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Bibliography on: Telomeres

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ESP: PubMed Auto Bibliography 27 Nov 2020 at 01:55 Created: 


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

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

Citations The Papers (from PubMed®)


RevDate: 2020-11-26

Baskind M, Hawkins J, Heyman MB, et al (2020)

Obesity at Age Six Months Is Associated with Shorter Preschool Leukocyte Telomere Length Independent of Parental Telomere Length.

The Journal of pediatrics pii:S0022-3476(20)31437-2 [Epub ahead of print].

OBJECTIVE: To assess whether early modifiable dietary factors and obesity measures are associated with leukocyte telomere length at 3-5 years after controlling for heritability of telomere length in a prospective cohort of low-income Latina mothers and their children in San Francisco.

STUDY DESIGN: We analyzed data from the Latinx, Eating and Diabetes (LEAD) cohort, a prospective study of 97 woman-infant dyads. We used linear regression models to evaluate associations between early dietary factors and obesity measures and child leukocyte telomere length at 3-5 years. Multivariable models included child age at the time of telomere collection, breastfeeding at 6 months (yes/no), obesity at 6 months, maternal education, child sex and maternal and paternal leukocyte telomere length.

RESULTS: Data for 73 of the 97 children at 3-5 years of age were analyzed. Any breastfeeding at 6 months was positively associated (β= 0.14, P = .02) and obesity at 6 months was negatively associated (β= -0.21, p<0.001) with leukocyte telomere length in bivariate analyses. In multivariable models including parental leukocyte telomere length, obesity at 6 months was associated with shorter leukocyte telomere length at 3-5 years of age (β= -0.15, p=0.02). Analyses of dietary factors showed high flavored milk consumption at 3 years of age was associated with shorter leukocyte telomere length after adjustment for possible confounders.

CONCLUSIONS: In a low-income Latinx population, obesity at 6 months is negatively associated with cellular health at 3-5 years of age after controlling for genetic factors (parent leukocyte telomere length) associated with leukocyte telomere length. Early life obesity may be more deleterious for cellular health than obesity later in childhood.

RevDate: 2020-11-26

Luxton JJ, McKenna MJ, Taylor LE, et al (2020)

Temporal Telomere and DNA Damage Responses in the Space Radiation Environment.

Cell reports pii:S2211-1247(20)31424-8 [Epub ahead of print].

Telomeres, repetitive terminal features of chromosomes essential for maintaining genome integrity, shorten with cell division, lifestyle factors and stresses, and environmental exposures, and so they provide a robust biomarker of health, aging, and age-related diseases. We assessed telomere length dynamics (changes over time) in three unrelated astronauts before, during, and after 1-year or 6-month missions aboard the International Space Station (ISS). Similar to our results for National Aeronautics and Space Administration's (NASA's) One-Year Mission twin astronaut (Garrett-Bakelman et al., 2019), significantly longer telomeres were observed during spaceflight for two 6-month mission astronauts. Furthermore, telomere length shortened rapidly after return to Earth for all three crewmembers and, overall, telomere length tended to be shorter after spaceflight than before spaceflight. Consistent with chronic exposure to the space radiation environment, signatures of persistent DNA damage responses were also detected, including mitochondrial and oxidative stress, inflammation, and telomeric and chromosomal aberrations, which together provide potential mechanistic insight into spaceflight-specific telomere elongation.

RevDate: 2020-11-26

Luxton JJ, McKenna MJ, Lewis A, et al (2020)

Telomere Length Dynamics and DNA Damage Responses Associated with Long-Duration Spaceflight.

Cell reports pii:S2211-1247(20)31446-7 [Epub ahead of print].

Telomere length dynamics and DNA damage responses were assessed before, during, and after one-year or shorter duration missions aboard the International Space Station (ISS) in a comparatively large cohort of astronauts (n = 11). Although generally healthy individuals, astronauts tended to have significantly shorter telomeres and lower telomerase activity than age- and sex-matched ground controls before and after spaceflight. Although telomeres were longer during spaceflight irrespective of mission duration, telomere length shortened rapidly upon return to Earth, and overall astronauts had shorter telomeres after spaceflight than they did before; inter-individual differences were identified. During spaceflight, all crewmembers experienced oxidative stress, which positively correlated with telomere length dynamics. Significantly increased frequencies of chromosomal inversions were observed during and after spaceflight; changes in cell populations were also detected. We propose a telomeric adaptive response to chronic oxidative damage in extreme environments, whereby the telomerase-independent Alternative Lengthening of Telomeres (ALT) pathway is transiently activated in normal somatic cells.

RevDate: 2020-11-26

Chartrand P, A Sfeir (2020)

A single-molecule view of telomerase regulation at telomeres.

Molecular & cellular oncology, 7(6):1818537 pii:1818537.

Telomerase plays a key role in the immortalization of cancer cells by maintaining telomeres length. Using single-molecule imaging of telomerase RNA molecules in cancer cells, we recently reported novel insights into the role of Cajal bodies in telomerase biogenesis and the regulation of telomerase recruitment to telomeres.

RevDate: 2020-11-26

Cherdsukjai P, Buddhachat K, Brown J, et al (2020)

Age relationships with telomere length, body weight and body length in wild dugong (Dugong dugon).

PeerJ, 8:e10319 pii:10319.

The ability to estimate age and determine the growth status of free-ranging dugongs (Dugong dugon) is vital to providing insight into the basic biology of this endangered species. Currently, age estimation in dugong carcasses relies on counting dentin growth layer groups (GLGs) in tusks, but a disadvantage is they need to be intact. We explored whether measures of telomere length could be used as an alternative approach to age estimation in dugongs given that in other species, telomere length and age are inversely related. In this study, relative telomere length (rTL) was measured by qPCR in skin samples from 24 dugongs of varying ages determined by counts of GLGs. In addition, relationships between age by GLG counts and body weight and length and were examined. Our findings indicate that age estimated by GLGs was negatively correlated with telomere length using the logistic formula with a rate of telomere attrition of approximately 0.036 rTL/year between the ages of 5-20 years. By comparison, both body weight and length were positively correlated with GLG-based age, with growth rates of ~8.8 kg/year for weight and ~3.58 cm/year for length, respectively. After that, growth rates slowed substantially and then plateaued. The results suggest that physical maturity in dugongs occurs at 20 years of age and that measures of rTL might serve as a tool for age estimation in dugongs, living and deceased.

RevDate: 2020-11-26

Markiewicz-Potoczny M, Lobanova A, Loeb AM, et al (2020)

TRF2-mediated telomere protection is dispensable in pluripotent stem cells.

Nature pii:10.1038/s41586-020-2959-4 [Epub ahead of print].

In mammals, telomere protection is mediated by the essential protein TRF2, which binds chromosome ends and ensures genome integrity1,2. TRF2 depletion results in end-to-end chromosome fusions in all cell types that have been tested so far. Here we find that TRF2 is dispensable for the proliferation and survival of mouse embryonic stem (ES) cells. Trf2-/- (also known as Terf2) ES cells do not exhibit telomere fusions and can be expanded indefinitely. In response to the deletion of TRF2, ES cells exhibit a muted DNA damage response that is characterized by the recruitment of γH2AX-but not 53BP1-to telomeres. To define the mechanisms that control this unique DNA damage response in ES cells, we performed a CRISPR-Cas9-knockout screen. We found a strong dependency of TRF2-null ES cells on the telomere-associated protein POT1B and on the chromatin remodelling factor BRD2. Co-depletion of POT1B or BRD2 with TRF2 restores a canonical DNA damage response at telomeres, resulting in frequent telomere fusions. We found that TRF2 depletion in ES cells activates a totipotent-like two-cell-stage transcriptional program that includes high levels of ZSCAN4. We show that the upregulation of ZSCAN4 contributes to telomere protection in the absence of TRF2. Together, our results uncover a unique response to telomere deprotection during early development.

RevDate: 2020-11-25

Kärkkäinen T, Teerikorpi P, Schuett W, et al (2020)

Interplays between pre- and post-natal environments affect early-life mortality, body mass and telomere dynamics in the wild.

The Journal of experimental biology pii:jeb.231290 [Epub ahead of print].

Early-life conditions are crucial determinants of phenotype and fitness. The effects of pre- and postnatal conditions on fitness prospects have been widely studied but their interactive effects have received less attention. In birds, asynchronous hatching creates challenging developmental conditions for the last-hatched chicks, but differential allocation in last-laid eggs might help to compensate this initial handicap. The relative importance and potential interaction between pre- and post-hatching developmental conditions for different fitness components remains mostly unknown. We manipulated hatching order in wild pied flycatchers (Ficedula hypoleuca), creating three groups: Natural asynchrony (last-laid eggs hatching last), Reversed asynchrony (last-laid eggs hatching first) and Hatching synchrony (all eggs hatching at once). We examined the effects of these manipulations on early-life survival, growth and telomere length, a potential cellular biomarker of fitness prospects. Mortality was mostly affected by hatching order, with last-hatched chicks being more likely to die. Early-life telomere dynamics and growth were influenced by the interplays between laying and hatching order. Last-laid but first-hatched chicks were heavier but had shorter telomeres 5 days after hatching than their siblings, indicating rapid early growth with potential adverse consequences on telomere length. Synchronous chicks did not suffer any apparent cost of hatching synchronously. Impaired phenotypes only occurred when reversing the natural hatching order (i.e. developmental mismatch), suggesting that maternal investment in last-laid eggs might indeed counterbalance the initial handicap of last-hatched chicks. Our experimental study thus highlights that potential interplays between pre- and post-natal environments are likely to shape fitness prospects in the wild.

RevDate: 2020-11-24

Gurung RL, M Y, Moh AMC, et al (2020)

Correlation of Telomere Length in Adipose Tissue and Leukocytes and its Association with Postsurgical Weight Loss.

Obesity (Silver Spring, Md.), 28(12):2424-2430.

OBJECTIVE: The aim of this study was to determine the relationship between telomere length (TL) in subcutaneous adipose tissue (SAT), visceral adipose tissues (VAT), and leukocytes, as well as to examine the associations of TL in these tissues with postsurgical weight loss in Asians with severe obesity.

METHODS: Presurgery TL was measured in leukocytes, SAT, and VAT of 91 patients who underwent weight loss surgery. Correlation between TL in multiple tissues was assessed using Pearson correlation. The association of presurgery TL and postsurgical weight loss at 6 or 12 months, expressed as a percentage of weight loss, was determined using linear regression in 70 patients.

RESULTS: Telomeres were longer in VAT compared with those in leukocytes and SAT (P < 0.001) but were highly correlated between tissues. The strongest correlation was observed between TL in VAT and leukocytes (r = 0.739, P = 6.22 × 10-17). Compared with individuals in the highest tertile, those in the lowest tertile of VAT TL showed greater weight loss (β = 6.23, SE = 3.10, P = 0.044) independent of age, sex, ethnicity, types of surgery, diabetes condition, preoperative BMI, and follow-up period.

CONCLUSIONS: Among patients with severe obesity, TL in leukocytes and adipose tissue was highly correlated. However, there was variability in the association of TL in these tissues with weight loss after surgery.

RevDate: 2020-11-24

Wight DJ, Aimola G, Aswad A, et al (2020)

Unbiased optical mapping of telomere-integrated endogenous human herpesvirus 6.

Proceedings of the National Academy of Sciences of the United States of America pii:2011872117 [Epub ahead of print].

Next-generation sequencing technologies allowed sequencing of thousands of genomes. However, there are genomic regions that remain difficult to characterize, including telomeres, centromeres, and other low-complexity regions, as well as transposable elements and endogenous viruses. Human herpesvirus 6A and 6B (HHV-6A and HHV-6B) are closely related viruses that infect most humans and can integrate their genomes into the telomeres of infected cells. Integration also occurs in germ cells, meaning that the virus can be inherited and result in individuals harboring the virus in every cell of their body. The integrated virus can reactivate and cause disease in humans. While it is well established that the virus resides in the telomere region, the integration locus is poorly defined due to the low sequence complexity (TTAGGG)n of telomeres that cannot be easily resolved through sequencing. We therefore employed genome imaging of the integrated HHV-6A and HHV-6B genomes using whole-genome optical site mapping technology. Using this technology, we identified which chromosome arm harbors the virus genome and obtained a high-resolution map of the integration loci of multiple patients. Surprisingly, this revealed long telomere sequences at the virus-subtelomere junction that were previously missed using PCR-based approaches. Contrary to what was previously thought, our technique revealed that the telomere lengths of chromosomes harboring the integrated virus genome were comparable to the other chromosomes. Taken together, our data shed light on the genetic structure of the HHV-6A and HHV-6B integration locus, demonstrating the utility of optical mapping for the analysis of genomic regions that are difficult to sequence.

RevDate: 2020-11-23

Tschirren B, Romero-Haro AÁ, Zahn S, et al (2020)

Sex-specific effects of experimental ectoparasite infestation on telomere length in great tit nestlings.

Journal of evolutionary biology [Epub ahead of print].

Telomere length is a biomarker of biological ageing and lifespan in various vertebrate taxa. Evidence is accumulating that telomeres shorten more rapidly when an individual is exposed to environmental stressors. Parasites are potent selective agents that can cause physiological stress directly or indirectly through the activation of the host's immune system. Yet to date, empirical evidence for a role of parasites in telomere dynamics in natural populations is limited. Here we show experimentally that exposure to ectoparasitic hen fleas (Ceratophyllus gallinae) during growth results in shorter telomeres in female, but not male, great tit (Parus major) nestlings. Females had longer telomeres than males when growing up in experimentally deparasitized nests but, likely because of the sex-specific effects of ectoparasitism on telomere length, this sexual dimorphism was absent in birds growing up in experimentally infested nests. Our results provide the first experimental evidence for a role of ectoparasitism in telomere dynamics in a natural vertebrate population, and suggest that the costs of infection manifest in sex-specific ways.

RevDate: 2020-11-22

Isaevska E, Moccia C, Asta F, et al (2020)

Exposure to ambient air pollution in the first 1000 days of life and alterations in the DNA methylome and telomere length in children: a systematic review.

Environmental research pii:S0013-9351(20)31401-8 [Epub ahead of print].

BACKGROUND: Exposure to air pollution during the first 1000 days of life (from conception to the 2nd year of life) might be of particular relevance for long-term child health. Changes in molecular markers such as DNA methylation and telomere length could underlie the association between air pollution exposure and pollution-related diseases as well as serve as biomarkers for past exposure. The objective of this systematic review was to assess the association between air pollution exposure during pregnancy and the first two years of life and changes in DNA methylation or telomere length in children.

METHODS: PubMed was searched in October 2020 by using terms relative to ambient air pollution exposure, DNA methylation, telomere length and the population of interest: mother/child dyads and children. Screening and selection of the articles was completed independently by two reviewers. Thirty-two articles matched our criteria. The majority of the articles focused on gestational air pollution exposure and measured DNA methylation/telomere length in newborn cord blood or placental tissue, to study global, candidate-gene or epigenome-wide methylation patterns and/or telomere length. The number of studies in children was limited.

RESULTS: Ambient air pollution exposure during pregnancy was associated with global loss of methylation in newborn cord blood and placenta, indicating the beginning of the pregnancy as a potential period of susceptibility. Candidate gene and epigenome-wide association studies provided evidence that gestational exposure to air pollutants can lead to locus-specific changes in methylation, in newborn cord blood and placenta, particularly in genes involved in cellular responses to oxidative stress, mitochondrial function, inflammation, growth and early life development. Telomere length shortening in newborns and children was seen in relation to gestational pollutant exposure.

CONCLUSIONS: Ambient air pollution during pregnancy is associated with changes in both global and locus-specific DNA methylation and with telomere length shortening. Future studies need to test the robustness of the association across different populations, to explore potential windows of vulnerability and assess the role of the methylation and telomere length as mediators in the association between early exposure to ambient air pollutants and specific childhood health outcomes.

RevDate: 2020-11-22

Takahashi S, Arima H, Nakano M, et al (2020)

Telomere shortening as a stress-related biomarker in children exposed to maternal chronic stress in utero measured 7 years after the Great East Japan Earthquake.

Psychiatry research pii:S0165-1781(20)33226-1 [Epub ahead of print].

Seven years after the Great East Japan Earthquake, we investigated telomeres as a potential biomarker of maternal chronic stress in children according to the timing of exposure to the disaster. The subjects were children aged 5-9 years living in Rikuzentakata, Japan. Relative telomere length (rTL) was measured with PCR in saliva samples. The partial regression coefficient of the rTL was significantly shorter in the group of children conceived after the disaster than in the children who were in utero on the day of the disaster. Telomere length should be investigated as a biomarker for assessing disaster-related trauma in future studies.

RevDate: 2020-11-21

T Baltrus P, Li C, A H Gaglioti (2020)

Having a Usual Source of Care Is Associated with Longer Telomere Length in a National Sample of Older Adults.

Journal of the American Board of Family Medicine : JABFM, 33(6):832-841.

OBJECTIVE: To provide a potential biological, mechanistic link for the well-established association between primary care access and reduced mortality, this study sought to measure the impact of having a usual source of health care on leukocyte telomere length (LTL).

DATA SOURCES: Our study population included 3202 participants aged 50 to 84 years from National Health and Nutrition Examination Survey 1999 to 2001.

STUDY DESIGN: Cross-sectional Study. LTLs between people with and without a usual source of care were compared using unadjusted and adjusted linear regression models. Fully adjusted models accounted for demographic characteristics, health conditions, and health behaviors.

PRINCIPAL FINDINGS: After controlling for individual factors, health conditions, and health behaviors, people who had a usual source of health care had significantly longer LTL (β = 89.8 base pairs, P-value = .005) compared with those without a usual source of care; corresponding to approximately 7 years of life.

CONCLUSIONS: Having a usual source of health care is associated with longer LTL among older adults. This study provides a potential biologic link for the noted association between primary care access and reduced mortality that has been observed at the individual and population level.

RevDate: 2020-11-21

Seehusen DA, MA Bowman (2020)

Must-Read Family Medicine Research-Glucosamine/Chondroitin Supplements and Mortality, Telomere Length and the Doctor-Patient Relationship, Reducing Opioid Use, and More.

Journal of the American Board of Family Medicine : JABFM, 33(6):823-826.

This issue of the Journal contains some exceptional research articles. A few are truly "must-reads," including a fascinating look at the relationship between having a usual source of care and telomere length. Glucosamine/chrondroitin supplementation seems to be helpful for more than just arthritis pain. There is a very practical advice on keeping patients discharged from the emergency department out of the hospital and on reducing patient requests for inappropriate antibiotics. This issue also features 5 articles addressing how family physicians can combat the opioid epidemic. Three articles highlight research on diabetes and another 3 on breast cancer. Payment reform, dermoscopy, and telemedicine are among many other topics covered.

RevDate: 2020-11-21

Li R, Li S, Pan M, et al (2020)

Physical activity attenuated the association of air pollutants with telomere length in rural Chinese adults.

The Science of the total environment pii:S0048-9697(20)37022-4 [Epub ahead of print].

BACKGROUND: Exposure to air pollutants (nitrogen dioxide (NO2) and particulate matters (PMs)) or physical inactivity is linked to telomere length (TL) shortening. However, there is a lack of research on combined effects of either NO2 or PMs and physical activity (PA) on TL. This study aimed to explore the joint associations of air pollutants (NO2 or PMs) and PA with relative TL in rural Chinese adults.

METHODS: This study was conducted among 2704 participants aged 18-79 years in rural China. Concentrations of NO2 and PMs (PM with an aerodynamics diameter ≤ 1.0 μm (PM1), ≤2.5 μm (PM2.5) or ≤10 μm (PM10)) were estimated using random forest models incorporated with satellites data, meteorological data, and land use information. Relative TL of each participant was measured by a quantitative real-time polymerase chain reaction. Linear regression models were applied to examine the independent associations between PA, NO2 or PMs and relative TL. Interaction plots were used to depict the altered associations between NO2, PM1, PM2.5, or PM10 and relative TL along with increasing PA levels.

RESULTS: Each 1 μg/m3 increment in NO2, PM1, PM2.5, or PM10 was associated with a 0.038 (95% confidence intervals (CI): -0.044, -0.033), 0.036 (95% CI: -0.041, -0.031), 0.052 (95% CI: -0.059, -0.045), or 0.022 (95% CI: -0.025, -0.019) decrease in relative TL among all participants; similar findings were observed among normal glucose tolerance or impaired fasting glucose (IFG) participants as well as type 2 diabetes mellitus (T2DM) patients. PA at certain levels counteracted the association of air pollutants (NO2, PM1, PM2.5, and PM10) with relative TL among IFG participants or T2DM patients.

CONCLUSIONS: Long-term exposure to NO2 and PMs was associated with relative TL shortening and these effects may be counteracted by PA at certain levels in IFG participants or T2DM patients.

RevDate: 2020-11-20

Nathan V, Johansson PA, Palmer JM, et al (2020)

A rare missense variant in protection of telomeres 1 (POT1) predisposes to a range of haematological malignancies.

RevDate: 2020-11-20

Lee KH, M Kimmel (2020)

Stationary Distribution of Telomere Lengths in Cells with Telomere Length Maintenance and its Parametric Inference.

Bulletin of mathematical biology, 82(12):150 pii:10.1007/s11538-020-00811-1.

Telomeres are nucleotide caps located at the ends of each eukaryotic chromosome. Under normal physiological conditions as well as in culture, they shorten during each DNA replication round. Short telomeres initiate a proliferative arrest of cells termed 'replicative senescence'. However, cancer cells possessing limitless replication potential can avoid senescence by the telomere maintenance mechanism, which offsets telomeric loss. Therefore, cancer cells have sufficiently long telomeres even though their lengths are significantly shorter than their normal counterparts. This implies that the attrition and elongation rates play crucial roles in deciding whether and when cells ultimately become carcinogenic. In this research, we propose a concise mathematical model that shows the shortest telomere length at each cell division and prove mathematical conditions related to the attrition and elongation rates, which are necessary and sufficient for the existence of stationary distribution of telomere lengths. Moreover, we estimate the parameters of the telomere length maintenance process based on frequentist and Bayesian approaches. This study expands our knowledge of the mathematical relationship between the telomere attrition and elongation rates in cancer cells, which is important because the telomere length dynamics is a useful biomarker of cancer diagnosis and prognosis.

RevDate: 2020-11-20

Justet A, Klay D, Porcher R, et al (2020)

Safety and efficacy of pirfenidone and nintedanib in patients with Idiopathic Pulmonary Fibrosis and carrying a telomere related gene mutation.

RevDate: 2020-11-19

Bicanova L, Kreilmeier-Berger T, Reifinger M, et al (2020)

Prevalence and potentially prognostic value of C-circles associated with alternative lengthening of telomeres in canine appendicular osteosarcoma.

Veterinary and comparative oncology [Epub ahead of print].

Alternative lengthening of telomeres (ALT) is a telomerase-independent telomere maintenance mechanism (TMM) with high prevalence in human osteosarcomas but remains unknown in canine osteosarcomas. The aim of this study was to evaluate the prevalence of ALT by detection of extra-chromosomal circles of telomeric DNA and to assess clinical outcome in canine patients with spontaneous occurring appendicular osteosarcoma. Fifty dogs with histopathological confirmed osteosarcomas were included into this study. Medical records were retrospectively analyzed for patient characteristics, oncologic therapy and survival. DNA was isolated from archived FFPE tumor tissue specimens and applied for C- and G-circle assay (CCA and GCA) and for telomeric content (TC) measurement with radiolabeled probes. ALT activity was detected for 10 of 50 (20%) cases by CCA. Four CCA positive cases were detected even with input DNA below 1ng and demonstrated the high sensitivity of CCA for canine tumors. G-circles and TC were not suitable to distinguish CCA positive and negative cases. CCA-status showed an association with male gender and Rottweiler breed. Dogs with CCA positive osteosarcomas had shorter overall survival times than patients with CCA- tumors and CCA-status was a significant prognostic factor besides treatment in the Cox proportional hazard model. These findings make canine osteosarcomas an interesting model for comparative TMM research, but future studies are warranted to investigate if CCA-status can serve as novel prognostic marker. This article is protected by copyright. All rights reserved.

RevDate: 2020-11-19

Salas-Huetos A, Tüttelmann F, Wyrwoll MJ, et al (2020)

Disruption of human meiotic telomere complex genes TERB1, TERB2 and MAJIN in men with non-obstructive azoospermia.

Human genetics pii:10.1007/s00439-020-02236-1 [Epub ahead of print].

Non-obstructive azoospermia (NOA), the lack of spermatozoa in semen due to impaired spermatogenesis affects nearly 1% of men. In about half of cases, an underlying cause for NOA cannot be identified. This study aimed to identify novel variants associated with idiopathic NOA. We identified a nonconsanguineous family in which multiple sons displayed the NOA phenotype. We performed whole-exome sequencing in three affected brothers with NOA, their two unaffected brothers and their father, and identified compound heterozygous frameshift variants (one novel and one extremely rare) in Telomere Repeat Binding Bouquet Formation Protein 2 (TERB2) that segregated perfectly with NOA. TERB2 interacts with TERB1 and Membrane Anchored Junction Protein (MAJIN) to form the tripartite meiotic telomere complex (MTC), which has been shown in mouse models to be necessary for the completion of meiosis and both male and female fertility. Given our novel findings of TERB2 variants in NOA men, along with the integral role of the three MTC proteins in spermatogenesis, we subsequently explored exome sequence data from 1495 NOA men to investigate the role of MTC gene variants in spermatogenic impairment. Remarkably, we identified two NOA patients with likely damaging rare homozygous stop and missense variants in TERB1 and one NOA patient with a rare homozygous missense variant in MAJIN. Available testis histology data from three of the NOA patients indicate germ cell maturation arrest, consistent with mouse phenotypes. These findings suggest that variants in MTC genes may be an important cause of NOA in both consanguineous and outbred populations.

RevDate: 2020-11-18

Tang J, Wu J, Zhu R, et al (2020)

Reversible photo-regulation on the folding/unfolding of telomere G-quadruplexes with solid-state nanopores.

The Analyst [Epub ahead of print].

The formation of G-quadruplexes (G4) in human telomere and other important biological regions inhibits the replication and transcription of DNA, thereby influencing further cell proliferation. The investigation of G4 formation and unfolding is vital for understanding their modulation in biological processes and life science. Photo regulation is a facile and sensitive approach for monitoring the structures of biomacromolecules and material surface properties. The nanopore-based technique is also prevalent for label-free single-molecule characterization with high accuracy. This study provides a combination of solid-state nanopore technology with light-switch as a platform for the modulation of human telomere G4 formation and splitting under switchable light exposure. The introduction of molecular switch, namely azobenzene moiety at different positions of the DNA sequence influences the formation and stability of G4. Three azobenzenes immobilized on each of the G-quartet plane (hTelo-3azo-p) or four azobenzenes on the same plane (hTelo-4azo-4p) of the human telomere G4 sequence realized the reversible control of G4 folding/unfolding at the temporal scale upon photo regulation, and the formation and splitting of G4 with hTelo-4azo-4p is slower and not thorough compared to that with hTelo-3azo-p due to the coplanar steric hindrance. Moreover, the G4 formation recorded with the combined nanopore and photo-responsive approach was also characterized with fluorescence, and the variation in the fluorescence intensity of the NMM and G4 complex exhibited a different tendency under reverse light irradiation due to the distinct interactions of NMM with the azobenzene-modified G4. Our study demonstrated a controllable and sensitive way for the manipulation of G4 structures, which will be inspiring for the intervention of G4-related cell senescence, cancer diagnosis and drug exploration.

RevDate: 2020-11-18

Hachmo Y, Hadanny A, Abu Hamed R, et al (2020)

Hyperbaric oxygen therapy increases telomere length and decreases immunosenescence in isolated blood cells : a prospective trial.

Aging, 12: pii:202188 [Epub ahead of print].

INTRODUCTION: Aging is characterized by the progressive loss of physiological capacity. At the cellular level, two key hallmarks of the aging process include telomere length (TL) shortening and cellular senescence. Repeated intermittent hyperoxic exposures, using certain hyperbaric oxygen therapy (HBOT) protocols, can induce regenerative effects which normally occur during hypoxia. The aim of the current study was to evaluate whether HBOT affects TL and senescent cell concentrations in a normal, non-pathological, aging adult population.

METHODS: Thirty-five healthy independently living adults, aged 64 and older, were enrolled to receive 60 daily HBOT exposures. Whole blood samples were collected at baseline, at the 30th and 60th session, and 1-2 weeks following the last HBOT session. Peripheral blood mononuclear cells (PBMCs) telomeres length and senescence were assessed.

RESULTS: Telomeres length of T helper, T cytotoxic, natural killer and B cells increased significantly by over 20% following HBOT. The most significant change was noticed in B cells which increased at the 30th session, 60th session and post HBOT by 25.68%±40.42 (p=0.007), 29.39%±23.39 (p=0.0001) and 37.63%±52.73 (p=0.007), respectively. There was a significant decrease in the number of senescent T helpers by -37.30%±33.04 post-HBOT (P<0.0001). T-cytotoxic senescent cell percentages decreased significantly by -10.96%±12.59 (p=0.0004) post-HBOT. In conclusion, the study indicates that HBOT may induce significant senolytic effects including significantly increasing telomere length and clearance of senescent cells in the aging populations.

RevDate: 2020-11-18

Cicconi A, Rai R, Xiong X, et al (2020)

Microcephalin 1/BRIT1-TRF2 interaction promotes telomere replication and repair, linking telomere dysfunction to primary microcephaly.

Nature communications, 11(1):5861 pii:10.1038/s41467-020-19674-0.

Telomeres protect chromosome ends from inappropriately activating the DNA damage and repair responses. Primary microcephaly is a key clinical feature of several human telomere disorder syndromes, but how microcephaly is linked to dysfunctional telomeres is not known. Here, we show that the microcephalin 1/BRCT-repeats inhibitor of hTERT (MCPH1/BRIT1) protein, mutated in primary microcephaly, specifically interacts with the TRFH domain of the telomere binding protein TRF2. The crystal structure of the MCPH1-TRF2 complex reveals that this interaction is mediated by the MCPH1 330YRLSP334 motif. TRF2-dependent recruitment of MCPH1 promotes localization of DNA damage factors and homology directed repair of dysfunctional telomeres lacking POT1-TPP1. Additionally, MCPH1 is involved in the replication stress response, promoting telomere replication fork progression and restart of stalled telomere replication forks. Our work uncovers a previously unrecognized role for MCPH1 in promoting telomere replication, providing evidence that telomere replication defects may contribute to the onset of microcephaly.

RevDate: 2020-11-18

Ferrer A, Mangaonkar AA, Stroik S, et al (2020)

Functional validation of TERT and TERC variants of uncertain significance in patients with short telomere syndromes.

Blood cancer journal, 10(11):120 pii:10.1038/s41408-020-00386-z.

RevDate: 2020-11-17

Criscuolo F, Pillay N, Zahn S, et al (2020)

Seasonal variation in telomere dynamics in African striped mice.

Oecologia pii:10.1007/s00442-020-04801-x [Epub ahead of print].

Telomere shortening has been used as an indicator of aging and is believed to accelerate under harsh environmental conditions. This can be attributed to the fact that telomere shortening has often been regarded as non-reversible and negatively impacting fitness. However, studies of laboratory mice indicate that they may be able to repair telomere loss to recover from environmental harshness, as indicated by recent studies in hibernating rodents. We studied seasonal variation in telomere dynamics in African striped mice (Rhabdomys pumilio) living in a highly seasonal environment. In our annual species, individuals born in the moist spring (high food availability) need to survive the harsh dry summer (low food availability) to be able to reproduce in the following spring. We studied the effect of the harsh dry vs. the benign moist season on telomere dynamics. We also tested if telomere length or the rate of change in telomere length over the dry season predicted the probablity of dissapearance from the population at the same time. Male, but not female, stripped mice showed age-related telomere erosion. Telomeres were longer at the beginning of the dry season compared to the rest of the year. Telomeres increased significantly in length during the moist season. Neither telomere length at the onset of the dry season nor telomere loss over the dry season predicted whether or not individuals disappeared. In conclusion, our data suggest that seasonal attrition and restoring of telomeres also occurs in non-hibernating wild rodents living in hot food restricted environments.

RevDate: 2020-11-17

Gaikwad AS, Mahmood R, B R, et al (2020)

Evaluation of telomere length and genotoxicity among asphalt associated workers.

Mutation research, 858-860:503255.

There are contradictory reports about bitumen exposure and malignancy risk worldwide. Also, the evidence for genotoxicity risk among workers occupationally exposed to asphalt is insufficient. The study intended to evaluate particulate matter 10 (PM10) at the workplace and biomarkers of genotoxicity effects among a group of asphalt workers in and around Bangalore, India. This study involved a total of 107 participants (54 exposed group and 53 unexposed control group). To evaluate the genotoxicity, the urinary 8-OHdG and relative telomere length as oxidative damage while micronucleus (MN) assay for cytogenetic damage was carried out during the study. The majority of workers have reported health complaints and 57.4% of them were not using any personal protective equipments (PPE's). The level of PM10 detected was 104 ± 9.5 μg/m3 and 619 ± 22.7 μg/m3 in the road paving and asphalt mixing sites respectively. The biomonitoring study observed a highly significant (p = <0.001) increase in the level of 8-hydroxy-2-deoxyguanosine (8-OHdG) in the exposed group (23.17 ± 8.65 ng/mg creatinine) compared to the control (13.6 ± 7.12 ng/mg creatinine), revealed age significant associated and non-smoking borderline significant associated for oxidative stress. The relative telomere length (TL) analysis revealed its highly significant (p = 0.004) reduction in the exposed group, adjusted mean 0.95 (95% CI 0.83-1.07) compared to the control 1.06 (95% CI 0.91-1.26). The job category (p = 0.028), non-smoking (p = 0.026), and tobacco chewing (p = 0.013) were associated with reduced relative TL in the asphalt exposed group. In cytogenotoxicity analysis, the mean micronucleus (MN) frequency per 100 cells in the exposed group (26.46 ± 19.8) was significantly (p = <0.001) increased over the control group (8.56 ± 7.18). Neither smoking habit nor age appeared to influence the MN frequencies in either group. In the present study, we have demonstrated genetic damage in workers occupationally exposed to asphalt and particulate matter, raising concern for an increased risk of malignancy in these workers.

RevDate: 2020-11-17

Xue Y, Guo X, Huang X, et al (2020)

Shortened telomere length in peripheral blood leukocytes of patients with lung cancer, chronic obstructive pulmonary disease in a high indoor air pollution region in China.

Mutation research, 858-860:503250.

Lung cancer and chronic obstructive pulmonary disease (COPD) are closely linked diseases. In Xuanwei, China, the extremely high incidence and mortality rates of lung cancer and COPD are associated with exposure to household smoky coal burning. Previous studies found that telomere length was related to lung disease. The objective of this study is to investigate the relationship of peripheral blood leukocyte telomere length to both lung cancer and COPD, as well as indoor coal smoke exposure in Xuanwei. We measured telomere length using quantitative polymerase chain reaction (qPCR) in peripheral blood leukocytes of 216 lung cancer patients, 296 COPD patients, and 426 healthy controls from Xuanwei. The telomere length ratios (mean ± SD) in patients with lung cancer (0.76 ± 0.35) and COPD (0.81 ± 0.35) were significantly shorter than in that of controls (0.95 ± 0.39). Individuals with the shortest tertile telomere length had 3.90- and 4.54-fold increased risks of lung cancer and COPD, respectively, compared with individuals with the longest tertile telomere length. No correlation was found between telomere length and pack-years of smoking. In healthy subjects, coal smoke exposure level affected telomere length. Lung function was positively and negatively associated with telomere length and environmental exposure, respectively, when combination the control and COPD groups. The result suggests that shortened telomere length in peripheral blood leukocytes was associated with lung cancer and COPD and might be affected by coal smoke exposure level in Xuanwei. Whether variation in telomere length caused by environmental exposure has a role in lung cancer and COPD development and exacerbation needs further research.

RevDate: 2020-11-17

Gadji M, Mathur S, Bélanger B, et al (2020)

Three-Dimensional Nuclear Telomere Profiling as a Biomarker for Recurrence in Oligodendrogliomas: A Pilot Study.

International journal of molecular sciences, 21(22): pii:ijms21228539.

Mechanisms of recurrence in oligodendrogliomas are poorly understood. Recurrence might be driven by telomere dysfunction-mediated genomic instability. In a pilot study, we investigated ten patients with oligodendrogliomas at the time of diagnosis (first surgery) and after recurrence (second surgery) using three-dimensional nuclear telomere analysis performed with quantitative software TeloView® (Telo Genomics Corp, Toronto, Ontario, Canada). 1p/19q deletion status of each patient was determined by fluorescent in situ hybridization on touch preparation slides. We found that a very specific 3D telomeric profile was associated with two pathways of recurrence in oligodendrogliomas independent of their 1p/19q status: a first group of 8 patients displayed significantly different 3D telomere profiles between both surgeries (p < 0.0001). Their recurrence happened at a mean of 231.375 ± 117.42 days and a median time to progression (TTP) of 239 days, a period defined as short-term recurrence; and a second group of three patients displayed identical 3D telomere profiles between both surgery samples (p > 0.05). Their recurrence happened at a mean of 960.666 ± 86.19 days and a median TTP of 930 days, a period defined as long-term recurrence. Our results suggest a potential link between nuclear telomere architecture and telomere dysfunction with time to recurrence in oligodendrogliomas, independently of the 1p/19q status.

RevDate: 2020-11-16

Duckworth A, Gibbons MA, Allen RJ, et al (2020)

Telomere length and risk of idiopathic pulmonary fibrosis and chronic obstructive pulmonary disease: a mendelian randomisation study.

The Lancet. Respiratory medicine pii:S2213-2600(20)30364-7 [Epub ahead of print].

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease accounting for 1% of UK deaths. In the familial form of pulmonary fibrosis, causal genes have been identified in about 30% of cases, and a majority of these causal genes are associated with telomere maintenance. Prematurely shortened leukocyte telomere length is associated with IPF and chronic obstructive pulmonary disease (COPD), a disease with similar demographics and shared risk factors. Using mendelian randomisation, we investigated evidence supporting a causal role for short telomeres in IPF and COPD.

METHODS: Mendelian randomisation inference of telomere length causality was done for IPF (up to 1369 cases) and COPD (13 538 cases) against 435 866 controls of European ancestry in UK Biobank. Polygenic risk scores were calculated and two-sample mendelian randomisation analyses were done using seven genetic variants previously associated with telomere length, with replication analysis in an IPF cohort (2668 cases vs 8591 controls) and COPD cohort (15 256 cases vs 47 936 controls).

FINDINGS: In the UK Biobank, a genetically instrumented one-SD shorter telomere length was associated with higher odds of IPF (odds ratio [OR] 4·19, 95% CI 2·33-7·55; p=0·0031) but not COPD (1·07, 0·88-1·30; p=0·51). Similarly, an association was found in the IPF replication cohort (12·3, 5·05-30·1; p=0·0015) and not in the COPD replication cohort (1·04, 0·71-1·53; p=0·83). Meta-analysis of the two-sample mendelian randomisation results provided evidence inferring that shorter telomeres cause IPF (5·81 higher odds of IPF, 95% CI 3·56-9·50; p=2·19 × 10-12). There was no evidence to infer that telomere length caused COPD (OR 1·07, 95% CI 0·90-1·27; p=0·46).

INTERPRETATION: Cellular senescence is hypothesised as a major driving force in IPF and COPD; telomere shortening might be a contributory factor in IPF, suggesting divergent mechanisms in COPD. Defining a key role for telomere shortening enables greater focus in telomere-related diagnostics, treatments, and the search for a cure in IPF. Investigation of therapies that improve telomere length is warranted.

FUNDING: Medical Research Council.

RevDate: 2020-11-16

Gao Y, Wei Y, Zhou X, et al (2020)

Assessing the Relationship Between Leukocyte Telomere Length and Cancer Risk/Mortality in UK Biobank and TCGA Datasets With the Genetic Risk Score and Mendelian Randomization Approaches.

Frontiers in genetics, 11:583106.

Background: Telomere length is an important indicator of tumor progression and survival for cancer patients. Previous work investigated the associations between genetically predicted telomere length and cancers; however, the types of cancers investigated in those studies were relatively limited or the telomere length-associated genetic variants employed often came from genome-wide association studies (GWASs) with small sample sizes.

Methods: We constructed the genetic risk score (GRS) for leukocyte telomere length based on 17 associated genetic variants available from the largest telomere length GWAS up to 78,592 individuals. Then, a comprehensive analysis was undertaken to evaluate the association between the constructed GRS and the risk or mortality of a wide range of cancers [i.e., 37 cancers in the UK Biobank and 33 cancers in The Cancer Genome Atlas (TCGA)]. We further applied the two-sample Mendelian randomization (MR) to estimate the causal effect of leukocyte telomere length on UK Biobank cancers via summary statistics.

Results: In the UK Biobank dataset, we found that the GRS of leukocyte telomere length was associated with a decreased risk of nine types of cancer (i.e., significant association with multiple myeloma, chronic lymphocytic leukemia, kidney/renal cell cancer, bladder cancer, malignant melanoma, basal cell carcinoma, and prostate cancer and suggestive association with sarcoma/fibrosarcoma and Hodgkin's lymphoma/Hodgkin's disease). In addition, we found that the GRS was suggestively associated with an increased risk of leukemia. In the TCGA dataset, we observed suggestive evidence that the GRS was associated with a high death hazard of rectum adenocarcinoma (READ), sarcoma (SARC), and skin cutaneous melanoma (SKCM), while the GRS was associated with a low death hazard of kidney renal papillary cell carcinoma (KIRP). The results of MR further supported the association for leukocyte telomere length on the risk of malignant melanoma, Hodgkin's lymphoma/Hodgkin's disease, chronic lymphocytic leukemia and multiple myeloma.

Conclusion: Our study reveals that telomere played diverse roles in different types of cancers. However, further validations in large-scale prospective studies and deeper investigations of the biologic mechanisms are warranted.

RevDate: 2020-11-16

Linghui D, Shi Q, Chi C, et al (2020)

The Association Between Leukocyte Telomere Length and Cognitive Performance Among the American Elderly.

Frontiers in aging neuroscience, 12:527658.

Background: Age-related cognitive decline begins in middle age and persists with age. Leukocyte telomere length (LTL) decreases with age and is enhanced by inflammation and oxidative stress. However, whether shorter LTL correlates with cognitive decline remains controversial.

Aims: We aimed to investigate the relationship between LTL and cognitive decline in the American elderly.

Methods: We used data from the 1999 to 2002 U.S. National Health and Nutrition Examination Survey (NHANES). We included participants aged 65-80 with available data on LTL and cognitive assessments. The cognitive function assessment used the digit symbol substitution test (DSST). We applied multivariate modeling to estimate the association between LTL and cognitive performance. Additionally, to ensure robust data analysis, we converted LTL into categorical variables through quartile and then calculated the P for trend.

Results: After adjusting for age, cardiovascular disease (CAD) score, gender, race, body mass index (BMI), and educational level, LTL showed a positive correlation with DSST score (odds ratio [OR] 3.47 [0.14, 6.79], P = 0.04). Additionally, to further quantify the LTL-DSST interaction, we found a similar trend when LTL was regarded as a categorical variable (quartile) (P for trend = 0.03).

Conclusion: LTL was associated with cognitive capabilities among the elderly, implying that LTL might be a biomarker of cognitive aging.

RevDate: 2020-11-15

El Assar M, Angulo J, Carnicero JA, et al (2020)

Association between telomere length, frailty and death in older adults.

GeroScience pii:10.1007/s11357-020-00291-0 [Epub ahead of print].

Frailty is considered a clinical marker of functional ageing. Telomere length (TL) has been proposed as a biomarker of biological age but its role in human ageing is controversial. The main aim of the study was to evaluate the longitudinal association of TL with incident frailty and mortality in two cohorts of Spanish community-dwelling older adults. TL was determined at baseline in blood samples from older adults included in Toledo Study for Healthy Aging and ENRICA cohorts while frailty was determined by frailty phenotype (FP) at baseline and at follow-up (3.5 years). Deaths occurring during follow-up were also recorded. Associations of TL with frailty and mortality were analysed by logistic regression with progressive adjustment. Data were separately analysed in the two cohorts and in all subjects by performing a meta-analysis. TL was not different between frail and non-frail subjects. Longer telomeres were not associated with lower risk of prevalent frailty. Similarly, TL at baseline failed to predict incident frailty (OR: 1.04 [0.88-1.23]) or even the development of a new FP criterion (OR: 0.97 [0.90-1.05]) at follow-up. Lack of association was also observed when analysing the development of specific FP criteria. Finally, while frailty at baseline was significantly associated with higher risk of death at follow-up (OR: 4.08 [1.97-8.43], p < 0.001), TL did not significantly change the mortality risk (OR: 1.05 [0.94-1.16]). Results show that TL does not predict incident frailty or mortality in older adults. This suggests that TL is not a reliable biomarker of functional age.

RevDate: 2020-11-14

Mangosh TL, Awadallah WN, Grabowska MM, et al (2020)

SLX4IP promotes telomere maintenance in androgen receptor-independent castration-resistant prostate cancer through ALT-like telomeric PML localization.

Molecular cancer research : MCR pii:1541-7786.MCR-20-0314 [Epub ahead of print].

In advanced prostate cancer, resistance to androgen deprivation therapy is achieved through numerous mechanisms, including loss of the androgen receptor (AR) allowing for AR-independent growth. Therapeutic options are limited for AR-independent castration-resistant prostate cancer (CRPC), and defining mechanisms critical for survival is of utmost importance for targeting this lethal disease. Our studies focus on identifying telomere maintenance mechanism (TMM) hallmarks adopted by CRPC to promote survival. TMMs are responsible for telomere elongation to instill replicative immortality and prevent senescence, with the two TMM pathways available being telomerase and alternative lengthening of telomeres (ALT). Here, we show that AR-independent CRPC demonstrates an atypical ALT-like phenotype with variable telomerase expression and activity, whereas AR-dependent models lack discernible ALT hallmarks. Additionally, AR-independent CRPC cells exhibited elevated levels of SLX4IP, a protein implicated in promoting ALT. SLX4IP overexpression in AR-dependent C4-2B cells promoted an ALT-like phenotype and telomere maintenance. SLX4IP knockdown in AR-independent DU145 and PC-3 cells led to ALT-like hallmark reduction, telomere shortening, and induction of senescence. In PC-3 xenografts, this effect translated to reduced tumor volume. Using an in vitro model of AR-independent progression, loss of AR in AR-dependent C4-2B cells promoted an atypical ALT-like phenotype in an SLX4IP-dependent manner. Insufficient SLX4IP expression diminished ALT-like hallmarks and resulted in accelerated telomere loss and senescence. Implications: This study demonstrates a unique reliance of AR-independent CRPC on SLX4IP-mediated ALT-like hallmarks and loss of these hallmarks induce telomere shortening and senescence, thereby impairing replicative immortality.

RevDate: 2020-11-14

Antwi SO, Bamlet WR, Cawthon RM, et al (2020)

Shorter treatment-naïve leukocyte telomere length is associated with poorer overall survival of patients with pancreatic ductal adenocarcinoma.

Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology pii:1055-9965.EPI-20-1279 [Epub ahead of print].

BACKGROUND: Critically shortened telomeres contribute to chromosomal instability and neoplastic transformation and are associated with early death of patients with certain cancer types. Shorter leukocyte telomere length (LTL) has been associated with higher risk for pancreatic ductal adenocarcinoma (PDAC) development and might be associated also with survival of patients with PDAC. We investigated the association between treatment-naïve LTL and overall survival of patients with incident PDAC.

METHODS: The study included 642 consecutively enrolled PDAC patients in the Mayo Clinic Biospecimen Resource for Pancreas Research. Blood samples were obtained at the time of diagnosis, before the start of cancer treatment, from which LTL was assayed by real-time quantitative polymerase chain reaction. LTL was modeled as a continuous variable (per-interquartile range decrease in LTL) and as a categorized variable (short, medium, long). Multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated for overall mortality using Cox proportional hazard models.

RESULTS: Shorter treatment-naïve LTL was associated with higher mortality among PDAC patients (HRcontinuous = 1.13, 95% CI: 1.01-1.28, p-value=0.03; HRshortest vs. longest LTL = 1.29, 95% CI: 1.05-1.59, Ptrend=0.01). There was evidence of a difference in the association between LTL and overall mortality by tumor stage at diagnosis; resectable tumors (HRcontinuous = 0.91, 95% CI: 0.73-1.12), locally advanced tumors (HRcontinuous = 1.29, 95% CI: 1.07-1.56), and metastatic tumors (HRcontinuous = 1.17, 95% CI: 0.96-1.42), Pinteraction=0.04.

CONCLUSIONS: Shorter treatment-naïve LTL is associated with poorer overall survival of incident PDAC patients.

IMPACT: Peripheral blood LTL might be a prognostic marker for PDAC.

RevDate: 2020-11-16

Nsereko E, Uwase A, Muvunyi CM, et al (2020)

Association between micronutrients and maternal leukocyte telomere length in early pregnancy in Rwanda.

BMC pregnancy and childbirth, 20(1):692 pii:10.1186/s12884-020-03330-y.

BACKGROUND: Exposure to environmental stressors can lead to shorter leukocyte telomere length and increase the risk of chronic diseases. Preservation of leukocyte telomere length by reducing oxidative stress exposure and reinforcing immunity may be a mechanism by which nutritional factors delay or prevent chronic disease development.

METHODS: Healthy pregnant women (aged 18-45 years) at 9-15 weeks of gestation living in Gasabo District, Kigali, Rwanda, were recruited from 10 health centers for a prospective, longitudinal study from September to October 2017 to determine possible associations between nutrition health, infectious disease and leukocyte telomere length. Anthropometric and laboratory measurements were performed using standard procedures; sociodemographic parameters and health histories were assessed via surveys, and leukocyte telomere length was assessed using quantitative PCR expressed as the ratio of a telomeric product to a single-copy gene product (T/S).

RESULTS: Mean gestational age of participants (n = 297) at enrollment was 13.04 ± 3.50 weeks, age was 28.16 ± 6.10 years and leukocyte telomere length was 1.16 ± 0.22 (T/S). Younger age; no schooling vs. primary schooling; and lower levels of ferritin, soluble transferrin receptors and retinol-binding protein were independent predictors of longer telomere length in multivariable models.

CONCLUSIONS: Leukocyte telomere length is an indicator of biological aging in pregnant Rwandan women. Maternal micronutrient status, specifically lower ferritin, soluble transferrin receptor levels, and retinol-binding protein levels were associated with longer maternal telomere length in contrast with some studies from North America and Europe. There were no associations between inflammation and infectious disease status and maternal leukocyte telomere length. Further studies are needed to enhance our understanding of the interplay between maternal nutritional status and infectious disease in relation to leukocyte telomere length in developing countries.

RevDate: 2020-11-13

Grill S, J Nandakumar (2020)

Molecular mechanisms of telomere biology disorders.

The Journal of biological chemistry pii:REV120.014017 [Epub ahead of print].

Genetic mutations that affect telomerase function or telomere maintenance result in a variety of diseases collectively called telomeropathies. This wide spectrum of disorders, which include dyskeratosis congenita (DC), pulmonary fibrosis (PF) and aplastic anemia (AA), is characterized by severely short telomeres, often resulting in hematopoietic stem cell failure in the most severe cases. Recent work has focused on understanding the molecular basis of these diseases. Mutations in the catalytic TERT and TR subunits of telomerase compromise activity, while others, such as those found in the telomeric protein TPP1, reduce the recruitment of telomerase to the telomere. Mutant telomerase-associated proteins TCAB1 and dyskerin, and the telomerase RNA maturation component PARN, affect the maturation and stability of telomerase. In contrast, disease-associated mutations in either CTC1 or RTEL1 are more broadly associated with telomere replication defects. Yet even with the recent surge in studies decoding the mechanisms underlying these diseases, a significant proportion of DC mutations remain uncharacterized or poorly understood. Here we review the current understanding of the molecular basis of telomeropathies and highlight experimental data that illustrate how genetic mutations drive telomere shortening and dysfunction in these patients. This review connects insights from both clinical and molecular studies to create a comprehensive view of the underlying mechanisms that drive these diseases. Through this, we emphasize recent advances in therapeutics and pin-point disease-associated variants that remain poorly defined in their mechanism of action. Finally, we suggest future avenues of research that will deepen our understanding of telomere biology and telomere-related disease.

RevDate: 2020-11-11

Bosquet Enlow M, Petty CR, Hacker MR, et al (2020)

Maternal psychosocial functioning, obstetric health history, and newborn telomere length.

Psychoneuroendocrinology, 123:105043 pii:S0306-4530(20)30466-2 [Epub ahead of print].

There is growing interest in elucidating the determinants of newborn telomere length, given its potential as a biomarker of lifetime disease risk affected by prenatal exposures. There is limited evidence that increased maternal stress during pregnancy predicts shorter newborn telomere length. However, the few studies published to date have been conducted primarily with small samples utilizing inconsistent definitions of maternal stress. Moreover, the potential influence of fetal sex as a moderator of maternal stress effects on newborn telomere length has been largely ignored despite compelling evidence of likely impact. In a prospective cohort study of pregnant women seeking routine prenatal care, we tested whether a range of maternal measures of stressor exposures, subjective feelings of stress, and mental health (depression, anxiety) were associated with newborn telomere length assessed from cord blood among 146 pregnant women and their newborn infants. We further examined whether the pattern of associations differed by infant sex. Sociodemographic and maternal and newborn health indicators were considered as potential covariates. When examined within the whole sample, none of the maternal psychosocial measures were associated with newborn telomere length. Among potential covariates, maternal history of smoking and preeclampsia in a previous pregnancy were negatively associated with newborn telomere length. In adjusted linear regression analyses that considered potential sex-specific effects, maternal depression, general anxiety, and pregnancy-specific anxiety symptoms were positively associated with newborn telomere length among males. Overall, the findings provide some evidence for an association between maternal psychosocial wellbeing in pregnancy and newborn telomere length in males, although in the opposite direction than previously reported. Maternal smoking and obstetric history prior to conception may be associated with shorter offspring telomere length.

RevDate: 2020-11-11

Shoeb M, Meier HCS, JM Antonini (2020)

Telomeres in toxicology: Occupational health.

Pharmacology & therapeutics pii:S0163-7258(20)30273-4 [Epub ahead of print].

The ends of chromosomes shorten at each round of cell division, and this process is thought to be affected by occupational exposures. Occupational hazards may alter telomere length homeostasis resulting in DNA damage, chromosome aberration, mutations, epigenetic alterations and inflammation. Therefore, for the protection of genetic material, nature has provided a unique nucleoprotein structure known as a telomere. Telomeres provide protection by averting an inappropriate activation of the DNA damage response (DDR) at chromosomal ends and preventing recognition of single and double strand DNA (ssDNA and dsDNA) breaks or chromosomal end-to-end fusion. Telomeres and their interacting six shelterin complex proteins in coordination act as inhibitors of DNA damage machinery by blocking DDR activation at chromosomes, thereby preventing the occurrence of genome instability, perturbed cell cycle, cellular senescence and apoptosis. However, inappropriate DNA repair may result in the inadequate distribution of genetic material during cell division, resulting in the eventual development of tumorigenesis and other pathologies. This article reviews the current literature on the association of changes in telomere length and its interacting proteins with different occupational exposures and the potential application of telomere length or changes in the regulatory proteins as potential biomarkers for exposure and health response, including recent findings and future perspectives.

RevDate: 2020-11-11

Drosopoulos WC, Deng Z, Twayana S, et al (2020)

TRF2 Mediates Replication Initiation within Human Telomeres to Prevent Telomere Dysfunction.

Cell reports, 33(6):108379.

The telomeric shelterin protein telomeric repeat-binding factor 2 (TRF2) recruits origin recognition complex (ORC) proteins, the foundational building blocks of DNA replication origins, to telomeres. We seek to determine whether TRF2-recruited ORC proteins give rise to functional origins in telomere repeat tracts. We find that reduction of telomeric recruitment of ORC2 by expression of an ORC interaction-defective TRF2 mutant significantly reduces telomeric initiation events in human cells. This reduction in initiation events is accompanied by telomere repeat loss, telomere aberrations and dysfunction. We demonstrate that telomeric origins are activated by induced replication stress to provide a key rescue mechanism for completing compromised telomere replication. Importantly, our studies also indicate that the chromatin remodeler SNF2H promotes telomeric initiation events by providing access for ORC2. Collectively, our findings reveal that active recruitment of ORC by TRF2 leads to formation of functional origins, providing an important mechanism for avoiding telomere dysfunction and rescuing challenged telomere replication.

RevDate: 2020-11-11

Sindi S, Solomon A, Kåreholt I, et al (2020)

Telomere length change in a multidomain lifestyle intervention to prevent cognitive decline: a randomized clinical trial.

The journals of gerontology. Series A, Biological sciences and medical sciences pii:5974120 [Epub ahead of print].

BACKGROUND: Shorter leukocyte telomere length (LTL) is associated with aging and dementia. Impact of lifestyle changes on LTL, and relation to cognition and genetic susceptibility for dementia has not been investigated in randomised controlled trials (RCT).

METHODS: Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) is a 2-year RCT enrolling 1260 participants at-risk for dementia from the general population, aged 60-77 years, randomly assigned (1:1) to multidomain lifestyle intervention or control group. Primary outcome was cognitive change (Neuropsychological Test Battery NTB z-score). Relative LTL was measured using quantitative real-time polymerase chain reaction. Trial registration: NCT01041989.

RESULTS: This exploratory LTL sub-study included 756 participants (377 intervention, 379 control) with baseline and 24-month LTL measurements. Mean annual LTL change (SD) was -0.016 (0.19) in intervention, and -0.023 (0.17) in control group. Between-group difference was non-significant (unstandardised β-coefficient 0.007, 95%CI -0.015-0.030). Interaction analyses indicated better LTL maintenance among APOEε4 carriers vs non-carriers: 0.054 (95%CI 0.007-0.102); younger vs older participants: -0.005 (95%CI -0.010 ‒ -0.001); and those with more vs less healthy lifestyle changes: 0.047 (95%CI 0.005-0.089). Cognitive intervention benefits were more pronounced among participants with better LTL maintenance for executive functioning (0.227, 95%CI 0.057-0.396) and long-term memory (0.257, 95%CI 0.024 - 0.489), with a similar trend for NTB total score (0.127, 95%CI -0.011-0.264).

CONCLUSION: This is the first large RCT showing that a multidomain lifestyle intervention facilitated LTL maintenance among sub-groups of elderly at-risk for dementia, including APOEε4 carriers. LTL maintenance was associated with more pronounced cognitive intervention benefits.

RevDate: 2020-11-12

Bastos MF, Matias MST, Alonso AC, et al (2020)

Moderate levels of physical fitness maintain telomere length in non-senescent T CD8+ cells of aged men.

Clinics (Sao Paulo, Brazil), 75:e1628 pii:S1807-59322020000100303.

OBJECTIVES: Immunosenescence is an age-associated change characterized by a decreased immune response. Although physical activity has been described as fundamental for maintaining the quality of life, few studies have evaluated the effects of different levels of exercise on telomere length in aged populations. The present study aimed to analyze the effects of different levels of physical activity, classified by the Maximal oxygen consumption (VO2 max) values, on the telomere length of memory Cluster of differentiation (CD) CD4+(CD45ROneg and CD45RO+), effector CD8+CD28neg, and CD8+CD28+ T cells in aged individuals.

METHODS: Fifty-three healthy elderly men (aged 65-85 years) were included in this study. Their fitness level was classified according to the American College of Sports Medicine (ACSM) for VO2 max (mL/kg/min). Blood samples were obtained from all participants to analyze the percentage of CD3, CD4, CD8, CD28+, naïve, and subpopulations of memory T cells by using flow cytometry. Furthermore, using the Flow-FISH methodology, the CD4+CD45RO+, CD4+CD45ROneg, CD8+CD28+, and CD8+CD28negT cell telomere lengths were measured.

RESULTS: There was a greater proportion of effector memory T CD4+ cells and longer telomeres in CD8+CD28+ T cells in the moderate physical fitness group than in the other groups. There was a higher proportion of terminally differentiated memory effector T cells in the low physical fitness group.

CONCLUSION: A moderate physical activity may positively influence the telomere shortening of CD28+CD8+T cells. However, additional studies are necessary to evaluate the importance of this finding with regard to immune function responses in older men.

RevDate: 2020-11-11

Clarity C, Trowbridge J, Gerona R, et al (2020)

Associations between polyfluoroalkyl substance and organophosphate flame retardant exposures and telomere length in a cohort of women firefighters and office workers in San Francisco.

medRxiv : the preprint server for health sciences.

Background Environmental chemical exposures can affect telomere length, which in turn has been associated with adverse health outcomes including cancer. Firefighters are occupationally exposed to many hazardous chemicals and have higher rates of certain cancers. As a potential marker of effect, we assessed associations between chemical exposures and telomere length in women firefighters and office workers from San Francisco, CA. Methods We measured serum levels of polyfluoroalkyl substances (PFAS), urinary metabolites of flame retardants, including organophosphate flame retardants (OPFRs), and telomere length in peripheral blood leukocytes in women firefighters and office workers who participated in the 2014-15 Women Workers Biomonitoring Collaborative. Multiple linear regression models were used to assess associations between chemical exposures and telomere length. Results Regression results revealed significant positive associations between perfluorooctanoic acid (PFOA) and telomere length and perfluorooctanesulfonic acid (PFOS) and telomere length among the whole cohort. Models stratified by occupation showed stronger and more significant associations among firefighters as compared to office workers. Among firefighters in models adjusted for age, we found positive associations between telomere length and log-transformed PFOA (β(95%CI) = 0.57(0.12, 1.02)), PFOS (0.44 (0.05, 0.83)), and perfluorodecanoic acid (PFDA) (0.43 (0.02, 0.84)). Modeling PFAS as categories of exposure showed significant associations between perfluorononanoic acid (PFNA) and telomere length among firefighters. Significant associations between OPFR metabolites and telomere length were seen for bis(1,3-dichloro-2-propyl) phosphate (BDCPP) and telomere length among office workers (0.21(0.03, 0.40)) and bis(2-chloroethyl) phosphate (BCEP) and telomere length among firefighters (-0.14(-0.28, -0.01)). For OPFRs, the difference in the direction of effect by occupational group may be due to the disparate detection frequencies and levels of exposure between the two groups and/or potential unmeasured confounding. Conclusion Our findings suggest positive associations between PFAS and telomere length in women workers, with larger effects seen among firefighters as compared to office workers. The OPFR metabolites BDCPP and BCEP are also associated with telomere length in firefighters and office workers. Associations between chemical exposures and telomere length reported here and by others suggest mechanisms by which these chemicals may affect carcinogenesis and other adverse health outcomes.

RevDate: 2020-11-10

Boniewska-Bernacka E, Pańczyszyn A, M Klinger (2020)

Telomeres and telomerase in risk assessment of cardiovascular diseases.

Experimental cell research pii:S0014-4827(20)30614-5 [Epub ahead of print].

Telomeres are repetitive nucleoprotein structures located at the ends of chromosomes. Reduction in the number of repetitions causes cell senescence. Cells with high proliferative potential age with each replication cycle. Post-mitotic cells (e.g. cardiovascular cells) have a different aging mechanism. During the aging of cardiovascular system cells, permanent DNA damage occurs in the telomeric regions caused by mitochondrial dysfunction, which is a phenomenon independent of cell proliferation and telomere length. Mitochondrial dysfunction is accompanied by increased production of reactive oxygen species and development of inflammation. This phenomenon in the cells of blood vessels can lead to atherosclerosis development. Telomere damage in cardiomyocytes leads to the activation of the DNA damage response system, histone H2A.X phosphorylation, p53 activation and p21 and p16 protein synthesis, resulting in the SASP phenotype (senescence-associated secretory phenotype), increased inflammation and cardiac dysfunction. Cardiovascular cells show the activity of the TERT subunit of telomerase, an enzyme that prevents telomere shortening. It turns out that disrupting the activity of this enzyme can also contribute to the formation of cardiovascular diseases. Measurements of telomere length according to the "blood-muscle" model may help in the future to assess the risk of cardiovascular complications in people undergoing cardiological procedures, as well as to assess the effectiveness of some drugs.

RevDate: 2020-11-10

Stier A, Hsu BY, Marciau C, et al (2020)

Born to be young? Prenatal thyroid hormones increase early-life telomere length in wild collared flycatchers.

Biology letters, 16(11):20200364.

The underlying mechanisms of the lifelong consequences of prenatal environmental condition on health and ageing remain little understood. Thyroid hormones (THs) are important regulators of embryogenesis, transferred from the mother to the embryo. Since prenatal THs can accelerate early-life development, we hypothesized that this might occur at the expense of resource allocation in somatic maintenance processes, leading to premature ageing. Therefore, we investigated the consequences of prenatal TH supplementation on potential hallmarks of ageing in a free-living avian model in which we previously demonstrated that experimentally elevated prenatal TH exposure accelerates early-life growth. Using cross-sectional sampling, we first report that mitochondrial DNA (mtDNA) copy number and telomere length significantly decrease from early-life to late adulthood, thus suggesting that these two molecular markers could be hallmarks of ageing in our wild bird model. Elevated prenatal THs had no effect on mtDNA copy number but counterintuitively increased telomere length both soon after birth and at the end of the growth period (equivalent to offsetting ca 4 years of post-growth telomere shortening). These findings suggest that prenatal THs might have a role in setting the 'biological' age at birth, but raise questions about the nature of the evolutionary costs of prenatal exposure to high TH levels.

RevDate: 2020-11-09

Yang T, Wang H, Xiong Y, et al (2020)

Vitamin D Supplementation Improves Cognitive Function Through Reducing Oxidative Stress Regulated by Telomere Length in Older Adults with Mild Cognitive Impairment: A 12-Month Randomized Controlled Trial.

Journal of Alzheimer's disease : JAD pii:JAD200926 [Epub ahead of print].

BACKGROUND: Cognitive decline in older adults is a serious public health problem today. Association between vitamin D supplementation and cognition remains controversial.

OBJECTIVE: To determine whether a 12-month vitamin D supplementation improves cognitive function in elderly subjects with mild cognitive impairment (MCI), and whether it is mediated through the mechanism in which telomere length (TL) regulate oxidative stress.

METHODS: This was a double-blind, randomized, placebo-controlled trial in Tianjin, China. Participants were all native Chinese speakers aged 65 years and older with MCI. 183 subjects were randomized to an intervention group (vitamin D 800 IU/day, n = 93) or a placebo group (the matching starch granules, n = 90), and followed up for 12 months. Tests of cognitive function and mechanism-related biomarkers were evaluated at baseline, 6 months, and 12 months.

RESULTS: Repeated-measures ANOVA showed substantial improvements in the full scale intelligence quotient (FSIQ), information, digit span, vocabulary, block design, and picture arrangement scores in the vitamin D group over the placebo group (p < 0.001). Leukocyte TL was significantly higher, while serum 8-OXO-dG, OGG1mRNA, and P16INK4amRNA revealed greater decreases in the vitamin D group over the placebo group (p < 0.001). According to mixed-model repeated-measures ANOVA analysis, vitamin D group showed a significant enhancement in the FSIQ score for 12 months compared with the control (estimate value = 5.132, p < 0.001).

CONCLUSION: Vitamin D supplementation for 12 months appears to improve cognitive function through reducing oxidative stress regulated by increased TL in order adults with MCI. Vitamin D may be a promising public health strategy to prevent cognitive decline.

RevDate: 2020-11-09

Alam MR, DK Kim (2020)

Alterations in telomere length and mitochondrial DNA copy number in human lymphocytes on short-term exposure to moderate hypoxia.

Toxicology reports, 7:1443-1447 pii:S2214-7500(20)30419-4.

Hypoxia is related to a variety of diseases, such as cardiovascular and inflammatory diseases and various cancers. Telomere length (TL) may vary according to the hypoxia level and cell types. To the best of our knowledge, no study has investigated the effect of moderate hypoxia on TL and mitochondrial DNA copy number (mtDNAcn) in human lymphocytes. Therefore, in this study, we analyzed the effect of moderate hypoxia on TL in correlation with mtDNAcn. This study included 32 healthy male nonsmoker's subjects; in this cohort, we had previously studied sister chromatid exchange and microsatellite instability. Blood samples from each subject were divided into three groups: a control group and two experimental groups exposed to moderate hypoxia for 12 or 24 h. Relative TL and mtDNAcn were measured by a quantitative real-time polymerase chain reaction. The TL in the control group did not significantly differ from that in the experimental group subjected to hypoxia for 12 h; however, the TL in the 24 h hypoxia-treated experimental group was significantly higher than that in the control group. The correlation between TL and mtDNAcn was not statistically significant in the two hypoxic states. The increase in TL was observed on exposure to hypoxia for 24 h and not for 12 h; thus, the findings suggest that telomere elongation is related to hypoxia exposure duration. The mtDNAcn in the two experimental groups did not significantly differ from that in the control group. These observations suggest that mtDNAcn alterations show more genetic stability than TL alterations. To the best of our knowledge, this is the first in vitro study on human lymphocytes reporting an increase in TL and no alteration in mtDNAcn after short-time exposure to moderate hypoxia.

RevDate: 2020-11-09

Chen M, Tsai CW, Chang WS, et al (2020)

Prognostic value of leukocyte telomere length in renal cell carcinoma patients.

American journal of cancer research, 10(10):3428-3439.

Telomeres play important roles in cancer initiation and progression. Leukocyte telomere length (LTL) can modulate cancer risk and outcome. We hypothesize that genetically predicted short LTL is associated with worse prognosis in renal cell carcinoma (RCC). A total of 1,086 histologically confirmed RCC patients were included in this study. A weighted genetic risk score (GRS) predictive of LTL was constructed using 10 confirmed LTL-associated single nucleotide polymorphisms (SNPs). The associations of individual SNPs and GRS with recurrence and survival were determined by multivariate Cox proportional hazards analysis. In individual SNP analysis, long LTL-associated allele of rs7675998 in NAF1 gene at chromosome 4 was significantly associated with a reduced risk of recurrence (HR=0.85, 95% CI, 0.73-0.99, P=0.043), while the long LTL-associated allele of rs10936599 in TERC at chromosome 3 conferred a reduced risk of death (HR=0.85, 95% CI, 0.73-1.00, P=0.047). More importantly, genetically predicted LTL was associated with both recurrence and survival. Dichotomized at the median value of GRS, patients with low GRS (indicating short LTL) exhibited significantly increased risks of recurrence (HR=1.26, 95% CI, 1.03-1.54, P=0.025) and death (HR=1.23, 95% CI, 1.00-1.50, P=0.045). Hence, we concluded that genetically predicted short LTL is associated with worse prognosis in RCC patients.

RevDate: 2020-11-08

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

Association between genetic polymorphisms of telomere pathway genes and hydrogen peroxide level in omethoate exposure workers.

Environmental toxicology and pharmacology pii:S1382-6689(20)30218-0 [Epub ahead of print].

OBJECTIVE: The aim of this study was to explore the association between genetic variations in telomere pathway genes and the level of hydrogen peroxide (H2O2) in omethoate exposure workers.

METHODS: A total of 180 omethoate exposure workers and 115 healthy controls were recruited. The level of H2O2 in plasma was determined with molybdenic acid colorimetry. Polymerase chain reaction and restriction fragment length was used to detect polymorphisms in POT1 rs1034794, POT1 rs10250202, TERF1 rs3863242, and TERT rs2736098.

RESULTS: The level of H2O2 in exposure group (4.26 ± 0.71) was significantly higher than that in control group (3.29 ± 0.46). Generalized linear models indicated that risk factors for the increase H2O2 level were exposure [β(95% CI) = 0.951 (0.806, 1.096), P < 0.001] and AA + AT genotype in POT1 rs034794 [β(95% CI) = 0.397 (0.049, 0.745), P = 0.025].

CONCLUSION: The increase H2O2 level was associated with omethoate exposure and AA + AT genotypes in POT1 gene rs1034794. It provided a new idea that polymorphisms in telomere pathway genes may indirectly regulate telomere length by influencing oxidative stress.

RevDate: 2020-11-06

McKnight I, Hart C, Park IH, et al (2020)

Genes causing congenital hydrocephalus: Their chromosomal characteristics of telomere proximity and DNA compositions.

Experimental neurology pii:S0014-4886(20)30354-X [Epub ahead of print].

Congenital hydrocephalus (CH) is caused by genetic mutations, but whether factors impacting human genetic mutations are disease-specific remains elusive. Given two factors associated with high mutation rates, we reviewed how many disease-susceptible genes match with (i) proximity to telomeres or (ii) high adenine and thymine (A + T) content in human CH as compared to other disorders of the central nervous system (CNS). We extracted genomic information using a genome data viewer. Importantly, 98 of 108 genes causing CH satisfied (i) or (ii), resulting in >90% matching rate. However, such a high accordance no longer sustained as we checked two factors in Alzheimer's disease (AD) and/or familial Parkinson's disease (fPD), resulting in 84% and 59% matching, respectively. A disease-specific matching of telomere proximity or high A + T content predicts causative genes of CH much better than neurodegenerative diseases and other CNS conditions, likely due to sufficient number of known causative genes (n = 108) and precise determination and classification of the genotype and phenotype. Our analysis suggests a need for identifying genetic basis of both factors before human clinical studies, to prioritize putative genes found in preclinical models into the likely (meeting at least one) and more likely candidate (meeting both), which predisposes human genes to mutations.

RevDate: 2020-11-06

Kabaha MM, Y Tzfati (2020)

Telomerase, the recombination machinery and Rap1 play redundant roles in yeast telomere protection.

Current genetics pii:10.1007/s00294-020-01125-4 [Epub ahead of print].

Telomeres are specialized nucleoprotein complexes that protect the ends of eukaryotic chromosomes and distinguish them from broken DNA ends. Disruption of telomere protection may cause aging-associated pathologies and cancer. Here, we examined what makes telomere protection durable and resistant to perturbations using a budding yeast model organism. The protein Rap1 binds the telomeric repeats, negatively regulates telomere length, and protects telomeres by repressing homologous recombination and non-homologous end joining (NHEJ). A single-nucleotide mutation in the Kluyveromyces lactis telomerase RNA (TER1) template, ter1-16T, is incorporated into the telomeric repeats, disrupting the binding of Rap1 and causing dramatic telomere elongation. However, cell viability is not significantly affected, suggesting the existence of additional mechanism(s) for telomere protection. To examine this hypothesis, we explored the contribution of the recombination factor Rad52 and telomerase to telomere protection in the background of ter1-16T. To disrupt the function of telomerase, we exploited small mutations in a stem-loop domain of TER1 (Reg2), which result in short but stable telomeres. We generated K. lactis strains with combinations of three different mutations: ter1-16T, RAD52 deletion, and a two-nucleotide substitution in Reg2. Our results show that upon Rap1 depletion from telomeres, telomerase and the recombination machinery compensate for the loss of Rap1 protection and play redundant but critical roles in preventing NHEJ and maintaining telomere integrity and cell viability. These results demonstrate how redundant pathways make the essential role of telomeres-protecting our genome integrity and preventing cancer-more robust and resistant to assaults and perturbations.

RevDate: 2020-11-07

Cagsin H, Uzan A, Tosun O, et al (2020)

Tissue-Specific Ultra-Short Telomeres in Chronic Obstructive Pulmonary Disease.

International journal of chronic obstructive pulmonary disease, 15:2751-2757.

Purpose: Telomere biology, especially tissue-specific ultra-short telomeres, might provide a strong contribution to our current knowledge in COPD development as well as a predictive marker for prognosis. To test this hypothesis, we investigated telomere lengths in lung tissue and leukocytes in patients diagnosed with COPD.

Patients and Methods: Thirty-two patients were included in the current study. All patients showed a post-bronchodilator ratio of less than 70% post-bronchodilator predicted value of forced expiratory volume in second (FEV1%), mean 56%; range [19% to 86%]. To be able to investigate ultra-short telomeres, universal single telomere length analysis (U-STELA) was used.

Results: Our results showed a higher level of the ultra-short telomere presence in bronchoalveolar lavage (BAL) cells when compared to leukocytes with statistical significance t(62)=5.771, p<0.00001. The FEV1% was lower in subjects with ultra-short telomeres in BAL (50.6% vs 81.6%: p<0.001) and in ultra-short telomeres in blood leukocytes (37.3% vs 58.5%: p=0.051) when compared to subjects without ultra-short telomeres in leukocytes. Furthermore, the patients who had ultra-short telomeres in BAL samples were significantly older (p=0.014) than patients who did not have ultra-short telomeres. Ultra-short telomeres in BAL (p=0.05) but not in leukocytes (p=0.33) were associated with FEV1% in a regressions model adjusting for age (p<0.0001), ever smoking (p<0.0001) and sex (p=0.71). The patients with ultra-short telomeres were graded higher in the Global Initiative for Chronic Obstructive Lung Disease (GOLD) classification (p=0.006).

Conclusion: This study emphasizes the need to investigate the correct tissue to get a representative evaluation of the stage or advancedness of COPD. To our knowledge, this is the first study to show that there is a correlation between the presence of ultra-short telomeres in lung tissue and COPD severity. Our results suggest that ultra-short telomeres are involved in the molecular pathogenesis of COPD and might be used as a tissue-specific predictive biomarker.

RevDate: 2020-11-04

Nogueira BMD, Machado CB, Montenegro RC, et al (2020)

Telomere Length and Hematological Disorders: A Review.

In vivo (Athens, Greece), 34(6):3093-3101.

Telomeres compose the end portions of human chromosomes, and their main function is to protect the genome. In hematological disorders, telomeres are shortened, predisposing to genetic instability that may cause DNA damage and chromosomal rearrangements, inducing a poor clinical outcome. Studies from 2010 to 2019 were compiled and experimental studies using samples of patients diagnosed with hematological malignancies that reported the size of the telomeres were described. Abnormal telomere shortening is described in cancer, but in hematological neoplasms, telomeres are still shortened even after telomerase reactivation. In this study, we compared the sizes of telomeres in leukemias, myelodysplastic syndrome and lymphomas, identifying that the smallest telomeres are present in patients at relapse. In conclusion, the experimental and clinical data analyzed in this review demonstrate that excessive telomere shortening is present in major hematological malignancies and its analysis and measurement is a crucial step in determining patient prognosis, predicting disease risk and assisting in the decision for targeted therapeutic strategies.

RevDate: 2020-11-04

Lemaître JF, Carbillet J, Rey B, et al (2020)

Short-term telomere dynamics is associated with glucocorticoid levels in wild populations of roe deer.

Comparative biochemistry and physiology. Part A, Molecular & integrative physiology pii:S1095-6433(20)30189-6 [Epub ahead of print].

While evidence that telomere length is associated with health and mortality in humans and birds is accumulating, a large body of research is currently seeking to identify factors that modulate telomere dynamics. We tested the hypothesis that high levels of glucocorticoids in individuals under environmental stress should accelerate telomere shortening in two wild populations of roe deer (Capreolus capreolus) living in different ecological contexts. From two consecutive annual sampling sessions, we found that individuals with faster rates of telomere shortening had higher concentrations of fecal glucocorticoid metabolites, suggesting a functional link between glucocorticoid levels and telomere attrition rate. This relationship was consistent for both sexes and populations. This finding paves the way for further studies of the fitness consequences of exposure to environmental stressors in wild vertebrates.

RevDate: 2020-11-04

Ojeda-Rodríguez A, Zazpe I, Alonso-Pedrero L, et al (2020)

Higher adherence to an empirically-derived Mediterranean dietary pattern is positively associated with telomere length: The SUN Project.

The British journal of nutrition pii:S0007114520004274 [Epub ahead of print].

Telomere integrity is influenced by oxidative stress. Also, inflammation-related factors, including nutritional factors could modulate them. The relationship between aposteriori derived dietary patterns and TL has been scarcely investigated. Thus, our objective was to examine the association between empirically dietary patterns ascertained through principal component (PCA) analysis and TL in an older adults' Spanish population. A total of 886 older adults (>55 years old; 645 males and 241 females) from the "Seguimiento Universidad de Navarra" (SUN) cohort were included in the study. TL was measured by monochrome multiplex real-time quantitative PCR (MMqPCR). Age-adjusted TL was used for all analyses. Dietary patterns were identified by PCA based on 30 predefined candidate food groups collected from a validated 136-food items frequency questionnaire. Generalized linear models were fitted to obtain beta coefficients and their 95% confidence intervals (95% CIs) evaluating differences in TL between each of the four upper quintiles of adherence to dietary patterns and the lowest quintile. Sensitivity analyses by rerunning all multiple linear models under different stratifications were performed to evaluate the robustness of our results. Two major dietary patterns were empirically identified, Western dietary pattern (WDP) and Mediterranean dietary pattern (MDP). After adjustment for potential confounders, longer TL was found among subjects in the highest quintile of MDP (β=0.064; 95% CI 0.004 to 0.123). The WDP showed no significant association with TL. In conclusion, higher adherence to aposteriori derived MDP was independently associated with longer telomeres in an older adults' Spanish population of the SUN project.

RevDate: 2020-11-04

Garrido-Navas MC, Tippins F, Barwell J, et al (2020)

Telomere Instability in Lynch Syndrome Families Leads to Some Shorter Telomeres in MSH2+/- Carriers.

Life (Basel, Switzerland), 10(11): pii:life10110265.

Lynch syndrome (LS) is an inherited predisposition to early onset of various cancers, caused by mutation in a DNA mismatch repair (MMR) gene. In heterozygous MMR+/- carriers, somatic mutation, loss or silencing of the wild type allele increases the mutation rate, facilitating the initiation of MMR-defective cancers. These cancers are characterized by instability at short tandem repeats (STRs) and in telomeric DNA. We have investigated telomere length in saliva DNA from LS and control families, using single telomere analysis at XpYp and 12q and by qPCR to measure total telomeric DNA. Single telomere analysis showed a trend for shorter XpYp telomeres in MSH2+/- carriers compared to MLH1+/- carriers or controls, but this was masked in the comparative analysis of total telomeric DNA. Comparison of age-adjusted telomere length within families showed that neither MSH2+/- or MLH1+/- children had consistently shorter or longer telomeres than their MMR+/- parent, indicating the absence of an inter-generational effect on telomere length. Unexpectedly however, wildtype children in families with MSH2 mutations, had significantly longer XpYp telomeres than their MMR+/- parent. Altogether our data suggest that MMR insufficiency, particularly in MSH2+/- carriers, increases telomere instability and somatic cell turnover during the lifetime of LS mutation carriers but has minimal consequences for telomere length in the germline.

RevDate: 2020-11-03

Yu QQ, Gao JJ, Lang XX, et al (2020)

Microenvironment-Sensitive Fluorescent Ligand Binds Ascaris Telomere Antiparallel G-Quadruplex DNA with Blue-Shift and Enhanced Emission.

Chembiochem : a European journal of chemical biology [Epub ahead of print].

The development of small molecules, which can selectively target G4 DNAs has drawn considerable attention due to their unique physiological and pathological functions. However, only a few molecules were found to selective binding of a particular G4 DNA structure. Herein, we have developed a fluorescence ligand Q1 , a molecular scaffold of carbazole-pyridine core bridged with a phenylboronic acid side chain, exhibited as a selective ascaris telomere antiparallel G4 DNA ASC20 ligand with about 18 nm blue-shifted and enhanced fluorescence intensity. Photophysical properties revealed that Q1 was sensitive to the microenvironment and gave the best selectivity to ASC20 with equilibrium binding constant (K a = 6.04 ´ 10 5 M -1). The time-resolved fluorescence studies also demonstrated that Q1 showed a longer fluorescence lifetime in the presence of ASC20. The binding characteristics of Q1 with ASC20 were described in detail by fluorescent intercalator displacement (FID) assay, 2-Ap titration experiment and molecular docking. Ligand Q1 could adopt an appropriate pose at terminal G-quartets of ASC20 via the multiple interactions including π-π stacking between aromatic rings, thus led to a strong fluorescence enhancement. In addition, co-staining image showed Q1 mainly distributed in the cytoplasm area. According, this work provides insights for the development of ligands that selectively targeting a specific G4 DNA structure.

RevDate: 2020-11-03

Navarro-Mateu F, Husky M, Cayuela-Fuentes P, et al (2020)

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

Addiction (Abingdon, England) [Epub ahead of print].

BACKGROUND AND AIMS: Several recent studies have investigated the relationship between telomere length and substance use disorders with inconsistent results. We aimed to assess this association and to identify moderators of the relationship.

METHODS: Systematic review and meta-analysis. Selection criteria were observational studies reporting telomere length in persons with a substance use disorder compared with a control group. Studies focused solely on nicotine addiction, employing other study designs, and non-human studies were excluded. Study selection and data extraction were independently conducted by two researchers following a standardized protocol and included studies up until December 2019. Standardized mean differences were used as the effect size index (d; 95%CI) and random-effects models were used for the meta-analysis. Cochran's Q-statistic, I2 index, visual inspection of the forest plot, and a 95% prediction interval were applied to verify study heterogeneity. Subgroup analyses and meta-regressions were conducted to explore heterogeneity. Small study effects were examined using the "funnel plot", the Egger test, Duval and Tweedie's trim-and-fill method, and the PET-PEESE method. The risk of bias and the quality of evidence were assessed.

RESULTS: Ten studies (12 analysis units with 2,671 cases and 4,532 controls) met the selection criteria. An overall effect size of moderate magnitude was found (d+ = -0.63; 95%CI: -1.00 and -0.26; p=.0008). A potential small study effect was detected, as well as large heterogeneity between studies (Q-statistic p<.001, I2 =97.3%). Selection of controls, reporting laboratory quality control procedures and total sample size significantly affected the effect size. The quality of the evidence was very low, based on risk of bias analysis and the GRADE system.

CONCLUSIONS: People with substance use disorders appear to have shorter telomere length than controls; however, this finding should be interpreted with caution due to the poor quality of the evidence.

RevDate: 2020-11-03

Criscuolo F, Torres R, Zahn S, et al (2020)

Telomere dynamics from hatching to sexual maturity and maternal effects in the "multivariate egg".

The Journal of experimental biology pii:jeb.232496 [Epub ahead of print].

Avian eggs contain a large number of molecules deposited by the mother that provide the embryo with energy but also potentially influence its development via the effects of maternally-derived hormones and antibodies: the avian egg is "multivariate". Multivariate effects on offspring phenotype were evaluated in a sister study on captive zebra finches, by simultaneously manipulating maternally derived antibodies after LPS-treatment of mothers and egg-treatment using yolk testosterone injection. LPS-treatment had a positive effect on body mass growth at 30 days after hatching and immune response at sexual maturity, while egg-testosterone positively influenced immune response at fledging and courtship behaviour in sexually mature male offspring. Maternal effects are known to modulate offspring telomere length. Still, the multivariate effects of egg-derived maternal components on offspring telomere dynamics from hatching to sexual maturity are undefined. Here, using the data of the sister study completed with telomere measurements, we tested a) the effects of LPS and T treatments on telomere length (TL) from hatching to sexual maturity (day 82), b) how LPS treatment modulated telomere length over reproduction in adult females, and c) the relationship between maternal and offspring TL. We predicted, a) TL would be shorter in LPS fledglings (as a cost of faster growth), and b) TL would be longer in sexually mature adults from T-treated (as a proxy of individual quality). In adult females, there was an overall negative relationship between laying and rearing investments and telomere length, this relationship being weaker in LPS treated females. In chicks, there was an overall negative effect of LPS treatment on telomere length measured at fledging and sexual maturity (day 25 - 82). In addition, at fledging, there was a sex x LPS x T-treatment interaction, suggesting the existence of antagonistic effects of our treatments. Our data partially support the hypothesis of telomeres are proxies of individual quality and that individual differences in telomere length are set-up very early in life.

RevDate: 2020-10-31

Minasi S, Baldi C, Gianno F, et al (2020)

Alternative lengthening of telomeres in molecular subgroups of paediatric high-grade glioma.

Child's nervous system : ChNS : official journal of the International Society for Pediatric Neurosurgery pii:10.1007/s00381-020-04933-8 [Epub ahead of print].

PURPOSE: The maintenance of telomere length prevents cancer cell senescence and occurs via two mutually exclusive mechanisms: (a) reactivation of telomerase expression and (b) activation of alternative lengthening of telomeres (ALT). ALT is frequently related to alterations on ATRX, a chromatin-remodelling protein. Recent data have identified different molecular subgroups of paediatric high-grade glioma (pHGG) with mutations of H3F3A, TERTp and ATRX; however, differences in telomere length among these molecular subgroups were not thoroughly examined.

METHODS: We investigated which genetic alterations trigger the ALT mechanism in 52 IDH-wildtype, 1p/19q-wildtype pHGG. Samples were analysed for telomere length using Tel-FISH. ATRX nuclear loss of expression was assessed by IHC, H3F3A and TERTp mutations by DNA sequencing, and TERTp methylation by MS-PCR.

RESULTS: Mutant H3.3 was found in 21 cases (40.3%): 19.2% with K27M mutation and 21.1% with G34R mutation. All H3.3G34R-mutated cases showed the ALT phenotype (100%); on the opposite, only 40% of the H3.3K27M-mutated showed ALT activation. ATRX nuclear loss was seen in 16 cases (30.7%), associated sometimes with the G34R mutation, and never with the K27M mutation. ATRX nuclear loss was always related to telomere elongation. TERTp C250T mutations were rare (5.4%) and were not associated with high intensity Tel-FISH signals, as TERTp hyper-methylation detected in 21% of the cases. H3.3/ATRX/TERTp-wildtype pHGG revealed all basal levels of telomere length.

CONCLUSION: Our results show a strong association between H3.3 mutations and ALT, and highlight the different telomeric profiles in histone-defined subgroups: H3.3-G34R mutants always trigger ALT to maintain telomere length, irrespective of ATRX status, whereas only some H3.3-K27M tumours activate ALT. These findings suggest that acquiring the gly34 mutation on H3.3 might suffice to trigger the ALT mechanism.

RevDate: 2020-10-31

Smith LE, Jones ME, Hamede R, et al (2020)

Telomere Length is a Susceptibility Marker for Tasmanian Devil Facial Tumor Disease.

EcoHealth pii:10.1007/s10393-020-01491-y [Epub ahead of print].

Telomeres protect chromosomes from degradation during cellular replication. In humans, it is well-documented that excessive telomere degradation is one mechanism by which cells can become cancerous. Increasing evidence from wildlife studies suggests that telomere length is positively correlated with survival and health and negatively correlated with disease infection intensity. The recently emerged devil facial tumor disease (DFTD) has led to dramatic and rapid population declines of the Tasmanian devil throughout its geographic range. Here, we tested the hypothesis that susceptibility to DFTD is negatively correlated with telomere length in devils across three populations with different infection histories. Our findings suggest telomere length is correlated with DFTD resistance in three ways. First, devils from a population with the slowest recorded increase in DFTD prevalence (West Pencil Pine) have significantly longer telomeres than those from two populations with rapid and exponential increases in prevalence (Freycinet and Narawantapu). Second, using extensive mark-recapture data obtained from a long-term demographic study, we found that individuals with relatively long telomeres tend to be infected at a significantly later age than those with shorter telomeres. Third, a hazard model showed devils with longer telomeres tended to become infected at a lower rate than those with shorter telomeres. This research provides a rare study of telomere length variation and its association with disease in a wildlife population. Our results suggest that telomere length may be a reliable marker of susceptibility to DFTD and assist with future management of this endangered species.

RevDate: 2020-10-31

Chang X, Dorajoo R, Sun Y, et al (2020)

Effect of plasma polyunsaturated fatty acid levels on leukocyte telomere lengths in the Singaporean Chinese population.

Nutrition journal, 19(1):119 pii:10.1186/s12937-020-00626-9.

BACKGROUND: Shorter telomere length (TL) has been associated with poor health behaviors, increased risks of chronic diseases and early mortality. Excessive shortening of telomere is a marker of accelerated aging and can be influenced by oxidative stress and nutritional deficiency. Plasma n6:n3 polyunsaturated fatty acid (PUFA) ratio may impact cell aging. Increased dietary intake of marine n-3 PUFA is associated with reduced telomere attrition. However, the effect of plasma PUFA on leukocyte telomere length (LTL) and its interaction with genetic variants are not well established.

METHODS: A nested coronary artery disease (CAD) case-control study comprising 711 cases and 638 controls was conducted within the Singapore Chinese Health Study (SCHS). Samples genotyped with the Illumina ZhongHua-8 array. Plasma n-3 and n-6 PUFA were quantified using mass spectrometry (MS). LTL was measured with quantitative PCR method. Linear regression was used to test the association between PUFA and LTL. The interaction between plasma PUFAs and genetic variants was assessed by introducing an additional term (PUFA×genetic variant) in the regression model. Analysis was carried out in cases and controls separately and subsequently meta-analyzed using the inverse-variance weighted method. We further assessed the association of PUFA and LTL with CAD risk by Cox Proportional-Hazards model and whether the effect of PUFA on CAD was mediated through LTL by using structural equation modeling.

RESULTS: Higher n6:n3 ratio was significantly associated with shorter LTL (p = 0.018) and increased CAD risk (p = 0.005). These associations were mainly driven by elevated plasma total n-3 PUFAs, especially eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) (p < 0.05). There was a statistically significant interaction for an intergenic single nucleotide polymorphism (SNP) rs529143 with plasma total n-3 PUFA and DHA on LTL beyond the genome-wide threshold (p < 5 × 10- 8). Mediation analysis showed that PUFA and LTL affected CAD risk independently.

CONCLUSIONS: Higher plasma n6:n3 PUFA ratio, and lower EPA and DHA n-3 PUFAs were associated with shorter LTL and increased CAD risk in this Chinese population. Furthermore, genetic variants may modify the effect of PUFAs on LTL. PUFA and LTL had independent effect on CAD risk in our study population.

RevDate: 2020-10-30

Grandin N, Gallego ME, White CI, et al (2020)

Inhibition of the alternative lengthening of telomeres pathway by subtelomeric sequences in Saccharomyces cerevisiae.

DNA repair, 96:102996 pii:S1568-7864(20)30256-1 [Epub ahead of print].

In the budding yeast Saccharomyces cerevisiae, telomerase is constitutively active and is essential for chromosome end protection and illimited proliferation of cell populations. However, upon inactivation of telomerase, alternative mechanims of telomere maintenance allow proliferation of only extremely rare survivors. S. cerevisiae type I and type II survivors differ by the nature of the donor sequences used for repair by homologous recombination of the uncapped terminal TG1-3 telomeric sequences. Type I amplifies the subtelomeric Y' sequences and is more efficient than type II, which amplifies the terminal TG1-3 repeats. However, type II survivors grow faster than type I survivors and can easily outgrow them in liquid cultures. The mechanistic interest of studying S. cerevisiae telomeric recombination is reinforced by the fact that type II recombination is the equivalent of the alternative lengthening of telomeres (ALT) pathway that is used by 5-15 % of cancer types as an alternative to telomerase reactivation. In budding yeast, only around half of the 32 telomeres harbor Y' subtelomeric elements. We report here that in strains harboring Y' elements on all telomeres, type II survivors are not observed, most likely due to an increase in the efficiency of type I recombination. However, in a temperature-sensitive cdc13-1 mutant grown at semi-permissive temperature, the increased amount of telomeric TG1-3 repeats could overcome type II inhibition by the subtelomeric Y' sequences. Strikingly, in the 100 % Y' strain the replicative senescence crisis normally provoked by inactivation of telomerase completely disappeared and the severity of the crisis was proportional to the percentage of chromosome-ends lacking Y' subtelomeric sequences. The present study highlights the fact that the nature of subtelomeric elements can influence the selection of the pathway of telomere maintenance by recombination, as well as the response of the cell to telomeric damage caused by telomerase inactivation.

RevDate: 2020-10-30

Warner ET, Zhang Y, Gu Y, et al (2020)

Physical and sexual abuse in childhood and adolescence and leukocyte telomere length: A pooled analysis of the study on psychosocial stress, spirituality, and health.

PloS one, 15(10):e0241363 pii:PONE-D-20-13222.

INTRODUCTION: We examined whether abuse in childhood and/or adolescence was associated with shorter telomere length in a pooled analysis of 3,232 participants from five diverse cohorts. We also assessed whether religion or spirituality (R/S) could buffer deleterious effects of abuse.

METHODS: Physical and sexual abuse in childhood (age <12) and adolescence (age 12-18) was assessed using the Revised Conflict Tactics Scale and questions from a 1995 Gallup survey. We measured relative leukocyte telomere lengths (RTL) using quantitative real time polymerase chain reaction. We used generalized estimating equations to assess associations of physical and sexual abuse with log-transformed RTL z-scores. Analyses were conducted in each cohort, overall, and stratified by extent of religiosity or spirituality and religious coping in adulthood. We pooled study-specific estimates using random-effects models and assessed between-study heterogeneity.

RESULTS: Compared to no abuse, severe sexual abuse was associated with lower RTL z-scores, in childhood: -15.6%, 95% CI: -25.9, -4.9; p-trend = 0.04; p-heterogeneity = 0.58 and in adolescence: -16.5%, 95% CI: -28.1, -3.0; p-trend = 0.08; p-heterogeneity = 0.68. Sexual abuse experienced in both childhood and adolescence was associated with 11.3% lower RTL z-scores after adjustment for childhood and demographic covariates (95% CI: -20.5%, -2.0%; p-trend = 0.03; p-heterogeneity = 0.62). There was no evidence of effect modification by R/S. Physical abuse was not associated with telomere length.

CONCLUSIONS: Sexual abuse in childhood or adolescence was associated with a marker of accelerated biological aging, decreased telomere length. The lack of moderation by R/S may be due to inability to capture the appropriate time period for those beliefs and practices.

RevDate: 2020-10-31

Polettini J, MG da Silva (2020)

Telomere-Related Disorders in Fetal Membranes Associated With Birth and Adverse Pregnancy Outcomes.

Frontiers in physiology, 11:561771.

Telomere disorders have been associated with aging-related diseases, including diabetes, vascular, and neurodegenerative diseases. The main consequence of altered telomere is the induction of the state of irreversible cell cycle arrest. Though several mechanisms responsible for the activation of senescence have been identified, it is still unclear how a cell is indeed induced to become irreversibly arrested. Most tissues in the body will experience senescence throughout its lifespan, but intrinsic and extrinsic stressors, such as chemicals, pollution, oxidative stress (OS), and inflammation accelerate the process. Pregnancy is a state of OS, as the higher metabolic demand of the growing fetus results in increased reactive oxygen species production. As a temporary organ in the mother, senescence in fetal membranes and placenta is expected and linked to term parturition (>37 weeks of gestation). However, a persistent, overwhelming, or premature OS affects placental antioxidant capacity, with consequent accumulation of OS causing damage to lipids, proteins, and DNA in the placental tissues. Therefore, senescence and its main inducer, telomere length (TL) reduction, have been associated with pregnancy complications, including stillbirth, preeclampsia, intrauterine growth restriction, and prematurity. Fetal membranes have a notable role in preterm births, which continue to be a major health issue associated with increased risk of neo and perinatal adverse outcomes and/or predisposition to disease in later life; however, the ability to mediate a delay in parturition during such cases is limited, because the pathophysiology of preterm births and physiological mechanisms of term births are not yet fully elucidated. Here, we review the current knowledge regarding the regulation of telomere-related senescence mechanisms in fetal membranes, highlighting the role of inflammation, methylation, and telomerase activity. Moreover, we present the evidences of TL reduction and senescence in gestational tissues by the time of term parturition. In conclusion, we verified that telomere regulation in fetal membranes requires a more complete understanding, in order to support the development of successful effective interventions of the molecular mechanisms that triggers parturition, including telomere signals, which may vary throughout placental tissues.

RevDate: 2020-10-30

Wu Y, Pei Y, Yang Z, et al (2020)

Accelerated telomere shortening independent of LRRK2 variants in Chinese patients with Parkinson's disease.

Aging, 12: pii:103878 [Epub ahead of print].

Oxidative stress and inflammation play vital roles in Parkinson's disease (PD) development. Thus, telomere length is expected to be shortened in this disease, but current data are inconclusive. We performed a case-control study of 261 patients with PD and 270 sex and age-matched healthy controls treated at the Peking Union Medical College Hospital. We found leucocyte telomere length (LTL) was significantly shortened in PD as compared with controls [1.02 (0.84-1.39) vs. 1.48 (1.08-1.94), P<0.001] and shorter LTL was associated with a dramatically increased risk of PD (lowest vs. highest quartile odds ratio (OR) =9.54, 95% CI: 5.33-17.06, P<0.001). We also investigated the roles of six LRRK2 variants in the susceptibility to PD. R1441C/G/H, G2019S, and I2020T variations were not detected in our study. No significant differences were found in the presence of variants R1398H (15.4% vs. 17.0%, P=0.619) and R1628P (2.3% vs. 0.7%, P=0.159) in PD and controls, while the G2385R variant was found to be a risk factor associated with increased PD susceptibility (OR=2.14, 95% CI: 1.12-4.10, P=0.021). No significant association was found between different LRRK2 variants and telomere length. These findings suggest that shorter LTL might be associated with PD in a manner independent of LRRK2 variants.

RevDate: 2020-10-30

Adegunsoye A, Morisset J, Newton CA, et al (2020)

Leukocyte Telomere Length and Mycophenolate Therapy in Chronic Hypersensitivity Pneumonitis.

RevDate: 2020-10-30

Pinzaru AM, Kareh M, Lamm N, et al (2020)

Replication stress conferred by POT1 dysfunction promotes telomere relocalization to the nuclear pore.

Genes & development pii:gad.337287.120 [Epub ahead of print].

Mutations in the telomere-binding protein POT1 are associated with solid tumors and leukemias. POT1 alterations cause rapid telomere elongation, ATR kinase activation, telomere fragility, and accelerated tumor development. Here, we define the impact of mutant POT1 alleles through complementary genetic and proteomic approaches based on CRISPR interference and biotin-based proximity labeling, respectively. These screens reveal that replication stress is a major vulnerability in cells expressing mutant POT1, which manifests as increased telomere mitotic DNA synthesis at telomeres. Our study also unveils a role for the nuclear pore complex in resolving replication defects at telomeres. Depletion of nuclear pore complex subunits in the context of POT1 dysfunction increases DNA damage signaling, telomere fragility and sister chromatid exchanges. Furthermore, we observed telomere repositioning to the nuclear periphery driven by nuclear F-actin polymerization in cells with POT1 mutations. In conclusion, our study establishes that relocalization of dysfunctional telomeres to the nuclear periphery is critical to preserve telomere repeat integrity.

RevDate: 2020-10-30

Michniacki TF, AC Weyand (2020)

Gastrointestinal Bleeding: Expanding the Shortened Telomere Disorder Phenotype.

RevDate: 2020-10-30

Torrance JB, S Goldband (2020)

Mathematical Connection between Short Telomere Induced Senescence Calculation and Mortality Rate Data.

International journal of molecular sciences, 21(21): pii:ijms21217959.

The last 20 years have seen a surge in scientific activity and promising results in the study of aging and longevity. Many researchers have focused on telomeres, which are composed of a series of TTAGGG repeat nucleotide sequences at the ends of each chromosome. Measurements of the length of these telomere strands show that they decrease in length with increasing age, leading many authors to propose that when the length of these telomere strands decreases sufficiently, the cells enter into a state of replicative senescence, eventually leading to disease and death. These ideas are supported by evidence that short telomere length is correlated with increased mortality. In this paper, we extend this idea to make an actual calculation of the predicted mortality rate caused by short telomere length induced senescence (STLIS). We derive a simple equation for the mathematical relationship between telomere length and mortality rate. Using only three parameters based on telomere length measurement data of Canadians, we have calculated both the magnitude and the age dependence of the mortality rate for both men and women. We show that these calculated data are in good quantitative agreement with the actual number of Canadians that die. This agreement demonstrates the quantitative correlation between the mortality calculated by the STLIS model and the mortality of the major diseases of aging (e.g., cardiovascular disease, many cancers and diabetes mellitus), which dominate human mortality. This result represents significant progress in our understanding of the factors behind the cause of aging.

RevDate: 2020-10-29

Harnung Scholten R, Møller P, Jovanovic Andersen Z, et al (2020)

Telomere length in newborns is associated with exposure to low levels of air pollution during pregnancy.

Environment international, 146:106202 pii:S0160-4120(20)32157-7 [Epub ahead of print].

Telomere length (TL) is a biomarker of biological aging that may be affected by prenatal exposure to air pollution. The aim of this study was to assess the association between prenatal exposure to air pollution and TL in maternal blood cells (leukocytes), placenta and umbilical cord blood cells, sampled immediately after birth in 296 Danish mother-child pairs from a birth cohort. Exposure data was obtained using the high-resolution and spatial-temporal air pollution modeling system DEHM-UBM-AirGIS for PM2.5, PM10, SO2, NH4+, black carbon (BC), organic carbon (OC), CO, O3, NO2, and NOx at residential and occupational addresses of the participating women for the full duration of the pregnancy. The association between prenatal exposure to air pollutants and TL was investigated using distributed lag models. There were significant and positive associations between TL in umbilical cord blood cells and prenatal exposure to BC, OC, NO2, NOx, CO, and O3 during the second trimester. TL in umbilical cord blood was significantly and inversely associated with prenatal exposure to PM2.5, BC, OC, SO2, NH4+, CO and NO2 during the third trimester. There were similar inverse associations between TL from umbilical cord blood cells and air pollution exposure at the residential and occupational addresses. There were weaker or no associations between air pollution exposure and TL in placenta tissue and maternal blood cells. In conclusion, both the second and third trimesters of pregnancy are shown to be sensitive windows of exposure to air pollution affecting fetal TL.

RevDate: 2020-10-29

Zhang C, Ostrom QT, Semmes EC, et al (2020)

Genetic predisposition to longer telomere length and risk of childhood, adolescent and adult-onset ependymoma.

Acta neuropathologica communications, 8(1):173 pii:10.1186/s40478-020-01038-w.

Ependymoma is the third most common brain tumor in children, with well-described molecular characterization but poorly understood underlying germline risk factors. To investigate whether genetic predisposition to longer telomere length influences ependymoma risk, we utilized case-control data from three studies: a population-based pediatric and adolescent ependymoma case-control sample from California (153 cases, 696 controls), a hospital-based pediatric posterior fossa type A (EPN-PF-A) ependymoma case-control study from Toronto's Hospital for Sick Children and the Children's Hospital of Philadelphia (83 cases, 332 controls), and a multicenter adult-onset ependymoma case-control dataset nested within the Glioma International Case-Control Consortium (GICC) (103 cases, 3287 controls). In the California case-control sample, a polygenic score for longer telomere length was significantly associated with increased risk of ependymoma diagnosed at ages 12-19 (P = 4.0 × 10-3), but not with ependymoma in children under 12 years of age (P = 0.94). Mendelian randomization supported this observation, identifying a significant association between genetic predisposition to longer telomere length and increased risk of adolescent-onset ependymoma (ORPRS = 1.67; 95% CI 1.18-2.37; P = 3.97 × 10-3) and adult-onset ependymoma (PMR-Egger = 0.042), but not with risk of ependymoma diagnosed before age 12 (OR = 1.12; 95% CI 0.94-1.34; P = 0.21), nor with EPN-PF-A (PMR-Egger = 0.59). These findings complement emerging literature suggesting that augmented telomere maintenance is important in ependymoma pathogenesis and progression, and that longer telomere length is a risk factor for diverse nervous system malignancies.

RevDate: 2020-10-29

Rampazzo E, Cecchin E, Del Bianco P, et al (2020)

Genetic Variants of the TERT Gene, Telomere Length, and Circulating TERT as Prognostic Markers in Rectal Cancer Patients.

Cancers, 12(11): pii:cancers12113115.

Single-nucleotide polymorphisms (SNPs) in the TERT gene can affect telomere length and TERT expression and have been associated with risk and/or outcome for several tumors, but very few data are available about their impact on rectal cancer. Eight SNPs (rs2736108, rs2735940, rs2736098, rs2736100, rs35241335, rs11742908, rs2736122 and rs2853690), mapping in regulatory and coding regions of the TERT gene, were studied in 194 rectal cancer patients to evaluate their association with constitutive telomere length, circulating TERT mRNA levels, response to neoadjuvant chemoradiotherapy (CRT) and disease outcome. At diagnosis, the rs2736100CC genotype was associated with longer telomeres measured pre-CRT, while the rs2736100CC, rs2736108TT and rs2735940AA were associated with greater telomere erosion evaluated post-CRT. The rs2736108CC and rs2853690AA/GG genotypes, respectively associated with lower telomere erosion and lower levels of circulating TERT post-CRT, were also independently associated with a better response to therapy [OR 4.6(1.1-19.1) and 3.0(1.3-6.9)]. Overall, post-CRT, low levels (≤ median value) of circulating TERT and its stable/decreasing levels compared to those pre-CRT, were independently associated with a better response to therapy [OR 5.8(1.9-17.8) and 5.3(1.4-19.4), respectively]. Furthermore, post-CRT, patients with long telomeres (>median value) and low levels of circulating TERT had a significantly lower risk of disease progression [HR 0.4(0.1-0.9) and 0.3(0.1-0.8), respectively]. These findings suggest that TERT SNPs could be a useful tool for improving the selection of patients who could benefit from CRT and support the role of telomere length and circulating TERT mRNA levels as useful markers for monitoring the response to therapy and disease outcome in rectal cancer patients.

RevDate: 2020-10-28

van Lieshout SHJ, Sparks AM, Bretman A, et al (2020)

Estimation of environmental, genetic and parental age at conception effects on telomere length in a wild mammal.

Journal of evolutionary biology [Epub ahead of print].

Understanding individual variation in fitness-related traits requires separating the environmental and genetic determinants. Telomeres are protective caps at the ends of chromosomes that are thought to be a biomarker of senescence as their length predicts mortality risk and reflect the physiological consequences of environmental conditions. The relative contribution of genetic and environmental factors to individual variation in telomere length is however unclear, yet important for understanding its evolutionary dynamics. In particular, the evidence for transgenerational effects, in terms of parental age at conception, on telomere length is mixed. Here, we investigate the heritability of telomere length, using the 'animal model', and parental age at conception effects on offspring telomere length in a wild population of European badgers (Meles meles). While we found no heritability of telomere length and low evolvability (<0.001), our power to detect heritability was low and a repeatability of 2% across individual lifetimes provides a low upper limit to ordinary narrow-sense heritability. However, year (25%) and cohort (3%) explained greater proportions of the phenotypic variance in telomere length. There was no support for cross-sectional or within-individual parental age at conception effects on offspring telomere length. Our results indicate a lack of transgenerational effects through parental age at conception and a low potential for evolutionary change in telomere length in this population. Instead, we provide evidence that individual variation in telomere length is largely driven by environmental variation in this wild mammal.

RevDate: 2020-10-26

Froidure A, Mahieu M, Hoton D, et al (2020)

Short telomeres increase the risk of severe COVID-19.

Aging, 12: pii:104097 [Epub ahead of print].

Telomeres are non-coding DNA sequences that protect chromosome ends and shorten with age. Short telomere length (TL) is associated with chronic diseases and immunosenescence. The main risk factor for mortality of coronavirus disease 2019 (COVID-19) is older age, but outcome is very heterogeneous among individuals of the same age group. Therefore, we hypothesized that TL influences COVID-19-related outcomes. In a prospective study, we measured TL by Flow-FISH in 70 hospitalized COVID-19 patients and compared TL distribution with our reference cohort of 491 healthy volunteers. We also correlated TL with baseline clinical and biological parameters. We stained autopsy lung tissue from six non-survivor COVID-19 patients to detect senescence-associated β-galactosidase activity, a marker of cellular aging. We found a significantly higher proportion of patients with short telomeres (<10th percentile) in the COVID-19 patients as compared to the reference cohort (P<0.001). Short telomeres were associated with a higher risk of critical disease, defined as admission to intensive care unit (ICU) or death without ICU. TL was negatively correlated with C-reactive protein and neutrophil-to-lymphocyte ratio. Finally, lung tissue from patients with very short telomeres exhibit signs of senescence in structural and immune cells. Our results suggest that TL influences the severity of the disease.

RevDate: 2020-10-23

Sun S, Shinya R, Dayi M, et al (2020)

Telomere-to-Telomere Genome Assembly of Bursaphelenchus okinawaensis Strain SH1.

Microbiology resource announcements, 9(43):.

Bursaphelenchus okinawaensis is a self-fertilizing, hermaphroditic, fungus-feeding nematode used as a laboratory model for the genus Bursaphelenchus, which includes the important pathogen Bursaphelenchus xylophilus Here, we report the nearly complete genome sequence of B. okinawaensis The 70-Mbp assembly contained six scaffolds (>11 Mbp each) with telomere repeats on their ends, indicating complete chromosomes.

RevDate: 2020-10-22

Mukherjee AK, Sharma S, Sengupta S, et al (2020)

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

PLoS genetics, 16(10):e1009152 pii:PGENETICS-D-20-01555.

[This corrects the article DOI: 10.1371/journal.pgen.1007782.].

RevDate: 2020-10-22

Brown DW, Lin SH, Loh PR, et al (2020)

Genetically predicted telomere length is associated with clonal somatic copy number alterations in peripheral leukocytes.

PLoS genetics, 16(10):e1009078 pii:PGENETICS-D-20-00433 [Epub ahead of print].

Telomeres are DNA-protein structures at the ends of chromosomes essential in maintaining chromosomal stability. Observational studies have identified associations between telomeres and elevated cancer risk, including hematologic malignancies; but biologic mechanisms relating telomere length to cancer etiology remain unclear. Our study sought to better understand the relationship between telomere length and cancer risk by evaluating genetically-predicted telomere length (gTL) in relation to the presence of clonal somatic copy number alterations (SCNAs) in peripheral blood leukocytes. Genotyping array data were acquired from 431,507 participants in the UK Biobank and used to detect SCNAs from intensity information and infer telomere length using a polygenic risk score (PRS) of variants previously associated with leukocyte telomere length. In total, 15,236 (3.5%) of individuals had a detectable clonal SCNA on an autosomal chromosome. Overall, higher gTL value was positively associated with the presence of an autosomal SCNA (OR = 1.07, 95% CI = 1.05-1.09, P = 1.61×10-15). There was high consistency in effect estimates across strata of chromosomal event location (e.g., telomeric ends, interstitial or whole chromosome event; Phet = 0.37) and strata of copy number state (e.g., gain, loss, or neutral events; Phet = 0.05). Higher gTL value was associated with a greater cellular fraction of clones carrying autosomal SCNAs (β = 0.004, 95% CI = 0.002-0.007, P = 6.61×10-4). Our population-based examination of gTL and SCNAs suggests inherited components of telomere length do not preferentially impact autosomal SCNA event location or copy number status, but rather likely influence cellular replicative potential.

RevDate: 2020-10-22

Arabadjiev B, Pankov R, Vassileva I, et al (2020)

Photobiomodulation with 590 nm Wavelength Delays the Telomere Shortening and Replicative Senescence of Human Dermal Fibroblasts In Vitro.

Photobiomodulation, photomedicine, and laser surgery [Epub ahead of print].

Background: Cellular senescence is one of the major factors contributing to the aging process. Photobiomodulation (PBM) is known to trigger an array of cellular responses, but there are no data on how it affects the process of cellular senescence. In this study, we analyze the effect of PBM on the cellular senescence and telomere dynamics. Methods: Human dermal fibroblasts were irradiated by a panel of light-emitting diodes with 590 nm and dose 30 J/cm2 accumulated over 1200 sec repeated in 4-day cycle within 40 days. After the last cycle of PBM treatment, the difference in number of senescent cells between PBM treated groups end nontreated control groups was measured by senescent sensitive β-galactosidase assay, and the difference in average telomere length between the experimental end control groups was analyzed using relative human telomere length quantitative Polymerase Chain Reaction (qPCR) assay. Results: After 10 cycles of irradiation, the percentage of senescent cells in PBM-treated cultures was 19.7% ± 4.5%, p < 0.05 smaller than the percentage of senescent cells in the control group, and their relative telomere length was 1.19 ± 0.09-fold, p < 0.05 greater than nontreated controls. Conclusions: Our study demonstrates for the first time that PBM with appropriate parameters can delay the attrition of the telomeres and the entry of cells into senescence, suggesting a potential involvement of telomerase reactivation. A hypothetical mechanism for this light-induced antiaging effect is discussed.

RevDate: 2020-10-21

Wang L, Chen R, Li G, et al (2020)

FBW7 Mediates Senescence and Pulmonary Fibrosis through Telomere Uncapping.

Cell metabolism pii:S1550-4131(20)30537-4 [Epub ahead of print].

Tissue stem cells undergo premature senescence under stress, promoting age-related diseases; however, the associated mechanisms remain unclear. Here, we report that in response to radiation, oxidative stress, or bleomycin, the E3 ubiquitin ligase FBW7 mediates cell senescence and tissue fibrosis through telomere uncapping. FBW7 binding to telomere protection protein 1 (TPP1) facilitates TPP1 multisite polyubiquitination and accelerates degradation, triggering telomere uncapping and DNA damage response. Overexpressing TPP1 or inhibiting FBW7 by genetic ablation, epigenetic interference, or peptidomimetic telomere dysfunction inhibitor (TELODIN) reduces telomere uncapping and shortening, expanding the pulmonary alveolar AEC2 stem cell population in mice. TELODIN, synthesized from the seventh β strand blade of FBW7 WD40 propeller domain, increases TPP1 stability, lung respiratory function, and resistance to senescence and fibrosis in animals chronically exposed to environmental stress. Our findings elucidate a pivotal mechanism underlying stress-induced pulmonary epithelial stem cell senescence and fibrosis, providing a framework for aging-related disorder interventions.

RevDate: 2020-10-21

Nie X, Xiao D, Ge Y, et al (2020)

TRF2 recruits nucleolar protein TCOF1 to coordinate telomere transcription and replication.

Cell death and differentiation pii:10.1038/s41418-020-00637-3 [Epub ahead of print].

Telomeres are transcribed into telomeric RNA termed as TERRA. However, the transcription itself and excessive TERRA may interfere with telomere replication during S phase. The mechanism that coordinates telomere transcription and replication is unknown. Here, we report that TCOF1 leaves the nucleolus and is recruited to telomeres specifically during S phase by interacting with TRF2. Therein, TCOF1 acts to suppress telomere transcription by binding and inhibiting Pol II. Thus, TERRA is limited to low levels in S phase. Depletion of TCOF1 leads to abnormally elevated TERRA and formation of DNA/RNA hybrids (R-loops) at telomeres, which induces replication fork stalling and fragile telomeres. Importantly, telomere replication defect induced by TCOF1 deficiency can be rescued by either masking TERRA or expressing an R-loop eraser RNase H1, demonstrating a critical role of TCOF1 in coordinating telomere transcription and replication. These findings link nucleolus to telomeres and uncover a novel function of TCOF1 on ensuring telomere integrity.

RevDate: 2020-10-21

Mazzucco G, Huda A, Galli M, et al (2020)

Telomere damage induces internal loops that generate telomeric circles.

Nature communications, 11(1):5297 pii:10.1038/s41467-020-19139-4.

Extrachromosomal telomeric circles are commonly invoked as important players in telomere maintenance, but their origin has remained elusive. Using electron microscopy analysis on purified telomeres we show that, apart from known structures, telomeric repeats accumulate internal loops (i-loops) that occur in the proximity of nicks and single-stranded DNA gaps. I-loops are induced by single-stranded damage at normal telomeres and represent the majority of telomeric structures detected in ALT (Alternative Lengthening of Telomeres) tumor cells. Our data indicate that i-loops form as a consequence of the exposure of single-stranded DNA at telomeric repeats. Finally, we show that these damage-induced i-loops can be excised to generate extrachromosomal telomeric circles resulting in loss of telomeric repeats. Our results identify damage-induced i-loops as a new intermediate in telomere metabolism and reveal a simple mechanism that links telomere damage to the accumulation of extrachromosomal telomeric circles and to telomere erosion.

RevDate: 2020-10-20

Weyburne E, G Bosco (2020)

Cancer-associated mutations in the condensin II subunit CAPH2 cause genomic instability through telomere dysfunction and anaphase chromosome bridges.

Journal of cellular physiology [Epub ahead of print].

Genome instability in cancer drives tumor heterogeneity, undermines the success of therapies, and leads to metastasis and recurrence. Condensins are conserved chromatin-binding proteins that promote genomic stability, mainly by ensuring proper condensation of chromatin and mitotic chromosome segregation. Condensin mutations are found in human tumors, but it is not known how or even if such mutations promote cancer progression. In this study, we focus on condensin II subunit CAPH2 and specific CAPH2 mutations reported to be enriched in human cancer patients, and we test how CAPH2 cancer-specific mutations may lead to condensin II complex dysfunction and contribute to genome instability. We find that R551P, R551S, and S556F mutations in CAPH2 cause genomic instability by causing DNA damage, anaphase defects, micronuclei, and chromosomal instability. DNA damage and anaphase defects are caused primarily by ataxia telangiectasia and Rad3-related-dependent telomere dysfunction, as anaphase bridges are enriched for telomeric repeat sequences. We also show that these mutations decrease the binding of CAPH2 to the ATPase subunit SMC4 as well as the rest of the condensin II complex, and decrease the amount of CAPH2 protein bound to chromatin. Thus, in vivo the R551P, R551S, and S556F cancer-specific CAPH2 mutant proteins are likely to impair condensin II complex formation, impede condensin II activity during mitosis and interphase, and promote genetic heterogeneity in cell populations that can lead to clonal outgrowth of cancer cells with highly diverse genotypes.

RevDate: 2020-10-19

Glousker G, Briod AS, Quadroni M, et al (2020)

Human shelterin protein POT1 prevents severe telomere instability induced by homology-directed DNA repair.

The EMBO journal [Epub ahead of print].

The evolutionarily conserved POT1 protein binds single-stranded G-rich telomeric DNA and has been implicated in contributing to telomeric DNA maintenance and the suppression of DNA damage checkpoint signaling. Here, we explore human POT1 function through genetics and proteomics, discovering that a complete absence of POT1 leads to severe telomere maintenance defects that had not been anticipated from previous depletion studies in human cells. Conditional deletion of POT1 in HEK293E cells gives rise to rapid telomere elongation and length heterogeneity, branched telomeric DNA structures, telomeric R-loops, and telomere fragility. We determine the telomeric proteome upon POT1-loss, implementing an improved telomeric chromatin isolation protocol. We identify a large set of proteins involved in nucleic acid metabolism that engage with telomeres upon POT1-loss. Inactivation of the homology-directed repair machinery suppresses POT1-loss-mediated telomeric DNA defects. Our results unravel as major function of human POT1 the suppression of telomere instability induced by homology-directed repair.

RevDate: 2020-10-17

Nickels M, Mastana S, Denniff M, et al (2020)

Elite swimmers possess shorter telomeres than recreationally active controls.

Gene pii:S0378-1119(20)30911-2 [Epub ahead of print].

RevDate: 2020-10-16

Noguera JC, da Silva A, A Velando (2020)

Egg corticosterone can stimulate telomerase activity and promote longer telomeres during embryo development.

Molecular ecology [Epub ahead of print].

It is often assumed that the transfer of maternal glucocorticoids (GCs; e.g. corticosterone or cortisol) to offspring is an inevitable cost associated with adverse or stressful conditions experienced by mothers. However, recent evidence indicates that maternal GCs may adaptively program particular physiological and molecular pathways during development to enhance offspring fitness. In this context, an important mechanism through which maternal GCs may lastingly affect offspring phenotypic quality and survival is via effects on embryo telomerase activity and so on offspring postnatal telomere length. Here, using a field experimental design for which we manipulated the corticosterone content in yellow-legged gull (Larus michahellis) eggs, we show that embryos from corticosterone-injected eggs not only had a higher telomerase activity but also longer telomeres just after hatching. A complementary analysis further revealed that gull hatchlings with longer telomeres had a higher survival probability during the period when most of the chick mortality occurs. Given the important role that telomere length and its restoring mechanisms have on ageing trajectories and disease risk, our findings provide a new mechanistic link by which mothers may presumably shape offspring life-history trajectories and phenotype.

RevDate: 2020-10-15

Feretzaki M, Pospisilova M, Valador Fernandes R, et al (2020)

RAD51-dependent recruitment of TERRA lncRNA to telomeres through R-loops.

Nature pii:10.1038/s41586-020-2815-6 [Epub ahead of print].

Telomeres-repeated, noncoding nucleotide motifs and associated proteins that are found at the ends of eukaryotic chromosomes-mediate genome stability and determine cellular lifespan1. Telomeric-repeat-containing RNA (TERRA) is a class of long noncoding RNAs (lncRNAs) that are transcribed from chromosome ends2,3; these RNAs in turn regulate telomeric chromatin structure and telomere maintenance through the telomere-extending enzyme telomerase4-6 and homology-directed DNA repair7,8. The mechanisms by which TERRA is recruited to chromosome ends remain poorly defined. Here we develop a reporter system with which to dissect the underlying mechanisms, and show that the UUAGGG repeats of TERRA are both necessary and sufficient to target TERRA to chromosome ends. TERRA preferentially associates with short telomeres through the formation of telomeric DNA-RNA hybrid (R-loop) structures that can form in trans. Telomere association and R-loop formation trigger telomere fragility and are promoted by the recombinase RAD51 and its interacting partner BRCA2, but counteracted by the RNA-surveillance factors RNaseH1 and TRF1. RAD51 physically interacts with TERRA and catalyses R-loop formation with TERRA in vitro, suggesting a direct involvement of this DNA recombinase in the recruitment of TERRA by strand invasion. Together, our findings reveal a RAD51-dependent pathway that governs TERRA-mediated R-loop formation after transcription, providing a mechanism for the recruitment of lncRNAs to new loci in trans.

RevDate: 2020-10-14

Normando P, Bezerra FF, Santana BA, et al (2020)

Association between socioeconomic markers and adult telomere length differs according to sex: Pro-Saúde study.

Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas, 53(11):e10223 pii:S0100-879X2020001100605.

Understanding the social determinants of telomere length is critical to evaluate the risk of early biological aging. We investigated sex differences on the association between socioeconomic status (SES) and demographic markers and leukocyte telomere length (LTL) in Brazilian adults. This cross-sectional study was conducted in a subsample (women=228; men=200) nested within the Pro-Saúde study, a prospective cohort study of university civil servants in Rio de Janeiro, Brazil (2012-2013). Adjusted multivariate models were used to test the relationship between SES markers (marital status, educational attainment, father's educational attainment, race/skin color, household income, and childhood experience of food deprivation) and LTL. After adjusting for age and potential health-related confounders, lower educational attainment was associated with shorter LTL among men (β=-0.05, 95% confidence interval (CI)=95%CI: -0.10, 0.00, P=0.03). In women, LTL was inversely associated with unmarried status (β=-0.05, 95%CI: -0.09, 0.00, P=0.03), lower father's educational attainment (β=-0.05, 95%CI: -0.13, 0.00, P=0.04), and childhood experience of food deprivation (β=-0.07, 95%CI: -0.13, 0.00, P=0.04). Our findings suggested that the association between SES markers and LTL differs according to sex. SES markers able to induce lifelong stress, reflected in LTL, appeared to be more related to individual factors in men, whereas in women they were family-related.

RevDate: 2020-10-14

Keng SL, Looi PS, Tan ELY, et al (2020)

Effects of Mindfulness-Based Stress Reduction on Psychological Symptoms and Telomere Length: A Randomized Active-Controlled Trial.

Behavior therapy, 51(6):984-996.

Much research has demonstrated the beneficial effects of mindfulness-based stress reduction (MBSR) on psychological and physical health, but it is not known whether MBSR may impact cellular aging in healthy populations. Further, little research has evaluated MBSR against an active control condition, which precludes strong conclusions regarding the unique effects of mindfulness on psychological functioning. The present study examined the effects of MBSR versus music therapy-based stress reduction (MTSR) on trait mindfulness, self-compassion, and several psychological health outcomes, as well as leukocyte telomere length (LTL). One hundred and fifty eight Singaporean Chinese adults were recruited and randomly assigned to an eight-week MBSR or MTSR course. Participants provided blood samples and completed a battery of self-report measures pre- and post-intervention. Analyses showed that participants in the MBSR condition demonstrated significantly greater improvements in depressive symptoms, trait mindfulness, and self-compassion compared to the control condition. Treatment condition did not predict changes in LTL, anxiety, stress, or happiness, though there was a trend for duration of home mindfulness practice to predict increases in LTL. Overall, the study demonstrated MBSR's unique effects in reducing depressive symptoms. Improvements in trait mindfulness and self-compassion correspond with theorized mechanisms of change underlying mindfulness training. The lack of intervention effect with regards to LTL suggests that a more intensive intervention may be required for mindfulness to exert noticeable impact on aging at the cellular level, or that the effect may only emerge over a longer term.

RevDate: 2020-10-13

Cleber Gama de Barcellos Filho P, Campos Zanelatto L, Amélia Aparecida Santana B, et al (2020)

Effects chronic administration of corticosterone and estrogen on HPA axis activity and telomere length in brain areas of female rats.

Brain research pii:S0006-8993(20)30510-2 [Epub ahead of print].

Chronic stress is related to the acceleration of telomere shortening. Recent work showed a correlation between chronic psychosocial stress and reduced telomere length in certain cells. The exposure of T lymphocytes to cortisol promoted a significant reduction in telomerase activity. Although stress can promote changes in telomere length, whether increased glucocorticoid concentrations alter telomere length in brain tissue cells is unclear. In addition to modulating the activity of the stress system, estrogen also influences telomere length. The objective of this study was to verify whether chronic exposure to glucocorticoids promotes changes in the telomere length of encephalic areas involved in the control of HPA axis activity and whether estrogen affects these changes. Wistar rats were ovariectomized and treated with estradiol cypionate [(50 or 100 μg/kg, subcutaneously)] or oil and 20 mg/kg corticosterone or vehicle (isotonic saline with 2% Tween 80, subcutaneously) for 28 days. On the day after the end of the hormonal treatment, the animals were euthanized for collection of blood, brain and pituitary gland samples. Estrogen modulated the activity of the HPA axis. CRH, AVP and POMC mRNA levels were reduced by estrogen. At least in doses and treatment time used, there was no correlation between effects of exposure to glucocorticoids and estrogen on telomere length in the brain areas of female rats. However, estrogen treatment reduced the telomere length in the central amygdala and dorsal hippocampus, but not in the PVN, indicating a variation of reaction of telomeres for estrogen in different brain areas.

RevDate: 2020-10-13

Power ML, Power S, Bertelsen MF, et al (2020)

Wing: A suitable non-lethal tissue type for repeatable and rapid telomere length estimates in bats.

Molecular ecology resources [Epub ahead of print].

Telomeres are used increasingly in ecology and evolution as biomarkers for ageing and environmental stress, and are typically measured from DNA extracted from non-lethally sampled blood. However, obtaining blood is not always possible in field conditions and only limited amounts can be taken from small mammals, such as bats, which moreover lack nucleated red blood cells and hence yield relatively low amounts of DNA. As telomere length can vary within species according to age and tissue, it is important to determine which tissues serve best as a representation of the organism as a whole. Here, we investigated whether wing tissue biopsies, a rapid and relatively non-invasive tissue collection method, could serve as a proxy for other tissues when measuring relative telomere length (rTL) in the Egyptian fruit bat (Rousettus aegyptiacus). Telomeres were measured from blood, brain, heart, kidney, liver lung, muscle and wing, and multiple wing biopsies were taken from the same individuals to determine intra-individual repeatability of rTL measured by using qPCR. Wing rTL correlated with rTL estimates from most tissues apart from blood. Blood rTL was not significantly correlated with rTL from any other tissue. Blood and muscle rTL were significantly longer compared with other tissues, while lung displayed the shortest rTLs. Individual repeatability of rTL measures from wing tissue was high (>76%). Here we show the relationships between tissue telomere dynamics for the first time in a bat, and our results provide support for the use of wing tissue for rTL measurements.

RevDate: 2020-10-13

Cao W, Zheng D, Zhang J, et al (2020)

Association between telomere length in peripheral blood leukocytes and risk of ischemic stroke in a Han Chinese population: a linear and non-linear Mendelian randomization analysis.

Journal of translational medicine, 18(1):385 pii:10.1186/s12967-020-02551-1.

BACKGROUND: Many contradictory conclusions pertaining to the telomere length in peripheral leukocyte chromosomes as a potential biomarker for ischemic stroke (IS) risk have been reported by the various observational studies in previous years. This study aims to investigate whether the leukocyte telomere length is associated with an increased IS risk or not, based on the Mendelian randomization (MR) approach.

METHODS: Based on the NHGRI-EBI GWAS Catalog database, the Chinese online genetic database as well as the previous published studies, twelve single nucleotide polymorphisms (SNPs) with minor allele frequency ≥ 0.05 were selected and the leukocyte telomere length was measured in 431 first-ever IS patients and 304 healthy controls (quantitative polymerase chain reaction). To explore linear and non-linear effect of telomere length on the IS risk, we preformed the linear MR analysis (the inverse-variance weighted method, the maximum likelihood method, and the mode-based estimation method), and the non-linear MR analysis (semiparametric method with three tests for non-linearity, including the quadratic test, Cochran's Q test, and the fractional polynomial test).

RESULTS: Two verified SNPs (rs11125529 and rs412658) were chosen as instrumental variables. In linear MR analysis, the adjusted odds ratios and 95% confidence intervals of IS for genetically predicted telomere lengths, based on the two SNPs, were 1.312 (0.979 to 1.759), 1.326 (0.932 to 1.888) and 1.226 (0.844 to 1.781) for the inverse-variance weighted method, the maximum likelihood method, and the mode-based estimation method, respectively. Three tests for nonlinearity failed to reject the null exactly, indicating that the relationship between telomere length and IS risk is unlikely to be non-linear.

CONCLUSION: This MR study based on individual data does not provide strong evidence for a positive linear or non-linear effect of telomere length on the IS risk.

RevDate: 2020-10-12

Chang X, Chua KY, Wang L, et al (2020)

Mid-life leukocyte telomere length as an indicator for handgrip strength in late-life.

The journals of gerontology. Series A, Biological sciences and medical sciences pii:5921149 [Epub ahead of print].

BACKGROUND: Telomere attrition has been proposed as a hallmark of ageing. We previously reported on the association between blood leukocyte telomere length (LTL) at mid-life and risk of chronic diseases and mortality.

METHODS: In this study, we investigated the effect of mid-life LTL and genetic proxies on five markers of ageing outcomes, namely handgrip strength, timed up-and-go (TUG), Singapore-modified Mini-Mental State Examination (SM-MMSE) scores, anxiety, and depression indices, measured after a median 20-year follow-up in the Singapore Chinese Health Study (N = 9,581).

RESULTS: We observed a significant association between mid-life LTL and handgrip strength later in life (P = 0.004, Padjust = 0.020), as well as a nominal significant association between mid-life LTL and TUG later in life (P = 0.036, Padjust = 0.180). The weighted Genetic Risk Score (wGRS) comprising 15 previously reported LTL reducing loci in East-Asians was not significantly associated with handgrip strength. However, results from Structural Equation Modeling (SEM) showed that the effect of this wGRS on handgrip strength was mediated through LTL (proportion of wGRS effect on handgrip strength mediated through LTL = 33.3%, P = 0.010).

CONCLUSIONS: Longer mid-life LTL was associated with increased handgrip strength later in life.

RevDate: 2020-10-13

Osum M, N Serakinci (2020)

Impact of circadian disruption on health; SIRT1 and Telomeres.

DNA repair, 96:102993 pii:S1568-7864(20)30252-4 [Epub ahead of print].

Circadian clock is a biochemical oscillator in organisms that regulates the circadian rhythm of numerous genes over 24 h. The circadian clock is involved in telomere homeostasis by regulating the diurnal rhythms of telomerase activity, TERT mRNA level, TERRA expression, and telomeric heterochromatin formation. Particularly, CLOCK and BMAL1 deficiency contribute to telomere shortening by preventing rhythmic telomerase activity and TERRA expression, respectively. Telomere shortening increases the number of senescent cells with impaired circadian rhythms. In return, telomerase reconstitution improves impaired circadian rhythms of senescent cells. SIRT1 that is an NAD+-dependent deacetylase positively regulates circadian clock and telomere homeostasis. SIRT1 contributes to the circadian clock by mediating CLOCK/BMAL1 complex formation, BMAL1 transcription and PER2 disruption. On the other hand, SIRT1 ensures telomere homeostasis by inducing telomerase and shelterin protein expression and regulating telomere heterochromatin formation. SIRT1 inhibition leads to both circadian clock and telomeres dysfunction that inhibit its activity. In light of this current evidence, we could suggest that the BMAL1/CLOCK complex regulates the telomere homeostasis in SIRT1 dependent manner, and also telomere dysfunction inhibits circadian clock function by suppressing SIRT1 activity to induce age-related diseases. We consider that increasing SIRT1 activity can prevent age-related diseases and help healthy aging by protecting telomere integrity and circadian clock function for individuals subjected to circadian rhythm disruption such as shift works, individuals with sleep disorders, and in the elderly population.

RevDate: 2020-10-10

Latour CD, O'Connell K, Romano ME, et al (2020)

Maternal age at last birth and leukocyte telomere length in a nationally representative population of perimenopausal and postmenopausal women.

Menopause (New York, N.Y.) [Epub ahead of print].

OBJECTIVE: The primary aim of this study was to evaluate if maternal age at birth of last child is associated with leukocyte telomere length in a nationally representative population of peri- and postmenopausal women.

METHODS: We conducted a cross-sectional analysis of 1,232 women from the National Health and Nutrition Examination Survey to examine maternal age at last birth and telomere length, surveyed between 1999 and 2002. We included peri- and postmenopausal women age 40 years and older. Maternal age at last live birth was self-reported, and leukocyte telomere length was measured using quantitative polymerase chain reaction. We calculated least-squares geometric mean telomere length across categories of maternal age adjusted for age, race/ethnicity, number of live births, survey cycle, and history of hysterectomy or oophorectomy. P-trend < 0.05 was considered statistically significant. For hypothesis-generation, we explored modification by reproductive and sociodemographic factors.

RESULTS: Maternal age at last birth was positively associated with telomere length: the multivariable-adjusted least-squares geometric mean leukocyte telomere length across categories of age at last birth (<25, 25-29, 30-34, 35-39, ≥40 years) was 0.90, 0.93, 0.93, 0.95, and 0.96, respectively (P-trend = 0.04). There was suggestive evidence this association may be restricted to those women with 1 or 2 live births or women who reported ever using oral contraceptives (P-interaction<0.10 for both).

CONCLUSIONS: Later maternal age was associated with longer telomere length in a nationally representative population of women. These data provide new insight into the biological relationship between reproductive history and long-term health. : Video Summary:

RevDate: 2020-10-12

Feurstein S, Adegunsoye A, Mojsilovic D, et al (2020)

Telomere biology disorder prevalence and phenotypes in adults with familial hematologic and/or pulmonary presentations.

Blood advances, 4(19):4873-4886.

Telomere biology disorders (TBDs) present heterogeneously, ranging from infantile bone marrow failure associated with very short telomeres to adult-onset interstitial lung disease (ILD) with normal telomere length. Yield of genetic testing and phenotypic spectra for TBDs caused by the expanding list of telomere genes in adults remain understudied. Thus, we screened adults aged ≥18 years with a personal and/or family history clustering hematologic disorders and/or ILD enrolled on The University of Chicago Inherited Hematologic Disorders Registry for causative variants in 13 TBD genes. Sixteen (10%) of 153 probands carried causative variants distributed among TERT (n = 6), TERC (n = 4), PARN (n = 5), or RTEL1 (n = 1), of which 19% were copy number variants. The highest yield (9 of 22 [41%]) was in families with mixed hematologic and ILD presentations, suggesting that ILD in hematology populations and hematologic abnormalities in ILD populations warrant TBD genetic testing. Four (3%) of 117 familial hematologic disorder families without ILD carried TBD variants, making TBD second to only DDX41 in frequency for genetic diagnoses in this population. Phenotypes of 17 carriers with heterozygous PARN variants included 4 (24%) with hematologic abnormalities, 67% with lymphocyte telomere lengths measured by flow cytometry and fluorescence in situ hybridization at or above the 10th percentile, and a high penetrance for ILD. Alternative etiologies for cytopenias and/or ILD such as autoimmune features were noted in multiple TBD families, emphasizing the need to maintain clinical suspicion for a TBD despite the presence of alternative explanations.

RevDate: 2020-10-09

Zhan Y, S Hägg (2020)

Association between genetically predicted telomere length and facial skin aging in the UK Biobank: a Mendelian randomization study.

GeroScience pii:10.1007/s11357-020-00283-0 [Epub ahead of print].

Are shorter telomeres causal risk factors for facial aging on a large population level? To examine if longer, genetically predicted telomeres were causally associated with less facial aging using Mendelian randomization analysis. Two-sample Mendelian randomization methods were applied to the summary statistics of a genome-wide association study (GWAS) for self-reported facial aging from 417, 772 participants of the UK Biobank data. Twenty single-nucleotide polymorphisms (SNPs) that were of genome-wide significance were selected as instrumental variables for leukocyte telomere length. The main analyses were performed primarily using the random-effects inverse-variance weighted method and were complemented with the MR-Egger regression, weighted median, and weighted mode approaches. The intercept of MR-Egger regression was used to assess horizontal pleiotropy. Longer genetically predicted telomeres were associated with a lower likelihood of facial aging (β = - 0.02, 95% confidence interval: - 0.04, - 0.002). Comparable results were obtained using MR-Egger regression, weighted median, and weighted mode approaches. The intercept of MR-Egger regression was close to zero (0.002) that was not suggestive of horizontal pleiotropy. Our findings provided evidence to support a potential causal relationship between longer genetically predicted telomeres and less facial aging.

RevDate: 2020-10-08

Protsenko E, Rehkopf D, Prather AA, et al (2020)

Are long telomeres better than short? Relative contributions of genetically predicted telomere length to neoplastic and non-neoplastic disease risk and population health burden.

PloS one, 15(10):e0240185 pii:PONE-D-20-19301.

BACKGROUND: Mendelian Randomization (MR) studies exploiting single nucleotide polymorphisms (SNPs) predictive of leukocyte telomere length (LTL) have suggested that shorter genetically determined telomere length (gTL) is associated with increased risks of degenerative diseases, including cardiovascular and Alzheimer's diseases, while longer gTL is associated with increased cancer risks. These varying directions of disease risk have long begged the question: when it comes to telomeres, is it better to be long or short? We propose to operationalize and answer this question by considering the relative impact of long gTL vs. short gTL on disease incidence and burden in a population.

METHODS AND FINDINGS: We used odds ratios (OR) of disease associated with gTL from a recently published MR meta-analysis to approximate the relative contributions of gTL to the incidence and burden of neoplastic and non-neoplastic disease in a European population. We obtained incidence data of the 9 cancers associated with long gTL and 4 non-neoplastic diseases associated with short gTL from the Institute of Health Metrics (IHME). Incidence rates of individual cancers from SEER, a database of United States cancer records, were used to weight the ORs in order to align with the available IHME data. These data were used to estimate the excess incidences due to long vs. short gTL, expressed as per 100,000 persons per standard deviation (SD) change in gTL. To estimate the population disease burden, we used the Disability Adjusted Life Years (DALY) metric from the IHME, a measure of overall disease burden that accounts for both mortality and morbidity, and similarly calculated the excess DALY associated with long vs. short gTL.

RESULTS: Our analysis shows that, despite the markedly larger ORs of neoplastic disease, the large incidence of degenerative diseases causes the excess incidence attributable to gTL to balance that of neoplastic diseases. Long gTL is associated with an excess incidence of 94.04 cases/100,000 persons/SD (45.49-168.84, 95%CI) from the 9 cancer, while short gTL is associated with an excess incidence of 121.49 cases/100,000 persons/SD (48.40-228.58, 95%CI) from the 4 non-neoplastic diseases. When considering disease burden using the DALY metric, long gTL is associated with an excess 1255.25 DALYs/100,000 persons/SD (662.71-2163.83, 95%CI) due to the 9 cancers, while short gTL is associated with an excess 1007.75 DALYs/100,000 persons/SD (411.63-1847.34, 95%CI) due to 4 non-neoplastic diseases.

CONCLUSIONS: Our results show that genetically determined long and short telomere length are associated with disease risk and burden of approximately equal magnitude. These results provide quantitative estimates of the relative impact of genetically-predicted short vs. long TL in a human population, and provide evidence in support of the cancer-aging paradox, wherein human telomere length is balanced by opposing evolutionary forces acting to minimize both neoplastic and non-neoplastic diseases. Importantly, our results indicate that odds ratios alone can be misleading in different clinical scenarios, and disease risk should be assessed from both an individual and population level in order to draw appropriate conclusions about the risk factor's role in human health.

RevDate: 2020-10-07

Martin M, Millan A, Ferraro F, et al (2020)


Bioscience reports pii:226596 [Epub ahead of print].

BACKGROUND: Hereditary hemochromatosis (HH) is a primary iron overload (IO) condition. Absolute telomere length (ATL) is a marker of cellular aging and DNA damage associated with chronic diseases and mortality.  Aim: To evaluate the relationship between ATL and IO in patients with HH.  Methods: Cross-sectional study including25 patients with HH: 8 with IO and 17 without IO (ferritin< 300ng/ml) and 25 healthy controls. Inclusion criteria were: age>18 years, male sex and HH diagnosis. Patients with diabetes or other endocrine and autoimmune diseases were excluded. ATL was measured by real-time PCR.  Results: HH patients with IO were older (p<0.001) and showed higher ferritin concentration (p<0.001). Patients with HH, disregarding the iron status, showed higher glucose and BMI than controls (both p<0.01). ATL was shorter in patients with IO than controls [with IO: 8 (6-14), without IO: 13 (9-20),and controls: 19 (15-25) kilobase pairs, p<0.01];with a linear trend within groups (p for trend<0.01). Differences in ATL remained statistically significant after adjusting by age, BMI and glucose(p<0.05).  Discussion: Patients with IO featured shorter ATL while patients without IO showed only mild alterations vs. controls. Screening for IO is encouraged to prevent iron-associated cellular damage and early telomere attrition.

RevDate: 2020-10-07

Benetos A, Lai TP, Toupance S, et al (2020)

A Mechanism for Severity of Disease in Older Patients with COVID-19: The Nexus between Telomere Length and Lymphopenia.

medRxiv : the preprint server for health sciences.

BACKGROUND: Lymphopenia due to a plummeting T-cell count is a major feature of severe COVID-19. T-cell proliferation is telomere length (TL)-dependent and TL shortens with age. Older persons are disproportionally affected by severe COVID-19, and we hypothesized that those with short TL have less capacity to mount an adequate T-cell proliferative response to SARS-CoV-2. This hypothesis predicts that among older patients with COVID-19, shorter telomeres of peripheral blood mononuclear cells (PBMCs) will be associated with a lower lymphocyte count.

METHODS: Our sample comprised 17 COVID-19 and 21 non-COVID-19 patients, aged 87(8) (mean(SD)) and 87 (9) years, respectively. We measured TL by the Telomere Shortest Length Assay, a novel method that measures and tallies the short telomeres directly relevant to telomere-mediated biological processes. The primary analysis quantified TL as the proportion of telomeres shorter than 2 kilobases. For comparison, we also quantified TL by Southern blotting, which measures the mean length of telomeres.

RESULTS: Lymphocyte count (109/L) was 0.91 (0.42) in COVID-19 patients and 1.50(0.50) in non-COVID-19 patients (P < 0.001). In COVID-19 patients, but not in non-COVID-19 patients, lymphocyte count was inversely correlated with the proportion of telomeres shorter than 2 kilobases (P = 0.005) and positively correlated with the mean of telomeres measured by TeSLA (P = 0.03). Lymphocyte counts showed no statistically significant correlations with Southern blotting results in COVID-19 or non-COVID-19 patients.

CONCLUSIONS: These results support the hypothesis that a compromised TL-dependent T-cell proliferative response contributes to lymphopenia and the resulting disproportionate severity of COVID-19 among old adults. We infer that infection with SARS-CoV-2 uncovers the limits of the TL reserves of older persons.

RevDate: 2020-10-09

Menshawy NE, Ashwah SE, MA Ebrahim (2020)

Short Dysfunctional Telomere Is Highly Predictive of Dismal Outcome in MDS but Not in AML Patients.

International journal of hematology-oncology and stem cell research, 14(3):188-199.

Background: A trigger for initiation the clonal hematopoietic stem cells disorders could be short telomere length probably due to chromosomal instability. The relationship between relative telomere length (RTL) and the two linked hematological stem cell disorders, myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) is still unclear. Materials and Methods: We evaluated the role of RTL in MDS (n=96) and AML (n=130) at the time of diagnosis using a real time quantitative polymerase chain reaction (RT-PCR) technique. The median value of RTL (1) was set as the cutoff for statistical comparison. Overall survival (OS) is defined as the time from diagnosis to death or last follow-up. Results: RTL was significantly longer in both MDS and AML cases versus control (p<0.0001) and was significantly longer in MDS versus AML cases (p =0.03). RTL correlated negatively with age in MDS (p <0.0001) but not in AML cases. RTL was also significantly shorter in MDS cases with pancytopenia and poor risk cytogenetics (p < 0.0001 for each) and short RTL was significantly associated with inferior survival (p = 0.007), while RTL showed no significant impact on OS in AML cases. Moreover, short RTL retained independent prognostic value in multivariate analysis (HR= 3.42 [95% CI, 8.97-19.35], p = 0.004). Conclusion: RTL showed an association with both AML and MDS; however, short RTL was an independent poor prognostic factor in MDS patients only.


ESP Quick Facts

ESP Origins

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

ESP Support

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

ESP Rationale

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

ESP Goal

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

ESP Usage

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

ESP Content

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

ESP Help

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

ESP Plans

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

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Good Beginner's Books

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

Electronic Scholarly Publishing
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Papers in Classical Genetics

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

Digital Books

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


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


Biographical information about many key scientists.

Selected Bibliographies

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

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