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Bibliography on: Telomeres

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ESP: PubMed Auto Bibliography 16 Jan 2019 at 01:44 Created: 

Telomeres

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

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

Citations The Papers (from PubMed®)

RevDate: 2019-01-14

Aguiar SS, Rosa TS, Sousa CV, et al (2019)

Influence of Body Fat on Oxidative Stress and Telomere Length of Master Athletes.

Journal of strength and conditioning research [Epub ahead of print].

Aguiar, SS, Rosa, TS, Sousa, CV, Santos, PA, Barbosa, LP, Deus, LA, Rosa, EC, Andrade, RV, and Simões, HG. Influence of body fat on oxidative stress and telomere length of master athletes. J Strength Cond Res XX(X): 000-000, 2019-The present investigation analyzed the role of body fat and training history on biological aging of master athletes by comparing and verifying the relationships between markers of adiposity, oxidative balance, and telomere length (TL) in middle-aged runners and untrained individuals. Master athletes (sprinters and endurance runners, n = 21; 51.62 ± 8.19 years) and untrained age-matched controls (n = 11; 45.41 ± 10.34 years) had blood samples collected for biochemical and biomolecular analyzes. Pro-oxidant and antioxidant measures as well as DNA extraction were performed using commercial kits. Relative TL (T/S) was determined in leukocytes through quantitative polymerase chain reaction analyses. Master athletes had lower body fat and longer TL than untrained controls (body fat: 12.21 ± 4.14% vs. 26.03 ± 4.29%; TL: 1.10 ± 0.84 vs. 0.56 ± 0.56 T/S; p < 0.05). Furthermore, master athletes also showed a better oxidative balance than untrained controls (p < 0.05). A negative correlation was observed between TL and body fat (r = -0.471; p = 0.007), and conicity index (r = -0.407; p = 0.021), catalase activity (r = -0.569; p = 0.001), and CAT/TBARS ratio (r = -0.463; p = 0.008) for the whole sample. In conclusion, master athletes have longer TL, better oxidative profile, and lower body fat than untrained individuals. Moreover, for this middle-aged sample, body fat was inversely correlated with both TL and markers of oxidative balance, demonstrating the key role of adiposity in biological aging.

RevDate: 2019-01-12

Newton CA, Oldham JM, Ley B, et al (2019)

Telomere Length and Genetic Variant Associations with Interstitial Lung Disease Progression and Survival.

The European respiratory journal pii:13993003.01641-2018 [Epub ahead of print].

Leukocyte telomere length (LTL), MUC5B rs35705950, and TOLLIP rs5743890 have been associated with idiopathic pulmonary fibrosis (IPF). In this observational cohort study, we assessed the associations between these genomic markers and outcomes of survival and rate of disease progression in patients with interstitial pneumonia with autoimmune features (IPAF, n=250) and connective tissue disease-associated interstitial lung disease (CTD-ILD, n=248). IPF (n=499) was used as a comparator.LTL of IPAF and CTD-ILD patients (mean age-adjusted log-transformed T/S of -0.05, [sd 0.29] and -0.04 [0.25], respectively) are longer than IPF (-0.17 [0.32]). For IPAF, LTL <10th percentile is associated with faster lung function decline compared to LTL ≥10th percentile (-6.43%/year versus -0.86%/year, p<0.0001) and worse transplant-free survival (HR 2.97 [95% CI 1.70-5.20], p=0.00014). The MUC5B rs35705950 minor allele frequency is greater for IPAF (23.2 [95% CI 18.8-28.2], p<0.0001) than controls and is associated with worse transplant-free IPAF survival (HR 1.92, [95% CI 1.18-3.13], p=0.0091). Rheumatoid arthritis-associated ILD (RA-ILD) has shorter LTL than non-RA CTD-ILD (-0.14 [sd 0.27] versus -0.01 [0.23], p=0.00055) and higher MUC5B minor allele frequency (34.6 [95% CI 24.4-46.3] versus 14.1 [9.8-20.0], p=0.00025). Neither LTL nor MUC5B are associated with transplant-free CTD-ILD survival.LTL and MUC5B minor allele frequency have different associations with lung function progression and survival for IPAF and CTD-ILD.

RevDate: 2019-01-11

Špoljarić AM, Rubelj I, M Huzak (2019)

Mathematical model and computer simulations of telomere loss.

Journal of theoretical biology pii:S0022-5193(19)30007-4 [Epub ahead of print].

The molecular mechanisms that control the limited number of human cell divisions has occupied researchers ever since its first description in 1961. There is evidence that this limited growth capacity, referred to as cellular or replicative senescence, is the basis for organismal ageing. Numerous studies point to the molecular mechanisms of telomere involvement in this phenomenon. A hallmark of cell senescence is high stochasticity where individual cells enter senescence in a completely random and stochastic fashion. Therefore, mathematical modelling and computational simulations of telomere dynamics are often used to explain this stochastic nature of cell ageing. Models published thus far were based on the molecular mechanisms of telomere biology and how they dictate the dynamics of cell culture proliferation. In the present work we propose an advanced model of telomere controlled cell senescence based on abrupt telomere shortening, thus explaining some important but thus far overlooked aspects of cell senescence. We test our theory by simulating the proliferative potential and two-sister experiment originally conducted by Smith and Whitney in 1980.

RevDate: 2019-01-11

Olbertova H, Plevova K, Stranska K, et al (2019)

Telomere dynamics in adult hematological malignancies.

Biomedical papers of the Medical Faculty of the University Palacky, Olomouc, Czechoslovakia [Epub ahead of print].

Telomeres are repetitive DNA sequences protecting physical ends of linear chromosomes against degradation and end-to-end chromosomal fusion. Telomeres shorten with each cell division, which regulates the cellular lifespan in somatic cells and limits their renewal capacity. Cancer cells are often able to overcome this physiological barrier and become immortal with unlimited replicative capacity. In this review, we present current knowledge on the role of telomeres in human aging with a focus on their behavior in hematological malignancies of adults. Associations of telomere length to age-related diseases and to the prevention of telomere shortening are also discussed.

RevDate: 2019-01-11

Horvath K, Eisenberg D, Stone R, et al (2019)

Paternal Age and Transgenerational Telomere Length Maintenance: A Simulation Model.

Scientific reports, 9(1):20 pii:10.1038/s41598-018-36923-x.

Telomere length (TL) in offspring is positively correlated with paternal age at the time of the offspring conception. The paternal-age-at-conception (PAC) effect on TL is puzzling, and its biological implication at the population level is unknown. Using a probabilistic model of transgenerational TL and population dynamics, we simulated the effect of PAC on TL in individuals over the course of 1,000 years. Findings suggest a key role for an isometric PAC midpoint (PACmp) in modulating TL across generations, such that offspring conceived by males younger than the isometric PACmp have comparatively short telomeres, while offspring conceived by males older than the isometric PACmp have comparatively long telomeres. We further show that when cancer incidence escalates, the average PAC drops below the isometric PACmp and transgenerational adaptation to cancer ensues through TL shortening. We propose that PAC serves to maintain an optimal TL across generations.

RevDate: 2019-01-10

Laberthonnière C, Magdinier F, JD Robin (2019)

Bring It to an End: Does Telomeres Size Matter?.

Cells, 8(1): pii:cells8010030.

Telomeres are unique nucleoprotein structures. Found at the edge of each chromosome, their main purpose is to mask DNA ends from the DNA-repair machinery by formation of protective loops. Through life and cell divisions, telomeres shorten and bring cells closer to either cell proliferation crisis or senescence. Beyond this mitotic clock role attributed to the need for telomere to be maintained over a critical length, the very tip of our DNA has been shown to impact transcription by position effect. TPE and a long-reach counterpart, TPE-OLD, are mechanisms recently described in human biology. Still in infancy, the mechanism of action of these processes and their respective genome wide impact remain to be resolved. In this review, we will discuss recent findings on telomere dynamics, TPE, TPE-OLD, and lessons learnt from model organisms.

RevDate: 2019-01-09

Tannous J, Mwangi B, Hasan KM, et al (2019)

Measures of possible allostatic load in comorbid cocaine and alcohol use disorder: Brain white matter integrity, telomere length, and anti-saccade performance.

PloS one, 14(1):e0199729 pii:PONE-D-18-17159.

Chronic cocaine and alcohol use impart significant stress on biological and cognitive systems, resulting in changes consistent with an allostatic load model of neurocognitive impairment. The present study measured potential markers of allostatic load in individuals with comorbid cocaine/alcohol use disorders (CUD/AUD) and control subjects. Measures of brain white matter (WM), telomere length, and impulsivity/attentional bias were obtained. WM (CUD/AUD only) was indexed by diffusion tensor imaging metrics, including radial diffusivity (RD) and fractional anisotropy (FA). Telomere length was indexed by the telomere to single copy gene (T/S) ratio. Impulsivity and attentional bias to drug cues were measured via eye-tracking, and were also modeled using the Hierarchical Diffusion Drift Model (HDDM). Average whole-brain RD and FA were associated with years of cocaine use (R2 = 0.56 and 0.51, both p < .005) but not years of alcohol use. CUD/AUD subjects showed more anti-saccade errors (p < .01), greater attentional bias scores (p < .001), and higher HDDM drift rates on cocaine-cue trials (Bayesian probability CUD/AUD > control = p > 0.99). Telomere length was shorter in CUD/AUD, but the difference was not statistically significant. Within the CUD/AUD group, exploratory regression using an elastic-net model determined that more years of cocaine use, older age, larger HDDM drift rate differences and shorter telomere length were all predictive of WM as measured by RD (model R2 = 0.79). Collectively, the results provide modest support linking CUD/AUD to putative markers of allostatic load.

RevDate: 2019-01-09

Molina-Molina M (2019)

Telomere Shortening Behind the Harm of Immunosuppressive Therapy In Idiopathic Pulmonary Fibrosis.

American journal of respiratory and critical care medicine [Epub ahead of print].

RevDate: 2019-01-09

Lu S, Zhong J, Wu M, et al (2019)

Genetic analysis of the relation of telomere length-related gene (RTEL1) and coronary heart disease risk.

Molecular genetics & genomic medicine [Epub ahead of print].

BACKGROUND: Regulator of telomere elongation helicase 1 (RTEL1), a telomere length-related gene, is closely linked to cancer and age-related diseases. The aim of this study was to investigate the association between genetic polymorphisms in the RTEL1 gene and coronary heart disease (CHD) risk.

METHODS: In this case-control study, which includes samples from 596 CHD patients and 603 healthy controls, five SNPs in RTEL1 were selected. The genotypes were studied using the Agena MassARRAY platform, and the statistical analyses were performed using the chi-square and Fisher's exact tests, genetic model analysis, and haplotype analysis.

RESULTS: In the allele model, using the chi-square test, we found that the patients with the "G" allele of rs6010620 and the "C" allele of rs4809324 in the RTEL1 gene showed a decreased risk of CHD once the results were adjusted for age and gender. In the genetic model, logistic regression analyses revealed that the rs6010620 polymorphism conferred a decreased risk of CHD in the codominant model (OR = 0.52, 95% CI: 0.31-0.88, p = 0.007 for the "G/G" genotype) and the recessive model (OR = 0.49, 95% CI: 0.30-0.80, p = 0.004 for the "G/G" genotype). In addition, the haplotype "Grs6010620 Trs6010621 Trs4809324 " of RTEL1 was associated with a 0.03-fold decreased risk of CHD once the results were adjusted for age and gender (OR = 0.03, 95% CI: 0.01-0.12, p < 0.001).

CONCLUSION: Our findings have demonstrated that the genetic variants of RTEL1 may have a protective role against CHD risk.

RevDate: 2019-01-08

Nomikos NN, Nikolaidis PT, Sousa CV, et al (2018)

Exercise, Telomeres, and Cancer: "The Exercise-Telomere Hypothesis".

Frontiers in physiology, 9:1798.

Telomeres are genomic complex at the end of chromosomes that protects the DNA and telomere length (TL) is related to several age-related diseases, lifespan, and cancer. On the other hand, cancer is a multifactorial disease that is responsible for reduce the quality of life and kills millions of people every year. Both, shorter TL and cancer are related and could be treated or prevented depending of the lifestyle. In this review we discuss the possible role of exercise in the relationship between shorter telomeres, telomerase activity, and cancer. In summary, there is evidence that exercise leads to less telomere attrition and exercise also may diminish the risk of cancer, these two outcomes are possible intermediated by a reduction in oxidative stress, and chronic inflammation. Although, there is evidence that shorter TL are associated with cancer, the possible mechanisms that one may lead to the other remains to be clarified. We assume that humans under cancer treatment may suffer a great decrease in quality of life, which may increase sedentary behavior and lead to increased telomere attrition. And those humans with already shorter TL likely lived under a poor lifestyle and might have an increased risk to have cancer.

RevDate: 2019-01-07

Kim N, Sung JY, Park JY, et al (2018)

Association between internet gaming addiction and leukocyte telomere length in Korean male adolescents.

Social science & medicine (1982), 222:84-90 pii:S0277-9536(18)30709-3 [Epub ahead of print].

Internet gaming addiction (IGA) has been associated with many negative health outcomes, especially for youth. In particular, the potential association between IGA and leukocyte telomere length (LTL) has yet to be examined. In this study we compared LTL in Korean male adolescents with and without IGA and examined the association between LTL and autonomic functions. Specifically, plasma catecholamine, serum cortisol, and psychological stress levels were measured as autonomic functions. Data were collected using participant blood samples analyzed for LTL, catecholamine, and cortisol levels and a set of questionnaires to assess IGA and psychological stress levels of the participants. The LTL measurements were made using a qPCR-based technique, and the relative LTL was calculated as the telomere/single copy (T/S) ratio. T/S ratio was significantly shorter in the IGA group than in the non-IGA group (150.43 ± 6.20 and 187.23 ± 6.42, respectively; p < .001) after adjusting for age. In a univariate regression analysis, age, daily Internet gaming time, IGA score, and catecholamine level (epinephrine and norepinephrine) were significantly associated with T/S ratio. However, duration of Internet gaming exposure, dopamine, cortisol, and psychological stress levels were not found to be associated with T/S ratio. In the final multiple linear regression model, age, daily Internet gaming time, and epinephrine level showed statistically significant relationships with T/S ratio. Our results indicate that in addition to age, involvement in excessive Internet gaming may induce LTL shortening in male adolescents, which may be partially attributable to changes in autonomic function such as catecholamine level. These findings further understanding of the health effects of IGA and highlight the need for screening and intervention strategies for male adolescents with IGA.

RevDate: 2019-01-07

Igari R, Davy P, Sato H, et al (2018)

Cognitive impairment, brain ischemia and shorter telomeres are predictors of mortality in the Japanese elderly: A 13-year prospective community-based study.

Journal of the neurological sciences, 397:129-134 pii:S0022-510X(18)30533-1 [Epub ahead of print].

OBJECTIVE: To examine whether cognitive impairment, deep white matter hyperintensity (DWMH) on brain MRI, and shorter telomere length would be predictors of mortality in community-dwelling Japanese elderly.

METHODS: We followed 259 individuals (74% of all the residents at age 70) from age 70 to 83 years. The mean observation period was 133 ± 34 months. The key clinical characteristics examined included DWMH on brain MRI and cognitive function. Telomere length was also measured in 81 subjects. Both univariate and multivariate analyses were performed.

RESULTS: Of the 259 subjects, 69 subjects (30 men, 39 women; 26.6%) died during the follow-up period. Cognitive impairment, smoking habits, diabetes mellitus, and moderate to severe DWMH were significant predictors of total mortality in univariate analysis. However, only cognitive impairment and moderate to severe DWMH remained as significant independent predictors of death in multivariate analysis. The rate of mortality increased with additional number of risk factors (cognitive impairment and DWMH). The total mortality of subjects with both cognitive impairment and DWMH was 71.4%. The median telomere length was 7.8 kb in the deceased and 8.2 kb in the living subjects. The deceased subjects had significantly shorter telomere length (P = .0025) than the living subjects. Telomere length with moderate to severe DWMH was higher than without moderate to severe DWMH on brain MRI (P = .017).

CONCLUSIONS: The present study revealed that cognitive impairment, DWMH, and shorter telomere length were significant predictors of total mortality in the community-dwelling Japanese elderly. Furthermore, the combination of cognitive impairment and DWMH increased the mortality rate, as compared with a single risk factor. It is also clarified that a significant difference was present in telomere length by severity of DWMH.

RevDate: 2019-01-07

Mensà E, Latini S, Ramini D, et al (2019)

The telomere world and aging: analytical challenges and future perspectives.

Ageing research reviews pii:S1568-1637(18)30234-4 [Epub ahead of print].

Telomeres, the terminal nucleoprotein structures of eukaryotic chromosomes, play pleiotropic functions in cellular and organismal aging. Telomere length (TL) varies throughout life due to the influence of genetic factors and to a complex balancing between "shortening" and "elongation" signals. Telomerase, the only enzyme that can elongate a telomeric DNA chain, and telomeric repeat-containing RNA (TERRA), a long non-coding RNA involved in looping maintenance, play key roles in TL during life. Despite recent advances in the knowledge of TL, TERRA and telomerase activity (TA) biology and their measurement techniques, the experimental and theoretical issues involved raise a number of problems that should carefully be considered by researchers approaching the "telomere world". The increasing use of such parameters - hailed as promising clinically relevant biomarkers - has failed to be paralleled by the development of automated and standardized measurement technology. Consequently, associating given TL values to specific pathological conditions involves on the one hand technological issues and on the other clinical-biological issues related to the planning of clinically relevant association studies. Addressing these issues would help avoid major biases in association studies involving TL and a number of outcomes, especially those focusing on psychological and bio-behavioral variables. The main challenge in telomere research is the development of accurate and reliable measurement methods to achieve simple and sensitive TL, TERRA, and TA detection. The discovery of the localization of telomeres and TERRA in cellular and extracellular compartments had added an additional layer of complexity to the measurement of these age-related biomarkers. Since combined analysis of TL, TERRA and TA may well provide more exhaustive clinical information than a single parameter, we feel it is important for researchers in the various fields to become familiar with their most common measurement techniques and to be aware of the respective merits and drawbacks of these approaches.

RevDate: 2019-01-07

Behrens YL, Thomay K, Hagedorn M, et al (2019)

Jumping translocations: Short telomeres or pathogenic TP53 variants as underlying mechanism in acute myeloid leukemia and myelodysplastic syndrome?.

Genes, chromosomes & cancer [Epub ahead of print].

Chromosomal rearrangements involving one donor chromosome and two or more recipient chromosomes are called jumping translocations. To date only few cases of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) with jumping translocations have been described and the underlying mechanisms remain unclear. Here, we analyzed 11 AML and 5 MDS cases with jumping translocations. The cases were analyzed by karyotyping, FISH, telomere length measurement, and next-generation sequencing with an AML/MDS gene panel. Cases with jumping translocations showed significantly (P < .01) shorter telomeres in comparison to healthy age-matched controls. Additional neo-telomeres were found in two cases. In total, eight cases showed recipient chromosomes with a breakpoint in the centromeric region all of them harboring a pathogenic variant in the TP53 gene (n = 6) and/or a loss of TP53 (n = 5). By contrast, no pathogenic variant or loss of TP53 was identified in the six cases showing recipient chromosomes with a breakpoint in the telomeric region. In conclusion, our results divide the cohort of AML and MDS cases with jumping translocations into two groups: the first group with a telomeric breakpoint of the recipient chromosome is characterized by short telomeres and a possibly telomere-based mechanism of chromosomal instability formation. The second group with a centromeric breakpoint of the recipient chromosome is defined by mutation and/or loss of TP53. We, therefore, assume that both critically short telomeres as well as pathogenic variants of TP53 influence jumping translocation formation.

RevDate: 2019-01-05

Coluzzi E, Leone S, A Sgura (2019)

Oxidative Stress Induces Telomere Dysfunction and Senescence by Replication Fork Arrest.

Cells, 8(1): pii:cells8010019.

Oxidative DNA damage, particularly 8-oxoguanine, represents the most frequent DNA damage in human cells, especially at the telomeric level. The presence of oxidative lesions in the DNA can hinder the replication fork and is able to activate the DNA damage response. In this study, we wanted to understand the mechanisms by which oxidative damage causes telomere dysfunction and senescence in human primary fibroblasts. After acute oxidative stress at telomeres, our data demonstrated a reduction in TRF1 and TRF2, which are involved in proper telomere replication and T-loop formation, respectively. Furthermore, we observed a higher level of γH2AX with respect to 53BP1 at telomeres, suggesting a telomeric replication fork stall rather than double-strand breaks. To confirm this finding, we studied the replication of telomeres by Chromosome Orientation-FISH (CO-FISH). The data obtained show an increase in unreplicated telomeres after hydrogen peroxide treatment, corroborating the idea that the presence of 8-oxoG can induce replication fork arrest at telomeres. Lastly, we analyzed the H3K9me3 histone mark after oxidative stress at telomeres, and our results showed an increase of this marker, most likely inducing the heterochromatinization of telomeres. These results suggest that 8-oxoG is fundamental in oxidative stress-induced telomeric damage, principally causing replication fork arrest.

RevDate: 2019-01-04

Wang Z, Zhang Z, Guo Y, et al (2018)

Shorter Telomere Length Is Associated with Increased Breast Cancer Risk in a Chinese Han Population: A Case-Control Analysis.

Journal of breast cancer, 21(4):391-398.

Purpose: The aim of this study was to investigate the association of telomere length with breast cancer risk. We simultaneously explored the association between telomerase reverse transcriptase gene polymorphisms and telomere length.

Methods: We used real-time quantitative polymerase chain reaction to measure relative telomere length (RTL) in genomic DNA extracted from peripheral blood from 183 breast cancer cases and 191 healthy controls. Genotyping was performed using the Sequenom MassARRAY platform.

Results: Our results show that breast cancer patients had significantly shorter RTLs than control subjects (p<0.05). When the RTLs were categorized into tertiles, we found that the lowest RTL was significantly associated with increased breast cancer risk compared with the highest RTL (odds ratio [OR], 2.33; 95% confidence interval [CI], 1.40-3.90; p=0.001). Subgroup analyses indicated that risk of breast cancer was also significantly increased in the lowest RTL compared with the highest RTL in age >40 years (OR, 2.41; 95% CI, 1.31-4.43; p=0.005), body mass index ≤24 kg/m2 (OR, 2.81; 95% CI, 1.55-5.10; p=0.001), and postmenopausal women (OR, 3.94; 95% CI, 1.63-9.51; p=0.002), respectively. In addition, individuals with the AA genotype of rs2853677 have longer telomeres than those of breast cancer patients with the AG genotype (p=0.011).

Conclusion: Our results suggest that shorter RTL was associated with an increased risk of breast cancer. An association was found between the AA genotype of rs2853677 and longer RTLs in the case group. Functional studies are warranted to validate this association and further investigate our findings.

RevDate: 2019-01-02

Santana VP, Miranda-Furtado CL, Pedroso DCC, et al (2019)

The relationship among sperm global DNA methylation, telomere length, and DNA fragmentation in varicocele: a cross-sectional study of 20 cases.

Systems biology in reproductive medicine [Epub ahead of print].

Varicocele pathophysiology is related to increased oxidative stress, which might result in loss sperm DNA integrity as well as in genomic instability. Sperm telomere shortening and loss of global DNA methylation are the main features of genomic instability, leading to cell senescence and death, whereas sperm DNA fragmentation (SDF) characterizes the loss of chromatin integrity. We hypothesize that sperm genomic stability and DNA integrity is reduced in infertile men with moderate and large-sized varicoceles, thus being candidate markers of sperm quality in varicocele-related infertility. Here, we assessed the sperm global DNA methylation, telomere length, and SDF in men with and without clinically palpable varicoceles. While the rates of SDF and telomere length were not statistically different between varicocele patients and controls, global sperm DNA methylation seems to be lower in men with varicocele (49.7% ± 20.7%) than controls (64.7% ± 17.1%). A negative correlation between SDF and sperm motility and a positive correlation between sperm morphology and telomere length were observed. Our results suggest that varicocele may result in genomic instability, in particular, global DNA hypomethylation. However, a large sample size may confirm these findings. The understanding of the molecular mechanisms involved in the pathophysiology of varicocele-related infertility may help to better select candidates for varicocele repair.

RevDate: 2018-12-31

Barraclough JY, Skilton MR, Garden FL, et al (2018)

Early and late childhood telomere length predict subclinical atherosclerosis at age 14 yrs. - The CardioCAPS study.

International journal of cardiology pii:S0167-5273(18)35114-3 [Epub ahead of print].

INTRODUCTION: Carotid Intima Media Thickness (CIMT) is a marker of subclinical atherosclerosis, associated with cardiovascular risk in adults. Telomere length (TL) is a marker of cellular ageing. We sought to determine whether telomere length in early childhood and/or at 14-years is associated with CIMT in adolescence, in a community-based cohort study.

METHODS: 118 children had TL measured at mean age 3.6-years and 165 children had TL and CIMT, measured at 14-years, from the community-based Childhood Asthma Prevention Study.

RESULTS: TL in early childhood was significantly inversely associated with CIMT at 14 years, p = 0.04. TL in teenage life was also significantly inversely associated with CIMT at 14 years, p = 0.03. This latter association was no longer significant, however, after adjusting for early life TL.

CONCLUSION: TL measured in early childhood and adolescence is significantly associated with CIMT at 14-years, suggesting that telomere length is a biological marker or even early determinant of late cardiovascular risk.

RevDate: 2018-12-31

Piplani S, Alemao NN, Prabhu M, et al (2018)

Correlation of the telomere length with type 2 diabetes mellitus in patients with ischemic heart disease.

Indian heart journal, 70 Suppl 3:S173-S176.

OBJECTIVE: The study aimed to explore the relationship of the telomere length with type 2 diabetes mellitus (DM) among patients with ischemic heart disease (IHD).

METHOD: This 2-year cross-sectional study included 130 male patients diagnosed with IHD through echocardiography and coronary angiography, wherein consecutive IHD patients with type 2 DM (65) and without type 2 DM (65) were selected. Baseline characteristics including age, gender, body mass index, and blood pressure were recorded. Laboratory investigations such as random blood sugar (RBS), fasting lipid profile, serum creatinine, and serum urea levels were measured. Quantitative real-time polymerase chain reaction was used for the measurement of the telomere length. The logistic regression analysis was used to predict the relationship of the telomere length with age and type 2 DM among patients with IHD.

RESULTS: All the patients in the study were men, and most of them (diabetics = 22; nondiabetics = 20) were aged between 56 and 65 years. Age (p = 0.003), telomere length (p < 0.001), RBS (p < 0.001), serum creatinine (p < 0013), and serum urea (p < 0.04) were significantly higher in the diabetic subset than in the nondiabetic subset. No significant relationship was observed between age and the telomere length (p = 0.813); however, the mean telomere length was significantly high among the patients with type 2 DM than those without type 2 DM (p = 0.005). The logistic regression analysis showed that the telomere shortening (p = 0.00019) and RBS (p < 0.0001) were the significant risk factors for type 2 DM in patients with IHD.

CONCLUSION: The telomere shortening was significantly correlated with type 2 DM among the patients with IHD. However, multicentric studies with larger samples are required to validate the current observation.

RevDate: 2018-12-28

Eastwood JR, Hall ML, Teunissen N, et al (2018)

Early-life telomere length predicts lifespan and lifetime reproductive success in a wild bird.

Molecular ecology [Epub ahead of print].

Poor conditions during early development can initiate trade-offs that favour current survival at the expense of somatic maintenance and subsequently, future reproduction. However, the mechanisms that link early and late life-history are largely unknown. Recently it has been suggested that telomeres, the nucleoprotein structures at the terminal end of chromosomes, could link early-life conditions to lifespan and fitness. In wild purple-crowned fairy-wrens, we combined measurements of nestling telomere length (TL) with detailed life-history data to investigate whether early-life TL predicts fitness prospects. Our study differs from previous studies in the completeness of our fitness estimates in a highly philopatric population. The association between TL and survival was age-dependent with early-life TL having a positive effect on lifespan only among individuals that survived their first year. Early-life TL was not associated with the probability or age of gaining a breeding position. Interestingly, early-life TL was positively related to breeding duration, contribution to population growth and lifetime reproductive success because of their association with lifespan. Thus, early-life TL, which reflects growth, accumulated early-life stress and inherited TL, predicted fitness in birds that reached adulthood but not noticeably among fledglings. These findings suggest that a lack of investment in somatic maintenance during development particularly affects late life performance. This study demonstrates that factors in early-life are related to fitness prospects through lifespan, and suggests that the study of telomeres may provide insight into the underlying physiological mechanisms linking early- and late-life performance and trade-offs across a lifetime. This article is protected by copyright. All rights reserved.

RevDate: 2018-12-27

Liddiard K, Ruis B, Kan Y, et al (2018)

DNA Ligase 1 is an essential mediator of sister chromatid telomere fusions in G2 cell cycle phase.

Nucleic acids research pii:5257352 [Epub ahead of print].

Fusion of critically short or damaged telomeres is associated with the genomic rearrangements that support malignant transformation. We have demonstrated the fundamental contribution of DNA ligase 4-dependent classical non-homologous end-joining to long-range inter-chromosomal telomere fusions. In contrast, localized genomic recombinations initiated by sister chromatid fusion are predominantly mediated by alternative non-homologous end-joining activity that may employ either DNA ligase 3 or DNA ligase 1. In this study, we sought to discriminate the relative involvement of these ligases in sister chromatid telomere fusion through a precise genetic dissociation of functional activity. We have resolved an essential and non-redundant role for DNA ligase 1 in the fusion of sister chromatids bearing targeted double strand DNA breaks that is entirely uncoupled from its requisite engagement in DNA replication. Importantly, this fusogenic repair occurs in cells fully proficient for non-homologous end-joining and is not compensated by DNA ligases 3 or 4. The dual functions of DNA ligase 1 in replication and non-homologous end-joining uniquely position and capacitate this ligase for DNA repair at stalled replication forks, facilitating mitotic progression.

RevDate: 2018-12-27

Bosquet Enlow M, Sideridis G, Bollati V, et al (2018)

Maternal cortisol output in pregnancy and newborn telomere length: Evidence for sex-specific effects.

Psychoneuroendocrinology, 102:225-235 pii:S0306-4530(18)30747-9 [Epub ahead of print].

Newborn telomere length is a potential biomarker of the effects of maternal-fetal processes on offspring long-term health. A number of maternal psychosocial and environmental factors in pregnancy (e.g., stress, health, socioeconomic status) have been associated with shortened telomere length at birth. The physiological mechanisms responsible for potential effects of maternal factors on newborn telomere length have yet to be identified. Indirect evidence suggests that disruptions in maternal hypothalamic-pituitary-adrenal (HPA) axis functioning in pregnancy may be involved. Studies are needed that test whether maternal HPA axis functioning in pregnancy is associated with newborn telomere length. This study examined whether maternal HPA axis functioning across pregnancy, reflected in hair cortisol collected within one week after delivery, predicted newborn telomere length assessed from leukocyte cord blood collected at birth among 93 sociodemographically diverse mother-infant dyads. We further tested whether associations between maternal hair cortisol and newborn telomere length differed by infant sex, given documented sex differences in prenatal environmental exposure effects on offspring health, patterns of cortisol exposure during gestation, and telomere biology across the lifespan. In a multi-group structural equation modeling analysis that accounted for cortisol exposures across trimesters, maternal cortisol levels in pregnancy were not associated with newborn telomere length in the sample as a whole. However, significant sex differences emerged, with a significant positive association among females and a lack of a significant association among males. In addition, analyses revealed that cortisol levels were higher across trimesters among mothers of male infants than mothers of female infants. The results suggest that functioning of the maternal HPA axis in pregnancy may differ by fetal sex and have sex-specific effects on newborn telomere biology. These findings have implications for understanding the mechanisms by which maternal psychosocial and environmental exposures influence newborn telomere length and for elucidating mechanisms contributing to sex disparities in health.

RevDate: 2018-12-27

Alves-Paiva RM, Gutierrez-Rodrigues F, Pereira-Martins DA, et al (2018)

Short telomere length in peripheral blood leukocytes in head and neck cancer: Findings in a Brazilian cohort.

Head & neck [Epub ahead of print].

BACKGROUND: Telomeres are specialized DNA structures that are critical to maintain cell homeostasis and to avoid genomic instability. Epidemiological studies have examined the association between leukocyte telomere length (LTL) and risk of cancers, but the findings remain conflicting.

METHODS: Mean LTL was measured by quantitative PCR in 97 patients with head and neck cancer (HNC) and 262 healthy controls. The association between LTL and patients' clinical status, such as smoke, alcoholism, and overall survival, were also evaluated.

RESULTS: The age-adjusted LTL was significantly shorter in patients with HNC in comparison to healthy controls (P = .0003). Patients with shortest LTL had an increased risk to develop HNC (P < 0.0001). No significant correlation was observed between LTL and patients' clinical features and personal habits.

CONCLUSIONS: Our data support the hypothesis that LTL is a risk factor for HNC. The use of LTL as a biomarker can help physicians to identify high-risk individuals for HNC.

RevDate: 2018-12-25

Chen CF, Sung TL, Chen LY, et al (2018)

Telomere maintenance during anterior regeneration and aging in the freshwater annelid Aeolosoma viride.

Scientific reports, 8(1):18078 pii:10.1038/s41598-018-36396-y.

Aging is a complex process involving declines in various cellular and physical functionalities, including regenerative ability. Telomere maintenance is thought to be necessary for regeneration, and telomere attrition is one mechanism that contributes to aging. However, it is unclear if aging affects regeneration owing to deterioration of telomeric maintenance. We introduce Aeolosoma viride-a freshwater annelid with strong regenerative abilities-as a new model for studying the effects of aging on telomere functions and regeneration. We show that the anterior regenerative ability of A. viride declines with age. We characterized the A. viride telomere sequence as being composed of TTAGGG repeats and identifyied the telomerase gene Avi-tert. In adult A. viride, telomerase was constantly active and telomere lengths were similar among different body sections and stably maintained with age. Notably, we found that regeneration did not result in telomere shortening at regenerating sites. Moreover, transient up-regulation of Avi-tert expression and telomerase activity was observed at regenerating sites, which might promote telomere lengthening to counteract telomere erosion resulting from cell proliferation. Our study suggests that although aging affects A. viride regeneration independent of steady-state telomere length, timely regulation of telomerase functions is critical for the regeneration process in A. viride.

RevDate: 2018-12-23

Mason AE, Adler JM, Puterman E, et al (2018)

Stress Resilience: Narrative Identity May Buffer the Longitudinal Effects of Chronic Caregiving Stress on Mental Health and Telomere Shortening.

Brain, behavior, and immunity pii:S0889-1591(18)30493-8 [Epub ahead of print].

BACKGROUND: Chronic caregiving stress may accelerate biological aging; however, the ability to integrate the meaning of caregiving through self-awareness, adaptation, and growth can buffer the negative effects of stress. Narrative researchers have shown that people who coherently integrate difficult experiences into their life story tend to have better mental health, but no prior study has examined the prospective association between narrative identity and biological indicators, such as telomere length. We tested whether narrative identity might be prospectively associated with resilience to long-term parenting stress, depressive symptoms, and protection from telomere shortening, especially among caregivers.

METHODS: We conducted a semi-structured interview about parenting and quantified narrative themes by applying well-validated, standardized coding systems with high interrater reliability among 88 mothers: 32 "caregivers" (mothers with a child diagnosed with an autism spectrum disorder), and 56 "controls" (mothers with a neurotypical child). To assess longitudinal changes, we measured mental health (parenting stress [PS], depressive symptoms [DS]) and leukocyte telomere length [LTL], a biomarker of aging, at baseline and again 18 months later. We examined whether narrative identity themes were related to these outcomes and whether associations differed across caregivers versus controls.

RESULTS: Caregivers exhibited significantly higher basal levels of PS and DS relative to controls (all p's<.05), but no significant difference in LTL (p>.05). Caregivers rated higher in the narrative theme of integration showed healthier future 18-month trajectories in PS [B=-0.832, 99% CI [-1.315, -0.155], p<.01) and LTL (B=1.193, 99% CI [0.526, 2.130], p<.01), but no differences in depressive symptoms (p>.05), adjusting for age and antidepressant use. Analyses examining affective themes in caregiver narratives did not demonstrate significant associations. Narrative themes did not predict outcomes in controls.

CONCLUSIONS: The data suggest that narratives reflecting coherent integration, but not necessarily affect, prospectively relate to psychological and biological stress resilience. Maternal caregivers' ability to tell an integrated story of their parenting experiences forecasts lower parenting stress and telomere shortening over time. This study suggests the possibility that helping individuals better integrate the meaning of stressful experiences, but not necessarily to affectively redeem them, may constitute a potential novel target for intervention among chronically stressed populations such as caregivers.

RevDate: 2018-12-22

Zheng GQ, Zhang GH, Wu HT, et al (2018)

Relative telomere length and gene expression of shelterin complex proteins among vinyl chloride monomer-exposed workers in China.

Environmental and molecular mutagenesis [Epub ahead of print].

Vinyl chloride monomer (VCM) is a confirmed carcinogen. The effects of VCM on telomeres and the gene expression of telomere complex proteins, shelterin, have not been well studied but could be of potential relevance to the carcinogenic mechanism of VCM and the health surveillance of VCM-exposed workers. Quantitative polymerase chain reaction was performed to measure relative telomere length (RTL) and gene expression of shelterin proteins among 241 VCM-exposed workers and 101 internal controls from the same plant in Shandong, China. VCM cumulative exposure dose (CED) was estimated for the exposed workers. The differences in RTL and gene expression between groups were compared by robust regression. Shorter RTL was observed in VCM-exposed workers than in the controls (P <0.001) and was related to CED of VCM. Shortened RTL was also significantly related to increasing age (P=0.012) and high blood pressure but of borderline significance (P=0.056). Levels of gene expression of shelterin components in exposed workers were all lower than in controls apart from increased TIN2 expression, and the expression differences in TIN2 and POT1 between exposed and control groups were significant (P=0.014 for TIN2 and P<0.001 for POT1, respectively). VCM exposure seems to alter telomere length and gene expression of shelterin components. This provides new insights into the potential carcinogenic mechanisms of VCM and could be helpful for the health surveillance for VCM-exposed workers. This article is protected by copyright. All rights reserved.

RevDate: 2018-12-21

Needham BL, Wang X, Carroll JE, et al (2018)

Sociodemographic correlates of change in leukocyte telomere length during mid- to late-life: The Multi-Ethnic Study of Atherosclerosis.

Psychoneuroendocrinology, 102:182-188 pii:S0306-4530(18)30904-1 [Epub ahead of print].

Although epidemiologic studies of telomere length have become increasingly common, few population-based, multi-ethnic studies include data on telomere shortening, which may be a better predictor of morbidity and mortality than a single measure of telomere length. This study used stored blood samples from 1169 participants in the Multi-Ethnic Study of Atherosclerosis (MESA) to examine age, sex, race/ethnicity, marital status, income, and education as predictors of change in telomere length over a 10-year period in linear mixed effects models. Mean age at baseline was 61 years, and the sample was 54% female, 27% white, 30% African-American, and 43% Hispanic. At baseline, 58% of the sample was married; 32% had household income below $25,000 per year, 35% had income between $25,000 and $49,999 per year, and 34% had income above $50,000 per year; 41% had a high school education or less, 30% had some college, and 29% had a college degree or more. Relative telomere length (T/S ratio) was measured by the quantitative polymerase chain reaction method. In general, ten-year telomere attrition was greater for groups that had longer telomere length at baseline, including younger people, whites, and women. After adjusting for baseline telomere length, race/ethnic differences in telomere attrition were attenuated, and age and sex differences were reversed, such that older people and men showed greater telomere shortening. There were no significant differences in telomere attrition by marital status, income, or education. There is not yet a consensus in the field regarding whether to adjust for baseline telomere length in models examining predictors of telomere attrition. To ensure comparability across studies, researchers should report results both with and without adjustment for baseline telomere length.

RevDate: 2018-12-21

Ding Y, Lin H, Zhou S, et al (2018)

Stronger Association between Insomnia Symptoms and Shorter Telomere Length in Old HIV-Infected Patients Compared with Uninfected Individuals.

Aging and disease, 9(6):1010-1019 pii:ad-9-6-1010.

Growing evidence suggests that HIV infection may accelerate biological aging. Insomnia symptoms, particularly in later life, exacerbate cellular aging. We examined the association between insomnia symptoms and leukocyte telomere length (LTL), and further explored how this association was affected by HIV serostatus and age. Data were assessed from 244 HIV-infected individuals ≥40 years and 244 HIV-uninfected individuals who were frequency-matched by age, gender and education level. Insomnia symptoms were assessed by responses to four sleep-related questions covering the past month. We performed multivariable linear regression with logarithmically transformed LTL and reported exponentiated coefficients. HIV-infected individuals had shorter LTL compared to uninfected individuals (geometric mean 0.82 vs 0.89, P=0.052), and this association remained after adjustment for gender, education level, and smoking history (-7.4%, P=0.051) but markedly attenuated after additional adjustment for insomnia and depressive symptoms (-3.7%, P=0.367). Significant interactions between age group (55-82 vs 40-54 years) and insomnia symptoms on LTL were observed in the HIV-infected individuals (-28.4%, P=0.033) but not the uninfected (-17.9%, P=0.250). After stratifying by age group, LTL was independently associated with insomnia symptoms in those 55 years and older among the HIV-infected individuals (-24.5%, P=0.026) but not those 40-54 years old (-9.8%, P=0.428). Our findings suggest that elevated insomnia and depressive symptoms may partly explain the correlation between HIV serostatus and shorter LTL. Significant association between insomnia and shorter LTL observed in elderly HIV-infected but not in uninfected individuals suggest that such adverse effect may begin at an earlier age or is more pronounced in HIV-infected individuals but requires further investigation.

RevDate: 2018-12-20

McPherson MC, Cheng HH, Smith JM, et al (2018)

Vaccination and Host Marek's Disease-Resistance Genotype Significantly Reduce Oncogenic Gallid alphaherpesvirus 2 Telomere Integration in Host Birds.

Cytogenetic and genome research pii:000495174 [Epub ahead of print].

Marek's disease (MD) is an infectious disease characterized by lymphomas and high mortality in susceptible chickens. The causative and ubiquitous alpha-herpesvirus known as MD virus (MDV) integrates into host telomeres during early infection through latency, known to be an important phase for oncogenic transformation. Herein, we sought to determine the influence of vaccination and host genetics on the temporal dynamics of MDV-host genome interactions. We studied integration profiles using 2 MD vaccines that vary in protective efficacy in 2 genetic lines that differ in MD resistance/susceptibility. Virus integration of both oncogenic MDV and vaccine strains was observed in both MD susceptible and resistant birds, however, the lines differed in their dynamic telomere-integration profiles. Notably, the resistant host genotype exhibited a smaller percentage of replicating cells with the virus telomere-integrated only phenotype as compared to the susceptible genotype. Vaccination with Rispens, the most protective MD vaccine, also reduced the establishment of the virus telomere-integrated only phenotype, suggesting a significant role of the phenotype in MD lymphoma development. The effect of Rispens vaccination was most dramatic in the susceptible genotype. These results suggest important connections between vaccinal immunity, MDV telomere integration, virus-induced oncogenesis, and virus-host genome interactions in the context of host genetics and disease susceptibility.

RevDate: 2018-12-20

Møller P, Wils RS, Jensen DM, et al (2018)

Telomere dynamics and cellular senescence: an emerging field in environmental and occupational toxicology.

Critical reviews in toxicology [Epub ahead of print].

There has been a steady output of epidemiological studies linking environmental and occupational exposures to altered telomere length, showing mainly positive associations with persistent organic pollutants, inverse association with cadmium and inconsistent results with arsenic and lead. A bell-shaped dose-response relationship has been observed for ionizing radiation with telomere shortening at a low dose. Long-term air pollution is associated with telomere shortening, whereas the short-term exposure studies have shown mixed results. There are surprisingly few studies on telomere dynamics in animals. Studies on telomere dynamics and senescence in target tissues of animal strains used in toxicology are warranted. Cell culture studies on ionizing radiation have shown mixed results on telomere length, whereas both telomerase activity and cellular senescence are increased. Studies on persistent organic pollutants indicate telomere shortening, decreased telomerase activity and increased cellular senescence. Cell culture studies on heavy metals and air pollution particles are inconsistent. There is no coherent relationship between exposures, oxidative stress, telomere length, telomerase activity and cellular senescence in experimental studies on environmental or occupational exposures. This may be due to differences in exposure levels (including dose rate), exposure time and models (i.e. cell types and animal strains). Guidelines are needed for best practices on assays for telomere dynamics and cellular senescence in toxicology. However, it deserves notice that experimental studies in cells and animals have revealed important information on the effects of environmental and occupational agents on the maintenance of telomeres and cellular senescence.

RevDate: 2018-12-19

Newton CA, Zhang D, Oldham JM, et al (2018)

Telomere Length and Use of Immunosuppressive Medications in Idiopathic Pulmonary Fibrosis.

American journal of respiratory and critical care medicine [Epub ahead of print].

Rationale Immunosuppression was associated with adverse events for idiopathic pulmonary fibrosis (IPF) patients in the PANTHER-IPF trial. The reason why some IPF patients experience harm is unknown. Objectives We sought to determine if leukocyte telomere length (LTL) was associated with the harmful effect of immunosuppression in IPF patients. Methods LTL was measured from available DNA samples from PANTHER-IPF (interim analysis, n=79; final analysis, n=118). Replication cohorts included ACE-IPF (n=101) and an independent observational cohort (UTSW-IPF, n=170). LTL-stratified and medication-stratified survival analyses were performed using multivariable Cox regression models for composite endpoint-free survival. Measurements and Main Results Of the subjects enrolled in the PANTHER-IPF and ACE-IPF, 62% (49/79) and 56% (28/50) had a LTL <10th percentile of normal, respectively. In PANTHER-IPF, exposure to prednisone/azathioprine/N-acetylcysteine was associated with a higher composite endpoint of death, lung transplantation, hospitalization, or forced vital capacity (FVC) decline for those with a LTL <10th percentile (HR 2.84, 95% CI 1.02-7.87, p=0.045). This finding was replicated in the placebo arm of ACE-IPF for those exposed to immunosuppression (HR 7.18, 95% CI 1.52-33.84, p=0.013). A propensity-matched UTSW IPF cohort showed a similar association between immunosuppression and composite endpoints (death, lung transplantation or FVC decline) for those with a LTL <10th percentile (HR 3.79, 95% CI 1.73-8.30, p=0.00085). An interaction was found between immunosuppression and LTL for the combined PANTHER-IPF and ACE-IPF clinical trials (pinteraction=0.048), as well as the UTSW IPF cohort (pinteraction=0.00049). Conclusions LTL is a biomarker that may identify IPF patients at risk for poor outcomes when exposed to immunosuppression.

RevDate: 2018-12-19

Morton JM, Garg T, N Leva (2018)

Association of Laparoscopic Gastric Bypass Surgery With Telomere Length in Patients With Obesity.

JAMA surgery pii:2718630 [Epub ahead of print].

RevDate: 2018-12-19

Graham JL, Bauer CM, Heidinger BJ, et al (2018)

Early breeding females experience greater telomere loss.

Molecular ecology [Epub ahead of print].

Annual reproductive success is often highest in individuals that initiate breeding early, yet relatively few individuals start breeding during this apparently optimal time. This suggests that individuals, particularly females who ultimately dictate when offspring are born, incur costs by initiating reproduction early in the season. We hypothesized that increases in the aging rate of somatic cells may be one such cost. Telomeres, the repetitive DNA sequences on the ends of chromosomes, may be good proxies of biological wear and tear as they shorten with age and in response to stress. Using historical data from a long-term study population of dark-eyed juncos (Junco hyemalis), we found that telomere loss between years was greater in earlier breeding females, regardless of chronological age. There was no relationship between telomere loss and the annual number of eggs laid or chicks that reached independence. However, telomere loss was greater when temperatures were cooler, and cooler temperatures generally occur early in the season. This suggests that environmental conditions could be the primary cause of accelerated telomere loss in early breeders. This article is protected by copyright. All rights reserved.

RevDate: 2018-12-19

Liu B, Sun Y, Xu G, et al (2018)

Association between Body Iron Status and Leukocyte Telomere Length, a Biomarker of Biological Aging, in a Nationally Representative Sample of US Adults.

Journal of the Academy of Nutrition and Dietetics pii:S2212-2672(18)30486-6 [Epub ahead of print].

BACKGROUND: Excess iron levels can induce oxidative stress and could therefore affect telomere attrition. However, little is known about the impact of body iron status on telomere length.

OBJECTIVE: Our aim was to examine the association between serum ferritin concentrations, an indicator of body iron status, and leukocyte telomere length in US adults.

DESIGN: We conducted a nationwide, population-based, cross-sectional study.

PARTICIPANTS/SETTING: We used data from the National Health and Nutrition Examination Survey (NHANES) 1999-2002. We included 7,336 adults aged 20 years or older who had available data on serum ferritin levels and telomere length. High ferritin levels were defined as a serum ferritin level >200 ng/mL (449.4 pmol/L) in women and >300 ng/mL (674.1 pmol/L) in men. Low ferritin levels were defined as a serum ferritin level <30 ng/mL (67.4 pmol/L).

MAIN OUTCOME MEASURES: Leukocyte telomere length was assayed using the quantitative polymerase chain reaction method.

STATISTICAL ANALYSES: Linear regression with survey weights was performed to estimate the association between serum ferritin levels and telomere length.

RESULTS: The prevalence of adults with high and low serum ferritin levels was 10.9% and 17.6%, respectively. High ferritin levels were inversely associated with telomere length compared to normal ferritin levels. After adjustment for demographic, socioeconomic and lifestyle factors, body mass index, C-reactive protein, and leukocyte cell type composition, the β coefficient for log-transformed telomere length was -0.020 (standard error [SE]=0.009; P=0.047). The association was stronger in adults aged 65 years or older (β coefficient -0.081, SE=0.017; P<0.001) than in adults 20 to 44 years old (β coefficient -0.023, SE=0.019; P=0.24) or adults aged 45 to 64 years old (β coefficient 0.024, SE=0.015; P=0.10) (P for interaction 0.003). Low ferritin levels were not significantly associated with telomere length compared with normal ferritin levels.

CONCLUSIONS: In a US nationally representative population, high body iron status was associated with shorter telomeres, especially in adults aged 65 years or older.

RevDate: 2018-12-18

Yeap BB, Hui J, Knuiman MW, et al (2018)

Cross-sectional associations of sex hormones with leucocyte telomere length, a marker of biological age, in a community-based cohort of older men.

Clinical endocrinology [Epub ahead of print].

CONTEXT: Telomeres protect chromosomes from damage, and shorter leucocyte telomere length (LTL) is a marker of advancing biological age. The association between testosterone (T) and its bioactive metabolites, dihydrotestosterone (DHT) and estradiol (E2) with telomere length, particularly in older men, is uncertain. The study aimed to clarify associations of sex hormones with LTL in older men.

PARTICIPANTS AND METHODS: We used cross-sectional data from 2,913 men aged 76.7±3.2 years with morning blood samples assayed for T, DHT, E2 (mass spectrometry), and sex hormone-binding globulin (SHBG, immunoassay), to correlate sex hormones with LTL measured using PCR and expressed as T/S ratio in multivariable linear regression models adjusted for age, cardiometabolic risk factors and cardiovascular disease history.

RESULTS: Average difference per decade of age was T -0.46 nmol/L, DHT -0.11 nmol/L, E2 -7.5 pmol/L, SHBG +10.2 nmol/L, and LTL (T/S ratio) -0.065. E2 correlated with T/S ratio (r=0.038, p=0.039) and SHBG was inversely correlated (r=-0.053, p=0.004). After multivariable adjustment, E2 was associated with T/S ratio (per 1SD increase E2: coefficient 0.011, p=0.043), T and DHT were not associated. When E2 and SHBG were simultaneously included, E2 remained positively (coefficient 0.014, p=0.014) and SHBG inversely (coefficient -0.013, p=0.037) associated with T/S ratio.

CONCLUSIONS: In older men, neither T nor DHT are associated with LTL while E2 is independently associated with LTL and SHBG is inversely associated, thus relating sex hormone exposure to lower biological age. Further research is needed to determine causality and clarify the role of sex hormones in male ageing. This article is protected by copyright. All rights reserved.

RevDate: 2018-12-18

Andersson U, Degerman S, Dahlin AM, et al (2018)

The association between longer relative leukocyte telomere length and risk of glioma is independent of the potentially confounding factors allergy, BMI, and smoking.

Cancer causes & control : CCC pii:10.1007/s10552-018-1120-2 [Epub ahead of print].

PURPOSE: Previous studies have suggested an association between relative leukocyte telomere length (rLTL) and glioma risk. This association may be influenced by several factors, including allergies, BMI, and smoking. Previous studies have shown that individuals with asthma and allergy have shortened relative telomere length, and decreased risk of glioma. Though, the details and the interplay between rLTL, asthma and allergies, and glioma molecular phenotype is largely unknown.

METHODS: rLTL was measured by qPCR in a Swedish population-based glioma case-control cohort (421 cases and 671 controls). rLTL was related to glioma risk and health parameters associated with asthma and allergy, as well as molecular events in glioma including IDH1 mutation, 1p/19q co-deletion, and EGFR amplification.

RESULTS: Longer rLTL was associated with increased risk of glioma (OR = 1.16; 95% CI 1.02-1.31). Similar to previous reports, there was an inverse association between allergy and glioma risk. Specific, allergy symptoms including watery eyes was most strongly associated with glioma risk. High body mass index (BMI) a year prior diagnosis was significantly protective against glioma in our population. Adjusting for allergy, asthma, BMI, and smoking did not markedly change the association between longer rLTL and glioma risk. rLTL among cases was not associated with IDH1 mutation, 1p/19q co-deletion, or EGFR amplification, after adjusting for age at diagnosis and sex.

CONCLUSIONS: In this Swedish glioma case-control cohort, we identified that long rLTL increases the risk of glioma, an association not confounded by allergy, BMI, or smoking. This highlights the complex interplay of the immune system, rLTL and cancer risk.

RevDate: 2018-12-18

Coutts F, Palmos AB, Duarte RRR, et al (2018)

The polygenic nature of telomere length and the anti-ageing properties of lithium.

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology pii:10.1038/s41386-018-0289-0 [Epub ahead of print].

Telomere length is a promising biomarker for age-related disease and a potential anti-ageing drug target. Here, we study the genetic architecture of telomere length and the repositioning potential of lithium as an anti-ageing medication. LD score regression applied to the largest telomere length genome-wide association study to-date, revealed SNP-chip heritability estimates of 7.29%, with polygenic risk scoring capturing 4.4% of the variance in telomere length in an independent cohort (p = 6.17 × 10-5). Gene-enrichment analysis identified 13 genes associated with telomere length, with the most significant being the leucine rich repeat gene, LRRC34 (p = 3.69 × 10-18). In the context of lithium, we confirm that chronic use in a sample of 384 bipolar disorder patients is associated with longer telomeres (p = 0.03). As complementary evidence, we studied three orthologs of telomere length regulators in a Caenorhabditis elegans model of lithium-induced extended longevity and found all transcripts to be affected post-treatment (p < 0.05). Lithium may therefore confer its anti-ageing effects by moderating the expression of genes responsible for normal telomere length regulation. This is supported by our bipolar disorder sample, which shows that polygenic risk scores explain a higher proportion of the variance in telomere length amongst chronic lifetime lithium users (variance explained = 8.9%, p = 0.01), compared to non-users (p > 0.05). Consequently, this suggests that lithium may be catalysing the activity of endogenous mechanisms that promote telomere lengthening, whereby its efficacy eventually becomes limited by each individual's inherent telomere maintenance capabilities. Our work indicates a potential use of polygenic risk scoring for the prediction of adult telomere length and consequently lithium's anti-ageing efficacy.

RevDate: 2018-12-18

Dunce JM, Milburn AE, Gurusaran M, et al (2018)

Structural basis of meiotic telomere attachment to the nuclear envelope by MAJIN-TERB2-TERB1.

Nature communications, 9(1):5355 pii:10.1038/s41467-018-07794-7.

Meiotic chromosomes undergo rapid prophase movements, which are thought to facilitate the formation of inter-homologue recombination intermediates that underlie synapsis, crossing over and segregation. The meiotic telomere complex (MAJIN, TERB1, TERB2) tethers telomere ends to the nuclear envelope and transmits cytoskeletal forces via the LINC complex to drive these rapid movements. Here, we report the molecular architecture of the meiotic telomere complex through the crystal structure of MAJIN-TERB2, together with light and X-ray scattering studies of wider complexes. The MAJIN-TERB2 2:2 hetero-tetramer binds strongly to DNA and is tethered through long flexible linkers to the inner nuclear membrane and two TRF1-binding 1:1 TERB2-TERB1 complexes. Our complementary structured illumination microscopy studies and biochemical findings reveal a telomere attachment mechanism in which MAJIN-TERB2-TERB1 recruits telomere-bound TRF1, which is then displaced during pachytene, allowing MAJIN-TERB2-TERB1 to bind telomeric DNA and form a mature attachment plate.

RevDate: 2018-12-17

Hayashi MT (2016)

Regulation of senescence by telomeres and telomerase.

Nihon rinsho. Japanese journal of clinical medicine, 74(9):1485-1490.

Telomeres are vital for chromosome end protection against activation of DNA damage response. Telomere attrition leads to cell cycle arrest, which underlies cellular senescence and can restrict tissue replenishment. Although stem cells express telomerase reverse tran- scriptase, which elongates telomeric DNA, its activity is not enough to fully compensate for chronic telomere shortening. Growing lines of evidence, including telomerase knockout mouse models and human genetic diseases, suggest that a decline in the cellular renewal capacity of stem cells is a consequence of such telomere shortening. These findings highlight the critical importance of telomere protection control for human aging process, and may lead to new strategies for healthy life extension.

RevDate: 2018-12-17

Grau-Perez M, Zhao J, Pierce B, et al (2018)

Urinary metals and leukocyte telomere length in American Indian communities: The Strong Heart and the Strong Heart Family Study.

Environmental pollution (Barking, Essex : 1987), 246:311-318 pii:S0269-7491(18)32780-5 [Epub ahead of print].

INTRODUCTION: While several mechanisms may explain metal-related health effects, the exact cellular processes are not fully understood. We evaluated the association between leukocyte telomere length (LTL) and urine arsenic (ΣAs), cadmium (Cd) and tungsten (W) exposure in the Strong Heart Study (SHS, N = 1702) and in the Strong Heart Family Study (SHFS, N = 1793).

METHODS: Urine metal concentrations were measured using ICP-MS. Arsenic exposure was assessed as the sum of inorganic arsenic, monomethylarsonate and dimethylarsinate levels (ΣAs). LTL was measured by quantitative polymerase chain reaction.

RESULTS: In the SHS, median levels were 1.09 for LTL, and 8.8, 1.01 and 0.11 μg/g creatinine for ΣAs, Cd, and W, respectively. In the SHFS, median levels were 1.01 for LTL, and 4.3, 0.44, and 0.10 μg/g creatinine. Among SHS participants, increased urine ΣAs, Cd, and W was associated with shorter LTL. The adjusted geometric mean ratio (95% confidence interval) of LTL per an increase equal to the difference between the percentiles 90th and 10th in metal distributions was 0.85 (0.79, 0.92) for ΣAs, 0.91 (0.84, 1.00) for Cd and 0.93 (0.88, 0.98) for W. We observed no significant associations among SHFS participants. The findings also suggest that the association between arsenic and LTL might be differential depending on the exposure levels or age.

CONCLUSIONS: Additional research is needed to confirm the association between metal exposures and telomere length.

RevDate: 2018-12-17

Kannengiesser C, Borie R, EA Renzoni (2018)

Pulmonary fibrosis: Genetic analysis of telomere-related genes, telomere length measurement-or both?.

RevDate: 2018-12-17

Sabale PM, Ambi UB, SG Srivatsan (2018)

Clickable PNA Probes for Imaging Human Telomeres and Poly(A) RNAs.

ACS omega, 3(11):15343-15352.

The ability to bind strongly to complementary nucleic acid sequences, invade complex nucleic acid structures, and resist degradation by cellular enzymes has made peptide nucleic acid (PNA) oligomers as very useful hybridization probes in molecular diagnosis. For such applications, the PNA oligomers have to be labeled with appropriate reporters as they lack intrinsic labels that can be used in biophysical assays. Although solid-phase synthesis is commonly used to attach reporters onto PNA, development of milder and modular labeling methods will provide access to PNA oligomers labeled with a wider range of biophysical tags. Here, we describe the establishment of a postsynthetic modification strategy based on bioorthogonal chemical reactions in functionalizing PNA oligomers in solution with a variety of tags. A toolbox composed of alkyne- and azide-modified monomers were site-specifically incorporated into PNA oligomers and postsynthetically click-functionalized with various tags, ranging from sugar, amino acid, biotin, to fluorophores, by using copper(I)-catalyzed azide-alkyne cycloaddition, strain-promoted azide-alkyne cycloaddition, and Staudinger ligation reactions. As a proof of utility of this method, fluorescent PNA hybridization probes were developed and used in imaging human telomeres in chromosomes and poly(A) RNAs in cells. Taken together, this simple approach of generating a wide range of functional PNA oligomers will expand the use of PNA in molecular diagnosis.

RevDate: 2018-12-16

Beatty Moody DL, Leibel DK, Darden TM, et al (2018)

Interpersonal-Level Discrimination Indices, Sociodemographic Factors, and Telomere Length in African-Americans and Whites.

Biological psychology pii:S0301-0511(18)30240-0 [Epub ahead of print].

OBJECTIVE: Studies have linked self-reported discrimination to telomere attrition, a biological marker of accelerated cellular aging. However, it is unknown whether intersections between social categories-race, socioeconomic status (SES), sex, and age-influence the association of varying forms of discrimination with telomere length. We examined these associations in a socioeconomically and racially/ethnically diverse urban sample.

METHODS: Cross-sectional data were from 341 middle-aged (30-64 years) African American and White, community participants in the Healthy Aging in Neighborhoods of Diversity across the Life Span Study (HANDLS). Multiple regression models examined up to 3-way interactions between a discrimination measure (i.e., everyday, racial, gender, lifetime burden, and frequency of discrimination across sources) and two social categories.

RESULTS: After adjusting for depressive symptoms, waist circumference, and lifetime substance use, two themes emerged: 1) among women with higher SES, a) greater lifetime discrimination burden (b = -0.23, p = .011), gender discrimination (b = -0.29, p = .040), and racial discrimination (b = -0.24, p = .023) and 2) among younger adults, irrespective of race and sex, greater frequency of discrimination across sources (b = 0.002, p = .008) was associated with shorter telomeres.

CONCLUSIONS: Irrespective of race, women with higher SES and younger adults reporting greater discrimination may be at particular risk for accelerated aging. Telomere attrition promotes and accelerates chronic health conditions for which there are health disparities. Future research explicating intersections among specific discrimination indices and social categories is warranted.

RevDate: 2018-12-15

Conklin QA, Crosswell AD, Saron CD, et al (2018)

Meditation, stress processes, and telomere biology.

Current opinion in psychology, 28:92-101 pii:S2352-250X(18)30200-8 [Epub ahead of print].

Both theoretical and empirical work support the notion that meditation training can improve telomere regulation, which may ultimately contribute to healthy aging. Yet, the psychological and biological mechanisms underlying these changes remain underspecified, as do the contexts and boundary conditions in which these changes occur. Here we summarize studies investigating the effects of various meditation-based interventions on telomere biology, making suggestions for future research. We then propose a model describing how meditation training may impact acute and habitual stress responses as pathways to improved cell aging.

RevDate: 2018-12-15

Rinelli M, Bellacchio E, Berardinelli F, et al (2018)

Correction to: Structural modeling of a novel TERC variant in a patient with aplastic anemia and short telomeres.

The original version of this article contained a mistake in the affiliation of E. Bellacchio. Correct affiliation is presented here.

RevDate: 2018-12-15

Rachakonda S, Srinivas N, Mahmoudpour SH, et al (2018)

Author Correction: Telomere length and survival in primary cutaneous melanoma patients.

Scientific reports, 8(1):17963 pii:10.1038/s41598-018-36657-w.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.

RevDate: 2018-12-14

Fernández-Eulate G, Alberro A, Muñoz-Culla M, et al (2018)

Blood Markers in Healthy-Aged Nonagenarians: A Combination of High Telomere Length and Low Amyloidβ Are Strongly Associated With Healthy Aging in the Oldest Old.

Frontiers in aging neuroscience, 10:380.

Many factors may converge in healthy aging in the oldest old, but their association and predictive power on healthy or functionally impaired aging has yet to be demonstrated. By detecting healthy aging and in turn, poor aging, we could take action to prevent chronic diseases associated with age. We conducted a pilot study comparing results of a set of markers (peripheral blood mononuclear cell or PBMC telomere length, circulating Aβ peptides, anti-Aβ antibodies, and ApoE status) previously associated with poor aging or cognitive deterioration, and their combinations, in a cohort of "neurologically healthy" (both motor and cognitive) nonagenarians (n = 20) and functionally impaired, institutionalized nonagenarians (n = 38) recruited between 2014 and 2015. We recruited 58 nonagenarians (41 women, 70.7%; mean age: 92.37 years in the neurologically healthy group vs. 94.13 years in the functionally impaired group). Healthy nonagenarians had significantly higher mean PBMC telomere lengths (mean = 7, p = 0.001), this being inversely correlated with functional impairment, and lower circulating Aβ40 (total in plasma fraction or TP and free in plasma fraction or FP), Aβ42 (TP and FP) and Aβ17 (FP) levels (FP40 131.35, p = 0.004; TP40 299.10, p = 0.007; FP42 6.29, p = 0.009; TP42 22.53, p = 0.019; FP17 1.32 p = 0.001; TP17 4.47, p = 0.3), after adjusting by age. Although healthy nonagenarians had higher anti-Aβ40 antibody levels (net adsorbed signal or NAS ± SD: 0.211 ± 0.107), the number of participants that pass the threshold (NAS > 3) to be considered as positive did not show such a strong association. There was no association with ApoE status. Additionally, we propose a "Composite Neurologically Healthy Aging Score" combining TP40 and mean PBMC telomere length, the strongest correlation of measured biomarkers with neurologically healthy status in nonagenarians (AUC = 0.904).

RevDate: 2018-12-14

Balan E, Decottignies A, L Deldicque (2018)

Physical Activity and Nutrition: Two Promising Strategies for Telomere Maintenance?.

Nutrients, 10(12): pii:nu10121942.

As the world demographic structure is getting older, highlighting strategies to counteract age-related diseases is a major public health concern. Telomeres are nucleoprotein structures that serve as guardians of genome stability by ensuring protection against both cell death and senescence. A hallmark of biological aging, telomere health is determined throughout the lifespan by a combination of both genetic and non-genetic influences. This review summarizes data from recently published studies looking at the effect of lifestyle variables such as nutrition and physical activity on telomere dynamics.

RevDate: 2018-12-13

Kaja R, Reyes SM, Rossetti HC, et al (2018)

Association between telomere length and cognitive ability in a community-based sample.

Neurobiology of aging, 75:51-53 pii:S0197-4580(18)30407-X [Epub ahead of print].

Prior research suggests that telomere length is a biomarker of cognitive aging; however, literature has demonstrated conflicting findings to date. The present study uses data from the Dallas Heart Study, N = 2606, to assess the association between telomere length and cognitive ability on the Montreal Cognitive Assessment. The data do not support a relationship between telomere length and general cognitive functioning, (β = 0.016, SE = 0.31, p = 0.407). The data further replicate the negative findings within current literature.

RevDate: 2018-12-13

Verhoeven JE, Penninx BWJH, Y Milaneschi (2018)

Unraveling the association between depression and telomere length using genomics.

Psychoneuroendocrinology, 102:121-127 pii:S0306-4530(18)30901-6 [Epub ahead of print].

OBJECTIVE: While there is robust evidence for a cross-sectional association between depression and shorter telomere length, suggestive of advanced biological aging, the nature of this association remains unclear. Here, we tested whether both traits share a common genetic liability with novel methods using genomics.

METHODS: Data were from 2032 participants of the Netherlands Study of Depression and Anxiety (NESDA) with genome-wide genetic information and multiple waves of data on DSM-IV lifetime depression diagnosis, depression severity, neuroticism and telomere length. Polygenic risk scores (PRS) for both traits were built using summary results from the largest genome-wide association studies (GWAS) on depression (59,851 cases and 113,154 controls) and telomere length (37,684 samples). Additionally, a PRS for neuroticism was built (337,000 samples). Genetic overlap between the traits was tested using PRS for same- and cross-trait associations. Furthermore, GWAS summary statistics were used to estimate the genome-wide genetic correlation between traits.

RESULTS: In NESDA data, the PRS for depression was associated with lifetime depression (odds ratio = 1.36; p = 6.49e-7) and depression severity level (β = 0.13; p = 1.24e-8), but not with telomere length. Similar results were found for the PRS for neuroticism. Conversely, the PRS for telomere length was associated with telomere length (β = 0.07; p = 8.42e-4) and 6-year telomere length attrition rate (β = 0.04; p = 2.15e-2), but not with depression variables. In summary-level analyses, the genetic correlation between the traits was small and not significant (rg=-0.08; p = .300).

CONCLUSION: The use of genetic methods in this paper indicated that the established phenotypic association between telomere length and depression is unlikely due to shared underlying genetic vulnerability. Our findings suggest that short telomeres in depressed patients may simply represent a generic marker of disease or may originate from non-genetic environmental factors.

RevDate: 2018-12-13

Guyatt AL, Rodriguez S, Gaunt TR, et al (2017)

Early life adiposity and telomere length across the life course: a systematic review and meta-analysis.

Wellcome open research, 2:118.

Background: The relationship between adiposity at birth and in childhood, and telomere length is yet to be determined. We aimed to systematically review and meta-analyse the results of studies assessing associations between neonatal and childhood adiposity, and telomere length. Methods: We searched Medline, EMBASE and PubMed for studies reporting associations between adiposity measured in the neonatal period or childhood, and leucocyte telomere length, measured at any age via quantitative polymerase chain reaction, or terminal restriction fragment analysis, either cross-sectionally, or longitudinally. Papers published before April 2017 were included. Results: Out of 230 abstracts assessed, 23 papers (32 estimates) were retained, from which 19 estimates were meta-analysed (15 cross-sectional, four longitudinal). Of the 15 cross-sectional estimates, seven reported on neonates: four used binary exposures of small-for-gestational-age vs. appropriate-for-gestational age (or appropriate- and large-for-gestational age), and three studied birth weight continuously. Eight estimates reported on childhood measures; five estimates were from studies of binary exposures (overweight/obese vs. non-obese children), and three studies used continuous measures of body mass index. All four longitudinal estimates were of neonatal adiposity, with two estimates for small-for-gestational-age vs. appropriate-for-gestational age neonates, and two estimates of birth weight studied continuously, in relation to adult telomere (49-61 years). There was no strong evidence of an association between neonatal or childhood adiposity, and telomere length. However, between study heterogeneity was high, and there were few combinable studies. Conclusions: Our systematic review and meta-analysis found no strong evidence of an association between neonatal or childhood adiposity and telomere length.

RevDate: 2018-12-07

Iodice S, Hoxha M, Ferrari L, et al (2018)

Particulate Air Pollution, Blood Mitochondrial DNA Copy Number, and Telomere Length in Mothers in the First Trimester of Pregnancy: Effects on Fetal Growth.

Oxidative medicine and cellular longevity, 2018:5162905.

Growing evidences have shown that particulate matter (PM) exposures during pregnancy are associated with impaired fetal development and adverse birth outcomes, possibly as a result of an exaggerated systemic oxidative stress and inflammation. Telomere length (TL) is strongly linked to biological age and is impacted by oxidative stress. We hypothesized that PM exposure during different time windows in the first trimester of pregnancy influences both mitochondrial DNA copy number (mtDNAcn), an established biomarker for oxidative stress, and TL. Maternal blood TL and mtDNAcn were analysed in 199 healthy pregnant women recruited at the 11th week of pregnancy by quantitative polymerase chain reaction. We also examined whether maternal mtDNAcn and TL were associated with fetal growth outcomes measured at the end of the first trimester of pregnancy (fetal heart rate, FHR; crown-rump length, CRL; and nuchal translucency, NT) and at delivery (birth weight, length, head circumference). The possible modifying effect of prepregnancy maternal body mass index was evaluated. PM10 exposure during the first pregnancy trimester was associated with an increased maternal mtDNAcn and a reduced TL. As regards ultrasound fetal outcomes, both FHR and CRL were positively associated with PM2.5, whereas the association with FHR was confirmed only when examining PM10 exposure. PM10 was also associated with a reduced birth weight. While no association was found between mtDNAcn and CRL, we found a negative relationship between mtDNAcn and fetal CRL only in overweight women, whereas normal-weight women exhibited a positive, albeit nonsignificant, association. As abnormalities of growth in utero have been associated with postnatal childhood and adulthood onset diseases and as PM is a widespread pollutant relevant to the large majority of the human population and obesity a rising risk factor, our results, if confirmed in a larger population, might represent an important contribution towards the development of more targeted public health strategies.

RevDate: 2018-12-14

Gutierrez-Rodrigues F, Donaires FS, Pinto A, et al (2018)

Pathogenic TERT promoter variants in telomere diseases.

Genetics in medicine : official journal of the American College of Medical Genetics pii:10.1038/s41436-018-0385-x [Epub ahead of print].

PURPOSE: The acquisition of pathogenic variants in the TERT promoter (TERTp) region is a mechanism of tumorigenesis. In nonmalignant diseases, TERTp variants have been reported only in patients with idiopathic pulmonary fibrosis (IPF) due to germline variants in telomere biology genes.

METHODS: We screened patients with a broad spectrum of telomeropathies (n = 136), their relatives (n = 52), and controls (n = 195) for TERTp variants using a customized massively parallel amplicon-based sequencing assay.

RESULTS: Pathogenic -124 and -146 TERTp variants were identified in nine (7%) unrelated patients diagnosed with IPF (28%) or moderate aplastic anemia (4.6%); five of them also presented cirrhosis. Five (10%) relatives were also found with these variants, all harboring a pathogenic germline variant in telomere biology genes. TERTp clone selection did not associate with peripheral blood counts, telomere length, and response to danazol treatment. However, it was specific for patients with telomeropathies, more frequently co-occurring with TERT germline variants and associated with aging.

CONCLUSION: We extend the spectrum of nonmalignant diseases associated with pathogenic TERTp variants to marrow failure and liver disease due to inherited telomerase deficiency. Specificity of pathogenic TERTp variants for telomerase dysfunction may help to assess the pathogenicity of unclear constitutional variants in the telomere diseases.

RevDate: 2018-12-07

Borie R, Bouvry D, Cottin V, et al (2018)

Regulator of telomere length 1 (RTEL1) mutations are associated with heterogeneous pulmonary and extra-pulmonary phenotypes.

The European respiratory journal pii:13993003.00508-2018 [Epub ahead of print].

RTEL1 mutations have been evidenced in 5-9% of familial pulmonary fibrosis, but the phenotype of patients with interstitial lung disease (ILD) and RTEL1 mutations is poorly known.Whole exome sequencing was performed in 252 probands with ILD and we included all patients with ILD and RTEL1 mutation. RTEL1 expression was evaluated by immunochemistry in the lung of controls, RTEL1 and TERT mutation carriers.We identified 35 subjects, from 17 families. Median age at diagnosis of ILD was 55.2 years [28.0-80.6]. The most frequent pulmonary diagnoses were idiopathic pulmonary fibrosis (n=20, 57%) secondary ILD (n=7, 20%) and unclassifiable fibrosis or IPAF (n=7, 20%). The median transplant-free- and overall-survival were 39.2 and 45.3 months, respectively. Forced vital capacity at diagnosis was the only factor associated with decreased transplant-free-survival. Extra-pulmonary manifestations were less frequent as compared to other telomere related gene mutation carriers. A systematic analysis of the literature identified 110 patients with ILD and RTEL1 mutations, including this series and confirmed the heterogeneity of the pulmonary phenotype, the prevalence of non idiopathic diseases, and the low prevalence of extra-pulmonary manifestations.Immunohistochemistry showed that RTEL1 was expressed by bronchial and alveolar epithelial cells, alveolar macrophages and lymphocytes but not by fibroblast.

RevDate: 2018-12-12

Courtwright AM, S El-Chemaly (2018)

Telomeres in Interstitial Lung Disease: The Short and the Long of It.

Annals of the American Thoracic Society [Epub ahead of print].

Telomeres are repetitive nucleotide sequences that cap linear chromosomes, thereby limiting progressive chromosomal shortening during cell replication. In conjunction with environmental factors, common single nucleotide polymorphisms and rare and ultra-rare telomere-related mutations are associated with accelerated telomere shortening resulting in organ dysfunction, including interstitial lung disease (ILD). The most common telomere-related mutation-associated ILD is idiopathic pulmonary fibrosis (IPF). Up to one-third of individuals with familial IPF have shortened telomeres and/or carry a telomere-related mutation and one in ten individuals with sporadic IPF have telomere-related mutations. Regardless of ILD phenotype, individuals with short telomeres and/or known telomere-related mutations have more rapid disease progression and shorter lung transplant-free survival. Management should include initiation of anti-fibrotic agents for those with an IPF phenotype and early referral to a transplant center. Patients with ILD being considered for transplant should be screened for short telomeres if there is a significant family history of pulmonary fibrosis or evidence of extra-pulmonary organ dysfunction associated with a short telomere syndrome. Post-transplant management of recipients with telomere-related mutations should include careful adjustment of immunosuppression regimens based on bone marrow reserve. Data on the impact of shortened telomeres on post-transplant outcomes, however, remain mixed.

RevDate: 2018-12-12

Ingles ED, JE Deakin (2018)

The methylation and telomere landscape in two families of marsupials with different rates of chromosome evolution.

Chromosome research : an international journal on the molecular, supramolecular and evolutionary aspects of chromosome biology pii:10.1007/s10577-018-9593-0 [Epub ahead of print].

Two marsupial families exemplify divergent rates of karyotypic change. The Dasyurid family has an extremely conserved karyotype. In contrast, there is significant chromosomal variation within the Macropodidae family, best exemplified by members of the genus Petrogale (rock-wallabies). Both families are also distinguished by their telomere landscape (length and epigenetics), with the dasyurids having a unique telomere length dimorphism not observed in other marsupials and hypothesised to be regulated in a parent-of-origin fashion. Previous work has shown that proximal ends of chromosomes are enriched in cytosine methylation in dasyurids, but that the chromosomes of a macropod, the tammar wallaby, have DNA methylation enrichment of pericentric regions. Using a combination of telomere and 5-methylcytosine immunofluorescence staining, we investigated the telomere landscape of four dasyurid and three Petrogale species. As part of this study, we also further examined the parent-of-origin hypothesis for the regulation of telomere length dimorphism in dasyurids, using epigenetic modifications known to differentiate the active maternal X chromosome, including 5-methylcytosine methylation and histone modifications H3K4me2, H3K9ac and H4Kac. Our results give further support to the parent-of-origin hypothesis for the regulation of telomere length dimorphism in dasyurids, where the paternally derived X chromosome in females was associated with long telomeres and the maternally derived with short telomeres. In contrast to the tammar wallaby, rock-wallabies demonstrated a similar 5-methylcytosine staining pattern across all chromosomes to that of dasyurids, suggesting that DNA methylation of telomeric regions is not responsible for differences in the rates of chromosome evolution between these two families.

RevDate: 2018-12-11

Delgado DA, Zhang C, Gleason K, et al (2018)

The contribution of parent-to-offspring transmission of telomeres to the heritability of telomere length in humans.

Human genetics pii:10.1007/s00439-018-1964-2 [Epub ahead of print].

Leukocyte telomere length (LTL) is a heritable trait with two potential sources of heritability (h2): inherited variation in non-telomeric regions (e.g., SNPs that influence telomere maintenance) and variability in the lengths of telomeres in gametes that produce offspring zygotes (i.e., "direct" inheritance). Prior studies of LTL h2 have not attempted to disentangle these two sources. Here, we use a novel approach for detecting the direct inheritance of telomeres by studying the association between identity-by-descent (IBD) sharing at chromosome ends and phenotypic similarity in LTL. We measured genome-wide SNPs and LTL for a sample of 5069 Bangladeshi adults with substantial relatedness. For each of the 6318 relative pairs identified, we used SNPs near the telomeres to estimate the number of chromosome ends shared IBD, a proxy for the number of telomeres shared IBD (Tshared). We then estimated the association between Tshared and the squared pairwise difference in LTL ((ΔLTL)2) within various classes of relatives (siblings, avuncular, cousins, and distant), adjusting for overall genetic relatedness (ϕ). The association between Tshared and (ΔLTL)2 was inverse among all relative pair types. In a meta-analysis including all relative pairs (ϕ > 0.05), the association between Tshared and (ΔLTL)2 (P = 0.01) was stronger than the association between ϕ and (ΔLTL)2 (P = 0.43). Our results provide strong evidence that telomere length (TL) in parental germ cells impacts TL in offspring cells and contributes to LTL h2 despite telomere "reprogramming" during embryonic development. Applying our method to larger studies will enable robust estimation of LTL h2 attributable to direct transmission of telomeres.

RevDate: 2018-12-11

Gielen M, Hageman GJ, Antoniou EE, et al (2018)

Body mass index is negatively associated with telomere length: a collaborative cross-sectional meta-analysis of 87 observational studies.

The American journal of clinical nutrition, 108(3):453-475.

Background: Even before the onset of age-related diseases, obesity might be a contributing factor to the cumulative burden of oxidative stress and chronic inflammation throughout the life course. Obesity may therefore contribute to accelerated shortening of telomeres. Consequently, obese persons are more likely to have shorter telomeres, but the association between body mass index (BMI) and leukocyte telomere length (TL) might differ across the life span and between ethnicities and sexes.

Objective: A collaborative cross-sectional meta-analysis of observational studies was conducted to investigate the associations between BMI and TL across the life span.

Design: Eighty-seven distinct study samples were included in the meta-analysis capturing data from 146,114 individuals. Study-specific age- and sex-adjusted regression coefficients were combined by using a random-effects model in which absolute [base pairs (bp)] and relative telomere to single-copy gene ratio (T/S ratio) TLs were regressed against BMI. Stratified analysis was performed by 3 age categories ("young": 18-60 y; "middle": 61-75 y; and "old": >75 y), sex, and ethnicity.

Results: Each unit increase in BMI corresponded to a -3.99 bp (95% CI: -5.17, -2.81 bp) difference in TL in the total pooled sample; among young adults, each unit increase in BMI corresponded to a -7.67 bp (95% CI: -10.03, -5.31 bp) difference. Each unit increase in BMI corresponded to a -1.58 × 10-3 unit T/S ratio (0.16% decrease; 95% CI: -2.14 × 10-3, -1.01 × 10-3) difference in age- and sex-adjusted relative TL in the total pooled sample; among young adults, each unit increase in BMI corresponded to a -2.58 × 10-3 unit T/S ratio (0.26% decrease; 95% CI: -3.92 × 10-3, -1.25 × 10-3). The associations were predominantly for the white pooled population. No sex differences were observed.

Conclusions: A higher BMI is associated with shorter telomeres, especially in younger individuals. The presently observed difference is not negligible. Meta-analyses of longitudinal studies evaluating change in body weight alongside change in TL are warranted.

RevDate: 2018-12-11

Zhang G, JW Shay (2018)

Inducing rapid telomere irreparable damage in telomerase-expressing cancers.

Oncotarget, 9(88):35803-35804 pii:26317.

RevDate: 2018-12-11

Garcia-Martin I, Penketh RJA, Janssen AB, et al (2018)

Metformin and insulin treatment prevent placental telomere attrition in boys exposed to maternal diabetes.

PloS one, 13(12):e0208533 pii:PONE-D-18-20602.

Shortened leukocyte and placental telomeres associated with gestational diabetes mellitus (GDM) suggest this exposure triggers telomere attrition contributing to adverse outcomes. We applied high resolution Single Telomere Length Analysis (STELA) to placenta from GDM pregnancies with different treatment pathways to determine their effectiveness at preventing telomere attrition. Differences in telomere length between control (N = 69), GDM lifestyle intervention (n = 14) and GDM treated with metformin and/or insulin (n = 17) was tested by Analysis of Covariance (ANCOVA) followed by group comparisons using Fisher's least significant difference. For male placenta only, there were differences in mean telomere length (F(2,54) = 4.98, P = 0.01) and percentage of telomeres under 5 kb (F(2,54) = 4.65, P = 0.01). Telomeres were shorter in the GDM lifestyle intervention group compared to both controls (P = 0.02) and medically treated pregnancies (P = 0.003). There were more telomeres under 5 kb in the GDM lifestyle intervention group compared to the other two groups (P = 0.03 and P = 0.004). Although further work is necessary, we suggest that early adoption of targeted medical treatment of GDM pregnancies where the fetus is known to be male may be an effective strategy for ameliorating adverse outcomes for children.

RevDate: 2018-12-11

Morin SJ, Tao X, Marin D, et al (2018)

DNA methylation-based age prediction and telomere length in white blood cells and cumulus cells of infertile women with normal or poor response to ovarian stimulation.

Aging pii:101670 [Epub ahead of print].

An algorithm assessing the methylation levels of 353 informative CpG sites in the human genome permits accurate prediction of the chronologic age of a subject. Interestingly, when there is discrepancy between the predicted age and chronologic age (age acceleration or "AgeAccel"), patients are at risk for morbidity and mortality. Identification of infertile patients at risk for accelerated reproductive senescence may permit preventative action. This study aimed to assess the accuracy of the "epigenetic clock" concept in reproductive age women undergoing fertility treatment by applying the age prediction algorithm in peripheral (white blood cells [WBCs]) and follicular somatic cells (cumulus cells [CCs]), and to identify whether women with premature reproductive aging (diminished ovarian reserve) were at risk of AgeAccel in their age prediction. Results indicated that the epigenetic algorithm accurately predicts age when applied to WBCs but not to CCs. The age prediction of CCs was substantially younger than chronologic age regardless of the patient's age or response to stimulation. In addition, telomeres of CCs were significantly longer than that of WBCs. Our findings suggest that CCs do not demonstrate changes in methylome-predicted age or telomere-length in association with increasing female age or ovarian response to stimulation.

RevDate: 2018-12-11

Provenzi L, Giorda R, Fumagalli M, et al (2018)

Telomere length and salivary cortisol stress reactivity in very preterm infants.

Early human development, 129:1-4 pii:S0378-3782(18)30538-3 [Epub ahead of print].

During the Neonatal Intensive Care Unit (NICU) stay, very preterm (VPT) infants are exposed to life-saving yet pain-inducing skin-breaking procedures (i.e., NICU pain-related stress) which contribute to the programming of hypo-responsive HPA axis development during the first months of life. Unfortunately, to date the mechanisms linking NICU pain-related stress and altered HPA axis regulation are only limitedly known. Telomere length (TL) regulation is an epigenetic mechanism previously shown to be affected by early stress exposures and capable of associating with HPA axis reactivity in children. In VPT infants, NICU pain-related stress was found to associate with decreased TL from birth to discharge, but there is no evidence for the association between TL and HPA axis in these infants. In this study, we prospectively examined the relationship between NICU pain-related stress and HPA axis reactivity to an age-appropriate socio-emotional condition (i.e., the Still-Face Procedure, SFP) in healthy VPT infants at 3-month corrected age. NICU pain-related stress was computed as the ratio between the number of skin-breaking procedures and length of NICU stay. A differential score (i.e., ∆TL) was obtained subtracting TL at birth from TL at discharge. A normalized (log10) cortisol reactivity index (CRI) was obtained by averaging post-stress (20 min after SFP) salivary cortisol sample on baseline value. A regression model controlling for neonatal and socio-demographic confounders showed that ∆TL was the only significant predictor of CRI. Although preliminary, these findings contribute to our knowledge of the mechanisms linking early exposures to adversity and later in life regulation of the HPA axis in VPT infants.

RevDate: 2018-12-06

Criscuolo F, Sorci G, Behaim-Delarbre M, et al (2018)

Age-related response to an acute innate immune challenge in mice: proteomics reveals a telomere maintenance-related cost.

Proceedings. Biological sciences, 285(1892): pii:rspb.2018.1877.

Ageing is characterized by the impairment of the acute innate immune response and the upregulation of low-grade inflammation, i.e. inflammaging. At the cellular level, telomeres are considered as a marker of biological ageing as their length is progressively eroded in the absence of repair mechanisms. However, the link between telomeres and inflammaging remains underexplored. We aimed to identify proteins that are differentially expressed between age classes in response to an acute inflammatory challenge. We challenged young (two months) and old (12 months) C57BL/6 mice using bacterial lipopolysaccharide (LPS) and measured telomere length and proteomic profiles in splenocytes. In total, 233 out of the 1966 proteins we quantified differed among experimental groups. A hierarchical clustering analysis revealed that nine of those 233 proteins were differently expressed among the experimental groups. Young mice responded to LPS by increasing the expression of proteins involved in the innate immune response, and interestingly, in telomere length maintenance. However, this regulation was impaired at older ages. These results are in agreement with the assumption that the strength of selection declines with age, potentially explaining the maintenance of costly, dysregulated, immune responses at old age. We suggest that the immune response is competing with the telomere maintenance process, highlighting how telomeres reflect the ageing trade-off even in a species where telomere length is not related to lifespan.

RevDate: 2018-12-06

Vgontzas AN, Fernandez-Mendoza J, EO Bixler (2018)

Short Telomere Length and Endophenotypes in Sleep Medicine.

Journal of clinical sleep medicine : JCSM : official publication of the American Academy of Sleep Medicine pii:jc-18-00729 [Epub ahead of print].

RevDate: 2018-12-06

Tempaku P, Hirotsu C, Mazzotti D, et al (2018)

Long Sleep Duration, Insomnia, and Insomnia With Short Objective Sleep Duration Are Independently Associated With Short Telomere Length.

Journal of clinical sleep medicine : JCSM : official publication of the American Academy of Sleep Medicine pii:jc-18-00113 [Epub ahead of print].

STUDY OBJECTIVES: We aimed to determine the association between short telomere length, sleep parameters, and sleep disorders in an adult general population sample.

METHODS: As part of the EPISONO cohort (São Paulo, Brazil), 925 individuals answered questionnaires, underwent a full-night polysomnography and clinical assessment, and had peripheral blood collected for DNA extraction. Insomnia was diagnosed based on the Diagnostic and Statistical Manual of Mental Disorders, 4th edition; and obstructive sleep apnea was defined according to apnea-hypopnea index. For the objective insomnia phenotype, we combined insomnia diagnosis with total sleep time from polysomnography with a cutoff of 360 minutes, allowing the classification of six groups. Self-reported sleep duration was used to classify the individuals as short (< 6 hours), average (6 to 8 hours) and long (> 8 hours) sleepers. The leukocyte telomere length was measured using quantitative real-time polymerase chain reaction. Based on its distribution, we considered leukocyte telomere length < 10th percentile as short telomere and leukocyte telomere length ≥ 10th percentile as non-short telomere.

RESULTS: After adjusting for sex, age, and body mass index, only insomnia disorder (odds ratio [OR] = 2.654, 95% confidence interval [CI] = 1.025-6.873, P = .044), insomnia disorder total sleep time < 360 minutes (OR = 4.205, 95% CI = 1.097-16.117, P = .036) and long sleepers (OR = 2.177, 95% CI = 1.189-3.987, P = .012) were associated with short telomere.

CONCLUSIONS: Our findings support the existence of an association among insomnia, insomnia phenotype, and self-reported long sleep duration with the maintenance of telomere length.

RevDate: 2018-12-06

Freitas-Simoes TM, Cofán M, Blasco MA, et al (2018)

Walnut Consumption for Two Years and Leukocyte Telomere Attrition in Mediterranean Elders: Results of a Randomized Controlled Trial.

Nutrients, 10(12): pii:nu10121907.

Randomized controlled trials on diet and shortening of leukocyte telomere length (LTL) mostly focus on marine-derived n-3 polyunsaturated fatty acids (PUFA). Walnuts are a sustainable source of n-3 PUFA. We investigated whether inclusion of walnuts (15% of energy) in the diet for 2 years would maintain LTL in cognitively healthy elders (63⁻79 years old) compared to a control group (habitual diet, abstaining from walnuts). This opportunistic sub-study was conducted within the Walnuts and Healthy Aging study, a dual-centre (Barcelona, Spain and Loma Linda University, California) parallel trial. A sub-set of the Barcelona site participants were randomly assigned to the walnut (n = 80) or control group (n = 69). We assessed LTL at baseline and at 2 years and we conducted repeated-measures ANCOVA with 2 factors: time (baseline, 2 years) and group (control, walnut) and their interaction. Adjusted means (95% confidence interval) of LTL (in kb) in controls were 7.360 (7.084,7.636) at baseline and 7.061 (6.835,7.288) after 2 years; corresponding values in the walnut group were 7.064 (6.807,7.320) and 7.074 (6.864,7.284). The time × intervention interaction was nearly significant (p = 0.079), suggestive of a trend of walnut consumption in preserving LTL. This exploratory research finding should be confirmed in trials with adequate statistical power.

RevDate: 2018-12-03

Colon M, Hodgson A, Donlon E, et al (2018)

Effects of Competitive Triathlon Training on Telomere Length.

Journal of aging and physical activity [Epub ahead of print].

Telomeres act as a mitotic clock and telomere related senescence has been linked to age related physiological decline. There is increasing evidence lifestyle factors can influence telomere length. The purpose of this study was to determine the effect of competitive triathlon training on telomere length. Seven competitive male triathletes and seven recreationally active males participated in the study. Relative telomere length was measured using quantitative polymerase chain reaction (qPCR). Physiological parameters key to athletic performance such as V̇O2max, lactate threshold and running economy were also measured. Triathletes had longer telomeres than the recreationally active (1.257 ± 0.028 vs. 1.002 ± 0.014, p<0.0001). Positive association was found between telomere length and V̇O2max, lactate threshold and running economy (R2 = 0.677, 0.683 and 0.696 respectively). This study indicates that competitive triathlon training buffers against age related telomere shortening and there is a correlation between exercise behaviours, higher V̇O2max and telomere length.

RevDate: 2018-12-03

Hu C, Inoue H, Sun W, et al (2018)

The Inner Nuclear Membrane Protein Bqt4 in Fission Yeast Contains a DNA-Binding Domain Essential for Telomere Association with the Nuclear Envelope.

Structure (London, England : 1993) pii:S0969-2126(18)30371-X [Epub ahead of print].

Telomeres, the protective caps at the end of the chromosomes, are often associated with the nuclear envelope (NE). Telomere positioning to the NE is dynamically regulated during mitosis and meiosis. One inner nuclear membrane protein, Bqt4, in Schizosaccharomyces pombe plays essential roles in connecting telomeres to the NE. However, the structural basis of Bqt4 in mediating telomere-NE association is not clear. Here, we report the crystal structure of the N-terminal domain of Bqt4. The N-terminal domain of Bqt4 structurally resembles the APSES-family DNA-binding domain and has a moderate double-stranded DNA-binding activity. Disruption of Bqt4-DNA interaction results in telomere detachment from the NE. These data suggest that the DNA-binding activity of Bqt4 may function to prime the chromosome onto the NE and promote telomere-NE association.

RevDate: 2018-12-03

Garrett Morgan R, Walker AE, Trott DW, et al (2018)

Induced Trf2 deletion leads to aging vascular phenotype in mice associated with arterial telomere uncapping, senescence signaling, and oxidative stress.

Journal of molecular and cellular cardiology pii:S0022-2828(18)30751-X [Epub ahead of print].

Age-related vascular dysfunction in large elastic and resistance arteries is associated with reductions in microvascular perfusion and elevations in blood pressure. Recent evidence indicates that telomere uncapping-induced senescence in vascular cells may be an important source of oxidative stress and vascular dysfunction in aging, but the causal relationship between these processes has yet to be elucidated. To test this important unexplored hypothesis, we measured arterial senescence signaling and oxidative stress, carotid and mesenteric artery endothelium-dependent vasodilatory capacity, markers of mesenteric microvascular perfusion and endothelial glycocalyx deterioration, and blood pressure in a novel mouse model of Cre-inducible whole body Trf2 deletion and telomere uncapping. Trf2 deletion led to a 320% increase in arterial senescence signaling (P < .05). There was a concurrent 29% and 22% reduction in peak endothelium-dependent vasodilation in carotid and mesenteric arteries, respectively, as well as a 63% reduction in mesenteric microvascular endothelial glycocalyx thickness (all P ≤ .01). Mesenteric microvascular perfusion was reduced by 8% and systolic blood pressure was increased by 9% following Trf2 deletion (both P < .05). Trf2 deletion also led to a pro-oxidative arterial phenotype characterized by increased in NADPH oxidase gene expression; a 210% increase in superoxide levels that was partly dependent on NADPH oxidase activity; and an oxidative stress-mediated reduction in carotid artery vasodilation (all P ≤ .05). Collectively, our findings demonstrate that induced Trf2 deletion leads to telomere uncapping, increased senescence signaling, and oxidative-stress mediated functional impairments in the vasculature similar to those seen in human aging.

RevDate: 2018-12-05

Sobecki M, Souaid C, Boulay J, et al (2018)

MadID, a Versatile Approach to Map Protein-DNA Interactions, Highlights Telomere-Nuclear Envelope Contact Sites in Human Cells.

Cell reports, 25(10):2891-2903.e5.

Mapping the binding sites of DNA- or chromatin-interacting proteins is essential to understanding biological processes. DNA adenine methyltransferase identification (DamID) has emerged as a comprehensive method to map genome-wide occupancy of proteins of interest. A caveat of DamID is the specificity of Dam methyltransferase for GATC motifs that are not homogenously distributed in the genome. Here, we developed an optimized method named MadID, using proximity labeling of DNA by the methyltransferase M.EcoGII. M.EcoGII mediates N6-adenosine methylation in any DNA sequence context, resulting in deeper and unbiased coverage of the genome. We demonstrate, using m6A-specific immunoprecipitation and deep sequencing, that MadID is a robust method to identify protein-DNA interactions at the whole-genome level. Using MadID, we revealed contact sites between human telomeres, repetitive sequences devoid of GATC sites, and the nuclear envelope. Overall, MadID opens the way to identification of binding sites in genomic regions that were largely inaccessible.

RevDate: 2018-12-05

Ravindranathan A, Cimini B, Diolaiti ME, et al (2018)

Preliminary development of an assay for detection of TERT expression, telomere length, and telomere elongation in single cells.

PloS one, 13(12):e0206525 pii:PONE-D-18-13372.

The telomerase enzyme enables unlimited proliferation of most human cancer cells by elongating telomeres and preventing replicative senescence. Despite the critical importance of telomerase in cancer biology, challenges detecting telomerase activity and expression in individual cells have hindered the ability to study patterns of telomerase expression and function across heterogeneous cell populations. While sensitive assays to ascertain telomerase expression and function exist, these approaches have proven difficult to implement at the single cell level. Here, we validate in situ RNAscope detection of the telomerase TERT mRNA and couple this assay with our recently described TSQ1 method for in situ detection of telomere elongation. This approach enables detection of TERT expression, telomere length, and telomere elongation within individual cells of the population. Using this assay, we show that the heterogeneous telomere elongation observed across a HeLa cell population is in part driven by variable expression of the TERT gene. Furthermore, we show that the absence of detectable telomere elongation in some TERT-positive cells is the result of inhibition by the telomeric shelterin complex. This combined assay provides a new approach for understanding the integrated expression, function, and regulation of telomerase at the single cell level.

RevDate: 2018-12-04

Powell TR, De Jong S, Breen G, et al (2018)

Telomere length as a predictor of emotional processing in the brain.

Human brain mapping [Epub ahead of print].

Shorter telomere length (TL) has been associated with the development of mood disorders as well as abnormalities in brain morphology. However, so far, no studies have considered the role TL may have on brain function during tasks relevant to mood disorders. In this study, we examine the relationship between TL and functional brain activation and connectivity, while participants (n = 112) perform a functional magnetic resonance imaging (fMRI) facial affect recognition task. Additionally, because variation in TL has a substantial genetic component we calculated polygenic risk scores for TL to test if they predict face-related functional brain activation. First, our results showed that TL was positively associated with increased activation in the amygdala and cuneus, as well as increased connectivity from posterior regions of the face network to the ventral prefrontal cortex. Second, polygenic risk scores for TL show a positive association with medial prefrontal cortex activation. The data support the view that TL and genetic loading for shorter telomeres, influence the function of brain regions known to be involved in emotional processing.

RevDate: 2018-12-04

Desai K, Berkman N, Cohen-Manheim I, et al (2018)

Rapid shortening of leukocyte telomeres is associated with poorer pulmonary function among healthy adults.

Respiratory medicine, 145:73-79.

AIM: The study aimed to examine the association between leukocyte telomere length (LTL) attrition over 13 years (between mean age 30 and mean age 43) and lung function at mean age 50.

MATERIALS & METHODS: In a longitudinal observational study LTL was determined twice on a population-based sample of 481 Jewish residents of Jerusalem at mean ages 30 and 43 years. Pulmonary function was determined at mean age 50 years. Multiple linear regression and multivariable ordinal logistic modeling were applied. Akaike's Information Criteria (AIC) was used for model selection.
 RESULTS: In unadjusted analysis, Forced Expiratory Volume in 1 s (FEV1%) was inversely associated with the LTL attrition rate (standardized beta = -0.110, P = 0.023) but not with the baseline LTL. Forced Vital Capacity (FVC%) was inversely associated with the LTL attrition rate (standardized beta = -0.108, P = 0.026). Multivariable adjustment mildly attenuated the association with the LTL attrition rate (standardized beta = -0.100, P = 0.034 for FEV1% and -0.093, P = 0.042 for FVC%). This would be consistent with a 3.3% [95% Confidence Interval (CI): 3.1-3.4%] decline in FEV1% and a 3.0% (95% CI:2.8-3.1%) decline in FVC% per year. In linear regression models the LTL-pulmonary function association did not differ by sex, social mobility, pack-years smoking exposure, or level of GlycA, a novel systemic inflammatory marker.

CONCLUSIONS: Greater LTL attrition between mean age 30 and mean age 43 was associated with poorer lung function at mean age 50 years. The availability of longitudinal data on LTL attrition for the first time in the current study strengthens the case for LTL change preceding change in lung function.

RevDate: 2018-11-30

Audry J, Wang J, Eisenstatt JR, et al (2018)

The inhibition of checkpoint activation by telomeres does not involve exclusion of dimethylation of histone H4 lysine 20 (H4K20me2).

F1000Research, 7:1027.

DNA double-strand (DSBs) breaks activate the DNA damage checkpoint machinery to pause or halt the cell cycle. Telomeres, the specific DNA-protein complexes at linear eukaryotic chromosome ends, are capped DSBs that do not activate DNA damage checkpoints. This "checkpoint privileged" status of telomeres was previously investigated in the yeast Schizosaccharomyces pombe lacking the major double-stranded telomere DNA binding protein Taz1. Telomeric DNA repeats in cells lacking Taz1 are 10 times longer than normal and contain single-stranded DNA regions. DNA damage checkpoint proteins associate with these damaged telomeres, but the DNA damage checkpoint is not activated. This severing of the DNA damage checkpoint signaling pathway was reported to stem from exclusion of histone H4 lysine 20 dimethylation (H4K20me2) from telomeric nucleosomes in both wild type cells and cells lacking Taz1. However, experiments to identify the mechanism of this exclusion failed, prompting our re-evaluation of H4K20me2 levels at telomeric chromatin. In this short report, we used an extensive series of controls to identify an antibody specific for the H4K20me2 modification and show that the level of this modification is the same at telomeres and internal loci in both wild type cells and those lacking Taz1. Consequently, telomeres must block activation of the DNA Damage Response by another mechanism that remains to be determined.

RevDate: 2018-11-29

Werner CM, Hecksteden A, Morsch A, et al (2018)

Differential effects of endurance, interval, and resistance training on telomerase activity and telomere length in a randomized, controlled study.

European heart journal pii:5193508 [Epub ahead of print].

Aims: It is unknown whether different training modalities exert differential cellular effects. Telomeres and telomere-associated proteins play a major role in cellular aging with implications for global health. This prospective training study examines the effects of endurance training, interval training (IT), and resistance training (RT) on telomerase activity and telomere length (TL).

Methods and results: One hundred and twenty-four healthy previously inactive individuals completed the 6 months study. Participants were randomized to three different interventions or the control condition (no change in lifestyle): aerobic endurance training (AET, continuous running), high-intensive IT (4 × 4 method), or RT (circle training on 8 devices), each intervention consisting of three 45 min training sessions per week. Maximum oxygen uptake (VO2max) was increased by all three training modalities. Telomerase activity in blood mononuclear cells was up-regulated by two- to three-fold in both endurance exercise groups (AET, IT), but not with RT. In parallel, lymphocyte, granulocyte, and leucocyte TL increased in the endurance-trained groups but not in the RT group. Magnet-activated cell sorting with telomerase repeat-ampliflication protocol (MACS-TRAP) assays revealed that a single bout of endurance training-but not RT-acutely increased telomerase activity in CD14+ and in CD34+ leucocytes.

Conclusion : This randomized controlled trial shows that endurance training, IT, and RT protocols induce specific cellular pathways in circulating leucocytes. Endurance training and IT, but not RT, increased telomerase activity and TL which are important for cellular senescence, regenerative capacity, and thus, healthy aging.

RevDate: 2018-11-29

Tedone E, Huang E, O'Hara R, et al (2018)

Telomere length and telomerase activity in T cells are biomarkers of high-performing centenarians.

Aging cell [Epub ahead of print].

It is generally recognized that the function of the immune system declines with increased age and one of the major immune changes is impaired T-cell responses upon antigen presentation/stimulation. Some "high-performing" centenarians (100+ years old) are remarkably successful in escaping, or largely postponing, major age-related diseases. However, the majority of centenarians ("low-performing") have experienced these pathologies and are forced to reside in long-term nursing facilities. Previous studies have pooled all centenarians examining heterogeneous populations of resting/unstimulated peripheral blood mononuclear cells (PBMCs). T cells represent around 60% of PBMC and are in a quiescence state when unstimulated. However, upon stimulation, T cells rapidly divide and exhibit dramatic changes in gene expression. We have compared stimulated T-cell responses and identified a set of transcripts expressed in vitro that are dramatically different in high- vs. low-performing centenarians. We have also identified several other measurements that are different between high- and low-performing centenarians: (a) The amount of proliferation following in vitro stimulation is dramatically greater in high-performing centenarians compared to 67- to 83-year-old controls and low-performing centenarians; (b) telomere length is greater in the high-performing centenarians; and (c) telomerase activity following stimulation is greater in the high-performing centenarians. In addition, we have validated a number of genes whose expression is directly related to telomere length and these are potential fundamental biomarkers of aging that may influence the risk and progression of multiple aging conditions.

RevDate: 2018-11-29

Mosquera A, Rego-Pérez I, Blanco FJ, et al (2018)

Leukocyte Telomere Length in Patients with Radiographic Knee Osteoarthritis.

Environmental and molecular mutagenesis [Epub ahead of print].

Relative mean telomere sequence amount was determined by quantitative PCR (qPCR) of peripheral blood leukocyte (PBL) samples obtained at recruitment (n = 310) from individuals from the Osteoarthritis (OA) Initiative consortium. Knees were radiologically evaluated according to the Kellgren-Lawrence (KL) score, ranging from 0 to 4, considering a KL grade ≥ 2 as radiographic evidence of OA (n = 124). Telomere size decreased as baseline KL score increased, being significantly shorter in subjects with KL ≥2 (Mann-Whitney U-test, P < 0.0001). PBL telomere size was also associated with age, hypertension, body mass index (BMI) and waist circumference. Nevertheless, logistic regression analysis showed that PBL telomere size was a consistent risk factor for concurrent knee OA, independent of these health parameters. Shorter PBL telomeres may indicate a premature aging status which enhances chondrocyte senescence and degenerative joint disease. Environ. Mol. Mutagen. 2018. © 2018 Wiley Periodicals, Inc.

RevDate: 2018-11-28

Pernickova K, Linc G, Gaal E, et al (2018)

Out-of-position telomeres in meiotic leptotene appear responsible for chiasmate pairing in an inversion heterozygote in wheat (Triticum aestivum L.).

Chromosoma pii:10.1007/s00412-018-0686-5 [Epub ahead of print].

Chromosome pairing in meiosis usually starts in the vicinity of the telomere attachment to the nuclear membrane and congregation of telomeres in the leptotene bouquet is believed responsible for bringing homologue pairs together. In a heterozygote for an inversion of a rye (Secale cereale L.) chromosome arm in wheat, a distal segment of the normal homologue is capable of chiasmate pairing with its counterpart in the inverted arm, located near the centromere. Using 3D imaging confocal microscopy, we observed that some telomeres failed to be incorporated into the bouquet and occupied various positions throughout the entire volume of the nucleus, including the centromere pole. Rye telomeres appeared ca. 21 times more likely to fail to be included in the telomere bouquet than wheat telomeres. The frequency of the out-of-bouquet rye telomere position in leptotene was virtually identical to the frequency of telomeres deviating from Rabl's orientation in the nuclei of somatic cells, and was similar to the frequency of synapsis of the normal and inverted chromosome arms, but lower than the MI pairing frequency of segments of these two arms normally positioned across the volume of the nucleus. Out-of-position placement of the rye telomeres may be responsible for reduced MI pairing of rye chromosomes in hybrids with wheat and their disproportionate contribution to aneuploidy, but appears responsible for initiating chiasmate pairing of distantly positioned segments of homology in an inversion heterozygote.

RevDate: 2018-11-28

von Morgen P, J Maciejowski (2018)

The ins and outs of telomere crisis in cancer.

Genome medicine, 10(1):89 pii:10.1186/s13073-018-0596-4.

Telomere crisis is linked with many of the genomic alterations found in cancer genomes. A new understanding of how these alterations arise points towards an active role for innate immune sensors during crisis and to new opportunities for the treatment and diagnosis of cancer.

RevDate: 2018-11-27

Sousa CV, Aguiar SS, Santos PA, et al (2018)

Telomere length and redox balance in master endurance runners: The role of nitric oxide.

Experimental gerontology pii:S0531-5565(18)30293-6 [Epub ahead of print].

Leukocyte telomere length (LTL), a biological marker of aging that is associated with age-related diseases, is longer in master endurance runners (ER) than age-matched controls, but the underlying mechanisms are poorly investigated. The LTL, nitric oxide (NO), and redox balance of ER master runners were analyzed and compared to untrained middle-aged and young adults. We hypothesized that NO and redox balance at baseline would be related to longer LTL in ER athletes. Participants (n = 38) were long-term ER runners (n = 10; 51.6 ± 5.2 yrs.; 28.4 ± 9.4 yrs. of experience) and untrained age-matched (n = 17; 46.6 ± 7.1 yrs) and young controls (n = 11; 21.8 ± 4.0 yrs). Volunteers were assessed for anamnesis, anthropometrics, and blood sampling. Pro-oxidants, antioxidants, and DNA extraction were measured using commercial kits. Relative LTL was determined with qPCR analyses (T/S). While the middle-aged controls had shorter LTL than the young group, no difference was observed between ER athletes and young participants. A large effect size between the LTL of ER athletes and middle-aged controls (d = 0.85) was also observed. The ER athletes and untrained young group had better redox balance according to antioxidant/pro-oxidant ratios compared to middle-aged untrained participants, which also had lower values for redox parameters (TEAC/TBARS, SOD/TBARS, and CAT/TBARS; all p < 0.05). Furthermore, the NO level of ER athletes (175.2 ± 31.9 μM) was higher (p < 0.05) than middle-aged controls (67.2 ± 23.3 μM) and young participants (129.2 ± 17.3 μM), with a significant correlation with LTL (r = 0.766; p = 0.02). In conclusion, ER runners have longer LTL than age-matched controls, which in turn may be related to better NO bioavailability and redox balance status.

RevDate: 2018-11-27

Abraham Punnoose J, Ma Y, Hoque ME, et al (2018)

Random formation of G-quadruplexes in human telomere overhangs leads to a kinetic folding pattern with targetable vacant G-tracts.

Biochemistry [Epub ahead of print].

G-quadruplexes formed in the 3 telomere overhang (~200 nucleotides) have shown to regulate biological functions of human telomeres. The mechanism governing the population pattern of multiple telomeric G-quadruplexes is yet to be elucidated inside the telomeric overhang in a time window shorter than thermodynamic equilibrium. Using a single-molecule force ramping assay, we quantified G-quadruplex populations in telomere overhangs in a full physiological range of 99 to 291 nucleotides. We found that G-quadruplexes randomly form in these overhangs within seconds, which leads to a population governed by a kinetic, rather than thermodynamic, folding pattern. The kinetic folding gives rise to vacant G-tracts between G-quadruplexes. By targeting these vacant G-tracts using complementary DNA fragments, we demonstrated that binding to the telomeric G-quadruplexes becomes more efficient and specific for telomestatin derivatives.

RevDate: 2018-11-26

Wang W, Zhang H, Duan X, et al (2018)

Telomere Length in workers was effected by Omethoate exposure, GSTM1 deletion, Interaction between Smoking and GSTP1 Polymorphisms.

Journal of occupational and environmental medicine [Epub ahead of print].

OBJECTIVE: The aim of this study was to explore the association between telomere length and metabolizing enzyme gene polymorphisms and environmental factors in omethoate-exposed workers.

METHODS: The gene-environment interactions were analyzed with generalized linear model method.

RESULTS: The relative telomere lengths in the individuals with GSTM1-deletion were longer than that in non-deletion genotype in the control group (P = 0.011); the relative telomere lengths with GG+AG genotypes in GSTP1 rs1695 were longer than that of AA genotype in the exposure group (P = 0.039). The interaction between the GG+AG genotypes in GSTP1 rs1695 and smoking exposure had significant effect on telomere length (P < 0.05).

CONCLUSIONS: The prolongation of relative telomere length in omethoate exposed workers was associated with GSTM1-deletion, GG+AG genotypes, and interactions of GG+AG genotypes and smoking factor.

RevDate: 2018-11-26

Vasilishina A, Kropotov A, Spivak I, et al (2019)

Relative Human Telomere Length Quantification by Real-Time PCR.

Methods in molecular biology (Clifton, N.J.), 1896:39-44.

Telomere measurement by quantitative PCR amplification is a well-known simple method to detect telomere length that involves large numbers of samples. The method has been developed by Cawthon in 2002 (Cawthon, Nucleic Acids Res 30:47e-47, 2002) and remains the most frequently used technique either in original or modified version. Telomere length is estimated by comparing the amount of telomere repeat amplification product (T) to a single copy gene (S) product. The T/S ratio correlates with the average telomere length. Cawthon suggested and recommended the use of 36B4 (RPLP0) as a single copy gene. However, Cawthon's suggestion was no longer considered a single copy gene and the gene was not suitable and appropriate for normalization.We thereby introduced a simple method for relative measurement of average human telomere length using quantitative real-time PCR. Our protocol was based on Cawthon's initial technique (Cawthon, Nucleic Acids Res 30:47e-47, 2002), modified by single-copy gene (SCG) primers and optimized.This technique is rapid, low cost, not demanding on DNA amount (or live cells), and can be used for a high-throughput screening and time monitoring.

RevDate: 2018-11-26

Farladansky-Gershnabel S, Gal H, Kidron D, et al (2018)

Telomere Homeostasis and Senescence Markers Are Differently Expressed in Placentas From Pregnancies With Early- Versus Late-Onset Preeclampsia.

Reproductive sciences (Thousand Oaks, Calif.) [Epub ahead of print].

BACKGROUND:: Early-onset preeclampsia (EOPE; <34 weeks' gestation) usually has more severe morbidity for the mother and fetus compared to late-onset preeclampsia (LOPE). Telomere homeostasis is disrupted in preeclampsia (PE) and senescence markers are increased. The pathophysiologic differences between early and LOPE are not fully unraveled yet.

METHODS:: We studied placental biopsies from 7 pregnancies with EOPE, 6 pregnancies with LOPE, and 13 healthy gestational age-matched controls. Telomere length and aggregate formation were assessed using qualitative fluorescence in situ hybridization and electronic quantitative methods. Senescence markers were evaluated including senescence-associated heterochromatin foci, β-galactosidase (SAβ-Gal), and P16 staining, as was the expression of P16 complementary DNA (cDNA) using real-time quantitative polymerase chain reaction (RT-qPCR).

RESULTS:: There were no differences in maternal age, gravidity, parity, body mass index, and mode of conception between the study and the control groups. The percentage of trophoblasts with short telomeres was higher in placental samples from EOPE (52.61% [12.27%]) versus LOPE (28.72% [10.14%]); both were higher compared to controls (7.53% [5.14%], P = .03). Aggregate formation was enhanced in EOPE (8.72% [2.49%]) compared to LOPE (4.54% [1.45%]); both were higher than in healthy controls (2.72% [1.08%], P = .03). Trophoblasts from EOPE versus LOPE were more likely to stain positive for SAβ-Gal and P16 compared to controls (P < .001). P16 cDNA expression assayed by RT-qPCR was 7.51 times higher in EOPE compared to controls and 5.86 times higher than in LOPE.

CONCLUSIONS:: Impaired telomere homeostasis and senescence markers are more prominent in EOPE versus LOPE. These findings may contribute to our understanding of the pathophysiology and explain their different clinical presentations and outcomes.

RevDate: 2018-11-26

Bikkul MU, Faragher RGA, Worthington G, et al (2018)

Telomere elongation through hTERT immortalisation leads to chromosome repositioning in control cells and genomic instability in Hutchinson-Gilford Progeria syndrome fibroblasts, expressing a novel SUN1 isoform.

Genes, chromosomes & cancer [Epub ahead of print].

Immortalising primary cells with hTERT has been common practice to enable primary cells to be of extended use in the laboratory since they avoid replicative senescence. Studying exogenously expressed hTERT in cells also affords scientists models of early carcinogenesis and telomere behaviour. Control and the premature ageing disease - Hutchinson-Gilford Progeria Syndrome primary dermal fibroblasts, with and without the classical G608G mutation have been immortalised with exogenous hTERT. However, hTERT immortalisation surprisingly elicits genome reorganisation, in disease cells but also in the normal control cells, such that whole chromosome territories normally located at the nuclear periphery in proliferating fibroblasts become mis-localised in the nuclear interior. This includes chromosome 18 in the control fibroblasts and both chromosomes 18 and X in HGPS cells, which physically express an isoform of the LINC complex protein SUN1 that has previously only been theoretical. Additionally, this HGPS cell line has also become genomically unstable and has a tetraploid karyotype, which could be due to the novel SUN1 isoform. Long term treatment with the hTERT inhibitor BIBR1532 enabled the reduction of telomere length in the immortalised cells and resulted in these mis-localised internal chromosomes to be located at the nuclear periphery, as assessed in actively proliferating cells. Taken together, these findings reveal that elongated telomeres lead to dramatic chromosome mis-localisation, which can be restored with a drug treatment that results in telomere re-shortening and that a novel SUN1 isoform combined with elongated telomeres leads to genomic instability. Thus, care should be taken when interpreting data from genomic studies in hTERT immortalised cell lines. This article is protected by copyright. All rights reserved.

RevDate: 2018-11-25

Ain Q, Schmeer C, Penndorf D, et al (2018)

Cell cycle-dependent and -independent telomere shortening accompanies murine brain aging.

Aging pii:101655 [Epub ahead of print].

Replication-based telomere shortening during lifetime is species- and tissue-specific, however, its impact on healthy aging is unclear. In particular, the contribution of telomere truncation to the aging process of the CNS, where replicative senescence alone fails to explain organ aging due to low to absent mitotic activity of intrinsic populations, is undefined. Here, we assessed changes in relative telomere length in non-replicative and replicative neural brain populations and telomerase activity as a function of aging in C57BL/6 mice. Telomeres in neural cells and sub-selected neurons shortened with aging in a cell cycle-dependent and -independent manner, with preponderance in replicative moieties, implying that proliferation accelerates, but is not prerequisite for telomere shortening. Consistent with this telomere erosion, telomerase activity and nuclear TERT protein were not induced with aging. Knockdown of the Rela subunit of NF-κB, which controls both telomerase enzyme and subcellular TERT protein allocation, did also not influence telomerase activity or telomere length, in spite of its naive up-regulation selectively under aging conditions. We conclude that telomere instability is intrinsic to physiological brain aging beyond cell replication, and appears to occur independently of a functional interplay with NF-κB, but rather as a failure to induce or relocate telomerase.

RevDate: 2018-11-24

Wight DJ, Wallaschek N, Sanyal A, et al (2018)

Viral Proteins U41 and U70 of Human Herpesvirus 6A Are Dispensable for Telomere Integration.

Viruses, 10(11): pii:v10110656.

Human herpesvirus-6A and -6B (HHV-6A and -6B) are two closely related betaherpesviruses that infect humans. Upon primary infection they establish a life-long infection termed latency, where the virus genome is integrated into the telomeres of latently infected cells. Intriguingly, HHV-6A/B can integrate into germ cells, leading to individuals with inherited chromosomally-integrated HHV-6 (iciHHV-6), who have the HHV-6 genome in every cell. It is known that telomeric repeats flanking the virus genome are essential for integration; however, the protein factors mediating integration remain enigmatic. We have previously shown that the putative viral integrase U94 is not essential for telomere integration; thus, we set out to assess the contribution of potential viral recombination proteins U41 and U70 towards integration. We could show that U70 enhances dsDNA break repair via a homology-directed mechanism using a reporter cell line. We then engineered cells to produce shRNAs targeting both U41 and U70 to inhibit their expression during infection. Using these cells in our HHV-6A in vitro integration assay, we could show that U41/U70 were dispensable for telomere integration. Furthermore, additional inhibition of the cellular recombinase Rad51 suggested that it was also not essential, indicating that other cellular and/or viral factors must mediate telomere integration.

RevDate: 2018-11-29

Yamaki N, Matsushita S, Hara S, et al (2018)

Telomere shortening in alcohol dependence: Roles of alcohol and acetaldehyde.

Journal of psychiatric research, 109:27-32 pii:S0022-3956(18)30428-X [Epub ahead of print].

Heavy drinking leads to premature aging and precipitates the onset of age-related diseases. Acetaldehyde (AcH), a toxic metabolite of ethanol, has been implicated in various types of cancer. However, whether alcohol accelerates biological aging at a cellular level is controversial and the mechanism involved is unclear. We addressed these questions by measuring telomere length (TL) in peripheral blood leukocytes of Japanese patients with alcohol dependence (AD) and examined the association between TL, genetic variants of alcohol dehydrogenase (ADH)1B and aldehyde dehydrogenase (ALDH)2, and other clinical characteristics. A total of 134 male AD patients and 121 age- and sex-matched healthy controls were evaluated. All patients received endoscopic screening for cancer of the upper aerodigestive tract (UADT). TL was almost 50% shorter in AD patients relative to controls. There were no significant differences in TL between AD patients with and without UADT cancer, and no associations between ADH1B and ALDH2 genotypes and TL. AD patients with thiamine (vitamin B1) deficiency at admission had significantly shorter TL than those with normal thiamine status. Although the exact mechanism underlying the shorter TL in AD patients remain unclear, our findings suggest that alcohol rather than AcH is associated with telomere shortening in AD, which may be accelerated by thiamine deficiency. Future studies should also focus on the association between telomere shortening and TD in the context of oxidative stress.

RevDate: 2018-11-21

Tsur N, Levin Y, Abumock H, et al (2018)

One 'knows': self-rated health and telomere length among ex-prisoners of war.

Psychology & health [Epub ahead of print].

OBJECTIVE: Ill-health and early mortality are amongst the most significant ramifications of trauma. Furthermore, trauma alters the subjective perception and experience of the body. The aim of this study is to examine the extent to which deteriorations in perceived health among traumatised individuals are associated with cellular health as manifested in telomere length.

METHODS: Specifically, 88 former prisoners of war (ex-POWs) evaluated their health (self-rated health; SRH) at 18 (T1), 35 (T2) and 42 (T3) years after the war, and were assessed for telomere length at T3. Health behaviour, BMI, morbidity and PTSD were also examined at T3.

RESULTS: The findings demonstrated that SRH was cross-sectionally correlated with telomere length. Furthermore, a significant sequential indirect effect was found, in which worse SRH in T1 was associated with shorter telomere length at T3, through worse SRH at T2 and at T3.

CONCLUSIONS: These findings demonstrate that long-term deteriorations in the subjective evaluations of health are implicated in actual cellular health among individuals exposed to trauma.

RevDate: 2018-11-23

Palmos AB, Breen G, Goodwin L, et al (2018)

Genetic Risk for Psychiatric Disorders and Telomere Length.

Frontiers in genetics, 9:468.

Background: Previous studies have revealed associations between psychiatric disorder diagnosis and shorter telomere length. Here, we attempt to discern whether genetic risk for psychiatric disorders, or use of pharmacological treatments (i.e., antidepressants), predict shorter telomere length and risk for aging-related disease in a United Kingdom population sample. Methods: DNA samples from blood were available from 351 participants who were recruited as part of the South East London Community Health (SELCoH) Study, and for which whole-genome genotype data was available. Leukocyte telomere length was characterized using quantitative polymerase chain reactions. Individualized polygenic risk scores for major depressive disorder (MDD), bipolar disorder (BD), and schizophrenia (SCZ) were calculated using Psychiatric Genomics Consortium summary statistics. We subsequently performed linear models, to discern the impact polygenic risk for psychiatric disorders (an etiological risk factor) and antidepressant use (common pharmacological treatment) have on telomere length, whilst accounting for other lifestyle/health factors (e.g., BMI, smoking). Results: There were no significant associations between polygenic risk for any of the psychiatric disorders tested and telomere length (p > 0.05). Antidepressant use was significantly associated with shorter telomere length and this was independent from a depression diagnosis or current depression severity (p ≤ 0.01). Antidepressant use was also associated with a significantly higher risk of aging-related disease, which was independent from depression diagnosis (p ≤ 0.05). Conclusion: Genetic risk for psychiatric disorders is not associated with shorter telomere length. Further studies are now needed to prospectively characterize if antidepressant use increases risk for aging-related disease and telomere shortening, or whether people who age faster and have aging-related diseases are just more likely to be prescribed antidepressants.

RevDate: 2018-11-22

Majerska J, Feretzaki M, Glousker G, et al (2018)

Transformation-induced stress at telomeres is counteracted through changes in the telomeric proteome including SAMHD1.

Life science alliance, 1(4):e201800121 pii:LSA-2018-00121.

Telomeres play crucial roles during tumorigenesis, inducing cellular senescence upon telomere shortening and extensive chromosome instability during telomere crisis. However, it has not been investigated if and how cellular transformation and oncogenic stress alter telomeric chromatin composition and function. Here, we transform human fibroblasts by consecutive transduction with vectors expressing hTERT, the SV40 early region, and activated H-RasV12. Pairwise comparisons of the telomeric proteome during different stages of transformation reveal up-regulation of proteins involved in chromatin remodeling, DNA repair, and replication at chromosome ends. Depletion of several of these proteins induces telomere fragility, indicating their roles in replication of telomeric DNA. Depletion of SAMHD1, which has reported roles in DNA resection and homology-directed repair, leads to telomere breakage events in cells deprived of the shelterin component TRF1. Thus, our analysis identifies factors, which accumulate at telomeres during cellular transformation to promote telomere replication and repair, resisting oncogene-borne telomere replication stress.

RevDate: 2018-11-22

Wang CY (2018)

Asynchronous Shortening of Telomere Length and Cardiovascular Outcomes.

JACC. Basic to translational science, 3(5):601-603 pii:S2452-302X(18)30233-X.

RevDate: 2018-11-22

Yin H, Akawi O, Fox SA, et al (2018)

Cardiac-Referenced Leukocyte Telomere Length and Outcomes After Cardiovascular Surgery.

JACC. Basic to translational science, 3(5):591-600 pii:S2452-302X(18)30146-3.

Leukocyte telomere shortening reflects stress burdens and has been associated with cardiac events. However, the patient-specific clinical value of telomere assessment remains unknown. Moreover, telomere shortening cannot be inferred from a single telomere length assessment. The authors investigated and developed a novel strategy for gauging leukocyte telomere shortening using autologous cardiac atrial referencing. Using multitissue assessments from 163 patients who underwent cardiovascular surgery, we determined that the cardiac atrium-leukocyte telomere length difference predicted post-operative complexity. This constituted the first evidence that a single-time assessment of telomere dynamics might be salient to acute cardiac care.

RevDate: 2018-11-26

Davinelli S, Trichopoulou A, Corbi G, et al (2018)

The potential nutrigeroprotective role of Mediterranean diet and its functional components on telomere length dynamics.

Ageing research reviews, 49:1-10 pii:S1568-1637(18)30198-3 [Epub ahead of print].

The Mediterranean diet (MD) is a gold standard for nutrition and the most evidence-based diet to delay the onset of age-associated pathologies. Telomeres are the heterochromatic repeat regions found at the ends of eukaryotic chromosomes, whose length is considered a reliable hallmark of biological ageing. Telomere shortening is, at least in part, a modifiable factor and there is evidence that adherence to the MD is associated with longer telomeres. Data from several studies indicate an association between "inflammatory/oxidative status" and telomere length (TL). The MD, as a complex exposome with thousands of nutrients and phytochemicals, may positively influence telomere attrition by reducing inflammation and oxidative stress. However, it is unclear whether the protective effects on TL provided by the MD result from its individual constituents or some combination of these. Furthermore, these properties of the MD and its components are not yet fully validated by clinical endpoints in randomized trials or observational studies. Here, we summarize the data from experimental and population-based studies on the effects of the MD on TL maintenance. We will both highlight the possible role of the MD in the prevention of age-associated diseases, and attempt to identify certain aspects of the diet that are particularly important for telomere maintenance.

RevDate: 2018-11-16

Demerdash HM, Elyamany AS, E Arida (2018)

Impact of direct-acting antivirals on leukocytic DNA telomere length in hepatitis C virus-related hepatic cirrhosis.

European journal of gastroenterology & hepatology [Epub ahead of print].

BACKGROUND: Direct-acting antiviral (DAAs) represent advancement in the management of hepatitis C virus (HCV)-related hepatic cirrhosis. A high proportion of patients achieve a sustained virologic response; eradication of HCV is coupled with a decreased risk of hepatocellular carcinoma. Recent evidence suggests that shortening of the DNA telomere may be linked to cellular senescence as well as predisposition to malignant transformation.

OBJECTIVE: This study aimed to assess pretreatment leukocytic DNA telomere length in HCV-related cirrhosis and post viral eradication using DAAs.

PATIENTS AND METHODS: This study included 24 patients with HCV-related cirrhosis, Child-Pugh A. Whole-blood samples were obtained from patients before treatment and 12 weeks after the end of treatment, as well as from 24 healthy controls. Terminal restriction fragment, corresponding to telomere length, was measured using a nonradioactive Southern blot technique, detected by chemiluminescence.

RESULTS: DNA telomere length was significantly shorter before treatment compared with 12 weeks after end of treatment in HCV-related cirrhotic patients. Also, it was significantly shorter in patients before treatment compared with healthy individuals.

CONCLUSION: Telomere elongation in blood leukocytes can be considered a marker of recovery of inflammation after DAAs-induced HCV eradication. Still, the possibility of activation by cancer initiation cannot be excluded.

RevDate: 2018-11-16

de Souza MR, Kahl VFS, Rohr P, et al (2018)

Shorter telomere length and DNA hypermethylation in peripheral blood cells of coal workers.

Mutation research, 836(Pt B):36-41.

Coal is a mixture of several chemicals, mainly inorganic elements and polycyclic aromatic hydrocarbons, many of which have mutagenic and carcinogenic effects. Pneumoconiosis, fibrosis, asbestosis, silicosis, emphysema, loss of lung function and cancer are some examples of coal-related disorders. The aim of this study was to analyze coal miners with respect to telomere length (TL) and percentage (%) of global DNA methylation. The study involved 82 participants divided into two groups: 55 workers exposed to coal and 27 non-exposed individuals. DNA was isolated from peripheral blood samples from all individuals. Telomeres were measured by quantitative real time polymerase chain reaction (qPCR) and global DNA methylation levels were performed by the relative quantitation of 5-methyl-2'-deoxycytidine (5-mdC) by high-performance liquid chromatography (HPLC). TL measurements showed a mean of 9,199 bp (±4,196) for non-exposed and 7,545 bp (±2,703) for exposed groups, and% of global DNA methylation a mean of 2.78% (±0.41) for non-exposed and 3.00% (±0.37) for exposed individuals. Occupationally exposed individuals showed a significant decrease of TL (P < 0.05; Mann-Whitney test) and increase in the percentage of global DNA methylation (P < 0.05; Mann-Whitney test) when compared to the non-exposed group. This study showed that occupational exposure to coal and products of combustion is positively associated with TL and DNA methylation. Previously, we have evaluated the same individuals using comet assay, micronucleus (MN) test, oxidative stress and inorganic elements. No correlations were observed between TL and methylation with previous data in the exposed group. Further studies are needed to determine whether these alterations are associated with induced disease outcomes and if these events could be determinants to identify cancer risk.

RevDate: 2018-11-29

Mukherjee AK, Sharma S, Sengupta S, et al (2018)

Telomere length-dependent transcription and epigenetic modifications in promoters remote from telomere ends.

PLoS genetics, 14(11):e1007782 pii:PGENETICS-D-18-00930.

Telomere-binding proteins constituting the shelterin complex have been studied primarily for telomeric functions. However, mounting evidence shows non-telomeric binding and gene regulation by shelterin factors. This raises a key question-do telomeres impact binding of shelterin proteins at distal non-telomeric sites? Here we show that binding of the telomere-repeat-binding-factor-2 (TRF2) at promoters ~60 Mb from telomeres depends on telomere length in human cells. Promoter TRF2 occupancy was depleted in cells with elongated telomeres resulting in altered TRF2-mediated transcription of distal genes. In addition, histone modifications-activation (H3K4me1 and H3K4me3) as well as silencing marks (H3K27me3)-at distal promoters were telomere length-dependent. These demonstrate that transcription, and the epigenetic state, of telomere-distal promoters can be influenced by telomere length. Molecular links between telomeres and the extra-telomeric genome, emerging from findings here, might have important implications in telomere-related physiology, particularly ageing and cancer.

RevDate: 2018-11-14

Guha M, Srinivasan S, Johnson FB, et al (2018)

hnRNPA2 mediated acetylation reduces telomere length in response to mitochondrial dysfunction.

PloS one, 13(11):e0206897 pii:PONE-D-17-40813.

Telomeres protect against chromosomal damage. Accelerated telomere loss has been associated with premature aging syndromes such as Werner's syndrome and Dyskeratosis Congenita, while, progressive telomere loss activates a DNA damage response leading to chromosomal instability, typically observed in cancer cells and senescent cells. Therefore, identifying mechanisms of telomere length maintenance is critical for understanding human pathologies. In this paper we demonstrate that mitochondrial dysfunction plays a causal role in telomere shortening. Furthermore, hnRNPA2, a mitochondrial stress responsive lysine acetyltransferase (KAT) acetylates telomere histone H4at lysine 8 of (H4K8) and this acetylation is associated with telomere attrition. Cells containing dysfunctional mitochondria have higher telomere H4K8 acetylation and shorter telomeres independent of cell proliferation rates. Ectopic expression of KAT mutant hnRNPA2 rescued telomere length possibly due to impaired H4K8 acetylation coupled with inability to activate telomerase expression. The phenotypic outcome of telomere shortening in immortalized cells included chromosomal instability (end-fusions) and telomerase activation, typical of an oncogenic transformation; while in non-telomerase expressing fibroblasts, mitochondrial dysfunction induced-telomere attrition resulted in senescence. Our findings provide a mechanistic association between dysfunctional mitochondria and telomere loss and therefore describe a novel epigenetic signal for telomere length maintenance.

RevDate: 2018-11-14

Warny M, Helby J, Sengeløv H, et al (2018)

Bone marrow mononuclear cell telomere length in acute myeloid leukaemia and high-risk myelodysplastic syndrome.

European journal of haematology [Epub ahead of print].

OBJECTIVE: Short telomere length is a known risk factor for developing clonal hematopoietic stem cell disorders, probably due to chromosomal instability. We tested the hypotheses that bone marrow mononuclear cell telomere length change from diagnosis through chemotherapy-induced remission and relapse, and that long telomere length is associated with low risk of relapse and all-cause mortality in patients with acute myeloid leukaemia or high-risk myelodysplastic syndrome.

METHODS: We measured telomere length in bone marrow mononuclear cells from 233 patients at diagnosis, 112 patients at chemotherapy-induced remission and 58 patients at relapse of disease.

RESULTS: In patients with acute myeloid leukaemia or high-risk myelodysplastic syndrome, bone marrow mononuclear cell telomere length was similar at diagnosis and relapse, but increased after chemotherapy-induced remission. Furthermore, bone marrow mononuclear cell telomere length was longer in patients with higher age at diagnosis. There was no association between telomere length at diagnosis, remission or relapse and all-cause mortality, nor did we find any association between telomere length at diagnosis or remission and risk of relapse.

CONCLUSION: In patients with acute myeloid leukaemia or high-risk myelodysplastic syndrome, bone marrow mononuclear cell telomere length increased from diagnosis to remission. Furthermore, telomere length paradoxically was longer at higher age at diagnosis, even after adjusting for known risk factors of disease severity. Finally, we did not detect any prognostic information in telomere length. This article is protected by copyright. All rights reserved.

RevDate: 2018-11-13

Ahvenainen TV, Mäkinen NM, von Nandelstadh P, et al (2018)

Loss of ATRX/DAXX expression and alternative lengthening of telomeres in uterine leiomyomas.

Cancer [Epub ahead of print].

BACKGROUND: Uterine leiomyomas (ULs) are the most common gynecologic tumors and affect 3 of every 4 women by the age of 50 years. The majority of ULs are classified as conventional tumors, whereas 10% represent various histopathological subtypes with features that mimic malignancy. These subtypes include cellular and mitotically active ULs and ULs with bizarre nuclei. Uterine leiomyosarcoma (ULMS), the malignant counterpart of UL, is an aggressive cancer with poor overall survival. The early diagnosis and preoperative differentiation of ULMS from UL are often challenging because their symptoms and morphology resemble one another. Recent studies have shown frequent loss of alpha-thalassemia/mental retardation syndrome X-linked (ATRX) or death domain-associated protein (DAXX) expression in ULMS, and this is often associated with an alternative lengthening of telomeres (ALT) phenotype.

METHODS: To investigate ATRX and DAXX expression and the presence of ALT in UL subtypes, immunohistochemical and telomere-specific fluorescence in situ hybridization analyses were performed. The study material consisted of 142 formalin-fixed, paraffin-embedded tissue samples representing various UL subtypes and 64 conventional ULs.

RESULTS: A loss of ATRX or DAXX and/or ALT was detected in 6.3% of the histopathological UL subtype samples (9 of 142). Two patients whose ULs showed either ATRX loss or ALT were later diagnosed with a pulmonary smooth muscle tumor. Pulmonary tumors displayed molecular alterations found in the corresponding uterine tumors, which indicated metastasis to the lungs. All conventional ULs displayed normal ATRX, DAXX, and telomeres.

CONCLUSIONS: These results highlight the differences between conventional and histopathologically atypical ULs and indicate that some UL subtype tumors may harbor long-term malignant potential.

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

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

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

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

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

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

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

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