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23 Sep 2020 at 01:54
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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: 2020-09-22

Bose S, Suescún AV, Song J, et al (2020)

tRNA ADENOSINE DEAMINASE 3 is required for telomere maintenance in Arabidopsis thaliana.

Plant cell reports pii:10.1007/s00299-020-02594-0 [Epub ahead of print].

KEY MESSAGE: tRNA Adenosine Deaminase 3 helps to sustain telomere tracts in a telomerase-independent fashion, likely through regulating cellular metabolism. Telomere length maintenance is influenced by a complex web of chromatin and metabolism-related factors. We previously reported that a lncRNA termed AtTER2 regulates telomerase activity in Arabidopsis thaliana in response to DNA damage. AtTER2 was initially shown to partially overlap with the 5' UTR of the tRNA ADENOSINE DEAMINASE 3 (TAD3) gene. However, updated genome annotation showed that AtTER2 was completely embedded in TAD3, raising the possibility that phenotypes ascribed to AtTER2 could be derived from TAD3. Here we show through strand-specific RNA-Seq, strand-specific qRT-PCR and bioinformatic analyses that AtTER2 does not encode a stable lncRNA. Further examination of the original tad3 (ter2-1/tad3-1) mutant revealed expression of an antisense transcript driven by a cryptic promoter in the T-DNA. Hence, a new hypomorphic allele of TAD3 (tad3-2) was examined. tad3-2 mutants showed hypersensitivity to DNA damage, but no deregulation of telomerase, suggesting that the telomerase phenotype of tad3-1 mutants reflects an off-target effect. Unexpectedly, however, tad3-2 plants displayed progressive loss of telomeric DNA over successive generations that was not accompanied by alteration of terminal architecture or end protection. The phenotype was exacerbated in plants lacking the telomerase processivity factor POT1a, indicating that TAD3 promotes telomere maintenance through a non-canonical, telomerase-independent pathway. The transcriptome of tad3-2 mutants revealed significant dysregulation of genes involved in auxin signaling and glucosinolate biosynthesis, pathways that intersect the stress response, cell cycle regulation and DNA metabolism. These findings indicate that the TAD3 locus indirectly contributes to telomere length homeostasis by altering the metabolic profile in Arabidopsis.

RevDate: 2020-09-22

Chakravarti D, Hu B, Mao X, et al (2020)

Telomere dysfunction activates YAP1 to drive tissue inflammation.

Nature communications, 11(1):4766 pii:10.1038/s41467-020-18420-w.

Germline telomere maintenance defects are associated with an increased incidence of inflammatory diseases in humans, yet whether and how telomere dysfunction causes inflammation are not known. Here, we show that telomere dysfunction drives pATM/c-ABL-mediated activation of the YAP1 transcription factor, up-regulating the major pro-inflammatory factor, pro-IL-18. The colonic microbiome stimulates cytosolic receptors activating caspase-1 which cleaves pro-IL-18 into mature IL-18, leading to recruitment of interferon (IFN)-γ-secreting T cells and intestinal inflammation. Correspondingly, patients with germline telomere maintenance defects exhibit DNA damage (γH2AX) signaling together with elevated YAP1 and IL-18 expression. In mice with telomere dysfunction, telomerase reactivation in the intestinal epithelium or pharmacological inhibition of ATM, YAP1, or caspase-1 as well as antibiotic treatment, dramatically reduces IL-18 and intestinal inflammation. Thus, telomere dysfunction-induced activation of the ATM-YAP1-pro-IL-18 pathway in epithelium is a key instigator of tissue inflammation.

RevDate: 2020-09-21

Tsubono Y, Kawamoto Y, Hidaka T, et al (2020)

A Near-Infrared Fluorogenic Pyrrole-Imidazole Polyamide Probe for Live-Cell Imaging of Telomeres.

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

Telomeres are closely associated with cellular senescence and cancer. Although some techniques have been developed to label telomeres in living cells for study of telomere dynamics, few biocompatible near-infrared probes based on synthetic molecules have been reported. In this study, we developed a near-infrared fluorogenic pyrrole-imidazole polyamide probe (SiR-TTet59B) to visualize telomeres by conjugating a silicon-rhodamine (SiR) fluorophore with a tandem tetramer pyrrole-imidazole polyamide targeting 24 bp in the telomeric double-stranded (ds)DNA. SiR-TTet59B was almost nonfluorescent in water but increased its fluorescence dramatically on binding to telomeric dsDNA. Using a peptide-based delivery reagent, we demonstrated the specific and effective visualization of telomeres in living human cells. Moreover, SiR-TTet59B could be used to observe the dynamic movements of telomeres during interphase and mitosis. This simple imaging method using a synthetic near-infrared probe could be a powerful tool for studies of telomeres and for diagnosis.

RevDate: 2020-09-21

Truta B, Wohler E, Sobreira N, et al (2020)

Role of telomere shortening in anticipation of inflammatory bowel disease.

World journal of gastrointestinal pharmacology and therapeutics, 11(4):69-78.

BACKGROUND: The existence of genetic anticipation has been long disputed in inflammatory bowel disease (IBD) in the absence of the explanatory mechanism.

AIM: To determine whether it was predictive of genetic anticipation, we evaluated telomere length in IBD. We hypothesized that multiplex IBD families exhibit a genetic defect impacting telomere maintenance mechanisms.

METHODS: We studied three IBD families with multiple affected members in three successive generations. We determined telomere length (TL) in lymphocytes and granulocytes from peripheral blood of the affected members using flow cytometry and fluorescence in-situ hybridization (flow FISH). We also performed whole exome sequencing in the blood of all available family members and used PhenoDB to identify potential candidate gene variants with recessive or dominant modes of inheritance.

RESULTS: Out of twenty-four patients of European descent selected to participate in the study, eleven patients, eight parent-child pairs affected by IBD, were included in the genetic anticipation analysis. Median difference in age at diagnosis between two successive generations was 16.5 years, with earlier age at onset in the younger generations. In most of the affected members, the disease harbored similar gastrointestinal and extraintestinal involvement but was more aggressive among the younger generations. TL was not associated with earlier age at onset or more severe disease in members of successive generations affected by IBD. NOD2 gene mutations were present in the Crohn's disease patients of one family. However, no gene variants were identified as potential candidates for inheritance.

CONCLUSION: Telomere shortening appears unlikely to be involved in mechanisms of possible genetic anticipation in IBD. Further studies using a larger sample size are required to confirm or refute our findings.

RevDate: 2020-09-21

Cao L, Li ZQ, Shi YY, et al (2020)

Telomere length and type 2 diabetes: Mendelian randomization study and polygenic risk score analysis.

Yi chuan = Hereditas, 42(9):882-888.

Recent epidemiological studies suggest an association between shorter telomere length and higher risk for type 2 diabetes (T2D). However, results from observational studies are susceptible to confounding and reverse causation, and it is not clear whether there is a causal association between telomere length and T2D. Using Mendelian randomization (MR) and polygenic risk score (PRS) approaches, we had evaluated the causal effect of telomere length on T2D in the Chinese Han population. Using 8 telomere-length associated genetic variants as instrumental variables, an analysis of genetically predicted telomere length and T2D risk was performed in the MR study based on data from a T2D genome-wide association study (GWAS) in 2632 individuals (1318 cases and 1314 controls). We also applied a PRS approach to investigate the causal relationship using Chinese GWAS data. The inverse-variance weighted, MR-Egger regression, simple median, and weighted median methods yielded no evidence of association between genetically predicted longer telomere length and risk of T2D (OR = 0.78, 95% CI: 0.36 ~ 1.68, P = 0.522; OR = 0.23, 95% CI: 0.01 ~ 7.64, P = 0.412; OR = 0.60, 95% CI: 0.28 ~ 1.28, P = 0.185; OR = 0.64, 95% CI: 0.31 ~ 1.33,P = 0.233; respectively). Further, PRS analysis did not produce consistent genetic overlap between telomere length and T2D. Accordingly, this study found no evidence supporting a causal association between telomere length and T2D. Further studies with larger cohorts could yield more reliable results and conclusions.

RevDate: 2020-09-20

Wang T, Tu Y, Zhang G, et al (2020)

Development of a benchmark dose for lead-exposure based on its induction of micronuclei, telomere length changes and hematological toxicity.

Environment international, 145:106129 pii:S0160-4120(20)32084-5 [Epub ahead of print].

BACKGROUND: Excessive lead exposure is associated with adverse health effects. However, there is a lack of systematic investigation using large populations to ascertain acceptable exposure limits.

OBJECTIVES: Our study was aimed to identify human exposure-response relationships between lead exposure and health-related outcomes, and to determine a benchmark dose (BMD).

METHODS: A total of 1896 participants from a lead-acid battery plant were recruited. Blood lead levels (BLLs) were detected for all participants. Hematological parameters (n = 1896), micronuclei (MN) frequencies (n = 934), and relative telomere length (rTL) (n = 757) were also determined. Multivariate linear/Poisson regression analyses were performed to examine associations between BLLs and these health outcomes. Restricted cubic splines were used to identify dose-response relationships. Three BMD approaches were used to calculate BMD and its 95% lower confidence limit (BMDL).

RESULTS: Among all participants, BLLs show a right-skewed distribution (median, 185.40 μg/L; 25th - 75th percentile, 104.63-271.70 μg/L). There existed significant differences for red blood cell (RBC), hemoglobin (Hb), MN and rTL among different BLL dose groups. After adjusting for possible confounders, all indicators were significantly associated with BLLs. Restricted cubic splines show that there were linear dose-response relationships for RBC and Hb with BLLs, while non-linear for MN and rTL. Results from the three BMD approaches indicate that the dichotomous models were better than continuous models to calculate BMD and BMDL of BLLs. The conservative BMDL obtained from RBC data was 135 for total, 104 for male and 175 μg/L for female. The corresponding BMDL obtained from Hb data was 105 for total, 116 for male and 70 μg/L for female. As for MN data, the BMDL estimate was 66 for total, 69 for male and 64 μg/L for female. Finally, the BMDL from rTL data was 35 for total, 32 for male and 43 μg/L for female.

CONCLUSIONS: Our data show significant dose-response relationships between lead exposure and expressions of hematological toxicity and genotoxicity. The new BMDLs of 135 and 105 μg/L based on RBC and Hb, and even more strict level of 66 and 35 μg/L based on MN and rTL are lower than current exposure limits in China. Therefore, the four values can be considered as novel exposure limits. In addition, sex effect should be taken into account when setting occupational health standard. Considering that different biomarkers have different sensitivities, better understanding their relationships will certainly improve the current emphasis on precision health risk assessment.

RevDate: 2020-09-21

Afrin M, Gaurav AK, Yang X, et al (2020)

TbRAP1 has an unusual duplex DNA binding activity required for its telomere localization and VSG silencing.

Science advances, 6(38): pii:6/38/eabc4065.

Localization of Repressor Activator Protein 1 (RAP1) to the telomere is essential for its telomeric functions. RAP1 homologs either directly bind the duplex telomere DNA or interact with telomere-binding proteins. We find that Trypanosoma brucei RAP1 relies on a unique double-stranded DNA (dsDNA) binding activity to achieve this goal. T. brucei causes human sleeping sickness and regularly switches its major surface antigen, variant surface glycoprotein (VSG), to evade the host immune response. VSGs are monoallelically expressed from subtelomeres, and TbRAP1 is essential for VSG regulation. We identify dsDNA and single-stranded DNA binding activities in TbRAP1, which require positively charged 737RKRRR741 residues that overlap with TbRAP1's nuclear localization signal in the MybLike domain. Both DNA binding activities are electrostatics-based and sequence nonspecific. The dsDNA binding activity can be substantially diminished by phosphorylation of two 737RKRRR741-adjacent S residues and is essential for TbRAP1's telomere localization, VSG silencing, telomere integrity, and cell proliferation.

RevDate: 2020-09-17

Cheng WH (2020)

Placental Telomere Length: Linking Maternal Nutrition to Transgenerational Healthy Aging?.

The Journal of nutrition pii:5906641 [Epub ahead of print].

RevDate: 2020-09-16

Luo Y, Viswanathan R, Hande MP, et al (2020)

Massively parallel single-molecule telomere length measurement with digital real-time PCR.

Science advances, 6(34): pii:6/34/eabb7944.

Telomere length is a promising biomarker for age-associated diseases and cancer, but there are still substantial challenges to routine telomere analysis in clinics because of the lack of a simple and rapid yet scalable method for measurement. We developed the single telomere absolute-length rapid (STAR) assay, a novel high-throughput digital real-time PCR approach for rapidly measuring the absolute lengths and quantities of individual telomere molecules. We show that this technique provides the accuracy and sensitivity to uncover associations between telomere length distribution and telomere maintenance mechanisms in cancer cell lines and primary tumors. The results indicate that the STAR assay is a powerful tool to enable the use of telomere length distribution as a biomarker in disease and population-wide studies.

RevDate: 2020-09-21

Pańczyszyn A, Boniewska-Bernacka E, A Goc (2020)

The role of telomeres and telomerase in the senescence of postmitotic cells.

DNA repair, 95:102956 pii:S1568-7864(20)30205-6 [Epub ahead of print].

Senescence is a process related to the stopping of divisions and changes leading the cell to the SASP phenotype. Permanent senescence of many SASP cells contributes to faster aging of the body and development of age-related diseases due to the release of pro-inflammatory factors. Both mitotically active and non-dividing cells can undergo senescence as a result of activation of different molecular pathways. Telomeres, referred to as the molecular clock, direct the dividing cell into the aging pathway when reaching a critical length. In turn, the senescence of postmitotic cells depends not on the length of telomeres, but their functionality. Dysfunctional telomeres are responsible for triggering the signaling of DNA damage response (DDR). Telomerase subunits in post-mitotic cells translocate between the nucleus, cytoplasm and mitochondria, participating in the regulation of their activity. Among other things, they contribute to the reduction of reactive oxygen species generation, which leads to telomere dysfunction and, consequently, senescence. Some proteins of the shelterin complex also play a protective role by inhibiting senescence-initiating kinases and limiting ROS production by mitochondria.

RevDate: 2020-09-16

M B AlDehaini D, Al-Bustan SA, Hasan Abdulla Malalla Z, et al (2020)

The influence of TERC, TERT and ACYP2 genes polymorphisms on plasma telomerase concentration, telomeres length and T2DM.

Gene pii:S0378-1119(20)30796-4 [Epub ahead of print].

Telomeres are duplex tandem repeats of DNA sequence 5'-TTAGGG-3' at chromosomal ends synthesized by telomerase enzyme (TE). Telomeres length (TL) shortening is associated with age and age-related disorders. Recently, we demonstrated marked leukocytes TL (LTL) shortening in T2DM. To set the relationship between the TE, LTL and T2DM, we analyzed samples from 212 Kuwaiti subjects, 112 patients withT2DM and 100 non-diabetic subjects. The plasma TE and fasting insulin were measured by ELISA, the LTL was estimated by qPCR and three SNPs of genes related to TL; TERC rs12696304(C/G), TERT rs2736100(C/A) and ACYP2 rs6713088(C/G) were genotyped by rtPCR. Results revealed comparable TE levels and alleles/genotypes between the cases and controls with no influence of either on the LTL. Interestingly, although the plasma concentration of the TE was generally low, it was significantly influenced by the TERT and ACYP2 but not TERC polymorphisms. The CC genotype carriers of rs2736100(C/A) had significantly higher plasma TE levels compared to CA and AA carriers, p 0.009 and p 0.047, respectively, and the A-allele was associated with low TE, p 0.018. Similarly, significantly higher TE levels were detected in CC carriers of ACYP2 rs6713088 (C/G) compared with GC carriers, p 0.002, and the G-allele was associated with low TE, p 0.009. Finally, the TERT and ACYP2 polymorphisms had an influence on blood glucose levels. In conclusion, the telomeres shortening in T2DM was not due to TE deficiency or gene polymorphisms, while the TE levels were significantly associated with the TERT and ACYP2 but not TERC polymorphisms.

RevDate: 2020-09-16

Sun C, Wang K, Stock AJ, et al (2020)

Re-equilibration of imbalanced NAD metabolism ameliorates the impact of telomere dysfunction.

The EMBO journal [Epub ahead of print].

Short telomeres are a principal defining feature of telomere biology disorders, such as dyskeratosis congenita (DC), for which there are no effective treatments. Here, we report that primary fibroblasts from DC patients and late generation telomerase knockout mice display lower nicotinamide adenine dinucleotide (NAD) levels, and an imbalance in the NAD metabolome that includes elevated CD38 NADase and reduced poly(ADP-ribose) polymerase and SIRT1 activities, respectively, affecting many associated biological pathways. Supplementation with the NAD precursor, nicotinamide riboside, and CD38 inhibition improved NAD homeostasis, thereby alleviating telomere damage, defective mitochondrial biosynthesis and clearance, cell growth retardation, and cellular senescence of DC fibroblasts. These findings reveal a direct, underlying role of NAD dysregulation when telomeres are short and underscore its relevance to the pathophysiology and interventions of human telomere-driven diseases.

RevDate: 2020-09-21

Carroll JE, Mahrer NE, Shalowitz M, et al (2020)

Prenatal maternal stress prospectively relates to shorter child buccal cell telomere length.

Psychoneuroendocrinology, 121:104841 pii:S0306-4530(20)30263-8 [Epub ahead of print].

Prenatal exposure to stress increases risk for suboptimal child and adult mental and physical health outcomes, hypothesized to occur via fetal exposure to maternal stress hormones that alter growth and development. One proposed pathway through which stress exposure in utero could affect the offspring is by accelerating cellular aging in the form of telomere attrition. We tested this hypothesis in a cohort of 111 mother-child dyads, where mothers were assessed over 6 or more years, beginning prior to conception, and later during pregnancy, postpartum, and when the children were 3-5 years old. Adjusting for child age and concurrent maternal stress, we found that higher maternal perceived stress in the 3rd trimesters of pregnancy was predictive of shorter child buccal telomere length (bTL) (β = -0.24, p < .05), while maternal preconception and postpartum maternal stress were not associated with bTL (all p's > 0.42). These findings suggest a vulnerable time period in pregnancy when maternal stress influences offspring telomere length, suggesting the early embedding of adult disease might occur through biological aging pathways.

RevDate: 2020-09-16

Cheng G, Dai M, Xin Q, et al (2020)

Patients with benign prostatic hyperplasia show shorter leukocyte telomere length but no association with telomerase gene polymorphisms in Han Chinese males.

International journal of clinical and experimental pathology, 13(8):2123-2129.

OBJECTIVE: Benign prostatic hyperplasia (BPH) is an age-related disease, occurring in >70% of men of age >60. Because telomeres and telomerase play a key role in aging and age-related diseases, and certain telomerase gene single nucleotide polymorphisms (SNPs) are shown to be associated with the susceptibility to age-related diseases, we wanted to determine the relationship between BPH and leukocyte telomere length (LTL) and telomere length-related single nucleotide polymorphisms (SNPs) of the telomerase holoenzyme genes.

METHODS: Peripheral blood was collected from both BPH patients and age-matched healthy male controls and genomic DNA was extracted. rs2736100 and rs2736098 at the TERT and rs12696304 at the TERC locus were analysed using pre-designed TaqMan SNP genotyping assay kits. LTL was determined using qPCR.

RESULTS: Patients with BPH had significantly shorter LTL (1.231 ± 0.532 vs 0.899 ± 0.322, P < 0.001). The genotyping results show similar frequencies in rs2736100, rs2736098 and rs12696304 between healthy and BPH individuals.

CONCLUSIONS: Shorter telomeres but not telomerase SNPs at the TERT and TERC loci, are associated with BPH. Short telomeres may promote senescence of a fraction of prostatic epithelial cells, while senescent cells in turn facilitate epithelial and stromal cell proliferation by the senescence-associated secretory phenotype mechanism, thereby eventually leading to BPH development.

RevDate: 2020-09-16

Cheng G, Wang L, Dai M, et al (2020)

Shorter Leukocyte Telomere Length coupled with lower expression of Telomerase Genes in patients with Essential Hypertension.

International journal of medical sciences, 17(14):2180-2186.

Background: The essential hypertension (EH) pathophysiology remains poorly understood. Many studies indicate that reduced leukocyte telomere length (LTL) is involved in the EH pathogenesis, however, the direct analysis of arterial telomere length (ATL) from EH patients and normotensive individuals did not show a difference. To address these discrepant observations between LTL and ATL, we performed comprehensive analyses of LTL, telomerase gene expression and their genetic variants in healthy normotensive controls and EH patients. Methods: Sex-matched 206 EH patients and equal numbers of healthy controls were recruited. LTL, and the expression of two key telomerase components, telomerase reverse transcriptase (TERT) and internal RNA template (TERC) were determined using qPCR. Genetic variants of rs2736100 at the TERT and rs12696304 at the TERC loci were determined using TaqMan genotyping kits. Results: LTL was significantly shorter in EH patients than in their normotensive controls (0.96 ± 0.52 vs 1.19 ± 0.58, P = 0.001). Moreover, TERT and TERC expression in patients' leukocytes were substantially lower compare to that in healthy controls (TERT, 0.98 ± 0.98 vs 1.76 ± 1.75, P = 0.003; TERC, 1.26 ± 1.62 vs 4.69 ± 3.61, P < 0.001). However, there were no differences in the genetic variants of rs2736100 and rs12696304 between patient and control groups. Conclusions: EH patients have significantly shorter LTL, which may result from defective TERT and TERC expression in leukocytes. Collectively, lower telomerase expression contributes to shorter LTL observed in EH patients, and telomerase activators may be considered for EH therapy.

RevDate: 2020-09-13

Palmos AB, Duarte RRR, Smeeth DM, et al (2020)

Telomere length and human hippocampal neurogenesis.

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology pii:10.1038/s41386-020-00863-w [Epub ahead of print].

Short telomere length is a risk factor for age-related disease, but it is also associated with reduced hippocampal volumes, age-related cognitive decline and psychiatric disorder risk. The current study explored whether telomere shortening might have an influence on cognitive function and psychiatric disorder pathophysiology, via its hypothesised effects on adult hippocampal neurogenesis. We modelled telomere shortening in human hippocampal progenitor cells in vitro using a serial passaging protocol that mimics the end-replication problem. Serially passaged progenitors demonstrated shorter telomeres (P ≤ 0.05), and reduced rates of cell proliferation (P ≤ 0.001), with no changes in the ability of cells to differentiate into neurons or glia. RNA-sequencing and gene-set enrichment analyses revealed an effect of cell ageing on gene networks related to neurogenesis, telomere maintenance, cell senescence and cytokine production. Downregulated transcripts in our model showed a significant overlap with genes regulating cognitive function (P ≤ 1 × 10-5), and risk for schizophrenia (P ≤ 1 × 10-10) and bipolar disorder (P ≤ 0.005). Collectively, our results suggest that telomere shortening could represent a mechanism that moderates the proliferative capacity of human hippocampal progenitors, which may subsequently impact on human cognitive function and psychiatric disorder pathophysiology.Fig. 1A summary of our in vitro protocol, which considered telomere length, mRNA expression, cell markers of proliferation, and cell markers of differentiation, in association with cell passaging.Fig. 2TELOMERES ARE SHORTER IN SERIALLY PASSAGED HIPPOCAMPAL PROGENITOR CELLS.: This bar chart shows the relative telomere length in cells at baseline (P21) and serially passaged cells (P29). There is a significant reduction in telomere length in serially passaged cells relative to cells at baseline. Group differences were detected using an independent samples t-test. Significant differences were considered when P ≤ 0.05, indicated by *.Fig. 3PROLIFERATION RATES ARE LOWER IN SERIALLY PASSAGED HIPPOCAMPAL PROGENITOR CELLS.: Bar charts (top) show the percentage of BrdU (a) and Ki67 (b) positive cells relative to the percentage of DAPI stained nuclei (y-axis) in cells at baseline and serially passaged cells (x-axis). Each datapoint represents one biological replicate (N = 4). * represents an uncorrected P ≤ 0.05, and *** represents an uncorrected P ≤ 0.001. Each of the images (below) are representative of a field of immuno-stained cells, taken using a ×10 objective with the CellInsight High Content Screening Platform. Each composite image includes the nuclear marker DAPI in blue. Scale bar = 100 μm.Fig. 4THERE ARE NO DIFFERENCES IN THE RATES OF CELL DIFFERENTIATION IN SERIALLY PASSAGED CELLS.: The bar charts (right) show the percentage of MAP-2 (a), CC3 (b), S100β (c) and doublecortin (DCX) (d) -positive cells relative to the percentage of DAPI stained nuclei in cells at baseline and serially passaged cells. Each datapoint represents one biological replicate (N = 4). * represents an uncorrected P ≤ 0.05. Each of the images (left) are representative of a field of immuno-stained cells, taken using a ×10 objective with the CellInsight High Content Screening Platform. Each composite image includes the nuclear marker DAPI in blue. Scale bar = 100 μm.Fig. 5DIFFERENTIALLY EXPRESSED GENES IN SERIALLY PASSAGED CELLS RELATIVE TO CELLS AT BASELINE, AND GENE SETS IMPLICATED IN CELL AGEING.: a A volcano plot summarising the RNA-sequencing results, where log2(Fold change) is shown on the x-axis, and the strength of the association given by -Log10(P), is shown on the y-axis. b Examples of gene sets which significantly overlap with the upregulated genes in our cell model. All gene sets represent those which surpassed a false discovery rate correction, PFDR < 0.05, in our enrichment analysis, as marked by the dashed line. c Examples of gene sets which significantly overlap with the downregulated genes in our cell model. d A bar plot showing the genetic overlap between various traits as assayed by GWAS (y-axis) and genes either upregulated or downregulated in association with cell ageing. The strength of the association is shown on the y-axis (-log(p)). The dashed line represents the threshold of significance (corrected for the number of tests).

RevDate: 2020-09-12

Squassina A, Manchia M, Pisanu C, et al (2020)

Telomere attrition and inflammatory load in severe psychiatric disorders and in response to psychotropic medications.

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology pii:10.1038/s41386-020-00844-z [Epub ahead of print].

Individuals with severe psychiatric disorders have a reduced life expectancy compared to the general population. At the biological level, patients with these disorders present features that suggest the involvement of accelerated aging, such as increased circulating inflammatory markers and shorter telomere length (TL). To date, the role of the interplay between inflammation and telomere dynamics in the pathophysiology of severe psychiatric disorders has been scarcely investigated. In this study we measured T-lymphocytes TL with quantitative fluorescent in situ hybridization (Q-FISH) and plasma levels of inflammatory markers in a cohort comprised of 40 patients with bipolar disorder (BD), 41 with schizophrenia (SZ), 37 with major depressive disorder (MDD), and 36 non-psychiatric controls (NPC). TL was shorter in SZ and in MDD compared to NPC, while it was longer in BD (model F6, 137 = 20.128, p = 8.73 × 10-17, effect of diagnosis, F3 = 31.870; p = 1.08 × 10-15). There was no effect of the different classes of psychotropic medications, while duration of treatment with mood stabilizers was associated with longer TL (Partial correlation controlled for age and BMI: correlation coefficient = 0.451; p = 0.001). Levels of high-sensitivity C-Reactive Protein (hsCRP) were higher in SZ compared to NPC (adjusted p = 0.027), and inversely correlated with TL in the whole sample (r = -0.180; p = 0.042). Compared to NPC, patients with treatment resistant (TR) SZ had shorter TL (p = 0.001), while patients with TR MDD had higher levels of tumor necrosis factor-α (TNFα) compared to NPC (p = 0.028) and to non-TR (p = 0.039). Comorbidity with cardio-metabolic disorders did not influence the observed differences in TL, hsCRP, and TNFα among the diagnostic groups. Our study suggests that patients with severe psychiatric disorders present reduced TL and increased inflammation.Fig. 1The figure shows diminished fluorescence intensity of telomeres of patients with schizophrenia (a) compared to major depressive disorder (b), bipolar disorder (c) and non-psychiatric controls (d). Telomere probe (red); DAPI-stained metaphases (blue). Note: no evidence of FISH signal randomly observed mainly in SZ chromosomes indicates that telomere shortening reached a size of the exameric sequence that is under the PNA-FISH resolution (200base pairs).Fig. 2a shows the difference in telomere length (TL) among the four diagnostic groups (effect of diagnosis F3 = 31.87, p = 1.08 × 10-15). b shows the difference in levels of high sensitivity C-reactive protein (hsCRP) among the four diagnostic groups (effect of diagnosis F3 = 4.680, p = 0.004). Levels are expressed as mg/L. Figure c shows the difference in levels of tumor necrosis factor alpha (TNFα) among the four diagnostic groups (effect of diagnosis F3 = 1.217, p = 0.306). Levels are expressed as pg/mL. Graphs were obtained using the raw values (unadjusted), while the statistical significance for TL, hsCRP and TNFα are based on post-hoc analysis with Bonferroni correction of the univariate models controlling of age, sex, and BMI as covariates. *p < 0.05; **p < 0.005; ***p < 0.0005; ns, not significant. Bars represent mean and standard errors on the mean. NPC non-psychiatric controls, BD bipolar disorder, SZ schizophrenia, MD major depressive disorder.Fig. 3a shows the difference in TL among non-psychiatric controls (NPC), patients with treatment-resistant schizophrenia (TR), and patients with non-treatment resistant schizophrenia (non-TR) (effect of diagnosis F2 = 6.927; p = 0.002). b shows the difference in levels of tumor necrosis factor alpha (TNFα) among non-psychiatric controls (NPC), patients with treatment-resistant major depressive disorder (TR), and patients with non-treatment resistant major depressive disorder (non-TR) (effect of diagnosis F2 = 3.998; p = 0.023). Graphs were obtained using the raw values (unadjusted), while the statistical significance for TL, hsCRP and TNFα are based on post-hoc analysis with Bonferroni correction of the univariate models controlling of age, sex, and BMI as covariates. *p < 0.05; **p < 0.005; ns, not significant. Bars represent mean and standard errors on the mean.Fig. 4Partial correlation between hsCRP and TL in the whole sample controlled for Body Mass Index (BMI) and age. Correlation coefficient = -0.180, p = 0.042. TL telomere length, hsCRP high sensitivity C-reactive protein.

RevDate: 2020-09-21

Yu J, Kanchi MM, Rawtaer I, et al (2020)

The functional and structural connectomes of telomere length and their association with cognition in mild cognitive impairment.

Cortex; a journal devoted to the study of the nervous system and behavior, 132:29-40 pii:S0010-9452(20)30304-X [Epub ahead of print].

Previous findings on the relationship between telomere length and cognition have inconclusive, despite the relatively consistent telomere-shortening associated atrophy in the subcortical regions. Perhaps, there could be other more important telomere-associated factors in the brain, such as functional connectivity (FC) and structural connectivity (SC) that modulate cognition. The current study examined the relationship between telomere length, connectivity, and cognition. Telomere length measurements, neurocognitive scores, diffusion tensor and resting-state functional magnetic resonance imaging scans were collected from 82 older adults with mild cognitive impairment. SC and FC matrices were derived from these scans and, in various combinations, entered into connectome-based predictive models to predict telomere length. The telomere-associated features were then used to predict memory and executive functions. Leave-one-out cross-validation was performed. Predictive accuracy was assessed via the correlation between predicted and observed scores (rpredicted-observed). Correlation analyses were carried out between cognition and telomere length. Telomere length was significantly and negatively correlated with executive functions (EF), after controlling for demographical confounds. Telomere length was best predicted by negative SC and positive FC features (rpredicted-observed = .57; p < .001). The telomere-associated negative SC features significantly predicted EF scores (rpredicted-observed = -.26; p = .015). Telomere-shortening was associated with better EF and alterations in both FC and SC. This enhanced EF can be partly attributed to the telomere-associated changes in SC. Given that telomere is known to be a nonspecific marker of health, our findings illustrated a potential clinical use of telomere length to predict individualized health-related information from FC and SC features.

RevDate: 2020-09-11

Miglani M, Rain M, Pasha Q, et al (2020)

Shorter telomere length, higher telomerase activity in association with Tankyrase gene Polymorphism contribute to High-altitude pulmonary edema.

Human molecular genetics pii:5904232 [Epub ahead of print].

High-altitude pulmonary edema (HAPE) is a non-cardiogenic form of pulmonary edema, which is induced upon exposure to hypobaric hypoxia at high-altitude (HA). Hypobaric hypoxia generates reactive oxygen species that may damage telomeres and disturb normal physiological processes. Telomere complex comprises of multiple proteins, of which, tankyrase (TNKS) is actively involved in DNA damage repairs. We hence investigated the association of TNKS and telomeres with HAPE to delineate their potential role at HA. The study was performed in three groups, High altitude pulmonary edema-patients (HAPE-p, n = 200), HAPE-resistant sojourners (HAPE-r, n = 200), and healthy-highlanders (HLs, n = 200). Variants of TNKS were genotyped using PCR-RFLP. Plasma tankyrase level was estimated using ELISA, expression of TNKS, and relative telomere length were assessed by RT-qPCR, and telomerase activity was assessed by TRAP assay. TNKS poly-ADP ribosylates the telomere-repeat factor (TRF), which is a negative regulator of telomere length. Consequently, TRF expression was also measured by RT-qPCR. The TNKS heterozygotes rs7015700GA were prevalent in HLs compared to the HAPE-p and HAPE-r. The plasma TNKS was significantly decreased in HAPE-p than HAPE-r (p = 0.006). TNKS was up-regulated 9.27 folds in HAPE-p (p = 1.01E-06) and down-regulated in HLs by 3.3 folds (p = 0.02). The telomere length was shorter in HAPE-p compared to HAPE-r (p = 0.03) and HLs (p = 4.25E-4). The telomerase activity was significantly higher in HAPE-p compared to both HAPE-r (p = 0.01) and HLs (p = 0.001). HAPE-p had the lowest TNKS levels (0.186 ± 0.031 ng/μl) and the highest telomerase activity (0.0268 amoles/μl). The findings of the study indicate the association of TNKS and telomeres with HA adaptation/maladaptation.

RevDate: 2020-09-11

Demanelis K, Jasmine F, Chen LS, et al (2020)

Determinants of telomere length across human tissues.

Science (New York, N.Y.), 369(6509):.

Telomere shortening is a hallmark of aging. Telomere length (TL) in blood cells has been studied extensively as a biomarker of human aging and disease; however, little is known regarding variability in TL in nonblood, disease-relevant tissue types. Here, we characterize variability in TLs from 6391 tissue samples, representing >20 tissue types and 952 individuals from the Genotype-Tissue Expression (GTEx) project. We describe differences across tissue types, positive correlation among tissue types, and associations with age and ancestry. We show that genetic variation affects TL in multiple tissue types and that TL may mediate the effect of age on gene expression. Our results provide the foundational knowledge regarding TL in healthy tissues that is needed to interpret epidemiological studies of TL and human health.

RevDate: 2020-09-14

Verner G, Epel E, Lahti-Pulkkinen M, et al (2020)

Maternal Psychological Resilience During Pregnancy and Newborn Telomere Length: A Prospective Study.

The American journal of psychiatry [Epub ahead of print].

OBJECTIVE: In the context of the importance of elucidating the determinants of the initial, newborn setting of telomere length (TL), it is increasingly evident that maternal stress and stress-related processes during pregnancy play a major role. Although psychological resilience may function as a buffer, research in this area has not yet examined its potential role vis-à-vis that of stress. The authors examined the relationship between maternal psychological resilience during pregnancy and newborn TL.

METHODS: In a sample of 656 mother-child dyads from the Prediction and Prevention of Preeclampsia and Intrauterine Growth Restriction cohort, multiple serial assessments were conducted over the course of pregnancy to quantify maternal stress, negative and positive emotional responses to pregnancy events, positive affect, and perceived social support. Principal component analysis identified two latent factors: stress and positivity. A measure of resilience was computed by regressing the positivity factor on the stress factor, in order to quantify positivity after accounting for stress. TL was measured using quantitative polymerase chain reaction in leukocytes extracted from cord blood shortly after birth. Linear regression was used to predict newborn TL from maternal resilience during pregnancy, adjusting for other potential determinants.

RESULTS: Maternal stress significantly predicted shorter newborn TL (β=-0.079), and positivity significantly predicted longer TL (β=0.135). Maternal resilience (positivity accounting for stress) was significantly and positively associated with newborn TL (β=0.114, 95% CI=0.035, 0.189), with each standard deviation increase in resilience predicting 12% longer newborn TL.

CONCLUSIONS: The results indicate that maternal psychological resilience may exert a salubrious effect on offspring telomere biology and highlight the importance of enhancing maternal mental health and well-being during pregnancy.

RevDate: 2020-09-10

Khanal S, Tang Q, Cao D, et al (2020)

Telomere and ATM dynamics in CD4 T cell depletion in active and virus-suppressed HIV infection.

Journal of virology pii:JVI.01061-20 [Epub ahead of print].

CD4 T cell depletion is a hallmark of HIV/AIDS, but the underlying mechanism is still unclear. We have recently shown that ataxia-telangiectasia mutated (ATM) deficiency in CD4 T cells accelerates DNA damage, telomere erosion, and cell apoptosis in HIV-infected individuals on antiretroviral therapy (ART). Whether these alterations in ART-treated HIV subjects occur in vitro in HIV-infected CD4 T cells remains unknown. In this study, we employed a cellular model of HIV infection to characterize the mechanisms underlying CD4 T cell destruction by analyzing the telomeric DNA damage response (DDR) and cellular apoptosis in highly permissive SupT1 cells, followed by the validation our observations in primary CD4 T cells with active or drug-suppressed HIV infection. Specifically, we established an in vitro HIV T cell culture system with viral replication and raltegravir (RAL, an integrase inhibitor) suppression, mimicking active and ART-controlled HIV infection in vivo We demonstrated that HIV-induced, telomeric DDR plays a pivotal role in triggering telomere erosion, premature T cell aging, and CD4 T cell apoptosis or depletion via dysregulation of the PI3K/ATM pathways. This in vitro model provides a new tool to investigate HIV pathogenesis, and our results shed new light on the molecular mechanisms of telomeric DDR and CD4 T cell homeostasis during HIV infection.Author Summary The hallmark of HIV infection is a gradual depletion of CD4 T cells, with a progressive decline of host immunity. How CD4 T cells are depleted in individuals with active and virus-suppressed HIV infection remains unclear. In this study, we employed a cellular model of HIV infection to characterize the mechanisms underlying CD4 T cell destruction by analyzing the chromosome end (telomere) DNA damage response (DDR) and cellular apoptosis in a T cell line (highly permissive SupT1 cells) as well as in primary CD4 T cells with active or drug-suppressed HIV infection. We demonstrated that HIV-induced telomeric DDR plays a critical role in inducing telomere loss, premature cell aging, and CD4 T cell apoptosis or depletion via dysregulation of the PI3K/ATM pathways. This study sheds new light on the molecular mechanisms of telomeric DDR and its role in CD4 T cell homeostasis during HIV infection.

RevDate: 2020-09-10

Muresanu C, Somasundaram SG, Vissarionov SV, et al (2020)

Updated Understanding of Cancer as a Metabolic and Telomere-Driven Disease, and Proposal for Complex Personalized Treatment, a Hypothesis.

International journal of molecular sciences, 21(18): pii:ijms21186521.

In this review, we propose a holistic approach to understanding cancer as a metabolic disease. Our search for relevant studies in medical databases concludes that cancer cells do not evolve directly from normal healthy cells. We hypothesize that aberrant DNA damage accumulates over time-avoiding the natural DNA controls that otherwise repair or replace the rapidly replicating cells. DNA damage starts to accumulate in non-replicating cells, leading to senescence and aging. DNA damage is linked with genetic and epigenetic factors, but the development of cancer is favored by telomerase activity. Evidence indicates that telomere length is affected by chronic inflammations, alterations of mitochondrial DNA, and various environmental factors. Emotional stress also influences telomere length. Chronic inflammation can cause oxidative DNA damage. Oxidative stress, in turn, can trigger mitochondrial changes, which ultimately alter nuclear gene expression. This vicious cycle has led several scientists to view cancer as a metabolic disease. We have proposed complex personalized treatments that seek to correct multiple changes simultaneously using a psychological approach to reduce chronic stress, immune checkpoint therapy with reduced doses of chemo and radiotherapy, minimal surgical intervention, if any, and mitochondrial metabolic reprogramming protocols supplemented by intermittent fasting and personalized dietary plans without interfering with the other therapies.

RevDate: 2020-09-09

Boyle JM, Hennick KM, Regalado SG, et al (2020)

Telomere length set point regulation in human pluripotent stem cells critically depends on the shelterin protein TPP1.

Molecular biology of the cell [Epub ahead of print].

Telomere maintenance is essential for the long-term proliferation of human pluripotent stem cells, while their telomere length set point determines the proliferative capacity of their differentiated progeny. The shelterin protein TPP1 is required for telomere stability and elongation, but its role in establishing a telomere length set point remains elusive. Here, we characterize the contribution of the shorter isoform of TPP1 (TPP1S) and the amino acid L104 outside the TEL patch, TPP1's telomerase interaction domain, to telomere length control. We demonstrate that cells deficient for TPP1S (TPP1S KO), as well as the complete TPP1 KO cell lines, undergo telomere shortening. However, TPP1S KO cells are able to stabilize short telomeres, while TPP1 KO cells die. We compare these phenotypes with those of TPP1L104A/L104A mutant cells, which have short and stable telomeres similar to the TPP1S KO. In contrast to TPP1S KO cells, TPP1L104A/L104A cells respond to increased telomerase levels and maintain protected telomeres. However, TPP1L104A/L104A shows altered sensitivity to expression changes of shelterin proteins suggesting the mutation causes a defect in telomere length feedback regulation. Together this highlights TPP1L104A/L104A as the first shelterin mutant engineered at the endogenous locus of human stem cells with an altered telomere length set point.

RevDate: 2020-09-17

Lee KH, M Kimmel (2020)

Analysis of two mechanisms of telomere maintenance based on the theory of g-Networks and stochastic automata networks.

BMC genomics, 21(Suppl 9):587.

*: Background Telomeres, which are composed of repetitive nucleotide sequences at the end of chromosomes, behave as a division clock that measures replicative senescence. Under the normal physiological condition, telomeres shorten with each cell division, and cells use the telomere lengths to sense the number of divisions. Replicative senescence has been shown to occur at approximately 50-70 cell divisions, which is termed the Hayflick's limit. However, in cancer cells telomere lengths are stabilized, thereby allowing continual cell replication by two known mechanisms: activation of telomerase and Alternative Lengthening of Telomeres (ALT). The connections between the two mechanisms are complicated and still poorly understood. *: Results In this research, we propose that two different approaches, G-Networks and Stochastic Automata Networks, which are stochastic models motivated by queueing theory, are useful to identify a set of genes that play an important role in the state of interest and to infer their previously unknown correlation by obtaining both stationary and joint transient distributions of the given system. Our analysis using G-Network detects five statistically significant genes (CEBPA, FOXM1, E2F1, c-MYC, hTERT) with either mechanism, contrasted to normal cells. A new algorithm is introduced to show how the correlation between two genes of interest varies in the transient state according not only to each mechanism but also to each cell condition. *: Conclusions This study expands our existing knowledge of genes associated with mechanisms of telomere maintenance and provides a platform to understand similarities and differences between telomerase and ALT in terms of the correlation between two genes in the system. This is particularly important because telomere dynamics plays a major role in many physiological and disease processes, including hematopoiesis.

RevDate: 2020-09-09

Bradfield A, Button L, Drury J, et al (2020)

Investigating the Role of Telomere and Telomerase Associated Genes and Proteins in Endometrial Cancer.

Methods and protocols, 3(3): pii:mps3030063.

Endometrial cancer (EC) is the commonest gynaecological malignancy. Current prognostic markers are inadequate to accurately predict patient survival, necessitating novel prognostic markers, to improve treatment strategies. Telomerase has a unique role within the endometrium, whilst aberrant telomerase activity is a hallmark of many cancers. The aim of the current in silico study is to investigate the role of telomere and telomerase associated genes and proteins (TTAGPs) in EC to identify potential prognostic markers and therapeutic targets. Analysis of RNA-seq data from The Cancer Genome Atlas identified differentially expressed genes (DEGs) in EC (568 TTAGPs out of 3467) and ascertained DEGs associated with histological subtypes, higher grade endometrioid tumours and late stage EC. Functional analysis demonstrated that DEGs were predominantly involved in cell cycle regulation, while the survival analysis identified 69 DEGs associated with prognosis. The protein-protein interaction network constructed facilitated the identification of hub genes, enriched transcription factor binding sites and drugs that may target the network. Thus, our in silico methods distinguished many critical genes associated with telomere maintenance that were previously unknown to contribute to EC carcinogenesis and prognosis, including NOP56, WFS1, ANAPC4 and TUBB4A. Probing the prognostic and therapeutic utility of these novel TTAGP markers will form an exciting basis for future research.

RevDate: 2020-09-07

Dhillon VS, Deo P, Chua A, et al (2020)

Telomere length in healthy adults is positively associated with polyunsaturated fatty acids, including arachidonic acid, and negatively with saturated fatty acids.

The journals of gerontology. Series A, Biological sciences and medical sciences pii:5902564 [Epub ahead of print].

Lymphocyte telomere length (LTL) is a biomarker of ageing that may be modified by dietary factors including fat. Red blood cell (RBCs) fatty acid status is a well-validated indicator of long-term dietary intake of fat from various sources. Recent findings from epidemiological studies of LTL in relation to fatty acids in RBCs are not conclusive. The present study was carried out to investigate if RBCs fatty acid status in 174 healthy elderly South Australians is associated with LTL. LTL was measured by real-time qPCR and fatty acid content in RBCs was measured by gas chromatography. Our results indicate that the majority of saturated fatty acids and mono-unsaturated fatty acids are negatively associated with LTL whereas polyunsaturated fatty acids are positively associated with LTL. Multiple regression analysis revealed that arachidonic acid (AA, C20:4n-6) is significantly, independently, positively correlated with LTL (β= .262; p = .000). The significant association of fatty acids, particularly C20:4n-6, with telomere length warrants further research.

RevDate: 2020-09-05

Leal AZ, Schwebs M, Briggs E, et al (2020)

Genome maintenance functions of a putative Trypanosoma brucei translesion DNA polymerase include telomere association and a role in antigenic variation.

Nucleic acids research pii:5901969 [Epub ahead of print].

Maintenance of genome integrity is critical to guarantee transfer of an intact genome from parent to offspring during cell division. DNA polymerases (Pols) provide roles in both replication of the genome and the repair of a wide range of lesions. Amongst replicative DNA Pols, translesion DNA Pols play a particular role: replication to bypass DNA damage. All cells express a range of translesion Pols, but little work has examined their function in parasites, including whether the enzymes might contribute to host-parasite interactions. Here, we describe a dual function of one putative translesion Pol in African trypanosomes, which we now name TbPolIE. Previously, we demonstrated that TbPolIE is associated with telomeric sequences and here we show that RNAi-mediated depletion of TbPolIE transcripts results in slowed growth, altered DNA content, changes in cell morphology, and increased sensitivity to DNA damaging agents. We also show that TbPolIE displays pronounced localization at the nuclear periphery, and that its depletion leads to chromosome segregation defects and increased levels of endogenous DNA damage. Finally, we demonstrate that TbPolIE depletion leads to deregulation of telomeric variant surface glycoprotein genes, linking the function of this putative translesion DNA polymerase to host immune evasion by antigenic variation.

RevDate: 2020-09-09

Sonnenberg ASM, Sedaghat-Telgerd N, Lavrijssen B, et al (2020)

Telomere-to-telomere assembled and centromere annotated genomes of the two main subspecies of the button mushroom Agaricus bisporus reveal especially polymorphic chromosome ends.

Scientific reports, 10(1):14653.

Agaricus bisporus, the most cultivated edible mushroom worldwide, is represented mainly by the subspecies var. bisporus and var. burnettii. var. bisporus has a secondarily homothallic life cycle with recombination restricted to chromosome ends, while var. burnettii is heterothallic with recombination seemingly equally distributed over the chromosomes. To better understand the relationship between genomic make-up and different lifestyles, we have de novo sequenced a burnettii homokaryon and synchronised gene annotations with updated versions of the published genomes of var. bisporus. The genomes were assembled into telomere-to-telomere chromosomes and a consistent set of gene predictions was generated. The genomes of both subspecies were largely co-linear, and especially the chromosome ends differed in gene model content between the two subspecies. A single large cluster of repeats was found on each chromosome at the same respective position in all strains, harbouring nearly 50% of all repeats and likely representing centromeres. Repeats were all heavily methylated. Finally, a mapping population of var. burnettii confirmed an even distribution of crossovers in meiosis, contrasting the recombination landscape of var. bisporus. The new findings using the exceptionally complete and well annotated genomes of this basidiomycete demonstrate the importance for unravelling genetic components underlying the different life cycles.

RevDate: 2020-09-04

Compton A, Liang J, Chen C, et al (2020)

The Beginning of the End: A Chromosomal Assembly of the New World Malaria Mosquito Ends with a Novel Telomere.

G3 (Bethesda, Md.) pii:g3.120.401654 [Epub ahead of print].

Chromosome level assemblies are accumulating in various taxonomic groups including mosquitoes. However, even in the few reference-quality mosquito assemblies, a significant portion of the heterochromatic regions including telomeres remain unresolved. Here we produce a de novo assembly of the New World malaria mosquito, Anopheles albimanus by integrating Oxford Nanopore sequencing, Illumina, Hi-C and optical mapping. This 172.6 Mbps female assembly, which we call AalbS3, is obtained by scaffolding polished large contigs (contig N50=13.7 Mbps) into three chromosomes. All chromosome arms end with telomeric repeats, which is the first in mosquito assemblies and represents a significant step towards the completion of a genome assembly. These telomeres consist of tandem repeats of a novel 30-32 bp telomeric repeat unit (TRU) and are confirmed by analysing the termini of long reads and through both chromosomal in situ hybridization and a Bal31 sensitivity assay. The AalbS3 assembly included previously uncharacterized centromeric and rDNA clusters and more than doubled the content of transposable elements and other repetitive sequences. This telomere-to-telomere assembly, although still containing gaps, represents a significant step towards resolving biologically important but previously hidden genomic components. The comparison of different scaffolding methods will also inform future efforts to obtain reference-quality genomes for other mosquito species.

RevDate: 2020-09-04

Yang Z, Takai KK, Lovejoy CA, et al (2020)

Break-induced replication promotes fragile telomere formation.

Genes & development pii:gad.328575.119 [Epub ahead of print].

TRF1 facilitates the replication of telomeric DNA in part by recruiting the BLM helicase, which can resolve G-quadruplexes on the lagging-strand template. Lagging-strand telomeres lacking TRF1 or BLM form fragile telomeres-structures that resemble common fragile sites (CFSs)-but how they are formed is not known. We report that analogous to CFSs, fragile telomeres in BLM-deficient cells involved double-strand break (DSB) formation, in this case by the SLX4/SLX1 nuclease. The DSBs were repaired by POLD3/POLD4-dependent break-induced replication (BIR), resulting in fragile telomeres containing conservatively replicated DNA. BIR also promoted fragile telomere formation in cells with FokI-induced telomeric DSBs and in alternative lengthening of telomeres (ALT) cells, which have spontaneous telomeric damage. BIR of telomeric DSBs competed with PARP1-, LIG3-, and XPF-dependent alternative nonhomologous end joining (alt-NHEJ), which did not generate fragile telomeres. Collectively, these findings indicate that fragile telomeres can arise from BIR-mediated repair of telomeric DSBs.

RevDate: 2020-09-03

Hernando B, Gil-Barrachina M, Tomas-Bort E, et al (2020)

The effect of long-term ultra-endurance exercise and SOD2 genotype on telomere shortening with age.

Journal of applied physiology (Bethesda, Md. : 1985) [Epub ahead of print].

Telomere shortening, a well-known biomarker of aging, is a complex process influenced by several intrinsic and lifestyle factors. Although habitual exercise may promote telomere length maintenance, extreme endurance exercise has been also associated with increased oxidative stress - presumed to be the major cause of telomere shortening. Therefore, the pace of telomere shortening with age may also depend on antioxidant system efficiency, which is in part genetically determined. In this study, we aimed at evaluating the impact of ultra-endurance exercise and oxidative stress susceptibility (determined by the rs4880 polymorphism in the superoxide dismutase 2 (SOD2) gene) on telomere length. Genomic DNA was obtained from 53 sedentary individuals (34 females, 19-67 years) and 96 ultra-trail runners (31 females, 23-58 years). Indeed, blood samples before and after finishing a 107km-trail race were collected from 32 runners to measure c-reactive protein (CRP) levels and thus analyse if acute inflammation response is modulated by the SOD2 rs4880 polymorphism. Our results revealed that telomere length was better preserved in ultra-trail runners compared to controls, especially in elderly runners who have been regularly training for many years. Carrying the SOD2 rs4880*A allele was significantly associated with having shorter telomeres, as well as with having increased CRP levels after the ultra-trail race. In conclusion, habitual ultra-endurance exercise had a beneficial effect on telomere length maintenance, especially at older ages. This study also suggested that the SOD2 rs4880 polymorphism may also impact on acute and chronic oxidative-related damage (inflammatory response and telomere length) after an ultra-trail race.

RevDate: 2020-09-07

Tsilingiris D, Tentolouris A, Eleftheriadou I, et al (2020)

Telomere length, epidemiology, and pathogenesis of severe COVID-19.

In December of 2019, an outbreak of pneumonia of unknown cause was reported in Wuhan, Hubei Province, China. By January 2020 a novel coronavirus - that was named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) - was isolated from patients in Wuhan and was identified as the causative pathogen of the disease, which was named Coronavirus disease of 2019 (COVID-19). In the middle of March the World Health Organization (WHO) announced COVID-19 outbreak a pandemic. According to the daily report of the WHO, as of 18 July 2020, COVID-19 has spread rapidly to infect more than 14000000 people and has caused roughly 597000 deaths globally.

RevDate: 2020-09-02

Lulkiewicz M, Bajsert J, Kopczynski P, et al (2020)

Telomere length: how the length makes a difference.

Molecular biology reports pii:10.1007/s11033-020-05551-y [Epub ahead of print].

Telomerase is perceived as an immortality enzyme that might provide longevity to cells and whole organisms. Importantly, it is generally inactive in most somatic cells of healthy, adult men. Consequently, its substrates, i.e. telomeres, get shorter in most human cells with time. Noteworthy, cell life limitation due to telomere attrition during cell divisions, may not be as bad as it looks since longer cell life means longer exposition to harmful factors. Consequently, telomere length (attrition rate) becomes a factor that is responsible for inducing the signaling that leads to the elimination of cells that lived long enough to acquire severe damage. It seems that telomere length that depends on many different factors (including telomerase activity but also genetic factors, a hormonal profile that reflects sex, etc.) might become a useful marker of aging and exposition to stress. Thus in the current paper, we review the factors that affect telomere length in human cells focusing on sex that all together with different environmental and hormonal regulations as well as parental aspect affect telomere attrition rate. We also raise some limitations in the assessment of telomere length that hinders a trustworthy meta-analysis that might lead to acknowledgment of the real value of this parameter.

RevDate: 2020-09-13

Giaccherini M, Macauda A, Sgherza N, et al (2020)

Genetic polymorphisms associated with telomere length and risk of developing myeloproliferative neoplasms.

Blood cancer journal, 10(8):89.

Telomere length measured in leukocyte (LTL) has been found to be associated with the risk of developing several cancer types, including myeloproliferative neoplasms (MPNs). LTL is genetically determined by, at least, 11 SNPs previously shown to influence LTL. Their combination in a score has been used as a genetic instrument to measure LTL and evaluate the causative association between LTL and the risk of several cancer types. We tested, for the first time, the "teloscore" in 480 MPN patients and 909 healthy controls in a European multi-center case-control study. We found an increased risk to develop MPNs with longer genetically determined telomeres (OR = 1.82, 95% CI 1.24-2.68, P = 2.21 × 10-3, comparing the highest with the lowest quintile of the teloscore distribution). Analyzing the SNPs individually we confirm the association between TERT-rs2736100-C allele and increased risk of developing MPNs and we report a novel association of the OBFC1-rs9420907-C variant with higher MPN risk (ORallelic = 1.43; 95% CI 1.15-1.77; P = 1.35 × 10-3). Consistently with the results obtained with the teloscore, both risk alleles are also associated with longer LTL. In conclusion, our results suggest that genetically determined longer telomeres could be a risk marker for MPN development.

RevDate: 2020-09-01

Ojeda-Rodríguez A, Morell-Azanza L, Martín-Calvo N, et al (2020)

Association between favourable changes in objectively measured physical activity and telomere length after a lifestyle intervention in pediatric patients with abdominal obesity.

Applied physiology, nutrition, and metabolism = Physiologie appliquee, nutrition et metabolisme [Epub ahead of print].

The purpose of this study was to assess the effect of physical activity (PA) changes, measured by accelerometry, on telomere length (TL) in pediatric patients with abdominal obesity after a lifestyle intervention. 121 children with abdominal obesity (7-16 years old) were randomized to the intervention (moderately hypocaloric Mediterranean Diet) or usual care group (standard pediatrics recommendations) for 22 months (a 2-month intensive phase and a subsequent 20-month follow-up). Both groups were encouraged to accumulate extra 200 min/week of PA. TL was measured by MMqPCR. Data were analyzed in 102 subjects after 2-month and 64 subjects at the first 10 months of follow-up. Light PA level decreased in both groups after 12-month of intervention. At month 2, moderate-to-vigorous PA (MVPA) incremented in the intervention group (+5.4 min/day, p=0.035) and so did sedentary time in the usual care group (+49.7 min/day, p=0.010). TL changes were positively associated (p<0.050) with metabolic equivalents (METs), MVPA level and number of steps; and inversely associated with sedentary and light PA levels in the intervention group after the intensive phase. In conclusion, favourable changes in PA levels in the intensive phase of a lifestyle intervention could contribute to TL maintenance in pediatric population with abdominal obesity. Novelty: • Changes in physical activity levels had a direct effect on telomere length, a biomarker of cellular aging and oxidative stress. • PA advice based on The American College of Sports Medicine included in this intervention is easy to implement in primary care.

RevDate: 2020-09-21

Fathi E, Farahzadi R, Javanmardi S, et al (2020)

L-carnitine Extends the Telomere Length of the Cardiac Differentiated CD117+- Expressing Stem Cells.

Tissue & cell, 67:101429 pii:S0040-8166(20)30288-3 [Epub ahead of print].

Stem cell-based therapy has emerged as an attractive method for regenerating and repairing the lost heart organ. On other hand, poor survival and maintenance of the cells transferred into the damaged heart tissue are broadly accepted as serious barriers to enhance the efficacy of the regenerative therapy. For this reason, external factors, such as antioxidants are used as a favorite strategy by the investigators to improve the cell survival and retention properties. Therefore, the present study was conducted to investigate the In -vitro effect of L-carnitine (LC) on the telomere length and human telomerase reverse transcriptase (hTERT) gene expression in the cardiac differentiated bone marrow resident CD117+ stem cells through Wnt3/β-catenin and ERK1/2 pathways. To do this, bone marrow resident CD117+ stem cells were enriched by the magnetic-activated cell sorting (MACS) method, and were differentiated to the cardiac cells in the absence (-LC) and presence of the LC (+LC). Also, characterization of the enriched c-kit+ cells was performed using the flow cytometry and immunocytochemistry. At the end of the treatment period, the cells were subjected to the real-time PCR technique along with western blotting assay for measurement of the telomere length and assessment of mRNA and protein, respectively. The results showed that 0.2 mM LC caused the elongation of the telomere length and increased the hTERT gene expression in the cardiac differentiated CD117+ stem cells. In addition, a significant increase was observed in the mRNA and protein expression of Wnt3, β-catenin and ERK1/2 as key components of these pathways. It can be concluded that the LC can increase the telomere length as an effective factor in increasing the cell survival and maintenance of the cardiac differentiated bone marrow resident CD117+ stem cells via Wnt3/β-catenin and ERK1/2 signaling pathway components.

RevDate: 2020-08-28

Uysal F, Kosebent EG, Toru HS, et al (2020)

Decreased expression of TERT and telomeric proteins as human ovaries age may cause telomere shortening.

Journal of assisted reproduction and genetics pii:10.1007/s10815-020-01932-1 [Epub ahead of print].

OBJECTIVE: Telomeres are repetitive sequences localized at the ends of eukaryotic chromosomes comprising noncoding DNA and telomere-binding proteins. TRF1 and TRF2 both bind to the double-stranded telomeric DNA to regulate its length throughout the lifespan of eukaryotic cells. POT1 interacts with single-stranded telomeric DNA and contributes to protecting genomic integrity. Previous studies have shown that telomeres gradually shorten as ovaries age, coinciding with fertility loss. However, the molecular background of telomere shortening with ovarian aging is not fully understood.

METHODS: The present study aimed to determine the spatial and temporal expression levels of the TERT, TRF1, TRF2, and POT1 proteins in different groups of human ovaries: fetal (n = 11), early postnatal (n = 10), premenopausal (n = 12), and postmenopausal (n = 14). Also, the relative telomere signal intensity of each group was measured using the Q-FISH method.

RESULTS: We found that the telomere signal intensities decreased evenly and significantly from fetal to postmenopausal groups (P < 0.05). The TERT, TRF1, TRF2, and POT1 proteins were localized in the cytoplasmic and nuclear regions of the oocytes, granulosa and stromal cells. Furthermore, the expression levels of these proteins reduced significantly from fetal to postmenopausal groups (P < 0.05).

CONCLUSION: These findings suggest that decreased TERT and telomere-binding protein expression may underlie the telomere shortening of ovaries with age, which may be associated with female fertility loss. Further investigations are required to elicit the molecular mechanisms regulating the gradual decrease in the expression of TERT and telomere-binding proteins in human oocytes and granulosa cells during ovarian aging.

RevDate: 2020-08-28

Hussien MT, Shaban S, Temerik DF, et al (2020)

Impact of DAXX and ATRX expression on telomere length and prognosis of breast cancer patients.

Journal of the Egyptian National Cancer Institute, 32(1):34 pii:10.1186/s43046-020-00045-1.

BACKGROUND: Telomere stability is one of the hallmarks of cancer that promotes cellular longevity, the accumulation of genetic alterations, and tumorigenesis. The loss of death domain-associated protein (DAXX) and α-thalassemia/mental retardation X-linked protein (ATRX) plays a role in telomere lengthening and stability. This study aims to evaluate the prognostic significance of telomere length (TL) and its association with DAXX and ATRX proteins in breast cancer (BC). Our study used the FISH technique to detect peptide nucleic acid (PNA) in the peripheral blood cells of a cohort of BC patients (n = 220) and a control group of apparently healthy individuals (n = 100). Expression of DAXX and ATRX proteins was evaluated using immunohistochemistry (IHC) in all BC tissues.

RESULTS: Patients with a shorter TL had worse disease-free survival (DFS) and overall survival (OS). There were significant associations between shorter TL and advanced disease stages, lymph node metastasis, and positive HER2/neu expression. DAXX protein expression was significantly correlated with TL. Lower DAXX expression was significantly with shorter DFS.

CONCLUSION: Assessing TL can be used as a worthy prognostic indicator in BC patients. Specifically, short TL had a poor impact on the prognosis of BC patients. Low DAXX expression is associated with poor outcomes in BC. Further mechanistic studies are warranted to reveal the underlying mechanisms of these associations.

RevDate: 2020-09-21

Maleki M, Khelghati N, Alemi F, et al (2020)

Stabilization of telomere by the antioxidant property of polyphenols: Anti-aging potential.

Life sciences, 259:118341 pii:S0024-3205(20)31093-6 [Epub ahead of print].

Aging is a form of a gradual loss of physiological integrity that results in impaired cellular function and ultimately increased vulnerability to disease and death. This process is a significant risk factor for critical age-related disorders such as cancer, diabetes, cardiovascular disease, and neurological conditions. Several mechanisms contribute to aging, most notably progressive telomeres shortening, which can be counteracted by telomerase enzyme activity and increasing in this enzyme activity associated with partly delaying the onset of aging. Individual behaviors and environmental factors such as nutrition affect the life-span by impact the telomerase activity rate. Healthy eating habits, including antioxidant intakes, such as polyphenols, can have a positive effect on telomere length by this mechanism. In this review, after studying the underlying mechanisms of aging and understanding the relationships between telomeres, telomerase, and aging, it has been attempted to explain the effect of polyphenols on reversing the oxidative stress and aging process.

RevDate: 2020-09-17

Stier A, Metcalfe NB, P Monaghan (2020)

Pace and stability of embryonic development affect telomere dynamics: an experimental study in a precocial bird model.

Proceedings. Biological sciences, 287(1933):20201378.

Prenatal effects on telomere length are increasingly recognized as a potential contributor to the developmental origin of health and adult disease. While it is becoming clear that telomere length is influenced by prenatal conditions, the factors affecting telomere dynamics during embryogenesis remain poorly understood. We manipulated both the pace and stability of embryonic development through varying incubation temperature and its stability in Japanese quail. We investigated the impact on telomere dynamics from embryogenesis to adulthood, together with three potential drivers of telomere shortening, growth rate, oxidative damage and prenatal glucocorticoid levels. Telomere length was not affected by our prenatal manipulation for the first 75% of embryogenesis, but was reduced at hatching in groups experiencing faster (i.e. high temperature) or less stable embryonic development. These early life differences in telomere length persisted until adulthood. The effect of developmental instability on telomere length at hatching was potentially mediated by an increased secretion of glucocorticoid hormones during development. Both the pace and the stability of embryo development appear to be key factors determining telomere length and dynamics into adulthood, with fast and less stable development leading to shorter telomeres, with the potential for adverse associated outcomes in terms of reduced longevity.

RevDate: 2020-09-17

Colicino E, Cowell W, Bozack A, et al (2020)

Association between prenatal immune phenotyping and cord blood leukocyte telomere length in the PRISM pregnancy cohort.

Environmental research, 191:110113 pii:S0013-9351(20)31010-0 [Epub ahead of print].

BACKGROUND: Environmental exposures including air pollutants, toxic metals, and psychosocial stress have been associated with shorter telomere length (TL) in newborns. These exposures have in turn been linked to an enhanced inflammatory immune response. Increased inflammation during pregnancy may be a central biological pathway linking environmental factors with reduced TL at birth. Approaches that more comprehensively characterize the prenatal inflammatory milieu rather than targeting specific individual cytokines in relation to newborn TL may better elucidate inflammatory mechanisms.

METHODS: Analyses included 129 mother-child dyads enrolled in the PRogramming of Intergenerational Stress Mechanisms (PRISM) pregnancy cohort. We measured 92 inflammation related proteins during pregnancy in maternal serum using the Olink protein array and quantified cord blood relative leukocyte TL (rLTL) via qPCR. We leveraged a tree-based machine learning algorithm to select the most important inflammatory related proteins jointly associated with rLTL. We then evaluated the combined association between the selected proteins with rLTL using Bayesian Weighted Quantile Sum (BWQS) Regression. Analyses were adjusted for gestational week of serum collection, maternal race/ethnicity, age, and education, and fetal sex. We evaluated major biological function of the identified proteins by using the UniProtKB, a centralized repository of curated functional information.

RESULTS: Three proteins were negatively and linearly associated with rLTL (CASP8 β: -0.22 p = 0.008, BNGF β: -0.43 p = 0.033, TRANCE β: 0.38 p = 0.004). Results from BWQS regression showed a significant overall decrease in rLTL (β: -0.26 95%CrI: -0.43, -0.07) per quartile increase of the mixture, with CASP8 contributing the greatest weight (CASP8 50%; BNGF 27%, and TRANCE 23%). The identified proteins were involved in the regulation of apoptotic processes and cell proliferation.

CONCLUSIONS: This proteomics approach identifies novel maternal prenatal inflammatory protein biomarkers associated with shortened rLTL in newborns.

RevDate: 2020-08-28

Simon MN, Churikov D, V Géli (2021)

Analysis of Recombination at Yeast Telomeres.

Methods in molecular biology (Clifton, N.J.), 2153:395-402.

Upon telomerase inactivation telomeres are getting shorter at each round of DNA replication and progressively lose capping functions and hence protection against homologous recombination. In addition, telomerase-minus cells undergo a round of stochastic DNA damage before the bulk of telomeres become critically short because telomeres are difficult regions to replicate. Although most of the cells will enter finally replicative senescence, those that unleash recombination can eventually recover functional telomeres and growth capacity. Formation of these survivors in yeast depends on various recombination mechanisms. Here, we present assays that we developed to analyze and quantify recombination at telomeres.

RevDate: 2020-08-24

Chen R, Y Zhan (2020)

Association between telomere length and Parkinson's disease: a Mendelian randomization study.

Neurobiology of aging pii:S0197-4580(20)30235-9 [Epub ahead of print].

In this study, we examined the potential association of telomere length with Parkinson's disease (PD) using the publicly available genome-wide association study summary statistics from the International Parkinson's Disease Genomics Consortium involving up to 37,688 patients with PD and 449,056 controls in Mendelian randomization framework. The Mendelian randomization approach has the potential to investigate a causal relationship between a risk factor and a disease, avoiding confounding and reverse causation that often present in conventional epidemiological studies. We did not find that longer telomeres were associated with higher risks of PD (odds ratio: 1.18, 95% confidence interval: 0.94, 1.48, p = 0.15). Our study, therefore, did not provide evidence to support a potential causal relationship between telomere length and PD.

RevDate: 2020-08-25

Fattet AJ, Toupance S, Thornton SN, et al (2020)

Telomere length in granulosa cells and leukocytes: a potential marker of female fertility? A systematic review of the literature.

Journal of ovarian research, 13(1):96.

In the context of a continuously increased delay of motherhood and of an increase of the incidence of premature ovarian failure, it is of the greatest interest to dispose of a predictive marker of the duration of the fertility window. Unfortunately, current available markers of women's fertility (hormonal rates or echography count of small follicles) have a poor predictive value of premature ovarian failure. In the last ten years, some studies have suggested that telomere length may be correlated with premature ovarian failure, but the results of these studies are contradictory.In accordance with guidelines from Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA), this systematic review of the literature selected studies evaluating telomere length or telomerase activity in granulosa cells and/or in leukocytes as a premature ovarian failure marker.Five publications (252 premature ovarian failure patients) were included in this review of experimental evidence. Two of them studied telomere length and/or telomerase activity in granulosa cells and 4 in leukocytes in women with premature ovarian failure. For each study, authors determined if there was a positive or a negative correlation between telomeric parameters and premature ovarian failure.3 studies (178 premature ovarian failure patients) found shorter telomere length in granulosa cells and/or leukocytes and/or lower telomerase activity in premature ovarian failure patients. 2 studies (74 premature ovarian failure patients) presented contradictory results about the correlation of leucocyte telomere length with premature ovarian failure.Shorter telomeres and diminished telomerase activity in granulosa cells appear to be associated with ovarian insufficiency. However, the number of studies and of subjects within are low and the methodology questionable. The confirmation of these results is essential with more subjects, better defined populations and more adapted methodology, in order to consider telomere length in granulosa cells and/or in leucocytes as an early and reliable marker for the decline of ovarian function.

RevDate: 2020-09-05

Bernabeu-Wittel M, Gómez-Díaz R, González-Molina Á, et al (2020)

Oxidative Stress, Telomere Shortening, and Apoptosis Associated to Sarcopenia and Frailty in Patients with Multimorbidity.

Journal of clinical medicine, 9(8):.

BACKGROUND: The presence of oxidative stress, telomere shortening, and apoptosis in polypathological patients (PP) with sarcopenia and frailty remains unknown.

METHODS: Multicentric prospective observational study in order to assess oxidative stress markers (catalase, glutathione reductase (GR), total antioxidant capacity to reactive oxygen species (TAC-ROS), and superoxide dismutase (SOD)), absolute telomere length (aTL), and apoptosis (DNA fragmentation) in peripheral blood samples of a hospital-based population of PP. Associations of these biomarkers to sarcopenia, frailty, functional status, and 12-month mortality were analyzed.

RESULTS: Of the 444 recruited patients, 97 (21.8%), 278 (62.6%), and 80 (18%) were sarcopenic, frail, or both, respectively. Oxidative stress markers (lower TAC-ROS and higher SOD) were significantly enhanced and aTL significantly shortened in patients with sarcopenia, frailty or both syndromes. No evidence of apoptosis was detected in blood leukocytes of any of the patients. Both oxidative stress markers (GR, p = 0.04) and telomere shortening (p = 0.001) were associated to death risk and to less survival days.

CONCLUSIONS: Oxidative stress markers and telomere length were enhanced and shortened, respectively, in blood samples of polypathological patients with sarcopenia and/or frailty. Both were associated to decreased survival. They could be useful in the clinical practice to assess vulnerable populations with multimorbidity and of potential interest as therapeutic targets.

RevDate: 2020-09-05

Bryan TM (2020)

G-Quadruplexes at Telomeres: Friend or Foe?.

Molecules (Basel, Switzerland), 25(16):.

Telomeres are DNA-protein complexes that cap and protect the ends of linear chromosomes. In almost all species, telomeric DNA has a G/C strand bias, and the short tandem repeats of the G-rich strand have the capacity to form into secondary structures in vitro, such as four-stranded G-quadruplexes. This has long prompted speculation that G-quadruplexes play a positive role in telomere biology, resulting in selection for G-rich tandem telomere repeats during evolution. There is some evidence that G-quadruplexes at telomeres may play a protective capping role, at least in yeast, and that they may positively affect telomere maintenance by either the enzyme telomerase or by recombination-based mechanisms. On the other hand, G-quadruplex formation in telomeric DNA, as elsewhere in the genome, can form an impediment to DNA replication and a source of genome instability. This review summarizes recent evidence for the in vivo existence of G-quadruplexes at telomeres, with a focus on human telomeres, and highlights some of the many unanswered questions regarding the location, form, and functions of these structures.

RevDate: 2020-08-21

Hunt SC, Hansen MEB, Verhulst S, et al (2020)

Genetics and Geography of Leukocyte Telomere Length in Sub-Saharan Africans.

Human molecular genetics pii:5894947 [Epub ahead of print].

Leukocyte telomere length (LTL) might be causal in cardiovascular disease and major cancers. To elucidate the roles of genetics and geography in LTL variability across humans, we compared LTL measured in 1295 sub-Saharan Africans (SSAs) with 559 African-Americans (AAms) and 2464 European-Americans (EAms). LTL differed significantly across SSAs (p = 0·003), with the San from Botswana (with the oldest genomic ancestry) having the longest LTL and populations from Ethiopia having the shortest LTL. SSAs had significantly longer LTL than AAms (p = 6·5e-16) whose LTL was significantly longer than EAms (p = 2·5e-7). Genetic variation in SSAs explained 52% of LTL variance versus 27% in AAms and 34% in EAms. Adjustment for genetic variation removed the LTL differences among SSAs. LTL genetic variation among SSAs, with the longest LTL in the San, supports the hypothesis that longer LTL was ancestral in humans. Identifying factors driving LTL variation in Africa may have important ramifications for LTL-associated diseases.

RevDate: 2020-08-22

Ämmälä AJ, Vitikainen EIK, Hovatta I, et al (2020)

Maternal stress or sleep during pregnancy are not reflected on telomere length of newborns.

Scientific reports, 10(1):13986.

Telomeres play an important role in maintaining chromosomal integrity. With each cell division, telomeres are shortened and leukocyte telomere length (LTL) has therefore been considered a marker for biological age. LTL is associated with various lifetime stressors and health-related outcomes. Transgenerational effects have been implicated in newborns, with maternal stress, depression, and anxiety predicting shorter telomere length at birth, possibly reflecting the intrauterine growth environment. Previous studies, with relatively small sample sizes, have reported an effect of maternal stress, BMI, and depression during pregnancy on the LTL of newborns. Here, we attempted to replicate previous findings on prenatal stress and newborn LTL in a sample of 1405 infants using a qPCR-based method. In addition, previous research has been expanded by studying the relationship between maternal sleep quality and LTL. Maternal prenatal stress, anxiety, depression, BMI, and self-reported sleep quality were evaluated with self-reported questionnaires. Despite sufficient power to detect similar or even considerably smaller effects than those previously reported in the literature, we were unable to replicate the previous correlation between maternal stress, anxiety, depression, or sleep with LTL. We discuss several possible reasons for the discrepancies between our findings and those previously described.

RevDate: 2020-08-18

Myllymäki M, Redd RA, Reilly CR, et al (2020)

Short Telomere Length Predicts Non-Relapse Mortality after Stem Cell Transplantation for Myelodysplastic Syndrome.

Blood pii:463323 [Epub ahead of print].

Allogeneic hematopoietic stem cell transplantation is the only potentially curative treatment for patients with myelodysplastic syndrome (MDS), but long-term survival is limited by the risk of transplant-related complications. Short telomere length, mediated by inherited or acquired factors, impairs cellular response to genotoxic and replicative stress and could identify patients at higher risk for toxicity after transplantation. We measured relative telomere length in pre-transplant recipient blood samples in 1514 MDS patients and evaluated the association of telomere length with MDS disease characteristics and transplantation outcomes. Shorter telomere length was significantly associated with older age, male sex, somatic mutations that impair the DNA damage response, and more severe pre-transplant cytopenias, but not with bone marrow blast count, MDS treatment history, or history of prior cancer therapy. Among 1267 patients ≥40 years old, telomere length in the shortest quartile was associated with inferior survival (p<0.001) due to a high risk of non-relapse mortality (p=0.001) after adjusting for significant clinical and genetic variables. The adverse impact of shorter telomeres on NRM was independent of recipient comorbidities and was observed selectively among patients receiving more intensive conditioning, including myeloablative regimens and higher-dose melphalan-based reduced-intensity regimens. The effect of shorter telomeres on NRM was prominent among patients who developed severe acute graft-versus-host disease, suggesting that short telomere length may limit regenerative potential of mucosal tissues after acute injury. MDS patients with shorter telomere length, who have inferior survival driven by excess toxicity, could be considered for strategies focused on minimizing toxic effects of transplantation.

RevDate: 2020-08-18

Öngel ME, Yıldız C, Akpınaroğlu C, et al (2020)

Why women may live longer than men do? A telomere-length regulated and diet-based entropic assessment.

Clinical nutrition (Edinburgh, Scotland) pii:S0261-5614(20)30395-2 [Epub ahead of print].

BACKGROUND & AIMS: Empirical analyses of the data available around the word concluded that women have longer life span now, when compared to the men. Available literature unfortunately could not offer full answers to this observation. The "entropic age" concept suggests that ageing related changes in the body, such as loss of molecular functions and overwhelming of the maintenance systems, may be explained in terms of entropy generation.

METHODS: Telomere-length regulated entropic assessment based on metabolic activity with four different diets carried out.

RESULTS: Estimates of the life expectancy of the women on all of these diets is longer than those of the men. Faster shortening of the telomere lengths in men was the major reason of the shorter life expectancy. The highest and the lowest life expectancy for women were estimated with Mediterranean and the vegetarian diets, respectively; men were estimated to have the longest life span with the vegetarian diet and the shortest life span with the ketogenic diet.

CONCLUSIONS: A higher rate of metabolism causes higher entropy generation and hints correlations that can be helpful in future ageing research. Faster shortening of the telomere lengths in men was the major reason of the estimation of the shorter life span for men.

RevDate: 2020-08-18

Piekna-Przybylska D, Bambara RA, Maggirwar SB, et al (2020)

G-quadruplex ligands targeting telomeres do not inhibit HIV promoter activity and cooperate with latency reversing agents in killing latently infected cells.

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

Altered telomere maintenance mechanism (TMM) is linked to increased DNA damage at telomeres and telomere uncapping. We previously showed that HIV-1 latent cells have altered TMM and are susceptible to ligands that target G-quadruplexes (G4) at telomeres. Susceptibility of latent cells to telomere targeting could potentially be used to support approaches to eradicate HIV reservoirs. However, G4 ligands also target G-quadruplexes in promoters blocking gene transcription. Since HIV promoter sequence can form G-quadruplexes, we investigated whether G4 ligands interfere with HIV-1 promoter activity and virus reactivation from latency, and whether telomere targeting could be combined with latency reversing agents (LRAs) to promote elimination of HIV reservoirs. Our results indicate that Sp1 binding region in HIV-1 promoter can adopt G4 structures in duplex DNA, and that in vitro binding of Sp1 to G-quadruplex is blocked by G4 ligand, suggesting that agents targeting telomeres interfere with virus reactivation. However, our studies show that G4 agents do not affect HIV-1 promoter activity in cell culture, and do not interfere with latency reversal. Importantly, primary memory CD4 + T cells infected with latent HIV-1 are more susceptible to combined treatment with LRAs and G4 ligands, indicating that drugs targeting TMM may enhance killing of HIV reservoirs. Using a cell-based DNA repair assay, we also found that HIV-1 infected cells have reduced efficiency of DNA mismatch repair (MMR), and base excision repair (BER), suggesting that altered TMM in latently infected cells could be associated with accumulation of DNA damage at telomeres and changes in telomeric caps.

RevDate: 2020-09-11

Leisen T, Bietz F, Werner J, et al (2020)

CRISPR/Cas with ribonucleoprotein complexes and transiently selected telomere vectors allows highly efficient marker-free and multiple genome editing in Botrytis cinerea.

PLoS pathogens, 16(8):e1008326.

CRISPR/Cas has become the state-of-the-art technology for genetic manipulation in diverse organisms, enabling targeted genetic changes to be performed with unprecedented efficiency. Here we report on the first establishment of robust CRISPR/Cas editing in the important necrotrophic plant pathogen Botrytis cinerea based on the introduction of optimized Cas9-sgRNA ribonucleoprotein complexes (RNPs) into protoplasts. Editing yields were further improved by development of a novel strategy that combines RNP delivery with cotransformation of transiently stable vectors containing telomeres, which allowed temporary selection and convenient screening for marker-free editing events. We demonstrate that this approach provides superior editing rates compared to existing CRISPR/Cas-based methods in filamentous fungi, including the model plant pathogen Magnaporthe oryzae. Genome sequencing of edited strains revealed very few additional mutations and no evidence for RNP-mediated off-targeting. The high performance of telomere vector-mediated editing was demonstrated by random mutagenesis of codon 272 of the sdhB gene, a major determinant of resistance to succinate dehydrogenase inhibitor (SDHI) fungicides by in bulk replacement of the codon 272 with codons encoding all 20 amino acids. All exchanges were found at similar frequencies in the absence of selection but SDHI selection allowed the identification of novel amino acid substitutions which conferred differential resistance levels towards different SDHI fungicides. The increased efficiency and easy handling of RNP-based cotransformation is expected to accelerate molecular research in B. cinerea and other fungi.

RevDate: 2020-09-17

Yamaguchi I, Ooe R, A Wang (2020)

Water-soluble oligofluorenes bearing N1-alkylcytosine side chains as turn-on and turn-off materials in telomere DNA length sensing.

Chemical communications (Cambridge, England), 56(74):10914-10917.

Water-soluble cationic and anionic oligofluorenes bearing N1-alkylcytosine side chains, namely OF-1 and OF-2, were synthesized. The photoluminescence (PL) intensity of an aqueous solution of OF-1 decreased on the addition of (TTAGGG)m as telomere DNA models. In contrast, the PL intensity of OF-2 increased on the addition of DNA.

RevDate: 2020-08-17

Koroleva AG, Evtushenko EV, Vershinin AV, et al (2020)

[Age Dynamics of Telomere Length in Endemic Baikal Planarians].

Molekuliarnaia biologiia, 54(4):616-625.

Age-related changes in telomere length (TL) in somatic tissues are not limited only to shortening. It is known that many organisms show different TL dynamics. Such species specificity indicates the complexity of the mechanisms involved in the regulation of TL. Owing to their morphological, physiological, and ecological features, Baikal planarians are an interesting model for studying the TL dynamics and the factors influencing it in comparison with species living outside Baikal. In this work, we investigated telomerase activity and age-related changes in TL in three endemic species of planarians from the Dendrocoelidae family. Two species are giant deep-water species (7-12 cm long, Sorocelis hepatizon and Rimacephalus arecepta), and one is a coastal shallow species (1 cm long, Baikalobia guttata). In addition, we investigated the telomere biology in another small Siberian species from the Planariidae family (2 cm in length, Phagocata sibirica), which is not found in Baikal. TL and telomerase activity were determined using real-time PCR and the TRAP method. Three types of age-related TL dynamics were detected with active telomerase: (1) TL shortening at the juvenile stage of development and subsequent maintenance (R. arecepta, Ph. sibirica), (2) gradual TL shortening during ontogeny (S. hepatizon) and (3) cyclic dynamics of TL (B. guttata). Thus, the changes of TL in the studied planarians does not have an obvious connection with body size, habitat depth, phylogenetic relationship and is probably a consequence of species features in the regulation of telomerase activity.

RevDate: 2020-08-18

Huang Z, Zhao X, Zhang H, et al (2020)

The association between mitochondrial DNA copy number, telomere length, and tubal pregnancy.

Placenta, 97:108-114.

Growing evidence has demonstrated association between the occurrence of tubal ectopic pregnancy (TP) and oxidative stress (OS) status, in which mitochondria and telomeres play important roles. However, little is known about the underlying correlation between TP and the mitochondrial DNA copy number (mtDNAcn) or telomere length (TL) abnormalities. In this study, we found OS level was elevated in TP patients. We hierarchically detected the relative mtDNAcn and TL of villi from normal pregnancy (NP) and TP samples according to different gestational age, fetal sex, maternal age, and BMI. The results revealed that the relative mtDNAcn was significantly lower in the villi in the TP group compared with the NP cohort, which was negatively correlated with OS status. In the NP group, the mtDNAcn in the female subgroup was apparently lower than that in the male subgroup, while no statistical difference was found in the mtDNAcn in the TP group between the female and male subgroups. Moreover, the relative TL in the TP group was at a similar level to the NP group, and no statistical correlation was observed between relative TL and OS level. In summary, our findings indicate that the abnormal level of mtDNAcn rather than TL is correlated with TP, which provides new insights into the mechanism of TP.

RevDate: 2020-08-18

Kohlrausch FB, DL Keefe (2020)

Telomere erosion as a placental clock: From placental pathologies to adverse pregnancy outcomes.

Placenta, 97:101-107.

The placenta provides nutritional and gas exchange between fetus and mother. Early in pregnancy, placental trophoblasts proliferate rapidly and invade aggressively. As pregnancy progresses, placental cells begin to age. Indeed, pregnancy itself has a tightly regulated duration, determined in large part by placental lifespan. Late in pregnancy, placental cells reach a senescent apoptotic state, activated by a number of intrinsic and extrinsic factors, including oxidative stress (OS), and DNA damage. Pregnancy complications, stillbirths and neonatal deaths have been related to OS and abnormal placental aging. Telomeres, the protective nucleoprotein structures at the ends of linear chromosomes, shorten both from cell replication and from exposure to OS. When telomeres become critically short they trigger cell cycle arrest and eventually cell death. Telomere attrition thus provide an intrinsic mechanism to explain tissue senescence and aging. Mounting evidence suggests that senescence of placental and fetal membrane cells results from telomere attrition. We review the studies that have addressed the role of telomere length (TL) in placentas from normal and complicated pregnancies, including pre-eclampsia, intrauterine growth restriction, gestational diabetes, and stillbirth. To date studies have uncovered associations between TL and a number of obstetrical complications. Future research is needed to determine whether these associations are causative, i.e. whether these clinical conditions result from telomere dysfunction, and whether particular features of telomeres, e.g. mean or shortest length, etc. could serve as clinically useful biomarkers of placental health.

RevDate: 2020-09-05

Sung JY, Lim HW, Joung JG, et al (2020)

Pan-Cancer Analysis of Alternative Lengthening of Telomere Activity.

Cancers, 12(8):.

Alternative lengthening of telomeres (ALT) is a telomerase-independent mechanism that extends telomeres in cancer cells. It influences tumorigenesis and patient survival. Despite the clinical significance of ALT in tumors, the manner in which ALT is activated and influences prognostic outcomes in distinct cancer types is unclear. In this work, we profiled distinct telomere maintenance mechanisms (TMMs) using 8953 transcriptomes of 31 different cancer types from The Cancer Genome Atlas (TCGA). Our results demonstrated that approximately 29% of cancer types display high ALT activity with low telomerase activity in the telomere-lengthening group. Among the distinct ALT mechanisms, homologous recombination was frequently observed in sarcoma, adrenocortical carcinoma, and kidney chromophobe. Five cancer types showed a significant difference in survival in the presence of high ALT activity. Sarcoma patients with elevated ALT had unfavorable risks (p < 0.038) coupled with a high expression of TOP2A, suggesting this as a potential drug target. On the contrary, glioblastoma patients had favorable risks (p < 0.02), and showed low levels of antigen-presenting cells. Together, our analyses highlight cancer type-dependent TMM activities and ALT-associated genes as potential therapeutic targets.

RevDate: 2020-09-05

Sharma R, N Martins (2020)

Telomeres, DNA Damage and Ageing: Potential Leads from Ayurvedic Rasayana (Anti-Ageing) Drugs.

Journal of clinical medicine, 9(8):.

Ageing, while a relentless, unidirectional and pleiotropic phenomenon of life, is a key trigger for several age-related disorders, such as cancer, cataract, osteoporosis, hypertension, cardiovascular (CV), metabolic and even neurodegenerative ailments, including Alzheimer's (AD) and Parkinson's (PD) disease [1] [...].

RevDate: 2020-08-12

Herrmann W, M Herrmann (2020)

The Importance of Telomere Shortening for Atherosclerosis and Mortality.

Journal of cardiovascular development and disease, 7(3): pii:jcdd7030029.

Telomeres are the protective end caps of chromosomes and shorten with every cell division. Short telomeres are associated with older age and adverse lifestyle factors. Leucocyte telomere length (LTL) has been proposed as a biomarker of biological age. The shortening of LTL with age is the result of the end-replication problem, environmental, and lifestyle-related factors. Epidemiologic studies have shown that LTL predicts cardiovascular disease, all-cause mortality, and death from vascular causes. Age appears to be an important co-variate that explains a substantial fraction of this effect. Although it has been proposed that short telomeres promote atherosclerosis and impair the repair of vascular lesions, existing results are inconsistent. Oxidative stress and chronic inflammation can both accelerate telomere shortening. Multiple factors, including homocysteine (HCY), vitamin B6, and vitamin B12 modulate oxidative stress and inflammation through direct and indirect mechanisms. This review provides a compact overview of telomere physiology and the utility of LTL measurements in atherosclerosis and cardiovascular disease. In addition, it summarizes existing knowledge regarding the impact of oxidative stress, inflammation, HCY, and B-vitamins on telomere function.

RevDate: 2020-09-21

Cowell W, Colicino E, Tanner E, et al (2020)

Prenatal toxic metal mixture exposure and newborn telomere length: Modification by maternal antioxidant intake.

Environmental research, 190:110009 pii:S0013-9351(20)30906-3 [Epub ahead of print].

BACKGROUND: Telomere length (TL) predicts the onset of cellular senescence and correlates with longevity and age-related disease risk. While telomeres erode throughout life, adults display fixed ranking and tracking of TL, supporting the importance of the early environment in determining inter-individual variability across the life course. Given their guanine-rich structure, telomeres are highly susceptible to oxidative stress (OS). We examined maternal metal exposure, which can induce OS, in relation to newborn TL. We also considered the modifying role of maternal antioxidant intake.

METHODS: Analyses included 100 mother-newborn pairs enrolled in the Boston and New York City-based PRogramming of Intergenerational Stress Mechanisms (PRISM) pregnancy cohort. We measured As, Ba, Cd, Ni, and Pb in maternal late-pregnancy urine by ICP-MS and quantified relative leukocyte TL (rLTL) in cord blood using qPCR. We used Weighted Quantile Sum (WQS) regression to estimate the metal mixture - rLTL association and conducted repeated holdout validation to improve the stability of estimates across data partitions. We examined models stratified by high (>median) versus low (≤median) maternal antioxidant intake, estimated from Block98 Food Frequency Questionnaires. We considered urinary creatinine, week of urine collection, maternal age, and race/ethnicity as covariates.

RESULTS: In adjusted models, urinary metals were inversely associated with newborn rLTL (βWQS = -0.50, 95% CI: -0.78, -0.21). The top metals contributing to the negative association included Ba (weight: 35.4%), Cd (24.5%) and Pb (26.9%). In models stratified by antioxidant intake, the significant inverse association between metals and rLTL remained only among mothers with low antioxidant intake (low: βWQS = -0.92, 95% CI: -1.53, -0.30; high: βWQS = -0.03, 95% CI: -0.58, 0.52). Results were similar in unadjusted models.

CONCLUSIONS: Relative LTL was shorter among newborns of mothers with higher exposure to metals during pregnancy. Higher maternal antioxidant intake may mitigate the negative influence of metals on newborn rLTL.

RevDate: 2020-08-16

Liu J, Hong X, Liang CY, et al (2020)

Simultaneous visualisation of the complete sets of telomeres from the MmeI generated terminal restriction fragments in yeasts.

Yeast (Chichester, England) [Epub ahead of print].

Telomere length is measured using Southern blotting of the chromosomal terminal restriction fragments (TRFs) released by endonuclease digestion in cells from yeast to human. In the budding yeast Saccharomyces cerevisiae, XhoI or PstI is applied to cut the subtelomere Y' element and release TRFs from the 17 subtelomeres. However, telomeres from other 15 X-element-only subtelomeres are omitted from analysis. Here, we report a method for measuring all 32 telomeres in S. cerevisiae using the endonuclease MmeI. Based on analyses of the endonuclease cleavage sites, we found that the TRFs generated by MmeI displayed two distinguishable bands in the sizes of ~500 and ~700 bp comprising telomeres (300 bp) and subtelomeres (200-400 bp). The modified MmeI-restricted TRF (mTRF) method recapitulated telomere shortening and lengthening caused by deficiencies of YKu and Rif1 respectively in S. cerevisiae. Furthermore, we found that mTRF was also applicable to telomere length analysis in S. paradoxus strains. These results demonstrate a useful tool for simultaneous detection of telomeres from all chromosomal ends with both X-element-only and Y'-element subtelomeres in S. cerevisiae species.

RevDate: 2020-08-10

Aramburu T, Plucinsky S, E Skordalakes (2020)

POT1-TPP1 telomere length regulation and disease.

Computational and structural biotechnology journal, 18:1939-1946.

Telomeres are DNA repeats at the ends of linear chromosomes and are replicated by telomerase, a ribonucleoprotein reverse transcriptase. Telomere length regulation and chromosome end capping are essential for genome stability and are mediated primarily by the shelterin and CST complexes. POT1-TPP1, a subunit of shelterin, binds the telomeric overhang, suppresses ATR-dependent DNA damage response, and recruits telomerase to telomeres for DNA replication. POT1 localization to telomeres and chromosome end protection requires its interaction with TPP1. Therefore, the POT1-TPP1 complex is critical to telomere maintenance and full telomerase processivity. The aim of this mini-review is to summarize recent POT1-TPP1 structural studies and discuss how the complex contributes to telomere length regulation. In addition, we review how disruption of POT1-TPP1 function leads to human disease.

RevDate: 2020-09-21

Utyro O, Perła-Kaján J, Kubalska J, et al (2020)

Telomere length and mtDNA copy number in human cystathionine β-synthase deficiency.

Free radical biology & medicine, 160:219-226 pii:S0891-5849(20)31183-7 [Epub ahead of print].

Telomere shortening and mitochondrial DNA (mtDNA) copy number are associated with human disease and a reduced life span. Cystathionine β-synthase (CBS) is a housekeeping enzyme that catalyzes the first step in metabolic conversion of homocysteine (Hcy) to cysteine. Mutations in the CBS gene cause CBS deficiency, a rare recessive metabolic disease, manifested by severe hyperhomocysteinemia (HHcy) and thromboembolism, which ultimately reduces the life span. However, it was not known whether telomere shortening or mtDNA is involved in the pathology of human CBS deficiency. We quantified leukocyte telomere length (TL), mtDNA copy number, and plasma Hcy levels in CBS-/- patients (n = 23) and in sex- and age-matched unaffected CBS+/+ control individuals (n = 28) 0.08-57 years old. We found that TL was significantly increased in severely HHcy CBS-/- female patients but unaffected in severely HHcy CBS-/- male patients, relative to the corresponding CBS+/+ controls who had normal plasma Hcy levels. In multiple regression analysis TL was associated with CBS genotype in women but not in men. MtDNA copy number was not significantly affected by the CBS-/- genotype. Taken together, these findings identify the CBS gene as a new locus in human DNA that affects TL in women and illustrate a concept that a housekeeping metabolic gene can be involved in telomere biology. Our findings suggest that neither telomere shortening nor reduced mtDNA copy number contribute to the reduced life span in CBS-/- patients.

RevDate: 2020-08-08

Lopes AC, Oliveira PF, Pinto S, et al (2020)

Discordance between human sperm quality and telomere length following differential gradient separation/swim-up.

Journal of assisted reproduction and genetics pii:10.1007/s10815-020-01897-1 [Epub ahead of print].

BACKGROUND: Strong evidence has suggested an important role of telomeres in meiosis, fertilization, and embryo development.

PURPOSE: To determine if sperm telomere length (STL) in sperm purified by differential gradient centrifugation followed by swim-up (selected STL) is correlated with sperm quality and clinical outcomes.

METHODS: Relative selected STL was assessed by quantitative polymerase chain reaction (Q-PCR) in 78 consecutive assisted reproductive technology (ART) treatments during 2017. Statistical analyses were performed in the totality of patients, and in normozoospermic and non-normozoospermic patients. These included correlations between selected STL and sperm quality parameters, embryological parameters (multivariable linear regression), and clinical parameters (multivariable logistic regression).

RESULTS: No significant correlations were found between selected STL and sperm quality in the total population. However, selected STL was significantly correlated with total sperm count (r = 0.361; P = 0.039) and sperm DNA fragmentation-post-acrosomal region pattern (r = - 0.464; P = 0.030) in normozoospermic patients. No relation was observed between selected STL and clinical outcomes in any clinical group.

CONCLUSIONS: As the correlations observed in normozoospermic patients were not representative of the whole heterogeneous population, differences in the sperm characteristics of the study population may lead to discrepant results when evaluating the association of STL with sperm quality. Since the total population selected STL was not related with sperm quality and with clinical outcomes, results do not support the use of selected STL measurement to evaluate the reproductive potential of the male patient or to predict the success rates of ART treatments.

RevDate: 2020-08-08

Ajaykumar A, Wong GC, Yindom LM, et al (2020)

Shorter granulocyte telomeres among children and adolescents with perinatally-acquired HIV infection and chronic lung disease in Zimbabwe.

Clinical infectious diseases : an official publication of the Infectious Diseases Society of America pii:5885189 [Epub ahead of print].

BACKGROUND: Chronic lung disease (CLD) has been reported among African children with perinatally-acquired HIV infection (C-PHIV), despite combination antiretroviral therapy (cART). In adults, shorter telomere length (TL) has been reported in association with both CLD and HIV. As little is known in children, our objective was to compare TL in HIV+ (cART-naïve or treated) and HIV-negative children with and without CLD.

METHODS: Participants included Zimbabwean C-PHIV, aged 6-16, who were either newly diagnosed and cART-naïve, or on cART for >6 months, and HIV-negative controls of similar age and sex. Packed blood cell (granulocyte) TL from 621 children were compared cross-sectionally between groups. For a subset of newly diagnosed C-PHIV, changes in TL following cART initiation was evaluated.

RESULTS: C-PHIV had shorter granulocyte TL compared to uninfected peers, regardless of cART. Among 255 C-PHIV without CLD, TL was shorter in cART-naïve participants. In multivariable analyses adjusted for age, sex, CLD, and HIV/cART status, shorter TL was independently associated with older age, being HIV+, and having reduced forced vital capacity (FVC). Lastly, cART initiation increased TL.

CONCLUSIONS: In this cohort, C-PHIV and those with reduced FVC have shorter granulocyte TL, possibly the result of increased immune activation and cellular turnover due to long-standing HIV infection with delayed cART initiation.

RevDate: 2020-08-11

Manoy P, Yuktanandana P, Tanavalee A, et al (2020)

Telomere shortening is associated with poor physical performance in knee osteoarthritis.

Biomedical reports, 13(4):27.

Telomere length is a hallmark characteristic of ageing and age-related diseases. Osteoarthritis (OA) is the most common cause of joint pain and physical disability in the elderly. Previous studies have revealed the role of telomere shortening in OA; however, the relationship between telomere length, muscle strength and physical performance in knee OA patients remains unknown. The aim of the present study was to investigate the association of telomere length and physical performance in patients with knee OA. A total of 202 patients with knee OA and 60 healthy controls were enrolled in the study. The quality of life was assessed using Western Ontario and McMaster Universities Osteoarthritis (WOMAC) index and Short Form Health Survey. The skeletal muscle mass was examined using bioelectrical impedance analysis, while the muscle strength was analyzed using hand grip force and isometric knee extension force. The physical performance of patients with knee OA was also investigated using gait speed, Timed up and go test (TUGT), Sit to stand test and 6-min walk test (6MWT). Blood leukocyte relative telomere length (RTL) was assessed using real time quantitative PCR. The mean blood leukocyte RTL in knee OA subjects was significantly lower compared with healthy controls (P<0.001). Knee OA patients with RTL values in the lowest quartile had a slow gait speed (P=0.006) and prolonged TUGT time (P=0.03). Multivariate regression analyses and multiple logistic regression analyses adjusted for age, sex, waist circumference, body mass index, fat mass, skeletal muscle index and the total WOMAC demonstrated that gait speed, TUGT and 6MWT were associated with longer RTL (P-trend<0.05). These findings suggested that poorer physical performance was associated with shorter RTL. Therefore, leukocyte telomere length and physical performance tests, especially gait speed, TUGT and 6MWT, could predict the health status and quality of life in patients with knee OA.

RevDate: 2020-09-15
CmpDate: 2020-09-15

Miri M, de Prado-Bert P, Alahabadi A, et al (2020)

Association of greenspace exposure with telomere length in preschool children.

Environmental pollution (Barking, Essex : 1987), 266(Pt 1):115228.

Exposure to greenspace has been associated with a wide range of health benefits; however, the available evidence on the association of this exposure with telomere length (TL), an early marker of ageing, is still scarce. We investigated the association of greenspace exposure with TL in a sample of 200 preschool children (aged 5-7 years) residing in Sabzevar, Iran (2017). We comprehensively characterized different aspects of greenspace exposure encompassing residential, kindergarten, and total (including both residential and kindergarten) surrounding greenspace (using satellite-derived Normalized Difference Vegetation Index), residential and kindergarten distance to green spaces, time spent in private gardens and public green spaces, and the number of plant pots at home. Relative leukocyte TL (LTL) in blood samples of the study participants was measured using quantitative polymerase chain reaction (qPCR). We applied mixed effects linear regression models with kindergarten and qPCR plate as random effects, to estimate the association of indicators of greenspace exposure (one at a time) with LTL, controlled for relevant covariates. We observed an inverse association between distance from home and kindergarten to green spaces larger than 5000 m2 and LTL. Moreover, higher total surrounding greenspace at 300m and 500m buffers and higher surrounding greenspace at 300m buffer around kindergarten and home were associated with longer LTL. Furthermore, longer time spent (h/week) in the public green spaces was associated with longer LTL. Our findings for residential and kindergarten distance to any green space (regardless of the size), residential surrounding greenspace at 100m and 500m buffers, kindergarten surrounding greenspace at 100m buffer, time spent in private gardens (h/week) and the number of plant pots at home were not conclusive. Our findings were generally suggestive for a positive association between greenspace exposure and LTL in preschool children. More studies are needed to confirm these findings in other settings with different climates and populations.

RevDate: 2020-08-27

Hudon SF, Palencia Hurtado E, Beck JD, et al (2020)

Primers to highly conserved elements optimized for qPCR-based telomere length measurement in vertebrates.

Molecular ecology resources [Epub ahead of print].

Telomere length dynamics are an established biomarker of health and ageing in animals. The study of telomeres in numerous species has been facilitated by methods to measure telomere length by real-time quantitative PCR (qPCR). In this method, telomere length is determined by quantifying the amount of telomeric DNA repeats in a sample and normalizing this to the total amount of genomic DNA. This normalization requires the development of genomic reference primers suitable for qPCR, which remains challenging in nonmodel organism with genomes that have not been sequenced. Here we report reference primers that can be used in qPCR to measure telomere lengths in any vertebrate species. We designed primer pairs to amplify genetic elements that are highly conserved between evolutionarily distant taxa and tested them in species that span the vertebrate tree of life. We report five primer pairs that meet the specificity and reproducibility standards of qPCR. In addition, we demonstrate an approach to choose the best primers for a given species by testing the primers on multiple individuals within a species and then applying an established computational tool. These reference primers can facilitate qPCR-based telomere length measurements in any vertebrate species of ecological or economic interest.

RevDate: 2020-08-07

Yeap BB, Hui J, Knuiman MW, et al (2020)

U-shaped relationship of leucocyte telomere length with all-cause and cancer-related mortality in older men.

The journals of gerontology. Series A, Biological sciences and medical sciences pii:5881858 [Epub ahead of print].

BACKGROUND: Telomeres are essential DNA-protein complexes whose attrition results in cellular dysfunction and senescence. Leucocyte telomere length (LTL) correlates with tissue telomere length, representing a biomarker for biological age. However its predictive value for mortality risk, and for cardiovascular vs cancer deaths, in older adults remains uncertain.

METHODS: We studied 3,608 community-dwelling men aged 77.0±3.6 years. LTL was measured using multiplex quantitative PCR, expressed as amount of telomeric DNA relative to single-copy control gene (T/S ratio). Deaths from any cause, cardiovascular disease (CVD) and cancer were ascertained using data linkage. Curve fitting used restricted cubic splines and Cox regression analyses adjusted for age, cardiometabolic risk factors and prevalent disease.

RESULTS: There was a U-shaped association of LTL with all-cause mortality. Men with T/S ratio in the middle quartiles had lower mortality (quartiles, Q2 vs Q1, hazard ratio HR=0.86, 95% confidence interval CI=0.77-0.97, p=0.012, Q3 vs Q1 HR=0.88, CI=0.79-0.99, p=0.032). There was no association of LTL with CVD mortality. There was a U-shaped association of LTL with cancer mortality. Men with LTL in the middle quartiles had lower risk of cancer death (Q2 vs Q1, HR=0.73, CI=0.59-0.90, p=0.004, Q3 vs Q1, HR=0.75, CI=0.61-0.92, p=0.007).

CONCLUSIONS: In older men both shorter and longer LTL are associated with all-cause mortality. A similar U-shaped association was seen with cancer deaths, with no association found for cardiovascular deaths. Further research is warranted to explore the prognostic utility of LTL in ageing.

RevDate: 2020-08-08

Levstek T, Kozjek E, Dolžan V, et al (2020)

Telomere Attrition in Neurodegenerative Disorders.

Frontiers in cellular neuroscience, 14:219.

Telomere attrition is increased in various disorders and is therefore a potential biomarker for diagnosis and/or prognosis of these disorders. The contribution of telomere attrition in the pathogenesis of neurodegenerative disorders is yet to be fully elucidated. We are reviewing the current knowledge regarding the telomere biology in two common neurodegenerative disorders, Alzheimer's disease (AD), and Parkinson's disease (PD). Furthermore, we are discussing future prospective of telomere research in these disorders. The majority of studies reported consistent evidence of the accelerated telomere attrition in AD patients, possibly in association with elevated oxidative stress levels. On the other hand in PD, various studies reported contradictory evidence regarding telomere attrition. Consequently, due to the low specificity and sensitivity, the clinical benefit of telomere length as a biomarker of neurodegenerative disease development and progression is not yet recognized. Nevertheless, longitudinal studies in large carefully selected cohorts might provide further elucidation of the complex involvement of the telomeres in the pathogenesis of neurodegenerative diseases. Telomere length maintenance is a complex process characterized by environmental, genetic, and epigenetic determinants. Thus, in addition to the selection of the study cohort, also the selection of analytical methods and types of biological samples for evaluation of the telomere attrition is of utmost importance.

RevDate: 2020-08-17

Segura-Bayona S, Villamor-Payà M, Attolini CS, et al (2020)

Tousled-Like Kinases Suppress Innate Immune Signaling Triggered by Alternative Lengthening of Telomeres.

Cell reports, 32(5):107983.

The Tousled-like kinases 1 and 2 (TLK1/2) control histone deposition through the ASF1 histone chaperone and influence cell cycle progression and genome maintenance, yet the mechanisms underlying TLK-mediated genome stability remain uncertain. Here, we show that TLK loss results in severe chromatin decompaction and altered genome accessibility, particularly affecting heterochromatic regions. Failure to maintain heterochromatin increases spurious transcription of repetitive elements and induces features of alternative lengthening of telomeres (ALT). TLK depletion culminates in a cGAS-STING-TBK1-mediated innate immune response that is independent of replication-stress signaling and attenuated by the depletion of factors required to produce extra-telomeric DNA. Analysis of human cancers reveals that chromosomal instability correlates with high TLK2 and low STING levels in many cohorts. Based on these findings, we propose that high TLK levels contribute to immune evasion in chromosomally unstable and ALT+ cancers.

RevDate: 2020-08-24

Fang B, Yan E, Tung K, et al (2020)

Association between elder abuse and telomere shortening in older adults: A 2-year prospective study.

International journal of geriatric psychiatry [Epub ahead of print].

BACKGROUNDS: Elder abuse is a public health issue associated with increased morbidity and mortality. Its impact on victims' health at the cellular level, however, remains unknown. This study assessed the association between abuse exposure and shortening of telomere length (TL), a promising molecular marker for biological aging, in older victims.

SETTING: The geriatric departments of three Grade-A hospitals in the People's Republic of China (PRC).

PARTICIPANTS: Six hundred Chinese older adults, including 300 abused victims and 300 non-abused controls were randomly drawn respectively from a larger sample of 467 abused and 518 non-abused older adults recruited at baseline. Participants were assessed for physical and psychological abuse exposure at baseline between September 2015 and February 2016 and assessed for TL 2 years after the abuse assessment.

MEASUREMENTS: TL was quantified using a quantitative PCR method and expressed as T/S ratio (the ratio of telomere repeat copy numbers to single-copy gene numbers). Physical and psychological abuse was measured using the Revised Conflicts Tactics Scale.

RESULTS: Adjusting for demographic, medical, and behavioral confounders, physical and psychological abuse exposure at baseline were independently associated with shorter TL at follow-up. The association was the most significant between multiple forms of abuse (physical and psychological) exposure and shorter TL.

CONCLUSION: This study provides the first evidence on the relationship between abuse and shortened TL in older victims, implying the potential effect of elder abuse on accelerated cellular aging. The findings suggest the importance of routinely assessing and intervening abuse in older adults by healthcare professionals, to promote and maintain physical health in older adults.

RevDate: 2020-09-07

Seeker LA (2020)

Telomere shortening correlates with harsh weather conditions in the bat species Myotis myotis.

Molecular ecology, 29(16):2951-2953.

The relationship of telomere shortening and cellular ageing in cultured cells such as fibroblasts is straightforward: telomeres shorten with an increasing number of cell divisions until they trigger replicative senescence which prevents further mitotic cycles. But studies investigating the relationship between telomere shortening and ageing in whole organisms show contrasting results: while there is a clear decline in telomere length (TL) with chronological age in some species such as humans, no such decline is observed in others. In this issue of Molecular Ecology, Foley et al. (2020) show that experiencing harsh weather conditions correlates with longitudinal telomere shortening in the bat species Myotis myotis, whereas chronological age does not (Foley et al., 2020). Further, the authors investigated whether genetics influence TL and find a low heritability (h2 = 0.01-0.06) again suggesting that environmental effects are the dominant drivers of variation in TL in this species. These are important findings as there is disagreement in the literature about the relative magnitude of genetic and environmental effects contributing to TL variation in different species. This paper investigating the impact of environmental effects makes a novel and important contribution to the literature on TL in free-living mammals.

RevDate: 2020-08-03

Kirschner M, Vieri M, Kricheldorf K, et al (2020)

Androgen derivatives improve blood counts and elongate telomere length in adult cryptic dyskeratosis congenita.

British journal of haematology [Epub ahead of print].

Dyskeratosis Congenita (DKC) is a systemic disorder caused by mutations resulting in impaired telomere maintenance. Clinical features include bone marrow failure and an increased risk of developing hematological malignancies. There are conflicting data whether androgen derivatives (AD) can elongate telomeres in vivo and whether AD treatment enhances the risk of gaining myelodysplastic syndrome-related mutations. Seven TERC or TERT-mutated DKC patients underwent AD treatment. All patients revealed hematological response. Telomere length of lymphocytes and granulocytes increased significantly and no MDS-related mutations were detected. Pending longer follow-up, treatment with AD seems to represent an efficient and safe therapy for DKC patients.

RevDate: 2020-08-04

Olsson M, Geraghty NJ, Wapstra E, et al (2020)

Telomere length varies substantially between blood cell types in a reptile.

Royal Society open science, 7(6):192136.

Telomeres are repeat sequences of non-coding DNA-protein molecules that cap or intersperse metazoan chromosomes. Interest in telomeres has increased exponentially in recent years, to now include their ongoing dynamics and evolution within natural populations where individuals vary in telomere attributes. Phylogenetic analyses show profound differences in telomere length across non-model taxa. However, telomeres may also differ in length within individuals and between tissues. The latter becomes a potential source of error when researchers use different tissues for extracting DNA for telomere analysis and scientific inference. A commonly used tissue type for assessing telomere length is blood, a tissue that itself varies in terms of nuclear content among taxa, in particular to what degree their thrombocytes and red blood cells (RBCs) contain nuclei or not. Specifically, when RBCs lack nuclei, leucocytes become the main source of telomeric DNA. RBCs and leucocytes differ in lifespan and how long they have been exposed to 'senescence' and erosion effects. We report on a study in which cells in whole blood from individual Australian painted dragon lizards (Ctenophorus pictus) were identified using flow cytometry and their telomere length simultaneously measured. Lymphocyte telomeres were on average 270% longer than RBC telomeres, and in azurophils (a reptilian monocyte), telomeres were more than 388% longer than those in RBCs. If this variation in telomere length among different blood cell types is a widespread phenomenon, and DNA for comparative telomere analyses are sourced from whole blood, evolutionary inference of telomere traits among taxa may be seriously complicated by the blood cell type comprising the main source of DNA.

RevDate: 2020-08-04

Li Z, Song Y, Xu Y, et al (2020)

Identification of Leukocyte telomere length-related genetic variants contributing to predisposition of Esophageal Squamous Cell Carcinoma.

Journal of Cancer, 11(17):5025-5031.

Background: Cancers may arise from cells with dysregulated telomeric functions due to shorten telomere length. We and others previously found that short leukocyte telomere length was associated with markedly evaluated risk of esophageal squamous cell carcinoma (ESCC). Hence, we hypothesized that single nucleotide polymorphisms (SNPs) associated with shorter telomere length may contribute to ESCC predisposition. Methods: We systematically evaluated association between seven candidate seven SNPs (CXCR4 rs6430612, TERT rs13172201, TERT rs10069690, TERT rs2853676, TERT rs451360, OBFC1 rs4387287, and VPS34 rs2162440) and ESCC risk in two case-control sets consisting of 1588 ESCC cases and 1600 controls. Logistic regression models were utilized to estimate associations between SNPs and ESCC susceptibility and odds ratios (ORs) and their 95% confidence intervals (95% CIs) were computed. Results: We firstly identified three SNPs (rs6430612, rs13172201 and rs4387287) which are significantly associated with telomere length in Chinese populations (all P<0.05). Importantly, CXCR4 rs6430612 and OBFC1 rs4387287 polymorphisms significantly confer reduced risk of ESCC (P=1.7×10-7 and P=3.9×10-5). On the contrary, we observed an evidently increased risk for ESCC development associated with TERT rs13172201 genetic variant (P=2.2×10-4). Conclusions: In summary, rs6430612, rs13172201 and rs4387287 might be key genetic components in complicated regulation of telomere length and contributing to ESCC predisposition. Our results elucidate the prevalent involvement of genetic variants in telomere biology and further provide pathogenic insights into the role of telomeres in cancer development.

RevDate: 2020-08-04

Davis SK, Xu R, Khan RJ, et al (2020)

Adiposity and Leukocyte Telomere Length in US Adults by Sex-Specific Race/Ethnicity: National Health and Nutrition Examination Survey.

Ethnicity & disease, 30(3):441-450.

Objective: Little is known about the relationship between adiposity and telomere length in the United States population. The objective of our research was to examine this relationship in a representative, socioeconomically and sex-specific, diverse racial/ethnic population in the United States.

Methods: Body mass index (BMI), % total body fat (TBF) and waist circumference (WC) with leukocyte telomere length (LTL) were examined according to sex-specific race/ethnicity using separate adjusted multivariate linear regressions on a sample of 4,919 respondents aged 20-84 years from the National Health and Nutrition Examination Survey's 1999-2002 data.

Results: LTL was shortened .41%, .44%, and .16% in African American (AA) women and was associated with increasing BMI, %TBF, and WC, (β:-.0041, 95%CI: -.0070, -.0012; P=.007; β:-.0044, 95% CI: -.0081, -.0007; P=.02; β:-.0016, 95%CI: -.0031, -.0001; P=.04, respectively). LTL was shortened .29% in White women and was associated with increasing %TBF (β:-.0029, 95%CI: -.0048, -.0009; P=.006). There were no associations among AA men, White men or Mexican American men and women.

Conclusions: LTL is associated with an obesity phenotype in AA women. Tailored intervention is needed to ameliorate the burden of excess adiposity and subsequent cellular aging.

RevDate: 2020-08-03

Peña E, Powell TR, Arenas C, et al (2020)

Longitudinal changes in telomere length in a cohort of obese patients submitted to bariatric surgery: a 2-year follow-up.

Surgery for obesity and related diseases : official journal of the American Society for Bariatric Surgery pii:S1550-7289(20)30347-6 [Epub ahead of print].

BACKGROUND: Telomere length (TL) is one biomarker of cell aging used to explore the effects of the environment on age-related pathologies. Obesity and high body mass index have been identified as a risk factors for shortened TL.

OBJECTIVE: To evaluate TL in different subtypes of obese patients, and to examine changes in TL in relation to weight loss after bariatric surgery.

SETTING: University Hospital in Spain.

METHODS: A cohort of 94 patients submitted to bariatric surgery were followed-up during 24 months (t24m: lost to follow-up = 0%). All patients were evaluated before surgery (t0) and during the postoperative period (t6m, t12m, and t24m) for body mass index and metabolic variables. We assessed TL at each timepoint using quantitative polymerase chain reactions and the telomere sequence to single-copy gene sequence ratio method.

RESULTS: Patients with class III obesity showed significantly shorter TL at baseline than those patients with class II obesity (P = .027). No differences in TL were found between patients with or without type 2 diabetes or metabolic syndrome. Longitudinal analysis did not show an effect of time, type of surgery, age, or sex on TL. However, a generalized estimating equation model showed that TL was shorter amongst class III obesity patients across the time course (P = .008). Comparison between patients with obesity class II and class III showed differences in TL at t6m (adjusted P = .024), whereby class II patients had longer TL. However, no difference was observed at the other evaluated times.

CONCLUSION: Obesity severity may have negative effects on TL independently of type 2 diabetes or metabolic syndrome. Although TL is significantly longer in class II obesity patients relative to class III 6 months after bariatric surgery. This difference is not apparent after 24 months.

RevDate: 2020-07-31

Heidinger BJ, RC Young (2020)

Cross-Generational Effects of Parental Age on Offspring Longevity: Are Telomeres an Important Underlying Mechanism?.

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

Parental age at offspring conception often influences offspring longevity, but the mechanisms underlying this link are poorly understood. One mechanism that may be important is telomeres, highly conserved, repetitive sections of non-coding DNA that form protective caps at chromosome ends and are often positively associated with longevity. Here, the potential pathways by which the age of the parents at the time of conception may impact offspring telomeres are described first, including direct effects on parental gamete telomeres and indirect effects on offspring telomere loss during pre- or post-natal development. Then a surge of recent studies demonstrating the effects of parental age on offspring telomeres in diverse taxa are reviewed. In doing so, important areas for future research and experimental approaches that will enhance the understanding of how and when these effects likely occur are highlighted. It is concluded by considering the potential evolutionary consequences of parental age on offspring telomeres.

RevDate: 2020-08-01

Achrem M, Szućko I, A Kalinka (2020)

The epigenetic regulation of centromeres and telomeres in plants and animals.

Comparative cytogenetics, 14(2):265-311.

The centromere is a chromosomal region where the kinetochore is formed, which is the attachment point of spindle fibers. Thus, it is responsible for the correct chromosome segregation during cell division. Telomeres protect chromosome ends against enzymatic degradation and fusions, and localize chromosomes in the cell nucleus. For this reason, centromeres and telomeres are parts of each linear chromosome that are necessary for their proper functioning. More and more research results show that the identity and functions of these chromosomal regions are epigenetically determined. Telomeres and centromeres are both usually described as highly condensed heterochromatin regions. However, the epigenetic nature of centromeres and telomeres is unique, as epigenetic modifications characteristic of both eu- and heterochromatin have been found in these areas. This specificity allows for the proper functioning of both regions, thereby affecting chromosome homeostasis. This review focuses on demonstrating the role of epigenetic mechanisms in the functioning of centromeres and telomeres in plants and animals.

RevDate: 2020-09-17

Yu J, Liu H, He S, et al (2020)

Corrigendum to "Dietary Magnesium Intake and Leukocyte Telomere Attrition in Adults: The Regulatory Role of Serum Tumor Necrosis Factor α".

Mediators of inflammation, 2020:2594730.

[This corrects the article DOI: 10.1155/2020/7610436.].

RevDate: 2020-09-05

Molina-Carrión S, Brochado-Kith Ó, González-García J, et al (2020)

Telomere Length Increase in HIV/HCV-Coinfected Patients with Cirrhosis after HCV Eradication with Direct-Acting Antivirals.

Journal of clinical medicine, 9(8):.

INTRODUCTION: Human immunodeficiency virus (HIV) infection and cirrhosis are associated with a senescent phenotype that decreases telomere length. We evaluated the impact of hepatitis C virus (HCV) elimination on telomere length in patients with advanced HCV-related cirrhosis after sustained virological response (SVR), with all-oral direct-acting antiviral agents (DAAs).

METHODS: Prospective study of 60 HIV/HCV-coinfected and 30 HCV-monoinfected patients with advanced HCV cirrhosis (liver decompensation or liver stiffness measurement (LSM) ≥ 25 kPa, hepatic liver pressure gradient (HVPG) ≥ 10 mmHg, or Child-Pugh-Turcotte (CPT) ≥ 7). The relative telomere length (RTL) was quantified by real-time multiplex PCR (MMqPCR) on peripheral blood mononuclear cells at baseline and 48 weeks after HCV treatment. Generalized linear models (GLMs) adjusted for the most relevant clinical and epidemiological variables and mixed GLMs were used.

RESULTS: In comparison with HCV-monoinfected patients, HIV/HCV-coinfected patients were younger (p < 0.001), had lower body mass index (BMI) (p = 0.002), and had been exposed less frequently to interferons (p = 0.011). In addition, they were more frequently men (p = 0.011), smokers (p = 0.005), prior intravenous drug users (IVDUs) (p < 0.001), and alcohol abusers (p = 0.005). RTL was significantly lower in HIV/HCV-coinfected patients than in HCV-monoinfected patients, both at baseline (p < 0.001), and at the end of follow-up (p = 0.032). A significant RTL increase over time was found only for HIV/HCV-coinfected patients (p < 0.001), especially in those patients with compensated cirrhosis (p < 0.001).

CONCLUSION: HCV eradication with all-oral DAAs was associated with an increase in telomere length in HIV/HCV-coinfected patients with advanced cirrhosis, particularly in compensated patients. This finding suggests that HCV clearance may have implications in age-related conditions in this population group.

RevDate: 2020-07-30

Canudas S, Becerra-Tomás N, Hernández-Alonso P, et al (2020)

Mediterranean Diet and Telomere Length: A Systematic Review and Meta-Analysis.

Advances in nutrition (Bethesda, Md.) pii:5879005 [Epub ahead of print].

Accelerated telomere shortening has been associated with several age-related diseases and/or decreased lifespan in humans. The Mediterranean diet (MedDiet) is considered to be 1 of the most recognized diets for disease prevention and healthy aging, partially due to its demonstrated anti-inflammatory and antioxidative properties which may impact on telomere length (TL). The aim of this meta-analysis was to determine the associations between MedDiet adherence and TL maintenance. MEDLINE-PubMed and Cochrane databases were searched up to December 2018 for studies evaluating the association between MedDiet adherence and TL in blood cells. Two reviewers, working independently, screened all titles and abstracts to identify studies that met the inclusion criteria [cross-sectional, case-control, and prospective cohort studies and randomized clinical trials (RCTs) published in English and excluded nonoriginal articles]. Data were pooled by the generic inverse variance method using the random effects model and expressed as standardized mean difference (SMD). Heterogeneity was identified using the Cochran Q test and quantified by the I2 statistic. A total of 8 original cross-sectional studies were included for the quantitative meta-analysis, comprising a total of 13,733 participants from 5 countries. A positive association between adherence to the MedDiet and TL was observed in all meta-analyses, with the exception of those conducted only in men: SMD (95% CI) of 0.130 (0.029; 0.231) for all subjects, 0.078 (0.005; 0.152) for women, and 0.095 (-0.005; 0.195) for men. Only 1 prospective cohort study and 1 RCT were identified, therefore, we could not undertake a meta-analysis for these study designs. The present meta-analysis of cross-sectional studies demonstrates that higher MedDiet adherence is associated with longer TL. At the same time, larger and high-quality prospective studies and clinical trials are warranted to confirm this association.

RevDate: 2020-09-08

McAninch D, Bianco-Miotto T, Gatford KL, et al (2020)

The metabolic syndrome in pregnancy and its association with child telomere length.

Diabetologia, 63(10):2140-2149.

AIMS/HYPOTHESIS: The aim of this study was to determine whether presence of the metabolic syndrome in pregnancy associates with child telomere length or child anthropometry (weight, BMI) and BP, measured at 10 years of age.

METHODS: The Screening for Pregnancy Endpoints study (SCOPE) was a multicentre, international prospective cohort of nulliparous pregnant women recruited from Australia, New Zealand, Ireland and the UK (N = 5628). The current analysis is a 10 year follow-up of SCOPE pregnant women and their children, from the Australian cohort. Clinical data collected at 14-16 weeks' gestation during the SCOPE study were used to diagnose the metabolic syndrome using IDF criteria. Telomere length, a biomarker of ageing, was assessed by quantitative PCR from children's saliva collected at 10 years of age.

RESULTS: In women who completed follow-up (n = 255), 20% had the metabolic syndrome in pregnancy. After adjusting for a range of confounders, children of mothers who had the metabolic syndrome in pregnancy had 14% shorter telomeres than children of mothers without the metabolic syndrome in pregnancy (mean difference -0.36 [95% CI -0.74, 0.01]). Height- and weight-for-age, and BMI z scores were similar in children of mothers who did and did not have the metabolic syndrome during pregnancy.

CONCLUSIONS/INTERPRETATION: Children of mothers who had the metabolic syndrome in pregnancy have shorter telomeres, a biomarker of accelerated ageing. These findings warrant further studies in larger cohorts of children, as well as investigations into whether telomere length measured in cord blood associates with telomere length in childhood.

RevDate: 2020-07-29

Engel T, Raffenberg M, Schoepf IC, et al (2020)

Telomere Length, Traditional Risk Factors, HIV-related Factors and Coronary Artery Disease Events in Swiss Persons Living with HIV.

Clinical infectious diseases : an official publication of the Infectious Diseases Society of America pii:5877846 [Epub ahead of print].

BACKGROUND: Leukocyte telomere length (TL) shortens with age and is associated with coronary artery disease (CAD) events in the general population. Persons living with HIV (PLWH) may have accelerated atherosclerosis and shorter TL than the general population. It is unknown whether TL is associated with CAD in PLWH.

METHODS: We measured TL by quantitative PCR in white Swiss HIV Cohort Study participants. Cases had a first CAD event during 01.01.2000-31.12.2017. We matched 1-3 PLWH controls without CAD events on sex, age, and observation time. We obtained univariable and multivariable odds ratios (OR) for CAD from conditional logistic regression analyses.

RESULTS: We included 333 cases (median age 54 years; 14% women; 83% with suppressed HIV RNA) and 745 controls. Median time (interquartile range) of TL measurement was 9.4 (5.9-13.8) years prior to CAD event. Compared to the 1st (shortest) TL quintile, participants in the 5th (longest) TL quintile had univariable and multivariable CAD event OR=0.56 (95% confidence interval, 0.35-0.91) and OR=0.54 (0.31-0.96). Multivariable OR for current smoking was 1.93 (1.27-2.92), dyslipidemia OR=1.92 (1.41-2.63), and for recent abacavir, cumulative lopinavir, indinavir, and darunavir exposure was OR=1.82 (1.27-2.59), OR=2.02 (1.34-3.04), OR=3.42 (2.14-5.45), and OR=1.66 (1.00-2.74), respectively. The TL-CAD association remained significant when adjusting only for Framingham risk score, when excluding TL outliers, and when adjusting for CMV-seropositivity, HCV-seropositivity, time spent with detectable HIV viremia, and injection drug use.

CONCLUSION: In PLWH, TL measured >9 years before, is independently associated with CAD events after adjusting for multiple traditional and HIV-related factors.

RevDate: 2020-07-31

Trybek T, Kowalik A, Góźdź S, et al (2020)

Telomeres and telomerase in oncogenesis.

Oncology letters, 20(2):1015-1027.

Telomeres are located at the ends of chromosomes and protect them from degradation. Suppressing the activity of telomerase, a telomere-synthesizing enzyme, and maintaining short telomeres is a protective mechanism against cancer in humans. In most human somatic cells, the expression of telomerase reverse transcriptase (TERT) is repressed and telomerase activity is inhibited. This leads to the progressive shortening of telomeres and inhibition of cell growth in a process called replicative senescence. Most types of primary cancer exhibit telomerase activation, which allows uncontrolled cell proliferation. Previous research indicates that TERT activation also affects cancer development through activities other than the canonical function of mediating telomere elongation. Recent studies have improved the understanding of the structure and function of telomeres and telomerase as well as key mechanisms underlying the activation of TERT and its role in oncogenesis. These advances led to a search for drugs that inhibit telomerase as a target for cancer therapy. The present review article summarizes the organization and function of telomeres, their role in carcinogenesis, and advances in telomerase-targeted therapy.

RevDate: 2020-09-05

In der Stroth L, Tharehalli U, Günes C, et al (2020)

Telomeres and Telomerase in the Development of Liver Cancer.

Cancers, 12(8):.

Liver cancer is one of the most common cancer types worldwide and the fourth leading cause of cancer-related death. Liver carcinoma is distinguished by a high heterogeneity in pathogenesis, histopathology and biological behavior. Dysregulated signaling pathways and various gene mutations are frequent in hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA), which represent the two most common types of liver tumors. Both tumor types are characterized by telomere shortening and reactivation of telomerase during carcinogenesis. Continuous cell proliferation, e.g., by oncogenic mutations, can cause extensive telomere shortening in the absence of sufficient telomerase activity, leading to dysfunctional telomeres and genome instability by breakage-fusion-bridge cycles, which induce senescence or apoptosis as a tumor suppressor mechanism. Telomerase reactivation is required to stabilize telomere functionality and for tumor cell survival, representing a genetic risk factor for the development of liver cirrhosis and liver carcinoma. Therefore, telomeres and telomerase could be useful targets in hepatocarcinogenesis. Here, we review similarities and differences between HCC and iCCA in telomere biology.

RevDate: 2020-09-13

Maciejowski J, Chatzipli A, Dananberg A, et al (2020)

APOBEC3-dependent kataegis and TREX1-driven chromothripsis during telomere crisis.

Nature genetics, 52(9):884-890.

Chromothripsis and kataegis are frequently observed in cancer and may arise from telomere crisis, a period of genome instability during tumorigenesis when depletion of the telomere reserve generates unstable dicentric chromosomes1-5. Here we examine the mechanism underlying chromothripsis and kataegis by using an in vitro telomere crisis model. We show that the cytoplasmic exonuclease TREX1, which promotes the resolution of dicentric chromosomes4, plays a prominent role in chromothriptic fragmentation. In the absence of TREX1, the genome alterations induced by telomere crisis primarily involve breakage-fusion-bridge cycles and simple genome rearrangements rather than chromothripsis. Furthermore, we show that the kataegis observed at chromothriptic breakpoints is the consequence of cytosine deamination by APOBEC3B. These data reveal that chromothripsis and kataegis arise from a combination of nucleolytic processing by TREX1 and cytosine editing by APOBEC3B.

RevDate: 2020-08-13

Khosravi S, Dreissig S, Schindele P, et al (2020)

Live-Cell CRISPR Imaging in Plant Cells with a Telomere-Specific Guide RNA.

Methods in molecular biology (Clifton, N.J.), 2166:343-356.

Chromatin organization is highly dynamic in living cells. Therefore, it might have a regulatory role over biological mechanisms like transcription, replication, and DNA repair. To elucidate how these mechanisms are regulated, it is required to establish imaging methods to visualize the chromatin dynamic in living cells. Here, we provide a protocol for a live plant cell imaging technique based on application of two orthologs of the bacterial clustered regularly interspaced short palindromic repeats (CRISPR)-associated protein 9 (Cas9) from Streptococcus pyogenes and Staphylococcus aureus. This technique uses the inactive variants of Cas9 combined with different fluorescent proteins (GFP and mRuby) and telomere-specific guide RNA to target telomeric repeats in Nicotiana benthamiana. Our immuno-FISH data revealed that signals arising from the CRISPR/dCas9 method are specifically belonging to telomeric regions.

RevDate: 2020-09-15

Wilson SH (2020)

Telomeres come to life thanks to an exciting review article in this issue.

DNA repair, 94:102904.

RevDate: 2020-08-18

Armendáriz-Castillo I, López-Cortés A, García-Cárdenas J, et al (2020)

TCGA Pan-Cancer Genomic Analysis of Alternative Lengthening of Telomeres (ALT) Related Genes.

Genes, 11(7):.

Telomere maintenance mechanisms (TMM) are used by cancer cells to avoid apoptosis, 85-90% reactivate telomerase, while 10-15% use the alternative lengthening of telomeres (ALT). Due to anti-telomerase-based treatments, some tumors switch from a telomerase-dependent mechanism to ALT; in fact, the co-existence between both mechanisms has been observed in some cancers. Although different elements in the ALT pathway are uncovered, some molecular mechanisms are still poorly understood. Therefore, with the aim to identify potential molecular markers for the study of ALT, we combined in silico approaches in a 411 telomere maintenance gene set. As a consequence, we conducted a genomic analysis of these genes in 31 Pan-Cancer Atlas studies from The Cancer Genome Atlas and found 325,936 genomic alterations; from which, we identified 20 genes highly mutated in the cancer studies. Finally, we made a protein-protein interaction network and enrichment analysis to observe the main pathways of these genes and discuss their role in ALT-related processes, like homologous recombination and homology directed repair. Overall, due to the lack of understanding of the molecular mechanisms of ALT cancers, we proposed a group of genes, which after ex vivo validations, could represent new potential therapeutic markers in the study of ALT.

RevDate: 2020-08-18

Razgonova MP, Zakharenko AM, Golokhvast KS, et al (2020)

Telomerase and telomeres in aging theory and chronographic aging theory (Review).

Molecular medicine reports, 22(3):1679-1694.

The current review focuses on the connection of telomerase and telomeres with aging. In this review, we describe the changes in telomerase and telomere length (TEL) during development, their role in carcinogenesis processes, and the consequences of reduced telomerase activity. More specifically, the connection of TEL in peripheral blood cells with the development of aging‑associated diseases is discussed. The review provides systematic data on the role of telomerase in mitochondria, the biology of telomeres in stem cells, as well as the consequences of the forced expression of telomerase (telomerization) in human cells. Additionally, it presents the effects of chronic stress exposure on telomerase activity, the effect of TEL on fertility, and the effect of nutraceutical supplements on TEL. Finally, a comparative review of the chronographic theory of aging, presented by Olovnikov is provided based on currently available scientific research on telomere, telomerase activity, and the nature of aging by multicellular organisms.

RevDate: 2020-07-24

Le Bras A (2020)

Telomeres and cancer.

Lab animal, 49(8):220.

RevDate: 2020-09-15

Hsieh AYY, Kimmel E, Pick N, et al (2020)

Inverse relationship between leukocyte telomere length attrition and blood mitochondrial DNA content loss over time.

Aging, 12(15):15196-15221.

Leukocyte telomere length (LTL) and whole blood mitochondrial DNA (WB mtDNA) content are aging markers impacted by chronic diseases such as human immunodeficiency virus (HIV) infection. We characterized the relationship between these two markers in 312 women ≥12 years of age living with HIV and 300 HIV-negative controls. We found no relationship between the two markers cross-sectionally. In multivariable models, age, ethnicity, HIV, and tobacco smoking were independently associated with shorter LTL, and the former three with lower WB mtDNA. Longitudinally, among a subgroup of 228 HIV participants and 68 HIV-negative controls with ≥2 biospecimens ≥1 year apart, an inverted pattern was observed between the rates of change in LTL and WB mtDNA content per year, whereby faster decline of one was associated with the preservation of the other. Furthermore, if HIV viral control was not maintained between visits, increased rates of both LTL attrition and WB mtDNA loss were observed. We describe a novel relationship between two established aging markers, whereby rates of change in LTL and WB mtDNA are inversely related. Our findings highlight the importance of maintaining HIV viral control, the complementary longitudinal relationship between the two markers, and the need to consider both in aging studies.

RevDate: 2020-09-06

Maremanda KP, Sundar IK, Li D, et al (2020)

Age-dependent assessment of genes involved in cellular senescence, telomere and mitochondrial pathways in human lung tissue of smokers, COPD and IPF: Associations with SARS-CoV-2 COVID-19 ACE2-TMPRSS2-Furin-DPP4 axis.

Research square.

Aging is one of the key contributing factors for chronic obstructive pulmonary diseases (COPD) and other chronic inflammatory lung diseases. Cigarette smoke is a major etiological risk factor that has been shown to alter cellular processes involving mitochondrial function, cellular senescence and telomeric length. Here we determined how aging contribute to the alteration in the gene expression of above mentioned cellular processes that play an important role in the progression of COPD and IPF. We hypothesized that aging may differentially alter the expression of mitochondrial, cellular senescence and telomere genes in smokers and patients with COPD and IPF compared to non-smokers. Total RNA from human lung tissues from non-smokers, smokers, and patients with COPD and IPF were processed and analyzed based on their ages (younger: <55 yrs and older: >55 yrs). NanoString nCounter panel was used to analyze the gene expression profiles using a custom designed codeset containing 112 genes including 6 housekeeping controls (mitochondrial biogenesis and function, cellular senescence, telomere replication and maintenance). mRNA counts were normalized, log2 transformed for differential expression analysis using linear models in the limma package (R/Bioconductor). Data from non-smokers, smokers and patients with COPD and IPF were analyzed based on the age groups (pairwise comparisons between younger vs. older groups). Several genes were differentially expressed in younger and older smokers, and patients with COPD and IPF compared to non-smokers which were part of the mitochondrial biogenesis/function (HSPD1, FEN1, COX18, COX10, UCP2 & 3), cellular senescence (PCNA, PTEN, KLOTHO, CDKN1C, TNKS2, NFATC1 & 2, GADD45A) and telomere replication/maintenance (PARP1, SIRT6, NBN, TERT, RAD17, SLX4, HAT1) target genes. Interestingly, NOX4 and TNKS2 were increased in the young IPF as compared to the young COPD patients. Genes in the mitochondrial dynamics and other quality control mechanisms like FIS1 and RHOT2 were decreased in young IPF compared to their age matched COPD subjects. ERCC1 (Excision Repair Cross-Complementation Group 1) and GADD45B were higher in young COPD as compared to IPF. Aging plays an important role in various infectious diseases. Elderly patients with chronic lung disease and smokers were found to have high incidence and mortality rates in the current pandemic of SARS-CoV-2 infection. Immunoblot analysis in the lung homogenates of smokers, COPD and IPF subjects revealed increased protein abundance of important proteases and spike proteins like TMPRSS2, furin and DPP4 in association with a slight increase in SARS-CoV-2 receptor ACE2 levels. This may further strengthen the observation that smokers, COPD and IPF subjects are more prone to COVID-19 infection. Overall, these findings suggest that altered transcription of target genes that regulate mitochondrial function, cellular senescence, and telomere attrition add to the pathobiology of lung aging in COPD and IPF and other smoking-related chronic lung disease in associated with alterations in SARS-CoV-2 ACE2-TMPRSS2-Furin-DPP4 axis for COVID-19 infection.

RevDate: 2020-07-25

Gao Y, Wang T, Yu X, et al (2020)

Mendelian randomization implies no direct causal association between leukocyte telomere length and amyotrophic lateral sclerosis.

Scientific reports, 10(1):12184.

We employed Mendelian randomization (MR) to evaluate the causal relationship between leukocyte telomere length (LTL) and amyotrophic lateral sclerosis (ALS) with summary statistics from genome-wide association studies (n = ~ 38,000 for LTL and ~ 81,000 for ALS in the European population; n = ~ 23,000 for LTL and ~ 4,100 for ALS in the Asian population). We further evaluated mediation roles of lipids in the pathway from LTL to ALS. The odds ratio per standard deviation decrease of LTL on ALS was 1.10 (95% CI 0.93-1.31, p = 0.274) in the European population and 0.75 (95% CI 0.53-1.07, p = 0.116) in the Asian population. This null association was also detected between LTL and frontotemporal dementia in the European population. However, we found that an indirect effect of LTL on ALS might be mediated by low density lipoprotein (LDL) or total cholesterol (TC) in the European population. These results were robust against extensive sensitivity analyses. Overall, our MR study did not support the direct causal association between LTL and the ALS risk in neither population, but provided suggestive evidence for the mediation role of LDL or TC on the influence of LTL and ALS in the European population.

RevDate: 2020-07-25

Adams CD, BB Boutwell (2020)

A Mendelian randomization study of telomere length and blood-cell traits.

Scientific reports, 10(1):12223.

Whether telomere attrition reducing proliferative reserve in blood-cell progenitors is causal has important public-health implications. Mendelian randomization (MR) is an analytic technique using germline genetic variants as instrumental variables. If certain assumptions are met, estimates from MR should be free from most environmental sources of confounding and reverse causation. Here, two-sample MR is performed to test whether longer telomeres cause changes to hematological traits. Summary statistics for genetic variants strongly associated with telomere length were extracted from a genome-wide association (GWA) study for telomere length in individuals of European ancestry (n = 9190) and from GWA studies of blood-cell traits, also in those of European ancestry (n ~ 173,000 participants). A standard deviation increase in genetically influenced telomere length increased red blood cell and white blood cell counts, decreased mean corpuscular hemoglobinand mean cell volume, and had no observable impact on mean corpuscular hemoglobin concentration, red cell distribution width, hematocrit, or hemoglobin. Sensitivity tests for pleiotropic distortion were mostly inconsistent with glaring violations to the MR assumptions. Similar to germline mutations in telomere biology genes leading to bone-marrow failure, these data provide evidence that genetically influenced common variation in telomere length impacts hematologic traits in the population.

RevDate: 2020-09-10

Wang CX, Zhang ZL, Yin QK, et al (2020)

Design, Synthesis, and Evaluation of New Quinazolinone Derivatives that Inhibit Bloom Syndrome Protein (BLM) Helicase, Trigger DNA Damage at the Telomere Region, and Synergize with PARP Inhibitors.

Journal of medicinal chemistry, 63(17):9752-9772.

DNA damage response (DDR) pathways are crucial for the survival of cancer cells and are attractive targets for cancer therapy. Bloom syndrome protein (BLM) is a DNA helicase that performs important roles in DDR pathways. Our previous study discovered an effective new BLM inhibitor with a quinazolinone scaffold by a screening assay. Herein, to better understand the structure-activity relationship (SAR) and biological roles of the BLM inhibitor, a series of new derivatives were designed, synthesized, and evaluated based on this scaffold. Among them, compound 9h exhibited nanomolar inhibitory activity and binding affinity for BLM. 9h could effectively disrupt BLM recruitment to DNA in cells. Furthermore, 9h inhibited the proliferation of the colorectal cell line HCT116 by significantly triggering DNA damage in the telomere region and inducing apoptosis, especially in combination with a poly (ADP-ribose) polymerase (PARP) inhibitor. This result suggested a synthetic lethal effect between the BLM and PARP inhibitors in DDR pathways.

RevDate: 2020-08-18

Sebastiano M, Angelier F, Blévin P, et al (2020)

Exposure to PFAS is Associated with Telomere Length Dynamics and Demographic Responses of an Arctic Top Predator.

Environmental science & technology, 54(16):10217-10226.

Environmental factors that can influence telomeres are diverse, but the association between telomeres and exposure to environmental contaminants is yet to be elucidated. To date, prior studies have focused on legacy persistent chlorinated pollutants (POPs), while the effects of poly- and perfluoroalkyl substances (PFAS) have been poorly documented. Here, we investigated the associations among PFAS congeners, absolute telomere length (cross-sectional approach), and telomere dynamics (rate of telomere length change over time, longitudinal approach) in one of the most contaminated arctic top predators, the glaucous gull Larus hyperboreus from Svalbard. We further estimated the effect of PFAS on apparent survival rates and re-sighting probabilities using a 10-year capture/recapture dataset (2010-2019). We found that birds exposed to higher concentrations of perfluorononadecanoate (PFNA) (median of 1565 pg/mL of ww in males and 1370 pg/mL of ww in females) and perfluorotetradecanoate (PFTeDA) (median of 370 pg/mL of ww in males and 210 pg/mL of ww in females) showed the slowest rate of telomere shortening. We also found that high blood concentrations of perfluorooctanoate (PFOA) (median of 120 pg/mL of ww in males and 150 pg/mL of ww in females) and perfluorohexanesulfonate (PFHxS) (median of 495 pg/mL of ww in males and 395 pg/mL of ww in females) were positively associated with higher re-sighting probabilities and apparent survival in males but not in females. Our work is the first to report an association between single PFAS compounds and telomeres, and the first to link PFAS exposure with survival probabilities, suggesting that the effect of PFAS exposure might be more tied to the type of compound rather than the total concentration of PFAS.


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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