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Bibliography on: Telomeres

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ESP: PubMed Auto Bibliography 20 Nov 2019 at 01:48 Created: 


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

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

Citations The Papers (from PubMed®)

RevDate: 2019-11-19

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

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

Nature communications, 10(1):4990 pii:10.1038/s41467-019-13018-3.

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

RevDate: 2019-11-18

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

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

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

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

RevDate: 2019-11-17

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

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

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

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

RevDate: 2019-11-16

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

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

Sleep pii:5626508 [Epub ahead of print].

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

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

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

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

RevDate: 2019-11-15

Wattis JAD, Qi Q, HM Byrne (2019)

Mathematical modelling of telomere length dynamics.

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

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

RevDate: 2019-11-15

Smith EM, Pendlebury DF, J Nandakumar (2019)

Structural biology of telomeres and telomerase.

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

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

RevDate: 2019-11-15

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

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

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

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

RevDate: 2019-11-15

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

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

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

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

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

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

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

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

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

RevDate: 2019-11-14

Swyers NC, Cody JP, McCaw ME, et al (2016)

Telomere-Mediated Chromosomal Truncation for Generating Engineered Minichromosomes in Maize.

Current protocols in plant biology, 1(3):488-500.

Minichromosomes have been generated in maize using telomere-mediated truncation. Telomere DNA, because of its repetitive nature, can be difficult to manipulate. The protocols in this unit describe two methods for generating the telomere DNA required for the initiation of telomere-mediated truncation. The resulting DNA can then be used with truncation cassettes for introduction into maize via transformation. © 2016 by John Wiley & Sons, Inc.

RevDate: 2019-11-14

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

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

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

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

RevDate: 2019-11-14

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

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

Journal of nutritional science, 8:e35 pii:00032.

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

RevDate: 2019-11-13

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

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

Asia Pacific allergy, 9(4):e33 pii:2019090404.

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

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

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

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

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

RevDate: 2019-11-12

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

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

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

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

RevDate: 2019-11-10

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

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

Aging, 11: pii:102439 [Epub ahead of print].

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

RevDate: 2019-11-10

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

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

Acta neuropathologica communications, 7(1):175 pii:10.1186/s40478-019-0833-0.

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

RevDate: 2019-11-09

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

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

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

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

RevDate: 2019-11-09

Muneer A (2019)

Interventions Addressing the Telomere-Telomerase System.

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

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

RevDate: 2019-11-07

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

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

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

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

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

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

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

RevDate: 2019-11-07

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

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

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

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

RevDate: 2019-11-06

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

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

Oncotarget, 10(58):6245-6259 pii:27264.

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

RevDate: 2019-11-06

Lirussi L, H Nilsen (2019)

Telomere maintenance: regulating hTERC fate through RNA modifications.

Molecular & cellular oncology, 6(6):e1670489 pii:1670489.

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

RevDate: 2019-11-05

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

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

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

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

RevDate: 2019-11-05

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

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

Psychosomatic medicine [Epub ahead of print].

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

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

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

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

RevDate: 2019-11-05

Tucker LA (2019)

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

Oxidative medicine and cellular longevity, 2019:4358717.

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

RevDate: 2019-11-05

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

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

Proceedings of the National Academy of Sciences of the United States of America pii:1905381116 [Epub ahead of print].

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

RevDate: 2019-11-04

Saha A, Nanavaty VP, B Li (2019)

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

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

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

RevDate: 2019-11-04

Verhulst S (2019)

Improving comparability between qPCR-based telomere studies.

Molecular ecology resources [Epub ahead of print].

Telomeres, the complex of the repeated DNA sequence TTAGGGn and associated proteins at the end of linear chromosomes, are attracting increasing attention because of associations of telomere length with morbidity and mortality (e.g. Boonekamp, Simons, Hemerik & Verhulst, 2013; Verhulst et al., 2016). There are multiple techniques to measure telomeres, each with their own advantages and disadvantages (Aubert & Lansdorp 2008; Nussey et al., 2014), but the majority of studies measured telomere length using either real time quantitative PCR (qPCR; Cawthon, 2002) or Southern blot (Kimura et al., 2010).

RevDate: 2019-11-01

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

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

Drug development research [Epub ahead of print].

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

RevDate: 2019-11-01

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

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

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

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

RevDate: 2019-10-30

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

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

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

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

RevDate: 2019-10-30

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

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

Nucleus (Austin, Tex.) [Epub ahead of print].

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

RevDate: 2019-10-30

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

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

Bioconjugate chemistry [Epub ahead of print].

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

RevDate: 2019-10-30

Liu P, Zhang Y, L Ma (2019)

Telomere length and associated factors in older adults with hypertension.

The Journal of international medical research [Epub ahead of print].

RevDate: 2019-10-28

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

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

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

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

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

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

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

RevDate: 2019-10-28

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

Diet, physical activity and telomere length in adults.

Nutricion hospitalaria [Epub ahead of print].

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

RevDate: 2019-10-26

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

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

Scientific reports, 9(1):15307 pii:10.1038/s41598-019-51902-6.

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

RevDate: 2019-10-25

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

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

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

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

RevDate: 2019-10-25

Alrefaei GI, Karim S, H Abduljabbar (2019)

Impact of mothers' age on telomere length and human telomerase reverse transcriptase expression in human foetal membrane-derived mesenchymal stem cells.

Stem cells and development [Epub ahead of print].

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

RevDate: 2019-10-24

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

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

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

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

RevDate: 2019-10-24

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

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

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

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

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

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

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

RevDate: 2019-10-25

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

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

Bioscience reports, 39(10):.

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

RevDate: 2019-10-24

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

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

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

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

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

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

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

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

RevDate: 2019-10-24

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

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

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

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

RevDate: 2019-10-24

Keener R, Connelly CJ, CW Greider (2019)

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

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

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

RevDate: 2019-10-24

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

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

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

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

RevDate: 2019-10-23

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

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

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

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

RevDate: 2019-10-22

Denham J (2019)

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

Animal genetics [Epub ahead of print].

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

RevDate: 2019-10-21

Germann CB (2019)

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

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

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

RevDate: 2019-10-21

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

Senescent human melanocytes drive skin ageing via paracrine telomere dysfunction.

The EMBO journal [Epub ahead of print].

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

RevDate: 2019-10-21

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

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

Communications biology, 2:376 pii:621.

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

RevDate: 2019-10-21

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

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

Science advances, 5(10):eaax6366 pii:aax6366.

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

RevDate: 2019-10-21

Niu Z, Li K, Xie C, et al (2019)

Adverse Birth Outcomes and Birth Telomere Length: A Systematic Review and Meta-Analysis.

The Journal of pediatrics pii:S0022-3476(19)31098-4 [Epub ahead of print].

OBJECTIVES: To synthesize previous findings on the difference in birth telomere length between newborns with and without intrauterine growth restriction (IUGR) or with and without preterm birth.

STUDY DESIGN: We systematically searched 3 databases (PubMed, Embase, and Web of Science) for publications that examined the relationships of IUGR or preterm birth with birth telomere length. We conducted meta-analysis to pool the estimated difference in birth telomere length either between IUGR and non-IUGR or between preterm birth and full-term birth. Subgroup analyses were conducted by tissues (newborn blood vs placenta) and techniques used for telomere length measurement (quantitative polymerase chain reaction [qPCR] vs telomere restriction fragment).

RESULTS: We included 11 articles on comparing birth telomere length between IUGR (combined n = 227) and non-IUGR (n = 1897) and 7 articles on comparing birth telomere length between preterm birth (n = 182) and full-term birth (n = 1320). We found IUGR was associated with shorter birth telomere length only when birth telomere length was measured in placenta (pooled standardized mean difference [SMD] = -0.85; 95% CI -1.13 to -0.57; IUGR/non-IUGR n = 87/173), but not in newborn blood (pooled SMD = 0.00, 95% CI -0.18 to 0.19; IUGR/non-IUGR n = 148/1733). Birth telomere length was significantly longer in preterm birth than in full-term birth when birth telomere length was measured by qPCR (pooled SMD = 0.40, 95% CI 0.18-0.63; preterm birth/full-term birth n = 137/682) but not by telomere restriction fragment (pooled SMD = 0.05, 95% CI -0.29 to 0.38; preterm birth/full-term birth n = 44/444).

CONCLUSIONS: IUGR is associated with shorter placental telomere length and preterm birth is associated with longer birth telomere length measured by qPCR.

RevDate: 2019-10-19

Humphreys KL, Sisk LM, Manczak EM, et al (2019)

Depressive Symptoms Predict Change in Telomere Length and Mitochondrial DNA Copy Number Across Adolescence.

Journal of the American Academy of Child and Adolescent Psychiatry pii:S0890-8567(19)32100-8 [Epub ahead of print].

OBJECTIVE: Several studies have found associations between a diagnosis or symptoms of major depressive disorder and markers of cellular aging and dysfunction. These investigations, however, are predominantly cross-sectional and focus on adults. In the present study, we used a prospective longitudinal design to test the cross-sectional association between depressive symptoms in adolescents and telomere length (TL) as well as mitochondrial DNA copy number (mtDNA-cn).

METHOD: 121 adolescents (Mean age=11.38, SD=1.03; 39 percent male) were followed for approximately two years. At baseline and follow-up, participants provided saliva for DNA extraction, from which measures of TL and mtDNA-cn were obtained. Depressive symptoms were obtained via the Children's Depression Inventory.

RESULTS: There was no association between depressive symptoms and markers of cellular aging at baseline; however, depressive symptoms at baseline predicted higher rates of telomere erosion (β=-.201, p=.016) and greater increases in mtDNA-cn (β=.190, p=.012) over the follow-up period. Markers of cellular aging at baseline did not predict subsequent changes in depressive symptoms. Furthermore, including number of stressful life events did not alter these patterns of findings.

CONCLUSION: These results indicate that depressive symptoms precede changes in cellular aging and dysfunction, rather than the reverse.

RevDate: 2019-10-18

Amir M, Mohammad T, Prasad K, et al (2019)

Virtual high-throughput screening of natural compounds in-search of potential inhibitors for protection of telomeres 1 (POT1).

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

Protection of telomeres 1 (POT1) is widely known to protect ends of chromosome from catastrophic chromosome instability, illegitimate recombination and abnormal segregation. Owing to its remarkable role in cancer progression, metastasis and other inflammatory diseases, POT1 presents a novel target for developing effective therapy for associated diseases. In this study, we have performed structure-based virtual high-throughput screening of natural compounds from ZINC database and resulted hits were subjected to predict drug likeness. Binding affinities and interaction analysis were performed to find best and selective POT1 inhibitors. Finally, two natural compounds (ZINC00005600 and ZINC00020258) bearing high affinity and specificity to binding pocket of POT1 were selected. These compounds preferentially interact to the functionally important residues of nucleotide-binding pocket of POT1. Docking results were further complemented by molecular dynamics simulations for 100 ns to assess the change in conformational dynamics, interaction mechanism and stability of POT1. Both compounds stabilize the structure of POT1 as suggested by RMSD, RMSF, essential dynamics and free energy landscape analysis. In conclusion, the identified compounds can further be exploited as lead to develop potential inhibitors of POT1 for therapeutic applications against associated diseases.

RevDate: 2019-10-18

Muñoz-Lorente MA, Cano-Martin AC, MA Blasco (2019)

Mice with hyper-long telomeres show less metabolic aging and longer lifespans.

Nature communications, 10(1):4723 pii:10.1038/s41467-019-12664-x.

Short telomeres trigger age-related pathologies and shorter lifespans in mice and humans. In the past, we generated mouse embryonic (ES) cells with longer telomeres than normal (hyper-long telomeres) in the absence of genetic manipulations, which contributed to all mouse tissues. To address whether hyper-long telomeres have deleterious effects, we generated mice in which 100% of their cells are derived from hyper-long telomere ES cells. We observe that these mice have longer telomeres and less DNA damage with aging. Hyper-long telomere mice are lean and show low cholesterol and LDL levels, as well as improved glucose and insulin tolerance. Hyper-long telomere mice also have less incidence of cancer and an increased longevity. These findings demonstrate that longer telomeres than normal in a given species are not deleterious but instead, show beneficial effects.

RevDate: 2019-10-17

Wan ES, Goldstein RL, Fan VS, et al (2019)

Telomere length in COPD: Relationships with physical activity, exercise capacity, and acute exacerbations.

PloS one, 14(10):e0223891 pii:PONE-D-19-14110.

RATIONALE: Shorter leukocyte telomere length (LTL) is associated with reduced health-related quality of life and increased risk for acute exacerbations (AEs) and mortality in chronic obstructive pulmonary disease (COPD). Increased physical activity and exercise capacity are associated with reduced risk for AEs and death. However, the relationships between LTL and physical activity, exercise capacity, and AEs in COPD are unknown.

METHODS: Data from 3 COPD cohorts were examined: Cohort 1 (n = 112, physical activity intervention trial), Cohorts 2 and 3 (n = 182 and 294, respectively, separate observational studies). Subjects completed a 6-minute walk test (6MWT) and provided blood for LTL assessment using real-time PCR. Physical activity was measured as average daily step count using an accelerometer or pedometer. Number of self-reported AEs was available for 1) the year prior to enrollment (Cohorts 1 and 3) and 2) prospectively after enrollment (all cohorts). Multivariate models examined associations between LTL and average daily step count, 6MWT distance, and AEs.

RESULTS: A significant association between longer LTL and increased 6MWT distance was observed in the three combined cohorts (β = 3x10-5, p = 0.045). No association between LTL and average daily step count was observed. Shorter LTL was associated with an increased number of AEs in the year prior to enrollment (Cohorts 1 and 3 combined, β = -1.93, p = 0.04) and with prospective AEs (Cohort 3, β = -1.3388, p = 0.0003).

CONCLUSIONS: Among COPD patients, increased LTL is associated with higher exercise capacity, but not physical activity. Shorter LTL was associated with AEs in a subgroup of cohorts.

RevDate: 2019-10-17

Fitzpatrick LJ, Olsson M, Parsley LM, et al (2019)

Temperature and telomeres: thermal treatment influences telomere dynamics through a complex interplay of cellular processes in a cold-climate skink.

Oecologia pii:10.1007/s00442-019-04530-w [Epub ahead of print].

Telomere dynamics vary fundamentally between endothermic populations and species as a result of differences in life history, yet we know little about these patterns in ectotherms. In ectotherms, the relationships between climate, metabolism and life history suggest that telomere attrition should be higher at relatively high environmental temperatures compared to relatively low environmental temperatures, but these effects may vary between populations due to local adaptation. To address this hypothesis, we sampled reactive oxygen species (ROS) and telomere length of lizards from warm lowland and cool highland populations of a climatically widespread lizard species that we exposed to hot or cold basking treatments. The hot treatment increased relative telomere length compared to the cold treatment independent of climatic origin or ROS levels. Lizards from the cool highland region had lower ROS levels than those from the warm lowland region. Within the highland lizards, ROS increased more in the cold basking treatment than the hot basking treatment. These results are in the opposite direction to those predicted, suggesting that the relationships between temperature, metabolism, ROS and telomere dynamics are not straightforward. Future work incorporating detailed understanding of the thermal reaction norms of these and other linked traits is needed to fully understand these processes.

RevDate: 2019-10-17

Liu S, Wang C, Green G, et al (2019)

Peripheral Blood Leukocyte Telomere Length is Associated with Survival of Sepsis Patients.

The European respiratory journal pii:13993003.01044-2019 [Epub ahead of print].

Shorter peripheral blood leukocyte (PBL) telomere length (TL) has been associated with poor outcomes in various chronic lung diseases. Whether PBL-TL is associated with survival from critical illness was tested in this study.We analysed data from a prospective observational cohort study of 937 critically ill patients at Vanderbilt University Medical Center (VUMC). TL was measured by qPCR of DNA isolated from PBL. Findings were validated in an independent cohort of 394 critically ill patients with sepsis admitted to the University of California San Francisco (UCSF).In the VUMC cohort, shorter PBL-TL was associated with worse 90-day survival (adjusted HR 1.3 per 1 kb TL decrease, 95%CI [1.1-1.6], p=0.004); in subgroup analyses, shorter PBL-TL was associated with worse 90-day survival for patients with sepsis (adjusted HR 1.5 per 1 kb TL decrease, 95%CI [1.2-2.0], p=0.001) but not trauma. Although not associated with development of ARDS, among ARDS subjects, shorter PBL-TL was associated with more severe ARDS (OR 1.7 per 1 kb TL decrease, 95%CI [1.2-2.5], p=0.006). The associations of PBL-TL with survival (adjusted HR 1.6 per 1 kb TL decrease, 95%CI [1.2-2.1], p=0.003) and risk for developing severe ARDS (OR 2.5 per 1 kb TL decrease, 95%CI [1.1-6.3], p-value=0.044) were validated in the UCSF cohort.Short PBL-TL is strongly associated with worse survival and more severe ARDS in critically ill patients, especially patients with sepsis. These findings suggest that telomere dysfunction may contribute to outcomes from critical illness.

RevDate: 2019-10-16

Perera ON, Sobinoff AP, Teber ET, et al (2019)

Telomerase promotes formation of a telomere protective complex in cancer cells.

Science advances, 5(10):eaav4409 pii:aav4409.

Telomerase is a ribonucleoprotein complex that catalyzes addition of telomeric DNA repeats to maintain telomeres in replicating cells. Here, we demonstrate that the telomerase protein hTERT performs an additional role at telomeres that is independent of telomerase catalytic activity yet essential for telomere integrity and cell proliferation. Short-term depletion of endogenous hTERT reduced the levels of heat shock protein 70 (Hsp70-1) and the telomere protective protein Apollo at telomeres, and induced telomere deprotection and cell cycle arrest, in the absence of telomere shortening. Short-term expression of hTERT promoted colocalization of Hsp70-1 with telomeres and Apollo and reduced numbers of deprotected telomeres, in a manner independent of telomerase catalytic activity. These data reveal a previously unidentified noncanonical function of hTERT that promotes formation of a telomere protective complex containing Hsp70-1 and Apollo and is essential for sustained proliferation of telomerase-positive cancer cells, likely contributing to the known cancer-promoting effects of both hTERT and Hsp70-1.

RevDate: 2019-10-16

Parolini M, Possenti CD, Romano A, et al (2019)

Perinatal variation and covariation of oxidative status and telomere length in yellow-legged gull chicks.

Current zoology, 65(5):509-516.

The perinatal period is critical to survival and performance of many organisms. In birds, rapid postnatal growth and sudden exposure to aerial oxygen around hatching markedly affect the chick redox status, with potentially negative consequences on physiology mediated by oxidative stress. In addition, telomere length (TL) undergoes reduction during birds' early life, partly depending on oxidative status. However, relatively few studies have focused specifically on the changes in oxidative status and TL that occur immediately after hatching. In this study of the yellow-legged gull Larus michahellis, we found that chicks undergo a marked increase in plasma total antioxidant capacity and a marked decrease in the concentration of pro-oxidant molecules during the first days after hatching. In addition, TL in erythrocytes decreased by 1 standard deviation over the 4 days post-hatching. Body mass and tarsus length covaried with total antioxidant capacity and concentration of pro-oxidants in a complex way, that partly depended on sex and laying order, suggesting that oxidative status can affect growth. Moreover, TL positively covaried with the concentration of pro-oxidant molecules, possibly because retention of high concentrations of pro-oxidant molecules results from mechanisms of prevention of their negative effects, including reduction in TL. Thus, this study shows that chicks undergo marked variation in oxidative status, which predicts growth and subsequent TL, prompting for more studies of the perinatal changes in the critical post-hatching stages.

RevDate: 2019-10-15

Li W, Mjekiqi E, Douma W, et al (2019)

Hole Migration In Telomere-Based Oligonucleotide Anions And G-Quadruplexes.

Chemistry (Weinheim an der Bergstrasse, Germany) [Epub ahead of print].

Vacuum ultraviolet photoionization of a gas-phase oligonucleotide anion leads to the formation of a valence hole. This hole migrates towards an energetically favorable site where it can weaken bonds and ultimately lead to bond cleavage. We have studied VUV photoionization of deprotonated oligonucleotides containing the human telomere sequence dTTAGGG and G-quadruplex structures consisting of four dTGGGGT single strands, stabilized by NH 4 + counter ions. The oligonucleotide and G-quadruplex anions were confined in a radiofrequency ion trap, interfaced with a synchrotron beamline and the photofragmentation was studied using time-of-flight mass spectrometry. Oligonucleotide 12-mers containing the 5´-TTAGGG sequence were found to predominantly break in the GGG region, whereas no selective bond cleavage region was observed for the reversed 5´-GGGATT sequence. For G-quadruplex structures, fragmentation was quenched and mostly non-dissociative single and double electron removal was observed.

RevDate: 2019-10-15

Leibel DK, Shaked D, Beatty Moody DL, et al (2019)

Telomere length and cognitive function: Differential patterns across sociodemographic groups.

Neuropsychology pii:2019-61502-001 [Epub ahead of print].

OBJECTIVE: The present study investigates whether associations between telomere length (TL) and cognitive performance across multiple domains are moderated by poverty status and race.

METHOD: Participants were 325 African American and White urban-dwelling adults (M age = 47.9 years; 49.5% African American; 50.2% female; 48.9% living in poverty) from the Healthy Aging in Neighborhoods of Diversity across the Life Span study. TL was assayed from peripheral blood mononuclear cells using quantitative polymerase chain reactions. Multivariable regression analyses examined interactions of TL, poverty status, and race with performance on the following cognitive tests: Trail-Making Test Parts A and B, Digit Span Forward and Backward, semantic verbal fluency, Brief Test of Attention, Benton Visual Retention Test (BVRT), and California Verbal Learning Test-II total learning, short-delay free recall, and long-delay free recall scores. Analyses adjusted for age, sex, and high school-or-greater educational attainment.

RESULTS: Significant three-way interactions of TL × Poverty Status × Race revealed that, among White participants living in poverty, shorter TL was associated with worse performance on Digit Span Forward and Backward (ps<.05). Additionally, significant two-way interactions of TL × Poverty Status revealed that, among all participants living in poverty, shorter TL was associated with worse performance on the Trail-Making Test Part B and the BVRT (ps<.05).

CONCLUSIONS: TL may be differentially associated with aspects of attention, executive functioning, and memory among individuals living in poverty, who may be uniquely vulnerable to adverse effects of shorter telomeres. Replication of these findings is needed to determine their generalizability. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

RevDate: 2019-10-15

Min J, JW Shay (2019)

Telomere clustering drives ALT.

Aging pii:102369 [Epub ahead of print].

RevDate: 2019-10-15

Kärkkäinen T, Teerikorpi P, Panda B, et al (2019)

Impact of continuous predator threat on telomere dynamics in parent and nestling pied flycatchers.

Oecologia pii:10.1007/s00442-019-04529-3 [Epub ahead of print].

In addition to direct mortality, predators can have indirect effects on prey populations by affecting prey behaviour or physiology. For example, predator presence can increase stress hormone levels, which can have physiological costs. Stress exposure accelerates the shortening of telomeres (i.e. the protective caps of chromosomes) and shorter telomeres have been linked to increased mortality risk. However, the effect of perceived predation risk on telomeres is not known. We investigated the effects of continuous predator threat (nesting Eurasian pygmy owl Glaucidium passerinum) on telomere dynamics of both adult and partially cross-fostered nestling pied flycatchers (Ficedula hypoleuca) in the wild. Females nesting at owl-inhabited sites showed impaired telomere maintenance between incubation and chick rearing compared to controls, and both males and females ended up with shorter telomeres at owl-inhabited sites in the end of chick rearing. On the contrary, both original and cross-fostered chicks reared in owl sites had consistently longer telomeres during growth than chicks reared at control sites. Thus, predation risk may cause a long-term cost in terms of telomeres for parents but not for their offspring. Predators may therefore affect telomere dynamics of their preys, which could have implications for their ageing rate and consequently for population dynamics.

RevDate: 2019-10-15

Graham MK, Kim J, Da J, et al (2019)

Functional loss of ATRX and TERC activates Alternative Lengthening of Telomeres (ALT) in LAPC4 prostate cancer cells.

Molecular cancer research : MCR pii:1541-7786.MCR-19-0654 [Epub ahead of print].

A key hallmark of cancer, unlimited replication, requires cancer cells to evade both replicative senescence and potentially lethal chromosomal instability induced by telomere dysfunction. The majority of cancers overcome these critical barriers by up-regulating telomerase, a telomere-specific reverse transcriptase. However, a subset of cancers maintains telomere lengths by the telomerase-independent Alternative Lengthening of Telomeres (ALT) pathway. The presence of ALT is strongly associated with recurrent cancer-specific somatic inactivating mutations in the ATRX-DAXX chromatin remodeling complex. Here, we generate an ALT-positive adenocarcinoma cell line following functional inactivation of ATRX and telomerase in a telomerase-positive adenocarcinoma cell line. Inactivating mutations in ATRX were introduced using CRISPR-cas9 nickase into two prostate cancer cell lines, LAPC-4 (derived from a lymph node metastasis) and CWR22Rv1 (sourced from a xenograft established from a primary prostate cancer). In LAPC-4, but not CWR22Rv1, abolishing ATRX was sufficient to induce multiple ALT-associated hallmarks, including the presence of ALT-associated PML bodies (APBs), extrachromosomal telomere C-circles, and dramatic telomere length heterogeneity. However, telomerase activity was still present in these ATRXKO cells. Telomerase activity was subsequently crippled in these LAPC-4 ATRXKO cells by introducing mutations in the TERC locus, the essential RNA component of telomerase. These LAPC-4 ATRXKO TERCmut cells continued to proliferate long-term and retained ALT-associated hallmarks, thereby demonstrating their reliance on the ALT mechanism for telomere maintenance. Implications: These prostate cancer cell line models provide a unique system to explore the distinct molecular alterations that occur upon induction of ALT, and may be useful tools to screen for ALT-specific therapies.

RevDate: 2019-10-14

Lamprokostopoulou A, Moschonis G, Manios Y, et al (2019)

Childhood obesity and leukocyte telomere length.

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

BACKGROUND: Obesity in adulthood is associated with decreased leukocyte telomere length (LTL), which is associated with cardiovascular disease and diabetes mellitus type 2. The aim of our study was to investigate whether increased body mass index (BMI) is associated with decreased LTL in children and adolescents, and to identify other risk factors of shorter LTL in this population.

MATERIALS AND METHODS: A cross-sectional study was conducted among 919 Greek children aged 9-13 years (The Healthy Growth Study). Participants were classified as obese (n=124), overweight (n=276) or of normal BMI (n=519). LTL was determined by monochrome multiplex quantitative real-time polymerase chain reaction. Univariate and multivariable linear regression analyses were applied to determine the predictive factors of LTL.

RESULTS: Both overweight and obese children had significantly shorter LTL than their normal-BMI counterparts. Following adjustment for age, sex, total daily energy intake, and average weekly physical activity (average total steps per day), increasing weight category was inversely associated with LTL in children and adolescents (β: -0.110 ± 0.035; p=0.002).

CONCLUSION: Overweight and obesity in childhood and adolescence are associated with shorter LTL, even following adjustment for potential confounding effects. Therefore, the increased BMI in childhood and adolescence may be associated with accelerated biological aging, and may have an adverse impact on future health in adulthood.

RevDate: 2019-10-12

Cao X, Huang M, Zhu M, et al (2019)

Mendelian randomization study of telomere length and lung cancer risk in East Asian population.

Cancer medicine [Epub ahead of print].

Associations between telomere length and cancer risk have been investigated in many epidemiological studies, but the results are controversial. These associations may be biased by reverse causation or confounded by environmental exposures. To avoid potential biases, we used Mendelian randomization method to evaluate whether TL is the causal risk factor for lung cancer. We conducted Mendelian randomization analysis in two published East Asian GWAS studies (7127 cases and 6818 controls). We used both weighted genetic risk score and inverse-variance weighting method to estimate the relationship between TL and lung cancer risk. Nonlinear test also used to detect potential association trends. We observed that increased weight GRS was associated with increased risk of lung cancer (OR = 2.25, 95%CI: 1.81-2.78, P = 1.18 × 10-13). In different subtypes, weight GRS was significantly associated with lung adenocarcinoma risk (OR = 2.69, 95% CI: 2.11-3.42, P = 7.20 × 10-16); while lung squamous cell carcinoma showed a marginal association (OR = 1.45, 95% CI = 1.01-2.10, P = .047). Nonlinear analysis suggested a log-linear dose-response relationship between increased weight GRS and lung cancer risk. Our results indicated that longer TL increases lung cancer risk. Those biological mechanisms changes caused by long TL may play an important role in lung carcinogenesis.

RevDate: 2019-10-11

Demanelis K, Tong L, BL Pierce (2019)

Genetically Increased Telomere Length and Aging-related Traits in the UK Biobank.

The journals of gerontology. Series A, Biological sciences and medical sciences pii:5585929 [Epub ahead of print].

Telomere length (TL) shortens over time in most human cell types and is a potential biomarker of aging. However, the causal association of TL on physical and cognitive traits that decline with age has not been extensively examined in middle-aged adults. Using a Mendelian randomization (MR) approach, we utilized genetically increased TL (GI-TL) to estimate the causal association of TL on aging-related traits among UK Biobank (UKB) participants (age 40-69 years). We manually curated 53 aging-related traits from the UKB and restricted to unrelated participants of British ancestry (n=337,522). We estimated GI-TL as a linear combination of nine TL-associated SNPs, each weighted by its previously-reported association with leukocyte TL. Regression models were used to assess the associations between GI-TL and each trait. We obtained MR estimates using the two-sample inverse variance weighted (IVW) approach. We identified 6 age-related traits associated with GI-TL (Bonferroni-corrected threshold p < 0.001): pulse pressure (PP) (p=5.2x10-14), systolic blood pressure (SBP) (p=2.9x10-15), diastolic blood pressure (DBP) (p=5.5x10-6), hypertension (p=5.5x10-11), forced expiratory volume (FEV1) (p=0.0001), and forced vital capacity (FVC) (p=3.8x10-6). Under MR assumptions, one standard deviation increase in TL (~1200 base pairs) increased PP, SBP, and DBP by 1.5, 2.3, and 0.8 mmHg, respectively, while FEV1 and FVC increased by 34.7 and 52.2 mL, respectively. The observed associations appear unlikely to be due to selection bias based on analyses including inverse probability weights and analyses of simulated data. These findings suggest that longer TL increases pulmonary function and blood pressure traits among middle-aged UKB participants.

RevDate: 2019-10-11

Rosero-Bixby L, Rehkopf DH, Dow WH, et al (2019)

Correlates of longitudinal leukocyte telomere length in the Costa Rican Longevity Study of Healthy Aging (CRELES): On the importance of DNA collection and storage procedures.

PloS one, 14(10):e0223766 pii:PONE-D-19-15530.

The objective is to identify cofactors of leukocyte telomere length (LTL) in a Latin American population, specifically the association of LTL with 36 socio-demographic, early childhood, and health characteristics, as well as with DNA sample collection and storage procedures. The analysis is based on longitudinal information from a subsample of 1,261 individuals aged 60+ years at baseline from the Costa Rican Study of Longevity and Healthy Aging (CRELES): a nationally representative sample of elderly population. Random effects regression models for panel data were used to estimate the associations with LTL and its longitudinal changes. Sample collection procedures and DNA refrigerator storage time were strongly associated with LTL: telomeres are longer in blood collected in October-December, in DNA extracted from <1-year-old blood cells, and in DNA stored at 4°C for longer periods of time up to five years. The data confirmed that telomeres are shorter at older ages, as well as among males, and diabetic individuals, whereas telomeres are longer in the high-longevity Nicoya region. Most health, biomarkers, and early childhood indicators did not show significant associations with LTL. Longitudinal LTL variation over approximately two years was mainly associated with baseline LTL levels, as found in other studies. Our findings suggest that if there is unavoidable variability in season of sample collection and DNA storage time, these factors should be controlled for in all demographic and epidemiologic studies of LTL. However, due to unobserved components of measurement variation, statistical control may be inadequate as compared to standardization of data collection procedures.

RevDate: 2019-10-11

Walker AE, Fenstermacher E, DA Ross (2019)

Telomeres, Trauma, and Training.

Biological psychiatry, 86(9):e29-e30.

RevDate: 2019-10-09

Li P, Meng Y, Wang Y, et al (2019)

Nuclear localization of Desmoplakin and its involvement in telomere maintenance.

International journal of biological sciences, 15(11):2350-2362 pii:ijbsv15p2350.

The interaction between genomic DNA and protein fundamentally determines the activity and the function of DNA elements. Capturing the protein complex and identifying the proteins associated with a specific DNA locus is difficult. Herein, we employed CRISPR, the well-known gene-targeting tool in combination with the proximity-dependent labeling tool BioID to capture a specific genome locus associated proteins and to uncover the novel functions of these proteins. By applying this research tool on telomeres, we identified DSP, out of many others, as a convincing telomere binding protein validated by both biochemical and cell-biological approaches. We also provide evidence to demonstrate that the C-terminal domain of DSP is required for its binding to telomere after translocating to the nucleus mediated by NLS sequence of DSP. In addition, we found that the telomere binding of DSP is telomere length dependent as hTERT inhibition or knockdown caused a decrease of telomere length and diminished DSP binding to the telomere. Knockdown of TRF2 also negatively influenced DSP binding to the telomere. Functionally, loss of DSP resulted in the shortened telomere DNA and induced the DNA damage response and cell apoptosis. In conclusion, our studies identified DSP as a novel potential telomere binding protein and highlighted its role in protecting against telomere DNA damage and resultant cell apoptosis.

RevDate: 2019-10-09

Lara-Molina EE, Franasiak JM, Marin D, et al (2019)

Cumulus cells have longer telomeres than leukocytes in reproductive-age women.

Fertility and sterility pii:S0015-0282(19)32299-X [Epub ahead of print].

OBJECTIVE: To investigate whether telomere length (TL) in granulosa cells (GC) or cumulus cells (CC) correlates with TL in leukocytes (L).

DESIGN: Prospective noninterventional study.

SETTING: Private assisted reproductive technology center.

PATIENT(S): Thirty-five egg donors were included in the study.


MAIN OUTCOME MEASURE(S): Average relative leukocyte telomere length (LTL), cumulus cell telomere length (CCTL), and granulosa cell telomere length (GCTL) measurements from each study subject.

RESULT(S): Participants had a mean age of 25.43 ± 4.57 years, antimüllerian hormone level of 1.90 ± 0.92 ng/mL, antral follicle count of 23.29 ± 5.11, and the mean number of mature oocytes retrieved was 23.29 ± 9.13. No significant association between these variables and GCTL, CCTL, or LTL was found. In addition, no correlation was observed between TL measurements of L vs. CC, L vs. GC, or CC vs. GC. Interestingly, CCTL was significantly higher than LTL (1.54-fold), although no significant differences were found between GCTL vs. CCTL or GCTL vs. LTL.

CONCLUSION(S): CC from mature follicles have significantly longer telomeres than L, suggesting that the follicular environment could possess different mechanisms to cope against telomere shortening compared with other somatic tissues. Furthermore, these data do not support the utility of telomere DNA measurement in L as an estimate of TL in follicular cells.

RevDate: 2019-10-04

Barroso-González J, García-Expósito L, Hoang SM, et al (2019)

RAD51AP1 Is an Essential Mediator of Alternative Lengthening of Telomeres.

Molecular cell, 76(1):217.

RevDate: 2019-10-03

Grozeva S, Anokhin BA, Simov N, et al (2019)

New evidence for the presence of the telomere motif (TTAGG) n in the family Reduviidae and its absence in the families Nabidae and Miridae (Hemiptera, Cimicomorpha).

Comparative cytogenetics, 13(3):283-295 pii:36676.

Male karyotype and meiosis in four true bug species belonging to the families Reduviidae, Nabidae, and Miridae (Cimicomorpha) were studied for the first time using Giemsa staining and FISH with 18S ribosomal DNA and telomeric (TTAGG)n probes. We found that Rhynocoris punctiventris (Herrich-Schäffer, 1846) and R. iracundus (Poda, 1761) (Reduviidae: Harpactorinae) had 2n = 28 (24 + X1X2X3Y), whereas Nabis sareptanus Dohrn, 1862 (Nabidae) and Horistus orientalis (Gmelin, 1790) (Miridae) had 2n = 34 (32 + XY) and 2n = 32 (30 + XY), respectively. FISH for 18S rDNA revealed hybridization signals on a sex chromosome, the X or the Y, in H. orientalis, on both X and Y chromosomes in N. sareptanus, and on two of the four sex chromosomes, Y and one of the Xs, in both species of Rhynocoris Hahn, 1834. The results of FISH with telomeric probes support with confidence the absence of the "insect" telomere motif (TTAGG)n in the families Nabidae and Miridae and its presence in both species of genus Rhynocoris of the Reduviidae, considered as a basal family of Cimicomorpha. Increasing evidence reinforces the hypothesis of the loss of the canonical "insect" telomere motif (TTAGG)n by at least four cimicomorphan families, Nabidae, Miridae, Tingidae, and Cimicidae, for which data are currently available.

RevDate: 2019-10-02

Liu B, Song L, Zhang L, et al (2019)

Prenatal second-hand smoke exposure and newborn telomere length.

Pediatric research pii:10.1038/s41390-019-0594-2 [Epub ahead of print].

BACKGROUND: Cigarette smoking is associated with shorter telomere lengths in adults, but evidence on the effect of prenatal tobacco exposure is limited. We aimed to investigate the association between prenatal second-hand smoke exposure and newborn telomere length.

METHODS: We recruited 762 mother-newborn pairs from Wuhan Children's Hospital (Wuhan Maternal and Child Healthcare Hospital) between November 2013 and March 2015. Information on second-hand smoke exposure was obtained via questionnaires. Relative telomere length was measured in DNA extracted from umbilical cord blood. We used linear regression to assess the associations between prenatal second-hand smoke exposure and newborn telomere length.

RESULTS: In the fully adjusted model, prenatal second-hand smoke exposure was associated with 9.7% shorter newborn telomere length (percent difference: -9.7%; 95% confidence interval (CI): -15.0, -4.0). The estimate for boys was lower (percent difference: -10.9%; 95% CI: -18.6, -2.5) than that for girls (percent difference: -8.5%; 95% CI: -15.8, -0.5), but the interaction term between newborn sex and prenatal second-hand smoke was not significant (P = 0.751).

CONCLUSIONS: This study demonstrated that prenatal second-hand smoke exposure may be a preventable risk factor for accelerated biological aging in the intrauterine stage, and further suggested possible sex differences in the susceptibility to prenatal second-hand smoke.

RevDate: 2019-10-02

Sudyka J (2019)

Does Reproduction Shorten Telomeres? Towards Integrating Individual Quality with Life-History Strategies in Telomere Biology.

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

Reproduction, a basic property of biological life, entails costs for an organism, ultimately detectable as reduction in survival prospects. Telomeres are an excellent candidate biomarker for explaining these reproductive costs, because their shortening correlates with increased mortality risk. For similar reasons, telomeres are perceived as biomarkers of individual "quality." The relationship between reproduction and telomere dynamics is reviewed, emphasizing that cost and quality perspectives, commonly presented in isolation, should be integrated. While a majority of correlative studies have confirmed the relationship between telomere dynamics and various reproductive outputs, only limited experimental support exists showing that reproduction causes telomeres to shorten. A shift of focus to experimental manipulations of reproductive effort/telomere dynamics is crucial. However, the observation of survival reduction in response to these manipulations is essential for establishing telomeres as genuine biomarkers, allowing to unravel trade-offs related to reproduction.

RevDate: 2019-10-02

Mukherjee AK, Sharma S, Bagri S, et al (2019)

Telomere repeat-binding factor 2 binds extensively to extra-telomeric G-quadruplexes and regulates the epigenetic status of several gene promoters.

The Journal of biological chemistry pii:RA119.008687 [Epub ahead of print].

The role of the telomere repeat-binding factor 2 (TRF2) in telomere maintenance is well established. However, recent findings suggest that TRF2 also functions outside telomeres, but relatively little is known about this function. Herein, using genome-wide ChIP-Seq assays of TRF2-bound chromatin from HT1080 fibrosarcoma cells, we identified thousands of TRF2-binding sites within the extra-telomeric genome. In light of this observation, we asked how TRF2 occupancy is organized within the genome. Interestingly, we found that extra-telomeric TRF2 sites throughout the genome are enriched in potential G-quadruplex-forming DNA sequences. Furthermore, we validated TRF2 occupancy at several promoter G-quadruplex motifs, which did adopt quadruplex forms in solution. TRF2 binding altered expression from and the epigenetic state of several target promoters, indicated by histone modifications resulting in transcriptional repression of eight of nine genes investigated here. Furthermore, TRF2 occupancy and target gene expression were also sensitive to the well-known intracellular G-quadruplex-binding ligand 360A. Together, these results reveal an extensive genome-wide association of TRF2 outside telomeres and that it regulates gene expression in a G-quadruplex-dependent fashion.

RevDate: 2019-10-02

Marasco V, Boner W, Griffiths K, et al (2019)

Intergenerational effects on offspring telomere length: interactions among maternal age, stress exposure and offspring sex.

Proceedings. Biological sciences, 286(1912):20191845.

Offspring produced by older parents often have reduced longevity, termed the Lansing effect. Because adults usually have similar-aged mates, it is difficult to separate effects of maternal and paternal age, and environmental circumstances are also likely to influence offspring outcomes. The mechanisms underlying the Lansing effect are poorly understood. Variation in telomere length and loss, particularly in early life, is linked to longevity in many vertebrates, and therefore changes in offspring telomere dynamics could be very important in this context. We examined the effect of maternal age and environment on offspring telomere length in zebra finches. We kept mothers under either control (ad libitum food) or more challenging (unpredictable food) circumstances and experimentally minimized paternal age and mate choice effects. Irrespective of the maternal environment, there was a substantial negative effect of maternal age on offspring telomere length, evident in longitudinal and cross-sectional comparisons (average of 39% shorter). Furthermore, in young mothers, sons reared by challenged mothers had significantly shorter telomere lengths than sons reared by control mothers. This effect disappeared when the mothers were old, and was absent in daughters. These findings highlight the importance of telomere dynamics as inter-generational mediators of the evolutionary processes determining optimal age-specific reproductive effort and sex allocation.

RevDate: 2019-10-01

Chen L, Zhu H, Gutin B, et al (2019)

Higher chocolate intake is associated with longer telomere length among adolescents.

Pediatric research pii:10.1038/s41390-019-0590-6 [Epub ahead of print].

BACKGROUND: Chocolate intake has shown cardiometabolic health benefits. Whether chocolate has any effect on cellular aging remains unknown. We aimed to test the hypothesis that higher chocolate intake is associated with longer leukocyte telomere length (LTL) in adolescents.

METHODS: A total of 660 adolescents (aged 14-18 years) were included in the analysis. The chocolate intake was assessed by 7-day, 24-h dietary recalls and split into three groups, which were none, <2 servings/week, and 2 servings/week or more. LTL (T/S ratio) was determined by a modified quantitative polymerase chain reaction-based assay.

RESULTS: Among the 660 adolescents, 58% did not take any chocolate, 25% consumed <2 servings/week, and 17% consumed ≥2 servings/week. Compared to non-consumers, adolescents who consumed chocolate of ≥2 servings/week had 0.27 standard deviation (SD) longer LTL (p = 0.014). Higher chocolate consumption was associated with increased apolipoprotein A1 (ApoA1) (p = 0.038) and ApoA1/high-density lipoprotein (HDL) (p = 0.046). Moreover, higher ApoA1/HDL levels were correlated with longer LTL (p = 0.026).

CONCLUSION: Adolescents who consume 2 servings/week or more of chocolate candy have longer LTL compared with non-consumers, and ApoA1/HDL pathway may be involved in this relationship.

RevDate: 2019-10-01

Nowack J, Tarmann I, Hoelzl F, et al (2019)

Always a price to pay: hibernation at low temperatures comes with a trade-off between energy savings and telomere damage.

Biology letters, 15(10):20190466.

We experimentally tested the costs of deep torpor at low temperatures by comparing telomere dynamics in two species of rodents hibernating at either 3 or 14°C. Our data show that hibernators kept at the warmer temperature had higher arousal frequencies, but maintained longer telomeres than individuals hibernating at the colder temperature. We suggest that the high-energy demand of frequent arousals is counteracted by a lower temperature differential between torpid and euthermic body temperature and that telomere length is restored during arousals when the body temperature is returned to normothermic values. Taken together, our study shows that hibernation at low body temperatures comes with costs on a cellular level and that hibernators need to actively counterbalance the shortening of telomeres.

RevDate: 2019-10-01

Chan KL, Lo CKM, Ho FK, et al (2019)

The association between intimate partner violence against women and newborn telomere length.

Translational psychiatry, 9(1):239 pii:10.1038/s41398-019-0575-6.

Intimate partner violence (IPV) against women negatively impacts infant health. However, its impact on infant's biology, in particular on telomere length (TL) is unknown. The aim of this study was to examine the association between IPV against women before childbirth and cord blood TL in their newborn. A total of 774 pregnant women in the 20th-24th week of gestation were recruited at a public hospital in Hong Kong. The mothers' exposure to IPV before childbirth, demographic characteristics, obstetric outcomes, health and mental health were measured at the time of recruitment and 4 weeks after childbirth. Umbilical cord blood was collected by midwives at the time of delivery. The newborn TL was quantified using quantitative PCR method and expressed in T/S ratio (the ratio of telomere repeat copy numbers to single-copy gene numbers). After adjusting for a number of confounding variables, the mothers' exposure to any IPV before childbirth (β = -0.08, 95% CI = -0.14, -0.01) was associated with shorter TL. Specifically, psychological abuse against women before childbirth (β = -0.08, 95% CI = -0.15, -0.02) and sexual abuse against women before childbirth (β = -0.22, 95% CI = -0.43 to -0.01) were significantly associated with reduced newborn TL. This study is the first to provide evidence of an association between IPV against women before childbirth and TL shortening in their newborns. Through TL- dependent transcription and epigenetic mechanisms, our finding suggests maternal exposure to IPV may exert a life-long impact on the offspring's health.

RevDate: 2019-10-01

Zribi B, Uziel O, Lahav M, et al (2019)

Telomere Length Changes during Critical Illness: A Prospective, Observational Study.

Genes, 10(10): pii:genes10100761.

OBJECTIVE: evaluation of telomere length change in acutely ill adult patients.

DESIGN: Blood samples were drawn on the first and seventh day of intensive care unit (ICU) stay to assess telomere length using a polymerase chain reaction (PCR)-based technique. Demographic data collected included age, weight, admission diagnosis, baseline laboratory values (pH, C- reactive protein (CRP), serum albumin level, white blood cell count (WBC) count, platelet count), and baseline SOFA and APACHE II scores. Additional data collected during the ICU stay included a repeated WBC count, the presence of positive blood cultures and outcome data, including death in the ICU or following discharge, whether ventilated or not at ICU discharge, and destination following discharge, i.e., medical ward or rehabilitation.

SETTING: General ICU in tertiary hospital.

PATIENTS: Forty patients admitted to the ICU within 72 h of hospital admission suffering from an acute illness were included in this prospective, observational study.

MAIN RESULTS: Of the 40 patients studied, telomere shortening was noted in 21, telomere lengthening in 11, and no significant change in the other eight. The age of patients demonstrating telomere shortening was statistically significantly younger (45.4 vs. 61.5 years, p < 0.023) compared to those showing increased telomere length. In addition, a significant correlation was observed between the difference in telomere length and the corresponding difference in WBC count (telomere shortening was associated with a decreased WBC count and vice versa). A trend toward shortening was seen in patients with sepsis (p = 0.07). No significant correlations were found for any other demographic or outcome parameter and changes in telomere length.

CONCLUSION: Changes in telomere length, both shortening and lengthening, were evident in the acute setting, but no associations between such changes with outcome were noted. Further studies in more homogeneous groups of patients appear to be warranted.

RevDate: 2019-09-30

Lin Y, Zhu Y, Wu J, et al (2019)

A Prospective Study of Leukocyte Telomere Length and Risk of Gestational Diabetes in a Multiracial Cohort.

Epidemiology (Cambridge, Mass.), 30 Suppl 2:S10-S16.

BACKGROUND: Short telomere length (TL), an indicator of cellular aging and oxidative stress, has been implicated in glucose homeostasis. Additionally, studies have illustrated that the association of TL with health outcomes may vary by age. Yet, data on the association between TL and gestational diabetes mellitus (GDM) are sparse and the potential effect modification by age remains unknown.

METHODS: We prospectively investigated TL in early pregnancy in relation to the subsequent GDM risk in a case-control study of 93 women with GDM and 186 randomly selected controls matched on age, race/ethnicity, and gestational weeks at blood collection. TL was measured using blood samples collected at 10-14 gestational weeks and reported as the T/S ratio, a ratio of telomere repeat length T to copy number of a single copy gene S. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using conditional logistic regression adjusted for major risk factors.

RESULTS: Overall, TL was not significantly associated with GDM risk. The TL-GDM association was significantly modified by age (Pinteraction = 0.02). Shorter TL in early pregnancy was associated with an increased GDM risk among women <30 years old (adjusted OR comparing the shortest vs. longest tertile: 3.1, 95% CI = 1.2, 8.1), but not associated with GDM risk among women ≥30 years.

CONCLUSION: Our findings suggest that TL in early pregnancy may be implicated in GDM development, particularly among younger women.

RevDate: 2019-09-29

Scheller Madrid A, Rasmussen KL, Rode L, et al (2019)

Observational and genetic studies of short telomeres and Alzheimer's disease in 67,000 and 152,000 individuals: a Mendelian randomization study.

European journal of epidemiology pii:10.1007/s10654-019-00563-w [Epub ahead of print].

Short telomeres might lead to increased risk of Alzheimer's disease, but observational analyses have been inconclusive and potentially confounded by the strong association of both telomere length and risk of Alzheimer's disease with age and adverse lifestyle. To circumvent this, analyses including single nucleotide polymorphisms associated with telomere length used in an instrumental variable analysis produces risk estimates likely free of distortions from reverse causation and of most confounding. We tested the hypothesis that short telomeres are associated with increased risk of Alzheimer's disease, observationally and causal, genetically. Telomere length was measured in 66,567 individuals, and genotyped for rs2487999 in OBFC1, rs7726159 in TERT, and rs1317082 in TERC causing lifelong telomere shortening in 98,146 individuals from two Copenhagen studies. Genetic data on 54,162 individuals from the International Genomics of Alzheimer's Project were also included. Observationally, multifactorially adjusted hazard ratio for Alzheimer's disease was 1.02 (95% CI 1.00-1.03) per 200 base pair shorter telomeres. Telomere length was 335 base pairs shorter in individuals with 6 versus 0-1 alleles (p = 5 × 10-105). Genetically, odds ratio for Alzheimer's disease was 1.08 (1.01-1.16) per 200 base pairs shorter telomeres. Similar results were found in strata of age and comorbidities. In comparative analyses, genetically predicted shorter telomeres were associated with increased risk of myocardial infarction, and with decreased risks of lung cancer and melanoma as previously reported. Short telomeres were associated observationally and causal, genetically with increased risk of Alzheimer's disease. Telomere biology is therefore a potential pathway involved in the development of Alzheimer's disease.

RevDate: 2019-09-25

Puhlmann LMC, Valk SL, Engert V, et al (2019)

Association of Short-term Change in Leukocyte Telomere Length With Cortical Thickness and Outcomes of Mental Training Among Healthy Adults: A Randomized Clinical Trial.

JAMA network open, 2(9):e199687 pii:2751893.

Importance: Telomere length is associated with the development of age-related diseases and structural differences in multiple brain regions. It remains unclear, however, whether change in telomere length is linked to brain structure change, and to what extent telomere length can be influenced through mental training.

Objectives: To assess the dynamic associations between leukocyte telomere length (LTL) and cortical thickness (CT), and to determine whether LTL is affected by a longitudinal contemplative mental training intervention.

An open-label efficacy trial of three 3-month mental training modules with healthy, meditation-naive adults was conducted. Data on LTL and CT were collected 4 times over 9 months between April 22, 2013, and March 31, 2015, as part of the ReSource Project. Data analysis was performed between September 23, 2016, and June 21, 2019. Of 1582 eligible individuals, 943 declined to participate; 362 were randomly selected for participation and assigned to training or retest control cohorts, with demographic characteristics matched. The retest control cohorts underwent all testing but no training. Intention-to-treat analysis was performed.

Interventions: Training cohort participants completed 3 modules cultivating interoception and attention (Presence), compassion (Affect), or perspective taking (Perspective).

Main Outcomes and Measures: Change in LTL and CT.

Results: Of the 362 individuals randomized, 30 participants dropped out before study initiation (initial sample, 332). Data were available for analysis of the training intervention in 298 participants (n = 222 training; n = 76 retest control) (175 women [58.7%]; mean [SD] age, 40.5 [9.3] years). The training modules had no effect on LTL. In 699 observations from all 298 participants, mean estimated changes in the relative ratios of telomere repeat copy number to single-copy gene (T/S) were for no training, 0.004 (95% CI, -0.010 to 0.018); Presence, -0.007 (95% CI, -0.025 to 0.011); Affect, -0.005 (95% CI, -0.019 to 0.010); and Perspective, -0.001 (95% CI, -0.017 to 0.016). Cortical thickness change data were analyzed in 167 observations from 67 retest control participants (37 women [55.2%], mean [SD] age, 39.6 [9.0] years). In this retest control cohort subsample, naturally occurring LTL change was related to CT change in the left precuneus extending to the posterior cingulate cortex (mean t161 = 3.22; P < .001; r = 0.246). At the individual participant level, leukocyte telomere shortening as well as lengthening were observed. Leukocyte telomere shortening was related to cortical thinning (t77 = 2.38; P = .01; r = 0.262), and leukocyte telomere lengthening was related to cortical thickening (t77 = 2.42; P = .009; r = 0.266). All analyses controlled for age, sex, and body mass index.

Conclusions and Relevance: The findings of this trial indicate an association between short-term change in LTL and concomitant change in plasticity of the left precuneus extending to the posterior cingulate cortex. This result contributes to the evidence that LTL changes more dynamically on the individual level than previously thought. Further studies are needed to determine potential long-term implications of such change in relation to cellular aging and the development of neurodegenerative disorders. No effect of contemplative mental training was noted in what may be, to date, the longest intervention with healthy adults.

Trial Registration: identifier: NCT01833104.

RevDate: 2019-09-27

Domingues-Silva B, Silva B, CM Azzalin (2019)

ALTernative Functions for Human FANCM at Telomeres.

Frontiers in molecular biosciences, 6:84.

The human FANCM ATPase/translocase is involved in various cellular pathways including DNA damage repair, replication fork remodeling and R-loop resolution. Recently, reports from three independent laboratories have disclosed a previously unappreciated role for FANCM in telomerase-negative human cancer cells that maintain their telomeres through the Alternative Lengthening of Telomeres (ALT) pathway. In ALT cells, FANCM limits telomeric replication stress and damage, and, in turn, ALT activity by suppressing accumulation of telomeric R-loops and by regulating the action of the BLM helicase. As a consequence, FANCM inactivation leads to exaggerated ALT activity and ultimately cell death. The studies reviewed here not only unveil a novel function for human FANCM, but also point to this enzyme as a promising target for anti-ALT cancer therapy.

RevDate: 2019-09-27

Yang Y, Tan J, Duan X, et al (2019)

The association between polymorphisms in tankyrase gene and telomere length in omethoate-exposed workers.

Chemosphere, 238:124863 pii:S0045-6535(19)32102-2 [Epub ahead of print].

Peripheral blood leukocyte telomere length in omethoate-exposed workers is related to environmental exposure and single nucleotide polymorphisms (SNPs) in genes including p21, GSTM1, miR-145, etc. However, the roles of SNPs in tankyrase (TNKS) gene in telomere length are still unknown. The aim of this study was to explore the association between SNPs in TNKS gene and telomere length in omethoate-exposed workers. Telomere length in peripheral blood leukocyte DNA from 180 omethoate-exposed workers and 115 healthy controls was measured using Real-time quantitative polymerase chain reaction (PCR). Genotyping of the selected functional and susceptible SNPs was performed by the flight mass spectrometry based on PCR and single-base extension. The analysis of covariance was performed to find effects of SNPs on telomere length. Generalized linear models were used to analyze the environment, gene, and interaction on telomere length. The results showed that telomere length in the CG + CC genotypes in rs1055328 in TNKS gene was significantly longer than that in the wild homozygous GG genotype both in exposure group (P = 0.017) and in control group (P = 0.038) after adjusting the covariates. The variables kept in the generalized linear models included omethoate-exposure (β = 0.580, P = 0.001) and rs1055328 (CG + CC) in TNKS gene (β = 0.339, P = 0.002). The study suggests that the prolongation of telomere length is associated with omethoate-exposure and the CG + CC genotypes in rs1055328 in TNKS gene.

RevDate: 2019-09-24

Rodriguez-Centeno J, Manguán-García C, Perona R, et al (2019)

Structure of Dictyostelium discoideum telomeres. Analysis of possible replication mechanisms.

PloS one, 14(9):e0222909 pii:PONE-D-18-34812.

Telomeres are nucleo-protein structures that protect the ends of eukaryotic chromosomes. They are not completely synthesized during DNA replication and are elongated by specific mechanisms. The structure of the telomeres and the elongation mechanism have not been determined in Dictyostelium discoideum. This organism presents extrachromosomal palindromic elements containing two copies of the rDNA, also present at the end of the chromosomes. In this article the structure of the terminal region of the rDNA is shown to consist of repetitions of the A(G)n sequence where the number of Gs is variable. These repeats extend as a 3' single stranded region. The G-rich region is preceded by four tandem repetitions of two different DNA motifs. D. discoideum telomere reverse transcriptase homologous protein (TERTHP) presented RNase-sensitive enzymatic activity and was required to maintain telomere structure since terthp-mutant strains presented reorganizations of the DNA terminal regions. These modifications were different in several terthp-mutants and changed with their prolonged culture and subcloning. However, the terthp gene is not essential for D. discoideum proliferation. Telomeres could be maintained in terthp-mutant strains by homologous recombination mechanisms such as ALT (Alternative Lengthening of Telomeres) or HAATI (heterochromatin amplification-mediated and telomerase-independent). In agreement with this hypothesis, the expression of mRNAs coding for several proteins involved in homologous recombination was induced in terthp-mutant strains. Extrachromosomal rDNA could serve as substrate in these DNA homologous recombination reactions.

RevDate: 2019-09-24

Criscuolo F, Cornell A, Zahn S, et al (2019)

Oxidative status and telomere length are related to somatic and physiological maturation in chicks of European starlings (Sturnus vulgaris).

The Journal of experimental biology pii:jeb.204719 [Epub ahead of print].

Telomere length can be considered as an indicator of an organism's somatic state, long telomeres reflecting higher energy investment in self-maintenance. Early-life is a period of intense investment in somatic growth and in physiological maturation but how this is reflected in telomere length remains unclear. Using European starling chicks we tested: (i) how telomere length measured at asymptotic mass is related to proxies of somatic growth and physiological maturity in 17 days-old nestlings; (ii) how telomere length measured at 17 days then predicts the changes in somatic and physiological maturity occurring in fledglings (between 17-21 days); (iii) how growth and telomere length co-vary when chicks are under experimentally good (fed) growth conditions. Depending on environmental conditions, our data suggest links between somatic growth, physiological maturation, and body maintenance parameters (positive with oxidative stress and negative with telomere length) in nestlings. Telomere length measured at day 17 predicted subsequent change in physiological maturation variables observed in fledglings, but only in second-brood chicks: chicks with shorter telomeres had a higher pre-fledging rate of increase in hematocrit, haemoglobin content and a greater decrease in reticulocytes count. Finally, food-supplementation of chicks did not change telomere length compared to control siblings. Our results suggest that physiological maturation prior to fledging may occur at the expense of telomere length but only when environmental conditions are sub-optimal.

RevDate: 2019-10-04

Wang L, Koenig HG, Al Shohaib S, et al (2019)

Religiosity, depression and telomere length in Chinese older adults.

Journal of affective disorders, 260:624-628 pii:S0165-0327(19)32101-9 [Epub ahead of print].

BACKGROUND: The mechanism explaining how religiosity is linked to telomere length (TL) is unclear. The current study examines depression as a possible mediator.

METHODS: In this cross-sectional study of 1,742 community-dwelling residents aged 55 or over, the Duke University Religion Index (DUREL) and Geriatric Depression Scale (GDS) were administrated during a routine health check. Peripheral blood leukocyte TL was determined using a q-PCR procedure. The Bootstrap methods PROCESS program was used to detect mediation.

RESULTS: After controlling for sociodemographic variables, the religiosity was positively correlated with TL (p<0.05) and negatively correlated with depressive symptom (p<0.001). Depressive symptoms, in turn, was negatively correlated with TL (p<0.05) in the overall sample. Depressive symptoms significantly mediated the relationship between religiosity and TL (explaining 31.8% of the total variance) in the 65 years and older subgroup (p = 0.015). No significant mediation was found in the 55-64 age subgroup.

LIMITATIONS: The cross-sectional design prevents making causal inferences. The non-random sampling method used in selecting participants may affect the external validity of the findings in terms of generalizing to Muslims throughout China or other religious groups. Potential mediators of the relationship between religiosity and TL and confounders such as physical health status, were not assessed.

CONCLUSION: Religiosity was positively associated with TL in older mainland Chinese adults, and this association was partially mediated by depressive symptom in the 65 or older age group. This finding helps to explain why religiosity is related to cellular aging in older adults.

RevDate: 2019-09-21

Dhillon VS, Deo P, Chua A, et al (2019)

Shorter telomere length in carriers of APOE-ε4 and high plasma concentration of glucose, glyoxal and other advanced glycation end products (AGEs).

The journals of gerontology. Series A, Biological sciences and medical sciences pii:5572352 [Epub ahead of print].

Apolipoprotein-ε4 (APOE-ε4) - common variant is a major genetic risk factor for cognitive decline and Alzheimer's disease (AD). An accelerated rate of biological aging could contribute to this increased risk. Glycation of serum proteins due to excessive glucose and reactive oxygen species leads to the formation of advanced glycation end products (AGEs) - a risk factor for diabetes and AD, and decline in motor functioning in elderly. Aim of present study was to investigate impact of APOE-ε4 allele containing genotype and accumulation of AGEs in plasma on telomere length (TL). Results showed that TL is significantly shorter in APOE-ε4 carriers compared to non-APOE-ε4 carriers (p = 0.0003). Higher plasma glucose level was associated with shorter TL irrespective of APOE-ε4 allele containing genotype (r = - 0.26; p = 0.0004). With regard to AGEs, higher plasma glyoxal and fluorescent AGEs concentrations were inversely related to TL (r = - 0.16; p = 0.03; r = - 0.28; p = 0001), however, plasma Nε-(carboxymethyl)lysine levels didn't correlate with TL (r = - 0.04; p = 0.57). Results support the hypotheses that APOE-ε4 carriers have shorter telomeres than non-carriers and telomere erosion is increased with higher concentration of glucose, fluorescent AGEs and glyoxal.

RevDate: 2019-09-18

Alejos B, Stella-Ascariz N, Montejano R, et al (2019)

Determinants of blood telomere length in antiretroviral treatment-naïve HIV-positive participants enrolled in the NEAT 001/ANRS 143 clinical trial.

HIV medicine [Epub ahead of print].

OBJECTIVES: Our aim was to investigate factors associated with baseline blood telomere length in participants enrolled in NEAT 001/ANRS 143, a randomized, open-label trial comparing ritonavir-boosted darunavir (DRV/r) plus raltegravir (RAL) with DRV/r plus tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) in antiretroviral therapy (ART)-naïve HIV-positive adults.

METHODS: A cross-sectional study of 201 randomly selected participants who had stored samples available was carried out. We measured telomere length (i.e. the relative telomere length, calculated as the telomere to single copy gene ratio) at baseline with monochrome quantitative multiplex polymerase chain reaction (PCR). We used multivariable predictive linear regression to calculate mean differences and 95% confidence intervals (CIs) for the association between baseline telomere length and baseline characteristics.

RESULTS: The baseline characteristics of the 201 participants did not differ from those of the 805 participants in the parent trial population: 89% were male, the mean age was 39 years, 83.6% were Caucasian, 93% acquired HIV infection via sexual transmission, the mean estimated time since HIV diagnosis was 2.1 years, the mean HIV-1 RNA load was 4.7 log10 HIV-1 RNA copies/mL, the mean nadir and baseline CD4 counts were 301 and 324 cells/μL, respectively, and the mean CD4:CD8 ratio was 0.4. In the univariate analysis, shorter telomere length was associated with older age (per 10 years) (P < 0.001), HIV-1 RNA ≥ 100 000 copies/mL (P = 0.001), CD4 count < 200 cells/μL (P = 0.037), lower CD4:CD8 ratio (P = 0.018), statin treatment (P = 0.004), and current alcohol consumption (P = 0.035). In the multivariable analysis, older age (P < 0.001) and HIV RNA ≥ 100 000 copies/mL (P = 0.054) were independently associated with shorter telomere length.

CONCLUSIONS: Both age and HIV RNA viral load correlated with shorter blood telomere length in untreated persons living with HIV. These results suggest that HIV infection and age have synergistic and independent impacts upon immunosenescence.

RevDate: 2019-09-21

Masamsetti VP, Low RRJ, Mak KS, et al (2019)

Replication stress induces mitotic death through parallel pathways regulated by WAPL and telomere deprotection.

Nature communications, 10(1):4224 pii:10.1038/s41467-019-12255-w.

Mitotic catastrophe is a broad descriptor encompassing unclear mechanisms of cell death. Here we investigate replication stress-driven mitotic catastrophe in human cells and identify that replication stress principally induces mitotic death signalled through two independent pathways. In p53-compromised cells we find that lethal replication stress confers WAPL-dependent centromere cohesion defects that maintain spindle assembly checkpoint-dependent mitotic arrest in the same cell cycle. Mitotic arrest then drives cohesion fatigue and triggers mitotic death through a primary pathway of BAX/BAK-dependent apoptosis. Simultaneously, a secondary mitotic death pathway is engaged through non-canonical telomere deprotection, regulated by TRF2, Aurora B and ATM. Additionally, we find that suppressing mitotic death in replication stressed cells results in distinct cellular outcomes depending upon how cell death is averted. These data demonstrate how replication stress-induced mitotic catastrophe signals cell death with implications for cancer treatment and cancer genome evolution.

RevDate: 2019-09-30

Noll B, Bahrani Mougeot F, Brennan MT, et al (2019)

Telomere erosion in Sjögren's syndrome: A multi-tissue comparative analysis.

Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology [Epub ahead of print].

BACKGROUND: Acinar progenitor cells within salivary glands have decreased regenerative capacity and exhibit shorter telomeres in primary Sjögren's syndrome (pSS) patients. We investigated whether DNA of saliva, PBMCs, and labial salivary gland (LSG) biopsy tissue have shorter telomeres in pSS compared to controls. mRNA expression of genes associated with pSS pathogenesis (ETS1, LEF1, and MMP9), telomere DNA damage response (ATM), senescence (CDKN2A), telomerase inhibition (IFN-y, TGFβ1), and the shelterin complex (TPP1, POT1) were assessed in LSG tissue by qRT-PCR to examine potential defects in telomere maintenance.

METHODS: Relative telomere length in DNA of saliva, PBMCs, and LSGs from non-pSS sicca and pSS patients was measured using qPCR. Saliva DNA telomere length was further compared to healthy controls. Expression of genes affecting telomere maintenance was analyzed in LSGs using qRT-PCR.

RESULTS: Primary Sjögren's syndrome patients have shorter telomeres in saliva DNA (n = 21) than healthy controls (n = 27) (P = .0035). ATM mRNA expression was higher in pSS LSG tissue (n = 16) vs non-pSS sicca patients (n = 13) (P = .0283) and strongly correlated with LEF1, TPP1, and POT1 (P < .01, r > 0.6).

CONCLUSIONS: Patients with pSS exhibited significant telomere erosion in saliva DNA. Overexpression of ATM in LSGs could represent a compensatory response to telomere shortening. The role of LEF1 in telomere erosion remains to be elucidated.

RevDate: 2019-09-20

Amano H, E Sahin (2019)

Telomeres and sirtuins: at the end we meet again.

Molecular & cellular oncology, 6(5):e1632613 pii:1632613.

Telomeres and sirtuins are independently implicated in causing disease and aging, but how they cooperate is not well understood. A recent study demonstrates that telomere shortening represses sirtuins and increasing sirtuin activity stabilizes telomeres and improves telomere-dependent disease, suggesting that these two pathways are tightly intertwined.

RevDate: 2019-09-29

Červenák F, Juríková K, Devillers H, et al (2019)

Identification of telomerase RNAs in species of the Yarrowia clade provides insights into the co-evolution of telomerase, telomeric repeats and telomere-binding proteins.

Scientific reports, 9(1):13365 pii:10.1038/s41598-019-49628-6.

Telomeric repeats in fungi of the subphylum Saccharomycotina exhibit great inter- and intra-species variability in length and sequence. Such variations challenged telomeric DNA-binding proteins that co-evolved to maintain their functions at telomeres. Here, we compare the extent of co-variations in telomeric repeats, encoded in the telomerase RNAs (TERs), and the repeat-binding proteins from 13 species belonging to the Yarrowia clade. We identified putative TER loci, analyzed their sequence and secondary structure conservation, and predicted functional elements. Moreover, in vivo complementation assays with mutant TERs showed the functional importance of four novel TER substructures. The TER-derived telomeric repeat unit of all species, except for one, is 10 bp long and can be represented as 5'-TTNNNNAGGG-3', with repeat sequence variations occuring primarily outside the vertebrate telomeric motif 5'-TTAGGG-3'. All species possess a homologue of the Yarrowia lipolytica Tay1 protein, YlTay1p. In vitro, YlTay1p displays comparable DNA-binding affinity to all repeat variants, suggesting a conserved role among these species. Taken together, these results add significant insights into the co-evolution of TERs, telomeric repeats and telomere-binding proteins in yeasts.

RevDate: 2019-09-18

Flynn RL, CM Heaphy (2019)

Surviving Telomere Attrition with the MiDAS Touch.

Trends in genetics : TIG pii:S0168-9525(19)30181-7 [Epub ahead of print].

Cancer cells maintain telomere lengths through telomerase activity or by alternative lengthening of telomeres (ALT). Using an engineered model system, a recent study by Min et al. reveals that the combination of BLM-mediated DNA resection and telomere clustering, a characteristic of ALT telomeres, catalyzes RAD52-dependent mitotic DNA synthesis (MiDAS) specifically at telomeres to drive ALT activity.

RevDate: 2019-09-25

Liu N, Yin Y, Wang H, et al (2019)

Telomere dysfunction impairs epidermal stem cell specification and differentiation by disrupting BMP/pSmad/P63 signaling.

PLoS genetics, 15(9):e1008368 pii:PGENETICS-D-19-00369.

Telomere shortening is associated with aging and age-associated diseases. Additionally, telomere dysfunction resulting from telomerase gene mutation can lead to premature aging, such as apparent skin atrophy and hair loss. However, the molecular signaling linking telomere dysfunction to skin atrophy remains elusive. Here we show that dysfunctional telomere disrupts BMP/pSmad/P63 signaling, impairing epidermal stem cell specification and differentiation of skin and hair follicles. We find that telomere shortening mediated by Terc loss up-regulates Follistatin (Fst), inhibiting pSmad signaling and down-regulating P63 and epidermal keratins in an ESC differentiation model as well as in adult development of telomere-shortened mice. Mechanistically, short telomeres disrupt PRC2/H3K27me3-mediated repression of Fst. Our findings reveal that skin atrophy due to telomere dysfunction is caused by a previously unappreciated link with Fst and BMP signaling that could be explored in the development of therapies.

RevDate: 2019-09-13

Hoffman TW, van der Vis JJ, van der Smagt JJ, et al (2019)

Pulmonary fibrosis linked to variants in the ACD gene, encoding the telomere protein TPP1.

RevDate: 2019-09-24

Wilbur SM, Barnes BM, Kitaysky AS, et al (2019)

Tissue-specific telomere dynamics in hibernating arctic ground squirrels (Urocitellus parryii).

The Journal of experimental biology, 222(Pt 18): pii:jeb.204925.

Hibernation is used by a variety of mammals to survive seasonal periods of resource scarcity. Reactive oxygen species (ROS) released during periodic rewarming throughout hibernation, however, may induce oxidative damage in some tissues. Telomeres, which are the terminal sequences of linear chromosomes, may shorten in the presence of ROS, and thus the telomere length of an individual reflects the degree of accrued oxidative damage. This study quantified telomere length dynamics throughout hibernation in arctic ground squirrels (Urocitellus parryii). We hypothesized that telomere dynamics are tissue specific and predicted that telomere shortening would be most pronounced in brown adipose tissue (BAT), the organ that directly supports non-shivering thermogenesis during arousals. We used qPCR to determine relative telomere length (RTL) in DNA extracted from liver, heart, skeletal muscle (SM) and BAT of 45 juvenile and adult animals sampled either at mid- or late hibernation. Age did not have a significant effect on RTL in any tissue. At mid-hibernation, RTL of juvenile females was longer in BAT and SM than in liver and heart. In juvenile females, RTL in BAT and SM, but not in liver and heart, was shorter at late hibernation than at mid-hibernation. At late hibernation, juvenile males had longer RTL in BAT than did juvenile females, perhaps due to the naturally shorter hibernation duration of male arctic ground squirrels. Finally, BAT RTL at late hibernation negatively correlated with arousal frequency. Overall, our results suggest that, in a hibernating mammal, telomere shortening is tissue specific and that metabolically active tissues might incur higher levels of molecular damage.


ESP Quick Facts

ESP Origins

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

ESP Support

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

ESP Rationale

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

ESP Goal

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

ESP Usage

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

ESP Content

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

ESP Help

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

ESP Plans

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

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Good Beginner's Books

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

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Papers in Classical Genetics

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

Digital Books

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


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


Biographical information about many key scientists.

Selected Bibliographies

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

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