driven mutational processes in yeast models and discuss how telomere dynamics may contribute to genome evolution.

RevDate: 2020-03-21

Herate C, L Sabatier (2020)

Telomere instability initiates and then boosts carcinogenesis by the butterfly effect.

Current opinion in genetics & development, 60:92-98 pii:S0959-437X(20)30011-3 [Epub ahead of print].

Telomeres are composed of DNA repeat sequences at the ends of chromosomes that recruit a multitude of proteins to form a complex loop structure at each extremity. The integrity of this structure is critical and correct conformation of the loop is essential for the protection of chromosome ends from DDR signaling. The properties of telomere composition and synthesis result in telomere shortening at each cell division, programming cellular lifespan by driving aged cells towards death. Indeed, many external factors, such as cellular stress, trigger cell-cycle dysfunction and, in some cases, enable the survival of cells with dysfunctionally short telomeres. Destabilized loops at chromosome ends can then lead to dramatic consequences, via a butterfly effect such as multiple chromosomal fusions and rearrangements causing large chromosomal deletions, XXL-LOH (loss of heterozygoty due to very large chromosome deletions, up to whole chromosome arm), the expression of recessive mutations, and potential cell transformation.

RevDate: 2020-03-21

Walsh KM (2020)

Telomere attrition in childhood cancer survivors.

Clinical cancer research : an official journal of the American Association for Cancer Research pii:1078-0432.CCR-20-0380 [Epub ahead of print].

Childhood cancer survivors experience substantial treatment-related morbidity and biomarkers of long-term survivor health are needed. Leukocyte telomere length is shortened in childhood cancer survivors and associates with the occurrence of numerous chronic health conditions. Healthy lifestyle factors can attenuate telomere attrition in young-adult survivors, implicating critical windows for intervention.

RevDate: 2020-03-20

Cherdyntseva V, S Gagos (2020)

Chromosome extremities under the microscopy lens: molecular cytogenetics in telomere research.

Current opinion in genetics & development, 60:69-76 pii:S0959-437X(20)30016-2 [Epub ahead of print].

At the crossroads of DNA damage repair and genomic instability, telomere research significantly expands our knowledge on fundamental mechanisms involved in cancer initiation and progression, pledging novel tools for targeted and universal onco-therapies. Molecular cytogenetics through the application of a battery of fluorescent hybridization technologies plays an important role toward understanding telomere homeostasis. Herein, we review distinct molecular cytogenetic phenotypes associated with telomere repair, functionality, and elongation. We discuss the underlying mechanisms responsible for their formation or repair, focusing on Break-induced-Replication (BIR)-mediated conservative telomeric neo-synthesis, recently shown to drive the enigmatic Alternative Lengthening of Telomeres in neoplasia.

RevDate: 2020-03-19

Rej PH, Bondy MH, Lin J, et al (2020)

Telomere length analysis from minimally-invasively collected samples: Methods development and meta-analysis of the validity of different sampling techniques: American Journal of Human Biology.

American journal of human biology : the official journal of the Human Biology Council [Epub ahead of print].

OBJECTIVES: Telomeres are the protective caps of chromosomes. They shorten with cell replication, age, and possibly environmental stimuli (eg, infection and stress). Short telomere length (TL) predicts subsequent worse health. Although venous whole blood (VWB) is most commonly used for TL measurement, other, more minimally invasive, sampling techniques are becoming increasingly common due to their field-friendliness, allowing for feasible measurement in low-resource contexts. We conducted statistical validation work for measuring TL in dried blood spots (DBS) and incorporated our results into a meta-analysis evaluating minimally invasive sampling techniques to measure TL.

METHODS: We isolated DNA extracts from DBS using a modified extraction protocol and tested how they endured different shipping conditions and long-term cryostorage. We then included our in-house DBS TL validation statistics (correlation values with VWB TL and age) in a series of meta-analyses of results from 24 other studies that published similar associations for values between TL measured in DBS, saliva, and buccal cells.

RESULTS: Our modified DBS extraction technique produced DNA yields that were roughly twice as large as previously recorded. Partially extracted DBS DNA was stable for 7 days at room temperature, and still provided reliable TL measurements, as determined by external validation statistics. In our meta-analysis, DBS TL had the highest external validity, followed by saliva, and then buccal cells-possibly reflecting similarities/differences in cellular composition vs VWB.

CONCLUSIONS: DBS DNA is the best proxy for VWB from the three minimally-invasively specimen types evaluated and can be used to expand TL research to diverse settings and populations.

RevDate: 2020-03-18

Schmidt CW (2020)

Telomere Length and Air Pollution: Observations in Women Who Use Biomass Cookstoves.

Environmental health perspectives, 128(3):34005.

RevDate: 2020-03-18

Morais M, Dias F, Teixeira AL, et al (2020)

Telomere Length in Renal Cell Carcinoma: The Jekyll and Hyde Biomarker of Ageing of the Kidney.

Cancer management and research, 12:1669-1679 pii:211225.

Renal cell carcinoma (RCC) is a heterogeneous group of cancers where the clear cell (ccRCC) is the most common and the most lethal. The absence of accurate diagnostic and follow-up biomarkers along with the time-limited response to therapies may explain the lethality and shows the necessity of new sensitive and specific biomarkers. One of the most studied molecules are the telomeres: specialized ribonucleoprotein structures that keep the structural integrity of the genome. Among other features, telomere length (TL) has been widely studied in several tumor models regarding its biomarker potential, due to the easy detection and quantification. The scope of this review was to analyze all the information about this parameter in RCC. There was some disparity in the results of the studies, since some pointed to an association between short TL and risk or poor outcome of RCC; others between long TL and RCC outcome and some did not find any association. We propose some epidemiological and biological explanations to these differences. The telomeres may play a dual role during RCC carcinogenesis in the early stages, short telomeres may increase RCC risk and in late carcinogenesis, long telomeres seem to be associated with tumor prognosis. However, the controversy of the results along with the lack of specificity are some problems that need to be clarified for the usage of TL as a prognostic biomarker.

RevDate: 2020-03-18

Zhang H, Wang D, Ma H, et al (2020)

Association between Leucocyte Telomere Length and Risk of Hearing Loss in the General Population: A Case-Control Study in Zhejiang Province, China.

International journal of environmental research and public health, 17(6): pii:ijerph17061881.

Limited studies have assessed the relation between telomere length and risk of hearing loss; moreover, they have reported equivocal associations. In the first case-control study, the subjects were chosen from the general population of Zhejiang province in order to assess the association between leucocyte telomere length and risk of hearing loss from 2016 to 2018. A total of 817 cases (55.93 ± 8.99 years) and 817 age-, sex- and residential city-matched controls (55.91 ± 9.03 years) were included for analysis. In the multivariable models, individuals in the top quartile of relative telomere length (RTL) had an odds ratio (OR) for hearing loss of 0.53 (95% confidence intervals [CI], 0.38-0.74) compared to those in the bottom quartile, and specifically, the OR was 0.45 (95% CI, 0.28-0.73) in females. In females, the risk of hearing loss decreased by 46% as RTL doubling increased; the standard deviation of RTL was associated with a 29% decrease in hearing loss risk. Additional analysis showed significant difference between participants in the female mild hearing loss group and corresponding controls. These results suggest that telomere length is associated with hearing loss in the general population, particularly in females with mild hearing loss. Telomere length might be a potential predictive biomarker of hearing loss at early stage.

RevDate: 2020-03-17

Yang M, Li J, N Zhang (2018)

Leukocyte telomere length is associated with survival and drug resistance in lung adenocarcinoma patients treated with EGFR-TKIs.

Annals of oncology : official journal of the European Society for Medical Oncology, 29 Suppl 6:vi9.

RevDate: 2020-03-17

Dolcini J, Wu H, Nwanaji-Enwerem JC, et al (2020)

Correction for: Mitochondria and aging in older individuals: an analysis of DNA methylation age metrics, leukocyte telomere length, and mitochondrial DNA copy number in the VA normative aging study.

Aging pii:102962 [Epub ahead of print].

RevDate: 2020-03-17

Anonymous (2020)

Correction to: Impact of Mothers' Age on Telomere Length and Human Telomerase Reverse Transcriptase Expression in Human Fetal Membrane-Derived Mesenchymal Stem Cells by Alrefaei GI, Alkarim SA, and Abduljabbar HS. Stem Cells Dev 2019;28;24;1632-1645 DOI:10.1089/scd.2019-0144.

Stem cells and development, 29(6):380-381.

RevDate: 2020-03-17

Gampawar P, Schmidt R, H Schmidt (2020)

Leukocyte Telomere Length Is Related to Brain Parenchymal Fraction and Attention/Speed in the Elderly: Results of the Austrian Stroke Prevention Study.

Frontiers in psychiatry, 11:100.

There are controversial results if leukocyte telomere length (LTL) is related to structural brain changes and cognitive decline in aging. Here, we investigated the association between LTL and 1) global MRI correlates of brain aging such as brain parenchymal fraction (BPF) and white matter hyperintensities (WMH) load and Fazekas score as well as 2) global (g-factor) and domain-specific cognition such as attention/speed, conceptualization, memory, and visuopractical skills. In total, 909 participants of the Austrian Stroke Prevention Study with LTL, MRI, and cognitive tests were included. There were 388 (42.7%) men, and the mean age was 65.9 years. Longer LTL was significantly associated with larger BPF (β = 0.43, p < 0.001), larger WMH load (β = 0.03, p = 0.04), and score (β = 0.05, p = 0.04) after adjusting for age, sex, vascular risk factors, and ApoE4 carrier status. The effect on BPF was more significant in the subgroups of women (β = 0.51, p = 0.001), age >65 years (β = 0.58, p = 0.002), BMI ≥ 25 (β = 0.40, p = 0.004), education ≤10 years (β = 0.42, p = 0.002), hypertensives (β = 0.51, p = 0.001), cardiovascular disease (CVD) (β = 0.58, p = 0.005), non-diabetics (β = 0.42, p < 0.001), and Apoe4 non-carriers (β = 0.49, p < 0.001). The effect on WMH was significant within the hypertensives (load: β = 0.04, p = 0.02), non-diabetics (load:β = 0.03, p = 0.01; score: β = 0.06, p = 0.02), in those with education ≤10 years (load: β = 0.03, p = 0.04; score: β = 0.07, p = 0.02), in ApoE4 non-carriers (load: β = 0.03, p = 0.02; score: β = 0.07, p = 0.01) and in subjects without CVD (score: β = 0.06, p = 0.05). We only observed a significant association between LTL and the cognitive domain of attention/speed, which was confined to the subgroups of BMI ≥ 25 (β = 0.04, p = 0.05) and education ≤10 years (β = 0.04, p = 0.05). The effect of LTL on attention/speed was partly mediated in both subgroups by BPF (β = 0.02, 95% CI = 0.01:0.03) when tested by bootstrapping. Our results support a strong protective role of longer LTL on global brain volume which in turn may contribute to better cognitive functions, especially in the attention/speed domain in the elderly.

RevDate: 2020-03-16

Ebeid DE, Khalafalla FG, Broughton KM, et al (2020)

Pim1 Maintains Telomere Length in Mouse Cardiomyocytes by Inhibiting TGFβ Signaling.

Cardiovascular research pii:5807612 [Epub ahead of print].

AIMS: Telomere attrition in cardiomyocytes is associated with decreased contractility, cellular senescence, and upregulation of proapoptotic transcription factors. Pim1 is a cardioprotective kinase that antagonizes the aging phenotype of cardiomyocytes and delays cellular senescence by maintaining telomere length, but the mechanism remains unknown. Another pathway responsible for regulating telomere length is the transforming growth factor beta (TGFβ) signaling pathway where inhibiting TGFβ signaling maintains telomere length. The relationship between Pim1 and TGFβ has not been explored. This study delineates the mechanism of telomere length regulation by the interplay between Pim1 and components of TGFβ signaling pathways in proliferating A549 cells and post-mitotic cardiomyocytes.

METHODS AND RESULTS: Telomere length was maintained by lentiviral-mediated overexpression of PIM1 and inhibition of TGFβ signaling in A549 cells. Telomere length maintenance was further demonstrated in isolated cardiomyocytes from mice with cardiac-specific overexpression of PIM1 and by pharmacological inhibition of TGFβ signaling. Mechanistically, Pim1 inhibited phosphorylation of Smad2, preventing its translocation into the nucleus and repressing expression of TGFβ pathway genes.

CONCLUSIONS: Pim1 maintains telomere lengths in cardiomyocytes by inhibiting phosphorylation of the TGFβ pathway downstream effectors Smad2 and Smad3, which prevents repression of TERT. Findings from this study demonstrate a novel mechanism of telomere length maintenance and provide a potential target for preserving cardiac function.

TRANSLATIONAL PERSPECTIVE: Telomere maintenance is associated with preservation of cardiomyocyte functional competency and survival, with telomeric shortening linked to cardiomyopathic disease. Aging also contributes to telomere erosion that contributes to deterioration of myocardial performance. Pim1 kinase mediates beneficial effects to preserve cardiomyocyte survival and function and this report demonstrates a novel molecular mechanism of Pim1 action to mitigate telomeric shortening. Findings linking Pim1 to telomere biology introduce another facet of cardioprotection that can be developed as a molecular interventional approach to treat myocardial injury and heart failure.

RevDate: 2020-03-16

Tucker LA (2020)

Walking and biologic ageing: Evidence based on NHANES telomere data.

Journal of sports sciences [Epub ahead of print].

The length of telomeres is an objective measure of biologic ageing. This study evaluated the extent minutes of walking per week are associated with leukocyte telomere length (LTL) in a random sample of 5,823 U.S. adults. The investigation was cross-sectional and data were obtained from the National Health and Nutrition Examination Survey (NHANES). LTL was measured by the quantitative polymerase chain reaction method. Walking minutes was calculated from walking frequency and duration measures. Results showed that for each year of chronological age, telomeres were 15.6 base pairs shorter (P < 0.0001). With walking minutes and LTL treated as continuous variables, the relationship was quadratic, not linear (F = 11.2, P = 0.0023). With walking time divided into three categories, adults who performed ≥ 150 minutes of walking per week had longer telomeres than those who did no regular walking, and those who did some, but less than the recommendation (F = 5.0, P = 0.0137). Regular walkers were estimated to have a biologic ageing advantage associated with 6.5-7.6 years less biologic ageing compared to non-walkers, after adjusting for covariates. Additional investigations designed to study causality and the mechanisms associated with the walking and LTL relationship are needed.

RevDate: 2020-03-16

Zhang JM, L Zou (2020)

Alternative lengthening of telomeres: from molecular mechanisms to therapeutic outlooks.

Cell & bioscience, 10:30 pii:391.

To escape replicative senescence, cancer cells have to overcome telomere attrition during DNA replication. Most of cancers rely on telomerase to extend and maintain telomeres, but 4-11% of cancers use a homologous recombination-based pathway called alternative lengthening of telomeres (ALT). ALT is prevalent in cancers from the mesenchymal origin and usually associates with poor clinical outcome. Given its critical role in protecting telomeres and genomic integrity in tumor cells, ALT is an Achilles heel of tumors and an attractive target for cancer therapy. Here, we review the recent progress in the mechanistic studies of ALT, and discuss the emerging therapeutic strategies to target ALT-positive cancers.

RevDate: 2020-03-15

Stroik S, EA Hendrickson (2020)

Telomere fusions and translocations: a bridge too far?.

Current opinion in genetics & development, 60:85-91 pii:S0959-437X(20)30015-0 [Epub ahead of print].

Telomere fusions inevitably arise as a cell's last-ditch effort to protect exposed chromosomal ends when telomeres are lost due to aging-associated erosion, breakage, failed replication, or a plethora of other cellular mistakes. Fusion of an exposed chromosomal end to another telomere presumably presents a superficially attractive option to the cell as opposed to the alternative of the impending degradation of the unprotected chromosomal terminus. However, when allowed to progress to mitosis these fusion events subsequently foster non-disjunction or bridge:breakage events - both of which drive highly pathogenic genomic instability and additional chromosomal translocations. Thus, the question becomes how and when telomere fusion events arise and, most importantly, is there a mechanism available to resolve these telomere bridges such that proper repair, and not genomic instability, results? Recent evidence suggests that the formation, and then the resolution of, ultrafine bridges may facilitate this process.

RevDate: 2020-03-15

Cicconi A, S Chang (2020)

Shelterin and the replisome: at the intersection of telomere repair and replication.

Current opinion in genetics & development, 60:77-84 pii:S0959-437X(20)30021-6 [Epub ahead of print].

Telomeres are G-rich repetitive sequences that are difficult to replicate, resulting in increased replication stress that can threaten genome stability. Shelterin protects telomeres from engaging in aberrant DNA repair and dictates the choice of DNA repair pathway at dysfunctional telomeres. Recently, shelterin has been shown to participate in telomere replication. Here we review the most recent discoveries documenting the mechanisms by which shelterin represses DNA repair pathways at telomeres while assisting its replication. The interplay between shelterin and the replisome complex highlights a novel connection between telomere maintenance and repair.

RevDate: 2020-03-14

Nelson CP, V Codd (2020)

Genetic determinants of telomere length and cancer risk.

Current opinion in genetics & development, 60:63-68 pii:S0959-437X(20)30012-5 [Epub ahead of print].

The relationship of telomere length with cancer risk has been the source of much debate within epidemiological studies, which have produced inconsistent finding both between and within different cancer types. Over recent years, genome-wide association studies of increasing size have identified variants that determine human telomere length. These variants have subsequently been utilised as instrumental variables in Mendelian randomisation based studies, allowing the investigation of potential causal relationships between telomere length and cancer. Here we discuss recent advances in both genomic discovery, studies that give increasing evidence towards a causal role for telomere length in cancer risk and considerations for future studies.

RevDate: 2020-03-13

Kresovich JK, Parks CG, Sandler DP, et al (2020)

The role of blood cell composition in epidemiologic studies of telomeres.

Epidemiology (Cambridge, Mass.) [Epub ahead of print].

RevDate: 2020-03-13

Del Brío Castillo R, Bleesing J, McCormick T, et al (2020)

Successful liver transplantation in short telomere syndromes without bone marrow failure due to DKC1 mutation.

Short telomere syndromes are a heterogenous spectrum of disorders leading to premature cellular aging. These may involve bone marrow failure, adult-onset idiopathic pulmonary fibrosis, and liver disease, and classical entities such as dyskeratosis congenita. We report a patient who presented with common variable immunodeficiency at 3 years of age and autoimmune cytopenias at 8 years of age. He was found to have short telomeres, and genetic testing confirmed a hemizygous mutation NM_001363.4: c.-142C > G in DKC1 gene. He subsequently developed cirrhosis with severe portal hypertension and hepatopulmonary syndrome, prompting liver transplantation at 11 years of age. He remains well 10 years after transplant with no progression of bone marrow failure or progressive lung disease. In conclusion, short telomere syndromes should be considered as a potential cause of pediatric liver disease of unknown etiology, and in severe cases, isolated liver transplantation may be both appropriate and successful.

RevDate: 2020-03-13

Mendioroz M, Puebla-Guedea M, Montero-Marín J, et al (2020)

Telomere length correlates with subtelomeric DNA methylation in long-term mindfulness practitioners.

Scientific reports, 10(1):4564 pii:10.1038/s41598-020-61241-6.

Mindfulness and meditation techniques have proven successful for the reduction of stress and improvement in general health. In addition, meditation is linked to longevity and longer telomere length, a proposed biomarker of human aging. Interestingly, DNA methylation changes have been described at specific subtelomeric regions in long-term meditators compared to controls. However, the molecular basis underlying these beneficial effects of meditation on human health still remains unclear. Here we show that DNA methylation levels, measured by the Infinium HumanMethylation450 BeadChip (Illumina) array, at specific subtelomeric regions containing GPR31 and SERPINB9 genes were associated with telomere length in long-term meditators with a strong statistical trend when correcting for multiple testing. Notably, age showed no association with telomere length in the group of long-term meditators. These results may suggest that long-term meditation could be related to epigenetic mechanisms, in particular gene-specific DNA methylation changes at distinct subtelomeric regions.

RevDate: 2020-03-12

Jenkins EC, Ye L, Marchi E, et al (2017)

An improved method for detecting telomere size differences in T-lymphocyte interphases from older people with Down syndrome with and without mild cognitive impairment.

Biology methods & protocols, 2(1):bpx005 pii:bpx005.

Telomere size (quantified by fluorescence intensity and physical lengths) in short-term T-lymphocyte cultures from adults with Down syndrome (DS) with and without mild cognitive impairment (MCI-DS) or dementia was compared. For these studies, dementia status was determined based on longitudinal assessments employing a battery of cognitive and functional assessments developed to distinguish adult-onset impairment from preexisting developmental disability. In the course of our studies using a MetaSystems Image Analyzer in combination with ISIS software and a Zeiss Axioskop 2, we found that Fluorescein isothiocyanate (FITC) telomere fluorescence referenced to chromosome 2-identified FITC probe fluorescence as a nontelomere standard (telomere/cen2 ratio) showed great promise as a biomarker of early decline associated with Alzheimer's disease (AD) in this high-risk population. We have now obtained a cen (2) CY3 probe that can clearly be distinguished from the blue-green FITC interphase telomere probe, providing a clear distinction between telomere and centromere fluorescence in both interphase and metaphase. We used FITC/CY3 light intensity ratios to compare telomere length in interphases in adults with DS with and without MCI-DS or dementia. Five age-matched female and five age-matched male pairs (n = 10) all showed clear evidence of telomere shortening associated with clinical progression of AD (P < 0.002 - P < 0.000001), with distributions of mean values for cases and controls showing no overlap. We also examined the time needed for microscopy using interphase versus metaphase fluorescence preparations. With interphase preparations, examination time was reduced by an order of magnitude compared with metaphase preparations, indicating that the methods employed herein have considerable practical promise for translation into broad diagnostic practice.

RevDate: 2020-03-12

Lorbeer FK, D Hockemeyer (2020)

TERT promoter mutations and telomeres during tumorigenesis.

Current opinion in genetics & development, 60:56-62 pii:S0959-437X(20)30004-6 [Epub ahead of print].

Telomerase regulation and telomere shortening act as a strong tumor suppressor mechanism in human somatic cells. Point mutations in the promoter of telomerase reverse transcriptase (TERT) are the most frequent non-coding mutation in cancer. These TERT promoter mutations (TPMs) create de novo ETS factor binding sites upstream of the start codon of the gene, which can be bound by different ETS factors. TPMs can occur early during tumorigenesis and are thought to be among the first mutations in melanoma, glioblastoma and hepatocellular carcinoma. Despite their association with increased TERT levels, TPMs do not prohibit telomere shortening and TPM-harboring cancers present with short telomeres. Their short telomere length combined with their high prevalence and specificity for cancer makes TPMs an attractive target for future therapeutic exploitation of telomerase inhibition and telomere deprotection-induced cell death.

RevDate: 2020-03-11

Matmati S, Lambert S, Géli V, et al (2020)

Telomerase Repairs Collapsed Replication Forks at Telomeres.

Cell reports, 30(10):3312-3322.e3.

Telomeres are difficult-to-replicate sites whereby replication itself may threaten telomere integrity. We investigate, in fission yeast, telomere replication dynamics in telomerase-negative cells to unmask problems associated with telomere replication. Two-dimensional gel analysis reveals that replication of telomeres is severely impaired and correlates with an accumulation of replication intermediates that arises from stalled and collapsed forks. In the absence of telomerase, Rad51, Mre11-Rad50-Nbs1 (MRN) complex, and its co-factor CtIPCtp1 become critical to maintain telomeres, indicating that homologous recombination processes these intermediates to facilitate fork restart. We further show that a catalytically dead mutant of telomerase prevents Ku recruitment to telomeres, suggesting that telomerase and Ku both compete for the binding of telomeric-free DNA ends that are likely to originate from a reversed fork. We infer that Ku removal at collapsed telomeric forks allows telomerase to repair broken telomeres, thereby shielding telomeres from homologous recombination.

RevDate: 2020-03-11

Wong SK, Ima-Nirwana S, KY Chin (2020)

Can telomere length predict bone health? A review of current evidence.

Bosnian journal of basic medical sciences [Epub ahead of print].

Telomeres are repetitive DNA sequences located at the end of chromosomes, which serve as a protective barrier against chromosomal deterioration during cell division. Approximately 50-200 base pairs of nucleotides are lost per cell division and new repetitive nucleotides are added by the enzyme telomerase allowing telomere maintenance. Telomere shortening has been proposed as an indicator for biological ageing, but its relationship with age-related osteoporosis is ambiguous. We summarize the current evidence on the relationship between telomere length and bone health in experimental and epidemiological studies, which may serve as a scientific reference for the development of novel diagnostic markers of osteoporosis or novel therapeutics targeting telomere and telomerase in bone cells to treat osteoporosis.

RevDate: 2020-03-10

Gong Y, Stock AJ, Y Liu (2020)

The enigma of excessively long telomeres in cancer: lessons learned from rare human POT1 variants.

Current opinion in genetics & development, 60:48-55 pii:S0959-437X(20)30005-8 [Epub ahead of print].

The discovery that rare POT1 variants are associated with extremely long telomeres and increased cancer predisposition has provided a framework to revisit the relationship between telomere length and cancer development. Telomere shortening is linked with increased risk for cancer. However, over the past decade, there is increasing evidence to show that extremely long telomeres caused by mutations in shelterin components (POT1, TPP1, and RAP1) also display an increased risk of cancer. Here, we will review current knowledge on germline mutations of POT1 identified from cancer-prone families. In particular, we will discuss some common features presented by the mutations through structure-function studies. We will further provide an overview of how POT1 mutations affect telomere length regulation and tumorigenesis.

RevDate: 2020-03-10

Saint-Leandre B, MT Levine (2020)

The Telomere Paradox: Stable Genome Preservation with Rapidly Evolving Proteins.

Trends in genetics : TIG, 36(4):232-242.

Telomeres ensure chromosome length homeostasis and protection from catastrophic end-to-end chromosome fusions. All eukaryotes require this essential, strictly conserved telomere-dependent genome preservation. However, recent evolutionary analyses of mammals, plants, and flies report pervasive rapid evolution of telomere proteins. The causes of this paradoxical observation - that unconserved machinery underlies an essential, conserved function - remain enigmatic. Indeed, these fast-evolving telomere proteins bind, extend, and protect telomeric DNA, which itself evolves slowly in most systems. We hypothesize that the universally fast-evolving subtelomere - the telomere-adjacent, repetitive sequence - is a primary driver of the 'telomere paradox'. Under this model, radical sequence changes in the subtelomere perturb subtelomere-dependent, telomere functions. Compromised telomere function then spurs adaptation of telomere proteins to maintain telomere length homeostasis and protection. We propose an experimental framework that leverages both protein divergence and subtelomeric sequence divergence to test the hypothesis that subtelomere sequence evolution shapes recurrent innovation of telomere machinery.

RevDate: 2020-03-10

Peska V, S Garcia (2020)

Origin, Diversity, and Evolution of Telomere Sequences in Plants.

Frontiers in plant science, 11:117.

Telomeres are basic structures of eukaryote genomes. They distinguish natural chromosome ends from double-stranded breaks in DNA and protect chromosome ends from degradation or end-to-end fusion with other chromosomes. Telomere sequences are usually tandemly arranged minisatellites, typically following the formula (TxAyGz)n. Although they are well conserved across large groups of organisms, recent findings in plants imply that their diversity has been underestimated. Changes in telomeres are of enormous evolutionary importance as they can affect whole-genome stability. Even a small change in the telomere motif of each repeat unit represents an important interference in the system of sequence-specific telomere binding proteins. Here, we provide an overview of telomere sequences, considering the latest phylogenomic evolutionary framework of plants in the broad sense (Archaeplastida), in which new telomeric sequences have recently been found in diverse and economically important families such as Solanaceae and Amaryllidaceae. In the family Lentibulariaceae and in many groups of green algae, deviations from the typical plant telomeric sequence have also been detected recently. Ancestry and possible homoplasy in telomeric motifs, as well as extant gaps in knowledge are discussed. With the increasing availability of genomic approaches, it is likely that more telomeric diversity will be uncovered in the future. We also discuss basic methods used for telomere identification and we explain the implications of the recent discovery of plant telomerase RNA on further research about the role of telomerase in eukaryogenesis or on the molecular causes and consequences of telomere variability.

RevDate: 2020-03-10

Dewhurst SM (2020)

Chromothripsis and telomere crisis: engines of genome instability.

Current opinion in genetics & development, 60:41-47 pii:S0959-437X(20)30014-9 [Epub ahead of print].

In the early stages of carcinogenesis cells confront two key suppressive checkpoints; senescence and telomere crisis. Telomere crisis is characterized by massive chromosomal instability and cell death. The genetic instability initiated during crisis leaves detectable scars on cancer genomes, the full scope of which is only just beginning to be appreciated. In particular, the dramatic genome reshuffling phenomenon chromothripsis has been mechanistically linked to the resolution of DNA bridges formed by dicentric chromosomes, and by the shattering of DNA inside micronuclei. Furthermore, an intriguing connection to innate immune signaling has begun to position telomere crisis as a crucial stage not only in the evolution of the cancer genome, but also in the interaction between the genome and the immune system.

RevDate: 2020-03-10

Xu Y, Xu J, Chancoco H, et al (2020)

Long Leukocyte Telomere Length Is Associated with Increased Risks of Soft Tissue Sarcoma: A Mendelian Randomization Study.

Cancers, 12(3): pii:cancers12030594.

BACKGROUND: Leukocyte telomere length (LTL) has been associated with the risks of several cancers in observational studies. Mendelian randomization (MR) studies, using genetic variants as instrumental variables, have also shown associations of genetically predicted LTL with cancer risks. In this study, we performed the first MR analysis on soft tissue sarcoma (STS) to investigate the causal relationship between LTL and the risk of STS.

METHODS: Genotypes from eleven LTL-associated single nucleotide polymorphisms (SNPs) in 821 STS cases and 851 cancer-free controls were aggregated into a weighted genetic risk score (GRS) to predict LTL. Multivariate logistic regression was used to assess the association of STS risk with individual SNPs and aggregated GRS.

RESULTS: Four SNPs displayed evidence for an individual association between long LTL-conferring allele and increased STS risk: rs7675998 (odds ratio (OR) = 1.21, 95% confidence interval (CI) = 1.02-1.43), rs9420907 (OR = 1.31, 95% CI = 1.08-1.59), rs8105767 (OR = 1.18, 95% CI = 1.02-1.37), and rs412658 (OR = 1.18, 95% CI = 1.02-1.36). Moreover, longer genetically predicted LTL, calculated as GRS, was strongly associated with an increased risk of STS (OR = 1.44, 95% CI = 1.18-1.75, p < 0.001), and there was a significant dose-response association (p for trend <0.001 in tertile and quartile analyses). The association of longer LTL with higher STS risk was more evident in women than in men. In stratified analyses by major STS subtypes, longer LTL was significantly associated with higher risks of leiomyosarcoma and gastrointestinal stromal tumors.

CONCLUSIONS: Longer LTL is associated with increased risks of STS.

RevDate: 2020-02-19

Guinobert I, Blondeau C, Colicchio B, et al (2020)

The Use of Natural Agents to Counteract Telomere Shortening: Effects of a Multi-Component Extract of Astragalus mongholicus Bunge and Danazol.

Biomedicines, 8(2): pii:biomedicines8020031.

A link between telomere shortening and oxidative stress was found in aging people and patients with cancer or inflammatory diseases. Extracts of Astragalus spp. are known to stimulate telomerase activity, thereby compensating telomere shortening. We characterized a multi-component hydroethanolic root extract (HRE) of Astragalus mongholicus Bunge and assessed its effects on telomeres compared to those of danazol. Astragalosides I to IV, flavonoids, amino acids and sugars were detected in the HRE. Samples of peripheral blood lymphocytes with short telomeres from 18 healthy donors (mean age 63.5 years; range 3286 years) were exposed to a single dose of 1 µg/mL HRE or danazol for three days. Telomere length and telomerase expression were then measured. Significant elongation of telomeres associated to a less toxicity was observed in lymphocytes from 13/18 donors following HRE treatment (0.54 kb (0.15-2.06 kb)) and in those from 9/18 donors after danazol treatment (0.95 kb (0.06-2.06 kb)). The rate of cells with short telomeres (<3 kb) decreased in lymphocytes from all donors after exposure to either HRE or danazol, telomere elongation being telomerase-dependent. These findings suggest that the HRE could be used for the management of age-related diseases.

RevDate: 2020-03-07

Bhargava R, Fischer M, RJ O'Sullivan (2020)

Genome rearrangements associated with aberrant telomere maintenance.

Current opinion in genetics & development, 60:31-40 pii:S0959-437X(20)30008-3 [Epub ahead of print].

There is unequivocal evidence that telomeres are crucial for cellular homeostasis and that telomere dysfunction can elicit genome instability and potentially initiate events that culminate in cancer. Mounting evidence points to telomeres having a crucial role in driving local and systemic structural rearrangements that drive cancer. These include the classical 'breakage-fusion-bridge' (BFB) cycles and more recently identified genome re-shaping events like kataegis and chromothripsis. In this brief review, we outline the established and most recent advances describing the roles that telomere dysfunction has in the origin of these catastrophic genome rearrangements. We discuss how local and systemic structural rearrangements enable telomere length maintenance, by either telomerase or the alternative lengthening of telomeres, that is essential to sustain cancer cell proliferation.

RevDate: 2020-03-06

Yang M, Li J, Zhang N, et al (2018)

Leukocyte telomere length and recurrence risk after EGFR-TKIs therapy in patients with advanced lung adenocarcinoma.

Annals of oncology : official journal of the European Society for Medical Oncology, 29 Suppl 8:viii21-viii22.

RevDate: 2020-03-06

Ropio J, Chebly A, Ferrer J, et al (2020)

Reliable blood cancer cells' telomere length evaluation by qPCR.

Cancer medicine [Epub ahead of print].

BACKGROUND: Telomere shortening is linked to a range of different human diseases, hence reliable measurement methods are needed to uncover such associations. Among the plethora of telomere length measurement methods, qPCR is reported as easy to conduct and a cost-effective approach to study samples with low DNA amounts.

METHODS: Cancer cells' telomere length was evaluated by relative and absolute qPCR methods.

RESULTS: Robust and reproducible telomere length measurements were optimized taking into account a careful reference gene selection and by knowing the cancer cells ploidy. qPCR data were compared to "gold standard" measurement from terminal restriction fragment (TRF).

CONCLUSIONS: Our study provides guidance and recommendations for accurate telomere length measurement by qPCR in cancer cells, taking advantage of our expertise in telomere homeostasis investigation in primary cutaneous T-cell lymphomas. Furthermore, our data emphasize the requirement of samples with both, high DNA quality and high tumor cells representation.

RevDate: 2020-03-06

Bauch C, Gatt MC, Granadeiro JP, et al (2020)

Sex-specific telomere length and dynamics in relation to age and reproductive success in Cory's Shearwaters.

Molecular ecology [Epub ahead of print].

Individuals in free-living animal populations generally differ substantially in reproductive success, lifespan and other fitness-related traits and the molecular mechanisms underlying this variation are poorly understood. Telomere length and dynamics are candidate traits explaining this variation, as long telomeres predict a higher survival probability and telomere loss has been shown to reflect experienced "life stress". However, telomere dynamics among very long-lived species are unresolved. Additionally, it is generally not well understood how telomeres relate with reproductive success or sex. We measured telomere length and dynamics in erythrocytes to assess their relation to age, sex and reproduction in Cory's Shearwaters (Calonectris borealis), a long-lived seabird, in the context of a long-term study. Adult males had on average 231 bp longer telomeres than females independent of age. In females, telomere length changed relatively little with age, whereas male telomere length declined significantly. Telomere shortening within males from one year to the next was three times higher than the inter-annual shortening rate based on cross-sectional data of males. Past long-term reproductive success was sex-specifically reflected in age-corrected telomere length: males with on average high fledgling production were characterised by shorter telomeres, whereas successful females had longer telomeres and we discuss hypotheses that may explain this contrast. In conclusion, telomere length and dynamics in relation to age and reproduction are sex dependent in Cory's Shearwaters and these findings contribute to our understanding of what characterises individual variation in fitness.

RevDate: 2020-03-06

Yuzurihara H, Aizawa Y, Saotome M, et al (2020)

Improved Methods for Preparing the Telomere Tethering Complex Bqt1-Bqt2 for Structural Studies.

The protein journal pii:10.1007/s10930-020-09887-z [Epub ahead of print].

In eukaryotes, chromosome ends (telomeres) are tethered to the inner nuclear membrane. During the early stages of meiosis, telomeres move along the nuclear membrane and gather near the spindle-pole body, resulting in a bouquet-like arrangement of chromosomes. This chromosomal configuration appears to be widely conserved among eukaryotes, and is assumed to play an important role in the normal progression of meiosis, by mediating the proper pairing of homologous chromosomes. In fission yeast, the Bqt1-Bqt2 protein complex plays a key role in tethering the telomere to the inner nuclear membrane. However, the structural details of the complex required to clarify how telomeres are gathered near the spindle-pole body remain enigmatic. Previously, we devised a preparation procedure for the Schizosaccharomyces japonicus Bqt1-Bqt2 complex, in which a SUMO tag was fused to the N-terminus of the Bqt1 protein. This allowed us to purify the Bqt1-Bqt2 complex from the soluble fraction. In the present study, we found that a maltose-binding protein homolog, Athe_0614, served as a better fusion partner than the SUMO protein, resulting in the marked increase in the solubility of the Bqt1-Bqt2 complex. The Athe_0614 fusion partner may open up new avenues for X-ray crystallographic analyses of the structure of the Bqt1-Bqt2 complex.

RevDate: 2020-03-05

Bevelacqua JJ, Welsh J, S Mortazavi (2020)

Comments on "Association of telomere length with chronic exposure to ionizing radiation among inhabitants of natural high background radiation areas of Ramsar, Iran".

RevDate: 2020-03-05

M'kacher R, Breton L, Colicchio B, et al (2019)

Benefit of an association of an antioxidative substrate and a traditional chinese medicine on telomere elongation.

Cellular and molecular biology (Noisy-le-Grand, France), 65(8):54-58.

Telomere shortening is involved in age-related disorders, such as cancer and cardiovascular diseases. Recently, telomerase re-activation strategies have been proposed to counteract telomere shortening and its consequences. Here, we investigated the benefit of dietary supplementation with a mix of S-adenosyl-methionine (SAMe) and a polysaccharide extract of Astragalus (APS) on telomere length of circulating lymphocytes of healthy volunteers. Blood lymphocytes of a cohort of 26 healthy volunteers who were administrated the mix of SAMe and APS in a food supplement for one year were collected. In vitro treatment of blood lymphocytes of healthy volunteers with the mix was also performed. A cohort of 150 healthy volunteers was used as a control. Telomere length was measured by Q-FISH. The micronucleus assay was performed to detect genotoxicity of the mix. The telomeres of circulating lymphocytes of the cohort of 26 donors supplemented with the mix were significantly longer than those of matched controls (p < 10-4). This elongation was essentially observed in the lymphocytes of older donors. Similarly, in vitro treatment of circulating lymphocytes with the mix significantly increased telomere length and decrease the proportion of cells with short telomeres. Here, we observed an increase in telomere length after in vivo and in vitro administration of a mix with SAMe and APS. The benefit of dietary supplementation with this mix opens a new horizon for the battle against aging and could be used in the treatment of chronic age-related disorders.

RevDate: 2020-03-05

Morinha F, Magalhães P, G Blanco (2020)

Standard guidelines for the publication of telomere qPCR results in evolutionary ecology.

Molecular ecology resources [Epub ahead of print].

Telomere length has been used as a proxy of fitness, aging and lifespan in vertebrates. In the last decade, dozens of articles reporting on telomere dynamics in the fields of ecology and evolution have been published for a wide range of taxa. With this growing interest, it is necessary to ensure the accuracy and reproducibility of telomere length measurement techniques. Real-time quantitative PCR (qPCR) is routinely applied to measure relative telomere length. However, this technique is highly sensitive to several methodological variables and the optimization of qPCR telomere assays remains highly variable between studies. Therefore, standardized guidelines are required to enable the optimization of robust protocols, and to help in judging the validity of the presented results. This review provides an overview of preanalytical and analytical factors that can lead to qPCR inconsistencies and biases, including (i) sample type, collection and storage; (ii) DNA extraction, storage and quality; (iii) qPCR primers, laboratory reagents, and assay conditions; and (iv) data analysis. We propose a minimum level of information for publication of qPCR telomere assays in evolutionary ecology considering the methodological pitfalls and sources of error. This review highlights the complexity of the optimization and validation of qPCR for telomere measurement per se, demonstrating the importance of transparency and clarity of reporting methodological details required for reliable, reproducible and comparable qPCR telomere assays. We encourage efforts to implement standardized protocols that ensure the rigour and quality of telomere dynamics studies.

RevDate: 2020-03-04

Monteforte S, Cattelan S, Morosinotto C, et al (2020)

Maternal predator-exposure affects offspring size at birth but not telomere length in a live-bearing fish.

Ecology and evolution, 10(4):2030-2039 pii:ECE36035.

The perception of predation risk could affect prey phenotype both within and between generations (via parental effects). The response to predation risk could involve modifications in physiology, morphology, and behavior and can ultimately affect long-term fitness. Among the possible modifications mediated by the exposure to predation risk, telomere length could be a proxy for investigating the response to predation risk both within and between generations, as telomeres can be significantly affected by environmental stress. Maternal exposure to the perception of predation risk can affect a variety of offspring traits but the effect on offspring telomere length has never been experimentally tested. Using a live-bearing fish, the guppy (Poecilia reticulata), we tested if the perceived risk of predation could affect the telomere length of adult females directly and that of their offspring with a balanced experimental setup that allowed us to control for both maternal and paternal contribution. We exposed female guppies to the perception of predation risk during gestation using a combination of both visual and chemical cues and we then measured female telomere length after the exposure period. Maternal effects mediated by the exposure to predation risk were measured on offspring telomere length and body size at birth. Contrary to our predictions, we did not find a significant effect of predation-exposure neither on female nor on offspring telomere length, but females exposed to predation risk produced smaller offspring at birth. We discuss the possible explanations for our findings and advocate for further research on telomere dynamics in ectotherms.

RevDate: 2020-03-04

Ferrara-Romeo I, Martinez P, Saraswati S, et al (2020)

The mTOR pathway is necessary for survival of mice with short telomeres.

Nature communications, 11(1):1168 pii:10.1038/s41467-020-14962-1.

Telomerase deficiency leads to age-related diseases and shorter lifespans. Inhibition of the mechanistic target of rapamycin (mTOR) delays aging and age-related pathologies. Here, we show that telomerase deficient mice with short telomeres (G2-Terc-/-) have an hyper-activated mTOR pathway with increased levels of phosphorylated ribosomal S6 protein in liver, skeletal muscle and heart, a target of mTORC1. Transcriptional profiling confirms mTOR activation in G2-Terc-/- livers. Treatment of G2-Terc-/- mice with rapamycin, an inhibitor of mTORC1, decreases survival, in contrast to lifespan extension in wild-type controls. Deletion of mTORC1 downstream S6 kinase 1 in G3-Terc-/- mice also decreases longevity, in contrast to lifespan extension in single S6K1-/- female mice. These findings demonstrate that mTOR is important for survival in the context of short telomeres, and that its inhibition is deleterious in this setting. These results are of clinical interest in the case of human syndromes characterized by critically short telomeres.

RevDate: 2020-03-03

Koh SH, Choi SH, Jeong JH, et al (2020)

Telomere shortening reflecting physical aging is associated with cognitive decline and dementia conversion in mild cognitive impairment due to Alzheimer's disease.

Aging, 12: pii:102893 [Epub ahead of print].

We investigated whether telomere length (TL) reflecting physical rather than chronological aging is associated with disease progression in the different cognitive stages of Alzheimer's disease (AD). Study participants included 89 subjects with amyloid pathology (A+), determined through amyloid PET or cerebrospinal fluid analysis, including 26 cognitively unimpaired (CU A+) individuals, 28 subjects with mild cognitive impairment (MCI A+), and 35 subjects with AD dementia (ADD A+). As controls, 104 CU A- individuals were selected. The participants were evaluated annually over two years from baseline. Compared to the highest TL quartile group of MCI A+ participants, the lowest TL quartile group yielded 2-year differences of -9.438 (95% confidence interval [CI] = -14.567 ~ -4.309), -26.708 (-41.576 ~ -11.839), 3.198 (1.323 ~ 5.056), and 2.549 (0.527 ~ 4.571) on the Mini-Mental State Examination, Consortium to Establish a Registry for AD, Clinical Dementia Rating-Sum of Boxes, and Blessed Dementia Scale-Activities of Daily Living, respectively. With this group, the lowest TL quartile group had a significantly greater probability of progressing to ADD than the highest TL quartile group (hazard ratio = 13.16, 95% CI = 1.11 ~ 156.61). Telomere shortening may be associated with rapid cognitive decline and conversion to dementia in MCI A+.

RevDate: 2020-03-03

Deng S, Liu S, Xu S, et al (2020)

Shorter Telomere Length in Peripheral Blood Leukocytes Is Associated with Post-Traumatic Chronic Osteomyelitis.

Surgical infections [Epub ahead of print].

Background: This study investigated the association between post-traumatic chronic osteomyelitis (COM) and peripheral leukocyte telomere length (PLTL) and explored factors associated with PLTL in COM. Methods: A total of 56 patients with post-traumatic COM of the extremity and 62 healthy control subjects were recruited. The PLTL was measured by real-time PCR. Binary logistic regression analysis was used to identify factors in correlation with telomere length. Sex, age, white blood cell (WBC) count, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and infection duration were included as independent variables in the logistic regression model. Results: Post-traumatic COM patients had significantly shorter PLTLs (5.39 ± 0.40) than healthy control subjects (5.69 ± 0.46; p < 0.001). Binary logistic regression analysis showed that PLTL had a statistically significant association with age (B = -0.072; p = 0.013) and CRP (B = -0.061; p = 0.033). The logistic regression model was statistically significant and explained 31.4% (Nagelkerke R2) of the change in telomere length and correctly classified 69.6% of the cases. Conclusions: Patients with post-traumatic COM have shorter PLTLs than healthy subjects. The PLTL erosion of post-traumatic COM was partially explained by age and CRP.

RevDate: 2020-03-03

Griffin I, Ibrahimou B, Navejar N, et al (2020)

Maternal Caffeine Consumption and Racial Disparities in Fetal Telomere Length.

International journal of MCH and AIDS, 9(1):14-21.

Background and Objectives: The identification of risk factors for shorter telomere length, especially during fetal development, would be important towards caffeine consumption recommendations for pregnant women on a global scale. The purpose of this study was to evaluate the association between caffeine intake and fetal telomere length as well as racial/ethnic differences in telomere length regardless of maternal caffeine consumption status.

Methods: Caffeine intake was measured using a food frequency questionnaire (FFQ). Three generalized linear models (GLM) were compared based on binary categorical variables of caffeine levels using data mean value of 117.3 mg as cut-off; the World Health Organization (WHO) recommendations of 300 mg; and the American College of Obstetricians and Gynecologists (ACOG) recommendations of 200 mg. The association between caffeine consumption and telomere length (telomere to single-copy [T/S] ratio) was then assessed.

Results: Among 57 maternal-fetal dyads, 77.2% reported less than 200 mg of caffeine (ACOG) and 89.5% less than 300 mg (WHO). Both WHO and ACOG models found that caffeine intake was significantly and positively associated with longer telomere length (p<0.05); and sodium (p<0.05). Other" race (p<0.001) and "white" race (p<0.001) were also significantly and positively associated with longer telomere length in the same models. Increasing maternal age shortened telomere length significantly in all models (p<0.001).

Caffeine intake, maternal age, and race may be associated with alterations in fetal telomere length. This indicates that caffeine consumption during pregnancy may have long-term implications for fetal development. The racial/ethnic differences in telomere length found in this study warrant larger studies to further confirm these associations.

RevDate: 2020-03-03

Srinivas N, Rachakonda S, R Kumar (2020)

Telomeres and Telomere Length: A General Overview.

Cancers, 12(3): pii:cancers12030558.

Telomeres are highly conserved tandem nucleotide repeats that include proximal double-stranded and distal single-stranded regions that in complex with shelterin proteins afford protection at chromosomal ends to maintain genomic integrity. Due to the inherent limitations of DNA replication and telomerase suppression in most somatic cells, telomeres undergo age-dependent incremental attrition. Short or dysfunctional telomeres are recognized as DNA double-stranded breaks, triggering cells to undergo replicative senescence. Telomere shortening, therefore, acts as a counting mechanism that drives replicative senescence by limiting the mitotic potential of cells. Telomere length, a complex hereditary trait, is associated with aging and age-related diseases. Epidemiological data, in general, support an association with varying magnitudes between constitutive telomere length and several disorders, including cancers. Telomere attrition is also influenced by oxidative damage and replicative stress caused by genetic, epigenetic, and environmental factors. Several single nucleotide polymorphisms at different loci, identified through genome-wide association studies, influence inter-individual variation in telomere length. In addition to genetic factors, environmental factors also influence telomere length during growth and development. Telomeres hold potential as biomarkers that reflect the genetic predisposition together with the impact of environmental conditions and as targets for anti-cancer therapies.

RevDate: 2020-03-02

Bosquet Enlow M, Kane-Grade F, De Vivo I, et al (2020)

Patterns of change in telomere length over the first three years of life in healthy children.

Psychoneuroendocrinology, 115:104602 pii:S0306-4530(20)30021-4 [Epub ahead of print].

There is growing interest in the use of telomere length as a biomarker of health and a predictor of later morbidity and mortality. However, little is known about developmentally expected telomere erosion over the first years of life. This gap hinders our ability to interpret the meaning of relative telomere length and rate of attrition in relation to risk factors and health outcomes. The overall goal of this study was to examine the rate of relative telomere length attrition in a large, normative sample of healthy children (N = 630) followed from infancy to three years of age. A secondary goal was to explore associations between sociodemographic characteristics and telomere erosion over this time period. Relative telomere length was assessed from DNA in saliva samples collected in infancy (M = 8.6 months), age 2 years (M = 25.2 months), and age 3 years (M = 38.3 months). In the sample as a whole, relative telomere length decreased from infancy to 2 years but remained stable from 2 years to 3 years. Notably, increases in relative telomere length were observed in 29 % of children between infancy and 2 years of age and in 46 % of children between 2 and 3 years of age; 62 % of children showed both increases and decreases in relative telomere length across the study period. Females showed longer relative telomere length than males, regardless of timepoint. There was some evidence that parental age and family finances were associated with changes in child relative telomere length across time. Overall, the findings suggest that telomere length attrition is not uniform across the early years of life, with the most rapid attrition occurring during the first two years, and that increases as well as decreases in telomere length during this period are commonly observed.

RevDate: 2020-03-02

Sobinoff AP, HA Pickett (2020)

Mechanisms that drive telomere maintenance and recombination in human cancers.

Current opinion in genetics & development, 60:25-30 pii:S0959-437X(20)30009-5 [Epub ahead of print].

Telomere maintenance is essential for the continued proliferation of mitotically active cells. Alternative Lengthening of Telomeres (ALT) is a recombination-dependent pathway of telomere maintenance analogous to break-induced replication (BIR) [1] that becomes activated in approximately 10-15% of human cancers. ALT is prevalent in tumours of mesenchymal or neuroepithelial origin, and typically confers a poor prognosis. The aggressiveness and lack of effective strategies to treat these cancers make the ALT pathway a compelling potential therapeutic target to prevent tumour formation and/or the appearance of secondary malignancies after conventional chemotherapy [2]. While the precise initiator of ALT during tumourigenesis remains elusive, substantial progress has been made in interrogating the underlying homology-directed repair mechanisms that converge at telomeres to enable telomere length maintenance. Here, we describe recent advances in our understanding of the ALT mechanism and highlight potential therapeutic targets that may offer future promise in the treatment of ALT cancers.

RevDate: 2020-03-01

Claude E, A Decottignies (2020)

Telomere maintenance mechanisms in cancer: telomerase, ALT or lack thereof.

Current opinion in genetics & development, 60:1-8 pii:S0959-437X(20)30002-2 [Epub ahead of print].

Cancer cells acquire replicative immortality by activating a telomere maintenance mechanism (TMM), either the telomerase or the Alternative Lengthening of Telomeres (ALT) mechanism. ALT is frequently activated in tumors derived from mesenchymal cells, which are more frequent in childhood cancers. Recent studies showed that, occasionally, cancer cells can arise without any TMM activation. Here, we discuss the challenge in assessing which TMM is activated in tumors. We also evaluate the prevalence of ALT mechanism in pediatric cancers and review the associated survival prognosis in different tumor types. Finally, we discuss about possible anti-TMM therapies for new emerging cancer treatments.

RevDate: 2020-02-29

Ghorbani-Sini R, Izadi T, Tavalaee M, et al (2020)

Comparison of Sperm Telomere Length between Two Sperm Selection Procedures: Density Gradient Centrifugation and Zeta Potential.

International journal of fertility & sterility, 14(1):51-56.

Background: Telomeres are particular sequences of DNA located at the end of the eukaryotic chromosomes that are essential for genome integrity. Telomere length in spermatozoa differs among males, as well as spermatozoa. Also, decreased telomere length in spermatozoa of infertile men is associated with the reduction of fertility potential and embryo quality. Density gradient centrifugation (DGC) and swim-up are useful techniques for separation of spermatozoa with longer telomeres. Also, the selection of sperm based on surface negative electric charge or "Zeta potential", can separate high percentage of spermatozoa with intact chromatin compared to DGC alone, and also the combination of DGC-Zeta can improve clinical outcomes of infertile men candidate for intracytoplasmic sperm injection (ICSI). Therefore, we compared sperm telomere length and DNA fragmentation between two sperm preparation procedures, namely DGC and zeta potential.

Materials and Methods: In this experimental study, we assessed sperm telomere length and DNA fragmentation by quantitative real-time polymerase chain reaction (PCR) and TUNEL assay methods, respectively. The spermatozoa were obtained from infertile men with normozoospermia between September 2017 and December 2017 and prepared either by DGC or zeta potential methods. Sperm telomere length was expressed as relative and absolute units.

Results: Compared with washed semen samples or control, no significant (P>0.05) difference was observed in the mean relative or absolute sperm telomere length when the two methods DGC or zeta potential were compared. However, the mean percentage of DNA fragmentation was significantly (P<0.05) lower in spermatozoa prepared by DGC or zeta potential methods than spermatozoa obtained from control samples.

Conclusion: This is the first study that compared the effect of DGC and zeta potential as the sperm preparation methods on sperm telomere length. It seems that both methods can select sperm population with high DNA integrity and the same sperm telomeres length.

RevDate: 2020-02-28

Toubiana S, S Selig (2020)

Human subtelomeric DNA methylation: regulation and roles in telomere function.

Current opinion in genetics & development, 60:9-16 pii:S0959-437X(20)30007-1 [Epub ahead of print].

Subtelomeres are the regions at chromosome ends, immediately adjacent to the terminal telomeric repeats. The majority of human subtelomeres are CpG-rich in their distal two kilobases, and are methylated during early embryonic development by the de novo DNA methyltransferase DNMT3B. The biological relevance of subtelomeric DNA methylation is highlighted by the presence of promoters for the long non-coding TERRA transcripts in these CpG-rich regions. Indeed, deviant subtelomeric methylation has been linked with abnormal telomeric phenotypes, as most strikingly found in ICF syndrome. Here we review recent studies that explore new aspects of subtelomeric methylation regulation and demonstrate the significance of maintaining proper DNA methylation at the extreme distal human subtelomeric regions.

RevDate: 2020-02-28

Li C, Stoma S, Lotta LA, et al (2020)

Genome-Wide Association Analysis in Humans Links Nucleotide Metabolism to Leukocyte Telomere Length.

American journal of human genetics pii:S0002-9297(20)30048-3 [Epub ahead of print].

Leukocyte telomere length (LTL) is a heritable biomarker of genomic aging. In this study, we perform a genome-wide meta-analysis of LTL by pooling densely genotyped and imputed association results across large-scale European-descent studies including up to 78,592 individuals. We identify 49 genomic regions at a false dicovery rate (FDR) < 0.05 threshold and prioritize genes at 31, with five highlighting nucleotide metabolism as an important regulator of LTL. We report six genome-wide significant loci in or near SENP7, MOB1B, CARMIL1, PRRC2A, TERF2, and RFWD3, and our results support recently identified PARP1, POT1, ATM, and MPHOSPH6 loci. Phenome-wide analyses in >350,000 UK Biobank participants suggest that genetically shorter telomere length increases the risk of hypothyroidism and decreases the risk of thyroid cancer, lymphoma, and a range of proliferative conditions. Our results replicate previously reported associations with increased risk of coronary artery disease and lower risk for multiple cancer types. Our findings substantially expand current knowledge on genes that regulate LTL and their impact on human health and disease.

RevDate: 2020-02-27

Foley NM, Petit EJ, Brazier T, et al (2020)

Drivers of longitudinal telomere dynamics in the long-lived bat species, Myotis myotis.

Molecular ecology [Epub ahead of print].

Age related telomere shortening is considered a hallmark of the ageing process. However, a recent cross-sectional ageing study of relative telomere length (rTL) in bats failed to detect a relationship between rTL and age in the long-lived genus Myotis (M. myotis and M. bechsteinii), suggesting some other factors are responsible for driving telomere dynamics in these species. Here, we test if longitudinal rTL data show signatures of age-associated telomere attrition in M. myotis and differentiate which intrinsic or extrinsic factors are likely to drive telomere length dynamics. Using qPCR, rTL was measured in 504 samples from a marked population, from Brittany, France, captured between 2013 and 2016. These represent 174 individuals with an age range of 0 to 7+ years. We find no significant relationship between rTL and age (p = 0.762), but demonstrate that within-individual rTL is highly variable from year to year. To investigate the heritability of rTL, a population pedigree (n=1744) was constructed from genotype data generated from a 16 microsatellite multiplex, designed from an initial, low coverage, Illumina genome for M. myotis. Heritability was estimated in a Bayesian, mixed model framework, and showed that little of the observed variance in rTL is heritable (h2 = 0.06 - 0.01). Rather, correlations of first differences, correlating yearly changes in telomere length and weather variables, demonstrate that, during the spring transition, average temperature, minimum temperature, rainfall and windspeed correlate with changes in longitudinal telomere dynamics. As such, rTL may represent a useful biomarker to quantify the physiological impact of various environmental stressors in bats.

RevDate: 2020-02-27

Fragkiadaki P, Nikitovic D, Kalliantasi K, et al (2020)

Telomere length and telomerase activity in osteoporosis and osteoarthritis.

Experimental and therapeutic medicine, 19(3):1626-1632.

Osteoarthritis (OA) and osteoporosis (OP) are associated skeletal pathologies and have as a distinct feature the abnormal reconstruction of the subchondral bone. OA and OP have been characterized as age-related diseases and have been associated with telomere shortening and altered telomerase activity (TA). This review discusses the role of telomeres and telomerase in OA and OP pathologies and focuses on the usability of telomere length (TL) and the rate of telomere shortening as potential disease biomarkers. A number of studies have demonstrated that telomere shortening may contribute to OA and OP as an epigenetic factor. Therefore, it has been claimed that the measurement of TL of chondrocytes and/or peripheral blood cells may be an appropriate marker for the evaluation of the progression of these diseases. However, there is a need to be perform further studies with larger cohorts, with the aim of obtaining objective results and a better understanding of the association between TL, inflammation and aging, in order to provide further insight into the pathophysiology of degenerative joint diseases.

RevDate: 2020-02-27

Qiao S, Jiang Y, X Li (2020)

The Impact of Health Promotion Interventions on Telomere Length: A Systematic Review.

American journal of health promotion : AJHP [Epub ahead of print].

OBJECTIVES: The aim of this study was to evaluate the effectiveness of health promotion interventions in delaying telomere shortening (a biomarker for aging).

DATA SOURCE: PubMed, PsychINFO, EMBASE, CINAHL, and Cochrane Library databases.

Inclusion criteria: (1) empirical studies involving human subjects; (2) health promotion intervention studies including both randomized control trials (RCTs) and non-RCTs.; (3) measured telomere length as an intervention outcome; and (4) were written in English. Exclusion criteria: (1) observational studies without any health promotion intervention practices and (2) did not report intervention effects.

DATA EXTRACTION: Data extraction was performed by two reviewers following the preferred reporting items for systematic reviews and meta-analysis guidelines.

DATA SYNTHESIS: Substantial heterogeneity in intervention type and study design in the included studies precluded a meta-analysis. We conducted a narrative synthesis instead.

RESULTS: Thirty studies were included in the review, of which 16 were RCTs. One-third of the included studies reported significant intervention impacts in delaying telomere shortening, with relatively consistent significant results emerged from weight-loss interventions and interventions involving multiple lifestyle modification components (eg, diet and exercise). Most of supplement intervention studies observed null effects in telomere length.

CONCLUSIONS: Weight-loss and comprehensive lifestyle intervention strategies show encouraging impacts in delaying telomere shortening. More rigorous studies targeting populations at different age stages through life span are needed.

RevDate: 2020-02-27

Hackeng WM, Schelhaas W, Morsink FHM, et al (2020)

Alternative Lengthening of Telomeres and Differential Expression of Endocrine Transcription Factors Distinguish Metastatic and Non-metastatic Insulinomas.

Endocrine pathology pii:10.1007/s12022-020-09611-8 [Epub ahead of print].

Insulin-producing pancreatic neuroendocrine tumors (PanNETs)/insulinomas are generally considered to be indolent tumors with an excellent prognosis after complete resection. However, some insulinomas have a poor prognosis due to relapses and metastatic disease. Recently, studies in non-functional PanNETs indicated that behavior can be stratified according to alpha- and beta-cell differentiation, as defined by expression of the transcription factors ARX and PDX1, respectively. It is unknown whether similar mechanisms play a role in insulinomas. Therefore, we determined ARX and PDX1 expression in a cohort of 35 sporadic primary insulinomas and two liver metastases of inoperable primary insulinomas. In addition, WHO grade and loss of ATRX or DAXX were determined by immunohistochemistry, and alternative lengthening of telomeres (ALT) and CDKN2A status by fluorescence in situ hybridization. These findings were correlated with tumor characteristics and clinical follow-up data. In total, five out of 37 insulinoma patients developed metastatic disease. Metastatic insulinomas were all larger than 3 cm, whereas the indolent insulinomas were smaller (p value < 0.05). All three primary insulinomas that metastasized showed ARX expression, 2/3 showed ALT, and 1/3 had a homozygous deletion of CDKN2A as opposed to absence of ARX expression, ALT, or CDKN2A deletions in the 32 non-metastatic cases. The two liver metastases also showed ARX expression and ALT (2/2). The presence of ARX expression, which is usually absent in beta-cells, and genetic alterations not seen in indolent insulinomas strongly suggest a distinct tumorigenic mechanism in malignant insulinomas, with similarities to non-functional PanNETs. These observations may inform future follow-up strategies after insulinoma surgery.

RevDate: 2020-02-26

Hoang SM, RJ O'Sullivan (2020)

Alternative Lengthening of Telomeres: Building Bridges To Connect Chromosome Ends.

Trends in cancer, 6(3):247-260.

Alternative lengthening of telomeres (ALT) is a mechanism of telomere maintenance that is observed in many of the most recalcitrant cancer subtypes. Telomeres in ALT cancer cells exhibit a distinctive nucleoprotein architecture shaped by the mismanagement of chromatin that fosters cycles of DNA damage and replicative stress that activate homology-directed repair (HDR). Mutations in specific chromatin-remodeling factors appear to be key determinants of the emergence and survival of ALT cancer cells. However, these may represent vulnerabilities for the targeted elimination of ALT cancer cells that infiltrate tissues and organs to become devastating tumors. In this review we examine recent findings that provide new insights into the factors and mechanisms that mediate telomere length maintenance and survival of ALT cancer cells.

RevDate: 2020-02-26

Berthezene J, Reyes C, Li T, et al (2020)

Aurora B and Condensin are dispensable for chromosome arm and telomere separation during meiosis II.

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

In mitosis, while the importance of kinetochore-microtubule attachment has been known for many years, increasing evidence suggests that telomere dysfunctions also perturb chromosome segregation by contributing to the formation of chromatin bridges at anaphase. Recent evidence suggests that Aurora B kinase ensures proper chromosome segregation during mitosis not only by controlling kinetochore-microtubule attachment but also by regulating telomere and chromosome arm separation. However, whether and how Aurora B governs telomere separation during meiosis has remained unknown. Here, we show that fission yeast Aurora B localizes at telomeres during meiosis I and promotes telomere separation independently of the meiotic cohesin Rec8. In meiosis II, Aurora B controls kinetochore-microtubule attachment but appears dispensable for telomere and chromosome arm separation. Likewise, condensin activity is nonessential in meiosis II for telomere and chromosome arm separation. Thus, in meiosis, the requirements for Aurora B are distinct at centromeres and telomeres, illustrating the critical differences in the control of chromosome segregation between mitosis and meiosis II. [Media: see text] [Media: see text] [Media: see text] [Media: see text] [Media: see text] [Media: see text] [Media: see text] [Media: see text].

RevDate: 2020-02-26

Arbeev KG, Verhulst S, Steenstrup T, et al (2020)

Association of Leukocyte Telomere Length With Mortality Among Adult Participants in 3 Longitudinal Studies.

JAMA network open, 3(2):e200023 pii:2761863.

Importance: Leukocyte telomere length (LTL) is a trait associated with risk of cardiovascular disease and cancer, the 2 major disease categories that largely define longevity in the United States. However, it remains unclear whether LTL is associated with the human life span.

Objective: To examine whether LTL is associated with the life span of contemporary humans.

This cohort study included 3259 adults of European ancestry from the Cardiovascular Health Study (CHS), Framingham Heart Study (FHS), and Women's Health Initiative (WHI). Leukocyte telomere length was measured in 1992 and 1997 in the CHS, from 1995 to 1998 in the FHS, and from 1993 to 1998 in the WHI. Data analysis was conducted from February 2017 to December 2019.

Main Outcomes and Measures: Death and LTL, measured by Southern blots of the terminal restriction fragments, were the main outcomes. Cause of death was adjudicated by end point committees.

Results: The analyzed sample included 3259 participants (2342 [71.9%] women), with a median (range) age of 69.0 (50.0-98.0) years at blood collection. The median (range) follow-up until death was 10.9 (0.2-23.0) years in CHS, 19.7 (3.4-23.0) years in FHS, and 16.6 (0.5-20.0) years in WHI. During follow-up, there were 1525 deaths (482 [31.6%] of cardiovascular disease; 373 [24.5%] of cancer, and 670 [43.9%] of other or unknown causes). Short LTL, expressed in residual LTL, was associated with increased mortality risk. Overall, the hazard ratio for all-cause mortality for a 1-kilobase decrease in LTL was 1.34 (95% CI, 1.21-1.47). This association was stronger for noncancer causes of death (cardiovascular death: hazard ratio, 1.28; 95% CI, 1.08-1.52; cancer: hazard ratio, 1.13; 95% CI, 0.93-1.36; and other causes: hazard ratio, 1.53; 95% CI, 1.32-1.77).

Conclusions and Relevance: The results of this study indicate that LTL is associated with a natural life span limit in contemporary humans.

RevDate: 2020-02-26

Nalobin D, Alipkina S, Gaidamaka A, et al (2020)

Telomeres and Telomerase in Heart Ontogenesis, Aging and Regeneration.

Cells, 9(2): pii:cells9020503.

The main purpose of the review article is to assess the contributions of telomere length and telomerase activity to the cardiac function at different stages of development and clarify their role in cardiac disorders. It has been shown that the telomerase complex and telomeres are of great importance in many periods of ontogenesis due to the regulation of the proliferative capacity of heart cells. The review article also discusses the problems of heart regeneration and the identification of possible causes of dysfunction of telomeres and telomerase.

RevDate: 2020-02-25

Dupoué A, Angelier F, Ribout C, et al (2020)

Chronic water restriction triggers sex-specific oxidative stress and telomere shortening in lizards.

Biology letters, 16(2):20190889.

Animals use a variety of strategies to avoid acute dehydration and death. Yet, how chronic exposure to sub-lethal dehydration may entail physiological and fitness costs remains elusive. In this study, we experimentally tested if water restriction causes increased oxidative stress (OS) and telomere length (TL) shortening, two well-described mediators of environment-fitness relationships. We exposed 100 yearling female and male common lizards (Zootoca vivipara) either to a 51-day period of water restriction or to water ad libitum, followed by 45 days in common garden outdoor conditions. We measured the kinetic changes in OS and TL and found that water-restricted males had enhanced antioxidant defences and decreased oxidative damage at day 36, whereas females did not immediately respond. A month and a half after water restriction, both sexes experienced a drop in antioxidant capacity but only males exhibited significant TL shortening. In the following 3 years, we found that lizards with longer initial TL and those who maintained stronger antioxidant defences experienced higher longevity, irrespective of sex and water restriction. Together, these results unravelled sex-specific responses to water restriction, with potential applications in better understanding the physiological costs of increasing summer droughts as a result of global climate change.

RevDate: 2020-02-25

Lototska L, Yue JX, Li J, et al (2020)

Human RAP1 specifically protects telomeres of senescent cells from DNA damage.

EMBO reports [Epub ahead of print].

Repressor/activator protein 1 (RAP1) is a highly evolutionarily conserved protein found at telomeres. Although yeast Rap1 is a key telomere capping protein preventing non-homologous end joining (NHEJ) and consequently telomere fusions, its role at mammalian telomeres in vivo is still controversial. Here, we demonstrate that RAP1 is required to protect telomeres in replicative senescent human cells. Downregulation of RAP1 in these cells, but not in young or dividing pre-senescent cells, leads to telomere uncapping and fusions. The anti-fusion effect of RAP1 was further explored in a HeLa cell line where RAP1 expression was depleted through an inducible CRISPR/Cas9 strategy. Depletion of RAP1 in these cells gives rise to telomere fusions only when telomerase is inhibited. We further show that the fusions triggered by RAP1 loss are dependent upon DNA ligase IV. We conclude that human RAP1 is specifically involved in protecting critically short telomeres. This has important implications for the functions of telomeres in senescent cells.

RevDate: 2020-02-25

Pejenaute Á, Cortés A, Marqués J, et al (2020)

NADPH Oxidase Overactivity Underlies Telomere Shortening in Human Atherosclerosis.

International journal of molecular sciences, 21(4): pii:ijms21041434.

Telomere shortening and oxidative stress are involved in the pathogenesis of atherosclerosis. Different studies have shown that phagocytic NADPH oxidase is associated with this disease. This study aimed to investigate the association between phagocytic NADPH oxidase and telomere shortening in human atherosclerosis. To assess this potential association, telomere length and phagocytic NADPH oxidase activity were determined by PCR and chemiluminescence, respectively, in a population of asymptomatic subjects free of overt clinical atherosclerosis. We also measured serum 8-hydroxy-2-deoxyguanosine (8-OHdG) levels (an index of oxidative stress) and carotid intima-media thickness (IMT), a surrogate marker of atherosclerosis. After adjusting them for age and sex, telomere length inversely correlated (p < 0.05) with NADPH oxidase-mediated superoxide production, with 8-OHdG values, and with carotid IMT. Interestingly, the asymptomatic subjects with plaques have a lower telomere length (p < 0.05), and higher values of plasma 8-OHdG and superoxide production (p < 0.05). These data were confirmed in a second population in which patients with coronary artery disease showed lower telomere length and higher 8-OHdG and superoxide production than the asymptomatic subjects. In both studies, NADPH oxidase-dependent superoxide production in phagocytic cells was only due to the specific expression of the Nox2 isoform. In conclusion, these findings suggest that phagocytic NADPH oxidase may be involved in oxidative stress-mediated telomere shortening, and that this axis may be critically involved in human atherosclerosis.

RevDate: 2020-02-23

Jantunen H, Wasenius NS, Guzzardi MA, et al (2020)

Physical Activity and Telomeres in Old Age: A Longitudinal 10-Year Follow-Up Study.

Gerontology pii:000505603 [Epub ahead of print].

BACKGROUND: Telomeres are crucial parts of chromosomes that protect the genome. They shorten every time the cell replicates, and shorter telomeres have been associated with increasing age and with many health behaviours. There is inconclusive evidence on the association between physical activity (PA) and telomere length.

OBJECTIVES: To examine how leisure-time PA (LTPA) is associated with telomere length and telomere attrition during 10 years of follow-up in elderly people.

DESIGN: This study is a 10-year prospective follow-up study.

METHOD: For this prospective study, we examined 1,014 subjects (mean age at baseline 60.8 years) from the Helsinki Birth Cohort Study (HBCS). Relative leukocyte telomere length (LTL) was measured with a quantitative real-time PCR and LTPA with a validated questionnaire. Multiple linear regression analyses were used to assess the association between sex-specific LTPA quartiles and LTL at baseline and change in LTL over 10 years. The analyses were adjusted for age, educational attainment, smoking, body fat percentage, oestrogen exposure in women and for follow-up time when applicable.

RESULTS: At baseline, volume of LTPA was not associated with LTL in men (p = 0.66) or in women (p = 0.33). Among women, however, higher volume of LTPA at baseline was associated with greater shortening of LTL (p for linearity 0.040) during the 10-year follow-up. No association was found among men (p for linearity 0.75).

CONCLUSIONS: Our findings suggest that PA has a sex-specific role in regulation of telomere length in the aging process as in our study a high volume of LTPA in elderly women, but not in men, was associated with more rapid telomere attrition.

RevDate: 2020-02-21

Lalonde M, P Chartrand (2020)

TERRA, a multifaceted regulator of telomerase activity at telomeres.

Journal of molecular biology pii:S0022-2836(20)30154-6 [Epub ahead of print].

In eukaryotes, telomeres are repetitive sequences at the end of chromosomes which are maintained in a constitutive heterochromatin state. We now know that telomeres can be actively transcribed, leading to the production of a telomeric repeat-containing non-coding RNA called TERRA. Due to its sequence complementarity to the telomerase template, it was suggested early on that TERRA could be an inhibitor of telomerase. Since then, TERRA has been shown to be involved in heterochromatin formation at telomeres, to invade telomeric dsDNA and form R-loops, and even to promote telomerase recruitment at short telomeres. All these functions depend on the diverse capacities of this lncRNA to bind various cofactors, act as a scaffold and promote higher-order complexes in cells. In this review, we will highlight how these properties of TERRA work together to regulate telomerase activity at telomeres.

RevDate: 2020-02-21

Tomasova K, Kroupa M, Forsti A, et al (2020)

Telomere maintenance in interplay with DNA repair in pathogenesis and treatment of colorectal cancer.

Mutagenesis pii:5743334 [Epub ahead of print].

Colorectal cancer (CRC) continues to be one of the leading malignancies and causes of tumour-related deaths worldwide. Both impaired DNA repair mechanisms and disrupted telomere length homeostasis represent key culprits in CRC initiation, progression and prognosis. Mechanistically, altered DNA repair results in the accumulation of mutations in the genome and, ultimately, in genomic instability. DNA repair also determines the response to chemotherapeutics in CRC treatment, suggesting its utilisation in the prediction of therapy response and individual approach to patients. Telomere attrition resulting in replicative senescence, simultaneously by-passing cell cycle checkpoints, is a hallmark of malignant transformation of the cell. Telomerase is almost ubiquitous in advanced solid cancers, including CRC, and its expression is fundamental to cell immortalisation. Therefore, there is a persistent effort to develop therapeutics, which are telomerase-specific and gentle to non-malignant tissues. However, in practice, we are still at the level of clinical trials. The current state of knowledge and the route, which the research takes, gives us a positive perspective that the problem of molecular models of telomerase activation and telomere length stabilisation will finally be solved. We summarise the current literature herein, by pointing out the crosstalk between proteins involved in DNA repair and telomere length homeostasis in relation to CRC.

RevDate: 2020-02-21

Moschouri E, Vionnet J, Giostra E, et al (2020)

Combined lung and liver transplantation for short telomere syndrome.

Telomeres are DNA-protein structures located at the chromosome ends and terminating with an essential single-stranded 3'-overhang.1 Their role is to maintain genomic integrity by protecting chromosomes from degradation and illegitimate recombination. Telomeres progressively shorten during cell division because of the inability of DNA polymerase to replicate the 3'-end of chromosomes. Telomerase limits telomere attrition by synthesizing de novo telomere sequences at the end of chromosomes.

RevDate: 2020-02-21

Vančevska A, Ahmed W, Pfeiffer V, et al (2020)

SMCHD1 promotes ATM-dependent DNA damage signaling and repair of uncapped telomeres.

The EMBO journal [Epub ahead of print].

Structural maintenance of chromosomes flexible hinge domain-containing protein 1 (SMCHD1) has been implicated in X-chromosome inactivation, imprinting, and DNA damage repair, and mutations in SMCHD1 can cause facioscapulohumeral muscular dystrophy. More recently, SMCHD1 has also been identified as a component of telomeric chromatin. Here, we report that SMCHD1 is required for DNA damage signaling and non-homologous end joining (NHEJ) at unprotected telomeres. Co-depletion of SMCHD1 and the shelterin subunit TRF2 reduced telomeric 3'-overhang removal in time-course experiments, as well as the number of chromosome end fusions. SMCHD1-deficient cells displayed reduced ATM S1981 phosphorylation and diminished formation of γH2AX foci and of 53BP1-containing telomere dysfunction-induced foci (TIFs), indicating defects in DNA damage checkpoint signaling. Removal of TPP1 and subsequent activation of ATR signaling rescued telomere fusion events in TRF2-depleted SMCHD1 knockout cells. Together, these data indicate that SMCHD1 depletion reduces telomere fusions in TRF2-depleted cells due to defects in ATM-dependent checkpoint signaling and that SMCHD1 mediates DNA damage response activation upstream of ATM phosphorylation at uncapped telomeres.

RevDate: 2020-02-21

Testori A (2020)

Short telomere syndromes, premature ageing syndromes, and biological ageing.

Hong Kong medical journal = Xianggang yi xue za zhi, 26(1):76-77.

RevDate: 2020-02-20

Zhou X, Wei W, Duan X, et al (2020)

Effect of TRF1 rs3863242 polymorphism on telomere length in omethoate-exposed workers.

Journal of environmental science and health. Part. B, Pesticides, food contaminants, and agricultural wastes [Epub ahead of print].

Telomere length was found to be associated with omethoate exposure and polymorphisms in certain genes among occupational workers. However, whether the polymorphisms in telomere-binding protein genes influence telomere length remains unclear. To explore the correlation between telomere length and polymorphisms in telomere-binding protein genes, telomere length in peripheral blood leukocytes was determined by real-time quantitative polymerase chain reaction in 180 omethoate-exposed workers and 115 healthy controls. Polymorphisms in 10 pairs of alleles were detected using flight mass spectrometry or polymerase chain reaction-restriction fragment length polymorphism technique. The results showed that individuals with GG genotype in TRF1 rs3863242 had longer telomere lengths than those with AG + AA genotype in the control group (p = 0.005). The multiple regression analysis suggested that both omethoate exposure (b = 0.526, p < 0.001) and TRF1 rs3863242 GG (b = 0.220, p = 0.002) were related to a longer telomere length. In conclusion, GG genotype in TRF1 rs3863242 is linked to prolongation of telomere length, and individuals with GG genotype are recommended to strengthen health protection in a Chinese occupational omethoate-exposed population.

RevDate: 2020-02-20

Schratz KE, Haley L, Danoff SK, et al (2020)

Cancer spectrum and outcomes in the Mendelian short telomere syndromes.

Blood pii:452523 [Epub ahead of print].

Short telomeres have been linked to cancer risk, yet other evidence supports they are tumor suppressive. Here, we report cancer outcomes in individuals with germline mutations in telomerase and other telomere maintenance genes. Among 180 individuals evaluated in a hospital-based setting, 12.8% had cancer. Solid tumors were rare (2.8%); nearly all were young male DKC1 mutation carriers, and they were generally resectable with good outcomes. Myelodysplastic syndrome (MDS) was most common, followed by acute myeloid leukemia (AML); they accounted for 75% of cancers. Age over 50 was the biggest risk factor, and MDS/AML manifested usually with marrow hypoplasia, monosomy 7, but the somatic mutation landscape was indistinct from unselected patients. One- and two-year survival were 61% and 39%, respectively, and two-thirds of MDS/AML patients died from pulmonary fibrosis and/or hepatopulmonary syndrome. In half the cases, MDS/AML patients showed a recurrent peripheral blood pattern of acquired, granulocyte-specific telomere shortening. This attrition was absent in age-matched mutation carriers who did not have MDS/AML. We tested if adult short telomere patients without MDS/AML also had evidence of clonal hematopoiesis of indeterminate potential (CHIP)-related mutations and found 30% were affected. These patients also primarily suffered morbidity from pulmonary fibrosis during followup. Our data show the Mendelian short telomere syndromes are associated with a relatively narrow cancer spectrum, primarily MDS and AML. They suggest short telomere length is sufficient to drive premature age-related clonal hematopoiesis in these inherited disorders.

RevDate: 2020-02-19

Zhou Y, Hambly BD, Simmons D, et al (2020)

Sex specific educational attainment is associated with telomere length in an Australian rural population.

QJM : monthly journal of the Association of Physicians pii:5740584 [Epub ahead of print].

BACKGROUND: there is limited understanding on whether and how socioeconomic status (SES), particularly educational attainment and household income, impacts on telomere length in an Australian rural context. Additionally, it is unknown whether access to health services via the Australian public or private health system influences telomere length.

AIM: this study investigates whether there is a relationship between telomere length and SES indicators (income, education) as well as health insurance status in a rural Australian population.

METHODS: samples were drawn from the Australian Rural Victoria cross-sectional Crossroads Study. Leukocyte telomere length (LTL) was measured using a multiplex quantitative PCR method.

RESULTS: among 1424 participants, we did not find a significant main effect association with LTL across education, income level, health insurance. An exploratory finding was sex may influence the relationship between educational attainment and LTL (P = 0.021). In males, but not females, higher education was associated with longer LTL by 0.033 (95%CI, 0.002 - 0.063, P = 0.035); In those with low education attainment, male participants had shorter LTL by 0.058 (95%CI, -0.086 - -0.029) than female participants (P < 0.0001).

CONCLUSION: being male and having lower education attainment was associated with shorter telomere length in our rural population. Evidence from our study supports the importance of education on LTL in males in rural Australia. Our studies also support previous findings that LTL in later life may not be closely associated with indicators of socio-economic status.

RevDate: 2020-02-19

Robinson NJ, Morrison-Smith CD, Gooding AJ, et al (2020)

SLX4IP and telomere dynamics dictate breast cancer metastasis and therapeutic responsiveness.

Life science alliance, 3(4): pii:3/4/e201900427.

Metastasis is the leading cause of breast cancer-related death and poses a substantial clinical burden owing to a paucity of targeted treatment options. The clinical manifestations of metastasis occur years-to-decades after initial diagnosis and treatment because disseminated tumor cells readily evade detection and resist therapy, ultimately giving rise to recurrent disease. Using an unbiased genetic screen, we identified SLX4-interacting protein (SLX4IP) as a regulator of metastatic recurrence and established its relationship in governing telomere maintenance mechanisms (TMMs). Inactivation of SLX4IP suppressed alternative lengthening of telomeres (ALT), coinciding with activation of telomerase. Importantly, TMM selection dramatically influenced metastatic progression and survival of patients with genetically distinct breast cancer subtypes. Notably, pharmacologic and genetic modulation of TMMs elicited telomere-dependent cell death and prevented disease recurrence by disseminated tumor cells. This study illuminates SLX4IP as a potential predictive biomarker for breast cancer progression and metastatic relapse. SLX4IP expression correlates with TMM identity, which also carries prognostic value and informs treatment selection, thereby revealing new inroads into combating metastatic breast cancers.

RevDate: 2020-02-19

Santa-Maria CA, Coughlin JW, Sharma D, et al (2020)

The Effects of a Remote-Based Weight Loss Program on Adipocytokines, Metabolic Markers, and Telomere Length in Breast Cancer Survivors: the POWER-Remote Trial.

Clinical cancer research : an official journal of the American Association for Cancer Research pii:1078-0432.CCR-19-2935 [Epub ahead of print].

PURPOSE: We initiated a clinical trial to determine the proportion of breast cancer survivors achieving ≥5% weight loss using a remotely-delivered weight loss intervention (POWER-remote) or a self-directed approach, and to determine the effects of the intervention on biomarkers of cancer risk including metabolism, inflammation, and telomere length.

EXPERIMENTAL DESIGN: Women with stage 0-III breast cancer, who completed local therapy and chemotherapy, with a body mass index ≥25 kg/m2 were randomized to a 12-month intervention (POWER-remote) versus a self-directed approach. The primary objective was to determine the number of women who achieved at least 5% weight loss at six-months. We assessed baseline and six-month change in a panel of adipocytokines (adiponectin, leptin, resistin, HGF, NGF, PAI1, TNFα, MCP1, IL1β, IL6, and IL8), metabolic factors (insulin, glucose, lipids, hs-CRP), and telomere length in peripheral blood mononuclear cells.

RESULTS: From 2013-2015, 96 women were enrolled, and 87 were evaluable for the primary analysis; 45 to POWER-remote and 42 to self-directed. At six-months 51% of women randomized to POWER-remote lost ≥5% of their baseline body weight, compared to 12% in the self-directed arm (OR=7.9, 95% CI 2.6-23.9, p=0.0003); proportion were similar at 12-months (51% versus 17%, respectively, p=0.003). Weight loss correlated with significant decreases in leptin, and favorable modulation of inflammatory cytokines and lipid profiles. There was no significant change in telomere length at six-months.

CONCLUSIONS: A remotely-delivered weight loss intervention resulted in significant weight loss in breast cancer survivors, and favorable effects on several biomarkers.

RevDate: 2020-02-19

Hailu EM, Needham BL, Lewis TT, et al (2019)

Discrimination, social support, and telomere length: the Multi-Ethnic Study of Atherosclerosis (MESA).

Annals of epidemiology pii:S1047-2797(19)30613-1 [Epub ahead of print].

PURPOSE: We sought to assess the association of reports of discrimination with leukocyte telomere length (LTL) and effect measure modification by social support.

METHODS: This study used data from the Multi-Ethnic Study of Atherosclerosis Stress Ancillary Study (n = 1153). Discrimination was measured using the everyday discrimination and the major experiences of discrimination scales. LTL was defined as the ratio of telomeric DNA to single-copy control gene (mean = 0.916, SD = 0.205). Linear regression models were used to examine the relationship between discrimination and LTL.

RESULTS: We found no association between either measure of discrimination and LTL, but there was evidence of effect modification by social support (P (χ2) = 0.001) for everyday discrimination only. Among those with low social support, reporting moderate and high everyday discrimination was associated with a 0.35 (95% CI: -0.54 to -0.16) and a 0.17 (95% CI: -0.34 to -0.01) shorter telomere length, respectively, compared to reporting no discrimination, after adjusting for demographic factors, health behaviors, and health conditions. There were no associations between discrimination and LTL among those reporting moderate or high social support.

CONCLUSIONS: These findings underscore the importance of continued investigation of the potential health consequences of chronic unfair treatment in the absence of supportive resources.

RevDate: 2020-02-18

Bonafè M, Sabbatinelli J, F Olivieri (2020)

Exploiting the telomere machinery to put the brakes on inflamm-aging.

Ageing research reviews pii:S1568-1637(19)30423-4 [Epub ahead of print].

Telomere shortening accompanies mammalian aging in vivo, and the burden of senescent cells with short telomeres and a senescence-associated secretory phenotype (SASP) increases with aging. The release into the cytoplasm and the extracellular vesicle-mediated intercellular exchange of telomeric TTAGGG repeats could exert an anti-inflammatory activity by preventing the activation of the misplaced nucleic acid-sensing pathway. Many pharmacological and genetic strategies have been developed to prevent telomere shortening or to achieve telomere elongation. Recently, it was demonstrated that telomere elongation can be obtained - without genetic manipulation - by culturing mice embryonic stem cells into appropriate media. Based on this observation, we hypothesize that environmental factors could affect the initial length of telomeres by modulating the activity of telomerase during the early stages of pregnancy. Therefore, organisms with longer telomeres could exploit the anti-inflammatory activity of telomeric sequences over an extended time span, eventually delaying the development and progression of age-related diseases.

RevDate: 2020-02-17

Victorelli S, JF Passos (2020)

Telomeres: beacons of autocrine and paracrine DNA damage during skin aging.

Cell cycle (Georgetown, Tex.) [Epub ahead of print].

Cellular senescence is an irreversible cell cycle arrest, which can be triggered by a number of stressors, including telomere damage. Among many other phenotypic changes, senescence is accompanied by increased secretion of pro-inflammatory molecules, also known as the senescence-associated secretory phenotype (SASP). It is thought that accumulation of senescent cells contributes to age-associated tissue dysfunction partly by inducing senescence in neighboring cells through mechanisms involving SASP factors. Here, we will review evidence suggesting that telomeres can become dysfunctional irrespectively of shortening, and that this may be a mechanism-driving senescence in post-mitotic or slow dividing cells. Furthermore, we review recent evidence that supports that senescent melanocytes induce paracrine telomere damage during skin aging, which may be the mechanism responsible for propagation of senescent cells. We propose that telomeres are sensors of imbalances in the cellular milieu and act as beacons of stress, contributing to autocrine and paracrine senescence.

RevDate: 2020-02-17

Licea-Cejudo RC, Arenas-Sandoval LK, Salazar-León J, et al (2020)

A dysfunctional family environment and a high body fat percentage negatively affect telomere length in Mexican boys aged 8-10 years.

Acta paediatrica (Oslo, Norway : 1992) [Epub ahead of print].

AIM: The aim of this study was to determine whether a direct relationship existed between absolute telomere length (aTL), obesity and familial functionality in a group of Mexican children.

METHODS: We recruited 134 children (52% boys) aged 8-10 years during regular primary care check-ups in 2016 and evaluated physical activity, feeding practices, anthropometrics, body fat percentage (BF%) and family dysfunction. Optimised quantitative PCR determined aTL from genomic deoxyribonucleic acid isolated from saliva samples.

RESULTS: Boys with a healthy BF% showed a higher aTL than their high BF% counterparts (p<0.01). aTL was higher in children who performed physical activity (PA) than their sedentary counterparts (p<0.05). Alarmingly, 90% of the children belonged to dysfunctional families and a dysfunctional family was correlated with a higher BF% (r= -0.57). Negative correlations between the BF% and aTL (r= -0.1765) and the BF% and time dedicated to PA (r= -0.031) were observed in boys. On the contrary, we found a positive correlation between the aTL and weekly PA (r= 0.1938). These correlations were not observed in girls.

CONCLUSION: Telomere shortening was associated with a high BF% in boys, but not girls. Dysfunctional families were also a key factor. School PA programmes should be mandatory.

RevDate: 2020-02-17

Oaks BM, Adu-Afarwuah S, Kumordzie S, et al (2020)

Impact of a nutritional supplement during gestation and early childhood on child salivary cortisol, hair cortisol, and telomere length at 4-6 years of age: a follow-up of a randomized controlled trial.

Stress (Amsterdam, Netherlands) [Epub ahead of print].

Dysregulation of the stress response can occur early in life and may be affected by nutrition. Our objective was to evaluate the long-term effect of nutritional supplementation during gestation and early childhood on child cortisol and buccal telomere length (a marker of cellular aging) at 4-6 years of age. We conducted a follow-up study of children born to women who participated in a nutritional supplementation trial in Ghana. In one group, a lipid-based nutrient supplement (LNS) was provided to women during gestation and the first 6 months postpartum and to their infants from age 6 to 18 months. The control groups received either iron and folic acid (IFA) during gestation or multiple micronutrients during gestation and the first 6 months postpartum, with no infant supplementation. At age 4-6 years, we measured hair cortisol, buccal telomere length, and salivary cortisol before and after a stressor. Salivary cortisol was available for 364 children across all three trial arms and hair cortisol and telomere length were available for a subset of children (n = 275 and 278, respectively) from the LNS and IFA groups. Telomere length, salivary cortisol, and hair cortisol did not differ by supplementation group. Overall, these findings suggest that nutritional supplementation given during gestation and early childhood does not have an effect on child stress response or chronic stress in children at 4-6 years. registration: NCT00970866.LAY SUMMARY: This study addressed a research gap about whether improved nutrition during pregnancy and early childhood impacts telomere length and cortisol in preschool children. There was no difference in child telomere length or cortisol between two trial arms of a nutritional supplementation trial that began during pregnancy. The research outcomes indicate lipid-based nutrient supplements, a relatively new form of supplementation, do not have an effect on markers of stress or cellular aging measured in later childhood.


ESP Quick Facts

ESP Origins

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

ESP Support

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

ESP Rationale

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

ESP Goal

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

ESP Usage

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

ESP Content

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

ESP Help

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

ESP Plans

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

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Good Beginner's Books

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

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Papers in Classical Genetics

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

Digital Books

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


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


Biographical information about many key scientists.

Selected Bibliographies

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

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