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19 Jun 2021 at 01:35
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Bibliography on: Telomeres


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RJR: Recommended Bibliography 19 Jun 2021 at 01:35 Created: 


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

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Citations The Papers (from PubMed®)


RevDate: 2021-06-12

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: 2021-06-11

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: 2021-06-09

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: 2021-06-08

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 find 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 signaling, which interacts with ecological aspects of the developmental environment to alter telomere dynamics.

RevDate: 2021-06-08

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 three 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) telomere lengths. 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 intra-sexual 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: 2021-06-08

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 compared to 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: 2021-06-08

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].

RevDate: 2021-06-04

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: pii:203117 [Epub ahead of print].

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: 2021-06-04

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: pii:203126 [Epub ahead of print].

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: 2021-06-03

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): pii:nu13061877.

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: 2021-06-02

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): pii:healthcare9060639.

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: 2021-06-02

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): pii:ijms22115579.

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: 2021-06-05

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: 2021-06-05

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: 2021-06-01

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 pii:268952 [Epub ahead of print].

In wild animals, telomere attrition during early development has been linked with several fitness penalties 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 rule 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 that 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: 2021-06-01

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: 2021-06-04

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 pii:S0306-4530(21)00150-5 [Epub ahead of print].

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: 2021-05-31

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: 2021-06-04

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 pii:S1389-9457(21)00032-0 [Epub ahead of print].

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: 2021-06-02

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: 2021-06-02

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.

RevDate: 2021-05-26

Mazidi M, Shekoohi N, Katsiki N, et al (2021)

Serum anti-inflammatory and inflammatory markers have no causal impact on telomere length: a Mendelian randomization study.

Archives of medical science : AMS, 17(3):739-751.

Introduction: The relationship between inflammatory and anti-inflammatory markers and telomere length (TL), a biological index of aging, is still poorly understood. By applying a 2-sample Mendelian randomization (MR), we investigated the causal associations between adiponectin, bilirubin, C-reactive protein (CRP), leptin, and serum uric acid (SUA) with TL.

Material and methods: MR was implemented by using summary-level data from the largest ever genome-wide association studies (GWAS) conducted on our interested exposure and TL. Inverse variance weighted method (IVW), weighted median (WM)-based method, MR-Egger, MR-Robust Adjusted Profile Score (RAPS), and MR-Pleiotropy RESidual Sum and Outlier (PRESSO) were applied. Sensitivity analysis was conducted using the leave-one-out method.

Results: With regard to adiponectin, CRP, leptin, and SUA levels, we found no effect on TL for all 4 types of tests (all p > 0.108). Results of the MR-Egger (p = 0.892) and IVW (p = 0.124) showed that bilirubin had no effect on telomere maintenance, whereas the results of the WM (p = 0.030) and RAPS (p = 0.022) were negative, with higher bilirubin concentrations linked to shorter TL. There was a low likelihood of heterogeneity for all the estimations, except for bilirubin (IVW p = 0.026, MR Egger p = 0.018). MR-PRESSO highlighted no outlier. For all the estimations, we observed negligible intercepts that were indicative of low likelihood of the pleiotropy (all p > 0.161). The results of leave-one-out method demonstrated that the links are not driven because of single nucleotide polymorphisms (SNPs).

Conclusions: Our results highlight that neither the anti-inflammatory nor pro-inflammatory markers tested have any significant causal effect on TL. The casual role of bilirubin on TL still needs to be investigated.

RevDate: 2021-05-22

Ali S, Lombardi EP, Ghosh D, et al (2021)

Pt-ttpy, a G-quadruplex binding platinum complex, induces telomere dysfunction and G-rich regions DNA damage.

Metallomics : integrated biometal science pii:6280987 [Epub ahead of print].

Pt-ttpy (tolyl terpyridin-Pt complex) covalently binds to G-quadruplex (G4) structures in vitro and to telomeres in cellulo via its Pt moiety. Here, we identified its targets in the human genome, in comparison to Pt-tpy, its derivative without G4 affinity, and cisplatin. Pt-ttpy, but not Pt-tpy, induces the release of the shelterin protein TRF2 from telomeres concomitantly to the formation of DNA damage foci at telomeres but also at other chromosomal locations. γ-H2AX chromatin immunoprecipitation (ChIP-seq) after treatment with Pt-ttpy or cisplatin revealed accumulation in G- and A-rich tandemly repeated sequences, but not particularly in potential G4 forming sequences. Collectively, Pt-ttpy presents dual targeting efficiency on DNA, by inducing telomere dysfunction and genomic DNA damage at specific loci.

RevDate: 2021-06-04

Uryga AK, Grootaert MOJ, Garrido AM, et al (2021)

Telomere damage promotes vascular smooth muscle cell senescence and immune cell recruitment after vessel injury.

Communications biology, 4(1):611.

Accumulation of vascular smooth muscle cells (VSMCs) is a hallmark of multiple vascular pathologies, including following neointimal formation after injury and atherosclerosis. However, human VSMCs in advanced atherosclerotic lesions show reduced cell proliferation, extensive and persistent DNA damage, and features of premature cell senescence. Here, we report that stress-induced premature senescence (SIPS) and stable expression of a telomeric repeat-binding factor 2 protein mutant (TRF2T188A) induce senescence of human VSMCs, associated with persistent telomeric DNA damage. VSMC senescence is associated with formation of micronuclei, activation of cGAS-STING cytoplasmic sensing, and induction of multiple pro-inflammatory cytokines. VSMC-specific TRF2T188A expression in a multicolor clonal VSMC-tracking mouse model shows no change in VSMC clonal patches after injury, but an increase in neointima formation, outward remodeling, senescence and immune/inflammatory cell infiltration or retention. We suggest that persistent telomere damage in VSMCs inducing cell senescence has a major role in driving persistent inflammation in vascular disease.

RevDate: 2021-05-24

Dasanayaka NN, Sirisena ND, N Samaranayake (2021)

The effects of meditation on length of telomeres in healthy individuals: a systematic review.

Systematic reviews, 10(1):151.

BACKGROUND: Meditation-based practices have been suggested to result in many biological benefits which include reduction of attrition of telomeres, the protective nucleotide-protein complexes at termini of eukaryotic chromosomes. This systematic review evaluated the effects of meditation on telomere length (TL) in healthy adults.

METHODS: Randomized controlled trials (RCTs) and observational studies conducted to determine the effects of meditation on TL in healthy individuals, published up to July 2020 were retrieved by searching seven electronic databases (PubMed, Scopus, PsycINFO, EMBASE, Cochrane Library, CINAHL and Google Scholar). The methodological quality of RCTs and observational studies was assessed using the Cochrane Collaboration Risk of Bias Tool and Joanna Briggs Institute critical appraisal checklist, respectively. The data was synthesized narratively and the effect estimates of TL in the RCTs were synthesized using alternative methods as a meta-analysis was not conducted. The certainty of evidence was classified according to the GRADE system.

RESULTS: A total of 1740 articles were screened. Five studies comprising two RCTs and three case-control studies (CCS) were included in the final review based on the inclusion and exclusion criteria. The combined sample consisted of 615 participants with 41.7% males. Average age of participants was 47.7 years. One CCS and one RCT reported significant beneficial effects of meditation on TL while the two remaining CCS and the RCT showed positive effects of meditation on TL which were not significant. For all CCS and one RCT, the methodological quality was high while the remaining RCT was of moderate quality. The quality of evidence for the primary outcome was moderate in RCTs.

CONCLUSION: The effect of meditation on TL per se is still unclear. Strictly designed and well-reported RCTs with larger sample sizes are required to provide evidence of higher quality.

The protocol of this review was registered with the International Prospective Register of Systematic Reviews (PROSPERO) database (registration number: CRD42020153977).

RevDate: 2021-06-08

Cowell W, Tang D, Yu J, et al (2021)

Telomere dynamics across the early life course: Findings from a longitudinal study in children.

Psychoneuroendocrinology, 129:105270 pii:S0306-4530(21)00144-X [Epub ahead of print].

Telomeres are protective caps on chromosome ends that shorten with each cell division. Telomere length (TL) predicts the onset of cellular senescence and correlates with longevity and age-related disease risk. Previous research suggests that adults display fixed ranking and tracking of TL by age 20 years, supporting the importance of TL at birth and attrition during childhood. However, longitudinal research examining telomere dynamics during early life is sparse. Here, we used monochrome multiplex quantitative polymerase chain reaction to measure relative TL in leukocytes isolated from cord blood and child blood collected at ages 3, 5, 7, and 9 years among 224 minority children enrolled in a New York City-based birth cohort. We also measured maternal TL at delivery in a subset of 197 participants with a biobanked blood sample. TL decreased most rapidly in the first years of life (birth to 3 years), followed by a period of maintenance into the pre-puberty period. Mothers with longer telomeres gave birth to newborns with longer telomeres that remained longer across childhood, suggesting that the fixed ranking and tracking of TL observed among adults may extend to early childhood or even the prenatal period with a potential transgenerational basis. We did not find significant sex differences in the pattern of child TL change across development. These findings emphasize the need to understand factors and mechanisms that determine TL during early childhood.

RevDate: 2021-05-29

Chang ACY, Pardon G, Chang ACH, et al (2021)

Increased tissue stiffness triggers contractile dysfunction and telomere shortening in dystrophic cardiomyocytes.

Stem cell reports pii:S2213-6711(21)00213-7 [Epub ahead of print].

Duchenne muscular dystrophy (DMD) is a rare X-linked recessive disease that is associated with severe progressive muscle degeneration culminating in death due to cardiorespiratory failure. We previously observed an unexpected proliferation-independent telomere shortening in cardiomyocytes of a DMD mouse model. Here, we provide mechanistic insights using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). Using traction force microscopy, we show that DMD hiPSC-CMs exhibit deficits in force generation on fibrotic-like bioengineered hydrogels, aberrant calcium handling, and increased reactive oxygen species levels. Furthermore, we observed a progressive post-mitotic telomere shortening in DMD hiPSC-CMs coincident with downregulation of shelterin complex, telomere capping proteins, and activation of the p53 DNA damage response. This telomere shortening is blocked by blebbistatin, which inhibits contraction in DMD cardiomyocytes. Our studies underscore the role of fibrotic stiffening in the etiology of DMD cardiomyopathy. In addition, our data indicate that telomere shortening is progressive, contraction dependent, and mechanosensitive, and suggest points of therapeutic intervention.

RevDate: 2021-05-21

Giri N, Alter BP, Savage SA, et al (2021)

Gynaecological and reproductive health of women with telomere biology disorders.

British journal of haematology [Epub ahead of print].

Reproductive health may be adversely impacted in women with dyskeratosis congenita (DC) and related telomere biology disorders (TBD). We evaluated gynaecological problems, fertility, and pregnancy outcomes in 39 females aged 10-81 years who were followed longitudinally in our DC/TBD cohort. Twenty-six had bone marrow failure and 12 underwent haematopoietic cell transplantation. All attained menarche at a normal age. Thirteen women reported menorrhagia; ten used hormonal contraception to reduce bleeding. Nine experienced natural normal-aged menopause. Gynaecological problems (endometriosis = 3, pelvic varicosities = 1, cervical intraepithelial neoplasia = 1, and uterine prolapse = 2) resulted in surgical menopause in seven. Twenty-five of 26 women attempting fertility carried 80 pregnancies with 49 (61%) resulting in livebirths. Ten (38%) women experienced 28 (35%) miscarriages, notably recurrent pregnancy loss in five (19%). Preeclampsia (n = 6, 24%) and progressive cytopenias (n = 10, 40%) resulted in maternal-fetal compromise, including preterm (n = 5) and caesarean deliveries (n = 18, 37%). Gynaecological/reproductive problems were noted mainly in women with autosomal-dominant inheritance; others were still young or died early. Although women with TBDs had normal menarche, fertility, and menopause, gynaecological problems and pregnancy complications leading to caesarean section, preterm delivery, or transfusion support were frequent. Women with TBDs will benefit from multidisciplinary, coordinated care by haematology, gynaecology and maternal-fetal medicine.

RevDate: 2021-06-10

Dong X, Sun S, Zhang L, et al (2021)

Age-related telomere attrition causes aberrant gene expression in sub-telomeric regions.

Aging cell [Epub ahead of print].

Telomere attrition has been proposed as a biomarker and causal factor in aging. In addition to causing cellular senescence and apoptosis, telomere shortening has been found to affect gene expression in subtelomeric regions. Here, we analyzed the distribution of age-related differentially expressed genes from the GTEx RNA sequencing database of 54 tissue types from 979 human subjects and found significantly more upregulated than downregulated genes in subtelomeric regions as compared to the genome-wide average. Our data demonstrate spatial relationships between telomeres and gene expression in aging.

RevDate: 2021-05-27

da Silva Neto Trajano LA, da Silva Sergio LP, de Oliveira DSL, et al (2021)

Low-power infrared laser modulates telomere length in heart tissue from an experimental model of acute lung injury.

Photochemical & photobiological sciences : Official journal of the European Photochemistry Association and the European Society for Photobiology, 20(5):653-661.

Acute lung injury and acute respiratory distress syndrome can occur as a result of sepsis. Cardiac dysfunction is a serious component of multi-organ failure caused by severe sepsis. Telomere shortening is related to several heart diseases. Telomeres are associated with the shelterin protein complex, which contributes to the maintenance of telomere length. Low-power infrared lasers modulate mRNA levels of shelterin complex genes. This study aimed to evaluate effects of a low-power infrared laser on mRNA relative levels of genes involved in telomere stabilization and telomere length in heart tissue of an experimental model of acute lung injury caused by sepsis. Animals were divided into six groups, treated with intraperitoneal saline solution, saline solution and exposed to a low-power infrared laser at 10 J cm-2 and 20 J cm-2, lipopolysaccharide (LPS), and LPS and, after 4 h, exposed to a low-power infrared laser at 10 J cm-2 and 20 J cm-2. The laser exposure was performed only once. Analysis of mRNA relative levels and telomere length by RT-qPCR was performed. Telomere shortening and reduction in mRNA relative levels of TRF1 mRNA in heart tissues of LPS-induced ALI animals were observed. In addition, laser exposure increased the telomere length at 10 J cm-2 and modulated the TRF1 mRNA relative levels of at 20 J cm-2 in healthy animals. Although the telomeres were shortened and mRNA levels of TRF1 gene were increased in nontreated controls, the low-power infrared laser irradiation increased the telomere length at 10 J cm-2 in cardiac tissue of animals affected by LPS-induced acute lung injury, which suggests that telomere maintenance is a part of the photobiomodulation effect induced by infrared radiation.

RevDate: 2021-05-19

Whitlock B (2021)

Telomere Length and Arsenic: Improving Animal Models of Toxicity by Choosing Mice With Shorter Telomeres.

International journal of toxicology, 40(3):211-217.

Arsenic is both a chemotherapeutic drug and an environmental toxicant that affects hundreds of millions of people each year. Arsenic exposure in drinking water has been called the worst poisoning in human history. How arsenic is handled in the body is frequently studied using rodent models to investigate how arsenic both causes and treats disease. These models, used in a variety of arsenic-related testing, from tumor formation to drug toxicity monitoring, have virtually always been developed from animals with telomeres that are unnaturally long, likely because of accidental artificial selective pressures. Mice that have been bred in captivity in laboratory conditions, often for over 100 years, are the standard in creating animal models for this research. Using these mice introduces challenges to any work that can be affected by the length of telomeres and the related capacities for tissue repair and cancer resistance. However, arsenic research is particularly susceptible to the misuse of such animal models due to the multiple and various interactions between arsenic and telomeres. Researchers in the field commonly find mouse models and humans behaving very differently upon exposure to acute and chronic arsenic, including drug therapies which seem safe in mice but are toxic in humans. Here, some complexities and apparent contradictions of the arsenic carcinogenicity and toxicity research are reconciled by an explanatory model that involves telomere length explained by the evolutionary pressures in laboratory mice. A low-risk hypothesis is proposed which has the power to determine whether researchers can easily develop more powerful and accurate mouse models by simply avoiding mouse lineages that are very old and have strangely long telomeres. Swapping in newer mouse lineages for the older, long-telomere mice may vastly improve our ability to research arsenic toxicity with virtually no increase in cost or difficulty of research.

RevDate: 2021-05-17

Teixeira MZ (2021)

Telomere and Telomerase: Biological Markers of Organic Vital Force State and Homeopathic Treatment Effectiveness.

Homeopathy : the journal of the Faculty of Homeopathy [Epub ahead of print].

BACKGROUND: Philosophical-scientific correlations described in previous studies suggest that the genome can be the biological representation of the vital force, whilst the disease-promoting epigenetic alterations would be the biological representation of the chronic miasmas. In this study, we expand the functional correlation between vital force and chromosomes, describing the mechanism of action of the telomere-telomerase complex in the context of physiological balance.

AIMS: The aim of the work is to study the role of the telomere-telomerase complex in cell vitality, biological aging, and the health-disease process, with the goal of proposing the use of telomere length as a biomarker of the vital force state and the effectiveness of homeopathic treatment.

RESULTS: Similar to the vital force, telomere length and telomerase enzyme activity play an important role in maintaining cellular vitality, biological longevity, and physiological homeostasis. Telomere shortening functions as a biomarker of vital imbalance and is associated with numerous diseases and health disorders. On the other hand, health-promotion practices neutralize the pathological shortening of the telomeres, acting therapeutically in diseases or age-dependent health disorders.

CONCLUSIONS: As a hypothetical biomarker of the vital force state, an intra-individual analysis of the mean leukocyte telomere length before, during, and after homeopathic treatment can be used as a biomarker of therapeutic effectiveness.

RevDate: 2021-06-10

Fernandes JR, Pinto TNC, Piemonte LL, et al (2021)

Long-term tobacco exposure and immunosenescence: Paradoxical effects on T-cells telomere length and telomerase activity.

Mechanisms of ageing and development, 197:111501 pii:S0047-6374(21)00073-7 [Epub ahead of print].

Immunosenescence are alterations on immune system that occurs throughout an individual life. The main characteristic of this process is replicative senescence, evaluated by telomere shortening. Several factors implicate on telomere shortening, such as smoking. In this study, we evaluated the influence of smoking and Chronic Obstructive Pulmonary Disease (COPD) on cytokines, telomere length and telomerase activity. Blood samples were collected from subjects aged over 60 years old: Healthy (never smokers), Smokers (smoking for over 30 years) and COPDs (ex-smokers for ≥15 years). A young group was included as control. PBMCs were cultured for assessment of telomerase activity using RT-PCR, and cytokines secretion flow cytometry. CD4+ and CD8+ purified lymphocytes were used to assess telomere length using FlowFISH. We observed that COPD patients have accelerated telomere shortening. Paradoxically, smokers without lung damage showed preserved telomere length, suggesting that tobacco smoking may affect regulatory mechanisms, such as telomerase. Telomerase activity showed diminished activity in COPDs, while Smokers showed increased activity compared to COPDs and Healthy groups. Extracellular environment reflected this unbalance, indicated by an anti-inflammatory profile in Smokers, while COPDs showed an inflammatory prone profile. Further studies focusing on telomeric maintenance may unveil mechanisms that are associated with cancer under long-term smoking.

RevDate: 2021-05-17

Alonso-Pedrero L, Ojeda-Rodríguez A, Zalba G, et al (2021)

Association between ideal cardiovascular health and telomere length in participants older than 55 years old from the SUN cohort.

Revista espanola de cardiologia (English ed.) pii:S1885-5857(21)00129-8 [Epub ahead of print].

INTRODUCTION AND OBJECTIVES: Telomeres are noncoding regions located at the end of chromosomes and their shortening has been associated with risk factors and cardiovascular disease. The aim of this study was to evaluate the association between ideal cardiovascular health (Life's simple 7) and the odds of having short telomeres in a subsample of participants older than 55 years from the Seguimiento Universidad de Navarra (SUN) study.

METHODS: We included 886 participants older than 55 years (645 men and 241 women). Telomere length was measured using a real-time quantitative polymerase chain reaction. Cardiovascular health score was defined by the American Heart Association as a composite score of 7 key risk factors (smoking status, physical activity, diet, body mass index, blood pressure, total cholesterol, and fasting blood glucose) with 0 to 2 points for each factor. We categorized this score in tertiles as poor (0-9 points), intermediate (10-11 points) and ideal (12-14 points). The odds of having short telomeres was defined as telomere length below the 20th percentile.

RESULTS: Individuals with higher ideal cardiovascular health had a lower prevalence of having short telomeres (adjusted OR, 0.60; 95%CI, 0.34-1.05; P trend=.052). This association was statistically significant in men (adjusted OR, 0.37; 95%CI, 0.17-0.83; P trend=.025) but not in women.

CONCLUSIONS: An inverse association between cardiovascular health score and short telomeres was found especially for men older than 55 years in the SUN population. The SUN project was registered at ClinicalTrials.gov (Identifier: NCT02669602).

RevDate: 2021-05-16

Choudhury A, Mohammad T, Samarth N, et al (2021)

Structural genomics approach to investigate deleterious impact of nsSNPs in conserved telomere maintenance component 1.

Scientific reports, 11(1):10202.

Conserved telomere maintenance component 1 (CTC1) is an important component of the CST (CTC1-STN1-TEN1) complex, involved in maintaining the stability of telomeric DNA. Several non-synonymous single-nucleotide polymorphisms (nsSNPs) in CTC1 have been reported to cause Coats plus syndrome and Dyskeratosis congenital diseases. Here, we have performed sequence and structure analyses of nsSNPs of CTC1 using state-of-the-art computational methods. The structure-based study focuses on the C-terminal OB-fold region of CTC1. There are 11 pathogenic mutations identified, and detailed structural analyses were performed. These mutations cause a significant disruption of noncovalent interactions, which may be a possible reason for CTC1 instability and consequent diseases. To see the impact of such mutations on the protein conformation, all-atom molecular dynamics (MD) simulations of CTC1-wild-type (WT) and two of the selected mutations, R806C and R806L for 200 ns, were carried out. A significant conformational change in the structure of the R806C mutant was observed. This study provides a valuable direction to understand the molecular basis of CTC1 dysfunction in disease progression, including Coats plus syndrome.

RevDate: 2021-05-28

He Y, Wang Y, Liu B, et al (2021)

Structures of telomerase at several steps of telomere repeat synthesis.

Nature, 593(7859):454-459.

Telomerase is unique among the reverse transcriptases in containing a noncoding RNA (known as telomerase RNA (TER)) that includes a short template that is used for the processive synthesis of G-rich telomeric DNA repeats at the 3' ends of most eukaryotic chromosomes1. Telomerase maintains genomic integrity, and its activity or dysregulation are critical determinants of human longevity, stem cell renewal and cancer progression2,3. Previous cryo-electron microscopy structures have established the general architecture, protein components and stoichiometries of Tetrahymena and human telomerase, but our understandings of the details of DNA-protein and RNA-protein interactions and of the mechanisms and recruitment involved remain limited4-6. Here we report cryo-electron microscopy structures of active Tetrahymena telomerase with telomeric DNA at different steps of nucleotide addition. Interactions between telomerase reverse transcriptase (TERT), TER and DNA reveal the structural basis of the determination of the 5' and 3' template boundaries, handling of the template-DNA duplex and separation of the product strand during nucleotide addition. The structure and binding interface between TERT and telomerase protein p50 (a homologue of human TPP17,8) define conserved interactions that are required for telomerase activation and recruitment to telomeres. Telomerase La-related protein p65 remodels several regions of TER, bridging the 5' and 3' ends and the conserved pseudoknot to facilitate assembly of the TERT-TER catalytic core.

RevDate: 2021-05-28
CmpDate: 2021-05-28

Roisné-Hamelin F, Pobiega S, Jézéquel K, et al (2021)

Mechanism of MRX inhibition by Rif2 at telomeres.

Nature communications, 12(1):2763.

Specific proteins present at telomeres ensure chromosome end stability, in large part through unknown mechanisms. In this work, we address how the Saccharomyces cerevisiae ORC-related Rif2 protein protects telomere. We show that the small N-terminal Rif2 BAT motif (Blocks Addition of Telomeres) previously known to limit telomere elongation and Tel1 activity is also sufficient to block NHEJ and 5' end resection. The BAT motif inhibits the ability of the Mre11-Rad50-Xrs2 complex (MRX) to capture DNA ends. It acts through a direct contact with Rad50 ATP-binding Head domains. Through genetic approaches guided by structural predictions, we identify residues at the surface of Rad50 that are essential for the interaction with Rif2 and its inhibition. Finally, a docking model predicts how BAT binding could specifically destabilise the DNA-bound state of the MRX complex. From these results, we propose that when an MRX complex approaches a telomere, the Rif2 BAT motif binds MRX Head in its ATP-bound resting state. This antagonises MRX transition to its DNA-bound state, and favours a rapid return to the ATP-bound state. Unable to stably capture the telomere end, the MRX complex cannot proceed with the subsequent steps of NHEJ, Tel1-activation and 5' resection.

RevDate: 2021-05-13

Moon DH, Kim J, Lim MN, et al (2021)

Correlation between Telomere Length and COPD-related Phenotypes: results from the chronic obstructive pulmonary disease in dusty areas (CODA) cohort.

Tuberculosis and respiratory diseases pii:trd.2021.0015 [Epub ahead of print].

Background: COPD is a common chronic respiratory disease with increased prevalence as older. Telomeres are repetitive DNA sequences found at the end of the chromosome, which progressively shorten as cells divide. Telomere length is known to be a molecular marker of aging. This study aimed to assess the relationship between telomere length and the risk of COPD, lung function, respiratory symptoms, and emphysema index in chronic obstructive pulmonary disease in dusty areas (CODA) cohort.

Methods: We extracted DNA from the peripheral blood samples of 446 participants, including 285 COPD patients and 161 control participants. We measured absolute telomere length using quantitative real-time polymerase chain reaction. All participants underwent spirometry and quantitative computed tomography scan. Questionnaires assessing respiratory symptoms and the COPD Assessment Test (CAT)) was conducted for all participants.

Results: The mean age of participants at the baseline visit was 72.5±7.1 years. Males accounted for 72%(321 participants) of the all participants. The mean telomere length was shorter in the COPD group compared to the non COPD group (COPD; 16.81±13.90, Non-COPD; 21.97±14.43 kb). In COPD patients, 112(75.7%) were distributed as tertile1(shortest), 91 (61.1%) as tertile2 and 82 (55%) as tertile3(longest). We did not find significant associations between telomere length and lung function, exacerbation, airway wall thickness and emphysema index after adjusting for sex, age, and smoking status.

Conclusion: In this study, the relationship between various COPD phenotypes and telomere length was analyzed, but no significant statistical associations were shown.

RevDate: 2021-06-09

Tichy ED, Ma N, Sidibe D, et al (2021)

Persistent NF-κB activation in muscle stem cells induces proliferation-independent telomere shortening.

Cell reports, 35(6):109098.

During the repeated cycles of damage and repair in many muscle disorders, including Duchenne muscular dystrophy (DMD), the muscle stem cell (MuSC) pool becomes less efficient at responding to and repairing damage. The underlying mechanism of such stem cell dysfunction is not fully known. Here, we demonstrate that the distinct early telomere shortening of diseased MuSCs in both mice and young DMD patients is associated with aberrant NF-κB activation. We find that prolonged NF-κB activation in MuSCs in chronic injuries leads to shortened telomeres and Ku80 dysregulation and results in severe skeletal muscle defects. Our studies provide evidence of a role for NF-κB in regulating stem-cell-specific telomere length, independently of cell replication, and could be a congruent mechanism that is applicable to additional tissues and/or diseases characterized by systemic chronic inflammation.

RevDate: 2021-05-11

McLennan D, Auer SK, McKelvey S, et al (2021)

Habitat restoration weakens negative environmental effects on telomere dynamics.

Molecular ecology [Epub ahead of print].

Habitat quality can have far-reaching effects on organismal fitness, an issue of concern given the current scale of habitat degradation. Many temperate upland streams have reduced nutrient levels due to human activity. Nutrient restoration confers benefits in terms of invertebrate food availability and subsequent fish growth rates. Here we test whether these mitigation measures also affect the rate of cellular ageing of the fish, measured in terms of the telomeres that cap the ends of eukaryotic chromosomes. We equally distributed Atlantic salmon eggs from the same 30 focal families into 10 human-impacted oligotrophic streams in northern Scotland. Nutrient levels in five of the streams were restored by simulating the deposition of a small number of adult Atlantic salmon Salmo salar carcasses at the end of the spawning period, while five reference streams were left as controls. Telomere lengths and expression of the telomerase reverse transcriptase (TERT) gene that may act to lengthen telomeres were then measured in the young fish when 15 months old. While TERT expression was unrelated to any of the measured variables, telomere lengths were shorter in salmon living at higher densities and in areas with a lower availability of the preferred substrate (cobbles and boulders). However, the adverse effects of these habitat features were much reduced in the streams receiving nutrients. These results suggest that adverse environmental pressures are weakened when nutrients are restored, presumably because the resulting increase in food supply reduces levels of both competition and stress.

RevDate: 2021-06-09

Ward SJ, Hill AM, Buckley JD, et al (2021)

Minimal changes in telomere length after a 12-week dietary intervention with almonds in mid-age to older, overweight and obese Australians: results of a randomised clinical trial.

The British journal of nutrition pii:S0007114521001549 [Epub ahead of print].

Diet is a modifiable risk factor for chronic disease and a potential modulator of telomere length (TL). The study aim was to investigate associations between diet quality and TL in Australian adults after a 12-week dietary intervention with an almond-enriched diet (AED). Participants (overweight/obese, 50-80 years) were randomised to an AED (n 62) or isoenergetic nut-free diet (NFD, n 62) for 12 weeks. Diet quality was assessed using a Dietary Guideline Index (DGI), applied to weighed food records, that consists of ten components reflecting adequacy, variety and quality of core food components and discretionary choices within the diet. TL was measured by quantitative PCR in samples of lymphocytes, neutrophils, and whole blood. There were no significant associations between DGI scores and TL at baseline. Diet quality improved with AED and decreased with NFD after 12 weeks (change from baseline AED + 9·8 %, NFD - 14·3 %; P < 0·001). TL increased in neutrophils (+9·6 bp, P = 0·009) and decreased in whole blood, to a trivial extent (-12·1 bp, P = 0·001), and was unchanged in lymphocytes. Changes did not differ between intervention groups. There were no significant relationships between changes in diet quality scores and changes in lymphocyte, neutrophil or whole blood TL. The inclusion of almonds in the diet improved diet quality scores but had no impact on TL mid-age to older Australian adults. Future studies should investigate the impact of more substantial dietary changes over longer periods of time.

RevDate: 2021-06-04

Ospanov O, Akilzhanova A, Buchwald JN, et al (2021)

Stapleless vs Stapled Gastric Bypass vs Hypocaloric Diet: a Three-Arm Randomized Controlled Trial of Body Mass Evolution with Secondary Outcomes for Telomere Length and Metabolic Syndrome Changes.

Obesity surgery, 31(7):3165-3176.

BACKGROUND: Obesity and metabolic syndrome (MetS) reduce life expectancy and are challenging to resolve. This randomized controlled trial (RCT) of patients with obesity and MetS undergoing surgical vs nonsurgical treatment compared changes in BMI, and secondarily, telomere length (as a biomarker of life expectancy) and changes in MetS components (insulin resistance, dyslipidemia, hypertension).

METHODS: Study design was a single-center, prospective, three-arm RCT. Group 1 patients underwent novel unstapled laparoscopic one anastomosis gastric bypass with an obstructive stapleless pouch and anastomosis (LOAGB-OSPAN); Group 2, stapled laparoscopic mini-gastric bypass-one anastomosis gastric bypass (LMGB-OAGB); and Group 3, nonsurgical weight loss therapy via a hypocaloric diet with energy restriction (HDER). The primary outcome measure was change in BMI; secondary outcome measures included change in leukocyte telomere length and other MetS components.

RESULTS: Of 96 participants screened, 60 were randomly allocated to 3 groups: LOAGB-OSPAN group (n = 20), LMGB-OAGB group (n = 20), and HDER group (n = 20). At post-treatment month 12, respective BMI changes: BMI -12.13 (-8.34, -15.93); -16.04 (-11.7, 20.37); -2,76 (-3.84, -9.36) (p < 0.01). The two surgical groups experienced significant change in telomere length: LOAGB-OSPAN 2.02 (1.61, 2.41), p = 0.001; LMGB-OAGB 2.07 (1.72, 2.43), p = 0.001; and HDER 0.28 (0.22, 0.78), p = 0.26. The surgical groups were also more effective in treating MetS components. There were no deaths. Adverse events: LOAGB-OSPAN (n = 2) (Clavien-Dindo grade II); LMGB-OAGB (n = 8) (grade I (n = 6) and grade II (n = 2).

CONCLUSIONS: Compared with hypocaloric diet therapy, both bariatric procedures resulted in greater BMI loss, and secondarily, a significant increase in telomere length, and greater MetS resolution.

TRIAL REGISTRATION: ClinicalTrials.gov , NCT03667469, registered on 11 September 2018.

RevDate: 2021-05-07

Inandiklioğlu N, Demir V, M Ercan (2021)

Telomere Length and Oxidative Stress in Patients with ST-Segment Elevation and Non-ST-Segment Elevation Myocardial Infarction.

Advances in experimental medicine and biology [Epub ahead of print].

PURPOSE: The telomere length is shown to act as a biomarker, especially for biological aging and cardiovascular diseases, and it is also suggested that with this correlation, increased exposure to the oxidative stress accelerates the vascular aging process. Therefore, this study aims to understand the correlation between the plasma oxidative stress index (OSI) status and leukocyte telomere length (LTL) and cardiologic parameters between the ST-segment elevation myocardial infarction (STEMI) and non-ST-segment elevation myocardial infarction (NSTEMI) groups.

METHOD: One hundred one newly diagnosed patients with STEMI (n = 55) and NSTEMI (n = 46) were included in the study, along with 100 healthy controls who matched the patients in terms of age and gender. Plasma total antioxidant status (TAS), total oxidant status (TOS), and LTL were measured.

RESULTS: When LTL, TAS, TOS, and OSI values were evaluated between the patient and control group, OSI (p = 0.000) and LTL (p = 0.05) values were statistically significant in the patient group compared to the control group. Evaluation was conducted to understand whether there is a difference between the STEMI and NSTEMI groups. The plasma OSI (p = 0.007) and LTL (p = 0.05) were found to be significantly lower in STEMI patients. However, LTL and OSI results were not statistically significant in NSTEMI patients.

CONCLUSION: This is the first study evaluating telomere length and oxidative stress in STEMI and NSTEMI patients in Turkey. Our results support the existence of short telomere length in STEMI patients. Future studies on telomere length and oxidative stress will support the importance of our findings.

RevDate: 2021-05-18

Toupance S, Simonici S, Labat C, et al (2021)

Number and Replating Capacity of Endothelial Colony-Forming Cells are Telomere Length Dependent: Implication for Human Atherogenesis.

Journal of the American Heart Association, 10(10):e020606.

Background Short leukocyte telomere length (TL) is associated with atherosclerotic cardiovascular disease. Endothelial repair plays a key role in the development of atherosclerosis. The objective was to examine associations between TL and proliferative dynamics of endothelial colony-forming cells (ECFCs), which behave as progenitor cells displaying endothelial repair activity. Methods and Results To isolate ECFCs, we performed a clonogenic assay on blood samples from 116 participants (aged 24-94 years) in the TELARTA (Telomere in Arterial Aging) cohort study. We detected no ECFC clones in 29 (group 1), clones with no replating capacity in other 29 (group 2), and clones with replating capacity in the additional 58 (group 3). Leukocyte TL was measured by Southern blotting and ECFCs (ECFC-TL). Age- and sex-adjusted leukocyte TL (mean±SEM) was the shortest in group 1 (6.51±0.13 kb), longer in group 2 (6.69±0.13 kb), and the longest in group 3 (6.78±0.09 kb) (P<0.05). In group 3, ECFC-TL was associated with the number of detected clones (P<0.01). ECFC-TL (7.98±0.13 kb) was longer than leukocyte TL (6.74±0.012 kb) (P<0.0001) and both parameters were strongly correlated (r=0.82; P<0.0001). Conclusions Individuals with longer telomeres display a higher number of self-renewing ECFCs. Our results also indicate that leukocyte TL, as a proxy of TL dynamics in ECFCs, could be used as a surrogate marker of endothelial repair capacity in clinical and laboratory practice because of easy accessibility of leukocytes. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT02176941.

RevDate: 2021-05-06

Mukherjee J, Pandita A, Kamalakar C, et al (2021)

A subset of PARP inhibitors induces lethal telomere fusion in ALT-dependent tumor cells.

Science translational medicine, 13(592):.

About 10% of all tumors, including most lower-grade astrocytoma, rely on the alternative lengthening of telomere (ALT) mechanism to resolve telomeric shortening and avoid limitations on their growth. Here, we found that dependence on the ALT mechanism made cells hypersensitive to a subset of poly(ADP-ribose) polymerase inhibitors (PARPi). We found that this hypersensitivity was not associated with PARPi-created genomic DNA damage as in most PARPi-sensitive populations but rather with PARPi-induced telomere fusion. Mechanistically, we determined that PARP1 was recruited to the telomeres of ALT-dependent cells as part of a DNA damage response. By recruiting MRE11 and BRCC3 to stabilize TRF2 at the ends of telomeres, PARP1 blocked chromosomal fusion. Exposure of ALT-dependent tumor cells to a subset of PARPi induced a conformational change in PARP1 that limited binding to MRE11 and BRCC3 and delayed release of the TRF2-mediated block on lethal telomeric fusion. These results therefore provide a basis for PARPi treatment of ALT-dependent tumors, as well as establish chromosome fusion as a biomarker of their activity.

RevDate: 2021-05-05

Badran M, Abuyassin B, Ayas N, et al (2021)

Vascular and renal telomere shortening in mice exposed to chronic intermittent hypoxia.

Canadian journal of physiology and pharmacology [Epub ahead of print].

Obstructive sleep apnea (OSA) is a chronic condition characterized by chronic intermittent hypoxia (IH) and is associated with cardiovascular (CVD) and chronic kidney diseases (CKD). Patients with OSA haveincreased biomarkers of aging such as telomere shortening. We used PCR to report shortened telomere lengths in aortic and renal tissues from mice exposed to 8 weeks of IH. Our data indicates that IH, a hallmark of OSA, accelerates vascular and renal aging that may contribute to OSA-induced CVD and CKD.

RevDate: 2021-05-05

Khan RJ, Needham BL, Advani S, et al (2021)

Association of Childhood Socioeconomic Status with Leukocyte Telomere Length Among African Americans and the Mediating Role of Behavioral and Psychosocial Factors: Results from the GENE-FORECAST Study.

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

PURPOSE: We examined if childhood socioeconomic status (SES) was related to adult leucocyte telomere length (TL) using the data of 361 African American (AA) participants from the GENE-FORECAST Study. We also assessed the mediating role of behavioral and psychosocial factors in the association between childhood SES and adult TL.

METHODS: Childhood SES was assessed individually by using participant's mother's education and occupation, father's education and occupation, parental home ownership, and family structure. TL was assessed using the quantitative polymerase chain reaction method. Information on potential confounders and mediators were collected. The associations of childhood SES with TL were assessed using multivariable linear regression models. We used path analysis to quantify and test the share of these associations that was statistically explained by each of the mediators (participant's educational attainment, smoking status, physical activity, dietary habit, perceived stress, and depressive symptoms).

RESULTS: Mother's education was associated with longer average TL (β: 0.021; 95% CI: 0.001, 0.04, p=0.038) in confounder adjusted models. Once mediators were introduced in the model, the estimates were reduced and remained marginally significant (β: 0.017; 95% CI: -0.003, 0.038, p=0.061). According to path model, approximately 19% of the effect of mother's education on TL (β: 0.004; 95% CI: -0.001, 0.01, p < 0.10) was mediated through participant's own education level. No significant mediation effect was observed for any other mediators.

CONCLUSIONS: These data provide evidence that participant's mother's education was positively linked to adult TL in AA population. Participant's own educational level partially explained this association.

RevDate: 2021-05-18

Jang JW, Kim JS, Kim HS, et al (2021)

Significance of TERT Genetic Alterations and Telomere Length in Hepatocellular Carcinoma.

Cancers, 13(9):.

Telomerase reverse transcriptase (TERT) mutations are reportedly the most frequent somatic genetic alterations in hepatocellular carcinoma (HCC). An integrative analysis of TERT-telomere signaling during hepatocarcinogenesis is lacking. This study aimed to investigate the clinicopathological association and prognostic value of TERT gene alterations and telomere length in HCC patients undergoing hepatectomy as well as transarterial chemotherapy (TACE). TERT promoter mutation, expression, and telomere length were analyzed by Sanger sequencing and real-time PCR in 305 tissue samples. Protein-protein interaction (PPI) analysis was performed to identify a set of genes that physically interact with TERT. The PPI analysis identified eight key TERT-interacting genes, namely CCT5, TUBA1B, mTOR, RPS6KB1, AKT1, WHAZ, YWHAQ, and TERT. Among these, TERT was the most strongly differentially expressed gene. TERT promoter mutations were more frequent, TERT expression was significantly higher, and telomere length was longer in tumors versus non-tumors. TERT promoter mutations were most frequent in HCV-related HCCs and less frequent in HBV-related HCCs. TERT promoter mutations were associated with higher TERT levels and longer telomere length and were an independent predictor of worse overall survival after hepatectomy. TERT expression was positively correlated with tumor differentiation and stage progression, and independently predicted shorter time to progression after TACE. The TERT-telomere network may have a crucial role in the development and progression of HCC. TERT-telomere abnormalities might serve as useful biomarkers for HCC, but the prognostic values may differ with tumor characteristics and treatment.

RevDate: 2021-06-04

Schürhoff F, Corfdir C, Pignon B, et al (2021)

No alteration of leukocyte telomere length in first episode psychosis.

Psychiatry research, 301:113941 pii:S0165-1781(21)00238-9 [Epub ahead of print].

Both shorter telomeres and schizophrenia have been associated with a decrease in life expectancy. Furthermore, several studies found a shorter telomere length (TL) in schizophrenia. Understanding whether or not telomere shortening is directly related to pathophysiology of schizophrenia or is a consequence of a cumulative exposure to chronic stress is of major importance. Comparing the TL of subjects at the very beginning of the disease (FEP) and control subjects could help to decide between these two hypotheses. The aim of the present study was to compare TL between FEP subjects (N=91) and controls (N=137). After accounting for multiple potential confounders, no significant association was observed between FEP and TL. Our result is consistent with the hypothesis that psycho-social stress / adversities and stressful situations in people with schizophrenia affect TL rather than that telomere erosion contributes to the development of this disorder.

RevDate: 2021-06-04

Sadhukhan R, U Ghosh (2021)

PARP1 modulates telomere sister chromatid exchange and telomere length homeostasis by regulating telomere localization of SLX4 in U2OS cells.

Life sciences, 277:119556 pii:S0024-3205(21)00542-7 [Epub ahead of print].

OBJECTIVE: Poly(ADP-ribose) polymerase1 (PARP1) interacts and poly(ADP-ribosyl)ates telomere repeat binding factor 2 (TRF2), which acts as a platform to recruit a large number of proteins at the telomere. Since the discovery of TRF2-SLX4 interaction, SLX4 is becoming the key player in telomere length (TL) maintenance and repair by telomere sister chromatid exchange (T-SCE). Defective TL maintenance pathway results in a spectrum of diseases called telomeropathies like dyskeratosis congenita, aplastic anemia, fanconi anemia, cancer. We aimed to study the role of SLX4 and PARP1 on each other's telomere localization, T-SCE, and TL maintenance in human telomerase-negative osteosarcoma U2OS cells to understand some of the molecular mechanisms of telomere homeostasis.

MATERIALS AND METHODS: We checked the role of SLX4 and PARP1 on each other's telomere localization by telomere immunofluorescence. We have cloned full-length wild-type and catalytically inactive mutant PARP1 to understand the role of poly(ADP-ribosyl)ation reaction by PARP1 in telomere length homeostasis. TL of U2OS cells was measured by Q-FISH. T-SCE was measured by Telomere-FISH.

KEY FINDINGS: We observed that SLX4 has no role in the telomere localization of PARP1. However, reduced localization of SLX4 at undamaged and damaged telomere upon PARP1 depletion was reversed by overexpression of exogenous wild-type PARP1 but not by overexpression of catalytically inactive mutant PARP1. PARP1 depletion synergized SLX4 depletion-mediated reduction of T-SCE. Furthermore, SLX4 depletion elongated TL, and combined insufficiency of SLX4 with PARP1 further elongated TL.

CONCLUSION: So, PARP1 controls SLX4 recruitment at telomere by poly(ADP-ribosyl)ation reaction, thereby regulating SLX4-mediated T-SCE and TL homeostasis.

RevDate: 2021-06-08

Piñeiro-Hermida S, Martínez P, MA Blasco (2021)

Short and dysfunctional telomeres protect from allergen-induced airway inflammation.

Aging cell, 20(5):e13352.

Asthma is a chronic inflammatory disease affecting 300 million people worldwide. As telomere shortening is a well-established hallmark of aging and that asthma incidence decreases with age, here we aimed to study the role of short telomeres in asthma pathobiology. To this end, wild-type and telomerase-deficient mice with short telomeres (third-generation (G3 Tert-/- mice)) were challenged with intranasal house dust mite (HDM) extract. We also challenged with HDM wild-type mice in which we induced a telomere dysfunction by the administration of 6-thio-2´-deoxyguanosine (6-thio-dG). Following HDM exposure, G3 Tert-/- and 6-thio-dG treated mice exhibited attenuated eosinophil counts and presence of hematopoietic stem cells in the bone marrow, as well as lower levels of IgE and circulating eosinophils. Accordingly, both G3 Tert-/- and 6-thio-dG treated wild-type mice displayed reduced airway hyperresponsiveness (AHR), as indicated by decreased airway remodeling and allergic airway inflammation markers in the lung. Furthermore, G3 Tert-/- and 6-thio-dG treated mice showed lower differentiation of Club cells, attenuating goblet cell hyperplasia. Club cells of G3 Tert-/- and 6-thio-dG treated mice displayed increased DNA damage and senescence and reduced proliferation. Thus, short/dysfunctional telomeres play a protective role in murine asthma by impeding both AHR and mucus secretion after HDM exposure. Therefore, our findings imply that telomeres play a relevant role in allergen-induced airway inflammation.

RevDate: 2021-05-07

Chang X, Gurung RL, Wang L, et al (2021)

Low frequency variants associated with leukocyte telomere length in the Singapore Chinese population.

Communications biology, 4(1):519.

The role of low frequency variants associated with telomere length homeostasis in chronic diseases and mortalities is relatively understudied in the East-Asian population. Here we evaluated low frequency variants, including 1,915,154 Asian specific variants, for leukocyte telomere length (LTL) associations among 25,533 Singapore Chinese samples. Three East Asian specific variants in/near POT1, TERF1 and STN1 genes are associated with LTL (Meta-analysis P 2.49×10-14-6.94×10-10). Rs79314063, a missense variant (p.Asp410His) at POT1, shows effect 5.3 fold higher and independent of a previous common index SNP. TERF1 (rs79617270) and STN1 (rs139620151) are linked to LTL-associated common index SNPs at these loci. Rs79617270 is associated with cancer mortality [HR95%CI = 1.544 (1.173, 2.032), PAdj = 0.018] and 4.76% of the association between the rs79617270 and colon cancer is mediated through LTL. Overall, genetically determined LTL is particularly associated with lung adenocarcinoma [HR95%CI = 1.123 (1.051, 1.201), Padj = 0.007]. Ethnicity-specific low frequency variants may affect LTL homeostasis and associate with certain cancers.

RevDate: 2021-05-04

Jogi R, Tager MJ, Perez D, et al (2021)

Bovine Colostrum, Telomeres, and Skin Aging.

Journal of drugs in dermatology : JDD, 20(5):538-545.

BACKGROUND: Applied topically, growth factors, cytokines, and other components in bovine colostrum are known to affect collagen biosynthesis, thus offering promise as a therapeutic modality in wound healing, delay in skin aging, and skin rejuvenation.

OBJECTIVE: To demonstrate the protective effect that liposomal bovine colostrum exerts on skin aging using telomere length as an aging biomarker.

METHODS: Human fibroblasts were cultured for 8 weeks with colostrum at three concentrations (0.125%, 0.25%, 0.50%). Cells were cultured and assayed both under standard conditions, as well as with H2O2 added as an agent of oxidative stress. Alterations in proliferation rates, telomere lengths, and telomere shortening rates (TSRs) were determined in each treatment group and compared.

RESULTS: Colostrum increased the proliferation rate of the fibroblast control cells and the addition of H2O2(without colostrum) decreased the proliferation rates of the fibroblast control cells. Under standard culture conditions, telomeres shortened progressively over 8 weeks and the addition of colostrum reduced the rate of telomere shortening. Under oxidative stress conditions (H2O2 &ndash; induced) the TSR increased; however, treatment with colostrum appeared to attenuate this increase.

CONCLUSIONS: Under normal culture conditions and after both 4 weeks and 8 weeks of treatment, liposomal bovine colostrum appears to exert a protective effect on telomere length erosion. Under culture conditions of oxidative stress and after 8 weeks of treatment, colostrum appears to exert a protective effect on telomere length erosion. These results suggest that topical treatment of the liposomal bovine colostrum formulation would enhance skin health as the skin ages. J Drugs Dermatol. 20(5):538-545. doi:10.36849/JDD.5851.

RevDate: 2021-05-04

Liu Y, Zhao X, Wang B, et al (2021)

miR-376a Provokes Rectum Adenocarcinoma Via CTC1 Depletion-Induced Telomere Dysfunction.

Frontiers in cell and developmental biology, 9:649328.

CTC1 is a component of the mammalian CST (CTC1-STN1-TEN1) complex which plays essential roles in resolving replication problems to facilitate telomeric DNA and genomic DNA replication. We previously reported that the depletion of CTC1 leads to stalled replication fork restart defects. Moreover, the mutation in CTC1 caused cancer-prone diseases including Coats plus (CP) or dyskeratosis congenita (DC). To better understand the CTC1 regulatory axis, the microRNAs (miRNAs) targeting to CTC1 were predicted by a bioinformatics tool, and the selected candidates were further confirmed by a dual-luciferase reporter assay. Here, our current results revealed that miR-376a significantly reduced CTC1 expression at the transcription level by recognizing CTC1 3'-UTR. In addition, the overexpression of miR-376a induced telomere replication defection and resulted in direct replicative telomere damage, which could be rescued by adding back CTC1. Telomere shortening was also observed upon miR-376a treatment. Furthermore, for the clinical patient samples, the high expression of miR-376a was associated with the deregulation of CTC1 and a poor outcome for the rectum adenocarcinoma patients. Together, our results uncovered a novel role of miR-376a in stimulating rectum adenocarcinoma progression via CTC1 downregulating induced telomere dysfunction.

RevDate: 2021-05-04

Mackintosh JA, Yerkovich ST, Tan ME, et al (2021)

Airway Telomere Length in Lung Transplant Recipients.

Frontiers in immunology, 12:658062.

Introduction: Chronic lung allograft dysfunction (CLAD) represents the major impediment to long term survival following lung transplantation. Donor and recipient telomere length have been shown to associate with lung transplant outcomes, including CLAD. In this study we aimed to measure the telomere lengths of bronchial and bronchiolar airway cells in lung allografts early after transplantation and to investigate associations with CLAD and all-cause mortality.

Methods: This prospective, longitudinal study was performed at The Prince Charles Hospital, Australia. Airway cells were collected via bronchial and bronchiolar airway brushings at post-transplant bronchoscopies. The relative telomere length in airway cells was determined by quantitative PCR based on the T/S ratio. All patients were censored for CLAD and all-cause mortality in August 2020.

Results: In total 231 bronchoscopies incorporating transbronchial brush and bronchial brush were performed in 120 patients. At the time of censoring, 43% and 35% of patients, respectively, had developed CLAD and had died. Airway bronchiolar and bronchial telomere lengths were strongly correlated (r=0.78, p<0.001), confirming conservation of telomere length with airway branch generation. Both the bronchiolar (r = -0.34, p<0.001) and bronchial (r = -0.31, p<0.001) telomere length decreased with age. Shorter airway telomere length was associated with older donor age and higher donor pack-year smoking history. Neither the bronchiolar nor the bronchial airway telomere length were associated with the development of CLAD (HR 0.39 (0.06-2.3), p=0.30; HR 0.66 (0.2-1.7), p=0.39, respectively) or all-cause mortality (HR 0.92 (0.2-4.5), p=0.92; HR 0.47 (0.1-1.9), p=0.28, respectively).

Conclusions: In this cohort, airway telomere length was associated with donor age and smoking history but was not associated with the future development of CLAD or all-cause mortality.

RevDate: 2021-06-09

Cecchini MJ, Tarmey T, Ferreira A, et al (2021)

Pathology, Radiology, and Genetics of Interstitial Lung Disease in Patients With Shortened Telomeres.

The American journal of surgical pathology, 45(7):871-884.

Interstitial lung diseases (ILDs) in patients with shortened telomeres have not been well characterized. We describe demographic, radiologic, histopathologic, and molecular features, and p16 expression in patients with telomeres ≤10th percentile (shortened telomeres) and compare them to patients with telomere length >10th percentile. Lung explants, wedge biopsies, and autopsy specimens of patients with telomere testing were reviewed independently by 3 pathologists using defined parameters. High-resolution computed tomography scans were reviewed by 3 radiologists. p16-positive fibroblast foci were quantified. A multidisciplinary diagnosis was recorded. Patients with shortened telomeres (N=26) were morphologically diagnosed as usual interstitial pneumonia (UIP) (N=11, 42.3%), chronic hypersensitivity pneumonitis (N=6, 23.1%), pleuroparenchymal fibroelastosis, fibrotic nonspecific interstitial pneumonia, desquamative interstitial pneumonia (N=1, 3.8%, each), and fibrotic interstitial lung disease (fILD), not otherwise specified (N=6, 23.1%). Patients with telomeres >10th percentile (N=18) showed morphologic features of UIP (N=9, 50%), chronic hypersensitivity pneumonitis (N=3, 16.7%), fibrotic nonspecific interstitial pneumonia (N=2, 11.1%), or fILD, not otherwise specified (N=4, 22.2%). Patients with shortened telomeres had more p16-positive foci (P=0.04). The number of p16-positive foci correlated with outcome (P=0.0067). Thirty-nine percent of patients with shortened telomeres harbored telomere-related gene variants. Among 17 patients with shortened telomeres and high-resolution computed tomography features consistent with or probable UIP, 8 (47.1%) patients showed morphologic features compatible with UIP; multidisciplinary diagnosis most commonly was idiopathic pulmonary fibrosis (N=7, 41.2%) and familial pulmonary fibrosis (N=5, 29%) in these patients. In conclusion, patients with shortened telomeres have a spectrum of fILDs. They often demonstrate atypical and discordant features on pathology and radiology leading to diagnostic challenges.

RevDate: 2021-05-02

Kim WT, Hennick K, Johnson J, et al (2021)

Cancer-associated POT1 mutations lead to telomere elongation without induction of a DNA damage response.

The EMBO journal [Epub ahead of print].

Mutations in the shelterin protein POT1 are associated with chronic lymphocytic leukemia (CLL), Hodgkin lymphoma, angiosarcoma, melanoma, and other cancers. These cancer-associated POT1 (caPOT1) mutations are generally heterozygous, missense, or nonsense mutations occurring throughout the POT1 reading frame. Cancers with caPOT1 mutations have elongated telomeres and show increased genomic instability, but which of the two phenotypes promotes tumorigenesis is unclear. We tested the effects of CAS9-engineered caPOT1 mutations in human embryonic and hematopoietic stem cells (hESCs and HSCs, respectively). HSCs with caPOT1 mutations did not show overt telomere damage. In vitro and in vivo competition experiments showed the caPOT1 mutations did not confer a selective disadvantage. Since DNA damage signaling is known to affect the fitness of HSCs, the data argue that caPOT1 mutations do not cause significant telomere damage. Furthermore, hESC lines with caPOT1 mutations showed no detectable telomere damage response while showing consistent telomere elongation. Thus, caPOT1 mutations are likely selected for during cancer progression because of their ability to elongate telomeres and extend the proliferative capacity of the incipient cancer cells.

RevDate: 2021-05-31

Ensminger DC, Siegel SR, Owen DAS, et al (2021)

Elevated glucocorticoids during gestation suggest sex-specific effects on offspring telomere lengths in a wild lizard.

Comparative biochemistry and physiology. Part A, Molecular & integrative physiology, 257:110971.

The effects of maternal glucocorticoids (e.g. corticosterone, CORT) on offspring interest biologists due to increasing environmental perturbations. While little is known about the impact of maternal CORT on offspring fitness, it may modulate telomere length and compromise offspring health. Here, we use a modified real-time quantitative PCR assay to assess telomere length using small DNA quantities (<60 ng). We tested the hypothesis that increased maternal CORT during gestation decreases offspring telomere length. While CORT-driven telomere shortening is well established within individuals, cross-generational effects remain unclear. We treated wild-caught gravid female eastern fence lizards (Sceloporus undulatus) with daily transdermal applications of CORT, at ecologically relevant levels, from capture to laying. Maternal CORT treatment did not alter maternal telomere length, although baseline maternal CORT concentrations had a weak, negative correlation with maternal telomere length. There was no relation between mother and offspring telomere length. There was a trend for maternal CORT treatment to shorten telomeres of sons but not daughters. Our treatment replicated exposure to a single stressor per day, likely underestimating effects seen in the wild where stressors may be more frequent. Future research should further explore fitness consequences of maternal CORT effects.

RevDate: 2021-05-24

Wang M (2021)

Telomere shortening promotes kidney fibrosis.

Nature reviews. Nephrology, 17(6):368.

RevDate: 2021-05-18

McGroder CF, Zhang D, Choudhury MA, et al (2021)

Pulmonary fibrosis 4 months after COVID-19 is associated with severity of illness and blood leucocyte telomere length.

Thorax [Epub ahead of print].

The risk factors for development of fibrotic-like radiographic abnormalities after severe COVID-19 are incompletely described and the extent to which CT findings correlate with symptoms and physical function after hospitalisation remains unclear. At 4 months after hospitalisation, fibrotic-like patterns were more common in those who underwent mechanical ventilation (72%) than in those who did not (20%). We demonstrate that severity of initial illness, duration of mechanical ventilation, lactate dehydrogenase on admission and leucocyte telomere length are independent risk factors for fibrotic-like radiographic abnormalities. These fibrotic-like changes correlate with lung function, cough and measures of frailty, but not with dyspnoea.

RevDate: 2021-06-03
CmpDate: 2021-06-03

Litwin I, Mucha S, Pilarczyk E, et al (2021)

Complex Mechanisms of Antimony Genotoxicity in Budding Yeast Involves Replication and Topoisomerase I-Associated DNA Lesions, Telomere Dysfunction and Inhibition of DNA Repair.

International journal of molecular sciences, 22(9):.

Antimony is a toxic metalloid with poorly understood mechanisms of toxicity and uncertain carcinogenic properties. By using a combination of genetic, biochemical and DNA damage assays, we investigated the genotoxic potential of trivalent antimony in the model organism Saccharomyces cerevisiae. We found that low doses of Sb(III) generate various forms of DNA damage including replication and topoisomerase I-dependent DNA lesions as well as oxidative stress and replication-independent DNA breaks accompanied by activation of DNA damage checkpoints and formation of recombination repair centers. At higher concentrations of Sb(III), moderately increased oxidative DNA damage is also observed. Consistently, base excision, DNA damage tolerance and homologous recombination repair pathways contribute to Sb(III) tolerance. In addition, we provided evidence suggesting that Sb(III) causes telomere dysfunction. Finally, we showed that Sb(III) negatively effects repair of double-strand DNA breaks and distorts actin and microtubule cytoskeleton. In sum, our results indicate that Sb(III) exhibits a significant genotoxic activity in budding yeast.

RevDate: 2021-05-27
CmpDate: 2021-05-26

Tucker LA (2021)

Fruit and Vegetable Intake and Telomere Length in a Random Sample of 5448 U.S. Adults.

Nutrients, 13(5):.

The relationship between fruit and vegetable intake and telomere length was examined using a cross-sectional design and an NHANES random sample of 5448 U.S. adults. Fruit and vegetable (F&V) consumption was assessed using a 24 h recall, and telomere length, an index of cellular aging, was measured using the quantitative polymerase chain reaction method. Telomere length was linearly related to F&V intake when combined (F = 22.7, p < 0.0001) and also when separated as fruit (F = 7.2, p < 0.0121) or vegetables (F = 15.4, p < 0.0005), after adjusting for covariates. Specifically, telomeres were 27.8 base pairs longer for each 100 g (3.5 ounces) of F&V consumed. Because each additional year of chronological age was associated with telomeres that were 14.9 base pairs shorter, when women and men were analyzed together, results indicated that a 100 g (3.5 oz) per day increment in F&V corresponded with 1.9 years less biological aging. When the 75th percentile of F&V intake was compared to the 25th, the difference was 4.4 years of cellular aging. When separated by sex, fruits and vegetables were both related to telomere length in women, but only vegetable intake was predictive of telomere length in men. In conclusion, evidence based on a random sample of U.S. adults indicates that the more the servings of F&V, the longer telomeres tend to be.

RevDate: 2021-05-02

Rangel-Pozzo A, Yu PLI, LaL S, et al (2021)

Telomere Architecture Correlates with Aggressiveness in Multiple Myeloma.

Cancers, 13(8):.

The prognosis of multiple myeloma (MM), an incurable B-cell malignancy, has significantly improved through the introduction of novel therapeutic modalities. Myeloma prognosis is essentially determined by cytogenetics, both at diagnosis and at disease progression. However, for a large cohort of patients, cytogenetic analysis is not always available. In addition, myeloma patients with favorable cytogenetics can display an aggressive clinical course. Therefore, it is necessary to develop additional prognostic and predictive markers for this disease to allow for patient risk stratification and personalized clinical decision-making. Genomic instability is a prominent characteristic in MM, and we have previously shown that the three-dimensional (3D) nuclear organization of telomeres is a marker of both genomic instability and genetic heterogeneity in myeloma. In this study, we compared in a longitudinal prospective study blindly the 3D telomeric profiles from bone marrow samples of 214 initially treatment-naïve patients with either monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM), or MM, with a minimum follow-up of 5 years. Here, we report distinctive 3D telomeric profiles correlating with disease aggressiveness and patient response to treatment in MM patients, and also distinctive 3D telomeric profiles for disease progression in smoldering multiple myeloma patients. In particular, lower average intensity (telomere length, below 13,500 arbitrary units) and increased number of telomere aggregates are associated with shorter survival and could be used as a prognostic factor to identify high-risk SMM and MM patients.

RevDate: 2021-05-18

Berby B, Bichara C, Rives-Feraille A, et al (2021)

Oxidative Stress Is Associated with Telomere Interaction Impairment and Chromatin Condensation Defects in Spermatozoa of Infertile Males.

Antioxidants (Basel, Switzerland), 10(4):.

Telomere length can be influenced by reactive oxygen species (ROS) generated by lifestyle factors or environmental exposure. We sought to determine whether oxidative stress has an impact on sperm nuclear alterations, especially on chromatin organization and telomere interactions in the spermatozoa of infertile males. We performed an observational and prospective study including fifty-two males, allocated in the "case group" (30 infertile males presenting conventional semen parameter alterations) and the "control group" (22 males with normal conventional semen parameters). ROS detection was determined on spermatozoa using CellROX© probes. Sperm nuclear damage was assessed using quantitative fluorescence in situ hybridization (Q-FISH) for relative telomere length and telomere number, aniline blue staining for chromatin condensation, terminal deoxynucleotidyl transferase dUTP nick-end labeling for DNA fragmentation, and FISH for aneuploidy and 8-hydroxy-2'-deoxyguanosine immunostaining for oxidative DNA damages. Infertile males had significantly increased levels of cytoplasmic ROS and chromatin condensation defects as well as a higher mean number of telomere signals per spermatozoon in comparison with controls. In addition, the mean number of sperm telomere signals were positively correlated with the percentage of spermatozoa with chromatin condensation defect. In infertile males with conventional semen parameter alterations, oxidative stress is associated with telomere interaction impairment and chromatin condensation defects.

RevDate: 2021-05-12
CmpDate: 2021-05-12

Gentiluomo M, Luddi A, Cingolani A, et al (2021)

Telomere Length and Male Fertility.

International journal of molecular sciences, 22(8):.

Over the past decade, telomeres have attracted increasing attention due to the role they play in human fertility. However, conflicting results have been reported on the possible association between sperm telomere length (STL) and leukocyte telomere length (LTL) and the quality of the sperm parameters. The aim of this study was to run a comprehensive study to investigate the role of STL and LTL in male spermatogenesis and infertility. Moreover, the association between the sperm parameters and 11 candidate single nucleotide polymorphisms (SNPs), identified in the literature for their association with telomere length (TL), was investigated. We observed no associations between sperm parameters and STL nor LTL. For the individual SNPs, we observed five statistically significant associations with sperm parameters: considering a p < 0.05. Namely, ACYP2-rs11125529 and decreased sperm motility (p = 0.03); PXK-rs6772228 with a lower sperm count (p = 0.02); NAF1-rs7675998 with increased probability of having abnormal acrosomes (p = 0.03) and abnormal flagellum (p = 0.04); ZNF208-rs8105767 and reduction of sperms with normal heads (p = 0.009). This study suggests a moderate involvement of telomere length in male fertility; however, in our analyses four SNPs were weakly associated with sperm variables, suggesting the SNPs to be pleiotropic and involved in other regulatory mechanisms independent of telomere homeostasis, but involved in the spermatogenic process.

RevDate: 2021-05-25
CmpDate: 2021-05-25

Imran SAM, Yazid MD, Idrus RBH, et al (2021)

Is There an Interconnection between Epithelial-Mesenchymal Transition (EMT) and Telomere Shortening in Aging?.

International journal of molecular sciences, 22(8):.

Epithelial-Mesenchymal Transition (EMT) was first discovered during the transition of cells from the primitive streak during embryogenesis in chicks. It was later discovered that EMT holds greater potential in areas other than the early development of cells and tissues since it also plays a vital role in wound healing and cancer development. EMT can be classified into three types based on physiological functions. EMT type 3, which involves neoplastic development and metastasis, has been the most thoroughly explored. As EMT is often found in cancer stem cells, most research has focused on its association with other factors involving cancer progression, including telomeres. However, as telomeres are also mainly involved in aging, any possible interaction between the two would be worth noting, especially as telomere dysfunction also contributes to cancer and other age-related diseases. Ascertaining the balance between degeneration and cancer development is crucial in cell biology, in which telomeres function as a key regulator between the two extremes. The essential roles that EMT and telomere protection have in aging reveal a potential mutual interaction that has not yet been explored, and which could be used in disease therapy. In this review, the known functions of EMT and telomeres in aging are discussed and their potential interaction in age-related diseases is highlighted.

RevDate: 2021-05-02

Liu J, Hong X, Wang L, et al (2021)

Sir4 Deficiency Reverses Cell Senescence by Sub-Telomere Recombination.

Cells, 10(4):.

Telomere shortening results in cellular senescence and the regulatory mechanisms remain unclear. Here, we report that the sub-telomere regions facilitate telomere lengthening by homologous recombination, thereby attenuating senescence in yeast Saccharomyces cerevisiae. The telomere protein complex Sir3/4 represses, whereas Rif1 promotes, the sub-telomere Y' element recombination. Genetic disruption of SIR4 increases Y' element abundance and rescues telomere-shortening-induced senescence in a Rad51-dependent manner, indicating a sub-telomere regulatory switch in regulating organismal senescence by DNA recombination. Inhibition of the sub-telomere recombination requires Sir4 binding to perinuclear protein Mps3 for telomere perinuclear localization and transcriptional repression of the telomeric repeat-containing RNA TERRA. Furthermore, Sir4 repression of Y' element recombination is negatively regulated by Rif1 that mediates senescence-evasion induced by Sir4 deficiency. Thus, our results demonstrate a dual opposing control mechanism of sub-telomeric Y' element recombination by Sir3/4 and Rif1 in the regulation of telomere shortening and cell senescence.

RevDate: 2021-05-19
CmpDate: 2021-05-19

Pericuesta E, Gutiérrez-Arroyo JL, Sánchez-Calabuig MJ, et al (2021)

Postnatal Catch-Up Growth Programs Telomere Dynamics and Glucose Intolerance in Low Birth Weight Mice.

International journal of molecular sciences, 22(7):.

Low birth weight and rapid postnatal weight gain are independent predictors of obesity and diabetes in adult life, yet the molecular events involved in this process remain unknown. In inbred and outbred mice, this study examines natural intrauterine growth restriction (IUGR) in relation to body weight, telomere length (TL), glucose tolerance, and growth factor gene (Igf1, Igf2, Insr, Igf1r, and Igf2r) mRNA expression levels in the brain, liver, and muscle at 2- and 10 days of age and then at 3- and 9 months of age. At birth, ~15% of the animals showed IUGR, but by 3 and 9 months, half of these animals had regained the same weight as controls without IUGR (recuperated group). At 10 days, there was no difference in TL between animals undergoing IUGR and controls. However, by 3 and 9 months of age, the recuperated animals had shorter TL than the control and IUGR-non recuperated animals and also showed glucose intolerance. Further, compared to controls, Igf1 and Igf2 growth factor mRNA expression was lower in Day 2-IUGR mice, while Igf2r and Insr mRNA expression was higher in D10-IUGR animals. Moreover, at 3 months of age, only in the recuperated group were brain and liver Igf1, Igf2, Insr, and Igf2r expression levels higher than in the control and IUGR-non-recuperated groups. These data indicate that catch-up growth but not IUGR per se affects TL and glucose tolerance, and suggest a role in this latter process of insulin/insulin-like growth signaling pathway gene expression during early development.

RevDate: 2021-06-08

Zhao R, Chenoweth DM, H Zhang (2021)

Chemical Dimerization-Induced Protein Condensates on Telomeres.

Journal of visualized experiments : JoVE.

Chromatin-associated condensates are implicated in many nuclear processes, but the underlying mechanisms remain elusive. This protocol describes a chemically-induced protein dimerization system to create condensates on telomeres. The chemical dimerizer consists of two linked ligands that can each bind to a protein: Halo ligand to Halo-enzyme and trimethoprim (TMP) to E. coli dihydrofolate reductase (eDHFR), respectively. Fusion of Halo enzyme to a telomere protein anchors dimerizers to telomeres through covalent Halo ligand-enzyme binding. Binding of TMP to eDHFR recruits eDHFR-fused phase separating proteins to telomeres and induces condensate formation. Because TMP-eDHFR interaction is non-covalent, condensation can be reversed by using excess free TMP to compete with the dimerizer for eDHFR binding. An example of inducing promyelocytic leukemia (PML) nuclear body formation on telomeres and determining condensate growth, dissolution, localization and composition is shown. This method can be easily adapted to induce condensates at other genomic locations by fusing Halo to a protein that directly binds to the local chromatin or to dCas9 that is targeted to the genomic locus with a guide RNA. By offering the temporal resolution required for single cell live imaging while maintaining phase separation in a population of cells for biochemical assays, this method is suitable for probing both the formation and function of chromatin-associated condensates.

RevDate: 2021-04-26

Wils RS, Jacobsen NR, Di Ianni E, et al (2021)

Reactive oxygen species production, genotoxicity and telomere length in FE1-Muta™Mouse lung epithelial cells exposed to carbon nanotubes.

Nanotoxicology [Epub ahead of print].

Carbon nanotubes (CNTs) are fiber-like nanomaterials, which are used in various applications with possible exposure to humans. The genotoxicity and carcinogenic potential of CNTs remain to be fully understood. This study assessed the genotoxicity of three different multi-walled carbon nanotubes (MWCNTs) (MWCNT-7, NM-401 and NM-403) and one single-walled carbon nanotube (SWCNT) (NM-411) in FE1-Muta™Mouse lung epithelial (MML) cells using the alkaline comet assay. With the 2',7'-dichlorodihydrofluorescein diacetate fluorescent probe, we assessed the effect of CNT-exposure on the intracellular production of reactive oxygen species (ROS). We measured the effect of a 10-week CNT exposure on telomere length using quantitative PCR. Two of the included MWCNTs (NM-401 and MWCNT-7) and the SWCNT (NM-411) caused a significant increase in the level of DNA damage at concentrations up to 40 µg/ml (all concentrations pooled, p < 0.05), but no concentration-response relationships were found. All of the CNTs caused an increase in intracellular ROS production compared to unexposed cells (ptrend < 0.05). Results from the long-term exposure showed longer telomere length in cells exposed to MWCNTs compared to unexposed cells (p < 0.01). In conclusion, our results indicated that the included CNTs cause ROS production and DNA strand breaks in FE1-MML cells. Moreover, the MWCNTs, but not the SWCNT, had an impact on telomere length in a long-term exposure scenario.

RevDate: 2021-05-11

Wang H, Gong P, Chen T, et al (2021)

Colorectal Cancer Stem Cell States Uncovered by Simultaneous Single-Cell Analysis of Transcriptome and Telomeres.

Advanced science (Weinheim, Baden-Wurttemberg, Germany), 8(8):2004320.

Cancer stem cells (CSCs) presumably contribute to tumor progression and drug resistance, yet their definitive features have remained elusive. Here, simultaneous measurement of telomere length and transcriptome in the same cells enables systematic assessment of CSCs in primary colorectal cancer (CRC). The in-depth transcriptome profiled by SMART-seq2 is independently validated by high-throughput scRNA-seq using 10 × Genomics. It is found that rare CSCs exist in dormant state and display plasticity toward cancer epithelial cells (EPCs) that essentially are presumptive tumor-initiating cells (TICs), while both retaining the prominent signaling pathways including WNT, TGF-β, and HIPPO/YAP. Moreover, CSCs exhibit chromosome copy number variation (CNV) pattern resembling cancer EPCs but distinct from normal stem cells, suggesting the phylogenetic relationship between CSCs and cancer EPCs. Notably, CSCs maintain shorter telomeres and possess minimal telomerase activity consistent with their nonproliferative nature, unlike cancer EPCs. Additionally, the specific signature of CSCs particularly NOTUM, SMOC2, BAMBI, PHLDA1, and TNFRSF19 correlates with the prognosis of CRC. These findings characterize the heterogeneity of CSCs and their linkage to cancer EPCs/TICs, some of which are conventionally regarded as CSCs.

RevDate: 2021-04-28

Wang G, Wang S, Chai X, et al (2021)

A strategy for complete telomere-to-telomere assembly of ciliate macronuclear genome using ultra-high coverage Nanopore data.

Computational and structural biotechnology journal, 19:1928-1932.

Ciliates contain two kinds of nuclei: the germline micronucleus (MIC) and the somatic macronucleus (MAC) in a single cell. The MAC usually have fragmented chromosomes. These fragmented chromosomes, capped with telomeres at both ends, could be gene size to several megabases in length among different ciliate species. So far, no telomere-to-telomere assembly of entire MAC genome in ciliate species has been finished. Development of the third generation sequencing technologies allows to generate sequencing reads up to megabases in length that could possibly span an entire MAC chromosome. Taking advantage of the ultra-long Nanopore reads, we established a simple strategy for the complete assembly of ciliate MAC genomes. Using this strategy, we assembled the complete MAC genomes of two ciliate species Tetrahymena thermophila and Tetrahymena shanghaiensis, composed of 181 and 214 chromosomes telomere-to-telomere respectively. The established strategy as well as the high-quality genome data will provide a useful approach for ciliate genome assembly, and a valuable community resource for further biological, evolutionary and population genomic studies.

RevDate: 2021-04-28

Nersisyan L, Simonyan A, Binder H, et al (2021)

Telomere Maintenance Pathway Activity Analysis Enables Tissue- and Gene-Level Inferences.

Frontiers in genetics, 12:662464.

Telomere maintenance is one of the mechanisms ensuring indefinite divisions of cancer and stem cells. Good understanding of telomere maintenance mechanisms (TMM) is important for studying cancers and designing therapies. However, molecular factors triggering selective activation of either the telomerase dependent (TEL) or the alternative lengthening of telomeres (ALT) pathway are poorly understood. In addition, more accurate and easy-to-use methodologies are required for TMM phenotyping. In this study, we have performed literature based reconstruction of signaling pathways for the ALT and TEL TMMs. Gene expression data were used for computational assessment of TMM pathway activities and compared with experimental assays for TEL and ALT. Explicit consideration of pathway topology makes bioinformatics analysis more informative compared to computational methods based on simple summary measures of gene expression. Application to healthy human tissues showed high ALT and TEL pathway activities in testis, and identified genes and pathways that may trigger TMM activation. Our approach offers a novel option for systematic investigation of TMM activation patterns across cancers and healthy tissues for dissecting pathway-based molecular markers with diagnostic impact.

RevDate: 2021-04-28

Abou-Elela DH, El-Edel RH, Shalaby AS, et al (2020)

Telomere length and 8-hydroxy-2-deoxyguanosine as markers for early prediction of Alzheimer disease.

Indian journal of psychiatry, 62(6):678-683.

Background: Becoming shorter by each cell division, telomere length (TL) is regarded as a marker of cellular aging. Relative TL (T/S) depends on the quantitation of telomere hexamer repeat copy number normalized to autosomal single-copy gene copy number. TL is influenced by several factors, including oxidative stress (OS) and inflammation. This study aimed to investigate the possible role of TL and OS as markers for Alzheimer's disease (AD).

Materials and Methods: One hundred and eighty participants were categorized into three groups. Group 1: Included 60 patients with AD. Group II: included 60 age-matched nondemented subjects. Group III (pregeriatric group): included 60 healthy controls with their ages ranging between 30 and 60 years. TL was determined by the quantitative Real time-PCR method, plasma levels of 8-OHdG by enzyme-linked immunosorbent assay, and total antioxidant capacity (TAC) by colorimetery.

Results: In comparison to the other two groups, patients with AD showed shortened TL, increased plasma 8-OHdG concentration, and decreased TAC. The sensitivity of T/S ratio to predict AD was 86.67%, whereas the specificity was 96.67%. The sensitivity of 8-OHdG to predict AD was 96.67%, whereas the specificity was 86.67%.

Conclusion: AD is associated with shortened TL and increased OS as manifested by decreased TAC and increased serum 8-OHdG. T/S and 8-OHdG could be used as early predictors for AD.

RevDate: 2021-04-22

Miwata S, Narita A, Okuno Y, et al (2021)

Clinical diagnostic value of telomere length measurement in inherited bone marrow failure syndromes.

Haematologica [Epub ahead of print].

Not available.

RevDate: 2021-05-14
CmpDate: 2021-05-14

Kan G, Wang Z, Sheng C, et al (2021)

Inhibition of DKC1 induces telomere-related senescence and apoptosis in lung adenocarcinoma.

Journal of translational medicine, 19(1):161.

BACKGROUND: Lung cancer is one of the most widely spread cancers in the world and half of the non-small cell lung cancers are lung adenocarcinoma (LUAD). Although there were several drugs been approved for LUAD therapy, a large portion of LUAD still cannot be effectively treated due to lack of available therapeutic targets. Here, we investigated the oncogenic roles of DKC1 in LUAD and its potential mechanism and explored the possibility of targeting DKC1 for LUAD therapy.

METHODS: The Gene Expression Omnibus (GEO) and The Cancer Genome Atlas Program (TCGA) databases were used to examine the DKC1 transcript levels. Gene expression with clinical information from tissue microarray of LUAD were analyzed for associations between DKC1 expression and LUAD prognosis. In addition, loss- and gain-of-function assays were used for oncogenic function of DKC1 both in vitro and in vivo.

RESULTS: DKC1 is overexpressed in LUAD compared with adjacent normal tissues. High expression of DKC1 predicts the poor overall survival. DKC1 knockdown in LUAD cell lines induced G1 phase arrest and inhibited cell proliferation. Ectopic expression of DKC1 could rescue the growth of LUAD cell lines. In addition, the abundance of DKC1 is positively correlated with telomerase RNA component (TERC) and telomerase reverse transcriptase (TERT) levels in LUAD. DKC1 downregulation resulted in decreased TERC expression, reduced telomerase activity and shorten telomere, and thus eventually led to cell senescence and apoptosis.

CONCLUSIONS: Our results show that high DKC1 expression indicates poor prognosis of LUAD and DKC1 downregulation could induce telomere-related cell senescence and apoptosis. This study suggests that DKC1 could serve as a candidate diagnostic biomarker and therapeutic target for LUAD.

RevDate: 2021-05-07

Froy H, Underwood SL, Dorrens J, et al (2021)

Heritable variation in telomere length predicts mortality in Soay sheep.

Proceedings of the National Academy of Sciences of the United States of America, 118(15):.

Telomere length (TL) is considered an important biomarker of whole-organism health and aging. Across humans and other vertebrates, short telomeres are associated with increased subsequent mortality risk, but the processes responsible for this correlation remain uncertain. A key unanswered question is whether TL-mortality associations arise due to positive effects of genes or early-life environment on both an individual's average lifetime TL and their longevity, or due to more immediate effects of environmental stressors on within-individual TL loss and increased mortality risk. Addressing this question requires longitudinal TL and life history data across the entire lifetimes of many individuals, which are difficult to obtain for long-lived species like humans. Using longitudinal data and samples collected over nearly two decades, as part of a long-term study of wild Soay sheep, we dissected an observed positive association between TL and subsequent survival using multivariate quantitative genetic models. We found no evidence that telomere attrition was associated with increased mortality risk, suggesting that TL is not an important marker of biological aging or exposure to environmental stress in our study system. Instead, we find that among-individual differences in average TL are associated with increased lifespan. Our analyses suggest that this correlation between an individual's average TL and lifespan has a genetic basis. This demonstrates that TL has the potential to evolve under natural conditions, and suggests an important role of genetics underlying the widespread observation that short telomeres predict mortality.

RevDate: 2021-04-21

Bonnell E, Pasquier E, RJ Wellinger (2021)

Telomere Replication: Solving Multiple End Replication Problems.

Frontiers in cell and developmental biology, 9:668171.

Eukaryotic genomes are highly complex and divided into linear chromosomes that require end protection from unwarranted fusions, recombination, and degradation in order to maintain genomic stability. This is accomplished through the conserved specialized nucleoprotein structure of telomeres. Due to the repetitive nature of telomeric DNA, and the unusual terminal structure, namely a protruding single stranded 3' DNA end, completing telomeric DNA replication in a timely and efficient manner is a challenge. For example, the end replication problem causes a progressive shortening of telomeric DNA at each round of DNA replication, thus telomeres eventually lose their protective capacity. This phenomenon is counteracted by the recruitment and the activation at telomeres of the specialized reverse transcriptase telomerase. Despite the importance of telomerase in providing a mechanism for complete replication of telomeric ends, the majority of telomere replication is in fact carried out by the conventional DNA replication machinery. There is significant evidence demonstrating that progression of replication forks is hampered at chromosomal ends due to telomeric sequences prone to form secondary structures, tightly DNA-bound proteins, and the heterochromatic nature of telomeres. The telomeric loop (t-loop) formed by invasion of the 3'-end into telomeric duplex sequences may also impede the passage of replication fork. Replication fork stalling can lead to fork collapse and DNA breaks, a major cause of genomic instability triggered notably by unwanted repair events. Moreover, at chromosomal ends, unreplicated DNA distal to a stalled fork cannot be rescued by a fork coming from the opposite direction. This highlights the importance of the multiple mechanisms involved in overcoming fork progression obstacles at telomeres. Consequently, numerous factors participate in efficient telomeric DNA duplication by preventing replication fork stalling or promoting the restart of a stalled replication fork at telomeres. In this review, we will discuss difficulties associated with the passage of the replication fork through telomeres in both fission and budding yeasts as well as mammals, highlighting conserved mechanisms implicated in maintaining telomere integrity during replication, thus preserving a stable genome.

RevDate: 2021-04-21

Afshar H, Abedini A, Nadji SA, et al (2021)

Telomere length assessment in blood leukocytes of patients with sarcoidosis.

Sarcoidosis, vasculitis, and diffuse lung diseases : official journal of WASOG, 38(1):e2021009.

Background: Accelerated aging and telomere shortening have been studied in many chronic diseases such as interstitial pulmonary fibrosis and chronic obstructive pulmonary disease. Different studies have shown that patients with these diseases have shorter telomere lengths than controls; this can be a marker of the progression and outcome of the disease. So far, a few studies have been evaluated the telomere length in sarcoidosis. In this study we determine the telomere length in patients with sarcoidosis and compare it with control subjects.

Objective: Our aim is to compare telomere length in patients with sarcoidosis and normal population. Methods: We select 58 patients with sarcoidosis who were visited in the sarcoidosis clinic of Masih Daneshvari Hospital. 58 sex and age-matched (with±2 years) healthy control subjects were selected. Telomere length was measured by quantitative real time PCR as described by Cawthon on peripheral blood sample. The telomere repeat copy number (T) to single-gene copy number(S) ratio was calculated using the comparative Ct method. Results: The mean and standard deviation of telomere length in the patient and control group was 0.65 ± 0.05 and 0.72 ± 0.07 respectively. There was a statistically significant difference between the two groups. (P = 0.031). Conclusion: Sarcoidosis is an inflammatory disease that can involve many organs. Like other chronic diseases, aging phenomenon occurs in that; which led to decrease cellular and tissue telomere length. This article demonstrates shorter telomere length in Iranian sarcoidosis patients compared to normal population.

RevDate: 2021-05-14
CmpDate: 2021-05-14

Yu P, Yang T, Zhang D, et al (2021)

An all-in-one telomerase assay based on CRISPR-Cas12a trans-cleavage while telomere synthesis.

Analytica chimica acta, 1159:338404.

As one of the crucial factors associated with human life span and cancer progression, telomerase is regarded as an emerging biomarker for cancer diagnosis. Therefore, a facile, rapid and sensitive approach for telomerase activity detection with point-of-care (POC) diagnosis potential is in great demands. Herein, an all-in-one telomerase activity detection assay was established based on the telomere synthesis activated CRISPR-Cas12a system. A telomerase extension reaction generated telomere repeats sequences (TTAGGG)n, which was recognized by a customized CRISPR-guided RNA (crRNA) simultaneously, and finally activated a typical trans-cleavage based CRISPR-Cas12a detection assay. With the inherent sensitivity of CRISPR-Cas12a, this approach achieved a great linear regression ranging from 100 to 2000 HeLa cells and a limitation of detection down to 26 HeLa cells. Moreover, by using the proposed method, telomerase can be detected in one pot under isothermal condition (37 °C) by a simple and fast workflow (one step within 1 h). Due to its excellent performance, this all-in-one method shows great potential in POC detection of the telomerase activity.

RevDate: 2021-05-25
CmpDate: 2021-05-25

Quque M, Paquet M, Zahn S, et al (2021)

Contrasting associations between nestling telomere length and pre and postnatal helpers' presence in a cooperatively breeding bird.

Oecologia, 196(1):37-51.

Studies on cooperative breeders have addressed the effects of non-breeding 'helpers' on reproduction and parental care, but the consequences for offspring physiology and long-term survival are less understood. Helpers are expected to benefit offspring, but their presence can also lead to decreased pre- or post-natal parental reproductive effort. To examine whether prenatal and postnatal helpers influence offspring condition, we conducted a whole-clutch cross-fostering experiment in sociable weavers (Philetairus socius) that altered the nestlings' social environment (presence/absence of helpers). We tested whether relative telomere length (rTL), an indicator of somatic maintenance, was influenced by prenatal and/or postnatal presence of helpers 9 and 17 days after hatching, and whether rTL predicted long-term survival. Nine days after hatching, we found an overall positive effect of postnatal helpers on rTL: for nestlings with prenatal helpers, a reduction in the number of helpers post-hatch was associated with shorter telomeres, while nestlings swapped from nests without helpers to nests with helpers had a larger rTL. However, when prenatal helpers were present, an increased number of helpers after hatching led to shorter telomeres. Nine-day old chicks with longer rTL tended to be more likely to survive over the 5 years following hatching. However, close to fledging, there was no detectable effect of the experiment on rTL and no link between rTL and survival. This experimental study of a wild cooperative breeder, therefore, presents partial support for the importance of the presence of helpers for offspring rTL and the link between early-life telomere length and long-term survival.

RevDate: 2021-04-17

Corfdir C, Pignon B, Szöke A, et al (2021)

[Accelerated telomere erosion in schizophrenia: A literature review].

L'Encephale pii:S0013-7006(21)00058-0 [Epub ahead of print].

Schizophrenia is associated with a weighted average of 14.5 years of potential life lost according to a recent meta-analysis. This is partly explained by high rates of suicide and a high prevalence of non-psychiatric comorbidity (cardiovascular diseases, diabetes, cancers…). However, all these causes could not fully explain the loss of life expectancy in people suffering from schizophrenia. Life expectancy has been strongly correlated with telomere length (TL). Telomeres are noncoding structures consisting of DNA TTAGGG tandem repeats and associated proteins located at the end of the chromosomes. Their role is to help preserve genome stability by protecting chromosomal ends from the loss of genetic material. The progressive loss of telomeric material during cell divisions has led researchers to consider telomeres as molecular clocks that measure the number of divisions left until cellular death. The fact that both shorter telomeres and schizophrenia have been associated with a decrease in life expectancy has fueled the interest in the study of TL in schizophrenia. In this article, after a detailed review of the literature on the relationships between telomere length and schizophrenia, we discuss the different pathophysiological mechanisms which might explain this association. Based on this analysis, in the last part of the article we discuss potential research, therapeutic and prevention prospects. To date, the majority of the studies and meta-analyses found a decrease in TL in subjects with schizophrenia compared to control subjects. Conversely, all the studies exploring the TL in subjects suffering from first episode psychosis (FEP) have shown no significant difference from TL in control subjects. This suggests that excessive shortening of telomeres occurs during the course of the disease, thus it seems more probable that schizophrenia (or processes associated with it) affects TL rather than telomere erosion being a cause of the disorder. Several pathophysiological, non-mutually exclusive mechanisms have been proposed to explain the observed data. A first hypothesis to explain the acceleration of the physiological process of telomere erosion in schizophrenia is the activation of inflammation processes and oxidative stress as a consequence of schizophrenia per se. However, it seems more probable that reduced TL may be a result of cumulative exposure to chronic stress related to schizophrenia. Indeed, in healthy individuals a growing body of evidence has linked chronic stress to accelerated shortening of TL. This might explain why telomere erosion is too small to be detected in FEP patients who are younger and have a shorter duration of illness than subjects with schizophrenia. Based on these both explanations, telomere alterations may be considered as a biomarker of illness progression and might be useful for illness staging. Identifying processes associated with TL reduction might improve our understanding of the increased mortality and morbidity in schizophrenia, improve reliability of diagnosis, and hopefully suggest means for prevention and/or treatment. Treatments that prevent exposure and/or vulnerability to stressful life events that ameliorate schizophrenia may also prevent or decelerate telomere erosion. In this perspective, engaging subjects suffering from schizophrenia in a healthy diet and regular activity could be both promising strategies to protect telomere maintenance and improve health span at old age. In addition, the inflammatory process and oxidative stress involved in the physiopathology in at least a subgroup of subjects with schizophrenia could also be responsible for telomere erosion. Thus, an efficient anti-inflammatory therapeutic approach that targets these specific pathways could be of interest in this subgroup to limit telomere erosion. Mindfulness-based stress reduction (MBSR) therapies have been shown to reduce telomere erosion by increasing telomerase activity, although these psychological therapies should be used carefully in psychosis. Finally, advancing our understanding of the relationship between stress, inflammation and TL is of great interest for psychiatric research and for understanding stress effects in this population.

RevDate: 2021-05-02

Giaccherini M, Macauda A, Orciuolo E, et al (2021)

Genetically determined telomere length and multiple myeloma risk and outcome.

Blood cancer journal, 11(4):74.

Telomeres are involved in processes like cellular growth, chromosomal stability, and proper segregation to daughter cells. Telomere length measured in leukocytes (LTL) has been investigated in different cancer types, including multiple myeloma (MM). However, LTL measurement is prone to heterogeneity due to sample handling and study design (retrospective vs. prospective). LTL is genetically determined; genome-wide association studies identified 11 SNPs that, combined in a score, can be used as a genetic instrument to measure LTL and evaluate its association with MM risk. This approach has been already successfully attempted in various cancer types but never in MM. We tested the "teloscore" in 2407 MM patients and 1741 controls from the International Multiple Myeloma rESEarch (IMMeNSE) consortium. We observed an increased risk for longer genetically determined telomere length (gdTL) (OR = 1.69; 95% CI 1.36-2.11; P = 2.97 × 10-6 for highest vs. lowest quintile of the score). Furthermore, in a subset of 1376 MM patients we tested the relationship between the teloscore and MM patients survival, observing a better prognosis for longer gdTL compared with shorter gdTL (HR = 0.93; 95% CI 0.86-0.99; P = 0.049). In conclusion, we report convincing evidence that longer gdTL is a risk marker for MM risk, and that it is potentially involved in increasing MM survival.

RevDate: 2021-05-19

Vessoni AT, Zhang T, Quinet A, et al (2021)

Telomere erosion in human pluripotent stem cells leads to ATR-mediated mitotic catastrophe.

The Journal of cell biology, 220(6):.

It is well established that short telomeres activate an ATM-driven DNA damage response that leads to senescence in terminally differentiated cells. However, technical limitations have hampered our understanding of how telomere shortening is signaled in human stem cells. Here, we show that telomere attrition induces ssDNA accumulation (G-strand) at telomeres in human pluripotent stem cells (hPSCs), but not in their differentiated progeny. This led to a unique role for ATR in the response of hPSCs to telomere shortening that culminated in an extended S/G2 cell cycle phase and a longer period of mitosis, which was associated with aneuploidy and mitotic catastrophe. Loss of p53 increased resistance to death, at the expense of increased mitotic abnormalities in hPSCs. Taken together, our data reveal an unexpected dominant role of ATR in hPSCs, combined with unique cell cycle abnormalities and, ultimately, consequences distinct from those observed in their isogenic differentiated counterparts.

RevDate: 2021-05-25

Hackeng WM, Brosens LAA, Kim JY, et al (2021)

Non-functional pancreatic neuroendocrine tumours: ATRX/DAXX and alternative lengthening of telomeres (ALT) are prognostically independent from ARX/PDX1 expression and tumour size.

Gut pii:gutjnl-2020-322595 [Epub ahead of print].

OBJECTIVE: Recent studies have found aristaless-related homeobox gene (ARX)/pancreatic and duodenal homeobox 1 (PDX1), alpha-thalassemia/mental retardation X-linked (ATRX)/death domain-associated protein (DAXX) and alternative lengthening of telomeres (ALT) to be promising prognostic biomarkers for non-functional pancreatic neuroendocrine tumours (NF-PanNETs). However, they have not been comprehensively evaluated, especially among small NF-PanNETs (≤2.0 cm). Moreover, their status in neuroendocrine tumours (NETs) from other sites remains unknown.

DESIGN: An international cohort of 1322 NETs was evaluated by immunolabelling for ARX/PDX1 and ATRX/DAXX, and telomere-specific fluorescence in situ hybridisation for ALT. This cohort included 561 primary NF-PanNETs, 107 NF-PanNET metastases and 654 primary, non-pancreatic non-functional NETs and NET metastases. The results were correlated with numerous clinicopathological features including relapse-free survival (RFS).

RESULTS: ATRX/DAXX loss and ALT were associated with several adverse prognostic findings and distant metastasis/recurrence (p<0.001). The 5-year RFS rates for patients with ATRX/DAXX-negative and ALT-positive NF-PanNETs were 40% and 42% as compared with 85% and 86% for wild-type NF-PanNETs (p<0.001 and p<0.001). Shorter 5-year RFS rates for ≤2.0 cm NF-PanNETs patients were also seen with ATRX/DAXX loss (65% vs 92%, p=0.003) and ALT (60% vs 93%, p<0.001). By multivariate analysis, ATRX/DAXX and ALT status were independent prognostic factors for RFS. Conversely, classifying NF-PanNETs by ARX/PDX1 expression did not independently correlate with RFS. Except for 4% of pulmonary carcinoids, ATRX/DAXX loss and ALT were only identified in primary (25% and 29%) and NF-PanNET metastases (62% and 71%).

CONCLUSIONS: ATRX/DAXX and ALT should be considered in the prognostic evaluation of NF-PanNETs including ≤2.0 cm tumours, and are highly specific for pancreatic origin among NET metastases of unknown primary.

RevDate: 2021-04-19

Cicconi A, Micheli E, Raffa GD, et al (2021)

Atomic Force Microscopy Reveals that the Drosophila Telomere-Capping Protein Verrocchio Is a Single-Stranded DNA-Binding Protein.

Methods in molecular biology (Clifton, N.J.), 2281:241-263.

Atomic force microscopy (AFM) is a scanning probe technique that allows visualization of biological samples with a nanometric resolution. Determination of the physical properties of biological molecules at a single-molecule level is achieved through topographic analysis of the sample adsorbed on a flat and smooth surface. AFM has been widely used for the structural analysis of nucleic acid-protein interactions, providing insights on binding specificity and stoichiometry of proteins forming complexes with DNA substrates. Analysis of single-stranded DNA-binding proteins by AFM requires specific single-stranded/double-stranded hybrid DNA molecules as substrates for protein binding. In this chapter we describe the protocol for AFM characterization of binding properties of Drosophila telomeric protein Ver using DNA constructs that mimic the structure of chromosome ends. We provide details on the methodology used, including the procedures for the generation of DNA substrates, the preparation of samples for AFM visualization, and the data analysis of AFM images. The presented procedure can be adapted for the structural studies of any single-stranded DNA-binding protein.

RevDate: 2021-04-19

de Oliveira Vitarelli M, MC Elias (2021)

Quantifying the Affinity of Trypanosoma cruzi RPA-1 to the Single-Stranded DNA Overhang of the Telomere Using Surface Plasmon Resonance.

Methods in molecular biology (Clifton, N.J.), 2281:217-228.

Surface plasmon resonance (SPR) biosensors provide real-time binding affinity measurements between a pair of biomolecules, characterizing its interaction dynamics. An example of Trypanosoma cruzi's RPA-1 and a single-stranded DNA telomere sequence is presented with detailed guidelines and fundamentals for SPR technology.

RevDate: 2021-05-21
CmpDate: 2021-05-21

Wei B, Shao Y, Liang J, et al (2021)

Maternal overweight but not paternal overweight before pregnancy is associated with shorter newborn telomere length: evidence from Guangxi Zhuang birth cohort in China.

BMC pregnancy and childbirth, 21(1):283.

BACKGROUND: Telomere length (TL) is variable at birth and is inversely associated with body mass index (BMI) in adulthood. A growing number of evidences suggested that a higher maternal pre-pregnancy BMI results in adverse offspring health outcomes, especially shorter newborn TL. However, a newborn's genetic endowment is equally derived from both parents, the association between parental pre-pregnancy BMI and newborn TL has been rarely discussed. We aimed to determine the association between parental pre-pregnancy BMI and newborn TL.

METHODS: A total of 1082 parent-newborn pairs were recruited from the Guangxi Zhuang Birth Cohort (GZBC). TL in cord blood was measured using quantitative real-time polymerase chain reaction (qPCR) and expressed as the ratio of telomere copy number to single-copy gene number (T/S). A series of linear regressions were performed to assess the associations between parental pre-pregnancy BMI and newborn TL.

RESULTS: Mothers who were overweight before pregnancy had significantly shorter cord blood telomere length in their newborns than those who were normal weight before pregnancy [percentage change: - 7.96% (95% CI: - 14.49 to - 0.69%; P = 0.032)]. Further analysis of the combined effects of parental weight status on newborn TL showed that TL was significantly shortened among newborns whose mothers were overweight and fathers were of healthy weight when compared with those whose mothers and fathers were both of normal weight [percentage change: - 8.38% (95% CI: - 15.47 to - 0.92%; P = 0.028)]. Subgroup analysis indicated these effects were more pronounced among male newborns and those whose paternal age < 31 years or maternal age ≥ 28 years at delivery.

CONCLUSIONS: Maternal pre-pregnancy overweight, but not paternal pre-pregnancy overweight is associated with shorter newborn TL. Weight control in reproductive women and effective healthy weight management before pregnancy may be of particular benefit for improving longevity and life quality of offspring.

RevDate: 2021-04-14

Cerveira de Baumont A, Hoffmann MS, Bortoluzzi A, et al (2021)

Telomere length and epigenetic age acceleration in adolescents with anxiety disorders.

Scientific reports, 11(1):7716.

Evidence on the relationship between genetics and mental health are flourishing. However, few studies are evaluating early biomarkers that might link genes, environment, and psychopathology. We aimed to study telomere length (TL) and epigenetic age acceleration (AA) in a cohort of adolescents with and without anxiety disorders (N = 234). We evaluated a representative subsample of participants at baseline and after 5 years (n = 76) and categorized them according to their anxiety disorder diagnosis at both time points: (1) control group (no anxiety disorder, n = 18), (2) variable group (anxiety disorder in one evaluation, n = 38), and (3) persistent group (anxiety disorder at both time points, n = 20). We assessed relative mean TL by real-time quantitative PCR and DNA methylation by Infinium HumanMethylation450 BeadChip. We calculated AA using the Horvath age estimation algorithm and analyzed differences among groups using generalized linear mixed models. The persistent group of anxiety disorder did not change TL over time (p = 0.495). The variable group had higher baseline TL (p = 0.003) but no accelerated TL erosion in comparison to the non-anxiety control group (p = 0.053). Furthermore, there were no differences in AA among groups over time. Our findings suggest that adolescents with chronic anxiety did not change telomere length over time, which could be related to a delay in neuronal development in this period of life.

RevDate: 2021-04-21

Lin YY, Li MH, Chang YC, et al (2021)

Dynamic DNA Shortening by Telomere-Binding Protein Cdc13.

Journal of the American Chemical Society, 143(15):5815-5825.

Telomeres are essential for chromosome maintenance. Cdc13 is a single-stranded telomeric DNA binding protein that caps telomeres and regulates telomerase function in yeast. Although specific binding of Cdc13 to telomeric DNA is critical for telomere protection, the detail mechanism how Cdc13-DNA complex protects telomere is unclear. Using two single-molecule methods, tethered particle motion and atomic force microscopy, we demonstrate that specific binding of Cdc13 on single-stranded telomeric DNA shortens duplex DNA into distinct states differed by ∼70-80 base pairs. DNA shortening by Cdc13 is dynamic and independent of duplex DNA sequences or length. Significantly, we found that Pif1 helicase is incapable of removing Cdc13 from the shortened DNA-Cdc13 complex, suggesting that Cdc13 forms structurally stable complex by shortening of the bound DNA. Together our data identified shortening of DNA by Cdc13 and provided an indication for efficient protection of telomere ends by the shortened DNA-Cdc13 complex.

RevDate: 2021-05-19

Pathak GA, Wendt FR, Levey DF, et al (2021)

Pleiotropic effects of telomere length loci with brain morphology, and brain tissue expression.

Human molecular genetics pii:6217475 [Epub ahead of print].

Several studies have reported association between leukocyte telomere length (LTL) and neuropsychiatric disorders. While telomere length is affected by environmental factors, genetic variants in certain loci are strongly associated with LTL. Thus, we aimed to identify the genomic relationship between genetic variants of LTL with brain-based regulatory changes and brain volume. We tested genetic colocalization of seven and nine LTL loci in two ancestry groups, European (EUR) and East-Asian (EAS), respectively with brain morphology measures for 101 T1-MRI based region-of-interests (ROI) (n = 21 821). The posterior probability (>90%) was observed for 'fourth ventricle', 'gray matter' and 'cerebellar vermal lobules I-IV' volumes. We then tested causal relationship using LTL loci for gene and methylation expression. We found causal pleiotropy for gene (EAS = 4 genes; EUR = 5 genes) and methylation expression (EUR = 17 probes; EAS = 4 probes) of brain tissues (p ≤ 2.47 x10-6). Integrating chromatin profiles with LTL-SNPs identified 45 genes (EUR) and 79 genes (EAS) p ≤ 9.78-7. We found additional 38 LTL-genes using chromatin-based gene mapping for EUR ancestry population. Gene variants in three LTL-genes-GPR37, OBFC1, and RTEL1/RTEL1-TNFRSF6B, show convergent evidence of pleiotropy with brain morphology, gene and methylation expression, and chromatin association. Mapping gene functions to drug-gene interactions, we identified process- 'transmission across chemical synapses' (p < 2.78x10-4). This study provides evidence that genetic variants of LTL have pleiotropic roles with brain-based effects that could explain the phenotypic association of LTL with several neuropsychiatric traits.

RevDate: 2021-06-08
CmpDate: 2021-04-22

Dewhurst SM, Yao X, Rosiene J, et al (2021)

Structural variant evolution after telomere crisis.

Nature communications, 12(1):2093.

Telomere crisis contributes to cancer genome evolution, yet only a subset of cancers display breakage-fusion-bridge (BFB) cycles and chromothripsis, hallmarks of experimental telomere crisis identified in previous studies. We examine the spectrum of structural variants (SVs) instigated by natural telomere crisis. Eight spontaneous post-crisis clones did not show prominent patterns of BFB cycles or chromothripsis. Their crisis-induced genome rearrangements varied from infrequent simple SVs to more frequent and complex SVs. In contrast, BFB cycles and chromothripsis occurred in MRC5 fibroblast clones that escaped telomere crisis after CRISPR-controlled telomerase activation. This system revealed convergent evolutionary lineages altering one allele of chromosome 12p, where a short telomere likely predisposed to fusion. Remarkably, the 12p chromothripsis and BFB events were stabilized by independent fusions to chromosome 21. The data establish that telomere crisis can generate a wide spectrum of SVs implying that a lack of BFB patterns and chromothripsis in cancer genomes does not indicate absence of past telomere crisis.

RevDate: 2021-04-07

Suliman ME, Ansari MGA, Rayis MA, et al (2021)

Telomere length and telomere repeat-binding protein in children with sickle cell disease.

Pediatric research [Epub ahead of print].

BACKGROUND: This study aimed to assess the telomere length and plasma telomere repeat-binding factor 2 (TRF2) levels in addition to other inflammatory markers in children with sickle cell disease (SCD).

METHODS: We enrolled 106 children (90 SCD and 26 controls) aged 1-15 years from the Hematology unit of King Fahad Medical City (KFMC), Saudi Arabia. Genomic DNA extracted from blood and leukocyte TL was determined using quantitative reverse transcription PCR, whereas TRF2, C-reactive protein, interleukin-6, and DNA oxidative damage were determined by using respective commercially available assays.

RESULTS: Leukocyte TL was inversely correlated with age in the SCD patients (r = -0.24, P = 0.02) and the controls (r = -0.68, P < 0.0001). In addition, SCD patients had significantly shorter TL (7.74 ± 0.81 kb) (P = 0.003) than controls (8.28 ± 0.73 kb). In contrast, no significant difference in TL among the SCD genotypes (HbSS and HbSβ0) has been observed. A modest, positive correlation was seen between TL and reticulocyte % (r = 0.21; P = 0.06). There were no significant differences in the TL and TRF2 concentrations between subjects with HbSS and HbSβ0 genotypes.

CONCLUSIONS: Short leukocyte TL was significantly associated with SCD. An inverse association was observed between TL and hemoglobin. Hydroxyurea treatment revealed no impact on TL.

IMPACT: This study explored the TL and plasma TRF2 in Saudi children with SCD. This is the first documentation that SCD children have shorter TL than their healthy counterparts, and no association between TL and TRF2 has been observed. Hydroxyurea treatment showed no impact on TL in children with SCD. This study is the first of its kind in children with SCD. It will pave the way for another study with a larger sample size in a diverse population to scrutinize these findings better.

RevDate: 2021-04-06

Raffenberg M, Engel T, Schoepf IC, et al (2021)

Impact of Delaying Antiretroviral Treatment during Primary HIV Infection on Telomere Length.

The Journal of infectious diseases pii:6211111 [Epub ahead of print].

BACKGROUND: Telomere length (TL) shortens during aging, HIV-seroconversion and untreated chronic HIV infection. It is unknown whether early antiretroviral therapy (ART) start is associated with less TL shortening during primary HIV infection (PHI).

METHODS: We measured TL in peripheral blood mononuclear cells by quantitative PCR in participants of the Zurich PHI Study with samples available for >6 years. We obtained uni-/multivariable estimates from mixed-effects models and evaluated the association of delaying ART start or interrupting ART with baseline and longitudinal TL.

RESULTS: In 105 participants with PHI (median age 36 years, 9% women), median ART delay was 25, 42, and 60 days, respectively, in the 1 st (shortest), 2 nd, and 3 rd (longest) ART delay tertile. First ART delay tertile was associated with longer baseline TL (p for trend=0.034), and longer TL over 6 years, but only with continuous ART (p<0.001), not if ART was interrupted >12 months (p=0.408). In multivariable analysis, participants in the 2 nd and 3 rd ART delay tertile had 17.6% (5.4-29.7%; p=0.004) and 21.5% (9.4-33.5%; p<0.001) shorter TL, after adjustment for age, with limited effect modification by clinical variables.

DISCUSSION: In PHI, delaying ART start for even a matter of weeks was associated with significant and sustained TL shortening.


RJR Experience and Expertise


Robbins holds BS, MS, and PhD degrees in the life sciences. He served as a tenured faculty member in the Zoology and Biological Science departments at Michigan State University. He is currently exploring the intersection between genomics, microbial ecology, and biodiversity — an area that promises to transform our understanding of the biosphere.


Robbins has extensive experience in college-level education: At MSU he taught introductory biology, genetics, and population genetics. At JHU, he was an instructor for a special course on biological database design. At FHCRC, he team-taught a graduate-level course on the history of genetics. At Bellevue College he taught medical informatics.


Robbins has been involved in science administration at both the federal and the institutional levels. At NSF he was a program officer for database activities in the life sciences, at DOE he was a program officer for information infrastructure in the human genome project. At the Fred Hutchinson Cancer Research Center, he served as a vice president for fifteen years.


Robbins has been involved with information technology since writing his first Fortran program as a college student. At NSF he was the first program officer for database activities in the life sciences. At JHU he held an appointment in the CS department and served as director of the informatics core for the Genome Data Base. At the FHCRC he was VP for Information Technology.


While still at Michigan State, Robbins started his first publishing venture, founding a small company that addressed the short-run publishing needs of instructors in very large undergraduate classes. For more than 20 years, Robbins has been operating The Electronic Scholarly Publishing Project, a web site dedicated to the digital publishing of critical works in science, especially classical genetics.


Robbins is well-known for his speaking abilities and is often called upon to provide keynote or plenary addresses at international meetings. For example, in July, 2012, he gave a well-received keynote address at the Global Biodiversity Informatics Congress, sponsored by GBIF and held in Copenhagen. The slides from that talk can be seen HERE.


Robbins is a skilled meeting facilitator. He prefers a participatory approach, with part of the meeting involving dynamic breakout groups, created by the participants in real time: (1) individuals propose breakout groups; (2) everyone signs up for one (or more) groups; (3) the groups with the most interested parties then meet, with reports from each group presented and discussed in a subsequent plenary session.


Robbins has been engaged with photography and design since the 1960s, when he worked for a professional photography laboratory. He now prefers digital photography and tools for their precision and reproducibility. He designed his first web site more than 20 years ago and he personally designed and implemented this web site. He engages in graphic design as a hobby.

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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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