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23 Mar 2019 at 01:47
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Bibliography on: Telomeres


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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: 2019-03-22

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

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

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

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

RevDate: 2019-03-22

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

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

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

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

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

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

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

RevDate: 2019-03-22

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

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

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

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

RevDate: 2019-03-20

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

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

British journal of haematology [Epub ahead of print].

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

RevDate: 2019-03-20

Casagrande S, M Hau (2019)

Telomere attrition: metabolic regulation and signalling function?.

Biology letters, 15(3):20180885.

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

RevDate: 2019-03-19

Niederberger C (2019)

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

The Journal of urology [Epub ahead of print].

RevDate: 2019-03-19

Ventura A, Pellegrini C, Cardelli L, et al (2019)

Telomeres and Telomerase in Cutaneous Squamous Cell Carcinoma.

International journal of molecular sciences, 20(6): pii:ijms20061333.

The role of telomere biology and telomerase activation in skin cancers has been investigated in melanoma and basal cell carcinoma but limited evidence is available for cutaneous squamous cell carcinoma (cSCC). We will review the current knowledge on the role of telomere and telomerase pathway in cSCC pathogenesis. At the somatic level, both long and short telomere lengths have been described in cSCC. This telomere dichotomy is probably related to two different mechanisms of tumour initiation which determines two tumour subtypes. Telomere shortening is observed during the invasive progression from in situ forms of cSCC, such as Bowen's disease (BD) and actinic keratosis (AK), to invasive cSCC. At the germline level, controversial results have been reported on the association between constitutive telomere length and risk of cSCC. Approximately 75⁻85% of cSCC tumours are characterized by a high level of telomerase activity. Telomerase activation has been also reported in AKs and BD and in sun-damaged skin, thus supporting the hypothesis that UV modulates telomerase activity in the skin. Activating TERT promoter mutations have been identified in 32⁻70% of cSCCs, with the majority showing the UV-signature. No significant correlation was observed between TERT promoter mutations and cSCC clinico-pathological features. However, TERT promoter mutations have been recently suggested to be independent predictors of an adverse outcome. The attention on telomere biology and telomerase activity in cSCC is increasing for the potential implications in the development of effective tools for prognostic assessment and of therapeutic strategies in patients with cutaneous cSCC.

RevDate: 2019-03-18

Mayer SE, Prather AA, Puterman E, et al (2019)

Cumulative lifetime stress exposure and leukocyte telomere length attrition: The unique role of stressor duration and exposure timing.

Psychoneuroendocrinology, 104:210-218 pii:S0306-4530(18)30293-2 [Epub ahead of print].

BACKGROUND: Stress exposure occurring across the lifespan increases risk for disease, potentially involving telomere length shortening. Stress exposure during childhood and adulthood has been cross-sectionally linked with shorter telomere length. However, few longitudinal studies have examined telomere length attrition over time, and none have investigated how stressor duration (acute life events vs. chronic difficulties), timing (childhood vs. adulthood), and perceived severity may be uniquely related to telomere length shortening.

METHODS: To address these issues, we administered a standardized instrument for assessing cumulative lifetime stress exposure (Stress and Adversity Inventory; STRAIN) to 175 mothers of children with Autism Spectrum Disorder or neurotypical children and measured their leukocyte telomere length (LTL) at baseline and 2 years later.

RESULTS: Greater count of lifetime stressors was associated with shorter LTL at baseline and greater LTL attrition over time. When separating lifetime stressors into acute life events and chronic difficulties, only greater count of chronic difficulties significantly predicted shorter baseline LTL and greater LTL attrition. Similarly, when examining timing of stressor exposure, only greater count of chronic childhood difficulties (age < 18) significantly predicted shorter baseline LTL and greater LTL attrition over the 2-year period in mid-life. Importantly, these results were robust while controlling for stressors occurring during the interim 2-year period. Post-hoc analyses suggested that chronic difficulties occurring during earlier childhood (0-12 years) were associated with greater LTL attrition. Cumulative stressor severity predicted LTL attrition in a parallel manner, but was less consistently associated with baseline LTL.

CONCLUSIONS: These data are the first to examine the effects of different aspects of cumulative lifetime stress exposure on LTL attrition over time, suggesting that accumulated chronic difficulties during childhood may play a unique role in shaping telomere shortening in midlife.

RevDate: 2019-03-17

Libertini G, Ferrara N, Rengo G, et al (2018)

Elimination of Senescent Cells: Prospects According to the Subtelomere-Telomere Theory.

Biochemistry. Biokhimiia, 83(12):1477-1488.

Cell senescence is an artificially reversible condition activated by various factors and characterized by replicative senescence and typical general alteration of cell functions, including extra-cellular secretion. The number of senescent cells increases with age and contributes strongly to the manifestations of aging. For these reasons, research is under way to obtain "senolytic" compounds, defined as drugs that eliminate senescent cells and therefore reduce aging-associated decay, as already shown in some experiments on animal models. This objective is analyzed in the context of the programmed aging paradigm, as described by the mechanisms of the subtelomere-telomere theory. In this regard, positive effects of the elimination of senescent cells and limits of this method are discussed. For comparison, positive effects and limits of telomerase activation are also analyzed, as well of the combined action of the two methods and the possible association of opportune gene modifications. Ethical issues associated with the use of these methods are outlined.

RevDate: 2019-03-16

Baek JH, Son H, Jeong YH, et al (2019)

Chronological Aging Standard Curves of Telomere Length and Mitochondrial DNA Copy Number in Twelve Tissues of C57BL/6 Male Mouse.

Cells, 8(3): pii:cells8030247.

The changes in telomere length and mitochondrial DNA copy number (mtDNAcn) are considered to be aging markers. However, many studies have provided contradictory or only fragmentary information about changes of these markers in animal models, due to inaccurate analysis methods and a lack of objective aging standards. To establish chronological aging standards for these two markers, we analyzed telomere length and mtDNAcn in 12 tissues-leukocytes, prefrontal cortex, hippocampus, pituitary gland, adrenal gland, retina, aorta, liver, kidney, spleen, skeletal muscle, and skin-from a commonly used rodent model, C57BL/6 male mice aged 2⁻24 months. It was found that at least one of the markers changed age-dependently in all tissues. In the leukocytes, hippocampus, retina, and skeletal muscle, both markers changed age-dependently. As a practical application, the aging marker changes were analyzed after chronic immobilization stress (CIS) to see whether CIS accelerated aging or not. The degree of tissue-aging was calculated using each standard curve and found that CIS accelerated aging in a tissue-specific manner. Therefore, it is expected that researchers can use our standard curves to objectively estimate tissue-specific aging accelerating effects of experimental conditions for least 12 tissues in C57BL/6 male mice.

RevDate: 2019-03-16

Bettin N, Oss Pegorar C, E Cusanelli (2019)

The Emerging Roles of TERRA in Telomere Maintenance and Genome Stability.

Cells, 8(3): pii:cells8030246.

The finding that transcription occurs at chromosome ends has opened new fields of study on the roles of telomeric transcripts in chromosome end maintenance and genome stability. Indeed, the ends of chromosomes are required to be protected from activation of DNA damage response and DNA repair pathways. Chromosome end protection is achieved by the activity of specific proteins that associate with chromosome ends, forming telomeres. Telomeres need to be constantly maintained as they are in a heterochromatic state and fold into specific structures (T-loops), which may hamper DNA replication. In addition, in the absence of maintenance mechanisms, chromosome ends shorten at every cell division due to limitations in the DNA replication machinery, which is unable to fully replicate the extremities of chromosomes. Altered telomere structure or critically short chromosome ends generate dysfunctional telomeres, ultimately leading to replicative senescence or chromosome instability. Telomere biology is thus implicated in multiple human diseases, including cancer. Emerging evidence indicates that a class of long noncoding RNAs transcribed at telomeres, known as TERRA for "TElomeric Repeat-containing RNA," actively participates in the mechanisms regulating telomere maintenance and chromosome end protection. However, the molecular details of TERRA activities remain to be elucidated. In this review, we discuss recent findings on the emerging roles of TERRA in telomere maintenance and genome stability and their implications in human diseases.

RevDate: 2019-03-15

Chahine MN, Toupance S, El-Hakim S, et al (2019)

Telomere length and age-dependent telomere attrition: the blood-and-muscle model 1.

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

Short telomere length (TL) is associated with atherosclerotic cardiovascular disease (ACVD) and other age-related diseases. It is unclear whether these associations originate from having inherently short TL or a faster TL attrition before or during disease development. We proposed the blood-and-muscle model to assess TL dynamics throughout life course. Our objective was to measure TL in leukocytes (LTL) and in skeletal muscle (MTL), which served as a proxy of TL at birth. The delta (MTL-LTL) represented life-long telomere attrition. Blood draws and skeletal muscle biopsies were performed on 35 Lebanese individuals undergoing surgery. Following DNA extraction, LTL and MTL were measured by Southern blot. In every individual aged between 30 and 85 years, MTL was longer than LTL. With age, MTL and LTL decreased, but the delta (MTL-LTL) increased by 14 bp/year. We validated the blood-and-muscle model that allowed us to identify TL, TL at birth, and lifelong TL attrition in a cross-sectional study. This model can be used in larger cross-sectional studies to evaluate the association of telomere dynamics with age-related diseases onset and progression.

RevDate: 2019-03-15

Srinivas N, Rachakonda S, Hielscher T, et al (2019)

Telomere length, arsenic exposure and risk of basal cell carcinoma of skin.

Carcinogenesis pii:5381153 [Epub ahead of print].

Telomere length per se a heritable trait has been reported to be associated with different diseases including cancers. In this study based on arsenic exposed 528 cases with basal cell carcinoma of skin (BCC) and 533 healthy controls we investigated effect of telomere length, measured by real-time PCR, on the disease risk. We observed a statistically significant association between decreased telomere length and increased BCC risk (OR = 5.92, 95% CI = 3.92-9.01, P<0.0001). Due to confounder effect of arsenic exposure, in a two-sample Mendelian randomization (MR), telomere-length associated single nucleotide polymorphisms as instrument variables violated valid assumptions; however, one-sample MR adjusted for arsenic exposure indicated an increased risk of BCC with short telomeres. The interaction between arsenic exposure and telomere length on BCC risk was statistically significant (P = 0.02). Within each tertile based on arsenic exposure, the individuals with shorter telomeres were at an increased risk of BCC, with highest risk being in the highest exposed group (OR = 16.13, 95% CI = 6.71-40.00, P<0.0001); followed by those in medium exposure group and low exposure group. The combined effect of highest arsenic exposure and shortest telomeres on BCC risk (OR = 10.56, 95% CI = 5.14-21.70) showed a statistically significant departure from additivity (interaction constant ratio 6.56, P = 0.03). Our results show that in the presence of arsenic exposure, decreased telomere length predisposes individuals to increased risk of BCC, with the effect being synergistic in individuals with highest arsenic exposure and shortest telomeres.

RevDate: 2019-03-15

Khalangot MD, Krasnienkov DS, Chizhova VP, et al (2019)

Additional Impact of Glucose Tolerance on Telomere Length in Persons With and Without Metabolic Syndrome in the Elderly Ukraine Population.

Frontiers in endocrinology, 10:128.

Rationale: Association between different components of metabolic syndrome and the rate of age-related telomere shortening was reported repeatedly, although some findings are inconsistent across studies, suggesting the need for further research on the topic. In the present study, we examined relationships between different components of metabolic syndrome (MetS); glucose tolerance reflected in 2-h post-load plasma glucose (2hPG) levels and age on the leukocyte telomere length (LTL) in Ukraine population. Methods: The study was conducted on the 115 adult individuals residing in the Kyiv region (Ukraine). Among them, 79 were diagnosed with MetS according to the International Diabetes Federation definition. LTL were determined by a qPCR-based method. Multivariate logistic regression (MLR) and artificial neural networks (ANN) modeling were used for the analysis of the results. ROC-analysis was also performed to compare the predictively values of this models. Results: MetS was associated with a high (OR = 3.0 CI 1.3-6.7; p = 0.01) risk of having shorter telomeres that remained significant after adjusting for age, gender and 2hPG levels. Fasting plasma glucose (FPG) levels and other MetS components did not affect the magnitude of the relationship and did not reveal the independent influence of these factors. The level of 2hPG in turn, demonstrated a significant relationship (OR = 1.3 CI 1.0-1.6 per 1 mmol/l; p = 0.04) with LTL regardless of the presence of MetS. The non-linearity of the interactions between age, gender and 2hPG level was revealed by neural network modeling (AUC = 0.76 CI 0.68-0.84). Conclusion: Our study found that impaired glucose tolerance, but not FPG levels, affected the association between LTL and MetS, which may be also indicative for pathophysiological differences in these hyperglycemia categories. 2hPG levels can provide an opportunity for a more accurate diagnostics of MetS and for evaluating the rate of aging in patients with MetS. Further research, however, is needed to verify this assumption.

RevDate: 2019-03-15

Cleal K, Jones RE, Grimstead JW, et al (2019)

Chromothripsis during telomere crisis is independent of NHEJ and consistent with a replicative origin.

Genome research pii:gr.240705.118 [Epub ahead of print].

Telomere erosion, dysfunction and fusion can lead to a state of cellular crisis characterized by large-scale genome instability. We investigated the impact of a telomere-driven crisis on the structural integrity of the genome by undertaking whole genome sequence analyses of clonal populations of cells that had escaped crisis. Quantification of large-scale structural variants revealed patterns of rearrangement consistent with chromothripsis, but formed in the absence of functional non-homologous end joining pathways. Rearrangements frequently consisted of short fragments with complex mutational patterns, with a repair topology that deviated from randomness showing preferential repair to local regions or exchange between specific loci. We find evidence of telomere involvement with an enrichment of fold-back inversions demarcating clusters of rearrangements. Our data suggest that chromothriptic rearrangements caused by telomere crisis arise via a replicative repair process involving template switching.

RevDate: 2019-03-15

Lawlor RT, Veronese N, Pea A, et al (2019)

Alternative lengthening of telomeres (ALT) influences survival in soft tissue sarcomas: a systematic review with meta-analysis.

BMC cancer, 19(1):232 pii:10.1186/s12885-019-5424-8.

BACKGROUND: Alternative lengthening of telomeres (ALT) is a telomerase-independent mechanism used by a broad range of neoplasms to maintain telomere length, permitting uncontrolled replication during their progression. ALT has been described in different types of sarcoma, but a comprehensive analysis of its clinical significance is still lacking. Therefore, we provide here the first meta-analysis on this topic.

METHODS: We searched SCOPUS and PubMed through July 2018 to identify all studies that investigated the prognostic role of ALT in sarcomas. We considered the risk of death (risk ratio, RR) calculated as the number of death vs. total participants during follow-up in ALT+ versus ALT- patients as the primary outcome. The secondary outcome was the hazard ratio (HR), adjusted for the maximum number of covariates available, using ALT- patients as reference.

RESULTS: Eight articles comprising a total of 551 patients with sarcomas (226 ALT+ and 325 ALT-) were selected. The ALT+ group showed a higher mitotic count and a higher tumor grade compared with the ALT- group (p < 0.01). Furthermore, we demonstrate a strong impact of ALT on survival. In fact, ALT+ patients showed a statistically significant higher risk of death than ALT- patients, when also considering data from multivariate analyses (RR = 1.50; 95% CI: 1.15-1.96; p = 0.003; HR = 2.02; 95% CI: 1.22-3.38; p = 0.007).

CONCLUSIONS: Our results indicate that ALT is associated with an increased risk of death in patients with sarcoma. In these neoplasms, ALT should be taken into account for a precise prognostic stratification and design of potential therapeutic strategies.

RevDate: 2019-03-14

Casavant SG, Cong X, Moore J, et al (2019)

Associations between preterm infant stress, epigenetic alteration, telomere length and neurodevelopmental outcomes: A systematic review.

Early human development, 131:63-74 pii:S0378-3782(19)30072-6 [Epub ahead of print].

BACKGROUND: Every year, an estimated 15 million babies are born preterm (<37 weeks' gestational age [GA]) globally. These preterm infants are exposed to repeated stressful and often painful procedures as part of routine life-saving care within the neonatal intensive care unit (NICU). Preterm birth continues to be a major health issue associated with increased risk of neurodevelopmental and behavioral disorders such as cerebral palsy, cognitive impairment, autism spectrum disorders and psychiatric disease.

OBJECTIVE: This paper identifies epigenetic alterations and incidence of telomere erosion that have been studied in preterm infants while in the NICU and as a long-term outcome measure. Better understanding of epigenetic alterations and telomere erosion might aid in early detection and prevention/alleviation of the negative effects of cumulative painful/stressful experiences in this population.

METHODS: The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) standards were used to guide this review. Systematic searches of databases included PubMed, CINAHL, SCOPUS and PsychInfo.

RESULTS: Twenty-one studies were included, appraised and then synthesized into a narrative summary.

DISCUSSION: Several putative epigenetic markers were identified although there was a paucity of studies related to telomere length. The interaction of disease entity combined with therapeutic interventions intended to treat may inadvertently increase infant allostatic load or ability to adapt to stress. Future research should include not only human studies but leverage newly available large data sets to conduct additional analysis.

RevDate: 2019-03-14

Wang J, Nguyen MT, Sung V, et al (2019)

Associations Between Telomere Length and Hearing Status in Mid-Childhood and Midlife: Population-Based Cross-Sectional study.

Ear and hearing [Epub ahead of print].

OBJECTIVES: The purpose of this study is to determine if telomere length (a biomarker of aging) is associated with hearing acuity in mid-childhood and midlife.

DESIGN: The study was based on the population-based cross-sectional study within the Longitudinal Study of Australian Children with telomere length and audiometry data. We calculated high Fletcher Index (hFI, mean threshold of 1, 2, and 4 kHz), defining hearing loss as threshold >15 dB HL (better ear). Linear and logistic regression analyses quantified associations of telomere length with continuous hearing threshold and binary hearing loss outcomes, respectively.

RESULTS: One thousand one hundred ninety-five children (mean age 11.4 years, SD 0.5) and 1334 parents (mean age 43.9 years, SD 5.1) were included in analyses. Mean (SD) telomere length (T/S ratio) was 1.09 (0.55) for children and 0.81 (0.38) for adults; hFI (dB HL) was 8.0 (5.6) for children and 13.1 (7.0) for adults, with 8.4% and 25.9%, respectively, showing hearing loss.Telomere length was not associated with hearing threshold or hearing loss in children (hFI: OR, 0.99; 95% confidence interval, 0.55 to 1.78) or adults (hFI: OR, 1.35; 95% confidence interval, 0.81 to 2.25).

CONCLUSIONS: Telomere length was not associated with hearing acuity in children or their midlife parents.

RevDate: 2019-03-14

Mohanty P, Jadhav P, Shanmukhaiah C, et al (2019)

A novel DKC1 gene mutation c.1177 A>T (p.I393F) in a case of dyskeratosis congenita with severe telomere shortening.

RevDate: 2019-03-14

Tahamtan S, Tavalaee M, Izadi T, et al (2019)

Reduced sperm telomere length in individuals with varicocele is associated with reduced genomic integrity.

Scientific reports, 9(1):4336 pii:10.1038/s41598-019-40707-2.

Varicocele, defined as enlarged varicose veins in the scrotum, is the most common identifiable cause of male infertility. There are significant correlations between oxidative stress and varicocele-related infertility due to testicular hyperthermia, which can result in low sperm function. In addition, recent excessive oxidative stress can affect sperm telomere length and integrity of sperm DNA. Therefore, we assessed sperm telomere length as a potential marker of paternal genome integrity and leukocyte telomere length as an internal control (real-time PCR), along with sperm chromatin status (TUNEL and chromomycin A3 assay), and lipid peroxidation (Bodipy probe) in 18 infertile men with grade II or III varicocele, and 20 fertile men. Means of sperm parameters, sperm and leukocyte telomere length were significantly lower, while means of sperm DNA fragmentation, protamine deficiency, and lipid peroxidation were significantly higher in infertile men with varicocele compared to fertile men. Therefore, shortened telomere length in sperm and leukocytes is likely associated with increased oxidative stress related to the state of varicocele, which also accounts for increase in sperm DNA fragmentation. Thus, assessment of leukocyte telomere length could be taken as an indicator of antioxidant capacity in an individual, which also affects sperm function.

RevDate: 2019-03-13

Koslow M, Shitrit D, Israeli-Shani L, et al (2019)

Peripheral blood telomere alterations in ground glass opacity (GGO) lesions may suggest malignancy.

Thoracic cancer [Epub ahead of print].

A ground glass opacity (GGO) lung lesion may represent early stage adenocarcinoma, which has an excellent prognosis upon prompt surgical resection. However, GGO lesions have broad differential diagnoses, including both benign and malignant lesions. Our objective was to study telomere length and telomerase activity in patients with suspected lung cancer in which GGO was the predominant radiographic feature. Knowledge of telomere biology may help distinguish malignant from benign radiographic lesions and guide risk assessment of these lesions. Peripheral blood samples were taken from 22 patients with suspected adenocarcinoma with the GGO radiographic presentation. Multidisciplinary discussion confirmed the need for surgery in all cases. We used an age and gender-matched group without known lung disease as a control. Telomere length and aggregates were assessed by quantitative fluorescence in situ hybridization (QFISH) and quantitative PCR. Cell senescence was evaluated by senescence-associated heterochromatin foci. Subjects with GGO lesions had a higher percentage of lymphocytes with shorter telomeres (Q-FISH, P = 0.003). Furthermore, relative telomere length was also reduced among the GGO cases (qPCR, P < 0.05). Increased senescence was observed in the GGO group compared to controls (P < 0.001), with significant correlation between the senescence-associated heterochromatin foci and aggregate formation (r = -0.7 and r = -0.44 for cases and controls, respectively). In conclusion, patients with resectable early adenocarcinoma demonstrate abnormal telomere length and cell senescence in peripheral blood leukocytes compared to control subjects. Abnormal telomere biology in the peripheral blood may increase suspicion of early adenocarcinoma among patients with GGO lesions.

RevDate: 2019-03-13

Keefe DL (2019)

Telomeres and genomic instability during early development.

European journal of medical genetics pii:S1769-7212(19)30058-8 [Epub ahead of print].

Genomic instability is widespread during early embryo development. Aneuploidy, mosaicism, and copy number variants (CNVs) commonly appear in human preimplantation embryos. Both age-dependent meiotic aneuploidy and age-independent mitotic aneuploidy and CNVs occur In human embryos. Telomere attrition, which contributes to genomic instability in somatic cells, also may promote genomic instability in preimplantation embryos. Telomere dynamics during gametogenesis are strikingly dimorphic between females and males. Sperm telomeres lengthen with advancing paternal age, while oocyte telomeres are among the shortest in the body. Spermatogonia express telomerase activity throughout the life of the male, while oocytes and cleavage stage embryos express low or un-measureable levels of telomerase activity. Telomere attrition in oocytes contributes to meiotic dysfunction, including spindle dysmorphologies, reduced synapsis and chiasmata, as well as delayed, arrested and fragmented embryos. Cleavage stage embryos, with such inefficient telomere reconstitution, likely undergo NHEJ, which produces anaphase lag, chromosome bridges, micronuclei, and genomic instability, including mosaicism and CNVs. Cleavage stage embryos reconstitute the short telomeres inherited from their mothers by Alternative Lengthening of Telomeres (ALT), a DNA recombination based method involving RAD 50, MRE 11, Werner and Bloom proteins, as well as telomere sister chromatid exchange. ALT robustly reconstitutes telomeres, but also predisposes to genomic instability.

RevDate: 2019-03-12

Steinmetz M, Schmitter C, Radecke T, et al (2019)

Brief report - Telomere length is a poor biomarker to predict 1-year mortality or cardiovascular comorbidity in patients with transcatheter aortic valve replacement.

PloS one, 14(3):e0213250 pii:PONE-D-18-14462.

BACKGROUND: Transcatheter aortic valve replacement (TAVR) is a therapeutic option for patients with aortic valve stenosis at increased surgical risk. Telomeres are an established marker for cellular senescence and have served to evaluate cardiovascular diseases including severe aortic valve stenosis. In our study, we hypothesized that telomere length may be a predictor for outcome and associated with comorbidities in patients with TAVR.

METHODS AND RESULTS: We analyzed leucocyte telomere length from 155 patients who underwent TAVR and correlated the results with 1-year mortality and severe comorbidities. The cohort was subdivided into 3 groups according to telomere length. Although a trend for a positive correlation of telomere length with a lower EuroSCORE could be found, telomere length was not associated with survival, aortic valve opening area or cardiovascular comorbidities (peripheral, coronary or cerebrovascular disease). Interestingly, long telomeres were significantly correlated to a reduced left ventricular ejection fraction (LVEF).

CONCLUSION: In elderly patients with severe aortic valve stenosis, leucocyte telomere length did not predict post-procedural survival. The correlation between long telomere length and reduced LVEF in these patients deserves further attention.

RevDate: 2019-03-12

Zeng JB, Liu HB, Ping F, et al (2019)

Insulin treatment affects leukocyte telomere length in patients with type 2 diabetes: 6-year longitudinal study.

Journal of diabetes and its complications pii:S1056-8727(18)31308-4 [Epub ahead of print].

OBJECTIVE: Many studies demonstrated a close relationship between type 2 diabetes mellitus (T2DM) and leukocyte telomere length (LTL). However, how the LTL changes in T2DM and what are the potential causal factors in it, particularly in patients during a long period treatment, have not been studied. Here we performed a longitudinal observation of LTL in trained T2DM patients during a 6-year follow-up and evaluated the possible risk factors that were associated with LTL alteration.

METHODS: Seventy-six patients with T2DM were enrolled in this 6-year longitudinal study. The enrolled patients had no severe complication and had never received insulin therapy by the time. Patients were scheduled to visit once every one or two months and their medication changes were recorded. The LTL at the time when patients were enrolled was used as baseline, which was compared with the LTL at 6 year. Multivariable linear regression and exact logistic regression model were adopted to identify independent predictors of telomere length change and telomere length shortening, respectively.

RESULTS: Sixty-four patients were successfully followed up. Although mean LTL decreased after 6 years, 30% (19/64) of patients demonstrated LTL lengthening and 70% (45/64) of patients demonstrated LTL shortening. Among them, 18 Patients received insulin treatment during the 6 years. Of these 18 patients, 16 patients showed decreased LTL and only two showed increased LTL. Linear regression analysis demonstrated that change in telomere length during the 6 years was associated inversely with insulin use (β-coefficients: -0.587, 95% CI: -0.198, -0.085, P < 0.001). Exact logistic regression analysis showed insulin use (OR: 17.355, 95% CI: 2.659, 35.627, P = 0.013) and LDL-C(OR: 3.493, 95% CI: 1.559, 10.063, P = 0.007)were independent predicts of telomere length shortening.

CONCLUSIONS: LTL may increase as well as decrease in T2DM who received antidiabetic treatment. Insulin use may accelerate telomere attrition. Insulin use and LDL-C can predict telomere shortening.

RevDate: 2019-03-12

Wang TH, Chen CC, Hsiao YC, et al (2019)

Heterogeneous Nuclear Ribonucleoproteins A1 and A2 Function in Telomerase-Dependent Maintenance of Telomeres.

Cancers, 11(3): pii:cancers11030334.

The A/B subfamily of heterogeneous nuclear ribonucleoproteins (hnRNPs A/B), which includes hnRNP A1, A2/B1, and A3, plays an important role in cell proliferation. The simultaneous suppression of hnRNP A1/A2, but not the suppression of hnRNP A1 or A2 alone, has been shown to inhibit cell proliferation and induce apoptosis in cancer cells, but not in mortal normal cells. However, the molecular basis for such a differential inhibition of cell proliferation remains unknown. Here, we show that the simultaneous suppression of hnRNP A1 and hnRNP A2 resulted in dysfunctional telomeres and induced DNA damage responses in cancer cells. The inhibition of apoptosis did not alleviate the inhibition of cell proliferation nor the formation of dysfunctional telomeres in cancer cells depleted of hnRNP A1/A2. Moreover, while proliferation of mortal normal fibroblasts was not sensitive to the depletion of hnRNP A1/A2, the ectopic expression of hTERT in normal fibroblasts rendered these cells sensitive to proliferation inhibition, which was associated with the production of dysfunctional telomeres. Our study demonstrates that hnRNP A1 and A2 function to maintain telomeres in telomerase-expressing cells only, suggesting that the maintenance of functional telomeres in telomerase-expressing cancer cells employs factors that differ from those used in the telomerase-negative normal cells.

RevDate: 2019-03-10

Jensen DM, Løhr M, Sheykhzade M, et al (2019)

Telomere length and genotoxicity in the lung of rats following intragastric exposure to food-grade titanium dioxide and vegetable carbon particles.

Mutagenesis pii:5372975 [Epub ahead of print].

Vegetable carbon (E153) and titanium dioxide (E171) are widely used as black and white food colour additives. The aim of this study was to assess gastrointestinal tight junction and systemic genotoxic effects in rats following exposure to E153 and E171 for 10 weeks by oral gavage once a week. The expression of tight junction proteins was assessed in intestinal tissues. Levels of DNA strand breaks, oxidatively damaged DNA and telomere length were assessed in secondary organs. Hydrodynamic suspensions of E153 and E173 indicated mean particles sizes of 230 and 270 nm, respectively, and only E153 gave rise to intracellular production of reactive oxygen species in colon epithelial (Caco-2) cells. Rats exposed to E153 (6.4 mg/kg/week) or E171 (500 mg/kg/week) had decreased gene expression of the tight junction protein TJP1 (P < 0.05). E153 (6.4 mg/kg/week) also decreased OCLN (P < 0.05) in the colon and occludin protein expression in the small intestine (P < 0.05). Furthermore, E153 or E171 exposed rats had shorter telomeres in the lung (P < 0.05). Plasma from particle-exposed rats also produced telomere shortening in cultured lung epithelial cells. There were unaltered levels of oxidatively damaged DNA in the liver and lung and no changes in the DNA repair activity of oxidatively damaged DNA in the lung. Altogether, these results indicate that intragastric exposure to E153 and E171 is associated with reduced tight junction protein expression in the intestinal barrier and telomere length shortening in the lung in rats.

RevDate: 2019-03-10

Rosa MJ, Hsu HL, Just AC, et al (2019)

Association between prenatal particulate air pollution exposure and telomere length in cord blood: Effect modification by fetal sex.

Environmental research, 172:495-501 pii:S0013-9351(19)30131-8 [Epub ahead of print].

INTRODUCTION: In utero particulate matter exposure produces oxidative stress that impacts cellular processes that include telomere biology. Newborn telomere length is likely critical to an individual's telomere biology; reduction in this initial telomere setting may signal increased susceptibility to adverse outcomes later in life. We examined associations between prenatal particulate matter with diameter ≤2.5 µm (PM2.5) and relative leukocyte telomere length (LTL) measured in cord blood using a data-driven approach to characterize sensitive windows of prenatal PM2.5 effects and explore sex differences.

METHODS: Women who were residents of Mexico City and affiliated with the Mexican Social Security System were recruited during pregnancy (n = 423 for analyses). Mothers' prenatal exposure to PM2.5 was estimated based on residence during pregnancy using a validated satellite-based spatio-temporally resolved prediction model. Leukocyte DNA was extracted from cord blood obtained at delivery. Duplex quantitative polymerase chain reaction was used to compare the relative amplification of the telomere repeat copy number to single gene (albumin) copy number. A distributed lag model incorporating weekly averages for PM2.5 over gestation was used in order to explore sensitive windows. Sex-specific associations were examined using Bayesian distributed lag interaction models.

RESULTS: In models that included child's sex, mother's age at delivery, prenatal environmental tobacco smoke exposure, pre-pregnancy BMI, gestational age, birth season and assay batch, we found significant associations between higher PM2.5 exposure during early pregnancy (4-9 weeks) and shorter LTL in cord blood. We also identified two more windows at 14-19 and 34-36 weeks in which increased PM2.5 exposure was associated with longer LTL. In stratified analyses, the mean and cumulative associations between PM2.5 and shortened LTL were stronger in girls when compared to boys.

CONCLUSIONS: Increased PM2.5 during specific prenatal windows was associated with shorter LTL and longer LTL. PM2.5 was more strongly associated with shortened LTL in girls when compared to boys. Understanding sex and temporal differences in response to air pollution may provide unique insight into mechanisms.

RevDate: 2019-03-07

Liu B, Anno K, Kobayashi T, et al (2019)

Influence of donor liver telomere and G-tail on clinical outcome after living donor liver transplantation.

PloS one, 14(3):e0213462 pii:PONE-D-18-30285.

It has been reported that donor age affects patient outcomes after liver transplantation, and that telomere length is associated with age. However, to our knowledge, the impact of donor age and donor liver telomere length in liver transplantation has not been well investigated. This study aimed to clarify the influence of the length of telomere and G-tail from donor livers on the outcomes of living donors and recipients after living donor liver transplantation. The length of telomere and G-tail derived from blood samples and liver tissues of 55 living donors, measured using the hybridization protection assay. The length of telomeres from blood samples was inversely correlated with ages, whereas G-tail length from blood samples and telomere and G-tail lengths from liver tissues were not correlated with ages. Age, telomere, and G-tail length from blood did not affect postoperative liver failure and early liver regeneration of donors. On the other hand, the longer the liver telomere, the poorer the liver regeneration tended to be, especially with significant difference in donor who underwent right hemihepatectomy. We found that the survival rate of recipients who received liver graft with longer telomeres was inferior to that of those who received liver graft with shorter ones. An elderly donor, longer liver telomere, and higher Model for End-Stage Liver Disease score were identified as independent risk factors for recipient survival after transplantation. In conclusion, telomere shortening in healthy liver does not correlate with age, whereas longer liver telomeres negatively influence donor liver regeneration and recipient survival after living donor liver transplantation. These results can direct future studies and investigations on telomere shortening in the clinical and experimental transplant setting.

RevDate: 2019-03-07

Wade M, Fox NA, Zeanah CH, et al (2019)

Telomere Length and Psychopathology: Specificity and Direction of Effects Within the Bucharest Early Intervention Project.

Journal of the American Academy of Child and Adolescent Psychiatry pii:S0890-8567(19)30136-4 [Epub ahead of print].

OBJECTIVE: Telomere length has been linked to several psychiatric conditions in children and adults. Telomere shortening is accelerated by early adversity, including maltreatment and psychosocial deprivation. These experiences also increase the risk of psychopathology in many domains. Two fundamental issues remain unresolved. The first concerns the specificity of the relations between TL and different dimensions of psychopathology; and the second relates to the direction of association between TL and psychopathology.

METHOD: This study addresses these shortcomings in a two-fold manner. First, we examined the association between TL and statistically-independent general, internalizing, and externalizing psychopathology factors to determine the specificity of this relation. Second, we used a two-wave longitudinal cross-lagged model to explicitly examine the direction of the relation between telomere length and each psychopathology factor. Data were drawn from the Bucharest Early Intervention Project (BEIP), a longitudinal study exploring the impact of severe psychosocial deprivation on child health and development (N = 195). At age 8-10 and 12-14, buccal DNA were collected and teachers and/or caregivers reported on different domains of psychopathology.

RESULTS: Longitudinal path analyses revealed that shorter telomere length was specifically associated with higher internalizing psychopathology at age 8-10. In contrast, at age 12-14, shorter telomere length was associated with higher general psychopathology. Most telling, internalizing psychopathology at age 8-10 predicted shorter telomere length at age 12-14, with no reciprocal effects.

CONCLUSION: Results suggest that telomere erosion may be a consequence of distress-related psychopathology rather than a selection mechanism for later psychiatric problems.

RevDate: 2019-03-06

Saberi S, Kalloger SE, Zhu MMT, et al (2019)

Dynamics of leukocyte telomere length in pregnant women living with HIV, and HIV-negative pregnant women: A longitudinal observational study.

PloS one, 14(3):e0212273 pii:PONE-D-18-17778.

BACKGROUND: HIV-mediated inflammation and immune activation can accelerate telomere attrition. In addition, antiretrovirals can inhibit telomerase, possibly shortening telomeres. We examined the longitudinal dynamics of leukocyte telomere length (LTL) during pregnancy in a unique cohort of women living with HIV (WLWH) treated with combination antiretroviral therapy (cART), and HIV-negative control women.

METHODS: Blood was collected at three visits during pregnancy, at 13-23, >23-30, and >30-40 weeks of gestation, and for WLWH only, at 6 weeks post-partum. LTL was measured by qPCR and both cross-sectional and longitudinal (MANOVA) models were used to examine possible predictors of LTL among participants who attended all three visits during pregnancy.

RESULTS: Among WLWH (n = 64) and HIV-negative women (n = 41), within participant LTL were correlated throughout pregnancy (p<0.001). LTL was shorter among WLWH at first visit, but this difference waned by the second visit. WLWH who discontinued cART post-partum experienced a decrease in LTL. Longitudinally, LTL was similar in both groups and increased as gestation progressed, a change that was more pronounced among women under 35 years. Among WLWH, both smoking throughout pregnancy (p = 0.04) and receiving a ritonavir-boosted protease inhibitor-based regimen (p = 0.03) were independently associated with shorter LTL.

CONCLUSIONS: LTL increases as pregnancy progresses; the reasons for this are unknown but may relate to changes in blood volume, hormones, and/or cell subset distribution. While our observations need confirmation in an independent cohort, our data suggest that although some cART regimens may influence LTL, being on cART appears overall protective and that stopping cART post-partum may negatively impact LTL. The effect of smoking on LTL is clearly negative, stressing the importance of smoking cessation.

RevDate: 2019-03-06

Pegan TM, Winkler DW, Haussmann MF, et al (2019)

Brief Increases in Corticosterone Affect Morphology, Stress Responses, and Telomere Length but Not Postfledging Movements in a Wild Songbird.

Physiological and biochemical zoology : PBZ, 92(3):274-285.

Organisms are frequently exposed to challenges during development, such as poor weather and food shortage. Such challenges can initiate the hormonal stress response, which involves secretion of glucocorticoids. Although the hormonal stress response helps organisms deal with challenges, long-term exposure to high levels of glucocorticoids can have morphological, behavioral, and physiological consequences, especially during development. Glucocorticoids are also associated with telomere shortening, and they have a complex relationship with survival. To investigate whether brief, acute exposures to glucocorticoids can also produce these phenotypic effects in free-living birds, we exposed wild tree swallow (Tachycineta bicolor) nestlings to a brief exogenous dose of corticosterone once per day for 5 d and then measured their morphology, baseline and stress-induced corticosterone levels, and telomere length. We also deployed radio tags on a subset of nestlings, which allowed us to determine the age at which tagged nestlings left the nest (fledged) and their pattern of presence and absence at the natal site during the postbreeding period. Corticosterone-treated nestlings had lower mass, higher baseline and stress-induced corticosterone, and reduced telomeres; other metrics of morphology were affected weakly or not at all. Our treatment resulted in no significant effect on survival to fledging, fledge age, or age at first departure from the natal site, and we found no negative effect of corticosterone on interannual return rate. These results show that brief acute corticosterone exposure during development can have measurable effects on phenotype in free-living tree swallows. Corticosterone may therefore mediate correlations between rearing environment and phenotype in developing organisms, even in the absence of prolonged stressors.

RevDate: 2019-03-06

Jørgensen SW, Liberti SE, Larsen NB, et al (2019)

Esc2 promotes telomere stability in response to DNA replication stress.

Nucleic acids research pii:5369941 [Epub ahead of print].

Telomeric regions of the genome are inherently difficult-to-replicate due to their propensity to generate DNA secondary structures and form nucleoprotein complexes that can impede DNA replication fork progression. Precisely how cells respond to DNA replication stalling within a telomere remains poorly characterized, largely due to the methodological difficulties in analysing defined stalling events in molecular detail. Here, we utilized a site-specific DNA replication barrier mediated by the 'Tus/Ter' system to define the consequences of DNA replication perturbation within a single telomeric locus. Through molecular genetic analysis of this defined fork-stalling event, coupled with the use of a genome-wide genetic screen, we identified an important role for the SUMO-like domain protein, Esc2, in limiting genome rearrangements at a telomere. Moreover, we showed that these rearrangements are driven by the combined action of the Mph1 helicase and the homologous recombination machinery. Our findings demonstrate that chromosomal context influences cellular responses to a stalled replication fork and reveal protective factors that are required at telomeric loci to limit DNA replication stress-induced chromosomal instability.

RevDate: 2019-03-06

Tsatsakis A, Tsoukalas D, Fragkiadaki P, et al (2019)

Developing BIOTEL: A Semi-Automated Spreadsheet for Estimating Telomere Length and Biological Age.

Frontiers in genetics, 10:84.

Introduction: Telomere length (TL) is causally related to aging and several age-related diseases. Specifically, the abundance of short telomeres and the rate of telomere shortening are strong determinants of cell homeostasis. Thus, tools for analyzing and manipulating TL data can vastly improve research focused on aging. Aim: In this study, we developed a semi-automated worksheet, BIOTEL, to generate individual and group TL statistics and provide a crude estimation of biological age. Results: Data from the Telomere Length Database Project (TLDP) were implemented to the spreadsheet to produce TL statistics. 150 participants were included, and their age was from 21 to 82 years, and the sex distribution ratio was 52.3%: 47.7% (male: female). Initially, we analyzed the fluorescence intensities of telomeres that were measured on metaphase spread leukocytes using three-dimensional (3D) quantitative-fluorescent in situ hybridization (Q-FISH) procedures (3D DNA FISH) with a (C3TA2)3 peptide nucleic acid (PNA) probe. Raw data of fluorescence intensities, demographic data and medical records from the participants were imported into the worksheet. Basic statistical analyses of TL data were provided through BIOTEL, including TL percentiles, specialized charts for TL distribution including the percentage of critically short telomeres (< 3,000 kilobases), individual telomere profiles, and graphs of biological age vs. chronological age. Conclusion: BIOTEL ver. 2.4 is a functional semi-automated worksheet that calculates a wide range of TL statistics, thus a useful tool with applications in research of telomeres and biological age estimation.

RevDate: 2019-03-05

Goffová I, Vágnerová R, Peška V, et al (2019)

Roles of RAD51 and RTEL1 in telomere and rDNA stability in Physcomitrella patens.

The Plant journal : for cell and molecular biology [Epub ahead of print].

Telomeres and ribosomal RNA genes (rDNA) are essential for cell survival and particularly sensitive to factors affecting genome stability. Here we examine the role of RAD51 and its antagonist, RTEL1, in the moss Physcomitrella patens. In corresponding mutants, we analyse their sensitivity to DNA damage, the maintenance of telomeres and rDNA, and repair of double strand breaks (DSBs) induced by genotoxins with various modes of action. While the loss of RTEL1 results in rapid telomere shortening, concurrent loss of both RAD51 genes has no effect on telomere lengths. We further demonstrate here the linked arrangement of 5S and 45S rRNA genes in P. patens. The spacer between 5S and 18S rRNA genes, especially the region downstream from the transcription start site, shows conspicuous clustering of sites with a high propensity to form quadruplex (G4) structures. Copy numbers of 5S and 18S rDNA are reduced moderately in pprtel1 mutant, and significantly in double pprad51-1-2 mutant, with no progression during subsequent cultivation. While reductions in 45S rDNA copy numbers observed in pprtel1 and pprad51-1-2 plants apply also to 5S rDNA, changes in transcript levels are different for 45S and 5S rRNA, indicating their independent transcription by RNA polymerase I and III, respectively. The loss of SOL (Sog One-Like), a transcription factor regulating numerous genes involved in DSB repair, increases the rate of DSB repair in dividing as well as differentiated tissue, and through deactivation of G2/M cell-cycle checkpoint allows the cell-cycle progression manifested as a phenotype resistant to bleomycin. This article is protected by copyright. All rights reserved.

RevDate: 2019-03-05

Kim J, Sun C, Tran AD, et al (2019)

The macroH2A1.2 histone variant links ATRX loss to alternative telomere lengthening.

Nature structural & molecular biology pii:10.1038/s41594-019-0192-3 [Epub ahead of print].

The growth of telomerase-deficient cancers depends on the alternative lengthening of telomeres (ALT), a homology-directed telomere-maintenance pathway. ALT telomeres exhibit a unique chromatin environment and generally lack the nucleosome remodeler ATRX, pointing to an epigenetic basis for ALT. Recently, we identified a protective role for the ATRX-interacting macroH2A1.2 histone variant during homologous recombination and replication stress (RS). Consistent with an inherent susceptibility to RS, we show that human ALT telomeres are highly enriched for macroH2A1.2. However, in contrast to ATRX-proficient cells, ALT telomeres transiently lose macroH2A1.2 during acute RS to facilitate DNA double-strand break (DSB) formation, a process that is almost completely prevented by ectopic ATRX expression. Telomeric macroH2A1.2 is re-deposited in a DNA damage response (DDR)-dependent manner to promote homologous recombination-associated ALT pathways. Our findings thus identify the dynamic exchange of macroH2A1.2 on chromatin as an epigenetic link among ATRX loss, RS-induced DDR initiation and telomere maintenance via homologous recombination.

RevDate: 2019-03-04

Minasi S, Baldi C, Pietsch T, et al (2019)

Telomere elongation via alternative lengthening of telomeres (ALT) and telomerase activation in primary metastatic medulloblastoma of childhood.

Journal of neuro-oncology pii:10.1007/s11060-019-03127-w [Epub ahead of print].

PURPOSE: Elongation of telomeres is necessary for tumor cell immortalization and senescence escape; neoplastic cells use to alternative pathways to elongate telomeres: telomerase reactivation or a telomerase-independent mechanism termed alternative lengthening of telomeres (ALT). Telomerase and ALT pathway has been explored in adult and pediatric gliomas and medulloblastomas (MDBs); however, these mechanisms were not previously investigated in MDBs metastatic at the onset. Therefore, we analyzed the activation of telomerase and ALT pathway in a homogenous cohort of 43 pediatric metastatic medulloblastomas, to investigate whether telomere elongation could play a role in the biology of metastatic MDB.

METHODS: We evaluated telomeres length via telomere-specific fluorescence in situ hybridization (Telo-FISH); we assessed nuclear expression of ATRX by immunohistochemistry (IHC). H3F3A and TERT promoter mutations were analyzed by pyrosequencing, while UTSS methylation status was analyzed via methylation-specific-PCR (MS-PCR).

RESULTS: H3F3A mutations were absent in all MDBs, 30% of samples showed ATRX nuclear loss, 18.2% of cases were characterized by TERT promoter mutations, while 60.9% harboured TERT promoter hyper-methylation in the UTSS region. Elongation of telomeres was found in 42.8% of cases. Metastatic MDBs control telomere elongation via telomerase activation (10.7%), induced by TERT promoter mutations in association with UTSS hyper-methylation, and ALT mechanism (32.1%), triggered by ATRX inactivation. Among non-metastatic MDBs, only 5.9% (1/17) showed ATRX nuclear loss with activation of ALT.

CONCLUSIONS: Our metastatic cases frequently activate ALT pathway, suggesting that it is a common process for senescence escape in primary metastatic medulloblastomas. Furthermore, the activation of mechanisms for telomere elongation is not restricted to certain molecular subgroups in this high-risk group of MDBs.

RevDate: 2019-03-03

Perales-Puchalt A, Soberón N, Monterde M, et al (2018)

Maternal telomere length is shorter in intrauterine growth restriction versus uncomplicated pregnancies, but not in the offspring or in IVF-conceived newborns.

Reproductive biomedicine online pii:S1472-6483(18)30636-9 [Epub ahead of print].

RESEARCH QUESTION: The study aimed to determine whether IVF or intrauterine growth restriction (IUGR) result in short neonatal telomeres, which could explain the higher risk of cardiovascular and metabolic disease described in these populations.

DESIGN: This was an observational, analytical, cross-sectional, prospective study with controls in a tertiary hospital. The main outcome was to determine the leukocyte telomere length in 126 newborns and their mothers (n = 109). Newborns were conceived spontaneously or by IVF, and uncomplicated and IUGR pregnancies were studied. Telomere lengths were measured using high-throughput telomere quantitative fluorescent in-situ hybridization.

RESULTS: There was no difference in average telomere length between newborns conceived by IVF or those with IUGR and spontaneously conceived healthy newborns (P = 0.466 and P = 0.732, respectively); this remained after controlling for confounders (P = 0.218 and P = 0.991, respectively). Mothers of newborns with IUGR had a shorter average telomere length than women with uncomplicated pregnancies (P = 0.023), which was confirmed after controlling for age, body mass index and smoking habit (P = 0.034).

CONCLUSIONS: The results support the safety of IVF and IUGR in terms of the postnatal health of the newborns. The shorter telomeres of IUGR mothers may represent a higher cardiovascular risk, which would have clinical implications under the stress of pregnancy in otherwise healthy adults.

RevDate: 2019-03-02

Petti E, Buemi V, Zappone A, et al (2019)

SFPQ and NONO suppress RNA:DNA-hybrid-related telomere instability.

Nature communications, 10(1):1001 pii:10.1038/s41467-019-08863-1.

In vertebrates, the telomere repeat containing long, non-coding RNA TERRA is prone to form RNA:DNA hybrids at telomeres. This results in the formation of R-loop structures, replication stress and telomere instability, but also contributes to alternative lengthening of telomeres (ALT). Here, we identify the TERRA binding proteins NONO and SFPQ as novel regulators of RNA:DNA hybrid related telomere instability. NONO and SFPQ locate at telomeres and have a common role in suppressing RNA:DNA hybrids and replication defects at telomeres. NONO and SFPQ act as heterodimers to suppress fragility and homologous recombination at telomeres, respectively. Combining increased telomere fragility with unleashing telomere recombination upon NONO/SFPQ loss of function causes massive recombination events, involving 35% of telomeres in ALT cells. Our data identify the RNA binding proteins SFPQ and NONO as novel regulators at telomeres that collaborate to ensure telomere integrity by suppressing telomere fragility and homologous recombination triggered by RNA:DNA hybrids.

RevDate: 2019-03-02

Jezek M, EM Green (2019)

Histone Modifications and the Maintenance of Telomere Integrity.

Cells, 8(2): pii:cells8020199.

Telomeres, the nucleoprotein structures at the ends of eukaryotic chromosomes, play an integral role in protecting linear DNA from degradation. Dysregulation of telomeres can result in genomic instability and has been implicated in increased rates of cellular senescence and many diseases, including cancer. The integrity of telomeres is maintained by a coordinated network of proteins and RNAs, such as the telomerase holoenzyme and protective proteins that prevent the recognition of the telomere ends as a DNA double-strand breaks. The structure of chromatin at telomeres and within adjacent subtelomeres has been implicated in telomere maintenance pathways in model systems and humans. Specific post-translational modifications of histones, including methylation, acetylation, and ubiquitination, have been shown to be necessary for maintaining a chromatin environment that promotes telomere integrity. Here we review the current knowledge regarding the role of histone modifications in maintaining telomeric and subtelomeric chromatin, discuss the implications of histone modification marks as they relate to human disease, and highlight key areas for future research.

RevDate: 2019-03-01

Mandal S, Kawamoto Y, Yue Z, et al (2019)

Submolecular dissection reveals strong and specific binding of polyamide-pyridostatin conjugates to human telomere interface.

Nucleic acids research pii:5367418 [Epub ahead of print].

To modulate biological functions, G-quadruplexes in genome are often non-specifically targeted by small molecules. Here, specificity is increased by targeting both G-quadruplex and its flanking duplex DNA in a naturally occurring dsDNA-ssDNA telomere interface using polyamide (PA) and pyridostatin (PDS) conjugates (PA-PDS). We innovated a single-molecule assay in which dissociation constant (Kd) of the conjugate can be separately evaluated from the binding of either PA or PDS. We found Kd of 0.8 nM for PA-PDS, which is much lower than PDS (Kd ∼ 450 nM) or PA (Kd ∼ 35 nM). Functional assays further indicated that the PA-PDS conjugate stopped the replication of a DNA polymerase more efficiently than PA or PDS. Our results not only established a new method to dissect multivalent binding into actions of individual monovalent components, they also demonstrated a strong and specific G-quadruplex targeting strategy by conjugating highly specific duplex-binding molecules with potent quadruplex ligands.

RevDate: 2019-03-01

Ventura Marra M, Drazba MA, Holásková I, et al (2019)

Nutrition Risk is Associated with Leukocyte Telomere Length in Middle-Aged Men and Women with at Least One Risk Factor for Cardiovascular Disease.

Nutrients, 11(3): pii:nu11030508.

Poor diet quality has been associated with several age-related chronic conditions, but its relationship to telomere length, a biological marker of cellular aging, is unclear. The purpose of this cross-sectional study was to determine whether overall diet quality was associated with relative leukocyte telomere length (rLTL) in a sample (n = 96) of nonsmoking middle-aged adults in Appalachia with at least one risk factor for cardiovascular disease. Diet quality was assessed using the Healthy Eating Index (HEI-2015), the alternate Mediterranean diet score (aMed), and the Dietary Screening Tool (DST). Peripheral rLTL was measured by quantitative real-time polymerase chain reaction. The associations between potentially confounding sociodemographic, lifestyle and health-related factors and the first and fourth rLTL quartile groups were examined using Chi-square or Fisher's Exact tests or logistic regression. The relationships between diet quality index scores and rLTL as a continuous variable were analyzed using simple linear regression and multivariate linear models, analogous to linear covariance analyses. The rLTL ranged from 0.46 to 1.49 (mean ± SEM was 1.02 ± 0.18). Smoking history, income level, and cardiovascular health (Life's Simple 7) were associated with the lowest and highest quartiles of rLTL and were used as covariates. In adjusted and unadjusted models, participants considered "at nutrition risk" by the DST were more likely to have shorter rLTL than those "not at risk or at potential risk" (p = 0.004). However, there was no evidence that adherence to the 2015⁻2020 Dietary Guidelines for Americans or to a Mediterranean diet was associated with rLTL in this sample. Intervention studies are needed to determine if improving the diet quality of those at nutrition risk results in reduced telomere attrition over time.

RevDate: 2019-02-28

Li J, An C, Zheng H, et al (2019)

Leukocyte telomere length and risk of papillary thyroid carcinoma.

The Journal of clinical endocrinology and metabolism pii:5365821 [Epub ahead of print].

CONTEXT: Telomere length may contribute to predisposition of papillary thyroid cancer (PTC).

OBJECTIVE: To test this hypothesis, we examined the association between leukocyte telomere length and PTC risk.

DESIGN/SETTING: Case-control study in a Chinese Han population.

PARTICIPANTS/INTERVENTION: A total of 1,200 PTC cases and 1,201 age- and sex-matched healthy controls were included in the study. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by logistic regression.

RESULTS: Short relative telomere length (RTL) was significantly associated with elevated risk of PTC (OR = 1.61, 95% CI = 1.35-1.92, P = 1.30×10-7). Interestingly, when individuals were categorized into four groups based on quartiles distribution of RTL in controls, we observed a reverse U-shape association between telomere length and PTC risk. As compared with those in the first quartile (the longest) as the reference group, ORs (95% CIs) are 5.61 (4.04-7.78) (P = 6.10×10-25), 9.33 (6.78-12.83) (P = 6.99×10-43) and 1.23 (0.83-1.81) (P = 0.300) for individuals in the second, third and fourth (the shortest) quartile. This reverse U-shaped relationship was more apparent in younger individuals.

CONCLUSIONS: Our findings suggest that RTL is significantly associated with susceptibility of PTC. There is an obvious reverse U-shape association between telomere length and PTC risk. Telomere length might be a potential, pronouncing biomarker to identify individuals with high-risk to develop PTC.

RevDate: 2019-02-28

Maciejowski J, T de Lange (2019)

Author Correction: Telomeres in cancer: tumour suppression and genome instability.

In the original Fig. 2a, telomeres are erroneously depicted having blunt ends following resection and CST-mediated fill-in. Instead, telomeres retain 3' overhangs, as depicted below.

RevDate: 2019-02-28

Subramanian VV, Zhu X, Markowitz TE, et al (2019)

Persistent DNA-break potential near telomeres increases initiation of meiotic recombination on short chromosomes.

Nature communications, 10(1):970 pii:10.1038/s41467-019-08875-x.

Faithful meiotic chromosome inheritance and fertility rely on the stimulation of meiotic crossover recombination by potentially genotoxic DNA double-strand breaks (DSBs). To avoid excessive damage, feedback mechanisms down-regulate DSBs, likely in response to initiation of crossover repair. In Saccharomyces cerevisiae, this regulation requires the removal of the conserved DSB-promoting protein Hop1/HORMAD during chromosome synapsis. Here, we identify privileged end-adjacent regions (EARs) spanning roughly 100 kb near all telomeres that escape DSB down-regulation. These regions retain Hop1 and continue to break in pachynema despite normal synaptonemal complex deposition. Differential retention of Hop1 requires the disassemblase Pch2/TRIP13, which preferentially removes Hop1 from telomere-distant sequences, and is modulated by the histone deacetylase Sir2 and the nucleoporin Nup2. Importantly, the uniform size of EARs among chromosomes contributes to disproportionately high DSB and repair signals on short chromosomes in pachynema, suggesting that EARs partially underlie the curiously high recombination rate of short chromosomes.

RevDate: 2019-02-27

Kwon MS, Lee JJ, Min J, et al (2019)

Brca2 abrogation engages with the Alternative Lengthening of Telomeres via Break-induced Replication.

The FEBS journal [Epub ahead of print].

A subset of cancer cells maintain their telomeres without telomerase through the recombination-based Alternative Lengthening of Telomeres (ALT) pathway. Currently, it is not yet clear in what context ALT is induced and how the pathway choice is made. Here, we show that abrogation of Brca2 reinforces break-induced replication (BIR) and engages with ALT pathway. Brca2 depletion in telomerase-null mouse cells alleviated the growth defect, accompanied by telomere elongation, suggesting the induction of ALT. We also found that Brca2-depleted telomerase-null cells exhibited dynamic clustering of telomeres from G2 phase in Promyelocytic Nuclear (PML) bodies. For Brca2-deficient ALT induction, Rad51 was dispensable but Mre11 and Rad52 were required. Congruently, conservative telomeric DNA synthesis was apparent in mitosis, indicating that the absence of Brca2 directed towards Rad52-mediated BIR. Collectively, we propose that Brca2 abrogation can instigate ALT tumorigenesis through the induction of BIR. This study implies that inhibitors of BIR may be useful for BRCA2-associated ALT-type cancers. Assessing ALT features may be considered for the tailored therapy of BRCA2-associated cancers. This article is protected by copyright. All rights reserved.

RevDate: 2019-02-26

Gürünlüoğlu K, Demircan M, Koç A, et al (2019)

The effects of different burn dressings on length of telomere and expression of telomerase in children with thermal burns.

Journal of burn care & research : official publication of the American Burn Association pii:5364814 [Epub ahead of print].

BACKGROUND: Burns are a common traumatic injury triggered by local tissue damage and a systemic response. In this study, we evaluated the effects of different burn dressings on telomere kinetics in children with thermal burn injury.

METHODS: Sixty children with thermal burn,were included in this prospective study. The burn area of the patients included 20-50% total body surface area. Three different dressings (HFAg; hydrofiber with silver, PLM; poylactic membrane and SSD; Silver Sulfadiazine), and control groups were created. Telomere length in nucleated blood cells and telomerase expression in the skin tissue were evaluated in control and burn groups.

RESULTS: In the whole burn groups, telomere length in blood cells increased. The length of telomeres increased the most in the SSD group. The PLM group is the treatment that increases the number of squamous cell counts in the basal layer and telomerase expression in the skin. In HFAg and SSD groups, the expression of telomerase in the skin is decreased. In the HFAg group, the basal layer in the skin was also reduced in squamous cells.

CONCLUSION: In all burn groups, the telomere length of nucleated cells in the blood was higher than in the control group. SSD dressing along used autografting application is the treatment method that maximizes telomere length in blood cells. The PLM has the most increased telomerase expression in the skin of burned patients. The PLM application increases the number of cells on both burned and normal skin.

RevDate: 2019-02-23

Injaian AS, Gonzalez-Gomez PL, Taff CC, et al (2019)

Traffic noise exposure alters nestling physiology and telomere attrition through direct, but not maternal, effects in a free-living bird.

General and comparative endocrinology pii:S0016-6480(18)30566-5 [Epub ahead of print].

Anthropogenic impacts, such as noise pollution from transportation networks, can serve as stressors to some wildlife species. For example, increased exposure to traffic noise has been found to alter baseline and stress-induced corticosterone levels, reduce body condition and reproductive success, and increase telomere attrition in free-living birds. However, it remains unknown if alterations in nestling phenotype are due to direct or indirect effects of noise exposure. For example, indirect (maternal) effects of noise may occur if altered baseline and stress-induced corticosterone in mothers results in differential deposition of yolk steroids or other components in eggs. Noise exposure may also alter nestling corticosterone levels directly, given that nestlings cannot escape the nest during development. Here, we examined maternal versus direct effects of traffic noise exposure on baseline and stress-induced corticosterone levels, and body condition (as measured by size-corrected mass) in nestling tree swallows (Tachycineta bicolor). We used a two-way factorial design and partially cross-fostered eggs between nests exposed to differing levels (i.e. amplitudes) of traffic noise. For nestlings that were not cross-fostered, we also investigated the effects of traffic noise on telomere dynamics. Our results show a positive relationship between nestling baseline and stress-induced corticosterone and nestling noise exposure, but not maternal noise exposure. While we did not find a relationship between noise and body condition in nestlings, nestling baseline corticosterone was negatively associated with body condition. We also found greater telomere attrition for nestlings from nests with greater traffic noise amplitudes. These results suggest that direct, rather than maternal, effects result in potentially long-lasting consequences of noise exposure. Reduced nestling body condition and increased telomere attrition have been shown to reduce post-fledging survival in this species. Given that human transportation networks continue to expand, strategies to mitigate noise exposure on wildlife during critical periods (i.e. breeding) may be needed to maintain local population health in free-living passerines, such as tree swallows.

RevDate: 2019-02-23

Muskens IS, Hansen HM, Smirnov IV, et al (2019)

Longer genotypically-estimated leukocyte telomere length is associated with increased meningioma risk.

Journal of neuro-oncology pii:10.1007/s11060-019-03119-w [Epub ahead of print].

PURPOSE: Telomere length-associated SNPs have been associated with incidence and survival rates for malignant brain tumors such as glioma. Here, we study the influence of genetically determined lymphocyte telomere length (LTL) by comparing telomerase associated SNPs between the most common non-malignant brain tumor, i.e. meningioma, and healthy controls.

METHODS/PATIENTS: One thousand fifty-three (1053) surgically treated meningioma patients and 4437 controls of Western European ancestry were included. Germline DNA was genotyped for 8 SNPs previously significantly associated with LTL. Genotypically-estimated LTL was then calculated by summing each SNP's genotypically-specified telomere length increase in base pairs (bp) for each person. Odds ratios for genotypically-estimated LTL in meningioma cases and controls were evaluated using logistic regression with the first two ancestral principal components and sex as covariates.

RESULTS: Three out of the eight evaluated LTL SNPs were significantly associated with increased meningioma risk (rs10936599: OR 1.14, 95% CI 1.01-1.28, rs2736100: OR 1.13, 95% CI 1.03-1.25, rs9420907: OR 1.22, 95% CI 1.07-1.39). Only rs9420907 remained significant after correction for multiple testing. Average genotypically-estimated LTL was significantly longer for those with meningioma compared to controls [mean cases: 560.2 bp (standard error (SE): 4.05 bp), mean controls: 541.5 bp (SE: 2.02 bp), logistic regression p value = 2.13 × 10-5].

CONCLUSION: Increased genotypically-estimated LTL was significantly associated with increased meningioma risk. A role for telomere length in the pathophysiology of meningioma is novel, and could lead to new insights on the etiology of meningioma.

RevDate: 2019-02-23

Zhang X, Liu Z, Liu X, et al (2019)

Telomere-dependent and telomere-independent roles of RAP1 in regulating human stem cell homeostasis.

Protein & cell pii:10.1007/s13238-019-0610-7 [Epub ahead of print].

RAP1 is a well-known telomere-binding protein, but its functions in human stem cells have remained unclear. Here we generated RAP1-deficient human embryonic stem cells (hESCs) by using CRISPR/Cas9 technique and obtained RAP1-deficient human mesenchymal stem cells (hMSCs) and neural stem cells (hNSCs) via directed differentiation. In both hMSCs and hNSCs, RAP1 not only negatively regulated telomere length but also acted as a transcriptional regulator of RELN by tuning the methylation status of its gene promoter. RAP1 deficiency enhanced self-renewal and delayed senescence in hMSCs, but not in hNSCs, suggesting complicated lineage-specific effects of RAP1 in adult stem cells. Altogether, these results demonstrate for the first time that RAP1 plays both telomeric and nontelomeric roles in regulating human stem cell homeostasis.

RevDate: 2019-02-23

Escudero L, Cleal K, Ashelford K, et al (2019)

Telomere fusions associate with coding sequence and copy number alterations in CLL.

RevDate: 2019-02-23

Escandell JM, Carvalho ES, Gallo-Fernandez M, et al (2019)

Ssu72 phosphatase is a conserved telomere replication terminator.

The EMBO journal pii:embj.2018100476 [Epub ahead of print].

Telomeres, the protective ends of eukaryotic chromosomes, are replicated through concerted actions of conventional DNA polymerases and elongated by telomerase, but the regulation of this process is not fully understood. Telomere replication requires (Ctc1/Cdc13)-Stn1-Ten1, a telomeric ssDNA-binding complex homologous to RPA Here, we show that the evolutionarily conserved phosphatase Ssu72 is responsible for terminating the cycle of telomere replication in fission yeast. Ssu72 controls the recruitment of Stn1 to telomeres by regulating Stn1 phosphorylation at Ser74, a residue located within its conserved OB-fold domain. Consequently, ssu72∆ mutants are defective in telomere replication and exhibit long 3'-ssDNA overhangs, indicative of defective lagging-strand DNA synthesis. We also show that hSSU72 regulates telomerase activation in human cells by controlling recruitment of hSTN1 to telomeres. These results reveal a previously unknown yet conserved role for the phosphatase SSU72, whereby this enzyme controls telomere homeostasis by activating lagging-strand DNA synthesis, thus terminating the cycle of telomere replication.

RevDate: 2019-02-23

Brane AC, TO Tollefsbol (2019)

Targeting Telomeres and Telomerase: Studies in Aging and Disease Utilizing CRISPR/Cas9 Technology.

Cells, 8(2): pii:cells8020186.

Telomeres and telomerase provide a unique and important avenue of study in improving both life expectancy and quality of life due to their close association with aging and disease. While major advances in our understanding of these two biological mediators have characterized the last two decades, previous studies have been limited by the inability to affect change in real time within living cells. The last three years, however, have witnessed a huge step forward to overcome this limitation. The advent of the clustered regularly interspaced short palindromic repeats/CRISPR-associated (CRISPR/Cas) system has led to a wide array of targeted genetic studies that are already being employed to modify telomeres and telomerase, as well as the genes that affect them. In this review, we analyze studies utilizing the technology to target and modify telomeres, telomerase, and their closely associated genes. We also discuss how these studies can provide insight into the biology and mechanisms that underlie aging, cancer, and other diseases.

RevDate: 2019-02-22

Giraudeau M, Angelier F, T Sepp (2019)

Do Telomeres Influence Pace-of-Life-Strategies in Response to Environmental Conditions Over a Lifetime and Between Generations?.

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

The complexity of the physiological phenotype currently prevents us from identifying an integrative measure to assess how the internal state and environmental conditions modify life-history strategies. In this article, it is proposed that shorter telomeres should lead to a faster pace-of-life where investment in self-maintenance is decreased as a means of saving energy for reproduction, but at the cost of somatic durability. Inversely, longer telomeres would favor an increased investment in soma maintenance and thus a longer reproductive lifespan (i.e., slower pace-of-life). Under this hypothesis, telomere dynamics could be such an integrative mediator, which will assemble the information about oxidative stress levels, inflammation status and stress reactivity, and relate this information to the potential lifespan of the organism and its pace-of-life strategy. The signaling function of telomere dynamics can also reach over generations, a phenomenon in which the telomere lengths of gametes would provide a channel through which offspring would receive information about their environment early in their development, hence increasing the possibilities for developmental plasticity.

RevDate: 2019-02-21

Kapuria D, Ben-Yakov G, Ortolano R, et al (2019)

The Spectrum of Hepatic Involvement in Patients with Telomere Disease.

Hepatology (Baltimore, Md.) [Epub ahead of print].

BACKGROUND: Loss-of-function mutations in genes that encode for components of the telomere repair complex cause accelerated telomere shortening. Hepatic involvement has been recognized as a cause of morbidity in telomere diseases, but very few studies have characterized the nature and extent of liver involvement in affected patients. We report the prevalence and characteristics of liver involvement in a large cohort of patients with telomere disease evaluated serially at the National Institutes of Health.

METHODS: One hundred twenty-one patients with known or suspected telomere disease were screened; 40 patients with liver involvement were included in the current study. Median follow up was 2.4 years. Data were collected regarding their demographic information, laboratory analysis, imaging and histopathology.

RESULTS: Forty patients (40% of the cohort) with a median age of 42 years were found to have liver involvement. Liver enzyme elevation was cholestatic in pattern; 8(21%) had drug related enzyme elevations. The most common imaging finding was increased hepatic echogenicity on ultrasound in 39% (9) patients, followed by hepatomegaly in 26% (6) subjects. Biopsies were infrequent due to risk associated with thrombocytopenia, but in six patients there were varying findings: nodular regenerative hyperplasia, steatohepatitis, hemosiderosis, cholestasis, and cirrhosis with hepatic steatosis. Almost half the cohort had pulmonary diffusion abnormalities, and 25% died during the follow up period.

CONCLUSION: In patients with telomere disease, hepatic involvement is common and can present in diverse ways, including elevated liver enzymes, histopathologic as well as imaging abnormalities. Liver disease has important implications for morbidity and mortality in patients with telomere disease. This article is protected by copyright. All rights reserved.

RevDate: 2019-02-21

Stögbauer L, Stummer W, Senner V, et al (2019)

Telomerase activity, TERT expression, hTERT promoter alterations, and alternative lengthening of the telomeres (ALT) in meningiomas - a systematic review.

Neurosurgical review pii:10.1007/s10143-019-01087-3 [Epub ahead of print].

Telomerase activity and (human) Telomerase Reverse Transcriptase (hTERT) expression are considered hallmarks in oncogenesis of neoplasms and are upregulated by alterations of the hTERT promoter. In meningiomas, numerous studies investigated hTERT expression, telomerase activity, promoter mutations, and methylations. Moreover, reports about hTERT-targeted chemotherapy in meningiomas have recently been published. We provide a systematic review of the literature about the role of hTERT in meningiomas. TERT expression and telomerase activity is found in benign and high-grade meningiomas and increase with WHO grade. Remarkably, rates of TERT expression/telomerase activity usually exceed mutation frequency and both telomerase activity and TERT expression have also been found in hTERT promoter wildtype meningiomas, indicating further mechanisms of TERT upregulation. Although hTERT promoter methylation has been reported in the vast majority of meningiomas, correlation with TERT expression remains controversial. Rates of promoter mutations, and methylation were shown to increase with rising WHO grade. Moreover, promoter methylation and mutations strongly correlate with prognosis. Although mutations predicted malignant progression, de novo mutations in high-grade recurrences of former benign lesions were also observed. Retroviral transduction of the TERT gene enabled immortalization in several grade I-III meningioma cell lines. In vitro analyses revealed significant effects on viability in hTERT-mutated meningioma cells after targeted treatment. Alternative mechanisms of telomere lengthening are usually absent in meningiomas. TERT and hTERT promoter alterations play a major role during oncogenesis of meningiomas with implications for prognosis and potentially treatment.

RevDate: 2019-02-21

Shin PK, Zoh Y, Choi J, et al (2019)

Walnut phenolic extracts reduce telomere length and telomerase activity in a colon cancer stem cell model.

Nutrition research and practice, 13(1):58-63.

BACKGROUND/OBJECTIVES: Telomeres are located at the chromosomal ends and progressively shortened during each cell cycle. Telomerase, which is regulated by hTERT and c-MYC, maintains telomeric DNA sequences. Especially, telomerase is active in cancer and stem cells to maintain telomere length for replicative immortality. Recently we reported that walnut phenolic extract (WPE) can reduce cell viability in a colon cancer stem cell (CSC) model. We, therefore, investigated the effect of WPE on telomere maintenance in the same model.

MATERIALS/METHODS: CD133+CD44+ cells from HCT116, a human colon cancer cell line, were sorted by Fluorescence-activated cell sorting (FACS) and treated with WPE at the concentrations of 0, 10, 20, and 40 µg/mL for 6 days. Telomere lengths were assessed by quantitative real-time PCR (qRT-PCR) using telomere specific primers and DNA extracted from the cells, which was further adjusted with single-copy gene and reference DNA (ddCt). Telomerase activity was also measured by qRT-PCR after incubating the PCR mixture with cell protein extracts, which was adjusted with reference DNA (dCt). Transcriptions of hTERT and c-MYC were determined using conventional RT-PCR.

RESULTS: Telomere length of WPE-treated cells was significantly decreased in a dose-dependent manner (5.16 ± 0.13 at 0 µg/mL, 4.79 ± 0.12 at 10 µg/mL, 3.24 ± 0.08 at 20 µg/mL and 3.99 ± 0.09 at 40 µg/mL; P = 0.0276). Telomerase activities concurrently decreased with telomere length (1.47 ± 0.04, 1.09 ± 0.01, 0.76 ± 0.08, and 0.88 ± 0.06; P = 0.0067). There was a positive correlation between telomere length and telomerase activity (r = 0.9090; P < 0.0001). Transcriptions of both hTERT and c-MYC were also significantly decreased in the same manner.

CONCLUSION: In the present cell culture model, WPE reduced telomere maintenance, which may provide a mechanistic link to the effect of walnuts on the viability of colon CSCs.

RevDate: 2019-02-20

Makino N, Maeda T, N Abe (2019)

Short Telomere Subtelomeric Hypomethylation is associated with Telomere Attrition in Elderly Diabetic Patients.

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

Telomere shortening is well known to be associated with the aging process and aging-associated diseases, including diabetes. The telomere length and subtelomeric methylation status in peripheral leucocytes (LTL) were compared in elderly type 2 diabetes patients (T2D) and diabetes free controls (C). The methylation status was analyzed the between of MspI-TRF lengths and HpaII-TRF lengths by using methylation-sensitive and -insensitive restriction enzyme isoschizomers, MspI and HpaII, respectively. Although the mean telomere lengths, MspI-TRF or HpaII-TRF, were no difference in patients between C and T2D. The percentage of fractionated densitometry showed that long and middle telomeres (>9.4kb, <9.9kb->4.4kb) were unaltered but short telomeres (<4.4kb) in T2D were increased compared with C. The methylation status revealed to subtelomeric hypomethylation in short telomeres of T2D. When some patients with T2D were treated with 3-hydroxy-3- methylglutaril coenzyme A (HMG-CoA) reductase inhibitors (statin), results seen in short telomere of T2D were not obtained and were not different from C. This suggested that altered subtelomeric hypomethylation may be associated with the accelerated telomere shortening in in elderly diabetic patients. Those results also means that the subtelomeric hypomethylation can be also influenced by the statin treatment in T2D.

RevDate: 2019-02-20

Turner K, Lynch C, Rouse H, et al (2019)

Direct Single-Cell Analysis of Human Polar Bodies and Cleavage-Stage Embryos Reveals No Evidence of the Telomere Theory of Reproductive Ageing in Relation to Aneuploidy Generation.

Cells, 8(2): pii:cells8020163.

Reproductive ageing in women, particularly after the age of 35, is associated with an exponential increase in the proportion of chromosomally abnormal oocytes produced. Several hypotheses have attempted to explain this observation, including the 'limited oocyte pool' hypothesis and the 'two-hit' hypothesis, the latter explaining that a depletion in oocyte quality with age results from the multiple opportune stages for errors to occur in meiosis. Recently however, the telomere theory of reproductive ageing in women has been proposed. This suggests that shortened telomeres in oocytes of women of advanced maternal age render oocytes unable to support fertilization and embryogenesis. Despite a credible rationale for the telomere theory of reproductive ageing in women, very few studies have assessed telomere length directly in human oocytes or preimplantation embryos. Therefore, we directly assessed relative telomere length in first polar bodies and blastomeres from cleavage stage (day 3) embryos. In both cell types we tested the hypothesis that (1) older women have shorter telomeres and (2) chromosomally abnormal (aneuploid) gametes/embryos have shorter telomeres. In all cases, we found no evidence of altered telomere length associated with age-related aneuploidy.

RevDate: 2019-02-19

Saretzki G (2018)

Telomeres, Telomerase and Ageing.

Sub-cellular biochemistry, 90:221-308.

Telomeres are specialised structures at the end of linear chromosomes. They consist of tandem repeats of the hexanucleotide sequence TTAGGG, as well as a protein complex called shelterin. Together, they form a protective loop structure against chromosome fusion and degradation. Shortening or damage to telomeres and opening of the loop induce an uncapped state that triggers a DNA damage response resulting in senescence or apoptosis.Average telomere length, usually measured in human blood lymphocytes, was thought to be a biomarker for ageing, survival and mortality. However, it becomes obvious that regulation of telomere length is very complex and involves multiple processes. For example, the "end replication problem" during DNA replication as well as oxidative stress are responsible for the shortening of telomeres. In contrast, telomerase activity can potentially counteract telomere shortening when it is able to access and interact with telomeres. However, while highly active during development and in cancer cells, the enzyme is down-regulated in most human somatic cells with a few exceptions such as human lymphocytes. In addition, telomeres can be transcribed, and the transcription products called TERRA are involved in telomere length regulation.Thus, telomere length and their integrity are regulated at many different levels, and we only start to understand this process under conditions of increased oxidative stress, inflammation and during diseases as well as the ageing process.This chapter aims to describe our current state of knowledge on telomeres and telomerase and their regulation in order to better understand their role for the ageing process.

RevDate: 2019-02-19

Darmishonnejad Z, Tavalaee M, Izadi T, et al (2018)

Evaluation of sperm telomere length in infertile men with failed/low fertilization after intracytoplasmic sperm injection.

Reproductive biomedicine online pii:S1472-6483(18)30651-5 [Epub ahead of print].

RESEARCH QUESTION: Telomeres are non-coding, repetitive DNA sequences (TTAGGG repeats) that play an important role in maintaining genome integrity. Unlike in somatic cells, telomere length in spermatozoa increases with male age and is considered as a molecular marker of sperm quality. The aetiology of failed fertilization following intracytoplasmic sperm injection (ICSI) is multifactorial; perhaps one of the reasons for this failure in these individuals is shortened sperm telomere length. This study therefore aimed to assess sperm telomere length in addition to DNA damage, lipid peroxidation and protamine deficiency in infertile men with previously failed/low fertilization post-ICSI.

DESIGN: Semen samples were obtained from infertile men with previous failed/low fertilization rates (n = 10). Chromatin integrity (chromomycin A3 staining and TUNEL assay), lipid peroxidation (BODIPY probe) and telomere length (real-time PCR) for semen samples from these men were compared with samples obtained from fertile individuals (n = 10).

RESULTS: The results showed significantly higher mean values for sperm DNA damage, lipid peroxidation and reduced telomere length in spermatozoa of infertile men with previous failed/low fertilization compared with fertile individuals (P < 0.05).

CONCLUSIONS: Failed/low fertilization rates could be related to oxidative stress resulting in short telomere length, and also increased sperm chromatin damage and lipid peroxidation. From literature sources, shortened telomere length may lead to detachment of chromosomes from the nuclear membrane, the consequences of which are defects in the process of spermatogenesis, pronuclei formation, and delayed or arrested cell cycle post-ICSI.

RevDate: 2019-02-18

Çevik B, Mançe-Çalışır Ö, Atbaşoğlu EC, et al (2019)

Psychometric liability to psychosis and childhood adversities are associated with shorter telomere length: A study on schizophrenia patients, unaffected siblings, and non-clinical controls.

Journal of psychiatric research, 111:169-185 pii:S0022-3956(18)31062-8 [Epub ahead of print].

Compared to the general population, individuals diagnosed with Schizophrenia (SCZ) experience a higher frequency and an earlier onset of chronic medical disorders, resulting in a reduction in life expectancy by an average of 15-25 years. Recently, it has been hypothesized that SCZ is a syndrome of accelerated aging. Childhood adversity was also associated with the pathogenesis and course of SCZ. Our hypothesis was that both SCZ patients and their unaffected siblings would have shorter telomere length (TL) compared to of non-clinical controls. Our additional goals were to determine (1) whether shorter TL correlates with intermediate phenotypes of SCZ (i.e. Psychosis-like symptoms and schizotypal traits); and (2) whether childhood adversities have a moderating role in TL shortening among SCZ and their unaffected siblings. To this end, SCZ patients (n = 100), their unaffected siblings (n = 100) and non-clinical controls (n = 100) were enrolled. The main variables were TL, measured by aTL-qPCR; psychotic-like and schizotypal symptoms, assessed by The Community Assessment of Psychic Experience (CAPE) and the Structured Interview for Schizotypy-Revised (SIS-R), respectively; and childhood adversities evaluated by the Childhood Experience of Care and Abuse (CECA)-Interview. Potentially relevant variables also included in the analyses were: Global Assessment of Functioning (GAF) scores, cognitive performance, and socio-demographic features. In contrast to our hypothesis patients had similar TL when compared to the non-clinical controls. Interestingly, unaffected siblings had longer TL compared to both patients and controls (p < 0.001). Independent from group status a negative correlation was observed between TL and psychotic-like symptoms as rated by the CAPE (p < 0.01). Childhood adversities, especially loneliness between ages 0 and 11 were also negatively associated with TL (p < 0.05). Our findings suggest that psychometric liability to psychosis and childhood adversities may be associated with shorter TL. Unaffected siblings had longer TL, suggesting the potential role of resilience on both the TL and the clinical presentation. These findings must be considered preliminary, calling for larger-scale replication efforts.

RevDate: 2019-02-18

Smith L, Luchini C, Demurtas J, et al (2019)


Ageing research reviews pii:S1568-1637(18)30323-4 [Epub ahead of print].

The aim of the present study was to map and grade evidence for the relationships between telomere length with a diverse range of health outcomes, using an umbrella review of systematic reviews with meta-analyses. We searched for meta-analyses of observational studies reporting on the association of telomere length with any health outcome (clinical disease outcomes and intermediate traits). For each association, random-effects summary effect size, 95% confidence interval (CI), and 95% prediction interval were calculated. To evaluate the credibility of the identified evidence, we assessed also heterogeneity, evidence for small-study effect and evidence for excess significance bias. Twenty-one relevant meta-analyses were identified reporting on 50 different outcomes and including a total of 326 observational studies. The level of evidence was high only for the association of short telomeres with higher risk of gastric cancer in the general population (relative risk, RR = 1.95, 95%CI: 1.68-2.26), and moderate for the association of shorter telomeres with diabetes or with Alzheimer's disease, even if limited to meta-analyses of case-control studies. There was weak evidence for twenty outcomes and not significant association for 27 health outcomes. The present umbrella review demonstrates that shorter telomere length may have an important role in incidence gastric cancer and, probably, diabetes and Alzheimer's disease. At the same time, conversely to general assumptions, it does not find strong evidence supporting the notion that shorter telomere length plays an important role in many health outcomes that have been studied thus far.

RevDate: 2019-02-18

Weeg N, Hershko Klement A, Haikin E, et al (2019)

The effect of maternal body mass index (BMI) and telomere function on in vitro fertilization (IVF) outcome: a preliminary cohort study.

Human fertility (Cambridge, England) [Epub ahead of print].

Telomeres are a specific base sequence of DNA, responsible for chromosome stability and DNA protection. We aimed to investigate the association between telomere systems and IVF outcomes according to patients' BMI. For all telomere characteristics, there was a distinct trend towards shorter telomeres and activation of telomere shortening compensatory mechanisms in the BMI group >25 kg/m2, reaching statistical significance for senescence only (r = 0.7, p value <0.01). There was a trend towards a relationship between telomere length and number of oocytes between telomere length and fertilization rate, but these did not reach a statistical significance. For pregnancy outcome, all telomere characteristics were better for the patients who achieved a pregnancy. While there is paucity of data in the literature concerning the association between telomere characteristics and infertility, telomeres might contribute to the association between obesity and sub-optimal IVF results.

RevDate: 2019-02-16

Brand T (2019)

Length doesn't matter-telomere damage triggers cellular senescence in the ageing heart.

The EMBO journal pii:embj.2019101571 [Epub ahead of print].

RevDate: 2019-02-16

Cao W, Li X, Zhang X, et al (2019)

No Causal Effect of Telomere Length on Ischemic Stroke and Its Subtypes: A Mendelian Randomization Study.

Cells, 8(2): pii:cells8020159.

BACKGROUND: Epidemiological studies observing inconsistent associations of telomere length (TL) with ischemic stroke (IS) are susceptible to bias according to reverse causation and residual confounding. We aimed to assess the causal association between TL, IS, and the subtypes of IS, including large artery stroke (LAS), small vessel stroke (SVS), and cardioembolic stroke (CES) by performing a series of two-sample Mendelian randomization (MR) approaches.

METHODS: Seven single nucleotide polymorphisms (SNPs) were involved as candidate instrumental variables (IVs), summarized from a genome-wide meta-analysis including 37,684 participants of European descent. We analyzed the largest ever genome-wide association studies of stroke in Europe from the MEGASTROKE collaboration with 40,585 stroke cases and 406,111 controls. The weighted median (WM), the penalized weighted median (PWM), the inverse variance weighted (IVW), the penalized inverse variance weighted (PIVW), the robust inverse variance weighted (RIVW), and the Mendelian randomization-Egger (MR-Egger) methods were conducted for the MR analysis to estimate a causal effect and detect the directional pleiotropy.

RESULTS: No significant association between genetically determined TL with overall IS, LAS, or CES were found (all p > 0.05). SVS was associated with TL by the RIVW method (odds ratio (OR) = 0.72, 95% confidence interval (CI): 0.54⁻0.97, p = 0.028), after excluding rs9420907, rs10936599, and rs2736100.

CONCLUSIONS: By a series of causal inference approaches using SNPs as IVs, no strong evidence to support the causal effect of shorter TL on IS and its subtypes were found.

RevDate: 2019-02-15

Lustig AJ (2019)

Towards the Mechanism of Yeast Telomere Dynamics.

Trends in cell biology pii:S0962-8924(19)30006-6 [Epub ahead of print].

A mechanistic understanding of the yeast telomere requires an integrated understanding of telomere chromatin structure (telosomes), telomeric origins of replications, telomere length homeostasis, and telosome epigenetics. Recent molecular and genetic studies of the yeast telosomal components Rap1, Rif1, and Rif2, the Mre11 complex, and Tel1ATM promise to increase our insight into the coordination between these processes. Here, an intricate relationship is proposed between these multiple components that has resulted in increased appreciation of the multiple levels of telomere length control and their differentiation from double-strand repair. The mre11A470 motif (A470-A482) alleles have also opened new avenues to the exploration of telosome structure and function.

RevDate: 2019-02-14

Eisenberg DTA (2019)

Paternal age at conception effects on offspring telomere length across species-What explains the variability?.

PLoS genetics, 15(2):e1007946 pii:PGENETICS-D-18-02305.

RevDate: 2019-02-14

Bauch C, Boonekamp JJ, Korsten P, et al (2019)

Epigenetic inheritance of telomere length in wild birds.

PLoS genetics, 15(2):e1007827 pii:PGENETICS-D-18-01652.

Telomere length (TL) predicts health and survival across taxa. Variation in TL between individuals is thought to be largely of genetic origin, but telomere inheritance is unusual, because zygotes already express a TL phenotype, the TL of the parental gametes. Offspring TL changes with paternal age in many species including humans, presumably through age-related TL changes in sperm, suggesting an epigenetic inheritance mechanism. However, present evidence is based on cross-sectional analyses, and age at reproduction is confounded with between-father variation in TL. Furthermore, the quantitative importance of epigenetic TL inheritance is unknown. Using longitudinal data of free-living jackdaws Corvus monedula, we show that erythrocyte TL of subsequent offspring decreases with parental age within individual fathers, but not mothers. By cross-fostering eggs, we confirmed the paternal age effect to be independent of paternal age dependent care. Epigenetic inheritance accounted for a minimum of 34% of the variance in offspring TL that was explained by paternal TL. This is a minimum estimate, because it ignores the epigenetic component in paternal TL variation and sperm TL heterogeneity within ejaculates. Our results indicate an important epigenetic component in the heritability of TL with potential consequences for offspring fitness prospects.

RevDate: 2019-02-14

Xiao J, Yuan Q, Zhang S, et al (2019)

The telomere length of peripheral blood cells is associated with the risk of ischemic stroke in Han population of northern China.

Medicine, 98(7):e14593.

BACKGROUND: Telomere length is closely related to the onset and prognosis of ischemic stroke. This study was to investigate the relationship between telomere length and the incidence of ischemic stroke in Han population of northern China.

METHODS: In the present study, 152 patients with ischemic stroke were selected as the case group, and 152 healthy persons were used as the control group. Detection of telomere length was done by real-time polymerase chain reaction after extraction of genomic DNA from peripheral venous blood.

RESULTS: Our results showed that the telomere length of the patients in the case group was significantly lower than that of the control group (Z = -11.843, P < .0001). Further analysis found that the telomere length of the control group was inversely correlated with age (r = -0.234, P = .004), and the telomere length and homocysteine (HCY) were inversely correlated in the case group (r = -0.176, P = .03), especially in women (r = -0.357, P = .024). Multivariate regression analysis showed that telomere length was a protective factor for ischemic stroke (odds ratio [OR] 95% confidence interval [95% CI] = 0.748 [0.681-0.823], β = -0.29, P < .0001). The receiver operating characteristic curve showed that telomere length was a good diagnostic biomarker of ischemic stroke (area under the curve: 0.894, sensitivity: 84.7%, specificity: 93.4%).

CONCLUSION: Our results indicate that shorter telomere length has some connection with the risk of ischemic stroke in the northern Chinese Han population. Telomere length might serve as a potential candidate biomarker for ischemic stroke. This requires a large sample to be further verified.

RevDate: 2019-02-14

Ye Y, Yang Z, J Lei (2019)

Stochastic Telomere Shortening and the Route to Limitless Replicative Potential.

Journal of computational biology : a journal of computational molecular cell biology [Epub ahead of print].

In human tissues, the replicative potential of stem cells is limited by the shortening of telomere, limitless replicative potential is a hallmark of cancer. Telomere length changes stochastically during cell division mainly due to the competition between the end replication problem and telomerase, short telomere can lead to replicative senescence and cell apoptosis. Here, we investigate how stochastic changes of telomere length in individual cells may affect the population dynamics of clonal growth. We established a computational model that couples telomerase-regulated stochastic telomere length changes with the replicative potential of clones. Model simulations reveal qualitative dependence of clone proliferation potential with activities of telomerase; mutations in cells to alter the activities of telomerase and its inhibitors can induce abnormal tissue growth and lead to limitless replicative potential.

RevDate: 2019-02-14

Wu Q, Han D, Zhang J, et al (2019)

Expression of telomere repeat binding factor 1 and TRF2 in Alzheimer's disease and correlation with clinical parameters.

Neurological research [Epub ahead of print].

OBJECTIVE: The objective of this study was to investigate the expression of serum telomere repeat binding factor 1 (TRF1) and TRF2 in patients with Alzheimer's disease (AD) and their correlation with clinicopathological features.

METHODS: Fifty AD subjects and 50 healthy controls were enrolled in this study. Enzyme-linked immunosorbent assay (ELISA) was used to determine the expression of TRF1 and TRF2 in the peripheral blood plasma. Correlation analysis was used to evaluate the correlation between the protein expression and AD clinical parameters.

RESULTS: The expression of TRF1 in peripheral blood serum of AD patients was significantly higher than that of the control group (t = 5.533, P < 0.01) and TRF2 was lower than the control group (t = 2.627, P = 0.010). The expression of TRF1 was positively correlated with the history of coronary heart disease (Spearman's r = 0.298,P = 0.035). The expression of TRF1 and TRF2 was positively correlated with age (Pearson's r1 = 0.830,P1 < 0.01;Pearson's r2 = 0.942,P2 < 0.01), BMI (Pearson's r1 = 0.791,P1 < 0.01;Pearson's r2 = 0.941,P2 < 0.01), Aβ42 (Pearson's r1 = 0.765,P1 < 0.01;Pearson's r2 = 0.926,P2 < 0.01) and Tau protein (Pearson's r1 = 0.648,P1 < 0.01;Pearson's r2 = 0.691,P2 < 0.01) in blood serum of AD patients. However, there was no significant difference between both proteins expression and the history of hypertension, diabetes or stroke.

CONCLUSION: TRF1 and TRF2 may be both specific to peripheral blood serum of AD, and may be related to the development of AD.

RevDate: 2019-02-14

Shay JW, WE Wright (2019)

Telomeres and telomerase: three decades of progress.

Nature reviews. Genetics pii:10.1038/s41576-019-0099-1 [Epub ahead of print].

Many recent advances have emerged in the telomere and telomerase fields. This Timeline article highlights the key advances that have expanded our views on the mechanistic underpinnings of telomeres and telomerase and their roles in ageing and disease. Three decades ago, the classic view was that telomeres protected the natural ends of linear chromosomes and that telomerase was a specific telomere-terminal transferase necessary for the replication of chromosome ends in single-celled organisms. While this concept is still correct, many diverse fields associated with telomeres and telomerase have substantially matured. These areas include the discovery of most of the key molecular components of telomerase, implications for limits to cellular replication, identification and characterization of human genetic disorders that result in premature telomere shortening, the concept that inhibiting telomerase might be a successful therapeutic strategy and roles for telomeres in regulating gene expression. We discuss progress in these areas and conclude with challenges and unanswered questions in the field.

RevDate: 2019-02-14

Antonini JM, Kodali V, Meighan TG, et al (2019)

Effect of Age, High-Fat Diet, and Rat Strain on Serum Biomarkers and Telomere Length and Global DNA Methylation in Peripheral Blood Mononuclear Cells.

Scientific reports, 9(1):1996 pii:10.1038/s41598-018-38192-0.

The objective of the current study was to determine if age, diet, and genetic disposition (animal strain) in an animal model had early effects on specific molecular markers in circulating peripheral blood mononuclear cells (PBMCs). Three strains [Sprague-Dawley (SD), Fischer 344 (F344), and Brown-Norway (BN)] of male rats were maintained on a high-fat (HF) or regular diet. Blood was collected at 4, 12, and 24 wk to assess chemistry and to recover PBMCs. Triglycerides and body weight gain increased at all time points in the HF diet group for each strain. Telomere length in PBMCs decreased in the HF diet group compared to the regular diet group up to 24 wk in all strains. Telomere length decreased in PBMCs at 24 wk compared to baseline in all strains, indicating an age-related effect. These findings highlight that diet and age cause changes in PBMCs recovered from different strains of rats. The next tier of studies will examine the contribution of an occupational exposure (e.g., welding fume inhalation) in combination with diet, age, and strain, to assess changes in the molecular responses of isolated PBMCs. In addition, studies involving lifestyle exposure (e.g., tobacco smoke) are in the planning stages and will assess the long-term effects of exposure in our animal model.

RevDate: 2019-02-12

Zhan Y, S Hägg (2019)

Telomere length and cardiovascular disease risk.

Current opinion in cardiology [Epub ahead of print].

PURPOSE OF REVIEW: Telomere length has been hypothesized as a putative biomarker for cardiovascular disease. However, the findings are mixed and shared confounding factors may explain these associations. The current review aims to summarize the recent literature on the role of telomere length in cardiovascular disease and give directions for future potential as a predictive biomarker.

RECENT FINDINGS: In this review, we outline the biology of telomeres as a biomarker of aging through its shortening capacity across the life course. Recent epidemiological evidence for its associations with cardiovascular risk factors and disease is discussed. Then we highlight the possible causal role of telomeres in coronary heart disease and summarize the potential biological mechanisms and pathways known.

SUMMARY: The current research and results presented on telomere length may implicate that short telomeres are causal risk factors for cardiovascular disease, partially through insulin-mediated pathways. Nevertheless, further studies with refined quantification methods and larger populations are needed to clarify the added role of telomere length in predicting future risks of cardiovascular disease on top of existing risk biomarkers, and whether it may be amenable for intervention.

RevDate: 2019-02-12

Shishkin SS, Kovalev LI, Pashintseva NV, et al (2019)

Heterogeneous Nuclear Ribonucleoproteins Involved in the Functioning of Telomeres in Malignant Cells.

International journal of molecular sciences, 20(3): pii:ijms20030745.

Heterogeneous nuclear ribonucleoproteins (hnRNPs) are structurally and functionally distinct proteins containing specific domains and motifs that enable the proteins to bind certain nucleotide sequences, particularly those found in human telomeres. In human malignant cells (HMCs), hnRNP-A1-the most studied hnRNP-is an abundant multifunctional protein that interacts with telomeric DNA and affects telomerase function. In addition, it is believed that other hnRNPs in HMCs may also be involved in the maintenance of telomere length. Accordingly, these proteins are considered possible participants in the processes associated with HMC immortalization. In our review, we discuss the results of studies on different hnRNPs that may be crucial to solving molecular oncological problems and relevant to further investigations of these proteins in HMCs.

RevDate: 2019-02-11

Jackson-Cook C (2019)

A hypothesis: Could telomere length and/or epigenetic alterations contribute to infertility in females with Turner syndrome?.

American journal of medical genetics. Part C, Seminars in medical genetics [Epub ahead of print].

One of the traits most consistently seen in females with Turner syndrome is premature ovarian insufficiency (POI). The biological mechanisms underlying the germ cell atresia that leads to infertility in most women with Turner syndrome are unclear. Given that telomeres are important for proper chromosomal pairing and other early steps in meiosis and oogenesis, one can conjecture that perturbations in telomere length and/or function might contribute to the POI associated with Turner syndrome. Also, one can speculate that epigenetic modifications that arise in response to asynapsis, as well as the resetting of the epigenome during embryogenesis, could contribute to monosomy X-related germ cell atresia. Moreover, errors in recombination-based DNA repair might contribute to the failure of cells lacking all, or a portion of, a second sex chromosome to successfully complete oogenesis. This article presents a review of the extant literature related to telomere length and/or epigenetic patterns associated with POI in females with a monosomy X complement (in humans and animal models). A goal of this review is to inspire researchers to use new technological advances to better characterize the components of the biological cascade leading to early germ cell loss in females with Turner syndrome.

RevDate: 2019-02-10

Slykerman RF, Joglekar MV, Hardikar AA, et al (2019)

Maternal stress during pregnancy and small for gestational age birthweight are not associated with telomere length at 11 years of age.

Gene pii:S0378-1119(19)30061-7 [Epub ahead of print].

BACKGROUND: Previous studies indicate that low birth weight and exposure to maternal stress during pregnancy may result in shortened telomeres in infants. Shorter telomere length has in turn been linked with accelerated ageing and with age-related diseases. This study aimed to investigate the association between pregnancy and birth factors and relative telomere length in offspring at 11 years of age.

METHODS: Participants were aged 11 years enrolled in the Auckland Birthweight Collaborative Study at birth (n = 380). Half of the children were born small for gestational age (SGA = birthweight ≤ 10th percentile) and half were appropriate for gestational age (AGA = birthweight > 10th percentile). Maternal stress during pregnancy was assessed using the Perceived Stress Scale. Relative leukocyte telomere length (RTL) in leukocytes was measured at 11 years of age using quantitative real-time PCR.

RESULTS: RTL was normally distributed (mean = 3.78, SD = 1.05). There were no significant associations between RTL at age 11 years and birthweight, sex, maternal smoking, maternal stress during pregnancy or maternal pre-pregnancy body mass index.

CONCLUSION: At age 11 years, RTL did not differ between children by birthweight or pregnancy-related stressors. Further telomere-related studies in newborns, children and adolescents are merited to increase knowledge of potential telomere modulating factors.

RevDate: 2019-02-09

Fali T, Papagno L, Bayard C, et al (2019)

New Insights into Lymphocyte Differentiation and Aging from Telomere Length and Telomerase Activity Measurements.

Journal of immunology (Baltimore, Md. : 1950) pii:jimmunol.1801475 [Epub ahead of print].

αβ CD8+, γδ, and NK lymphocytes are fundamental effector cells against viruses and tumors. These cells can be divided into multiple subsets according to their phenotype. Based on progressive telomere attrition from naive to late effector memory cells, human CD8+ T cell subsets have been positioned along a pathway of differentiation, which is also considered as a process of lymphocyte aging or senescence. A similar categorization has not been clearly established for γδ and NK cell populations. Moreover, the distinction between the aging of these populations due to cellular differentiation or due to the chronological age of the donor has not been formally considered. In this study, we performed systematic measurements of telomere length and telomerase activity in human αβ CD8+, γδ, and NK lymphocytes based on subset division and across age to address these points and better understand the dichotomy between differentiation and temporal aging. This approach enables us to position phenotypically distinct γδ or NK subsets along a putative pathway of differentiation, such as for CD8+ T cells. Moreover, our data show that both cellular differentiation and donor aging have profound but independent effects on telomere length and telomerase activity of lymphocyte subpopulations, implying distinct mechanisms and consequences on the immune system.

RevDate: 2019-02-09

Anderson R, Lagnado A, Maggiorani D, et al (2019)

Length-independent telomere damage drives post-mitotic cardiomyocyte senescence.

The EMBO journal pii:embj.2018100492 [Epub ahead of print].

Ageing is the biggest risk factor for cardiovascular disease. Cellular senescence, a process driven in part by telomere shortening, has been implicated in age-related tissue dysfunction. Here, we address the question of how senescence is induced in rarely dividing/post-mitotic cardiomyocytes and investigate whether clearance of senescent cells attenuates age-related cardiac dysfunction. During ageing, human and murine cardiomyocytes acquire a senescent-like phenotype characterised by persistent DNA damage at telomere regions that can be driven by mitochondrial dysfunction and crucially can occur independently of cell division and telomere length. Length-independent telomere damage in cardiomyocytes activates the classical senescence-inducing pathways, p21CIP and p16INK4a, and results in a non-canonical senescence-associated secretory phenotype, which is pro-fibrotic and pro-hypertrophic. Pharmacological or genetic clearance of senescent cells in mice alleviates detrimental features of cardiac ageing, including myocardial hypertrophy and fibrosis. Our data describe a mechanism by which senescence can occur and contribute to age-related myocardial dysfunction and in the wider setting to ageing in post-mitotic tissues.

RevDate: 2019-02-09

Hwang IP, Mailliet P, Hossard V, et al (2019)

Investigating the Effect of Mono- and Dimeric 360A G-Quadruplex Ligands on Telomere Stability by Single Telomere Length Analysis (STELA).

Molecules (Basel, Switzerland), 24(3): pii:molecules24030577.

Telomeres are nucleoprotein structures that cap and protect the natural ends of chromosomes. Telomeric DNA G-rich strands can form G-quadruplex (or G4) structures. Ligands that bind to and stabilize G4 structures can lead to telomere dysfunctions by displacing shelterin proteins and/or by interfering with the replication of telomeres. We previously reported that two pyridine dicarboxamide G4 ligands, 360A and its dimeric analogue (360A)2A, were able to displace in vitro hRPA (a single-stranded DNA-binding protein of the replication machinery) from telomeric DNA by stabilizing the G4 structures. In this paper, we perform for the first time single telomere length analysis (STELA) to investigate the effect of G4 ligands on telomere length and stability. We used the unique ability of STELA to reveal the full spectrum of telomere lengths at a chromosome terminus in cancer cells treated with 360A and (360A)2A. Upon treatment with these ligands, we readily detected an increase of ultrashort telomeres, whose lengths are significantly shorter than the mean telomere length, and that could not have been detected by other methods.

RevDate: 2019-02-08

Shoeb M, Kodali VK, Farris BY, et al (2017)

Oxidative Stress, DNA Methylation, and Telomere Length Changes in Peripheral Blood Mononuclear Cells after Pulmonary Exposure to Metal-Rich Welding Nanoparticles.

NanoImpact, 5:61-69.

Welding fume is a complex mixture of different potentially cytotoxic and genotoxic metals, such as chromium (Cr), manganese (Mn), nickel (Ni), and iron (Fe). Documented health effects have been observed in workers exposed to welding fume. The objective of the study was to use an animal model to identify potential biomarkers of epigenetic changes (e.g., changes in telomere length, DNA methylation) in isolated peripheral blood mononuclear cells (PBMCs) after exposure to different welding fumes. Male Sprague-Dawley rats were exposed by intratracheal instillation (ITI) of 2.0 mg/rat of gas metal arc-mild steel (GMA-MS) or manual metal arc-stainless steel (MMA-SS) welding fume. Vehicle controls received sterile saline by ITI. At 4 h, 14 h, 1 d, 3 d, 10 d, and 30 d, bronchoalveolar lavage (BAL) was performed to assess lung inflammation. Whole blood was collected, and PBMCs were isolated. Dihydroethidium (DHE) fluorescence and 4-hydroxylnonenal protein adduct (P-HNE) formation were measured in PBMCs to assess reactive oxygen species (ROS) production. DNA alterations in PBMCs were determined by evaluating changes in DNA methylation and telomere length. Metal composition of the two fumes was different: MMA-SS (41 % Fe, 29 % Cr, 17 % Mn, 3 % Ni) versus GMA-MS (85 % Fe, 14 % Mn). The more soluble and chemically complex MMA-SS sample induced a more persistent and greater inflammatory response compared to the other groups. Also, oxidative stress markers increased at 24 h in the PBMCs recovered from the MMA-SS group compared to other group. No significant differences were observed when comparing DNA methylation between the welding fume and control groups at any of the time points, whereas the MMA-SS sample significantly increased telomere length at 1 and 30 d after a single exposure compared to the other groups. These findings suggest that genotoxic metals in MMA-SS fume (e.g., Cr and Ni), that are absent in the GMA-MS fume, may enhance lung toxicity, as well as induce markers of oxidative stress and increase telomere length in PBMCs. Importantly, the measurement of telomere length in cells isolated from peripheral blood may serve as a potential biomarker of response in the assessment of toxicity associated with welding fumes.

RevDate: 2019-02-08

Abrahin O, Cortinhas-Alves EA, Vieira RP, et al (2019)

Elite athletes have longer telomeres than sedentary subjects: A meta-analysis.

Experimental gerontology pii:S0531-5565(18)30645-4 [Epub ahead of print].

The aim of this meta-analysis was to investigate the effects of high levels of physical activity (in elite athletes) and sedentary lifestyle on telomere length. Our meta-analysis was carried out using the following electronic databases: PubMed, Cochrane Library, LILACS, Science Direct and EBSCO. After study selection, nine articles were included in our meta-analysis. All of the included subjects were elite athletes (with experience in national or international competitions) or sedentary subjects, which served as the control group. The analysis showed that elite athletes (n = 306) had longer telomeres (P = 0.001) compared with the control group (n = 322). The difference in the standardized means was 0.91 (95% CI = 0.43-1.33; I2 83.4% P value for heterogeneity = 0.001), favoring the athlete group. The analysis of the funnel plot did not detect any risk of publication bias in the studies that reported differences in means. Our results suggest that high level chronic physical training may provide protective effects on telomere length.

RevDate: 2019-02-08

Avogaro L, Oss Pegorar C, Bettin N, et al (2019)

Generation of Cancer Cell Clones to Visualize Telomeric Repeat-containing RNA TERRA Expressed from a Single Telomere in Living Cells.

Journal of visualized experiments : JoVE.

Telomeres are transcribed, giving rise to telomeric repeat-containing long noncoding RNAs (TERRA), which have been proposed to play important roles in telomere biology, including heterochromatin formation and telomere length homeostasis. Recent findings revealed that TERRA molecules also interact with internal chromosomal regions to regulate gene expression in mouse embryonic stem (ES) cells. In line with this evidence, RNA fluorescence in situ hybridization (RNA-FISH) analyses have shown that only a subset of TERRA transcripts localize at chromosome ends. A better understanding of the dynamics of TERRA molecules will help define their function and mechanisms of action. Here, we describe a method to label and visualize single-telomere TERRA transcripts in cancer cells using the MS2-GFP system. To this aim, we present a protocol to generate stable clones, using the AGS human stomach cancer cell line, containing MS2 sequences integrated at a single subtelomere. Transcription of TERRA from the MS2-tagged telomere results in the expression of MS2-tagged TERRA molecules that are visualized by live-cell fluorescence microscopy upon co-expression of a MS2 RNA-binding protein fused to GFP (MS2-GFP). This approach enables researchers to study the dynamics of single-telomere TERRA molecules in cancer cells, and it can be applied to other cell lines.

RevDate: 2019-02-06

Dixit S, Whooley MA, Vittinghoff E, et al (2019)

Alcohol consumption and leukocyte telomere length.

Scientific reports, 9(1):1404 pii:10.1038/s41598-019-38904-0.

The relationship between alcohol consumption and mortality generally exhibits a U-shaped curve. The longevity observed with moderate alcohol consumption may be explained by other confounding factors, and, if such a relationship is present, the mechanism is not well understood. Indeed, the optimal amount of alcohol consumption for health has yet to be determined. Leukocyte telomere length is an emerging quantifiable marker of biological age and health, and a shorter telomere length is a predictor of increased mortality. Because leukocyte telomere length is a quantifiable and objectively measurable biomarker of aging, we sought to identify the amount of alcohol consumption associated with the longest telomere length and least telomere length attrition. Among over 2,000 participants from two distinct cohort studies, we found no pattern of alcohol consumption that was associated with longer telomere length or less telomere length attrition over time. Binge drinking may reduce telomere length. Using telomere length as a marker of age and health, these data fail to demonstrate any benefits of alcohol consumption, even when consumed in moderation.

RevDate: 2019-02-06

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

Prenatal cadmium exposure is associated with shorter leukocyte telomere length in Chinese newborns.

BMC medicine, 17(1):27 pii:10.1186/s12916-019-1262-4.

BACKGROUND: Newborn telomere length (TL) is considered a potential marker for future disease and lifelong health, but few epidemiological studies have examined the determinants of TL in early life. The study aim was to investigate whether there is an association between prenatal cadmium exposure and relative cord blood TL in Chinese newborns.

METHODS: Participants were 410 mother-newborn pairs drawn from a prospective birth cohort study conducted in Wuhan, China, between November 2013 and March 2015. Urine samples were collected from pregnant women during their period of institutional delivery. Urinary cadmium concentrations were measured by inductively coupled plasma mass spectrometry. The real-time quantitative polymerase chain reaction detection was used to measure relative TL using genomic DNA isolated from umbilical cord blood leukocytes. Multivariate linear regression models were used to estimate the effect of prenatal urinary cadmium concentration on relative cord blood TL.

RESULTS: The geometric mean of maternal urinary cadmium concentration was 0.68 μg/g creatinine. In the multivariate-adjusted linear regression model, per doubling of maternal urinary cadmium concentration was associated with 6.83% (95% CI - 11.44%, - 1.97%; P = 0.006) shorter relative cord blood TL. Stratified analyses indicated that the inverse association between prenatal urinary cadmium and newborn relative TL was more pronounced among female infants and mothers < 29 years, while there were no significant effect modification according to infant sex (P for interaction = 0.907) and maternal age (P for interaction = 0.797).

CONCLUSIONS: The findings indicated that increased maternal urinary cadmium was associated with shortened relative cord blood TL. The results provide more evidence of the negative effects of environmental cadmium exposure and suggest that accelerated aging or cadmium-related diseases may begin in early life.

RevDate: 2019-02-05

Luo X, Sturgis EM, Yang Z, et al (2019)

Lymphocyte Telomere Length Predicts Clinical Outcomes of HPV-Positive Oropharyngeal Cancer Patients after Definitive Radiotherapy.

Carcinogenesis pii:5306965 [Epub ahead of print].

Since lymphocyte telomere length (LTL) plays critical roles in the maintenance of genomic stability and integrity, LTL thus may influence the etiology and prognosis of squamous cell carcinoma of the oropharynx (SCCOP). However, given the association between LTL and risk of HPV-associated SCCOP and between LTL and tumor HPV status of SCCOP, we hypothesized that LTL is associated with SCCOP prognosis, particularly in HPV-positive patients after definitive radiotherapy. LTL and tumor HPV type 16 (HPV16) status were determined in 564 incident SCCOP patients before radiotherapy or chemoradiation. Both univariate and multivariable Cox regression analyses were performed to estimate the association between LTL and prognosis. Eighty-five percent of the patients had HPV16-positive tumors. Patients with shorter telomeres had significantly better overall, disease-specific, and disease-free survival than did those with longer telomeres (log-rank p < 0.001). Moreover, patients with shorter telomeres had significantly lower risk of death overall (hazard ratio [HR], 0.2; 95% confidence interval [CI], 0.1-0.4), death due to SCCOP (HR, 0.2; 95% CI, 0.1-0.4), and SCCOP recurrence (HR, 0.3; 95% CI, 0.2-0.5) after adjusting for other important prognostic confounders. Finally, we found more pronounced effects of LTL on survival in HPV16-positive SCCOP patients after stratified analysis according to tumor HPV status. These findings indicate that LTL plays a significant role in the survival of patients with SCCOP, especially HPV16-positive patients who undergo definitive radiotherapy. Therefore, pretreatment LTL may be an independent prognostic biomarker for HPV16-positive SCCOP. Prospective studies with larger sample sizes are needed to confirm these findings.

RevDate: 2019-02-05

Dickinson SL, Golzarri-Arroyo L, Brown AW, et al (2019)

Change in study randomization allocation needs to be included in statistical analysis: comment on 'Randomized controlled trial of weight loss versus usual care on telomere length in women with breast cancer: the lifestyle, exercise, and nutrition (LEAN) study'.

RevDate: 2019-02-05

Mizuno Y, Konishi S, Imai H, et al (2019)

Cadmium Exposure and Blood Telomere Length in Female University Students in Japan.

Biological trace element research pii:10.1007/s12011-019-1656-3 [Epub ahead of print].

Cadmium is a toxic metal found ubiquitously throughout the world. Our study evaluated whether cadmium exposure was associated with telomere length in 73 female university students. Determination of telomere length was performed by quantitative polymerase chain reaction using DNA in blood. Urinary cadmium concentration was measured by inductively coupled plasma mass spectrometry. The students' physiological attributes and lifestyle were surveyed by means of a self-administered questionnaire. The geometric mean of urinary cadmium concentration was 0.312 μg/g creatinine, which was lower than the levels previously reported for Japan. Urinary cadmium concentration was not significantly associated with telomere length, though the exposure level of the present subjects was similar to that of previous study subjects which found significantly negative associations. It is possible that other factors affected telomere length in this study population.

RevDate: 2019-02-05

Wang Y, Chen Y, Chen J, et al (2019)

The meiotic TERB1-TERB2-MAJIN complex tethers telomeres to the nuclear envelope.

Nature communications, 10(1):564 pii:10.1038/s41467-019-08437-1.

During meiotic prophase I, telomeres attach to and move on the nuclear envelope (NE), regulating chromosome movement to promote homologous pairing. Meiosis-specific proteins TERB1, TERB2 and MAJIN play a key role in this process. Here, we report the crystal structures of human TERB1-TERB2 and TERB2-MAJIN subcomplexes. Specific disruption of the TERB1-TERB2 or the TERB2-MAJIN interaction in the mouse Terb2 gene abolishes the telomere attachment to the NE and causes aberrant homologous pairing and disordered synapsis. In addition, depletion of SUN1 also partially disrupts the telomere-NE connection. We propose that the telomere-TRF1-TERB1-TERB2-MAJIN-NE interaction network and the telomere-LINC complex connection are likely two separate but cooperative pathways to stably recruit telomeres to the NE in meiosis prophase I. Our work provides a molecular model of the connection between telomeres and the NE and reveals the correlation between aberrant synapsis and the defective telomere attachment to the NE.

RevDate: 2019-02-05

Cao DW, Han WB, He JS, et al (2018)

[Tea polyphenols delays human glomerular mesangial cells senescence induced by high glucose via regulating STAT3/miR-126/telomere signaling pathway activation].

Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica, 43(23):4678-4684.

The aim of this paper was to explore the effects and possible mechanisms in vitro of tea polyphenols (TP) delaying human glomerular mesangial cells (HGMCs) senescence induced by high glucose (HG). HGMCs were cultured in vitro and divided into the normal group (N, 5.5 mmol·L⁻¹ glucose), the mannitol group(MNT, 5.5 mmol·L⁻¹ glucose plus 24.5 mmol·L⁻¹ mannitol), the high dose of D-glucose group (HG, 30 mmol·L⁻¹ glucose), the low dose of TP group (L-TP, 30 mmol·L⁻¹ glucose plus 5 mg·L⁻¹ TP) and the high dose of TP group (H-TP, 30 mmol·L⁻¹ glucose plus 20 mg·L⁻¹ TP), which were cultured in 5% CO₂ at 37 °C, respectively. Firstly, the effects of TP on the cell morphology of HGMCs were observed after 72 h-intervention. Secondly, the cell cycle, the positive rate of senescence-associated-β-galactosidase (SA-β-gal) staining and the telomere length were detected, respectively. Finally, the protein expressions of p53, p21 and Rb in the p53-p21-Rb signaling pathway were investigated, respectively. And the expressions of p-STAT3 and miR-126 were examined severally. The results indicated that HG not only arrested the cell cycle in G₁ phase but also increased the positive rate of SA-β-gal staining, and shortened the telomere length. HG led to the protein over-expressions of p53, p21 and Rb and HGMCs senescence by activating the p53-p21-Rb signaling pathway. In addition, L-TP delayed HGMCs senescence by improving the cell cycle G₁ arrest, reducing SA-β-gal staining positive rate and lengthening the telomere length. L-TP reduced the protein over-expressions of p53, P21 and Rb induced by HG and inhibited the telomere-p53-p21-Rb signaling pathway. Moreover, the expression of p-STAT3 was increased and the expression of miR-126 was decreased in HGMCs induced by HG. L-TP reduced the expression of p-STAT3 and increased the expression of miR-126 in HGMCs. In conclusion, HG could induce HGMCs senescence by activating the telomere-p53-p21-Rb signaling pathway in vitro. L-TP could delay HGMCs senescence through regulating STAT3/miR-126 expressions and inhibiting the telomere-p53-p21-Rb signaling pathway activation. These findings could provide the effective interventions in clinic for preventing and treating renal cell senescence in diabetic kidney disease.

RevDate: 2019-02-04

McKenna MJ, Robinson E, Taylor L, et al (2019)

Chromosome Translocations, Inversions and Telomere Length for Retrospective Biodosimetry on Exposed U.S. Atomic Veterans.

Radiation research [Epub ahead of print].

It is now approaching six decades since U.S. nuclear testing was conducted in the Pacific islands, exposing military personnel to varying levels of ionizing radiation. Actual doses are not well-established, as film badges in the 1950s had many limitations. We sought a means of independently assessing dose for comparison with historical film badge records and dose reconstruction conducted in parallel. For the purpose of quantitative retrospective biodosimetry, peripheral blood samples from 12 exposed veterans and 12 age-matched (>80 years) veteran controls were collected and evaluated for radiation-induced chromosome damage utilizing directional genomic hybridization (dGH), a cytogenomics-based methodology that facilitates simultaneous detection of translocations and inversions. Standard calibration curves were constructed from six male volunteers in their mid-20s to reflect the age range of the veterans at time of exposure. Doses were estimated for each veteran using translocation and inversion rates independently; however, combining them by a weighted-average generally improved the accuracy of dose estimations. Various confounding factors were also evaluated for potential effects on chromosome aberration frequencies. Perhaps not surprisingly, smoking and age-associated increases in background frequencies of inversions were observed. Telomere length was also measured, and inverse relationships with both age and combined weighted dose estimates were observed. Interestingly, smokers in the non-exposed control veteran cohort displayed similar telomere lengths as those in the never-smoker exposed veteran group, suggesting that chronic smoking had as much effect on telomere length as a single exposure to radioactive fallout. Taken together, we find that our approach of combined chromosome aberration-based retrospective biodosimetry provided reliable dose estimation capability, particularly on a group average basis, for exposures above statistical detection limits.

RevDate: 2019-02-03

Chen X, Zeng C, Gong C, et al (2019)

Associations between early life parent-child separation and shortened telomere length and psychopathological outcomes during adolescence.

Psychoneuroendocrinology, 103:195-202 pii:S0306-4530(18)31234-4 [Epub ahead of print].

BACKGROUND: Given the ethical limitations of exposing children to experimentally manipulated adverse experiences, evidence of the effects of parent-child separation on subsequent psychopathology are based mostly on animal studies. Left-behind children phenomenon resulting from rural-urban mobility in China offers unique "natural experiments" to explore the long-term physical and mental health consequences of parent-child separation in childhood.

OBJECTIVE: To test the associations between parent-child separation with telomere length (TL) and psychopathology during adolescence.

METHOD: A total of 710 adolescents (age: M = 16.86, SD = 1.52) were recruited from local schools in rural area of Fuyang, one of the top inland areas for outward migration in Anhui province, China. Parent-child separation was collected through face to face interview. The MacArthur Health & Behavior Questionnaire (HBQ) was used to assess internalizing and externalizing symptoms. Quantitative polymerase chain reaction was used to measure buccal TL.

RESULTS: Nearly 60% (399/695) of the participants experienced separation from both parents. Childhood or persistent separation from parents was associated with increased internalizing symptoms (childhood: β = 0.13, 95% CI: 0.02, 0.23; persistent: β = 0.23, 95% CI: 0.14, 0.31), increased externalizing symptoms (childhood: β = 0.17, 95% CI: 0.03, 0.32; persistent: β = 0.23, 95% CI: 0.10, 0.35) and shorter telomere length (childhood: β = -0.16, 95% CI: -0.26, -0.05; persistent: β = -0.13, 95% CI: -0.22, -0.03). Shortened TL was estimated to explain 15.2% and 12.7% of the total effect of separation on internalizing and externalizing symptoms, while internalizing and externalizing symptoms explained 23.4% and 12.3% of the effect of separation on shortened TL.

CONCLUSION: Childhood and persistent parent-child separation, as experienced by rural left-behind children in China, associates with increased vulnerability for psychopathological symptoms and makers of cellular aging. The challenge for future research is to determine whether short telomere length is in fact a long-term consequence or an underlying vulnerability factor for future mental disorders.

RevDate: 2019-02-03

Rej PH, Tennyson RL, Lee NR, et al (2019)

Years of caregiving for chronically ill and disabled family members is not associated with telomere length in the Philippines.

Psychoneuroendocrinology, 103:188-194 pii:S0306-4530(18)31104-1 [Epub ahead of print].

BACKGROUND: Caring for chronically disabled family members is a stressful experience. In turn, psychosocial stress is linked to premature aging. Telomere length (TL) is a plastic genetic trait that is a biomarker of aging, and a possible mechanism linking psychosocial stress and accelerated aging.

METHODS: TL was measured using qPCR method from blood samples in 1233 Filipino adults from Cebu, Philippines. Caregiving was measured as chronicity of care, or the sum total number of years an individual was the primary caregiver for any household member with a chronic illness or disability. Linear regression models were used to test for associations between chronicity of care and TL. Interaction terms were used to test whether or not the association between chronicity of care and TL differed by sex, age, and relationship to the caregiver. Specific statistical designs were publicly pre-registered before analysis began.

RESULTS: Chronicity of care was not associated with TL. Neither did we find any evidence for caregiving varying in its effect on TL by caregiver sex, age, or relationship to the chronically ill/disabled.

CONCLUSIONS: We found no evidence of an association between chronicity of care and TL. This result coupled with a recent study of a similarly sized cohort suggests that previous significant results linking caregiving and TL may be due to very particular types of caregiving populations or are possibly artifacts of small sample sizes.

RevDate: 2019-02-02

Shamim Nassrally M, Lau A, Wise K, et al (2019)

Cell cycle arrest in replicative senescence is not an immediate consequence of telomere dysfunction.

Mechanisms of ageing and development pii:S0047-6374(18)30091-5 [Epub ahead of print].

In replicative senescence, cells with critically-short telomeres activate a DNA-damage response leading to cell-cycle arrest, while those without telomere dysfunction would be expected to cycle normally. However, population growth declines more gradually than such a simple binary switch between cycling and non-cycling states would predict. We show here that late-passage cultures of human fibroblasts are not a simple mixture of cycling and non-cycling cells. Rather, although some cells had short cycle times comparable to those of younger cells, others continued to divide but with greatly extended cycle times, indicating a more-gradual approach to permanent arrest. Remarkably, in late passage cells, the majority showed prominent DNA-damage foci positive for 53BP1, yet many continued to divide. Evidently, the DNA-damage-response elicited by critically-short telomeres is not initially strong enough for complete cell-cycle arrest. A similar continuation of the cell cycle in the face of an active DNA-damage response was also seen in cells treated with a low dose of doxorubicin sufficient to produce multiple 53BP1 foci in all nuclei. Cell cycle checkpoint engagement in response to DNA damage is thus weaker than generally supposed, explaining why an accumulation of dysfunctional telomeres is needed before marked cell cycle elongation or permanent arrest is achieved.

RevDate: 2019-02-02

Okamoto K, H Seimiya (2019)

Revisiting Telomere Shortening in Cancer.

Cells, 8(2): pii:cells8020107.

Telomeres, the protective structures of chromosome ends are gradually shortened by each cell division, eventually leading to senescence or apoptosis. Cancer cells maintain the telomere length for unlimited growth by telomerase reactivation or a recombination-based mechanism. Recent genome-wide analyses have unveiled genetic and epigenetic alterations of the telomere maintenance machinery in cancer. While telomerase inhibition reveals that longer telomeres are more advantageous for cell survival, cancer cells often have paradoxically shorter telomeres compared with those found in the normal tissues. In this review, we summarize the latest knowledge about telomere length alterations in cancer and revisit its rationality. Finally, we discuss the potential utility of telomere length as a prognostic biomarker.

RevDate: 2019-02-01

Huang Y, Yim OS, Lai PS, et al (2019)

Successful aging, cognitive function, socioeconomic status, and leukocyte telomere length.

Psychoneuroendocrinology, 103:180-187 pii:S0306-4530(18)30721-2 [Epub ahead of print].

In a rapidly greying world, the notion that some individuals maintain successful aging trajectories, viz. high physical, cognitive, emotional, and social functioning in older age, is increasingly germane. Biomarkers of such successful aging are increasingly sought. Leukocyte telomere length (LTL), an emerging yardstick of cellular aging that is influenced by but distinct from chronological age, may also be associated to successful aging. Furthermore, given that socio-economic status (SES) influences successful aging trajectories, socioeconomic status may also moderate the association between chronological age and LTL. The goals of this study are to examine 1) whether successful aging is associated with LTL; 2) whether successful aging accounts for age-related LTL and 3) whether SES moderates the effect of age on LTL. Singaporean Chinese (n = 353) aged 65-80 completed a multidimensional assessment of successful aging and provided blood samples for LTL analysis. Results show that LTL negatively correlates with chronological age and positively correlates with successful aging. Successful aging mediates the association between chronological age and LTL. Moderated mediation analyses show that lower SES is associated with stronger negative associations of chronological age with successful aging and LTL. Moreover, the cognitive functioning dimension of successful aging is uniquely associated with LTL and its association with chronological age is moderated by SES. This study provides evidence that among older Singaporean Chinese with lower SES, declines in successful aging and in cognitive functioning are linked to age-related LTL shortening and hence to accelerated aging at the cellular level.

RevDate: 2019-01-31

Sudyka J, Podmokła E, Drobniak SM, et al (2019)

Sex-specific effects of parasites on telomere dynamics in a short-lived passerine-the blue tit.

Die Naturwissenschaften, 106(1-2):6 pii:10.1007/s00114-019-1601-5.

Parasitic infections potentially drive host's life-histories since they can have detrimental effects on host's fitness. Telomere dynamics is a candidate mechanism to underlie life-history trade-offs and as such may correlate with observed fitness reduction in infected animals. We examined the relationship of chronic infection with two genera of haemosporidians causing avian malaria and malaria-like disease with host's telomere length (TL) in a longitudinal study of free-ranging blue tits. The observed overall infection prevalence was 80% and increased with age, constituting a potentially serious selective pressure in our population. We found longer telomeres in individuals infected with a parasite causing lesser blood pathologies i.e. Haemoproteus compared to Plasmodium genus, but this only held true among males. Female TL was independent of the infection type. Our results indicate that parasitic infections could bring about other types of costs to females than to males with respect to TL. Additionally, we detected linear telomere loss with age, however a random regression analysis did not confirm significant heterogeneity in TL of first breeders and telomere shortening rates in further life.

RevDate: 2019-01-31

Norris K, Hillmen P, Rawstron A, et al (2019)

Telomere length predicts for outcome to FCR chemotherapy in CLL.

Leukemia pii:10.1038/s41375-019-0389-9 [Epub ahead of print].

We have previously shown that dividing patients with CLL into those with telomeres inside the fusogenic range (TL-IFR) and outside the fusogenic range (TL-OFR) is powerful prognostic tool. Here, we used a high-throughput version of the assay (HT-STELA) to establish whether telomere length could predict for outcome to fludarabine, cyclophosphamide, rituximab (FCR)-based treatment using samples collected from two concurrent phase II studies, ARCTIC and ADMIRE (n = 260). In univariate analysis, patients with TL-IFR had reduced progression-free survival (PFS) (P < 0.0001; HR = 2.17) and shorter overall survival (OS) (P = 0.0002; HR = 2.44). Bifurcation of the IGHV-mutated and unmutated subsets according to telomere length revealed that patients with TL-IFR in each subset had shorter PFS (HR = 4.35 and HR = 1.48, respectively) and shorter OS (HR = 3.81 and HR = 2.18, respectively). In addition, the OS of the TL-OFR and TL-IFR subsets were not significantly altered by IGHV mutation status (P = 0.61; HR = 1.24 and P = 0.41; HR = 1.47, respectively). In multivariate modeling, telomere length was the dominant co-variable for PFS (P = 0.0002; HR = 1.85) and OS (P = 0.05; HR = 1.61). Taken together, our data suggest that HT-STELA is a powerful predictor of outcome to FCR-based treatment and could be used to inform the design of future risk-adapted clinical trials.

RevDate: 2019-01-31

Zlotorynski E (2019)

Telomere crisis activates autophagic death.

Nature reviews. Molecular cell biology pii:10.1038/s41580-019-0105-7 [Epub ahead of print].

RevDate: 2019-01-30

Tomáška Ĺ, Nosek J, Sepšiová R, et al (2018)

Commentary: Single-stranded telomere-binding protein employs a dual rheostat for binding affinity and specificity that drives function.

Frontiers in genetics, 9:742.


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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