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Bibliography on: Telomeres

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Robert J. Robbins is a biologist, an educator, a science administrator, a publisher, an information technologist, and an IT leader and manager who specializes in advancing biomedical knowledge and supporting education through the application of information technology. More About:  RJR | OUR TEAM | OUR SERVICES | THIS WEBSITE

RJR: Recommended Bibliography 16 Jan 2020 at 01:47 Created: 

Telomeres

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

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

Citations The Papers (from PubMed®)

RevDate: 2020-01-14

Praveen G, Shalini T, Sivaprasad M, et al (2020)

Relative Telomere Length and Mitochondrial DNA Copy Number Variation with Age: Association with Plasma Folate and Vitamin B12.

Mitochondrion pii:S1567-7249(19)30283-1 [Epub ahead of print].

Telomere attrition and mitochondrial DNA variations are implicated in the biological aging process and genomic stability can be influenced by nutritional factors. This study aims to analyze the relative telomere length (rTL) and mitochondrial DNA copy number (mtCN) in aged individuals and their association with plasma folate and vitamin B12 levels. This community-based cross-sectional study involves 428 subjects (<60 years: 242 & ≥60 years: 186). Quantitative real-time PCR was used to measure rTL and mtCN variation, and radioimmunoassay to measure plasma folate and vitamin B12 levels. The subjects in the ≥60 years age group have significantly shorter telomeres and lower mtCN compared to the <60 years age group. A significant positive correlation was observed between the rTL and mtCN, and both of them were positively associated with plasma folate and vitamin B12 levels. In the ≥60 age group; folate and vitamin B12 positively correlated with rTL and vitamin B12 with mtCN. The study revealed a decline of rTL and mtCN with age in the Indian population and their association suggests that they may co-regulate each other with age. In conclusion, folate and vitamin B12 may delay aging by preventing the reduction in rTL length and mtCN.

RevDate: 2020-01-14

Porreca RM, Herrera-Moyano E, Skourti E, et al (2020)

TRF1 averts chromatin remodelling, recombination and replication dependent-Break Induced Replication at mouse telomeres.

eLife, 9: pii:49817 [Epub ahead of print].

Telomeres are a significant challenge to DNA replication and are prone to replication stress and telomere fragility. The shelterin component TRF1 facilitates telomere replication but the molecular mechanism remains uncertain. By interrogating the proteomic composition of telomeres, we show that mouse telomeres lacking TRF1 undergo protein composition reorganisation associated with the recruitment of DNA damage response and chromatin remodellers. Surprisingly, mTRF1 suppresses the accumulation of promyelocytic leukemia (PML) protein, BRCA1 and the SMC5/6 complex at telomeres, which is associated with increased Homologous Recombination (HR) and TERRA transcription. We uncovered a previously unappreciated role for mTRF1 in the suppression of telomere recombination, dependent on SMC5 and also POLD3 dependent Break Induced Replication at telomeres. We propose that TRF1 facilitates S-phase telomeric DNA synthesis to prevent illegitimate mitotic DNA recombination and chromatin rearrangement.

RevDate: 2020-01-14

Axelsson J, Wapstra E, Miller E, et al (2020)

Contrasting seasonal patterns of telomere dynamics in response to environmental conditions in the ectothermic sand lizard, Lacerta agilis.

Scientific reports, 10(1):182 pii:10.1038/s41598-019-57084-5.

Telomeres, the protective, terminal parts of the chromosomes erode during cell division and as a result of oxidative damage by reactive oxygen species (ROS). Ectotherms rely on the ambient temperature for maintaining temperature-dependent metabolic rate, regulated through behavioural thermoregulation. Their temperature-dependant metabolism, hence also the ROS production, is indirectly regulated through thermoregulation. Consequently, a potential causal chain affecting telomere length and attrition is: temperature (in particular, its deviation from a species-specific optimum) - metabolism - ROS production - anti-oxidation - telomere erosion. We measured telomere length in sand lizards (Lacerta agilis) using qPCR on blood samples from 1998-2006. Effects of climatological parameters (mean temperature and average sunshine hours) in the summer and winter preceding telomere sampling were used as predictors of telomere length in mixed model analysis. During the lizards' active period (summer), there was a largely negative effect of mean temperature and sun on telomere length, whereas a combined measure of age and size (head length) was positively related to telomere length. During the inactive period of lizards (winter), the results were largely the opposite with a positive relationship between temperature and sunshine hours and telomere length. In all four cases, thermal and age effects on telomere length appeared to be non-linear in the two sexes and seasons, with complex response surface effects on telomere length from combined age and thermal effects.

RevDate: 2020-01-14

Barg-Wojas A, Muraszko J, Kramarz K, et al (2020)

S. pombe DNA translocases Rrp1 and Rrp2 have distinct roles at centromeres and telomeres that ensure genome stability.

Journal of cell science pii:jcs.230193 [Epub ahead of print].

The regulation of telomere and centromere structure and function is essential for maintaining genome integrity. Schizosaccharomyces pombe Rrp1 and Rrp2 are orthologues of Saccharomyces cerevisiae Uls1, a SWI2/SNF2 DNA translocase and SUMO-Targeted Ubiquitin Ligase. Here we show that Rrp1 or Rrp2 overproduction leads to chromosome instability and growth defects, a reduction of global histone levels and mislocalisation of centromere-specific histone Cnp1. These phenotypes depend on putative DNA translocase activities of Rrp1 and Rrp2, suggesting that Rrp1 and Rrp2 may be involved in modulating nucleosome dynamics. Furthermore, we confirm that Rrp2, but not Rrp1, acts at telomeres, reflecting a previously described interaction between Rrp2 and Top2. In conclusion, we identify roles for Rrp1 and Rrp2 in maintaining centromere function by modulating histone dynamics, contributing to the preservation of genome stability during vegetative cell growth.

RevDate: 2020-01-13

He H, Li W, Comiskey DF, et al (2020)

A truncating germline mutation of TINF2 in individuals with thyroid cancer or melanoma results in longer telomeres.

Thyroid : official journal of the American Thyroid Association [Epub ahead of print].

BACKGROUND: Our genome sequencing analysis revealed a frameshift mutation in the shelterin gene TINF2 gene in a large family with individuals affected with papillary thyroid carcinoma (PTC) and melanoma. Here we further characterized the mutation and screened for coding variants in the six shelterin genes in 24 families.

METHODS: Sanger sequencing was performed to screen for the TINF2 mutation in the key family. Quantitative RT-PCR was used for TINF2 gene expression analysis. Exogenous expression and co-immunoprecipitation techniques were used for assessing TINF2 binding to TERF1. Relative telomere length (RTL) was quantified in DNAs from lymphocytes using quantitative real-time PCR. Whole exome sequencing (WES) was performed in 7 families with individuals affected with PTC and other cancer types. Screening for DNA variants in shelterin genes was performed using whole genome sequencing data from 17 families and WES data from 7 families.

RESULTS: The TINF2 mutation (TINF2 p.Trp198fs) showed complete co-segregation with PTC and melanoma in the key family. The mutation is not reported in databases and not identified in 23 other families we screened. The expression of TINF2 was borderline reduced in individuals with the mutation. The truncated TINF2 protein showed abolished binding to TERF1. The RTL in the individuals with the mutation was significantly longer when compared with those without the mutation from the same family as well as compared with 62 healthy controls. Among the 24 families we identified 3 missense and 1 synonymous variant(s) in two shelterin genes (TINF2 and ACD).

CONCLUSIONS: The rare frameshift mutation in the TINF2 gene and the associated longer telomere length suggest that dysregulated telomeres could be a mechanism predisposing to PTC and melanoma. DNA coding variants in shelterin genes are rare. Further studies are required to evaluate the roles of variants in shelterin genes in thyroid cancer and melanoma.

RevDate: 2020-01-13

Chae DH, Wang Y, Martz CD, et al (2020)

Racial discrimination and telomere shortening among African Americans: The Coronary Artery Risk Development in Young Adults (CARDIA) Study.

Health psychology : official journal of the Division of Health Psychology, American Psychological Association pii:2020-00718-001 [Epub ahead of print].

OBJECTIVE: Telomeres are protective sequences of DNA capping the ends of chromosomes that shorten over time. Leukocyte telomere length (LTL) is posited to reflect the replicative history of cells and general systemic aging of the organism. Chronic stress exposure leads to accelerated LTL shortening, which has been linked to increased susceptibility to and faster progression of aging-related diseases. This study examined longitudinal associations between LTL and experiences of racial discrimination, a qualitatively unique source of minority psychosocial stress, among African Americans.

METHOD: Data are from 391 African Americans in the Coronary Artery Risk Development in Young Adults (CARDIA) Telomere Ancillary Study. We examined the number of domains in which racial discrimination was experienced in relation to LTL collected in Years 15 and 25 (Y15: 2000/2001; Y25: 2010/2011). Multivariable linear regression examined if racial discrimination was associated with LTL. Latent change score analysis (LCS) examined changes in racial discrimination and LTL in relation to one another.

RESULTS: Controlling for racial discrimination at Y15, multivariable linear regression analyses indicated that racial discrimination at Y25 was significantly associated with LTL at Y25. This relationship remained robust after adjusting for LTL at Y15 (b = -.019, p = .015). Consistent with this finding, LCS revealed that increases in experiences of racial discrimination were associated with faster 10-year LTL shortening (b = -.019, p = .015).

CONCLUSIONS: This study adds to evidence that racial discrimination contributes to accelerated physiologic weathering and health declines among African Americans through its impact on biological systems, including via its effects on telomere attrition. (PsycINFO Database Record (c) 2020 APA, all rights reserved).

RevDate: 2020-01-13

Wieczór M, J Czub (2020)

Telomere uncapping by common oxidative guanine lesions: Insights from atomistic models.

Free radical biology & medicine pii:S0891-5849(19)32325-1 [Epub ahead of print].

Oxidative damage to DNA is widely known to contribute to aging and disease. This relationship has been extensively studied for telomeres - structures that cap chromosome ends - due to their role in cell proliferation and senescence, and exceptional susceptibility to oxidation. Indeed, the repetitive telomeric DNA sequence contains the 5'-GGG-3' motif that has the lowest ionization potential of all trinucleotides. Accordingly, experiments consistently show that telomeric oxidative lesions are more abundant and persistent than elsewhere in the genome. This led to a hypothesis that telomeres act as sensors of prolonged oxidative stress and prevent carcinogenesis, as disruption of telomeric integrity triggers senescence or apoptosis. Here, we use atomistic alchemical Molecular Dynamics simulations to perform a combinatorial assessment of changes in DNA binding affinity of telomeric proteins induced by oxidative guanine lesions. We rank lesions by their effect on telomere integrity, as well as telomeric proteins by their sensitivity to DNA oxidation. While the binding of most proteins is abolished by DNA oxidation, HOT1 emerges as a notable exception, suggesting its potential role in sensing of oxidative damage. Through statistical analysis and free energy decomposition, we also identify common trends in structural responses of protein-DNA complexes that contribute to decreased binding affinity.

RevDate: 2020-01-11

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

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

Communications biology, 2(1):451 pii:10.1038/s42003-019-0692-z.

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

RevDate: 2020-01-11

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

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

Communications biology, 2(1):376 pii:10.1038/s42003-019-0621-1.

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

RevDate: 2020-01-11

Mennie AK, Moser BA, Hoyle A, et al (2019)

Tpz1TPP1 prevents telomerase activation and protects telomeres by modulating the Stn1-Ten1 complex in fission yeast.

Communications biology, 2(1):297 pii:10.1038/s42003-019-0546-8.

In both mammalian and fission yeast cells, conserved shelterin and CST (CTC1-STN1-TEN1) complexes play critical roles in protection of telomeres and regulation of telomerase, an enzyme required to overcome the end replication problem. However, molecular details that govern proper coordination among shelterin, CST, and telomerase have not yet been fully understood. Here, we establish a conserved SWSSS motif, located adjacent to the Lys242 SUMOylation site in the fission yeast shelterin subunit Tpz1, as a new functional regulatory element for telomere protection and telomere length homeostasis. The SWSSS motif works redundantly with Lys242 SUMOylation to promote binding of Stn1-Ten1 at telomere and sub-telomere regions to protect against single-strand annealing (SSA)-dependent telomere fusions, and to prevent telomerase accumulation at telomeres. In addition, we provide evidence that the SWSSS motif defines an unanticipated role of Tpz1 in limiting telomerase activation at telomeres to prevent uncontrolled telomere elongation.

RevDate: 2020-01-11

da Silva GG, Morais KS, Arcanjo DS, et al (2020)

Clinical relevance of Alternative lengthening of telomeres in cancer.

Current topics in medicinal chemistry pii:CTMC-EPUB-103600 [Epub ahead of print].

The alternative lengthening of telomere (ALT) is a pathway responsible for cell immortalization in some kinds of tumors. Since the first description of ALT is relatively recent in the oncology field, its mechanism remains elusive, but recent works address ALT-related proteins or cellular structures as potential druggable targets for more specific and efficient antitumor therapies. Also, some new generation compounds for antitelomerase therapy in cancer were able to provoke acquisition of ALT phenotype in treated tumors, enhancing the importance of studies on this alternative lengthening of telomere. However, ALT has been implicated in different - sometimes opposite - outcomes, according to tumor type studied. Then, in order to design and to develop new drugs for ALT+ cancer in an effective way, it is crucial to understand its clinical implications. In this review, we gathered works published in the last two decades to highlight the clinical relevance of ALT on oncology.

RevDate: 2020-01-10

Michels KB, De Vivo I, Calafat AM, et al (2019)

In utero exposure to endocrine-disrupting chemicals and telomere length at birth.

Environmental research, 182:109053 pii:S0013-9351(19)30850-3 [Epub ahead of print].

Telomere length correlates with morbidity and mortality. While telomere length appears to be influenced by hormone levels, the potential impact of exposure to endocrine-disrupting chemicals (EDCs) has not been studied. We examined the association between maternal gestational concentrations of biomarkers of EDC exposure and telomere length at birth in the Harvard Epigenetic Birth Cohort. EDC (phenols and phthalates) biomarker concentrations were measured in maternal spot urine samples during the first trimester and telomere length in maternal and cord blood collected at delivery among 181 mother-newborn singleton dyads. Maternal and newborn telomere length exhibited a positive correlation (Spearman ρ = 0.20 (p-value< 0.01). Infant telomere length was associated with maternal biomarker concentrations of specific EDCs, and most of these associations were observed to be infant sex-specific. Prenatal exposure to triclosan, a non-paraben phenol with antimicrobial properties, was one of the most strongly associated EDCs with telomere length; telomere length was 20% (95% CI 5%-33%) shorter among boys in the highest quartile of maternal biomarker concentrations compared to the lowest quartile. In contrast, we observed longer telomere length associated with increased gestational concentrations of mono-isobutyl phthalate, and among boys, with increased concentrations of mono-2-ethylhexyl phthalate. In this birth cohort, we observed associations between maternal gestational exposure to select EDC biomarkers and telomere length, most of which were sex-specific. These findings need to be confirmed in future studies.

RevDate: 2020-01-10

Ma Y, Bellini N, Harnung Scholten R, et al (2020)

Effect of combustion-derived particles on genotoxicity and telomere length: a study on human cells and exposed populations.

Toxicology letters pii:S0378-4274(20)30002-3 [Epub ahead of print].

Particulate matter (PM) from combustion processes has been associated with oxidative stress to DNA, whereas effects related to telomere dysfunction are less investigated. We collected air-borne PM from a passenger cabin of a diesel-propelled train and at a training facility for smoke diving exercises. Effects on oxidative stress biomarkers, genotoxicity measured by the comet assay and telomere length in PM-exposed A549 cells were compared with the genotoxicity and telomere length in peripheral blood mononuclear cells (PBMCs) from human volunteers exposed to the same aerosol source. Although elevated levels of DNA strand breaks and oxidatively damaged DNA in terms of Fpg-sensitive sites were observed in PBMCs from exposed humans, the PM collected at same locations did not cause genotoxicity in the comet assay in A549 cells. Nevertheless, A549 cells displayed telomere length shortening after four weeks exposure to PM. This is in line with slightly shorter telomere length in PBMCs from exposed humans, although it was not statistically significant. In conclusion, the results indicate that genotoxic potency measured by the comet assay of PM in A549 cells may not predict genotoxicity in exposed humans, whereas telomere length measurements may be a novel indicator of genotoxic stress in cell cultures and humans.

RevDate: 2020-01-10

Chan D, Martin-Ruiz C, Saretzki G, et al (2020)

The association of telomere length and telomerase activity with adverse outcomes in older patients with non-ST-elevation acute coronary syndrome.

PloS one, 15(1):e0227616 pii:PONE-D-19-23361.

BACKGROUND: Non-ST elevation acute coronary syndrome (NSTEACS) occurs more frequently in older patients with an increased occurrence of recurrent cardiac events following the index presentation. Telomeres are structures consisting of repeated DNA sequences as associated shelterin proteins at the ends of chromosomes. We aim to determine whether telomere length (TL) and telomerase activity (TA) predicted poor outcomes in older patients presenting with NSTEACS undergoing invasive care.

METHOD: Older patients undergoing invasive management for NSTEACS were recruited to the ICON-1 biomarker study (NCT01933581). Peripheral blood mononuclear cells (PBMC) were recovered on 153 patients. DNA was isolated and mean TL was measured by quantitative PCR expressed as relative T (telomere repeat copy number) to S (single copy gene number) ratio (T/S ratio), and a telomere repeat amplification assay was used to assess TA during index presentation with NSTEACS. Primary clinical outcomes consisted of death, myocardial infarction (MI), unplanned revascularisation, stroke and significant bleeding recorded at 1 year. TL and TA were divided into tertile groups for analysis. Cox proportional hazards regression was performed. Ordinal regression was performed to evaluate the relationship between TL and TA and traditional cardiovascular risk factors at baseline.

RESULTS: 298 patients were recruited in the ICON-1 study of which 153 had PBMC recovered. The mean age was 81.0 ± 4.0 years (64% male). Mean telomere length T/S ratio was 0.47 ± 0.25 and mean TA was 1.52 ± 0.61 units. The primary composite outcome occurred in 44 (28.8%) patients. There was no association between short TL or low TA and incidence of the primary composite outcome (Hazard Ratio [HR] 1.50, 95% Confidence Interval [CI] 0.68-3.34, p = 0.32 and HR 1.33, 95% CI 0.52-3.36, p = 0.51 respectively).

CONCLUSION: TL and TA are not found to be associated with the incidence of adverse outcomes in older patients presenting with NSTEACS undergoing invasive care.

CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov Unique identifier: NCT01933581.

RevDate: 2020-01-10

Ma TZ, Zhang MJ, Liao TC, et al (2020)

Dimers formed with the mixed-type G-quadruplex binder pyridostatin specifically recognize human telomere G-quadruplex dimers.

Organic & biomolecular chemistry [Epub ahead of print].

By choosing pyridostatin (PDS) with high thermal stabilization towards mixed-type G-quadruplexes as the monomer in dimers, three novel polyether-tethered PDS dimers (1a-c) were first synthesized and their interaction with human telomere G-quadruplex dimers (G2T1) was studied. Through the regulation of the linker length in PDS dimers, the dimer with a medium-length polyether linker (1b) showed higher binding selectivity and thermal stabilization (ΔTm = 29.5 °C) towards antiparallel G2T1 over G-quadruplex monomers (G1). Furthermore, the dimer with the longest-length polyether linker (1c) showed higher binding selectivity and thermal stabilization towards mixed-type G2T1 over mixed-type G1, c-kit 1, c-kit 2, c-myc and ds DNA. This work provides new insights into the development of G2T1 binders, especially mixed-type G2T1 binders, which could be promoted by a polymer formed with a mixed-type G-quadruplex binder. In addition, dimer 1c exhibited stronger telomerase inhibition than dimers 1a and 1b.

RevDate: 2020-01-10

Shi Y, Zhang Y, Zhang L, et al (2019)

Telomere Length of Circulating Cell-Free DNA and Gastric Cancer in a Chinese Population at High-Risk.

Frontiers in oncology, 9:1434.

Background: Telomeres have long been found to be involved in cancer development, while little was known about the dynamic changes of telomere length in carcinogenesis process. Methods: The present study longitudinally investigated telomere alterations of cell-free DNA (cfDNA) in 86 gastric cancer (GC) subjects recruited through a 16-year prospective cohort with 2-4 serums collected before each GC-diagnosis from baseline and three follow-up time-points (a total of 276 samples). As the control, 86 individual-matched cancer-free subjects were enrolled with 276 serums from the matched calendar year. Results: In the 73 pairs of baseline serums from GC and control subjects, shortened telomeres showed increased subsequent GC risk [odds ratio (OR) = 9.17, 95% CI: 2.72-31.25 for 1 unit shortening]. In each baseline gastric lesion category, higher risks of GC progression were also found with shortened cfDNA telomeres; ORs per 1 unit shortening were 6.99 (95% CI: 1.63-30.30) for mild gastric lesions, 6.06 (95% CI: 1.89-19.61) for intestinal metaplasia and 15.63 (95% CI: 1.91-125.00) for dysplasia. With all measurements from baseline and follow-up time-points, shortened telomeres also showed significant association with GC risk (OR = 7.37, 95% CI: 2.06-26.32 for 1 unit shortening). In temporal trend analysis, shortened telomeres were found in GC subjects compared to corresponding controls more than 3 years ahead of GC-diagnosis (most P < 0.05), while no significant difference was found between two groups within 3 years approaching to GC-diagnosis. Conclusion: Our findings suggest that telomere shortening may be associated with gastric carcinogenesis, which supports further etiological study and potential biomarker for risk stratification.

RevDate: 2020-01-10

Xu C, Wang Z, Su X, et al (2020)

Association between leucocyte telomere length and cardiovascular disease in a large general population in the United States.

Scientific reports, 10(1):80 pii:10.1038/s41598-019-57050-1.

Leucocyte telomere length (LTL) has been reported to be linked to ageing, cancer and cardiovascular disease (CVD). This study aimed to explore the association between LTL and CVD risk in a nationally representative sample of U.S. adults. Complex associations, including nonlinearity and interaction, were also examined. A total of 7,378 subjects from the National Health and Nutrition Examination Survey (NHANES) 1999-2002 were collected. Telomere length was detected from DNA samples and expressed as the mean T/S ratio (telomere repeats per single-copy gene). We performed multiple logistic regression models and interactive analysis to explore the associations between LTL and CVD risk by adjusting for potential confounders. We also performed a sensitivity analysis to investigate the robustness of our results. Among all participants, LTL was associated with the risk of CVD (OR = 0.79, 95% CI: 0.63~0.98, P = 0.033) in a linear manner rather than in a nonlinear manner (P = 0.874). Interaction effects of LTL with both education (P = 0.017) and hypertension (P = 0.007) were observed. Furthermore, using subgroup analyses, protective effects of LTL on CVD risk were found in females and in individuals who were college graduates or above, had serum cotinine >10 ng/ml, did not have hypertension, or had normal white blood cell levels. LTL is linearly inversely associated with CVD risk in the general population of the United States.

RevDate: 2020-01-09

Berei J, Eckburg A, Miliavski E, et al (2020)

Potential Telomere-Related Pharmacological Targets.

Current topics in medicinal chemistry pii:CTMC-EPUB-103579 [Epub ahead of print].

Telomeres function as protective caps at the terminal portion of chromosomes, containing non-coding nucleotide sequence repeats. As part of their protective function, telomeres preserve genomic integrity and minimize chromosomal exposure, thus limiting DNA damage responses. With continued mitotic divisions in normal cells, telomeres progressively shorten until they reach a threshold at which point they activate senescence or cell death pathways. However, the presence of the enzyme telomerase can provide functional immortality to cells that have reached or progressed past senescence. In senescent cells that amass several oncogenic mutations, cancer formation can occur due to genomic instability and the induction of telomerase activity. Telomerase has been found to be expressed in over 85% of human tumors and is labeled as a near-universal marker for cancer. Due to this feature being present in a majority of tumors but absent in most somatic cells, telomerase and telomeres have become promising targets for the development of new and effective anticancer therapeutics. In this review, we evaluate novel anticancer targets in development which aim to alter telomerase or telomere function. Additionally, we analyze the progress that has been made, including preclinical studies and clinical trials, with therapeutics directed at telomere-related targets. Furthermore, we review the potential telomere-related therapeutics that are used in combination therapy with more traditional cancer treatments. Throughout the review, topics related to medicinal chemistry are discussed, including drug bioavailability and delivery, chemical structure-activity relationships of select therapies, and the development of a unique telomere assay to analyze compounds affecting telomere elongation.

RevDate: 2020-01-09

Lara-Cerrillo S, Gual-Frau J, Benet J, et al (2020)

Microsurgical varicocelectomy effect on sperm telomere length, DNA fragmentation and seminal parameters.

Human fertility (Cambridge, England) [Epub ahead of print].

Varicocele is one of the main causes of male infertility and microsurgical varicocelectomy (MV) seems to be the best procedure for its repair and to reduce testicular oxidative stress (ROS). As ROS causes guanine modifications, we postulated that DNA damage could be more intense in telomeres due to their G-rich nature. We studied the effect of MV on sperm telomere length (TL), single- and double-strand DNA fragmentation (ssSDF and dsSDF) and seminal parameters. Sperm telomeres from 12 fertile donors and 20 varicocele patients before and nine months after MV were labelled using FITC-PNA qFISH (a new method to obtain absolute TL from relative fluorescence intensity using FITC-fluorescent spheres). Both ssSDF and dsSDF were analysed using the alkaline and neutral Comet assays, respectively. The results showed that varicocele and MV had no effect on TL. Seminal parameters, ssSDF and dsSDF of varicocele patients were altered. Although these parameters improved after MV, values did not reach those seen in fertile donors. A good estimation of absolute TL was developed based on FITC-fluorescent spheres. The results showed that TL is not affected by varicocele or surgery. However, MV is able to partially reduce altered seminal parameters, ssSDF and dsSDF values in varicocele patients.

RevDate: 2020-01-09

Heaphy CM, Joshu CE, Barber JR, et al (2020)

Racial difference in prostate cancer cell telomere lengths in men with higher-grade prostate cancer: a clue to the racial disparity in prostate cancer outcomes.

Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology pii:1055-9965.EPI-19-1462 [Epub ahead of print].

BACKGROUND: Black men have worse prostate cancer outcomes following treatment than White men even accounting for prognostic factors. However, biological explanations for this racial disparity have not been fully identified. We previously showed that more variable telomere lengths among cancer cells and shorter telomere lengths in cancer-associated stromal (CAS) cells individually and together ("telomere biomarker") are associated with prostate cancer death in surgically-treated men independent of currently used prognostic indicators. Here, we hypothesize that Black-White differences in the telomere biomarker and/or in its components may help explain the racial disparity in prostate cancer outcomes.

METHODS: Black (higher-grade [Gleason >/=4+3]=34, lower-grade=93) and White (higher-grade=34, lower-grade=89) surgically-treated men were frequency matched on age, pathologic stage, and grade. We measured telomere lengths in cancer and CAS cells using a robust telomere-specific fluorescence in situ hybridization assay. Tissue microarray and grade-specific distributional cutpoints without regard to race were evaluated.

RESULTS: Among men with higher-grade disease, the proportion of Black men (47.1%) with more variable cancer cell telomere lengths was 2.3-times higher (p=0.02) than that in White men (20.6%). In contrast, among men with lower-grade disease, cancer cell telomere length variability did not differ by race. The proportion of men with shorter CAS cell telomeres did not differ by race for either higher- or lower-grade disease.

CONCLUSIONS: A greater proportion of Black men with higher-grade disease have an adverse prostate cancer cell telomere phenotype than White men with higher-grade disease.

IMPACT: Our findings suggest a possible explanation for the racial disparity in prostate cancer outcomes.

RevDate: 2020-01-09

Peters-Hall JR, Min J, Tedone E, et al (2020)

Proliferation of adult human bronchial epithelial cells without a telomere maintenance mechanism for over 200 population doublings.

FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 34(1):386-398.

To date, there is no direct evidence of telomerase activity in adult lung epithelial cells, but typical culture conditions only support cell proliferation for 30-40 population doublings (PD), a point at which telomeres remain relatively long. Here we report that in in vitro low stress culture conditions consisting of a fibroblast feeder layer, rho-associated coiled coil protein kinase inhibitor (ROCKi), and low oxygen (2%), normal human bronchial epithelial basal progenitor cells (HBECs) divide for over 200 PD without engaging a telomere maintenance mechanism (almost four times the "Hayflick limit"). HBECs exhibit critically short telomeres at 200 PD and the population of cells start to undergo replicative senescence. Subcloning these late passage cells to clonal density, to mimic lung injury in vivo, selects for rare subsets of HBECs that activate low levels of telomerase activity to maintain short telomeres. CRISPR/Cas9 knockout of human telomerase reverse transcriptase or treatment with the telomerase-mediated telomere targeting agent 6-thio-2'deoxyguanosine abrogates colony growth in these late passage cultures (>200 PD) but not in early passage cultures (<200 PD). To our knowledge, this is the first study to report such long-term growth of HBECs without a telomere maintenance mechanism. This report also provides direct evidence of telomerase activation in HBECs near senescence when telomeres are critically short. This novel cell culture system provides an experimental model to understand how telomerase is regulated in normal adult tissues.

RevDate: 2020-01-08

Steiner B, Ferrucci LM, Mirabello L, et al (2020)

Association between coffee drinking and telomere length in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial.

PloS one, 15(1):e0226972 pii:PONE-D-19-12491.

Mounting evidence indicates that coffee, a commonly consumed beverage worldwide, is inversely associated with various chronic diseases and overall mortality. Few studies have evaluated the effect of coffee drinking on telomere length, a biomarker of chromosomal integrity, and results have been inconsistent. Understanding this association may provide mechanistic insight into associations of coffee with health. The aim of our study was to test the hypothesis that heavier coffee intake is associated with greater likelihood of having above-median telomere length. We evaluated the cross-sectional association between coffee intake and relative telomere length using data from 1,638 controls from four previously conducted case-control studies nested in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Coffee intake was assessed using a food frequency questionnaire, and relative telomere length was measured from buffy-coat, blood, or buccal cells. We used unconditional logistic regression models to generate multivariable-adjusted, study-specific odds ratios for the association between coffee intake and relative telomere length. We then conducted a random-effects meta-analysis to determine summary odds ratios. We found that neither summary continuous (OR = 1.01, 95% CI = 0.99-1.03) nor categorical (OR <3 cups/day vs. none = 1.37, 95% CI = 0.71-2.65; OR ≥3 cups/day vs. none = 1.47, 95% CI = 0.81-2.66) odds ratio estimates of coffee drinking and relative telomere length were statistically significant. However, in the largest of the four contributing studies, moderate (<3 cups/day) and heavy coffee drinkers (≥3 cups/day) were 2.10 times (95% CI = 1.25, 3.54) and 1.93 times as likely (95% CI = 1.17, 3.18) as nondrinkers to have above-median telomere length, respectively. In conclusion, we found no evidence that coffee drinking is associated with telomere length. Thus, it is unlikely that telomere length plays a role in potential coffee-disease associations.

RevDate: 2020-01-07

van Batenburg AA, Kazemier KM, van Oosterhout MFM, et al (2020)

From organ to cell: Multi-level telomere length assessment in patients with idiopathic pulmonary fibrosis.

PloS one, 15(1):e0226785 pii:PONE-D-19-27797.

RATIONALE: A subset of patients with idiopathic pulmonary fibrosis (IPF) contains short leukocyte telomeres or telomere related mutations. We previously showed that alveolar type 2 cells have short telomeres in fibrotic lesions. Our objectives were to better understand how telomere shortening associates with fibrosis in IPF lung and identify a subset of patients with telomere-related disease.

METHODS: Average telomere length was determined in multiple organs, basal and apical lung, and diagnostic and end-stage fibrotic lung biopsies. Alveolar type 2 cells telomere length was determined in different areas of IPF lungs.

RESULTS: In IPF but not in controls, telomere length in lung was shorter than in other organs, providing rationale to focus on telomere length in lung. Telomere length did not correlate with age and no difference in telomere length was found between diagnostic and explant lung or between basal and apical lung, irrespective of the presence of a radiological apicobasal gradient or fibrosis. Fifteen out of 28 IPF patients had average lung telomere length in the range of patients with a telomerase (TERT) mutation, and formed the IPFshort group. Only in this IPFshort and TERT group telomeres of alveolar type 2 cells were extremely short in fibrotic areas. Additionally, whole exome sequencing of IPF patients revealed two genetic variations in RTEL1 and one in PARN in the IPFshort group.

CONCLUSIONS: Average lung tissue telomere shortening does not associated with fibrotic patterns in IPF, however, approximately half of IPF patients show excessive lung telomere shortening that is associated with pulmonary fibrosis driven by telomere attrition.

RevDate: 2020-01-07

Udroiu I, A Sgura (2019)

Alternative Lengthening of Telomeres and Chromatin Status.

Genes, 11(1): pii:genes11010045.

Telomere length is maintained by either telomerase, a reverse transcriptase, or alternative lengthening of telomeres (ALT), a mechanism that utilizes homologous recombination (HR) proteins. Since access to DNA for HR enzymes is regulated by the chromatin status, it is expected that telomere elongation is linked to epigenetic modifications. The aim of this review is to elucidate the epigenetic features of ALT-positive cells. In order to do this, it is first necessary to understand the telomeric chromatin peculiarities. So far, the epigenetic nature of telomeres is still controversial: some authors describe them as heterochromatic, while for others, they are euchromatic. Similarly, ALT activity should be characterized by the loss (according to most researchers) or formation (as claimed by a minority) of heterochromatin in telomeres. Besides reviewing the main works in this field and the most recent findings, some hypotheses involving the role of telomere non-canonical sequences and the possible spatial heterogeneity of telomeres are given.

RevDate: 2020-01-07

Ock J, Kim J, YH Choi (2019)

Organophosphate insecticide exposure and telomere length in U.S. adults.

The Science of the total environment, 709:135990 pii:S0048-9697(19)35985-6 [Epub ahead of print].

BACKGROUND: Organophosphate insecticides have been widely used for >30 years, and are reported to be associated with various age-related chronic diseases. While shortening of telomere length has been considered as a marker of cellular aging, only a few small studies have been conducted to examine any difference of telomere length in workers exposed to organophosphates versus controls. Epidemiologic studies of the dose-response associations between environmental organophosphate exposure and telomere length in the general population are few.

OBJECTIVE: This study aimed to evaluate the association between levels of organophosphate insecticide exposure and telomere length in the general population.

METHODS: We analyzed data for 1724 participants aged 20 years or more from the National Health and Nutrition Examination Survey 1999-2002. Organophosphate insecticide exposure was estimated using measures of urinary concentrations for 3,5,6-trichloro-2-pyridinol (TCPY) and six non-specific dialkyl phosphate metabolites, e.g., diethyl thiophosphate (DETP). Multiple linear regression was conducted to assess the association between organophosphate exposure and telomere length.

RESULTS: After controlling for sociodemographic and physical factors and urinary creatinine, participants in the second quartile for urinary TCPY had 0.06 (95% CI: 0.02-0.10) T/S ratio shorter telomere length than those in the lowest quartile. By contrast, participants in the second and third tertiles of urinary DETP had 0.08 (95% CI: 0.02-0.14) and 0.06 (95% CI, 0.01-0.11) T/S ratio longer telomere length than those in the lowest tertile. For other five metabolites, there was no association with telomere length.

CONCLUSIONS: Levels of environmental exposures to certain organophosphate insecticides may be linked to altered telomere length in adults in the general population. Although our findings may need to be replicated, we provide the first evidence that environmental exposure to organophosphates may contribute to the alteration of telomere length, which is potentially related to biological aging and to the development of various chronic diseases.

RevDate: 2020-01-06

Yuan X, Dai M, D Xu (2020)

TELOMERE- RELATED MARKERS FOR CANCER.

Current topics in medicinal chemistry pii:CTMC-EPUB-103506 [Epub ahead of print].

Telomeres are structurally nucleoprotein complexes at termini of linear chromosomes and essential to chromosome stability/integrity. In normal human cells, telomere length erodes progressively with each round of cell divisions, which serves as an important barrier to uncontrolled proliferation and malignant transformation. In sharp contrast, telomere maintenance is a key feature of human malignant cells and required for their infinite proliferation and maintenance of other cancer hallmarks as well. Thus, a telomere-based anti-cancer strategy has long been suggested. However, clinically efficient and specific drugs targeting cancer telomere-maintenance have still been in their infancy thus far. To achieve this goal, it is highly necessary to elucidate how exactly cancer cells maintain functional telomeres. In the last two decades, numerous studies have provided profound mechanistic insights, and the identified mechanisms include the aberrant activation of telomerase or the alternative-lengthening of telomere pathway responsible for telomere elongation, dysregulation and mutation of telomere-associated factors, and other telomere homeostasis-related signaling nodes. In the present review, we summarize these various strategies employed by malignant cells to regulate their telomere length, structure and function, and discuss potential implications of these findings in the rational development of telomere-based cancer therapy and other clinical applications for precision oncology.

RevDate: 2020-01-06

Schutte NS, Malouff JM, SL Keng (2020)

Meditation and telomere length: a meta-analysis.

Psychology & health [Epub ahead of print].

Objective: Telomeres are the caps at the end of chromosomes. Short telomeres are a biomarker for worsening health and early death.Design: The present study consolidated research on meditation and telomere length through a meta-analysis of results of studies examining the effect of meditation on telomere length by comparing the telomere length of meditating participants with participants in control conditions.Results: A search of the literature identified 11 studies reporting 12 comparisons of meditating individuals with individuals in control conditions. An overall significant weighted effect size of g =.40 indicated that the individuals in meditation conditions had longer telomeres. When an outlier effect size was trimmed from the analysis, the effect size was smaller, g =.16. Across studies, a greater number of hours of meditation among participants in meditation conditions was associated with larger effect sizes.Conclusion: These findings provide tentative support for the hypothesis that participants in meditation conditions have longer telomeres than participants in comparison conditions, and that a greater number of hours of meditation is associated with a greater impact on telomere biology. The results of the meta-analysis have potential clinical significance in that they suggest that meditation-based interventions may prevent telomere attrition or increase telomere length.

RevDate: 2020-01-06

Mazidi M, Mikhailidis DP, Banach M, et al (2019)

Impact of serum 25-hydroxyvitamin D 25(OH) on telomere attrition: A Mendelian Randomization study.

Clinical nutrition (Edinburgh, Scotland) pii:S0261-5614(19)33177-2 [Epub ahead of print].

BACKGROUND: Conventional observational studies have suggested that 25-hydroxyvitamin D (25(OH)D) is inversely associated with telomere shortening. We aimed to apply two-sample Mendelian randomization (MR) to assess the causal association between serum 25(OH) D and telomere length (TL).

METHODS: MR was implemented by using summary-level data from the largest genome-wide association studies (GWAS) on vitamin D (n = 73 699) and TL (n = 37 684). Inverse variance weighted method (IVW) was used to estimate the causal estimates. Weighted median (WM)-based method, and MR-Egger, leave-one-out were applied as sensitivity analysis.

RESULTS: The results of MR demonstrated no effect of 25(OH)D on TL (IVW = β:-0.104, p = 0.219, WM = β:-0.109, p = 0.188; MR Egger = β:-0.127, p = 0.506). None of the 25(OH)D-related single nucleotide polymorphisms (SNPs) were significantly associated with TL. Heterogeneity tests did not detect heterogeneity. Furthermore, MR pleiotropy residual sum and outlier (MR-PRESSO) did not highlight any outliers (p = 0.424). Results of leave-one-out method demonstrated that the links are not driven because of the single SNPs.

CONCLUSIONS: Our study does not support any causal effect of 25(OH) D on TL.

RevDate: 2020-01-05

Hiam D, Smith C, Voisin S, et al (2020)

Aerobic capacity and telomere length in human skeletal muscle and leukocytes across the lifespan.

Aging, 11: pii:102627 [Epub ahead of print].

A reduction in aerobic capacity and the shortening of telomeres are hallmarks of the ageing process. We examined whether a lower aerobic capacity is associated with shorter TL in skeletal muscle and/or leukocytes, across a wide age range of individuals. We also tested whether TL in human skeletal muscle (MTL) correlates with TL in leukocytes (LTL). Eighty-two recreationally active, healthy men from the Gene SMART cohort (31.4±8.2 years; body mass index (BMI)=25.3±3.3kg/m2), and 11 community dwelling older men (74.2±7.5years-old; BMI=28.7±2.8kg/m2) participated in the study. Leukocytes and skeletal muscle samples were collected at rest. Relative telomere length (T/S ratio) was measured by RT-PCR. Associations between TL, aerobic capacity (VO2 peak and peak power) and age were assessed with robust linear models. Older age was associated with shorter LTL (45% variance explained, P<0.001), but not MTL (P= 0.7). Aerobic capacity was not associated with MTL (P=0.5), nor LTL (P=0.3). MTL and LTL were correlated across the lifespan (rs=0.26, P=0.03). In healthy individuals, age explain most of the variability of LTL and this appears to be independent of individual aerobic capacity. Individuals with longer LTL also have a longer MTL, suggesting that there might be a shared molecular mechanism regulating telomere length.

RevDate: 2020-01-04

Rentscher KE, Carroll JE, C Mitchell (2020)

Psychosocial Stressors and Telomere Length: A Current Review of the Science.

Annual review of public health [Epub ahead of print].

A growing literature suggests that exposure to adverse social conditions may accelerate biological aging, offering one mechanism through which adversity may increase risk for age-related disease. As one of the most extensively studied biological markers of aging, telomere length (TL) provides a valuable tool to understand potential influences of social adversity on the aging process. Indeed, a sizeable literature now links a wide range of stressors to TL across the life span. The aim of this article is to review and evaluate this extant literature with a focus on studies that investigate psychosocial stress exposures and experiences in early life and adulthood. We conclude by outlining potential biological and behavioral mechanisms through which psychosocial stress may influence TL, and we discuss directions for future research in this area. Expected final online publication date for the Annual Review of Public Health, Volume 41 is April 1, 2020. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

RevDate: 2020-01-03

Márquez-Ruiz AB, González-Herrera L, Luna JD, et al (2020)

DNA methylation levels and telomere length in human teeth: usefulness for age estimation.

International journal of legal medicine pii:10.1007/s00414-019-02242-7 [Epub ahead of print].

In the last decade, increasing knowledge of epigenetics has led to the development of DNA methylation-based models to predict age, which have shown high predictive accuracy. However, despite the value of teeth as forensic samples, few studies have focused on this source of DNA. This study used bisulfite pyrosequencing to measure the methylation levels of specific CpG sites located in the ELOVL2, ASPA, and PDE4C genes, with the aim of selecting the most age-informative genes and determining their associations with age, in 65 tooth samples from individuals 15 to 85 years old. As a second aim, methylation data and measurements of relative telomere length in the same set of samples were used to develop preliminary age prediction models to evaluate the accuracy of both biomarkers together and separately in estimating age from teeth for forensic purposes. In our sample, several CpG sites from ELOVL2 and PDE4C genes, as well as telomere length, were significantly associated with chronological age. We developed age prediction quantile regression models based on DNA methylation levels, with and without telomere length as an additional variable, and adjusted for type of tooth and sex. Our results suggest that telomere length may have limited usefulness as a supplementary marker for DNA methylation-based age estimation in tooth samples, given that it contributed little improvement in the prediction errors of the models. In addition, even at older ages, DNA methylation appeared to be more informative in predicting age than telomere length when both biomarkers were evaluated separately.

RevDate: 2020-01-03

Chan R, Leung J, Tang N, et al (2020)

Dietary patterns and telomere length in community-dwelling Chinese older men and women: a cross-sectional analysis.

European journal of nutrition pii:10.1007/s00394-019-02168-1 [Epub ahead of print].

PURPOSE: Environmental and lifestyle factors that affect oxidative stress and inflammation may influence telomere length (TL). There are limited data to relate dietary patterns with TL. This study examined the association of various dietary patterns with TL in Chinese older adults.

METHODS: We conducted a cross-sectional analysis and performed multivariate linear regression analyses using available data from 1981 (965 men, 1016 women) community-dwelling Chinese adults aged 65 years and over in Hong Kong. The interviewer administered questionnaires that covered dietary intake estimation and dietary pattern generation from the food frequency questionnaire, demographic and lifestyle factors, and self-reported medical history. TL was measured by quantitative real-time polymerase chain reaction.

RESULTS: None of the dietary pattern scores including the Diet Quality Index-International (DQI-I) score, the Dietary Approaches to Stop Hypertension (DASH) score, the Mediterranean-DASH Intervention for Neurodegenerative Delay Diet (MIND) score, the Mediterranean Diet Score (MDS), the Okinawan diet score, as well as the "vegetables-fruits" pattern score, the "snacks-drinks-milk" pattern score, and the "meat-fish" pattern score were associated with TL in the age- and sex-adjusted model and the multivariate adjusted model.

CONCLUSION: Our findings suggest a minimal role of dietary patterns in telomere length in community-dwelling Chinese older adults.

RevDate: 2020-01-02

Todendi PF, Martínez JA, Reuter CP, et al (2019)

Biochemical profile, eating habits, and telomere length among Brazilian children and adolescents.

Nutrition (Burbank, Los Angeles County, Calif.), 71:110645 pii:S0899-9007(19)30228-X [Epub ahead of print].

OBJECTIVES: Lifestyle, obesity, and eating habits are emerging as determinants for the instability of telomeres. The increase in childhood and adolescent obesity and the association of biochemical profiles and dietary components with telomere length (TL) makes it an important issue in nutritional research. The aim of the present study was to investigate TL and its association with ethnic background, adiposity, clinical and biochemical parameters, and dietary patterns among Brazilian children and adolescents.

METHODS: A cross-sectional study encompassing 981 children and adolescents between 7 and 17 y of age was performed. Dietary intake habits, anthropometry, and clinical data were collected. TL analysis was performed by quantitative polymerase chain reaction.

RESULTS: Children presented significantly longer TL than adolescents (P = 0.046). Participants who self-declared as black, mulatto, or brown (P < 0.001) also showed longer TL than those who were white. Regarding biochemical parameters, individuals with altered glucose levels had shorter TL than normoglycemic participants in the total sample (P = 0.014). Such difference remained statistically significant in adolescents (P = 0.019). Participants who reported eating fruits and vegetables regularly had longer TL than those who did not (P < 0.001).

CONCLUSION: The results suggested that both biochemical parameters and the intake of antioxidant-rich food, such as fruits and vegetables, are associated with the stability of telomere biology among young Brazilians.

RevDate: 2020-01-02

Wang Z, Li J, Liu J, et al (2020)

Molecular insights into the selective binding mechanism of the negatively charged stabilizer to human telomere G-quadruplex.

Clinical and experimental pharmacology & physiology [Epub ahead of print].

The single-stranded overhang of human telomere DNA intramolecularly forms a high-order nucleic acid structure named as G-quadruplex (G4) under physiological conditions. Stabilization of telomere G4 prevents telomere lengthening by the over-activated telomerase in cancer cells and thus represents a promising strategy in cancer therapy. Using molecular docking and molecular dynamics (MD) simulations, specific binding of the anionic phthalocyanine 3,4',4'',4'''-tetrasulfonic acid (APC) to the human hybrid (3 + 1) G4s was investigated at the atomic level. For the first time, APC was showed to prefer the end-stacking binding with the telomere hybrid type II (hybrid-II) G4 to the groove binding with the hybrid type I (hybrid-I) G4, with remarkable stabilizing effect besides much more favorable binding free energies. The groove binding that usually represents the most stable binding mode of double-stranded DNA and its ligand was found inferior in binding with hybrid G4, elucidating the selective binding mechanism of APC towards telomere G4. Non-covalent interaction analysis and decomposition of the binding free energy revealed that van der Waals interaction played a leading role in the binding of APC and telomere hybrid G4s, with the most energetically favorable model presenting most extensive van der Waals interactions through the end-stacking binding mode. These findings provide evidence to shed new light on designs of selective stabilizers targeting telomere G4.

RevDate: 2020-01-01

Epel ES (2020)

Can Childhood Adversity Affect Telomeres of the Next Generation? Possible Mechanisms, Implications, and Next-Generation Research.

The American journal of psychiatry, 177(1):7-9.

RevDate: 2019-12-31

Mahoney ER, Dumitrescu L, Seto M, et al (2019)

Telomere length associations with cognition depend on Alzheimer's disease biomarkers.

Alzheimer's & dementia (New York, N. Y.), 5:883-890 pii:S2352-8737(19)30089-7.

Introduction: While telomere shortening, a marker of cellular aging, may impact the progression of age-related neurodegenerative diseases, its association with cognition is unclear, particularly in the context of Alzheimer's disease (AD) pathology.

Methods: Telomere, cognitive, and CSF data from 482 participants in the AD Neuroimaging Initiative (148 cognitively normal, 283 mild cognitive impairment, 51 AD) was leveraged to assess telomere length associations with cognition (measured by memory and executive function) and interactions with CSF amyloid-β, tau, and APOE-ε4. Secondary analyses assessed brain volume and thickness outcomes.

Results: Longer telomeres at baseline were associated with faster executive function decline. Amyloid-β and tau interacted with telomere length on cognition, with longer telomeres related to faster decline among biomarker-positive individuals.

Discussion: Telomere associations with cognition shift with AD progression, with longer telomeres related to worse outcomes as pathology increases, highlighting the need for further investigation of telomere length along the AD neuropathological cascade.

RevDate: 2019-12-30

Gu D, Li J, Little J, et al (2020)

Associations between Serum Sex Hormone Concentrations and Telomere Length among U.S. Adults, 1999-2002.

The journal of nutrition, health & aging, 24(1):48-54.

BACKGROUND AND OBJECTIVES: Sex hormone concentrations and telomere length are age related responses of human body, while whether there is a direct relation between sex hormone and telomere length is uncertain. Therefore, we used the data of National Health and Nutrition Examination Survey (NHANES) to quantify their direct association.

RESEARCH DESIGN AND METHODS: A total of 710 women aged 35-60 years and 539 men aged 20-85 years were included from two cycles of the NHANES (1999-2002). Telomere length relative to standard reference DNA (T/S ratio) was measured using quantitative polymerase chain reaction method. Seven hormones in serum (5 in men and 2 in women) were assayed. Logistic regressions were used to calculate the odds ratios to evaluate the telomere length-sex hormones association.

RESULTS: Men with vigorous physical activity (71.1%) and without history of cardiovascular diseases, diabetes, and lipid-lowering drugs using tended to have a longer telomere length (all P-values < 0.05); while women with longer sedentary time, smaller pregnant or live birth, and with older ages of firth/last birth were likely with longer telomere length (all P-values < 0.05). After adjusted for potential confounders, only anti-Mullerian hormone was positively and stably associated with short leukocytes telomere length in men (OR: 1.098; 95% CI: 1.034, 1.165). We did not detect any significant association of short telomere length with sex hormones in men and women. Discussion and Implications: Serum anti-Mullerian hormone in men was positively and stably associated with telomere length. More large-scaled and well-designed prospective studies are warranted to reconfirm our conclusions.

RevDate: 2019-12-30

Shen G, Huang JY, Huang YQ, et al (2020)

The Relationship between Telomere Length and Cancer Mortality: Data from the 1999-2002 National Healthy and Nutrition Examination Survey (NHANES).

The journal of nutrition, health & aging, 24(1):9-15.

OBJECTIVES: The association between telomeres length (TL) and cancer mortality is uncertain. We tested the hypotheses that long TL are associated with reduced cancer mortality.

DESIGN: Prospective cohort study.

SETTING: the National Health and Nutrition Survey (NHANES, 1999-2002).

PARTICIPANTS: The analytic sample included adults (n = 7183) who had TL measurements.

MEASUREMENTS: DNA was obtained via blood samples. Telomere length was assessed using the quantitative polymerase chain reaction method.

RESULTS: During follow-up (0.08-12.7 person-years, median = 9.5 years), we observed 195 participants had cancer as causes of death. TL was negatively corelated with age, body mass index (BMI), systolic blood pressure (SBP), C-reactive protein (CRP), race, diabetes, hypertension, cardiovascular diseases (CVD) and cancer mortality, conversely, positively corelated with alcohol use, but not related to diastolic blood pressure (DBP) and smoking. Kaplan-Meier analysis revealed that TL was significantly associated with cancer mortality (log-rank, P <0.001).

CONCLUSIONS: Our study expands upon previous evidence of a relationship between TL and cancer mortality. TL may be a useful tool for evaluating risk of cancer mortality in American adults.

RevDate: 2019-12-28

Li M, K Liu (2019)

Protection of the shelterin complex is key for tethering telomeres to the nuclear envelope during meiotic prophase I.

Biology of reproduction pii:5688711 [Epub ahead of print].

RevDate: 2019-12-28

Kalstad AA, Tveit S, Myhre PL, et al (2019)

Leukocyte telomere length and serum polyunsaturated fatty acids, dietary habits, cardiovascular risk factors and features of myocardial infarction in elderly patients.

BMC geriatrics, 19(1):376 pii:10.1186/s12877-019-1383-9.

BACKGROUND: Telomeres are non-coding sequences at the end of eukaryote chromosomes, which in complex with associated proteins serve to protect subtelomeric DNA. Telomeres shorten with each cell division, are regarded as a biomarker for aging and have also been suggested to play a role in atherosclerosis and cardiovascular disease (CVD). The aim of the present study was to explore the associations between leukocyte telomere length and serum polyunsaturated fatty acids, diet, cardiovascular risk factors and features of myocardial infarction (MI) in elderly patients.

METHODS: The material is based upon the first 299 included patients in the OMEMI trial, where patients aged 70-82 years of age are randomized to receive omega-3 supplements or corn oil (placebo) after MI. Patients were included 2-8 weeks after the index MI. DNA was extracted from whole blood, and leukocyte telomere length (LTL) was analyzed by qPCR and reported as a number relative to a reference gene. Serum long chain polyunsaturated fatty acid (LCPUFA) content was analyzed by gas chromatography. Diet was evaluated with the validated SmartDiet food frequency questionnaire. Medical records, patient interviews and clinical examination provided previous medical history and anthropometric data. Non-parametric statistical tests were used.

RESULTS: Median (25, 75 percentile) LTL was 0.55 (0.42, 0.72). Patients had a median age of 75 years, 70.2% were male and 45.2% used omega-3 supplements. There was a weak, but significant correlation between LTL and linoleic acid (r = 0.139, p = 0.017), but not with other LCPUFAs. There was a trend towards longer telomeres with a healthier diet, but this did not reach statistical significance (p = 0.073). No associations were found between LTL and CVD risk factors or features of MI.

CONCLUSIONS: In our population of elderly with a recent myocardial infarction LTL was associated with linoleic acid concentrations, but not with other LCPUFAs. Patients with a healthy diet tended to have longer telomeres. The limited associations may be due to age and the narrow age-span in our population. Further studies, designed to detect longitudinal changes should be performed to explore the role of telomeres in cardiovascular aging.

TRIAL REGISTRATION: Clinical trials no. NCT01841944, registration date April 29, 2013.

RevDate: 2019-12-27

Normando P, Santos-Rebouças C, Leung C, et al (2019)

Variants in gene encoding for vitamin D binding protein were associated with leukocyte telomere length: The Pró-Saúde Study.

Nutrition (Burbank, Los Angeles County, Calif.), 71:110618 pii:S0899-9007(19)30201-1 [Epub ahead of print].

OBJECTIVE: The aim of this study was to investigate the association between single-nucleotide polymorphisms (SNPs) in vitamin D metabolic pathway genes, serum 25-hydroxyvitamin D [25(OH)D] concentrations, and leukocyte telomere length (LTL) in Brazilian adults.

METHODS: The study population comprised 461 participants (33-79 y of age; 51% women) from the Pró-Saúde Study, a cohort of civil servants at a university campus in Rio de Janeiro, Brazil. LTL, genotypes of vitamin D-related SNPs (rs12785878, rs10741657, rs6013897, and rs2282679), and serum 25(OH)D concentrations were determined cross-sectionally. Differences in age- and sex-adjusted LTL means by categories of genotypes and 25(OH)D serum concentrations were evaluated. LTL associations with genotypes and 25(OH)D were investigated using multiple linear regression models adjusted for sociodemographic characteristics and markers of health behavior.

RESULTS: Participants with CC genotype (rs2282679) had shorter age- and sex-adjusted mean LTL than those with AC and AA genotypes (mean ± SE: 0.51 ± 0.03, 0.58 ± 0.01 and 0.5 ± 0.01, respectively, P < 0.05). In adjusted analyses, the CC genotype (rs2282679) was inversely associated with LTL (β = -0.061; 95% confidence interval, -0.120 to -0.001). Other vitamin D-related SNPs and serum 25(OH)D concentrations were not associated with LTL.

CONCLUSIONS: Genetic variations in the gene encoding vitamin D binding protein (GC - rs2282679) were associated with LTL, suggesting an influence of vitamin D status on telomere length that may start early in life.

RevDate: 2019-12-27

Bonetti D, Rinaldi C, Vertemara J, et al (2019)

DNA binding modes influence Rap1 activity in the regulation of telomere length and MRX functions at DNA ends.

Nucleic acids research pii:5687828 [Epub ahead of print].

The cellular response to DNA double-strand breaks (DSBs) is initiated by the Mre11-Rad50-Xrs2 (MRX) complex that has structural and catalytic functions. MRX association at DSBs is counteracted by Rif2, which is known to interact with Rap1 that binds telomeric DNA through two tandem Myb-like domains. Whether and how Rap1 acts at DSBs is unknown. Here we show that Rif2 inhibits MRX association to DSBs in a manner dependent on Rap1, which binds to DSBs and promotes Rif2 association to them. Rap1 in turn can negatively regulate MRX function at DNA ends also independently of Rif2. In fact, a characterization of Rap1 mutant variants shows that Rap1 binding to DNA through both Myb-like domains results in formation of Rap1-DNA complexes that control MRX functions at both DSBs and telomeres primarily through Rif2. By contrast, Rap1 binding to DNA through a single Myb-like domain results in formation of high stoichiometry complexes that act at DNA ends mostly in a Rif2-independent manner. Altogether these findings indicate that the DNA binding modes of Rap1 influence its functional properties, thus highlighting the structural plasticity of this protein.

RevDate: 2019-12-27

Guachalla LM, Ju Z, Koziel R, et al (2019)

Correction for: Sod2 haploinsufficiency does not accelerate aging of telomere dysfunctional mice.

Aging, 11(23):11793-11794.

RevDate: 2019-12-24

Bhala S, Best AF, Giri N, et al (2019)

CNS manifestations in patients with telomere biology disorders.

Neurology. Genetics, 5(6):370 pii:NG2019010843.

Objective: We systematically evaluated CNS manifestations in patients with inherited telomere biology disorders (TBDs) to better understand the clinical and biological consequences of germline aberrations in telomere biology.

Methods: Forty-four participants with TBDs (31 dyskeratosis congenita, 12 Hoyeraal-Hreidarsson syndrome, and 1 Revesz syndrome) enrolled in an institutional review board-approved longitudinal cohort study underwent detailed clinical assessments, brain MRI, and genetic testing. Lymphocyte telomere length Z-scores were calculated to adjust for age.

Results: In this cohort, 25/44 (57%) patients with a TBD had at least 1 structural brain abnormality or variant, most commonly cerebellar hypoplasia (39%). Twenty-one patients (48%) had neurodevelopmental disorder or psychomotor abnormality. Twelve had psychiatric diagnoses, including depression and/or anxiety disorders. Other findings such as hypomyelination, prominent cisterna magna, and cavum septum pellucidum were more frequent than in the general population (p < 0.001). Shorter lymphocyte telomere length was associated with an increased number of MRI findings (p = 0.02) and neurodevelopmental abnormalities (p < 0.001). Patients with autosomal recessive or X-linked TBDs had more neurologic findings than those with autosomal dominant disease.

Conclusions: Structural brain abnormalities and variants are common in TBDs, as are neurologic and psychiatric symptoms. The connection between neurodevelopment and telomere biology warrants future study.

RevDate: 2019-12-24

Powell-Wiley TM, Gebreab SY, Claudel SE, et al (2020)

The relationship between neighborhood socioeconomic deprivation and telomere length: The 1999-2002 National Health and Nutrition Examination Survey.

SSM - population health, 10:100517 pii:100517.

Socioeconomically disadvantaged neighborhoods have been associated with poor health outcomes. Little is known about the biological mechanism by which deprived neighborhood conditions exert negative influences on health. Data from the 1999-2002 National Health and Nutrition Examination Surveys (NHANES) were used to assess the relationship between neighborhood deprivation index (NDI) and log-transformed leukocyte telomere length (LTL) via multilevel modeling to control for census tract level clustering. Models were constructed using tertiles of NDI (ref = low NDI). NDI was calculated using census tract level socioeconomic indicators from the 2000 U.S. Census. The sample (n = 5,106 adults) was 49.8% female and consisted of 82.9% non-Hispanic whites, 9.4% non-Hispanic blacks, and 7.6% Mexican Americans. Mean age was 45.8 years. Residents of neighborhoods with high NDI were younger, non-white, had lower educational attainment, and had a lower poverty to income ratio (all p < 0.0001). Neighborhood deprivation was inversely associated with LTL among individuals living in neighborhoods with medium NDI (β = -0.043, SE = 0.012, p = 0.0005) and high NDI (β = -0.039, SE = 0.013, p = 0.003). Among men, both medium (β = -0.042, SE = 0.015, p = 0.006) and high (β = -0.047, SE = 0.015, p = 0.001) NDI were associated with shorter LTL. Among women, only medium NDI (β = -0.020, SE = 0.016, p = 0.009) was associated with shorter LTL. After controlling for individual characteristics, including individual-level socioeconomic status, increasing neighborhood socioeconomic deprivation is associated with shorter LTL among a nationally representative sample of US adults. This suggests that telomere shortening may be a mechanism through which neighborhood deprivation results in poor health outcomes.

RevDate: 2019-12-23

Rej PH, HEAT Steering Committee, Gravlee CC, et al (2019)

Shortened telomere length is associated with unfair treatment attributed to race in African Americans living in Tallahassee, Florida.

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

OBJECTIVES: Experiences of interpersonal discrimination are pervasive stressors in the lives of African Americans. Increased discrimination stress may cause premature aging. Telomere length (TL) is a plastic genetic trait that is an emerging indicator of cellular health and aging. Short TL is a risk factor for the earlier onset of disease. TL shortens with age, a process that may be accelerated by psychosocial stress. Our study explores the relationship between TL and experiences of discrimination in the form of self-reported unfair treatment (UT).

METHODS: Using a qPCR-based method, we measured TL in DNA from saliva samples provided by 135 African American adults from Tallahassee, FL. We developed discrimination measures using a modified survey that explores nine social domains of self-reported unfair treatment experienced both directly and indirectly. We used multiple regression to examine associations between UT and TL.

RESULTS: We found that racial discrimination in the form of self-reported unfair treatment attributed to race (UT-Race-Self) is inversely associated with TL.

CONCLUSIONS: The significant association between increased UT-Race-Self and shorter telomeres supports the hypothesis that psychosocial stress stemming from racial discrimination may affect TL. The potential impact of discrimination on TL may contribute to premature biological aging and racial health inequalities seen in African Americans.

RevDate: 2019-12-21

Li W, Ma Y, Li Z, et al (2019)

Folic Acid Decreases Astrocyte Apoptosis by Preventing Oxidative Stress-Induced Telomere Attrition.

International journal of molecular sciences, 21(1): pii:ijms21010062.

Astrocytes are the most widely distributed cells in the brain, and astrocyte apoptosis may play an important role in the pathogenesis of neurodegenerative diseases. Folate is required for the normal development of the nervous system, but its effect on astrocyte apoptosis is unclear. In this study, we hypothesized that folic acid (the therapeutic form of folate) decreases astrocyte apoptosis by preventing oxidative stress-induced telomere attrition. Primary cultures of astrocytes were incubated for 12 days with various concentrations of folic acid (0-40 μmol/L), then cell proliferation, apoptosis, intracellular folate concentration, intracellular homocysteine (Hcy) concentration, intracellular reactive oxygen species (ROS) levels, telomeric DNA oxidative damage, and telomere length were determined. The results showed that folic acid deficiency decreased intracellular folate, cell proliferation, and telomere length, whereas it increased Hcy concentration, ROS levels, telomeric DNA oxidative damage, and apoptosis. In contrast, folic acid dose-dependently increased intracellular folate, cell proliferation, and telomere length but it decreased Hcy concentration, ROS levels, telomeric DNA oxidative damage, and apoptosis. In conclusion, folic acid inhibited apoptosis in astrocytes. The underlying mechanism for this protective effect may be that folic acid decreased oxidative stress and thereby prevented telomeric DNA oxidative damage and telomere attrition.

RevDate: 2019-12-20

Luo M, Teng X, Wang B, et al (2019)

Protection of telomeres 1 (POT1) of Pinus tabuliformis bound the telomere ssDNA.

Tree physiology pii:5681426 [Epub ahead of print].

Protection of telomeres 1 (POT1) is a telomeric protein that binds to the telomere single-stranded (ss) region. It plays an essential role in maintaining genomic stability in both plants and animals. In this study, we investigated the properties of POT1 in Pinus tabuliformis (PtPOT1) through electrophoretic mobility shift assay. PtPOT1 harbored affinity for telomeric ssDNA, and could bind plant- and mammalian-type ssDNA sequences. Notably, there were two oligonucleotide/oligosaccharide binding (OB) folds, and OB1 or OB2 alone, or both together, could bind ssDNA, which is significantly different from human POT1. Based on our data, we hypothesized that the two OB folds of PtPOT1 bound the same ssDNA. This model not only provides new insight into the ssDNA binding of PtPOT1, but also sheds light on the functional divergence of POT1 proteins in gymnosperms and humans.

RevDate: 2019-12-20

Groer M, Louis-Jacques A, Szalacha L, et al (2019)

Relationship of Anxiety, Inflammation, and Telomere Length in Postpartum Women: A Pilot Study.

Biological research for nursing [Epub ahead of print].

BACKGROUND: The postpartum period can be a vulnerable time during which many women are prone to mood disturbances. Since telomere length (TL) is known to be associated with dysphoric moods, inflammation, and stress in many populations, this study's objective was to assess the relationships among TL, dysphoric moods, stress, and inflammation during the postpartum period.

METHOD: This cross-sectional pilot study is a secondary analysis of data collected in a larger parent study of anti-thyroid peroxidase (TPO) enzyme antibody positive versus negative women. The parent study followed selected mothers every month for 6 postpartum months. From this parent study, a random sample of preserved peripheral blood mononuclear cells from 97 participants collected at 2-4 months postpartum were measured for TL. Data were available on the production of interleukin-6 (IL-6), an inflammatory cytokine, in stimulated ex vivo cultures for 59 of these women. Dysphoric moods and stress were measured. Pearson correlations and linear regressions were performed, controlling for postpartum thyroiditis status and age.

RESULTS: There were no statistically significant relationships between TL and demographic factors, stress, depression, or TPO status. There were significant negative correlations between TL and anxiety and a trend for a relationship between TL and IL-6 levels. IL-6 levels were significantly, positively associated with negative moods.

CONCLUSIONS: Higher anxiety scores and inflammation were associated with shorter TL. Inflammation was related to anxiety and other dysphoric moods and was marginally associated with shorter TLs.

RevDate: 2019-12-18

Peker Eyüboğlu İ, Yenmiş G, Bingöl EN, et al (2019)

Next-Generation Sequencing Identifies BRCA1 and/or BRCA2 Mutations in Women at High Hereditary Risk for Breast Cancer with Shorter Telomere Length.

Omics : a journal of integrative biology [Epub ahead of print].

Telomeres, and telomere length in particular, have broad significance for genome biology and thus are prime research targets for complex diseases such as cancers. In this context, BRCA1 and BRCA2 gene mutations have been implicated in relationship to telomere length, and breast cancer susceptibility. Yet, the linkages among human genetic variation and telomere length in persons with high hereditary cancer risk are inadequately mapped. We report here original findings in 113 unrelated women at high hereditary risk for breast cancer, who were characterized for the BRCA1 and BRCA2 mutations using next-generation sequencing. Thirty-one BRCA2 and 21 BRCA1 mutations were identified in 47 subjects (41.6%). The women with a mutation in BRCA1 and/or BRCA2 genes had, on average, 12% shorter telomere compared to women with no BRCA1 or BRCA2 mutation (p = 0.0139). Moreover, the association between telomere length and BRCA mutation status held up upon stratified analysis in those with or without a breast cancer diagnosis. We also indentified two rare mutations, c.536_537insT and c.10078A>G, and a novel mutation c.8680C>G in BRCA2 that was studied further by homology modeling of the DNA binding tower domain of BRCA2 and the structure of the protein. These data collectively lend evidence to the idea that BRCA1 and BRCA2 mutations play a role in telomere length in women at high hereditary risk for breast cancer. Further clinical and diagnostics discovery research on BRCA1 and BRCA2 variation, telomere length, and breast cancer mechanistic linkages are called for in larger study samples.

RevDate: 2019-12-18

Amir M, Ahamad S, Mohammad T, et al (2019)

Investigation of conformational dynamics of Tyr89Cys mutation in protection of telomeres 1 gene associated with familial melanoma.

Journal of biomolecular structure & dynamics [Epub ahead of print].

Protection of telomeres 1 (POT1) is a component of the shelterin complex which is crucial for the regulation of telomere length and maintenance. Many naturally occurring mutations in the POT1 gene have been found to be associated with cardiac angiosarcoma, glioma, familial melanoma, and chronic lymphocytic leukemia. In particular, Y89C is a naturally occurring mutation of POT1, responsible for familial melanoma, and the molecular basis of this mutation is unexplored. In this study, we have extensively analyzed the structure of WT and Y89C mutants of POT1 to see the change in the conformational dynamics, free energy landscape, molecular motions and configurational frustration using molecular dynamics (MD) and other bioinformatics approaches. Y89C mutation shows a significant in the backbone orientation, compactness, residual fluctuation, solvent accessibility, and hydrogen bonding, suggesting an overall destabilization of protein structure. In addition, essential dynamics, conformational, magnitude and direction of motion and frustration analysis further suggesting the structural loss in POT1 due to Y89C mutation. Free energy landscape analysis also indicates the presence of a single well-defined free-energy minima in case of WT compared to compare to multiple wells defined free energy minima observed in Y89C, clearly suggesting that this mutation leads to reduce the stability of POT1. This study possibly provides a valuable path to understand the molecular basis of Y89C-mediated development of cancer.

RevDate: 2019-12-17

Aschacher T, Wolf B, Aschacher O, et al (2019)

Long interspersed element-1 ribonucleoprotein particles protect telomeric ends in alternative lengthening of telomeres dependent cells.

Neoplasia (New York, N.Y.), 22(2):61-75 pii:S1476-5586(19)30296-9 [Epub ahead of print].

Malignant cells ensure telomere maintenance by the alternative lengthening of telomeres (ALT) in the absence of telomerase activity (TA). The retrotransposons "long interspersed nuclear element-1" (LINE-1, L1) are expressed in malignant cells and are primarily known to contribute to complex karyotypes. Here we demonstrate that LINE-1 ribonucleoprotein particles (L1-RNPs) expression is significantly higher in ALT+- versus in TA+-human glioma. Analyzing a role of L1-RNP in ALT, we show that L1-RNPs bind to telomeric repeat containing RNA (TERRA), which is critical for telomere stabilization and which is overexpressed in ALT+ cells. In turn, L1-RNP knockdown (KD) abrogated the nuclear retention of TERRA, resulted in increased telomeric DNA damage, decreased cell growth and reduced expression of ALT characteristics such as c-circles and PML-bodies. L1-RNP KD also decreased the expression of Shelterin- and the ALT-regulating protein Topoisomerase IIIα (TopoIIIα) indicating a more general role of L1-RNPs in supporting telomeric integrity in ALT. Our findings suggest an impact of L1-RNP on telomere stability in ALT+ dependent tumor cells. As L1-RNPs are rarely expressed in normal adult human tissue those elements might serve as a novel target for tumor ablative therapy.

RevDate: 2019-12-17

Eisenberg DTA, Rej PH, Duazo P, et al (2019)

Testing for paternal influences on offspring telomere length in a human cohort in the Philippines.

American journal of physical anthropology [Epub ahead of print].

OBJECTIVES: Telomeres, emerging biomarkers of aging, are comprised of DNA repeats located at chromosomal ends that shorten with cellular replication and age in most human tissues. In contrast, spermatocyte telomeres lengthen with age. These changes in telomere length (TL) appear to be heritable, as older paternal ages of conception (PAC) predict longer offspring TL. Mouse-model studies raise questions about the potential for effects of paternal experiences on human offspring TL, as they suggest that smoking, inflammation, DNA damage, and stressors all shorten sperm TL. Here, we examined whether factors from the paternal environment predict offspring TL as well as interact with PAC to predict offspring TL.

MATERIALS AND METHODS: Using data from the Philippines, we tested if smoking, psychosocial stressors, or shorter knee height (a measure of early life adversity) predict shorter offspring TL. We also tested if these interacted with PAC in predicting offspring TL.

RESULTS: While we did not find the predicted associations, we observed a trend toward fathers with shorter knee height having offspring with longer TL. In addition, we found that knee height interacted with PAC to predict offspring TL. Specifically, fathers with shorter knee heights showed a stronger positive effect of PAC on offspring TL.

DISCUSSION: While the reasons for these associations remain uncertain, shorter knee height is characteristic of earlier puberty. Since spermatocyte TL increases with the production of sperm, we speculate that individuals with earlier puberty, and its concomitant commencement of production of sperm, had more time to accumulate longer sperm telomeres.

RevDate: 2019-12-16

Powolny T, Bassin N, Crini N, et al (2019)

Corticosterone mediates telomere length in raptor chicks exposed to chemical mixture.

The Science of the total environment, 706:135083 pii:S0048-9697(19)35075-2 [Epub ahead of print].

Stressors experience early in life by animals may have carry over impacts on life-traits over the life cycle. Accelerated telomere attrition induced by stress during development and growth could play a role in such delayed effects. Among stressors, exposure to chemicals may modify telomere dynamic but, to date, the trends evidenced between exposure and telomere shortening remains inconsistent. Moreover, the role of corticosterone as a possible mediator of chemical impact on telomere is not yet clearly established. Here, we investigated in wild populations of Red kite whether nestling exposure to metals and pesticides was related to corticosterone concentrations in feathers and telomere length measured in 47 individuals. Lead and mercury concentrations in blood ranged from 2.3 to 59.0 µg L-1 and to 1.4 to 115.7 µg L-1, respectively, and were below the toxicity thresholds proposed for wildlife. Rodenticides were detected in 30% of the chicks. Corticosterone increased with mercury and lead in interaction, showing a synergistic effect of these 2 non-essential metals on this stress hormone. Telomere length was not linked to metals and/or rodenticide exposure while it was related negatively to corticosterone. The relationship between telomere and corticosterone was modulated by nestling's age, which suggests that the rate of telomere shortening is higher when corticosterone increases. Our findings propose an effect of low exposure of Red Kite nestlings to mercury and lead mixture to raise baseline corticosterone in feathers. The relationships established suggest the hypothesis that telomere attrition could be an indirect consequence of metal exposure mediated by corticosterone.

RevDate: 2019-12-16

Shvaiko LI, Bazyka KD, Sushko VO, et al (2019)

LUNG FUNCTION AND TELOMERE RELATIVE LENGTH IN CLEAN-UP WORKERS OF CHORNOBYL NPP ACCIDENT IN A REMOTE POST-ACCIDENT PERIOD.

Problemy radiatsiinoi medytsyny ta radiobiolohii, 24:503-515.

OBJECTIVE: The objective was to study the relationship between functional status of bronchopulmonary system and telomere length in clean-up workers of Chornobyl NPP accident in a remote post-accident period.

MATERIALS AND METHODS: A study was performed in 113 clean-up workers of Chornobyl NPP accident. Individual do- cumented doses of irradiation in clean-up workers ranged from 1,0 to 880 mSv (330.4 ± 317.7 (M ± SD)). The aver- age age of the Chornobyl NPP participants was (62.21 ± 6.99) years. A complex of functional pulmonary tests (spirometry, body plethysmography, examination of lung diffusion capacity) was performed. Relative telomere length (RTL) was analysed by flow-FISH.

RESULTS: There was a tendency to decrease the relative telomere length in clean-up workers with COPD I-II stage and COPD III-IV, compared with patients with the absence of bronchopulmonary diseases (RTL 15,2 ± 2,7). Significantly shorter telomeres were observed in patients with COPD who were exposed to radiation at a dose of more than 500 mSv (13.6 ± 2.5) compared with COPD patients who were exposed at a dose <10 mSv (RTL 15.3 ± 2.3). When analyzing the correlation relationships of the studied indicators, no significant associations were found with the relative telomere length. At this stage of the study no association of relative telomere length with age, body mass index, and functional criteria (FEV1 (l), intrathoracic pressure (ITGV), total lung capacity (TLC), diffusion lung capac- ity (DLCO)) was detected.

CONCLUSIONS: The analyzed telomere length relationship from liquidators of the Chernobyl found no direct associa- tion with indicators of lung function tests, however, showed a trend towards reducing the relative telomere length in clean-up workers who suffer from COPD and exposed to doses from 100 to 500 mSv and above 500 mSv.

RevDate: 2019-12-16

Bichet C, Bouwhuis S, Bauch C, et al (2019)

Telomere length is repeatable, shortens with age and reproductive success, and predicts remaining lifespan in a long-lived seabird.

Molecular ecology [Epub ahead of print].

Telomeres are protective caps at the end of chromosomes, and their length is positively correlated with individual health and lifespan across taxa. Longitudinal studies have provided mixed results regarding the within-individual repeatability of telomere length. While some studies suggest telomere length to be highly dynamic and sensitive to resource-demanding or stressful conditions, others suggest that between-individual differences are mostly present from birth and relatively little affected by the later environment. This dichotomy could arise from differences between species, but also from methodological issues. In our study, we used the highly reliable Terminal Restriction Fragment analysis method to measure telomeres over a 10-year period in adults of a long-lived seabird, the common tern (Sterna hirundo). Telomeres shortened with age within individuals. The individual repeatability of age-dependent telomere length was high (> 0.53), and independent of the measurement interval (i.e. 1 vs. 6 years). A small (R2 = 0.01), but significant part of the between-individual variation in telomere length was, however, explained by the number of fledglings produced in the previous year, while reproduction in years prior to the previous year had no effect. We confirmed that age-dependent telomere length predicted an individual's remaining lifespan. Overall, our study suggests that the majority of between-individual variation in adult telomere length is consistent across adult life, and that a smaller part of the variation can be explained by dynamic factors, such as reproduction.

RevDate: 2019-12-16

Fani L, Hilal S, Sedaghat S, et al (2019)

Telomere Length and the Risk of Alzheimer's Disease: The Rotterdam Study.

Journal of Alzheimer's disease : JAD pii:JAD190759 [Epub ahead of print].

There is a wide interest in biomarkers that capture the burden of detrimental factors as these accumulate with the passage of time, i.e., increasing age. Telomere length has received considerable attention as such a marker, because it is easily quantified and it may aid in disentangling the etiology of dementia or serve as predictive marker. We determined the association of telomere length with risk of Alzheimer's disease and all-cause dementia in a population-based setting. Within the Rotterdam Study, we performed quantitative PCR to measure mean leukocyte telomere length in blood. We determined the association of telomere length with risk of Alzheimer's disease until 2016, using Cox regression models. Of 1,961 participants (mean age 71.4±9.3 years, 57.1% women) with a median follow-up of 8.3 years, 237 individuals were diagnosed with Alzheimer's disease. We found a U-shaped association between telomere length and risk of Alzheimer's disease: compared to the middle tertile the adjusted hazard ratio was 1.59 (95% confidence interval (CI), 1.13-2.23) for the lowest tertile and 1.47 (1.03-2.10) for the highest tertile. Results were similarly U-shaped but slightly attenuated for all-cause dementia. In conclusion, shorter and longer telomere length are both associated with an increased risk of Alzheimer's disease in the general population.

RevDate: 2019-12-15

Bhattacharjee P, Das A, Giri AK, et al (2019)

Epigenetic regulations in alternative telomere lengthening: Understanding the mechanistic insight in arsenic-induced skin cancer patients.

The Science of the total environment pii:S0048-9697(19)35381-1 [Epub ahead of print].

Telomere integrity is considered to be one of the primary mechanisms during malignant transformation. Arsenic, a group 1 carcinogenic metalloid, has been reported to cause telomere lengthening in a telomerase-independent manner. Recent studies suggest a significant role for epigenetic modifications in regulating telomeric length and integrity. Here, we have explored the role of epigenetic deregulation in alternative lengthening of telomeres (ALT) in arsenic-exposed skin cancer tissues and corresponding non-tumor tissues. The relative telomere length (RTL) was analyzed by qRT-PCR using 2-ΔΔCt method. The subtelomeric methylation pattern of the four chromosomes (7q, 18p, 21q and XpYp) were analysed by Methylation Specific PCR (MSP) in 40 pairs of arsenic exposed skin cancer tissues and its corresponding control. The role of constitutive heterochromatin histone marks in the regulation of telomere length (TL) was analyzed by targeted ELISA. A 2-fold increase of relative telomere length in 85% of the arsenic-induced skin cancer tissues was observed. Among the four chromosomes, subtelomere of XpYp was found to be hypermethylated (p < 0.001) whereas 18p was hypomethylated (p < 0.01). Additionally, the level of H4K20me3, a heterochromatic mark was found to be significantly down-regulated (p < 0.0003), and inversely correlated with telomere length indicating loss of heterochromatinization of telomeric DNA. These observations highlight the novel role of epigenetic regulation in the maintenance of constitutive heterochromatin structure at telomere. Alteration in subtelomeric DNA methylation patterns and depletion of H4K20me3 might lead to loss of heterochromatinization resulting in arsenic-induced telomeric elongation. We provide novel data indicating possible alternative determinants of telomere elongation through epigenetic modifications during arsenic-induced skin carcinogenesis which could be used as early 'epimarkers' in the near future. The findings provide new insights about the mechanism of arsenic-induced carcinogenesis.

RevDate: 2019-12-14

Storti CB, de Oliveira RA, de Carvalho M, et al (2019)

Telomere-associated genes and telomeric lncRNAs are biomarker candidates in lung squamous cell carcinoma (LUSC).

Experimental and molecular pathology pii:S0014-4800(19)30746-4 [Epub ahead of print].

In the past decade, research efforts were made to identify molecular biomarkers useful as therapeutic targets in Non-Small Cell Lung Cancer (NSCLC), the most frequent type of lung carcinoma. NSCLC presents different histological subtypes being the most prevalent LUSC (Lung Squamous Cell Cancer) and LUAD (Lung Adenocarcinoma), and only a subset of LUAD patients' present tumors expressing known targetable genetic alterations. Telomeres and its components, including telomerase, the enzyme that replenishes telomeres, have been considered potential cancer biomarkers due to their crucial role in cell proliferation and genome stability. Our study aims to quantify expression changes affecting telomere-associated genes and ncRNAs associated with telomere regulation and maintenance in NSCLC. We first assessed the transcriptome (RNA-Seq) data of NSCLC patients from The Cancer Genome Atlas (TCGA) and then we tested the expression of telomere-associated genes and telomeric ncRNAs (TERC, telomerase RNA component, and TERRA, telomere repeat-containing RNA) in Brazilian NCSLC patient samples by quantitative RT-PCR, using matched normal adjacent tissue samples as the control. We also estimated the mean size of terminal restriction fragments (TRF) of some Brazilian NSCLC patients using telomeric Southern blot. The TCGA analysis identified alterations in the expression profile of TERT and telomere damage repair genes, mainly in the LUSC subtype. The study of Brazilian NSCLC samples by RT-qPCR showed that LUSC and LUAD express high amounts of TERT and that although the mean TRF size of tumor samples was shorter compared to normal cells, telomeres in NSCLC are probably maintained by telomerase. Also, the expression analysis of Brazilian NSCLC samples identified statistically significant alterations in the expression of genes involved with telomere damage repair, as well as in TERC and TERRA, mainly in the LUSC subtype. We, therefore, concluded that telomere maintenance genes are significantly deregulated in NSCLC, representing potential biomarkers in the LUSC subtype.

RevDate: 2019-12-14

Pan X, Chen Y, Biju B, et al (2019)

FANCM suppresses DNA replication stress at ALT telomeres by disrupting TERRA R-loops.

Scientific reports, 9(1):19110 pii:10.1038/s41598-019-55537-5.

Cancer cells maintain their telomeres by either re-activating telomerase or adopting the homologous recombination (HR)-based Alternative Lengthening of Telomere (ALT) pathway. Among the many prominent features of ALT cells, C-circles (CC) formation is considered to be the most specific and quantifiable biomarker of ALT. However, the molecular mechanism behind the initiation and maintenance of CC formation in ALT cells is still largely unknown. We reported previously that depletion of the FANCM complex (FANCM-FAAP24-MHF1&2) in ALT cells induced pronounced replication stress, which primarily takes place at their telomeres. Here, we characterized the changes in ALT associated phenotypes in cells deficient of the FANCM complex. We found that depletion of FAAP24 or FANCM, but not MHF1&2, induces a dramatic increase of CC formation. Most importantly, we identified multiple DNA damage response (DDR) and DNA repair pathways that stimulate the dramatic increase of CC formation in FANCM deficient cells, including the dissolvase complex (BLM-TOP3A-RMI1/2, or BTR), DNA damage checkpoint kinases (ATR and Chk1), HR proteins (BRCA2, PALB2, and Rad51), as well as proteins involved in Break-Induced Replication (BIR) (POLD1 and POLD3). In addition, FANCD2, another Fanconi Anemia (FA) protein, is also required for CC formation, likely through promoting the recruitment of BLM to the replication stressed ALT telomeres. Finally, we demonstrated that TERRA R-loops accumulate at telomeres in FANCM deficient ALT cells and downregulation of which attenuates the ALT-associated PML bodies (APBs), replication stress and CC formation. Taken together, our data suggest that FANCM prevents replisomes from stalling/collapsing at ALT telomeres by disrupting TERRA R-loops.

RevDate: 2019-12-14

Zhao S, Wang F, L Liu (2019)

Alternative Lengthening of Telomeres (ALT) in Tumors and Pluripotent Stem Cells.

Genes, 10(12): pii:genes10121030.

A telomere consists of repeated DNA sequences (TTAGGG)n as part of a nucleoprotein structure at the end of the linear chromosome, and their progressive shortening induces DNA damage response (DDR) that triggers cellular senescence. The telomere can be maintained by telomerase activity (TA) in the majority of cancer cells (particularly cancer stem cells) and pluripotent stem cells (PSCs), which exhibit unlimited self-proliferation. However, some cells, such as telomerase-deficient cancer cells, can add telomeric repeats by an alternative lengthening of the telomeres (ALT) pathway, showing telomere length heterogeneity. In this review, we focus on the mechanisms of the ALT pathway and potential clinical implications. We also discuss the characteristics of telomeres in PSCs, thereby shedding light on the therapeutic significance of telomere length regulation in age-related diseases and regenerative medicine.

RevDate: 2019-12-13

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

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

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

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

RevDate: 2019-12-13

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

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

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

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

RevDate: 2019-12-12

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

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

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

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

RevDate: 2019-12-12

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

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

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

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

RevDate: 2019-12-11

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

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

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

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

RevDate: 2019-12-11

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

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

BioTechniques [Epub ahead of print].

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

RevDate: 2019-12-11

Bateson M, Eisenberg DTA, D Nettle (2019)

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

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

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

RevDate: 2019-12-11

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

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

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

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

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

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

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

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

RevDate: 2019-12-11

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

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

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

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

RevDate: 2019-12-11

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

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

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

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

RevDate: 2019-12-11

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

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

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

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

RevDate: 2019-12-09

Markova DN, Christensen SM, E Betrán (2019)

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

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

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

RevDate: 2019-12-09

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

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

Communications biology, 2:451 pii:692.

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

RevDate: 2019-12-09

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

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

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

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

RevDate: 2019-12-09

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

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

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

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

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

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

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

RevDate: 2019-12-06

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

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

Chinese medical journal [Epub ahead of print].

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

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

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

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

RevDate: 2019-12-06

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

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

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

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

RevDate: 2019-12-06

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

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

Rejuvenation research [Epub ahead of print].

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

RevDate: 2019-12-05

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

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

Frontiers in psychiatry, 10:843.

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

RevDate: 2019-12-04

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

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

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

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

RevDate: 2019-12-04

Noguera JC, A Velando (2019)

Reduced telomere length in embryos exposed to predator cues.

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

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

RevDate: 2019-12-03

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

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

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

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

RevDate: 2019-12-02

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

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

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

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

RevDate: 2019-12-02

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

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

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

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

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

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

PROSPERO registration number CRD42019119785.

RevDate: 2019-11-30

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

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

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

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

RevDate: 2019-11-30

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

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

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

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

RevDate: 2019-11-29

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

Heritability of telomere length across three generations of Korean families.

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

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

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

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

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

RevDate: 2019-11-29

Zheng Q, Huang J, G Wang (2019)

Mitochondria, Telomeres and Telomerase Subunits.

Frontiers in cell and developmental biology, 7:274.

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

RevDate: 2019-11-29

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

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

Frontiers in immunology, 10:2531.

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

RevDate: 2019-11-27

Chatelain M, Drobniak SM, M Szulkin (2019)

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

Ecology letters [Epub ahead of print].

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

RevDate: 2019-11-27

Tucker LA (2019)

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

Oxidative medicine and cellular longevity, 2019:1574021.

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

RevDate: 2019-11-27

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

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

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

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

RevDate: 2019-11-26

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

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

Andrology [Epub ahead of print].

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

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

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

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

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

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

RevDate: 2019-11-26

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

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

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

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

RevDate: 2019-11-26

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

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

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

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

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

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

RevDate: 2019-11-25

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

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

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

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

RevDate: 2019-11-25

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

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

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

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

RevDate: 2019-11-25

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

Distinct telomere differences within a reproductively bimodal common lizard population.

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

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

RevDate: 2019-11-25

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

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

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

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

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Researcher

Robbins holds BS, MS, and PhD degrees in the life sciences. He served as a tenured faculty member in the Zoology and Biological Science departments at Michigan State University. He is currently exploring the intersection between genomics, microbial ecology, and biodiversity — an area that promises to transform our understanding of the biosphere.

Educator

Robbins has extensive experience in college-level education: At MSU he taught introductory biology, genetics, and population genetics. At JHU, he was an instructor for a special course on biological database design. At FHCRC, he team-taught a graduate-level course on the history of genetics. At Bellevue College he taught medical informatics.

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Robbins has been involved in science administration at both the federal and the institutional levels. At NSF he was a program officer for database activities in the life sciences, at DOE he was a program officer for information infrastructure in the human genome project. At the Fred Hutchinson Cancer Research Center, he served as a vice president for fifteen years.

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Robbins has been involved with information technology since writing his first Fortran program as a college student. At NSF he was the first program officer for database activities in the life sciences. At JHU he held an appointment in the CS department and served as director of the informatics core for the Genome Data Base. At the FHCRC he was VP for Information Technology.

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While still at Michigan State, Robbins started his first publishing venture, founding a small company that addressed the short-run publishing needs of instructors in very large undergraduate classes. For more than 20 years, Robbins has been operating The Electronic Scholarly Publishing Project, a web site dedicated to the digital publishing of critical works in science, especially classical genetics.

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Robbins is well-known for his speaking abilities and is often called upon to provide keynote or plenary addresses at international meetings. For example, in July, 2012, he gave a well-received keynote address at the Global Biodiversity Informatics Congress, sponsored by GBIF and held in Copenhagen. The slides from that talk can be seen HERE.

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Robbins is a skilled meeting facilitator. He prefers a participatory approach, with part of the meeting involving dynamic breakout groups, created by the participants in real time: (1) individuals propose breakout groups; (2) everyone signs up for one (or more) groups; (3) the groups with the most interested parties then meet, with reports from each group presented and discussed in a subsequent plenary session.

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Robbins has been engaged with photography and design since the 1960s, when he worked for a professional photography laboratory. He now prefers digital photography and tools for their precision and reproducibility. He designed his first web site more than 20 years ago and he personally designed and implemented this web site. He engages in graphic design as a hobby.

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

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