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Bibliography on: Telomeres

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ESP: PubMed Auto Bibliography 27 Jul 2021 at 01:36 Created: 

Telomeres

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

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

Citations The Papers (from PubMed®)

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RevDate: 2021-07-22

Kang JI, Park CI, Lin J, et al (2021)

Alterations of cellular aging markers in obsessive- compulsive disorder: mitochondrial DNA copy number and telomere length.

Journal of psychiatry & neuroscience : JPN, 46(4):E451-E458.

Background: The present study examined whether mitochondrial DNA copy number (mtDNAcn) and telomere length - key markers of cellular aging - were altered in male and female participants with obsessive-compulsive disorder (OCD) compared to healthy controls. We also tested for associations between these alterations and OCD-related clinical features and inflammatory index.

Methods: A total of 235 patients with OCD (38.7% female) and 234 healthy controls (41.5% female) were included. We quantified whole-blood mtDNAcn and leukocyte telomere length using quantitative polymerase chain reaction. We also calculated the neutrophil-to-lymphocyte ratio from complete blood cell counts.

Results: Multivariate analysis of covariance showed that OCD status had a significant overall effect on cellular aging markers in men (Wilks λ = 0.889, F2,275 = 17.13, p < 0.001) and women (Wilks λ = 0.742, F2,182 = 31.61, p < 0.001) after controlling for age, body mass index and childhood trauma. In post-hoc comparisons, men with OCD had lower mtDNAcn than controls (p < 0.001), but we found no between-group difference for telomere length (p = 0.55). Women with OCD had a significantly lower mtDNAcn (p < 0.001) and shortened telomere length (p = 0.023) compared to controls. Moreover, the lower mtDNAcn shown in the OCD group was significantly correlated with an increase in systemic inflammation for both sexes, as measured by neutrophil-to-lymphocyte ratio.

Limitations: The present cross-sectional design did not allow us to infer a causal relationship between OCD disease status and cellular aging markers.

Conclusion: The present study is, to our knowledge, the first to demonstrate alterations in mtDNAcn and telomere shortening in OCD. These results suggest that aging-associated molecular mechanisms may be important in the pathophysiology of OCD.

RevDate: 2021-07-22

Li B (2021)

Keeping Balance Between Genetic Stability and Plasticity at the Telomere and Subtelomere of Trypanosoma brucei.

Frontiers in cell and developmental biology, 9:699639.

Telomeres, the nucleoprotein complexes at chromosome ends, are well-known for their essential roles in genome integrity and chromosome stability. Yet, telomeres and subtelomeres are frequently less stable than chromosome internal regions. Many subtelomeric genes are important for responding to environmental cues, and subtelomeric instability can facilitate organismal adaptation to extracellular changes, which is a common theme in a number of microbial pathogens. In this review, I will focus on the delicate and important balance between stability and plasticity at telomeres and subtelomeres of a kinetoplastid parasite, Trypanosoma brucei, which causes human African trypanosomiasis and undergoes antigenic variation to evade the host immune response. I will summarize the current understanding about T. brucei telomere protein complex, the telomeric transcript, and telomeric R-loops, focusing on their roles in maintaining telomere and subtelomere stability and integrity. The similarities and differences in functions and underlying mechanisms of T. brucei telomere factors will be compared with those in human and yeast cells.

RevDate: 2021-07-21

Gu R, Cao J, Wei S, et al (2021)

Evaluation of pretreatment telomere length as a prognostic marker in intermediate-risk acute myeloid leukemia.

International journal of laboratory hematology [Epub ahead of print].

INTRODUCTION: The current framework for risk stratification is still insufficient for highly heterogeneous intermediate-risk acute myeloid leukemia (IRC-AML), which lacks specific genomic abnormalities.

METHODS: In order to incorporate novel biomarkers to refine current risk stratification strategies for patients with this subtype, we investigated pretreatment telomere length (TL), which is essential for maintaining genomic stability, in 204 adults with de novo AML (non-acute promyelocytic leukemia).

RESULTS: We found that TL measured at diagnosis did not decrease with advancing age in 204 patients with AML (R2 = 0.001, P = .695). A multivariate analysis demonstrated that short TL was independently associated with an inferior relapse-free survival (hazard ratio [HR] 3.08, 95% confidence interval [CI] 1.48-6.41, P = .003); event-free survival (HR 2.14, 95% CI 1.12-4.08, P = .021); and overall survival (HR 2.26, 95% CI 1.09-4.67, P = .028) in IRC-AML patients. In addition, IRC-AML patients with short TL also exhibited an increased cumulative incidence of hematologic relapse (HR 2.32, 95% CI 1.08-5.26, P = .032).

CONCLUSION: Short TL is an independent prognostic factor for poor prognosis in patients with IRC-AML and may represent a novel mechanism that links genomic stability and disease progression.

RevDate: 2021-07-21

Seimiya H, Nagasawa K, K Shin-Ya (2021)

Chemical targeting of G-quadruplexes in telomeres and beyond for molecular cancer therapeutics.

The Journal of antibiotics [Epub ahead of print].

G-quadruplexes (G4s) are higher-order structures formed by guanine-rich sequences of nucleic acids, such as the telomeric 5'-TTAGGG-3'/5'-UUAGGG-3' repeats and those in gene regulatory regions. G4s regulate various biological events, including replication, transcription, and translation. Imbalanced G4 dynamics is associated with diseases, such as cancer and neurodegenerative diseases. Telomestatin is a natural macrocyclic compound derived from Streptomyces anulatus 3533-SV4. It interacts with the guanine quartet via π-π stacking and potently stabilizes G4. Because G4 stabilization at the telomeric repeat inhibits the telomere-synthesizing enzyme telomerase, telomestatin was originally identified as a telomerase inhibitor. Whereas non-toxic doses of telomestatin induce gradual shortening of telomeres and eventual crisis in human cancer cells, higher doses trigger prompt replication stress and DNA damage responses, resulting in acute cell death. Suppression of the transcription and translation of G4-containing genes is also implicated in the anticancer effects of telomestatin. Because telomestatin is rare, labile, and insoluble, synthetic oxazole telomestatin derivatives have been developed and verified for their therapeutic efficacies in preclinical cancer models. Furthermore, a variety of G4-stabilizing compounds have been reported as promising seeds for molecular cancer therapeutics. To improve the design of future clinical studies, it will be important to identify predictive biomarkers of drug efficacy.

RevDate: 2021-07-20

Hailu EM, Lewis TT, Needham BL, et al (2021)

Longitudinal Associations between Discrimination, Neighborhood Social Cohesion, and Telomere Length: The Multi-Ethnic Study of Atherosclerosis (MESA).

The journals of gerontology. Series A, Biological sciences and medical sciences pii:6324315 [Epub ahead of print].

BACKGROUND: We aimed to examine if neighborhood social cohesion moderated longitudinal associations between baseline reports of discrimination and 10-year changes in Leukocyte Telomere Length (LTL).

METHODS: Data are from the Multi-Ethnic Study of Atherosclerosis (MESA; N=1,064; age range 45-84 years). Baseline discrimination was measured using the Major Experiences of Discrimination Scale (MDS; none, 1 domain, ≥2 domains) and the Experiences of Discrimination Scale (EDS; none, moderate, high). Neighborhood social cohesion at baseline was assessed via a community survey within census tract defined neighborhoods. 10-year change in LTL was defined as Regression to the Mean corrected 10-year difference in the ratio of telomeric DNA to a single copy gene (T/S).

RESULTS: In linear mixed effects models, we found that neighborhood social cohesion modified the effect of baseline reports of MDS on 10-year changes in LTL, independent of sociodemographic characteristics, health behaviors, and health conditions (p(χ 2)=0.01). Among those residing in neighborhoods with low social cohesion, experiencing major discrimination in ≥2 domains was associated with faster LTL attrition over 10-years, compared to reporting no discrimination (β=-0.03; 95% CI: -0.06, -0.003). We found no main associations for either discrimination measure and no interaction between EDS and neighborhood social cohesion.

CONCLUSIONS: Results indicate that neighborhood social cohesion is an important dimension of the neighborhood context that may moderate the impact of major experiences of discrimination on telomere length attrition. These findings help advance our understanding of the integral role that neighborhood environments play in attenuating the effect of discrimination on accelerated cell aging.

RevDate: 2021-07-20

Lakota K, J Varga (2021)

Linking autoimmunity, short telomeres and lung fibrosis in SSc.

Nature reviews. Rheumatology [Epub ahead of print].

RevDate: 2021-07-19

Wang Z, X Wu (2021)

Abnormal function of telomere protein TRF2 induces cell mutation and the effects of environmental tumor‑promoting factors (Review).

Oncology reports, 46(2):.

Recent studies have found that somatic gene mutations and environmental tumor‑promoting factors are both indispensable for tumor formation. Telomeric repeat‑binding factor (TRF)2 is the core component of the telomere shelterin complex, which plays an important role in chromosome stability and the maintenance of normal cell physiological states. In recent years, TRF2 and its role in tumor formation have gradually become a research hot topic, which has promoted in‑depth discussions into tumorigenesis and treatment strategies, and has achieved promising results. Some cells bypass elimination, due to either aging, apoptosis via mutations or abnormal prolongation of the mitotic cycle, and enter the telomere crisis period, where large‑scale DNA reorganization occurs repeatedly, which manifests as the precancerous cell cycle. Finally, at the end of the crisis cycle, the mutation activates either the expression level of telomerase or activates the alternative lengthening of telomere mechanism to extend the local telomeres. Under the protection of TRF2, chromosomes are gradually stabilized, immortal cells are formed and the stagewise mutation‑driven transformation of normal cells to cancer cells is completed. In addition, TRF2 also shares the characteristics of environmental tumor‑promoting factors. It acts on multiple signal transduction pathway‑related proteins associated with cell proliferation, and affects peripheral angiogenesis, inhibits the immune recognition and killing ability of the microenvironment, and maintains the stemness characteristics of tumor cells. TRF2 levels are abnormally elevated by a variety of tumor control proteins, which are more conducive to the protection of telomeres and the survival of tumor cells. In brief, the various regulatory mechanisms which tumor cells rely on to survive are organically integrated around TRF2, forming a regulatory network, which is conducive to the optimization of the survival direction of heterogeneous tumor cells, and promotes their survival and adaptability. In terms of clinical application, TRF2 is expected to become a new type of cancer prognostic marker and a new tumor treatment target. Inhibition of TRF2 overexpression could effectively cut off the core network regulating tumor cell survival, reduce drug resistance, or bypass the mutation under the pressure of tumor treatment selection, which may represent a promising therapeutic strategy for the complete eradication of tumors in the clinical setting. Based on recent research, the aim of the present review was to systematically elaborate on the basic structure and functional characteristics of TRF2 and its role in tumor formation, and to analyze the findings indicating that TRF2 deficiency or overexpression could cause severe damage to telomere function and telomere shortening, and induce DNA damage response and chromosomal instability.

RevDate: 2021-07-19

García-Martínez S, González-Gamo D, Fernández-Marcelo T, et al (2021)

Obesity and telomere status in the prognosis of patients with colorectal cancer submitted to curative intention surgical treatment.

Molecular and clinical oncology, 15(3):184.

The risk of colorectal cancer (CRC) development has been associated with telomere dysfunction and obesity. However, clinical relevance of these parameters in CRC prognosis is not clear. Therefore, the aim of the present study was to evaluate the impact of obesity and telomere status in the prognosis of patients affected by CRC and submitted to curative surgical treatment. According to published data, this is the first work in which obesity and telomere status are jointly considered in relation to CRC prognosis. A prospective study including 162 patients with CRC submitted to curative surgical treatment was performed. Subjects were classified according to their BMI. Telomere status was established through telomere length and telomerase activity evaluation. Statistical analyses were performed using the SPSS software package version 22. Telomere shortening was inversely associated with BMI in patients with CRC. Notably, among patients with CRC, subjects with obesity exhibited less shortening of tumor telomeres than non-obese patients (P=0.047). Patients with shorter telomeres, both in the tumor (median telomere length <6.5 kb) and their non-tumor paired tissues (median telomere length <7.1 kb), had the best clinical evolution, regardless of the Dukes' stage of cancers (P=0.025, for tumor samples; P=0.003, for non-tumor samples). Additionally, subjects with a BMI >31.85 kg/m2 showed the worse clinical outcomes compared with subjects with other BMI values. Interestingly, the impact of BMI showed sex dependence, since only the group of men displayed significant differences in CRC prognosis in relation to obesity status (P=0.037). From the results of the present study, based on a multivariate prediction model to establish prognosis, it was concluded that telomere length is a useful biomarker to predict prognosis in patients with CRC. Regardless of BMI values, the improved clinical evolution was associated with shorter telomeres. The impact of BMI seems to be associated with other factors, such as sex.

RevDate: 2021-07-17

Farzan SF, Shahriar M, Kibriya MG, et al (2021)

Urinary arsenic and relative telomere length in 5-7 year old children in Bangladesh.

Environment international, 156:106765 pii:S0160-4120(21)00390-1 [Epub ahead of print].

BACKGROUND: Telomere length has been associated with the occurrence and progression of common chronic and age-related diseases, and in younger populations, may represent a biomarker of disease susceptibility. Early childhood is a critical period for telomere biology as this period is characterized by a rapid decline in telomere length due to a large turnover of highly proliferative cells and may represent a period of unique sensitivity to environmental insults. Arsenic (As) exposure has been associated with both telomere lengthening and shortening in adults and children and some evidence suggests the effects may differ by level and timing of exposure.

OBJECTIVES: Given the lack of clarity across studies, we investigated the association between urinary As and leukocyte telomere length among 476 five- to seven-year-old children enrolled in the Bangladesh Environmental Research in Children's Health (BiRCH) cohort.

METHODS: In a series of multivariable models, adjusted for key covariates, we examined associations between urinary As and relative telomere length (RTL) of whole blood DNA.

RESULTS: We observed small but consistent, negative associations between urinary As and RTL, such that a doubling of urinary As was associated with a -0.017 (95% CI: -0.030, -0.005; p = 0.0056) decrease in RTL, in fully adjusted models. We also observed a somewhat stronger inverse relationship between urinary As concentration and RTL among children born to fathers ≥ 30 years of age at the time of birth, than those < 30 years; however, we did not observe a statistically significant interaction.

DISCUSSION: Our study suggests that As influences RTL, with detectable associations in early to mid-childhood. Further studies are needed to confirm our findings and investigate the potential long-term impacts of telomere shortening in childhood on later life health outcomes. Additional studies exploring how dose and timing of exposure may relate to RTL are critical to understanding As's relationship to telomere length.

RevDate: 2021-07-17

Liu S, Chung MP, Ley B, et al (2021)

Peripheral blood leucocyte telomere length is associated with progression of interstitial lung disease in systemic sclerosis.

Thorax pii:thoraxjnl-2020-215918 [Epub ahead of print].

BACKGROUND: Peripheral blood leucocyte telomere length (PBL-TL) is associated with outcomes in patients with idiopathic pulmonary fibrosis. Whether PBL-TL is associated with progression of systemic sclerosis-associated interstitial lung disease (SSc-ILD) is unknown.

METHODS: A retrospective observational cohort study was performed using prospectively collected data from 213 patients with SSc followed at the University of California San Francisco (UCSF) Scleroderma Center. PBL-TL was measured by quantitative PCR of DNA isolated from peripheral blood. Associations between PBL-TL and pulmonary function test trends in patients with SSc-ILD were assessed by longitudinal analysis using Generalised Linear Mixed Models. Findings were validated in a cohort of 61 patients with SSc-ILD enrolled in the Stanford University Scleroderma Center database.

RESULTS: Patients with UCSF SSc with ILD were found to have shorter PBL-TL compared with those without ILD (6554±671 base pairs (bp) vs 6782±698 bp, p=0.01). Shorter PBL-TL was associated with the presence of ILD (adjusted OR 2.1 per 1000 bp TL decrease, 95% CI [1.25 to 3.70], p=0.006). PBL-TL was shorter in patients with SSc-ILD lacking SSc-specific autoantibodies compared with seropositive subjects (6237±647 bp vs 6651±653 bp, p=0.004). Shorter PBL-TL was associated with increased risk for lung function deterioration with an average of 67 mL greater loss in per year for every 1000 bp decrease in PBL-TL in the combined SSc-ILD cohorts (longitudinal analysis, adjusted model: 95% CI -104 mL to -33 mL, p<0.001).

CONCLUSIONS: These findings suggest that telomere dysfunction may be associated with SSc-ILD progression and that PBL-TL measurement may be useful for stratifying risk for SSc-ILD progression.

RevDate: 2021-07-16

Bailey SM, Luxton JJ, McKenna MJ, et al (2021)

Ad astra - Telomeres in Space!.

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

Purpose: My journey to the stars began as I - along with the whole world - stood still and watched Neil Armstrong take those first small steps on the Moon. Fast forward 50 years and NASA astronauts Scott Kelly and Christina Koch each spend nearly a year in space aboard the International Space Station (ISS), a remarkable multinational collaborative project and floating U.S. National Laboratory that has supported continuous human presence in low Earth orbit for the past 20 years. Marking a new era of human space exploration, the first commercial rocket, SpaceX Falcon 9, recently launched NASA astronauts Doug Hurley and Bob Behnken in the Crew Dragon spacecraft Endeavour to the ISS and returned safely to Earth. NASA and its commercial partners are rapidly advancing innovative space technologies, and with the recently announced Artemis team of astronauts, plans to send the first woman and next man back to the moon and establish sustainable exploration by the end of the decade. Humankind will then be poised to take the next giant leap - pioneering human exploration of Mars.Conclusions. Historically, fewer than 600 individuals have participated in spaceflight, the vast majority of whom have been middle aged males (35-55 years) on short duration missions (less than 20 days) (Smith 2020). Thus, as the number and diversity of space travelers increase, a better understanding of how long-duration spaceflight affects human health is essential to maintaining individual astronaut performance during, and improving disease and aging trajectories following, future exploration missions. Here, I review findings from our NASA Twins Study and Telomeres investigations, highlighting potential mechanistic roles of chronic space radiation exposure in changes in telomere length and persistent DNA damage responses associated with long-duration spaceflight. Importantly, similar trends were observed in prostate cancer patients undergoing intensity-modulated radiation therapy (IMRT), additional support specifically for the role of radiation exposure. Individual differences in response were also observed in both cohorts, underscoring the importance of developing personalized approaches for evaluating human health effects and long-term outcomes associated with radiation exposures, whether on Earth or living in the extreme environment of space.

RevDate: 2021-07-16

Luchini C, Lawlor RT, Bersani S, et al (2021)

Alternative Lengthening of Telomeres (ALT) in Pancreatic Neuroendocrine Tumors: Ready for Prime-Time in Clinical Practice?.

Current oncology reports, 23(9):106.

PURPOSE OF REVIEW: Alternative lengthening of telomeres (ALT) is a telomerase-independent mechanism used by some types of malignancies, including pancreatic neuroendocrine tumors, to overcome the issue of telomere shortening, thus supporting tumor growth and cell proliferation. This review is focused on the most important achievements and opportunities deriving from ALT assessment in PanNET onco-pathology, highlighting the most promising fields in which such biomarker could be implemented in clinical practice.

RECENT FINDINGS: In pancreatic neuroendocrine tumors (PanNET), ALT is strongly correlated with the mutational status of two chromatin remodeling genes, DAXX and ATRX. Recent advances in tumor biology permitted to uncover important roles of ALT in the landscape of PanNET, potentially relevant for introducing this biomarker into clinical practice. Indeed, ALT emerged as a reliable indicator of worse prognosis for PanNET, helping in clinical stratification and identification of "high-risk" patients. Furthermore, it is a very specific marker supporting the pancreatic origin of neuroendocrine neoplasms and can be used for improving the diagnostic workflow of patients presenting with neuroendocrine metastasis from unknown primary. The activation of this process can be determined by specific FISH analysis. ALT should be introduced in clinical practice for identifying "high-risk" PanNET patients and improving their clinical management, and as a marker of pancreatic origin among neuroendocrine tumors.

RevDate: 2021-07-16

Anderson JJ, Susser E, Arbeev KG, et al (2021)

Short Telomeres and a T-Cell Shortfall in COVID-19: The Aging Effect.

medRxiv : the preprint server for health sciences.

The slow pace of global vaccination and the rapid emergence of SARS-CoV-2 variants suggest recurrent waves of COVID-19 in coming years. Therefore, understanding why deaths from COVID-19 are highly concentrated among older adults is essential for global health. Severe COVID-19 T-cell lymphopenia is more common among older adults, and it entails poor prognosis. Much about the primary etiology of this form of lymphopenia remains unknown, but regardless of its causes, offsetting the decline in T-cell count during SARS-CoV-2 infection demands fast and massive T-cell clonal expansion, which is telomere length (TL)-dependent. We have built a model that captures the effect of age-dependent TL shortening in hematopoietic cells and its effect on T-cell clonal expansion capacity. The model shows that an individual with average hematopoietic cell TL (HCTL) at age twenty years maintains maximal T-cell clonal expansion capacity until the 6th decade of life when this capacity plummets by more than 90% over the next ten years. The collapse coincides with the steep increase in COVID-19 mortality with age. HCTL metrics may thus explain the vulnerability of older adults to COVID-19. That said, the wide inter-individual variation in HCTL across the general population means that some younger adults with inherently short HCTL might be at risk of severe COVID-19 lymphopenia and mortality from the disease.

Significance Statement: Declining immunity with advancing age is a general explanation for the increased mortality from COVID-19 among older adults. This mortality far exceeds that from viral illnesses such as the seasonal influenza, and it thus requires specific explanations. One of these might be diminished ability with age to offset the development of severe T-cell lymphopenia (a low T-cell count in the blood) that often complicates COVID-19. We constructed a model showing that age-dependent shortening of telomeres might constrain the ability of T-cells of some older COVID-19 patients to undertake the massive proliferation required to clear the virus that causes the infection. The model predicts that individuals with short telomeres, principally seniors, might be at a higher risk of death from COVID-19.

RevDate: 2021-07-16

Harrigan AM, MacDonald S, Crooks B, et al (2021)

A Case Series of TERC Variant Telomere Biology Disorders in Unrelated Families From Atlantic Canada.

Journal of hematology, 10(3):130-135.

TERC variant telomere biology disorders (TBDs) are a rare, heterogenous group of disorders that arise from germline variants in TERC, a gene that encodes for the RNA component of telomerase. Variants in TERC lead to accelerated telomere attrition and can manifest as many different phenotypes. In this case series, we aimed to add to the literature describing TERC variant TBDs by reporting cases from two unrelated families from Atlantic Canada. The first case, a previously described germline TERC variant, n.107G>T (NR_001566.1), was identified in a young woman with myelodysplastic syndrome (MDS) and found to segregate with cytopenias in the family. This case represents a unique phenotypic presentation: this variant has not previously been described in patients with MDS and adds important segregation data to the literature. The second case, a novel TERC n.437T>G variant, was identified in a patient with both aplastic anemia and pulmonary fibrosis manifesting in his early 30s. We report these novel cases of germline TERC variants in order to help clinicians recognize TBDs, as well as to add important supporting information for the pathogenicity of these variants.

RevDate: 2021-07-16

Hackenhaar FS, Josefsson M, Adolfsson AN, et al (2021)

Short leukocyte telomeres predict 25-year Alzheimer's disease incidence in non-APOE ε4-carriers.

Alzheimer's research & therapy, 13(1):130.

BACKGROUND: Leukocyte telomere length (LTL) has been shown to predict Alzheimer's disease (AD), albeit inconsistently. Failing to account for the competing risks between AD, other dementia types, and mortality, can be an explanation for the inconsistent findings in previous time-to-event analyses. Furthermore, previous studies indicate that the association between LTL and AD is non-linear and may differ depending on apolipoprotein E (APOE) ε4 allele carriage, the strongest genetic AD predictor.

METHODS: We analyzed whether baseline LTL in interaction with APOE ε4 predicts AD, by following 1306 initially non-demented subjects for 25 years. Gender- and age-residualized LTL (rLTL) was categorized into tertiles of short, medium, and long rLTLs. Two complementary time-to-event models that account for competing risks were used; the Fine-Gray model to estimate the association between the rLTL tertiles and the cumulative incidence of AD, and the cause-specific hazard model to assess whether the cause-specific risk of AD differed between the rLTL groups. Vascular dementia and death were considered competing risk events. Models were adjusted for baseline lifestyle-related risk factors, gender, age, and non-proportional hazards.

RESULTS: After follow-up, 149 were diagnosed with AD, 96 were diagnosed with vascular dementia, 465 died without dementia, and 596 remained healthy. Baseline rLTL and other covariates were assessed on average 8 years before AD onset (range 1-24). APOE ε4-carriers had significantly increased incidence of AD, as well as increased cause-specific AD risk. A significant rLTL-APOE interaction indicated that short rLTL at baseline was significantly associated with an increased incidence of AD among non-APOE ε4-carriers (subdistribution hazard ratio = 3.24, CI 1.404-7.462, P = 0.005), as well as borderline associated with increased cause-specific risk of AD (cause-specific hazard ratio = 1.67, CI 0.947-2.964, P = 0.07). Among APOE ε4-carriers, short or long rLTLs were not significantly associated with AD incidence, nor with the cause-specific risk of AD.

CONCLUSIONS: Our findings from two complementary competing risk time-to-event models indicate that short rLTL may be a valuable predictor of the AD incidence in non-APOE ε4-carriers, on average 8 years before AD onset. More generally, the findings highlight the importance of accounting for competing risks, as well as the APOE status of participants in AD biomarker research.

RevDate: 2021-07-15

Heba AC, Toupance S, Arnone D, et al (2021)

Telomeres: New players in immune-mediated inflammatory diseases?.

Journal of autoimmunity, 123:102699 pii:S0896-8411(21)00107-4 [Epub ahead of print].

Telomeres are repetitive DNA sequences located at the ends of linear chromosomes that preserve the integrity and stability of the genome. Telomere dysfunctions due to short telomeres or altered telomere structures can ultimately lead to replicative cellular senescence and chromosomal instability, both mechanisms being hallmarks of ageing. Chronic inflammation, oxidative stress and finally telomere length (TL) dynamics have been shown to be involved in various age-related non-communicable diseases (NCDs). Immune-mediated inflammatory diseases (IMIDs), including affections such as inflammatory bowel disease, psoriasis, rheumatoid arthritis, spondyloarthritis and uveitis belong to this group of age-related NCDs. Although in recent years, we have witnessed the emergence of studies in the literature linking these IMIDs to TL dynamics, the causality between these diseases and telomere attrition is still unclear and controversial. In this review, we provide an overview of available studies on telomere dynamics and discuss the utility of TL measurements in immune-mediated inflammatory diseases.

RevDate: 2021-07-15

Lee RS, Zandi PP, Santos A, et al (2021)

Cross-species Association Between Telomere Length and Glucocorticoid Exposure.

The Journal of clinical endocrinology and metabolism pii:6321972 [Epub ahead of print].

CONTEXT: Chronic exposure to glucocorticoids (GCs) or stress increases the risk of medical disorders, including cardiovascular and neuropsychiatric disorders. GCs contribute to an accelerated aging, while the link between chronic GCs exposure and disease onset is well established, the underpinning mechanisms are not clear.

OBJECTIVE: we explored the potential nexus between GCs or stress exposure and telomere length.

rats exposed to three weeks of chronic stress; an iatrogenic mouse model of Cushing's syndrome (CS); a mouse neuronal cell line; 33 patients with CS and 75 healthy human people were studied.

RESULTS: 1.Telomere length is associated with exposure to stress in rats: 54.5% (P=0.036) reduction in telomere length in the stressed animals. Genomic DNA extracted from the dentate gyrus of stressed and unstressed rats showed 43.2% reduction in telomere length (P=0.006). 2. Mice were exposed to corticosterone (CORT), this treatment produced a 61.4% reduction in telomere length in the blood gDNA (P=5.75x 10-5). 3. We observed a 40.8% reduction in the telomere length in patients with active CS compared to healthy controls (P=0.006). There was a 17.8% reduction in telomere length in cured CS patients, no different from controls (P=0.08). For both cured and active CS, telomere length correlated significantly with the duration of hypercortisolism (R2=0.22, P=0.007). 4. There was a 27.6% reduction in telomere length between low vs. high tertiles in bedtime cortisol levels (P=0.019).

CONCLUSIONS: Our findings demonstrate that exposure to stress and/or glucocorticoids is associated with shortened telomeres, and that shortening may be partially reversible.

RevDate: 2021-07-13

Aguiar SS, Rosa TS, Neves RVP, et al (2021)

Telomere Length, SIRT1, and Insulin in Male Master Athletes: The Path to Healthy Longevity?.

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

Lower SIRT1 and insulin resistance are associated with accelerated telomere shortening. This study investigated whether the lifestyle of master athletes can attenuate these age-related changes and thereby slow aging. We compared insulin, SIRT1, and telomere length in highly trained male master athletes (n=52; aged 49.9±7.2 yrs) and age-matched non-athletes (n=19; aged 47.3±8.9 yrs). This is a cross-sectional study, in which all data were collected in one visit. Overnight fasted SIRT1 and insulin levels in whole blood were assessed using commercial kits. Relative telomere length was determined in leukocytes through qPCR analyses. Master athletes had higher SIRT1, lower insulin, and longer telomere length than age-matched non-athletes (p<0.05 for all). Insulin was inversely associated with SIRT1 (r=-0.38; p=0.001). Telomere length correlated positively with SIRT1 (r=0.65; p=0.001), whereas telomere length and insulin were not correlated (r=0.03; p=0.87). In conclusion, master athletes have higher SIRT1, lower insulin, and longer telomeres than age-matched non-athletes. Furthermore, SIRT1 was negatively associated with insulin and positively associated with telomere length. These findings suggest that in this sample of middle-aged participants reduced insulin, increased SIRT1 activity, and attenuation of biological aging are connected.

RevDate: 2021-07-13

Liu J, Hu X, Bao K, et al (2021)

The cooperative assembly of shelterin bridge provides a kinetic gateway that controls telomere length homeostasis.

Nucleic acids research pii:6320402 [Epub ahead of print].

Shelterin is a six-protein complex that coats chromosome ends to ensure their proper protection and maintenance. Similar to the human shelterin, fission yeast shelterin is composed of telomeric double- and single-stranded DNA-binding proteins, Taz1 and Pot1, respectively, bridged by Rap1, Poz1 and Tpz1. The assembly of the proteinaceous Tpz1-Poz1-Rap1 complex occurs cooperatively and disruption of this shelterin bridge leads to unregulated telomere elongation. However, how this biophysical property of bridge assembly is integrated into shelterin function is not known. Here, utilizing synthetic bridges with a range of binding properties, we find that synthetic shelterin bridge lacking cooperativity requires a linker pair that matches the native bridge in complex lifespan but has dramatically higher affinity. We find that cooperative assembly confers kinetic properties on the shelterin bridge allowing disassembly to function as a molecular timer, regulating the duration of the telomere open state, and consequently telomere lengthening to achieve a defined species-specific length range.

RevDate: 2021-07-13

Chakravarti D, Lee R, Multani AS, et al (2021)

Telomere dysfunction instigates inflammation in inflammatory bowel disease.

Proceedings of the National Academy of Sciences of the United States of America, 118(29):.

Inflammatory bowel disease (IBD) is a chronic inflammatory condition driven by diverse genetic and nongenetic programs that converge to disrupt immune homeostasis in the intestine. We have reported that, in murine intestinal epithelium with telomere dysfunction, DNA damage-induced activation of ataxia-telangiectasia mutated (ATM) results in ATM-mediated phosphorylation and activation of the YAP1 transcriptional coactivator, which in turn up-regulates pro-IL-18, a pivotal immune regulator in IBD pathogenesis. Moreover, individuals with germline defects in telomere maintenance genes experience increased occurrence of intestinal inflammation and show activation of the ATM/YAP1/pro-IL-18 pathway in the intestinal epithelium. Here, we sought to determine the relevance of the ATM/YAP1/pro-IL-18 pathway as a potential driver of IBD, particularly older-onset IBD. Analysis of intestinal biopsy specimens and organoids from older-onset IBD patients documented the presence of telomere dysfunction and activation of the ATM/YAP1/precursor of interleukin 18 (pro-IL-18) pathway in the intestinal epithelium. Employing intestinal organoids from healthy individuals, we demonstrated that experimental induction of telomere dysfunction activates this inflammatory pathway. In organoid models from ulcerative colitis and Crohn's disease patients, pharmacological interventions of telomerase reactivation, suppression of DNA damage signaling, or YAP1 inhibition reduced pro-IL-18 production. Together, these findings support a model wherein telomere dysfunction in the intestinal epithelium can initiate the inflammatory process in IBD, pointing to therapeutic interventions for this disease.

RevDate: 2021-07-13

Xue L, Gao Y, Wu M, et al (2021)

Telomere-to-telomere assembly of a fish Y chromosome reveals the origin of a young sex chromosome pair.

Genome biology, 22(1):203.

BACKGROUND: The origin of sex chromosomes requires the establishment of recombination suppression between the proto-sex chromosomes. In many fish species, the sex chromosome pair is homomorphic with a recent origin, providing species for studying how and why recombination suppression evolved in the initial stages of sex chromosome differentiation, but this requires accurate sequence assembly of the X and Y (or Z and W) chromosomes, which may be difficult if they are recently diverged.

RESULTS: Here we produce a haplotype-resolved genome assembly of zig-zag eel (Mastacembelus armatus), an aquaculture fish, at the chromosomal scale. The diploid assembly is nearly gap-free, and in most chromosomes, we resolve the centromeric and subtelomeric heterochromatic sequences. In particular, the Y chromosome, including its highly repetitive short arm, has zero gaps. Using resequencing data, we identify a ~7 Mb fully sex-linked region (SLR), spanning the sex chromosome centromere and almost entirely embedded in the pericentromeric heterochromatin. The SLRs on the X and Y chromosomes are almost identical in sequence and gene content, but both are repetitive and heterochromatic, consistent with zero or low recombination. We further identify an HMG-domain containing gene HMGN6 in the SLR as a candidate sex-determining gene that is expressed at the onset of testis development.

CONCLUSIONS: Our study supports the idea that preexisting regions of low recombination, such as pericentromeric regions, can give rise to SLR in the absence of structural variations between the proto-sex chromosomes.

RevDate: 2021-07-10

Chico-Sordo L, Córdova-Oriz I, Polonio AM, et al (2021)

Reproductive aging and telomeres: are women and men equally affected?.

Mechanisms of ageing and development pii:S0047-6374(21)00113-5 [Epub ahead of print].

Successful reproduction is very important for individuals and for society. Currently, the human health span and lifespan are the object of intense and productive investigation with great achievements, compared to the last century. However, reproduction span does not progress concomitantly with lifespan. Reproductive organs age, decreasing the levels of sexual hormones, which are protectors of health through their action on several organs of the body. Thus, this is the starting point of the organismal decay and infertility. This starting point is easily detected in women. In men, it goes under the surface, undetected, but it goes, nevertheless. Regarding fertility, aging alters the hormonal equilibrium, decreases the potential of reproductive organs, diminishes the quality of the gametes and worsen the reproductive outcomes. All these events happen at a different pace and affecting different organs in women and men. The question is what molecular pathways are involved in reproductive aging and if there is a possible halting or even reversion of the aging events. Answers to all these points will be explained in the present review.

RevDate: 2021-07-10

Apte MS, Masuda H, Wheeler DL, et al (2021)

RNAi and Ino80 complex control rate limiting translocation step that moves rDNA to eroding telomeres.

Nucleic acids research pii:6318500 [Epub ahead of print].

The discovery of HAATIrDNA, a telomerase-negative survival mode in which canonical telomeres are replaced with ribosomal DNA (rDNA) repeats that acquire chromosome end-protection capability, raised crucial questions as to how rDNA tracts 'jump' to eroding chromosome ends. Here, we show that HAATIrDNA formation is initiated and limited by a single translocation that juxtaposes rDNA from Chromosome (Chr) III onto subtelomeric elements (STE) on Chr I or II; this rare reaction requires RNAi and the Ino80 nucleosome remodeling complex (Ino80C), thus defining an unforeseen relationship between these two machineries. The unique STE-rDNA junction created by this initial translocation is efficiently copied to the remaining STE chromosome ends, independently of RNAi or Ino80C. Intriguingly, both RNAi and Ino80C machineries contain a component that plays dual roles in HAATI subtype choice. Dcr1 of the RNAi pathway and Iec1 of Ino80C both promote HAATIrDNA formation as part of their respective canonical machineries, but both also inhibit formation of the exceedingly rare HAATISTE (where STE sequences mobilize throughout the genome and assume chromosome end protection capacity) in non-canonical, pathway-independent manners. This work provides a glimpse into a previously unrecognized crosstalk between RNAi and Ino80C in controlling unusual translocation reactions that establish telomere-free linear chromosome ends.

RevDate: 2021-07-08

Chang-Chien J, Huang JL, Tsai HJ, et al (2021)

Particulate matter causes telomere shortening and increase in cellular senescence markers in human lung epithelial cells.

Ecotoxicology and environmental safety, 222:112484 pii:S0147-6513(21)00596-0 [Epub ahead of print].

Exposure to particulate matter (PM) has been associated with DNA damage, but the relationships between PM, telomere length and cellular senescence remain unclear. This study aimed to investigate the effects and potential mechanisms of PM on telomere length and cellular senescence in human lung epithelial cells. Human lung epithelial A549 cells were exposed to PM for 24 h. Cell viability and cytotoxicity were measured by the WST-1 assay and the lactate dehydrogenase release, respectively. Cellular uptake of PM was observed using transmission electron microscopy. Telomere length was measured using qPCR and expressed as T/S ratio. Cell cycle progression was analyzed by flow cytometry. Expression of human telomerase reverse transcriptase (hTERT) and cell cycle regulators was measured using mRNA by qPCR and protein levels by Western blot. Cellular senescence was determined by the expression of senescence-associated β-galactosidase (SA-β-Gal) with fluorescent microscopy and flow cytometry. Exposed to PM at the concentration of 200 μg/ml decreased cell viability and increased LDH levels in culture medium. Remarkably increased uptake of PM, shortening of telomere length, induction of G0/G1 phase arrest, and increased expression of senescence hallmarks were observed after exposure to PM in A549 cells. PM exposure induced upregulation of p21 and downregulation of proliferating cell nuclear antigen (PCNA) and hTERT expression, but no significant change in p53 expression, in A549 cells. Overall, exposure to PM may downregulate hTERT and PCNA through p53-independent induction of p21 expression, leading to telomere shortening, G0/G1 arrest and the onset of cellular senescence in human lung epithelial cells.

RevDate: 2021-07-08

Wojcicki JM, Lustig RH, Jacobs LM, et al (2021)

Longer Leukocyte Telomere Length Predicts Stronger Response to a Workplace Sugar-Sweetened Beverage Sales Ban: An Exploratory Study.

Current developments in nutrition, 5(7):nzab084 pii:nzab084.

Background: Shorter leukocyte telomere length (LTL) is associated with increased risk of a number of metabolic diseases including insulin resistance and the development of type 2 diabetes mellitus. Shorter LTL is also associated with stress reactivity suggestive of a possible role for LTL to predict response to behavioral interventions. However, few studies have evaluated how interventions, such as weight loss or dietary changes, are associated with LTL changes or whether LTL can predict behavioral responses to interventions.

Objectives: We evaluated metabolic changes in relation to LTL changes and LTL at baseline in a cohort of at-risk adults in response to a 10-mo workplace-based sugar-sweetened beverage (SSB) intervention.

Methods: At baseline, metabolic health and LTL measurements were assessed through standard blood draws on 212 participants. Multivariable linear regression models were used to assess changes in anthropometrics, SSB consumption, and 13 blood-based metabolic risk factors, in relation to LTL at baseline and changes in LTL.

Results: Longer LTL at baseline was associated with decreases in SSB consumption over the 6-mo follow-up period (B = -29.67; P = 0.04). Slower LTL attrition rates were associated with decreases in waist circumference (B = -0.27; P = 0.03), HDL cholesterol (B = -0.20; P = 0.05), and apoA1 (B = -0.09; P = 0.01).

Conclusions: Longer LTL at baseline predicted a favorable overall response to a behavioral intervention: decreases in SSB consumption. Abdominal adiposity losses paralleled slower declines in LTL suggestive of overall health benefits, but we found differences in the relations between metabolic changes and LTL at baseline compared with LTL attrition rates. Longer LTL may be a proxy marker of a positive behavioral response.This trial was registered at clinicaltrials.gov as NCT02585336.

RevDate: 2021-07-06

Jin M, Li J, Chen Y, et al (2021)

Near-Infrared Small Molecule as a Specific Fluorescent Probe for Ultrasensitive Recognition of Antiparallel Human Telomere G-Quadruplexes.

ACS applied materials & interfaces [Epub ahead of print].

In the past 10 years, many fluorescent probes have been developed to recognize G-quadruplexes (G4s) since G4s play an important role in biological systems. However, the selectivity and sensitivity of existing probes for G4s limit their further applications. Herein, we design and synthesize a new probe (TOVJ) by introducing 9-vinyljulolidine into TO. The new probe exhibits almost no fluorescence in an aqueous solution. Upon interacting with G4s, especially the antiparallel G4s, the fluorescence intensity was greatly enhanced (maximum 2742-fold) with a large Stokes shift of 198 nm and the maximum emission peak at 694 nm (near-infrared region). TOVJ showed high sensitivity and selectivity to G4s over other DNA topologies (ssDNA/dsDNA), especially to antiparallel G4s. For antiparallel human telomere G4 detection, the limits of detection of Hum24 and 22AG Na+ were as low as 164 and 231 pM, respectively. This indicates that TOVJ is a highly sensitive fluorescence sensor that can be effectively used for antiparallel human telomere G4 detection. The result of live-cell imaging showed that TOVJ could enter live cells and locate in the mitochondria.

RevDate: 2021-07-07

Needham BL, Straight B, Hilton CE, et al (2021)

Family socioeconomic status and child telomere length among the Samburu of Kenya.

Social science & medicine (1982), 283:114182 pii:S0277-9536(21)00514-1 [Epub ahead of print].

Previous research in high-income countries suggests that children from families with lower socioeconomic status (SES) tend to have shorter telomere length - a biomarker of stress and cell aging - than children from families with greater social and economic resources. However, little is known about predictors of child telomere length in low-income settings. Data for the current study are from a sample of 214 Samburu children aged 1-9 years. The Samburu are semi-nomadic pastoralists who live in the Rift Valley of north-central Kenya. Samburu livelihood is based primarily on livestock, and polygynous marriage is common. Drawing on prior ethnographic research, we measured 14 culturally relevant indicators of family SES, including mother's education, head of household's education, whether the child is currently attending school, household spending, mother's employment history, head of household's employment history, mother's perceived wealth, whether the child lives in a modern house, livestock holdings (total, cows, sheep/goats, and camels), mother's wife number, and whether the child lives in a polygynous household. Telomere length was measured in salivary DNA by the quantitative polymerase chain reaction (qPCR) method. Using latent class analysis, we identified four groups of children that are similar based on the 14 indicators of family SES: Lower SES; Middle SES, Traditional; Middle SES, Modern; and Higher SES. SES classes were not significantly associated with child telomere length. In models examining individual indicators of SES, we found that telomere length was 0.57 standard deviations greater for children who lived in families in the lowest quartile of total livestock holdings compared to those in the highest quartile (b = 0.57, p = 0.03). While additional research is needed to identify the mechanisms underlying this counterintuitive finding, the current study highlights the importance of cultural context in shaping the social gradient in health.

RevDate: 2021-07-05

Li Z, Zhou D, Zhang D, et al (2021)

Folic Acid Inhibits Aging-Induced Telomere Attrition and Apoptosis in Astrocytes In Vivo and In Vitro.

Cerebral cortex (New York, N.Y. : 1991) pii:6314695 [Epub ahead of print].

Folic acid (FA) has been reported to inhibit astrocyte apoptosis and improve aging-induced disorders; however, its role in telomere attrition remains unclear. In present study, 4-month-old senescence-accelerated mouse prone 8 (SAMP8) mice were assigned to four treatment groups for the in vivo experiment: FA-deficient diet (FA-D) group, FA-normal diet (FA-N) group, low FA-supplemented diet (FA-L) group, and high FA-supplemented diet (FA-H) group. These mice were euthanized when 10 months old. There was also a young SAMP8 (4 months old) control group (Con-Y) fed with FA-normal diet. In in vitro study, primary cultures of astrocytes from hippocampus and cerebral cortex were incubated for five generations with various concentrations of FA (0-40 μM) and were assigned to five groups: FA 0 μM (generation 5), FA 10 μM (generation 5), FA 20 μM (generation 5), FA 40 μM (generation 5), and FA 10 μM (generation 1). The results showed that FA supplementation inhibited aging-induced astrocytosis, astrocyte apoptosis, neurodegeneration, and prevented telomere attrition in hippocampus and cortex of SAMP8 mice. FA supplementation also decreased apoptosis and telomere attrition, and increased telomerase activity, in primary cultures of astrocytes. These results showed that it may be one of the mechanisms that FA inhibiting aging-induced apoptosis of astrocyte by alleviating telomere attrition.

RevDate: 2021-07-06

Piplani S, Prabhu M, Alemao NN, et al (2021)

Conventional Risk Factors, Telomere Length, and Ischemic Heart disease: Insights into the Mediation Analysis.

Genome integrity, 12:1.

Telomere length is regarded as a potential biomarker of biological ageing and is associated with various age-related diseases, such as ischemic heart disease (IHD), myocardial infarction, peripheral vascular disease, and cancer. As there is a paucity of study that deals with this influence, this study aimed to assess how the cardiovascular risk factors influence the risk of IHD by performing mediation analysis. A total of 407 males were included in the study. IHD was diagnosed through echocardiography and coronary angiography by determining the number of coronary vessels involved. Demographic data, clinical history, and laboratory investigations such as random blood sugar (RBS), fasting lipid profile, serum creatinine, and serum urea levels of all the subjects were measured and recorded. Serum uric acid and blood urea nitrogen (BUN) levels were significantly higher in IHD subjects compared to non-IHD subjects (P < 0.05). Body mass index (BMI), glycosylated hemoglobin (HbA1c), RBS, serum uric acid, serum creatinine, BUN, total cholesterol, triglycerides, and telomere length significantly differed between subjects with and without IHD (P < 0.05). Further, telomere length (P < 0.001), BMI (P < 0.001), and total cholesterol level (P < 0.001) were risk factors that significantly affected the incidence of IHD, as proved by logistic regression. It indicates that shorter telomeres contribute to increased risk of IHD, influenced by BMI, HbA1c, BUN, total cholesterol levels, and RBS (P < 0.001). The study established a link between telomere shortening, conventional risk factors, and IHD; moreover, the study takes care in the role of mediation analysis which is a novel idea as little is done in this area of biostatistics with telomere length. Overall, this further establishes that telomeres length might serve as the promising biomarkers in predicting the risk of IHD.

RevDate: 2021-07-05

Brown TJ, Spurgin L, Dugdale HL, et al (2021)

Causes and Consequences of Telomere Lengthening in a Wild Vertebrate Population.

Molecular ecology [Epub ahead of print].

Telomeres have been advocated to be important markers of biological age in evolutionary and ecological studies. Telomeres usually shorten with age and shortening is frequently associated with environmental stressors and increased subsequent mortality. Telomere lengthening - an apparent increase in telomere length between repeated samples from the same individual - also occurs. However, the exact circumstances, and consequences, of telomere lengthening are poorly understood. Using longitudinal data from the Seychelles warbler (Acrocephalus sechellensis), we tested whether telomere lengthening - which occurs in adults of this species - is associated with specific stressors (reproductive effort, food availability, malarial infection and cooperative breeding) and predicts subsequent survival. In females, telomere shortening was observed under greater stress (i.e. low food availability, malaria infection), while telomere lengthening was observed in females experiencing lower stress (i.e. high food availability, assisted by helpers, without malaria). The telomere dynamics of males were not associated with the key stressors tested. These results indicate that, at least for females, telomere lengthening occurs in circumstances more conducive to self-maintenance. Importantly, both females and males with lengthened telomeres had improved subsequent survival relative to individuals that displayed unchanged, or shortened, telomeres - indicating that telomere lengthening is associated with individual fitness. These results demonstrate that telomere dynamics are bidirectionally responsive to the level of stress that an individual faces, but may poorly reflect the accumulation of stress over the lifetime.

RevDate: 2021-07-02

Hu X, Gao S, Wang P, et al (2021)

The knockdown efficiency of telomere associated genes with specific methodology in a zebrafish cell line.

Biochimie pii:S0300-9084(21)00158-9 [Epub ahead of print].

Zebrafish is broadly used as a model organism in gene loss-of-function studies in vivo, but its employment in vitro is greatly limited by the lack of efficient gene knockdown approaches in zebrafish cell lines such as ZF4. In this article, we attempt to induce silencing of telomere associated genes in ZF4 by applying the frequently-used siRNA transfection technology and a novel moiety-linked morpholino(vivo-MO). By proceeding with integrated optimization of siRNAs transfection and vivo-MOs treatment, we compared five transfection reagents and vivo-MOs simultaneously to evaluate the efficiency of terfa silencing in ZF4. 48 hours after siRNAs transfection, Lipofectamine™ 3000 and X-tremeGENE™ HP leaded to knockdown in 35% and 43% of terfa mRNA, respectively, while vivo-MO-terfa modulated 58% down-expression of zfTRF2 in contrast to vivo-MO-ctrl 72 hours after treatment. Further siRNA transfection targeting telomere associated genes by X-tremeGENE™ HP showed silencing in 40-68% of these genes without significant cytotoxicity and off-target effect. Our results confirmed the feasibility of gene loss-of-function studies in a zebrafish cell line, offered a systematic optimizing strategy to employ gene silencing experiments, and presented Lipofectamine™ 3000, X-tremeGENE™ HP and vivo-morpholinos as candidate gene silencing approaches for zebrafish in vitro gene loss-of-function studies. Successfully knockdown of shelterin genes further opened a new field for telomeric study in zebrafish.

RevDate: 2021-07-02

Chatain J, Blond A, Phan AT, et al (2021)

GGGCTA repeats can fold into hairpins poorly unfolded by replication protein A: a possible origin of the length-dependent instability of GGGCTA variant repeats in human telomeres.

Nucleic acids research pii:6313238 [Epub ahead of print].

Human telomeres are composed of GGGTTA repeats and interspersed with variant repeats. The GGGCTA variant motif was identified in the proximal regions of human telomeres about 10 years ago and was shown to display a length-dependent instability. In parallel, a structural study showed that four GGGCTA repeats folded into a non-canonical G-quadruplex (G4) comprising a Watson-Crick GCGC tetrad. It was proposed that this non-canonical G4 might be an additional obstacle for telomere replication. In the present study, we demonstrate that longer GGGCTA arrays fold into G4 and into hairpins. We also demonstrate that replication protein A (RPA) efficiently binds to GGGCTA repeats structured into G4 but poorly binds to GGGCTA repeats structured into hairpins. Our results (along with results obtained with a more stable variant motif) suggest that GGGCTA hairpins are at the origin of GGGCTA length-dependent instability. They also suggest, as working hypothesis, that failure of efficient binding of RPA to GGGCTA structured into hairpins might be involved in the mechanism of GGGCTA array instability. On the basis of our present and past studies about telomeric G4 and their interaction with RPA, we propose an original point of view about telomeric G4 and the evolution of telomeric motifs.

RevDate: 2021-07-05

Daneels L, Martens DS, Arredouani S, et al (2021)

Maternal Vitamin D and Newborn Telomere Length.

Nutrients, 13(6):.

Nutrition is important during pregnancy for offspring health. Gestational vitamin D intake may prevent several adverse outcomes and might have an influence on offspring telomere length (TL). In this study, we want to assess the association between maternal vitamin D intake during pregnancy and newborn TL, as reflected by cord blood TL. We studied mother-child pairs enrolled in the Maternal Nutrition and Offspring's Epigenome (MANOE) cohort, Leuven, Belgium. To calculate the dietary vitamin D intake, 108 women were asked to keep track of their diet using the seven-day estimated diet record (EDR) method. TL was assessed in 108 cord blood using a quantitative real-time PCR method. In each trimester of pregnancy, maternal serum 25-hydroxyvitamin D (25-OHD) concentration was measured. We observed a positive association (β = 0.009, p-value = 0.036) between newborn average relative TL and maternal vitamin D intake (diet + supplement) during the first trimester. In contrast, we found no association between average relative TL of the newborn and mean maternal serum 25-OHD concentrations during pregnancy. To conclude, vitamin D intake (diet + supplements), specifically during the first trimester of pregnancy, is an important factor associated with TL at birth.

RevDate: 2021-07-02

Karow A, Haubitz M, Oppliger Leibundgut E, et al (2021)

Targeting Telomere Biology in Acute Lymphoblastic Leukemia.

International journal of molecular sciences, 22(13): pii:ijms22136653.

Increased cell proliferation is a hallmark of acute lymphoblastic leukemia (ALL), and genetic alterations driving clonal proliferation have been identified as prognostic factors. To evaluate replicative history and its potential prognostic value, we determined telomere length (TL) in lymphoblasts, B-, and T-lymphocytes, and measured telomerase activity (TA) in leukocytes of patients with ALL. In addition, we evaluated the potential to suppress the in vitro growth of B-ALL cells by the telomerase inhibitor imetelstat. We found a significantly lower TL in lymphoblasts (4.3 kb in pediatric and 2.3 kb in adult patients with ALL) compared to B- and T-lymphocytes (8.0 kb and 8.2 kb in pediatric, and 6.4 kb and 5.5 kb in adult patients with ALL). TA in leukocytes was 3.2 TA/C for pediatric and 0.7 TA/C for adult patients. Notably, patients with high-risk pediatric ALL had a significantly higher TA of 6.6 TA/C compared to non-high-risk patients with 2.2 TA/C. The inhibition of telomerase with imetelstat ex vivo led to significant dose-dependent apoptosis of B-ALL cells. These results suggest that TL reflects clonal expansion and indicate that elevated TA correlates with high-risk pediatric ALL. In addition, telomerase inhibition induces apoptosis of B-ALL cells cultured in vitro. TL and TA might complement established markers for the identification of patients with high-risk ALL. Moreover, TA seems to be an effective therapeutic target; hence, telomerase inhibitors, such as imetelstat, may augment standard ALL treatment.

RevDate: 2021-07-05

Krapivin MI, Tikhonov AV, Efimova OA, et al (2021)

Telomere Length in Chromosomally Normal and Abnormal Miscarriages and Ongoing Pregnancies and Its Association with 5-hydroxymethylcytosine Patterns.

International journal of molecular sciences, 22(12):.

The present study investigates telomere length (TL) in dividing chorionic cytotrophoblast cells from karyotypically normal and abnormal first trimester miscarriages and ongoing pregnancies. Using Q-FISH, we measured relative TLs in the metaphase chromosomes of 61 chorionic villous samples. Relative TLs did not differ between karyotypically normal samples from miscarriages and those from ongoing pregnancies (p = 0.3739). However, among the karyotypically abnormal samples, relative TLs were significantly higher in ongoing pregnancies than in miscarriages (p < 0.0001). Relative TLs were also significantly higher in chorion samples from karyotypically abnormal ongoing pregnancies than in those from karyotypically normal ones (p = 0.0018) in contrast to miscarriages, where relative TL values were higher in the karyotypically normal samples (p = 0.002). In the karyotypically abnormal chorionic cytotrophoblast, the TL variance was significantly lower than in any other group (p < 0.05). Assessed by TL ratios between sister chromatids, interchromatid TL asymmetry demonstrated similar patterns across all of the chorion samples (p = 0.22) but significantly exceeded that in PHA-stimulated lymphocytes (p < 0.0001, p = 0.0003). The longer telomere was predominantly present in the hydroxymethylated sister chromatid in chromosomes featuring hemihydroxymethylation (containing 5-hydroxymethylcytosine in only one sister chromatid)-a typical sign of chorionic cytotrophoblast cells. Our results suggest that the phenomena of interchromatid TL asymmetry and its association to 5hmC patterns in chorionic cytotrophoblast, which are potentially linked to telomere lengthening through recombination, are inherent to the development programme. The TL differences in chorionic cytotrophoblast that are associated with karyotype and embryo viability seem to be determined by heredity rather than telomere elongation mechanisms. The inheritance of long telomeres by a karyotypically abnormal embryo promotes his development, whereas TL in karyotypically normal first-trimester embryos does not seem to have a considerable impact on developmental capacity.

RevDate: 2021-07-05

Azcona-Sanjulian MC (2021)

Telomere Length and Pediatric Obesity: A Review.

Genes, 12(6):.

Obesity is a chronic disease, which needs to be early detected early and treated in order prevent its complications. Changes in telomere length (TL) have been associated with obesity and its complications, such as diabetes mellitus and metabolic syndrome. Therefore, we conducted a systematic review to summarize results of studies that have measured TL in children and adolescents with obesity. Fourteen studies aiming to assess TL in pediatric patients with either obesity or who were overweight were included in this review. In conclusion, obesity and adiposity parameters are negatively associated with TL. Shorter telomeres are observed in children with obesity compared with their lean counterparts. Factors involved in obesity etiology, such as diet and physical activity, may contribute to maintenance of TL integrity. In the long term, TL change could be used as a biomarker to predict response to obesity treatment.

RevDate: 2021-07-05

Rassoulzadegan M, Sharifi-Zarchi A, L Kianmehr (2021)

DNA-RNA Hybrid (R-Loop): From a Unified Picture of the Mammalian Telomere to the Genome-Wide Profile.

Cells, 10(6):.

Local three-stranded DNA/RNA hybrid regions of genomes (R-loops) have been detected either by binding of a monoclonal antibody (DRIP assay) or by enzymatic recognition by RNaseH. Such a structure has been postulated for mouse and human telomeres, clearly suggested by the identification of the complementary RNA Telomeric repeat-containing RNA "TERRA". However, the tremendous disparity in the information obtained with antibody-based technology drove us to investigate a new strategy. Based on the observation that DNA/RNA hybrids in a triplex complex genome co-purify with the double-stranded chromosomal DNA fraction, we developed a direct preparative approach from total protein-free cellular extract without antibody that allows their physical isolation and determination of their RNA nucleotide sequence. We then define in the normal mouse and human sperm genomes the notion of stable DNA associated RNA terminal R-loop complexes, including TERRA molecules synthesized from local promoters of every chromosome. Furthermore, the first strong evidence of all telomeric structures, applied additionally to the whole murine sperm genome compared to the testes, showed reproducible R-loop complexes of the whole genome and suggesting a defined profile in the sperm genome for the next generation.

RevDate: 2021-07-05

Chronowski C, Akhanov V, Chan D, et al (2021)

Fructose Causes Liver Damage, Polyploidy, and Dysplasia in the Setting of Short Telomeres and p53 Loss.

Metabolites, 11(6):.

Studies in humans and model systems have established an important role of short telomeres in predisposing to liver fibrosis through pathways that are incompletely understood. Recent studies have shown that telomere dysfunction impairs cellular metabolism, but whether and how these metabolic alterations contribute to liver fibrosis is not well understood. Here, we investigated whether short telomeres change the hepatic response to metabolic stress induced by fructose, a sugar that is highly implicated in non-alcoholic fatty liver disease. We find that telomere shortening in telomerase knockout mice (TKO) imparts a pronounced susceptibility to fructose as reflected in the activation of p53, increased apoptosis, and senescence, despite lower hepatic fat accumulation in TKO mice compared to wild type mice with long telomeres. The decreased fat accumulation in TKO is mediated by p53 and deletion of p53 normalizes hepatic fat content but also causes polyploidy, polynuclearization, dysplasia, cell death, and liver damage. Together, these studies suggest that liver tissue with short telomers are highly susceptible to fructose and respond with p53 activation and liver damage that is further exacerbated when p53 is lost resulting in dysplastic changes.

RevDate: 2021-07-05

Jacczak B, Rubiś B, E Totoń (2021)

Potential of Naturally Derived Compounds in Telomerase and Telomere Modulation in Skin Senescence and Aging.

International journal of molecular sciences, 22(12):.

Proper functioning of cells-their ability to divide, differentiate, and regenerate-is dictated by genomic stability. The main factors contributing to this stability are the telomeric ends that cap chromosomes. Telomere biology and telomerase activity have been of interest to scientists in various medical science fields for years, including the study of both cancer and of senescence and aging. All these processes are accompanied by telomere-length modulation. Maintaining the key levels of telomerase component (hTERT) expression and telomerase activity that provide optimal telomere length as well as some nontelomeric functions represents a promising step in advanced anti-aging strategies, especially in dermocosmetics. Some known naturally derived compounds contribute significantly to telomere and telomerase metabolism. However, before they can be safely used, it is necessary to assess their mechanisms of action and potential side effects. This paper focuses on the metabolic potential of natural compounds to modulate telomerase and telomere biology and thus prevent senescence and skin aging.

RevDate: 2021-07-02

Sellami M, Al-Muraikhy S, Al-Jaber H, et al (2021)

Age and Sport Intensity-Dependent Changes in Cytokines and Telomere Length in Elite Athletes.

Antioxidants (Basel, Switzerland), 10(7): pii:antiox10071035.

BACKGROUND: Exercise-associated immune response plays a crucial role in the aging process. The aim of this study is to investigate the effect of sport intensity on cytokine levels, oxidative stress markers and telomere length in aging elite athletes.

METHODS: In this study, 80 blood samples from consenting elite athletes were collected for anti-doping analysis at an anti-doping laboratory in Italy (FMSI). Participants were divided into three groups according to their sport intensity: low-intensity skills and power sports (LI, n = 18); moderate-intensity mixed soccer players (MI, n = 31); and high-intensity endurance sports (HI, n = 31). Participants were also divided into two age groups: less than 25 (n = 45) and above 25 years old (n = 35). Serum levels of 10 pro and anti-inflammatory cytokines and two antioxidant enzymes were compared in age and sport intensity groups and telomere lengths were measured in their respective blood samples.

RESULTS: Tumor necrosis factor-alpha (TNF-α) was the only cytokine showing significantly higher concentration in older athletes, regardless of sport intensity. Interleukin (IL)-10 increased significantly in HI regardless of age group, whereas IL-6 concentration was higher in the older HI athletes. IL-8 showed a significant interaction with sport intensity in different age groups. Overall, significant positive correlations among levels of IL-6, IL-10, IL-8 and TNF-α were identified. The antioxidant catalase activity was positively correlated with levels of TNF-α. Telomere length increased significantly with sport intensity, especially in the younger group.

CONCLUSION: HI had longer telomeres and higher levels of pro- and anti-inflammatory cytokines, suggesting less aging in HI compared to low and moderate counterparts in association with heightened immune response. Investigation of the functional significance of these associations on the health and performance of elite athletes is warranted.

RevDate: 2021-07-02

Maestri E, Duszka K, VA Kuznetsov (2021)

Immunity Depletion, Telomere Imbalance, and Cancer-Associated Metabolism Pathway Aberrations in Intestinal Mucosa upon Short-Term Caloric Restriction.

Cancers, 13(13): pii:cancers13133180.

Systems cancer biology analysis of calorie restriction (CR) mechanisms and pathways has not been carried out, leaving therapeutic benefits unclear. Using metadata analysis, we studied gene expression changes in normal mouse duodenum mucosa (DM) response to short-term (2-weeks) 25% CR as a biological model. Our results indicate cancer-associated genes consist of 26% of 467 CR responding differential expressed genes (DEGs). The DEGs were enriched with over-expressed cell cycle, oncogenes, and metabolic reprogramming pathways that determine tissue-specific tumorigenesis, cancer, and stem cell activation; tumor suppressors and apoptosis genes were under-expressed. DEG enrichments suggest telomeric maintenance misbalance and metabolic pathway activation playing dual (anti-cancer and pro-oncogenic) roles. The aberrant DEG profile of DM epithelial cells is found within CR-induced overexpression of Paneth cells and is coordinated significantly across GI tract tissues mucosa. Immune system genes (ISGs) consist of 37% of the total DEGs; the majority of ISGs are suppressed, including cell-autonomous immunity and tumor-immune surveillance. CR induces metabolic reprogramming, suppressing immune mechanics and activating oncogenic pathways. We introduce and argue for our network pro-oncogenic model of the mucosa multicellular tissue response to CR leading to aberrant transcription and pre-malignant states. These findings change the paradigm regarding CR's anti-cancer role, initiating specific treatment target development. This will aid future work to define critical oncogenic pathways preceding intestinal lesion development and biomarkers for earlier adenoma and colorectal cancer detection.

RevDate: 2021-07-05

Pousa PA, Souza RM, Melo PHM, et al (2021)

Telomere Shortening and Psychiatric Disorders: A Systematic Review.

Cells, 10(6):.

Telomeres are aging biomarkers, as they shorten while cells undergo mitosis. The aim of this study was to evaluate whether psychiatric disorders marked by psychological distress lead to alterations to telomere length (TL), corroborating the hypothesis that mental disorders might have a deeper impact on our physiology and aging than it was previously thought. A systematic search of the literature using MeSH descriptors of psychological distress ("Traumatic Stress Disorder" or "Anxiety Disorder" or "depression") and telomere length ("cellular senescence", "oxidative stress" and "telomere") was conducted on PubMed, Cochrane Library and ScienceDirect databases. A total of 56 studies (113,699 patients) measured the TL from individuals diagnosed with anxiety, depression and posttraumatic disorders and compared them with those from healthy subjects. Overall, TL negatively associates with distress-related mental disorders. The possible underlying molecular mechanisms that underly psychiatric diseases to telomere shortening include oxidative stress, inflammation and mitochondrial dysfunction linking. It is still unclear whether psychological distress is either a cause or a consequence of telomere shortening.

RevDate: 2021-07-05

Mongelli A, Barbi V, Gottardi Zamperla M, et al (2021)

Evidence for Biological Age Acceleration and Telomere Shortening in COVID-19 Survivors.

International journal of molecular sciences, 22(11):.

The SARS-CoV-2 infection determines the COVID-19 syndrome characterized, in the worst cases, by severe respiratory distress, pulmonary and cardiac fibrosis, inflammatory cytokine release, and immunosuppression. This condition has led to the death of about 2.15% of the total infected world population so far. Among survivors, the presence of the so-called persistent post-COVID-19 syndrome (PPCS) is a common finding. In COVID-19 survivors, PPCS presents one or more symptoms: fatigue, dyspnea, memory loss, sleep disorders, and difficulty concentrating. In this study, a cohort of 117 COVID-19 survivors (post-COVID-19) and 144 non-infected volunteers (COVID-19-free) was analyzed using pyrosequencing of defined CpG islands previously identified as suitable for biological age determination. The results show a consistent biological age increase in the post-COVID-19 population, determining a DeltaAge acceleration of 10.45 ± 7.29 years (+5.25 years above the range of normality) compared with 3.68 ± 8.17 years for the COVID-19-free population (p < 0.0001). A significant telomere shortening parallels this finding in the post-COVID-19 cohort compared with COVID-19-free subjects (p < 0.0001). Additionally, ACE2 expression was decreased in post-COVID-19 patients, compared with the COVID-19-free population, while DPP-4 did not change. In light of these observations, we hypothesize that some epigenetic alterations are associated with the post-COVID-19 condition, particularly in younger patients (< 60 years).

RevDate: 2021-07-01

Gao K, Zhou Y, Lu Q, et al (2021)

High-Throughput Human Telomere Length Analysis at the Single-Chromosome Level by FISH Coupled with Nano-Flow Cytometry.

Analytical chemistry [Epub ahead of print].

Telomere length (TL) is a highly relevant biomarker for age-associated diseases and cancer, yet its clinical applications have been hindered by the inability of existing methods to rapidly measure the TL distribution and the percentage of chromosomes with critically short telomeres (CSTs, < 3 kb). Herein, we report the development of a high-throughput method to measure TL at the single-chromosome level. Metaphase chromosomes are isolated, hybridized with the Alexa Fluor 488-labeled telomeric peptide nucleic acid probe, and analyzed using a laboratory-built ultrasensitive nano-flow cytometer. The fluorescence intensity of individual chromosomes is converted to TL in kilobases upon external calibration. With an analysis rate of several thousand chromosomes per minute, a statistically robust TL distribution histogram is acquired in minutes, and the percentage of chromosomes with CSTs can be quickly assessed. By analyzing peripheral blood lymphocytes of 158 healthy donors, TL is found to shorten with age at a rate of 64 ± 3 bp/year and the percentage of chromosomes with CSTs increases with age at a rate of 0.32 ± 0.02%/year. Moreover, the data of 28 patients with chronic myeloid leukemia (CML) indicate that telomeres are significantly shorter at the time of diagnosis and the clinical phases of CML are closely associated with TL and the percentage of chromosomes with CSTs. This powerful tool could greatly deepen our understanding of telomere biology and improve the clinical utility of telomere biomarkers.

RevDate: 2021-07-01

Dweck A, R Maitra (2021)

The advancement of telomere quantification methods.

Molecular biology reports [Epub ahead of print].

Telomeres, guanine rich DNA sequences, which are found at both ends of human chromosomes, play a vital role in genome protection. These repetitive nucleotide sequences protect the genome from nucleolytic degradation, unnecessary recombination, and interchromosomal fusion. Though, as somatic cells go through replication cycles, their telomeres shrink until they reach a critical length called the Hayflick limit. At this limit, cellular senescence, an irreversible cell cycle arrest, is prompted. For all the above reasons, telomere length is a hopeful biomarker for age-associated diseases and cancer. While there are numerous methods for telomere measurement and quantification, there are still challenges for routine analysis in clinics as these methods are not simple and rapid. Recently, a new method has been developed that measures absolute length and absolute quantities of single telomere molecules. This method, single telomere absolute-length rapid (STAR) assay, which promises to measure telomere length rapidly and accurately, is also expected to be scalable. This review will discuss different telomere length measurement methods, including STAR assay, and will highlight each of their advantages and drawbacks. It will culminate in determining if STAR assay has the potential to be the superior method for telomere measurement.

RevDate: 2021-07-02

Wang L, Wang Z, JP Liu (2021)

Identification of peptidomimetic telomere dysfunction inhibitor (TELODIN) through telomere dysfunction-induced foci (TIF) assay.

STAR protocols, 2(3):100620.

Telomere dysfunction-induced focus (TIF) assay allows efficient profiling of telomere dysfunctions in cells and tissues. Here, we describe the use of the TIF assay to screen synthetic peptides from E3 ubiquitin ligase FBW7, a tumor suppressor gene product, to prevent TIFs caused by environmental radiation stress. We demonstrate peptidomimetic telomere dysfunction inhibitor as a potentially intervening therapeutic drug candidate in aging-related diseases. This work demonstrates a novel utility of the TIF assay protocol in identifying telomere dysfunction inhibitors. For complete details on the use and execution of this protocol, please refer to Wang et al (2020).

RevDate: 2021-07-07

Eick SM, Goin DE, Cushing L, et al (2021)

Mixture effects of prenatal exposure to per- and polyfluoroalkyl substances and polybrominated diphenyl ethers on maternal and newborn telomere length.

Environmental health : a global access science source, 20(1):76.

BACKGROUND: Per- and polyfluoroalkyl substances (PFAS) and polybrominated diphenyl ethers (PBDEs) are endocrine disrupting chemicals with widespread exposures across the U.S. given their abundance in consumer products. PFAS and PBDEs are associated with reproductive toxicity and adverse health outcomes, including certain cancers. PFAS and PBDEs may affect health through alternations in telomere length. In this study, we examined joint associations between prenatal exposure to PFAS, PBDEs, and maternal and newborn telomere length using mixture analyses, to characterize effects of cumulative environmental chemical exposures.

METHODS: Study participants were enrolled in the Chemicals in Our Bodies (CIOB) study, a demographically diverse cohort of pregnant people and children in San Francisco, CA. Seven PFAS (ng/mL) and four PBDEs (ng/g lipid) were measured in second trimester maternal serum samples. Telomere length (T/S ratio) was measured in delivery cord blood of 292 newborns and 110 second trimester maternal whole blood samples. Quantile g-computation was used to assess the joint associations between groups of PFAS and PBDEs and newborn and maternal telomere length. Groups considered were: (1) all PFAS and PBDEs combined, (2) PFAS, and (3) PBDEs. Maternal and newborn telomere length were modeled as separate outcomes.

RESULTS: T/S ratios in newborn cord and maternal whole blood were moderately correlated (Spearman ρ = 0.31). In mixtures analyses, a simultaneous one quartile increase in all PFAS and PBDEs was associated with a small increase in newborn (mean change per quartile increase = 0.03, 95% confidence interval [CI] = -0.03, 0.08) and maternal telomere length (mean change per quartile increase = 0.03 (95% CI = -0.03, 0.09). When restricted to maternal-fetal paired samples (N = 76), increasing all PFAS and PBDEs combined was associated with a strong, positive increase in newborn telomere length (mean change per quartile increase = 0.16, 95% CI = 0.03, 0.28). These associations were primarily driven by PFAS (mean change per quartile increase = 0.11 [95% CI = 0.01, 0.22]). No associations were observed with maternal telomere length among paired samples.

CONCLUSIONS: Our findings suggest that PFAS and PBDEs may be positively associated with newborn telomere length.

RevDate: 2021-06-30

Marasco V, Boner W, Griffiths K, et al (2021)

Repeated exposure to challenging environmental conditions influences telomere dynamics across adult life as predicted by changes in mortality risk.

FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 35(8):e21743.

The effects of stress exposure are likely to vary depending on life-stage and stressor. While it has been postulated that mild stress exposure may have beneficial effects, the duration of such effects and the underlying mechanisms are unclear. While the long-term effects of early-life stress are relatively well studied, we know much less about the effects of exposure in adulthood since the early- and adult-life environments are often similar. We previously reported that repeated experimental exposure to a relatively mild stressor in female zebra finches, first experienced in young adulthood, initially had no effect on mortality risk, reduced mortality in middle age, but the apparently beneficial effects disappeared in old age. We show here that this is underpinned by differences between the control and stress-exposed group in the pattern of telomere change, with stress-exposed birds showing reduced telomere loss in middle adulthood. We thereby provide novel experimental evidence that telomere dynamics play a key role linking stress resilience and aging.

RevDate: 2021-06-30

Robinson NJ, Miyagi M, Scarborough JA, et al (2021)

SLX4IP promotes RAP1 SUMOylation by PIAS1 to coordinate telomere maintenance through NF-κB and Notch signaling.

Science signaling, 14(689): pii:14/689/eabe9613.

The maintenance of telomere length supports repetitive cell division and therefore plays a central role in cancer development and progression. Telomeres are extended by either the enzyme telomerase or the alternative lengthening of telomeres (ALT) pathway. Here, we found that the telomere-associated protein SLX4IP dictates telomere proteome composition by recruiting and activating the E3 SUMO ligase PIAS1 to the SLX4 complex. PIAS1 SUMOylated the telomere-binding protein RAP1, which disrupted its interaction with the telomere-binding protein TRF2 and facilitated its nucleocytoplasmic shuttling. In the cytosol, RAP1 bound to IκB kinase (IKK), resulting in activation of the transcription factor NF-κB and its induction of Jagged-1 expression, which promoted Notch signaling and the institution of ALT. This axis could be targeted therapeutically in ALT-driven cancers and in tumor cells that develop resistance to antitelomerase therapies. Our results illuminate the mechanisms underlying SLX4IP-dependent telomere plasticity and demonstrate the role of telomere proteins in directly coordinating intracellular signaling and telomere maintenance dynamics.

RevDate: 2021-06-29

Oh BK, Choi Y, JS Choi (2021)

Telomere shortening and expression of TRF1 and TRF2 in uterine leiomyoma.

Molecular medicine reports, 24(2):.

Uterine leiomyoma is a benign smooth muscle tumor of the uterus that can exhibit histopathological traits that mimic malignancy. Telomere shortening is an early event in tumorigenesis and telomerase activation facilitates tumor progression later in the course of carcinogenesis. Telomeric repeat‑binding factor (TRF)1 and TRF2 protect telomeres, and their gene expression levels are dysregulated in various cancer types. However, the roles of telomeres and telomere protection proteins in uterine leiomyoma remain largely unknown. In this study, telomere length and the mRNA levels of various telomere‑related genes in normal tissues and leiomyoma were determined, and their relationships were evaluated. Uterine leiomyoma and normal myometrium were surgically obtained from 18 and 13 patients, respectively. Telomere length and gene expression were determined by Southern blot analysis and reverse transcription‑quantitative PCR, respectively. In matched samples, telomeres were consistently shorter in leiomyoma tissue than in adjacent normal tissue. TRF1, TRF2, PIN2‑interacting telomerase inhibitor 1 (PINX1), and telomerase RNA component were expressed at comparable levels in both leiomyoma and normal tissues. None of these genes were associated with telomere length in leiomyoma. All tested tissues were negative for telomerase reverse transcriptase, which encodes the catalytic component of telomerase, indicating that cells in uterine leiomyoma were not immortalized. In summary, telomere erosion, which reflects active proliferation during tumor evolution, was evident in uterine leiomyoma. Steady‑state expression of TRF1, TRF2 and PINX1 may be important for maintenance of telomere integrity in leiomyoma, where telomere length is shortened.

RevDate: 2021-06-29

Moore S, Patel R, Stewart J, et al (2021)

Social inequalities in accelerated aging among southern U.S. women: an analysis of the biosocial and behavioral pathways linking social determinants to telomere length.

Biodemography and social biology, 66(2):118-131.

Few studies have examined the biosocial pathways linking socioeconomic status (SES) to accelerated aging in a population-based sample of southern US women. Even fewer have examined the importance of chronic compared to perceived stress in linking SES to women's salivary telomere length (STL). Using data from a probability-based sample of 156 US women and structural equation modeling, we examined three pathways - chronic stress exposure, stress appraisal, and coping behavior - linking SES to STL. SES was positively associated with STL (βTE = 0.16, p < .05). Everyday discrimination was negatively associated with STL (βDE = -0.21, p < .05), but perceived stress was positively associated with STL (βDE = 0.20, p < .05). Current smoking decreased STL (βDE = -0.19, p < .01). Perceived stress acted to suppress the negative relationship of chronic stress exposure on STL. Given the dearth of STL studies that include measures of both perceived and chronic stress, our study supports the importance of disentangling stress measures and a biosocial approach to the study of accelerated aging.

RevDate: 2021-06-28

Watanabe S, Hibiya S, Katsukura N, et al (2021)

Importance of telomere shortening in the pathogenesis of ulcerative colitis: A new treatment from the aspect of telomeres in intestinal epithelial cells.

Journal of Crohn's & colitis pii:6310549 [Epub ahead of print].

BACKGROUND AND AIMS: Ulcerative colitis (UC) is a chronic inflammatory disease of the colon with frequent relapses. Telomere shortening in intestinal epithelial cells has been reported in severe or longstanding cases. However, its influence on UC pathogenesis remains unelucidated. To this end, we evaluated telomere shortening using a long-term organoid inflammation model that we had originally established.

METHODS: A UC model using human colon organoids was established to assess telomere changes chronologically. MST-312 was used for the telomerase inhibition assay. The potential of telomerase activators as a novel UC treatment was evaluated with an in vitro model, including microarray analysis, and histologic changes were assessed using xenotransplantation into mouse colonic mucosa.

RESULTS: Our UC model reproduced telomere shortening in vitro, which was induced by the continuous suppression of telomerase activity via P53. MST-312-based analysis revealed that telomere shortening was involved in the pathogenesis of UC. Madecassoside (MD) improved the telomere length of the UC model and UC patient-derived organoids, which further promoted cell proliferation in vitro and improved the graft take-rate of xenotransplantation. Moreover, histologic analysis revealed that MD induced normal crypt structure with abundant goblet cells.

CONCLUSIONS: This study is the first to reveal the mechanism and importance of telomere shortening in the pathogenesis of UC. MD could be a novel candidate for UC treatment beyond endoscopic mucosal healing.

RevDate: 2021-06-26

Casavant SG, Li H, Reese B, et al (2021)

Pilot Study of Absolute Telomere Lengths in Preterm Infants.

Nursing research pii:00006199-900000000-99653 [Epub ahead of print].

BACKGROUND: Annually, approximately 15 million babies are born preterm (< 37 weeks gestational age) globally. In the neonatal intensive care unit (NICU) environment, infants are exposed to repeated stressful or painful procedures as part of routine lifesaving care. These procedures have been associated with epigenetic alterations that may lead to an increased risk of neurodevelopmental disorders. Telomere length has been negatively associated with adverse life experiences in studies of adults.

OBJECTIVES: This pilot study aimed to describe telomere length in a sample of preterm infants at NICU discharge and examine any associations with pain, feeding method, and neurodevelopment.

METHODS: This descriptive pilot study sample includes baseline absolute telomere length (aTL) of 36 preterm infants immediately prior to discharge. Quantitative polymerase chain reaction (qPCR) was used to determine absolute telomere length. Infant demographics, pain/stress, type of feeding, antibiotic use, neurodevelopment, and buccal swab data were collected. Descriptive data analysis was used to describe the telomere length using graphs.

RESULTS: Among our preterm infant samples, the mean absolute telomere length was far greater than the average adult telomere length. While no significant associations were found between absolute telomere length and pain, feeding method, and neurodevelopment, a trend between sex was noted where male telomere lengths were shorter than females as they aged.

DISCUSSION: This is one of few studies to evaluate preterm infant telomere length. While other researchers have used relative telomere length, we used the more accurate absolute telomere length. We found nonsignificant shorter telomere lengths among males. Additional large-scale, longitudinal studies are needed to better identify the predictors of telomere length at the time of discharge from NICU.

RevDate: 2021-06-27

Kychygina A, Dall'Osto M, Allen JAM, et al (2021)

Progerin impairs 3D genome organization and induces fragile telomeres by limiting the dNTP pools.

Scientific reports, 11(1):13195.

Chromatin organization within the nuclear volume is essential to regulate many aspects of its function and to safeguard its integrity. A key player in this spatial scattering of chromosomes is the nuclear envelope (NE). The NE tethers large chromatin domains through interaction with the nuclear lamina and other associated proteins. This organization is perturbed in cells from Hutchinson-Gilford progeria syndrome (HGPS), a genetic disorder characterized by premature aging features. Here, we show that HGPS-related lamina defects trigger an altered 3D telomere organization with increased contact sites between telomeres and the nuclear lamina, and an altered telomeric chromatin state. The genome-wide replication timing signature of these cells is perturbed, with a shift to earlier replication for regions that normally replicate late. As a consequence, we detected a higher density of replication forks traveling simultaneously on DNA fibers, which relies on limiting cellular dNTP pools to support processive DNA synthesis. Remarkably, increasing dNTP levels in HGPS cells rescued fragile telomeres, and improved the replicative capacity of the cells. Our work highlights a functional connection between NE dysfunction and telomere homeostasis in the context of premature aging.

RevDate: 2021-06-24

Grigorev K, Foox J, Bezdan D, et al (2021)

Haplotype diversity and sequence heterogeneity of human telomeres.

Genome research pii:gr.274639.120 [Epub ahead of print].

Telomeres are regions of repetitive nucleotide sequences capping the ends of eukaryotic chromosomes that protect against deterioration, and whose lengths can be correlated with age and adverse health risk factors. Yet, given their length and repetitive nature, telomeric regions are not easily reconstructed from short-read sequencing, thus making telomere sequencing, mapping, and variant resolution challenging problems. Recently, long-read sequencing, with read lengths measuring in hundreds of kilobase pairs, has made it possible to routinely read into telomeric regions and inspect their sequence structure. Here, we describe a framework for extracting telomeric reads from whole-genome single-molecule sequencing experiments, including de novo identification of telomere repeat motifs and repeat types, and also describe their sequence variation. We find that long, complex telomeric stretches and repeats can be accurately captured with long-read sequencing, observe extensive sequence heterogeneity of human telomeres, discover and localize noncanonical telomere sequence motifs (both previously reported, as well as novel), and validate them in short-read sequence data. These data reveal extensive intra- and inter-population diversity of repeats in telomeric haplotypes, reveal higher paternal inheritance of telomeric variants, and represent the first motif composition maps of multi-kilobase-pair human telomeric haplotypes across three distinct ancestries (Ashkenazi, Chinese, and Utah), which can aid in future studies of genetic variation, aging, and genome biology.

RevDate: 2021-06-23

Valente C, Andrade R, Alvarez L, et al (2021)

Effect of physical activity and exercise on telomere length: Systematic review with meta-analysis.

Journal of the American Geriatrics Society [Epub ahead of print].

PURPOSE: To compare a physically active lifestyle or structured exercise program to physically inactive lifestyle or control groups on telomere length (TL).

METHOD: We searched PubMed, EMBASE, Cochrane Library, and Open Gray databases up to March 31, 2020. We calculated standardized mean differences (SMD) with 95% confidence intervals (CI) of TL comparing physically active to physically inactive individuals and exercise intervention to control groups. Risk of bias was judged using the Risk of Bias Assessment tool for Non-randomized Studies (RoBANS) for physical activity (PA) studies and the Cochrane risk-of-bias (RoB2) for exercise intervention studies. Certainty of evidence was judged using Grading of Recommendations Assessment, Development and Evaluation (GRADE).

RESULTS: We included 30 studies (24 assessing the effects of PA and 6 assessing the effects of exercise interventions) comprising 7418 individuals. Physically active individuals had longer telomeres (SMD = 0.70, 95% CI 0.12-1.28, very-low certainty), especially in middle-aged individuals (SMD = 0.90, 95% CI 0.08-1.72, very-low certainty) and when considering only athletes (SMD = 0.54, 95% CI 0.18-0.90, very-low certainty). Trim-and-fill analyses revealed that most of the pooled effects were overestimated. Exercise interventions did not yield any significant effect on TL.

CONCLUSION: There is very-low certainty that physically active individuals have longer telomeres with a moderate effect, but this effect is probably overestimated.

RevDate: 2021-06-28

Khayat F, Cannavo E, Alshmery M, et al (2021)

Inhibition of MRN activity by a telomere protein motif.

Nature communications, 12(1):3856.

The MRN complex (MRX in Saccharomyces cerevisiae, made of Mre11, Rad50 and Nbs1/Xrs2) initiates double-stranded DNA break repair and activates the Tel1/ATM kinase in the DNA damage response. Telomeres counter both outcomes at chromosome ends, partly by keeping MRN-ATM in check. We show that MRX is disabled by telomeric protein Rif2 through an N-terminal motif (MIN, MRN/X-inhibitory motif). MIN executes suppression of Tel1, DNA end-resection and non-homologous end joining by binding the Rad50 N-terminal region. Our data suggest that MIN promotes a transition within MRX that is not conductive for endonuclease activity, DNA-end tethering or Tel1 kinase activation, highlighting an Achilles' heel in MRN, which we propose is also exploited by the RIF2 paralog ORC4 (Origin Recognition Complex 4) in Kluyveromyces lactis and the Schizosaccharomyces pombe telomeric factor Taz1, which is evolutionarily unrelated to Orc4/Rif2. This raises the possibility that analogous mechanisms might be deployed in other eukaryotes as well.

RevDate: 2021-06-21

Gao X, Li S, Dong S, et al (2021)

Association between Body Weight and Telomere Length is Predominantly Mediated through C-Reactive Protein.

The Journal of clinical endocrinology and metabolism pii:6307348 [Epub ahead of print].

BACKGROUND: To dissect the direct effect of body mass index (BMI) and its indirect effect through C-reactive protein (CRP) on leukocyte telomere length (LTL) to determine the mediation effect of CRP on the BMI-LTL association.

METHODS: The study cohort included 5,451 adults (1,404 Mexican Americans, 3,114 Whites and 933 Blacks; 53.5% males; mean age=49.2 years) from the 1999-2002 National Health and Nutrition Examination Survey. General mediation models were used to examine the mediation effect of CRP on the BMI-LTL association.

RESULTS: After adjusting for age, race, sex, physical activity, alcohol use and serum cotinine, the total effect of BMI on LTL was significant (standardized regression coefficient, β= -0.054, p<0.001) without CRP included in the model. With inclusion of CRP in the model, the indirect effect of BMI on LTL through CRP was estimated at β= -0.023 (p<0.001), and the direct effect of BMI on LTL in its absolute value decreased to β= -0.031 (p=0.025). The mediation effect of CRP was estimated at 42.6%. The mediation model parameters did not differ significantly between race and sex groups.

CONCLUSION: These results suggest that the inverse BMI-LTL association is partly mediated by obesity-induced inflammation. The significant direct effect of BMI on LTL with removal of the mediation effect through CRP indicates that obesity is associated with LTL attrition also through other non-inflammatory mechanisms.

RevDate: 2021-06-21

Manet IGJ, Manoli F, Doria F, et al (2021)

The Binding Pocket at the Interface of Multimeric Telomere G-quadruplexes: Myth or Reality?.

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

Human telomeric DNA with hundreds of repeats of the 5'-TTAGGG-3' motif plays a crucial role in several biological processes. It folds into G-quadruplex (G4) structures and features a pocket at the interface of two contiguous G4 blocks. Up to now no structural NMR and crystallographic data are available for ligands interacting with contiguous G4s. We investigated naphthalene diimide monomers and dyads as ligands of a dimeric G4 of human telomeric DNA comparing the results with those of the model monomeric G4. Time-resolved fluorescence, circular dichroism, isothermal titration calorimetry and molecular modeling were used to elucidate binding features. Ligand fluorescence lifetime and induced circular dichroism unveiled occupancy of the binding site at the interface. Thermodynamic parameters confirmed the hypothesis as they remarkably change for the dyad complexes of the monomeric and dimeric telomeric G4. The bi-functional ligand structure of the dyads is a fundamental requisite for binding at the G4 interface as only the dyads engage in complexes with 1:1 stoichiometry, lodging in the pocket at the interface and establishing multiple interactions with the DNA skeleton. In the absence of NMR and crystallographic data, our study affords important proofs of binding at the interface pocket and clues on the role played by the ligand structure.

RevDate: 2021-06-21

Mendes-Silva AP, Vieira ELM, Xavier G, et al (2021)

Telomere shortening in late-life depression: A potential marker of depression severity.

Brain and behavior [Epub ahead of print].

OBJECTIVES: Telomeres are structures at the extremity of chromosomes that prevents genomic instability, and its shortening seems to be a hallmark of cellular aging. Past studies have shown contradictory results of telomere length (TL) in major depression, and are a few studies in late-life depression (LLD). This explores the association between TL as a molecular marker of aging and diagnosis of LLD, the severity of depressive symptoms, and cognitive performance in older adults.

METHODS/DESIGN: We included 78 older adults (45 with LLD and 33 nondepressed controls, according to DSM-V criteria), aged 60-90 years. TL was measured in leukocytes by a quantitative polymerase chain reaction, determining the relative ratio (T/S) between the telomere region copy number (T) and a single copy gene (S), using a relative standard curve.

RESULTS: TL was significantly shorter in the LLD compared with control participants (p = .039). Comparing groups through the severity of depressive symptoms, we found a negative correlation with the severity of depressive symptoms (Hamilton Depression Rating Scale-21, r = -0.325, p = .004) and medical burden (r = -0.271, p = .038). There was no significant correlation between TL and cognitive performance (Mattis Dementia Rating Scale, r = 0.152, p = .21).

CONCLUSIONS: We found that older adults with LLD have shorter telomere than healthy controls, especially those with a more severe depressive episode. Our findings suggest that shorter TL can be a marker of the severity of depressive episodes in older adults and indicate that these individuals may be at higher risk of age-associated adverse outcomes linked to depression.

RevDate: 2021-06-22

Dos Santos GA, Pimenta R, Viana NI, et al (2021)

Shorter leukocyte telomere length is associated with severity of COVID-19 infection.

Biochemistry and biophysics reports, 27:101056.

The infection by COVID-19 is a serious global public health problem. An efficient way to improve this disease's clinical management would be to characterize patients at higher risk of progressing to critically severe infection using prognostic biomarkers. The telomere length could be used for this purpose. Telomeres are responsible for controlling the number of maximum cell divisions. The telomere length is a biomarker of aging and several diseases. We aimed to compare leukocyte telomere length (LTL) between patients without COVID-19 and patients with different clinical severity of the infection. Were included 53 patients who underwent SARS-CoV-2 PCR divided in four groups. The first group was composed by patients with a negative diagnosis for COVID-19 (n = 12). The other three groups consisted of patients with a confirmed diagnosis of COVID-19 divided according to the severity of the disease: mild (n = 15), moderate (n = 17) and severe (n = 9). The LTL was determined by Q-PCR. The severe group had the shortest LTL, followed by the moderate group. The negative and mild groups showed no differences. There is an increase of patients with hypertension (p = 0.0099) and diabetes (p = 0.0067) in moderate and severe groups. Severe group was composed by older patients in comparison with the other three groups (p = 0.0083). Regarding sex, there was no significant difference between groups (p = 0.6279). In an ordinal regression model, only LTL and diabetes were significantly associated with disease severity. Shorter telomere length was significantly associated with the severity of COVID-19 infection, which can be useful as a biomarker or to better understand the SARS-CoV-2 pathophysiology.

RevDate: 2021-06-22

Aguilar M, P Prieto (2021)

Telomeres and Subtelomeres Dynamics in the Context of Early Chromosome Interactions During Meiosis and Their Implications in Plant Breeding.

Frontiers in plant science, 12:672489.

Genomic architecture facilitates chromosome recognition, pairing, and recombination. Telomeres and subtelomeres play an important role at the beginning of meiosis in specific chromosome recognition and pairing, which are critical processes that allow chromosome recombination between homologs (equivalent chromosomes in the same genome) in later stages. In plant polyploids, these terminal regions are even more important in terms of homologous chromosome recognition, due to the presence of homoeologs (equivalent chromosomes from related genomes). Although telomeres interaction seems to assist homologous pairing and consequently, the progression of meiosis, other chromosome regions, such as subtelomeres, need to be considered, because the DNA sequence of telomeres is not chromosome-specific. In addition, recombination operates at subtelomeres and, as it happens in rye and wheat, homologous recognition and pairing is more often correlated with recombining regions than with crossover-poor regions. In a plant breeding context, the knowledge of how homologous chromosomes initiate pairing at the beginning of meiosis can contribute to chromosome manipulation in hybrids or interspecific genetic crosses. Thus, recombination in interspecific chromosome associations could be promoted with the aim of transferring desirable agronomic traits from related genetic donor species into crops. In this review, we summarize the importance of telomeres and subtelomeres on chromatin dynamics during early meiosis stages and their implications in recombination in a plant breeding framework.

RevDate: 2021-06-20

Pepper AGS, Zucchetto A, Norris K, et al (2021)

Combined analysis of IGHV mutations, telomere length and CD49d identifies long-term progression-free survivors in TP53 wild-type CLL treated with FCR-based therapies.

Leukemia [Epub ahead of print].

RevDate: 2021-06-20

Boyle EM, Williams L, Blaney P, et al (2021)

Improving prognostic assignment in older adults with multiple myeloma using acquired genetic features, clonal hemopoiesis and telomere length.

Leukemia [Epub ahead of print].

RevDate: 2021-07-07

Akcha F, Cahuc C, Rouxel J, et al (2021)

Development in the European flounder (Platichthys flesus) of a q-PCR assay for the measurement of telomere length, a potential biomarker of pollutant effects for biomonitoring studies.

Marine pollution bulletin, 170:112610 pii:S0025-326X(21)00644-5 [Epub ahead of print].

Telomeres protect the coding sequence of chromosome ends and Telomere Length (TL) has been proposed as a biomarker of cellular aging, cumulative stress exposure and life-span in humans. With the aim to propose new biomarkers, a q-PCR protocol was adapted for the measurement of TL in the European flounder Platichthys flesus. The protocol was then applied in 2-year-old flounders from the Seine Estuary. The absolute TL in the flounder is 54 ± 13 kbp per genome (mean ± standard error). Considering relative or absolute TL, no correlation was observed with DNA damage and any of the measured contaminant concentrations (trace elements, metabolites of polycyclic aromatic hydrocarbons, polychlorobiphenyls, organochlorinated pesticides, polybrominated diphenyl ethers, perfluoroalkyl substances). Because sampling was limited, further investigations are required to state a possible impact of chemical pollution on flatfish telomeres. This is motivated by correlations observed with organochlorinated compounds when decreasing statistical significance (p ≤ 0.10).

RevDate: 2021-07-06
CmpDate: 2021-07-06

Silva B, Arora R, Bione S, et al (2021)

TERRA transcription destabilizes telomere integrity to initiate break-induced replication in human ALT cells.

Nature communications, 12(1):3760.

Alternative Lengthening of Telomeres (ALT) is a Break-Induced Replication (BIR)-based mechanism elongating telomeres in a subset of human cancer cells. While the notion that spontaneous DNA damage at telomeres is required to initiate ALT, the molecular triggers of this physiological telomere instability are largely unknown. We previously proposed that the telomeric long noncoding RNA TERRA may represent one such trigger; however, given the lack of tools to suppress TERRA transcription in cells, our hypothesis remained speculative. We have developed Transcription Activator-Like Effectors able to rapidly inhibit TERRA transcription from multiple chromosome ends in an ALT cell line. TERRA transcription inhibition decreases marks of DNA replication stress and DNA damage at telomeres and impairs ALT activity and telomere length maintenance. We conclude that TERRA transcription actively destabilizes telomere integrity in ALT cells, thereby triggering BIR and promoting telomere elongation. Our data point to TERRA transcription manipulation as a potentially useful target for therapy.

RevDate: 2021-06-28
CmpDate: 2021-06-28

Noguera JC, A Velando (2021)

Telomerase activity can mediate the effects of growth on telomeres during post-natal development in a wild bird.

The Journal of experimental biology, 224(12):.

In wild animals, telomere attrition during early development has been linked with several fitness disadvantages throughout life. Telomerase enzyme can elongate telomeres, but it is generally assumed that its activity is suppressed in most somatic tissues upon birth. However, recent evidence suggests that this may not be the case for long-lived bird species. We have therefore investigated whether telomerase activity is maintained during the postnatal growth period in a wild yellow-legged gull (Larus michahellis) population. Our results indicate that telomerase activity is not negligible in the blood cells, but activity levels sharply decline from hatching to fledging following a similar pattern to the reduction observed in telomere length. Our results further suggest that the observed variation in telomere length may be the result of a negative effect of fast growth on telomerase activity, thus providing a new mechanism through which growth rates may affect telomere dynamics and potentially life-history trajectories.

RevDate: 2021-06-19

Delgado M, Buffington CAT, Bain M, et al (2021)

Early maternal separation is not associated with changes in telomere length in domestic kittens (Felis catus).

PeerJ, 9:e11394.

Objective: Studies of multiple species have found that adverse early life experiences, including childhood trauma and maternal separation, can result in accelerated telomere shortening. The objective of this study was to determine if premature separation from the mother affected telomere length in domestic kittens (Felis catus). Subjects were 42 orphaned kittens and 10 mother-reared kittens from local animal rescue groups and shelters. DNA was extracted from whole blood collected from kittens at approximately 1 week and 2 months of age. Telomere length was assessed by qPCR (quantitative polymerase chain reaction) from a total of 86 samples and expressed as a ratio of telomere PCR relative to a single copy gene PCR (T/S).

Results: A generalized linear mixed model found there were no detectable differences in telomere length based on survival (F 1, 76.2 = 3.35, p = 0.07), orphan status (F 1, 56.5 = 0.44, p = 0.51), time point (F 1, 43.5 = 0.19, p = 0.67), or the interaction between orphan status and time (F 1, 43.5 = 0.86, p = 0.36). Although in other species telomere shortening is commonly associated with aging, even early in life, we did not find evidence for telomere shortening by two months of age. Our results suggest that the experience of early maternal separation in domestic cats who are subsequently hand-reared by humans does not accelerate telomere shortening compared to mother-reared kittens, at least in the first few months of life.

RevDate: 2021-06-24

Peska V, Fajkus P, Bubeník M, et al (2021)

Extraordinary diversity of telomeres, telomerase RNAs and their template regions in Saccharomycetaceae.

Scientific reports, 11(1):12784.

Telomerase RNA (TR) carries the template for synthesis of telomere DNA and provides a scaffold for telomerase assembly. Fungal TRs are long and have been compared to higher eukaryotes, where they show considerable diversity within phylogenetically close groups. TRs of several Saccharomycetaceae were recently identified, however, many of these remained uncharacterised in the template region. Here we show that this is mainly due to high variability in telomere sequence. We predicted the telomere sequences using Tandem Repeats Finder and then we identified corresponding putative template regions in TR candidates. Remarkably long telomere units and the corresponding putative TRs were found in Tetrapisispora species. Notably, variable lengths of the annealing sequence of the template region (1-10 nt) were found. Consequently, species with the same telomere sequence may not harbour identical TR templates. Thus, TR sequence alone can be used to predict a template region and telomere sequence, but not to determine these exactly. A conserved feature of telomere sequences, tracts of adjacent Gs, led us to test the propensity of individual telomere sequences to form G4. The results show highly diverse values of G4-propensity, indicating the lack of ubiquitous conservation of this feature across Saccharomycetaceae.

RevDate: 2021-06-19

Idilli AI, Segura-Bayona S, Lippert TP, et al (2021)

A C-circle assay for detection of alternative lengthening of telomere activity in FFPE tissue.

STAR protocols, 2(2):100569.

Alternative lengthening of telomeres (ALT) is a telomerase-independent, recombination-based telomere maintenance mechanism that allows cancer cells to acquire unlimited proliferative capacity. The C-circle assay (CCA) has emerged as the gold standard for quantitative measurement of ALT activity. Here, we present a modified CCA protocol to examine ALT activity in formalin-fixed paraffin-embedded specimens. We optimized several aspects of the procedure including genomic DNA isolation and hybridization steps, which allows for sensitive and robust quantitation of ALT activity in patient biopsies. For complete details on the use and execution of this protocol, please refer to Lippert et al. (2021).

RevDate: 2021-07-07
CmpDate: 2021-06-21

Santos GAD, Reis ST, Leite KRM, et al (2021)

Telomere Attrition and p53 Response 1 (TAPR1): a new player in cancer biology?.

Clinics (Sao Paulo, Brazil), 76:e2997.

RevDate: 2021-06-14

Pobiega S, Alibert O, S Marcand (2021)

A new assay capturing chromosome fusions shows a protection trade-off at telomeres and NHEJ vulnerability to low-density ionizing radiation.

Nucleic acids research pii:6298619 [Epub ahead of print].

Chromosome fusions threaten genome integrity and promote cancer by engaging catastrophic mutational processes, namely chromosome breakage-fusion-bridge cycles and chromothripsis. Chromosome fusions are frequent in cells incurring telomere dysfunctions or those exposed to DNA breakage. Their occurrence and therefore their contribution to genome instability in unchallenged cells is unknown. To address this issue, we constructed a genetic assay able to capture and quantify rare chromosome fusions in budding yeast. This chromosome fusion capture (CFC) assay relies on the controlled inactivation of one centromere to rescue unstable dicentric chromosome fusions. It is sensitive enough to quantify the basal rate of end-to-end chromosome fusions occurring in wild-type cells. These fusions depend on canonical nonhomologous end joining (NHEJ). Our results show that chromosome end protection results from a trade-off at telomeres between positive effectors (Rif2, Sir4, telomerase) and a negative effector partially antagonizing them (Rif1). The CFC assay also captures NHEJ-dependent chromosome fusions induced by ionizing radiation. It provides evidence for chromosomal rearrangements stemming from a single photon-matter interaction.

RevDate: 2021-06-21

Xu Y, Xie CB, Yang J, et al (2021)

Association between telomere length in the DNA of peripheral blood leukocytes and the propofol dose in anesthesia induction: an observational study.

Brazilian journal of anesthesiology (Elsevier) pii:S0104-0014(21)00237-2 [Epub ahead of print].

INTRODUCTION: Propofol is a widely used anesthetic and its dose is closely related to aging. Telomere length (TL) is a unique heritable trait, and emerging as a biomarker of aging, health and disease. Telomerase RNA component (TERC) plays an important role in maintaining TL. We proposed a hypothesis that propofol dose in general anesthesia can be predicted by measuring TL before operation, which greatly reduced the risk of anesthesia, especially the elderly.

METHODS: The association between the propofol dose in anesthesia induction and: TL in the DNA of peripheral blood leukocytes; body weight; sex; difference of the Bispectral Index (BIS) before and after anesthesia induction in patients was evaluated by multivariable linear regression analyses. The mutation at the 5'end or 3'end of TERC was detected. We recruited 100 patients of elective surgery.

RESULTS: We found that propofol dose in anesthesia induction was clearly correlated significantly with TL (r = 0.78, p < 0.001), body weight (r = 0.84, p = 0.004), sex (r = 0.83, p= 0.84, p = 0.004), sex (r = 0.83, p = 0.004), and difference of BIS before and after anesthesia induction (r = 0.85, p = 0.029). By comparing the absolute values of standardized regression coefficients (0.58, 0.21, 0.19, and 0.12) of the four variables, it can be seen that TL contributes the most to the propofol dose in anesthesia induction. However, the mutation at the 5' end or 3' end of TERC was not found.

CONCLUSIONS: These findings provide preliminary evidence that the propofol dose in anesthesia induction was clearly correlated with genetically determined TL. TL may be a promising predictor of the propofol dose, which is beneficial to improve the safety of anesthesia and reduce perioperative complications.

RevDate: 2021-06-16

Bijnens EM, Derom C, Thiery E, et al (2021)

Serum gamma-glutamyl transferase, a marker of alcohol intake, is associated with telomere length and cardiometabolic risk in young adulthood.

Scientific reports, 11(1):12407.

Studies based on self-reported alcohol consumption and telomere length show inconsistent results. Therefore, we studied the association between gamma-glutamyl transferase (GGT), a widely used biomarker of alcohol intake, and telomere length. The possible health relevance in young adulthood was explored by investigating cardiometabolic risk factors. Mixed modelling was performed to examine GGT and alcohol consumption in association with telomere length in buccal cells of 211 adults between 18 and 30 years old of the East Flanders Prospective Twin Survey. In addition, we investigated the association between GGT and cardiometabolic risk factors; waist circumference, systolic blood pressure, fasting glucose, HDL cholesterol, and triglycerides. Although we did not observe an association between self-reported alcohol consumption and telomere length, our results show that a doubling in serum GGT is associated with 7.80% (95% CI - 13.9 to - 1.2%; p = 0.02) shorter buccal telomeres, independently from sex, chronological age, educational level, zygosity and chorionicity, waist-to-hip ratio and smoking. The association between GGT was significant for all five cardiometabolic risk factors, while adjusting for age. We show that GGT, a widely used biomarker of alcohol consumption, is associated with telomere length and with risk factors of cardiometabolic syndrome, despite the young age of this study population.

RevDate: 2021-06-24
CmpDate: 2021-06-24

Wang S, Gao Y, Zhao L, et al (2021)

Shortened leukocyte telomere length as a potential biomarker for predicting the progression of atrial fibrillation from paroxysm to persistence in the short-term.

Medicine, 100(23):e26020.

ABSTRACT: This study aimed to assess the role of leukocyte telomere length (LTL) in the development of atrial fibrillation (AF) among Chinese patients.This is a cross-sectional study. A total of 350 patients from June 2016 to December 2017 were retrospectively analyzed. These included 219 AF patients and 131 with sinus rhythm in the control group. Quantitative real-time PCR was used to measure relative LTL.The relative LTLs of all subjects (n = 350) ranged from 0.4 to 2.41 (0.98 ± 0.29), showing a significant negative correlation (P < .001) with age. The AF-group had significantly shorter LTLs (0.93 ± 0.26 vs 1.07 ± 0.33, P < .001) and were older (61.50 ± 6.49 vs 59.95 ± 6.17, P = .028) than controls. LTLs among patients with persistent AF (PsAF), paroxysmal AF (PAF), and controls were significantly different (P < .001), with LTLs of PsAF patients being the shortest and controls being the longest. After adjusting for possible confounding factors, the PsAF group still showed significantly shorter LTLs than the PAF and control groups (P = .013 and P = .001, respectively). After an 18-month follow-up, 20 out of 119 PAF patients had progressed into PsAF and a relative LTL of ≤0.73 was an independent predictor for progression of PAF into PsAF.LTL was found to be shorter in patients with AF than in age-matched individuals with sinus rhythm and positively correlated with severity of AF. LTL shortening could be an independent risk factor for progression from paroxysmal AF to persistent AF in the short term.

RevDate: 2021-06-12

AlDehaini DMB, Al-Bustan SA, Malalla ZHA, et al (2021)

Analogous telomeres shortening and different metabolic profile: hypertension versus hypertension/type 2 diabetes mellitus comorbidity.

Cardiovascular endocrinology & metabolism, 10(2):106-112.

Background: Eukaryotes chromosomal ends are capped and protected by telomeres, which are noncoding DNA repeats synthesized by telomerase enzyme. The telomerase enzyme is a nucleoprotein encoded by TERC and TERT genes. Naturally, the length of the telomeres shortens with each cell cycle but the shortening is fastened in certain age-related diseases like hypertension (HTN) and type 2 diabetes mellitus (T2DM).

Materials and methods: Blood samples (n = 171) were obtained from Kuwaiti subjects with HTN, and HTN/T2DM comorbidity (HTN-DM) and healthy subjects. The leukocyte telomere length (LTL) was measured by SYBR green quantitative rtPCR, and plasma telomerase enzyme was measured by ELISA, in addition, three single nucleotide polymorphisms (SNPs) in telomere-related genes; TERC rs12696304GC, TERT rs2736100CA, and ACYP2 rs6713088GC were genotyped by real-time PCR.

Results: Marked LTL shortening in subjects with HTN and HTN-DM compared to healthy subjects, P = 0.043 and P < 0.001, respectively, was noticed. On the contrary, the plasma telomerase enzyme levels and minor allele frequencies and genotypes of the tested SNPs were comparable between the study groups, except for TERT (CA) genotype which was over-represented in HTN (P = 0.037). Furthermore, the comparisons between HTN and HTN-DM revealed significantly higher total cholesterol (P = 0.015) and LDL-C (P = 0.008) in HTN, while higher insulin levels (P < 001), HOMA-IR (P < 001), and BMI (P = 0.004) were observed in HTN-DM.

Conclusion: This study showed comparable LTL shortening in HTN and HTN-DM, irrespective of plasma telomerase enzyme levels or tested TERC, TERT, and ACYP2 gene polymorphisms, although HTN and HTN-DM differed in several metabolic markers. More studies are required to affirm these observations.

RevDate: 2021-06-09

Brosnan-Cashman JA, Davis CM, Diplas BH, et al (2021)

SMARCAL1 loss and alternative lengthening of telomeres (ALT) are enriched in giant cell glioblastoma.

Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc [Epub ahead of print].

Subsets of high-grade gliomas, including glioblastoma (GBM), are known to utilize the alternative lengthening of telomeres (ALT) pathway for telomere length maintenance. However, the telomere maintenance profile of one subtype of GBM-giant cell GBM-has not been extensively studied. Here, we investigated the prevalence of ALT, as well as ATRX and SMARCAL1 protein loss, in a cohort of classic giant cell GBM and GBM with giant cell features. To determine the presence of ALT, a telomere-specific fluorescence in situ hybridization assay was performed on 15 cases of classic giant cell GBM, 28 additional GBMs found to have giant cell features, and 1 anaplastic astrocytoma with giant cell features. ATRX, SMARCAL1, and IDH1 protein status were assessed in a proportion of cases by immunohistochemistry and were compared to clinical-pathologic and molecular characteristics. In the overall cohort of 44 cases, 19 (43%) showed evidence of ALT. Intriguingly, of the ALT-positive cases, only 9 (47.4%) displayed loss of the ALT suppressor ATRX by immunohistochemistry. Since inactivating mutations in SMARCAL1 have been identified in ATRX wild-type ALT-positive gliomas, we developed an immunohistochemistry assay for SMARCAL1 protein expression using genetically validated controls. Of the 19 ALT-positive cases, 6 (31.5%) showed loss or mis-localization of SMARCAL1 by immunohistochemistry. Of these cases, four retained ATRX protein expression, while two cases also displayed ATRX loss. Additionally, we assessed five cases from which multiple temporal samples were available and ALT status was concordant between both tumor biopsies. In summary, we have identified a subset of giant cell GBM that utilize the ALT telomere maintenance mechanism. Importantly, in addition to ATRX loss, ALT-positive tumors harboring SMARCAL1 alterations are prevalent in giant cell GBM.

RevDate: 2021-06-27

Bae J, Bertucci EM, Bock SL, et al (2021)

Intrinsic and extrinsic factors interact during development to influence telomere length in a long-lived reptile.

Molecular ecology [Epub ahead of print].

The mechanisms connecting environmental conditions to plasticity in biological aging trajectories are fundamental to understanding individual variation in functional traits and life history. Recent findings suggest that telomere biology is especially dynamic during early life stages and has long-term consequences for subsequent reproduction and survival. However, our current understanding is mostly derived from studies investigating ecological and anthropogenic factors separately, leaving the effects of complex environmental interactions unresolved. American alligators (Alligator mississippiensis) are long-lived apex predators that rely on incubation temperature during a discrete period during development and endocrine cues to determine sex, making them especially vulnerable to current climatic variability and exposure to anthropogenic contaminants interfering with hormone function. Here, we combine field studies with a factorial design to understand how the developmental environment, along with intrinsic biological variation contribute to persistent telomere variation. We found that exposure to a common endocrine disrupting contaminant, DDE, affects telomere length, but that the directionality is highly dependent upon incubation temperature. Variation in hatchling growth, underlies a strong clutch effect. We also assess concentrations of a panel of glucocorticoid hormones and find that contaminant exposure elicits an increase in circulating glucocorticoids. Consistent with emerging evidence linking stress and aging trajectories, GC levels also appear to trend with shorter telomere length. Thus, we add support for a mechanistic link between contaminants and glucocorticoid signalling, which interacts with ecological aspects of the developmental environment to alter telomere dynamics.

RevDate: 2021-07-05

van Lieshout SHJ, Badás EP, Bright Ross JG, et al (2021)

Early-life seasonal, weather and social effects on telomere length in a wild mammal.

Molecular ecology [Epub ahead of print].

Early-life environmental conditions can provide a source of individual variation in life-history strategies and senescence patterns. Conditions experienced in early life can be quantified by measuring telomere length, which can act as a biomarker of survival probability in some species. Here, we investigate whether seasonal changes, weather conditions and group size are associated with early-life and/or early-adulthood telomere length in a wild population of European badgers (Meles meles). We found substantial intra-annual changes in telomere length during the first 3 years of life, where within-individual effects showed shorter telomere lengths in the winter following the first spring and a trend for longer telomere lengths in the second spring compared to the first winter. In terms of weather conditions, cubs born in warmer, wetter springs with low rainfall variability had longer early-life (3-12 months old) telomeres. Additionally, cubs born in groups with more cubs had marginally longer early-life telomeres, providing no evidence of resource constraint from cub competition. We also found that the positive association between early-life telomere length and cub survival probability remained when social and weather variables were included. Finally, after sexual maturity, in early adulthood (i.e., 12-36 months) we found no significant association between same-sex adult group size and telomere length (i.e., no effect of intrasexual competition). Overall, we show that controlling for seasonal effects, which are linked to food availability, is important in telomere length analyses, and that variation in telomere length in badgers reflects early-life conditions and also predicts first year cub survival.

RevDate: 2021-06-21

Lin L, Qin K, Chen D, et al (2021)

Systematic review and meta-analysis of the association between paediatric obesity and telomere length.

Acta paediatrica (Oslo, Norway : 1992) [Epub ahead of print].

AIM: This systematic review and meta-analysis aimed to assess the association between paediatric obesity and telomere length.

METHODS: We conducted a comprehensive literature search for original studies assessing the associations between obesity and telomere length in children. Fixed or random effects with inverse-variance meta-analysis were used to estimate the standardised mean difference (SMD) and its 95% confidence interval (95% CI) between overweight or obese and normal-weight children. Heterogeneity was assessed using the I2 statistic, and meta-regression analyses were used to evaluate the potential source of heterogeneity. Subgroup analysis was further conducted by sex.

RESULTS: A total of 11 studies were included. The meta-analysis showed that children who were overweight or obese had shorter telomere length than normal-weight children (SMD: -0.85; 95% CI: -1.42 to -0.28; p < 0.01). However, significant heterogeneity was present (I2 = 97%; p < 0.01). Study design, methods used for measuring telomere length, tissue types, mean age, and percentage of boys were not the source of heterogeneity revealed by meta-regression analysis. The inverse trend was significant only in boys, but not in girls.

CONCLUSION: There was a negative association between paediatric obesity and telomere length. Weight control in children might have beneficial effect on telomere length.

RevDate: 2021-07-05

Tian XP, Qian D, He LR, et al (2021)

Corrigendum to ‟The telomere/telomerase binding factor PinX1 regulates paclitaxel sensitivity depending on spindle assembly checkpoint in human cervical squamous cell carcinomas" [Canc. Lett. 353 (2014) 104-114].

Cancer letters, 516:61-63.

RevDate: 2021-06-27

Wang C, Nawrot TS, Van Der Stukken C, et al (2021)

Different epigenetic signatures of newborn telomere length and telomere attrition rate in early life.

Aging, 13(11):14630-14650.

Telomere length (TL) and telomere shortening are biological indicators of aging, and epigenetic associates have been found for TL in adults. However, the role of epigenetic signatures in setting newborn TL and early life telomere dynamics is unknown. In the present study, based on 247 participating newborns from the ENVIRONAGE birth cohort, whole-genome DNA methylation, profiled on the Illumina MethylationEPIC BeadChip microarray, and TL were measured in cord blood. In a follow-up visit at a mean age of 4.58 years, leukocyte TL was evaluated. We combined an epigenome-wide association study and a statistical learning method with re-sampling to select CpGs and their two-way interactions to model baseline (cord blood) TL and early-life telomere attrition rate, where distinct epigenetic signatures were identified for the two outcomes. In addition, a stronger epigenetic regulation was suggested in setting newborn TL than that of telomere dynamics in early life: 47 CpGs and 7 between-CpG interactions explained 76% of the variance in baseline TLs, while 72% of the total variance in telomere attrition rate was explained by 31 CpGs and 5 interactions. Functional enrichment analysis based on the selected CpGs in the two models revealed GLUT4 translocation and immune cell signaling pathways, respectively. These CpGs and interactions, as well as the cellular pathways, are potential novel targets of further investigation of telomere biology and aging.

RevDate: 2021-06-05

van Batenburg AA, Kazemier KM, van Oosterhout MFM, et al (2021)

Telomere shortening and DNA damage in culprit cells of different types of progressive fibrosing interstitial lung disease.

ERJ open research, 7(2):.

Pulmonary fibrosis is strongly associated with telomere shortening and increased DNA damage. Key cells in the pathogenesis involve alveolar type 2 (AT2) cells, club cells and myofibroblasts; however, to what extent these cells are affected by telomere shortening and DNA damage is not yet known. We sought to determine the degree of, and correlation between, telomere shortening and DNA damage in different cell types involved in the pathogenesis of progressive fibrosing interstitial lung disease. Telomere length and DNA damage were quantified, using combined fluorescence in situ hybridisation and immunofluorescence staining techniques, in AT2 cells, club cells and myofibroblasts of controls and patients with pulmonary fibrosis and a telomerase reverse transcriptase mutation (TERT-PF), idiopathic pulmonary fibrosis (IPF) and fibrotic hypersensitivity pneumonitis (fHP). In IPF and TERT-PF lungs, AT2 cells contained shorter telomeres and expressed higher DNA damage signals than club cells and myofibroblasts. In fHP lungs, club cells contained highly elevated levels of DNA damage, while telomeres were not obviously short. In vitro, we found significantly shorter telomeres and higher DNA damage levels only in AT2 surrogate cell lines treated with telomerase inhibitor BIBR1532. Our study demonstrated that in IPF and TERT-PF lungs, telomere shortening and accumulation of DNA damage primarily affects AT2 cells, further supporting the importance of AT2 cells in these diseases, while in fHP the particularly high telomere-independent DNA damage signals in club cells underscores its bronchiolocentric pathogenesis. These findings suggest that cell type-specific telomere shortening and DNA damage may help to discriminate between different drivers of fibrogenesis.

RevDate: 2021-06-28

Pearce EE, Horvath S, Katta S, et al (2021)

DNA-methylation-based telomere length estimator: comparisons with measurements from flow FISH and qPCR.

Aging, 13(11):14675-14686.

Telomere length (TL) is a marker of biological aging associated with several health outcomes. High throughput reproducible TL measurements are needed for large epidemiological studies. We compared the novel DNA methylation-based estimator (DNAmTL) with the high-throughput quantitative PCR (qPCR) and the highly accurate flow cytometry with fluorescent in situ hybridization (flow FISH) methods using blood samples from healthy adults. We used Pearson's correlation coefficient, Bland Altman plots and linear regression models for statistical analysis. Shorter DNAmTL was associated with older age, male sex, white race, and cytomegalovirus seropositivity (p<0.01 for all). DNAmTL was moderately correlated with qPCR TL (N=635, r=0.41, p < 0.0001) and flow FISH total lymphocyte TL (N=144, r=0.56, p < 0.0001). The agreements between flow FISH TL and DNAmTL or qPCR were acceptable but with wide limits of agreement. DNAmTL correctly classified >70% of TL categorized above or below the median, but the accuracy dropped with increasing TL categories. The ability of DNAmTL to detect associations with age and other TL-related factors in the absence of strong correlation with measured TL may indicate its capture of aspects of telomere maintenance mechanisms and not necessarily TL. The inaccuracy of DNAmTL prediction should be considered during data interpretation and across-study comparisons.

RevDate: 2021-06-27

Steele SL, Hsieh AYY, Gadawski I, et al (2021)

Daily Oral Supplementation with 60 mg of Elemental Iron for 12 Weeks Alters Blood Mitochondrial DNA Content, but Not Leukocyte Telomere Length in Cambodian Women.

Nutrients, 13(6):.

There is limited evidence regarding the potential risk of untargeted iron supplementation, especially among individuals who are iron-replete or have genetic hemoglobinopathies. Excess iron exposure can increase the production of reactive oxygen species, which can lead to cellular damage. We evaluated the effect of daily oral supplementation on relative leukocyte telomere length (rLTL) and blood mitochondrial DNA (mtDNA) content in non-pregnant Cambodian women (18-45 years) who received 60 mg of elemental iron as ferrous sulfate (n = 190) or a placebo (n = 186) for 12 weeks. Buffy coat rLTL and mtDNA content were quantified by monochrome multiplex quantitative polymerase chain reaction. Generalized linear mixed-effects models were used to predict the absolute and percent change in rLTL and mtDNA content after 12 weeks. Iron supplementation was not associated with an absolute or percent change in rLTL after 12 weeks compared with placebo (ß-coefficient: -0.04 [95% CI: -0.16, 0.08]; p = 0.50 and ß-coefficient: -0.96 [95% CI: -2.69, 0.77]; p = 0.28, respectively). However, iron supplementation was associated with a smaller absolute and percent increase in mtDNA content after 12 weeks compared with placebo (ß-coefficient: -11 [95% CI: -20, -2]; p = 0.02 and ß-coefficient: -11 [95% CI: -20, -1]; p= 0.02, respectively). Thus, daily oral iron supplementation for 12 weeks was associated with altered mitochondrial homeostasis in our study sample. More research is needed to understand the risk of iron exposure and the biological consequences of altered mitochondrial homeostasis in order to inform the safety of the current global supplementation policy.

RevDate: 2021-06-27

Glover LM, Cené CW, Reiner A, et al (2021)

Discrimination and Leukocyte Telomere Length by Depressive Symptomatology: The Jackson Heart Study.

Healthcare (Basel, Switzerland), 9(6):.

BACKGROUND: Psychosocial stressors, such as perceived discrimination and depressive symptoms, may shorten telomeres and exacerbate aging-related illnesses.

METHODS: Participants from the Jackson Heart Study at visit 1 (2000-2004) with LTL data and Center for Epidemiological Studies-Depression (CES-D) scores (n = 580 men, n = 910 women) were utilized. The dimensions of discrimination scores (everyday, lifetime, burden of lifetime, and stress from lifetime discrimination) were standardized and categorized as low, moderate, and high. Coping responses to everyday and lifetime discrimination were categorized as passive and active coping. Multivariable linear regression analyses were performed to estimate the mean difference (standard errors-SEs) in LTL by dimensions of discrimination and coping responses stratified by CES-D scores < 16 (low) and ≥ 16 (high) and sex. Covariates were age, education, waist circumference, smoking and CVD status.

RESULTS: Neither everyday nor lifetime discrimination was associated with mean differences in LTL for men or women by levels of depressive symptoms. Burden of lifetime discrimination was marginally associated with LTL among women who reported low depressive symptoms after full adjustment (b = 0.11, SE = 0.06, p = 0.08). Passive coping with lifetime discrimination was associated with longer LTL among men who reported low depressive symptoms after full adjustment (b = 0.18, SE = 0.09, p < 0.05); and active coping with lifetime discrimination was associated with longer LTL among men who reported high depressive symptoms after full adjustment (b = 1.18, SE = 0.35, p < 0.05).

CONCLUSIONS: The intersection of perceived discrimination and depressive symptomatology may be related to LTL, and the effects may vary by sex.

RevDate: 2021-06-17
CmpDate: 2021-06-17

Pendina AA, Krapivin MI, Efimova OA, et al (2021)

Telomere Length in Metaphase Chromosomes of Human Triploid Zygotes.

International journal of molecular sciences, 22(11):.

The human lifespan is strongly influenced by telomere length (TL) which is defined in a zygote-when two highly specialised haploid cells form a new diploid organism. Although TL is a variable parameter, it fluctuates in a limited range. We aimed to establish the determining factors of TL in chromosomes of maternal and paternal origin in human triploid zygotes. Using Q-FISH, we examined TL in the metaphase chromosomes of 28 human triploid zygotes obtained from 22 couples. The chromosomes' parental origin was identified immunocytochemically through weak DNA methylation and strong hydroxymethylation in the sperm-derived (paternal) chromosomes versus strong DNA methylation and weak hydroxymethylation in the oocyte-derived (maternal) ones. In 24 zygotes, one maternal and two paternal chromosome sets were identified, while the four remaining zygotes contained one paternal and two maternal sets. For each zygote, we compared mean relative TLs between parental chromosomes, identifying a significant difference in favour of the paternal chromosomes, which attests to a certain "imprinting" of these regions. Mean relative TLs in paternal or maternal chromosomes did not correlate with the respective parent's age. Similarly, no correlation was observed between the mean relative TL and sperm quality parameters: concentration, progressive motility and normal morphology. Based on the comparison of TLs in chromosomes inherited from a single individual's gametes with those in chromosomes inherited from different individuals' gametes, we compared intraindividual (intercellular) and interindividual variability, obtaining significance in favour of the latter and thus validating the role of heredity in determining TL in zygotes. A comparison of the interchromatid TL differences across the chromosomes from sets of different parental origin with those from PHA-stimulated lymphocytes showed an absence of a significant difference between the maternal and paternal sets but a significant excess over the lymphocytes. Therefore, interchromatid TL differences are more pronounced in zygotes than in lymphocytes. To summarise, TL in human zygotes is determined both by heredity and parental origin; the input of other factors is possible within the individual's reaction norm.

RevDate: 2021-06-15

Tung KTS, Wong RS, Tsang HW, et al (2021)

Impact of Snoring on Telomere Shortening in Adolescents with Atopic Diseases.

Genes, 12(5):.

Atopic diseases can impose a significant burden on children and adolescents. Telomere length is a cellular marker of aging reflecting the impact of cumulative stress exposure on individual health. Since elevated oxidative stress and inflammation burden induced by chronic atopy and snoring may impact telomere length, this study aimed to investigate whether snoring would moderate the relationship between atopic diseases and telomere length in early adolescence. We surveyed 354 adolescents and their parents. Parents reported the adolescents' history of atopic diseases, recent snoring history as well as other family sociodemographic characteristics. Buccal swab samples were also collected from the adolescents for telomere length determination. Independent and combined effects of atopic diseases and snoring on telomere length were examined. Among the surveyed adolescents, 174 were reported by parents to have atopic diseases (20 had asthma, 145 had allergic rhinitis, 53 had eczema, and 25 had food allergy). Shorter TL was found in participants with a history of snoring and atopic diseases (β = -0.34, p = 0.002) particularly for asthma (β = -0.21, p = 0.007) and allergic rhinitis (β = -0.22, p = 0.023). Our findings suggest that snoring in atopic patients has important implications for accelerated telomere shortening. Proper management of atopic symptoms at an early age is important for the alleviation of long-term health consequences at the cellular level.

RevDate: 2021-06-21
CmpDate: 2021-06-21

Maugeri A, Barchitta M, Magnano San Lio R, et al (2021)

The Effect of Alcohol on Telomere Length: A Systematic Review of Epidemiological Evidence and a Pilot Study during Pregnancy.

International journal of environmental research and public health, 18(9):.

Several studies-albeit with still inconclusive and limited findings-began to focus on the effect of drinking alcohol on telomere length (TL). Here, we present results from a systematic review of these epidemiological studies to investigate the potential association between alcohol consumption, alcohol-related disorders, and TL. The analysis of fourteen studies-selected from PubMed, Medline, and Web of Science databases-showed that people with alcohol-related disorders exhibited shorter TL, but also that alcohol consumption per se did not appear to affect TL in the absence of alcohol abuse or dependence. Our work also revealed a lack of studies in the periconceptional period, raising the need for evaluating this potential relationship during pregnancy. To fill this gap, we conducted a pilot study using data and samples form the Mamma & Bambino cohort. We compared five non-smoking but drinking women with ten non-smoking and non-drinking women, matched for maternal age, gestational age at recruitment, pregestational body mass index, and fetal sex. Interestingly, we detected a significant difference when analyzing relative TL of leukocyte DNA of cord blood samples from newborns. In particular, newborns from drinking women exhibited shorter relative TL than those born from non-drinking women (p = 0.024). Although these findings appeared promising, further research should be encouraged to test any dose-response relationship, to adjust for the effect of other exposures, and to understand the molecular mechanisms involved.

RevDate: 2021-06-15

Velazquez ME, Millan AL, Rojo M, et al (2021)

Telomere Length Differently Associated to Obesity and Hyperandrogenism in Women With Polycystic Ovary Syndrome.

Frontiers in endocrinology, 12:604215.

Background: Polycystic Ovary Syndrome (PCOS) often present metabolic disorders and hyperandrogenism (HA), facts that may influence the telomere length (TL).

Aims: To compare the absolute TL (aTL) between women with PCOS and control women, and their association with the presence of obesity and HA parameters.

Materials and methods: The PCOS group included 170 unrelated women outpatients and the control group, 64 unrelated donor women. Anthropometric, biochemical-clinical parameters and androgen profile were determined. The PCOS patients were divided accordingly to the presence of obesity and androgenic condition. The aTL was determined from peripheral blood leukocytes by Real Time quantitative PCR.

Results: Women with PCOS exhibited a significantly longer aTL than controls after age adjustment (p=0.001). A stepwise multivariate linear regression in PCOS women, showed that WC (waist circumference) contributed negatively (b=-0.17) while testosterone levels contributed positively (b=7.24) to aTL. The non-Obese PCOS (noOB-PCOS) presented the longest aTL when compared to controls (p=0.001). Meanwhile, the aTL was significantly higher in the hyperandrogenic PCOS phenotype (HA-PCOS) than in the controls (p=0.001) and non hyperandrogenic PCOS phenotype (NHA-PCOS) (p=0.04). Interestingly, when considering obesity and HA parameters in PCOS, HA exerts the major effect over the aTL as non-obese HA exhibited the lengthiest aTL (23.9 ± 13.13 Kbp). Conversely, the obese NHA patients showed the shortest aTL (16.5 ± 10.59 Kbp).

Conclusions: Whilst a shorter aTL could be related to the presence of obesity, a longer aTL would be associated with HA phenotype. These findings suggest a balance between the effect produced by the different metabolic and hormonal components, in PCOS women.

RevDate: 2021-06-21

Ämmälä AJ, Suvisaari J, Kananen L, et al (2021)

Childhood adversities are associated with shorter leukocyte telomere length at adult age in a population-based study.

Psychoneuroendocrinology, 130:105276.

Telomeres are repeat sequences and an associated protein complex located at the end of the chromosomes. They shorten with every cell division and are regarded markers for cellular aging. Shorter leukocyte telomere length (LTL) has been observed in many complex diseases, including psychiatric disorders. However, analyses focusing on psychiatric disorders are mainly based on clinical samples and the significance of shorter LTL on the population level remains uncertain. We addressed this question in a population-based sample from Finland (N = 7142). The survey was performed and the blood samples were collected in 2000-2001 to assess major public health problems and their determinants. DSM-IV diagnoses of major psychiatric illnesses were obtained by interview using the Composite International Diagnostic Interview. Information regarding their risk factors, including the number of self-reported childhood adversities, recent psychological distress, and sleep difficulties was collected by questionnaires. LTL was measured by qPCR. None of the studied psychiatric illnesses, sleep difficulties, or recent psychological distress associated with LTL. However, individuals with three or more childhood adversities had shorter LTL at adult age (β = -0.006, P = 0.005). Also, current occupational status was associated with LTL (β = -0.03, P = 0.04). These effects remained significant after adjusting for known LTL-associated lifestyle or sociodemographic factors. In conclusion, relatively common childhood adversities were associated with shorter LTL at adult age in a nationally representative population-based cohort, implying that childhood adversities may cause accelerated telomere shortening. Our finding has potentially important implications as it supports the view that childhood adversities have an impact on psychological and somatic well-being later in life.

RevDate: 2021-06-11

Kam MLW, Nguyen TTT, JYY Ngeow (2021)

Telomere biology disorders.

NPJ genomic medicine, 6(1):36.

Telomere biology disorders (TBD) are a heterogeneous group of diseases arising from germline mutations affecting genes involved in telomere maintenance. Telomeres are DNA-protein structures at chromosome ends that maintain chromosome stability; their length affects cell replicative potential and senescence. A constellation of bone marrow failure, pulmonary fibrosis, liver cirrhosis and premature greying is suggestive, however incomplete penetrance results in highly variable manifestations, with idiopathic pulmonary fibrosis as the most common presentation. Currently, the true extent of TBD burden is unknown as there is no established diagnostic criteria and the disorder often is unrecognised and underdiagnosed. There is no gold standard for measuring telomere length and not all TBD-related mutations have been identified. There is no specific cure and the only treatment is organ transplantation, which has poor outcomes. This review summarises the current literature and discusses gaps in understanding and areas of need in managing TBD.

RevDate: 2021-07-05
CmpDate: 2021-07-05

Tempaku PF, D'Almeida V, da Silva SMA, et al (2021)

Klotho genetic variants mediate the association between obstructive sleep apnea and short telomere length.

Sleep medicine, 83:210-213.

The core features of obstructive sleep apnea (OSA) can potentially contribute to the acceleration of telomere shortening mechanisms. Other factor associated with telomeres is Klotho gene as it can negatively regulates telomerase activity. Noteworthy, KLOTHO protein level has recently been associated with OSA. In this sense, it was plausible to hypothesize that OSA would be associated with short telomere length and those with OSA plus risk single nucleotide polymorphisms (SNPs) in Klotho gene would present even shorter telomere length. As part of the EPISONO cohort, 1042 individuals answered questionnaires, underwent polysomnography and had blood collected for DNA extraction. OSA was defined according to AHI≥ 15 events/hour. Leukocyte telomere length (LTL) was measured through real-time polymerase chain reaction (qPCR) and Klotho SNPs were genotyped by array. Mediation analyses considered the presence of SNPs in Klotho gene and how this interaction can affect OSA and its consequence in telomere length. All the analyses were corrected for multiple comparisons. LTL was significantly shorter in OSA compared to controls in a severity-dependent manner (B = 0.055; CI = 0.007-0.102; p = 0.02). Among the 43 Klotho SNPs analyzed, we observed that 4 SNPs (rs525014, rs7982726, rs685417 and rs9563124) significantly mediated the association between OSA and short LTL. Klotho gene opens a new venue in OSA research since it can contribute in the increase of knowledge of the mechanisms involved in the consequences of short telomeres in individuals with OSA.

RevDate: 2021-05-31

Niño MD (2021)

Poverty, Material Hardship, and Telomere Length Among Latina/o Children.

Journal of racial and ethnic health disparities [Epub ahead of print].

BACKGROUND: Despite increased attention on the links between poverty and the health and wellbeing of youth, few have attempted to understand the physiological consequences associated with different forms of economic disadvantage among Latina/o children. The present study begins to address this gap by (1) examining whether different forms of economic disadvantage were related to telomere length for Latina/o children and (2) determining whether parents' nativity shapes economic disadvantage-telomere length relationships.

METHODS: Data were drawn from the Fragile Families and Child Wellbeing Study, a longitudinal, stratified multistage probability sample of couples and children in 20 large US cities. The sample consisted of 417 Latina/o children and their parents that were followed from birth to age 9. Ordinary least squares regressions were used to examine relationships between economic disadvantage and telomere length.

RESULTS: Findings revealed that poverty status was not significantly related to telomere length, whereas some forms of material hardship were shown to play a role in the risk of premature cellular aging. More specifically, medical hardship and difficulty paying bills were associated with shorter telomere length at age 9. Results also provide minimal evidence economic disadvantage-telomere length patterns varied by parents' nativity. Only medical hardship was related to shorter telomere length at age 9 for children with at least one foreign-born parent.

CONCLUSION: Overall, results indicate that the risk of premature cellular aging depends on the measure of economic disadvantage under investigation. Findings from this study can inform targeted strategies designed to reduce the deleterious consequences associated with economic deprivation.

RevDate: 2021-05-28

Zhao Z, Gad H, Benitez-Buelga C, et al (2021)

NEIL3 prevents senescence in hepatocellular carcinoma by repairing oxidative lesions at telomeres during mitosis.

Cancer research pii:0008-5472.CAN-20-1028 [Epub ahead of print].

Hepatocellular carcinoma (HCC) patients suffer from few treatment options and poor survival rates. Here we report that endonuclease VIII-like protein 3 (NEIL3) is overexpressed in HCC and correlates with poor survival. All six HCC cell lines investigated were dependent on NEIL3 catalytic activity for survival and prevention of senescence, while NEIL3 was dispensable for non-transformed cells. NEIL3-depleted HCC cell lines accumulated oxidative DNA lesions specifically at telomeres, resulting in telomere dysfunctional foci and 53BP1 foci formation. Following oxidative DNA damage during mitosis, NEIL3 relocated to telomeres and recruited apurinic endonuclease 1 (APE1), indicating activation of base excision repair. META-FISH revealed that NEIL3, but not NEIL1 or NEIL2, is required to initiate APE1 and Polβ-dependent base excision repair at oxidized telomeres. Repeated exposure of NEIL3-depleted cells to oxidizing damage induced chromatin bridges and damaged telomeres. These results demonstrate a novel function for NEIL3 in repair of oxidative DNA damage at telomeres in mitosis, which is important to prevent senescence of HCC cells. Furthermore, these data suggest that NEIL3 could be a target for therapeutic intervention for HCC.

RevDate: 2021-05-27

Oseini AM, Hamilton JP, Hammam MB, et al (2021)

Liver transplantation in short-telomere-mediated hepatopulmonary syndrome following bone marrow transplantion, using HCV positive allografts: a case series.

Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society [Epub ahead of print].

Short telomere syndromes (STS) are the most common premature aging disorders; mutations in telomerase and other telomere maintenance genes underlie their etiology(1). Their biology is defined by short telomere length which provokes senescence and apoptosis, leading to organ failure. The majority of STS are autosomal dominant, but X-linked, de novo and recessive forms exist.

RevDate: 2021-05-30

Yetim E, Topcuoglu MA, Yurur Kutlay N, et al (2021)

The association between telomere length and ischemic stroke risk and phenotype.

Scientific reports, 11(1):10967.

The chronological age of a person is a key determinant of etiology and prognosis in the setting of ischemic stroke. Telomere length, an indicator of biological aging, progressively shortens with every cell cycle. Herein, we determined telomere length from peripheral blood leukocytes by Southern blot analyses in a prospective cohort of ischemic stroke patients (n = 163) and equal number of non-stroke controls and evaluated its association with various ischemic stroke features including etiology, severity, and outcome. A shorter telomere length (i.e. lowest quartile; ≤ 5.5 kb) was significantly associated with ischemic stroke (OR 2.95, 95% CI 1.70-5.13). This significant relationship persisted for all stroke etiologies, except for other rare causes of stroke. No significant association was present between admission lesion volume and telomere length; however, patients with shorter telomeres had higher admission National Institutes of Health Stroke Scale scores when adjusted for chronological age, risk factors, etiology, and infarct volume (p = 0.046). On the other hand, chronological age, but not telomere length, was associated with unfavorable outcome (modified Rankin scale > 2) and mortality at 90 days follow-up. The association between shorter telomere length and more severe clinical phenotype at the time of admission, might reflect reduced resilience of cerebral tissue to ischemia as part of biological aging.

RevDate: 2021-06-25
CmpDate: 2021-06-25

Fitzpatrick LJ, Olsson M, Pauliny A, et al (2021)

Individual telomere dynamics and their links to life history in a viviparous lizard.

Proceedings. Biological sciences, 288(1951):20210271.

Emerging patterns suggest telomere dynamics and life history are fundamentally linked in endotherms through life-history traits that mediate the processes underlying telomere attrition. Unlike endotherms, ectotherms maintain the ability to lengthen somatic telomeres throughout life and the link between life-history strategies and ectotherm telomere dynamics is unknown. In a well-characterized model system (Niveoscincus ocellatus), we used long-term longitudinal data to study telomere dynamics across climatically divergent populations. We found longer telomeres in individuals from the cool highlands than those from the warm lowlands at birth and as adults. The key determinant of adult telomere length across populations was telomere length at birth, with population-specific effects of age and growth on adult telomere length. The reproductive effort had no proximate effect on telomere length in either population. Maternal factors influenced telomere length at birth in the warm lowlands but not the cool highlands. Our results demonstrate that life-history traits can have pervasive and context-dependent effects on telomere dynamics in ectotherms both within and between populations. We argue that these telomere dynamics may reflect the populations' different life histories, with the slow-growing cool highland population investing more into telomere lengthening compared to the earlier-maturing warm lowland population.

RevDate: 2021-06-25
CmpDate: 2021-06-25

Heidinger BJ, Kucera AC, Kittilson JD, et al (2021)

Longer telomeres during early life predict higher lifetime reproductive success in females but not males.

Proceedings. Biological sciences, 288(1951):20210560.

The mechanisms that contribute to variation in lifetime reproductive success are not well understood. One possibility is that telomeres, conserved DNA sequences at chromosome ends that often shorten with age and stress exposures, may reflect differences in vital processes or influence fitness. Telomere length often predicts longevity, but longevity is only one component of fitness and little is known about how lifetime reproductive success is related to telomere dynamics in wild populations. We examined the relationships between telomere length beginning in early life, telomere loss into adulthood and lifetime reproductive success in free-living house sparrows (Passer domesticus). We found that females, but not males, with longer telomeres during early life had higher lifetime reproductive success, owing to associations with longevity and not reproduction per year or attempt. Telomeres decreased with age in both sexes, but telomere loss was not associated with lifetime reproductive success. In this species, telomeres may reflect differences in quality or condition rather than the pace of life, but only in females. Sexually discordant selection on telomeres is expected to influence the stability and maintenance of within population variation in telomere dynamics and suggests that any role telomeres play in mediating life-history trade-offs may be sex specific.

RevDate: 2021-05-25

Liang J, Shao Y, Huang D, et al (2021)

Effects of prenatal exposure to bisphenols on newborn leucocyte telomere length: a prospective birth cohort study in China.

Environmental science and pollution research international [Epub ahead of print].

Telomere length (TL) at birth is related to diseases that may arise in the future and long-term health. Bisphenols exhibit toxic effects and can cross the placenta barrier. However, the effects of prenatal exposure to bisphenols on newborn TL remain unknown. We aimed to explore the effects of prenatal exposure to bisphenols (i.e., bisphenol A [BPA], bisphenol B [BPB], bisphenol F [BPF], bisphenol S [BPS] and tetrabromobisphenol A [TBBPA]) on relative TL in newborns. A total of 801 mother-infant pairs were extracted from the Guangxi Zhuang Birth Cohort. The relationship between bisphenol levels in maternal serum and relative TL in cord blood was examined by generalized linear models and restricted cubic spline (RCS) models. After adjusting for confounders, we observed a 3.19% (95% CI: -6.08%, -0.21%; P = 0.037) reduction in relative cord blood TL among mothers ≥ 28 years old, with each onefold increase in BPS. However, in each onefold increase of TBBPA, we observed a 3.31% (95% CI: 0.67%, 6.01%; P = 0.014) increase in relative cord blood TL among mothers < 28 years old. The adjusted RCS models revealed similar results (P overall < 0.05, P non-linear > 0.05). This study was the first to establish a positive association between serum TBBPA levels and relative TL in newborns born to young mothers. However, BPS levels were inversely correlated with TL in fetus born to old mothers. The results suggested that the fetus of old pregnant women may be more sensitive to BPS exposure. Moreover, BPS exposure early in life may accelerate aging or increase the risk of developing BPS-related diseases in later life.

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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.

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

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.

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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.

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

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

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Papers in Classical Genetics

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

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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).

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Selected Bibliographies

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

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