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Bibliography on: Telomeres

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ESP: PubMed Auto Bibliography 19 Aug 2019 at 01:38 Created: 


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

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

Citations The Papers (from PubMed®)

RevDate: 2019-08-16

Ding X, Cheng J, Pang Q, et al (2019)

BIBR1532, a selective telomerase inhibitor, enhances radiosensitivity of non-small cell lung cancer through increasing telomere dysfunction and ATM/CHK1 inhibition.

International journal of radiation oncology, biology, physics pii:S0360-3016(19)33642-9 [Epub ahead of print].

PURPOSE: Telomerase is reactivated in non-small-cell lung cancer (NSCLC) and increases cell resistance to irradiation through protecting damaged telomeres and enhancing DNA damage repair. Herein, we investigated the radiosensitizing effect of BIBR1532, a highly selective telomerase inhibitor, and its corresponding mechanism in NSCLC.

METHODS: Cell proliferation, telomerase activity, and telomere dysfunction-induced foci were measured by CCK-8 assay, real-time fluorescent quantitative PCR, and immunofluorescence. The effect of BIBR1532 on the response of NSCLC cells to radiation was analyzed by clonogenic survival and xenograft tumor assays. Cell death and cell senescence induced by BIBR1532 and/or ionizing radiation (IR) were detected by western blotting, flow cytometry, and SA-β-gal staining assay.

RESULTS: We observed dose-dependent direct cytotoxicity of BIBR1532 at relatively high concentrations in NSCLC cells. Low concentrations of BIBR1532 did not appear toxic to NSCLC cells, however, they substantially increased the therapeutic efficacy of IR in vitro by enhancing IR-induced apoptosis, senescence, and mitotic catastrophe. Moreover, in a mouse xenograft model, BIBR1532 treatment synergized with IR significantly promoted the anti-tumor efficacy of IR without toxicity to hematological and internal organs at non-toxic dose levels. Mechanistically, lower concentrations BIBR1532 effectively inhibited telomerase activity and increased IR-induced telomere dysfunction, resulting in disruption of chromosomal stability and inhibition of the ATM/CHK1 pathway, which impaired DNA damage repair.

CONCLUSIONS: Our findings demonstrated that disturbances in telomerase function by non-toxic dose levels of BIBR1532 effectively enhanced the radiosensitivity of NSCLC cells. This provides a rationale for the clinical assessment of BIBR1532 as a radiosensitizer.

RevDate: 2019-08-16

Nemtsova V, Bilovol O, Vysotska O, et al (2019)


Georgian medical news.

Aim - to determine the influence of different levels of lipid metabolism on the relative blood leukocytes telomeres length (RLTL), relative buccal epithelium cells telomeres length (RBTL) in hypertensive (H) individuals with type 2 diabetes mellitus (DM2T) and without DM2T. In 60 patients with H stage II (group 1), and 96 patients with H and DM2T (group 2) lipid metabolism indexes (total cholesterol (TC), triglycerides (TG), low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C)), anthropometric parameters were measured. Relative telomeres length (RTL) was determined by a real time quantitative PCR. The most significant shortening of RLTL and RBTL were found in group 2. In both groups, the achievement of target blood lipid levels was accompanied by multidirectional changes in RTL. Analysis of variance revealed a significant effect of TC (p=0.036) on the RBTL, LDL -C (p=0.036) on the RBTL in group 1, and significant influence of TG (p = 0.049) on RBTL, TC (p=0.019) and HDL-C (p=0.032) on RLTL in group 2. Achieving target levels of lipid metabolism did not demonstrate the expected significant effect on the elongation of the relative length of telomeres, both with isolated hypertension and with a combined course of hypertension and DM2T.

RevDate: 2019-08-16

Wark L, Quon H, Ong A, et al (2019)

Long-Term Dynamics of Three Dimensional Telomere Profiles in Circulating Tumor Cells in High-Risk Prostate Cancer Patients Undergoing Androgen-Deprivation and Radiation Therapy.

Cancers, 11(8): pii:cancers11081165.

Patient-specific assessment, disease monitoring, and the development of an accurate early surrogate of the therapeutic efficacy of locally advanced prostate cancer still remain a clinical challenge. Contrary to prostate biopsies, circulating tumor cell (CTC) collection from blood is a less-invasive method and has potential as a real-time liquid biopsy and as a surrogate marker for treatment efficacy. In this study, we used size-based filtration to isolate CTCs from the blood of 100 prostate cancer patients with high-risk localized disease. CTCs from five time points: +0, +2, +6, +12 and +24 months were analyzed. Consenting treatment-naïve patients with cT3, Gleason 8-10, or prostate-specific antigen > 20 ng/mL and non-metastatic prostate cancer were included. For all time points, we performed 3D telomere-specific quantitative fluorescence in situ hybridization on a minimum of thirty isolated CTCs. The patients were divided into five groups based on the changes of number of telomeres vs telomere lengths over time and into three clusters based on all telomere parameters found on diagnosis. Group 2 was classified as non-respondent to treatment and the Cluster 3 presented more aggressive phenotype. Additionally, we compared our telomere results with the PSA levels for each patient at 6 months of ADT, at 6 months of completed RT, and at 36 months post-initial therapy. CTCs of patients with PSA levels above or equal to 0.1 ng/mL presented significant increases of nuclear volume, number of telomeres, and telomere aggregates. The 3D telomere analysis of CTCs identified disease heterogeneity among a clinically homogeneous group of patients, which suggests differences in therapeutic responses. Our finding suggests a new opportunity for better treatment monitoring of patients with localized high-risk prostate cancer.

RevDate: 2019-08-14

Kroustallaki P, Lirussi L, Carracedo S, et al (2019)

SMUG1 Promotes Telomere Maintenance through Telomerase RNA Processing.

Cell reports, 28(7):1690-1702.e10.

Telomerase biogenesis is a complex process where several steps remain poorly understood. Single-strand-selective uracil-DNA glycosylase (SMUG1) associates with the DKC1-containing H/ACA ribonucleoprotein complex, which is essential for telomerase biogenesis. Herein, we show that SMUG1 interacts with the telomeric RNA component (hTERC) and is required for co-transcriptional processing of the nascent transcript into mature hTERC. We demonstrate that SMUG1 regulates the presence of base modifications in hTERC, in a region between the CR4/CR5 domain and the H box. Increased levels of hTERC base modifications are accompanied by reduced DKC1 binding. Loss of SMUG1 leads to an imbalance between mature hTERC and its processing intermediates, leading to the accumulation of 3'-polyadenylated and 3'-extended intermediates that are degraded in an EXOSC10-independent RNA degradation pathway. Consequently, SMUG1-deprived cells exhibit telomerase deficiency, leading to impaired bone marrow proliferation in Smug1-knockout mice.

RevDate: 2019-08-13

van der Spek A, Broer L, Draisma HHM, et al (2019)

Metabolomics reveals a link between homocysteine and lipid metabolism and leukocyte telomere length: the ENGAGE consortium.

Scientific reports, 9(1):11623 pii:10.1038/s41598-019-47282-6.

Telomere shortening has been associated with multiple age-related diseases such as cardiovascular disease, diabetes, and dementia. However, the biological mechanisms responsible for these associations remain largely unknown. In order to gain insight into the metabolic processes driving the association of leukocyte telomere length (LTL) with age-related diseases, we investigated the association between LTL and serum metabolite levels in 7,853 individuals from seven independent cohorts. LTL was determined by quantitative polymerase chain reaction and the levels of 131 serum metabolites were measured with mass spectrometry in biological samples from the same blood draw. With partial correlation analysis, we identified six metabolites that were significantly associated with LTL after adjustment for multiple testing: lysophosphatidylcholine acyl C17:0 (lysoPC a C17:0, p-value = 7.1 × 10-6), methionine (p-value = 9.2 × 10-5), tyrosine (p-value = 2.1 × 10-4), phosphatidylcholine diacyl C32:1 (PC aa C32:1, p-value = 2.4 × 10-4), hydroxypropionylcarnitine (C3-OH, p-value = 2.6 × 10-4), and phosphatidylcholine acyl-alkyl C38:4 (PC ae C38:4, p-value = 9.0 × 10-4). Pathway analysis showed that the three phosphatidylcholines and methionine are involved in homocysteine metabolism and we found supporting evidence for an association of lipid metabolism with LTL. In conclusion, we found longer LTL associated with higher levels of lysoPC a C17:0 and PC ae C38:4, and with lower levels of methionine, tyrosine, PC aa C32:1, and C3-OH. These metabolites have been implicated in inflammation, oxidative stress, homocysteine metabolism, and in cardiovascular disease and diabetes, two major drivers of morbidity and mortality.

RevDate: 2019-08-13

Hu Y, Bennett HW, Liu N, et al (2019)

RNA-DNA Hybrids Support Recombination-Based Telomere Maintenance in Fission Yeast.

Genetics pii:genetics.119.302606 [Epub ahead of print].

A subset of cancers rely on telomerase-independent mechanisms to maintain their chromosome ends. The predominant "alternative lengthening of telomeres" pathway appears dependent on homology-directed repair (HDR) to maintain telomeric DNA. However, the molecular changes needed for cells to productively engage in telomeric HDR are poorly understood. To gain new insights into this transition, we monitored the state of telomeres during serial culture of fission yeast (Schizosaccharomyces pombe) lacking the telomerase recruitment factor Ccq1. Rad52 is loaded onto critically short telomeres shortly after germination despite continued telomere erosion, suggesting that recruitment of recombination factors is not sufficient to maintain telomeres in the absence of telomerase function. Instead, survivor formation coincides with the derepression of telomeric repeat-containing RNA (TERRA). In this context, degradation of TERRA associated with the telomere in the form of R-loops drives a severe growth crisis, ultimately leading to a novel type of survivor with linear chromosomes and altered cytological telomere characteristics, including the loss of the shelterin component Rap1 (but not the TRF1/TRF2 orthologue, Taz1) from the telomere. We demonstrate that deletion of Rap1 is protective in this context, preventing the growth crisis that is otherwise triggered by degradation of telomeric R-loops in survivors with linear chromosomes. These findings suggest that up-regulation of telomere-engaged TERRA or altered recruitment of shelterin components can support telomerase-independent telomere maintenance.

RevDate: 2019-08-13

Wang W, Liu B, Duan X, et al (2019)

Telomere length in workers was effected by omethoate exposure and interaction between smoking and p21 polymorphisms.

Journal of environmental science and health. Part. B, Pesticides, food contaminants, and agricultural wastes [Epub ahead of print].

Omethoate is an organophosphorus pesticide that poses a major health hazard, especially DNA damage. The purpose of this study was to investigate the factors affecting telomere length in workers exposed to omethoate by analyzing the interaction between cell cycle gene polymorphism and environmental factors. The exposure group consisted of 118 workers exposed to omethoate for 8-10 years, the control group comprised 115 healthy people without occupational toxicant exposure history. The telomere length of genomic DNA from peripheral blood leucocyte was determined with real-time PCR. Polymerase chain reaction and restriction fragment length polymorphism was used to detect the polymorphisms in p53, p21 and MDM2 gene. The telomere length in the (CA + AA) genotypes for p21 rs1801270 polymorphism was longer than that in the CC genotype in control group (P = 0.015). The generalized linear model analysis indicated the interaction of the p21 rs1801270 polymorphic (CA + AA) genotypes and smoking has a significant effect on telomere length (β = -0.258, P = 0.085). The prolongation of telomere length in omethoate-exposed workers was associated with genotypes (CA + AA) of p21 rs1801270, and interactions of (CA + AA) genotypes and smoking factor.

RevDate: 2019-08-12

Gatinois V, Desprat R, Becker F, et al (2019)

Reprogramming of Human Peripheral Blood Mononuclear Cell (PBMC) from a patient suffering of a Werner syndrome resulting in iPSC line (REGUi003-A) maintaining a short telomere length.

Stem cell research, 39:101515 pii:S1873-5061(19)30145-X [Epub ahead of print].

Werner syndrome (WS) is a rare human autosomal recessive disorder characterized by early onset of aging-associated diseases, chromosomal instability, and cancer predisposition, without therapeutic treatment solution. Major clinical symptoms of WS include common age-associated diseases, such as insulin-resistant diabetes mellitus, and atherosclerosis. WRN, the gene responsible for the disease, encodes a RECQL-type DNA helicase with a role in telomere metabolism. We derived a stable iPSC line from 53 years old patient's PBMC, with a normal karyotype, but exhibiting a short telomere length, as a major aspect of the cellular phenotype involved in the pathology.

RevDate: 2019-08-12

Zhdanova NS, Vaskova EA, Karamysheva TV, et al (2019)

Dysfunction telomeres in embryonic fibroblasts and cultured in vitro pluripotent stem cells of Rattus norvegicus (Rodentia, Muridae).

Comparative cytogenetics, 13(3):1-14 pii:34732.

We studied the level of spontaneous telomere dysfunction in Rattus norvegicus (Berkenhout, 1769) (Rodentia, Muridae) embryonic fibroblasts (rEFs) and in cultured in vitro rat pluripotent stem cells (rPSCs), embryonic stem cells (rESCs) and induced pluripotent stem cells (riPSCs), on early passages and after prolonged cultivation. Among studied cell lines, rESCs showed the lowest level of telomere dysfunction, while the riPSCs demonstrated an elevated level on early passages of cultivation. In cultivation, the frequency of dysfunctional telomeres has increased in all studied cell lines; this is particularly true for dysfunctional telomeres occurring in G1 stage in riPSCs. The obtained data are mainly discussed in the connection with the specific structure of the telomere regions and their influence on the differential DNA damage response in them.

RevDate: 2019-08-12

Aida J, Yokoyama A, Hara S, et al (2019)

Telomere Shortening in the Oral Epithelium in Relation to Alcohol Intake, Alcohol Dehydrogenase (ADH-1B) and Acetaldehyde Dehydrogenase (ALDH-2) Genotypes and Clinicopathologic Features.

Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology [Epub ahead of print].

BACKGROUND: Progressive telomere shortening with age or chronic inflammation may lead to genomic instability that characterizes the early stage of carcinogenesis. Certain risk factors, such as drinking alcoholic beverages, or smoking, predispose the oral mucosa to squamous cell carcinoma. The ADH1B and ALDH2 genotypes can influence the risk of cancer due to alcohol drinking. In the present study, we analyzed chromosomal instability due to telomere shortening in the oral mucosa in relation to cancer risk factors.

DESIGN: Using our quantitative fluorescence in situ hybridization (Q-FISH) technique, we estimated telomere lengths (TL) in the background mucosa from 23 cases of mucosal carcinoma, 12 cases of oral epithelial dysplasia, and 21 non-neoplasia cases. ALDH2 and ADH1B genotypes were determined using DNA extracted from paraffin sections. We analyzed TL in relation to alcohol drinking, smoking, and cancer multiplicity.

RESULTS: Telomeres in the backgrounds of dysplasia and mucosal carcinoma were significantly shorter than in controls. In comparison with adult controls, telomeres were significantly (p = 0.038) shorter in the ADH1B less-active type (ADH1B*1/*1), but not (p = 0.841) in the ALDH2 inactive type (ALDH2 *1/*2 or *2/*2). Cancer multiplicity and smoking had no significant relationship with TL.

CONCLUSION: Telomeres in the oral epithelium are shorter in cases of oral dysplasia or mucosal carcinoma than in non-neoplasia. Unlike the esophageal epithelium of alcoholics, they are also shorter in individuals with the less-active rather than the active ADH1B gene. Telomeres in the oral epithelium may be directly affected by alcohol drinking. This article is protected by copyright. All rights reserved.

RevDate: 2019-08-11

Bilsland AE, Liu Y, Turnbull A, et al (2019)

A Novel Pyrazolopyrimidine Ligand of Human PGK1 and Stress Sensor DJ1 Modulates the Shelterin Complex and Telomere Length Regulation.

Neoplasia (New York, N.Y.), 21(9):893-907 pii:S1476-5586(19)30266-0 [Epub ahead of print].

Telomere signaling and metabolic dysfunction are hallmarks of cell aging. New agents targeting these processes might provide therapeutic opportunities, including chemoprevention strategies against cancer predisposition. We report identification and characterization of a pyrazolopyrimidine compound series identified from screens focused on cell immortality and whose targets are glycolytic kinase PGK1 and oxidative stress sensor DJ1. We performed structure-activity studies on the series to develop a photoaffinity probe to deconvolute the cellular targets. In vitro binding and structural analyses confirmed these targets, suggesting that PGK1/DJ1 interact, which we confirmed by immunoprecipitation. Glucose homeostasis and oxidative stress are linked to telomere signaling and exemplar compound CRT0063465 blocked hypoglycemic telomere shortening. Intriguingly, PGK1 and DJ1 bind to TRF2 and telomeric DNA. Compound treatment modulates these interactions and also affects Shelterin complex composition, while conferring cellular protection from cytotoxicity due to bleomycin and desferroxamine. These results demonstrate therapeutic potential of the compound series.

RevDate: 2019-08-11

Barroso-González J, García-Expósito L, Hoang SM, et al (2019)

RAD51AP1 Is an Essential Mediator of Alternative Lengthening of Telomeres.

Molecular cell pii:S1097-2765(19)30500-3 [Epub ahead of print].

Alternative lengthening of telomeres (ALT) is a homology-directed repair (HDR) mechanism of telomere elongation that controls proliferation in aggressive cancers. We show that the disruption of RAD51-associated protein 1 (RAD51AP1) in ALT+ cancer cells leads to generational telomere shortening. This is due to RAD51AP1's involvement in RAD51-dependent homologous recombination (HR) and RAD52-POLD3-dependent break induced DNA synthesis. RAD51AP1 KO ALT+ cells exhibit telomere dysfunction and cytosolic telomeric DNA fragments that are sensed by cGAS. Intriguingly, they activate ULK1-ATG7-dependent autophagy as a survival mechanism to mitigate DNA damage and apoptosis. Importantly, RAD51AP1 protein levels are elevated in ALT+ cells due to MMS21 associated SUMOylation. Mutation of a single SUMO-targeted lysine residue perturbs telomere dynamics. These findings indicate that RAD51AP1 is an essential mediator of the ALT mechanism and is co-opted by post-translational mechanisms to maintain telomere length and ensure proliferation of ALT+ cancer cells.

RevDate: 2019-08-09

Pathak S, Multani AS, Narayan S, et al (2004)

Germline Telomere Length Dynamics and Mutagen Sensitivity Studies in a Family with Acute Reactions to Sun Exposure: Involvement of Three Generations.

Cancer genomics & proteomics, 1(3):199-208.

Most cancers are the result of an interaction between germline genetic susceptibility and exposure to environmental carcinogens. We studied chromosomal aberrations, telomeric associations, telomere signal intensity by fluorescence in situ hybridization, p53 germline mutation, bleomycin (Bleo) and 4-nitroquinoline-1-oxide (4NQO) sensitivity, and chromosome-specific telomere signals in T and B lymphocytes in a Caucasian family involving three generations and 13 family members. This family was chosen because eight of its members are extremely sensitive to sunlight and burn easily even upon short exposure. The family members have shown: (a) hypersensitivity either to Bleo or 4NQO mutagens, with values much higher than 1.00 breaks/cell (b/c) for Bleo and 0.40 b/c for 4NQO; (b) an increased rate of telomeric associations; (c) variable amounts of telomeric DNA not common for the person's age; (d) the presence of intron 7 polymorphism in the proband and no significant effect on N-methyl-N'-nitosoguanidine (MNNG)-induced p53 expression in two key family members; and (e) an incidence of epithelial malignancies in two family members. Seven additional members showed polymorphism of telomeric signals in the short arm of two homologous chromosome 17s, where the p53 gene is localized. A 78-year-old grandmother, who had developed colon cancer, was predicted to have metastatic cancer based on the telomeric DNA amount in her lymphocytes (2.90%); she subsequently developed metastatic lesions within a year and died. Based on these observations, we conclude that telomere erosion is the initial cause of genomic instability/susceptibility which, in turn, may be causal for the reproductive complications, premature aging phenotypes and, in some cases, predisposition to cancer development.

RevDate: 2019-08-09

Fali T, K'Ros C, Appay V, et al (2019)

Assessing T Lymphocyte Aging Using Telomere Length and Telomerase Activity Measurements in Low Cell Numbers.

Methods in molecular biology (Clifton, N.J.), 2048:231-243.

As T lymphocytes proliferate and differentiate in vivo or in vitro, their functional capacity can change dramatically. In particular, extensive cell division is often associated with telomere shortening and the onset of cellular senescence, thus impacting the proliferative potential of the cells. Telomere length and integrity represent therefore key molecular markers of the status and aging of the cells. To assess these markers, we established qPCR-based methods to measure telomere length as well as telomerase activity, applied to low cell numbers, which is necessary when working with rare or small subsets of T lymphocytes.

RevDate: 2019-08-09

Mennie AK, Moser BA, Hoyle A, et al (2019)

Tpz1TPP1 prevents telomerase activation and protects telomeres by modulating the Stn1-Ten1 complex in fission yeast.

Communications biology, 2:297 pii:546.

In both mammalian and fission yeast cells, conserved shelterin and CST (CTC1-STN1-TEN1) complexes play critical roles in protection of telomeres and regulation of telomerase, an enzyme required to overcome the end replication problem. However, molecular details that govern proper coordination among shelterin, CST, and telomerase have not yet been fully understood. Here, we establish a conserved SWSSS motif, located adjacent to the Lys242 SUMOylation site in the fission yeast shelterin subunit Tpz1, as a new functional regulatory element for telomere protection and telomere length homeostasis. The SWSSS motif works redundantly with Lys242 SUMOylation to promote binding of Stn1-Ten1 at telomere and sub-telomere regions to protect against single-strand annealing (SSA)-dependent telomere fusions, and to prevent telomerase accumulation at telomeres. In addition, we provide evidence that the SWSSS motif defines an unanticipated role of Tpz1 in limiting telomerase activation at telomeres to prevent uncontrolled telomere elongation.

RevDate: 2019-08-08

Clemente DBP, Vrijheid M, Martens DS, et al (2019)

Prenatal and Childhood Traffic-Related Air Pollution Exposure and Telomere Length in European Children: The HELIX Project.

Environmental health perspectives, 127(8):87001.

BACKGROUND: Telomere length is a molecular marker of biological aging.

OBJECTIVE: Here we investigated whether early-life exposure to residential air pollution was associated with leukocyte telomere length (LTL) at 8 y of age.

METHODS: In a multicenter European birth cohort study, HELIX (Human Early Life Exposome) ([Formula: see text]), we estimated prenatal and 1-y childhood exposure to nitrogen dioxide ([Formula: see text]), particulate matter with aerodynamic diameter [Formula: see text] ([Formula: see text]), and proximity to major roads. Average relative LTL was measured using quantitative real-time polymerase chain reaction (qPCR). Effect estimates of the association between LTL and prenatal, 1-y childhood air pollution, and proximity to major roads were calculated using multiple linear mixed models with a random cohort effect and adjusted for relevant covariates.

RESULTS: LTL was inversely associated with prenatal and 1-y childhood [Formula: see text] and [Formula: see text] exposures levels. Each standard deviation (SD) increase in prenatal [Formula: see text] was associated with a [Formula: see text] (95% CI: [Formula: see text], [Formula: see text]) change in LTL. Prenatal [Formula: see text] was nonsignificantly associated with LTL ([Formula: see text] per SD increase; 95% CI: [Formula: see text], 0.6). For each SD increment in 1-y childhood [Formula: see text] and [Formula: see text] exposure, LTL shortened by [Formula: see text] (95% CI: [Formula: see text], [Formula: see text]) and [Formula: see text] (95% CI: [Formula: see text], 0.1), respectively. Each doubling in residential distance to nearest major road during childhood was associated with a 1.6% (95% CI: 0.02, 3.1) lengthening in LTL.

CONCLUSION: Lower exposures to air pollution during pregnancy and childhood were associated with longer telomeres in European children at 8 y of age. These results suggest that reductions in traffic-related air pollution may promote molecular longevity, as exemplified by telomere length, from early life onward.

RevDate: 2019-08-08

Li S, Yang M, Carter E, et al (2019)

Exposure-Response Associations of Household Air Pollution and Buccal Cell Telomere Length in Women Using Biomass Stoves.

Environmental health perspectives, 127(8):87004.

BACKGROUND: Telomere shortening is associated with early mortality and chronic disease. Recent studies indicate that environmental exposures, including urban and traffic-related air pollution, may shorten telomeres. Associations between exposure to household air pollution from solid fuel stoves and telomere length have not been evaluated.

METHODS: Among 137 rural Chinese women using biomass stoves ([Formula: see text] of age), we measured 48-h personal exposures to fine particulate matter [PM [Formula: see text] in aerodynamic diameter ([Formula: see text])] and black carbon and collected oral DNA on up to three occasions over a period of 2.5 y. Relative telomere length (RTL) was quantified using a modified real-time polymerase chain reaction protocol. Mixed effects regression models were used to investigate the exposure-response associations between household air pollution and RTL, adjusting for key sociodemographic, behavioral, and environmental covariates.

RESULTS: Women's daily exposures to air pollution ranged from [Formula: see text] for [Formula: see text] ([Formula: see text]) and [Formula: see text] for black carbon ([Formula: see text]). Natural cubic spline models indicated a mostly linear association between increased exposure to air pollution and shorter RTL, except at very high concentrations where there were few observations. We thus modeled the linear associations with all observations, excluding the highest 3% and 5% of exposures. In covariate-adjusted models, an interquartile range (IQR) increase in exposure to black carbon ([Formula: see text]) was associated with shorter RTL [all observations: [Formula: see text] (95% CI: [Formula: see text], [Formula: see text]); excluding highest 5% exposures: [Formula: see text] (95% CI: [Formula: see text], [Formula: see text])]. Further adjustment for outdoor temperature brought the estimates closer to zero [all observations: [Formula: see text] (95% CI: [Formula: see text], 0.06); excluding highest 5% exposures: [Formula: see text] (95% CI: [Formula: see text], [Formula: see text])]. Models with [Formula: see text] as the exposure metric followed a similar pattern.

CONCLUSION: Telomere shortening, which is a biomarker of biological aging and chronic disease, may be associated with exposure to air pollution in settings where household biomass stoves are commonly used.

RevDate: 2019-08-07

Wang S, Chang E, Byanyima P, et al (2019)

Association between common telomere length genetic variants and telomere length in an African population and impacts of HIV and TB.

Journal of human genetics pii:10.1038/s10038-019-0646-9 [Epub ahead of print].

Prior studies in predominantly European (Caucasian) populations have discovered common genetic variants (single nucleotide polymorphisms, SNPs) associated with leukocyte telomere length (LTL), but whether these same variants affect LTL in non-Caucasian populations are largely unknown. We investigated whether six genetic variants previously associated with LTL (TERC (rs10936599), TERT (rs2736100), NAF1 (7675998), OBFC1 (rs9420907), ZNF208 (rs8105767), and RTEL1 (rs755017)) are correlated with telomere length (TL) in peripheral blood mononuclear cells (PBMCs) in a cohort of Africans living with and without HIV and undergoing evaluation for tuberculosis (TB). We found OBFC1 and the genetic sum score of the effect alleles across all six loci to be associated with shorter TL (adjusted for age, gender, HIV status, and smoking pack-years (p < 0.02 for both OBFC1 and the genetic sum score). In an analysis stratified by HIV status, the genetic sum score is associated with LTL in both groups with and without HIV. On the contrary, a stratified analysis according to TB status revealed that in the TB-positive subgroup, the genetic sum score is not associated with LTL, whereas the relationship remains in the TB-negative subgroup. The different impacts of HIV and TB on the association between the genetic sum score and LTL indicate different modes of modification and suggest that the results found in this cohort with HIV and TB participants may not be applied to the African general population. Future studies need to carefully consider these confounding factors.

RevDate: 2019-08-07

Lu D, Palmer JR, Rosenberg L, et al (2019)

Perceived racism in relation to telomere length among African American women in the Black Women's Health Study.

Annals of epidemiology pii:S1047-2797(19)30089-4 [Epub ahead of print].

PURPOSE: Telomere length is considered a biomarker of human aging and premature morbidity and mortality which has been associated with chronic stress.

METHODS: We assessed the relation between perceived racism and telomere length in the Black Women's Health Study, a follow-up study of U.S. black women begun in 1995. Participants were asked about frequency of "everyday racism" (e.g., "people act as if they think you are not intelligent") and "institutional racism" (e.g., "ever treated unfairly due to race by police"). Using quantitative real-time polymerase chain reaction assay, relative telomere lengths (RTL) were measured as the copy number ratio of telomere repeat to a single control gene in 997 participants. Associations of racism variables with log-RTL were estimated by multivariable linear regression, with adjustment for age at blood draw and potential confounders.

RESULTS: Participants were aged 40-70 years (mean = 55.6 years), and mean telomere length was 0.77 (range 0.21-1.38). In stratified analyses, there was an inverse association between everyday racism and log-RTL among women who did not discuss their experiences of racism with others (β = -0.1104; 95% CI = -0.2140 to -0.0067; P = .045).

CONCLUSIONS: Everyday racism was associated with shorter telomere length among women who reported not discussing those experiences with others.

RevDate: 2019-08-06

Monroe DM, Goldstein RL, Teylan MA, et al (2019)

Clinical associations with telomere length in chronic spinal cord injury.

Spinal cord pii:10.1038/s41393-019-0336-7 [Epub ahead of print].

STUDY DESIGN: Cross-sectional study OBJECTIVES: To determine clinical factors associated with telomere length in persons with chronic spinal cord injury (SCI).

SETTING: Veterans Affairs Medical Center, Boston, MA.

METHODS: Two hundred seventy-eight participants with chronic SCI provided blood samples for measurement of C-reactive protein (CRP), interleukin-6 (IL-6), and telomere length, completed respiratory health questionnaires, underwent dual X-ray absorptiometry (DXA) to assess body fat, and completed spirometry. High-throughput real-time PCR assays were used to assess telomere length in leukocyte genomic DNA. Linear regression models were used to assess cross-sectional associations with telomere length.

RESULTS: Telomere length was inversely related to age (p < 0.0001). In age-adjusted models, gender, race, injury duration, %-total and %-trunk fat, body mass index (BMI), %-predicted forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV1), chronic cough or phlegm, CRP, IL-6, wheeze, smoking, diabetes, heart disease, chronic obstructive pulmonary disease (COPD), skin ulcer, urinary tract infection (UTI), or chest illness history were not significantly associated with telomere length. There was a suggestive age-adjusted association between persons with the most severe SCI (cervical motor complete and AIS C) and shorter telomere length (p = 0.055), an effect equivalent to ~8.4 years of premature aging. There were similar age-adjusted associations with telomere length between persons using a wheelchair (p = 0.059) and persons with chronic urinary catheter use (p = 0.082) compared to persons without these characteristics.

CONCLUSIONS: Our results suggest that clinical characteristics such as decreased mobility and bladder dysfunction that are common in individuals with more severe SCI are associated with shorter telomere length.

RevDate: 2019-08-05

McNally EJ, Luncsford PJ, M Armanios (2019)

Long telomeres and cancer risk: the price of cellular immortality.

The Journal of clinical investigation, 130: pii:120851.

The distribution of telomere length in humans is broad, but it has finite upper and lower boundaries. Growing evidence shows that there are disease processes that are caused by both short and long telomere length extremes. The genetic basis of these short and long telomere syndromes may be linked to mutations in the same genes, such as the telomerase reverse transcriptase (TERT), but through differential effects on telomere length. Short telomere syndromes have a predominant degenerative phenotype marked by organ failure that most commonly manifests as pulmonary fibrosis and are associated with a relatively low cancer incidence. In contrast, insights from studies of cancer-prone families as well as genome-wide association studies (GWAS) have identified both rare and common variants that lengthen telomeres as being strongly associated with cancer risk. We have hopothesized that these cancers represent a long telomere syndrome that is associated with a high penetrance of cutaneous melanoma and chronic lymphocytic leukemia. In this Review, we will synthesize the clinical and human genetic observations with data from mouse models to define the role of telomeres in cancer etiology and biology.

RevDate: 2019-08-05

Masterson EE, Hayes MG, Kuzawa CW, et al (2019)

Early life growth and adult telomere length in a Filipino cohort study.

American journal of human biology : the official journal of the Human Biology Council [Epub ahead of print].

OBJECTIVE: We investigated the relationship between early life growth patterns and blood telomere length (TL) in adulthood using conditional measures of lean and fat mass growth to evaluate potentially sensitive periods of early life growth.

METHODS: This study included data from 1562 individuals (53% male; age 20-22 years) participating in the Cebu Longitudinal Health and Nutrition Survey, located in metropolitan Cebu, Philippines. Primary exposures included length-for-age z-score (HAZ) and weight-for-age z-score (WAZ) at birth and conditional measures of linear growth and weight gain during four postnatal periods: 0-6, 6-12, and 12-24 months, and 24 months to 8.5 years. TL was measured at ~21 years of age. We estimated associations using linear regression.

RESULTS: The study sample had an average gestational age (38.5 ± 2 weeks) and birth size (HAZ = -0.2 ± 1.1, WAZ = -0.7 ± 1.0), but by age 8.5 years had stunted linear growth (HAZ = -2.1 ± 0.9) and borderline low weight (WAZ = -1.9 ± 1.0) relative to World Health Organization references. Heavier birth weight was associated with longer TL in early adulthood (P = .03), but this association was attenuated when maternal age at birth was included in the model (P = .07). Accelerated linear growth between 6 and 12 months was associated with longer TL in adulthood (P = .006), whereas weight gain between 12 and 24 months was associated with shorter TL in adulthood (P = .047).

CONCLUSIONS: In Cebu, individuals who were born heavier have longer TL in early adulthood, but that birthweight itself may not explain the association. Findings suggest that childhood growth is associated with the cellular senescence process in adulthood, implying early life well-being may be linked to adult health.

RevDate: 2019-08-05

Belmaker A, Hallinger KK, Glynn RA, et al (2019)

The environmental and genetic determinants of chick telomere length in Tree Swallows (Tachycineta bicolor).

Ecology and evolution, 9(14):8175-8186 pii:ECE35386.

Conditions during early life can have dramatic effects on adult characteristics and fitness. However, we still know little about the mechanisms that mediate these relationships. Telomere shortening is one possibility. Telomeres are long sequences of DNA that protect the ends of chromosomes. They shorten naturally throughout an individual's life, and individuals with short telomeres tend to have poorer health and reduced survival. Given this connection between telomere length (TL) and fitness, natural selection should favor individuals that are able to retain longer telomeres for a greater portion of their lives. However, the ability of natural selection to act on TL depends on the extent to which genetic and environmental factors influence TL. In this study, we experimentally enlarged broods of Tree Swallows (Tachycineta bicolor) to test the effects of demanding early-life conditions on TL, while simultaneously cross-fostering chicks to estimate heritable genetic influences on TL. In addition, we estimated the effects of parental age and chick sex on chick TL. We found that TL is highly heritable in Tree Swallow chicks, and that the maternal genetic basis for TL is stronger than is the paternal genetic basis. In contrast, the experimental manipulation of brood size had only a weak effect on chick TL, suggesting that the role of environmental factors in influencing TL early in life is limited. There was no effect of chick sex or parental age on chick TL. While these results are consistent with those reported in some studies, they are in conflict with others. These disparate conclusions might be attributable to the inherent complexity of telomere dynamics playing out differently in different populations or to study-specific variation in the age at which subjects were measured.

RevDate: 2019-08-05

Stroik S, Kurtz K, EA Hendrickson (2019)

CtIP is essential for telomere replication.

Nucleic acids research pii:5542874 [Epub ahead of print].

The maintenance of telomere length is critical to longevity and survival. Specifically, the failure to properly replicate, resect, and/or form appropriate telomeric structures drives telomere shortening and, in turn, genomic instability. The endonuclease CtIP is a DNA repair protein that is well-known to promote genome stability through the resection of endogenous DNA double-stranded breaks. Here, we describe a novel role for CtIP. We show that in the absence of CtIP, human telomeres shorten rapidly to non-viable lengths. This telomere dysfunction results in an accumulation of fusions, breaks, and frank telomere loss. Additionally, CtIP suppresses the generation of circular, extrachromosomal telomeric DNA. These latter structures appear to arise from arrested DNA replication forks that accumulate in the absence of CtIP. Hence, CtIP is required for faithful replication through telomeres via its roles at stalled replication tracts. Our findings demonstrate a new role for CtIP as a protector of human telomere integrity.

RevDate: 2019-08-07

Li Y, Han H, Wu Y, et al (2019)

Telomere elongation-based DNA-Catalytic amplification strategy for sensitive SERS detection of telomerase activity.

Biosensors & bioelectronics, 142:111543 pii:S0956-5663(19)30622-0 [Epub ahead of print].

Telomerase has been regarded as a biomarker for cancer diagnosis as well as the clinical treatment and the reliable detection of intracellular telomerase activity is of great significance. By developing a telomere elongation-based DNA-catalytic amplification strategy, a novel surface-enhanced Raman scattering (SERS) method is proposed for the assay of telomerase activity. In the presence of telomerase and nucleotide mixture dNTPs, the telomerase substrate (TS) primer extended and generated a long single-strand DNA (ssDNA) containing the telomere repeat units (TTAGGG)n, which could catalyze the entropy-driven circuit reaction (EDCR). One of the products of EDCR was ingeniously used as the catalyst of catalytic hairpin assembly (CHA) occured on magnetic beads (MBs). As a result, a large amount of ROX-labeled Raman probes could be anchored on the surface of MBs and used for SERS detection. Using this strategy, the assay can detect telomerase activity from cell extracts equivalent down to single HeLa cell.

RevDate: 2019-08-04

Wisse RPL, Kuiper JJW, Radstake TRD, et al (2019)

Quantification of Double Stranded DNA Breaks and Telomere Length as Proxies for Corneal Damage and Replicative Stress in Human Keratoconus Corneas.

Translational vision science & technology, 8(4):10 pii:TVST-18-1260.

Purpose: The pathogenesis of keratoconus (KC) is multifactorial, and associated with oxidative stress and subsequent DNA damage. We investigate differences in DNA damage and replicative stress in patients with KC, and in healthy and diseased controls.

Methods: We obtained 64 corneal buttons from 27 patients with KC after corneal transplant surgery, 21 with a decompensated graft (DG), and 16 healthy controls (HC). The amount of intact Alu elements per genome copy as measured by quantitative polymerase chain reaction (qPCR) was used to quantify intact DNA. Telomere length was measured as a proxy for replicative stress. In addition, telomerase reverse transcriptase (hTERT) gene expression level was assessed.

Results: Mean (± standard deviation [SD]) DNA damage was similar between the KC (5.56 ± 14.08), DG (3.16 ± 8.22), and HC (3.51 ± 6.66) groups (P = 0.807). No associations were found between DNA damage and patient age (P = 0.523), atopic constitution (P = 0.240), or contact lens wear (P = 0.393). Telomere length differed (P = 0.034), most notably in the KC group, and hTERT was not detected in any corneal sample. Three cross-linked (CXL) KC corneas did not contain significantly more DNA damage (×2.6, P = 0.750).

Conclusions: Based on these findings, differences in actual corneal DNA damage in KC could not be identified, and the longer telomere length in KC did not support replicative stress as a major etiologic factor in the pathogenesis of KC. Future longitudinal investigations on KC etiology should assess progressively early cases to better comprehend the cellular and molecular processes preceding the archetypical morphologic changes.

Translational Relevance: The standard treatment for progressive keratoconus promotes the crosslinking of collagen fibers through ultraviolet radiation and the subsequent formation of reactive oxygen species. Our study helps to underline the safety of this treatment approach.

RevDate: 2019-08-02

Momany AM, Lussier S, Nikolas MA, et al (2019)

Telomere Length and ADHD Symptoms in Young Adults.

Journal of attention disorders [Epub ahead of print].

Objective: Previous research examining telomeres in individuals with neuropsychiatric disorders shows that greater illness, symptoms, or cognitive impairment are linked with shorter telomeres. However, the relationships of telomere length and neuropsychological processes or psychiatric symptoms are not understood in individuals with Attention Deficit/Hyperactivity Disorder (ADHD). Method: 390 young adults with and without ADHD completed a multi-informant diagnostic assessment and neuropsychological testing battery. Participant DNA was isolated from saliva samples, and telomere length was determined using qPCR. Results: Linear regression models demonstrated the only significant association to survive correction for multiple testing was for childhood hyperactivity-impulsivity symptoms and longer telomere length. Conclusion: Contrary to expectations, longer telomere length in young adults was associated only with childhood ADHD symptoms, particularly hyperactivity-impulsivity, in this sample. These findings are an important demonstration that the neuropsychological deficits and symptoms experienced by individuals diagnosed with ADHD during adulthood may not be negatively associated with telomere length.

RevDate: 2019-07-31

Parolini M, Possenti CD, Caprioli M, et al (2019)

Egg Testosterone Differentially Affects Telomere Length in Somatic Tissues of Yellow-Legged Gull Embryos.

Physiological and biochemical zoology : PBZ, 92(5):459-462.

Maternal decisions on egg composition have major consequences for offspring. Maternal egg androgens have diverse, often contrasting, effects depending on offspring trait and life stage, suggesting that mothers face trade-offs in egg hormone transfer. However, the effect of egg androgens on embryonic telomere length, which is a major trait potentially affecting performance, has been never investigated. We administered a physiological dose of testosterone (T) to yellow-legged gull (Larus michahellis) eggs and found that, compared to controls, telomere length shortly before hatching was reduced in the liver but unaffected in the brain, heart, and pectoralis muscle. Telomere length varied across somatic tissues, and, independent of egg treatment, it was not correlated between them, suggesting independent telomere dynamics. Thus, we showed for the first time that increased egg T can increase telomere shortening in the embryo and that maternal T allocation strategies may evolve also in response to such effect. Moreover, contrary to observations in adult birds, at the embryonic stage telomere length in one somatic tissue may not reflect telomere length in other body districts.

RevDate: 2019-07-30

Cavalcante SG, Silva CPN, Sola PR, et al (2019)

ATRX-DAXX Complex Expression Levels and Telomere Length in Normal Young and Elder Autopsy Human Brains.

DNA and cell biology [Epub ahead of print].

The chromatin-remodeling complex ATRX/DAXX is one of the major epigenetic factors that controls heterochromatin maintenance due to its role in histone deposition. ATRX is involved in nucleosome configuration and maintenance of higher order chromatin structure, and DAXX is a specific histone chaperone for H3.3 deposition. Dysfunctions in this complex have been associated with telomere shortening, which influences cell senescence. However, data about this complex in brain tissue related to aging are still scarce. Therefore, in the present study, we analyzed ATRX and DAXX expressions in autopsied human brain specimens and the telomere length. A significant decrease in gene and protein expressions was observed in the brain tissues from the elderly compared with those from the young, which were related to short telomeres. These findings may motivate further functional analysis to confirm the ATRX-DAXX complex involvement in telomere maintenance and brain aging.

RevDate: 2019-07-29

Iglesias M, Felix DA, Gutiérrez-Gutiérrez Ó, et al (2019)

Downregulation of mTOR Signaling Increases Stem Cell Population Telomere Length during Starvation of Immortal Planarians.

Stem cell reports pii:S2213-6711(19)30231-0 [Epub ahead of print].

Reduction of caloric intake delays and prevents age-associated diseases and extends the life span in many organisms. It may be that these benefits are due to positive effects of caloric restriction on stem cell function. We use the planarian model Schmidtea mediterranea, an immortal animal that adapts to long periods of starvation by shrinking in size, to investigate the effects of starvation on telomere length. We show that the longest telomeres are a general signature of planarian adult stem cells. We also observe that starvation leads to an enrichment of stem cells with the longest telomeres and that this enrichment is dependent on mTOR signaling. We propose that one important effect of starvation for the rejuvenation of the adult stem cell pool is through increasing the median telomere length in somatic stem cells. Such a mechanism has broad implications for how dietary effects on aging are mediated at the whole-organism level.

RevDate: 2019-07-29

Muneer A, FA Minhas (2019)

Telomere Biology in Mood Disorders: An Updated, Comprehensive Review of the Literature.

Clinical psychopharmacology and neuroscience : the official scientific journal of the Korean College of Neuropsychopharmacology, 17(3):343-363.

Major psychiatric disorders are linked to early mortality and patients afflicted with these ailments demonstrate an increased risk of developing physical diseases that are characteristically seen in the elderly. Psychiatric conditions like major depressive disorder, bipolar disorder and schizophrenia may be associated with accelerated cellular aging, indicated by shortened leukocyte telomere length (LTL), which could underlie this connection. Telomere shortening occurs with repeated cell division and is reflective of a cell's mitotic history. It is also influenced by cumulative exposure to inflammation and oxidative stress as well as the availability of telomerase, the telomere-lengthening enzyme. Precariously short telomeres can cause cells to undergo senescence, apoptosis or genomic instability; shorter LTL correlates with compromised general health and foretells mortality. Important data specify that LTL may be reduced in principal psychiatric illnesses, possibly in proportion to exposure to the ailment. Telomerase, as measured in peripheral blood monocytes, has been less well characterized in psychiatric illnesses, but a role in mood disorder has been suggested by preclinical and clinical studies. In this manuscript, the most recent studies on LTL and telomerase activity in mood disorders are comprehensively reviewed, potential mediators are discussed, and future directions are suggested. An enhanced comprehension of cellular aging in psychiatric illnesses could lead to their re-conceptualizing as systemic ailments with manifestations both inside and outside the brain. At the same time this paradigm shift could identify new treatment targets, helpful in bringing about lasting cures to innumerable sufferers across the globe.

RevDate: 2019-08-07

Louzon M, Coeurdassier M, Gimbert F, et al (2019)

Telomere dynamic in humans and animals: Review and perspectives in environmental toxicology.

Environment international, 131:105025 pii:S0160-4120(19)30580-X [Epub ahead of print].

Telomeres (TLs) play major roles in stabilizing the genome and are usually shortened with ageing. The maintenance of TLs is ensured by two mechanisms involving telomerase (TA) enzyme and alternative lengthening telomeres (ALT). TL shortening and/or TA inhibition have been related to health effects on organisms (leading to reduced reproductive lifespan and survival), suggesting that they could be key processes in toxicity mechanisms (at molecular and cellular levels) and relevant as an early warning of exposure and effect of chemicals on human health and animal population dynamics. Consequently, a critical analysis of knowledge about relationships between TL dynamic and environmental pollution is essential to highlight the relevance of TL measurement in environmental toxicology. The first objective of this review is to provide a survey on the basic knowledge about TL structure, roles, maintenance mechanisms and causes of shortening in both vertebrates (including humans) and invertebrates. Overall, TL length decreases with ageing but some unexpected exceptions are reported (e.g., in species with different lifespans, such as the nematode Caenorhabditis elegans or the crustacean Homarus americanus). Inconsistent results reported in various biological groups or even between species of the same genus (e.g., the microcrustacean Daphnia sp.) indicate that the relation usually proposed between TL shortening and a decrease in TA activity cannot be generalized and depends on the species, stage of development or lifespan. Although the scientific literature provides evidence of the effect of ageing on TL shortening, much less information on the relationships between shortening, maintenance of TLs, influence of other endogenous and environmental drivers, including exposure to chemical pollutants, is available, especially in invertebrates. The second objective of this review is to connect knowledge on TL dynamic and exposure to contaminants. Most of the studies published on humans rely on correlative epidemiological approaches and few in vitro experiments. They have shown TL attrition when exposed to contaminants, such as polycyclic aromatic hydrocarbons (PAH), polychlorinated biphenyls (PCB), pesticides and metallic elements (ME). In other vertebrates, the studies we found deals mainly with birds and, overall, report a disturbance of TL dynamic consecutively to exposure to chemicals, including metals and organic compounds. In invertebrates, no data are available and the potential of TL dynamic in environmental risk assessment remains to be explored. On the basis of the main gaps identified some research perspectives (e.g., impact of endogenous and environmental drivers, dose response effects, link between TL length, TA activity, longevity and ageing) are proposed to better understand the potential of TL and TA measurements in humans and animals in environmental toxicology.

RevDate: 2019-07-27

Li F, Ge Y, Liu D, et al (2019)

The role of telomere-binding modulators in pluripotent stem cells.

Protein & cell pii:10.1007/s13238-019-0651-y [Epub ahead of print].

Pluripotent stem cells (PSCs) such as embryonic stem cells (ESCs), ESCs derived by somatic cell nuclear transfer (ntESCs), and induced pluripotent stem cells (iPSCs) have unlimited capacity for self-renewal and pluripotency and can give rise to all types of somatic cells. In order to maintain their self-renewal and pluripotency, PSCs need to preserve their telomere length and homeostasis. In recent years, increasing studies have shown that telomere reprogramming is essential for stem cell pluripotency maintenance and its induced pluripotency process. Telomere-associated proteins are not only required for telomere maintenance in both stem cells, their extra-telomeric functions have also been found to be critical as well. Here, we will discuss how telomeres and telomere-associated factors participate and regulate the maintenance of stem cell pluripotency.

RevDate: 2019-08-08

Wang W, Wang P, Wang S, et al (2019)

Benchmark dose assessment for coke oven emissions-induced telomere length effects in occupationally exposed workers in China.

Ecotoxicology and environmental safety, 182:109453.

Telomeres are DNA-protein structures that protect chromosome ends from degradation and fusion, which are shortened by oxidative stress, for example air pollution including benzene, toluene, Coke Oven Emissions (COEs), and so on. As a biomarker of health and disease, telomere length is associated with cardiovascular, diabetes and cancers. The aim of this study was to estimate the effects of COEs exposure on telomere length and the benchmark dose (BMD) of COEs. A total of 542 coke oven workers and 235 healthy controls without exposure to toxicants were recruited. Quantitative PCR was used to determine the telomere length in human peripheral blood leukocytes DNA. Propensity scoring was used to match coke oven workers to healthy controls. Linear regression models and trend tests were used to the relationship between COEs exposure and telomere length. Telomere length in COEs exposed group 0.764 (0.536, 1.092) was significantly shorter than that in the control group 1.064(0.762, 1.438), (P < 0.001). There were significantly dose-response relationships between COEs exposure and telomere damage with telomere length as a biomarker. A BMDL value lower than the present occupational exposure limits (OELs) of COEs exposure was evaluated using the BMD approach in coke oven workers. Our results suggested that shorter telomere length is related to occupational exposure to COEs and the level of COEs exposure lower than the current national OELs in China and many other countries could induce telomere damage.

RevDate: 2019-07-26

Tempaku PF, D'Almeida V, S Tufik (2019)

Is klotho a potential mediator between obstructive sleep apnoea and telomere length?.

Rejuvenation research [Epub ahead of print].


RevDate: 2019-07-28

J W, J J B, M K, et al (2019)

Is Telomere Length a Biomarker of Adaptive Response in Space? Curious Findings from NASA and Residents of High Background Radiation Areas.

Journal of biomedical physics & engineering, 9(3):381-388 pii:JBPE-9-3.

Telomere length and stability is a biomarker of aging, stress, and cancer. Shortening of telomeres and high level of DNA damages are known to be associated with aging. Telomere shortening normally occurs during cell division in most cells and when telomeres reach a critically short length, DNA damage signaling and cellular senescence can be triggered. The induction of an adaptive response by space radiation was first documented in 2003. Telomere length alterations are among the most fascinating observations in astronauts and residents of high background radiation areas. While study of the chronic exposure to high levels of background ionizing radiation in Kerala, India failed to show a significant influence on telomere length, limited data about the NASA astronaut Scott Kelly show that exposure to space radiation can induce telomeres to regain length. Interestingly, his telomeres shortened again only a couple of days after returning to Earth. The difference between these situations may be due to the differences in radiation dose, dose-rate, and/or type of radiation. Moreover, Scott Kelly's spacewalks (EVA) could have significantly increased his cumulative radiation dose. It is worth noting that the spacewalks not only confer a higher dose activity but are also characterized by a different radiation spectrum than inside the space craft since the primary particles would not interact with the vehicle shell to generate secondary radiation. Generally, these differences can possibly indicate the necessity of a minimum dose/dose-rate for induction of adaptive response (the so called Window effect).

RevDate: 2019-07-25

Gao J, Xiao H, Li J, et al (2019)

N-3 Polyunsaturated Fatty Acids Decrease Long-Term Diabetic Risk of Offspring of Gestational Diabetes Rats by Postponing Shortening of Hepatic Telomeres and Modulating Liver Metabolism.

Nutrients, 11(7): pii:nu11071699.

The long-term influence of gestational diabetes mellitus (GDM) on offspring and the effect of omega-3 polyunsaturated fatty acids (n-3 PUFA) on GDM offspring are poorly understood. We studied the long-term diabetic risk in GDM offspring and evaluated the effect of n-3 PUFA intervention. Healthy offspring rats were fed standard diet (soybean oil) after weaning. GDM offspring were divided into three groups: GDM offspring (soybean oil), n-3 PUFA adequate offspring (fish oil), and n-3 PUFA deficient offspring (safflower oil), fed up to 11 months old. The diabetic risk of GDM offspring gradually increased from no change at weaning to obvious impaired glucose and insulin tolerance at 11 months old. N-3 PUFA decreased oxidative stress and inflammation in the liver of older GDM offspring. There was a differential effect of n-3 PUFA and n-6 PUFA on hepatic telomere length in GDM offspring. Non-targeted metabolomics showed that n-3 PUFA played a modulating role in the liver, in which numerous metabolites and metabolic pathways were altered when GDM offspring grew to old age. Many metabolites were related to diabetes risk, such as α-linolenic acid, palmitic acid, ceramide, oxaloacetic acid, tocotrienol, tetrahydro-11-deoxycortisol, andniacinamide. In summary, GDM offspring exhibited obvious diabetes risk at old age, whereas n-3 PUFA decreased this risk.

RevDate: 2019-07-24

Maeda T, Horiuchi T, N Makino (2019)

The approximate formulas predicting personal somatic telomere length using patient blood test data.

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

Biological aging underlies lifestyle related diseases. It can be assessed by measuring personal somatic cell telomere length. However, measuring the telomere length is laborious, and its clinical surrogate parameters have not been developed. This study analyzed the correlation between telomere length in peripheral leukocytes and laboratory data to select test items relating closely to biological aging. We established formulas from these clinical data to predict the personal telomere length. The subjects were patients having visited Kyushu University Beppu Hospital from 2012 to 2015. Two hundred thirty-two patients were enrolled. The blood data were collected and telomere lengths were measured by Southern blotting method. The patients showed significant correlations between the telomere length and several blood test data with a gender-related difference. Candidate formulas are as follows; Predicted telomere length (kb) for men = 8.59 - 0.037 x Age (years) + 0.024 x Hemoglobin (g/dL) Predicted telomere length (kb) for women = 4.83 - 0.019 x Age (years) + 0.23 x Albumin (g/dL) + 0.0001 x White Blood Cells (/mm3) +0.0020 x Red Blood Cells (x 104/mm3) + 0.0032 x Total Cholesterol (mg/dL) Thus the derived formulae allow for the accurate differential prediction of telomeric length in male and female patients.

RevDate: 2019-07-24

Wang L, Koenig HG, He Z, et al (2019)

Religiosity and Telomere Length: Moderating Effect of Religiosity on the Relationship Between High-Risk Polymorphisms of the Apolipoprotein E and TOMM40 Gene and Telomere Length.

Journal of applied gerontology : the official journal of the Southern Gerontological Society [Epub ahead of print].

Objective: The current study seeks to examine the relationship between religiosity and telomere length (TL) in an older Chinese Muslim sample and to explore the moderating effect of religiosity on the relationship between high-risk polymorphisms and TL. Methods: A cross-sectional study of 1,692 community-dwelling adults aged 55 or older was conducted. Apolipoprotein E and TOMM40 (rs2075650) gene polymorphisms and TL were determined using standard procedures. Ordinal logistic regression was used to examine the associations. Results: Religiosity was significantly and positively related to TL. A significant interaction emerged between religiosity and the rs2075650 G polymorphism in predicting TL. Stratified multivariate analyses demonstrated that the relationship between the rs2075650 G state and TL was particularly strong among those who were more religious, as hypothesized. Conclusion: The findings revealed that religiosity may influence cellular aging in part by modifying the effect that high-risk genes have on increasing vulnerability to dementia and cognitive impairment.

RevDate: 2019-07-31

Lemon LD, Morris DK, AA Bertuch (2019)

Loss of Ku's DNA end binding activity affects telomere length via destabilizing telomere-bound Est1 rather than altering TLC1 homeostasis.

Scientific reports, 9(1):10607 pii:10.1038/s41598-019-46840-2.

Saccharomyces cerevisiae telomerase, which maintains telomere length, is comprised of an RNA component, TLC1, the reverse transcriptase, Est2, and regulatory subunits, including Est1. The Yku70/Yku80 (Ku) heterodimer, a DNA end binding (DEB) protein, also contributes to telomere length maintenance. Ku binds TLC1 and telomere ends in a mutually exclusive fashion, and is required to maintain levels and nuclear localization of TLC1. Ku also interacts with Sir4, which localizes to telomeres. Here we sought to determine the role of Ku's DEB activity in telomere length maintenance by utilizing yku70-R456E mutant strains, in which Ku has reduced DEB and telomere association but proficiency in TLC1 and Sir4 binding, and TLC1 nuclear retention. Telomere lengths in a yku70-R456E strain were nearly as short as those in yku∆ strains and shorter than in strains lacking either Sir4, Ku:Sir4 interaction, or Ku:TLC1 interaction. TLC1 levels were decreased in the yku70-R456E mutant, yet overexpression of TLC1 failed to restore telomere length. Reduced DEB activity did not impact Est1's ability to associate with telomerase but did result in decreased association of Est1 with the telomere. These findings suggest Ku's DEB activity maintains telomere length homeostasis by preserving Est1's interaction at the telomere rather than altering TLC1 levels.

RevDate: 2019-07-24

Fice HE, B Robaire (2019)

Telomere Dynamics Throughout Spermatogenesis.

Genes, 10(7): pii:genes10070525.

Telomeres are repeat regions of DNA that cap either end of each chromosome, thereby providing stability and protection from the degradation of gene-rich regions. Each cell replication causes the loss of telomeric repeats due to incomplete DNA replication, though it is well-established that progressive telomere shortening is evaded in male germ cells by the maintenance of active telomerase. However, germ cell telomeres are still susceptible to disruption or insult by oxidative stress, toxicant exposure, and aging. Our aim was to examine the relative telomere length (rTL) in an outbred Sprague Dawley (SD) and an inbred Brown Norway (BN) rat model for paternal aging. No significant differences were found when comparing pachytene spermatocytes (PS), round spermatids (RS), and sperm obtained from the caput and cauda of the epididymis of young and aged SD rats; this is likely due to the high variance observed among individuals. A significant age-dependent decrease in rTL was observed from 115.6 (±6.5) to 93.3 (±6.3) in caput sperm and from 142.4 (±14.6) to 105.3 (±2.5) in cauda sperm from BN rats. Additionally, an increase in rTL during epididymal maturation was observed in both strains, most strikingly from 115.6 (±6.5) to 142 (±14.6) in young BN rats. These results confirm the decrease in rTL in rodents, but only when an inbred strain is used, and represent the first demonstration that rTL changes as sperm transit through the epididymis.

RevDate: 2019-07-26

Song DY, Kim JA, Jeong D, et al (2019)

Telomere length and its correlation with gene mutations in chronic lymphocytic leukemia in a Korean population.

PloS one, 14(7):e0220177 pii:PONE-D-18-33276.

Telomere length (TL) is a prognostic indicator in Caucasian chronic lymphocytic leukemia (CLL), but its significance in Asian CLL remains unknown. To investigate the prognostic significance of TL and its correlation with cytogenetic aberrations and somatic mutations, we analyzed TL measurements at the cellular level by interphase fluorescence in situ hybridization in patients with CLL in Korea. The present study enrolled 110 patients (41 females and 69 males) diagnosed with CLL according to the World Health Organization criteria (2001-2017). TLs of bone marrow nucleated cells at the single-cell level were measured by quantitative fluorescence in situ hybridization (Q-FISH) in 71 patients. The correlations of TL with clinical characteristics, cytogenetic aberrations, genetic mutations, and overall survival were assessed. The median value of mean TL in CLL patients (T/C ratio 7.46 (range 1.19-18.14) was significantly shorter than that in the normal controls (T/C ratio 15.28 (range 8.59-24.93) (p < 0.001). Shorter TLs were associated with complex karyotypes (p = 0.030), del(11q22) (p = 0.023), presence of deletion and/or mutation in ATM and/or TP53 (p = 0.019), and SH2B3 mutation (p = 0.015). A shorter TL was correlated with lower hemoglobin levels and adverse survival (mean TL < 9.35, p = 0.021). When the proportion of cells with extremely short TLs (< 7.61) was greater than 90%, CLL patients showed poor survival (p = 0.002). Complex karyotypes, TP53 mutation, and the number of mutated genes were determined to be significant adverse variables by multivariable Cox analysis (p = 0.011, p = 0.002, and p = 0.002, respectively). TL was attrited in CLL, and attrited telomeres were correlated with adverse survival and other well-known adverse prognostic factors. We infer that TL is an independent adverse prognostic predictor in Korean CLL.

RevDate: 2019-07-23

Wang Y, Brummel SS, Beilstein-Wedel E, et al (2019)

Association between zidovudine-containing antiretroviral therapy exposure in utero and leukocyte telomere length at birth.

AIDS (London, England) [Epub ahead of print].

OBJECTIVES: Zidovudine (ZDV) is a nucleoside reverse transcriptase inhibitor that could cause telomere shortening through inhibition of telomerase. We examined the association between in utero exposure to ZDV and telomere length (TL) at birth in HIV-exposed uninfected (HEU) newborns.

METHODS: We selected 94 ZDV-exposed HEU children and 85 antiretroviral therapy (ART)-unexposed HEU children from the Surveillance Monitoring for ART Toxicities Study and the Women and Infants Transmission Study. We assessed relative TL in stored peripheral blood mononuclear cells taken in the first 7 days of life using quantitative polymerase chain reaction. We used linear regression to compare relative TL between ZDV-exposed and ART-unexposed children. We additionally evaluated relative TL according to maternal and infant characteristics.

RESULTS: Relative TL was longer in ZDV-exposed children compared to ART-unexposed individuals (adjusted mean ratio difference 0.21, 95%CI 0.15-0.28, p < 0.001). We found an inverse correlation between maternal HIV RNA levels and infant relative TL (-0.06 per log10 copies, 95%CI -0.08 to -0.03, p < 0.001). Relative TL was not associated with maternal CD4 count, maternal age, gestational age, sex, sample storage time, or maternal substance use (p > 0.05).

CONCLUSION: Relative TL was longer in ZDV-exposed infants. This difference may reflect beneficial health effects of antiretroviral therapy during pregnancy, since we observed an inverse association with maternal HIV RNA levels.

RevDate: 2019-08-07

Wood EM, AJ Young (2019)

Telomere attrition predicts reduced survival in a wild social bird, but short telomeres do not.

Molecular ecology [Epub ahead of print].

Attempts to understand the causes of variation in senescence trajectories would benefit greatly from biomarkers that reflect the progressive declines in somatic integrity (SI) that lead to senescence. While telomere length has attracted considerable interest in this regard, sources of variation in telomere length potentially unrelated to declines in SI could, in some contexts, leave telomere attrition rates a more effective biomarker than telomere length alone. Here, we investigate whether telomere length and telomere attrition rates predict the survival of wild white-browed sparrow-weaver nestlings (Plocepasser mahali). Our analyses of telomere length reveal counterintuitive patterns: telomere length soon after hatching negatively predicted nestling survival to fledging, a pattern that appears to be driven by differentially high in-nest predation of broods with longer telomeres. Telomere length did not predict survival outside this period: neither hatchling telomere length nor telomere length in the mid-nestling period predicted survival from fledging to adulthood. Our analyses using within-individual telomere attrition rates, by contrast, revealed the expected relationships: nestlings that experienced a higher rate of telomere attrition were less likely to survive to adulthood, regardless of their initial telomere length and independent of effects of body mass. Our findings support the growing use of telomeric traits as biomarkers of SI, but lend strength to the view that longitudinal assessments of within-individual telomere attrition since early life may be a more effective biomarker in some contexts than telomere length alone.

RevDate: 2019-07-23

Xu YJ, Khan S, Didier AC, et al (2019)

A tel2 mutation that destabilizes the Tel2-Tti1-Tti2 complex eliminates Rad3ATR kinase signaling in the DNA replication checkpoint and leads to telomere shortening in fission yeast.

Molecular and cellular biology pii:MCB.00175-19 [Epub ahead of print].

In response to perturbed DNA replication, ATR (ataxia telangiectasia and Rad3-related) kinase is activated to initiate the checkpoint signaling necessary for maintaining genome integrity and cell survival. To better understand the signaling mechanism, we carried out a large-scale genetic screen in fission yeast looking for mutants with enhanced sensitivity to hydroxyurea. From a collection of ∼370 primary mutants, we found a few mutants in which Rad3 (ATR ortholog)-mediated phospho-signaling was significantly compromised. One such mutant carried an uncharacterized mutation in tel2, a gene encoding an essential and highly conserved eukaryotic protein. Previous studies in various biological models have shown that Tel2 mainly functions in Tel2-Tti1-Tti2 (TTT) complex that regulates the steady-state levels of all phosphatidylinositol 3-kinase-like protein kinases (PIKKs), including ATR. We show here that although the levels of Rad3 and Rad3-mediated phospho-signaling in DNA damage checkpoint were moderately reduced in the tel2 mutant, the phospho-signaling in DNA replication checkpoint was almost completely eliminated. In addition, the tel2 mutation caused telomere shortening. Since the interactions of Tel2 with Tti1 and Tti2 were significantly weakened by the mutation, destabilization of the TTT complex likely contributes to the observed checkpoint and telomere defects.

RevDate: 2019-08-02

Keng SL, Yim OS, Lai PS, et al (2019)

Association among dispositional mindfulness, self-compassion, and leukocyte telomere length in Chinese adults.

BMC psychology, 7(1):47 pii:10.1186/s40359-019-0323-y.

BACKGROUND: Whereas meditation training has been purported to support slower cellular aging, little work has explored the association among different facets of dispositional mindfulness, self-compassion, and cellular aging. The present study aimed to examine the relationship between leukocyte telomere length (LTL), an index of cellular aging, dispositional mindfulness, and self-compassion in a sample of Singaporean Chinese adults.

METHODS: One hundred and fifty-eight Chinese adults (mean age = 27.24 years; 63.3% female) were recruited from the community and completed self-report measures assessing dispositional mindfulness, self-compassion, and psychological symptoms, as well as provided blood samples for analyses of LTL. Multiple regression analyses were conducted to examine the role of trait mindfulness and self-compassion in predicting LTL, taking into consideration potential covariates such as chronological age and psychological symptoms.

RESULTS: Results showed that nonreactivity, one of the five facets of dispositional mindfulness, was significantly associated with LTL, after controlling for chronological age. There was also a trend for dispositional mindfulness, self-compassion, and their selected facets (i.e., nonjudging, common humanity, and de-identification) to each be associated with longer LTL.

CONCLUSIONS: Overall, the findings provide preliminary support for the association among aspects of dispositional mindfulness, self-compassion, and aging. In particular, individuals high on nonreactivity experience slower aging at the cellular level, likely through engaging in more adaptive coping mechanisms.

RevDate: 2019-08-02

Muhsen K, Sinnreich R, Merom D, et al (2019)

Helicobacter pylori infection, serum pepsinogens as markers of atrophic gastritis, and leukocyte telomere length: a population-based study.

Human genomics, 13(1):32 pii:10.1186/s40246-019-0217-3.

BACKGROUND: Persistent infections that induce prolonged inflammation might negatively affect the leukocyte telomere length (LTL); however, the role in LTL of Helicobacter pylori (H. pylori) infection, which persistently colonizes the stomach, remains unknown. The study objective was to examine associations of sero-prevalence of H. pylori immunoglobulin G (IgG) antibody and serum pepsinogens (PGs), as markers of atrophic gastritis, with LTL. A cross-sectional study was performed among 934 Arab residents of East Jerusalem, aged 27-78 years, randomly selected from Israel's national population registry. Sera were tested for H. pylori IgG and PG levels by ELISA. LTL was measured by southern blots. Multiple linear regression models were fitted to adjust for sociodemographic and lifestyle factors.

RESULTS: LTL decreased significantly with age (p < 0.001) and was shorter in men than women (p = 0.032). The mean LTL was longer in H. pylori sero-positive persons than negative ones: mean difference 0.13 kb (95% CI 0.02, 0.24), p = 0.016. Participants with atrophic gastritis (PGI < 30 μg/L or a PGI: PGII < 3.0) had shorter LTL than did those without: mean difference - 0.18 (95% CI - 0.32, - 0.04). The difference was of larger magnitude between persons who had past H. pylori infection (sero-negative to H. pylori IgG antibody) and atrophic gastritis, compared to those who were H. pylori sero-negative and did not have atrophic gastritis: mean difference - 0.32 kb (95% CI - 0.55, - 0.10). This association remained significant after adjustment for age, sex, and religiosity: beta coefficient - 0.21 kb (95% CI - 0.41, - 0.001), p = 0.049. The results were similar after further adjustment for lifestyle factors. In bivariate analysis, mean LTL was longer in physically active persons than non-active ones, and shorter in persons with than without obesity; however, these differences were diminished and were not significant in the multivariable model.

CONCLUSIONS: H. pylori IgG sero-positivity per se was not related to reduced LTL. However, persons with past H. pylori infection (i.e., lacking H. pylori IgG serum antibody) and with serological evidence of atrophic gastritis, had a significantly shorter LTL than did those without atrophic gastritis.

RevDate: 2019-08-06

Cinegaglia N, Antoniazzi L, Rosa D, et al (2019)

Shortening telomere is associated with subclinical atherosclerosis biomarker in omnivorous but not in vegetarian healthy men.

Aging, 11(14):5070-5080.

Telomere length is considered to be a biomarker of biological aging and age-related disease. There are few studies that have evaluated the association between telomere length and diet, and none of them have evaluated the impact of a vegetarian diet on telomere length and its correlation with cardiovascular biomarkers in apparently healthy subjects. Therefore, our objectives were to evaluate leukocyte telomere length (LTL) in vegetarians and omnivorous subjects and its association with classical cardiovascular risk biomarkers. From the total of 745 participants initially recruited, 44 omnivorous and 44 vegetarian men apparently healthy were selected for this study and LTL was measured in 39 omnivorous and 41 vegetarians by Real-Time Quantitative PCR reaction. Although telomere length was not different between omnivorous and vegetarians, we found a strong negative correlation between LTL and IMT (intima-media thickness) in omnivorous, but not in vegetarian group. In addition, omnivorous who were classified with short telomere length had higher carotid IMT compared to vegetarians. Our data suggest that telomere length can be a marker of subclinical atherosclerosis in the omnivorous group.

RevDate: 2019-07-20

Chiriacò M, Georgiopoulos G, Duranti E, et al (2019)

Inflammation and Vascular Ageing: From Telomeres to Novel Emerging Mechanisms.

High blood pressure & cardiovascular prevention : the official journal of the Italian Society of Hypertension pii:10.1007/s40292-019-00331-7 [Epub ahead of print].

Cardiovascular disease (CVD) remains the leading cause of morbility and mortality worldwide. The identification of common cardiovascular risk factors has led to the development of effective treatments that enabled a significant reduction of the global cardiovascular disease burden. However, a significant proportion of cardiovascular risk remains unexplained by these risk factors leaving many individuals at risk of cardiovascular events despite good control of the risk factors. Recent randomized clinical trials and Mendelian randomization studies have suggested that inflammation explains a significant proportion of the residual cardiovascular risk in subjects with good control of risk factors. An accelerated process of vascular ageing is increasingly recognized as a potential mechanism by which inflammation might increase the risk of CVD. In turn, cellular ageing represents an important source of inflammation within the vascular wall, potentially creating a vicious cycle that might promote progression of atherosclerosis, independently from the individual cardiovascular risk factor burden. In this review, we summarise current evidence suggesting a role for biological ageing in CVD and how inflammation might act as a key mediator of this association.

RevDate: 2019-07-19

Nudelman KNH, Lin J, Lane KA, et al (2019)

Telomere Shortening in the Alzheimer's Disease Neuroimaging Initiative Cohort.

Journal of Alzheimer's disease : JAD pii:JAD190010 [Epub ahead of print].

BACKGROUND: Although shorter telomeres have been associated with Alzheimer's disease (AD), it is unclear whether longitudinal change in telomere length is associated with AD progression.

OBJECTIVE: To investigate the association of telomere length change with AD diagnosis and progression.

METHODS: In 653 individuals from the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort, T/S ratio (telomere versus single copy gene), a proxy of telomere length, was measured for up to five visits per participant (N = 1918 samples post-QC) using quantitative PCR (qPCR). T/S ratio was adjusted for batch effects and DNA storage time. A mixed effects model was used to evaluate association of telomere length with AD diagnostic group and interaction of age and diagnosis. Another mixed effects model was used to compare T/S ratio changes pre- to post-conversion to MCI or AD to telomere change in participants with stable diagnoses.

RESULTS: Shorter telomeres were associated with older age (Effect Size (ES) = -0.23) and male sex (ES = -0.26). Neither baseline T/S ratio (ES = -0.036) nor T/S ratio change (ES = 0.046) differed significantly between AD diagnostic groups. MCI/AD converters showed greater, but non-significant, telomere shortening compared to non-converters (ES = -0.186).

CONCLUSIONS: Although AD compared to controls showed small, non-significant effects for baseline T/S ratio and T/S ratio shortening, we did observe a larger, though still non-significant effect for greater telomere shortening in converters compared to non-converters. Although our results do not support telomere shortening as a robust biomarker of AD progression, further investigation in larger samples and for subgroups of participants may be informative.

RevDate: 2019-07-18

Kogure GS, Miranda-Furtado CL, Pedroso DCC, et al (2019)

Effects of Progressive Resistance Training on Obesity Indices in Polycystic Ovary Syndrome and the Relationship With Telomere Length.

Journal of physical activity & health pii:jpah.2018-0256 [Epub ahead of print].

BACKGROUND: Physical activity is prescribed as a component of primary management for polycystic ovary syndrome (PCOS). This nonrandomized, therapeutic, open, single-arm study investigated the effects of progressive resistance training (PRT) on obesity indices in women with PCOS, and the relationship between obesity indices and telomere content.

METHODS: A total of 45 women with PCOS and 52 with non-PCOS (controls), aged 18 to 37 years, with body mass indexes of 18 to 39.9 kg/m2, performed three 1-hour sessions of PRT per week, for 16 weeks. Before and after PRT, measures included anthropometric indices and regions of interest of fat mass distribution, quantified by dual-energy X-ray absorptiometry, metabolic and hormonal parameters, and telomere content. The general linear mixed models were used to determine the effects of PRT.

RESULTS: PRT did reduce the waist-to-height ratio, waist circumference, and the index of conicity among PCOS (P < .01). However, PRT did not influence regions of interest, body mass index, and WHR. After PRT, the telomere content was associated with regions of interest and anthropometric indices in whole group independent of PCOS (P < .05).

CONCLUSION: Resistance exercise improves obesity indices in PCOS, independent of changes in body weight, and the relationship between telomeres and obesity parameters in PCOS remain to be fully clarified.

RevDate: 2019-07-26

Ly K, Walker C, Berry S, et al (2019)

Telomere length in early childhood is associated with sex and ethnicity.

Scientific reports, 9(1):10359 pii:10.1038/s41598-019-46338-x.

Telomeres are repetitive DNA sequences at the end of chromosomes that function to protect chromosomes from degradation. Throughout the life course, telomere length decreases with age and is influenced by environmental factors and health conditions. This study aimed to determine the relative telomere lengths in a diverse cohort of about 4000 four-year-old children in New Zealand. Linear regression was used to investigate the relationship between telomere length, child gender, ethnicity, paternal age and deprivation. We observed substantial variation in telomere length according to sex and self-identified ethnicity. Telomere length was longer in females compared to males (coefficient of 0.042, 95% confidence interval (CI) 0.024-0.060). European children had shorter telomere than both the indigenous Māori (coefficient of 0.03, CI 0.007-0.055) and Pacific children (coefficient of 0.15, CI 0.12-0.18). The data suggest that telomere lengths are highly variable and variability between individuals arise from early age, influenced partly by sex and ethnicity. Longer telomeres in indigenous Māori and Pacific children may reflect the heritability of telomere length in genetically less complex populations. This study increases our understanding of telomere dynamics in young children since the majority of telomere studies are conducted in adults.

RevDate: 2019-07-19

Bateson M, Aviv A, Bendix L, et al (2019)

Smoking does not accelerate leucocyte telomere attrition: a meta-analysis of 18 longitudinal cohorts.

Royal Society open science, 6(6):190420 pii:rsos190420.

Smoking is associated with shorter leucocyte telomere length (LTL), a biomarker of increased morbidity and reduced longevity. This association is widely interpreted as evidence that smoking causes accelerated LTL attrition in adulthood, but the evidence for this is inconsistent. We analysed the association between smoking and LTL dynamics in 18 longitudinal cohorts. The dataset included data from 12 579 adults (4678 current smokers and 7901 non-smokers) over a mean follow-up interval of 8.6 years. Meta-analysis confirmed a cross-sectional difference in LTL between smokers and non-smokers, with mean LTL 84.61 bp shorter in smokers (95% CI: 22.62 to 146.61). However, LTL attrition was only 0.51 bp yr-1 faster in smokers than in non-smokers (95% CI: -2.09 to 1.08), a difference that equates to only 1.32% of the estimated age-related loss of 38.33 bp yr-1. Assuming a linear effect of smoking, 167 years of smoking would be required to generate the observed cross-sectional difference in LTL. Therefore, the difference in LTL between smokers and non-smokers is extremely unlikely to be explained by a linear, causal effect of smoking. Selective adoption, whereby individuals with short telomeres are more likely to start smoking, needs to be considered as a more plausible explanation for the observed pattern of telomere dynamics.

RevDate: 2019-07-17

Kroupa M, Rachakonda SK, Liska V, et al (2019)

Relationship of telomere length in colorectal cancer patients with cancer phenotype and patient prognosis.

British journal of cancer pii:10.1038/s41416-019-0525-3 [Epub ahead of print].

BACKGROUND: Telomeres, repetitive DNA capping ends of eukaryotic chromosomes, are important in the maintenance of genomic integrity. Perturbed telomeres are common features of many human malignancies, including colorectal cancer.

METHODS: Telomere length (TL), measured by a Monochrome Multiplex Real-Time qPCR, was investigated in tumour tissues, adjacent mucosa, and blood from patients with colorectal cancer with different clinicopathological features and its impact on patient survival. TL was also measured in a limited number of liver metastases, non-cancerous liver tissues or corresponding tissues from the same patients.

RESULTS: TL in tumour tissues was shorter than in the adjacent mucosa (P < 0.0001). Shorter TL was observed in tumours with lower stage than in those with advanced stages (P = 0.001). TL was shorter in tumours at the proximal than at the distal sites of the colon (P < 0.0001). Shorter TL was also associated with microsatellite instability (P = 0.001) and mucinous tumour histology (P < 0.0001). Patients with a smaller TL ratio between tumour tissues and the adjacent mucosa were associated with increased overall survival (P = 0.022). Metastasised tumours had shorter telomeres than the adjacent non-cancerous liver tissues (P = 0.0005).

CONCLUSIONS: Overall, the results demonstrate differences in TL between tumours and the adjacent mucosa, between tumours located at different sites and association with patient survival.

RevDate: 2019-08-04

Liew PS, Chen Q, Ng AWR, et al (2019)

Phage N15 protelomerase resolves its tos recognition site into hairpin telomeres within mammalian cells.

Analytical biochemistry, 583:113361 pii:S0003-2697(19)30220-9 [Epub ahead of print].

Phage N15 protelomerase (TelN) cleaves double-stranded circular DNA containing a telomerase-occupancy-site (tos) and rejoins the resulting linear-ends to form closed-hairpin-telomeres in Escherichia coli (E. coli). Continued TelN expression is essential to support resolution of the linear structure. In mammalian cells, no enzyme with TelN-like activities has been found. In this work, we show that phage TelN, expressed transiently and stably in human and mouse cells, recapitulates its native activities in these exogenous environments. We found TelN to accurately resolve tos-DNA in vitro and in vivo within human and mouse cells into linear DNA-containing terminal telomeres that are resistant to RecBCD degradation, a hallmark of protelomerase processing. In stable cells, TelN activity was detectable for at least 60 days, which suggests the possibility of limited silencing of its expression. Correspondingly, linear plasmid containing a 100 kb human β-globin gene expressed for at least 120 h in non-β-globin-expressing mouse cells with TelN presence. Our results demonstrate TelN is able to cut and heal DNA as hairpin-telomeres within mammalian cells, providing a tool for creating novel structures by DNA resolution in these hosts. The TelN protelomerase may be useful for exploring novel technologies for genome interrogation and chromosome engineering.

RevDate: 2019-07-12

Endén K, Tainio J, Hou M, et al (2019)

Telomere length regulators are activated in young men after pediatric kidney transplantation compared to healthy controls and survivors of childhood cancer-A cross-sectional study.

Pediatric transplantation [Epub ahead of print].

Chronic diseases are known to cause premature aging and frailty. Data about telomere length and telomere length-regulating proteins after pediatric KTx are scarce. Leukocyte telomere length and gene expression level of eight telomere-binding proteins were analyzed in 20 KTx recipients, eight childhood NBL survivors, and nine healthy controls. The influence of key clinical parameters on telomere length and on regulators of telomere length was evaluated. The telomere length in the KTx recipients tended to be shorter (0.53 AU) than in the healthy controls (0.64 AU) but longer than in the NBL survivors (0.38 AU). There was no significant difference in telomere length between the NBL survivors and the KTx recipients (P = .110). The gene expression level of telomere length-preserving protein RPA1 was significantly higher in the KTx recipients than among the NBL survivors or healthy controls, while the expression of TRF2 and the tumor suppressor gene p16 was significantly higher in the KTX recipients when compared to the controls. TRF2 and TIN2 correlated significantly with hsCRP; additionally, TRF2 showed significant correlation with plasma creatinine and eGFR. KTx recipients have near to normal telomere length, but they have significantly higher gene expression levels of telomere regulatory proteins compared with healthy controls, suggesting activation of mechanisms preserving telomere length among KTx recipients. Our results suggest that declined graft function and consequent inflammatory response may have influence on telomerase activity.

RevDate: 2019-07-16

Liu R, Liu J, Wang S, et al (2019)

Combined treatment with emodin and a telomerase inhibitor induces significant telomere damage/dysfunction and cell death.

Cell death & disease, 10(7):527 pii:10.1038/s41419-019-1768-x.

G-quadruplex telomeric secondary structures represent natural replication fork barriers and must be resolved to permit efficient replication. Stabilization of telomeric G4 leads to telomere dysfunctions demonstrated by telomere shortening or damage, resulting in genome instability and apoptosis. Chemical compounds targeting G4 structures have been reported to induce telomere disturbance and tumor suppression. Here, virtual screening was performed in a natural compound library using PyRx to identify novel G4 ligands. Emodin was identified as one of the best candidates, showing a great G4-binding potential. Subsequently, we confirmed that emodin could stabilize G4 structures in vitro and trigger telomere dysfunctions including fragile telomeres, telomere loss, and telomeric DNA damage. However, this telomere disturbance could be rescued by subsequent elevation of telomerase activity; in contrast, when we treated the cells with the telomerase inhibitor BIBR1532 upon emodin treatment, permanent telomere disturbance and obvious growth inhibition of 4T1-cell xenograft tumors were observed in mice. Taken together, our results show for the first time that emodin-induced telomeric DNA damage can upregulate telomerase activity, which may weaken its anticancer effect. The combined use of emodin and the telomerase inhibitor synergistically induced telomere dysfunction and inhibited tumor generation.

RevDate: 2019-07-14

Shin YA (2019)

How Does Obesity and Physical Activity Affect Aging?: Focused on Telomere as a Biomarker of Aging.

Journal of obesity & metabolic syndrome, 28(2):92-104.

Obesity is known to continuously increase systemic inflammation and oxidative stress, leading to shorter telomere length. However, research regarding the correlation between physical activity, exercise, obesity, and telomere length is not consistent. Therefore, this review aims to summarize the effects of obesity, physical activity, and exercise on telomere length. Our search for effects of obesity, physical activity, and exercise, on telomeres was conducted using three computerized databases: Medline, PubMed, and EBSCO. Keywords in the search were "physical activity, exercise and obesity," "physical activity, exercise and telomere," and "obesity and telomere." Improving chronic inflammation and oxidative stress levels can prevent telomere attrition due to obesity. In addition, differences in the anti-aging effects of physical activity and exercise are shown in the post-middle-age period, when telomere length changes, rather than in past exercise habits. Maintaining high cardiorespiratory fitness levels through regular exercise and physical activity in the post-middle-age period minimizes obesity-related diseases and helps maintain telomere length, which is an index of cell senescence.

RevDate: 2019-07-10

Ma S, Sun G, Yang S, et al (2019)

Effects of telomere length on leukemogenesis.

RevDate: 2019-07-19

Hasegawa Y, Yamamoto M, Miyamori J, et al (2019)

Telomere DNA length-dependent regulation of DNA replication timing at internal late replication origins.

Scientific reports, 9(1):9946 pii:10.1038/s41598-019-46229-1.

DNA replication is initiated at replication origins on chromosomes at their scheduled time during S phase of the cell cycle. Replication timing control is highly conserved among eukaryotes but the underlying mechanisms are not fully understood. Recent studies have revealed that some telomere-binding proteins regulate replication timing at late-replicating origins throughout the genome. To investigate the molecular basis of this process, we analyzed the effects of excessive elongation of telomere DNA on replication timing by deleting telomere-associated shelterin proteins in Schizosaccharomyces pombe. We found that rap1∆ and poz1∆ cells showed abnormally accelerated replication at internal late origins but not at subtelomere regions. These defects were suppressed by removal of telomere DNA and by deletion of the telomere-binding protein Taz1. Furthermore, Sds21-a counter protein phosphatase against Dbf4-dependent kinase (DDK)-accumulated at elongated telomeres in a Taz1-dependent manner but was depleted at internal late origins, indicating that highly elongated telomeres sequester Sds21 at telomeres and perturb replication timing at internal regions. These results demonstrate that telomere DNA length is an important determinant of replication timing at internal regions of chromosomes in eukaryotes.

RevDate: 2019-07-10

Fitzpatrick LJ, Olsson M, Parsley LM, et al (2019)

Tail loss and telomeres: consequences of large-scale tissue regeneration in a terrestrial ectotherm.

Biology letters, 15(7):20190151.

Large-scale tissue regeneration has potential consequences for telomere length through increases in cell division and changes in metabolism which increase the potential for oxidative stress damage to telomeres. The effects of regeneration on telomere dynamics have been studied in fish and marine invertebrates, but the literature is scarce for terrestrial species. We experimentally induced tail autotomy in a lizard (Niveoscincus ocellatus) and assessed relative telomere length (RTL) in blood samples before and after partial tail regeneration while concurrently measuring reactive oxygen species (ROS) levels. The change in ROS levels was a significant explanatory variable for the change in RTL over the 60-day experiment. At the average value of ROS change, the mean RTL increased significantly in the control group (intact tails), but there was no such evidence in the regenerating group. By contrast, ROS levels decreased significantly in the regenerating group, but there was no such evidence in the control group. Combined, these results suggest that tail regeneration following autotomy involves a response to oxidative stress and this potentially comes at a cost to telomere repair. This change in telomere maintenance demonstrates a potential long-term cost of tail regeneration beyond the regrowth of tissue itself.

RevDate: 2019-07-11

Ji Y, Dang X, Nguyen LNT, et al (2019)

Topological DNA damage, telomere attrition and T cell senescence during chronic viral infections.

Immunity & ageing : I & A, 16:12 pii:153.

Background: T cells play a key role in controlling viral infections; however, the underlying mechanisms regulating their functions during human viral infections remain incompletely understood. Here, we used CD4 T cells derived from individuals with chronic viral infections or healthy T cells treated with camptothecin (CPT) - a topoisomerase I (Top 1) inhibitor - as a model to investigate the role of DNA topology in reprogramming telomeric DNA damage responses (DDR) and remodeling T cell functions.

Results: We demonstrated that Top 1 protein expression and enzyme activity were significantly inhibited, while the Top 1 cleavage complex (TOP1cc) was trapped in genomic DNA, in T cells derived from individuals with chronic viral (HCV, HBV, or HIV) infections. Top 1 inhibition by CPT treatment of healthy CD4 T cells caused topological DNA damage, telomere attrition, and T cell apoptosis or dysfunction via inducing Top1cc accumulation, PARP1 cleavage, and failure in DNA repair, thus recapitulating T cell dysregulation in the setting of chronic viral infections. Moreover, T cells from virally infected subjects with inhibited Top 1 activity were more vulnerable to CPT-induced topological DNA damage and cell apoptosis, indicating an important role for Top 1 in securing DNA integrity and cell survival.

Conclusion: These findings provide novel insights into the molecular mechanisms for immunomodulation by chronic viral infections via disrupting DNA topology to induce telomeric DNA damage, T cell senescence, apoptosis and dysfunction. As such, restoring the impaired DNA topologic machinery may offer a new strategy for maintaining T cell function against human viral diseases.

RevDate: 2019-08-04

Whittemore K, Vera E, Martínez-Nevado E, et al (2019)

Telomere shortening rate predicts species life span.

Proceedings of the National Academy of Sciences of the United States of America, 116(30):15122-15127.

Telomere shortening to a critical length can trigger aging and shorter life spans in mice and humans by a mechanism that involves induction of a persistent DNA damage response at chromosome ends and loss of cellular viability. However, whether telomere length is a universal determinant of species longevity is not known. To determine whether telomere shortening can be a single parameter to predict species longevities, here we measured in parallel the telomere length of a wide variety of species (birds and mammals) with very different life spans and body sizes, including mouse (Mus musculus), goat (Capra hircus), Audouin's gull (Larus audouinii), reindeer (Rangifer tarandus), griffon vulture (Gyps fulvus), bottlenose dolphin (Tursiops truncatus), American flamingo (Phoenicopterus ruber), and Sumatran elephant (Elephas maximus sumatranus). We found that the telomere shortening rate, but not the initial telomere length alone, is a powerful predictor of species life span. These results support the notion that critical telomere shortening and the consequent onset of telomeric DNA damage and cellular senescence are a general determinant of species life span.

RevDate: 2019-07-18

Benyelles M, Episkopou H, O'Donohue MF, et al (2019)

Impaired telomere integrity and rRNA biogenesis in PARN-deficient patients and knock-out models.

EMBO molecular medicine, 11(7):e10201.

PARN, poly(A)-specific ribonuclease, regulates the turnover of mRNAs and the maturation and stabilization of the hTR RNA component of telomerase. Biallelic PARN mutations were associated with Høyeraal-Hreidarsson (HH) syndrome, a rare telomere biology disorder that, because of its severity, is likely not exclusively due to hTR down-regulation. Whether PARN deficiency was affecting the expression of telomere-related genes was still unclear. Using cells from two unrelated HH individuals carrying novel PARN mutations and a human PARN knock-out (KO) cell line with inducible PARN complementation, we found that PARN deficiency affects both telomere length and stability and down-regulates the expression of TRF1, TRF2, TPP1, RAP1, and POT1 shelterin transcripts. Down-regulation of dyskerin-encoding DKC1 mRNA was also observed and found to result from p53 activation in PARN-deficient cells. We further showed that PARN deficiency compromises ribosomal RNA biogenesis in patients' fibroblasts and cells from heterozygous Parn KO mice. Homozygous Parn KO however resulted in early embryonic lethality that was not overcome by p53 KO. Our results refine our knowledge on the pleiotropic cellular consequences of PARN deficiency.

RevDate: 2019-07-18

Cherfils-Vicini J, E Gilson (2019)

Inhibiting TRF1 upstream signaling pathways to target telomeres in cancer cells.

EMBO molecular medicine, 11(7):e10845.

In the context of tumorigenesis, telomere shortening is associated with apparent antagonistic outcomes: On one side, it favors cancer initiation through mechanisms involving genome instability, while on the other side, it prevents cancer progression, due to the activation of the DNA damage response (DDR) checkpoint behaving as a cell-intrinsic proliferation barrier. Consequently, telomerase, which can compensate for replicative erosion by adding telomeric DNA repeats at the chromosomal DNA extremities, is crucial for cancer progression and is upregulated in nearly 90% of human cancers. Therefore, telomeres are considered potential anti-cancer targets and, to date, most of the studies have focused on telomerase inhibition. However, the development of clinically efficient telomerase targeting therapies is still in its infancy. In this context, the findings reported in this issue of EMBO Molecular Medicine by Bejarano et al (2019) open new avenues for alternative telomere therapies.

RevDate: 2019-07-18

Bejarano L, Bosso G, Louzame J, et al (2019)

Multiple cancer pathways regulate telomere protection.

EMBO molecular medicine, 11(7):e10292.

Telomeres are considered as universal anti-cancer targets, as telomere maintenance is essential to sustain indefinite cancer growth. Mutations in telomerase, the enzyme that maintains telomeres, are among the most frequently found in cancer. In addition, mutations in components of the telomere protective complex, or shelterin, are also found in familial and sporadic cancers. Most efforts to target telomeres have focused in telomerase inhibition; however, recent studies suggest that direct targeting of the shelterin complex could represent a more effective strategy. In particular, we recently showed that genetic deletion of the TRF1 essential shelterin protein impairs tumor growth in aggressive lung cancer and glioblastoma (GBM) mouse models by direct induction of telomere damage independently of telomere length. Here, we screen for TRF1 inhibitory drugs using a collection of FDA-approved drugs and drugs in clinical trials, which cover the majority of pathways included in the Reactome database. Among other targets, we find that inhibition of several kinases of the Ras pathway, including ERK and MEK, recapitulates the effects of Trf1 genetic deletion, including induction of telomeric DNA damage, telomere fragility, and inhibition of cancer stemness. We further show that both bRAF and ERK2 kinases phosphorylate TRF1 in vitro and that these modifications are essential for TRF1 location to telomeres in vivo. Finally, we use these new TRF1 regulatory pathways as the basis to discover novel drug combinations based on TRF1 inhibition, with the goal of effectively blocking potential resistance to individual drugs in patient-derived glioblastoma xenograft models.

RevDate: 2019-07-29

Nguyen MT, Lycett K, Vryer R, et al (2019)

Telomere length: population epidemiology and concordance in Australian children aged 11-12 years and their parents.

BMJ open, 9(Suppl 3):118-126 pii:bmjopen-2017-020263.

OBJECTIVES: To (1) describe the epidemiology of child and adult telomere length, and (2) investigate parent-child telomere length concordance.

DESIGN: Population-based cross-sectional study within the Longitudinal Study of Australian Children.

SETTING: Assessment centres in seven major Australian cities and eight selected regional towns; February 2015 to March 2016.

PARTICIPANTS: Of 1874 participating families, telomere data were available for analysis for 1206 children and 1343 parents, of whom 1143 were parent-child pairs. There were 589 boys and 617 girls; 175 fathers and 1168 mothers.

OUTCOME MEASURES: Relative telomere length (T/S ratio), calculated by comparing telomeric DNA (T) level with the single copy (S) beta-globin gene in venous blood-derived genomic DNA by quantitative real-time PCR.

RESULTS: Mean T/S ratio for all children, boys and girls was 1.09 (SD 0.56), 1.05 (SD 0.53) and 1.13 (SD 0.59), respectively. Mean T/S ratio for all parents, fathers and mothers was 0.81 (SD 0.37), 0.82 (SD 0.36) and 0.81 (SD 0.38), respectively. Parent-child T/S ratio concordance was moderate (correlation 0.24). In adjusted regression models, one unit higher parent T/S ratio was associated with 0.36 (estimated linear regression coefficient (β); 95% CI 0.28 to 0.45) higher child T/S ratio. Concordance was higher in the youngest parent-age tertile (β 0.49; 95% CI 0.34 to 0.64) compared with the middle (β 0.35; 95% CI 0.21 to 0.48) and oldest tertile (β 0.26; 95% CI 0.11 to 0.41; p-trend 0.04). Father-child concordance was 0.34 (95% CI 0.18 to 0.48), while mother-child was 0.22 (95% CI 0.17 to 0.28).

CONCLUSIONS: We provide telomere length population values for children aged 11-12 years and their mid-life parents. Relative telomere length was shorter in adults than children, as expected. There was modest evidence of parent-child concordance, which diminished with increasing parent age.

RevDate: 2019-07-04

Wynchank DS, Bijlenga D, Penninx BW, et al (2019)

Delayed sleep-onset and biological age: late sleep-onset is associated with shorter telomere length.

Sleep pii:5528107 [Epub ahead of print].

OBJECTIVES: We evaluated the relationship between leukocyte telomere length (LTL) and sleep duration, insomnia symptoms, and circadian rhythm, to test whether sleep and chronobiological dysregulations are associated with cellular aging.

METHODS: Data from the Netherlands Study of Depression and Anxiety (N=2,936) were used at two waves six years apart, to measure LTL. Telomeres shorten during the lifespan and are important biomarkers for cellular aging. LTL was assessed by qualitative polymerase chain reaction and converted into base pair number. Sleep parameters were: sleep duration and insomnia symptoms from the Insomnia Rating Scale. Circadian rhythm variables were: indication of Delayed Sleep Phase Syndrome (DSPS), mid-sleep corrected for sleep debt on free days (MSFsc), sleep-onset time, and self-reported chronotype, from the Munich Chronotype Questionnaire. Generalized estimating equations analysed the associations between LTL, sleep and chronobiological factors, adjusted for baseline age, sex, North European ancestry, and additionally for current smoking, depression severity, obesity and childhood trauma.

RESULTS: Indicators of delayed circadian rhythm showed a strong and consistent effect on LTL, after adjustment for sociodemographic and health indicators. Late MSFsc (B=-49.9, p=.004), late sleep-onset time (B=-32.4, p=.001), indication of DSPS (B=-73.8, p=.036) and moderately late chronotype in adulthood (B=-71.6, p=.003) were associated with significantly shorter LTL across both waves; whereas sleep duration and insomnia symptoms were not. Extremely early chronotype showed significantly less LTL shortening than intermediate chronotype (B=161.40, p=.037). No predictors showed accelerated LTL attrition over 6 years.

CONCLUSIONS: Individuals with delayed circadian rhythm have significantly shorter LTL, but not faster LTL attrition rates.

RevDate: 2019-07-03

Szczotka M, Kocki J, Iwan E, et al (2019)

Determination of telomere length and telomerase activity in cattle infected with bovine leukaemia virus (BLV).

Polish journal of veterinary sciences, 22(2):391-403.

Telomeres are repetitive sequence structures at the ends of chromosomes. They consist of the double stranded DNA repeats followed by the short single stranded DNA. In humans and other verterbrates the telomeric sequence is composed of tandem of TTAGGG repeats. With each cells division telomeres shorten by up to 200 base pairs. Telomerase is an enzyme responsible for continuous cell growth and is repressed in most somatic cells, except proliferating progenitor cells, but in more than 85% of cancer cells telomerase expression is observed. Tumour cells with metastatic potential may demonstrate a high telomerase activity, allowing cells to escape from the inhibition of cell proliferation due to shortened telomeres. Determination of telomerase expression was performed with the use of PCR ELISA in samples isolated from bovine leukaemia virus (BLV) infected cows. Telomerase activity was found in almost all investigated samples. The relative telomerase activity (RTA) was higher in infected cows than in healthy animals and the differences were statistically significant (α=0.05). In blood lymphocytes of BLV-infected cows the mean values of telomerase expression determined in real-time PCR were 3534.12 copies, in the healthy group there were 1010.10 copies and these differences were also statistically significant. For telomere length evaluation the Telomere PNA/FITC FISH and Telomere PNA/FITC FISH for flow cytometry were used. The mean fluorescence intensity of telomere sequences calculated on the surface of interphase nuclei of leukaemic blood lymphocytes was lower than that in the control animals and the difference was statistically significant. The mean length of telomeres in BLV- infected and healthy cows was 31.63 ± 12.62 and 38.4 ± 4.03, (p=0.112), respectively.

RevDate: 2019-07-08

Ley B, Torgerson DG, Oldham JM, et al (2019)

Rare Protein-altering Telomere-related Gene Variants in Patients with Chronic Hypersensitivity Pneumonitis.

American journal of respiratory and critical care medicine [Epub ahead of print].

RATIONALE: Rare genetic variants in telomere-related genes have been identified in familial, idiopathic, and rheumatoid arthritis-associated pulmonary fibrosis. Short peripheral blood leukocyte (PBL) telomere length predicts poor outcomes in chronic hypersensitivity pneumonitis (CHP).

OBJECTIVES: Determine the prevalence and clinical relevance of rare protein-altering variants in telomere-related genes in patients with CHP.

METHODS: Next generation sequences from two CHP cohorts were analyzed to identify variants in TERT, TERC, DKC1, RTEL1, PARN, and TINF2. To qualify, variants were required to have a minor allele frequency <0.005 and be predicted to be damaging to protein function. Variant status (binary variable) was used in statistical association tests including Cox proportional hazard models for transplant-free survival. PBL telomere length was measured using qPCR.

MEASUREMENTS AND MAIN RESULTS: Qualifying variants were identified in 16/144 patients (11.1%, 95% CI 6.5-17.4) in the discovery cohort and 17/209 patients (8.1%, 95% CI 4.8-12.7) in the replication cohort. Age and ancestry-adjusted PBL telomere length was significantly shorter in the presence of a variant in both cohorts (discovery: -561 base pairs [bp], 95% CI -933 to -190, p=0.003; replication: -612 bp, 95% CI -870 to -354, p=5.30x10-6) cohorts. Variant status was significantly associated with transplant-free survival in both cohorts (discovery: age-sex-ancestry-adjusted hazard ratio [HR] 3.73, 95% CI 1.92-7.28, p=0.0001; replication: HR 2.72, 95% CI 1.26-5.88, p=0.011).

CONCLUSIONS: A substantial proportion of patients diagnosed with CHP have rare, protein-altering variants in telomere-related genes, which are associated with short peripheral blood telomere length and significantly reduced transplant-free survival.

RevDate: 2019-07-03

Cartwright IM (2019)

Modified PNA Telomere and Centromere FISH Protocols.

Methods in molecular biology (Clifton, N.J.), 1984:101-105.

Fluorescence in situ Hybridization (FISH) utilizes peptide nucleic acid (PNA) probes to identify specific DNA sequences. PNA probes have been effectively used to identify chromosome aberrations and have been shown to greatly aid in biodosimetery assays involved in identifying dicentrics. Traditional techniques have required the heat denaturing of the DNA in formamide followed by multiple hours at moderated temperatures to allow the probe to hybridize to its specific target. Over the past 30 years, advancements in both protocols and probes have made FISH a more reliable technique for both biological research and medical diagnostics, additionally the protocol has been shortened to several minutes. We will introduce two modified PNA FISH protocols, a rapid microwave-based approach and nonclassical hybridization protocol.

RevDate: 2019-07-03

Cartwright IM, Haskins JS, TA Kato (2019)

PNA Telomere and Centromere FISH Staining for Accurate Analysis of Radiation-Induced Chromosomal Aberrations.

Methods in molecular biology (Clifton, N.J.), 1984:95-100.

Dicentric and centric ring chromosomes are used for radiation-induced damage analysis and biodosimetry after radiation exposure. However, Giemsa stain-based cytogenetic analysis is labor-intense and time-consuming. Moreover, the disadvantage of Giemsa based chromosome analysis is a potential poor reproducibility when researchers are not fully trained for analysis. These problems come from analysis of morphological abnormality of chromosomal aberrations. Locus-specific FISH probes were used to overcome this problem. Centromere probes can visualize centromere locations and help identify dicentric chromosomes and centric rings. Telomere probes help to identify terminal deletion and telomere fusions. Probes were originally designed with a DNA probe but Peptide nucleic acid (PNA) probes took the place of DNA probes. This chapter introduces PNA telomere and centromere FISH staining and accurate analysis of chromosomal aberrations.

RevDate: 2019-07-03

Adwan Shekhidem H, Sharvit L, Leman E, et al (2019)

Telomeres and Longevity: A Cause or an Effect?.

International journal of molecular sciences, 20(13): pii:ijms20133233.

Telomere dynamics have been found to be better predictors of survival and mortality than chronological age. Telomeres, the caps that protect the end of linear chromosomes, are known to shorten with age, inducing cell senescence and aging. Furthermore, differences in age-related telomere attrition were established between short-lived and long-lived organisms. However, whether telomere length is a "biological thermometer" that reflects the biological state at a certain point in life or a biomarker that can influence biological conditions, delay senescence and promote longevity is still an ongoing debate. We cross-sectionally tested telomere length in different tissues of two long-lived (naked mole-rat and Spalax) and two short-lived (rat and mice) species to tease out this enigma. While blood telomere length of the naked mole-rat (NMR) did not shorten with age but rather showed a mild elongation, telomere length in three tissues tested in the Spalax declined with age, just like in short-lived rodents. These findings in the NMR, suggest an age buffering mechanism, while in Spalax tissues the shortening of the telomeres are in spite of its extreme longevity traits. Therefore, using long-lived species as models for understanding the role of telomeres in longevity is of great importance since they may encompass mechanisms that postpone aging.

RevDate: 2019-07-04

Tian Y, Wang S, Jiao F, et al (2019)

Telomere Length: A Potential Biomarker for the Risk and Prognosis of Stroke.

Frontiers in neurology, 10:624.

Stroke is one of the leading causes of death and disability worldwide. Age is associated with increased risk of stroke, while telomere length shortening plays a pivotal role in the process of aging. Moreover, telomere length shortening is associated with many risk factors of stroke in addition to age. Accumulated evidence shows that short leukocyte telomere length is not only associated with stroke occurrence but also associated with post-stroke recovery in the elderly population. In this review, we aimed to summarize the association between leukocyte telomere length and stroke, and discuss that telomere length might serve as a potential biomarker to predict the risk and prognosis of stroke.

RevDate: 2019-07-04

Kachuri L, Helby J, Bojesen SE, et al (2019)

Investigation of Leukocyte Telomere Length and Genetic Variants in Chromosome 5p15.33 as Prognostic Markers in Lung Cancer.

Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, 28(7):1228-1237.

BACKGROUND: Lung cancer remains the leading cause of cancer mortality with relatively few prognostic biomarkers. We investigated associations with overall survival for telomere length (TL) and genetic variation in chromosome 5p15.33, an established telomere maintenance locus.

METHODS: Leukocyte TL was measured after diagnosis in 807 patients with non-small cell lung cancer (NSCLC) from the Princess Margaret Cancer Center in Toronto and assessed prospectively in 767 NSCLC cases from the Copenhagen City Heart Study and the Copenhagen General Population Study. Associations with all-cause mortality were tested for 723 variants in 5p15.33, genotyped in 4,672 NSCLC cases.

RESULTS: Short telomeres (≤10th percentile) were associated with poor prognosis for adenocarcinoma in both populations: TL measured 6 months after diagnosis [HR = 1.65; 95% confidence intervals (CI), 1.04-2.64] and for those diagnosed within 5 years after blood sampling (HR = 2.42; 95% CI, 1.37-4.28). Short TL was associated with mortality in never smokers with NSCLC (HR = 10.29; 95% CI, 1.86-56.86) and adenocarcinoma (HR = 11.31; 95% CI, 1.96-65.24). Analyses in 5p15.33 identified statistically significant prognostic associations for rs56266421-G in LPCAT1 (HR = 1.86; 95% CI, 1.38-2.52; P = 4.5 × 10-5) in stage I-IIIA NSCLC, and for the SLC6A3 gene with OS in females with NSCLC (P = 1.6 × 10-3).

CONCLUSIONS: Our findings support the potential clinical utility of TL, particularly for adenocarcinoma patients, while associations in chromosome 5p15.33 warrant further exploration.

IMPACT: This is the largest lung cancer study of leukocyte TL and OS, and the first to examine the impact of the timing of TL measurement. Our findings suggest that extremely short telomeres are indicative of poor prognosis in NSCLC.

RevDate: 2019-07-02

Carugno M, Maggioni C, Crespi E, et al (2019)

Night Shift Work, DNA Methylation and Telomere Length: An Investigation on Hospital Female Nurses.

International journal of environmental research and public health, 16(13): pii:ijerph16132292.

Increased breast cancer risk has been reported in some night shift (NS) workers but underlying biological mechanisms are still unclear. We assessed the association between NS work and DNA methylation of tumor suppressor (TP53, CDKN2A, BRCA1, BRCA2) and estrogen receptor (ESR1, ESR2) genes, methylation of repetitive elements (LINE-1, Alu), and telomere length (TL). Forty six female nurses employed in NS for at least two years were matched by age (30-45 years) and length of service (≥1 year) with 51 female colleagues not working in NS. Each subject underwent a semi-structured interview and gave a blood sample. We applied linear regression and spline models adjusted for age, BMI, smoking habit, oral contraceptive use, parity and marital status/age at marriage. Currently working in NS was associated with ESR1 hypomethylation (β: -1.85 (95%CI: -3.03; -0.67), p = 0.003). In current and former NS workers we observed TP53 (-0.93 (-1.73; -0.12), p = 0.03) and BRCA1 (-1.14 (-1.71; -0.58), p <0.001) hypomethylation. We found an increase between TL and number of years in NS in subjects employed in NS <12 years (0.06 (0.03; 0.09), p <0.001), while a decrease if employed in NS ≥12 years (-0.07 -0.10; -0.04), p <0.001). Our findings show NS-associated markers potentially involved in cellular aging, genomic instability, and cancer development.

RevDate: 2019-07-04

Toland AE (2019)

POT1 pathogenic variants: not all telomere pathway genes are equal in risk of hereditary cutaneous melanoma.

The British journal of dermatology, 181(1):14-15.

RevDate: 2019-08-07

Konečná K, Lyčka M, Nohelová L, et al (2019)

Holocaust history is not reflected in telomere homeostasis in survivors and their offspring.

Journal of psychiatric research, 117:7-14 pii:S0022-3956(19)30161-X [Epub ahead of print].

Telomeres, nucleoprotein structures at the ends of eukaryotic chromosomes, are crucial for the maintenance of genome integrity. While the lengths of telomeres at birth are determined genetically, many factors including environmental and living conditions affect the telomere lengths during a lifespan. In this context, extreme and long-term stress has been shown to negatively impact telomeres and their protective function, with even offspring being influenced by the stress experienced by parents. Using quantitative PCR, the relative lengths of telomeres of survivors of the Holocaust during World War II and two generations of their offspring were analyzed. These data were related to those of control groups, persons of comparable age without a strong life stress experience. In contrast to previous studies of other stress-exposed groups, the relative lengths of telomeres were comparable in groups of persons exposed to Holocaust-related stress and their progenies, and in control groups. Interestingly, shorter telomeres of Holocaust survivors of the age under 12 in the year 1945 compared to Holocaust survivors of the age above 12 were detected. Our results are discussed with respect to certain exceptionality of persons having been able to cope with an extreme stress more than 70 years ago and living to a very old age.

RevDate: 2019-07-25

Welendorf C, Nicoletti CF, Pinhel MAS, et al (2019)

Obesity, weight loss, and its influence on telomere length: New insights for personalized nutrition.

Nutrition (Burbank, Los Angeles County, Calif.), 66:115-121 pii:S0899-9007(19)30026-7 [Epub ahead of print].

Telomeres are structures located at the ends of chromosomes associated with proteins, from the shelterin complex, which are responsible for the protection and preservation of the genetic material. The telomere length (TL) progressively decreases with each cell division, and recent evidence suggests that lifestyle can lead to telomere shortening. In individuals with obesity, excess adipose tissue plays a key role in inducing a chronic and systemic inflammatory state, which can cause TL shortening. Thus, the aim of the present review was to show the relationship between obesity and TL in addition to the possible risk factors for its shortening and how the different strategies for weight loss can modulate TL. As the crucial result, we can consider the association between TL and weight loss and adiposity changes after different interventions, showing that TL may be used as a biomarker of responses to obesity treatment.

RevDate: 2019-06-29

Nault JC, Ningarhari M, Rebouissou S, et al (2019)

The role of telomeres and telomerase in cirrhosis and liver cancer.

Nature reviews. Gastroenterology & hepatology pii:10.1038/s41575-019-0165-3 [Epub ahead of print].

Telomerase is a key enzyme for cell survival that prevents telomere shortening and the subsequent cellular senescence that is observed after many rounds of cell division. In contrast, inactivation of telomerase is observed in most cells of the adult liver. Absence of telomerase activity and shortening of telomeres has been implicated in hepatocyte senescence and the development of cirrhosis, a chronic liver disease that can lead to hepatocellular carcinoma (HCC) development. During hepatocarcinogenesis, telomerase reactivation is required to enable the uncontrolled cell proliferation that leads to malignant transformation and HCC development. Part of the telomerase complex, telomerase reverse transcriptase, is encoded by TERT, and several mechanisms of telomerase reactivation have been described in HCC that include somatic TERT promoter mutations, TERT amplification, TERT translocation and viral insertion into the TERT gene. An understanding of the role of telomeres and telomerase in HCC development is important to develop future targeted therapies and improve survival of this disease. In this Review, the roles of telomeres and telomerase in liver carcinogenesis are discussed, in addition to their potential translation to clinical practice as biomarkers and therapeutic targets.

RevDate: 2019-07-02

Manna S, McCarthy C, FP McCarthy (2019)

Placental Ageing in Adverse Pregnancy Outcomes: Telomere Shortening, Cell Senescence, and Mitochondrial Dysfunction.

Oxidative medicine and cellular longevity, 2019:3095383.

Preeclampsia is a multisystemic pregnancy disorder and a major cause of maternal and neonatal morbidity and mortality worldwide. The exact pathophysiology of preeclampsia remains unclear; however, it is speculated that the various pathologies can be attributed to impaired vascular remodelling and elevated oxidative stress within the placenta. Oxidative stress plays a key role in cell ageing, and the persistent presence of elevated oxidative stress precipitates cellular senescence and mitochondrial dysfunction, resulting in premature ageing of the placenta. Premature ageing of the placenta is associated with placental insufficiency, which reduces the functional capacity of this critical organ and leads to abnormal pregnancy outcomes. The changes brought about by oxidative insults are irreversible and often lead to deleterious modifications in macromolecules such as lipids and proteins, DNA mutations, and alteration of mitochondrial functioning and dynamics. In this review, we have summarized the current knowledge of placental ageing in the aetiology of adverse pregnancy outcomes and discussed the hallmarks of ageing which could be potential markers for preeclampsia and fetal growth restriction.

RevDate: 2019-07-24

Arish N, Petukhov D, SB Wallach-Dayan (2019)

The Role of Telomerase and Telomeres in Interstitial Lung Diseases: From Molecules to Clinical Implications.

International journal of molecular sciences, 20(12): pii:ijms20122996.

Telomeres are distal chromosome regions associated with specific protein complexes that protect the chromosome against degradation and aberrations. Telomere maintenance capacity is an essential indication of healthy cell populations, and telomere damage is observed in processes such as malignant transformation, apoptosis, or cell senescence. At a cellular level, telomere damage may result from genotoxic stress, decreased activity of telomerase enzyme complex, dysfunction of shelterin proteins, or changes in expression of telomere-associated RNA such as TERRA. Clinical evidence suggests that mutation of telomerase genes (Tert/Terc) are associated with increased risk of congenital as well as age-related diseases (e.g., pneumonitis, idiopathic pulmonary fibrosis (IPF), dyskeratosis congenita, emphysema, nonspecific interstitial pneumonia, etc.). Thus, telomere length and maintenance can serve as an important prognostic factor as well as a potential target for new strategies of treatment for interstitial lung diseases (ILDs) and associated pulmonary pathologies.

RevDate: 2019-07-30

Lee EY, Oh SS, White MJ, et al (2019)

Ambient air pollution, asthma drug response, and telomere length in African American youth.

The Journal of allergy and clinical immunology pii:S0091-6749(19)30820-6 [Epub ahead of print].

BACKGROUND: Telomere length (TL) can serve as a potential biomarker for conditions associated with chronic oxidative stress and inflammation, such as asthma. Air pollution can induce oxidative stress. Understanding the relationship between TL, asthma, and air pollution is important for identifying risk factors contributing to unhealthy aging in children.

OBJECTIVES: We sought to investigate associations between exposures to ambient air pollutants and TL in African American children and adolescents and to examine whether African ancestry, asthma status, and steroid medication use alter the association.

METHODS: Linear regression was used to examine associations between absolute telomere length (aTL) and estimated annual average residential ozone (O3) and fine particulate matter with a diameter of 2.5 μm or less (PM2.5) exposures in a cross-sectional analysis of 1072 children in an existing asthma case-control study. African ancestry, asthma status, and use of steroid medications were examined as effect modifiers.

RESULTS: Participants' aTLs were measured by using quantitative PCR. A 1-ppb and 1 μg/m3 increase in annual average exposure to O3 and PM2.5 were associated with a decrease in aTL of 37.1 kilo-base pair (kb; 95% CI, -66.7 to -7.4 kb) and 57.1 kb (95% CI, -118.1 to 3.9 kb), respectively. African ancestry and asthma were not effect modifiers; however, exposure to steroid medications modified the relationships between TL and pollutants. Past-year exposure to O3 and PM2.5 was associated with shorter TLs in patients without steroid use.

CONCLUSION: Exposure to air pollution was associated with shorter TLs in nonasthmatic children and adolescents. This was not the case for asthmatic children as a group, but those receiving steroid medication had less shortening than those not using steroids. Reduced exposure to air pollution in childhood might help to preserve TL.

RevDate: 2019-07-07

Minami R, Takahama S, M Yamamoto (2019)

Correlates of telomere length shortening in peripheral leukocytes of HIV-infected individuals and association with leukoaraiosis.

PloS one, 14(6):e0218996 pii:PONE-D-19-02380.

Telomere length (TL) is a marker of cellular and biological aging. Human immunodeficiency virus (HIV) infection has been reported to be associated with short TLs, which suggests that accelerated biological aging occurs in some cellular compartments of HIV+ individuals. In this study, we measured the TLs of peripheral leukocytes of HIV+ and healthy individuals and examined the biological and environmental correlates of TL. We also investigated the influence of TL on leukoaraiosis, an indicator of cerebral small vessel disease, in HIV+ individuals. Three hundred and twenty-five HIV+ individuals who received stable combination antiretroviral therapy (cART) for >1 year and achieved viral loads of <40 RNA copies/mL were enrolled along with 147 healthy individuals. Relative TLs of leukocytes were estimated by quantitative real-time polymerase chain reaction. Leukoaraiosis was assessed in 184 HIV+ individuals by fluid-attenuated inversion recovery magnetic resonance imaging. We analyzed several covariates, including markers of HIV infection, cART, and social/environmental factors; variables associated with TL length in univariate analyses were incorporated into multivariate models. The TLs of peripheral leukocytes of HIV+ individuals were significantly shorter than those of healthy individuals, and the rate of LT length decline with increasing age was greater. Linear regression analysis showed that in HIV+ individuals, increasing age, cART without integrase-stand transfer inhibitors (INSTI), failure to achieve viral loads of <40 copies/mL within 1 year of initiating cART, and substance use were significantly associated with shorter TLs, even after adjustment for the effects of age. Logistic regression analysis indicated an increasing risk of leukoaraiosis was associated with older age, shorter TLs, hypertension, and carotid artery plaque. Multivariate regression analysis indicated that older age and shorter TLs were significant risk factors for leukoaraiosis. In summary, our data showed that TL shortening in HIV+ individuals was independently associated with leukoaraiosis, and was associated with age, control of viral loads, use of INSTI, and substance use. Our results suggest that effective viral control and less toxic cART can help reduce TL shortening and improve outcomes among HIV+ individuals.

RevDate: 2019-06-27

Chen X, Wei S, Ma H, et al (2019)

Telomere length in cervical exfoliated cells, interaction with HPV genotype, and cervical cancer occurrence among high-risk HPV-positive women.

Cancer medicine [Epub ahead of print].

BACKGROUND: Although high-risk human papillomavirus (HR-HPV) infection is recognized as the main cause of cervical cancer, only a minority of HPV-infected women develop this malignancy. Increasing evidence suggests that alterations of telomere length might be implicated in carcinogenesis. However, the association between cervical cancer and telomere length remains unknown.

METHODS: This case-control study included 591 cervical cancer patients and 373 cancer-free controls, all of whom were infected with HR-HPV. Relative telomere length (RTL) in cervical cancer exfoliated cells was measured by quantitative PCR. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by logistic regression analysis.

RESULTS: HPV16, 18, 52, and 58 were common in both case and control groups. The proportion of HPV16 infection tended to increase across the quartiles of RTL (Ptrend < 0.001). There was no statistically significant association of RTL with tumor differentiation, histological type, and FIGO stage. After adjustment for age and HPV types, the lowest quartile of RTL presented a 49% lower risk (OR = 0.51, 95% CI: 0.35, 0.76; P < 0.001) than those with the highest quartile of RTL. There was also a dose-response relationship of shorter RTL on lower risk of cervical cancer (Ptrend < 0.001).

CONCLUSION: Shortened telomere length in cervical exfoliated cells was related to the lower risk of cervical cancer among HR-HPV-positive women, which might help to improve cervical cancer screening and surveillance. Further prospective studies with large sample should be designed to validate our preliminary findings, and evaluate the potential efficacy of telomere length for cervical cancer screening.

RevDate: 2019-06-28

Wysoczanska B, Dratwa M, Gebura K, et al (2019)

Variability within the human TERT gene, telomere length and predisposition to chronic lymphocytic leukemia.

OncoTargets and therapy, 12:4309-4320 pii:198313.

Background: The human telomerase reverse transcriptase (TERT) gene encodes the catalytic subunit of telomerase that is essential for maintenance of telomere length. We aimed to find out whether variability within the TERT gene could be associated with telomere length and development of the disease in non-treated patients with chronic lymphocytic leukemia (CLL). Materials and methods: Telomere length, rs2736100, rs2853690, rs33954691, rs35033501 single-nucleotide polymorphisms, and variable number of tandem repeats (VNTR-MNS16A) were assessed in patients at diagnosis. In addition, blood donors served as controls for the polymorphism studies. Results: The minor rs35033501 A variant was more frequent among CLL patients than in healthy controls (OR=3.488, p=0.039). CLL patients over 60 years of age were characterized with lower disease stage at diagnosis (p=0.001 and p=0.008, for the Rai and Binet criteria, respectively). The MNS16A VNTR-243 short allele was more frequent in patients with a low disease stage (p=0.020 and p=0.028, for the Rai and Binet staging system) and also among older patients having longer telomeres (p=0.046). Patients with Rai 0-I stage were characterized with longer telomeres than those with more advanced disease (p=0.030). This relationship was especially pronounced in patients carrying the rs2736100 C allele, independently of the criteria used, ie, Binet (p=0.048) or Rai (p=0.001). Conclusion: Our results showed that the genetic variation within the TERT gene seems to play a regulatory role in CLL and telomere length.

RevDate: 2019-06-28

Singchat W, Kraichak E, Tawichasri P, et al (2019)

Dynamics of telomere length in captive Siamese cobra (Naja kaouthia) related to age and sex.

Ecology and evolution, 9(11):6366-6377 pii:ECE35208.

Telomeres comprise tandem repeated DNA sequences that protect the ends of chromosomes from deterioration or fusion with neighboring chromosomes, and their lengths might vary with sex and age. Here, age- and sex-related telomere lengths in male and female captive Siamese cobras (Naja kaouthia) were investigated using quantitative real-time polymerase chain reaction based on cross-sectional data. A negative correlation was shown between telomere length and body size in males but not in females. Age-related sex differences were also recorded. Juvenile female snakes have shorter telomeres relative to males at up to 5 years of age, while body size also rapidly increases during this period. This suggests that an accelerated increase in telomere length of female cobra results from sex hormone stimulation to telomerase activity, reflecting sexually dimorphic phenotypic traits. This might also result from amplification of telomeric repeats on sex chromosomes. By contrast, female Siamese cobras older than 5 years had longer telomeres than males. Diverse sex hormone levels and oxidative stress parameters between sexes may affect telomere length.

RevDate: 2019-06-28

Rollings N, Friesen CR, Whittington CM, et al (2019)

Sex- And tissue-specific differences in telomere length in a reptile.

Ecology and evolution, 9(11):6211-6219 pii:ECE35164.

The usage of telomere length (TL) in blood as a proxy for the TL of other tissues relies on the assumption that telomere dynamics across all tissues are similar. However, telomere attrition can be caused by reactive oxygen species (ROS) which may vary with metabolic rate, which itself varies across organs depending upon the life history strategy of an organism. Thus, we chose to measure the telomeres of various cell types in juvenile painted dragon lizards, Ctenophorus pictus, given their unusual life history strategy. Individuals typically only experience a single mating season. We measured the TL of male and female dragons using qPCR and observed that TL varied with tissue type and sex. Telomeres of blood cells were longer than those of liver, heart, brain, and spleen, and females had longer telomeres than males. Brain telomeres in males were approximately half the length of those in females. Telomeric attrition in the male brain may be due to the need for rapid learning of reproductive tactics (territory patrol and defense, mate-finding). Significant correlations between the TL of tissue types suggest that blood TL may be a useful proxy for the TL of other tissues. Our comparison of organ-specific telomere dynamics, the first in a reptile, suggests that the usage of blood TL as a proxy requires careful consideration of the life history strategy of the organism.

RevDate: 2019-08-06

Banszerus VL, Vetter VM, Salewsky B, et al (2019)

Exploring the Relationship of Relative Telomere Length and the Epigenetic Clock in the LipidCardio Cohort.

International journal of molecular sciences, 20(12): pii:ijms20123032.

Telomere length has been accepted widely as a biomarker of aging. Recently, a novel candidate biomarker has been suggested to predict an individual's chronological age with high accuracy: The epigenetic clock is based on the weighted DNA methylation (DNAm) fraction of a number of cytosine-phosphate-guanine sites (CpGs) selected by penalized regression analysis. Here, an established methylation-sensitive single nucleotide primer extension method was adapted, to estimate the epigenetic age of the 1005 participants of the LipidCardio Study, a patient cohort characterised by high prevalence of cardiovascular disease, based on a seven CpGs epigenetic clock. Furthermore, we measured relative leukocyte telomere length (rLTL) to assess the relationship between the established and the promising new measure of biological age. Both rLTL (0.79 ± 0.14) and DNAm age (69.67 ± 7.27 years) were available for 773 subjects (31.6% female; mean chronological age= 69.68 ± 11.01 years; mean DNAm age acceleration = -0.01 ± 7.83 years). While we detected a significant correlation between chronological age and DNAm age (n = 779, R = 0.69), we found neither evidence of an association between rLTL and the DNAm age (β = 3.00, p = 0.18) nor rLTL and the DNAm age acceleration (β = 2.76, p = 0.22) in the studied cohort, suggesting that DNAm age and rLTL measure different aspects of biological age.

RevDate: 2019-08-02

Subedi P, Nembrini S, An Q, et al (2019)

Telomere length and cancer mortality in American Indians: the Strong Heart Study.

GeroScience pii:10.1007/s11357-019-00080-4 [Epub ahead of print].

The objective of this study was to investigate whether leukocyte telomere length (LTL) predicts the risk for cancer mortality among American Indians participating in the Strong Heart Study (1989-1991). Participants (aged 45-74 years) were followed annually until December 2015 to collect information on morbidity/mortality. LTL was measured by qPCR using genomic DNA isolated from peripheral blood. The association between LTL and risk for cancer mortality was examined using a multivariable Cox proportional hazard model, adjusting for age, gender, education, study site, smoking, alcohol use, physical activity, systolic blood pressure, fasting blood glucose, obesity, and low- and high-density lipoprotein. Of 1945 participants (mean age 56.10 ± 8.17 at baseline, 57% women) followed for an average 20.5 years, 220 died of cancer. Results showed that longer LTL at baseline significantly predicts an increased risk of cancer death among females (HR 1.57, 95% CI 1.08-2.30), but not males (HR 0.74, 95% CI 0.49-1.12) (p for interaction 0.009). Specifically, compared with the women with the longest LTL (fourth quartile), those in the third, second, and first quartiles showed 53%, 41%, and 44% reduced risk for cancer death, respectively. The findings highlight the importance of sex-specific analysis in future telomere research.

RevDate: 2019-06-20

Nonaka K, Aida J, Takubo K, et al (2019)

Correlation between Differentiation of Adrenocortical Zones and Telomere Lengths measured by Q-FISH.

The Journal of clinical endocrinology and metabolism pii:5520382 [Epub ahead of print].

CONTEXT: Adrenocortical zonation is associated with a markedly complex developmental process, and the pathogenesis and/or etiology of many disorders of adrenocortical zonal development have remained unknown. Cells from the three adrenocortical zones are morphologically and functionally differentiated, and the mature stage of cell development or senescence has been recently reported to be correlated with telomere length. However, the telomere length of each adrenocortical zonal cell has not yet been studied in human adrenal glands.

OBJECTIVE: We aimed to study the telomere lengths of adrenocortical parenchymal cells from three different zones of the adrenal glands present during childhood, adolescence, and adulthood.

METHODS: Adrenal glands of 30 autopsied subjects, aged between 0 and 68 years, were retrieved from pathology files. The normalized telomere to centromere ratio (NTCR), an index of telomere length, was determined in the parenchymal cells of the zona glomerulosa (ZG), zona fasciculata (ZF), and zona reticularis (ZR), using quantitative fluorescence in situ hybridization.

RESULTS: NTCR of ZR cells was the longest, followed in decreasing order by that of ZG and ZF cells in subjects aged 20-68 years, but no significant differences in NTCR were detected among these three zones in the group under 20 years of age. NTCR of ZR increased with age in subjects aged 20-68 years, while no significant age-dependent changes in NTCR were detected in the group under 20 years of age.

CONCLUSION: The telomere lengths for three zones in adrenal cortex were correlated with their differentiation in adulthood but not in childhood and adolescence.

RevDate: 2019-06-23

Tutton S, Deng Z, Gulve N, et al (2019)

Elevated telomere dysfunction in cells containing the African-centric Pro47Ser cancer-risk variant of TP53.

Oncotarget, 10(38):3581-3591 pii:26980.

Subtelomeric transcription and chromatin can have a significant impact on telomere repeat maintenance and chromosome stability. We have previously found that tumor suppressor protein p53 (TP53) can bind to retrotransposon-like elements in a majority of human subtelomeres to regulate TERRA transcription and telomeric histone acetylation in response to DNA damage. TP53 also prevents the accumulation of γH2AX DNA-damage signaling at telomeres. We now show that the inherited TP53 polymorphism Pro47Ser (hereafter S47), which is enriched in populations of African descent, is associated with elevated marks of telomere dysfunction. We found that human and mouse cells carrying the S47 variant show increased γH2AX DNA-damage signals at telomeres, as well as reduced TERRA transcription and subtelomeric histone acetylation in response to DNA damage stress. Cell-lines containing inducible genes for P47 or S47 versions of p53, as well mouse embryo fibroblasts (MEFs) reconstituted with human p53, showed elevated telomere-induced DNA damage foci and metaphase telomere signal loss in cells with S47. Human lymphoblastoid cell lines (LCLs) derived from individuals homozygous for S47, show increased accumulation of subtelomeric γH2AX and unstable telomere repeats in response to DNA damage relative to age matched LCLs homozygous for P47. Furthermore, LCLs with S47 had reduced replicative lifespan. These studies indicate that the naturally occurring S47 variant of p53 can affect telomeric chromatin, telomere repeat stability, and replicative capacity. We discuss the potential evolutionary significance of the S47 variant to African populations with respect to telomere regulation and the implications for inherited health disparities.

RevDate: 2019-07-17

Tarik M, Ramakrishnan L, Sinha S, et al (2019)

Association of birth outcomes and postnatal growth with adult leukocyte telomere length: Data from New Delhi Birth Cohort.

Maternal & child nutrition [Epub ahead of print].

Born small for gestational age due to undernutrition in utero and subsequent catch-up growth is associated with risk of developing chronic diseases in adulthood. Telomere length has been shown to be a predictor of these age-related diseases and may be a link between birth size, a surrogate for foetal undernutrition, and adult chronic diseases. We assessed the relationship of leukocyte telomere length in adult life with birth outcomes and serial change in body mass index (BMI) from birth to adulthood. Leukocyte relative telomere length (RTL) was measured by MMqPCR in 1,309 subjects from New Delhi Birth Cohort who participated in two phases of the study between 2006-2009 (Phase 6) and 2012-2015 (Phase 7) at a mean age of 39.08 (±3.29), and its association with birth outcomes and conditional BMI gain at 2, 11, and 29 years was assessed in a mixed regression model. We did not find any significant association of RTL with body size at birth including birthweight, birth length, and birth BMI. Gestational age was positively associated with RTL (P = .017, multivariate model: P = .039). Conditional BMI gain at 2 and 11 years was not associated with RTL. BMI gain at 29 year was negatively associated with RTL in multivariate model (P = .015). Born small for gestational age was not associated with RTL in adulthood. Leukocyte telomere attrition was observed in those born before 37 weeks of gestational age as well as in those who gained weight as adults, which may predispose to chronic diseases.

RevDate: 2019-06-18

Soumboundou M, Nkengurutse I, Dossou J, et al (2019)

Biological Dosimetry Network in Africa: Establishment of a Dose-response Curve Using Telomere and Centromere Staining.

Health physics [Epub ahead of print].

PURPOSE: Biological dosimetry, based on the relationship between the absorbed dose after exposure to ionizing radiation and the frequency of scored aberrations, has been and continues to be an important tool for estimating the dose after exposure. Dicentric chromosomes are considered to be the most specific and sensitive aberration related to radiation exposure. Here, we established the dose-response curve following in vitro irradiation of circulating lymphocytes from healthy donors from three African countries after scoring unstable chromosomal aberrations.

MATERIALS AND METHODS: Blood samples from 16 African donors were exposed to various doses (0 to 4 Gy) using an X-RAD320 x-ray system with a maximum photon energy of 250 kV at a dose rate of 0.1 Gy min. Blood lymphocytes were cultured for 48 h, and chromosomal aberrations were scored during the first mitosis by telomere and centromere staining. The distribution of dicentric chromosomes was determined.

RESULTS: No dicentric chromosomes were found after the analysis of 2,669 first-division metaphases before in vitro exposure. We established a linear-quadratic dose-response curve based on the frequency of dicentric and ring chromosomes and calculated double-strand breaks, taking into account all scored aberrations.

CONCLUSION: The generation of a specific dose-response curve for African donors will allow the practice of precise biological dosimetry in these countries. This work is the first step towards realizing an African biodosimetry network and the establishment of a biological dosimetry laboratory, which could play a major role in the application of radioprotection norms.

RevDate: 2019-06-18

Borbora D, Dutta HK, Devi KR, et al (2019)

Long telomeres cooperate with p53, MDM2, and p21 polymorphisms to elevate pediatric solid tumor risk.

Pediatrics international : official journal of the Japan Pediatric Society [Epub ahead of print].

BACKGROUND: While leukocyte telomere length has been linked with the altered risks of adult cancers, limited information is available regarding its association with the risk of pediatric solid tumors. We investigated the association of telomeric alterations with the risk of pediatric solid tumors. We also investigated, whether altered telomeres cooperated with the TP53 rs1042522, MDM2 rs2279744 and CDKN1A (p21cip1) rs1059234 single nucleotide polymorphisms to modify cancer risk.

METHODS: A total of 101 tumor cases and 202 controls were recruited for this age and gender matched case-control study. The relative telomere length (RTL) was determined in peripheral blood leukocytes using quantitative real-time PCR and the polymorphisms were genotyped using polymerase chain reaction-restriction fragment length polymorphism technique.

RESULTS: By using median RTL in the healthy controls as a cutoff, children with longer telomeres were at an increased risk of developing a solid tumor (odds ratio [OR] 2.70; P < 0.01). When participants were categorized according to quartile RTL values of controls, a significant dose-response relation was observed (χ2 - 10.95; P < 0.001). The risk for tumors increased nearly 3-fold (P = 0.001) for the triple interaction among RTL * TP53 rs1042522 * p21 cip1 rs1059234 compared with the maximum effect of any single factor, although the interaction effect was less than additive. The MDM2 rs2279744 GG genotype reduced pediatric solid tumor risk significantly (OR 0.51).

CONCLUSION: These findings suggest that, combined analysis of telomeres and genetic polymorphisms in the TP53 pathway can provide important clues to understanding pediatric solid tumor etiology.

RevDate: 2019-06-18

Ramos-Ibeas P, Pericuesta E, Peral-Sanchez I, et al (2019)

Longitudinal analysis of somatic and germ-cell telomere dynamics in outbred mice.

Molecular reproduction and development [Epub ahead of print].

Although telomere length (TL) shortens with age in most tissues, an age-related increase in length has been described in sperm through a mechanism that is not yet fully understood. Changes in TL with age in the same individual have not been explored. This longitudinal study examines TL dynamics in somatic tissue and gametes during an entire lifespan in an outbred mouse population (from 8 to up to 114 weeks of age). Our findings indicate a reduced life expectancy in males compared to females (84.75 ± 9.23 vs. 113.16 ± 0.20 weeks) and significant variability in TL dynamics between individuals. While with aging, a clear reduction in TL was produced in somatic cells and oocytes, telomeres in sperm cells significantly lengthened. Finally, we found evidence indicating that telomere elongation in sperm during aging may be dependent on different mechanisms, such as the survival of spermatogonia with longer telomeres and the alternative lengthening of telomeres mechanism in meiotic and postmeiotic spermatogenic cells.

RevDate: 2019-07-16

Gong P, Wang H, Zhang J, et al (2019)

Telomere Maintenance-Associated PML Is a Potential Specific Therapeutic Target of Human Colorectal Cancer.

Translational oncology, 12(9):1164-1176 pii:S1936-5233(19)30202-5 [Epub ahead of print].

Telomere length maintenance is essential for cell proliferation, which is particularly prominent in cancer. We validate that the primary colorectal tumors exhibit heterogeneous telomere lengths but mostly (90%) short telomeres relative to normal tissues. Intriguingly, relatively short telomeres are associated with tumor malignancy as indicated by poorly differentiated state, and these tumors contain more cancer stem-like cells (CSLCs) identified by several commonly used markers CD44, EPHB2 or LGR5. Moreover, promyelocytic leukemia (PML) and ALT-associated PML nuclear bodies (APBs) are frequently found in tumors with short telomeres and high proliferation. In contrast, distant normal tissues rarely or only minimally express PML. Inhibition of PML and APBs by an ATR inhibitor decreases proliferation of CSLCs and organoids, suggesting a potential therapeutic target to progressive colorectal tumors. Together, telomere maintenance underling tumor progression is connected with CSLCs.

RevDate: 2019-07-12

Guérin TM, Béneut C, Barinova N, et al (2019)

Condensin-Mediated Chromosome Folding and Internal Telomeres Drive Dicentric Severing by Cytokinesis.

Molecular cell, 75(1):131-144.e3.

In Saccharomyces cerevisiae, dicentric chromosomes stemming from telomere fusions preferentially break at the fusion. This process restores a normal karyotype and protects chromosomes from the detrimental consequences of accidental fusions. Here, we address the molecular basis of this rescue pathway. We observe that tandem arrays tightly bound by the telomere factor Rap1 or a heterologous high-affinity DNA binding factor are sufficient to establish breakage hotspots, mimicking telomere fusions within dicentrics. We also show that condensins generate forces sufficient to rapidly refold dicentrics prior to breakage by cytokinesis and are essential to the preferential breakage at telomere fusions. Thus, the rescue of fused telomeres results from a condensin- and Rap1-driven chromosome folding that favors fusion entrapment where abscission takes place. Because a close spacing between the DNA-bound Rap1 molecules is essential to this process, Rap1 may act by stalling condensins.

RevDate: 2019-06-16

Sutanto SSI, McLennan SV, Keech AC, et al (2019)

Shortening of telomere length by metabolic factors in diabetes: protective effects of fenofibrate.

Journal of cell communication and signaling pii:10.1007/s12079-019-00521-x [Epub ahead of print].

People with diabetes mellitus have shorter telomeres compared with non-diabetic subjects. The aim of this study was to investigate an in-vitro model of telomere shortening under diabetes metabolic conditions. The mechanisms of the accelerated telomere length attrition and the potential telomere protective action of fenofibrate with related cellular mechanisms were also examined. Human dermal fibroblasts were passaged and cultured in normal (5.5 mM) or high (25 mM) D-glucose, across 7 days with hydrogen peroxide (H2O2), glucosamine (GA), or glycated albumin (AGEs-BSA). Relative telomere length (RTL) was determined by qPCR. The expression of shelterin complex members which regulate telomere stability were measured by qRT-PCR and Western immunoblot. Culture in high glucose decreased RTL compared with normal glucose: H2O2 and GA lowered the RTL after 7 days (each P < 0.05 vs untreated control), whereas AGEs-BSA had no effect compared with control-BSA. At day 7 the mRNA levels of most shelterin complex members, were induced by H2O2 and to a lesser extent by GA. Trf1 and Trf2 protein were induced by H2O2. Co-treatment with fenofibrate (100 μM) significantly attenuated the reduction in RTL caused by H2O2 and GA and prevented Trf induction by H2O2. However knockdown of Trf1 and Trf2 expression using specific siRNA did not prevent H2O2 effects to lower RTL, thus implicating factors other than these Trfs alone in the fenofibrate protection against the H2O2 induction of RTL lowering. These in vitro findings demonstrate that diabetic conditions can induce telomere shortening and that fenofibrate has protective effects on telomere attrition, through as yet undefined mechanisms.

RevDate: 2019-07-07

Miura A, A Matsuura (2019)

Phosphatase-dependent fluctuations in DNA-damage checkpoint activation at partially defective telomeres.

Biochemical and biophysical research communications, 516(1):133-137.

Telomeres protect the ends of eukaryotic chromosomes, and telomere shortening causes irreversible cell-cycle arrest through activation of the DNA-damage checkpoint. In this study, we found that deletion of PPH3, encoding a 2A-like protein phosphatase, accelerated telomere-shortening-mediated senescence without affecting normal telomere length or the telomere erosion rate in Saccharomyces cerevisiae. Moreover, the loss of PPH3 increased sensitivity to telomere dysfunction. The detection of telomere abnormalities by DNA-damage sensors was not an all-or-none response, implying that Pph3 helps determine the border between normal and dysfunctional telomeres by suppressing premature activation of the DNA-damage checkpoint.


ESP Quick Facts

ESP Origins

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

ESP Support

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

ESP Rationale

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

ESP Goal

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

ESP Usage

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

ESP Content

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

ESP Help

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

ESP Plans

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

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Good Beginner's Books

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

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Papers in Classical Genetics

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

Digital Books

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


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


Biographical information about many key scientists.

Selected Bibliographies

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

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