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Bibliography on: Telomeres

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ESP: PubMed Auto Bibliography 23 May 2019 at 01:47 Created: 

Telomeres

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

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

Citations The Papers (from PubMed®)

RevDate: 2019-05-22

Chamorro CI, Muhammad A, Ekblad Å, et al (2019)

Urothelial cell senescence is not linked with telomere shortening.

Journal of tissue engineering and regenerative medicine [Epub ahead of print].

The success of regenerative medicine relies in part on the quality of the cells implanted. Cell cultures from cells isolated from bladder washes have been successfully established but molecular changes and cell characteristics have not been explored in detail. In this work, we analysed the role of telomere shortening in relation to the regenerative potential and senescence of cells isolated form bladder washes and expanded in culture. We also analysed, whether bladder washes would be a potential source for attaining stem cells or promoting stem cell proliferation by using two different substrates to support their growth: a feeder layer of growth arrested murine fibroblasts J2 3T3 cells and a xeno-free human recombinant laminin coated surface. We found no association between telomere shortening and senescence in urothelial cells in vitro. Urothelial cells had a stable telomere length and expressed mesenchymal stem cells markers but failed to differentiate into bone or adipocytes. Feeder layer showed an advantage to laminin-coated surfaces in respect to proliferative capacity with the expense of risking that feeder layer cells could persist in later passages. This emphasizes the importance of using carefully controlled culture conditions and molecular quality controls before auto-transplantation in future clinical settings. In conclusion, urothelial cells isolated by bladder washes show regenerative potential that need further understanding. Senescence in vitro might be due to cellular stress and, if so, further improvements in culture conditions may lead to longer cell life and higher proliferative capacity.

RevDate: 2019-05-22

Luu HN, Qi M, Wang R, et al (2019)

Association Between Leukocyte Telomere Length and Colorectal Cancer Risk in the Singapore Chinese Health Study.

Clinical and translational gastroenterology, 10(5):1-9.

OBJECTIVES: Telomeres and telomerase play important roles in maintaining chromosome integrity and genomic stability. To address a lack of consensus about the association between leukocyte telomere length and colorectal cancer, we investigated this association in the Singapore Chinese Health Study.

METHODS: Relative telomere length in white blood cells was quantified using a validated quantitative polymerase chain reaction method in 26,761 participants, including 776 incident colorectal cancer cases. The Cox proportional hazard regression method was used to calculate the hazard ratio and the corresponding 95% confidence interval (CI) for colorectal cancer associated with longer telomeres.

RESULTS: Longer telomeres were significantly associated with a higher risk of colorectal cancer (Ptrend = 0.02). Compared with the lowest quartile, subjects with the highest quartile of telomere length had a hazard ratio of 1.32 (95% CI: 1.08-1.62) for developing colorectal cancer. The corresponding elevation in rectal cancer risk for the highest quartile of telomere length was 71% (95% CI: 22-140, Ptrend = 0.02). There was no statistically significant association between telomere length and risk of colon cancer.

DISCUSSION: This large cohort study of Singapore Chinese, the first study using a cohort study design with more than 26,000 participants that yielded 776 incidence colorectal cancer cases during 12 years of follow-up, provides evidence in support of longer telomeres being associated with a higher risk of colorectal cancer, particularly rectal cancer.

RevDate: 2019-05-22

Tsoukalas D, Fragkiadaki P, Docea AO, et al (2019)

Association of nutraceutical supplements with longer telomere length.

International journal of molecular medicine [Epub ahead of print].

Telomeres are nucleotide tandem repeats located at the tip of eukaryotic chromosomes that maintain genomic integrity. The gradual shortening of telomeres leads to cellular senescence and apoptosis, a key mechanism of aging and age‑related chronic diseases. Epigenetic factors, such as nutrition, exercise and tobacco can affect the rate at which telomeres shorten and can modify the risk of developing chronic diseases. In this study, we evaluated the effects of a combination of nutraceutical supplements (NS) on telomere length (TL) in healthy volunteers with no medical history of any disease. Participants (n=47) were selected from healthy outpatients visiting a private clinic and were divided into the experimental group (n=16), that received the NS and the control group (n=31). We estimated the length of single telomeres in metaphase spread leukocytes, isolated from peripheral blood, using quantitative‑fluorescent in situ hybridization (Q‑FISH) analysis. The length of the whole telomere genome was significantly increased (P<0.05) for the mean, 1st quartile and median measurements in the experimental group. Similar findings were observed for short TL (20th percentile) (P<0.05) for the median and 3rd quartile measurements in the NS group, compared to the control group. The beneficial effects of the supplements on the length of short telomeres remained significant (P<0.05) following adjustment for age and sex. Telomeres were moderately longer in female patients compared to the male patients. On the whole, the findings of this study suggest that the administration of NS may be linked to sustaining the TL.

RevDate: 2019-05-22

Li N, Wang J, Ma K, et al (2019)

The dynamics of forming a triplex in an artificial telomere inferred by DNA mechanics.

Nucleic acids research pii:5494778 [Epub ahead of print].

A telomere carrying repetitive sequences ends with a single-stranded overhang. The G-rich overhang could fold back and bind in the major groove of its upstream duplex, forming an antiparallel triplex structure. The telomeric triplex has been proposed to function in protecting chromosome ends. However, we lack strategies to mechanically probe the dynamics of a telomeric triplex. Here, we show that the topological dynamics of a telomeric triplex involves 3' overhang binding at the ds/ssDNA junction inferred by DNA mechanics. Assisted by click chemistry and branched polymerase chain reaction, we developed a rescue-rope-strategy for mechanically manipulating an artificial telomeric DNA with a free end. Using single-molecule magnetic tweezers, we identified a rarely forming (5%) telomeric triplex which pauses at an intermediate state upon unzipping the Watson-Crick paired duplex. Our findings revealed that a mechanically stable triplex formed in a telomeric DNA can resist a force of 20 pN for a few seconds in a physiological buffer. We also demonstrated that the rescue-rope-strategy assisted mechanical manipulation can directly rupture the interactions between the third strand and its targeting duplex in a DNA triplex. Our single-molecule rescue-rope-strategy will serve as a general tool to investigate telomere dynamics and further develop triplex-based biotechnologies.

RevDate: 2019-05-22

Grunnet LG, Pilgaard K, Alibegovic A, et al (2019)

Leukocyte telomere length is associated with elevated plasma glucose and HbA1c in young healthy men independent of birth weight.

Scientific reports, 9(1):7639 pii:10.1038/s41598-019-43387-0.

Telomeres are protein-bound regions of repetitive nucleotide sequences (TTAGGG) at the end of human chromosomes, and their length is a marker of cellular aging. Intrauterine growth restriction is associated with shorter blood cell telomeres at birth and individuals with type 2 diabetes have shorter telomeres. Individuals with a low birth weight (LBW) have an increased risk of metabolic disease and type 2 diabetes. Therefore, we aimed to investigate the relationship between birth weight and telomere length and the association between birth weight, telomere length and cardiometabolic phenotype in adulthood. Young, healthy men with LBW (n = 55) and normal birth weight (NBW) (n = 65) were examined including blood pressure, blood samples and body composition. Leukocyte telomere length was determined using a high-throughput qPCR method. The LBW men were more insulin resistant as determined by the HOMA-IR index. There was no difference in telomere length between LBW and NBW subjects. When adjusting for birth weight and cohort effect, significant negative associations between telomere length and fasting glucose (P = 0.003) and HbA1c (P = 0.0008) were found. In conclusion, no significant difference in telomere length was found between LBW and NBW men. The telomere length was negatively associated with glucose concentrations and HbA1c levels within the normal non-diabetic range independent of birth weight.

RevDate: 2019-05-22

Giraudeau M, Heidinger B, Bonneaud C, et al (2019)

Telomere shortening as a mechanism of long-term cost of infectious diseases in natural animal populations.

Biology letters, 15(5):20190190.

Pathogens are potent selective forces that can reduce the fitness of their hosts. While studies of the short-term energetic costs of infections are accumulating, the long-term costs have only just started to be investigated. Such delayed costs may, at least in part, be mediated by telomere erosion. This hypothesis is supported by experimental investigations conducted on laboratory animals which show that infection accelerates telomere erosion in immune cells. However, the generalizability of such findings to natural animal populations and to humans remains debatable. First, laboratory animals typically display long telomeres relative to their wild counterparts. Second, unlike humans and most wild animals, laboratory small-bodied mammals are capable of telomerase-based telomere maintenance throughout life. Third, the effect of infections on telomere shortening and ageing has only been studied using single pathogen infections, yet hosts are often simultaneously confronted with a range of pathogens in the wild. Thus, the cost of an infection in terms of telomere-shortening-related ageing in natural animal populations is likely to be strongly underestimated. Here, we discuss how investigations into the links between infection, immune response and tissue ageing are now required to improve our understanding of the long-term impact of disease.

RevDate: 2019-05-21

Meier HCS, Hussein M, Needham B, et al (2019)

Cellular response to chronic psychosocial stress: Ten-year longitudinal changes in telomere length in the Multi-Ethnic Study of Atherosclerosis.

Psychoneuroendocrinology, 107:70-81 pii:S0306-4530(18)30891-6 [Epub ahead of print].

Previous studies have demonstrated an inverse association between chronic psychosocial stress and leukocyte telomere length (LTL), a potential marker of cellular aging. However, due to paucity of longitudinal data, responses of LTL and the LTL aging trajectory to changes in chronic stress exposure remain less well understood. Using data from the Stress I and II ancillary studies of the Multi-Ethnic Study of Atherosclerosis, we estimated the 10-year longitudinal (n = 1,158) associations of within-person changes in chronic stress with changes in LTL, as well as the pooled, cross-sectional associations of chronic stress and LTL (total n = 2,231). We measured chronic stress from both individual and neighborhood-environment sources. At the individual level, we calculated a summary score of each participant's rating of their ongoing (>6 months) material/social problems as moderately/very stressful on the Chronic Burden Scale. Neighborhood-level stress was measured using a summary score of reverse-coded MESA Neighborhood safety, aesthetic quality, and social cohesion scales. Quantiles of these scores were empirically categorized as high, moderate, or low stress. We then summed these individual- and neighborhood-level categorical variables for a total stress measure. Longitudinal within-person associations were estimated with fixed-effects models, which control for all time-invariant confounding, with additional control for time-varying demographics, lagged behaviors and chronic conditions, and specimen storage duration, as well as correction for regression to the mean. Change from low to high total chronic stress was associated with telomere shortening by 0.054 units [95% confidence interval: -0.095, -0.013] over 10 years. This was consistent with, though stronger in magnitude than, cross-sectional estimates. Change in individual-level stress was the primary driver of this effect. We also found suggestive evidence that 1) individuals with persistently high stress experienced the least shortening of telomeres, and 2) changes in individual-level stress were associated with stronger telomere shortening among women, whereas changes in neighborhood stress were associated with stronger shortening among men. Our findings provide longitudinal support to existing evidence, and point to interesting dynamics in telomere attrition across stress levels and genders.

RevDate: 2019-05-21

Pavanello S, Stendardo M, Mastrangelo G, et al (2019)

Higher Number of Night Shifts Associates with Good Perception of Work Capacity and Optimal Lung Function but Correlates with Increased Oxidative Damage and Telomere Attrition.

BioMed research international, 2019:8327629.

Sleep deprivation and the consequent circadian clock disruption has become an emergent health question being associated with premature aging and earlier chronic diseases onset. Night-shift work leads to circadian clock misalignment, which is linked to several age-related diseases. However, mechanisms of this association are not well understood. Aim of this study is to explore in night-shift workers early indicators of oxidative stress response and biological aging [oxidized/methylated DNA bases and leukocytes telomere length (LTL)] and late indicators of functional aging [lung function measurements (FEV1 and FVC)] in relation to personal evaluation of work capacity, measured by work ability index (WAI). One hundred fifty-five hospital workers were studied within the framework of a cross-sectional study. We collected physiological, pathological, and occupational history including pack-years, alcohol consumption, physical activity, and night shifts, together with blood and urine samples. Relationships were appraised by univariate and multivariate ordered-logistic regression models. We found that workers with good and excellent WAI present higher FEV1 (p< 0.01) and number of night-work shifts (p<0.05), but they reveal higher urinary levels of 8-oxoGua (p<0.01) and shorter LTL (p<0.05). We confirmed that higher work ability was prevalent among chronological younger workers (p<0.05), who have also a significant reduced number of diseases, particularly chronic (p<0.01) and musculoskeletal diseases (p<0.01). The new findings which stem from our work are that subjects with the highest work ability perception may have more demanding and burdensome tasks; they in fact present the highest number of night-shift work and produce unbalanced oxidative stress response that might induce premature aging.

RevDate: 2019-05-21

Zhan Y, H Song (2019)

Editorial: Telomeres and Epigenetics in Endocrinology.

Frontiers in endocrinology, 10:257.

RevDate: 2019-05-21

Shin D, Shin J, KW Lee (2019)

Effects of Inflammation and Depression on Telomere Length in Young Adults in the United States.

Journal of clinical medicine, 8(5): pii:jcm8050711.

Little is known about the associations of inflammation and depression with telomere length. Using data from the National Health and Nutrition Examination Survey (NHANES) 1999-2002, the current study assessed the effects of inflammation and depression on telomere length in 1141 young adults in the USA. Depression status was assessed from the World Health Organization Composite International Diagnostic Interview and inflammation status was measured based on C-reactive protein (CRP) concentrations. Information on telomere length was obtained using the quantitative polymerase chain reaction method to measure telomere length relative to standard reference DNA (T/S ratio). Unadjusted and adjusted linear and logistic regression models were used to assess the relationship between the tertiles of CRP concentration and the telomere length stratified by the status of depression such as major depression or depressed affect vs. no depression. The adjusted models were controlled for age, family poverty income ratio, race/ethnicity, marital status, physical activity, body mass index, and alcohol drinking status. A significant and decreasing linear trend in telomere length was found as CRP levels increased in men, regardless of the depression status, and women with major depression or depressed affect (p values < 0.05). Among men without depression, those with an elevated CRP level had increased odds of having a shortened telomere length compared to men with low CRP levels after controlling for covariates (adjusted odds ratio 1.77, 95% confidence interval (CI) 1.09-2.90). In women, there was no association between CRP and telomere length, regardless of the depression status. In conclusion, there was a significant and inverse association between inflammation and telomere length according to the depression status in men but not in women. The present findings may be of clinical significance for the monitoring of inflammation levels and depression status as determinants of telomere length.

RevDate: 2019-05-21

Koriath M, Müller C, Pfeiffer N, et al (2019)

Relative Telomere Length and Cardiovascular Risk Factors.

Biomolecules, 9(5): pii:biom9050192.

(1) Background: Telomeres are repetitive DNA sequences located at the extremities of chromosomes that maintain genetic stability. Telomere biology is relevant to several human disorders and diseases, specifically cardiovascular disease. To better understand the link between cardiovascular disease and telomere length, we studied the effect of relative telomere length (RTL) on cardiovascular risk factors in a large population-based sample. (2) Methods: RTL was measured by a real-time quantitative polymerase chain reaction in subjects of the population-based Gutenberg Health Study (n = 4944). We then performed an association study of RTL with known cardiovascular risk factors of smoking status as well as systolic and diastolic blood pressure, body mass index (BMI), LDL cholesterol, HDL cholesterol, and triglycerides. (3) Results: A significant correlation was shown for RTL, with age as a quality control in our study (effect = -0.004, p = 3.2 × 10-47). Analysis of the relation between RTL and cardiovascular risk factors showed a significant association of RTL in patients who were current smokers (effect = -0.016, p = 0.048). No significant associations with RTL were seen for cardiovascular risk factors of LDL cholesterol (p = 0.127), HDL cholesterol (p = 0.713), triglycerides (p = 0.359), smoking (p = 0.328), diastolic blood pressure (p = 0.615), systolic blood pressure (p = 0.949), or BMI (p = 0.903). In a subsequent analysis, we calculated the tertiles of RTL. No significant difference across RTL tertiles was detectable for BMI, blood pressure, lipid levels, or smoking status. Finally, we studied the association of RTL and cardiovascular risk factors stratified by tertiles of age. We found a significant association of RTL and LDL cholesterol in the oldest tertile of age (effect = 0.0004, p = 0.006). (4) Conclusions: We determined the association of relative telomere length and cardiovascular risk factors in a population setting. An association of telomere length with age, current smoking status, as well as with LDL cholesterol in the oldest tertile of age was found, whereas no associations were observed between telomere length and triglycerides, HDL cholesterol, blood pressure, or BMI.

RevDate: 2019-05-20

Asaka S, Davis C, Lin SF, et al (2019)

Analysis of Telomere Lengths in p53 Signatures and Incidental Serous Tubal Intraepithelial Carcinomas Without Concurrent Ovarian Cancer.

The American journal of surgical pathology [Epub ahead of print].

Telomere alterations represent one of the major molecular changes in the development of human cancer. We have previously reported that telomere lengths in most serous tubal intraepithelial carcinomas (STIC) are shorter than they are in ovarian high-grade serous carcinomas (HGSC) or in normal-appearing fallopian tube epithelium from the same patients. However, it remains critical to determine if similar telomere alterations occur in TP53-mutated but histologically unremarkable "p53 signature" lesions, as well as incidental STICs without concurrent HGSC. In this study, we quantitatively measured telomere lengths by performing telomere-specific fluorescence in situ hybridization in conjunction with p53 immunolabeling in 15 p53 signatures and 30 incidental STICs without concurrent HGSC. We compared these new results with our previous data in paired STICs and concurrent HGSCs. We found that most p53 signatures (80%) and incidental STICs without HGSC (77%) exhibited significant telomere shortening compared with adjacent normal-appearing fallopian tube epithelium (P<0.01). Interestingly, however, p53 signatures and incidental STICs without HGSC displayed longer telomeres and less cell-to-cell telomere length heterogeneity than STICs associated with HGSC (P<0.001). These findings indicate that telomere shortening occurs in p53 signatures, the earliest precancer lesion. Moreover, incidental STICs without concurrent HGSC are indeed similar to p53 signatures as they have less telomere shortening and less cell-to-cell telomere length heterogeneity than STICs associated with HGSC.

RevDate: 2019-05-20

Sayed ME, Slusher AL, AT Ludlow (2019)

Droplet Digital TRAP (ddTRAP): Adaptation of the Telomere Repeat Amplification Protocol to Droplet Digital Polymerase Chain Reaction.

Journal of visualized experiments : JoVE.

The telomere repeat amplification protocol (TRAP) is the most widely used assay to detect telomerase activity within a given a sample. The polymerase chain reaction (PCR)-based method allows for robust measurements of enzyme activity from most cell lysates. The gel-based TRAP with fluorescently labeled primers limits sample throughput, and the ability to detect differences in samples is restricted to two fold or greater changes in enzyme activity. The droplet digital TRAP, ddTRAP, is a highly sensitive approach that has been modified from the traditional TRAP assay, enabling the user to perform a robust analysis on 96 samples per run and obtain absolute quantification of the DNA (telomerase extension products) input within each PCR. Therefore, the newly developed ddTRAP assay overcomes the limitations of the traditional gel-based TRAP assay and provides a more efficient, accurate, and quantitative approach to measuring telomerase activity within laboratory and clinical settings.

RevDate: 2019-05-20

Stenbäck V, Mutt SJ, Leppäluoto J, et al (2019)

Association of Physical Activity With Telomere Length Among Elderly Adults - The Oulu Cohort 1945.

Frontiers in physiology, 10:444.

Introduction: Physical activity (PA) has been associated with telomere shortening. The association of PA intensity or volume with telomere length (TL) is nonetheless unclear. The aim of our study was to investigate the associations of exercise intensity and volume with TL in elderly adults from Northern Finland (65° latitude North). Methods: Seven hundred elderly subjects born in 1945 in the Oulu region were investigated. PA was measured during a 2-week period with a wrist-worn accelerometer. In addition, a questionnaire was used to assess sedentary time and to achieve a longitudinal PA history and intensity. Relative telomere lengths (RTL) were determined from frozen whole blood samples using a qPCR-based method. Results: Relative telomere lengths were significantly longer in women than men and negatively correlated with age in both genders (men r = -0.210, p = 0.000, women r = -0.174, and p = 0.000). During the 2-week study period, women took more steps than men (p = 0.001), but the association between steps and RTL was only seen in men (p = 0.05). Total steps taken (r = 0.202 and p = 0.04) and sedentary time (r = -0.247 and p = 0.007) significantly correlated with RTLs in 70-year old subjects. Moderate PA was associated with RTL in subjects with the highest quartile of moderate PA compared to the three lower quartiles (p-values: 0.023 between 4th and 1st, 0.04 between 4th and 2nd, and 0.027 between 4th and 3rd) in the 70-year old subjects. Conclusion: Women had longer RTL and a higher step count compared to men. However, exercise volume and RTL correlated positively only in men. Surprisingly, age correlated negatively with RTL already within an age difference of 2 years. This suggests that telomere attrition rate may accelerate in older age. Moderate physical activity at the time of study was associated with RTL.

RevDate: 2019-05-18

Dlouha D, Vymetalova J, Hubacek JA, et al (2019)

Association between aortic telomere length and cardiac post-transplant allograft function.

International journal of cardiology pii:S0167-5273(18)35641-9 [Epub ahead of print].

BACKGROUND: In patients having undergone orthotopic heart transplantation, a number of complications exist that are known to be connected to both telomerase activity and telomere length. The aim of this study was to determine how telomere length in aortic DNA correlates with the subsequent post-transplantation development of the patients.

MATERIALS AND METHODS: Between 2005 and 2015, we collected aortic samples from 376 heart recipients (age 50.8 ± 11.8 years) and 383 donors (age 38.6 ± 12.2 years). Relative telomere length in aortic tissue DNA was determined using quantitative PCR.

RESULTS: Shorter telomere length was detected in heart allograft recipients compared to donors (P < 0.0001). Patients suffering acute cellular rejection had significantly shorter telomere length (P < 0.01) than patients without rejection. Shorter telomere length was observed in patients with implanted mechanical circulatory support before heart transplantation (P < 0.03), as well as in subjects with cardiac allograft vasculopathy (P < 0.05). Overall survival time after heart transplantation was associated with shorter donor telomeres (P < 0.004).

CONCLUSIONS: Telomere length differed between donors and recipients independent of the sex and age of the patients. Our findings suggest a potential new linkage between the aortic telomere length of recipients and post-heart transplant complications. Further studies focusing on epigenetic modifications and gene regulation involved in telomere maintenance in transplanted patients should verify our results.

RevDate: 2019-05-18

Fouquerel E, Barnes RP, Uttam S, et al (2019)

Targeted and Persistent 8-Oxoguanine Base Damage at Telomeres Promotes Telomere Loss and Crisis.

Molecular cell pii:S1097-2765(19)30316-8 [Epub ahead of print].

Telomeres are essential for genome stability. Oxidative stress caused by excess reactive oxygen species (ROS) accelerates telomere shortening. Although telomeres are hypersensitive to ROS-mediated 8-oxoguanine (8-oxoG) formation, the biological effect of this common lesion at telomeres is poorly understood because ROS have pleiotropic effects. Here we developed a chemoptogenetic tool that selectively produces 8-oxoG only at telomeres. Acute telomeric 8-oxoG formation increased telomere fragility in cells lacking OGG1, the enzyme that removes 8-oxoG, but did not compromise cell survival. However, chronic telomeric 8-oxoG induction over time shortens telomeres and impairs cell growth. Accumulation of telomeric 8-oxoG in chronically exposed OGG1-deficient cells triggers replication stress, as evidenced by mitotic DNA synthesis at telomeres, and significantly increases telomere losses. These losses generate chromosome fusions, leading to chromatin bridges and micronucleus formation upon cell division. By confining base damage to the telomeres, we show that telomeric 8-oxoG accumulation directly drives telomere crisis.

RevDate: 2019-05-18

Weale CJ, Davison GM, Hon GM, et al (2019)

Leucocyte Telomere Length and Glucose Tolerance Status in Mixed-Ancestry South Africans.

Cells, 8(5): pii:cells8050464.

Telomeres are DNA-tandem repeats situated at the ends of chromosomes and are responsible for genome stabilization. They are eroded by increased cell division, age and oxidative stress with shortened leucocyte telomeres (LTL) being associated with inflammatory disorders, including Type II diabetes. We assessed LTL in 205 participants across glucose tolerance groups at baseline and after three years in the mixed ancestry population of South Africa which have been shown to have high rates of obesity and T2DM. Baseline and follow-up data included glucose tolerance status, anthropometric measurements, lipids, insulin, γ-glutamyl transferase (GGT), cotinine, and HbA1c. Telomere length was measured using the absolute telomere q-PCR method performed on a Bio-Rad MiniOpticon Detector. No significant difference was detected in LTL across glucose tolerance groups at both time points, including in subjects who showed a deterioration of their glucose tolerance status. There was, however, a significant negative correlation between LTL and age which was more pronounced in diabetes (r = -0.18, p = 0.04) and with GGT (r = -0.16, p = 0.027). This longitudinal study has demonstrated that LTL shortening is not evident within three years, nor is it associated with glycaemia. Further studies in a larger sample and over a longer time period is required to confirm these results.

RevDate: 2019-05-17

Iberl S, Meyer AL, Müller G, et al (2019)

Effects of continuous high-dose G-CSF administration on hematopoietic stem cell mobilization and telomere length in patients with amyotrophic lateral sclerosis - a pilot study.

Cytokine, 120:192-201 pii:S1043-4666(19)30120-6 [Epub ahead of print].

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease of complex and still poorly understood etiology. Loss of upper and lower motoneurons results in death within few years after diagnosis. Recent studies have proposed neuroprotective and disease-slowing effects of granulocyte-colony stimulating factor (G-CSF) treatment in ALS mouse models as well as humans. In this study, six ALS patients were monitored up to 3.5 years during continuous high-dose G-CSF administration. Repetitive analyses were performed including blood count parameters, CD34+ hematopoietic stem and progenitor cell (HSPC) and colony forming cell (CFC) counts, serum cytokine levels and leukocyte telomere length. We demonstrate that continuous G-CSF therapy was well tolerated and safe resulting in only mild adverse events during the observation period. However, no mobilization of CD34+ HSPC was detected as compared to baseline values. CFC mobilization was equally low and even a decrease of myeloid precursors was observed in some patients. Assessment of telomere length within ALS patients' leukocytes revealed that G-CSF did not significantly shorten telomeres, while those of ALS patients were shorter compared to age-matched healthy controls, irrespective of G-CSF treatment. During G-CSF stimulation, TNF-alpha, CRP, IL-16, sVCAM-1, sICAM-1, Tie-2 and VEGF were significantly increased in serum whereas MCP-1 levels decreased. In conclusion, our data show that continuous G-CSF treatment fails to increase circulating CD34+ HSPC in ALS patients. Cytokine profiles revealed G-CSF-mediated immunomodulatory and proteolytic effects. Interestingly, despite intense G-CSF stimulation, telomere length was not significantly shortened.

RevDate: 2019-05-17

Farooqi A, Yang J, Sharin V, et al (2019)

Identification of patient-derived glioblastoma stem cell (GSC) lines with the alternative lengthening of telomeres phenotype.

Acta neuropathologica communications, 7(1):76 pii:10.1186/s40478-019-0732-4.

RevDate: 2019-05-16

Lin X, Zhou J, B Dong (2019)

Effect of different levels of exercise on telomere length: A systematic review and meta-analysis.

Journal of rehabilitation medicine [Epub ahead of print].

OBJECTIVE: To investigate the effect of different levels of exercise on telomere length.

METHODS: CINAHL, SPORTDiscus (EBSCO), OVID (Medline) and EMBASE databases were searched for eligible studies. Methodological quality was evaluated using the Newcastle-Ottawa Scale, and heterogeneity among the studies was assessed using the I-squared test. When heterogeneity among studies was high (I2 > 50%), a random-effects model was used (Review Manager version 5, Cochrane Collaboration, Copenhagen, Denmark); otherwise, a fixed-effects model was used.

RESULTS: Eleven eligible studies involving 15,645 participants were included in this meta-analysis. Longer telomere length was associated with physically active individuals, with a mean difference (MD) of 0.15; 95% confidence interval; 95% CI 0.05, 0.24; I2 = 99%. Longer telomere length was significantly associated with robust exercise (MD 0.08; 95% CI 0.04, 0.12); I2 = 99%, as was moderate exercise (MD 0.07; 95% CI 0.03, 0.11); I2 = 100%. Subgroup analysis revealed that longer telomere length was positively associated with exercise, regardless of sex, but was not statistically significant in elderly populations.

CONCLUSION: Compared with inactive individuals, telomere lengths were longer in active subjects, regardless of the intensity of exercise.

RevDate: 2019-05-15

Hu R, Hua XG, QC Jiang (2019)

Associations of telomere length in risk and recurrence of prostate cancer: A meta-analysis.

Andrologia [Epub ahead of print].

Over the past decades, there is an increasing number of association studies of telomere length (TL) and the risk and recurrence of prostate cancer (PCa), but the results are inconsistent. Hence, we identify the relevant studies published in English on or before 10 January 2019 conducting a literature review in the electronic databases including PubMed, EMBASE and Cochrane Library. Twelve studies (with 19 data sets) were included in this meta-analysis, five of which were associated with risk assessment, six of which reported recurrence of PCa and one of which included them. Our meta-analysis demonstrated a positive association of shorter telomeres in patients with PCa, but without statistical significance (OR, 1.23; 95% CI: 0.91-1.66). Shorter telomeres in stroma (OR, 2.40; 95% CI: 1.61-3.56) and epithelium (OR, 1.70; 95% CI: 1.33-2.16) were positively correlated with PCa, but in leucocyte (OR, 0.81; 95% CI: 0.73-0.91) had negative association with PCa. Furthermore, two studies combined yielded a pooled OR of 2.87 (95% CI: 1.22-6.76) for the association between shorter TL and metastasis. These results are novel and give further strength to formulate eligible individualising treatment and surveillance strategies.

RevDate: 2019-05-15

Gauchier M, Kan S, Barral A, et al (2019)

SETDB1-dependent heterochromatin stimulates alternative lengthening of telomeres.

Science advances, 5(5):eaav3673 pii:aav3673.

Alternative lengthening of telomeres, or ALT, is a recombination-based process that maintains telomeres to render some cancer cells immortal. The prevailing view is that ALT is inhibited by heterochromatin because heterochromatin prevents recombination. To test this model, we used telomere-specific quantitative proteomics on cells with heterochromatin deficiencies. In contrast to expectations, we found that ALT does not result from a lack of heterochromatin; rather, ALT is a consequence of heterochromatin formation at telomeres, which is seeded by the histone methyltransferase SETDB1. Heterochromatin stimulates transcriptional elongation at telomeres together with the recruitment of recombination factors, while disrupting heterochromatin had the opposite effect. Consistently, loss of SETDB1, disrupts telomeric heterochromatin and abrogates ALT. Thus, inhibiting telomeric heterochromatin formation in ALT cells might offer a new therapeutic approach to cancer treatment.

RevDate: 2019-05-14

Reddy V, Iskander A, Hwang C, et al (2019)

Castration-resistant prostate cancer: Androgen receptor inactivation induces telomere DNA damage, and damage response inhibition leads to cell death.

PloS one, 14(5):e0211090 pii:PONE-D-19-00420.

Telomere stability is important for cell viability, as cells with telomere DNA damage that is not repaired do not survive. We reported previously that androgen receptor (AR) antagonist induces telomere DNA damage in androgen-sensitive LNCaP prostate cancer cells; this triggers a DNA damage response (DDR) at telomeres that includes activation of ATM, and blocking ATM activation prevents telomere DNA repair and leads to cell death. Remarkably, AR antagonist induces telomere DNA damage and triggers ATM activation at telomeres also in 22Rv1 castration-resistant prostate cancer (CRPC) cells that are not growth inhibited by AR antagonist. Treatment with AR antagonist enzalutamide (ENZ) or ATM inhibitor (ATMi) by itself had no effect on growth in vitro or in vivo, but combined treatment with ENZ plus ATMi significantly inhibited cell survival in vitro and tumor growth in vivo. By inducing telomere DNA damage and activating a telomere DDR, an opportunity to inhibit DNA repair and promote cell death was created, even in CRPC cells. 22Rv1 cells express both full-length AR and AR splice variant AR-V7, but full-length AR was found to be the predominant form of AR associated with telomeres and required for telomere stability. Although 22Rv1 growth of untreated 22Rv1 cells appears to be driven by AR-V7, it is, ironically, expression of full-length AR that makes them sensitive to growth inhibition by combined treatment with ENZ plus ATMi. Notably, this combined treatment approach to induce telomere DNA damage and inhibit the DDR was effective in inducing cell death also in other CRPC cell lines (LNCaP/AR and C4-2B). Thus, the use of ENZ in combination with a DDR inhibitor, such as ATMi, may be effective in prolonging disease-free survival of patients with AR-positive metastatic CRPC, even those that co-express AR splice variant.

RevDate: 2019-05-10

Ghanem NZ, Malla SRL, Araki N, et al (2019)

Quantitative assessment of changes in cell growth, size and morphology during telomere-initiated cellular senescence in Saccharomyces cerevisiae.

Experimental cell research pii:S0014-4827(19)30238-1 [Epub ahead of print].

Telomerase-deficient cells of the budding yeast S. cerevisiae experience progressive telomere shortening and undergo senescence in a manner similar to that seen in cultured human fibroblasts. The cells exhibit a DNA damage checkpoint-like stress response, undergo changes in size and morphology, and eventually stop dividing. In this study, a new assay is described that allowed quantitation of senescence in telomerase-deficient est2 cells with applied statistics. Use of the new technique revealed that senescence was strongly accelerated in est2 mutants that had homologous recombination genes RAD51, RAD52 or RAD54 co-inactivated, but was only modestly affected when RAD55, RAD57 or RAD59 were knocked out. Additionally, a new approach for calculating population doublings indicated that loss of growth capacity occurred after approximately 64 generations in est2 cells but only 42 generations in est2 rad52 cells. Phase contrast microscopy experiments demonstrated that senescing est2 cells became enlarged in a time-dependent manner, ultimately exhibiting a 60% increase in cell size. Progressive alterations in physical properties were also observed, including striking changes in light scattering characteristics and cellular sedimentation rates. The results described herein will facilitate future studies of genetic and environmental factors that affect telomere shortening-associated cell senescence rates using the yeast model system.

RevDate: 2019-05-09

Tanpaisankit M, Hongsaprabhas C, Chareonlap C, et al (2019)

Relative telomere length and oxidative stress in musculoskeletal tumors.

Molecular biology reports pii:10.1007/s11033-019-04847-y [Epub ahead of print].

Telomeres are capped at the end of the chromosome and gradually shorten when the cell divides. When there is an oxidative stress, it can cause the DNA to be damaged. Hence, 8-hydroxy-2'-deoxyguanosine (8-OHdG) has been shown to be an indicator for oxidative DNA damage. This study aimed to determine the relative telomere length (RTL) and 8-OHdG levels in neoplastic tissues, adjacent non-neoplastic tissues, and blood leukocytes of musculoskeletal (MS) tumor patients. Neoplastic tissues were compared to adjacent non-neoplastic tissues in MS tumor patients (n = 46). Peripheral blood leukocytes (PBLs) of MS tumor subjects were compared to those of age-matched healthy controls (n = 107). RTL was evaluated by quantitative real-time polymerase chain reaction and 8-OHdG levels were quantified by enzyme-linked immunosorbent assay. The RTL in neoplastic tissues was significantly shorter than that in non-neoplastic tissues [1.12 (0.86-1.46) vs 1.45 (1.25-1.65), P = 0.001]. PBLs had lower RTL than non-neoplastic tissues in MS tumor patients [1.04 (0.85-1.13) vs 1.45 (1.25-1.65), P < 0.001]. However, there was no significant difference between RTL in PBLs and in neoplastic tissues. In addition, PBLs of MS tumor patients had higher RTL than those of the controls [1.04 (0.85-1.13) versus 0.78 (0.68-0.90), P < 0.001]. The 8-OHdG levels in neoplastic tissues were remarkably higher than those in non-neoplastic tissues [8.14 (6.81-11.37) nM/μg/μl vs. 3.79 (2.53-6.17) nM/μg/μl, P < 0.001]. Furthermore, plasma 8-OHdG levels in MS tumor patients were markedly greater than those in the controls [102.50 (73.16-133.50) nM vs. 41.09 (6.81-11.37) nM, P < 0.001]. Area under the curve (AUC) was 0.7536 (95% confident interval (CI) 0.6602-0.8469) when the cut-off value of RTL in PBLs was 0.97. Also, plasma 8-OHdG levels depicted that when the cut-off value was 38.67 nM, the AUC was 0.7723 (95% CI 0.6920-0.8527). Moreover, ROC curve analysis showed that both RTL and 8-OHdG appeared to improve the sensitivity (85.68%) and specificity (70.91%) with the AUC 0.8639 (95% CI 0.7500-0.9500). This study suggested that blood leukocyte RTL and plasma 8-OHdG could serve as promising non-invasive biomarkers to differentiate between MS tumor patients and healthy controls. Additionally, telomere attrition and increased oxidative DNA damage might play contributory roles in the pathogenesis of MS tumors.

RevDate: 2019-05-09

Wang J, Peng X, Chen C, et al (2019)

Intra-Familial Phenotypic Heterogeneity and Telomere Abnormality in von Hippel- Lindau Disease: Implications for Personalized Surveillance Plan and Pathogenesis of VHL-Associated Tumors.

Frontiers in genetics, 10:358.

von Hippel-Lindau (VHL) disease is a hereditary cancer syndrome with poor survival. The current recommendations have proposed uniform surveillance strategies for all patients, neglecting the obvious phenotypic varieties. In this study, we aim to confirm the phenotypic heterogeneity in VHL disease and the underlying mechanism. A total of 151 parent-child pairs were enrolled for genetic anticipation analysis, and 77 sibling pairs for birth order effect analysis. Four statistical methods were used to compare the onset age of patients among different generations and different birth orders. The results showed that the average onset age was 18.9 years earlier in children than in their parents, which was statistically significant in all of the four statistical methods. Furthermore, the first-born siblings were affected 8.3 years later than the other ones among the maternal patients. Telomere shortening was confirmed to be associated with genetic anticipation in VHL families, while it failed to explain the birth order effect. Moreover, no significant difference was observed for overall survival between parents and children (p = 0.834) and between first-born patients and the other siblings (p = 0.390). This study provides definitive evidence and possible mechanisms of intra-familial phenotypic heterogeneity in VHL families, which is helpful to the update of surveillance guidelines.

RevDate: 2019-05-09

Niederberger C (2019)

Re: Non-Obstructive Azoospermia and Shortened Leukocyte Telomere Length: Further Evidence Linking Poor Health and Infertility.

The Journal of urology, 201(6):1040-1041.

RevDate: 2019-05-07

Sugarman ET, Zhang G, JW Shay (2019)

In perspective: An update on telomere targeting in cancer.

Molecular carcinogenesis [Epub ahead of print].

Engaging a telomere maintenance mechanism during DNA replication is essential for almost all advanced cancers. The conversion from normal and premalignant somatic cells to advanced malignant cells often results (85%-90%) from the reactivation of the functional ribonucleoprotein holoenzyme complex, referred to as telomerase. Modulation of the human telomerase reverse transcriptase (hTERT) appears to be rate limiting to produce functional telomerase and engage a telomere maintenance mechanism. The remaining 10% to 15% of cancers overcome progressively shortened telomeres by activating an alternative lengthening of telomeres (ALT) maintenance mechanism, through a DNA recombination pathway. Exploration into the specific mechanisms of telomere maintenance in cancer have led to the development of drugs such as Imetelstat (GRN163L), BIBR1532, 6-thio-dG, VE-822, and NVP-BEZ235 being investigated as therapeutic approaches for treating telomerase and ALT tumors. The successful use of 6-thio-dG (a nucleoside preferentially recognized by telomerase) that targets and uncaps telomeres in telomerase positive but not normal telomerase silent cells has recently shown impressive effects on multiple types of cancer. For example, 6-thio-dG overcomes therapy-resistant cancers in a fast-acting mechanism potentially providing an alternative or additional route of treatment for patients with cancer. In this perspective, we provide a synopsis of the current landscape of telomeres and telomerase processing in cancer development and how this new knowledge may improve outcomes for patients with cancer.

RevDate: 2019-05-07

Huda N, Xu Y, Bates AM, et al (2019)

Onset of Telomere Dysfunction and Fusions in Human Ovarian Carcinoma.

Cells, 8(5): pii:cells8050414.

Telomere dysfunction has been strongly implicated in the initiation of genomic instability and is suspected to be an early event in the carcinogenesis of human solid tumors. Recent findings have established the presence of telomere fusions in human breast and prostate malignancies; however, the onset of this genomic instability mechanism during progression of other solid cancers is not well understood. Herein, we explored telomere dynamics in patient-derived epithelial ovarian cancers (OC), a malignancy characterized by multiple distinct subtypes, extensive molecular heterogeneity, and widespread genomic instability. We discovered a high frequency of telomere fusions in ovarian tumor tissues; however, limited telomere fusions were detected in normal adjacent tissues or benign ovarian samples. In addition, we found relatively high levels of both telomerase activity and hTERT expression, along with anaphase bridges in tumor tissues, which were notably absent in adjacent normal ovarian tissues and benign lesions. These results suggest that telomere dysfunction may occur early in ovarian carcinogenesis and, importantly, that it may play a critical role in the initiation and progression of the disease. Recognizing telomere dysfunction as a pervasive feature of this heterogeneous malignancy may facilitate the future development of novel diagnostic tools and improved methods of disease monitoring and treatment.

RevDate: 2019-05-06

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

Effects of maternal exposure to ambient air pollution on newborn telomere length.

Environment international, 128:254-260 pii:S0160-4120(19)30041-8 [Epub ahead of print].

BACKGROUND: Telomere length (TL) is considered as a surrogate of biological aging and has been related to aging-related diseases. The initial setting of newborn TL has important implications for telomere dynamics in adulthood, and is affected by the intrauterine environment. However, the effects of prenatal air pollution exposure on the initial setting of newborn TL are poor understood.

OBJECTIVES: We aimed to explore the trimester-specific relationships between maternal air pollution exposure and newborn TL.

METHODS: Between November 2013 and March 2015, a total of 762 mother-newborn pairs were recruited in a birth cohort study in Wuhan, China. Relative cord blood TL was assessed using quantitative real-time polymerase chain reaction. Maternal exposures to PM2.5, PM10, SO2, CO, and NO2, were determined using spatial-temporal land use regression models. Multiple informant models were applied to explore the trimester-specific associations of maternal air pollution exposure with cord blood TL.

RESULTS: In single-pollutant models, a 10 μg/m3 increase in PM2.5, PM10, SO2, and a 100 μg/m3 increase in CO during the third trimester were related to 3.71% (95% confidence interval [CI]: -6.06%, -1.30%), 3.24% (95% CI: -5.29%, -1.14%), 11.07% (95% CI: -18.86%, -2.53%), and 3.67% (95% CI: -6.27%, -1.00%) shorter cord blood TL, respectively. The inverse relationships between exposures to PM2.5, PM10, SO2, and CO during the third trimester and cord blood TL were more evident in male infants. In multi-pollutant models, exposures to PM2.5 and PM10 during the third trimester were both related to shorter cord blood TL, but not SO2 and CO.

CONCLUSION: This study suggested that maternal exposures to PM2.5, PM10, CO, and SO2 during the third trimester were related to shorter newborn TL, which highlights the importance of improving air quality in favor of subsequent health in later life of newborns.

RevDate: 2019-05-06

Krishna R, Bhat V, Zachariah B, et al (2019)

Are Global DNA methylation and telomere length useful biomarkers for identifying intrauterine growth restricted neonates ?.

The journal of maternal-fetal & neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians [Epub ahead of print].

BACKGROUND: Intrauterine growth restriction (IUGR) is manifested by decreased growth rate of fetus than its normal genetic growth potential. Global DNA methylation is a crucial investigation for identification of epigenetic changes. Epigenetic change regulates Gene transcription, maintenance of genomic stability, and telomere length.

OBJECTIVES: To investigate whether the global DNA methylation and telomere length are useful for identifying intrauterine growth restriction.

METHODS: This cohort study was conducted in the Neonatology Department of JIPMER during the period of November 2016 to December 2017. Forty (40) IUGR and forty (40) AGA neonates were recruited. Umbilical cord blood samples were collected at birth. DNA has been separated from the blood samples and using 5-mC DNA ELISA method, the percentage of genomic DNA methylated in these neonates was established. Telomere length (T/S ratio) was measured by using quantitative real time PCR. Data were expressed as a mean ± standard deviation.

RESULTS: Genomic DNA methylation varied significantly between IUGR and AGA neonates (IUGR: 3.12 ± 1.24; AGA: 4.40 ± 2.03; P : < 0.01). There was significant DNA hypo methylation in IUGR neonates. However telomere length (T/S ratio) was (IUGR: 1.25 ± 0.13; AGA: 1.26 ± 0.22; P : 0.228 (NS)) similar in both groups.

CONCLUSION: Although there is no significant difference in telomere length between IUGR and AGA neonates, global DNA methylation of 3.45 would identify IUGR with a sensitivity and specificity of 69 and 65% respectively.

RevDate: 2019-05-05

Nie J, Li J, Cheng L, et al (2019)

Prenatal polycyclic aromatic hydrocarbons metabolites, cord blood telomere length, and neonatal neurobehavioral development.

Environmental research, 174:105-113 pii:S0013-9351(19)30240-3 [Epub ahead of print].

BACKGROUND: Prenatal exposure to polycyclic aromatic hydrocarbon (PAH) is a potential risk factor for child neurobehavioral development. Telomere length (TL) has important implications for health over the life course.

OBJECTIVE: In this study, we aimed to investigate whether prenatal urinary PAH metabolites were associated with adverse neonatal neurobehavioral development and altered cord blood TL and to explore whether the change of TL was a predictor of neonatal neurobehavioral development.

METHOD: We enrolled 283 nonsmoking pregnant women in Taiyuan city. Eleven PAH metabolites were measured in maternal urine samples. TL in cord blood was measured by real time quantitative polymerase chain reaction. Neonatal behavioral neurological assessment (NBNA) tests were conducted when the infants were three days old. Multiple linear regression models were used to analyze the associations of maternal urinary PAH metabolites with NBNA scores and cord blood TL, and restricted cubic spline models were further used to examine the shapes of dose-response relationships. A mediation analysis was also conducted.

RESULT: We observed dose-response associations of maternal urinary 2-hydroxyfluorene (2-OHFlu) and 2-hydroxyphenanthrene (2-OH Phe) with decreased active tone scores, sum of NBNA scores, and cord blood TL (P for trend<0.05). Each 1 unit increase in urinary levels of Ln (2-OH Flu) or Ln (2-OH Phe) was associated with a 0.092 or 0.135 decrease in the active tone scores and a 0.174 or 0.199 decrease in the sum of NBNA scores. Mediation analysis showed TL could explained 21.74% of the effect of sum of NBNA scores change related to prenatal exposure to 2-OH Phe (P for mediator = 0.047).

CONCLUSION: Our data indicates maternal urinary specific PAH metabolites are inversely associated with neonatal neurobehavioral development and cord blood TL. TL mediates the associations of 2-OH Phe with neonatal neurobehavioral development and partly explains the effect of 2-OH Phe on neonatal neurobehavioral development.

RevDate: 2019-05-03

Canudas S, Hernández-Alonso P, Galié S, et al (2019)

Pistachio consumption modulates DNA oxidation and genes related to telomere maintenance: a crossover randomized clinical trial.

The American journal of clinical nutrition pii:5485482 [Epub ahead of print].

BACKGROUND: Telomere attrition may play an important role in the pathogenesis and severity of type 2 diabetes (T2D), increasing the probability of β cell senescence and leading to reduced cell mass and decreased insulin secretion. Nutrition and lifestyle are known factors modulating the aging process and insulin resistance/secretion, determining the risk of T2D.

OBJECTIVES: The aim of this study was to evaluate the effects of pistachio intake on telomere length and other cellular aging-related parameters of glucose and insulin metabolism.

METHODS: Forty-nine prediabetic subjects were included in a randomized crossover clinical trial. Subjects consumed a pistachio-supplemented diet (PD, 50 E% [energy percentage] carbohydrates and 33 E% fat, including 57 g pistachios/d) and an isocaloric control diet (CD, 55 E% carbohydrates and 30 E% fat) for 4 mo each, separated by a 2-wk washout period. DNA oxidation was evaluated by DNA damage (via 8-hydroxydeoxyguanosine). Leucocyte telomere length and gene expression related to either oxidation, telomere maintenance or glucose, and insulin metabolism were analyzed by multiplexed quantitative reverse transcriptase-polymerase chain reaction after the dietary intervention.

RESULTS: Compared with the CD, the PD reduced oxidative damage to DNA (mean: -3.5%; 95% CI: -8.07%, 1.05%; P = 0.009). Gene expression of 2 telomere-related genes (TERT and WRAP53) was significantly upregulated (164% and 53%) after the PD compared with the CD (P = 0.043 and P = 0.001, respectively). Interestingly, changes in TERT expression were negatively correlated to changes in fasting plasma glucose concentrations and in the homeostatic model assessment of insulin resistance.

CONCLUSIONS: Chronic pistachio consumption reduces oxidative damage to DNA and increases the gene expression of some telomere-associated genes. Lessening oxidative damage to DNA and telomerase expression through diet may represent an intriguing way to promote healthspan in humans, reversing certain deleterious metabolic consequences of prediabetes. This study was registered at clinicaltrials.gov as NCT01441921.

RevDate: 2019-05-03

Agrusa JE, Bertuch AA, DiNardo CD, et al (2019)

Severe therapy-related toxicities after treatment for Hodgkin lymphoma due to a pathogenic TERT variant and shortened telomeres.

Pediatric blood & cancer [Epub ahead of print].

Telomere biology disorders predispose affected individuals to specific malignancies and organ fibrosis in tissues sensitive to telomere length (TL) shortening, especially after exposure to chemotherapy and radiation. We report a case of a 17-year-old female with Hodgkin lymphoma who developed severe chemotherapy-related toxicities. She was subsequently found to have peripheral blood lymphocyte TL < 1st percentile and a pathogenic variant in TERT inherited from her father. This case demonstrates that early genetic evaluation of patients who experience greater than expected therapy-related toxicities may be warranted to help guide further decisions regarding therapy, imaging modalities, and lifelong cancer prevention surveillance.

RevDate: 2019-05-02

Nettle D, Seeker L, Nussey D, et al (2019)

Consequences of measurement error in qPCR telomere data: A simulation study.

PloS one, 14(5):e0216118 pii:PONE-D-18-35272.

The qPCR method provides an inexpensive, rapid method for estimating relative telomere length across a set of biological samples. Like all laboratory methods, it involves some degree of measurement error. The estimation of relative telomere length is done subjecting the actual measurements made (the Cq values for telomere and a control gene) to non-linear transformations and combining them into a ratio (the TS ratio). Here, we use computer simulations, supported by mathematical analysis, to explore how errors in measurement affect qPCR estimates of relative telomere length, both in cross-sectional and longitudinal data. We show that errors introduced at the level of Cq values are magnified when the TS ratio is calculated. If the errors at the Cq level are normally distributed and independent of true telomere length, those in the TS ratio are positively skewed and proportional to true telomere length. The repeatability of the TS ratio declines sharply with increasing error in measurement of the Cq values for telomere and/or control gene. In simulated longitudinal data, measurement error alone can produce a pattern of low correlation between successive measures of relative telomere length, coupled with a strong negative dependency of the rate of change on initial relative telomere length. Our results illustrate the importance of reducing measurement error: a small increase in error in Cq values can have large consequences for the power and interpretability of qPCR estimates of relative telomere length. The findings also illustrate the importance of characterising the measurement error in each dataset-coefficients of variation are generally unhelpful, and researchers should report standard deviations of Cq values and/or repeatabilities of TS ratios-and allowing for the known effects of measurement error when interpreting patterns of TS ratio change over time.

RevDate: 2019-05-02

Athanasoulia-Kaspar AP, Auer MK, Stalla GK, et al (2018)

Shorter telomeres associated with high doses of glucocorticoids: the link to increased mortality?.

Endocrine connections [Epub ahead of print].

OBJECTIVE: Patients with non-functioning pituitary adenomas exhibit high morbidity and mortality rates. Growth hormone deficiency and high doses of glucocorticoid substitution therapy have been identified as corresponding risk factors. Interestingly, high levels of endogenous cortisol in, e.g., patients with post-traumatic stress disorder or patients with Cushing's disease have been linked to shorter telomere length. Telomeres are noncoding DNA regions located at the end of chromosomes consisting of repetitive DNA sequences which shorten with ageing and hereby determine cell survival. Therefore, telomere length can serve as a predictor for the onset of disease and mortality in some endocrine disorders (e.g., Cushing's disease).

DESIGN/METHODS: We examine telomere length from blood in patients (n = 115) with non-functioning pituitary adenomas (NFPA) in a cross-sectional case control (n = 106, age-, gender- matched) study using qPCR. Linear regression models were used to identify independent predictors of telomere length.

RESULTS: We show that patients with NFPA exhibited shorter telomeres than controls. No significant association of indices of growth hormone deficiency (IGF-1-level-SDS, years of unsubstituted growth hormone deficiency etc.) with telomere length was detected. Interestingly, linear regression analysis showed that hydrocortisone replacement dosage in patients with adrenal insufficiency (n = 52) was a significant predictor for shorter telomere length (β = 0.377; p = 0.018) independent of potential confounders. Median split analysis revealed that higher hydrocortisone intake (> 20 mg) was associated with significantly shorter telomeres.

CONCLUSION: These observations strengthen the importance of adjusted glucocorticoid treatment in NFPA patients with respect to morbidity and mortality rates.

RevDate: 2019-05-01

Kaufman ES (2019)

Recurrent atrial fibrillation after ablation: can telomere length identify patients who are young at heart?.

RevDate: 2019-05-01

Su C, Liu Z, Gao Y, et al (2019)

Study on the relationship between telomere length changes and recurrence of atrial fibrillation after radiofrequency catheter ablation.

Journal of cardiovascular electrophysiology [Epub ahead of print].

INTRODUCTION: Advanced age is the foremost risk factor for atrial fibrillation (AF). Telomere length is a surrogate for biological aging, but the association between shortened leukocyte telomere length (LTL) and recurrence of AF after ablation remains inconclusive.

METHODS: In this prospective analysis, 282 patients underwent an initial catheter ablation for paroxysmal or persistent AF. The association between recurrence of AF (RAF) and LTL was analyzed by univariate and multivariate Cox regression, as well as time-dependent receiver operating characteristic (ROC) analysis and Kaplan-Meier analysis.

RESULTS: After a mean follow-up of 14.20 ± 5.04 months, RAF was documented in 78 of the 277 patients who completed the study (28.16%). In Cox proportional hazards models, LTL, age, diagnosis to ablation time (DTAT), NT-proBNP, and CHA2DS2-VASc score were significantly associated with RAF. After multivariable adjustment, LTL and DTAT were predicted as independent risk factors for RAF with hazard ratio (HR) of 3.17 (95% CI, 1.23-8.15, p=0.017) and 1.43(95%CI 1.10-1.86, p=0.007), respectively. In addition, ROC analysis indicated the potential diagnostic value of LTL with an AUC of 0.64 (p<0.001; sensitivity=60.3%, specificity=57.8%), and an optimum cut-off value of 1.040. LTL≤1.040 was defined as shortened LTL, while LTL>1.040 non-shortened LTL. Kaplan-Meier analysis showed RAF rate curve was separated significantly between two groups (21.2% vs 35.9%, log-rank test result p=0.007). Patients with shortened LTL might have a higher risk for RAF with HR=1.84 (p=0.008).

CONCLUSIONS: Shortened LTL is an independent risk factor for AF recurrence. Shortened LTL could be a potential biomarker in predicting RAF after ablation. This article is protected by copyright. All rights reserved.

RevDate: 2019-05-01

Morsczeck C, Reck A, TE Reichert (2019)

Short telomeres correlate with a strong induction of cellular senescence in human dental follicle cells.

BMC molecular and cell biology, 20(1):5 pii:10.1186/s12860-019-0185-4.

BACKGROUND: Dental follicle cells (DFCs) are dental stem cells and interesting options for regenerative therapies in dentistry. However, DFCs acquire replicative senescence in long-term cultures, but little is known about molecular processes. In previous studies, we observed that DFC cell lines become senescent at different rates. We hypothesized that short telomere length and increased DNA damage with genomic instability correlate with the accelerated induction of cellular senescence.

RESULTS: For this study we compared DFC cell lines that became senescent at different rates (DFC_F: strong senescent phenotype; DFC_S: weak senescent phenotype). The telomeres of DFC_F were shorter than those of the telomeres of DFC_S prior senescence. Interestingly, telomere lengths of both cell lines were nearly unchanged after induction of senescence. Gene expression analyses with genes associated with DNA damage before and after the induction of cellular senescence revealed that almost all genes in DFCs_F were down-regulated while the gene expression in DFC_S was almost constitutive. Moreover, number of aneuploid DFC_F were significantly higher after induction of cellular senescence.

CONCLUSION: Our results supported our initial hypothesis that telomere length and genomic instability correlate with the accelerated induction of cellular senescence in DFC_F.

RevDate: 2019-04-30

Zhang L, Xian-Zhang H, Russell DW, et al (2019)

Association between leukocyte telomere length and hostility in US Army Service Members.

Neuroscience letters pii:S0304-3940(19)30254-X [Epub ahead of print].

Hostility is a common form of emotionally charged anger which can lead to maladaptive and unhealthy behaviors. Significant association between shortened telomeres and greater levels of hostility has been observed in civilian populations, but has not yet been comprehensively studied in military populations. Our study investigates the relationship between hostility, post-traumatic stress disorder (PTSD), and leukocyte telomere length (LTL) in a sample of United States Army Special Operations personnel (n = 474) who deployed to Iraq and/or Afghanistan as part of combat operations. Hostility was measured with five items from the Brief Symptom Inventory (BSI). PTSD was determined using the PTSD Checklist (PCL) total score. The LTL was assessed using quantitative polymerase chain reaction methods and regression analyses were conducted to determine the association of hostility and telomere length. PTSD subjects reported higher hostility scores compared with those without PTSD. Among the participants with PTSD, those with medium or high level of hostility had shorter LTL than those with low level hostility (P < 0.01). Stepwise regression indicated that hostility level and age, but not gender and PTSD, were negatively correlated with LTL. Univariate regression showed that total hostility score was negatively associated with LTL (CI= -0.06 to -0.002, Beta= -0.095, p < 0.039) as well as a significant correlation between LTL and hostility impulses (HI) (CI= -0.108 to -0.009, Beta= -0.106, p < 0.021) and hostility controlling (HC) (CI= -0.071 to -0.002, Beta= -0.095, p < 0.004). Multiple regression analyses revealed that, while HC has no significant association with LTL, HI was still negatively correlated with LTL (p = 0.021). Our data indicates that LTL is associated with HI levels. Prevention and treatment efforts designed to reduce hostility may help mitigate risk for LTL shortening, a process of cellular aging, and thus slow accelerated aged-related health outcomes.

RevDate: 2019-04-30

Movahedi A, Mostajaboddavati M, Rajabibazl M, et al (2019)

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

International journal of radiation biology [Epub ahead of print].

PURPOSE: There are few areas in the world where ionizing radiation (IR) dose received by the public from radon gas and other radioactive elements are much higher than recommended limits. Telomere length is a potential biomarker of genomic instability due to oxidative stress from IR exposure. In this study, we investigated the impact of chronic exposure to environmental IR on relative telomere length (RTL) in white blood cells (WBC) among inhabitants of high background radiation areas (HBRA) of Ramsar, Iran.

MATERIALS AND METHODS: One hundred and four individuals from HBRAs of Ramsar and 104 age-matched subjects from normal background radiation areas (NBRA) of Iran were enrolled in the study. The RTLs of WBC DNA samples were measured by a quantitative polymerase chain reaction (q-PCR) approach.

RESULTS: Mean RTL in HBRA and NBRA groups did not show any significant difference (1.21 ± 0.71 versus 1.22 ± 0.66, p = .306). After controlling for all demographic variables, less than 1% of the variances in RTL values were related to background radiation exposure.

CONCLUSION: We conclude that chronic exposure to natural IR has no statistically significant effect on RTL among the inhabitants of HBRAs of Ramsar compared with a control group.

RevDate: 2019-04-30

Hong J, CO Yun (2019)

Telomere Gene Therapy: Polarizing Therapeutic Goals for Treatment of Various Diseases.

Cells, 8(5): pii:cells8050392.

Modulation of telomerase maintenance by gene therapy must meet two polarizing requirements to achieve different therapeutic outcomes: Anti-aging/regenerative applications require upregulation, while anticancer applications necessitate suppression of various genes integral to telomere maintenance (e.g., telomerase, telomerase RNA components, and shelterin complex). Patients suffering from aging-associated illnesses often exhibit telomere attrition, which promotes chromosomal instability and cellular senescence, thus requiring the transfer of telomere maintenance-related genes to improve patient outcomes. However, reactivation and overexpression of telomerase are observed in 85% of cancer patients; this process is integral to cancer immortality. Thus, telomere-associated genes in the scope of cancer gene therapy must be inactivated or inhibited to induce anticancer effects. These contradicting requirements for achieving different therapeutic outcomes mean that any vector-mediated upregulation of telomere-associated genes must be accompanied by rigorous evaluation of potential oncogenesis. Thus, this review aims to discuss how telomere-associated genes are being targeted or utilized in various gene therapy applications and provides some insight into currently available safety hazard assessments.

RevDate: 2019-04-30

Izumi H, K Funa (2019)

Telomere Function and the G-Quadruplex Formation are Regulated by hnRNP U.

Cells, 8(5): pii:cells8050390.

We examine the role of the heterogenous ribonucleoprotein U (hnRNP U) as a G-quadruplex binding protein in human cell lines. Hypothesizing that hnRNP U is associated with telomeres, we investigate what other telomere-related functions it may have. Telomeric G-quadruplexes have been fully characterized in vitro, but until now no clear evidence of their function or in vivo interactions with proteins has been revealed in mammalian cells. Techniques used were immunoprecipitation, DNA pull-down, binding assay, and Western blots. We identified hnRNP U as a G-quadruplex binding protein. Immunoprecipitations disclosed that endogenous hnRNP U associates with telomeres, and DNA pull-downs showed that the hnRNP U C-terminus specifically binds telomeric G-quadruplexes. We have compared the effect of telomere repeat containing RNA (TERRA) on binding between hnRNP U and telomeric (Tel) or single- stranded Tel (ssTel) oligonucleotides and found that ssTel binds stronger to TERRA than to Tel. We also show that hnRNP U prevents replication protein A (RPA) accumulation at telomeres, and the recognition of telomeric ends by hnRNP suggests that a G-quadruplex promoting protein regulates its accessibility. Thus, hnRNP U-mediated formation has important functions for telomere biology.

RevDate: 2019-04-29

Seibt KD, Häussler S, Vecchio D, et al (2019)

Comparison of telomere lengths in leukocytes and in nasal and vaginal epithelial cells from Water Buffaloes (Bubalus bubalis) of different ages.

Research in veterinary science, 124:328-333 pii:S0034-5288(19)30061-X [Epub ahead of print].

Telomeres are short and repetitive sequences at the ends of linear chromosomes which shorten with every cell-division in vitro. Telomere length (TL) is reported to decrease with age and stress. The domesticated water buffalo (Bubalus bubalis) is the second most important milk producing animal worldwide. The productive lifespan of water buffalo cows is reported to be longer than that of dairy cows (Bos taurus). With this background, we aimed to compare TL in leukocytes obtained from blood samples from water buffaloes across different ages. In addition, we tested the suitability of assessing TL in DNA derived from nasal and vaginal epithelial cells via swabs as potential non-invasive alternatives to blood sampling Samples were collected from 20 calves (3 months of age), 20 heifers (2 years old), 20 cows (1st lactation, 3 years old), and 13 cows (3rd lactation, about 5 years old). We found that TL in leukocytes from water buffalo calves, heifers, and from cows in their first lactation was not different, but shorter telomeres were observed in cows in their third lactation. The results thus support an age-dependent decrease of TL in water buffaloes. Leukocyte TL was weakly correlated with TL measured in DNA from nasal epithelial cells (r = 0.327; P = .025), but not with TL from vaginal epithelial cells. Due to the poor correlation between epithelial cell and leukocyte TL and to the difficulties with collecting nasal swabs, we conclude that they are no suitable alternatives to blood samples for telomere studies in water buffaloes.

RevDate: 2019-04-27

Polonis K, Sompalli S, Becari C, et al (2019)

Telomere Length and Risk of Major Adverse Cardiac Events and Cancer in Obstructive Sleep Apnea Patients.

Cells, 8(5): pii:cells8050381.

Telomere length (TL) is associated with cardiovascular disease (CVD) and cancer. Obstructive sleep apnea (OSA) is also linked to higher risk of CVD and cancer, and to TL. We investigated the association between TL and risk of major adverse cardiac events (MACE) and cancer in OSA patients. We studied 210 individuals undergoing sleep-related studies between 2000 and 2007. Baseline characteristics and follow-up data (available in 164 subjects) were obtained from clinic records. Incidence rates were calculated for the entire group and by OSA status. Hazard ratios were calculated to estimate effects of OSA and TL on risk of MACE and cancer. In total, 32 individuals (20%) developed MACE and/or cancer during 12.7-year follow-up. The OSA group had a higher likelihood of cancer (16.0 vs. 4.9 events per 1000 person-years, P = 0.044) but no clear evidence of an elevated incidence of MACE (10.8 vs. 4.8 events per 1000 person-years, P = 0.293) compared to the non-OSA group. There was no association between TL and MACE- (HR = 1.01, 95% CI 0.78-1.28), or cancer-risk (HR = 1.18, 95% CI 0.96-1.43). Our study warrants further investigation of any modulating effect of OSA on TL and the risk of MACE and cancer.

RevDate: 2019-04-26

Yu Z, Fenk K, Huang D, et al (2019)

Rapid Telomere Reduction in Cancer Cells Induced by G-Quadruplex-Targeting Copper Complexes.

Journal of medicinal chemistry [Epub ahead of print].

Telomere length determines the replicative capacity of mammalian cells. Successive telomere reduction to a critically short length can lead to cellular senescence that irreversibly prevents cells from further cell division. A series of Cu complexes has been designed as selective artificial nucleases that degrade G-quadruplex telomeric DNA and exhibit selective DNA binding affinity and cleavage reactivity towards G-quadruplex telomeric DNA over duplex DNA. In contrast to protein-based nucleases that usually lack membrane permeability, significant cellular uptake and nuclear localization of these Cu complexes was observed. Rapid telomere reduction of cancer cells was also observed after only 1-day incubation, while the absence of DNA fragmentation indicates a low level of non-selective DNA cleavage. Robust telomere reduction by the designed Cu complexes is an S-phase-specific event that is associated with increased formation of the G-quadruplex structure during DNA replication.

RevDate: 2019-04-26

Udroiu I, Marinaccio J, A Sgura (2019)

Epigallocatechin-3-gallate (EGCG) induces telomere shortening and clastogenic damage in glioblastoma cells.

Environmental and molecular mutagenesis [Epub ahead of print].

Epigallocatechingallate (EGCG) is the major polyphenol in green tea, to which many anticancer features, such as anti-oxidative, anti-genotoxic and anti-angiogenetic properties, are attributed. Moreover, it is also well known as a telomerase inhibitor. In this work, we have chronically treated U251 glioblastoma cells with low, physiologically realistic concentrations, of EGCG, in order to investigate its effects both on telomeres and on genome integrity. Inhibition of telomerase activity caused telomere shortening, ultimately leading to senescence and telomere dysfunction at 98 days. Remarkably, we have observed DNA damage through an increase of phosphorylation of γ-H2AX histone and micronuclei also with doses and at timepoints when telomere shortening was not present. Therefore, we concluded that this DNA damage was not correlated with telomere shortening and that EGCG treatment induced not only an increase of telomere-shortening-induced senescence, but also telomere-independent genotoxicity. This study questions the common knowledge about EGCG properties, but confirms the few works that indicated the clastogenic properties of this molecule, probably due to DNA reductive damage and topoisomerase II poisoning.

RevDate: 2019-04-26

Wallace HA, Rana V, Nguyen HQ, et al (2019)

Condensin II subunit NCAPH2 associates with shelterin protein TRF1 and is required for telomere stability.

Journal of cellular physiology [Epub ahead of print].

Condensin II subunits are known to be expressed and localized to interphase nuclei of eukaryotic cells. Although some studies have shown that condensin II likely exerts axial compaction forces, organizes chromosome territories, and has possible transcriptional modulatory functions, the full range of condensin II interphase activities are not known. In particular, it is not known if condensin II interphase activities are generally genome-wide or if they have additional local activities unique to specific chromosomal structures such as telomeres. Here, we find that NCAPH2 interacts with TRF1 and these two proteins co-localize at telomeres. Depletion of NCAPH2 leads to ATR-dependent accumulation of 53BP1 and γH2AX DNA damage foci, including damage specific to telomeres. Furthermore, depletion of NCAPH2 results in a fragile telomere phenotype and apparent sister-telomere fusions only days after NCAPH2 depletion. Taken together these observations suggest that NCAPH2 promotes telomere stability, possibly through a direct interaction with the TRF1 shelterin component, and prevents telomere dysfunction resulting from impaired DNA replication. Because proper telomere function is essential for chromosome integrity these observations reveal a previously unappreciated function for NCAPH2 in ensuring genome and telomere stability.

RevDate: 2019-04-26

Tao L, Huang Q, Yang R, et al (2019)

The age modification to leukocyte telomere length effect on bone mineral density and osteoporosis among Chinese elderly women.

Journal of bone and mineral metabolism pii:10.1007/s00774-019-01004-0 [Epub ahead of print].

Critically short telomeres indicate cellular senescence. Leukocyte telomere length (LTL) is regarded as an aging predictor. Osteoporosis is an age-related disease. The purpose of our study is to examine the association between LTL, and BMD and osteoporosis among an elderly Chinese population. A total of 1017 participants (584 postmenopausal women) with a mean age of 66.4 years were recruited from April 2016 to August 2017. Dual-energy X-ray absorptiometry was used for BMD measurement at skeleton sites of lumbar spine (LS), femoral neck (FN), and total hip (TH). LTL was measured using quantitative real-time polymerase chain reaction. Among women, age significantly modified the effect of LTL on BMD at FN. Additionally, significant age modification was observed for the association between LTL and LS BMD category (indicative of control or osteopenia or osteoporosis), and the number of osteoporotic sites at LS or TH. The corresponding estimates (95% CI) for the relative excess risk due to interaction (RERI) were - 0.07 (- 0.11, - 0.01) and - 0.11 (- 0.16, - 0.03) sequentially in ordinal logistic regression models. The estimated RERIs (95% CI) were - 0.11 (- 0.25, - 0.02) and - 0.23 (- 0.39, - 0.10) in multinomial logistic regression models for LS/FN/TH BMD category, and - 0.20 (- 0.31, - 0.09) and - 0.34 (- 0.49, - 0.21) for FN BMD category. However, similar findings did not show in men. The effect of LTL on BMD and osteoporosis risk is modified by age in elderly women but not in men, suggesting that the predictive role of LTL in bone loss differs by sex.

RevDate: 2019-04-26

Boccardi M, V Boccardi (2019)

Psychological Wellbeing and Healthy Aging: Focus on Telomeres.

Geriatrics (Basel, Switzerland), 4(1): pii:geriatrics4010025.

Stress and depression are known to modulate the aging process, and might also affect telomere biology. In fact, exposure to some biochemical pathways involved in stress-related depression may contribute to an ''accelerated aging" phenotype, as well as the incidence of age-related diseases, including metabolic disorders and dementia. Basic studies support the notion that the telomere and telomerase system plays a pivotal role in the aging process and disease promotion. Interestingly, short and dysfunctional telomeres are associated with reduced lifespan, as shown in animal models. In this context, telomeres are very sensitive to stress, mindset, and lifestyle, and their rescue may be sufficient to restore cell and organism viability. This mini-review discusses conceptual models of healthy and active aging and their relationship with telomere biology and mental health.

RevDate: 2019-04-26

Doksani Y (2019)

The Response to DNA Damage at Telomeric Repeats and Its Consequences for Telomere Function.

Genes, 10(4): pii:genes10040318.

Telomeric repeats, coated by the shelterin complex, prevent inappropriate activation of the DNA damage response at the ends of linear chromosomes. Shelterin has evolved distinct solutions to protect telomeres from different aspects of the DNA damage response. These solutions include formation of t-loops, which can sequester the chromosome terminus from DNA-end sensors and inhibition of key steps in the DNA damage response. While blocking the DNA damage response at chromosome ends, telomeres make wide use of many of its players to deal with exogenous damage and replication stress. This review focuses on the interplay between the end-protection functions and the response to DNA damage occurring inside the telomeric repeats, as well as on the consequences that telomere damage has on telomere structure and function.

RevDate: 2019-04-25

Fathi E, Charoudeh HN, Sanaat Z, et al (2019)

Telomere shortening as a hallmark of stem cell senescence.

Stem cell investigation, 6:7 pii:sci-06-2019.02.04.

Stem cells, especially mesenchymal stem cells (MSCs)-based therapies have been greatly attentioned in regenerative medicine through multi-lineage differentiation, self-renewal properties, etc. Despite the above advantages of MSCs, the defined properties of these cells are strongly affected by aging. Thus, the use of MSCs from older donors is lower than younger one, which limits clinical applications in cell therapy. According to the theories of aging, it is determined that aging is most likely caused by telomere shortening and telomere shortening is considered hallmarks of aging. Finding out the most mechanisms of these changes will probably reveal novel therapeutic targets for prolonging human health and for ameliorating age-associated phenotypes. This review focuses on prevalent knowledge about the mechanisms of stem cell senescence by telomere shortening and the molecular mechanism details involved in it.

RevDate: 2019-04-25

Jansson LI, Hentschel J, Parks JW, et al (2019)

Telomere DNA G-quadruplex folding within actively extending human telomerase.

Proceedings of the National Academy of Sciences of the United States of America pii:1814777116 [Epub ahead of print].

Telomerase reverse transcribes short guanine (G)-rich DNA repeat sequences from its internal RNA template to maintain telomere length. G-rich telomere DNA repeats readily fold into G-quadruplex (GQ) structures in vitro, and the presence of GQ-prone sequences throughout the genome introduces challenges to replication in vivo. Using a combination of ensemble and single-molecule telomerase assays, we discovered that GQ folding of the nascent DNA product during processive addition of multiple telomere repeats modulates the kinetics of telomerase catalysis and dissociation. Telomerase reactions performed with telomere DNA primers of varying sequence or using GQ-stabilizing K+ versus GQ-destabilizing Li+ salts yielded changes in DNA product profiles consistent with formation of GQ structures within the telomerase-DNA complex. Addition of the telomerase processivity factor POT1-TPP1 altered the DNA product profile, but was not sufficient to recover full activity in the presence of Li+ cations. This result suggests GQ folding synergizes with POT1-TPP1 to support telomerase function. Single-molecule Förster resonance energy transfer experiments reveal complex DNA structural dynamics during real-time catalysis in the presence of K+ but not Li+, supporting the notion of nascent product folding within the active telomerase complex. To explain the observed distributions of telomere products, we globally fit telomerase time-series data to a kinetic model that converges to a set of rate constants describing each successive telomere repeat addition cycle. Our results highlight the potential influence of the intrinsic folding properties of telomere DNA during telomerase catalysis, and provide a detailed characterization of GQ modulation of polymerase function.

RevDate: 2019-04-24

Zhu J, Liu W, Chen C, et al (2019)

TPP1 OB-fold domain protein suppresses cell proliferation and induces cell apoptosis by inhibiting telomerase recruitment to telomeres in human lung cancer cells.

Journal of cancer research and clinical oncology pii:10.1007/s00432-019-02921-3 [Epub ahead of print].

PURPOSE: Maintaining telomeres by recruiting telomerase-to-chromosome ends is essential for cancer cell survival. Inhibiting telomerase recruitment to telomeres represents a novel strategy for telomere-based lung cancer therapy. However, approaches for interrupting telomerase recruitment for cancer therapy still need to be explored.

METHODS: The telomere-binding protein TPP1 is responsible for recruiting telomerase to telomeres and synthesizing telomeres through the association between the oligosaccharide/oligonucleotide-binding (OB)-fold domain of TPP1 and telomerase reverse transcriptase. We overexpressed the TPP1 OB domain (TPP1-OB) by lentivirus infection in lung cancer cells. Telomere length was examined by Southern blot analysis of terminal restriction fragments. The effects of TPP1-OB on cell proliferation, the cell cycle, apoptosis, chemosensitivity, and tumor growth were evaluated in vitro and in vivo.

RESULT: TPP1-OB inhibited the recruitment of telomerase to telomeres and shortened telomere length by acting as a dominant-negative mutant of TPP1. TPP1-OB resulted in reduced cell proliferation, G1 cell cycle arrest, and increased cell apoptosis in lung cancer cells. Cell apoptosis occurred mainly through the caspase-3-dependent signaling pathway. TPP1-OB also suppressed anchorage-independent growth and tumor growth in vivo. Moreover, we demonstrated that TPP1-OB enhances the sensitivity of lung cancer cells to the chemotherapeutic drug paclitaxel.

CONCLUSION: Our results suggest that inhibiting TPP1-mediated telomerase recruitment by expressing the TPP1-OB domain is a potential novel strategy for telomere-targeted lung cancer therapy.

RevDate: 2019-04-24

Udomsinprasert W, Poovorawan Y, Chongsrisawat V, et al (2019)

Leukocyte mitochondrial DNA copy number as a potential biomarker indicating poor outcome in biliary atresia and its association with oxidative DNA damage and telomere length.

Mitochondrion pii:S1567-7249(18)30229-0 [Epub ahead of print].

Biliary atresia (BA) is a chronic obstructive liver disease, leading to advanced liver failure. Mitochondria dysfunction-mediated aberrant telomere length has been implicated in various pathological processes including cholestasis. Herein, we aimed to investigate associations between mitochondrial DNA (mtDNA) copy number, oxidative DNA damage, telomere length, and disease severity in BA patients. mtDNA copy number and relative telomere length (RTL) were assessed using real-time PCR. Circulating 8-hydroxy-2'-deoxyguanosine (8-OHdG) was measured using ELISA. Our findings showed that BA patients had significantly lower mtDNA copy number and RTL than healthy controls, whereas plasma 8-OHdG levels were significantly elevated in BA patients. mtDNA copy number was remarkably reduced in advanced BA patients. Furthermore, mtDNA copy number was independently associated with age and degree of liver fibrosis in BA patients. Decreased mtDNA copy number was significantly associated with elevated risks of BA, severe fibrosis, jaundice, and hepatic dysfunction. Low mtDNA copy number can be utilized to distinguish patients with poor-outcome from those with good-outcome. Survival curve analysis revealed that low mtDNA copy number was significantly associated with poor survival of BA patients. Interestingly, there was a positive association between mtDNA copy number and plasma 8-OHdG in BA patients, while a negative association of mtDNA copy number with RTL was observed in BA patients. Alternatively, RTL was negatively correlated with plasma 8-OHdG in BA patients. These data demonstrated relationships between leukocytes mtDNA copy number, oxidative stress, telomere length, and clinical parameters in BA patients. Accordingly, our findings indicate that mtDNA copy number may serve as a potential biomarker reflecting BA severity.

RevDate: 2019-04-24

Amir M, Ahmad S, Ahamad S, et al (2019)

Impact of Gln94Glu mutation on the structure and function of Protection of telomere 1, a cause of cutaneous familial melanoma.

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

Protection of telomere 1 (POT1) is a key component of shelterin complex, essential for maintaining telomere length and regulation. It consists of N-terminal domain (residues 1-299) which interacts with telomeric ssDNA, and the C-terminal domain (residues 320-634) that binds to the tripeptidyl-peptidase I (TPP1). A large number of naturally occurring mutations in the POT1 gene are associated with glioma, cardiac angiosarcoma and cutaneous familial melanoma (FM). Due to Q94E mutation, the interaction of POT1 with telomeric DNA get disrupted which subsequently enhances telomere uncapping, elongation and promotes development of cutaneous familial melanoma. To understand the underlying mechanism of familial melanoma development by Q94E-mutation, we have performed extensive structure analysis of WT and mutant protein followed by molecular dynamics simulations. Q94E mutation causes a dramatic change in the structure and stability POT1 protein. A considerable decrease in the flexibility, fluctuation and solvent accessibility of Q94E was observed in comparison to the WT, indicating overall destabilization of protein. Essential dynamics and Anisotropic Network Mode analysis have quantified a significant change in direction and magnitude of conformational motion in Q94E mutant compared to WT. A significant loss of frustration due to Q94E mutation was also observed. Our findings indicate the loss of protein stability and dynamics of POT1 protein by Q94E mutation may be associated with the familial melanoma.

RevDate: 2019-04-24

Wu G, Chen L, Liu W, et al (2019)

Molecular Recognition of the Hybrid-Type G-Quadruplexes in Human Telomeres.

Molecules (Basel, Switzerland), 24(8): pii:molecules24081578.

G-quadruplex (G4) DNA secondary structures formed in human telomeres have been shown to inhibit cancer-specific telomerase and alternative lengthening of telomere (ALT) pathways. Thus, human telomeric G-quadruplexes are considered attractive targets for anticancer drugs. Human telomeric G-quadruplexes are structurally polymorphic and predominantly form two hybrid-type G-quadruplexes, namely hybrid-1 and hybrid-2, under physiologically relevant solution conditions. To date, only a handful solution structures are available for drug complexes of human telomeric G-quadruplexes. In this review, we will describe two recent solution structural studies from our labs. We use NMR spectroscopy to elucidate the solution structure of a 1:1 complex between a small molecule epiberberine and the hybrid-2 telomeric G-quadruplex, and the structures of 1:1 and 4:2 complexes between a small molecule Pt-tripod and the hybrid-1 telomeric G-quadruplex. Structural information of small molecule complexes can provide important information for understanding small molecule recognition of human telomeric G-quadruplexes and for structure-based rational drug design targeting human telomeric G-quadruplexes.

RevDate: 2019-04-23

Morais KDS, Arcanjo DDS, Lopes GPF, et al (2019)

Long-term in vitro treatment with telomerase inhibitor MST-312 induces resistance by selecting long telomeres cells.

Cell biochemistry and function [Epub ahead of print].

Telomerase is a good target for new anticancer drug development because it is present in over 85% of human tumours. However, despite chronic therapy is a condition for anti-telomerase approach, the effects of long-term treatment with telomerase inhibitors remain not well understood. In this work, it was evaluated the effects of long-term treatment of human MDA-MB-231 breast cancer cells with the telomerase inhibitor MST-312. Cells were treated for 72 hours or 140 days, and it was accessed their viability, proliferation rate, morphology, telomeric DNA content, and resistance mechanism. The drug had a clear short-term effect, including chemosensitizing cells for docetaxel and irinotecan, but the chronic exposition led to selection of long telomeres clones, changing characteristics of original cell line. This effect was confirmed in a clonal culture with homogenous karyotype. MRP-1 expression and alternative lengthening of telomeres (ALT) were discarded as additional mechanisms of resistance. This data suggest that, considering the intra-tumour heterogeneity (ITH), what is already a big challenge for treatment of cancer, chronic exposition to telomerase inhibitors can promote tumour adaptations with potential clinical repercussion, drawing attention to ongoing clinical trials and pointing important considerations most times neglected on studies about use of these inhibitors on cancer therapy. SIGNIFICANCE OF THE STUDY: Antitumour action of telomerase inhibitors is well known, but it depends on a long-term exposition because cells will undergo telomere erosion only after many duplication cycles. Recently, the frustrating results of clinical trials with these inhibitors aroused the interest of the scientific community to understand the mechanisms of resistance to anti-telomerase therapy. In this study, we conducted an 18-week experiment to show that telomerase inhibition can lead to cell adaptations and selection of long-telomeres clones, leading to acquisition of resistance. However, we also showed that this inhibitor can sensitize cells to the chemotherapeutic drugs docetaxel and irinotecan.

RevDate: 2019-04-21

Flannagan KS, Bowman AA, Mora-Plazas M, et al (2019)

Micronutrient status and leukocyte telomere length in school-age Colombian children.

European journal of nutrition pii:10.1007/s00394-019-01966-x [Epub ahead of print].

PURPOSE: Leukocyte telomere length (LTL) is a biomarker of inflammation and oxidative stress that predicts chronic disease risk. Nutritional factors are related to LTL in adulthood, but these associations are not well characterized in children. We examined whether micronutrient status biomarkers were associated with LTL in school-age children.

METHODS: We conducted a cross-sectional study of 330 boys and 393 girls aged 5-12 years from Bogotá, Colombia. We quantified blood concentrations of hemoglobin, ferritin, zinc, vitamin A, folate, and vitamin B-12; and measured LTL using qPCR in DNA extracted from buffy coat. We estimated mean differences in LTL by quartiles of micronutrient status biomarkers and categories of relevant sociodemographic and anthropometric covariates with the use of linear regression.

RESULTS: In girls, plasma vitamin B-12 was positively associated with LTL (adjusted LTL difference between extreme vitamin B-12 quartiles = 0.11; P, trend = 0.02). LTL was also positively associated with birth order in girls (P, trend = 0.02). In boys, LTL was not related to the micronutrient status biomarkers but, unexpectedly, it was positively associated with birth weight (P = 0.02), height-for-age Z score (P, trend = 0.01), and serum C-reactive protein (P, trend = 0.01).

CONCLUSIONS: LTL is associated with vitamin B-12 status among girls. LTL is also associated with birth weight, height, and C-reactive protein in boys.

RevDate: 2019-04-21

Zole E, R Ranka (2019)

Mitochondrial DNA copy number and telomere length in peripheral blood mononuclear cells in comparison with whole blood in three different age groups.

Archives of gerontology and geriatrics, 83:131-137 pii:S0167-4943(19)30101-3 [Epub ahead of print].

There are more and more studies on telomere length (TL) and mitochondrial DNA (mtDNA), and it has been proven that these factors play a significant role in the aging of the immune system thereby it is important to understand how it varies in different cell types for more accurate conclusions. The aim of this study was to look into dynamics of mtDNA amount in conjunction with TL in peripheral blood mononuclear cells (PBMC) during aging in comparison with whole blood (WB) cells. Overall, 53 samples were divided into three age groups: 20-39 year age group, 40-59 year age group and 60-79 year age group. MtDNA amount was determined by qPCR TaqMan, and TL was measured by Southern blotting of terminal restriction fragments (TRFs). PBMC had much higher mtDNA copy number (CN) amount than WB samples. Furthermore, with age, it increased in PBMC, while in WB mtDNA CN count did not change. TL in the elderly group was shorter in PBMC fraction than in WB cells. It also looked like that in PBMC TL shortened faster than in WB. In conclusions, it appears that during the aging process both mtDNA CN and TL were more stable in WB than in PBMC fraction where changes were more drastically pronounced, but more studies using larger sample cohorts should be performed to confirm this observation.

RevDate: 2019-04-20

Matzenbacher CA, Da Silva J, Garcia ALH, et al (2019)

Anthropogenic Effects on Natural Mammalian Populations: Correlation Between Telomere Length and Coal Exposure.

Scientific reports, 9(1):6325 pii:10.1038/s41598-019-42804-8.

The Candiota coal mine in Rio Grande do Sul (RS) is one of the largest in Brazil. Coal is a fossil fuel that causes environmental impacts from its extraction to combustion due to the release of different agents, such as polycyclic aromatic hydrocarbons (PAH) and heavy metals. Ctenomys torquatus are herbivorous and subterranean rodents that dig tunnels with their paws and teeth and can be exposed to coal through contaminated food. Exposure to pollutants can cause DNA damage and affect different tissues, inducing alterations in the population structure and genetic diversity. Our study aimed to evaluate the effect of exposure to coal and its derivatives on the C. torquatus population and to examine the relationship of coal exposure with variations in absolute telomere length (aTL), global DNA methylation and genotoxicity. Our study showed an inverse correlation between telomere length and coal exposure in addition to an increase in DNA damage. The results indicate that coal and its byproducts can contribute to the alteration of the C. torquatus population structure, as evidenced by a reduction in the number of adults.

RevDate: 2019-04-19

Daechavijit P, Siridonthanakasem J, Wongsupha P, et al (2019)

Relative Telomere Length in Blood Leukocytes of Patients with Anterior Cruciate Ligament Injury: A Pilot Study.

Malaysian orthopaedic journal, 13(1):8-13.

Introduction: Anterior cruciate ligament (ACL) tear is the most common knee ligament injury, especially in athletes. The objective of this study was to investigate relative telomere length (RTL) in blood leukocytes of patients with ACL injury compared with that of controls. Materials and Methods: A total of 187 subjects were invited to participate in this study. Ninety-two patients with clinically diagnosed ACL rupture were enrolled. Ninety-five age and gender-matched healthy controls were also recruited. Blood leukocyte RTL were analysed using quantitative real-time polymerase chain reaction. Results: Patients with ACL rupture had significantly longer relative telomere length than healthy controls (P=0.002). The patients with ACL rupture were classified into two groups according to the sport history of patients which are contact sports and non-contact sports. RTL in patients with non-contact sports was significantly greater than those with contact sports (P=0.006). Moreover, RTL was inversely correlated with body mass index of patients with ACL injury (r=-0.34, P=0.001). Logistic regression analysis indicated that long RTL was associated with a higher risk of ACL rupture. Conclusion: The present study showed that subjects with ACL rupture had significantly greater telomere length compared with their age and gender-matched controls. This finding may result from the increases in physical activity and overexpression of telomerase which acts as a protective mechanism against ACL injury. RTL in blood leukocytes is associated with a risk of ACL rupture.

RevDate: 2019-04-18

Samavat H, Xun X, Jin A, et al (2019)

Association between prediagnostic leukocyte telomere length and breast cancer risk: the Singapore Chinese Health Study.

Breast cancer research : BCR, 21(1):50 pii:10.1186/s13058-019-1133-0.

BACKGROUND: Telomeres and telomerase play key roles in the chromosomal maintenance and stability. Recent epidemiological studies have shown that longer telomeres are associated with increased risk of several cancer types. However, epidemiological data for telomere length and risk of breast cancer are sparse.

METHODS: We prospectively studied the association between telomere length and risk of breast cancer in 14,305 middle-aged or older Chinese women of the Singapore Chinese Health Study including 442 incident breast cancer cases after 12.3 years of follow-up. Relative telomere length in peripheral blood leukocytes was quantified using a validated monochrome multiple quantitative polymerase chain reaction method. The Cox proportional hazard regression method was used to estimate hazard ratios (HRs) and the corresponding 95% confidence intervals (CIs) for breast cancer associated with longer telomeres after adjustment for potential confounders.

RESULTS: Longer telomeres were significantly associated with higher risk of breast cancer in a dose-dependent manner (Ptrend = 0.006); the highest quartile of telomere length was associated with a statistically significant 47% higher risk of breast cancer compared with the lowest quartile of telomere length after the adjustment for age and other known risk factors for breast cancer (HRQ4 vs Q1 = 1.47, 95% CI = 1.11, 1.94).

CONCLUSIONS: The findings of the present study support the hypothesis that longer telomeres may be a risk factor for breast cancer. Telomere length in peripheral blood leukocytes may be developed as a biomarker for breast cancer risk prediction.

RevDate: 2019-04-18

Arias-Salgado EG, Galvez E, Planas-Cerezales L, et al (2019)

Genetic analyses of aplastic anemia and idiopathic pulmonary fibrosis patients with short telomeres, possible implication of DNA-repair genes.

Orphanet journal of rare diseases, 14(1):82 pii:10.1186/s13023-019-1046-0.

BACKGROUND: Telomeres are nucleoprotein structures present at the terminal region of the chromosomes. Mutations in genes coding for proteins involved in telomere maintenance are causative of a number of disorders known as telomeropathies. The genetic origin of these diseases is heterogeneous and has not been determined for a significant proportion of patients.

METHODS: This article describes the genetic characterization of a cohort of patients. Telomere length was determined by Southern blot and quantitative PCR. Nucleotide variants were analyzed either by high-resolution melting analysis and Sanger sequencing of selected exons or by massive sequencing of a panel of genes.

RESULTS: Forty-seven patients with telomere length below the 10% of normal population, affected with three telomeropathies: dyskeratosis congenita (4), aplastic anemia (22) or pulmonary fibrosis (21) were analyzed. Eighteen of these patients presented known pathogenic or novel possibly pathogenic variants in the telomere-related genes TERT, TERC, RTEL1, CTC1 and ACD. In addition, the analyses of a panel of 188 genes related to haematological disorders indicated that a relevant proportion of the patients (up to 35%) presented rare variants in genes related to DNA repair or in genes coding for proteins involved in the resolution of complex DNA structures, that participate in telomere replication. Mutations in some of these genes are causative of several syndromes previously associated to telomere shortening.

CONCLUSION: Novel variants in telomere, DNA repair and replication genes are described that might indicate the contribution of variants in these genes to the development of telomeropathies. Patients carrying variants in telomere-related genes presented worse evolution after diagnosis than the rest of patients analyzed.

RevDate: 2019-04-17

Carroll JE, Irwin MR, Seeman TE, et al (2019)

Obstructive sleep apnea, nighttime arousals, and leukocyte telomere length: The Multi-Ethnic Study of Atherosclerosis (MESA).

Sleep pii:5473546 [Epub ahead of print].

STUDY OBJECTIVES: Sleep disturbances and sleep apnea are associated with increased vulnerability to age-related disease, altering molecular pathways affecting biological aging. Telomere length captures one component of biological aging. We evaluated whether objectively assessed sleep and sleep apnea relate to leukocyte telomere length (LTL) in the Multi-Ethnic Study of Atherosclerosis (MESA).

METHODS: Men and women aged 44-84 years (n=672) from the MESA Stress and MESA Sleep studies underwent polysomnography and 7-day actigraphy (at Exam 5) and assessment of LTL (at baseline (Exam 1) and about 10 years later (Exam 5).

RESULTS: General linear models adjusting for age, sex, race/ethnicity, BMI, physical activity, and smoking, found that severe obstructive sleep apnea (OSA; apnea hypopnea index >30) was cross-sectionally associated with shorter LTL (P=0.007). Modest associations of shorter LTL with less rapid eye movement sleep, more stage 1 sleep, wake after sleep onset >30 minutes, and long sleep duration were found, but these effects were diminished after adjusting for lifestyle and OSA. Exploratory analyses found that higher arousal index at Exam 5 was associated with greater LTL decline over the prior 10 years (P=0.004).

CONCLUSIONS: OSA was associated with shorter leukocyte telomere length. Individuals with high arousal frequency had greater leukocyte telomere attrition over the prior decade. These findings suggest that sleep apnea and sleep fragmentation are associated with accelerated biological aging.

RevDate: 2019-04-16

Rangel-Pozzo A, Corrêa de Souza D, Schmid-Braz AT, et al (2019)

3D Telomere Structure Analysis to DetectGenomic Instability and Cytogenetic Evolutionin Myelodysplastic Syndromes.

Cells, 8(4): pii:cells8040304.

The disease course of myelodysplastic syndromes (MDS) features chromosome instability and clonal evolution, leading to the sequential acquisition of novel cytogenetic aberrations and the accumulation of these abnormalities in the bone marrow. Although clonal cytogenetic abnormalities can be detected by conventional cytogenetics in 50% of patients with MDS, such distinguishing patterns are lacking in the other 50%. Despite the increase in the prognostic value of some biomarkers, none of them is specific and able to discriminate between stable and unstable patients that subsequently progress to acute myeloid leukemia. This pilot study aimed to investigate the potential use of the 3D telomere profiling to detect genomic instability in MDS patients with or without clonal cytogenetic evolution. The comparison between different time points in patients with cytogenetic changes showed that in the CD34+ MDS cells, there was a significant decrease in the total number of telomeric signals, the average intensity of signals and the total intensity of telomeres. By contrast, the number of aggregates increased during cytogenetic evolution (p < 0.001). This pattern was observed only for MDS patients with cytogenetic evolution but was absent in patients without cytogenetic changes. In conclusion, we demonstrated that the 3D nuclear telomere organization was significantly altered during the MDS disease course, and may have contributed to cytogenetic clonal evolution.

RevDate: 2019-04-15

Sweetlove L, C Gutierrez (2019)

The journey to the end of the chromosome: delivering active telomerase to telomeres in plants.

The Plant journal : for cell and molecular biology, 98(2):193-194.

RevDate: 2019-04-13

Jongbloed F, Meijers RWJ, IJzermans JNM, et al (2019)

Effects of bariatric surgery on telomere length and T-cell aging.

International journal of obesity (2005) pii:10.1038/s41366-019-0351-y [Epub ahead of print].

BACKGROUND: Obesity adversely affects health and is associated with subclinical systemic inflammation and features of accelerated aging, including the T-cell immune system. The presence of metabolic syndrome (MetS) may accelerate, while bariatric surgery might reverse these phenomena. To examine the effects of MetS and bariatric surgery on T-cell aging, we measured relative telomere length (RTL) and T-cell differentiation status in obese patients before and after bariatric surgery.

METHODS: WHO II/III classified obese patients scheduled for bariatric surgery were included: 41 without MetS and 67 with MetS. RTL and T-cell differentiation status were measured in circulating CD4+ and CD8+ T cells via flow cytometry. T-cell characteristics were compared between patients with and without MetS prior to and at 3, 6, and 12 months after surgery considering effects of age, cytomegalovirus-serostatus, and weight loss.

RESULTS: Thymic output, represented by numbers of CD31-expressing naive T cells, showed an age-related decline in patients with MetS. MetS significantly enhanced CD8+ T-cell differentiation. Patients with MetS had significant lower CD4+ RTL than patients without MetS. Within the first 6 months after bariatric surgery, RTL increased in CD4+ T cells after which it decreased at month 12. A decline in both thymic output and more differentiated T cells was seen following bariatric surgery, more pronounced in the MetS group and showing an association with percentage of body weight loss.

CONCLUSIONS: In obese patients, MetS results in attrition of RTL and accelerated T-cell differentiation. Bariatric surgery temporarily reverses these effects. These data suggest that MetS is a risk factor for accelerated aging of T cells and that MetS should be a more prominent factor in the decision making for eligibility for bariatric surgery.

RevDate: 2019-04-13

Omidpanah N, Darvishi FZ, M Saadat (2019)

No alteration in leukocyte telomere length in schizophrenia; evidence from a meta-analysis.

RevDate: 2019-04-17

Sullivan S, Hammadah M, Al Mheid I, et al (2019)

An investigation of racial/ethnic and sex differences in the association between experiences of everyday discrimination and leukocyte telomere length among patients with coronary artery disease.

Psychoneuroendocrinology, 106:122-128 pii:S0306-4530(18)30744-3 [Epub ahead of print].

Leukocyte telomere length (LTL) may be sensitive to psychosocial stressors such as discrimination. An inclusive examination of experiences of discrimination on LTL across racial/ethnic and sex groups is currently lacking. Baseline data were obtained from 369 White and African American patients with coronary artery disease (CAD) in the Mental Stress Ischemia Mechanisms and Prognosis Study. LTL was measured from peripheral blood leukocytes by quantitative polymerase chain reaction and calculated in kilobase pairs. Discrimination was measured using the 10-item Everyday Discrimination Scale (EDS). Responses were rated using 4-point Likert scales ranging from never = 1 to often = 4 and summed. Regression models were stratified by race/ethnicity and sex to estimate associations between discrimination and LTL. Each 10-unit increase in experiences of everyday discrimination was associated with an average of .20 fewer kilobase pairs (or 200 base pairs) among both African American women (β = -0.19; 95% CI: -0.35, -0.04; p-value: 0.02) and White women (β = -0.19; 95% CI: -0.37, -0.01; p-value: 0.04), after adjusting for basic demographic factors. Results were similar after further adjusting for behavioral, disease, and psychosocial risk factors (depression and stress). There were no significant associations between experiences of everyday discrimination and LTL for White men or African American men. Overall, experiences of discrimination were associated with shorter LTL among women and not in men. Discrimination may be a potential source of stress associated with shorter LTL among women with CAD. Future studies should explore longitudinal associations between everyday experiences of discrimination and telomere length and also with adverse cardiovascular outcomes.

RevDate: 2019-04-12

Swaminathan AC, Neely ML, Frankel CW, et al (2019)

Lung Transplant Outcomes in Pulmonary Fibrosis Patients with Telomere-Related Gene Variants.

Chest pii:S0012-3692(19)30819-0 [Epub ahead of print].

BACKGROUND: Pulmonary fibrosis (PF) is the most common disease indication for lung transplantation. Our recent work implicated an excess of rare genetic variants in the telomere-related genes TERT, RTEL1, and PARN in PF disease risk. The impact of such variants upon post-transplant outcomes is uncertain. The objective of this study was to determine if patients with these PF-associated variants have altered rates of post-transplant acute rejection (AR), chronic lung allograft dysfunction (CLAD), and survival.

METHODS: The study cohort consisted of 262 PF lung transplant recipients previously genetically characterized by whole exome sequencing. Thirty-one patients (31/262, 11.8%) had variants in TERT, RTEL1, or PARN while 231 (231/262, 88.2%) did not. Multivariate Cox proportional hazards models adjusted for relevant clinical variables were used to assess the outcomes of death and CLAD. The AR burden was quantified and compared over the first post-transplant year.

RESULTS: PF patients with disease associated variants in TERT, RTEL1, or PARN had a significantly higher risk of death (adjusted HR 1.82, 95% CI 1.07 - 3.08, p = 0.03) and CLAD (adjusted HR 2.88, 95% CI 1.42 - 5.87, p = 0.004) than patients without these variants. There was no difference in AR burden or rates of grade 3 primary graft dysfunction between the two groups.

CONCLUSION: Rare variants in the telomere-related genes TERT, RTEL1, or PARN are associated with poor post-transplant outcomes among PF lung transplant recipients. Further research is needed to understand the biological mechanisms by which telomere-related variants increase the risk for death and CLAD.

RevDate: 2019-04-12

Bao HL, Liu HS, Y Xu (2019)

Hybrid-type and two-tetrad antiparallel telomere DNA G-quadruplex structures in living human cells.

Nucleic acids research pii:5446250 [Epub ahead of print].

Although the telomeric sequence has been reported to form various G-quadruplex topologies in vitro and in Xenopus laevis oocytes, in living human cells, the topology of telomeric DNA G-quadruplex remains a challenge. To investigate the human telomeric DNA G-quadruplex in a more realistic human cell environment, in the present study, we demonstrated that the telomeric DNA sequence can form two hybrid-type and two-tetrad antiparallel G-quadruplex structures by in-cell 19F NMR in living human cells (HELA CELLS). This result provides valuable information for understanding the structures of human telomeric DNA in living human cells and for the design of new drugs that target telomeric DNA.

RevDate: 2019-04-11

Lazarides C, Epel ES, Lin J, et al (2019)

Maternal Pro-Inflammatory State During Pregnancy and Newborn Leukocyte Telomere Length: A Prospective Investigation.

Brain, behavior, and immunity pii:S0889-1591(19)30096-0 [Epub ahead of print].

RevDate: 2019-04-11

Herlin M, Broberg K, Igra AM, et al (2019)

Exploring telomere length in mother-newborn pairs in relation to exposure to multiple toxic metals and potential modifying effects by nutritional factors.

BMC medicine, 17(1):77 pii:10.1186/s12916-019-1309-6.

BACKGROUND: The uterine environment may influence telomere length at birth, which is essential for cellular function, aging, and disease susceptibility over the lifespan. However, little is known about the impact of toxic chemicals on early-life telomeres. Therefore, we assessed the potential impact of multiple toxic metals on relative telomere length (rTL) in the maternal blood, cord blood, and placenta, as well as the potential modifying effects of pro-oxidants.

METHOD: In a mother-child cohort in northern Argentina (n = 169), we measured multiple toxic metals in the maternal blood or urine collected during late pregnancy, as well as the placenta and cord blood collected at delivery, using inductively coupled plasma mass spectrometry (ICP-MS). We assessed associations of log2-transformed metal concentrations with rTL, measured in maternal and cord blood leukocytes and the placenta by real-time PCR, using multivariable-adjusted linear regression. Additionally, we tested for modifications by antioxidants (zinc, selenium, folate, and vitamin D3).

RESULTS: Exposure to boron and antimony during pregnancy was associated with shorter maternal rTL, and lithium with longer maternal rTL; a doubling of exposure was associated with changes corresponding to 0.2-0.4 standard deviations (SD) of the rTL. Arsenic concentrations in the placenta (n = 98), blood, and urine were positively associated with placental rTL, about 0.2 SD by doubled arsenic. In the cord blood (n = 88), only lead was associated with rTL (inversely), particularly in boys (p for interaction 0.09). Stratifying by newborn sex showed ten times stronger association in boys (about 0.6 SD) than in girls. The studied antioxidants did not modify the associations, except that with antimony.

CONCLUSIONS: Elevated exposure to boron, lithium, arsenic, and antimony was associated with maternal or newborn rTL in a tissue-specific, for lead also sex-specific, manner. Nutritional antioxidants did not generally influence the associations.

RevDate: 2019-04-10

Lang J, McKie J, Smith H, et al (2019)

Adverse childhood experiences, epigenetics and telomere length variation in childhood and beyond: a systematic review of the literature.

European child & adolescent psychiatry pii:10.1007/s00787-019-01329-1 [Epub ahead of print].

A systematic review following PRISMA guidelines was conducted to answer the question: What epigenetic, telomeric and associated biological changes are associated with exposure to adverse childhood experiences (ACEs) in the under 12s? Using PRISMA guidelines, appropriate databases were searched. 190 papers were returned with 38 articles fully reviewed. Articles were each independently quality rated by two authors using the Crowe Critical Appraisal Tool and data were extracted. Of the 38 articles, 23 were rated as very high quality. Most study participants were adults (n = 7769) with n = 727 child participants. Only seven of the very/high-quality studies were prospective and involved children. Methylation was the most studied method of epigenetic modification. There is some evidence supporting epigenetic modification of certain markers in participants exposed to ACEs measured in adulthood. Research is lacking on non-coding aspects of the epigenome and on coding aspects other than DNA methylation. There is some evidence of a more powerful effect on telomere length if physical neglect was involved. Much further work is required to model biological and psychological effects of epigenetic changes during childhood using prospective study designs. The effect of ACEs on the cellular ageing process during childhood is inadequately investigated and relies solely on measure of telomere length. Future research suggestions are proposed.

RevDate: 2019-04-09

Karimi B, Yunesian M, Nabizadeh R, et al (2019)

Serum Level of Total Lipids and Telomere Length in the Male Population: A Cross-Sectional Study.

American journal of men's health, 13(2):1557988319842973.

Telomeres contain TTAGGG (T; Thymine, A; Adenine and G; Guanine) repetitive sequences and are placed at the end of human chromosomes. Telomere dysfunction is implicated in some age-related and chronic diseases, but its association with total serum lipids and obesity is unknown. Our objective was to determine influenced of total serum lipids on leukocyte telomere lengths (TLs). Participants were selected by cluster sampling from 22 districts of Tehran. The questionnaires were completed by 500 subjects and after the initial assessment in terms of lifestyle, nutrition, home, and job, 300 healthy people, aged 25-40 years were finally selected. TLs and serum level of total lipids were measured by quantitative real-time PCR and the Phillips method, respectively. The average telomere length (T/S) and total lipids were 1.05 ± 0.3 mg/dl and 643.3 ± 70.8 mg/dl, respectively. We found that a one unit difference in the following parameters were associated with kilo base pair differences in TL: Age -0.0002 (95% CI [-0.0022, -0.0018]), BMI -0.0019 (95% CI [-0.0003, -0.0034]), TC 0.0001 (95% CI [-0.0006, -0.0007]), TG -0.0010 (95% CI [-0.0015, -0.0004]), PL 0.0001 (95% CI [-0.0005, -0.0007]), and TSL -0.0003 (95% CI [-0.0008, 0.0001]). Spearman correlation analysis revealed an inverse relationship between TC (R = -0.53; 95% CI [-0.61, -0.44]), TG (R = -0.50; 95% CI [-0.58, -0.41]), PL (R = -0.46; 95% CI [-0.54-0.36]), and TSL (R = -0.63; 95% CI [-0.69, -0.56]) with T/S. Our research suggests that the inverse relationship was found between TL and weight, BMI, age, and TSL which were associated with obesity. High serum lipids concentration may be associated with systemic inflammation and atherosclerosis and may lead to oxidative stress, resulting in telomere shortening.

RevDate: 2019-04-18

Gillis JC, Chang SC, Wang W, et al (2019)

The relation of telomere length at midlife to subsequent 20-year depression trajectories among women.

Depression and anxiety [Epub ahead of print].

BACKGROUND: Telomeres cap and protect DNA but shorten with each somatic cell division. Aging and environmental and lifestyle factors contribute to the speed of telomere attrition. Current evidence suggests a link between relative telomere length (RTL) and depression but the directionality of the relationship remains unclear. We prospectively examined associations between RTL and subsequent depressive symptom trajectories.

METHODS: Among 8,801 women of the Nurses' Health Study, depressive symptoms were measured every 4 years from 1992 to 2012; group-based trajectories of symptoms were identified using latent class growth-curve analysis. Multinomial logistic models were used to relate midlife RTLs to the probabilities of assignment to subsequent depressive symptom trajectory groups.

RESULTS: We identified four depressive symptom trajectory groups: minimal depressive symptoms (62%), worsening depressive symptoms (14%), improving depressive symptoms (19%), and persistent-severe depressive symptoms (5%). Longer midlife RTLs were related to significantly lower odds of being in the worsening symptoms trajectory versus minimal trajectory but not to other trajectories. In comparison with being in the minimal symptoms group, the multivariable-adjusted odds ratio of being in the worsening depressive symptoms group was 0.78 (95% confidence interval, 0.62-0.97; p = 0.02), for every standard deviation increase in baseline RTL.

CONCLUSIONS: In this large prospective study of generally healthy women, longer telomeres at midlife were associated with significantly lower risk of a subsequent trajectory of worsening mood symptoms over 20 years. The results raise the possibility of telomere shortening as a novel contributing factor to late-life depression.

RevDate: 2019-04-10

Sudyka J, Arct A, Drobniak SM, et al (2019)

Birds with high lifetime reproductive success experience increased telomere loss.

Biology letters, 15(1):20180637.

Lifetime reproductive success (LRS) is what counts in terms of evolution, but investments in reproduction entail costs for an organism. The idea that telomere dynamics may be shaped in response to such costs is already established; however, we still lack information on whether this relation translates to overall fitness. Here, we quantified LRS (number of fledged young) and longitudinal telomere dynamics of small passerine birds-the blue tits (Cyanistes caeruleus). We found that individual telomere erosion rate was positively associated with lifetime fledgling number. Birds with more fledged young experienced increased telomere attrition. We show that telomere attrition rate, but not telomere length, is related to individual fitness and suggest that telomere dynamics may underlie reproductive costs experienced by animals as a consequence of prioritizing their lifetime fitness. This is the first study, to our knowledge, to provide evidence that more pronounced telomere erosion is associated with higher fitness gain.

RevDate: 2019-04-03

Marshall WF, JC Fung (2019)

Modeling meiotic chromosome pairing: a tug of war between telomere forces and a pairing-based Brownian ratchet leads to increased pairing fidelity.

Physical biology [Epub ahead of print].

Meiotic homolog pairing involves associations between homologous DNA regions scattered along the length of a chromosome. When homologs associate, they tend to do so by a processive zippering process, which apparently results from avidity effects. Using a computational model, we show that this avidity-driven processive zippering reduces the selectivity of pairing. When active random forces are applied to telomeres, this drop in selectivity is eliminated in a force-dependent manner. Further simulations suggest that active telomere forces are engaged in a tug-of-war against zippering, which can be interpreted as a Brownian ratchet with a stall force that depends on the dissociation constant of pairing. When perfectly homologous regions of high affinity compete with homeologous regions of lower affinity, the affinity difference can be amplified through this tug of war effect provided the telomere force acts in a range that is strong enough to oppose zippering of homeologs while still permitting zippering of correct homologs. The degree of unzippering depends on the radius of the nucleus, such that complete unzippering of homeologous regions can only take place if the nucleus is large enough to pull the two chromosomes completely apart. A picture of meiotic pairing thus emerges that is fundamentally mechanical in nature, possibly explaining the purpose of active telomere forces, increased nuclear diameter, and the presence of "Maverick" chromosomes in meiosis.

RevDate: 2019-04-02

Derenzini E, Risso A, Ruella M, et al (2019)

INFLUENCE OF DONOR AND RECIPIENT GENDER ON TELOMERE MAINTENANCE FOLLOWING UMBILICAL CORD BLOOD CELL TRANSPLANTATION: A STUDY BY GITMO (GRUPPO ITALIANO TRAPIANTO DI MIDOLLO OSSEO).

Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation pii:S1083-8791(19)30210-1 [Epub ahead of print].

Physiological loss of telomerase activity in adult life determines progressive telomere length (TL) shortening. Inflammation and oxidative damage are established causes of TL loss; moreover, males have shorter telomeres compared to females. Despite these notions, mechanisms regulating TL maintenance are poorly defined. As umbilical cord blood (UCB) cells harbor very long telomeres, not yet exposed to environmental damages, UCB transplantation (UCB-T) provides a unique experimental setting to study determinants of TL in humans. TL dynamics was analyzed on peripheral blood mononucleated cells (MNCs) from 36 patients (median age: 42 yrs.) undergoing UCB-T. TL was studied at a median of 20 months since UCB-T. A significantly longer TL (mean 8,698 bp, range 6521-11960) was documented in UCB-T recipients compared to age-matched healthy controls (mean 7,396 bp, range 4,375-11,108) (p<0.01). Among variables potentially influencing TL maintenance, including recipient features, graft type, transplant procedure, and engraftment kinetics, only donor/recipient gender combination was associated to TL, with longest TL in females receiving a male UCB (mean 10,063 bp, range 8,381-11,960). To further investigate this trend, telomerase activation was assessed in vitro. Experiments showed that telomerase subunits were preferentially up-regulated in male-derived bone marrow MNCs exposed ex-vivo to estradiol as compared to female MNCs. This implies an increased sensitivity of male-derived MNCs to telomerase activation induced by estradiol. The results suggest that extrinsic and modifiable factors such as hormonal status and female milieu could be major determinants of TL in humans providing the rationale for investigating hormonal-based approaches to counteract telomere erosion and aging-related diseases.

RevDate: 2019-04-12

Chen YF, Zhou KW, Yang GZ, et al (2019)

Association between lipoproteins and telomere length in US adults: data from the NHANES 1999-2002.

Lipids in health and disease, 18(1):80 pii:10.1186/s12944-019-1030-7.

BACKGROUND: Evidence regarding the correlation between lipoproteins and telomere length in US adults is limited. We aimed to investigate whether lipoproteins was associated with telomere length using US National Health and Nutrition Examination Survey (NHANES) database.

METHODS: A total of 6468 selected participants were identified in the NHANES Data Base (1999-2002). The independent and dependent variables were lipoproteins and telomere length, respectively. The covariates included demographic data, dietary data, physical examination data, and comorbidities.

RESULTS: In fully-adjusted model, we found that 0.1 differences of telomere length were positively associated with HDL-C [0.19 (95% CI 0.07, 0.31)], while the associations between LDL-C [0.19 (95% CI -0.27, 0.65)], TG [- 1.00 (95% CI -2.09, 0.07) and telomere length were not detected. By nonlinearity test, only the relationship between HDL-C and telomere length was nonlinear. The inflection point we got was 1.25. On the left side of the inflection point (telomere length ≤ 1.25), a difference in 0.1 of telomere length was associated with 0.50 difference in HDL-C.

CONCLUSION: After adjusting for demographic data, dietary data, physical examination data, and comorbidities, telomere length is not associated with LDL-C and TG, but is positively associated with HDL-C when telomere length is less than 1.25.

RevDate: 2019-04-01

Al Khleifat A, Iacoangeli A, Shatunov A, et al (2019)

Telomere length is greater in ALS than in controls: a whole genome sequencing study.

Amyotrophic lateral sclerosis & frontotemporal degeneration [Epub ahead of print].

BACKGROUND: Amyotrophic lateral sclerosis is a neurodegenerative disease of motor neurons resulting in progressive paralysis and death, typically within 3-5 years. Although the heritability of ALS is about 60%, only about 11% is explained by common gene variants, suggesting that other forms of genetic variation are important. Telomeres maintain DNA integrity during cellular replication and shorten naturally with age. Gender and age are risk factors for ALS and also associated with telomere length. We therefore investigated telomere length in ALS.

METHODS: We estimated telomere length by applying a bioinformatics analysis to whole genome sequence data of leukocyte-derived DNA from people with ALS and age and gender-matched matched controls in a UK population. We tested the association of telomere length with ALS and ALS survival.

RESULTS: There were 1241 people with ALS and 335 controls. The median age for ALS was 62.5 years and for controls, 60.1 years, with a male-female ratio of 62:38. Accounting for age and sex, there was a 9% increase of telomere length in ALS compared to matched controls. Those with longer telomeres had a 16% increase in median survival. Of nine SNPs associated with telomere length, two were also associated with ALS: rs8105767 near the ZNF208 gene (p = 1.29 × 10-4) and rs6772228 (p = 0.001), which is in an intron for the PXK gene.

CONCLUSIONS: Longer telomeres in leukocyte-derived DNA are associated with ALS, and with increased survival in those with ALS.

RevDate: 2019-04-01

Kaewtunjai N, Summart R, Wongnoppavich A, et al (2019)

Telomerase Inhibition, Telomere Shortening, and Cellular Uptake of the Perylene Derivatives PM2 and PIPER in Prostate Cancer Cells.

Biological & pharmaceutical bulletin [Epub ahead of print].

Prostate cancer is the second most common cancer among men worldwide, and it is ranked first in the United States and Europe. Since prostate cancer is slow-growing, active surveillance for low-risk cancer has been increasingly supported by various guidelines. Most prostate cancers reactivate telomerase to circumvent the replicative senescence caused by the end replication problem; therefore, telomerase inhibition is potentially useful for the suppression of prostate cancer progression during this active surveillance or for the prevention of cancer recurrence after conventional therapies. In this study, we demonstrated that the perylene derivatives, PM2 and PIPER, could suppress hTERT expression and telomerase activity in the short-term treatment of LNCaP and PC3 prostate cancer cells. Long-term treatment with subcytotoxic doses of these compounds in both prostate cancer cells showed telomere shortening and a significant increase in senescent cells. Although the acute cytotoxicity of PM2 was about 30 times higher than that of PIPER in both prostate cancer cells, the cellular uptake of both compounds was comparable as determined by flow cytometry and fluorescent microscopy.

RevDate: 2019-04-16

Amano H, Chaudhury A, Rodriguez-Aguayo C, et al (2019)

Telomere Dysfunction Induces Sirtuin Repression that Drives Telomere-Dependent Disease.

Cell metabolism pii:S1550-4131(19)30129-9 [Epub ahead of print].

Telomere shortening is associated with stem cell decline, fibrotic disorders, and premature aging through mechanisms that are incompletely understood. Here, we show that telomere shortening in livers of telomerase knockout mice leads to a p53-dependent repression of all seven sirtuins. P53 regulates non-mitochondrial sirtuins (Sirt1, 2, 6, and 7) post-transcriptionally through microRNAs (miR-34a, 26a, and 145), while the mitochondrial sirtuins (Sirt3, 4, and 5) are regulated in a peroxisome proliferator-activated receptor gamma co-activator 1 alpha-/beta-dependent manner at the transcriptional level. Administration of the NAD(+) precursor nicotinamide mononucleotide maintains telomere length, dampens the DNA damage response and p53, improves mitochondrial function, and, functionally, rescues liver fibrosis in a partially Sirt1-dependent manner. These studies establish sirtuins as downstream targets of dysfunctional telomeres and suggest that increasing Sirt1 activity alone or in combination with other sirtuins stabilizes telomeres and mitigates telomere-dependent disorders.

RevDate: 2019-04-01

Kim H, Cho SJ, Yoo SH, et al (2019)

Association between telomere length and completed suicide observed in 71 suicide victims - Preliminary findings.

Journal of psychosomatic research, 120:8-11.

OBJECTIVE: Telomere length has emerged as a cumulative marker for lifestyle, psychosocial stress, and cytotoxic environments. We aimed to examine the possible association between leukocyte telomere length (LTL) and completed suicide.

METHODS: This study included 71 suicide completers and 117 healthy controls for whom LTL was determined by the ratio of the telomere repeat copy number to the single-copy gene copy number (T/S ratio). We compared the LTL between the suicide completers and the healthy controls and estimated the odds ratio (OR) for suicide for each age group, applying a generalized estimating equation (GEE).

RESULTS: LTL was significantly shortened in the suicide completers as compared with the controls, overall subjects, or within-age categories (≤29 and 30-49 years). Furthermore, a longer LTL was associated with significantly decreased odds of completed suicide for those aged ≤29 years and 30-49 years (OR = 0.11, 95% confidence interval [CI] 0.03-0.37, p < .001 for the ≤29-year age group; OR = 0.54, 95% CI 0.34-0.84, p = .006 for the 30- to 49-year age group).

CONCLUSIONS: This study provides evidence regarding the relationship between shortened LTL and completed suicide, especially in those aged <50 years. Future research should further assess potential confounders and examine underlying mechanisms.

RevDate: 2019-03-30

Martin LF, Richardson LS, da Silva MG, et al (2019)

Dexamethasone Induces Primary Amnion Epithelial Cell Senescence through Telomere-P21 Associated Pathway.

Biology of reproduction pii:5423875 [Epub ahead of print].

INTRODUCTION: Dexamethasone (Dex), a corticosteroid hormone, is used during the perinatal period to help fetal lung and other organ development. Conversely, Dex-induced cell proliferation has been associated with accelerated aging. Using primary amnion epithelial cells (AECs) from term, not in labor, fetal membranes, we tested the effects of Dex on cell proliferation, senescence, and inflammation.

METHOD: Primary AECs treated with Dex (100 nM and 200 nM) for 48 h were tested for cell viability (crystal violet dye exclusion), cell cycle progression and/or type of cell death (flow cytometry), expression patterns of steroid receptors (Glucocorticoid Receptor, Progesterone Receptor Membrane Component 1&2), inflammatory mediators (IL-6 and IL-8), and telomere length (quantitative RT-PCR). Mechanistic mediators of senescence (p38MAPK and p21) were determined by Western blot analysis.

RESULTS: Dex treatment did not induce AEC proliferation, cell cycle, influence viability, or morphology. However, Dex caused dependent telomere length reduction and p38MAPK-independent but p21-dependent (confirmed by treatment with p21 inhibitor UC2288). Senescence was not associated with an increase in inflammatory mediators, which is often associated with senescence. Co-treatment with RU486 produced DNA damage, cell cycle arrest, and cellular necrosis with an increase in inflammatory mediators. The effect of Dex was devoid of changes to steroid receptors, whereas RU486 increased GR expression.

CONCLUSION: Dex treatment of AECs produced non-replicative and non-inflammatory senescence. Extensive use of Dex during the perinatal period may lead to cellular senescence, contributing to cellular aging associated pathologies during the perinatal and neonatal periods.

RevDate: 2019-04-18

Ge J, Li C, Li C, et al (2019)

SIRT6 participates in the quality control of aged oocytes via modulating telomere function.

Aging, 11(7):1965-1976.

It has been well recognized that oocyte quality declines in aging animals. However, to date, the underlying mechanism remains to be explored. In the present study, we report that oocytes and embryos from aged mice (42-45 weeks old) display the reduced expression of SIRT6 protein, accompanying with telomere shortening and DNA lesions. Moreover, we demonstrate that specific depletion of SIRT6 in oocytes induces dysfunctional telomeres and apoptosis of the resultant early embryos, leading to the developmental delay and cytoplasmic fragmentation. Importantly, we further find that overexpression of SIRT6 in aged oocytes promotes the telomere elongation in 2-cell embryos and lowers the incidence of apoptotic blastomeres. In summary, our data indicate a role for SIRT6 in modulating telomere function during oocyte maturation and embryonic development, and discover that SIRT6 reduction is an important point connecting maternal aging and quality control of oocyte/embryos.

RevDate: 2019-04-10

Wang XB, Cui NH, Zhang S, et al (2019)

Leukocyte telomere length, mitochondrial DNA copy number, and coronary artery disease risk and severity: A two-stage case-control study of 3064 Chinese subjects.

Atherosclerosis, 284:165-172 pii:S0021-9150(19)30139-X [Epub ahead of print].

BACKGROUND AND AIMS: Leukocyte telomere length (TL) and mitochondrial DNA copy number (mtDNA-CN), as hallmarks of cellular aging, may be involved in the development of coronary artery disease (CAD) by modulating oxidative stress. This study aimed to investigate the effects of leukocyte TL and mtDNA-CN alone or in combination on CAD risk and severity in the Chinese population.

METHODS: In this two-stage case-control study with 1511 CAD patients and 1553 controls, leukocyte TL and mtDNA-CN were determined by a quantitative PCR assay. Three oxidative parameters, including leukocyte 8-hydroxy-2'-deoxyguanosine (8-OHdG), plasma malondialdehyde, and plasma reactive oxygen species (ROS), were quantified by ELISA or colorimetric kits in a subset of 129 cases and 129 controls.

RESULTS: In the combined cohort, each 1-SD decrease in TL and mtDNA-CN was significantly associated with a 1.17-fold and 1.14-fold increased risk of CAD (p < 0.001 for all), respectively, after adjusting for confounders. The aggregated score, which reflected the cumulative dosage of the tertiles of TL and mtDNA-CN, showed inverse dose-response correlations with CAD risk (ptrend < 0.001), and severity, as determined by the severity of clinical presentations (ptrend = 0.037), the presence of multi-vessel CAD (ptrend = 0.004), and modified Gensini scores (ptrend = 0.009). Similar dose-response relations of the aggregated score to leukocyte 8-OHdG and plasma ROS were also identified.

CONCLUSIONS: Our data suggested reductions in both TL and mtDNA-CN as independent risk factors for CAD. The combination of TL and mtDNA-CN might jointly contribute to CAD risk, CAD severity, and oxidative stress.

RevDate: 2019-04-14

Ellaway A, Dundas R, Robertson T, et al (2019)

More miles on the clock: Neighbourhood stressors are associated with telomere length in a longitudinal study.

PloS one, 14(3):e0214380 pii:PONE-D-18-26852.

BACKGROUND: There is a substantial gap in health and longevity between more affluent and more deprived areas, and more knowledge of the determinants of this health divide is required. Experience of the local residential environment is important for health although few studies have examined this in relation to biological markers of age such as telomere length. We sought to examine if residents' perceptions of neighbourhood stressors over time were associated with telomere length in a community study.

In a prospective cohort study of 2186 adults in the West of Scotland, we measured neighbourhood stressors at three time points over a 12-year period and telomere length at the end of the study. Using linear regression models, we found that a higher accumulation of neighbourhood stressors over time was associated with shorter telomere length, even after taking cohort, social class, health behaviours (smoking status, diet, physical activity), BMI and depression into account among females only (Beta = 0.007; 95%CI [0.001, 0.012]; P<0.014).

CONCLUSIONS/SIGNIFICANCE: Neighborhood environments are potentially modifiable, and future efforts directed towards improving deleterious local environments may be useful to lessen telomere attrition.

RevDate: 2019-03-28

Hubacek JA, Pelclova D, Dlouha D, et al (2019)

Leukocyte telomere length is not affected by long-term occupational exposure to nano metal oxides.

Industrial health [Epub ahead of print].

The aim of this study was to ascertain whether long-term occupational exposure to nanoparticles would affect relative leukocyte telomere length (LrTL). We analysed occupational exposure to size-resolved aerosol particles, with special emphasis on nanoparticles at two workshops: i/ the production of nanocomposites containing metal oxides; ii/ laboratory to test experimental exposure of nano-CuO to rodents. Thirty-five exposed researchers (age 39.5 ± 12.6 yr; exposure duration 6.0 ± 3.7 yr) and 43 controls (40.4 ± 10.5 yr) were examined. LrTL did not significantly (p=0.14) differ between the exposed researchers (0.92 ± 0.13) and controls (0.86 ± 0.15). In addition, no significant correlation (r=-0.22, p=0.22) was detected between the duration of occupational exposure and LrTL. The results remained non-significant after multiple adjustments for age, sex and smoking status. Our pilot results suggest that relative leukocyte telomere length is not affected by occupational exposure to nanoparticles.

RevDate: 2019-03-26

Mangge H, Renner W, Almer G, et al (2019)

Subcutaneous adipose tissue distribution and telomere length.

Clinical chemistry and laboratory medicine pii:/j/cclm.ahead-of-print/cclm-2018-0801/cclm-2018-0801.xml [Epub ahead of print].

Background Overweight and obese individuals have a reduced life expectancy due to cardiovascular disease (CVD), type 2 diabetes, stroke and cancer. Systemic inflammation and premature telomere shortening have been discussed as potential mechanisms linking these conditions. We investigated the relation of subcutaneous adipose tissue (SAT) distribution to leukocyte relative telomere length (RTL). Methods We measured RTL in 375 participants of the observational STYJOBS/EDECTA cohort (ClinicalTrials.gov Identifier NCT00482924) using a qPCR based method. SAT distribution was determined by lipometry yielding a percent body fat value and SAT thicknesses at 15 standardized locations across the entire body. A correlation analysis between RTL, age, sex, lipometry data and conventional body measures (body mass index [BMI], waist-, hip circumference, waist-to-hip ratio, waist-to-height ratio) was calculated. The strongest determinants of RTL were determined by a stepwise multiple regression analysis. Results RTL was not associated with age or sex. RTL was significantly negatively correlated with BMI, percent body fat, waist-, hip circumference and waist-to-height ratio. Furthermore, RTL correlated with SAT at the following locations: neck, triceps, biceps, upper back, front chest, lateral chest, upper abdomen, lower abdomen, lower back, hip, front thigh, lateral thigh, rear thigh and calf. Stepwise regression analysis revealed nuchal and hip SAT as the strongest predictors of RTL. No significant association was seen between RTL and waist-to-hip ratio. Conclusions RTL is negatively associated with parameters describing body fat composure. Nuchal and hip SAT thicknesses are the strongest predictors of RTL. Central obesity appears to correlate with premature genomic aging.

RevDate: 2019-04-03

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

Leukocyte Telomere Length Reflects Prenatal Stress Exposure, But Does Not Predict Atopic Dermatitis Development at 1 Year.

Allergy, asthma & immunology research, 11(3):357-366.

PURPOSE: Prenatal maternal stress affects offspring's atopic dermatitis (AD) development, which is thought to be mediated by the oxidative stress. We aimed to evaluate the difference in leukocyte telomere length (LTL), a marker for exposure to oxidative stress, according to the prenatal stress exposure and the later AD development.

METHODS: From a birth cohort (the COhort for Childhood Origin of Asthma and allergic diseases) that had displayed a good epidemiologic association between the exposure to prenatal stress and AD development in the offspring, we selected 68 pairs of samples from 4 subject groups based on the level of prenatal maternal stress and later AD development. The LTL was measured from both cord blood and 1-year peripheral blood, and their LTLs were compared between subject groups. Finally, the proportion of AD development was examined in the subject groups that are reclassified based on subjects' exposure to prenatal stress and there LTL.

RESULTS: Cord-blood LTL was shorter in prenatally stressed infants than in unstressed ones (P = 0.026), which difference was still significant when subjects became 1 year old (P = 0.008). LTL of cord blood, as well as one of the 1-year peripheral blood, was not different according to later AD development at 1 year (P = 0.915 and 0.174, respectively). Shorter LTL made no increase in the proportion of later AD development in either prenatally high-stressed or low-stressed groups (P = 1.000 and 0.473, respectively).

CONCLUSIONS: Cord-blood LTL may reflect subjects' exposure to maternal prenatal stress. However, the LTL shortening is not a risk factor of increasing AD development until the age of 1, and a longer investigation may be necessary for validation. Currently, the results doubt the role of LTL shortening as a marker for risk assessment tool for the prenatal stress associated with AD development in the offspring.

RevDate: 2019-03-26

Jebaraj BMC, Tausch E, Landau DA, et al (2019)

Short telomeres are associated with inferior outcome, genomic complexity, and clonal evolution in chronic lymphocytic leukemia.

Leukemia pii:10.1038/s41375-019-0446-4 [Epub ahead of print].

Telomere length in chronic lymphocytic leukemia (CLL) has been shown to be of prognostic importance, but the analyses have largely been executed on heterogeneous patient cohorts outside of clinical trials. In the present study, we performed a comprehensive analysis of telomere length associations in the well characterized CLL8 trial (n = 620) of the German CLL study group, with validation in a representative cohort of the CLL4 trial (n = 293). Absolute telomere length was analyzed using quantitative-PCR. Apart from identifying associations of short telomere length with adverse prognostic factors and survival, the study identified cases with 17p- and 11q- associated with TP53 and ATM loss, respectively, to have the shortest telomeres, even when these aberrations were present in small subclones. Thus, telomere shortening may precede acquisition of the high-risk aberrations, contributing to disease evolution. In line with this, telomere shortening was associated with an increase in genomic complexity as well as clonal evolution, highlighting its importance as a biomarker especially in monitoring disease progression in non-high-risk CLL.

RevDate: 2019-04-08

Nera B, Huang HS, Hendrickson EA, et al (2019)

Both the classical and alternative non-homologous end joining pathways contribute to the fusion of drastically shortened telomeres induced by TRF2 overexpression.

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

The double-stranded telomeric binding protein TRF2 is expressed in many human cancers at elevated levels. Moreover, experimental overexpression of TRF2 in human cells causes replication stalling in telomeric tracts, which leads to drastic telomere shortening and fusion of deprotected chromosome ends. To understand which end joining pathway is involved in mediating these chromosome fusions, we overexpressed TRF2 in human HCT116 cell lines that were deficient for the DNA Ligase 4 (Lig4)-dependent classical non-homologous end joining (C-NHEJ) or the DNA Ligase 3 (Lig3)-dependent alternative non-homologous end joining (A-NHEJ) pathway. Surprisingly, abrogation of either Lig4 or nuclear Lig3 significantly reduced inter-chromosomal fusion of drastically shortened telomeres, suggesting that both the C-NHEJ and A-NHEJ pathways are involved in mediating this type of fusion. Fusion between deprotected sister chromatids, however, only required the Lig3-dependent A-NHEJ pathway. Interestingly, a previous study reported similar end joining pathway requirements for the fusion of critically shortened telomeres during a telomere attrition-based cellular crisis. We speculate that, as in cellular crisis, the same repair pathway(s) may drive clonal and genomic evolution in human cancers containing elevated TRF2 levels.

RevDate: 2019-04-17

Lewinska A, Klukowska-Rötzler J, Deregowska A, et al (2019)

c-Myc activation promotes cofilin-mediated F-actin cytoskeleton remodeling and telomere homeostasis as a response to oxidant-based DNA damage in medulloblastoma cells.

Redox biology, 24:101163 pii:S2213-2317(19)30261-7 [Epub ahead of print].

Medulloblastoma (MB) is a common and highly aggressive pediatric brain tumor of a heterogeneous nature. According to transcriptome-based profiling, four molecular subgroups of MB have been revealed, namely WNT, SHH, Group 3 and Group 4. High MYC mRNA expression and MYC gene amplification in MB have been considered as indicators of poor prognosis. However, the role of c-Myc in MB biology is still not well established. In the present study, the effects of c-Myc activation in UW228-MycER MB cell line were investigated using 4-hydroxytamoxifen (4-OHT) induction system. Upon 4-OHT stimulation, an increase in metabolic activity, large-cell/anaplastic (LC/A) phenotype and oxidative stress-mediated DNA damage were observed. However, 53BP1 foci were not implicated in DNA damage response. Instead, cofilin nuclear translocation, changes in F-actin cytoskeleton and the levels of cytoskeletal proteins were shown. Moreover, the telomere length was found to be unaffected that may be associated with the upregulation of TRF proteins. Transcription of nascent RNA (synthesis of new rRNA) and the expression of RNA polymerase I-specific transcription initiation factor RRN3/TIF-IA were also elevated. Moreover, increased levels of DNMT2, a modulator of stress responses, were observed. A small fraction of cells responded differently as oncogene-induced senescence was also noticed. We postulate that c-Myc-mediated modulation of genetic stability of MB cells may trigger cellular heterogeneity and affect adaptive responses to changing environment.

RevDate: 2019-03-22

Zhang N, Zheng Y, Liu J, et al (2019)

Genetic variations associated with telomere length confer risk of gastric cardia adenocarcinoma.

Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association pii:10.1007/s10120-019-00954-8 [Epub ahead of print].

BACKGROUND: Aberrant telomere lengthening is a critical feature of malignant cells. Short leukocyte telomere length (LTL) confers elevated risk of gastric cardia adenocarcinoma (GCA). Multiple genome-wide association studies (GWAS) identified various single-nucleotide polymorphisms (SNPs) associated with LTL in different ethnic populations. However, it remains largely unexplored how these genetic variants are involved in GCA susceptibility.

METHODS: We systematically screened GWAS-identified candidate SNPs and tested the impact of 30 polymorphisms in genes associated with interindividual LTL variation on GCA using two-stage case-control comparisons consisting of 1024 GCA patients and 1118 controls.

RESULTS: We observed that CXCR4 rs6430612, TERT rs10069690, and rs2853676 as well as VPS34 rs2162440 are significantly associated with GCA development. A 0.64-fold decreased risk of GCA is associated with the CXCR4 rs6430612 CT genotype compared with the CC genotype (P = 0.002). On the contrary, the TERT rs10069690 TT genotype carriers had a 1.83-fold increased risk to develop GCA compared to the CC genotype carriers (P = 5.8×10-6). We also detected a 2.17-fold increased OR for GCA that was associated with the TERT rs2853676 TT genotype (P = 2.6×10-6). In addition, the odds of having the VPS34 rs2162440 GA genotype in GCA patients were 1.35 compared with the GG genotype (P = 0.002). In stratified analyses, the association between TERT rs10069690 polymorphism and GCA was more pronounced in nonsmokers (Pinteraction = 9.7 × 10-5) and nondrinkers (Pinteraction = 4.6 × 10-5).

CONCLUSIONS: Our results highlight the importance of both LTL and LTL-related genetic variants to GCA predisposition.

RevDate: 2019-03-29

Aas M, Elvsåshagen T, Westlye LT, et al (2019)

Telomere length is associated with childhood trauma in patients with severe mental disorders.

Translational psychiatry, 9(1):97 pii:10.1038/s41398-019-0432-7.

Reduced telomere length (TL) and structural brain abnormalities have been reported in patients with schizophrenia (SZ) and bipolar disorder (BD). Childhood traumatic events are more frequent in SZ and BD than in healthy individuals (HC), and based on recent findings in healthy individuals could represent one important factor for TL and brain aberrations in patients. The study comprised 1024 individuals (SZ [n = 373]; BD [n = 249] and HC [n = 402]). TL was measured by quantitative polymerase chain reaction (qPCR), and childhood trauma was assessed using the Childhood Trauma Questionnaire (CTQ). Diagnosis was obtained by the Structured Clinical Interview (SCID) for the diagnostic and statistical manual of mental disorders-IV (DSM-IV). FreeSurfer was used to obtain regional and global brain volumes from T1-weighted magnetic resonance imaging (MRI) brain scans. All analyses were adjusted for current age and sex. Patients had on average shorter TL (F = 7.87, p = 0.005, Cohen's d = 0.17) and reported more childhood trauma experiences than HC (χ2 = 148.9, p < 0.001). Patients with a history of childhood sexual, physical or emotional abuse had shorter TL relative to HC and to patients without a history of childhood abuse (F = 6.93, p = 0.006, Cohen's d = 0.16). After adjusting for childhood abuse, no difference in TL was observed between patients and HC (p = 0.12). There was no statistically significant difference in reported childhood abuse exposure or TL between SZ and BD. Our analyses revealed no significant associations between TL and clinical characteristics or brain morphometry. We demonstrate shorter TL in SZ and BD compared with HC and showed that TL is sensitive to childhood trauma experiences. Further studies are needed to identify the biological mechanisms of this relationship.

RevDate: 2019-04-01

Shen W, Kerr CM, Przychozen B, et al (2019)

Impact of germline CTC1 alterations on telomere length in acquired bone marrow failure.

British journal of haematology [Epub ahead of print].

Compound heterozygous germline mutations in CTC1 gene have been found in patients with atypical dyskeratosis congenita (DC), whereas heterozygous carriers are unaffected. Through screening of a large cohort of adult patients with acquired bone marrow failure syndromes, in addition to a DC case, we have also found extremely rare or novel heterozygous deleterious germline variants of CTC1 in patients with aplastic anaemia (AA; n = 5), paroxysmal nocturnal haemoglobinuria (PNH; n = 3) and myelodysplastic syndrome (MDS; n = 2). A compound heterozygous case of AA showed clonal evolution. Our results suggest that some of the inherited CTC1 variants may represent predisposition factors for acquired bone marrow failure.

RevDate: 2019-04-11

Casagrande S, M Hau (2019)

Telomere attrition: metabolic regulation and signalling function?.

Biology letters, 15(3):20180885.

Stress exposure can leave long-term footprints within the organism, like in telomeres (TLs), protective chromosome caps that shorten during cell replication and following exposure to stressors. Short TLs are considered to indicate lower fitness prospects, but why TLs shorten under stressful conditions is not understood. Glucocorticoid hormones (GCs) increase upon stress exposure and are thought to promote TL shortening by increasing oxidative damage. However, evidence that GCs are pro-oxidants and oxidative stress is causally linked to TL attrition is mixed . Based on new biochemical findings, we propose the metabolic telomere attrition hypothesis: during times of substantially increased energy demands, TLs are shortened as part of the transition into an organismal 'emergency state', which prioritizes immediate survival functions over processes with longer-term benefits. TL attrition during energy shortages could serve multiple roles including amplified signalling of cellular energy debt to re-direct critical resources to immediately important processes. This new view of TL shortening as a strategy to resolve major energetic trade-offs can improve our understanding of TL dynamics. We suggest that TLs are master regulators of cell homeostasis and propose future research avenues to understand the interactions between energy homeostasis, metabolic regulators and TL.

RevDate: 2019-04-15

Niederberger C (2019)

Re: Shorter Leukocyte Telomere Length is Associated with Risk of Nonobstructive Azoospermia.

The Journal of urology [Epub ahead of print].

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

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