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Sample records for human telomere length

  1. Variation of the 3' telomeric overhang lengths in human cells.

    PubMed

    Lee, Myung Eun; Rha, Sun Young; Jeung, Hei-Cheul; Kim, Tae Soo; Chung, Hyun Cheol; Oh, Bong-Kyeong

    2008-06-01

    The telomeric G-rich 3' overhang is important for the maintenance of chromosomal integrity by stabilizing T-loop structure in which the 3' overhang invades the double-stranded telomeric DNA. However, the 3' overhang length has not been examined in different human cell lines, and its regulatory mechanism has not been revealed. In this study, we examined overhang length in 56 human cancerous cell lines and five normal cell lines, originated from various tissues. In cancer cells, relative overhang length existed in a wide range from 23% to 308% and showed no significant association with tissue types although short overhang was noted in brain, cervix, and colorectal cells. Normal cells exhibited overhangs in the range from 92% to 202%, which were relatively longer than those seen in cancer cells (p = 0.002). The overhang length was positively correlated with telomere length (p < 0.001), and showed no correlation with mRNA levels of hTERT, a catalytic protein of telomerase, POT1, an overhang binding protein and TPP1, a POT1 interacting protein. This study demonstrates a broad distribution of overhang length in human cells, suggesting a dynamic regulation of 3' overhang length. The overhang length seems to be closely associated with telomere length and might be regulated by multiple mechanisms.

  2. Heregulin, a new regulator of telomere length in human cells.

    PubMed

    Menendez, Javier A; Rubio, Miguel A; Campisi, Judith; Lupu, Ruth

    2015-11-24

    The growth factor heregulin (HRG) promotes breast cancer (BC) tumorigenesis and metastasis and differentially modulates BC cell responses to DNA-damaging agents via its dual extracellular and nuclear localization. Given the central role of telomere dysfunction to drive carcinogenesis and to alter the chemotherapeutic profile of transformed cells, we hypothesized that an unanticipated nuclear function of HRG might be to regulate telomere length. Engineered overexpression of the HRGβ2 isoform in non-aggressive, HRG-negative MCF-7 BC cells resulted in a significant shortening of telomeres (up to 1.3 kb) as measured by Southern blotting of telomere terminal restriction fragments. Conversely, antisense-mediated suppression of HRGβ2 in highly aggressive, HRG-overexpressing MDA-MB-231 and Hs578T cells increased telomere length up to 3.0 kb. HRGβ2 overexpression promoted a marked upregulation of telomere-binding protein 2 (TRF2) protein expression, whereas its knockdown profoundly decreased TRF2 expression. Double staining of endogenous HRGβ2 with telomere-specific peptide nucleic acid probe/fluorescence in situ hybridization (PNA/FISH) revealed the partial localization of HRG at the chromosome ends. Moreover, a predominantly nucleoplasmic staining pattern of endogenous HRGβ2 appeared to co-localize with TRF2 and, concomitantly with RAP1, a telomere regulator that specifically interacts with TRF2. Small interfering RNA-mediated knockdown of HRG decreased the expression of TRF2 and RAP1, decreased their presence at chromosome ends, and coincidentally resulted in the formation of longer telomeres. This study uncovers a new function for HRGβ2 in controlling telomere length, in part due to its ability to regulate and interact with the telomere-associated proteins TRF2 and RAP1.

  3. Telomere length homeostasis and telomere position effect on a linear human artificial chromosome are dictated by the genetic background

    PubMed Central

    Weuts, An; Voet, Thierry; Verbeeck, Jelle; Lambrechts, Nathalie; Wirix, Evelyne; Schoonjans, Luc; Danloy, Sophie; Marynen, Peter; Froyen, Guy

    2012-01-01

    Telomere position effect (TPE) is the influence of telomeres on subtelomeric epigenetic marks and gene expression. Previous studies suggested that TPE depends on genetic background. As these analyses were performed on different chromosomes, cell types and species, it remains unclear whether TPE represents a chromosome—rather than genetic background-specific regulation. We describe the development of a Linear Human Artificial Chromosome (L-HAC) as a new tool for telomere studies. The L-HAC was generated through the Cre-loxP-mediated addition of telomere ends to an existing circular HAC (C-HAC). As it can be transferred to genetically distinct cell lines and animal models the L-HAC enables the study of TPE in an unprecedented manner. The HAC was relocated to four telomerase-positive cell lines via microcell-mediated chromosome transfer and subsequently to mice via blastocyst injection of L-HAC+-ES-cells. We could show consistent genetic background-dependent adaptation of telomere length and telomere-associated de novo subtelomeric DNA methylation in mouse ES-R1 cells as well as in mice. Expression of the subtelomeric neomycin gene was inversely correlated with telomere length and subtelomeric methylation. We thus provide a new tool for functional telomere studies and provide strong evidence that telomere length, subtelomeric chromatin marks and expression of subtelomeric genes are genetic background dependent. PMID:23066103

  4. Telomere length homeostasis and telomere position effect on a linear human artificial chromosome are dictated by the genetic background.

    PubMed

    Weuts, An; Voet, Thierry; Verbeeck, Jelle; Lambrechts, Nathalie; Wirix, Evelyne; Schoonjans, Luc; Danloy, Sophie; Marynen, Peter; Froyen, Guy

    2012-12-01

    Telomere position effect (TPE) is the influence of telomeres on subtelomeric epigenetic marks and gene expression. Previous studies suggested that TPE depends on genetic background. As these analyses were performed on different chromosomes, cell types and species, it remains unclear whether TPE represents a chromosome-rather than genetic background-specific regulation. We describe the development of a Linear Human Artificial Chromosome (L-HAC) as a new tool for telomere studies. The L-HAC was generated through the Cre-loxP-mediated addition of telomere ends to an existing circular HAC (C-HAC). As it can be transferred to genetically distinct cell lines and animal models the L-HAC enables the study of TPE in an unprecedented manner. The HAC was relocated to four telomerase-positive cell lines via microcell-mediated chromosome transfer and subsequently to mice via blastocyst injection of L-HAC(+)-ES-cells. We could show consistent genetic background-dependent adaptation of telomere length and telomere-associated de novo subtelomeric DNA methylation in mouse ES-R1 cells as well as in mice. Expression of the subtelomeric neomycin gene was inversely correlated with telomere length and subtelomeric methylation. We thus provide a new tool for functional telomere studies and provide strong evidence that telomere length, subtelomeric chromatin marks and expression of subtelomeric genes are genetic background dependent.

  5. Decreasing initial telomere length in humans intergenerationally understates age-associated telomere shortening.

    PubMed

    Holohan, Brody; De Meyer, Tim; Batten, Kimberly; Mangino, Massimo; Hunt, Steven C; Bekaert, Sofie; De Buyzere, Marc L; Rietzschel, Ernst R; Spector, Tim D; Wright, Woodring E; Shay, Jerry W

    2015-08-01

    Telomere length shortens with aging, and short telomeres have been linked to a wide variety of pathologies. Previous studies suggested a discrepancy in age-associated telomere shortening rate estimated by cross-sectional studies versus the rate measured in longitudinal studies, indicating a potential bias in cross-sectional estimates. Intergenerational changes in initial telomere length, such as that predicted by the previously described effect of a father's age at birth of his offspring (FAB), could explain the discrepancy in shortening rate measurements. We evaluated whether changes occur in initial telomere length over multiple generations in three large datasets and identified paternal birth year (PBY) as a variable that reconciles the difference between longitudinal and cross-sectional measurements. We also clarify the association between FAB and offspring telomere length, demonstrating that this effect is substantially larger than reported in the past. These results indicate the presence of a downward secular trend in telomere length at birth over generational time with potential public health implications.

  6. Decreasing initial telomere length in humans intergenerationally understates age-associated telomere shortening

    PubMed Central

    Holohan, Brody; De Meyer, Tim; Batten, Kimberly; Mangino, Massimo; Hunt, Steven C; Bekaert, Sofie; De Buyzere, Marc L; Rietzschel, Ernst R; Spector, Tim D; Wright, Woodring E; Shay, Jerry W

    2015-01-01

    Telomere length shortens with aging, and short telomeres have been linked to a wide variety of pathologies. Previous studies suggested a discrepancy in age-associated telomere shortening rate estimated by cross-sectional studies versus the rate measured in longitudinal studies, indicating a potential bias in cross-sectional estimates. Intergenerational changes in initial telomere length, such as that predicted by the previously described effect of a father’s age at birth of his offspring (FAB), could explain the discrepancy in shortening rate measurements. We evaluated whether changes occur in initial telomere length over multiple generations in three large datasets and identified paternal birth year (PBY) as a variable that reconciles the difference between longitudinal and cross-sectional measurements. We also clarify the association between FAB and offspring telomere length, demonstrating that this effect is substantially larger than reported in the past. These results indicate the presence of a downward secular trend in telomere length at birth over generational time with potential public health implications. PMID:25952108

  7. Telomere Lengths and Telomerase Activity in Dog Tissues: A Potential Model System to Study Human Telomere and Telomerase Biology

    PubMed Central

    Nasir, Lubna; Devlin, Pauline; Mckevitt, Tom; Rutteman, Gerard; Argyle, David J

    2001-01-01

    Abstract Studies on telomere and telomerase biology are fundamental to the understanding of aging and age-related diseases such as cancer. However, human studies have been hindered by differences in telomere biology between humans and the classical murine animal model system. In this paper, we describe basic studies of telomere length and telomerase activity in canine normal and neoplastic tissues and propose the dog as an alternative model system. Briefly, telomere lengths were measured in normal canine peripheral blood mononuclear cells (PBMCs), a range of normal canine tissues, and in a panel of naturally occurring soft tissue tumours by terminal restriction fragment (TRF) analysis. Further, telomerase activity was measured in canine cell lines and multiple canine tissues using a combined polymerase chain reaction/enzyme-linked immunosorbent assay method. TRF analysis in canine PBMCs and tissues demonstrated mean TRF lengths to range between 12 and 23 kbp with heterogeneity in telomere lengths being observed in a range of normal somatic tissues. In soft tissue sarcomas, two subgroups were identified with mean TRFs of 22.2 and 18.2 kbp. Telomerase activity in canine tissue was present in tumour tissue and testis with little or no activity in normal somatic tissues. These results suggest that the dog telomere biology is similar to that in humans and may represent an alternative model system for studying telomere biology and telomerase-targeted anticancer therapies. PMID:11571635

  8. Human leukocyte telomere length is associated with DNA methylation levels in multiple subtelomeric and imprinted loci.

    PubMed

    Buxton, Jessica L; Suderman, Matthew; Pappas, Jane J; Borghol, Nada; McArdle, Wendy; Blakemore, Alexandra I F; Hertzman, Clyde; Power, Christine; Szyf, Moshe; Pembrey, Marcus

    2014-05-14

    In humans, leukocyte telomere length (LTL) is positively correlated with lifespan, and shorter LTL is associated with increased risk of age-related disease. In this study we tested for association between telomere length and methylated cytosine levels. Measurements of mean telomere length and DNA methylation at >450,000 CpG sites were obtained for both blood (N = 24) and EBV-transformed cell-line (N = 36) DNA samples from men aged 44-45 years. We identified 65 gene promoters enriched for CpG sites at which methylation levels are associated with leukocyte telomere length, and 36 gene promoters enriched for CpG sites at which methylation levels are associated with telomere length in DNA from EBV-transformed cell-lines. We observed significant enrichment of positively associated methylated CpG sites in subtelomeric loci (within 4 Mb of the telomere) (P < 0.01), and also at loci in imprinted regions (P < 0.001). Our results pave the way for further investigations to help elucidate the relationships between telomere length, DNA methylation and gene expression in health and disease.

  9. TIN2, a new regulator of telomere length in human cells

    SciTech Connect

    Kim, Sahn-Ho

    1999-11-05

    Telomeres are DNA-protein structures that cap linear chromosomes and are essential for maintaining genomic stability and cell phenotype. The authors identified a novel human telomere-associated protein, TIN2, by interaction cloning using the telomeric DNA binding protein TRF1 as a bait. TIN2 interacted with TRF1 in vitro and in cells, and co-localized with TRF1 in nuclei and metaphase chromosomes. A TIN2 mutant that lacks N-terminal sequences markedly elongated human telomeres in a telomerase-dependent manner. These findings suggest that TRF1 is insufficient for telomere length control in human cells, and that TIN2 is an essential mediator of TRF1 function.

  10. Telomerase activity and telomere length in human tumor cells with acquired resistance to anticancer agents.

    PubMed

    Smith, V; Dai, F; Spitz, M; Peters, G J; Fiebig, H H; Hussain, A; Burger, A M

    2009-11-01

    Telomeres and telomerase are targets for anticancer drug development and specific inhibitors are currently under clinical investigation. However, it has been reported that standard cytotoxic agents can affect telomere length and telomerase activity suggesting that they also have of a role in drug resistance. in this study, telomere lengths and telomerase activity as well as drug efflux pump expression, glutathione (GSH) levels and polyadenosine-ribose polymerase (PARP) cleavage were assessed in a panel of human tumor cell lines made resistant to vindesine, gemcitabine and cisplatin. these included two lung cancer cell lines resistant to vindesine (LXFL 529L/Vind, LXFA 526L/Vind), a renal cancer cell line (RXF944L/Gem) and an ovarian cancer cell line (AG6000) resistant to gemcitabine, and one resistant to cisplatin (ADDP). The resistant clones were compared to their parental lines and evaluated for cross resistance to other cytotoxic agents. Several drug specific resistance patterns were found, and various complex patterns of cross resistance emerged from some cell lines, but these mechanisms of resistance could not be related to drug efflux pump expression, GSH levels or pARp cleavage. However, all displayed changes in telomerase activity and/or telomere length. Our studies present evidence that telomere maintenance should be taken into consideration in efforts not only to overcome drug resistance, but also to optimize the use of telomere-based therapeutics.

  11. Quantitative proteomic analysis of human breast epithelial cells with differential telomere length

    SciTech Connect

    Yu, Li-Rong . E-mail: lyu@ncifcrf.gov; Chan, King C.; Tahara, Hidetoshi; Lucas, David A.; Chatterjee, Koushik; Issaq, Haleem J.; Veenstra, Timothy D. . E-mail: veenstra@ncifcrf.gov

    2007-05-18

    Telomeres play important functional roles in cell proliferation, cell cycle regulation, and genetic stability, in which telomere length is critical. In this study, quantitative proteome comparisons for the human breast epithelial cells with short and long telomeres (184-hTERT{sub L} vs. 184-hTERT{sub S} and 90P-hTERT{sub L} vs. 90P-hTERT{sub S}), resulting from transfection of the human telomerase reverse transcriptase (hTERT) gene, were performed using cleavable isotope-coded affinity tags. More than 2000 proteins were quantified in each comparative experiment, with approximately 77% of the proteins identified in both analyses. In the cells with long telomeres, significant and consistent alterations were observed in metabolism (amino acid, nucleotide, and lipid metabolism), genetic information transmission (transcription and translation regulation, spliceosome and ribosome complexes), and cell signaling. Interestingly, the DNA excision repair pathway is enhanced, while integrin and its ligands are downregulated in the cells with long telomeres. These results may provide valuable information related to telomere functions.

  12. Changes in telomere length distribution in low-dose X-ray-irradiated human umbilical vein endothelial cells.

    PubMed

    Guan, Jing-Zhi; Guan, Wei Ping; Maeda, Toyoki; Makino, Naoki

    2014-11-01

    Ionizing radiation (IR) is known to be a cause of telomere dysfunction in tumor cells; however, very few studies have investigated X-ray-related changes in telomere length and the telomerase activity in normal human cells, such as umbilical vein endothelial cells (HUVECs). The loss of a few hundred base pairs from a shortened telomere has been shown to be important with respect to cellular senescence, although it may not be detected according to traditional mean telomere length [assessed as the terminal restriction fragment (TRF)] analyses. In the present study, a continuous time window from irradiation was selected to examine changes in the telomere length, including the mean TRF length, percentage of the telomere length, telomerase activity, apoptotic rate, and survival rate in HUVECs from the first day to the fourth day after the administration of a 0.5-Gy dose of irradiation. The mean TRF length in the irradiated HUVECs showed shorter telomere length in first 3 days, but they were not statistically significant. On the other hand, according to the percentage analysis of the telomere length, a decreasing tendency was noted in the longer telomere lengths (9.4-4.4 kb), with a significant increase in the shortest telomeres (4.4-2.3 kb) among the irradiated cells versus the controls from the first day to the third after irradiation; no significant differences were noted on the fourth day. These results suggest that the shortest telomeres are sensitive to the late stage of radiation damage. The proliferation of irradiated cells was suppressed after IR in contrast to the non-irradiated cells. The apoptotic rate was elevated initially both in IR- and non-IR-cells, but that of IR-cells was maintained at an elevated level thereafter in contrast to that of non-IR-cells decreasing promptly. Therefore, a 0.5-Gy dose of IR induces persistent apoptosis leading to an apparent growth arrest of the normal HUVECs.

  13. Role of TERRA in the Regulation of Telomere Length

    PubMed Central

    Wang, Caiqin; Zhao, Li; Lu, Shiming

    2015-01-01

    Telomere dysfunction is closely associated with human diseases such as cancer and ageing. Inappropriate changes in telomere length and/or structure result in telomere dysfunction. Telomeres have been considered to be transcriptionally silent, but it was recently demonstrated that mammalian telomeres are transcribed into telomeric repeat-containing RNA (TERRA). TERRA, a long non-coding RNA, participates in the regulation of telomere length, telomerase activity and heterochromatinization. The correct regulation of telomere length may be crucial to telomeric homeostasis and functions. Here, we summarize recent advances in our understanding of the crucial role of TERRA in the maintenance of telomere length, with focus on the variety of mechanisms by which TERRA is involved in the regulation of telomere length. This review aims to enable further understanding of how TERRA-targeted drugs can target telomere-related diseases. PMID:25678850

  14. Role of TERRA in the regulation of telomere length.

    PubMed

    Wang, Caiqin; Zhao, Li; Lu, Shiming

    2015-01-01

    Telomere dysfunction is closely associated with human diseases such as cancer and ageing. Inappropriate changes in telomere length and/or structure result in telomere dysfunction. Telomeres have been considered to be transcriptionally silent, but it was recently demonstrated that mammalian telomeres are transcribed into telomeric repeat-containing RNA (TERRA). TERRA, a long non-coding RNA, participates in the regulation of telomere length, telomerase activity and heterochromatinization. The correct regulation of telomere length may be crucial to telomeric homeostasis and functions. Here, we summarize recent advances in our understanding of the crucial role of TERRA in the maintenance of telomere length, with focus on the variety of mechanisms by which TERRA is involved in the regulation of telomere length. This review aims to enable further understanding of how TERRA-targeted drugs can target telomere-related diseases.

  15. Comparative analysis of telomere length, telomerase and reverse transcriptase activity in human dental stem cells.

    PubMed

    Jeon, Byeong-Gyun; Kang, Eun-Ju; Kumar, B Mohana; Maeng, Geun-Ho; Ock, Sun-A; Kwack, Dae-Oh; Park, Bong-Wook; Rho, Gyu-Jin

    2011-01-01

    Stem cells from dental tissues have been isolated and established for tooth regenerative applications. However, basic characterization on their biological properties still needs to be investigated before employing them for effective clinical trials. In this study, we compared the telomere length, relative telomerase activity (RTA), and relative reverse transcriptase activity (RRA) as well as the surface antigen profile and mesenchymal differentiation ability in human dental papilla stem cells (DPaSCs), dental pulp stem cells (DPuSCs), and dental follicle stem cells (DFSCs) with mesenchymal stem cells (MSCs) derived from bone marrow. Dental stem cells (DSCs) were strongly positive for cell surface markers, such as CD44 and CD90. However, slightly lower expression of CD105 was observed in DPaSCs and DPuSCs compared to DFSCs and MSCs. Following specific induction, DPaSCs, DFSCs, and MSCs were successfully differentiated into adipocytes and osteocytes. However, DPuSCS, in particular, were able to differentiate into adipocytes but failed to induce into osteogenic differentiation. Further, all DSCs, MSCs, and MRC-5 fibroblasts as control were investigated for telomere length by nonradioactive chemiluminescent assay, RTA by relative-quantitative telomerase repeat amplification protocol (RQ-TRAP), and RRA by PCR-based assay. Mean telomere lengths in DPaSCs, DPuSCs, DFSCs, and MSCs was ∼11 kb, and the values did not differ significantly (p < 0.05) among the cells analyzed. RTA levels in DPaSCs were significantly (p < 0.05) higher than in MSCs, DPuSCs, DFSCs, and MRC-5 fibroblasts and among DSCs, DFSCs showed a significantly (p < 0.05) lower RTA. Moreover, RRA levels were significantly (p < 0.05) higher in DPaSCs, DPuSCs, and MSCs than in DFSCs. Based on these observations, we conclude that among DSCs, DPaSCs possessed ideal characteristics on telomere length, telomerase activity and reverse transcriptase (RTase) activity, and may serve as suitable alternative candidates

  16. Telomere length in Hepatitis C.

    PubMed

    Kitay-Cohen, Y; Goldberg-Bittman, L; Hadary, R; Fejgin, M D; Amiel, A

    2008-11-01

    Telomeres are nucleoprotein structures located at the termini of chromosomes that protect the chromosomes from fusion and degradation. Hepatocyte cell-cycle turnover may be a primary mechanism of telomere shortening in hepatitis C virus (HCV) infection, inducing fibrosis and cellular senescence. HCV infection has been recognized as potential cause of B-cell lymphoma and hepatocellular carcinoma. The present study sought to assess relative telomere length in leukocytes from patients with chronic HCV infection, patients after eradication of HCV infection (in remission), and healthy controls. A novel method of manual evaluation was applied. Leukocytes derived from 22 patients with chronic HCV infection and age- and sex-matched patients in remission and healthy control subjects were subjected to a fluorescence-in-situ protocol (DAKO) to determine telomere fluorescence intensity and number. The relative, manual, analysis of telomere length was validated against findings on applied spectral imaging (ASI) in a random sample of study and control subjects. Leukocytes from patients with chronic HCV infection had shorter telomeres than leukocytes from patients in remission and healthy controls. On statistical analysis, more cells with low signal intensity on telomere FISH had shorter telomeres whereas more cells with high signal intensity had longer telomeres. The findings were corroborated by the ASI telomere software. Telomere shortening in leukocytes from patients with active HCV infection is probably due to the lower overall telomere level rather than higher cell cycle turnover. Manual evaluation is an accurate and valid method of assessing relative telomere length between patients with chronic HCV infection and healthy subjects. PMID:18992639

  17. Telomere length, cardiovascular risk and arteriosclerosis in human kidneys: an observational cohort study

    PubMed Central

    De Vusser, Katrien; Pieters, Nicky; Janssen, Bram; Lerut, Evelyne; Kuypers, Dirk; Jochmans, Ina; Monbaliu, Diethard; Pirenne, Jacques; Nawrot, Tim; Naesens, Maarten

    2015-01-01

    Background Replicative senescence, associated with telomere shortening, plays an important role in aging and cardiovascular disease. The relation between telomere length, cardiovascular risk, and renal disease is unknown. Methods Our study consisted of a cohort of 257 kidney donors for transplantation, divided into a test and a validation cohort. We used quantitative RT‐PCR to measure relative telomere length (log T/S ratio) in peripheral blood leucocytes, and in kidney biopsies performed prior to implantation. The association between leucocyte and intrarenal telomere length, cardiovascular risk factors, and renal histology, was studied using multiple regression models, adjusted for calendar age, gender and other donor demographics. Results Subjects with intrarenal arteriosclerosis had significantly shorter leucocyte telomere length compared with patients without arteriosclerosis (log T/S ratio ‐0.3 ± 0.4 vs. 0.1 ± 0.2 with vs. without arteriosclerosis; p = 0.0008). Intrarenal arteriosclerosis was associated with shorter telomere length, independent of gender, calendar age, history of hypertension and history of cardiovascular events. For each increase of one standard deviation of the log T/S ratio, the odds for intrarenal arteriosclerosis decreased with 64% (Odds ratio 0.36; 95% CI 0.17‐0.77; p = 0.02). In accordance with leucocyte telomere length, shorter intrarenal telomere length associated significantly with the presence of renal arteriosclerosis (log T/S ratio ‐0.04 ± 0.06 vs. 0.08 ± 0.01 with vs. without arteriosclerosis, p = 0.007), and not with other histological lesions. Interpretation We demonstrate that arteriosclerosis in smaller intrarenal arteries is associated with shorter telomere length. Our study suggests a central role of replicative senescence in the progression of renovascular disease, independent of calendar age. PMID:26539975

  18. Telomere Length Reprogramming in Embryos and Stem Cells

    PubMed Central

    Robinson, LeRoy G.; Wang, Fang; Liu, Lin; Keefe, David

    2014-01-01

    Telomeres protect and cap linear chromosome ends, yet these genomic buffers erode over an organism's lifespan. Short telomeres have been associated with many age-related conditions in humans, and genetic mutations resulting in short telomeres in humans manifest as syndromes of precocious aging. In women, telomere length limits a fertilized egg's capacity to develop into a healthy embryo. Thus, telomere length must be reset with each subsequent generation. Although telomerase is purportedly responsible for restoring telomere DNA, recent studies have elucidated the role of alternative telomeres lengthening mechanisms in the reprogramming of early embryos and stem cells, which we review here. PMID:24719895

  19. TERRA Expression Levels Do Not Correlate with Telomere Length and Radiation Sensitivity in Human Cancer Cell Lines.

    PubMed

    Smirnova, Alexandra; Gamba, Riccardo; Khoriauli, Lela; Vitelli, Valerio; Nergadze, Solomon G; Giulotto, Elena

    2013-01-01

    Mammalian telomeres are transcribed into long non-coding telomeric repeat-containing RNA (TERRA) molecules that seem to play a role in the maintenance of telomere stability. In human cells, CpG-island promoters drive TERRA transcription and are regulated by methylation. It was suggested that the amount of TERRA may be related to telomere length. To test this hypothesis we measured telomere length and TERRA levels in single clones isolated from five human cell lines: HeLa (cervical carcinoma), BRC-230 (breast cancer), AKG and GK2 (gastric cancers), and GM847 (SV40 immortalized skin fibroblasts). However, these two parameters did not correlate with each other. Moreover, cell survival to γ-rays did not show a significant variation among the clones, suggesting that, in this cellular system, the intra-population variability in telomere length and TERRA levels does not influence sensitivity to ionizing radiation. This conclusion was supported by the observation that in a cell line in which telomeres were greatly elongated by the ectopic expression of telomerase, TERRA expression levels and radiation sensitivity were similar to the parental HeLa cell line.

  20. Telomere length is inherited with resetting of the telomere set-point.

    PubMed

    Chiang, Y Jeffrey; Calado, Rodrigo T; Hathcock, Karen S; Lansdorp, Peter M; Young, Neal S; Hodes, Richard J

    2010-06-01

    We have studied models of telomerase haploinsufficiency in humans and mice to analyze regulation of telomere length and the significance of "set points" in inheritance of telomere length. In three families with clinical syndromes associated with short telomeres resulting from haploinsufficient mutations in TERT, the gene encoding telomerase reverse transcriptase, we asked whether restoration of normal genotypes in offspring of affected individuals would elongate inherited short telomeres. Telomeres were shorter than normal in some but not all genotypically normal offspring of telomerase-mutant parents or grandparents. Analysis of these findings was complicated by heterogeneity of telomere length among individuals, as well as by the admixing of telomeres inherited from affected parents with those inherited from unaffected ("wild-type" TERT) parents. To understand further the inheritance of telomere length, we established a shortened-telomere mouse model. When Tert(+/-) heterozygous mice were successively cross-bred through 17 generations, telomere length shortened progressively. The late-generation Tert(+/-) mice were intercrossed to produce genotypically wild-type Tert(+/+) mice, for which telomere length was characterized. Strikingly, telomere length in these Tert(+/+) mice was not longer than that of their Tert(+/-) parents. Moreover, when successive crosses were carried out among these short-telomere Tert(+/+) offspring mice, telomere length was stable, with no elongation up to six generations. This breeding strategy therefore has established a mouse strain, B6.ST (short telomeres), with C57BL/6 genotype and stable short telomeres. These findings suggest that the set point of telomere lengths of offspring is determined by the telomere lengths of their parents in the presence of normal expression of telomerase.

  1. Donor Telomere Length SAA

    Cancer.gov

    A new NCI study has found that, among patients with severe aplastic anemia who received a hematopoietic cell transplant from an unrelated donor, those whose donor white blood cells had longer telomeres had higher survival rates five-years after transplant

  2. Determination of Arabidopsis thaliana telomere length by PCR

    PubMed Central

    Vaquero-Sedas, María I.; Vega-Palas, Miguel A.

    2014-01-01

    In humans, telomere length studies have acquired great relevance because the length of telomeres has been related to natural processes like disease, aging and cancer. However, very little is known about the influence of telomere length on the biology of wild type plants. The length of plant telomeres has been usually studied by Terminal Restriction Fragment (TRF) analyses. This technique requires high amounts of tissue, including multiple cell types, which might be the reason why very little is known about the influence of telomere length on plant natural processes. In contrast, many of the human telomere length studies have focused on homogenous cell populations. Most of these studies have been performed by PCR, using telomeric degenerated primers, which allow the determination of telomere length from small amounts of human cells. Here, we have adapted the human PCR procedure to analyze the length of Arabidopsis thaliana telomeres. This PCR approach will facilitate the analysis of telomere length from low amounts of tissue. We have used it to determine that CG and non CG DNA methylation positively regulates Arabidopsis telomere length. PMID:24986269

  3. Determination of Arabidopsis thaliana telomere length by PCR.

    PubMed

    Vaquero-Sedas, María I; Vega-Palas, Miguel A

    2014-07-02

    In humans, telomere length studies have acquired great relevance because the length of telomeres has been related to natural processes like disease, aging and cancer. However, very little is known about the influence of telomere length on the biology of wild type plants. The length of plant telomeres has been usually studied by Terminal Restriction Fragment (TRF) analyses. This technique requires high amounts of tissue, including multiple cell types, which might be the reason why very little is known about the influence of telomere length on plant natural processes. In contrast, many of the human telomere length studies have focused on homogenous cell populations. Most of these studies have been performed by PCR, using telomeric degenerated primers, which allow the determination of telomere length from small amounts of human cells. Here, we have adapted the human PCR procedure to analyze the length of Arabidopsis thaliana telomeres. This PCR approach will facilitate the analysis of telomere length from low amounts of tissue. We have used it to determine that CG and non CG DNA methylation positively regulates Arabidopsis telomere length.

  4. Determination of Arabidopsis thaliana telomere length by PCR.

    PubMed

    Vaquero-Sedas, María I; Vega-Palas, Miguel A

    2014-01-01

    In humans, telomere length studies have acquired great relevance because the length of telomeres has been related to natural processes like disease, aging and cancer. However, very little is known about the influence of telomere length on the biology of wild type plants. The length of plant telomeres has been usually studied by Terminal Restriction Fragment (TRF) analyses. This technique requires high amounts of tissue, including multiple cell types, which might be the reason why very little is known about the influence of telomere length on plant natural processes. In contrast, many of the human telomere length studies have focused on homogenous cell populations. Most of these studies have been performed by PCR, using telomeric degenerated primers, which allow the determination of telomere length from small amounts of human cells. Here, we have adapted the human PCR procedure to analyze the length of Arabidopsis thaliana telomeres. This PCR approach will facilitate the analysis of telomere length from low amounts of tissue. We have used it to determine that CG and non CG DNA methylation positively regulates Arabidopsis telomere length. PMID:24986269

  5. Telomere length differences between subcutaneous and visceral adipose tissue in humans

    SciTech Connect

    Lakowa, Nicole; Trieu, Nhu; Flehmig, Gesine; Lohmann, Tobias; Schön, Michael R.; Dietrich, Arne; Zeplin, Philip Helge; Langer, Stefan; Stumvoll, Michael; Blüher, Matthias; Klöting, Nora

    2015-02-13

    Adipocyte hypertrophy and hyperplasia have been shown to be associated with shorter telomere length, which may reflect aging, altered cell proliferation and adipose tissue (AT) dysfunction. In individuals with obesity, differences in fat distribution and AT cellular composition may contribute to obesity related metabolic diseases. Here, we tested the hypotheses that telomere lengths (TL) are different between: (1) abdominal subcutaneous and omental fat depots, (2) superficial and deep abdominal subcutaneous AT (SAT), and (3) adipocytes and cells of the stromal vascular fraction (SVF). We further asked whether AT TL is related to age, anthropometric and metabolic traits. TL was analyzed by quantitative PCR in total human genomic DNA isolated from paired subcutaneous and visceral AT of 47 lean and 50 obese individuals. In subgroups, we analyzed TL in isolated small and large adipocytes and SVF cells. We find significantly shorter TL in subcutaneous compared to visceral AT (P < 0.001) which is consistent in men and subgroups of lean and obese, and individuals with or without type 2 diabetes (T2D). Shorter TL in SAT is entirely due to shorter TL in the SVF compared to visceral AT (P < 0.01). SAT TL is most strongly correlated with age (r = −0.205, P < 0.05) and independently of age with HbA1c (r = −0.5, P < 0.05). We found significant TL differences between superficial SAT of lean and obese as well as between individuals with our without T2D, but not between the two layers of SAT. Our data indicate that fat depot differences in TL mainly reflect shorter TL of SVF cells. In addition, we found an age and BMI-independent relationship between shorter TL and HbA1c suggesting that chronic hyperglycemia may impair the regenerative capacity of AT more strongly than obesity alone. - Highlights: • Telomere lengths (TL) differ between fat depots mainly due to different lengths in SVF. • TL is not associated with gender, BMI and T2D. • The tendency for

  6. [Association study of telomere length with idiopathic male infertility].

    PubMed

    Shuyuan, Liu; Changjun, Zhang; Haiying, Peng; Xiaoqin, Huang; Hao, Sun; Keqin, Lin; Kai, Huang; Jiayou, Chu; Zhaoqing, Yang

    2015-11-01

    Telomeres are evolutionary conserved, multifunctional DNA-protein complexes located at the ends of eukaryotic chromosomes. Telomeres maintain chromosome stability and genome integrity and also play an important role in meiosis which aid in synapsis, homologous recombination, and segregation. Sperm telomere has been reported to play an important role in fertilization and embryo development. Nowadays, the association between telomere and reproduction is one of the major areas of interest, however whether sperm telomere associated with male infertility is not clear. In this study, in order to find out the association between Chinese idiopathic infertility and sperm telomere length, we analyzed the difference of sperm telomere length between idiopathic infertile men and normal fertile men, as well as the correlations between sperm telomere length and human semen characteristics. We analyzed 126 Chinese idiopathic infertile men and 138 normal fertile men for sperm telomere length by using quantitative PCR. We found that the relative sperm mean telomere length of infertile men was significantly shorter than that of fertile men (2.894 ± 0.115 vs. 4.016 ± 0.603, P=5.097 x 10⁻⁵). Both sperm count and semen progressive motility are related with telomere length. Our results suggest that sperm telomere length is associated with idiopathic male infertility of China and we proposed the possibility that shorter telomeres in sperm chromosome will reduce spermatogenesis and sperm functions, which finally affected the fertility of male.

  7. Telomere Rapid Deletion Regulates Telomere Length in Arabidopsis thaliana▿

    PubMed Central

    Watson, J. Matthew; Shippen, Dorothy E.

    2007-01-01

    Telomere length is maintained in species-specific equilibrium primarily through a competition between telomerase-mediated elongation and the loss of terminal DNA through the end-replication problem. Recombinational activities are also capable of both lengthening and shortening telomeres. Here we demonstrate that elongated telomeres in Arabidopsis Ku70 mutants reach a new length set point after three generations. Restoration of wild-type Ku70 in these mutants leads to discrete telomere-shortening events consistent with telomere rapid deletion (TRD). These findings imply that the longer telomere length set point is achieved through competition between overactive telomerase and TRD. Surprisingly, in the absence of telomerase, a subset of elongated telomeres was further lengthened, suggesting that in this background a mechanism of telomerase-independent lengthening of telomeres operates. Unexpectedly, we also found that plants possessing wild-type-length telomeres exhibit TRD when telomerase is inactivated. TRD is stochastic, and all chromosome ends appear to be equally susceptible. The frequency of TRD decreases as telomeres shorten; telomeres less than 2 kb in length are rarely subject to TRD. We conclude that TRD functions as a potent force to regulate telomere length in Arabidopsis. PMID:17189431

  8. Environmental and occupational exposure to chemicals and telomere length in human studies.

    PubMed

    Zhang, Xiao; Lin, Shao; Funk, William E; Hou, Lifang

    2013-12-01

    Telomeres are complexes of tandem repeats of DNA (5'-TTAGGG-3') and protein that cap eukaryotic chromosomes and play a critical role in chromosome stability. Telomeres shorten with aging and this process can be accelerated by increased oxidative stress and episodes of inflammation. Evidence is rapidly growing that telomere length (TL) may be affected by environmental chemicals that have frequently been associated with chronic diseases. In this article, we review the published data on TL in relation to environmental and occupational exposure to several chemicals based on our own and others' studies. The environmental and occupational exposures associated with shorter TL include traffic-related air pollution (ie, particulate matter (PM), black carbon (BC), and benzene and toluene), polycyclic aromatic hydrocarbons (PAHs), N-nitrosamines, pesticides, lead, exposure in car mechanical workshops, and hazardous waste exposure. Arsenic, persistent organic pollutants (POPs) and short-term exposure to PM are associated with longer TL. We discuss the possible reasons for the differences in results, including time- and dose-related issues, study design, and possible mechanisms involved in telomere regulation. We also discuss the future directions and challenges for TL-related environmental and occupational health research, such as investigation of TL in subpopulations of blood leukocytes, and the study of genetic and epigenetic factors that may regulate telomere integrity using longitudinal designs.

  9. Environmental and occupational exposure to chemicals and telomere length in human studies.

    PubMed

    Zhang, Xiao; Lin, Shao; Funk, William E; Hou, Lifang

    2013-10-01

    Telomeres are complexes of tandem repeats of DNA (5'-TTAGGG-3') and protein that cap eukaryotic chromosomes and play a critical role in chromosome stability. Telomeres shorten with aging and this process can be accelerated by increased oxidative stress and episodes of inflammation. Evidence is rapidly growing that telomere length (TL) may be affected by environmental chemicals that have frequently been associated with chronic diseases. In this article, we review the published data on TL in relation to environmental and occupational exposure to several chemicals based on our own and others' studies. The environmental and occupational exposures associated with shorter TL include traffic-related air pollution (ie, particulate matter (PM), black carbon (BC), and benzene and toluene), polycyclic aromatic hydrocarbons (PAHs), N-nitrosamines, pesticides, lead, exposure in car mechanical workshops, and hazardous waste exposure. Arsenic, persistent organic pollutants (POPs) and short-term exposure to PM are associated with longer TL. We discuss the possible reasons for the differences in results, including time- and dose-related issues, study design, and possible mechanisms involved in telomere regulation. We also discuss the future directions and challenges for TL-related environmental and occupational health research, such as investigation of TL in subpopulations of blood leukocytes, and the study of genetic and epigenetic factors that may regulate telomere integrity using longitudinal designs.

  10. Human age estimation from blood using mRNA, DNA methylation, DNA rearrangement, and telomere length.

    PubMed

    Zubakov, Dmitry; Liu, Fan; Kokmeijer, Iris; Choi, Ying; van Meurs, Joyce B J; van IJcken, Wilfred F J; Uitterlinden, André G; Hofman, Albert; Broer, Linda; van Duijn, Cornelia M; Lewin, Jörn; Kayser, Manfred

    2016-09-01

    Establishing the age of unknown persons, or persons with unknown age, can provide important leads in police investigations, disaster victim identification, fraud cases, and in other legal affairs. Previous methods mostly relied on morphological features available from teeth or skeletal parts. The development of molecular methods for age estimation allowing to use human specimens that possess no morphological age information, such as bloodstains, is extremely valuable as this type of samples is commonly found at crime scenes. Recently, we introduced a DNA-based approach for human age estimation from blood based on the quantification of T-cell specific DNA rearrangements (sjTRECs), which achieves accurate assignment of blood DNA samples to one of four 20-year-interval age categories. Aiming at improving the accuracy of molecular age estimation from blood, we investigated different types of biomarkers. We started out by systematic genome-wide surveys for new age-informative mRNA and DNA methylation markers in blood from the same young and old individuals using microarray technologies. The obtained candidate markers were validated in independent samples covering a wide age range using alternative technologies together with previously proposed DNA methylation, sjTREC, and telomere length markers. Cross-validated multiple regression analysis was applied for estimating and validating the age predictive power of various sets of biomarkers within and across different marker types. We found that DNA methylation markers outperformed mRNA, sjTREC, and telomere length in age predictive power. The best performing model included 8 DNA methylation markers derived from 3 CpG islands reaching a high level of accuracy (cross-validated R(2)=0.88, SE±6.97 years, mean absolute deviation 5.07 years). However, our data also suggest that mRNA markers can provide independent age information: a model using a combined set of 5 DNA methylation markers and one mRNA marker could provide

  11. Human age estimation from blood using mRNA, DNA methylation, DNA rearrangement, and telomere length.

    PubMed

    Zubakov, Dmitry; Liu, Fan; Kokmeijer, Iris; Choi, Ying; van Meurs, Joyce B J; van IJcken, Wilfred F J; Uitterlinden, André G; Hofman, Albert; Broer, Linda; van Duijn, Cornelia M; Lewin, Jörn; Kayser, Manfred

    2016-09-01

    Establishing the age of unknown persons, or persons with unknown age, can provide important leads in police investigations, disaster victim identification, fraud cases, and in other legal affairs. Previous methods mostly relied on morphological features available from teeth or skeletal parts. The development of molecular methods for age estimation allowing to use human specimens that possess no morphological age information, such as bloodstains, is extremely valuable as this type of samples is commonly found at crime scenes. Recently, we introduced a DNA-based approach for human age estimation from blood based on the quantification of T-cell specific DNA rearrangements (sjTRECs), which achieves accurate assignment of blood DNA samples to one of four 20-year-interval age categories. Aiming at improving the accuracy of molecular age estimation from blood, we investigated different types of biomarkers. We started out by systematic genome-wide surveys for new age-informative mRNA and DNA methylation markers in blood from the same young and old individuals using microarray technologies. The obtained candidate markers were validated in independent samples covering a wide age range using alternative technologies together with previously proposed DNA methylation, sjTREC, and telomere length markers. Cross-validated multiple regression analysis was applied for estimating and validating the age predictive power of various sets of biomarkers within and across different marker types. We found that DNA methylation markers outperformed mRNA, sjTREC, and telomere length in age predictive power. The best performing model included 8 DNA methylation markers derived from 3 CpG islands reaching a high level of accuracy (cross-validated R(2)=0.88, SE±6.97 years, mean absolute deviation 5.07 years). However, our data also suggest that mRNA markers can provide independent age information: a model using a combined set of 5 DNA methylation markers and one mRNA marker could provide

  12. Telomere length variations in aging and age-related diseases.

    PubMed

    Rizvi, Saliha; Raza, Syed Tasleem; Mahdi, Farzana

    2014-01-01

    Telomeres are gene sequences present at chromosomal ends and are responsible for maintaining genome integrity. Telomere length is maximum at birth and decreases progressively with advancing age and thus is considered as a biomarker of chronological aging. This age associated decrease in the length of telomere is linked to various ageing associated diseases like diabetes, hypertension, Alzheimer's disease, cancer etc. and their associated complications. Telomere length is a result of combined effect of oxidative stress, inflammation and repeated cell replication on it, and thus forming an association between telomere length and chronological aging and related diseases. Thus, decrease in telomere length was found to be important in determining both, the variations in longevity and age-related diseases in an individual. Ongoing and progressive research in the field of telomere length dynamics has proved that aging and age-related diseases apart from having a synergistic effect on telomere length were also found to effect telomere length independently also. Here a short description about telomere length variations and its association with human aging and age-related diseases is reviewed.

  13. Conserved Telomere Length in Human Ectopic Thyroids: An Argument Against Premature Differentiation Causing Arrested Migration

    PubMed Central

    Larrivée-Vanier, Stéphanie; Magne, Fabien; Patey, Natalie; Chanoine, Jean-Pierre; Vuissoz, Jean-Marc; Van Vliet, Guy; Deladoëy, Johnny

    2016-01-01

    Background In humans, the cause of arrested migration of the median thyroid anlage resulting in an ectopic sublingual gland is unknown. These ectopic glands have a normal follicular architecture but their thyrotropin-induced growth is insufficient, leading to congenital hypothyroidism in the vast majority of affected subjects. We hypothesized that arrested migration is due to premature differentiation [reflected by decreased telomere length (TL)], as observed in neural tube defects in mice. Methods Absolute TL and telomerase reverse transcriptase (hTERT) expression was measured in four ectopic and six orthotopic thyroids. TL was measured by quantitative polymerase chain reaction of genomic DNA, whereas hTERT expression was measured by quantitative polymerase chain reaction of total RNA. Results The mean ± standard deviation TL (in kilobases per diploid genome) was 140.45 ± 40.07 in ectopic and 97.50 ± 30.48 in orthotopic thyroids (p = 0.12). Expression of hTERT was quiescent in both ectopic and orthotopic thyroids. Conclusions Compared with orthotopic thyroids, TL shortening is not observed in ectopic thyroid tissues and, consequently, no compensatory hTERT expression was measured. This makes premature differentiation an unlikely cause of arrested migration and it suggests, indirectly, that ectopic thyroids are not at higher risk of cancer than orthotopic thyroids. PMID:26131731

  14. Telomere length alterations unique to invasive lobular carcinoma.

    PubMed

    Heaphy, Christopher M; Asch-Kendrick, Rebecca; Argani, Pedram; Meeker, Alan K; Cimino-Mathews, Ashley

    2015-08-01

    Telomeres are nucleoprotein complexes located at the extreme ends of eukaryotic chromosomes and protect chromosomal ends from degradation and recombination. Dysfunctional telomeres contribute to genomic instability, promote tumorigenesis, and, in breast cancer, have been associated with increased cancer risk and poor prognosis. Short telomere lengths have been previously associated with triple-negative and human epidermal growth factor receptor (Her2)--positive ductal carcinomas. However, these investigations have not specifically assessed invasive lobular carcinomas (ILCs), which accounts for 5% to 15% of all invasive breast cancers. Here, we evaluate telomere lengths within 48 primary ILCs with complete characterization of estrogen receptor (ER), progesterone receptor (PR), and Her2 status, including 32 luminal/Her2- (ER+/PR+/Her2-), 8 luminal/Her2+ (ER+/PR+/Her2+), 3 Her2+ (ER-/PR-/Her2+), and 5 triple-negative (ER-/PR-/Her2-) carcinomas. A telomere-specific fluorescence in situ hybridization assay, which provides single-cell telomere length resolution, was used to evaluate telomere lengths and compare with standard clinicopathological markers. In contrast to breast ductal carcinoma, in which more than 85% of cases display abnormally short telomeres, approximately half (52%) of the ILCs displayed either normal or long telomeres. Short telomere length was associated with older patient age. Interestingly, 3 cases (6%) displayed a unique telomere pattern consisting of 1 or 2 bright telomere spots among the normal telomere signals within each individual cancer cell, a phenotype that has not been previously described. Additional studies are needed to further evaluate the significance of the unique bright telomere spot phenotype and the potential utility of telomere length as a prognostic marker in ILC.

  15. Telomerase and telomere length in pulmonary fibrosis.

    PubMed

    Liu, Tianju; Ullenbruch, Matthew; Young Choi, Yoon; Yu, Hongfeng; Ding, Lin; Xaubet, Antoni; Pereda, Javier; Feghali-Bostwick, Carol A; Bitterman, Peter B; Henke, Craig A; Pardo, Annie; Selman, Moises; Phan, Sem H

    2013-08-01

    In addition to its expression in stem cells and many cancers, telomerase activity is transiently induced in murine bleomycin (BLM)-induced pulmonary fibrosis with increased levels of telomerase transcriptase (TERT) expression, which is essential for fibrosis. To extend these observations to human chronic fibrotic lung disease, we investigated the expression of telomerase activity in lung fibroblasts from patients with interstitial lung diseases (ILDs), including idiopathic pulmonary fibrosis (IPF). The results showed that telomerase activity was induced in more than 66% of IPF lung fibroblast samples, in comparison with less than 29% from control samples, some of which were obtained from lung cancer resections. Less than 4% of the human IPF lung fibroblast samples exhibited shortened telomeres, whereas less than 6% of peripheral blood leukocyte samples from patients with IPF or hypersensitivity pneumonitis demonstrated shortened telomeres. Moreover, shortened telomeres in late-generation telomerase RNA component knockout mice did not exert a significant effect on BLM-induced pulmonary fibrosis. In contrast, TERT knockout mice exhibited deficient fibrosis that was independent of telomere length. Finally, TERT expression was up-regulated by a histone deacetylase inhibitor, while the induction of TERT in lung fibroblasts was associated with the binding of acetylated histone H3K9 to the TERT promoter region. These findings indicate that significant telomerase induction was evident in fibroblasts from fibrotic murine lungs and a majority of IPF lung samples, whereas telomere shortening was not a common finding in the human blood and lung fibroblast samples. Notably, the animal studies indicated that the pathogenesis of pulmonary fibrosis was independent of telomere length.

  16. PCB153 reduces telomerase activity and telomere length in immortalized human skin keratinocytes (HaCaT) but not in human foreskin keratinocytes (NFK)

    SciTech Connect

    Senthilkumar, P.K.; Robertson, L.W.; Ludewig, G.

    2012-02-15

    Polychlorinated biphenyls (PCBs), ubiquitous environmental pollutants, are characterized by long term-persistence in the environment, bioaccumulation, and biomagnification in the food chain. Exposure to PCBs may cause various diseases, affecting many cellular processes. Deregulation of the telomerase and the telomere complex leads to several biological disorders. We investigated the hypothesis that PCB153 modulates telomerase activity, telomeres and reactive oxygen species resulting in the deregulation of cell growth. Exponentially growing immortal human skin keratinocytes (HaCaT) and normal human foreskin keratinocytes (NFK) were incubated with PCB153 for 48 and 24 days, respectively, and telomerase activity, telomere length, superoxide level, cell growth, and cell cycle distribution were determined. In HaCaT cells exposure to PCB153 significantly reduced telomerase activity, telomere length, cell growth and increased intracellular superoxide levels from day 6 to day 48, suggesting that superoxide may be one of the factors regulating telomerase activity, telomere length and cell growth compared to untreated control cells. Results with NFK cells showed no shortening of telomere length but reduced cell growth and increased superoxide levels in PCB153-treated cells compared to untreated controls. As expected, basal levels of telomerase activity were almost undetectable, which made a quantitative comparison of treated and control groups impossible. The significant down regulation of telomerase activity and reduction of telomere length by PCB153 in HaCaT cells suggest that any cell type with significant telomerase activity, like stem cells, may be at risk of premature telomere shortening with potential adverse health effects for the affected organism. -- Highlights: ► Human immortal (HaCaT) and primary (NFK) keratinocytes were exposed to PCB153. ► PCB153 significantly reduced telomerase activity and telomere length in HaCaT. ► No effect on telomere length and

  17. The Genetic Basis of Natural Variation in Caenorhabditis elegans Telomere Length.

    PubMed

    Cook, Daniel E; Zdraljevic, Stefan; Tanny, Robyn E; Seo, Beomseok; Riccardi, David D; Noble, Luke M; Rockman, Matthew V; Alkema, Mark J; Braendle, Christian; Kammenga, Jan E; Wang, John; Kruglyak, Leonid; Félix, Marie-Anne; Lee, Junho; Andersen, Erik C

    2016-09-01

    Telomeres are involved in the maintenance of chromosomes and the prevention of genome instability. Despite this central importance, significant variation in telomere length has been observed in a variety of organisms. The genetic determinants of telomere-length variation and their effects on organismal fitness are largely unexplored. Here, we describe natural variation in telomere length across the Caenorhabditis elegans species. We identify a large-effect variant that contributes to differences in telomere length. The variant alters the conserved oligonucleotide/oligosaccharide-binding fold of protection of telomeres 2 (POT-2), a homolog of a human telomere-capping shelterin complex subunit. Mutations within this domain likely reduce the ability of POT-2 to bind telomeric DNA, thereby increasing telomere length. We find that telomere-length variation does not correlate with offspring production or longevity in C. elegans wild isolates, suggesting that naturally long telomeres play a limited role in modifying fitness phenotypes in C. elegans.

  18. The Genetic Basis of Natural Variation in Caenorhabditis elegans Telomere Length.

    PubMed

    Cook, Daniel E; Zdraljevic, Stefan; Tanny, Robyn E; Seo, Beomseok; Riccardi, David D; Noble, Luke M; Rockman, Matthew V; Alkema, Mark J; Braendle, Christian; Kammenga, Jan E; Wang, John; Kruglyak, Leonid; Félix, Marie-Anne; Lee, Junho; Andersen, Erik C

    2016-09-01

    Telomeres are involved in the maintenance of chromosomes and the prevention of genome instability. Despite this central importance, significant variation in telomere length has been observed in a variety of organisms. The genetic determinants of telomere-length variation and their effects on organismal fitness are largely unexplored. Here, we describe natural variation in telomere length across the Caenorhabditis elegans species. We identify a large-effect variant that contributes to differences in telomere length. The variant alters the conserved oligonucleotide/oligosaccharide-binding fold of protection of telomeres 2 (POT-2), a homolog of a human telomere-capping shelterin complex subunit. Mutations within this domain likely reduce the ability of POT-2 to bind telomeric DNA, thereby increasing telomere length. We find that telomere-length variation does not correlate with offspring production or longevity in C. elegans wild isolates, suggesting that naturally long telomeres play a limited role in modifying fitness phenotypes in C. elegans. PMID:27449056

  19. The Genetic Basis of Natural Variation in Caenorhabditis elegans Telomere Length

    PubMed Central

    Cook, Daniel E.; Zdraljevic, Stefan; Tanny, Robyn E.; Seo, Beomseok; Riccardi, David D.; Noble, Luke M.; Rockman, Matthew V.; Alkema, Mark J.; Braendle, Christian; Kammenga, Jan E.; Wang, John; Kruglyak, Leonid; Félix, Marie-Anne; Lee, Junho; Andersen, Erik C.

    2016-01-01

    Telomeres are involved in the maintenance of chromosomes and the prevention of genome instability. Despite this central importance, significant variation in telomere length has been observed in a variety of organisms. The genetic determinants of telomere-length variation and their effects on organismal fitness are largely unexplored. Here, we describe natural variation in telomere length across the Caenorhabditis elegans species. We identify a large-effect variant that contributes to differences in telomere length. The variant alters the conserved oligonucleotide/oligosaccharide-binding fold of protection of telomeres 2 (POT-2), a homolog of a human telomere-capping shelterin complex subunit. Mutations within this domain likely reduce the ability of POT-2 to bind telomeric DNA, thereby increasing telomere length. We find that telomere-length variation does not correlate with offspring production or longevity in C. elegans wild isolates, suggesting that naturally long telomeres play a limited role in modifying fitness phenotypes in C. elegans. PMID:27449056

  20. Telomere length and expression of human telomerase reverse transcriptase splice variants in chronic lymphocytic leukemia.

    PubMed

    Palma, Marzia; Parker, Anton; Hojjat-Farsangi, Mohammad; Forster, Jade; Kokhaei, Parviz; Hansson, Lotta; Osterborg, Anders; Mellstedt, Håkan

    2013-07-01

    Telomerase activity and telomere length (TL) are prognostic markers in chronic lymphocytic leukemia (CLL). The rate-limiting component of telomerase is human telomerase reverse transcriptase (hTERT), for which multiple transcripts exist. Two splicing sites, α and β, have been described that generate deleted transcripts. Only the full-length (FL; α⁺β⁺) transcript translates into a functional protein. The aim of this work was to characterize hTERT splice variants in CLL in relation to disease activity, clinical stage, immunoglobulin heavy chain variable (IGHV) genes mutational status, and TL. Real-time polymerase chain reaction assays were validated for quantification of the hTERT transcripts with either α deletion (del-α; α⁻β⁺)), β deletion (del-β; α⁺β⁻) or both α and β deletions (del-αβ; α⁻β⁻). The splice variant expression pattern was studied in 97 patients with CLL, 6 healthy control subjects, and one CD34 cell sample. TL was assessed with real-time polymerase chain reaction in 71 of 97 samples. Thirty-two percent of the cases did not express any of the splice variants. Average FL expression was 5.5-fold higher in IGHV-unmutated (n = 35) compared with mutated (n = 59) patients (p < 0.0001). FL levels correlated directly with the percentage of IGHV homology (r = 0.34; p = 0.0007) and inversely with TL (r = -0.44; p = 0.0001). Overall, FL expression correlated significantly with that of the other splice variants. All transcripts were more frequently expressed in progressive compared with nonprogressive patients (p < 0.0001 for FL and del-α; p = 0.01 for del-β; and p = 0.006 for del-αβ). This study provides a detailed insight into the hTERT transcript pattern in CLL, highlighting the necessity of subgrouping patients according to IGHV mutation status when analyzing hTERT expression.

  1. Telomerase Activity and Telomere Length in Daphnia

    PubMed Central

    Schumpert, Charles; Nelson, Jacob; Kim, Eunsuk; Dudycha, Jeffry L.; Patel, Rekha C.

    2015-01-01

    Telomeres, comprised of short repetitive sequences, are essential for genome stability and have been studied in relation to cellular senescence and aging. Telomerase, the enzyme that adds telomeric repeats to chromosome ends, is essential for maintaining the overall telomere length. A lack of telomerase activity in mammalian somatic cells results in progressive shortening of telomeres with each cellular replication event. Mammals exhibit high rates of cell proliferation during embryonic and juvenile stages but very little somatic cell proliferation occurs during adult and senescent stages. The telomere hypothesis of cellular aging states that telomeres serve as an internal mitotic clock and telomere length erosion leads to cellular senescence and eventual cell death. In this report, we have examined telomerase activity, processivity, and telomere length in Daphnia, an organism that grows continuously throughout its life. Similar to insects, Daphnia telomeric repeat sequence was determined to be TTAGG and telomerase products with five-nucleotide periodicity were generated in the telomerase activity assay. We investigated telomerase function and telomere lengths in two closely related ecotypes of Daphnia with divergent lifespans, short-lived D. pulex and long-lived D. pulicaria. Our results indicate that there is no age-dependent decline in telomere length, telomerase activity, or processivity in short-lived D. pulex. On the contrary, a significant age dependent decline in telomere length, telomerase activity and processivity is observed during life span in long-lived D. pulicaria. While providing the first report on characterization of Daphnia telomeres and telomerase activity, our results also indicate that mechanisms other than telomere shortening may be responsible for the strikingly short life span of D. pulex. PMID:25962144

  2. Telomerase activity and telomere length in Daphnia.

    PubMed

    Schumpert, Charles; Nelson, Jacob; Kim, Eunsuk; Dudycha, Jeffry L; Patel, Rekha C

    2015-01-01

    Telomeres, comprised of short repetitive sequences, are essential for genome stability and have been studied in relation to cellular senescence and aging. Telomerase, the enzyme that adds telomeric repeats to chromosome ends, is essential for maintaining the overall telomere length. A lack of telomerase activity in mammalian somatic cells results in progressive shortening of telomeres with each cellular replication event. Mammals exhibit high rates of cell proliferation during embryonic and juvenile stages but very little somatic cell proliferation occurs during adult and senescent stages. The telomere hypothesis of cellular aging states that telomeres serve as an internal mitotic clock and telomere length erosion leads to cellular senescence and eventual cell death. In this report, we have examined telomerase activity, processivity, and telomere length in Daphnia, an organism that grows continuously throughout its life. Similar to insects, Daphnia telomeric repeat sequence was determined to be TTAGG and telomerase products with five-nucleotide periodicity were generated in the telomerase activity assay. We investigated telomerase function and telomere lengths in two closely related ecotypes of Daphnia with divergent lifespans, short-lived D. pulex and long-lived D. pulicaria. Our results indicate that there is no age-dependent decline in telomere length, telomerase activity, or processivity in short-lived D. pulex. On the contrary, a significant age dependent decline in telomere length, telomerase activity and processivity is observed during life span in long-lived D. pulicaria. While providing the first report on characterization of Daphnia telomeres and telomerase activity, our results also indicate that mechanisms other than telomere shortening may be responsible for the strikingly short life span of D. pulex.

  3. Direct Comparison of Flow-FISH and qPCR as Diagnostic Tests for Telomere Length Measurement in Humans

    PubMed Central

    Gutierrez-Rodrigues, Fernanda; Santana-Lemos, Bárbara A.; Scheucher, Priscila S.; Alves-Paiva, Raquel M.; Calado, Rodrigo T.

    2014-01-01

    measurement of human leukocyte's telomere length in comparison to qPCR. In conclusion, flow-FISH appears to be a more appropriate method for diagnostic purposes. PMID:25409313

  4. Telomere Length as a Quantitative Trait: Genome-Wide Survey and Genetic Mapping of Telomere Length-Control Genes in Yeast

    PubMed Central

    Gatbonton, Tonibelle; Imbesi, Maria; Nelson, Melisa; Akey, Joshua M; Ruderfer, Douglas M; Kruglyak, Leonid; Simon, Julian A; Bedalov, Antonio

    2006-01-01

    Telomere length-variation in deletion strains of Saccharomyces cerevisiae was used to identify genes and pathways that regulate telomere length. We found 72 genes that when deleted confer short telomeres, and 80 genes that confer long telomeres relative to those of wild-type yeast. Among identified genes, 88 have not been previously implicated in telomere length control. Genes that regulate telomere length span a variety of functions that can be broadly separated into telomerase-dependent and telomerase-independent pathways. We also found 39 genes that have an important role in telomere maintenance or cell proliferation in the absence of telomerase, including genes that participate in deoxyribonucleotide biosynthesis, sister chromatid cohesion, and vacuolar protein sorting. Given the large number of loci identified, we investigated telomere lengths in 13 wild yeast strains and found substantial natural variation in telomere length among the isolates. Furthermore, we crossed a wild isolate to a laboratory strain and analyzed telomere length in 122 progeny. Genome-wide linkage analysis among these segregants revealed two loci that account for 30%–35% of telomere length-variation between the strains. These findings support a general model of telomere length-variation in outbred populations that results from polymorphisms at a large number of loci. Furthermore, our results laid the foundation for studying genetic determinants of telomere length-variation and their roles in human disease. PMID:16552446

  5. Insights into Cdc13 Dependent Telomere Length Regulation

    SciTech Connect

    M Mason; E Skordalakes

    2011-12-31

    Cdc13 is a single stranded telomere binding protein that specifically localizes to the telomere ends of budding yeasts and is essential for cell viability. It caps the ends of chromosomes thus preventing chromosome end-to-end fusions and exonucleolytic degradation, events that could lead to genomic instability and senescence, the hallmark of aging. Cdc13 is also involved in telomere length regulation by recruiting or preventing access of telomerase to the telomeric overhang. Recruitment of telomerase to the telomeres for G-strand extension is required for continuous cell division, while preventing its access to the telomeres through capping the chromosome ends prevents mitotic events that could lead to cell immortality, the hall mark of carcinogenesis. Cdc13 and its putative homologues human CTC1 and POT1 are therefore key to many biological processes directly associated with life extension and cancer prevention and can be viewed as an ideal target for cancer and age related therapies.

  6. Telomere Length and the Cancer-Atherosclerosis Trade-Off.

    PubMed

    Stone, Rivka C; Horvath, Kent; Kark, Jeremy D; Susser, Ezra; Tishkoff, Sarah A; Aviv, Abraham

    2016-07-01

    Modern humans, the longest-living terrestrial mammals, display short telomeres and repressed telomerase activity in somatic tissues compared with most short-living small mammals. The dual trait of short telomeres and repressed telomerase might render humans relatively resistant to cancer compared with short-living small mammals. However, the trade-off for cancer resistance is ostensibly increased age-related degenerative diseases, principally in the form of atherosclerosis. In this communication, we discuss (a) the genetics of human telomere length, a highly heritable complex trait that is influenced by genetic ancestry, sex, and paternal age at conception, (b) how cancer might have played a role in the evolution of telomere biology across mammals, (c) evidence that in modern humans telomere length is a determinant (rather than only a biomarker) of cancer and atherosclerosis, and (d) the potential influence of relatively recent evolutionary forces in fashioning the variation in telomere length across and within populations, and their likely lasting impact on major diseases in humans. Finally, we propose venues for future research on human telomere genetics in the context of its potential role in shaping the modern human lifespan. PMID:27386863

  7. Telomere Length and the Cancer–Atherosclerosis Trade-Off

    PubMed Central

    Stone, Rivka C.; Horvath, Kent; Kark, Jeremy D.; Susser, Ezra; Tishkoff, Sarah A.; Aviv, Abraham

    2016-01-01

    Modern humans, the longest-living terrestrial mammals, display short telomeres and repressed telomerase activity in somatic tissues compared with most short-living small mammals. The dual trait of short telomeres and repressed telomerase might render humans relatively resistant to cancer compared with short-living small mammals. However, the trade-off for cancer resistance is ostensibly increased age-related degenerative diseases, principally in the form of atherosclerosis. In this communication, we discuss (a) the genetics of human telomere length, a highly heritable complex trait that is influenced by genetic ancestry, sex, and paternal age at conception, (b) how cancer might have played a role in the evolution of telomere biology across mammals, (c) evidence that in modern humans telomere length is a determinant (rather than only a biomarker) of cancer and atherosclerosis, and (d) the potential influence of relatively recent evolutionary forces in fashioning the variation in telomere length across and within populations, and their likely lasting impact on major diseases in humans. Finally, we propose venues for future research on human telomere genetics in the context of its potential role in shaping the modern human lifespan. PMID:27386863

  8. The relationship between telomere length and beekeeping among Malaysians.

    PubMed

    Nasir, Nurul Fatihah Mohamad; Kannan, Thirumulu Ponnuraj; Sulaiman, Siti Amrah; Shamsuddin, Shaharum; Azlina, Ahmad; Stangaciu, Stefan

    2015-06-01

    The belief that beekeepers live longer than anyone else is present since ages. However, no research has been done to explore the longevity of life in beekeepers. Here, we investigated the telomere length in 30 male beekeepers and 30 male non-beekeepers and associated them with the longevity of life using Southern analysis of terminal restriction fragments (TRFs) generated by Hinf I/Rsa I digestion of human genomic DNA using TeloTAGGG Telomere Length Assay. Interestingly, we found that the telomere length of male beekeepers was significantly longer than those of male non-beekeepers with a p value of less than 0.05, suggesting that beekeepers may have longer life compared to non-beekeepers. We further found that the consumption of bee products for a long period and frequent consumption of bee products per day are associated with telomere length. An increase of year in consuming bee products is associated with a mean increase in telomere length of 0.258 kbp. In addition, an increase in frequency of eating bee products per day was also associated with a mean increase of 2.66 kbp in telomere length. These results suggested that bee products might play some roles in telomere length maintenance.

  9. Genetic variation in TERT and TERC and human leukocyte telomere length and longevity: a cross-sectional and longitudinal analysis.

    PubMed

    Soerensen, Mette; Thinggaard, Mikael; Nygaard, Marianne; Dato, Serena; Tan, Qihua; Hjelmborg, Jacob; Andersen-Ranberg, Karen; Stevnsner, Tinna; Bohr, Vilhelm A; Kimura, Masayuki; Aviv, Abraham; Christensen, Kaare; Christiansen, Lene

    2012-04-01

    Telomerase is of key importance for telomere maintenance, and variants of the genes encoding its major subunits, telomerase reverse transcriptase (TERT) and telomerase RNA component (TERC), are candidates for interindividual variation in telomere length. Recently, the two SNPs rs3772190 and rs12696304 in the TERC locus were reported to be associated with leukocyte telomere length (LTL) in two genome-wide association studies, while one haplotype of TERT (rs2853669, rs2736098, rs33954691, and rs2853691) has been reported to be associated with both LTL and longevity in a candidate gene study. In this study, we investigated the two TERC and four TERT SNPs in middle-aged, old, and oldest-old Danes (58-100 years) and their association with LTL (n = 864) and longevity (n = 1069). Furthermore, data on 11 TERT tagging SNPs in 1089 oldest-old and 736 middle-aged Danes were investigated with respect to longevity. For all SNPs, the association with longevity was investigated using both a cross-sectional and a longitudinal approach. Applying an additive model, we found association of LTL with the minor TERC alleles of rs3772190 (A) and rs12696304 (G), such that a shorter LTL was seen in rs3772190 A carriers (regression coefficient = -0.08, P = 0.011) and in male rs12696304 G carriers (regression coefficient = -0.13, P = 0.014). No TERT variations showed association. Moreover, the A allele of rs3772190 (TERC) was found to be associated with longevity [hazard rate (AG + AA) = 1.31, P = 0.006]. No associations with longevity were observed for the TERT SNPs or haplotypes. Our study, thus, indicates that TERC is associated with both LTL and longevity in humans.

  10. Variable telomere length across post-mortem human brain regions and specific reduction in the hippocampus of major depressive disorder.

    PubMed

    Mamdani, F; Rollins, B; Morgan, L; Myers, R M; Barchas, J D; Schatzberg, A F; Watson, S J; Akil, H; Potkin, S G; Bunney, W E; Vawter, M P; Sequeira, P A

    2015-09-15

    Stress can be a predisposing factor to psychiatric disorders and has been associated with decreased neurogenesis and reduced hippocampal volume especially in depression. Similarly, in white blood cells chronic psychological stress has been associated with telomere shortening and with mood disorders and schizophrenia (SZ). However, in previous post-mortem brain studies from occipital cortex and cerebellum, no difference in telomere length was observed in depression. We hypothesized that in psychiatric disorders, stress-driven accelerated cellular aging can be observed in brain regions particularly sensitive to stress. Telomere length was measured by quantitative-PCR in five brain regions (dorsolateral prefrontal cortex, hippocampus (HIPP), amygdala, nucleus accumbens and substantia nigra (SN)) in major depressive disorder (MDD), bipolar disorder, SZ and normal control subjects (N = 40, 10 subjects per group). We observed significant differences in telomere length across brain regions suggesting variable levels of cell aging, with SN and HIPP having the longest telomeres and the dorsolateral prefrontal cortex the shortest. A significant decrease (P < 0.02) in telomere length was observed specifically in the HIPP of MDD subjects even after controlling for age. In the HIPP of MDD subjects, several genes involved in neuroprotection and in stress response (FKBP5, CRH) showed altered levels of mRNA. Our results suggest the presence of hippocampal stress-mediated accelerated cellular aging in depression. Further studies are needed to investigate the cellular specificity of these findings.

  11. Variable telomere length across post-mortem human brain regions and specific reduction in the hippocampus of major depressive disorder

    PubMed Central

    Mamdani, F; Rollins, B; Morgan, L; Myers, R M; Barchas, J D; Schatzberg, A F; Watson, S J; Akil, H; Potkin, S G; Bunney, W E; Vawter, M P; Sequeira, P A

    2015-01-01

    Stress can be a predisposing factor to psychiatric disorders and has been associated with decreased neurogenesis and reduced hippocampal volume especially in depression. Similarly, in white blood cells chronic psychological stress has been associated with telomere shortening and with mood disorders and schizophrenia (SZ). However, in previous post-mortem brain studies from occipital cortex and cerebellum, no difference in telomere length was observed in depression. We hypothesized that in psychiatric disorders, stress-driven accelerated cellular aging can be observed in brain regions particularly sensitive to stress. Telomere length was measured by quantitative-PCR in five brain regions (dorsolateral prefrontal cortex, hippocampus (HIPP), amygdala, nucleus accumbens and substantia nigra (SN)) in major depressive disorder (MDD), bipolar disorder, SZ and normal control subjects (N=40, 10 subjects per group). We observed significant differences in telomere length across brain regions suggesting variable levels of cell aging, with SN and HIPP having the longest telomeres and the dorsolateral prefrontal cortex the shortest. A significant decrease (P<0.02) in telomere length was observed specifically in the HIPP of MDD subjects even after controlling for age. In the HIPP of MDD subjects, several genes involved in neuroprotection and in stress response (FKBP5, CRH) showed altered levels of mRNA. Our results suggest the presence of hippocampal stress-mediated accelerated cellular aging in depression. Further studies are needed to investigate the cellular specificity of these findings. PMID:26371764

  12. Quantification of telomere length by FISH and laser scanning cytometry

    NASA Astrophysics Data System (ADS)

    Mahoney, John E.; Sahin, Ergun; Jaskelioff, Mariela; Chin, Lynda; DePinho, Ronald A.; Protopopov, Alexei I.

    2008-02-01

    Telomeres play a critical role in the maintenance of chromosomal stability. Telomere erosion, coupled with loss of DNA damage checkpoint function, results in genomic instability that promotes the development of cancer. The critical role of telomere dynamics in cancer has motivated the development of technologies designed to monitor telomere reserves in a highly quantitative and high-throughput manner in humans and model organisms. To this end, we have adapted and modified two established technologies, telomere-FISH and laser scanning cytometry. Specifically, we have produced a number of enhancements to the iCys LSC (CompuCyte) package including software updates, use of 60X dry objectives, and increased spatial resolution by 0.2 um size of stage steps. In addition, the 633 nm HeNe laser was replaced with a 532 nm green diode laser to better match the viewing options. Utilization of telomere-deficient mouse cells with short dysfunctional telomeres and matched telomerase reconstituted cultures demonstrated significantly higher mean integral specific fluorescence values for mTR transfectants relative to empty vector controls: 4.485M vs. 1.362M (p<0.0001). Histograms of average telomere intensities for individual cells were obtained and demonstrated intercellular heterogeneity in telomere lengths. The validation of the approach derives from a strong correlation between iCys LSC values and Southern blotting. This validated method greatly increases our experimental throughput and objectivity.

  13. Insomnia and Telomere Length in Older Adults

    PubMed Central

    Carroll, Judith E.; Esquivel, Stephanie; Goldberg, Alyssa; Seeman, Teresa E.; Effros, Rita B.; Dock, Jeffrey; Olmstead, Richard; Breen, Elizabeth C.; Irwin, Michael R.

    2016-01-01

    Study Objectives: Insomnia, particularly in later life, may raise the risk for chronic diseases of aging and mortality through its effect on cellular aging. The current study examines the effects of insomnia on telomere length, a measure of cellular aging, and tests whether insomnia interacts with chronological age to increase cellular aging. Methods: A total of 126 males and females (60–88 y) were assessed for insomnia using the Diagnostic and Statistical Manual IV criterion for primary insomnia and the International Classification of Sleep Disorders, Second Edition for general insomnia (45 insomnia cases; 81 controls). Telomere length in peripheral blood mononuclear cells (PBMC) was determined using real-time quantitative polymerase chain reaction (qPCR) methodology. Results: In the analysis of covariance model adjusting for body mass index and sex, age (60–69 y versus 70–88 y) and insomnia diagnosis interacted to predict shorter PBMC telomere length (P = 0.04). In the oldest age group (70–88 y), PBMC telomere length was significantly shorter in those with insomnia, mean (standard deviation) M(SD) = 0.59(0.2) compared to controls with no insomnia M(SD) = 0.78(0.4), P = 0.04. In the adults aged 60–69 y, PBMC telomere length was not different between insomnia cases and controls, P = 0.44. Conclusions: Insomnia is associated with shorter PBMC telomere length in adults aged 70–88 y, but not in those younger than 70 y, suggesting that clinically severe sleep disturbances may increase cellular aging, especially in the later years of life. These findings highlight insomnia as a vulnerability factor in later life, with implications for risk for diseases of aging. Citation: Carroll JE, Esquivel S, Goldberg A, Seeman TE, Effros RB, Dock J, Olmstead R, Breen EC, Irwin MR. Insomnia and telomere length in older adults. SLEEP 2016;39(3):559–564. PMID:26715231

  14. Associations of TERC Single Nucleotide Polymorphisms with Human Leukocyte Telomere Length and the Risk of Type 2 Diabetes Mellitus.

    PubMed

    Al Khaldi, Rasha; Mojiminiyi, Olusegun; AlMulla, Fahd; Abdella, Nabila

    2015-01-01

    Previous Studies have mapped putative loci that may probably regulate leukocyte telomere length (LTL). The strongest associations with LTL were reported for SNP rs12696304 and rs16847897 near the non-coding Ribose Nucleic Acid (RNA) molecule component (TERC) of telomerase enzyme on 3q26. It is unclear whether these identified loci coding functional components of telomerase, exert a similar effect on LTL in other populations or influence risk factors of Type 2 Diabetes Mellitus (T2DM). The present study was performed to: study the influence of TERC polymorphisms on LTL, human telomerase reverse transcriptase (hTERT), indices of obesity and explore the potential associations with T2DM. 225 T2DM patients and 245 age and sex matched controls were studied. Allelic Discrimination (AD) genotyping was utilized to determine TERC SNPs [rs12696304 and rs16847897]. hTERT, adiponectin, Insulin, Homeostasis Model Assessment (HOMA-IR), and LTL were measured. Body Mass Index (BMI) and waist circumference (WC) were recorded. [CC] genotype of rs16847897 was significantly associated with shorter LTL [OR = 1.6, p = 0.004], lower hTERT levels [OR = 0.4, p = 0.006], higher BMI [OR = 2.2, p = 0.006], larger WC [OR = 23.4, p = 0.007] and hypo-adiponectemia [OR = 0.6, p = 0.006]. [GG] genotype of rs12696304 was also significantly associated with shorter LTL [OR = 1.5, p = 0.004], lower hTERT [OR = 0.7, p = 0.006] but with larger WC[OR = 5.3, p = 0.004]. [CC] genotype of rs16847897 and [GG] genotype of rs12696304 together increased the risk of T2DM significantly [OR = 1.7, p = 0.004]. We provide insights connecting a structure that is critically involved in maintaining genomic stability with obesity and T2DM. Given the central role of telomere length in determining telomere function our findings may expand our understanding of the pathological mechanisms underlying age associated conditions such as T2DM. PMID:26720590

  15. Spermatozoa telomeres determine telomere length in early embryos and offspring.

    PubMed

    de Frutos, C; López-Cardona, A P; Fonseca Balvís, N; Laguna-Barraza, R; Rizos, D; Gutierrez-Adán, A; Bermejo-Álvarez, P

    2016-01-01

    Offspring telomere length (TL) has been correlated with paternal TL, but the mechanism for this parent of origin-specific inheritance remains unclear. The objective of this study has been to determine the role of spermatozoa TL in embryonic telomere lengthening by using two mouse models showing dimorphism in their spermatozoa TL: Mus musculus vs Mus spretus and old vs young Mus musculus. Mus spretus spermatozoa displayed a shorter TL than Mus musculus. Hybrid offspring exhibited lower TL compared with Mus musculus starting at the two-cell stage, before the onset of telomerase expression. To analyze the role of spermatozoa telomeres in early telomere lengthening, we compared the TL in oocytes, zygotes, two-cell embryos and blastocysts produced by parthenogenesis or by fertilization with Mus musculus or Mus spretus spermatozoa. TL was significantly higher in spermatozoa compared with oocytes, and it increased significantly from the oocyte to the zygote stage in those embryos fertilized with Mus musculus spermatozoa, but not in those fertilized with Mus spretus spermatozoa or produced by parthenogenesis. A further increase was noted from the zygote to the two-cell stage in fertilized Mus musculus embryos, whereas hybrid embryos maintained the oocyte TL. Spermatozoa TL shortened with age in Mus musculus and the offspring from young males showed a significantly higher TL compared with that fathered by old males. These significant differences were already noticeable at the two-cell stage. These results suggest that spermatozoa telomeres act as a guide for telomerase-independent telomere lengthening resulting in differences in TL that persist after birth.

  16. Spermatozoa telomeres determine telomere length in early embryos and offspring.

    PubMed

    de Frutos, C; López-Cardona, A P; Fonseca Balvís, N; Laguna-Barraza, R; Rizos, D; Gutierrez-Adán, A; Bermejo-Álvarez, P

    2016-01-01

    Offspring telomere length (TL) has been correlated with paternal TL, but the mechanism for this parent of origin-specific inheritance remains unclear. The objective of this study has been to determine the role of spermatozoa TL in embryonic telomere lengthening by using two mouse models showing dimorphism in their spermatozoa TL: Mus musculus vs Mus spretus and old vs young Mus musculus. Mus spretus spermatozoa displayed a shorter TL than Mus musculus. Hybrid offspring exhibited lower TL compared with Mus musculus starting at the two-cell stage, before the onset of telomerase expression. To analyze the role of spermatozoa telomeres in early telomere lengthening, we compared the TL in oocytes, zygotes, two-cell embryos and blastocysts produced by parthenogenesis or by fertilization with Mus musculus or Mus spretus spermatozoa. TL was significantly higher in spermatozoa compared with oocytes, and it increased significantly from the oocyte to the zygote stage in those embryos fertilized with Mus musculus spermatozoa, but not in those fertilized with Mus spretus spermatozoa or produced by parthenogenesis. A further increase was noted from the zygote to the two-cell stage in fertilized Mus musculus embryos, whereas hybrid embryos maintained the oocyte TL. Spermatozoa TL shortened with age in Mus musculus and the offspring from young males showed a significantly higher TL compared with that fathered by old males. These significant differences were already noticeable at the two-cell stage. These results suggest that spermatozoa telomeres act as a guide for telomerase-independent telomere lengthening resulting in differences in TL that persist after birth. PMID:26475708

  17. Assessment of Telomere Length in Archived Formalin-Fixed, Paraffinized Human Tissue Is Confounded by Chronological Age and Storage Duration

    PubMed Central

    2016-01-01

    Telomeres shorten with physiological aging but undergo substantial restoration during cancer immortalization. Increasingly, cancer studies utilize the archive of formalin-fixed, paraffin-embedded (FFPE) tissues in diagnostic pathology departments. Conceptually, such studies would be confounded by physiological telomere attrition and loss of DNA integrity from prolonged tissue storage. Our study aimed to investigate these two confounding factors. 145 FFPE tissues of surgically-resected, non-diseased appendixes were retrieved from our pathology archive, from years 2008 to 2014. Cases from 2013 to 2014 were categorized by patient chronological age (0–20 years, 21–40 years, 41–60 years, > 60 years). Telomere lengths of age categories were depicted by telomere/chromosome 2 centromere intensity ratio (TCR) revealed by quantitative fluorescence in situ hybridization. Material from individuals aged 0–20 years from years 2013/2014, 2011/2012, 2009/2010, and 2008 were compared for storage effect. Telomere integrity was assessed by telomere fluorescence intensity (TFI). Epithelial TCRs (mean ± SD) for the respective age groups were 4.84 ± 2.08, 3.64 ± 1.21, 2.03 ± 0.37, and 1.93 ± 0.45, whereas corresponding stromal TCRs were 5.16 ± 2.55, 3.84 ± 1.36, 2.49 ± 1.20, and 2.93 ± 1.24. A trend of inverse correlation with age in both epithelial and stromal tissues is supported by r = -0.69, p < 0.001 and r = -0.42, p < 0.001 respectively. Epithelial TFIs (mean ± SD) of years 2013/2014, 2011/2012, 2009/2010 and 2008 were 852.60 ± 432.46, 353.04 ± 127.12, 209.24 ± 55.57 and 429.22 ± 188.75 respectively. Generally, TFIs reduced with storage duration (r = -0.42, p < 0.001). Our findings agree that age-related telomere attrition occurs in normal somatic tissues, and suggest that an age-based reference can be established for telomere studies on FFPE tissues. We also showed that FFPE tissues archived beyond 2 years are suboptimal for telomere analysis. PMID:27598341

  18. Assessment of Telomere Length in Archived Formalin-Fixed, Paraffinized Human Tissue Is Confounded by Chronological Age and Storage Duration.

    PubMed

    Kong, Po-Lian; Looi, Lai-Meng; Lau, Tze-Pheng; Cheah, Phaik-Leng

    2016-01-01

    Telomeres shorten with physiological aging but undergo substantial restoration during cancer immortalization. Increasingly, cancer studies utilize the archive of formalin-fixed, paraffin-embedded (FFPE) tissues in diagnostic pathology departments. Conceptually, such studies would be confounded by physiological telomere attrition and loss of DNA integrity from prolonged tissue storage. Our study aimed to investigate these two confounding factors. 145 FFPE tissues of surgically-resected, non-diseased appendixes were retrieved from our pathology archive, from years 2008 to 2014. Cases from 2013 to 2014 were categorized by patient chronological age (0-20 years, 21-40 years, 41-60 years, > 60 years). Telomere lengths of age categories were depicted by telomere/chromosome 2 centromere intensity ratio (TCR) revealed by quantitative fluorescence in situ hybridization. Material from individuals aged 0-20 years from years 2013/2014, 2011/2012, 2009/2010, and 2008 were compared for storage effect. Telomere integrity was assessed by telomere fluorescence intensity (TFI). Epithelial TCRs (mean ± SD) for the respective age groups were 4.84 ± 2.08, 3.64 ± 1.21, 2.03 ± 0.37, and 1.93 ± 0.45, whereas corresponding stromal TCRs were 5.16 ± 2.55, 3.84 ± 1.36, 2.49 ± 1.20, and 2.93 ± 1.24. A trend of inverse correlation with age in both epithelial and stromal tissues is supported by r = -0.69, p < 0.001 and r = -0.42, p < 0.001 respectively. Epithelial TFIs (mean ± SD) of years 2013/2014, 2011/2012, 2009/2010 and 2008 were 852.60 ± 432.46, 353.04 ± 127.12, 209.24 ± 55.57 and 429.22 ± 188.75 respectively. Generally, TFIs reduced with storage duration (r = -0.42, p < 0.001). Our findings agree that age-related telomere attrition occurs in normal somatic tissues, and suggest that an age-based reference can be established for telomere studies on FFPE tissues. We also showed that FFPE tissues archived beyond 2 years are suboptimal for telomere analysis. PMID:27598341

  19. Molecular basis of telomere dysfunction in human genetic diseases.

    PubMed

    Sarek, Grzegorz; Marzec, Paulina; Margalef, Pol; Boulton, Simon J

    2015-11-01

    Mutations in genes encoding proteins required for telomere structure, replication, repair and length maintenance are associated with several debilitating human genetic disorders. These complex telomere biology disorders (TBDs) give rise to critically short telomeres that affect the homeostasis of multiple organs. Furthermore, genome instability is often a hallmark of telomere syndromes, which are associated with increased cancer risk. Here, we summarize the molecular causes and cellular consequences of disease-causing mutations associated with telomere dysfunction.

  20. Single-cell telomere-length quantification couples telomere length to meristem activity and stem cell development in Arabidopsis.

    PubMed

    González-García, Mary-Paz; Pavelescu, Irina; Canela, Andrés; Sevillano, Xavier; Leehy, Katherine A; Nelson, Andrew D L; Ibañes, Marta; Shippen, Dorothy E; Blasco, Maria A; Caño-Delgado, Ana I

    2015-05-12

    Telomeres are specialized nucleoprotein caps that protect chromosome ends assuring cell division. Single-cell telomere quantification in animals established a critical role for telomerase in stem cells, yet, in plants, telomere-length quantification has been reported only at the organ level. Here, a quantitative analysis of telomere length of single cells in Arabidopsis root apex uncovered a heterogeneous telomere-length distribution of different cell lineages showing the longest telomeres at the stem cells. The defects in meristem and stem cell renewal observed in tert mutants demonstrate that telomere lengthening by TERT sets a replicative limit in the root meristem. Conversely, the long telomeres of the columella cells and the premature stem cell differentiation plt1,2 mutants suggest that differentiation can prevent telomere erosion. Overall, our results indicate that telomere dynamics are coupled to meristem activity and continuous growth, disclosing a critical association between telomere length, stem cell function, and the extended lifespan of plants.

  1. Maternal telomere length inheritance in the king penguin

    PubMed Central

    Reichert, S; Rojas, E R; Zahn, S; Robin, J-P; Criscuolo, F; Massemin, S

    2015-01-01

    Telomeres are emerging as a biomarker for ageing and survival, and are likely important in shaping life-history trade-offs. In particular, telomere length with which one starts in life has been linked to lifelong survival, suggesting that early telomere dynamics are somehow related to life-history trajectories. This result highlights the importance of determining the extent to which telomere length is inherited, as a crucial factor determining early life telomere length. Given the scarcity of species for which telomere length inheritance has been studied, it is pressing to assess the generality of telomere length inheritance patterns. Further, information on how this pattern changes over the course of growth in individuals living under natural conditions should provide some insight on the extent to which environmental constraints also shape telomere dynamics. To fill this gap partly, we followed telomere inheritance in a population of king penguins (Aptenodytes patagonicus). We tested for paternal and maternal influence on chick initial telomere length (10 days old after hatching), and how these relationships changed with chick age (at 70, 200 and 300 days old). Based on a correlative approach, offspring telomere length was positively associated with maternal telomere length early in life (at 10 days old). However, this relationship was not significant at older ages. These data suggest that telomere length in birds is maternally inherited. Nonetheless, the influence of environmental conditions during growth remained an important factor shaping telomere length, as the maternal link disappeared with chicks' age. PMID:25052413

  2. Maternal telomere length inheritance in the king penguin.

    PubMed

    Reichert, S; Rojas, E R; Zahn, S; Robin, J-P; Criscuolo, F; Massemin, S

    2015-01-01

    Telomeres are emerging as a biomarker for ageing and survival, and are likely important in shaping life-history trade-offs. In particular, telomere length with which one starts in life has been linked to lifelong survival, suggesting that early telomere dynamics are somehow related to life-history trajectories. This result highlights the importance of determining the extent to which telomere length is inherited, as a crucial factor determining early life telomere length. Given the scarcity of species for which telomere length inheritance has been studied, it is pressing to assess the generality of telomere length inheritance patterns. Further, information on how this pattern changes over the course of growth in individuals living under natural conditions should provide some insight on the extent to which environmental constraints also shape telomere dynamics. To fill this gap partly, we followed telomere inheritance in a population of king penguins (Aptenodytes patagonicus). We tested for paternal and maternal influence on chick initial telomere length (10 days old after hatching), and how these relationships changed with chick age (at 70, 200 and 300 days old). Based on a correlative approach, offspring telomere length was positively associated with maternal telomere length early in life (at 10 days old). However, this relationship was not significant at older ages. These data suggest that telomere length in birds is maternally inherited. Nonetheless, the influence of environmental conditions during growth remained an important factor shaping telomere length, as the maternal link disappeared with chicks' age. PMID:25052413

  3. Maternal telomere length inheritance in the king penguin.

    PubMed

    Reichert, S; Rojas, E R; Zahn, S; Robin, J-P; Criscuolo, F; Massemin, S

    2015-01-01

    Telomeres are emerging as a biomarker for ageing and survival, and are likely important in shaping life-history trade-offs. In particular, telomere length with which one starts in life has been linked to lifelong survival, suggesting that early telomere dynamics are somehow related to life-history trajectories. This result highlights the importance of determining the extent to which telomere length is inherited, as a crucial factor determining early life telomere length. Given the scarcity of species for which telomere length inheritance has been studied, it is pressing to assess the generality of telomere length inheritance patterns. Further, information on how this pattern changes over the course of growth in individuals living under natural conditions should provide some insight on the extent to which environmental constraints also shape telomere dynamics. To fill this gap partly, we followed telomere inheritance in a population of king penguins (Aptenodytes patagonicus). We tested for paternal and maternal influence on chick initial telomere length (10 days old after hatching), and how these relationships changed with chick age (at 70, 200 and 300 days old). Based on a correlative approach, offspring telomere length was positively associated with maternal telomere length early in life (at 10 days old). However, this relationship was not significant at older ages. These data suggest that telomere length in birds is maternally inherited. Nonetheless, the influence of environmental conditions during growth remained an important factor shaping telomere length, as the maternal link disappeared with chicks' age.

  4. Telomere length and heredity: Indications of paternal inheritance.

    PubMed

    Nordfjäll, Katarina; Larefalk, Asa; Lindgren, Petter; Holmberg, Dan; Roos, Göran

    2005-11-01

    Cellular telomere length is linked to replicative life span. Telomere repeats are lost in peripheral blood cells in vivo by age, and women show less telomere attrition than men. Previous reports have indicated that telomere length and chromosome-specific telomere-length patterns partly are inherited. The mode of heredity has not been clarified, but a link to the X chromosome was recently suggested. We analyzed peripheral mononuclear cells from 49 unrelated families for telomere length using a real-time PCR method. Short-term cultured Epstein-Barr virus-transformed lymphoblasts from the same individuals (n = 130) were analyzed for ability to maintain telomere length and possible gender-linked inheritance. A statistically significant association between telomere lengths comparing father-son (P = 0.011, n = 20) and father-daughter (P = 0.005, n = 22) pairs was found. However, no correlation was observed between mother-daughter (P = 0.463, n = 23) or mother-son (P = 0.577, n = 18). The father-offspring correlation was highly significant (P < 0.0001), in contrast to mother-offspring (P = 0.361). Epstein-Barr virus cultures demonstrated in most cases telomere preservation inversely related to initial mononuclear cell telomere length with short telomeres displaying the most pronounced elongation. Telomere length is inherited, and evidence for a father-to-offspring heritage of this trait was obtained, whereas in vitro telomere length maintenance was found to be dependent on the initial telomere length.

  5. Genome-wide association study of relative telomere length.

    PubMed

    Prescott, Jennifer; Kraft, Peter; Chasman, Daniel I; Savage, Sharon A; Mirabello, Lisa; Berndt, Sonja I; Weissfeld, Joel L; Han, Jiali; Hayes, Richard B; Chanock, Stephen J; Hunter, David J; De Vivo, Immaculata

    2011-05-10

    Telomere function is essential to maintaining the physical integrity of linear chromosomes and healthy human aging. The probability of forming proper telomere structures depends on the length of the telomeric DNA tract. We attempted to identify common genetic variants associated with log relative telomere length using genome-wide genotyping data on 3,554 individuals from the Nurses' Health Study and the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial that took part in the National Cancer Institute Cancer Genetic Markers of Susceptibility initiative for breast and prostate cancer. After genotyping 64 independent SNPs selected for replication in additional Nurses' Health Study and Women's Genome Health Study participants, we did not identify genome-wide significant loci; however, we replicated the inverse association of log relative telomere length with the minor allele variant [C] of rs16847897 at the TERC locus (per allele β = -0.03, P = 0.003) identified by a previous genome-wide association study. We did not find evidence for an association with variants at the OBFC1 locus or other loci reported to be associated with telomere length. With this sample size we had >80% power to detect β estimates as small as ±0.10 for SNPs with minor allele frequencies of ≥0.15 at genome-wide significance. However, power is greatly reduced for β estimates smaller than ±0.10, such as those for variants at the TERC locus. In general, common genetic variants associated with telomere length homeostasis have been difficult to detect. Potential biological and technical issues are discussed.

  6. Arsenic exposure through drinking water leads to senescence and alteration of telomere length in humans: A case-control study in West Bengal, India.

    PubMed

    Chatterjee, Debmita; Bhattacharjee, Pritha; Sau, Tanmoy J; Das, Jayanta K; Sarma, Nilendu; Bandyopadhyay, Apurba K; Roy, Sib Sankar; Giri, Ashok K

    2015-09-01

    Arsenic (As) induces pre-malignant and malignant dermatological lesions, non-dermatological health effects and cancers in humans. Senescence involves telomere length changes and acquisition of senescence-associated secretory phenotype (SASP), which promotes carcinogenesis. Though in vitro studies have shown that As induces senescence, population based studies are lacking. We investigated the arsenic-induced senescence, telomere length alteration and its contribution towards development of As-induced skin cancer. The study participants included 60 each of As-exposed individuals with skin lesion (WSL), without skin lesions (WOSL) and 60 unexposed controls. Exposure assessment of drinking water and urine was done. SA β-gal activity, ELISA, and quantification of senescence proteins, alternative lengthening of telomere (ALT) associated proteins and telomerase activity were performed. Relative telomere length (RTL) was determined by qPCR. A significantly higher number of senescent cells, over-expression of p53 and p21 were observed in the As-exposed individuals when compared to unexposed. SASP markers, MMP-1/MMP-3 were significantly higher in the WSL but not IL-6/IL-8. A significant increase of RTL was observed in the WSL group, which was telomerase-independent but exhibited an over-expression of ALT associated proteins TRF-1 and TRF-2 with higher increase in TRF-2. An increased risk for developing As-induced skin lesions was found for individuals having RTL greater than 0.827 (odds ratio, 13.75; 95% CI: 5.66-33.41; P < 0.0001). Arsenic induces senescence in vivo, but the SASP markers are not strictly over-expressed in the As-induced skin lesion group, whereas telomerase-independent elongation of telomere length might be useful for predicting the risk of development of As-induced skin lesions.

  7. The association of telomere length and genetic variation in telomere biology genes.

    PubMed

    Mirabello, Lisa; Yu, Kai; Kraft, Peter; De Vivo, Immaculata; Hunter, David J; Prescott, Jennifer; Wong, Jason Y Y; Chatterjee, Nilanjan; Hayes, Richard B; Savage, Sharon A

    2010-09-01

    Telomeres cap chromosome ends and are critical for genomic stability. Many telomere-associated proteins are important for telomere length maintenance. Recent genome-wide association studies (GWAS) have identified single nucleotide polymorphisms (SNPs) in genes encoding telomere-associated proteins (RTEL1 and TERT-CLPTM1) as markers of cancer risk. We conducted an association study of telomere length and 743 SNPs in 43 telomere biology genes. Telomere length in peripheral blood DNA was determined by Q-PCR in 3,646 participants from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial and Nurses' Health Study. We investigated associations by SNP, gene, and pathway (functional group). We found no associations between telomere length and SNPs in TERT-CLPTM1L or RTEL1. Telomere length was not significantly associated with specific functional groups. Thirteen SNPs from four genes (MEN1, MRE11A, RECQL5, and TNKS) were significantly associated with telomere length. The strongest findings were in MEN1 (gene-based P=0.006), menin, which associates with the telomerase promoter and may negatively regulate telomerase. This large association study did not find strong associations with telomere length. The combination of limited diversity and evolutionary conservation suggest that these genes may be under selective pressure. More work is needed to explore the role of genetic variants in telomere length regulation.

  8. Nestling telomere shortening, but not telomere length, reflects developmental stress and predicts survival in wild birds.

    PubMed

    Boonekamp, Jelle J; Mulder, G A; Salomons, H Martijn; Dijkstra, Cor; Verhulst, Simon

    2014-06-22

    Developmental stressors often have long-term fitness consequences, but linking offspring traits to fitness prospects has remained a challenge. Telomere length predicts mortality in adult birds, and may provide a link between developmental conditions and fitness prospects. Here, we examine the effects of manipulated brood size on growth, telomere dynamics and post-fledging survival in free-living jackdaws. Nestlings in enlarged broods achieved lower mass and lost 21% more telomere repeats relative to nestlings in reduced broods, showing that developmental stress accelerates telomere shortening. Adult telomere length was positively correlated with their telomere length as nestling (r = 0.83). Thus, an advantage of long telomeres in nestlings is carried through to adulthood. Nestling telomere shortening predicted post-fledging survival and recruitment independent of manipulation and fledgling mass. This effect was strong, with a threefold difference in recruitment probability over the telomere shortening range. By contrast, absolute telomere length was neither affected by brood size manipulation nor related to survival. We conclude that telomere loss, but not absolute telomere length, links developmental conditions to subsequent survival and suggest that telomere shortening may provide a key to unravelling the physiological causes of developmental effects on fitness.

  9. Extreme Telomere Length Dimorphism in the Tasmanian Devil and Related Marsupials Suggests Parental Control of Telomere Length

    PubMed Central

    Bender, Hannah S.; Murchison, Elizabeth P.; Pickett, Hilda A.; Deakin, Janine E.; Strong, Margaret A.; Conlan, Carly; McMillan, Daniel A.; Neumann, Axel A.; Greider, Carol W.; Hannon, Gregory J.; Reddel, Roger R.; Graves, Jennifer A. Marshall.

    2012-01-01

    Telomeres, specialised structures that protect chromosome ends, play a critical role in preserving chromosome integrity. Telomere dynamics in the Tasmanian devil (Sarcophilus harrisii) are of particular interest in light of the emergence of devil facial tumour disease (DFTD), a transmissible malignancy that causes rapid mortality and threatens the species with extinction. We used fluorescent in situ hybridisation to investigate telomere length in DFTD cells, in healthy Tasmanian devils and in four closely related marsupial species. Here we report that animals in the Order Dasyuromorphia have chromosomes characterised by striking telomere length dimorphism between homologues. Findings in sex chromosomes suggest that telomere length dimorphism may be regulated by events in the parental germlines. Long telomeres on the Y chromosome imply that telomere lengthening occurs during spermatogenesis, whereas telomere diminution occurs during oogenesis. Although found in several somatic cell tissue types, telomere length dimorphism was not found in DFTD cancer cells, which are characterised by uniformly short telomeres. This is, to our knowledge, the first report of naturally occurring telomere length dimorphism in any species and suggests a novel strategy of telomere length control. Comparative studies in five distantly related marsupials and a monotreme indicate that telomere dimorphism evolved at least 50 million years ago. PMID:23049977

  10. The human telomere

    SciTech Connect

    Moyzis, R.K.

    1989-01-01

    An ultimate goal of human genetics is the generation of a complete physical and ''functional'' map of the human genome. Twenty-five percent of human DNA, however, consists of repetitive DNA sequences. These repetitive DNA sequences are thought to arise by many mechanisms, from direct sequence amplification by the unequal recombination of homologous DNA regions to the reverse flow of genetic information. A general outline of the chromosomal organization of these repetitive sequences will be discussed. Our working hypothesis is that certain classes of human repetitive DNA sequences ''encode'' the information necessary for defining long-range genomic structure. Evidence will be presented that the first goal of this research, the identification and cloning of the human telomere, has been achieved. A human repetitive DNA library was constructed from randomly sheared, reassociated, and oligo(G/center dot/C)-tailed DNA, a method that minimizes the potential loss of sequences devoid of a given restriction enzyme site. Sequences too large to clone efficiently in cosmid or /lambda/ vectors, such as centromeric repeats, or telomeric sequences with an end incompatible for cloning, should be present in this library. In order to isolate highly conserved repetitive DNA sequences, this library was screened with radiolabeled hamster Cot50 repetitive DNA. Two clones, containing tandem arrays of the sequence (TTAGGG), were isolated by this method. 30 refs., 1 fig., 2 tabs.

  11. Genetic variation in telomere maintenance genes, telomere length, and lung cancer susceptibility.

    PubMed

    Hosgood, H Dean; Cawthon, Richard; He, Xingzhou; Chanock, Stephen; Lan, Qing

    2009-11-01

    Telomeres are responsible for the protection of the chromosome ends and shortened telomere length has been associated with risk of multiple cancers. Genetic variation in telomere-related genes may alter cancer risk associated with telomere length. Using lung cancer cases (n=120) and population-based controls (n=110) from Xuanwei, China, we analyzed telomere length separately and in conjunction with single nucleotide polymorphisms in the telomere maintenance genes POT1, TERT, and TERF2, which we have previously reported were associated with risk of lung cancer in this study. POT1 rs10244817, TERT rs2075786, and TERF2 rs251796 were significantly associated with lung cancer (p(trend)< or =0.05). The shortest tertile of telomere length was not significantly associated with risk of lung cancer (OR=1.58; 95% CI=0.79-3.18) when compared to the longest tertile of telomere length. When stratified by genotype, there was a suggestion of a dose-response relationship between tertiles of telomere length and risk of lung cancer among the POT1 rs10244817 common variant carriers (OR (95% CI)=1.33 (0.47-3.75), 3.30 (1.14-9.56), respectively) but not among variant genotype carriers (p(interaction)=0.05). Our findings provide evidence that telomere length and genetic variation in telomere maintenance genes may be associated with risk of lung cancer susceptibility and warrant replication in larger studies.

  12. Paternal age and telomere length in twins: the germ stem cell selection paradigm.

    PubMed

    Hjelmborg, Jacob B; Dalgård, Christine; Mangino, Massimo; Spector, Tim D; Halekoh, Ulrich; Möller, Sören; Kimura, Masayuki; Horvath, Kent; Kark, Jeremy D; Christensen, Kaare; Kyvik, Kirsten O; Aviv, Abraham

    2015-08-01

    Telomere length, a highly heritable trait, is longer in offspring of older fathers. This perplexing feature has been attributed to the longer telomeres in sperm of older men and it might be an 'epigenetic' mechanism through which paternal age plays a role in telomere length regulation in humans. Based on two independent (discovery and replication) twin studies, comprising 889 twin pairs, we show an increase in the resemblance of leukocyte telomere length between dizygotic twins of older fathers, which is not seen in monozygotic twins. This phenomenon might result from a paternal age-dependent germ stem cell selection process, whereby the selected stem cells have longer telomeres, are more homogenous with respect to telomere length, and share resistance to aging.

  13. Telomere Length: A Review of Methods for Measurement

    PubMed Central

    Montpetit, Alison J.; Alhareeri, Areej A.; Montpetit, Marty; Starkweather, Angela R.; Elmore, Lynne W.; Filler, Kristin; Mohanraj, Lathika; Burton, Candace W.; Menzies, Victoria S.; Lyon, Debra E.; Collins, Judith B.; Teefey, Joseph M.; Jackson-Cook, Colleen K.

    2014-01-01

    Background The exciting discovery that telomere shortening is associated with many health conditions, and that telomere lengths can be altered in response to social and environmental exposures, has underscored the need for methods to accurately and consistently quantify telomere length. Objectives The purpose of this paper is to provide a comprehensive summary that compares and contrasts the current technologies used to assess telomere length. Discussion Multiple methods have been developed for the study of telomeres. These techniques include quantification of telomere length by terminal restriction fragmentation—which was one of the earliest tools used for length assessment—making it the gold standard in telomere biology. Quantitative-PCR provides the advantage of being able to use smaller amounts of DNA, thereby making it amenable to epidemiology studies involving large numbers of people. An alternative method uses fluorescent probes to quantify not only mean telomere lengths, but also chromosome-specific telomere lengths; however, the downside of this approach is that it can only be used on mitotically active cells. Additional methods that permit assessment of the length of a subset of chromosome-specific telomeres, or the subset of telomeres that demonstrate shortening, are also reviewed. Conclusion Given the increased utility for telomere assessments as a biomarker in physiological, psychological and biobehavioral research, it is important that investigators become familiar with the methodological nuances of the various procedures used for measuring telomere length. This will ensure that they are empowered to select an optimal assessment approach to meet the needs of their study designs. Gaining a better understanding of the benefits and drawbacks of various measurement techniques is important not only in individual studies, but also to further establish the science of telomere associations with biobehavioral phenomena. PMID:24977726

  14. Telomere Length Measurement - caveats and a critical assessment of the available technologies and tools

    PubMed Central

    Aubert, Geraldine; Hills, Mark; Lansdorp, Peter M.

    2012-01-01

    Studies of telomeres and telomere biology often critically rely on the detection of telomeric DNA and measurements of the length of telomere repeats in either single cells or populations of cells. Several methods are available that provide this type of information and it is often not clear what method is most appropriate to address a specific research question. The major variables that need to be considered are the material that is or can be made available and the accuracy of measurements that is required. The goal of this review is to provide a comprehensive summary of the most commonly used methods and discuss the advantages and disadvantages of each. Methods that start with genomic DNA include telomere restriction fragment (TRF) length analysis, PCR amplification of telomere repeats relative to a single copy gene by Q-PCR or MMQPCR and single telomere length analysis (STELA), a PCR-based approach that accurately measures the full spectrum of telomere lengths from individual chromosomes. A different set of methods relies on fluorescent in situ hybridization (FISH) to detect telomere repeats in individual cells or chromosomes. By including essential calibration steps and appropriate controls these methods can be used to measure telomere repeat length or content in chromosomes and cells. Such methods include quantitative FISH (Q-FISH) and flow FISH which are based on digital microscopy and flow cytometry respectively. Here the basic principles of various telomere length measurement methods are described and their strengths and weaknesses are highlighted. Some recent developments in telomere length analysis are also discussed. The information in this review should facilitate the selection of the most suitable method to address specific research question about telomeres in either model organisms or human subjects. PMID:21663926

  15. Telomere length and the risk of lung cancer.

    PubMed

    Jang, Jin Sung; Choi, Yi Young; Lee, Won Kee; Choi, Jin Eun; Cha, Sung Ick; Kim, Yeon Jae; Kim, Chang Ho; Kam, Sin; Jung, Tae Hoon; Park, Jae Yong

    2008-07-01

    Telomeres play a key role in the maintenance of chromosome integrity and stability. There is growing evidence that short telomeres induce chromosome instability and thereby promote the development of cancer. We investigated the association of telomere length and the risk of lung cancer. Relative telomere length in peripheral blood lymphocytes was measured by quantitative polymerase chain reaction in 243 lung cancer patients and 243 healthy controls that were frequency-matched for age, sex and smoking status. Telomere length was significantly shorter in lung cancer patients than in controls (mean +/- standard deviation: 1.59 +/- 0.75 versus 2.16 +/- 1.10, P < 0.0001). When the subjects were categorized into quartiles based on telomere length, the risk of lung cancer was found to increase as telomere length shortened (P(trend) < 0.0001). In addition, when the median of telomere length was used as the cutoff between long and short telomeres, individuals with short telomeres were at a significantly higher risk of lung cancer than those with long telomeres (adjusted odds ratio = 3.15, 95% confidence interval = 2.12-4.67, P < 0.0001). When the cases were categorized by tumor histology, the effect of short telomere length on the risk of lung cancer was more pronounced in patients with small cell carcinoma than in those with squamous cell carcinoma and adenocarcinoma (P = 0.001, test for homogeneity). These findings suggest that shortening of the telomeres may be a risk factor for lung cancer, and therefore, the presence of shortened telomeres may be used as a marker for susceptibility to lung cancer.

  16. Does Reproductive Investment Decrease Telomere Length in Menidia menidia?

    PubMed Central

    Gao, Jin; Munch, Stephan B.

    2015-01-01

    Given finite resources, intense investment in one life history trait is expected to reduce investment in others. Although telomere length appears to be strongly tied to age in many taxa, telomere maintenance requires energy. We therefore hypothesize that telomere maintenance may trade off against other life history characters. We used natural variation in laboratory populations of Atlantic silversides (Menidia menidia) to study the relationship between growth, fecundity, life expectancy, and relative telomere length. In keeping with several other studies on fishes, we found no clear dependence of telomere length on age. However, we did find that more fecund fish tended to have both reduced life expectancy and shorter telomeres. This result is consistent with the hypothesis that there is a trade-off between telomere maintenance and reproductive output. PMID:25938489

  17. Maternal and genetic factors determine early life telomere length

    PubMed Central

    Asghar, Muhammad; Bensch, Staffan; Tarka, Maja; Hansson, Bengt; Hasselquist, Dennis

    2015-01-01

    In a broad range of species—including humans—it has been demonstrated that telomere length declines throughout life and that it may be involved in cell and organismal senescence. This potential link to ageing and thus to fitness has triggered recent interest in understanding how variation in telomere length is inherited and maintained. However, previous studies suffer from two main drawbacks that limit the possibility of understanding the relative importance of genetic, parental and environmental influences on telomere length variation. These studies have been based on (i) telomere lengths measured at different time points in different individuals, despite the fact that telomere length changes over life, and (ii) parent–offspring regression techniques, which do not enable differentiation between genetic and parental components of inheritance. To overcome these drawbacks, in our study of a songbird, the great reed warbler, we have analysed telomere length measured early in life in both parents and offspring and applied statistical models (so-called ‘animal models') that are based on long-term pedigree data. Our results showed a significant heritability of telomere length on the maternal but not on the paternal side, and that the mother's age was positively correlated with their offspring's telomere length. Furthermore, the pedigree-based analyses revealed a significant heritability and an equally large maternal effect. Our study demonstrates strong maternal influence on telomere length and future studies now need to elucidate possible underlying factors, including which types of maternal effects are involved. PMID:25621325

  18. Assessing Telomere Length Using Surface Enhanced Raman Scattering

    NASA Astrophysics Data System (ADS)

    Zong, Shenfei; Wang, Zhuyuan; Chen, Hui; Cui, Yiping

    2014-11-01

    Telomere length can provide valuable insight into telomeres and telomerase related diseases, including cancer. Here, we present a brand-new optical telomere length measurement protocol using surface enhanced Raman scattering (SERS). In this protocol, two single strand DNA are used as SERS probes. They are labeled with two different Raman molecules and can specifically hybridize with telomeres and centromere, respectively. First, genome DNA is extracted from cells. Then the telomere and centromere SERS probes are added into the genome DNA. After hybridization with genome DNA, excess SERS probes are removed by magnetic capturing nanoparticles. Finally, the genome DNA with SERS probes attached is dropped onto a SERS substrate and subjected to SERS measurement. Longer telomeres result in more attached telomere probes, thus a stronger SERS signal. Consequently, SERS signal can be used as an indicator of telomere length. Centromere is used as the inner control. By calibrating the SERS intensity of telomere probe with that of the centromere probe, SERS based telomere measurement is realized. This protocol does not require polymerase chain reaction (PCR) or electrophoresis procedures, which greatly simplifies the detection process. We anticipate that this easy-operation and cost-effective protocol is a fine alternative for the assessment of telomere length.

  19. ATM kinase is required for telomere elongation in mouse and human cells

    PubMed Central

    Lee, Stella Suyong; Bohrson, Craig; Pike, Alexandra Mims; Wheelan, Sarah Jo; Greider, Carol Widney

    2015-01-01

    Summary Short telomeres induce a DNA damage response, senescence and apoptosis; thus, maintaining telomere length equilibrium is essential for cell viability. Telomerase addition of telomere repeats is tightly regulated in cells. To probe pathways that regulate telomere addition, we developed the ADDIT assay to measure new telomere addition at a single telomere in vivo. Sequence analysis showed telomerase specific addition of repeats onto a new telomere occurred in just 48 hr. Using the ADDIT assay, we found that ATM is required for addition of new repeats onto telomeres in mouse cells. Evaluation of bulk telomeres, in both human and mouse cells, showed that blocking ATM inhibited telomere elongation. Finally, the activation of ATM through the inhibition of PARP1 resulted in increased telomere elongation, supporting the central role of the ATM pathway in regulating telomere addition. Understanding this role of ATM may yield new areas for possible therapeutic intervention in telomere-mediated disease. PMID:26586427

  20. ATM Kinase Is Required for Telomere Elongation in Mouse and Human Cells.

    PubMed

    Lee, Stella Suyong; Bohrson, Craig; Pike, Alexandra Mims; Wheelan, Sarah Jo; Greider, Carol Widney

    2015-11-24

    Short telomeres induce a DNA damage response, senescence, and apoptosis, thus maintaining telomere length equilibrium is essential for cell viability. Telomerase addition of telomere repeats is tightly regulated in cells. To probe pathways that regulate telomere addition, we developed the ADDIT assay to measure new telomere addition at a single telomere in vivo. Sequence analysis showed telomerase-specific addition of repeats onto a new telomere occurred in just 48 hr. Using the ADDIT assay, we found that ATM is required for addition of new repeats onto telomeres in mouse cells. Evaluation of bulk telomeres, in both human and mouse cells, showed that blocking ATM inhibited telomere elongation. Finally, the activation of ATM through the inhibition of PARP1 resulted in increased telomere elongation, supporting the central role of the ATM pathway in regulating telomere addition. Understanding this role of ATM may yield new areas for possible therapeutic intervention in telomere-mediated disease.

  1. Telomere length in Hutchinson-Gilford progeria syndrome.

    PubMed

    Decker, Michelle L; Chavez, Elizabeth; Vulto, Irma; Lansdorp, Peter M

    2009-06-01

    Hutchinson-Gilford Progeria Syndrome (HGPS) is a rare premature aging disorder caused by mutations in the gene LMNA, which encodes the nuclear matrix protein lamin A. Previous research has shown that the average telomere length in fibroblasts from HGPS patients is shorter than in age-matched controls. How mutations in lamin A lead to shortened telomere lengths is not known nor is the contribution of individual chromosome ends to the low average length understood. To measure the telomere length of individual chromosomes, we used quantitative fluorescence in situ hybridization (Q-FISH). In agreement with previous studies, we found that the average telomere length in HPGS fibroblasts is greatly reduced; however, the telomere length at chromosome ends was variable. In contrast, the telomere length in hematopoietic cells which typically do not express lamin A, was within the normal range for three out of four HGPS patient samples. Our results suggest that mutant lamin A decreases telomere length via a direct effect and that expression of mutant LMNA is necessary for telomere loss in HGPS.

  2. Benign metastasizing leiomyoma: clonality, telomere length and clinicopathologic analysis.

    PubMed

    Patton, Kurt T; Cheng, Liang; Papavero, Veronica; Blum, Matthew G; Yeldandi, Anjana V; Adley, Brian P; Luan, Chunyan; Diaz, Leslie K; Hui, Pei; Yang, Ximing J

    2006-01-01

    Benign metastasizing leiomyoma is a rare condition affecting women with a history of uterine leiomyomata and is characterized by multiple histologically benign pulmonary smooth muscle tumors. Speculations on its pathogenesis include a benign uterine leiomyoma colonizing the lung, a metastatic low-grade uterine leiomyosarcoma, and primary pulmonary leiomyomatosis. To elucidate its pathogenesis, we analyzed the clinical, pathological and immunohistochemical features, clonality, and telomere length of multiple lung and uterine tumors in three patients with benign metastasizing leiomyoma. In all cases, pulmonary tumors had benign histology and immunohistochemical profiles (estrogen receptor positive, progesterone receptor positive, and very low proliferative index) identical to uterine leiomyoma. In eight tumors from three patients, clonality was assessed by analyzing the variable length of the polymorphic CAG repeat sequence within the human androgen receptor gene. In the two informative patients pulmonary and uterine tumors showed identical patterns of androgen receptor allelic inactivation, indicating that they were clonal. The telomere length measured by fluorescence in situ hybridization in pulmonary leiomyomas of all three patients were either long or very long and were identical to the uterine counterparts, indicating significant telomere shortening is not a crucial step for developing metastases. Our evidence supports the notion that benign metastasizing leiomyoma is clonally derived from benign-appearing uterine leiomyomas.

  3. Socioecological variables predict telomere length in wild spotted hyenas.

    PubMed

    Lewin, Nora; Treidel, Lisa A; Holekamp, Kay E; Place, Ned J; Haussmann, Mark F

    2015-02-01

    Telomeres are regarded as important biomarkers of ageing and serve as useful tools in revealing how stress acts at the cellular level. However, the effects of social and ecological factors on telomere length remain poorly understood, particularly in free-ranging mammals. Here, we investigated the influences of within-group dominance rank and group membership on telomere length in wild adult spotted hyenas (Crocuta crocuta). We found large effects of both factors; high-ranking hyenas exhibited significantly greater mean telomere length than did subordinate animals, and group membership significantly predicted mean telomere length within high-ranking females. We further inquired whether prey availability mediates the observed effect of group membership on telomere length, but this hypothesis was not supported. Interestingly, adult telomere length was not predicted by age. Our work shows for the first time, to the best of our knowledge, the effects of social rank on telomere length in a wild mammal and enhances our understanding of how social and ecological variables may contribute to organismal senescence. PMID:25716089

  4. Socioecological variables predict telomere length in wild spotted hyenas.

    PubMed

    Lewin, Nora; Treidel, Lisa A; Holekamp, Kay E; Place, Ned J; Haussmann, Mark F

    2015-02-01

    Telomeres are regarded as important biomarkers of ageing and serve as useful tools in revealing how stress acts at the cellular level. However, the effects of social and ecological factors on telomere length remain poorly understood, particularly in free-ranging mammals. Here, we investigated the influences of within-group dominance rank and group membership on telomere length in wild adult spotted hyenas (Crocuta crocuta). We found large effects of both factors; high-ranking hyenas exhibited significantly greater mean telomere length than did subordinate animals, and group membership significantly predicted mean telomere length within high-ranking females. We further inquired whether prey availability mediates the observed effect of group membership on telomere length, but this hypothesis was not supported. Interestingly, adult telomere length was not predicted by age. Our work shows for the first time, to the best of our knowledge, the effects of social rank on telomere length in a wild mammal and enhances our understanding of how social and ecological variables may contribute to organismal senescence.

  5. Human RECQL1 participates in telomere maintenance.

    PubMed

    Popuri, Venkateswarlu; Hsu, Joseph; Khadka, Prabhat; Horvath, Kent; Liu, Yie; Croteau, Deborah L; Bohr, Vilhelm A

    2014-05-01

    A variety of human tumors employ alternative and recombination-mediated lengthening for telomere maintenance (ALT). Human RecQ helicases, such as BLM and WRN, can efficiently unwind alternate/secondary structures during telomere replication and/or recombination. Here, we report a novel role for RECQL1, the most abundant human RecQ helicase but functionally least studied, in telomere maintenance. RECQL1 associates with telomeres in ALT cells and actively resolves telomeric D-loops and Holliday junction substrates. RECQL1 physically and functionally interacts with telomere repeat-binding factor 2 that in turn regulates its helicase activity on telomeric substrates. The telomeric single-stranded binding protein, protection of telomeres 1 efficiently stimulates RECQL1 on telomeric substrates containing thymine glycol, a replicative blocking lesion. Loss of RECQL1 results in dysfunctional telomeres, telomere loss and telomere shortening, elevation of telomere sister-chromatid exchanges and increased aphidicolin-induced telomere fragility, indicating a role for RECQL1 in telomere maintenance. Further, our results indicate that RECQL1 may participate in the same pathway as WRN, probably in telomere replication.

  6. Do telomeres adapt to physiological stress? Exploring the effect of exercise on telomere length and telomere-related proteins.

    PubMed

    Ludlow, Andrew T; Ludlow, Lindsay W; Roth, Stephen M

    2013-01-01

    Aging is associated with a tissue degeneration phenotype marked by a loss of tissue regenerative capacity. Regenerative capacity is dictated by environmental and genetic factors that govern the balance between damage and repair. The age-associated changes in the ability of tissues to replace lost or damaged cells is partly the cause of many age-related diseases such as Alzheimer's disease, cardiovascular disease, type II diabetes, and sarcopenia. A well-established marker of the aging process is the length of the protective cap at the ends of chromosomes, called telomeres. Telomeres shorten with each cell division and with increasing chronological age and short telomeres have been associated with a range of age-related diseases. Several studies have shown that chronic exposure to exercise (i.e., exercise training) is associated with telomere length maintenance; however, recent evidence points out several controversial issues concerning tissue-specific telomere length responses. The goals of the review are to familiarize the reader with the current telomere dogma, review the literature exploring the interactions of exercise with telomere phenotypes, discuss the mechanistic research relating telomere dynamics to exercise stimuli, and finally propose future directions for work related to telomeres and physiological stress.

  7. Computing the Length of the Shortest Telomere in the Nucleus

    NASA Astrophysics Data System (ADS)

    Dao Duc, K.; Holcman, D.

    2013-11-01

    The telomere length can either be shortened or elongated by an enzyme called telomerase after each cell division. Interestingly, the shortest telomere is involved in controlling the ability of a cell to divide. Yet, its dynamics remains elusive. We present here a stochastic approach where we model this dynamics using a Markov jump process. We solve the forward Fokker-Planck equation to obtain the steady state distribution and the statistical moments of telomere lengths. We focus specifically on the shortest one and we estimate its length difference with the second shortest telomere. After extracting key parameters such as elongation and shortening dynamics from experimental data, we compute the length of telomeres in yeast and obtain as a possible prediction the minimum concentration of telomerase required to ensure a proper cell division.

  8. Obesity and weight gain in adulthood and telomere length.

    PubMed

    Kim, Sangmi; Parks, Christine G; DeRoo, Lisa A; Chen, Honglei; Taylor, Jack A; Cawthon, Richard M; Sandler, Dale P

    2009-03-01

    Obesity and weight gain in adulthood are associated with an increased risk of several cancers. Telomeres play a critical role in maintaining genomic integrity and may be involved in carcinogenesis. Using data from 647 women ages 35 to 74 years in the United States and Puerto Rico (2003-2004), we examined the association between current and past anthropometric characteristics and telomere length in blood. In a multivariate linear regression model, higher current body mass index (BMI) and hip circumference were inversely associated with telomere length. Higher BMI in the 30s was associated with shorter telomere length among women ages>or=40 years (Ptrend<0.01). Weight gain since the age 30s (Ptrend=0.07) and weight cycling (Ptrend=0.04) were also inversely associated with telomere length. When current BMI and BMI at ages 30 to 39 years were considered together, the most marked decrease in telomere length was found for women who had overweight or obese BMI at both time points (mean telomere repeat copy number to single-copy gene copy number ratio=1.26; 95% confidence interval, 1.21-1.30) compared with women who had normal BMI at both times (mean telomere repeat copy number to single-copy gene copy number ratio=1.33; 95% confidence interval, 1.30-1.36). These findings support the hypothesis that obesity may accelerate aging, and highlight the importance of maintaining a desirable weight in adulthood.

  9. Short telomere length and breast cancer risk: a study in sister sets.

    PubMed

    Shen, Jing; Terry, Mary Beth; Gurvich, Irina; Liao, Yuyan; Senie, Ruby T; Santella, Regina M

    2007-06-01

    Telomeres consist of a tandem repeats of the sequence TTAGGG at the ends of chromosomes and play a key role in the maintenance of chromosomal stability. Previous studies indicated that short telomeres are associated with increased risk for human bladder, head and neck, lung, and renal cell cancer. We investigated the association between white blood cell telomere length and breast cancer risk among 268 family sets (287 breast cancer cases and 350 sister controls). Telomere length was assessed by quantitative PCR. The mean telomere length was shorter in cases (mean, 0.70; range, 0.03-1.95) than in unaffected control sisters (mean, 0.74; range, 0.03-2.29), but no significant difference was observed (P = 0.11). When subjects were categorized according to the median telomere length in controls (0.70), affected sisters had shorter telomeres compared with unaffected sisters after adjusting for age at blood donation and smoking status [odds ratio (OR), 1.3; 95% confidence interval (95% CI), 0.9-1.8], but the association was not statistically significant. The association by quartile of telomere length (Q4 shortest versus Q1 longest) also supported an increase in risk from shorter telomere length, although the association was not statistically significant (OR, 1.6; 95% CI, 0.9-2.7). This association was more pronounced among premenopausal women (OR, 2.1; 95% CI, 0.8-5.5) than postmenopausal women (OR, 1.3; 95% CI, 0.5-3.6 for Q4 versus Q1). If these associations are replicated in larger studies, they provide modest epidemiologic evidence that shortened telomere length may be associated with breast cancer risk.

  10. Assessment of Telomere Length, Phenotype, and DNA Content

    PubMed Central

    Kelesidis, Theodoros; Schmid, Ingrid

    2016-01-01

    Telomere sequences at the end of chromosomes control somatic cell division; therefore, telomere length in a given cell population provides information about its replication potential. This unit describes a method for flow cytometric measurement of telomere length in subpopulations using fluorescence in situ hybridization of fluorescently-labeled probes (Flow-FISH) without prior cell separation. After cells are stained for surface immunofluorescence, antigen-antibody complexes are covalently cross-linked onto cell membranes before FISH with a telomere-specific probe. Cells with long telomeres are included as internal standards. Addition of a DNA dye permits exclusion of proliferating cells during data analysis. DNA ploidy measurements of cells of interest and internal standard are performed on separate aliquots in parallel to Flow-FISH. Telomere fluorescence of G0/1 cells of subpopulations and internal standards obtained from Flow-FISH are normalized for DNA ploidy and telomere length in subsets of interest is expressed as a fraction of the internal standard telomere length. PMID:18770803

  11. Normal telomere lengths found in cloned cattle.

    PubMed

    Tian, X C; Xu, J; Yang, X

    2000-11-01

    Success of cloning using adult somatic cells has been reported in sheep, mice and cattle. The report that 'Dolly' the sheep, the first clone from an adult mammal, inherited shortened telomeres from her cell donor and that her telomeres were further shortened by the brief culture of donor cells has raised serious scientific and public concerns about the 'genetic age' and potential developmental problems of cloned animals. This observation was challenged by a recent report that showed calves cloned from fetal cells have longer telomeres than their age-matched controls. The question remains whether Dolly's short telomeres were an exception or a general fact, which would differ from the telomeres of fetal-derived clones. PMID:11062462

  12. Telomere length and cortisol reactivity in children of depressed mothers.

    PubMed

    Gotlib, I H; LeMoult, J; Colich, N L; Foland-Ross, L C; Hallmayer, J; Joormann, J; Lin, J; Wolkowitz, O M

    2015-05-01

    A growing body of research demonstrates that individuals diagnosed with major depressive disorder (MDD) are characterized by shortened telomere length, which has been posited to underlie the association between depression and increased instances of medical illness. The temporal nature of the relation between MDD and shortened telomere length, however, is not clear. Importantly, both MDD and telomere length have been associated independently with high levels of stress, implicating dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis and anomalous levels of cortisol secretion in this relation. Despite these associations, no study has assessed telomere length or its relation with HPA-axis activity in individuals at risk for depression, before the onset of disorder. In the present study, we assessed cortisol levels in response to a laboratory stressor and telomere length in 97 healthy young daughters of mothers either with recurrent episodes of depression (i.e., daughters at familial risk for depression) or with no history of psychopathology. We found that daughters of depressed mothers had shorter telomeres than did daughters of never-depressed mothers and, further, that shorter telomeres were associated with greater cortisol reactivity to stress. This study is the first to demonstrate that children at familial risk of developing MDD are characterized by accelerated biological aging, operationalized as shortened telomere length, before they had experienced an onset of depression; this may predispose them to develop not only MDD but also other age-related medical illnesses. It is critical, therefore, that we attempt to identify and distinguish genetic and environmental mechanisms that contribute to telomere shortening.

  13. Increased in vitro glial fibrillary acidic protein expression, telomerase activity, and telomere length after productive human immunodeficiency virus-1 infection in murine astrocytes.

    PubMed

    Ojeda, Diego; López-Costa, Juan José; Sede, Mariano; López, Ester María; Berria, María Isabel; Quarleri, Jorge

    2014-02-01

    Although HIV-associated neurocognitive disorders (HAND) result from injury and loss of neurons, productive infection routinely takes place in cells of macrophage lineage. In such a complex context, astrocytosis induced by local chemokines/cytokines is one of the hallmarks of HIV neuropathology. Whether this sustained astrocyte activation is able to alter telomere-aging process is unknown. We hypothesized that interaction of HIV with astrocytes may impact astrocyte telomerase activity (TA) and telomere length in a scenario of astrocytic activation measured by expression of glial fibrillary acidic protein (GFAP). To test this hypothesis, cultured murine astrocytes were challenged with pseudotyped HIV/vesicular stomatitis virus (HIV/VSV) to circumvent the absence of viral receptors; and GFAP, telomerase activity, and telomere length were quantified. As an early and transient event after HIV infection, both TA activity and telomere length were significantly augmented (P < 0.001). Later, a strong negative correlation (-0.8616, P < 0.0001) between virus production and telomerase activity was demonstrated. Once HIV production had reached a peak (7 dpi), the TA decreased, showing levels similar to those of noninfected cells. In contrast, the astrocyte became activated, exhibiting significantly increased levels of GFAP expression directly related to the level of HIV/VSV replication (P < 0.0001). Our results suggest that HIV-infected astrocytes exhibit early disturbance in their cellular functions, such as telomerase activity and telomere length, that may attenuate cell proliferation and enhance the astrocyte dysregulation, contributing to HIV neuropathogenesis. Understanding the mechanisms involved in HIV-mediated persistence by altering the telomere-related aging processes could aid in the development of therapeutic modalities for neurological complications of HIV infection.

  14. Reconstructing the in vivo dynamics of hematopoietic stem cells from telomere length distributions.

    PubMed

    Werner, Benjamin; Beier, Fabian; Hummel, Sebastian; Balabanov, Stefan; Lassay, Lisa; Orlikowsky, Thorsten; Dingli, David; Brümmendorf, Tim H; Traulsen, Arne

    2015-10-15

    We investigate the in vivo patterns of stem cell divisions in the human hematopoietic system throughout life. In particular, we analyze the shape of telomere length distributions underlying stem cell behavior within individuals. Our mathematical model shows that these distributions contain a fingerprint of the progressive telomere loss and the fraction of symmetric cell proliferations. Our predictions are tested against measured telomere length distributions in humans across all ages, collected from lymphocyte and granulocyte sorted telomere length data of 356 healthy individuals, including 47 cord blood and 28 bone marrow samples. We find an increasing stem cell pool during childhood and adolescence and an approximately maintained stem cell population in adults. Furthermore, our method is able to detect individual differences from a single tissue sample, i.e. a single snapshot. Prospectively, this allows us to compare cell proliferation between individuals and identify abnormal stem cell dynamics, which affects the risk of stem cell related diseases.

  15. The assessment of CD146-based cell sorting and telomere length analysis for establishing the identity of mesenchymal stem cells in human umbilical cord

    PubMed Central

    Kouroupis, Dimitrios; Churchman, Sarah M.; McGonagle, Dennis; Jones, Elena A.

    2014-01-01

    Adult stem cells are characterised by longer telomeres compared to mature cells from the same tissue. In this study, candidate CD146 + umbilical cord (UC) mesenchymal stem cells (MSCs) were purified by cell sorting from UC tissue digests and their telomere lengths were measured in comparison to donor-matched CD146-negative fraction. UC tissue fragments were enzymatically treated with collagenase and the cells were used for cell sorting, colony-forming fibroblast (CFU-F) assay or for long-term MSC cultivation. Telomere lengths were measured by qPCR in both culture-expanded MSCs and candidate native UC MSCs. Immunohistochemistry was undertaken to study the topography of CD146 + cells. Culture-expanded UC MSCs had a stable expression of CD73, CD90 and CD105, whereas CD146 declined in later passages which correlated with the shortening of telomeres in the same cultures. In five out of seven donors, telomeres in candidate native UC MSCs (CD45 -CD235α -CD31 -CD146 +) were longer compared to donor-matched CD146 - population (CD45 -CD235α -CD31 -CD146 -). The frequency of CD45 -CD235α -CD31 -CD146 + cells measured by flow cytometry was ~1000-fold above that of CFU-Fs (means 10.4% and 0.01%, respectively). CD146 + cells were also abundant in situ having a broad topography including high levels of positivity in muscle areas in addition to vessels. Although qPCR-based telomere length analysis in sorted populations could be limited in its sensitivity, very high frequency of CD146 + cells in UC tissue suggests that CD146 expression alone is unlikely to be sufficient to identify and purify native MSCs from the UC tissue. PMID:25232467

  16. Telomere length reflects phenotypic quality and costs of reproduction in a long-lived seabird.

    PubMed

    Bauch, Christina; Becker, Peter H; Verhulst, Simon

    2013-02-01

    Telomere length is associated with cellular senescence, lifestyle and ageing. Short telomeres indicate poor health in humans and reduced life expectancy in several bird species, but little is known about telomeres in relation to phenotypic quality in wild animals. We investigated telomere lengths in erythrocytes of known-age common terns (Sterna hirundo), a migratory seabird, in relation to arrival date and reproductive performance. Cross-sectional data revealed that, independent of age, individuals with short telomeres performed better: they arrived and reproduced earlier in the season and had more chicks in the nest. The latter effect was stronger the older the brood and stronger in males, which do most of the chick provisioning. Longitudinal data confirmed this pattern: compared with birds that lost their brood, birds that raised chicks beyond the 10th nestling day experienced higher telomere attrition from one year to the next. However, more detailed analysis revealed that the least and most successful individuals lost the fewest base pairs compared with birds with intermediate success. Our results suggest that reproductive success is achieved at the expense of telomeres, but that individual heterogeneity in susceptibility to such detrimental effects is important, as indicated by low telomere loss in the most successful birds.

  17. Mild oxidative stress is beneficial for sperm telomere length maintenance

    PubMed Central

    Mishra, Swetasmita; Kumar, Rajeev; Malhotra, Neena; Singh, Neeta; Dada, Rima

    2016-01-01

    AIM: To evaluate telomere length in sperm DNA and its correlation with oxidative stress (normal, mild, severe). METHODS: The study included infertile men (n = 112) and age matched fertile controls (n = 102). The average telomere length from the sperm DNA was measured using a quantitative real time PCR based assay. Seminal reactive oxygen species (ROS) and 8-Isoprostane (8-IP) levels were measured by chemiluminescence assay and ELISA respectively. RESULTS: Average sperm telomere length in infertile men and controls was 0.609 ± 0.15 and 0.789 ± 0.060, respectively (P < 0.0001). Seminal ROS levels in infertile was higher [66.61 ± 28.32 relative light units (RLU)/s/million sperm] than in controls (14.04 ± 10.67 RLU/s/million sperm) (P < 0.0001). The 8-IP level in infertile men was significantly higher (421.55 ± 131.29 pg/mL) than in controls (275.94 ± 48.13 pg/mL) (P < 0.001). When correlated to oxidative stress, in normal range of oxidative stress (ROS, 0-21.3 RLU/s/million sperm) the average telomere length in cases was 0.663 ± 0.14, in mild oxidative stress (ROS, 21.3-35 RLU/s/million sperm) it was elevated (0.684 ± 0.12) and in severe oxidative stress (ROS > 35 RLU/s/million sperm) average telomere length was decreased to 0.595 ± 0.15. CONCLUSION: Mild oxidative stress results in lengthening of telomere length, but severe oxidative stress results in shorter telomeres. Although telomere maintenance is a complex trait, the study shows that mild oxidative stress is beneficial in telomere length maintenance and thus a delicate balance needs to be established to maximize the beneficial effects of free radicals and prevent harmful effects of supra physiological levels. Detailed molecular evaluation of telomere structure, its correlation with oxidative stress would aid in elucidating the cause of accelerated telomere length attrition. PMID:27376021

  18. The influence of oxidative stress induced by iron on telomere length.

    PubMed

    Kepinska, Marta; Szyller, Jakub; Milnerowicz, Halina

    2015-11-01

    Oxidative stress can be induced by increased concentrations of iron in the body and consequently can cause shortening of telomeres. Telomeres, called mitotic clocks, are non-coding fragments at the end of chromosomes. During the replication of genetic material they are shortened, playing the role of ageing biomarkers in eukaryotes. In human endothelial cells, oxidative stress causes a decrease in telomerase activity. Shortening of chromosomes in telomeric parts was found in patients with primary hemochromatosis and in patients taking supplements containing iron. Increased level of transferrin saturation is associated with the presence of shorter telomeres in the chromosomes of leukocytes. The relationship between iron status and telomere length is still not fully understood.

  19. The role of telomeres and telomerase complex in haematological neoplasia: the length of telomeres as a marker of carcinogenesis and prognosis of disease.

    PubMed

    Gancarcíková, M; Zemanová, Z; Brezinová, J; Berková, A; Vcelíková, S; Smigová, J; Michalová, K

    2010-01-01

    Human telomeres (discovery of telomere structure and function has been recently awarded The Nobel Prize) consist of approximately 5-12 kb of tandem repeated sequences (TTAGGG)n and associated proteins capping chromosome ends which prevent degradation, loss of genetic information, end-to-end fusion, senescence and apoptosis. Due to the end-replication problem, telomere repeats are lost with each cell division, eventually leading to genetic instability and cellular senescence when telomeres become critically short. Stabilization of the telomeric DNA through telomerase activation, unique reverse transcriptase, or activation of the alternative mechanism of telomere maintenance is essential if the cells are to survive and proliferate indefinitely. Telomerase is expressed during early development and remains fully active in specific germline cells, but is undetectable in most normal somatic cells. High level of telomerase activity is detected in almost 90% of human tumours and immortalized cell lines. The hematopoietic compartment may develop genetic instability as a consequence of telomere erosion, resulting in aplastic anaemia (AA) and increased risk of myelodysplastic syndrome (MDS) and acute myeloid leukaemia (AML). Genetic instability associated with telomere dysfunction (i.e. short telomeres) is an early event in carcinogenesis. The molecular cytogenetic method telomere/centromere fluorescence in situ hybridization (T/C-FISH) can be used to characterize the telomere length of hematopoietic cells. This review describes recent advances in the molecular characterization of telomere system, the regulation of telomerase activity in cancer pathogenesis and shows that the telomeric length could be a potential clinical marker of hematologic neoplasia and prognosis of disease.

  20. Intratumoral diversity of telomere length in individual neuroblastoma tumors

    PubMed Central

    Pezzolo, Annalisa; Pistorio, Angela; Gambini, Claudio; Haupt, Riccardo; Ferraro, Manuela; Erminio, Giovanni; De Bernardi, Bruno; Garaventa, Alberto; Pistoia, Vito

    2015-01-01

    The purpose of the work was to investigate telomere length (TL) and mechanisms involved in TL maintenance in individual neuroblastoma (NB) tumors. Primary NB tumors from 102 patients, ninety Italian and twelve Spanish, diagnosed from 2000 to 2008 were studied. TL was investigated by quantitative fluorescence in situ hybridization (IQ-FISH) that allows to analyze individual cells in paraffin-embedded tissues. Fluorescence intensity of chromosome 2 centromere was used as internal control to normalize TL values to ploidy. Human telomerase reverse transcriptase (hTERT) expression was detected by immunofluorescence in 99/102 NB specimens. The main findings are the following: 1) two intratumoral subpopulations of cancer cells displaying telomeres of different length were identified in 32/102 tumors belonging to all stages. 2) hTERT expression was detected in 99/102 tumors, of which 31 displayed high expression and 68 low expression. Alternative lengthening of telomeres (ALT)-mechanism was present in 60/102 tumors, 20 of which showed high hTERT expression. Neither ALT-mechanism nor hTERT expression correlated with heterogeneous TL. 3) High hTERT expression and ALT positivity were associated with significantly reduced Overall Survival. 4) High hTERT expression predicted relapse irrespective of patient age. Intratumoral diversity in TL represents a novel feature in NB. In conclusion, diversity of TL in individual NB tumors was strongly associated with disease progression and death, suggesting that these findings are of translational relevance. The combination of high hTERT expression and ALT positivity may represent a novel biomarker of poor prognosis that deserves further investigation. PMID:25595889

  1. Longer leukocyte telomere length in Costa Rica's Nicoya Peninsula: a population-based study.

    PubMed

    Rehkopf, David H; Dow, William H; Rosero-Bixby, Luis; Lin, Jue; Epel, Elissa S; Blackburn, Elizabeth H

    2013-11-01

    Studies in humans suggest that leukocyte telomere length may act as a marker of biological aging. We investigated whether individuals in the Nicoya region of Costa Rica, known for exceptional longevity, had longer telomere length than those in other parts of the country. After controlling for age, age squared, rurality, rainy season and gender, the mean leukocyte telomere length in Nicoya was substantially longer (81 base pairs, p<0.05) than in other areas of Costa Rica, providing evidence of a biological pathway to which this notable longevity may be related. This relationship remains unchanged (79 base pairs, p<0.05) after statistically controlling for nineteen potential biological, dietary and social and demographic mediators. Thus the difference in the mean leukocyte telomere length that characterizes this unique region does not appear to be explainable by traditional behavioral and biological risk factors. More detailed examination of mean leukocyte telomere length by age shows that the regional telomere length difference declines at older ages.

  2. Restoration of telomeres in human papillomavirus-immortalized human anogenital epithelial cells.

    PubMed Central

    Klingelhutz, A J; Barber, S A; Smith, P P; Dyer, K; McDougall, J K

    1994-01-01

    Loss of telomeres has been hypothesized to be important in cellular senescence and may play a role in carcinogenesis. In this study, we have measured telomere length in association with the immortalization and transformation of human cervical and foreskin epithelial cells by the human papillomavirus type 16 or 18 E6 and E7 open reading frames. By using a telomeric TTAGGG repeat probe, it was shown that the telomeres of precrisis normal and E6-, E7-, and E6/E7-expressing cells gradually shortened with passaging (30 to 100 bp per population doubling). Cells that expressed both E6 and E7 went through a crisis period and gave rise to immortalized lines. In contrast to precrisis cells, E6/E7-immortalized cells generally showed an increase in telomere length as they were passaged in culture, with some later passage lines having telomeres that were similar to or longer than the earliest-passage precrisis cells examined. No consistent association could be made between telomere length and tumorigenicity of cells in nude mice. However, of the three cell lines that grew in vivo, two had long telomeres, thus arguing against the hypothesis that cancer cells favor shortened telomeres. Our results indicate that arrest of telomere shortening may be important in human papillomavirus-associated immortalization and that restoration of telomere length may be advantageous to cells with regard to their ability to proliferate. Images PMID:8289836

  3. Restoration of telomeres in human papillomavirus-immortalized human anogenital epithelial cells

    SciTech Connect

    Klingelhutz, A.J.; Barber, S.A.; Smith, P.P.

    1994-02-01

    Loss of telomeres has been hypothesized to be important in cellular senescence and may play a role in carcinogenesis. In this study, we have measured telomere length in association with the immortalization and transformation of human cervical and foreskin epithelial cells by the human papillomavirus type 16 or 18 E6 and E7 open reading frames. By using a telomeric TTAGGG repeat probe, it was shown that the telomeres of precrisis normal and E6-, E7-, and E6/E7-expressing cells gradually shortened with passaging (30 to 100 bp per population doubling). Cells that expressed both E6 and E7 went through a crisis period and gave rise to immortalized lines. In contrast to precrisis cells, E6/E7-immortalized cells generally showed an increase in telomere length as they were passaged in culture, with some later passage lines having telomeres that were similar to or longer than the earliest-passage precrisis cells examined. No consistent association could be made between telomere length and tumorigenicity of cells in nude mice. However, of the three cell lines that grew in vivo, two had long telomeres, thus arguing against the hypothesis that cancer cells favor shortened telomeres. Our results indicate that arrest of telomere shortening may be important in human papillomavirus-associated immortalization and that restoration of telomere length may be advantageous to cells with regard to their ability to proliferate. 55 refs., 7 figs., 1 tab.

  4. QTL mapping and candidate gene analysis of telomere length control factors in maize (Zea mays L.)

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Telomere length is under genetic control and important for essential telomere functions. Failure to regulate telomere length homeostasis contributes to cancers and aging-related diseases in animals, but the effects of telomere length defects in plants remains poorly understood. To learn more about t...

  5. The yeast telomere length regulator TEL2 encodes a protein that binds to telomeric DNA.

    PubMed Central

    Kota, R S; Runge, K W

    1998-01-01

    TEL2 is required for telomere length regulation and viability in Saccharomyces cerevisiae. To investigate the mechanism by which Tel2p regulates telomere length, the majority (65%) of the TEL2 ORF was fused to the 3'-end of the gene for maltose binding protein, expressed in bacteria and the purified protein used in DNA binding studies. Rap1p, the major yeast telomere binding protein, recognizes a 13 bp duplex site 5'-GGTGTGTGGGTGT-3' in yeast telomeric DNA with high affinity. Gel shift experiments revealed that the MBP-Tel2p fusion binds the double-stranded yeast telomeric Rap1p site in a sequence-specific manner. Analysis of mutated sites showed that MBP-Tel2p could bind 5'-GTGTGTGG-3' within this 13 bp site. Methylation interference analysis revealed that Tel2p contacts the 5'-terminal guanine in the major groove. MBP-Tel2p did not bind duplex telomeric DNA repeats from vertebrates, Tetrahymena or Oxytricha. These results suggest that Tel2p is a DNA binding protein that recognizes yeast telomeric DNA. PMID:9490802

  6. Multiple Yeast Genes, Including Paf1 Complex Genes, Affect Telomere Length via Telomerase RNA Abundance▿ †

    PubMed Central

    Mozdy, Amy D.; Podell, Elaine R.; Cech, Thomas R.

    2008-01-01

    Twofold reductions in telomerase RNA levels cause telomere shortening in both humans and the yeast Saccharomyces cerevisiae. To test whether multiple genes that affect telomere length act by modulating telomerase RNA abundance, we used real-time reverse transcription-PCR to screen S. cerevisiae deletion strains reported to maintain shorter or longer telomeres to determine the levels of their telomerase RNA (TLC1) abundance. Of 290 strains screened, 5 had increased TLC1 levels; 4 of these maintained longer telomeres. Twenty strains had decreased TLC1 levels; 18 of these are known to maintain shorter telomeres. Four strains with decreased TLC1 RNA levels contained deletions of subunits of Paf1C (polymerase II-associated factor complex). While Paf1C had been implicated in the transcription of both polyadenylated and nonpolyadenylated RNAs, Paf1C had not been associated previously with the noncoding telomerase RNA. In Paf1C mutant strains, TLC1 overexpression partially rescues telomere length and cell growth defects, suggesting that telomerase RNA is a critical direct or indirect Paf1C target. Other factors newly identified as affecting TLC1 RNA levels include cyclin-dependent kinase, the mediator complex, protein phosphatase 2A, and ribosomal proteins L13B and S16A. This report establishes that a subset of telomere length genes act by modulating telomerase RNA abundance. PMID:18411302

  7. Mathematical model of alternative mechanism of telomere length maintenance

    NASA Astrophysics Data System (ADS)

    Kollár, Richard; Bod'ová, Katarína; Nosek, Jozef; Tomáška, L'ubomír

    2014-03-01

    Biopolymer length regulation is a complex process that involves a large number of biological, chemical, and physical subprocesses acting simultaneously across multiple spatial and temporal scales. An illustrative example important for genomic stability is the length regulation of telomeres—nucleoprotein structures at the ends of linear chromosomes consisting of tandemly repeated DNA sequences and a specialized set of proteins. Maintenance of telomeres is often facilitated by the enzyme telomerase but, particularly in telomerase-free systems, the maintenance of chromosomal termini depends on alternative lengthening of telomeres (ALT) mechanisms mediated by recombination. Various linear and circular DNA structures were identified to participate in ALT, however, dynamics of the whole process is still poorly understood. We propose a chemical kinetics model of ALT with kinetic rates systematically derived from the biophysics of DNA diffusion and looping. The reaction system is reduced to a coagulation-fragmentation system by quasi-steady-state approximation. The detailed treatment of kinetic rates yields explicit formulas for expected size distributions of telomeres that demonstrate the key role played by the J factor, a quantitative measure of bending of polymers. The results are in agreement with experimental data and point out interesting phenomena: an appearance of very long telomeric circles if the total telomere density exceeds a critical value (excess mass) and a nonlinear response of the telomere size distributions to the amount of telomeric DNA in the system. The results can be of general importance for understanding dynamics of telomeres in telomerase-independent systems as this mode of telomere maintenance is similar to the situation in tumor cells lacking telomerase activity. Furthermore, due to its universality, the model may also serve as a prototype of an interaction between linear and circular DNA structures in various settings.

  8. Integration of Telomere Length Dynamics into Systems Biology Framework: A Review

    PubMed Central

    Nersisyan, Lilit

    2016-01-01

    Telomere length dynamics plays a crucial role in regulation of cellular processes and cell fate. In contrast to epidemiological studies revealing the association of telomere length with age, age-related diseases, and cancers, the role of telomeres in regulation of transcriptome and epigenome and the role of genomic variations in telomere lengthening are not extensively analyzed. This is explained by the fact that experimental assays for telomere length measurement are resource consuming, and there are very few studies where high-throughput genomics, transcriptomics, and/or epigenomics experiments have been coupled with telomere length measurements. Recent development of computational approaches for assessment of telomere length from whole genome sequencing data pave a new perspective on integration of telomeres into high-throughput systems biology analysis framework. Herein, we review existing methodologies for telomere length measurement and compare them to computational approaches, as well as discuss their applications in large-scale studies on telomere length dynamics. PMID:27346946

  9. Smoking and health: association between telomere length and factors impacting on human disease, quality of life and life span in a large population-based cohort under the effect of smoking duration.

    PubMed

    Babizhayev, Mark A; Yegorov, Yegor E

    2011-08-01

    Reactive oxygen species (ROS) are of primary importance as they cause damage to lipids, proteins, and DNA either endogenously by cellular mechanism, or through exogenous exposure to environmental injury factors, including oxidation insult factors, such as tobacco smoke. Currently 46.3 million adults (25.7 percent of the population) are smokers. This includes 24 million men (28.1 percent of the total) and more than 22 million women (23.5 percent). The prevalence is highest among persons 25-44 years of age. Cigarette smokers have a higher risk of developing several chronic disorders. These include fatty buildups in arteries, several types of cancer and chronic obstructive pulmonary disease (lung problems). As peripheral leukocytes have been the main target of human telomere research, most of what is known about human telomere dynamics in vivo is based on these cells. Leukocyte telomere length (TL) is a complex trait that is shaped by genetic, epigenetic, and environmental determinants. In this article, we consider that smoking modifies leukocyte TL in humans and contributes to its variability among individuals, although the smoking effect on TL and its relation with other metabolic indices may accelerate biological aging and development of smoking-induced chronic diseases in a large human population-based cohorts with smoking behavior. Recent studies confirmed that individuals with shorter telomeres present a higher prevalence of arterial lesions and higher risk of cardiovascular disease mortality. This study originally suggests that efficient therapeutic protection of TL and structure in response to stresses that are known to reduce TL, such as oxidative damage or inflammation associated with tobacco smoking, would lead to better telomere maintenance. Recently, we have discovered the potential use of telomere-restorative imidazole-containing dipeptide (non-hydrolized carnosine, carcinine) based therapy for better survival of smokers. We conclude that a better

  10. TP53-dependent chromosome instability is associated with transient reductions in telomere length in immortal telomerase-positive cell lines

    NASA Technical Reports Server (NTRS)

    Schwartz, J. L.; Jordan, R.; Liber, H.; Murnane, J. P.; Evans, H. H.

    2001-01-01

    Telomere shortening in telomerase-negative somatic cells leads to the activation of the TP53 protein and the elimination of potentially unstable cells. We examined the effect of TP53 gene expression on both telomere metabolism and chromosome stability in immortal, telomerase-positive cell lines. Telomere length, telomerase activity, and chromosome instability were measured in multiple clones isolated from three related human B-lymphoblast cell lines that vary in TP53 expression; TK6 cells express wild-type TP53, WTK1 cells overexpress a mutant form of TP53, and NH32 cells express no TP53 protein. Clonal variations in both telomere length and chromosome stability were observed, and shorter telomeres were associated with higher levels of chromosome instability. The shortest telomeres were found in WTK1- and NH32-derived cells, and these cells had 5- to 10-fold higher levels of chromosome instability. The primary marker of instability was the presence of dicentric chromosomes. Aneuploidy and other stable chromosome alterations were also found in clones showing high levels of dicentrics. Polyploidy was found only in WTK1-derived cells. Both telomere length and chromosome instability fluctuated in the different cell populations with time in culture, presumably as unstable cells and cells with short telomeres were eliminated from the growing population. Our results suggest that transient reductions in telomere lengths may be common in immortal cell lines and that these alterations in telomere metabolism can have a profound effect on chromosome stability. Copyright 2000 Wiley-Liss, Inc.

  11. Telomere length analysis in monocytes and lymphocytes from patients with systemic lupus erythematosus using multi-color flow-FISH.

    PubMed

    Beier, F; Balabanov, S; Amberger, C C; Hartmann, U; Manger, K; Dietz, K; Kötter, I; Brummendorf, T H

    2007-01-01

    In order to analyse telomere length in subsets of human peripheral blood lymphocytes and monocytes, we modified a recently developed multicolor flow- fluorescent in situ hybridization (FISH) methodology that combines flow-FISH and antibody staining for cell surface antigens. We analysed telomere length of peripheral blood mononuclear cells in a group of 22 patients with systemic lupus erythematosus (SLE) and 20 age-matched healthy donors. We found that neither CD4+, CD8+, CD19+ cells nor CD14+ monocytes have significantly shorter telomeres compared with their healthy counterparts. On the basis of these findings, we then used monocyte telomere length as internal reference in order to control for intra-individual variability in telomere length. By using this approach, we could demonstrate significant telomere shortening in all three lymphocyte subsets (in all cases P < 0.05) compared with monocytes. However, these differences did not vary significantly between SLE patients and controls. In summary, telomere lengths in subpopulations of hematopoietic cells can be monitored in patients with SLE using multicolor flow-FISH. While confirming data by other groups on telomere length in lymphocyte subpopulations, our data argue against an increased proliferation rate of peripheral blood monocytes reflected by accelerated telomere shortening in patients with SLE.

  12. Age-related telomere uncapping is associated with cellular senescence and inflammation independent of telomere shortening in human arteries.

    PubMed

    Morgan, Richard G; Ives, Stephen J; Lesniewski, Lisa A; Cawthon, Richard M; Andtbacka, Robert H I; Noyes, R Dirk; Richardson, Russell S; Donato, Anthony J

    2013-07-15

    Arterial telomere dysfunction may contribute to chronic arterial inflammation by inducing cellular senescence and subsequent senescence-associated inflammation. Although telomere shortening has been associated with arterial aging in humans, age-related telomere uncapping has not been described in non-cultured human tissues and may have substantial prognostic value. In skeletal muscle feed arteries from 104 younger, middle-aged, and older adults, we assessed the potential role of age-related telomere uncapping in arterial inflammation. Telomere uncapping, measured by p-histone γ-H2A.X (ser139) localized to telomeres (chromatin immunoprecipitation; ChIP), and telomeric repeat binding factor 2 bound to telomeres (ChIP) was greater in arteries from older adults compared with those from younger adults. There was greater tumor suppressor protein p53 (P53)/cyclin-dependent kinase inhibitor 1A (P21)-induced senescence, measured by P53 bound to P21 gene promoter (ChIP), and greater expression of P21, interleukin 8, and monocyte chemotactic protein 1 mRNA (RT-PCR) in arteries from older adults compared with younger adults. Telomere uncapping was a highly influential covariate for the age-group difference in P53/P21-induced senescence. Despite progressive age-related telomere shortening in human arteries, mean telomere length was not associated with telomere uncapping or P53/P21-induced senescence. Collectively, these findings demonstrate that advancing age is associated with greater telomere uncapping in arteries, which is linked to P53/P21-induced senescence independent of telomere shortening.

  13. The effect of Ku on telomere replication time is mediated by telomere length but is independent of histone tail acetylation

    PubMed Central

    Lian, Hui-Yong; Robertson, E. Douglas; Hiraga, Shin-ichiro; Alvino, Gina M.; Collingwood, David; McCune, Heather J.; Sridhar, Akila; Brewer, Bonita J.; Raghuraman, M. K.; Donaldson, Anne D.

    2011-01-01

    DNA replication in Saccharomyces cerevisiae proceeds according to a temporal program. We have investigated the role of the telomere-binding Ku complex in specifying late replication of telomere-proximal sequences. Genome-wide analysis shows that regions extending up to 80 kb from telomeres replicate abnormally early in a yku70 mutant. We find that Ku does not appear to regulate replication time by binding replication origins directly, nor is its effect on telomere replication timing mediated by histone tail acetylation. We show that Ku instead regulates replication timing through its effect on telomere length, because deletion of the telomerase regulator Pif1 largely reverses the short telomere defect of a yku70 mutant and simultaneously rescues its replication timing defect. Consistent with this conclusion, deleting the genome integrity component Elg1 partially rescued both length and replication timing of yku70 telomeres. Telomere length–mediated control of replication timing requires the TG1–3 repeat-counting component Rif1, because a rif1 mutant replicates telomeric regions early, despite having extended TG1–3 tracts. Overall, our results suggest that the effect of Ku on telomere replication timing results from its impact on TG1–3 repeat length and support a model in which Rif1 measures telomere repeat length to ensure that telomere replication timing is correctly programmed. PMID:21441303

  14. Dimensions of religious involvement and leukocyte telomere length.

    PubMed

    Hill, Terrence D; Ellison, Christopher G; Burdette, Amy M; Taylor, John; Friedman, Katherine L

    2016-08-01

    Although numerous studies suggest that religious involvement is associated with a wide range of favorable health outcomes, it is unclear whether this general pattern extends to cellular aging. In this paper, we tested whether leukocyte telomere length varies according to several dimensions of religious involvement. We used cross-sectional data from the Nashville Stress and Health Study (2011-2014), a large probability sample of 1252 black and white adults aged 22 to 69 living in Davidson County, TN, USA. Leukocyte telomere length was measured using the monochrome multiplex quantitative polymerase chain reaction method with albumin as the single-copy reference sequence. Dimensions of religious involvement included religiosity, religious support, and religious coping. Our multivariate analyses showed that religiosity (an index of religious attendance, prayer frequency, and religious identity) was positively associated with leukocyte telomere length, even with adjustments for religious support, religious coping, age, gender, race, education, employment status, income, financial strain, stressful life events, marital status, family support, friend support, depressive symptoms, smoking, heavy drinking, and allostatic load. Unlike religiosity, religious support and religious coping were unrelated to leukocyte telomere length across models. Depressive symptoms, smoking, heavy drinking, and allostatic load failed to explain any of the association between religiosity and telomere length. To our knowledge, this is the first population-based study to link religious involvement and cellular aging. Although our data suggest that adults who frequently attend religious services, pray with regularity, and consider themselves to be religious tend to exhibit longer telomeres than those who attend and pray less frequently and do not consider themselves to be religious, additional research is needed to establish the mechanisms underlying this association.

  15. Association of Telomere Length with Breast Cancer Prognostic Factors

    PubMed Central

    Têtu, Bernard; Maunsell, Elizabeth; Poirier, Brigitte; Montoni, Alicia; Rochette, Patrick J.; Diorio, Caroline

    2016-01-01

    Introduction Telomere length, a marker of cell aging, seems to be affected by the same factors thought to be associated with breast cancer prognosis. Objective To examine associations of peripheral blood cell-measured telomere length with traditional and potential prognostic factors in breast cancer patients. Methods We conducted a cross-sectional analysis of data collected before surgery from 162 breast cancer patients recruited consecutively between 01/2011 and 05/2012, at a breast cancer reference center. Data on the main lifestyle factors (smoking, alcohol consumption, physical activity) were collected using standardized questionnaires. Anthropometric factors were measured. Tumor biological characteristics were extracted from pathology reports. Telomere length was measured using a highly reproducible quantitative PCR method in peripheral white blood cells. Spearman partial rank-order correlations and multivariate general linear models were used to evaluate relationships between telomere length and prognostic factors. Results Telomere length was positively associated with total physical activity (rs = 0.17, P = 0.033; Ptrend = 0.069), occupational physical activity (rs = 0.15, P = 0.054; Ptrend = 0.054) and transportation-related physical activity (rs = 0.19, P = 0.019; P = 0.005). Among post-menopausal women, telomere length remained positively associated with total physical activity (rs = 0.27, P = 0.016; Ptrend = 0.054) and occupational physical activity (rs = 0.26, P = 0.021; Ptrend = 0.056) and was only associated with transportation-related physical activity among pre-menopausal women (rs = 0.27, P = 0.015; P = 0.004). No association was observed between telomere length and recreational or household activities, other lifestyle factors or traditional prognostic factors. Conclusions Telomeres are longer in more active breast cancer patients. Since white blood cells are involved in anticancer immune responses, these findings suggest that even regular low

  16. Age-Related Declines and Disease-Associated Variation in Immune Cell Telomere Length in a Wild Mammal

    PubMed Central

    Beirne, Christopher; Delahay, Richard; Hares, Michelle; Young, Andrew

    2014-01-01

    Immunosenescence, the deterioration of immune system capability with age, may play a key role in mediating age-related declines in whole-organism performance, but the mechanisms that underpin immunosenescence are poorly understood. Biomedical research on humans and laboratory models has documented age and disease related declines in the telomere lengths of leukocytes (‘immune cells’), stimulating interest their having a potentially general role in the emergence of immunosenescent phenotypes. However, it is unknown whether such observations generalise to the immune cell populations of wild vertebrates living under ecologically realistic conditions. Here we examine longitudinal changes in the mean telomere lengths of immune cells in wild European badgers (Meles meles). Our findings provide the first evidence of within-individual age-related declines in immune cell telomere lengths in a wild vertebrate. That the rate of age-related decline in telomere length appears to be steeper within individuals than at the overall population level raises the possibility that individuals with short immune cell telomeres and/or higher rates of immune cell telomere attrition may be selectively lost from this population. We also report evidence suggestive of associations between immune cell telomere length and bovine tuberculosis infection status, with individuals detected at the most advanced stage of infection tending to have shorter immune cell telomeres than disease positive individuals. While male European badgers are larger and show higher rates of annual mortality than females, we found no evidence of a sex difference in either mean telomere length or the average rate of within-individual telomere attrition with age. Our findings lend support to the view that age-related declines in the telomere lengths of immune cells may provide one potentially general mechanism underpinning age-related declines in immunocompetence in natural populations. PMID:25268841

  17. Age-related declines and disease-associated variation in immune cell telomere length in a wild mammal.

    PubMed

    Beirne, Christopher; Delahay, Richard; Hares, Michelle; Young, Andrew

    2014-01-01

    Immunosenescence, the deterioration of immune system capability with age, may play a key role in mediating age-related declines in whole-organism performance, but the mechanisms that underpin immunosenescence are poorly understood. Biomedical research on humans and laboratory models has documented age and disease related declines in the telomere lengths of leukocytes ('immune cells'), stimulating interest their having a potentially general role in the emergence of immunosenescent phenotypes. However, it is unknown whether such observations generalise to the immune cell populations of wild vertebrates living under ecologically realistic conditions. Here we examine longitudinal changes in the mean telomere lengths of immune cells in wild European badgers (Meles meles). Our findings provide the first evidence of within-individual age-related declines in immune cell telomere lengths in a wild vertebrate. That the rate of age-related decline in telomere length appears to be steeper within individuals than at the overall population level raises the possibility that individuals with short immune cell telomeres and/or higher rates of immune cell telomere attrition may be selectively lost from this population. We also report evidence suggestive of associations between immune cell telomere length and bovine tuberculosis infection status, with individuals detected at the most advanced stage of infection tending to have shorter immune cell telomeres than disease positive individuals. While male European badgers are larger and show higher rates of annual mortality than females, we found no evidence of a sex difference in either mean telomere length or the average rate of within-individual telomere attrition with age. Our findings lend support to the view that age-related declines in the telomere lengths of immune cells may provide one potentially general mechanism underpinning age-related declines in immunocompetence in natural populations. PMID:25268841

  18. Cloning and molecular characterization of telomerase reverse transcriptase (TERT) and telomere length analysis of Peromyscus leucopus.

    PubMed

    Zhao, Xin; Ueda, Yasutaka; Kajigaya, Sachiko; Alaks, Glen; Desierto, Marie J; Townsley, Danielle M; Dumitriu, Bogdan; Chen, Jichun; Lacy, Robert C; Young, Neal S

    2015-08-15

    Telomerase reverse transcriptase (TERT) is the catalytic subunit of telomerase complex that regulates telomerase activity to maintain telomere length for all animals with linear chromosomes. As the Mus musculus (MM) laboratory mouse has very long telomeres compared to humans, a potential alternative animal model for telomere research is the Peromyscus leucopus (PL) mouse that has telomere lengths close to the human range and has the wild counterparts for comparison. We report the full TERT coding sequence (pTERT) from PL mice to use in the telomere research. Comparative analysis with eight other mammalian TERTs revealed a pTERT protein considerably homologous to other TERTs and preserved all TERT specific-sequence signatures, yet with some distinctive features. pTERT displayed the highest nucleotide and amino acid sequence homology with hamster TERT. Unlike human but similar to MM mice, pTERT expression was detected in various adult somatic tissues of PL mice, with the highest expression in testes. Four different captive stocks of PL mice and wild-captured PL mice each displayed group-specific average telomere lengths, with the longest and shortest telomeres in inbred and outbred stock mice, respectively. pTERT showed considerable numbers of synonymous and nonsynonymous mutations. A pTERT proximal promoter region cloned was homologous among PL and MM mice and rat, but with species-specific features. From PL mice, we further cloned and characterized ribosomal protein, large, P0 (pRPLP0) to use as an internal control for various assays. Peromyscus mice have been extensively used for various studies, including human diseases, for which pTERT and pRPLP0 would be useful tools. PMID:25962353

  19. Cloning and molecular characterization of telomerase reverse transcriptase (TERT) and telomere length analysis of Peromyscus leucopus.

    PubMed

    Zhao, Xin; Ueda, Yasutaka; Kajigaya, Sachiko; Alaks, Glen; Desierto, Marie J; Townsley, Danielle M; Dumitriu, Bogdan; Chen, Jichun; Lacy, Robert C; Young, Neal S

    2015-08-15

    Telomerase reverse transcriptase (TERT) is the catalytic subunit of telomerase complex that regulates telomerase activity to maintain telomere length for all animals with linear chromosomes. As the Mus musculus (MM) laboratory mouse has very long telomeres compared to humans, a potential alternative animal model for telomere research is the Peromyscus leucopus (PL) mouse that has telomere lengths close to the human range and has the wild counterparts for comparison. We report the full TERT coding sequence (pTERT) from PL mice to use in the telomere research. Comparative analysis with eight other mammalian TERTs revealed a pTERT protein considerably homologous to other TERTs and preserved all TERT specific-sequence signatures, yet with some distinctive features. pTERT displayed the highest nucleotide and amino acid sequence homology with hamster TERT. Unlike human but similar to MM mice, pTERT expression was detected in various adult somatic tissues of PL mice, with the highest expression in testes. Four different captive stocks of PL mice and wild-captured PL mice each displayed group-specific average telomere lengths, with the longest and shortest telomeres in inbred and outbred stock mice, respectively. pTERT showed considerable numbers of synonymous and nonsynonymous mutations. A pTERT proximal promoter region cloned was homologous among PL and MM mice and rat, but with species-specific features. From PL mice, we further cloned and characterized ribosomal protein, large, P0 (pRPLP0) to use as an internal control for various assays. Peromyscus mice have been extensively used for various studies, including human diseases, for which pTERT and pRPLP0 would be useful tools.

  20. Cloning and molecular characterization of telomerase reverse transcriptase (TERT) and telomere length analysis of Peromyscus leucopus

    PubMed Central

    Zhao, Xin; Ueda, Yasutaka; Kajigaya, Sachiko; Alaks, Glen; Desierto, Marie J; Townsley, Danielle M.; Dumitriu, Bogdan; Chen, Jichun; Lacy, Robert C.; Young, Neal S.

    2015-01-01

    Telomerase reverse transcriptase (TERT) is the catalytic subunit of telomerase complex that regulates telomerase activity to maintain telomere length for all animals with linear chromosomes. As the Mus musculus (MM) laboratory mouse has very long telomeres compared to humans, a potential alternative animal model for telomere research is the Peromyscus leucopus (PL) mouse that has telomere lengths close to the human range and has the wild counterparts for comparison. We report the full TERT coding sequence (pTERT) from PL mice to use in the telomere research. Comparative analysis with eight other mammalian TERTs revealed a pTERT protein considerably homologous to other TERTs and preserved all TERT specific-sequence signatures, yet with some distinctive features. pTERT displayed the highest nucleotide and amino acid sequence homology with hamster TERT. Unlike human but similar to MM mice, pTERT expression was detected in various adult somatic tissues of PL mice, with the highest expression in testes. Four different captive stocks of PL mice and wild-captured PL mice each displayed group-specific average telomere lengths, with the longest and shortest telomeres in inbred and outbred stock mice, respectively. pTERT showed considerable numbers of synonymous and nonsynonymous mutations. A pTERT proximal promoter region cloned was homologous among PL and MM mice and rat, but with species-specific features. From PL mice, we further cloned and characterized ribosomal protein, large, P0 (pRPLP0) to use as an internal control for various assays. Peromyscus mice have been extensively used for various studies, including human diseases, for which pTERT and pRPLP0 would be useful tools. PMID:25962353

  1. Adipocyte telomere length associates negatively with adipocyte size, whereas adipose tissue telomere length associates negatively with the extent of fibrosis in severely obese women.

    PubMed

    el Bouazzaoui, F; Henneman, P; Thijssen, P; Visser, A; Koning, F; Lips, M A; Janssen, I; Pijl, H; Willems van Dijk, K; van Harmelen, V

    2014-05-01

    Telomere length can be considered as a biological marker for cell proliferation and aging. Obesity is associated with adipocyte hypertrophy and proliferation as well as with shorter telomeres in adipose tissue. As adipose tissue is a mixture of different cell types and the cellular composition of adipose tissue changes with obesity, it is unclear what determines telomere length of whole adipose tissue. We aimed to investigate telomere length in whole adipose tissue and isolated adipocytes in relation to adiposity, adipocyte hypertrophy and adipose tissue inflammation and fibrosis. Telomere length was measured by real-time PCR in visceral adipose tissue, and isolated adipocytes of 21 obese women with a waist ranging from 110 to 147 cm and age from 31 to 61 years. Telomere length in adipocytes was shorter than in whole adipose tissue. Telomere length of adipocytes but not whole adipose tissue correlated negatively with waist and adipocyte size, which was still significant after correction for age. Telomere length of whole adipose tissue associated negatively with fibrosis as determined by collagen content. Thus, in extremely obese individuals, adipocyte telomere length is a marker of adiposity, whereas whole adipose tissue telomere length reflects the extent of fibrosis and may indicate adipose tissue dysfunction.

  2. Religious Involvement and Telomere Length in Women Family Caregivers.

    PubMed

    Koenig, Harold G; Nelson, Bruce; Shaw, Sally F; Saxena, Salil; Cohen, Harvey Jay

    2016-01-01

    Telomere length (TL) is an indicator of cellular aging associated with longevity and psychosocial stress. We examine here the relationship between religious involvement and TL in 251 stressed female family caregivers recruited into a 2-site study. Religious involvement, perceived stress, caregiver burden, depressive symptoms, and social support were measured and correlated with TL in whole blood leukocytes. Results indicated a U-shaped relationship between religiosity and TL. Those scoring in the lowest 10% on religiosity tended to have the longest telomeres (5743 bp ± 367 vs. 5595 ± 383, p = 0.069). However, among the 90% of caregivers who were at least somewhat religious, religiosity was significantly and positively related to TL after controlling for covariates (B = 1.74, SE = 0.82, p = 0.034). Whereas nonreligious caregivers have relatively long telomeres, we found a positive relationship between religiosity and TL among those who are at least somewhat religious.

  3. Systematic and Cell Type-Specific Telomere Length Changes in Subsets of Lymphocytes

    PubMed Central

    Lin, Jue; Cheon, Joshua; Brown, Rashida; Coccia, Michael; Puterman, Eli; Aschbacher, Kirstin; Sinclair, Elizabeth; Epel, Elissa; Blackburn, Elizabeth H.

    2016-01-01

    Telomeres, the protective DNA-protein complexes at the ends of linear chromosomes, are important for genome stability. Leukocyte or peripheral blood mononuclear cell (PBMC) telomere length is a potential biomarker for human aging that integrates genetic, environmental, and lifestyle factors and is associated with mortality and risks for major diseases. However, only a limited number of studies have examined longitudinal changes of telomere length and few have reported data on sorted circulating immune cells. We examined the average telomere length (TL) in CD4+, CD8+CD28+, and CD8+CD28− T cells, B cells, and PBMCs, cross-sectionally and longitudinally, in a cohort of premenopausal women. We report that TL changes over 18 months were correlated among these three T cell types within the same participant. Additionally, PBMC TL change was also correlated with those of all three T cell types, and B cells. The rate of shortening for B cells was significantly greater than for the three T cell types. CD8+CD28− cells, despite having the shortest TL, showed significantly more rapid attrition when compared to CD8+CD28+ T cells. These results suggest systematically coordinated, yet cell type-specific responses to factors and pathways contribute to telomere length regulation. PMID:26977417

  4. Transposition as a mechanism for maintaining telomere length in Drosophila

    SciTech Connect

    Mason, J.M.; Biessmann, H.

    1993-12-31

    Telomeres are structures at the termini of linear chromosomes that serve to maintain the stability of those ends. Several functions have been attributed to telomeres, at least two of these are vital. The vital functions are (a) to {open_quotes}cap{close_quotes} the natural chromosome ends in order to distinguish them from broken ends and, thus, to protect them from recombination, repair, and degradation, and (b) to maintain chromosome length by periodic elongation and, thus, to counteract the inability of DNA polymerases to replicate linear chromosomes completely. While very little is known about capping, the mechanisms of telomere elongation in a number of organisms are being elucidated. Several models for elongation have been proposed. Recent evidence suggests that two of these may operate in different organisms or under different conditions. In many species elongation is accomplished by the interaction of two telomeric DNA repeats. The repeating unit is generally 6-8 basepairs (bp) long and guanine-rich on one strand. The sequence of the repeating unit is evolutionarily conserved, being very similar in ciliated protozoa, flowering plants and vertebrates. The second component is an enzyme, telomerase, that adds more copies of the repeating unit at the terminus. Telomerase resembles reverse transcriptases in structure and carries an associated RNA that is used as a template for the telomere extension.

  5. The Association of Telomere Length With Family Violence and Disruption

    PubMed Central

    Mabile, Emily; Brett, Zoë H.; Esteves, Kyle; Jones, Edward; Shirtcliff, Elizabeth A.; Theall, Katherine P.

    2014-01-01

    BACKGROUND: To enhance the understanding of biological mechanisms connecting early adversity and negative health, we examine the association between family interpersonal violence and disruption and telomere length in youth. These specific exposures were selected because of their established links with negative health consequences across the life-course. METHODS: Children, age 5 to 15, were recruited from the greater New Orleans area, and exposure to family disruption and violence was assessed through caregiver report. Telomere length, from buccal cell DNA (buccal telomere length [bTL]), was determined by using monochrome multiplex quantitative real-time polymerase chain reaction. The association between bTL and adversity exposure was tested (n = 80). RESULTS: Cumulative exposure to interpersonal violence and family disruption was correlated with bTL. Controlling for other sociodemographic factors, bTL was significantly shorter in children with higher exposure to family violence and disruption. Witnessing family violence exerted a particularly potent impact. A significant gender interaction was found (β = −0.0086, SE = 0.0031, z test= −2.79, P = .0053) and analysis revealed the effect only in girls. CONCLUSIONS: bTL is a molecular biomarker of adversity and allostatic load that is detectable in childhood. The present results extend previous studies by demonstrating that telomeres are sensitive to adversity within the overarching family domain. These findings suggest that the family ecology may be an important target for interventions to reduce the biological impact of adversity in the lives of children. PMID:24936002

  6. Telomere length in non-neoplastic colonic mucosa in ulcerative colitis (UC) and its relationship to the severe clinical phenotypes.

    PubMed

    Tahara, Tomomitsu; Shibata, Tomoyuki; Okubo, Masaaki; Kawamura, Tomohiko; Sumi, Kazuya; Ishizuka, Takamitsu; Nakamura, Masakatsu; Nagasaka, Mitsuo; Nakagawa, Yoshihito; Ohmiya, Naoki; Arisawa, Tomiyasu; Hirata, Ichiro

    2015-08-01

    Telomere shortening occurs with human aging in many organs and tissues and is accelerated by rapid cell turnover and oxidative injury. To clarify the clinical importance of telomere shortening in colonic mucosa in ulcerative colitis (UC), we measured average telomere length using quantitative real-time PCR in non-neoplastic colonic mucosa in UC patients and assessed its relationship to various clinical subtypes. Relative telomere length in genomic DNA was measured in colonic biopsies obtained from rectal inflammatory mucosa from 86 UC patients as well as paired non-inflammatory proximal colonic mucosae from 10 patients. Data were correlated with various clinical phenotypes. In paired samples, average relative telomere length of rectal inflammatory mucosa was shortened compared to normal appearing proximal colon in eight out of ten cases (p = 0.01). Telomere length shortening was significantly associated with more severe Mayo endoscopic subscore (p < 0.0001) and cases needing surgery due to toxic megacolon or cancer occurrence (p = 0.043). When the severe clinical phenotype was defined as having at least one of following phenotypes, more than two times of hospitalization, highest Mayo endoscopic subscore, steroid dependent, refractory, or needing operation, average relative telomere length was significantly shortened in the same phenotypes than the others (p = 0.003). Telomere shortening is associated with more severe clinical phenotypes of UC, reflecting severe inflammatory state in the colonic mucosa.

  7. Telomere length and telomerase expression in atypical adenomatous hyperplasia and small bronchioloalveolar carcinoma of the lung.

    PubMed

    Kawai, Toshiaki; Hiroi, Sadayuki; Nakanishi, Kuniaki; Meeker, Alan K

    2007-02-01

    Telomeres are located at the ends of every human chromosome and are subject to shortening at each cycle of cell division in cell senescence and early carcinogenesis. We examined the expression of telomeric DNA in 21 atypical adenomatous hyperplasias (AAHs) and 40 bronchioloalveolar carcinomas (BACs) measuring 2 cm or less in greatest diameter using fluorescent in situ hybridization and the expression of human telomerase reverse transcriptase (hTERT) messenger RNA (mRNA) in 35 AAHs and 37 BACs. The mean numbers of telomeric signals per nucleus were 5.0 in AAH and 7.4 in BAC, each significantly less than for normal cells (14.7; P < .0001), but the mean number of telomeric signals for AAH and BAC was not statistically different (P = .22). In "benign" lung samples, the pattern of expression of hTERT mRNA was barely detected in the nonciliated cells of the bronchioles and alveolar type II cells. Positive expression of hTERT mRNA was recognized in 66% of AAHs and 97% of BACs. Our results demonstrate telomere shortening, indicating its presence in the earliest phase of pulmonary carcinogenesis. Telomere length and telomerase may be involved in carcinogenesis in the lung.

  8. Offspring's leukocyte telomere length, paternal age, and telomere elongation in sperm.

    PubMed

    Kimura, Masayuki; Cherkas, Lynn F; Kato, Bernet S; Demissie, Serkalem; Hjelmborg, Jacob B; Brimacombe, Michael; Cupples, Adrienne; Hunkin, Janice L; Gardner, Jefferey P; Lu, Xiaobin; Cao, Xiaojian; Sastrasinh, Malinee; Province, Michael A; Hunt, Steven C; Christensen, Kaare; Levy, Daniel; Spector, Tim D; Aviv, Abraham

    2008-02-01

    Leukocyte telomere length (LTL) is a complex genetic trait. It shortens with age and is associated with a host of aging-related disorders. Recent studies have observed that offspring of older fathers have longer LTLs. We explored the relation between paternal age and offspring's LTLs in 4 different cohorts. Moreover, we examined the potential cause of the paternal age on offspring's LTL by delineating telomere parameters in sperm donors. We measured LTL by Southern blots in Caucasian men and women (n=3365), aged 18-94 years, from the Offspring of the Framingham Heart Study (Framingham Offspring), the NHLBI Family Heart Study (NHLBI-Heart), the Longitudinal Study of Aging Danish Twins (Danish Twins), and the UK Adult Twin Registry (UK Twins). Using Southern blots, Q-FISH, and flow-FISH, we also measured telomere parameters in sperm from 46 young (<30 years) and older (>50 years) donors. Paternal age had an independent effect, expressed by a longer LTL in males of the Framingham Offspring and Danish Twins, males and females of the NHLBI-Heart, and females of UK Twins. For every additional year of paternal age, LTL in offspring increased at a magnitude ranging from half to more than twice of the annual attrition in LTL with age. Moreover, sperm telomere length analyses were compatible with the emergence in older men of a subset of sperm with elongated telomeres. Paternal age exerts a considerable effect on the offspring's LTL, a phenomenon which might relate to telomere elongation in sperm from older men. The implications of this effect deserve detailed study. PMID:18282113

  9. Telomere Length in Aged Mayak PA Nuclear Workers Chronically Exposed to Internal Alpha and External Gamma Radiation.

    PubMed

    Scherthan, Harry; Sotnik, Natalia; Peper, Michel; Schrock, Gerrit; Azizova, Tamara; Abend, Michael

    2016-06-01

    Telomeres consist of GC-rich DNA repeats and the "shelterin" protein complex that together protect chromosome ends from fusion and degradation. Telomeres shorten with age due to incomplete end replication and upon exposure to environmental and intrinsic stressors. Exposure to ionizing radiation is known to modulate telomere length. However, the response of telomere length in humans chronically exposed to radiation is poorly understood. Here, we studied relative telomere length (RTL) by IQ-FISH to leukocyte nuclei in a group of 100 workers from the plutonium production facility at the Mayak Production Association (PA) who were chronically exposed to alpha-emitting ((239)Pu) radiation and/or gamma (photon) radiation, and 51 local residents serving as controls, with a similar mean age of about 80 years. We applied generalized linear statistical models adjusted for age at biosampling and the second exposure type on a linear scale and observed an age-dependent telomere length reduction. In those individuals with the lowest exposure, a significant reduction of about 20% RTL was observed, both for external gamma radiation (≤1 Gy) and internal alpha radiation (≤0.05-0.1 Gy to the red bone marrow). In highly exposed individuals (>0.1 Gy alpha, 1-1.5 Gy gamma), the RTL was similar to control. Stratification by gender revealed a significant (∼30%) telomere reduction in low-dose-exposed males, which was absent in females. While the gender differences in RTL may reflect different working conditions, lifestyle and/or telomere biology, absence of a dose response in the highly exposed individuals may reflect selection against cells with short telomeres or induction of telomere-protective effects. Our observations suggest that chronic systemic exposure to radiation leads to variable dose-dependent effects on telomere length. PMID:27340887

  10. Telomere Length in Aged Mayak PA Nuclear Workers Chronically Exposed to Internal Alpha and External Gamma Radiation.

    PubMed

    Scherthan, Harry; Sotnik, Natalia; Peper, Michel; Schrock, Gerrit; Azizova, Tamara; Abend, Michael

    2016-06-01

    Telomeres consist of GC-rich DNA repeats and the "shelterin" protein complex that together protect chromosome ends from fusion and degradation. Telomeres shorten with age due to incomplete end replication and upon exposure to environmental and intrinsic stressors. Exposure to ionizing radiation is known to modulate telomere length. However, the response of telomere length in humans chronically exposed to radiation is poorly understood. Here, we studied relative telomere length (RTL) by IQ-FISH to leukocyte nuclei in a group of 100 workers from the plutonium production facility at the Mayak Production Association (PA) who were chronically exposed to alpha-emitting ((239)Pu) radiation and/or gamma (photon) radiation, and 51 local residents serving as controls, with a similar mean age of about 80 years. We applied generalized linear statistical models adjusted for age at biosampling and the second exposure type on a linear scale and observed an age-dependent telomere length reduction. In those individuals with the lowest exposure, a significant reduction of about 20% RTL was observed, both for external gamma radiation (≤1 Gy) and internal alpha radiation (≤0.05-0.1 Gy to the red bone marrow). In highly exposed individuals (>0.1 Gy alpha, 1-1.5 Gy gamma), the RTL was similar to control. Stratification by gender revealed a significant (∼30%) telomere reduction in low-dose-exposed males, which was absent in females. While the gender differences in RTL may reflect different working conditions, lifestyle and/or telomere biology, absence of a dose response in the highly exposed individuals may reflect selection against cells with short telomeres or induction of telomere-protective effects. Our observations suggest that chronic systemic exposure to radiation leads to variable dose-dependent effects on telomere length.

  11. The principal role of Ku in telomere length maintenance is promotion of Est1 association with telomeres.

    PubMed

    Williams, Jaime M; Ouenzar, Faissal; Lemon, Laramie D; Chartrand, Pascal; Bertuch, Alison A

    2014-08-01

    Telomere length is tightly regulated in cells that express telomerase. The Saccharomyces cerevisiae Ku heterodimer, a DNA end-binding complex, positively regulates telomere length in a telomerase-dependent manner. Ku associates with the telomerase RNA subunit TLC1, and this association is required for TLC1 nuclear retention. Ku-TLC1 interaction also impacts the cell-cycle-regulated association of the telomerase catalytic subunit Est2 to telomeres. The promotion of TLC1 nuclear localization and Est2 recruitment have been proposed to be the principal role of Ku in telomere length maintenance, but neither model has been directly tested. Here we study the impact of forced recruitment of Est2 to telomeres on telomere length in the absence of Ku's ability to bind TLC1 or DNA ends. We show that tethering Est2 to telomeres does not promote efficient telomere elongation in the absence of Ku-TLC1 interaction or DNA end binding. Moreover, restoration of TLC1 nuclear localization, even when combined with Est2 recruitment, does not bypass the role of Ku. In contrast, forced recruitment of Est1, which has roles in telomerase recruitment and activation, to telomeres promotes efficient and progressive telomere elongation in the absence of Ku-TLC1 interaction, Ku DNA end binding, or Ku altogether. Ku associates with Est1 and Est2 in a TLC1-dependent manner and enhances Est1 recruitment to telomeres independently of Est2. Together, our results unexpectedly demonstrate that the principal role of Ku in telomere length maintenance is to promote the association of Est1 with telomeres, which may in turn allow for efficient recruitment and activation of the telomerase holoenzyme.

  12. A retrospective examination of mean relative telomere length in the Tasmanian Familial Hematological Malignancies Study

    PubMed Central

    BLACKBURN, NICHOLAS B.; CHARLESWORTH, JAC C.; MARTHICK, JAMES R.; TEGG, ELIZABETH M.; MARSDEN, KATHERINE A.; SRIKANTH, VELANDAI; BLANGERO, JOHN; LOWENTHAL, RAY M.; FOOTE, SIMON J.; DICKINSON, JOANNE L.

    2015-01-01

    Telomere length has a biological link to cancer, with excessive telomere shortening leading to genetic instability and resultant malignant transformation. Telomere length is heritable and genetic variants determining telomere length have been identified. Telomere biology has been implicated in the development of hematological malignancies (HMs), therefore, closer examination of telomere length in HMs may provide further insight into genetic etiology of disease development and support for telomere length as a prognostic factor in HMs. We retrospectively examined mean relative telomere length in the Tasmanian Familial Hematological Malignancies Study using a quantitative PCR method on genomic DNA from peripheral blood samples. Fifty-five familial HM cases, 191 unaffected relatives of familial HM cases and 75 non-familial HM cases were compared with 758 population controls. Variance components modeling was employed to identify factors influencing variation in telomere length. Overall, HM cases had shorter mean relative telomere length (P=2.9×10−6) and this was observed across both familial and non-familial HM cases (P=2.2×10−4 and 2.2×10−5, respectively) as well as additional subgroupings of HM cases according to broad subtypes. Mean relative telomere length was also significantly heritable (62.6%; P=4.7×10−5) in the HM families in the present study. We present new evidence of significantly shorter mean relative telomere length in both familial and non-familial HM cases from the same population adding further support to the potential use of telomere length as a prognostic factor in HMs. Whether telomere shortening is the cause of or the result of HMs is yet to be determined, but as telomere length was found to be highly heritable in our HM families this suggests that genetics driving the variation in telomere length is related to HM disease risk. PMID:25351806

  13. Regulating telomere length from the inside out: the replication fork model

    PubMed Central

    2016-01-01

    Telomere length is regulated around an equilibrium set point. Telomeres shorten during replication and are lengthened by telomerase. Disruption of the length equilibrium leads to disease; thus, it is important to understand the mechanisms that regulate length at the molecular level. The prevailing protein-counting model for regulating telomerase access to elongate the telomere does not explain accumulating evidence of a role of DNA replication in telomere length regulation. Here I present an alternative model: the replication fork model that can explain how passage of a replication fork and regulation of origin firing affect telomere length. PMID:27401551

  14. Telomere length and variation in telomere biology genes in individuals with osteosarcoma.

    PubMed

    Mirabello, Lisa; Richards, Elliott G; Duong, Linh M; Yu, Kai; Wang, Zhaoming; Cawthon, Richard; Berndt, Sonja I; Burdett, Laurie; Chowdhury, Salma; Teshome, Kedest; Douglass, Chester; Savage, Sharon A

    2011-01-01

    Osteosarcoma, the most common primary bone tumor, occurs most frequently in adolescents. Chromosomal aneuploidy is common in osteosarcoma cells, suggesting underlying chromosomal instability. Telomeres, located at chromosome ends, are essential for genomic stability; several studies have suggested that germline telomere length (TL) is associated with cancer risk. We hypothesized that TL and/or common genetic variation in telomere biology genes may be associated with risk of osteosarcoma. We investigated TL in peripheral blood DNA and 713 single nucleotide polymorphisms (SNPs) from 39 telomere biology genes in 98 osteosarcoma cases and 69 orthopedic controls. For the genotyping component, we added 1363 controls from the Prostate, Lung, Colorectal, and Ovarian Cancer ScreeningTrial. Short TL was not associated with osteosarcoma risk overall (OR 1.39, P=0.67), although there was a statistically significant association in females (OR 4.35, 95% Cl 1.20-15.74, P=0.03). Genotype analyses identified seven SNPs in TERF1 significantly associated with osteosarcoma risk after Bonferroni correction by gene. These SNPs were highly linked and associated with a reduced risk of osteosarcoma (OR 0.48-0.53, P=0.0001-0.0006). We also investigated associations between TL and telomere gene SNPs in osteosarcoma cases and orthopedic controls. Several SNPs were associated with TL prior to Bonferroni correction; one SNP in NOLA2 and one in MEN1 were marginally non-significant after correction (P(adj)=0.057 and 0.066, respectively). This pilot-study suggests that females with short telomeres may be at increased risk of osteosarcoma, and that SNPs in TERF1 are inversely associated with osteosarcoma risk.

  15. PML is required for telomere stability in non-neoplastic human cells.

    PubMed

    Marchesini, M; Matocci, R; Tasselli, L; Cambiaghi, V; Orleth, A; Furia, L; Marinelli, C; Lombardi, S; Sammarelli, G; Aversa, F; Minucci, S; Faretta, M; Pelicci, P G; Grignani, F

    2016-04-01

    Telomeres interact with numerous proteins, including components of the shelterin complex, whose alteration, similarly to proliferation-induced telomere shortening, initiates cellular senescence. In tumors, telomere length is maintained by Telomerase activity or by the Alternative Lengthening of Telomeres mechanism, whose hallmark is the telomeric localization of the promyelocytic leukemia (PML) protein. Whether PML contributes to telomeres maintenance in normal cells is unknown. We show that in normal human fibroblasts the PML protein associates with few telomeres, preferentially when they are damaged. Proliferation-induced telomere attrition or their damage due to alteration of the shelterin complex enhances the telomeric localization of PML, which is increased in human T-lymphocytes derived from patients genetically deficient in telomerase. In normal fibroblasts, PML depletion induces telomere damage, nuclear and chromosomal abnormalities, and senescence. Expression of the leukemia protein PML/RARα in hematopoietic progenitors displaces PML from telomeres and induces telomere shortening in the bone marrow of pre-leukemic mice. Our work provides a novel view of the physiologic function of PML, which participates in telomeres surveillance in normal cells. Our data further imply that a diminished PML function may contribute to cell senescence, genomic instability, and tumorigenesis.

  16. Telomere Transcripts Target Telomerase in Human Cancer Cells.

    PubMed

    Kreilmeier, Theresa; Mejri, Doris; Hauck, Marlene; Kleiter, Miriam; Holzmann, Klaus

    2016-01-01

    Long non-coding transcripts from telomeres, called telomeric repeat-containing RNA (TERRA), were identified as blocking telomerase activity (TA), a telomere maintenance mechanism (TMM), in tumors. We expressed recombinant TERRA transcripts in tumor cell lines with TA and with alternative lengthening of telomeres (ALT) to study effects on TMM and cell growth. Adeno- and lentivirus constructs (AV and LV) were established for transient and stable expression of approximately 130 units of telomere hexanucleotide repeats under control of cytomegalovirus (CMV) and human RNase P RNA H1 (hH1) promoters with and without polyadenylation, respectively. Six human tumor cell lines either using telomerase or ALT were infected and analyzed for TA levels. Pre-infection cells using telomerase had 1%-3% of the TERRA expression levels of ALT cells. AV and LV expression of recombinant TERRA in telomerase positive cells showed a 1.3-2.6 fold increase in TERRA levels, and a decrease in TA of 25%-58%. Dominant-negative or small hairpin RNA (shRNA) viral expression against human telomerase reverse transcriptase (hTERT) results in senescence, not induced by TERRA expression. Population doubling time, cell viability and TL (telomere length) were not impacted by ectopic TERRA expression. Clonal growth was reduced by TERRA expression in TA but not ALT cell lines. ALT cells were not affected by treatments applied. Established cell models and tools may be used to better understand the role of TERRA in the cell, especially for targeting telomerase. PMID:27537914

  17. Tankyrase 2 Poly(ADP-Ribose) Polymerase Domain-Deleted Mice Exhibit Growth Defects but Have Normal Telomere Length and Capping

    SciTech Connect

    Hsiao, Susan J; Poitras, Marc; Cook, Brandoch; Liu, Yie; Smith, Susan

    2006-03-01

    Regulation of telomere length maintenance and capping are a critical cell functions in both normal and tumor cells. Tankyrase 2 (Tnks2) is a poly(ADP-ribose) polymerase (PARP) that has been shown to modify itself and TRF1, a telomere-binding protein. We show here by overexpression studies that tankyrase 2, like its closely related homolog tankyrase 1, can function as a positive regulator of telomere length in human cells, dependent on its catalytic PARP activity. To study the role of Tnks2 in vivo, we generated mice with the Tnks2 PARP domain deleted. These mice are viable and fertile but display a growth retardation phenotype. Telomere analysis by quantitative fluorescence in situ hybridization (FISH), flow-FISH, and restriction fragment analysis showed no change in telomere length or telomere capping in these mice. To determine the requirement foTnks2 in long-term maintenance of telomeres, we generated embryonic stem cells with the Tnks2 PARP domain deleted and observed no change, even upon prolonged growth, in telomere length or telomere capping. Together these results suggest that Tnkjs2 has a role in normal growth and development but is not essential for telomere length maintenance or telomere capping in mice.

  18. Telomeric G-Tail Length and Hospitalization for Cardiovascular Events in Hemodialysis Patients

    PubMed Central

    Hirashio, Shuma; Nakashima, Ayumu; Doi, Shigehiro; Anno, Kumiko; Aoki, Eriko; Shimamoto, Akira; Yorioka, Noriaki; Kohno, Nobuoki; Masaki, Takao

    2014-01-01

    Background and objectives Telomeric G-tails play a pivotal role in maintaining the intramolecular loop structure of telomeres. Previous in vitro studies have suggested that the erosion of telomeric G-tails triggers cellular senescence, leading to organ dysfunction and atherosclerosis. The authors recently established a method to measure telomeric G-tail length using a hybridization protection assay. Using this method, this study investigated whether telomeric G-tail length could be used as a novel predictor for future cardiovascular events in hemodialysis patients. Design, setting, participants, & measurements A prospective observational study was performed involving a cohort of 203 Japanese hemodialysis patients to examine the lengths of telomeric G-tails and total telomeres and subsequent cardiovascular events during a median follow-up period of 48 months. The lengths of telomeric G-tails and total telomeres were also measured in 203 participants who did not have CKD and who were age- and sex-matched to hemodialysis patients. Results The lengths of telomeric G-tails and total telomeres were significantly shorter in hemodialysis patients than in control subjects. Telomeric G-tails, but not total telomeres, were independently and negatively associated with clinical history of cardiovascular disease. During follow-up, 80 cardiovascular events occurred. Total telomere length did not predict cardiovascular events. However, the length of telomeric G-tails was associated with new-onset cardiovascular events (hazard ratio per log luminescence signals, 0.12; 95% confidence interval, 0.12 to 0.50) that persisted after adjustment for age, sex, diabetes mellitus, clinical history of cardiovascular disease, inflammation, use of vitamin D, and serum levels of phosphate and intact parathyroid hormone. Conclusions Longer telomeric G-tail length is associated with a lower risk of future cardiovascular events in hemodialysis patients. PMID:25237070

  19. Metabolomics profiling reveals novel markers for leukocyte telomere length

    PubMed Central

    Zierer, Jonas; Kastenmüller, Gabi; Suhre, Karsten; Gieger, Christian; Codd, Veryan; Tsai, Pei-Chien; Bell, Jordana; Peters, Annette; Strauch, Konstantin; Schulz, Holger; Weidinger, Stephan; Mohney, Robert P.; Samani, Nilesh J.; Spector, Tim; Mangino, Massimo; Menni, Cristina

    2016-01-01

    Leukocyte telomere length (LTL) is considered one of the most predictive markers of biological aging. The aim of this study was to identify novel pathways regulating LTL using a metabolomics approach. To this end, we tested associations between 280 blood metabolites and LTL in 3511 females from TwinsUK and replicated our results in the KORA cohort. We furthermore tested significant metabolites for associations with several aging-related phenotypes, gene expression markers and epigenetic markers to investigate potential underlying pathways. Five metabolites were associated with LTL: Two lysolipids, 1-stearoylglycerophosphoinositol (P=1.6×10−5) and 1-palmitoylglycerophosphoinositol (P=1.6×10−5), were found to be negatively associated with LTL and positively associated with phospholipase A2 expression levels suggesting an involvement of fatty acid metabolism and particularly membrane composition in biological aging. Moreover, two gamma-glutamyl amino acids, gamma-glutamyltyrosine (P=2.5×10−6) and gamma-glutamylphenylalanine (P=1.7×10−5), were negatively correlated with LTL. Both are products of the glutathione cycle and markers for increased oxidative stress. Metabolites were also correlated with functional measures of aging, i.e. higher blood pressure and HDL cholesterol levels and poorer lung, liver and kidney function. Our results suggest an involvement of altered fatty acid metabolism and increased oxidative stress in human biological aging, reflected by LTL and age-related phenotypes of vital organ systems. PMID:26797767

  20. Nature vs nurture: interplay between the genetic control of telomere length and environmental factors.

    PubMed

    Harari, Yaniv; Romano, Gal-Hagit; Ungar, Lior; Kupiec, Martin

    2013-11-15

    Telomeres are nucleoprotein structures that cap the ends of the linear eukaryotic chromosomes, thus protecting their stability and integrity. They play important roles in DNA replication and repair and are central to our understanding of aging and cancer development. In rapidly dividing cells, telomere length is maintained by the activity of telomerase. About 400 TLM (telomere length maintenance) genes have been identified in yeast, as participants of an intricate homeostasis network that keeps telomere length constant. Two papers have recently shown that despite this extremely complex control, telomere length can be manipulated by external stimuli. These results have profound implications for our understanding of cellular homeostatic systems in general and of telomere length maintenance in particular. In addition, they point to the possibility of developing aging and cancer therapies based on telomere length manipulation. PMID:24091626

  1. Nature vs nurture: interplay between the genetic control of telomere length and environmental factors.

    PubMed

    Harari, Yaniv; Romano, Gal-Hagit; Ungar, Lior; Kupiec, Martin

    2013-11-15

    Telomeres are nucleoprotein structures that cap the ends of the linear eukaryotic chromosomes, thus protecting their stability and integrity. They play important roles in DNA replication and repair and are central to our understanding of aging and cancer development. In rapidly dividing cells, telomere length is maintained by the activity of telomerase. About 400 TLM (telomere length maintenance) genes have been identified in yeast, as participants of an intricate homeostasis network that keeps telomere length constant. Two papers have recently shown that despite this extremely complex control, telomere length can be manipulated by external stimuli. These results have profound implications for our understanding of cellular homeostatic systems in general and of telomere length maintenance in particular. In addition, they point to the possibility of developing aging and cancer therapies based on telomere length manipulation.

  2. Genetic Architecture of Natural Variation of Telomere Length in Arabidopsis thaliana

    PubMed Central

    Fulcher, Nick; Teubenbacher, Astrid; Kerdaffrec, Envel; Farlow, Ashley; Nordborg, Magnus; Riha, Karel

    2015-01-01

    Telomeres represent the repetitive sequences that cap chromosome ends and are essential for their protection. Telomere length is known to be highly heritable and is derived from a homeostatic balance between telomeric lengthening and shortening activities. Specific loci that form the genetic framework underlying telomere length homeostasis, however, are not well understood. To investigate the extent of natural variation of telomere length in Arabidopsis thaliana, we examined 229 worldwide accessions by terminal restriction fragment analysis. The results showed a wide range of telomere lengths that are specific to individual accessions. To identify loci that are responsible for this variation, we adopted a quantitative trait loci (QTL) mapping approach with multiple recombinant inbred line (RIL) populations. A doubled haploid RIL population was first produced using centromere-mediated genome elimination between accessions with long (Pro-0) and intermediate (Col-0) telomere lengths. Composite interval mapping analysis of this population along with two established RIL populations (Ler-2/Cvi-0 and Est-1/Col-0) revealed a number of shared and unique QTL. QTL detected in the Ler-2/Cvi-0 population were examined using near isogenic lines that confirmed causative regions on chromosomes 1 and 2. In conclusion, this work describes the extent of natural variation of telomere length in A. thaliana, identifies a network of QTL that influence telomere length homeostasis, examines telomere length dynamics in plants with hybrid backgrounds, and shows the effects of two identified regions on telomere length regulation. PMID:25488978

  3. Genetic architecture of natural variation of telomere length in Arabidopsis thaliana.

    PubMed

    Fulcher, Nick; Teubenbacher, Astrid; Kerdaffrec, Envel; Farlow, Ashley; Nordborg, Magnus; Riha, Karel

    2015-02-01

    Telomeres represent the repetitive sequences that cap chromosome ends and are essential for their protection. Telomere length is known to be highly heritable and is derived from a homeostatic balance between telomeric lengthening and shortening activities. Specific loci that form the genetic framework underlying telomere length homeostasis, however, are not well understood. To investigate the extent of natural variation of telomere length in Arabidopsis thaliana, we examined 229 worldwide accessions by terminal restriction fragment analysis. The results showed a wide range of telomere lengths that are specific to individual accessions. To identify loci that are responsible for this variation, we adopted a quantitative trait loci (QTL) mapping approach with multiple recombinant inbred line (RIL) populations. A doubled haploid RIL population was first produced using centromere-mediated genome elimination between accessions with long (Pro-0) and intermediate (Col-0) telomere lengths. Composite interval mapping analysis of this population along with two established RIL populations (Ler-2/Cvi-0 and Est-1/Col-0) revealed a number of shared and unique QTL. QTL detected in the Ler-2/Cvi-0 population were examined using near isogenic lines that confirmed causative regions on chromosomes 1 and 2. In conclusion, this work describes the extent of natural variation of telomere length in A. thaliana, identifies a network of QTL that influence telomere length homeostasis, examines telomere length dynamics in plants with hybrid backgrounds, and shows the effects of two identified regions on telomere length regulation.

  4. Stn1 is critical for telomere maintenance and long-term viability of somatic human cells.

    PubMed

    Boccardi, Virginia; Razdan, Neetu; Kaplunov, Jessica; Mundra, Jyoti J; Kimura, Masayuki; Aviv, Abraham; Herbig, Utz

    2015-06-01

    Disruption of telomere maintenance pathways leads to accelerated entry into cellular senescence, a stable proliferative arrest that promotes aging-associated disorders in some mammals. The budding yeast CST complex, comprising Cdc13, Stn1, and Ctc1, is critical for telomere replication, length regulation, and end protection. Although mammalian homologues of CST have been identified recently, their role and function for telomere maintenance in normal somatic human cells are still incompletely understood. Here, we characterize the function of human Stn1 in cultured human fibroblasts and demonstrate its critical role in telomere replication, length regulation, and function. In the absence of high telomerase activity, shRNA-mediated knockdown of hStn1 resulted in aberrant and fragile telomeric structures, stochastic telomere attrition, increased telomere erosion rates, telomere dysfunction, and consequently accelerated entry into cellular senescence. Oxidative stress augmented the defects caused by Stn1 knockdown leading to almost immediate cessation of cell proliferation. In contrast, overexpression of hTERT suppressed some of the defects caused by hStn1 knockdown suggesting that telomerase can partially compensate for hStn1 loss. Our findings reveal a critical role for human Stn1 in telomere length maintenance and function, supporting the model that efficient replication of telomeric repeats is critical for long-term viability of normal somatic mammalian cells.

  5. Global methylation, oxidative stress, and relative telomere length in biliary atresia patients.

    PubMed

    Udomsinprasert, Wanvisa; Kitkumthorn, Nakarin; Mutirangura, Apiwat; Chongsrisawat, Voranush; Poovorawan, Yong; Honsawek, Sittisak

    2016-01-01

    Alu and LINE-1 elements are retrotransposons with a ubiquitous presence in the human genome that can cause genomic instability, specifically relating to telomere length. Genotoxic agents may induce methylation of retrotransposons, in addition to oxidative DNA damage in the form of 8-hydroxy-2'-deoxyguanosine (8-OHdG). Methylation of retrotransposons induced by these agents may contribute to biliary atresia (BA) etiology. Here, we investigated correlations between global methylation, 8-OHdG, and relative telomere length, as well as reporting on Alu and LINE-1 hypomethylation in BA patients. Alu and LINE-1 hypomethylation were found to be associated with elevated risk of BA (OR = 4.07; 95% CI: 2.27-7.32; P < 0.0001 and OR = 3.51; 95% CI: 1.87-6.59; P < 0.0001, respectively). Furthermore, LINE-1 methylation was associated with liver stiffness in BA patients (β coefficient = -0.17; 95% CI: -0.24 to -0.10; P < 0.0001). Stratified analysis revealed negative correlations between Alu and LINE-1 methylation and 8-OHdG in BA patients (P < 0.0001). In contrast, positive relationships were identified between Alu and LINE-1 methylation and relative telomere length in BA patients (P < 0.0001). These findings suggest that retrotransposon hypomethylation is associated with plasma 8-OHdG and telomere length in BA patients. PMID:27243754

  6. Seasonal variation in telomere length of a hibernating rodent.

    PubMed

    Turbill, Christopher; Ruf, Thomas; Smith, Steve; Bieber, Claudia

    2013-04-23

    Small hibernating rodents have greater maximum lifespans and hence appear to age more slowly than similar-sized non-hibernators. We tested for a direct effect of hibernation on somatic maintenance and ageing by measuring seasonal changes in relative telomere length (RTL) in the edible dormouse Glis glis. Average RTL in our population did not change significantly over the hibernation season, and a regression model explaining individual variation in post-hibernation RTL suggested a significant negative effect of the reduction in body mass over the inactive hibernation period (an index of time spent euthermic), supporting the idea that torpor slows ageing. Over the active season, RTL on average decreased in sub-adults but increased in adults, supporting previous findings of greater telomere shortening at younger ages. Telomere length increase might also have been associated with reproduction, which occurred only in adults. Our study reveals how seasonal changes in physiological state influence the progress of life-history traits, such as somatic maintenance and ageing, in a small hibernating rodent. PMID:23389666

  7. Longer telomere length in COPD patients with α1-antitrypsin deficiency independent of lung function.

    PubMed

    Saferali, Aabida; Lee, Jee; Sin, Don D; Rouhani, Farshid N; Brantly, Mark L; Sandford, Andrew J

    2014-01-01

    Oxidative stress is involved in the pathogenesis of airway obstruction in α1-antitrypsin deficient patients. This may result in a shortening of telomere length, resulting in cellular senescence. To test whether telomere length differs in α1-antitrypsin deficient patients compared with controls, we measured telomere length in DNA from peripheral blood cells of 217 α1-antitrypsin deficient patients and 217 control COPD patients. We also tested for differences in telomere length between DNA from blood and DNA from lung tissue in a subset of 51 controls. We found that telomere length in the blood was significantly longer in α1-antitrypsin deficient COPD patients compared with control COPD patients (p = 1×10(-29)). Telomere length was not related to lung function in α1-antitrypsin deficient patients (p = 0.3122) or in COPD controls (p = 0.1430). Although mean telomere length was significantly shorter in the blood when compared with the lungs (p = 0.0078), telomere length was correlated between the two tissue types (p = 0.0122). Our results indicate that telomere length is better preserved in α1-antitrypsin deficient COPD patients than in non-deficient patients. In addition, measurement of telomere length in the blood may be a suitable surrogate for measurement in the lung.

  8. Dynamics of telomere length in different age groups in a Latvian population.

    PubMed

    Zole, Egija; Pliss, Liana; Ranka, Renate; Krumina, Astrida; Baumanis, Viesturs

    2013-12-01

    The shortening of telomeres with ageing is a well-documented observation; however, the reported number of nucleotides in telomeres varies between different laboratories and studies. Such variability is likely caused by ethnic differences between the populations studied. Until now, there were no studies that investigated the variability of telomere length in a senescent Latvian population of the most common mitochondrial haplogroups, defined as H (45%), U (25%), Y chromosomal N1c (40%) and R1a1 (40%). Telomere length was determined in 121 individuals in different age groups, including a control group containing individuals of 20-40 years old and groups of individuals between 60-70 years old, 71-80 years old, 81-90 years old, and above 90 years old. Telomere length was determined using the Southern blot telomeric restriction fragment assay (TRF). Decreased telomere length with ageing was confirmed, but a comparison of centenarians and individuals between 60-90 years of age did not demonstrate a significant difference in telomere length. However, significant variability in telomere length was observed in the control group, indicating probable rapid telomere shortening in some individuals that could lead up to development of health status decline appearing with ageing. Telomere length measured in mononuclear blood cells (MNC) was compared with the telomere length measured in whole peripheral white blood cells (WBC) using TRF. Telomere length in MNC was longer than in WBC for the control group with individuals 20 to 40 years old; in contrast, for the group of individuals aged 65 to 85 years old, measured telomere length was shorter in MNC when compared to WBC.

  9. Effects of donor cells' sex on nuclear transfer efficiency and telomere lengths of cloned goats.

    PubMed

    Liu, H-J; Peng, H; Hu, C-C; Li, X-Y; Zhang, J-L; Zheng, Z; Zhang, W-C

    2016-10-01

    The aim of this study was to investigate the effects of donor cells' sex on nuclear transfer efficiency and telomere length of cloned goats from adult skin fibroblast cells. The telomere length of somatic cell cloned goats and their offspring was determined by measuring their mean terminal restriction fragment (TRF) length. The result showed that (i) reconstructed embryos with fibroblast cells from males Boer goats obtained significantly higher kids rate and rate of live kids than those of female embryos and (ii) the telomere lengths of four female cloned goats were shorter compared to their donor cells, but five male cloned goats had the same telomere length with their donor cells, mainly due to great variation existed among them. The offspring from female cloned goats had the same telomere length with their age-matched counterparts. In conclusion, the donor cells' sex had significant effects on nuclear transfer efficiency and telomere lengths of cloned goats.

  10. Effects of donor cells' sex on nuclear transfer efficiency and telomere lengths of cloned goats.

    PubMed

    Liu, H-J; Peng, H; Hu, C-C; Li, X-Y; Zhang, J-L; Zheng, Z; Zhang, W-C

    2016-10-01

    The aim of this study was to investigate the effects of donor cells' sex on nuclear transfer efficiency and telomere length of cloned goats from adult skin fibroblast cells. The telomere length of somatic cell cloned goats and their offspring was determined by measuring their mean terminal restriction fragment (TRF) length. The result showed that (i) reconstructed embryos with fibroblast cells from males Boer goats obtained significantly higher kids rate and rate of live kids than those of female embryos and (ii) the telomere lengths of four female cloned goats were shorter compared to their donor cells, but five male cloned goats had the same telomere length with their donor cells, mainly due to great variation existed among them. The offspring from female cloned goats had the same telomere length with their age-matched counterparts. In conclusion, the donor cells' sex had significant effects on nuclear transfer efficiency and telomere lengths of cloned goats. PMID:27558653

  11. Human Rap1 modulates TRF2 attraction to telomeric DNA

    PubMed Central

    Janoušková, Eliška; Nečasová, Ivona; Pavloušková, Jana; Zimmermann, Michal; Hluchý, Milan; Marini, Victoria; Nováková, Monika; Hofr, Ctirad

    2015-01-01

    More than two decades of genetic research have identified and assigned main biological functions of shelterin proteins that safeguard telomeres. However, a molecular mechanism of how each protein subunit contributes to the protecting function of the whole shelterin complex remains elusive. Human Repressor activator protein 1 (Rap1) forms a multifunctional complex with Telomeric Repeat binding Factor 2 (TRF2). Rap1–TRF2 complex is a critical part of shelterin as it suppresses homology-directed repair in Ku 70/80 heterodimer absence. To understand how Rap1 affects key functions of TRF2, we investigated full-length Rap1 binding to TRF2 and Rap1–TRF2 complex interactions with double-stranded DNA by quantitative biochemical approaches. We observed that Rap1 reduces the overall DNA duplex binding affinity of TRF2 but increases the selectivity of TRF2 to telomeric DNA. Additionally, we observed that Rap1 induces a partial release of TRF2 from DNA duplex. The improved TRF2 selectivity to telomeric DNA is caused by less pronounced electrostatic attractions between TRF2 and DNA in Rap1 presence. Thus, Rap1 prompts more accurate and selective TRF2 recognition of telomeric DNA and TRF2 localization on single/double-strand DNA junctions. These quantitative functional studies contribute to the understanding of the selective recognition of telomeric DNA by the whole shelterin complex. PMID:25675958

  12. Computel: computation of mean telomere length from whole-genome next-generation sequencing data.

    PubMed

    Nersisyan, Lilit; Arakelyan, Arsen

    2015-01-01

    Telomeres are the ends of eukaryotic chromosomes, consisting of consecutive short repeats that protect chromosome ends from degradation. Telomeres shorten with each cell division, leading to replicative cell senescence. Deregulation of telomere length homeostasis is associated with the development of various age-related diseases and cancers. A number of experimental techniques exist for telomere length measurement; however, until recently, the absence of tools for extracting telomere lengths from high-throughput sequencing data has significantly obscured the association of telomere length with molecular processes in normal and diseased conditions. We have developed Computel, a program in R for computing mean telomere length from whole-genome next-generation sequencing data. Computel is open source, and is freely available at https://github.com/lilit-nersisyan/computel. It utilizes a short-read alignment-based approach and integrates various popular tools for sequencing data analysis. We validated it with synthetic and experimental data, and compared its performance with the previously available software. The results have shown that Computel outperforms existing software in accuracy, independence of results from sequencing conditions, stability against inherent sequencing errors, and better ability to distinguish pure telomeric sequences from interstitial telomeric repeats. By providing a highly reliable methodology for determining telomere lengths from whole-genome sequencing data, Computel should help to elucidate the role of telomeres in cellular health and disease.

  13. Telomere Length, Proviral Load and Neurologic Impairment in HTLV-1 and HTLV-2-Infected Subjects.

    PubMed

    Usadi, Benjamin; Bruhn, Roberta; Lin, Jue; Lee, Tzong-Hae; Blackburn, Elizabeth; Murphy, Edward L

    2016-01-01

    Short or damaged telomeres have been implicated in degenerative conditions. We hypothesized that analysis of telomere length (TL) in human T-cell lymphotropic virus (HTLV) infection and HTLV-associated neuropathy might provide clues to the etiology of HTLV-associated disease and viral dynamics. A subset of 45 human T-cell lymphotropic virus type 1 (HTLV-1), 45 human T-cell lymphotropic virus type 2 (HTLV-2), and 45 seronegative subjects was selected from the larger HTLV Outcomes Study (HOST) cohort, matched on age, sex and race/ethnicity. Telomere-to-single-copy gene (T/S) ratio (a measure of TL) and HTLV-1 and HTLV-2 proviral loads were measured in peripheral blood mononuclear cells (PBMCs) using quantitative PCR (qPCR). Vibration sensation measured by tuning fork during neurologic examinations performed as part of the HOST study allowed for an assessment of peripheral neuropathy. TL was compared between groups using t-tests, linear and logistic regression. Mean T/S ratio was 1.02 ± 0.16 in HTLV-1, 1.03 ± 0.17 in HTLV-2 and 0.99 ± 0.18 in HTLV seronegative subjects (p = 0.322). TL was not associated with HTLV-1 or -2 proviral load. Shorter TL was significantly associated with impaired vibration sense in the HTLV-2 positive group only. Overall, we found no evidence that telomere length was affected by chronic HTLV-1 and HTLV-2 infection. That TL was only associated with peripheral neuropathy in the HTLV-2-positive group is intriguing, but should be interpreted cautiously. Studies with larger sample size and telomere length measurement in lymphocyte subsets may clarify the relationship between TL and HTLV-infection. PMID:27529270

  14. Telomere Length, Proviral Load and Neurologic Impairment in HTLV-1 and HTLV-2-Infected Subjects

    PubMed Central

    Usadi, Benjamin; Bruhn, Roberta; Lin, Jue; Lee, Tzong-Hae; Blackburn, Elizabeth; Murphy, Edward L.

    2016-01-01

    Short or damaged telomeres have been implicated in degenerative conditions. We hypothesized that analysis of telomere length (TL) in human T-cell lymphotropic virus (HTLV) infection and HTLV-associated neuropathy might provide clues to the etiology of HTLV-associated disease and viral dynamics. A subset of 45 human T-cell lymphotropic virus type 1 (HTLV-1), 45 human T-cell lymphotropic virus type 2 (HTLV-2), and 45 seronegative subjects was selected from the larger HTLV Outcomes Study (HOST) cohort, matched on age, sex and race/ethnicity. Telomere-to-single-copy gene (T/S) ratio (a measure of TL) and HTLV-1 and HTLV-2 proviral loads were measured in peripheral blood mononuclear cells (PBMCs) using quantitative PCR (qPCR). Vibration sensation measured by tuning fork during neurologic examinations performed as part of the HOST study allowed for an assessment of peripheral neuropathy. TL was compared between groups using t-tests, linear and logistic regression. Mean T/S ratio was 1.02 ± 0.16 in HTLV-1, 1.03 ± 0.17 in HTLV-2 and 0.99 ± 0.18 in HTLV seronegative subjects (p = 0.322). TL was not associated with HTLV-1 or -2 proviral load. Shorter TL was significantly associated with impaired vibration sense in the HTLV-2 positive group only. Overall, we found no evidence that telomere length was affected by chronic HTLV-1 and HTLV-2 infection. That TL was only associated with peripheral neuropathy in the HTLV-2-positive group is intriguing, but should be interpreted cautiously. Studies with larger sample size and telomere length measurement in lymphocyte subsets may clarify the relationship between TL and HTLV-infection. PMID:27529270

  15. Human UPF1 interacts with TPP1 and telomerase and sustains telomere leading-strand replication

    PubMed Central

    Chawla, Raghav; Redon, Sophie; Raftopoulou, Christina; Wischnewski, Harry; Gagos, Sarantis; Azzalin, Claus M

    2011-01-01

    Eukaryotic up-frameshift 1 (UPF1) is a nucleic acid-dependent ATPase and 5′-to-3′ helicase, best characterized for its roles in cytoplasmic RNA quality control. We previously demonstrated that human UPF1 binds to telomeres in vivo and its depletion leads to telomere instability. Here, we show that UPF1 is present at telomeres at least during S and G2/M phases and that UPF1 association with telomeres is stimulated by the phosphoinositide 3-kinase (PI3K)-related protein kinase ataxia telangiectasia mutated and Rad3-related (ATR) and by telomere elongation. UPF1 physically interacts with the telomeric factor TPP1 and with telomerase. Akin to UPF1 binding to telomeres, this latter interaction is mediated by ATR. Moreover, the ATPase activity of UPF1 is required to prevent the telomeric defects observed upon UPF1 depletion, and these defects stem predominantly from inefficient telomere leading-strand replication. Our results portray a scenario where UPF1 orchestrates crucial aspects of telomere biology, including telomere replication and telomere length homeostasis. PMID:21829167

  16. DCAF4, a novel gene associated with leucocyte telomere length

    PubMed Central

    Mangino, Massimo; Christiansen, Lene; Stone, Rivka; Hunt, Steven C; Horvath, Kent; Eisenberg, Dan T A; Kimura, Masayuki; Petersen, Inge; Kark, Jeremy D; Herbig, Utz; Reiner, Alex P; Benetos, Athanase; Codd, Veryan; Nyholt, Dale R; Sinnreich, Ronit; Christensen, Kaare; Nassar, Hisham; Hwang, Shih-Jen; Levy, Daniel; Bataille, Veronique; Fitzpatrick, Annette L; Chen, Wei; Berenson, Gerald S; Samani, Nilesh J; Martin, Nicholas G; Tishkoff, Sarah; Schork, Nicholas J; Kyvik, Kirsten Ohm; Dalgård, Christine; Spector, Timothy D; Aviv, Abraham

    2015-01-01

    Background Leucocyte telomere length (LTL), which is fashioned by multiple genes, has been linked to a host of human diseases, including sporadic melanoma. A number of genes associated with LTL have already been identified through genome-wide association studies. The main aim of this study was to establish whether DCAF4 (DDB1 and CUL4-associated factor 4) is associated with LTL. In addition, using ingenuity pathway analysis (IPA), we examined whether LTL-associated genes in the general population might partially explain the inherently longer LTL in patients with sporadic melanoma, the risk for which is increased with ultraviolet radiation (UVR). Results Genome-wide association (GWA) meta-analysis and de novo genotyping of 20 022 individuals revealed a novel association (p=6.4×10−10) between LTL and rs2535913, which lies within DCAF4. Notably, eQTL analysis showed that rs2535913 is associated with decline in DCAF4 expressions in both lymphoblastoid cells and sun-exposed skin (p=4.1×10−3 and 2×10−3, respectively). Moreover, IPA revealed that LTL-associated genes, derived from GWA meta-analysis (N=9190), are over-represented among genes engaged in melanoma pathways. Meeting increasingly stringent p value thresholds (p<0.05, <0.01, <0.005, <0.001) in the LTL-GWA meta-analysis, these genes were jointly over-represented for melanoma at p values ranging from 1.97×10−169 to 3.42×10−24. Conclusions We uncovered a new locus associated with LTL in the general population. We also provided preliminary findings that suggest a link of LTL through genetic mechanisms with UVR and melanoma in the general population. PMID:25624462

  17. Genetically predicted longer telomere length is associated with increased risk of B-cell lymphoma subtypes.

    PubMed

    Machiela, Mitchell J; Lan, Qing; Slager, Susan L; Vermeulen, Roel C H; Teras, Lauren R; Camp, Nicola J; Cerhan, James R; Spinelli, John J; Wang, Sophia S; Nieters, Alexandra; Vijai, Joseph; Yeager, Meredith; Wang, Zhaoming; Ghesquières, Hervé; McKay, James; Conde, Lucia; de Bakker, Paul I W; Cox, David G; Burdett, Laurie; Monnereau, Alain; Flowers, Christopher R; De Roos, Anneclaire J; Brooks-Wilson, Angela R; Giles, Graham G; Melbye, Mads; Gu, Jian; Jackson, Rebecca D; Kane, Eleanor; Purdue, Mark P; Vajdic, Claire M; Albanes, Demetrius; Kelly, Rachel S; Zucca, Mariagrazia; Bertrand, Kimberly A; Zeleniuch-Jacquotte, Anne; Lawrence, Charles; Hutchinson, Amy; Zhi, Degui; Habermann, Thomas M; Link, Brian K; Novak, Anne J; Dogan, Ahmet; Asmann, Yan W; Liebow, Mark; Thompson, Carrie A; Ansell, Stephen M; Witzig, Thomas E; Tilly, Hervé; Haioun, Corinne; Molina, Thierry J; Hjalgrim, Henrik; Glimelius, Bengt; Adami, Hans-Olov; Roos, Göran; Bracci, Paige M; Riby, Jacques; Smith, Martyn T; Holly, Elizabeth A; Cozen, Wendy; Hartge, Patricia; Morton, Lindsay M; Severson, Richard K; Tinker, Lesley F; North, Kari E; Becker, Nikolaus; Benavente, Yolanda; Boffetta, Paolo; Brennan, Paul; Foretova, Lenka; Maynadie, Marc; Staines, Anthony; Lightfoot, Tracy; Crouch, Simon; Smith, Alex; Roman, Eve; Diver, W Ryan; Offit, Kenneth; Zelenetz, Andrew; Klein, Robert J; Villano, Danylo J; Zheng, Tongzhang; Zhang, Yawei; Holford, Theodore R; Turner, Jenny; Southey, Melissa C; Clavel, Jacqueline; Virtamo, Jarmo; Weinstein, Stephanie; Riboli, Elio; Vineis, Paolo; Kaaks, Rudolph; Boeing, Heiner; Tjønneland, Anne; Angelucci, Emanuele; Di Lollo, Simonetta; Rais, Marco; De Vivo, Immaculata; Giovannucci, Edward; Kraft, Peter; Huang, Jinyan; Ma, Baoshan; Ye, Yuanqing; Chiu, Brian C H; Liang, Liming; Park, Ju-Hyun; Chung, Charles C; Weisenburger, Dennis D; Fraumeni, Joseph F; Salles, Gilles; Glenn, Martha; Cannon-Albright, Lisa; Curtin, Karen; Wu, Xifeng; Smedby, Karin E; de Sanjose, Silvia; Skibola, Christine F; Berndt, Sonja I; Birmann, Brenda M; Chanock, Stephen J; Rothman, Nathaniel

    2016-04-15

    Evidence from a small number of studies suggests that longer telomere length measured in peripheral leukocytes is associated with an increased risk of non-Hodgkin lymphoma (NHL). However, these studies may be biased by reverse causation, confounded by unmeasured environmental exposures and might miss time points for which prospective telomere measurement would best reveal a relationship between telomere length and NHL risk. We performed an analysis of genetically inferred telomere length and NHL risk in a study of 10 102 NHL cases of the four most common B-cell histologic types and 9562 controls using a genetic risk score (GRS) comprising nine telomere length-associated single-nucleotide polymorphisms. This approach uses existing genotype data and estimates telomere length by weighing the number of telomere length-associated variant alleles an individual carries with the published change in kb of telomere length. The analysis of the telomere length GRS resulted in an association between longer telomere length and increased NHL risk [four B-cell histologic types combined; odds ratio (OR) = 1.49, 95% CI 1.22-1.82,P-value = 8.5 × 10(-5)]. Subtype-specific analyses indicated that chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL) was the principal NHL subtype contributing to this association (OR = 2.60, 95% CI 1.93-3.51,P-value = 4.0 × 10(-10)). Significant interactions were observed across strata of sex for CLL/SLL and marginal zone lymphoma subtypes as well as age for the follicular lymphoma subtype. Our results indicate that a genetic background that favors longer telomere length may increase NHL risk, particularly risk of CLL/SLL, and are consistent with earlier studies relating longer telomere length with increased NHL risk. PMID:27008888

  18. Urinary antimony and leukocyte telomere length: An analysis of NHANES 1999-2002.

    PubMed

    Scinicariello, Franco; Buser, Melanie C

    2016-10-01

    Telomeres are repetitive DNA sequences (TTAGGG) at the end of chromosomes. Cells with critically short telomeres enter replicative senescence and apoptosis. Several in vitro studies report that antimony causes cell apoptosis in human leukocyte cell lines. The goal of this analysis was to investigate whether there is an association between antimony exposure and leukocyte telomere length (LTL) among US adults aged 20 and older based on the National Health and Nutrition Examination Survey (NHANES) 1999-2002. We used multivariate linear regression to analyze the association of urinary antimony with LTL. LTL was log-natural transformed and the results were re-transformed and presented as percent differences. After adjustment for potential confounders, individuals in the 3rd and 4th quartiles of urinary antimony had statistically significantly shorter LTL (-4.78%, 95% CI: -8.42,-0.90; and -6.11%, 95% CI: -11.04,-1.00, respectively) compared to the lowest referent quartile, with evidence of a dose-response relationship (p-value for trend =0.03). Shorter LTL with antimony was driven by middle aged (40-59 years) and older (60-85 years) adult groups. The association may be biologically plausible because of reported oxidative stress and apoptosis effects of antimony on blood cells, effects known to shorten telomere length. PMID:27423705

  19. Urinary antimony and leukocyte telomere length: An analysis of NHANES 1999-2002.

    PubMed

    Scinicariello, Franco; Buser, Melanie C

    2016-10-01

    Telomeres are repetitive DNA sequences (TTAGGG) at the end of chromosomes. Cells with critically short telomeres enter replicative senescence and apoptosis. Several in vitro studies report that antimony causes cell apoptosis in human leukocyte cell lines. The goal of this analysis was to investigate whether there is an association between antimony exposure and leukocyte telomere length (LTL) among US adults aged 20 and older based on the National Health and Nutrition Examination Survey (NHANES) 1999-2002. We used multivariate linear regression to analyze the association of urinary antimony with LTL. LTL was log-natural transformed and the results were re-transformed and presented as percent differences. After adjustment for potential confounders, individuals in the 3rd and 4th quartiles of urinary antimony had statistically significantly shorter LTL (-4.78%, 95% CI: -8.42,-0.90; and -6.11%, 95% CI: -11.04,-1.00, respectively) compared to the lowest referent quartile, with evidence of a dose-response relationship (p-value for trend =0.03). Shorter LTL with antimony was driven by middle aged (40-59 years) and older (60-85 years) adult groups. The association may be biologically plausible because of reported oxidative stress and apoptosis effects of antimony on blood cells, effects known to shorten telomere length.

  20. The relationship between telomere length and mortality in chronic obstructive pulmonary disease (COPD).

    PubMed

    Lee, Jee; Sandford, Andrew J; Connett, John E; Yan, Jin; Mui, Tammy; Li, Yuexin; Daley, Denise; Anthonisen, Nicholas R; Brooks-Wilson, Angela; Man, S F Paul; Sin, Don D

    2012-01-01

    Some have suggested that chronic obstructive pulmonary disease (COPD) is a disease of accelerated aging. Aging is characterized by shortening of telomeres. The relationship of telomere length to important clinical outcomes such as mortality, disease progression and cancer in COPD is unknown. Using quantitative polymerase chain reaction (qPCR), we measured telomere length of peripheral leukocytes in 4,271 subjects with mild to moderate COPD who participated in the Lung Health Study (LHS). The subjects were followed for approximately 7.5 years during which time their vital status, FEV(1) and smoking status were ascertained. Using multiple regression methods, we determined the relationship of telomere length to cancer and total mortality in these subjects. We also measured telomere length in healthy "mid-life" volunteers and patients with more severe COPD. The LHS subjects had significantly shorter telomeres than those of healthy "mid-life" volunteers (p<.001). Compared to individuals in the 4(th) quartile of relative telomere length (i.e. longest telomere group), the remaining participants had significantly higher risk of cancer mortality (Hazard ratio, HR, 1.48; p = 0.0324) and total mortality (HR, 1.29; p = 0.0425). Smoking status did not make a significant difference in peripheral blood cells telomere length. In conclusion, COPD patients have short leukocyte telomeres, which are in turn associated increased risk of total and cancer mortality. Accelerated aging is of particular relevance to cancer mortality in COPD.

  1. Telomere G-tail Length is a Promising Biomarker Related to White Matter Lesions and Endothelial Dysfunction in Patients With Cardiovascular Risk: A Cross-sectional Study☆

    PubMed Central

    Nezu, Tomohisa; Hosomi, Naohisa; Takahashi, Tetsuya; Anno, Kumiko; Aoki, Shiro; Shimamoto, Akira; Maruyama, Hirofumi; Hayashi, Tomonori; Matsumoto, Masayasu; Tahara, Hidetoshi

    2015-01-01

    Background The telomeric 3′-overhang (G-tail) length is essential for the biological effects of telomere dysfunction in vitro, but the association of length with aging and cardiovascular risk is unclear in humans. We investigated the association between the telomere G-tail length of leukocytes and cardiovascular risk, age-related white matter changes (ARWMCs), and endothelial function. Methods Patients with a history of cerebrovascular disease and comorbidity were enrolled (n = 102; 69 males and 33 females, 70.1 ± 9.2 years). Total telomere and telomere G-tail lengths were measured using a hybridization protection assay. Endothelial function was evaluated by ultrasound assessment of brachial flow-mediated dilation (FMD). Findings Shortened telomere G-tail length was associated with age and Framingham risk score (P = 0.018 and P = 0.012). In addition, telomere G-tail length was positively correlated with FMD values (P = 0.031) and negatively with the severity of ARWMCs (P = 0.002). On multivariate regression analysis, telomere G-tail length was independently associated with FMD values (P = 0.022) and the severity of ARWMCs (P = 0.033), whereas total telomere length was not associated with these indicators. Interpretation Telomere G-tail length is associated with age and vascular risk factors, and might be superior to total telomere length as a marker of endothelial dysfunction and ARWMC severity. PMID:26425704

  2. Activity of telomerase and telomeric length in Apis mellifera.

    PubMed

    Korandová, Michala; Frydrychová, Radmila Čapková

    2016-06-01

    Telomerase is an enzyme that adds repeats of DNA sequences to the ends of chromosomes, thereby preventing their shortening. Telomerase activity is associated with proliferative status of cells, organismal development, and aging. We report an analysis of telomerase activity and telomere length in the honeybee, Apis mellifera. Telomerase activity was found to be regulated in a development and caste-specific manner. During the development of somatic tissues of larval drones and workers, telomerase activity declined to 10 % of its level in embryos and remained low during pupal and adult stages but was upregulated in testes of late pupae, where it reached 70 % of the embryo level. Upregulation of telomerase activity was observed in the ovaries of late pupal queens, reaching 160 % of the level in embryos. Compared to workers and drones, queens displayed higher levels of telomerase activity. In the third larval instar of queens, telomerase activity reached the embryo level, and an enormous increase was observed in adult brains of queens, showing a 70-fold increase compared to a brain of an adult worker. Southern hybridization of terminal TTAGG fragments revealed a high variability of telomeric length between different individuals, although the same pattern of hybridization signals was observed in different tissues of each individual.

  3. Activity of telomerase and telomeric length in Apis mellifera.

    PubMed

    Korandová, Michala; Frydrychová, Radmila Čapková

    2016-06-01

    Telomerase is an enzyme that adds repeats of DNA sequences to the ends of chromosomes, thereby preventing their shortening. Telomerase activity is associated with proliferative status of cells, organismal development, and aging. We report an analysis of telomerase activity and telomere length in the honeybee, Apis mellifera. Telomerase activity was found to be regulated in a development and caste-specific manner. During the development of somatic tissues of larval drones and workers, telomerase activity declined to 10 % of its level in embryos and remained low during pupal and adult stages but was upregulated in testes of late pupae, where it reached 70 % of the embryo level. Upregulation of telomerase activity was observed in the ovaries of late pupal queens, reaching 160 % of the level in embryos. Compared to workers and drones, queens displayed higher levels of telomerase activity. In the third larval instar of queens, telomerase activity reached the embryo level, and an enormous increase was observed in adult brains of queens, showing a 70-fold increase compared to a brain of an adult worker. Southern hybridization of terminal TTAGG fragments revealed a high variability of telomeric length between different individuals, although the same pattern of hybridization signals was observed in different tissues of each individual. PMID:26490169

  4. The relationship between telomere length and clinicopathologic characteristics in colorectal cancers among Tunisian patients.

    PubMed

    Mzahma, Raja; Kharrat, Maher; Fetiriche, Fadhel; Bouasker; Ben Moussa, Mounir; Ben Safta, Zoubeir; Dziri, Chadli; Zaouche, AbdelJelil; Chaabouni-Bouhamed, Habiba

    2015-11-01

    Alterations in telomere dynamics have emerged as having a causative role in carcinogenesis. Both the telomere attrition contribute to tumor initiation via increasing chromosomal instability and that the telomere elongation induces cell immortalization and leads to tumor progression. The objectives of this study are to investigate the dynamics of telomere length in colorectal cancer (CRC) and the clinicopathological parameters implicated. We measured the relative telomere length (RTL) in cancerous tissues and in corresponding peripheral blood leukocytes (PBL) using quantitative PCR (Q-PCR) from 94 patients with CRC. Telomere length correlated significantly in cancer tissues and corresponding PBL (r = 0.705). Overall, cancer tissue had shorter telomeres than PBL (p = 0.033). In both cancer tissue and PBL, the RTL was significantly correlated with age groups (p = 0.008 and p = 0.012, respectively). The RTL in cancer tissue was significantly longer in rectal tumors (p = 0.04) and in the late stage of tumors (p = 0.01). In PBL, the RTL was significantly correlated with the macroscopic aspect of tumors (p = 0.02). In addition, the telomere-length ratio of cancer to corresponding PBL increased significantly with late-stage groups. Shortening of the telomere was detected in 44.7%, elongation in 36.2%, and telomeres were unchanged in 19.1% of 94 tumors. Telomere shortening occurred more frequently in the early stage of tumors (p = 0.01). This study suggests that the telomere length in PBL is affected by the macroscopic aspect of tumors and that telomere length in cancer tissues is a marker for progression of CRC and depends on tumor-origin site.

  5. Telomere Transcripts Target Telomerase in Human Cancer Cells

    PubMed Central

    Kreilmeier, Theresa; Mejri, Doris; Hauck, Marlene; Kleiter, Miriam; Holzmann, Klaus

    2016-01-01

    Long non-coding transcripts from telomeres, called telomeric repeat-containing RNA (TERRA), were identified as blocking telomerase activity (TA), a telomere maintenance mechanism (TMM), in tumors. We expressed recombinant TERRA transcripts in tumor cell lines with TA and with alternative lengthening of telomeres (ALT) to study effects on TMM and cell growth. Adeno- and lentivirus constructs (AV and LV) were established for transient and stable expression of approximately 130 units of telomere hexanucleotide repeats under control of cytomegalovirus (CMV) and human RNase P RNA H1 (hH1) promoters with and without polyadenylation, respectively. Six human tumor cell lines either using telomerase or ALT were infected and analyzed for TA levels. Pre-infection cells using telomerase had 1%–3% of the TERRA expression levels of ALT cells. AV and LV expression of recombinant TERRA in telomerase positive cells showed a 1.3–2.6 fold increase in TERRA levels, and a decrease in TA of 25%–58%. Dominant-negative or small hairpin RNA (shRNA) viral expression against human telomerase reverse transcriptase (hTERT) results in senescence, not induced by TERRA expression. Population doubling time, cell viability and TL (telomere length) were not impacted by ectopic TERRA expression. Clonal growth was reduced by TERRA expression in TA but not ALT cell lines. ALT cells were not affected by treatments applied. Established cell models and tools may be used to better understand the role of TERRA in the cell, especially for targeting telomerase. PMID:27537914

  6. Analysis of the age of Panax ginseng based on telomere length and telomerase activity.

    PubMed

    Liang, Jiabei; Jiang, Chao; Peng, Huasheng; Shi, Qinghua; Guo, Xiang; Yuan, Yuan; Huang, Luqi

    2015-01-23

    Ginseng, which is the root of Panax ginseng (Araliaceae), has been used in Oriental medicine as a stimulant and dietary supplement for more than 7,000 years. Older ginseng plants are substantially more medically potent, but ginseng age can be simulated using unscrupulous cultivation practices. Telomeres progressively shorten with each cell division until they reach a critical length, at which point cells enter replicative senescence. However, in some cells, telomerase maintains telomere length. In this study, to determine whether telomere length reflects ginseng age and which tissue is best for such an analysis, we examined telomerase activity in the main roots, leaves, stems, secondary roots and seeds of ginseng plants of known age. Telomere length in the main root (approximately 1 cm below the rhizome) was found to be the best indicator of age. Telomeric terminal restriction fragment (TRF) lengths, which are indicators of telomere length, were determined for the main roots of plants of different ages through Southern hybridization analysis. Telomere length was shown to be positively correlated with plant age, and a simple mathematical model was formulated to describe the relationship between telomere length and age for P. ginseng.

  7. Telomere length of the colonial coral Galaxea fascicularis at different developmental stages

    NASA Astrophysics Data System (ADS)

    Tsuta, H.; Hidaka, M.

    2013-06-01

    The ability to estimate coral age using soft tissue would be useful for population biology or aging studies on corals. In this study, we investigated whether telomere length can be used to estimate coral age. We applied single telomere length analysis to a colonial coral, Galaxea fascicularis, and estimated telomere lengths of specific coral chromosomes at different developmental stages. If the telomere shortened at each cell division, the telomere length of the coral would be longest in sperm and shortest in adult colonies. However, the mean telomere length of sperm, planula larvae, and polyps was approximately 4 kb, with no significant differences among the developmental stages. The telomerase restriction fragment (TRF) analysis also showed no significant difference in the mean TRF length among the developmental stages. Our results suggested that telomere length is maintained during developmental stages and that estimating the age of colonial coral based on telomere length may not be possible. However, our findings can be used to examine avoidance of aging and rejuvenation during regeneration and asexual reproduction in colonial corals.

  8. Telomere length, current perceived stress, and urinary stress hormones in women.

    PubMed

    Parks, Christine G; Miller, Diane B; McCanlies, Erin C; Cawthon, Richard M; Andrew, Michael E; DeRoo, Lisa A; Sandler, Dale P

    2009-02-01

    Telomeres are repetitive DNA sequences that cap and protect the ends of chromosomes; critically short telomeres may lead to cellular senescence or carcinogenic transformation. Previous findings suggest a link between psychosocial stress, shorter telomeres, and chronic disease risk. This cross-sectional study examined relative telomere length in relation to perceived stress and urinary stress hormones in a sample of participants (n = 647) in the National Institute of Environmental Health Sciences Sister Study, a cohort of women ages 35 to 74 years who have a sister with breast cancer. Average leukocyte telomere length was determined by quantitative PCR. Current stress was assessed using the Perceived Stress Scale and creatinine-adjusted neuroendocrine hormones in first morning urines. Linear regression models estimated differences in telomere length base pairs (bp) associated with stress measures adjusted for age, race, smoking, and obesity. Women with higher perceived stress had somewhat shorter telomeres [adjusted difference of -129bp for being at or above moderate stress levels; 95% confidence interval (CI), -292 to 33], but telomere length did not decrease monotonically with higher stress levels. Shorter telomeres were independently associated with increasing age (-27bp/year), obesity, and current smoking. Significant stress-related differences in telomere length were seen in women ages 55 years and older (-289bp; 95% CI, -519 to -59), those with recent major losses (-420bp; 95% CI, -814 to -27), and those with above-average urinary catecholamines (e.g., epinephrine: -484bp; 95% CI, -709 to -259). Although current perceived stress was only modestly associated with shorter telomeres in this broad sample of women, our findings suggest the effect of stress on telomere length may vary depending on neuroendocrine responsiveness, external stressors, and age.

  9. The heritability of telomere length among the elderly and oldest-old.

    PubMed

    Bischoff, Claus; Graakjaer, Jesper; Petersen, Hans Christian; Hjelmborg, Jacob v B; Vaupel, James W; Bohr, Vilhelm; Koelvraa, Steen; Christensen, Kaare

    2005-10-01

    A tight link exists between telomere length and both population doublings of a cell culture and age of a given organism. The more population doublings of the cell culture or the higher the age of the organism, the shorter the telomeres. The proposed model for telomere shortening, called the end replication problem, explains why the telomere erodes at each cellular turnover. Telomere length is regulated by a number of associated proteins through a number of different signaling pathways. The determinants of telomere length were studied using whole blood samples from 287 twin pairs aged 73 to 95 years. Structural equation models revealed that a model including additive genetic effects and non-shared environment was the best fitting model and that telomere length was moderately heritable, with an estimate that was sensitive to the telomere length standardization procedure. Sex-specific analyses showed lower heritability in males, although not statistically significant, which is in line with our earlier finding of a sex difference in telomere dynamics among the elderly and oldest-old.

  10. Neighborhood characteristics and leukocyte telomere length: the Multi-Ethnic Study of Atherosclerosis.

    PubMed

    Needham, Belinda L; Carroll, Judith E; Diez Roux, Ana V; Fitzpatrick, Annette L; Moore, Kari; Seeman, Teresa E

    2014-07-01

    Telomeres are the protective caps at the ends of eukaryotic chromosomes. Telomeres get shorter each time a cell divides, and critically shortened telomeres trigger cellular senescence. Thus, telomere length is hypothesized to be a biological marker of aging. The purpose of this study was to examine the association between neighborhood characteristics and leukocyte telomere length. Using data from a subsample (n=978) of the Multi-Ethnic Study of Atherosclerosis, a population-based study of women and men aged 45-84, we found that neighborhood social environment (but not neighborhood socioeconomic disadvantage) was associated with telomere length. Respondents who lived in neighborhoods characterized by lower aesthetic quality, safety, and social cohesion had shorter telomeres than those who lived in neighborhoods with a more salutary social environment, even after adjusting for individual-level socioeconomic status and biomedical and lifestyle factors related to telomere length. Telomere length may be one biological mechanism by which neighborhood characteristics influence an individual׳s risk of disease and death.

  11. Global methylation, oxidative stress, and relative telomere length in biliary atresia patients

    PubMed Central

    Udomsinprasert, Wanvisa; Kitkumthorn, Nakarin; Mutirangura, Apiwat; Chongsrisawat, Voranush; Poovorawan, Yong; Honsawek, Sittisak

    2016-01-01

    Alu and LINE-1 elements are retrotransposons with a ubiquitous presence in the human genome that can cause genomic instability, specifically relating to telomere length. Genotoxic agents may induce methylation of retrotransposons, in addition to oxidative DNA damage in the form of 8-hydroxy-2′-deoxyguanosine (8-OHdG). Methylation of retrotransposons induced by these agents may contribute to biliary atresia (BA) etiology. Here, we investigated correlations between global methylation, 8-OHdG, and relative telomere length, as well as reporting on Alu and LINE-1 hypomethylation in BA patients. Alu and LINE-1 hypomethylation were found to be associated with elevated risk of BA (OR = 4.07; 95% CI: 2.27–7.32; P < 0.0001 and OR = 3.51; 95% CI: 1.87–6.59; P < 0.0001, respectively). Furthermore, LINE-1 methylation was associated with liver stiffness in BA patients (β coefficient = −0.17; 95% CI: −0.24 to −0.10; P < 0.0001). Stratified analysis revealed negative correlations between Alu and LINE-1 methylation and 8-OHdG in BA patients (P < 0.0001). In contrast, positive relationships were identified between Alu and LINE-1 methylation and relative telomere length in BA patients (P < 0.0001). These findings suggest that retrotransposon hypomethylation is associated with plasma 8-OHdG and telomere length in BA patients. PMID:27243754

  12. Parental responsiveness moderates the association between early-life stress and reduced telomere length.

    PubMed

    Asok, A; Bernard, K; Roth, T L; Rosen, J B; Dozier, M

    2013-08-01

    Early-life stress, such as maltreatment, institutionalization, and exposure to violence, is associated with accelerated telomere shortening. Telomere shortening may thus represent a biomarker of early adversity. Previous studies have suggested that responsive parenting may protect children from the negative biological and behavioral consequences of early adversity. This study examined the role of parental responsiveness in buffering children from telomere shortening following experiences of early-life stress. We found that high-risk children had significantly shorter telomeres than low-risk children, controlling for household income, birth weight, gender, and minority status. Further, parental responsiveness moderated the association between risk and telomere length, with more responsive parenting associated with longer telomeres only among high-risk children. These findings suggest that responsive parenting may have protective benefits on telomere shortening for young children exposed to early-life stress. Therefore, this study has important implications for early parenting interventions. PMID:23527512

  13. Telomere length, genetic variants and gastric cancer risk in a Chinese population.

    PubMed

    Du, Jiangbo; Zhu, Xun; Xie, Cuiwei; Dai, Ningbin; Gu, Yayun; Zhu, Meng; Wang, Cheng; Gao, Yong; Pan, Feng; Ren, Chuanli; Ji, Yong; Dai, Juncheng; Ma, Hongxia; Jiang, Yue; Chen, Jiaping; Yi, Honggang; Zhao, Yang; Hu, Zhibin; Shen, Hongbing; Jin, Guangfu

    2015-09-01

    Telomeres maintain chromosomal stability and integrity and are crucial in carcinogenesis. Telomere length is implicated in multiple cancer risk, but the results are conflicting. Genome-wide association studies have identified several genetic loci associated with telomere length in Caucasians. However, the roles of telomere length and related variants on gastric cancer development are largely unknown. We conducted a case-control study including 1136 gastric cancer cases and 1012 controls to evaluate the associations between telomere length, eight telomere length-related variants identified in Caucasians and gastric cancer risk in Chinese population. We observed an obvious U-shaped association between telomere length and gastric cancer risk (P < 0.001), with odds ratios (95% confidence intervals) being 3.81 (2.82-5.13), 1.65 (1.21-2.26), 1.28 (0.93-1.77) and 1.78 (1.30-2.44) for individuals in the first (the shortest), second, third and fifth (the longest) quintile as compared with those in the fourth quintile as reference group. The weighted genetic score (WGS) of eight variants was significantly associated with telomere length (P < 0.001), and in particular, the G allele of rs2736100 in TERT at 5p15.33 exhibited a significant association with long telomeres (P = 0.047). However, we did not observe significant associations between these genetic variants and gastric cancer risk for both single-variant and WGS analyses. These findings suggest that either short or extreme long telomeres may be risk factor for gastric cancer. Genetic variants identified in Caucasians may also contribute to the variation of telomere length in Chinese but seems not to gastric cancer susceptibility.

  14. Loss of telomeric DNA during aging of normal and trisomy 21 human lymphocytes

    SciTech Connect

    Vaziri, H.; Uchida, I.; Lan Wei; Harley, C.B. ); Schaechter, F.; Cohen, D. ); Xiaoming Zhu; Effros, R. )

    1993-04-01

    The telomere hypothesis of cellular aging proposes that loss of telomeric DNA (TTAGGG) from human chromosomes may ultimately cause cell-cycle exit during replicative senescence. Since lymphocytes have a limited replicative capacity and since blood cells were previously shown to lose telomeric DNA during aging in vivo, the authors wished to determine (a) whether accelerated telomere loss is associated with the premature immunosenescence of lymphocytes in individuals with Down syndrome (DS) and (b) whether telomeric DNA is also lost during aging of lymphocytes in vitro. To investigate the effects of aging and trisomy 21 on telomere loss in vivo, genomic DNA was isolated from peripheral blood lymphocytes of 140 individuals (age 0--107 years), including 21 DS patients (age 0--45 years). Digestion with restriction enzymes HinfI and RsaI generated terminal restriction fragments (TRFs), which were detected by Southern analysis using a telomere-specific probe ([sup 32]P-(C[sub 3]TA[sub 2])[sub 3]). The rate of telomere loss was calculated from the decrease in mean TRF length, as a function of donor age. DS patients showed a significantly higher rate of telomere loss with donor age (133 [+-] 15 bp/year) compared with age-matched controls (41 [+-] 7.7 bp/year) (P < .0005), suggesting that accelerated telomere loss is a biomarker of premature immunosenescence of DS patients and that it may play a role in this process. Telomere loss during aging in vitro was calculated for lymphocytes from four normal individuals, grown in culture for 10--30 population doublings. The rate of telomere loss was [approximately]120 bp/cell doubling, comparable to that seen in other somatic cells. Moreover, telomere lengths of lymphocytes from centenarians and from older DS patients were similar to those of senescent lymphocytes in culture, which suggests that replicative senescence could partially account for aging of the immune system in DS patients and in elderly individuals. 31 refs., 3 figs.

  15. The effect on melanoma risk of genes previously associated with telomere length.

    PubMed

    Iles, Mark M; Bishop, D Timothy; Taylor, John C; Hayward, Nicholas K; Brossard, Myriam; Cust, Anne E; Dunning, Alison M; Lee, Jeffrey E; Moses, Eric K; Akslen, Lars A; Andresen, Per A; Avril, Marie-Françoise; Azizi, Esther; Scarrà, Giovanna Bianchi; Brown, Kevin M; Dębniak, Tadeusz; Elder, David E; Friedman, Eitan; Ghiorzo, Paola; Gillanders, Elizabeth M; Goldstein, Alisa M; Gruis, Nelleke A; Hansson, Johan; Harland, Mark; Helsing, Per; Hočevar, Marko; Höiom, Veronica; Ingvar, Christian; Kanetsky, Peter A; Landi, Maria Teresa; Lang, Julie; Lathrop, G Mark; Lubiński, Jan; Mackie, Rona M; Martin, Nicholas G; Molven, Anders; Montgomery, Grant W; Novaković, Srdjan; Olsson, Håkan; Puig, Susana; Puig-Butille, Joan Anton; Radford-Smith, Graham L; Randerson-Moor, Juliette; van der Stoep, Nienke; van Doorn, Remco; Whiteman, David C; MacGregor, Stuart; Pooley, Karen A; Ward, Sarah V; Mann, Graham J; Amos, Christopher I; Pharoah, Paul D P; Demenais, Florence; Law, Matthew H; Newton Bishop, Julia A; Barrett, Jennifer H

    2014-10-01

    Telomere length has been associated with risk of many cancers, but results are inconsistent. Seven single nucleotide polymorphisms (SNPs) previously associated with mean leukocyte telomere length were either genotyped or well-imputed in 11108 case patients and 13933 control patients from Europe, Israel, the United States and Australia, four of the seven SNPs reached a P value under .05 (two-sided). A genetic score that predicts telomere length, derived from these seven SNPs, is strongly associated (P = 8.92x10(-9), two-sided) with melanoma risk. This demonstrates that the previously observed association between longer telomere length and increased melanoma risk is not attributable to confounding via shared environmental effects (such as ultraviolet exposure) or reverse causality. We provide the first proof that multiple germline genetic determinants of telomere length influence cancer risk. PMID:25231748

  16. Effects of Telomerase and Telomere Length on Epidermal Stem Cell Behavior

    NASA Astrophysics Data System (ADS)

    Flores, Ignacio; Cayuela, María L.; Blasco, María A.

    2005-08-01

    A key process in organ homeostasis is the mobilization of stem cells out of their niches. We show through analysis of mouse models that telomere length, as well as the catalytic component of telomerase, Tert, are critical determinants in the mobilization of epidermal stem cells. Telomere shortening inhibited mobilization of stem cells out of their niche, impaired hair growth, and resulted in suppression of stem cell proliferative capacity in vitro. In contrast, Tert overexpression in the absence of changes in telomere length promoted stem cell mobilization, hair growth, and stem cell proliferation in vitro. The effects of telomeres and telomerase on stem cell biology anticipate their role in cancer and aging.

  17. Breast cancer survival is associated with telomere length in peripheral blood cells.

    PubMed

    Svenson, Ulrika; Nordfjäll, Katarina; Stegmayr, Birgitta; Manjer, Jonas; Nilsson, Peter; Tavelin, Björn; Henriksson, Roger; Lenner, Per; Roos, Göran

    2008-05-15

    Telomeres are essential for maintaining chromosomal stability. Previous studies have indicated that individuals with shorter blood telomeres may be at higher risk of developing various types of cancer, such as in lung, bladder, and kidney. We have analyzed relative telomere length (RTL) of peripheral blood cells in relation to breast cancer incidence and prognosis. The study included 265 newly diagnosed breast cancer patients and 446 female controls. RTL was measured by real-time PCR, and our results show that the patient group displayed significantly longer telomeres compared with controls (P < 0.001). Age-adjusted odds ratios (OR) for breast cancer risk increased with increasing telomere length, with a maximal OR of 5.17 [95% confidence interval (95% CI), 3.09-8.64] for the quartile with the longest telomeres. Furthermore, RTL carried prognostic information for patients with advanced disease. Node positive (N+) patients with short telomeres (telomeres (P = 0.001). For patients with ages <50 years with tumors >16 mm (median tumor diameter), short telomeres were associated with a significantly better outcome than longer telomeres (P = 0.006). Cox regression analysis showed that long RTL was a significant independent negative prognostic factor (hazards ratio, 2.92; 95% CI, 1.33-6.39; P = 0.007). Our results indicate that blood RTL may serve as a prognostic indicator in breast cancer patients with advanced disease.

  18. The relationship between DNA methylation and telomere length in dyskeratosis congenita.

    PubMed

    Gadalla, Shahinaz M; Katki, Hormuzd A; Shebl, Fatma M; Giri, Neelam; Alter, Blanche P; Savage, Sharon A

    2012-02-01

    The regulation of telomere length (TL) is a complex process, requiring the telomerase enzyme complex and numerous regulatory proteins. Epigenetic regulation may also be important in telomere maintenance. Specifically, methylation at subtelomeres is associated with changes in TL in vitro and in mouse models. Dyskeratosis congenita (DC) is an inherited bone marrow failure syndrome characterized by exceedingly short telomeres and mutations in telomere biology genes. To understand the interaction between methylation and TL in humans, we measured LINE-1, pericentromeric (NBL2), and subtelomeric (D4Z4) methylation in peripheral blood DNA derived from 40 patients with DC and 51 mutation-negative relatives. Pearson's correlation coefficient and linear regression models were used to evaluate the relationship between age-standardized lymphocyte TL measured by flow FISH and % DNA methylation. No differences in % subtelomeric, LINE-1, or pericentromeric methylation between patients with DC and relatives were noted except for an increase in % subtelomeric methylation in DC patients with a telomerase-complex mutation (TERC, TERT, DKC1, or TCAB1) (63.0% in DC vs. 61.8% in relatives, P = 0.03). Positive correlations between TL and DNA methylation at LINE-1 (r = 0.39, P = 0.01) and subtelomeric (r = 0.32, P = 0.05) sites were present in patients with DC. The positive correlation between TL and % LINE-1 methylation was restricted to TINF2 mutations. In contrast, statistically nonsignificant inverse correlations between TL and % LINE-1 (r = -0.17), subtelomeric (r = -0.20) were present in unaffected relatives. This study suggests an interaction between TL and both subtelomeric and LINE-1 methylation, which may be altered based on mutation status of telomere biology genes. PMID:21981348

  19. Association of leukocyte telomere length in peripheral blood leukocytes with endometrial cancer risk in Caucasian Americans.

    PubMed

    Sun, Yuhui; Zhang, Liren; Zhao, Lina; Wu, Xifeng; Gu, Jian

    2015-11-01

    Telomeres are the protective structure at the ends of each chromosome and play an important role in maintaining genomic integrity. Interindividual variation of telomere length in peripheral blood leukocytes has been associated with the risks of developing many human diseases including several cancers. The association between leukocyte telomere length (LTL) and endometrial cancer risk is still inconsistent. Using a case-control study of endometrial cancer patients (n = 139) and control subjects (n = 139) in a Caucasian population, we assessed the association of relative LTL with the risk of endometrial cancer. We calculated odds ratios and 95% confidence intervals using multivariate logistic regression. We also determined the joint effects of LTL with established risk factors of endometrial cancer. The normalized LTL was significantly longer in endometrial cancer cases (median, 0.93; range, 0.19-1.62) than in controls (median, 0.70; range, 0.03-2.14) (P < 0.001). When individuals were dichotomized into long and short groups based on the median LTL value in the controls, individuals with long LTL had a significantly increased risk of endometrial cancer (adjusted OR, 3.84; 95%CI, 2.16-6.85; P < 0.001) compared to those with short LTL. When individuals were categorized into three groups or four groups according to tertile or quartile LTL value in the controls, there was a significant dose-response association between LTL and the risk of endometrial cancer (P < 0.001). Joint effects between LTL and smoking status, body mass index and a history of hypertension or diabetes in elevating endometrial cancer risk were observed. Long telomere length in peripheral blood leukocytes is associated with a significantly increased risk of endometrial cancer.

  20. Analysis of telomere length in Dolly, a sheep derived by nuclear transfer.

    PubMed

    Shiels, P G; Kind, A J; Campbell, K H; Wilmut, I; Waddington, D; Colman, A; Schnieke, A E

    1999-01-01

    We have used a (TTAGGG) oligonucleotide probe to demonstrate that ovine telomeres are composed of (TTAGGG) repeat arrays and to compare the terminal restriction fragment lengths of sheep derived by natural mating and nuclear transfer. Here we show that ovine somatic telomeres decrease in length with age, and that Dolly, derived by the transfer of 6-year-old adult somatic nucleus, exhibits diminished terminal restriction fragment lengths. The decrease is consistent with the age of the donor tissue and telomere erosion during in vitro culture. Nuclear transfer does not restore telomere lengths. Dolly otherwise appears physiologically and phenotypically normal for her breed and age. We further report on apparent telomere lengthening in sheep, occurring during the first year in naturally derived lambs.

  1. Analysis of telomere length in Dolly, a sheep derived by nuclear transfer.

    PubMed

    Shiels, P G; Kind, A J; Campbell, K H; Wilmut, I; Waddington, D; Colman, A; Schnieke, A E

    1999-01-01

    We have used a (TTAGGG) oligonucleotide probe to demonstrate that ovine telomeres are composed of (TTAGGG) repeat arrays and to compare the terminal restriction fragment lengths of sheep derived by natural mating and nuclear transfer. Here we show that ovine somatic telomeres decrease in length with age, and that Dolly, derived by the transfer of 6-year-old adult somatic nucleus, exhibits diminished terminal restriction fragment lengths. The decrease is consistent with the age of the donor tissue and telomere erosion during in vitro culture. Nuclear transfer does not restore telomere lengths. Dolly otherwise appears physiologically and phenotypically normal for her breed and age. We further report on apparent telomere lengthening in sheep, occurring during the first year in naturally derived lambs. PMID:16218837

  2. Association of Donor and Recipient Telomere Length with Clinical Outcomes following Lung Transplantation

    PubMed Central

    Courtwright, Andrew M.; Fried, Sabrina; Villalba, Julian A.; Moniodis, Anna; Guleria, Indira; Wood, Isabelle; Milford, Edgar; Mallidi, Hari H.; Hunninghake, Gary M.; Raby, Benjamin A.; Agarwal, Suneet; Camp, Philip C.; Rosas, Ivan O.; Goldberg, Hilary J.; El-Chemaly, Souheil

    2016-01-01

    Background Patients with short telomere syndromes and pulmonary fibrosis have increased complications after lung transplant. However, the more general impact of donor and recipient telomere length in lung transplant has not been well characterized. Methods This was an observational cohort study of patients who received lung transplant at a single center between January 1st 2012 and January 31st 2015. Relative donor lymphocyte telomere length was measured and classified into long (third tertile) and short (other tertiles). Relative recipient lung telomere length was measured and classified into short (first tertile) and long (other tertiles). Outcome data included survival, need for modification of immunosuppression, liver or kidney injury, cytomegalovirus reactivation, and acute rejection. Results Recipient lung tissue telomere lengths were measured for 54 of the 79 patients (68.3%) who underwent transplant during the study period. Donor lymphocyte telomeres were measured for 45 (83.3%) of these recipients. Neither long donor telomere length (hazard ratio [HR] = 0.58, 95% confidence interval [CI], 0.12–2.85, p = 0.50) nor short recipient telomere length (HR = 1.01, 95% CI = 0.50–2.05, p = 0.96) were associated with adjusted survival following lung transplant. Recipients with short telomeres were less likely to have acute cellular rejection (23.5% vs. 58.8%, p = 0.02) but were not more likely to have other organ dysfunction. Conclusions In this small cohort, neither long donor lymphocyte telomeres nor short recipient lung tissue telomeres were associated with adjusted survival after lung transplantation. Larger studies are needed to confirm these findings. PMID:27589328

  3. Telomere DNA Deficiency Is Associated with Development of Human Embryonic Aneuploidy

    PubMed Central

    Treff, Nathan R.; Su, Jing; Taylor, Deanne; Scott, Richard T.

    2011-01-01

    Aneuploidy represents the most prevalent form of genetic instability found in human embryos and is the leading genetic cause of miscarriage and developmental delay in newborns. Telomere DNA deficiency is associated with genomic instability in somatic cells and may play a role in development of aneuploidy commonly found in female germ cells and human embryos. To test this hypothesis, we developed a method capable of quantifying telomere DNA in parallel with 24-chromosome aneuploidy screening from the same oocyte or embryo biopsy. Aneuploid human polar bodies possessed significantly less telomere DNA than euploid polar bodies from sibling oocytes (−3.07 fold, P = 0.016). This indicates that oocytes with telomere DNA deficiency are prone to aneuploidy development during meiosis. Aneuploid embryonic cells also possessed significantly less telomere DNA than euploid embryonic cells at the cleavage stage (−2.60 fold, P = 0.002) but not at the blastocyst stage (−1.18 fold, P = 0.340). The lack of a significant difference at the blastocyst stage was found to be due to telomere DNA normalization between the cleavage and blastocyst stage of embryogenesis and not due to developmental arrest of embryos with short telomeres. Heterogeneity in telomere length within oocytes may provide an opportunity to improve the treatment of infertility through telomere-based selection of oocytes and embryos with reproductive competence. PMID:21738493

  4. Tired telomeres: Poor global sleep quality, perceived stress, and telomere length in immune cell subsets in obese men and women.

    PubMed

    Prather, Aric A; Gurfein, Blake; Moran, Patricia; Daubenmier, Jennifer; Acree, Michael; Bacchetti, Peter; Sinclair, Elizabeth; Lin, Jue; Blackburn, Elizabeth; Hecht, Frederick M; Epel, Elissa S

    2015-07-01

    Poor sleep quality and short sleep duration are associated with increased incidence and progression of a number of chronic health conditions observed at greater frequency among the obese and those experiencing high levels of stress. Accelerated cellular aging, as indexed by telomere attrition in immune cells, is a plausible pathway linking sleep and disease risk. Prior studies linking sleep and telomere length are mixed. One factor may be reliance on leukocytes, which are composed of varied immune cell types, as the sole measure of telomere length. To better clarify these associations, we investigated the relationships of global sleep quality, measured by the Pittsburgh Sleep Quality Index (PSQI), and diary-reported sleep duration with telomere length in different immune cell subsets, including granulocytes, peripheral blood mononuclear cells (PBMCs), CD8+ and CD4+ T lymphocytes, and B lymphocytes in a sample of 87 obese men and women (BMI mean=35.4, SD=3.6; 81.6% women; 62.8% Caucasian). Multiple linear regression analyses were performed adjusting for age, gender, race, education, BMI, sleep apnea risk, and perceived stress. Poorer PSQI global sleep quality was associated with statistically significantly shorter telomere length in lymphocytes but not granulocytes and in particular CD8+ T cells (b=-56.8 base pairs per one point increase in PSQI, SE=20.4, p=0.007) and CD4+ T cells (b=-37.2, SE=15.9, p=0.022). Among separate aspects of global sleep quality, low perceived sleep quality and decrements in daytime function were most related to shorter telomeres. In addition, perceived stress moderated the sleep-CD8+ telomere association. Poorer global sleep quality predicted shorter telomere length in CD8+ T cells among those with high perceived stress but not in low stress participants. These findings provide preliminary evidence that poorer global sleep quality is related to telomere length in several immune cell types, which may serve as a pathway linking sleep and

  5. Tired telomeres: Poor global sleep quality, perceived stress, and telomere length in immune cell subsets in obese men and women.

    PubMed

    Prather, Aric A; Gurfein, Blake; Moran, Patricia; Daubenmier, Jennifer; Acree, Michael; Bacchetti, Peter; Sinclair, Elizabeth; Lin, Jue; Blackburn, Elizabeth; Hecht, Frederick M; Epel, Elissa S

    2015-07-01

    Poor sleep quality and short sleep duration are associated with increased incidence and progression of a number of chronic health conditions observed at greater frequency among the obese and those experiencing high levels of stress. Accelerated cellular aging, as indexed by telomere attrition in immune cells, is a plausible pathway linking sleep and disease risk. Prior studies linking sleep and telomere length are mixed. One factor may be reliance on leukocytes, which are composed of varied immune cell types, as the sole measure of telomere length. To better clarify these associations, we investigated the relationships of global sleep quality, measured by the Pittsburgh Sleep Quality Index (PSQI), and diary-reported sleep duration with telomere length in different immune cell subsets, including granulocytes, peripheral blood mononuclear cells (PBMCs), CD8+ and CD4+ T lymphocytes, and B lymphocytes in a sample of 87 obese men and women (BMI mean=35.4, SD=3.6; 81.6% women; 62.8% Caucasian). Multiple linear regression analyses were performed adjusting for age, gender, race, education, BMI, sleep apnea risk, and perceived stress. Poorer PSQI global sleep quality was associated with statistically significantly shorter telomere length in lymphocytes but not granulocytes and in particular CD8+ T cells (b=-56.8 base pairs per one point increase in PSQI, SE=20.4, p=0.007) and CD4+ T cells (b=-37.2, SE=15.9, p=0.022). Among separate aspects of global sleep quality, low perceived sleep quality and decrements in daytime function were most related to shorter telomeres. In addition, perceived stress moderated the sleep-CD8+ telomere association. Poorer global sleep quality predicted shorter telomere length in CD8+ T cells among those with high perceived stress but not in low stress participants. These findings provide preliminary evidence that poorer global sleep quality is related to telomere length in several immune cell types, which may serve as a pathway linking sleep and

  6. Tired Telomeres: poor global sleep quality, perceived stress, and telomere length in immune cell subsets in obese men and women

    PubMed Central

    Prather, Aric A.; Gurfein, Blake; Moran, Patricia; Daubenmier, Jennifer; Acree, Michael; Bacchetti, Peter; Sinclair, Elizabeth; Lin, Jue; Blackburn, Elizabeth; Hecht, Frederick M.; Epel, Elissa S.

    2014-01-01

    Poor sleep quality and short sleep duration are associated with increased incidence and progression of a number of chronic health conditions observed at greater frequency among the obese and those experiencing high levels of stress. Accelerated cellular aging, as indexed by telomere attrition in immune cells, is a plausible pathway linking sleep and disease risk. Prior studies linking sleep and telomere length are mixed. One factor may be reliance on leukocytes, which are composed of varied immune cell types, as the sole measure of telomere length. To better clarify these associations, we investigated the relationships of global sleep quality, measured by the Pittsburgh Sleep Quality Index (PSQI), and diary-reported sleep duration with telomere length in different immune cell subsets, including granulocytes, peripheral blood mononuclear cells (PBMCs), CD8+ and CD4+ T lymphocytes, and B lymphocytes in a sample of 87 obese men and women (BMI mean = 35.4, SD = 3.6; 81.6% women; 62.8% Caucasian). Multiple linear regression analyses were performed adjusting for age, gender, race, education, BMI, sleep apnea risk, and perceived stress. Poorer PSQI global sleep quality was associated with statistically significantly shorter telomere length in lymphocytes but not granulocytes and in particular CD8+ T cells (b = −56.8 base pairs per one point increase in PSQI, SE = 20.4, p=0.007) and CD4+ T cells (b = −37.2, SE = 15.9, p = 0.022). Among separate aspects of global sleep quality, low perceived sleep quality and decrements in daytime function were most related to shorter telomeres. In addition, perceived stress moderated the sleep-CD8+ telomere association. Poorer global sleep quality predicted shorter telomere length in CD8+ T cells among those with high perceived stress but not in low stress participants. These findings provide preliminary evidence that poorer global sleep quality is related to telomere length in several immune cell types, which may serve as a pathway

  7. Telomere length in non-neoplastic gastric mucosa and its relationship to H. pylori infection, degree of gastritis, and NSAID use.

    PubMed

    Tahara, Tomomitsu; Shibata, Tomoyuki; Kawamura, Tomohiko; Ishizuka, Takamitsu; Okubo, Masaaki; Nagasaka, Mitsuo; Nakagawa, Yoshihito; Arisawa, Tomiyasu; Ohmiya, Naoki; Hirata, Ichiro

    2016-02-01

    Telomere shortening occurs with human aging in many organs and tissues and is accelerated by rapid cell turnover and oxidative injury. We measured average telomere length using quantitative real-time PCR in non-neoplastic gastric mucosa and assessed its relationship to H. pylori-related gastritis, DNA methylation, ulcer disease, and nonsteroidal anti-inflammatory drug (NSAID) usage. Gastric biopsies were obtained from 151 cancer-free subjects including 49 chronic NSAID users and 102 nonusers. Relative telomere length in genomic DNA was measured by real-time PCR. H. pylori infection status, histological severity of gastritis, and serum pepsinogens (PGs) were also investigated. E-cadherin (CDH1) methylation status was determined by methylation-specific PCR (MSP). Average relative telomere length of H. pylori-infected subjects was significantly shortened when compared to H. pylori-negative subjects (p = 0.002) and was closely associated with all histological parameter of gastritis (all p values <0.01) and CDH1 methylation (p = 0.0002). In H. pylori-negative subjects, NSAID users presented significantly shorter telomere length than nonusers (p = 0.028). Shorter telomere length was observed in duodenal and gastric ulcer patients compared with non-ulcer subjects among NSAID users. Telomere shortening is closely associated with severity of H. pylori-induced gastritis and CDH1 methylation status. Also, telomere shortening is accelerated by NSAID usage especially in H. pylori-negative subjects.

  8. Emotions and family interactions in childhood: Associations with leukocyte telomere length emotions, family interactions, and telomere length.

    PubMed

    Robles, Theodore F; Carroll, Judith E; Bai, Sunhye; Reynolds, Bridget M; Esquivel, Stephanie; Repetti, Rena L

    2016-01-01

    Conceptualizations of links between stress and cellular aging in childhood suggest that accumulating stress predicts shorter leukocyte telomere length (LTL). At the same time, several models suggest that emotional reactivity to stressors may play a key role in predicting cellular aging. Using intensive repeated measures, we tested whether exposure or emotional "reactivity" to conflict and warmth in the family were related to LTL. Children (N=39; 30 target children and 9 siblings) between 8 and 13 years of age completed daily diary questionnaires for 56 consecutive days assessing daily warmth and conflict in the marital and the parent-child dyad, and daily positive and negative mood. To assess exposure to conflict and warmth, diary scale scores were averaged over the 56 days. Mood "reactivity" was operationalized by using multilevel modeling to generate estimates of the slope of warmth or conflict scores (marital and parent-child, separately) predicting same-day mood for each individual child. After diary collection, a blood sample was collected to determine LTL. Among children aged 8-13 years, a stronger association between negative mood and marital conflict, suggesting greater negative mood reactivity to marital conflict, was related to shorter LTL (B=-1.51, p<.01). A stronger association between positive mood and marital affection, suggesting positive mood reactivity, was related to longer LTL (B=1.15, p<.05). These effects were independent of exposure to family and marital conflict and warmth, and positive and negative mood over a two-month period. To our knowledge, these findings, although cross-sectional, represent the first evidence showing that link between children's affective responses and daily family interactions may have implications for telomere length.

  9. The association between global DNA methylation and telomere length in a longitudinal study of boilermakers.

    PubMed

    Wong, Jason Y Y; De Vivo, Immaculata; Lin, Xihong; Grashow, Rachel; Cavallari, Jennifer; Christiani, David C

    2014-04-01

    The objectives of this study were to determine if global DNA methylation, as reflected in LINE-1 and Alu elements, is associated with telomere length and whether it modifies the rate of telomeric change. A repeated-measures longitudinal study was performed with a panel of 87 boilermaker subjects. The follow-up period was 29 months. LINE-1 and Alu methylation was determined using pyrosequencing. Leukocyte relative telomere length was assessed via real-time qPCR. Linear-mixed models were used to estimate the association between DNA methylation and telomere length. A structural equation model (SEM) was used to explore the hypothesized relationship between DNA methylation, proxies of particulate matter exposure, and telomere length at baseline. There appeared to be a positive association between both LINE-1 and Alu methylation levels, and telomere length. For every incremental increase in LINE-1 methylation, there was a statistically significant 1.0 × 10(-1) (95% CI: 4.6 × 10(-2), 1.5 × 10(-1), P < 0.01) unit increase in relative telomere length, controlling for age at baseline, current and past smoking status, work history, BMI (log kg/m(2) ) and leukocyte differentials. Furthermore, for every incremental increase in Alu methylation, there was a statistically significant 6.2 × 10(-2) (95% CI: 1.0 × 10(-2), 1.1 × 10(-1), P = 0.02) unit increase in relative telomere length. The interaction between LINE-1 methylation and follow-up time was statistically significant with an estimate -9.8 × 10(-3) (95% CI: -1.8 × 10(-2), -1.9 × 10(-3), P = 0.02); suggesting that the rate of telomeric change was modified by the degree of LINE-1 methylation. No statistically significant association was found between the cumulative PM exposure construct, with global DNA methylation and telomere length at baseline.

  10. Telomere Length, TERT, and miRNA Expression

    PubMed Central

    Slattery, Martha L.; Herrick, Jennifer S.; Pellatt, Andrew J.; Wolff, Roger K.; Mullany, Lila E.

    2016-01-01

    It has been proposed that miRNAs are involved in the control of telomeres. We test that hypothesis by examining the association between miRNAs and telomere length (TL). Additionally, we evaluate if genetic variation in telomerase reverse transcriptase (TERT) is associated with miRNA expression levels. We use data from a population-based study of colorectal cancer (CRC), where we have previously shown associations between TL and TERT and CRC, to test associations between TL and miRNA expression and TERT and miRNA expression. To gain insight into functions of miRNAs associated with TERT we tested linear associations between miRNAs and their targeted gene mRNAs. An Agilent platform that contained information on over 2000 miRNAs was used. TL was measured using a multiplexed quantitative PCR (qPCR). RNAseq was used to assess gene expression. Our sample consisted of 1152 individuals with SNP data and miRNA expression data; 363 individuals with both TL and miRNA; and 148 individuals with miRNA and mRNA data. Thirty-three miRNAs were directly associated with TL after adjusting for age and sex (false discovery rate (FDR) of 0.05). TERT rs2736118 was associated with differences in miRNA expression between carcinoma and normal colonic mucosa for 75 miRNAs (FDR <0.05). Genes regulated by these miRNAs, as indicated by mRNA/miRNA associations, were associated with major signaling pathways beyond their TL-related functions, including PTEN, and PI3K/AKT signaling. Our data support a direct association between miRNAs and TL; differences in miRNA expression levels by TERT genotype were observed. Based on miRNA and targeted mRNA associations our data suggest that TERT is involved in non-TL-related functions by acting through altered miRNA expression. PMID:27627813

  11. Telomere Length, TERT, and miRNA Expression.

    PubMed

    Slattery, Martha L; Herrick, Jennifer S; Pellatt, Andrew J; Wolff, Roger K; Mullany, Lila E

    2016-01-01

    It has been proposed that miRNAs are involved in the control of telomeres. We test that hypothesis by examining the association between miRNAs and telomere length (TL). Additionally, we evaluate if genetic variation in telomerase reverse transcriptase (TERT) is associated with miRNA expression levels. We use data from a population-based study of colorectal cancer (CRC), where we have previously shown associations between TL and TERT and CRC, to test associations between TL and miRNA expression and TERT and miRNA expression. To gain insight into functions of miRNAs associated with TERT we tested linear associations between miRNAs and their targeted gene mRNAs. An Agilent platform that contained information on over 2000 miRNAs was used. TL was measured using a multiplexed quantitative PCR (qPCR). RNAseq was used to assess gene expression. Our sample consisted of 1152 individuals with SNP data and miRNA expression data; 363 individuals with both TL and miRNA; and 148 individuals with miRNA and mRNA data. Thirty-three miRNAs were directly associated with TL after adjusting for age and sex (false discovery rate (FDR) of 0.05). TERT rs2736118 was associated with differences in miRNA expression between carcinoma and normal colonic mucosa for 75 miRNAs (FDR <0.05). Genes regulated by these miRNAs, as indicated by mRNA/miRNA associations, were associated with major signaling pathways beyond their TL-related functions, including PTEN, and PI3K/AKT signaling. Our data support a direct association between miRNAs and TL; differences in miRNA expression levels by TERT genotype were observed. Based on miRNA and targeted mRNA associations our data suggest that TERT is involved in non-TL-related functions by acting through altered miRNA expression. PMID:27627813

  12. Peripheral telomere length and hippocampal volume in adolescents with major depressive disorder.

    PubMed

    Henje Blom, E; Han, L K M; Connolly, C G; Ho, T C; Lin, J; LeWinn, K Z; Simmons, A N; Sacchet, M D; Mobayed, N; Luna, M E; Paulus, M; Epel, E S; Blackburn, E H; Wolkowitz, O M; Yang, T T

    2015-01-01

    Several studies have reported that adults with major depressive disorder have shorter telomere length and reduced hippocampal volumes. Moreover, studies of adult populations without major depressive disorder suggest a relationship between peripheral telomere length and hippocampal volume. However, the relationship of these findings in adolescents with major depressive disorder has yet to be explored. We examined whether adolescent major depressive disorder is associated with altered peripheral telomere length and hippocampal volume, and whether these measures relate to one another. In 54 unmedicated adolescents (13-18 years) with major depressive disorder and 63 well-matched healthy controls, telomere length was assessed from saliva using quantitative polymerase chain reaction methods, and bilateral hippocampal volumes were measured with magnetic resonance imaging. After adjusting for age and sex (and total brain volume in the hippocampal analysis), adolescents with major depressive disorder exhibited significantly shorter telomere length and significantly smaller right, but not left hippocampal volume. When corrected for age, sex, diagnostic group and total brain volume, telomere length was not significantly associated with left or right hippocampal volume, suggesting that these cellular and neural processes may be mechanistically distinct during adolescence. Our findings suggest that shortening of telomere length and reduction of hippocampal volume are already present in early-onset major depressive disorder and thus unlikely to be only a result of accumulated years of exposure to major depressive disorder. PMID:26556285

  13. Peripheral telomere length and hippocampal volume in adolescents with major depressive disorder.

    PubMed

    Henje Blom, E; Han, L K M; Connolly, C G; Ho, T C; Lin, J; LeWinn, K Z; Simmons, A N; Sacchet, M D; Mobayed, N; Luna, M E; Paulus, M; Epel, E S; Blackburn, E H; Wolkowitz, O M; Yang, T T

    2015-11-10

    Several studies have reported that adults with major depressive disorder have shorter telomere length and reduced hippocampal volumes. Moreover, studies of adult populations without major depressive disorder suggest a relationship between peripheral telomere length and hippocampal volume. However, the relationship of these findings in adolescents with major depressive disorder has yet to be explored. We examined whether adolescent major depressive disorder is associated with altered peripheral telomere length and hippocampal volume, and whether these measures relate to one another. In 54 unmedicated adolescents (13-18 years) with major depressive disorder and 63 well-matched healthy controls, telomere length was assessed from saliva using quantitative polymerase chain reaction methods, and bilateral hippocampal volumes were measured with magnetic resonance imaging. After adjusting for age and sex (and total brain volume in the hippocampal analysis), adolescents with major depressive disorder exhibited significantly shorter telomere length and significantly smaller right, but not left hippocampal volume. When corrected for age, sex, diagnostic group and total brain volume, telomere length was not significantly associated with left or right hippocampal volume, suggesting that these cellular and neural processes may be mechanistically distinct during adolescence. Our findings suggest that shortening of telomere length and reduction of hippocampal volume are already present in early-onset major depressive disorder and thus unlikely to be only a result of accumulated years of exposure to major depressive disorder.

  14. Peripheral telomere length and hippocampal volume in adolescents with major depressive disorder

    PubMed Central

    Henje Blom, E; Han, L K M; Connolly, C G; Ho, T C; Lin, J; LeWinn, K Z; Simmons, A N; Sacchet, M D; Mobayed, N; Luna, M E; Paulus, M; Epel, E S; Blackburn, E H; Wolkowitz, O M; Yang, T T

    2015-01-01

    Several studies have reported that adults with major depressive disorder have shorter telomere length and reduced hippocampal volumes. Moreover, studies of adult populations without major depressive disorder suggest a relationship between peripheral telomere length and hippocampal volume. However, the relationship of these findings in adolescents with major depressive disorder has yet to be explored. We examined whether adolescent major depressive disorder is associated with altered peripheral telomere length and hippocampal volume, and whether these measures relate to one another. In 54 unmedicated adolescents (13–18 years) with major depressive disorder and 63 well-matched healthy controls, telomere length was assessed from saliva using quantitative polymerase chain reaction methods, and bilateral hippocampal volumes were measured with magnetic resonance imaging. After adjusting for age and sex (and total brain volume in the hippocampal analysis), adolescents with major depressive disorder exhibited significantly shorter telomere length and significantly smaller right, but not left hippocampal volume. When corrected for age, sex, diagnostic group and total brain volume, telomere length was not significantly associated with left or right hippocampal volume, suggesting that these cellular and neural processes may be mechanistically distinct during adolescence. Our findings suggest that shortening of telomere length and reduction of hippocampal volume are already present in early-onset major depressive disorder and thus unlikely to be only a result of accumulated years of exposure to major depressive disorder. PMID:26556285

  15. Is Chronic Asthma Associated with Shorter Leukocyte Telomere Length at Midlife?

    PubMed Central

    Shalev, Idan; Sears, Malcolm R.; Hancox, Robert J.; Lee Harrington, Hona; Houts, Renate; Moffitt, Terrie E.; Sugden, Karen; Williams, Benjamin; Poulton, Richie; Caspi, Avshalom

    2014-01-01

    Rationale: Asthma is prospectively associated with age-related chronic diseases and mortality, suggesting the hypothesis that asthma may relate to a general, multisystem phenotype of accelerated aging. Objectives: To test whether chronic asthma is associated with a proposed biomarker of accelerated aging, leukocyte telomere length. Methods: Asthma was ascertained prospectively in the Dunedin Multidisciplinary Health and Development Study cohort (n = 1,037) at nine in-person assessments spanning ages 9–38 years. Leukocyte telomere length was measured at ages 26 and 38 years. Asthma was classified as life-course-persistent, childhood-onset not meeting criteria for persistence, and adolescent/adult-onset. We tested associations between asthma and leukocyte telomere length using regression models. We tested for confounding of asthma-leukocyte telomere length associations using covariate adjustment. We tested serum C-reactive protein and white blood cell counts as potential mediators of asthma-leukocyte telomere length associations. Measurements and Main Results: Study members with life-course-persistent asthma had shorter leukocyte telomere length as compared with sex- and age-matched peers with no reported asthma. In contrast, leukocyte telomere length in study members with childhood-onset and adolescent/adult-onset asthma was not different from leukocyte telomere length in peers with no reported asthma. Adjustment for life histories of obesity and smoking did not change results. Study members with life-course-persistent asthma had elevated blood eosinophil counts. Blood eosinophil count mediated 29% of the life-course-persistent asthma-leukocyte telomere length association. Conclusions: Life-course-persistent asthma is related to a proposed biomarker of accelerated aging, possibly via systemic eosinophilic inflammation. Life histories of asthma can inform studies of aging. PMID:24956257

  16. Prediagnostic Obesity and Physical Inactivity Are Associated with Shorter Telomere Length in Prostate Stromal Cells.

    PubMed

    Joshu, Corinne E; Peskoe, Sarah B; Heaphy, Christopher M; Kenfield, Stacey A; Van Blarigan, Erin L; Mucci, Lorelei A; Giovannucci, Edward L; Stampfer, Meir J; Yoon, GhilSuk; Lee, Thomas K; Hicks, Jessica L; De Marzo, Angelo M; Meeker, Alan K; Platz, Elizabeth A

    2015-08-01

    Obesity and inactivity have been associated with advanced-stage prostate cancer, and poor prostate cancer outcomes, though the underlying mechanism(s) is unknown. To determine whether telomere shortening, which has been associated with lethal prostate cancer, may be a potential underlying mechanism, we prospectively evaluated the association between measures of adiposity, physical activity, and telomere length in 596 participants in the Health Professionals Follow-up Study, who were surgically treated for prostate cancer. Using tissue microarrays, we measured telomere length in cancer and benign cells using a telomere-specific FISH assay. Adiposity and activity were assessed via questionnaire within 2 years of diagnosis. Adjusting for age, pathologic stage, and grade, the median and SD of the per cell telomere signals were determined for each man for stromal cells and cancer cells by adiposity and activity categories. Overweight/obese men (54%) were similar to normal weight men on most factors, but had higher Gleason sum and lower activity levels. Overweight/obese men had 7.4% shorter telomeres in stromal cells than normal weight men (P = 0.06). The least active men had shorter telomeres in stromal cells than more active men (Ptrend = 0.002). Men who were overweight/obese and the least active had the shortest telomeres in stromal cells (20.7% shorter; P = 0.0005) compared with normal weight men who were the most active. Cancer cell telomere length and telomere length variability did not differ by measures of adiposity or activity. Telomere shortening in prostate cells may be one mechanism through which lifestyle influences prostate cancer risk and outcomes.

  17. Origin of human chromosome 2: An ancestral telomere-telomere fusion

    SciTech Connect

    Ijdo, J.W.; Baldini, A.; Ward, D.C.; Reeders, S.T.; Wells, R.A. )

    1991-10-15

    The authors identified two allelic genomic cosmids from human chromosome 2, c8.1 and c29B, each containing two inverted arrays of the vertebrate telomeric repeat in a head-to-head arrangement, 5{prime}(TTAGGG){sub n}-(CCCTAA){sub m}3{prime}. Sequences flanking this telomeric repeat are characteristic of present-day human pretelomeres. BAL-31 nuclease experiments with yeast artificial chromosome clones of human telomeres and fluorescence in situ hybridization reveal that sequences flanking these inverted repeats hybridize both to band 2q13 and to different, but overlapping, subsets of human chromosome ends. They conclude that the locus cloned in cosmids c8.1 and c29B is the relic of an ancient telomere-telomere fusion and marks the point at which two ancestral ape chromosomes fused to give rise to human chromosome 2.

  18. Lifespan adversity and later adulthood telomere length in the nationally representative US Health and Retirement Study

    PubMed Central

    Gemmill, Alison; Weir, David; Adler, Nancy E.; Prather, Aric A.

    2016-01-01

    Stress over the lifespan is thought to promote accelerated aging and early disease. Telomere length is a marker of cell aging that appears to be one mediator of this relationship. Telomere length is associated with early adversity and with chronic stressors in adulthood in many studies. Although cumulative lifespan adversity should have bigger impacts than single events, it is also possible that adversity in childhood has larger effects on later life health than adult stressors, as suggested by models of biological embedding in early life. No studies have examined the individual vs. cumulative effects of childhood and adulthood adversities on adult telomere length. Here, we examined the relationship between cumulative childhood and adulthood adversity, adding up a range of severe financial, traumatic, and social exposures, as well as comparing them to each other, in relation to salivary telomere length. We examined 4,598 men and women from the US Health and Retirement Study. Single adversities tended to have nonsignificant relations with telomere length. In adjusted models, lifetime cumulative adversity predicted 6% greater odds of shorter telomere length. This result was mainly due to childhood adversity. In adjusted models for cumulative childhood adversity, the occurrence of each additional childhood event predicted 11% increased odds of having short telomeres. This result appeared mainly because of social/traumatic exposures rather than financial exposures. This study suggests that the shadow of childhood adversity may reach far into later adulthood in part through cellular aging. PMID:27698131

  19. Salivary Telomere Length and Lung Function in Adolescents Born Very Preterm: A Prospective Multicenter Study

    PubMed Central

    Hadchouel, Alice; Marchand-Martin, Laetitia; Franco-Montoya, Marie-Laure; Peaudecerf, Laetitia; Ancel, Pierre-Yves; Delacourt, Christophe

    2015-01-01

    Preterm birth is associated with abnormal respiratory functions throughout life. The mechanisms underlying these long-term consequences are still unclear. Shortening of telomeres was associated with many conditions, such as chronic obstructive pulmonary disease. We aimed to search for an association between telomere length and lung function in adolescents born preterm. Lung function and telomere length were measured in 236 adolescents born preterm and 38 born full-term from the longitudinal EPIPAGE cohort. Associations between telomere length and spirometric indices were tested in univariate and multivariate models accounting for confounding factors in the study population. Airflows were significantly lower in adolescents born preterm than controls; forced expiratory volume in one second was 12% lower in the extremely preterm born group than controls (p<0.001). Lower birth weight, bronchopulmonary dysplasia and postnatal sepsis were significantly associated with lower airflow values. Gender was the only factor that was significantly associated with telomere length. Telomere length correlated with forced expiratory flow 25–75 in the extremely preterm adolescent group in univariate and multivariate analyses (p = 0.01 and p = 0.02, respectively). We evidenced an association between telomere length and abnormal airflow in a population of adolescents born extremely preterm. There was no evident association with perinatal events. This suggests other involved factors, such as a continuing airway oxidative stress leading to persistent inflammation and altered lung function, ultimately increasing susceptibility to chronic obstructive pulmonary disease. PMID:26355460

  20. Shorter telomere length in peripheral blood leukocytes is associated with childhood autism

    PubMed Central

    Li, Zongchang; Tang, Jinsong; Li, Hong; Chen, Shan; He, Ying; Liao, Yanhui; Wei, Zhen; Wan, Guobin; Xiang, Xi; Xia, Kun; Chen, Xiaogang

    2014-01-01

    Telomeres are protective chromosomal structures that play a key role in preserving genomic stability. Epidemiologic studies have shown that the abnormal telomere length in leukocytes is associated with some mental disorders and age-related diseases. However, the association between leukocyte telomere length and autism has not been investigated. Here we investigated the possible association between relative telomere length (RTL) in peripheral blood leukocytes and childhood autism by using an established real-time polymerase chain reaction method. We observed significantly shorter RTL in patients with childhood autism than in controls (p = 0.006). Individuals with shorter RTL had a significantly increased presence of childhood autism compared with those who had long RTL. In patients, we found that family training interventions have a significant effect on telomere length (P = 0.012), but no correlations between RTL and clinical features (paternal age, maternal age, age of onset, illness of duration, CARS score and ABC score) were observed in this study. These results provided the first evidence that shorter leukocytes telomere length is significantly associated with childhood autism. The molecular mechanism underlying telomere length may be implicated in the development of autism. PMID:25399515

  1. Effect of healthy lifestyle behaviors on the association between leukocyte telomere length and coronary artery calcium.

    PubMed

    Diaz, Vanessa A; Mainous, Arch G; Everett, Charles J; Schoepf, U Joseph; Codd, Veryan; Samani, Nilesh J; Samanii, Nilesh J

    2010-09-01

    The telomere length is an indicator of biologic aging, and shorter telomeres have been associated with coronary artery calcium (CAC), a validated indicator of coronary atherosclerosis. It is unclear, however, whether healthy lifestyle behaviors affect the relation between telomere length and CAC. In a sample of subjects aged 40 to 64 years with no previous diagnosis of coronary heart disease, stroke, diabetes mellitus, or cancer (n = 318), healthy lifestyle behaviors of greater fruit and vegetable consumption, lower meat consumption, exercise, being at a healthy weight, and the presence of social support were examined to determine whether they attenuated the association between a shorter telomere length and the presence of CAC. Logistic regression analyses controlling for age, gender, race/ethnicity, and Framingham risk score revealed that the relation between having shorter telomeres and the presence of CAC was attenuated in the presence of high social support, low meat consumption, and high fruit and vegetable consumption. Those with shorter telomeres and these characteristics were not significantly different from those with longer telomeres. Conversely, the subjects with shorter telomeres and less healthy lifestyles had a significantly increased risk of the presence of CAC: low fruit and vegetable consumption (odds ratio 3.30, 95% confidence interval 1.61 to 6.75), high meat consumption (odds ratio 3.33, 95% confidence interval 1.54 to 7.20), and low social support (odds ratio 2.58, 95% confidence interval 1.24 to 5.37). Stratification by gender yielded similar results for men; however, among women, only fruit and vegetable consumption attenuated the shorter telomere length and CAC relation. In conclusion, the results of the present study suggest that being involved in healthy lifestyle behaviors might attenuate the association between shorter telomere length and coronary atherosclerosis, as identified using CAC.

  2. Reduced telomere length in individuals with FMR1 premutations and full mutations.

    PubMed

    Jenkins, Edmund C; Tassone, Flora; Ye, Lingling; Hoogeveen, André T; Brown, W Ted; Hagerman, Randi J; Hagerman, Paul J

    2012-05-01

    We reported previously that 10 older men (66.4 ± 4.6 years) with premutation alleles (55-200 CGG repeats) of the FMR1 gene, with or without FXTAS, had decreased telomere length when compared to sex- and age-matched controls. Extending our use of light intensity measurements from a telomere probe hybridized to interphase preparations, we have now found shortened telomeres in 9 younger male premutation carriers (31.7 ± 17.6 years). We have also shown decreased telomere length in T lymphocytes from 6 male individuals (12.0 ± 1.8 years) with full mutation FMR1 alleles (>200 CGG repeats). These findings support our hypothesis that reduced telomere length is a component of the sub-cellular pathology of FMR1-associated disorders. The experimental approach involved pair-wise comparisons of light intensity values of 20 cells from an individual with either premutation or full mutation CGG-repeat expansions relative to an equivalent number of cells from a sex- and age-matched control. In addition, we demonstrated reduced telomere size in T-lymphocyte cultures from eight individuals with the FMR1 premutation using six different measures. Four relied on detection of light intensity differences, and two involved measuring the whole chromosome, including the telomere, in microns. This new approach confirmed our findings with light intensity measurements and demonstrated the feasibility of direct linear measurements for detecting reductions in telomere size. We have thus confirmed our hypothesis that reduced telomere length is associated with both premutation and full mutation-FMR1 alleles and have demonstrated that direct measurements of telomere length can reliably detect such reductions. PMID:22489017

  3. Delay discounting, genetic sensitivity, and leukocyte telomere length

    PubMed Central

    Yim, Onn-Siong; Zhang, Xing; Shalev, Idan; Monakhov, Mikhail; Zhong, Songfa; Hsu, Ming; Chew, Soo Hong; Lai, Poh San; Ebstein, Richard P.

    2016-01-01

    In a graying world, there is an increasing interest in correlates of aging, especially those found in early life. Leukocyte telomere length (LTL) is an emerging marker of aging at the cellular level, but little is known regarding its link with poor decision making that often entails being overly impatient. Here we investigate the relationship between LTL and the degree of impatience, which is measured in the laboratory using an incentivized delay discounting task. In a sample of 1,158 Han Chinese undergraduates, we observe that steeper delay discounting, indexing higher degree of impatience, is negatively associated with LTL. The relationship is robust after controlling for health-related variables, as well as risk attitude—another important determinant of decision making. LTL in females is more sensitive to impatience than in males. We then asked if genes possibly modulate the effect of impatient behavior on LTL. The oxytocin receptor gene (OXTR) polymorphism rs53576, which has figured prominently in investigations of social cognition and psychological resources, and the estrogen receptor β gene (ESR2) polymorphism rs2978381, one of two gonadal sex hormone genes, significantly mitigate the negative effect of impatience on cellular aging in females. The current results contribute to understanding the relationship between preferences in decision making, particularly impatience, and cellular aging, for the first time to our knowledge. Notably, oxytocin and estrogen receptor polymorphisms temper accelerated cellular aging in young females who tend to make impatient choices. PMID:26903639

  4. Delay discounting, genetic sensitivity, and leukocyte telomere length.

    PubMed

    Yim, Onn-Siong; Zhang, Xing; Shalev, Idan; Monakhov, Mikhail; Zhong, Songfa; Hsu, Ming; Chew, Soo Hong; Lai, Poh San; Ebstein, Richard P

    2016-03-01

    In a graying world, there is an increasing interest in correlates of aging, especially those found in early life. Leukocyte telomere length (LTL) is an emerging marker of aging at the cellular level, but little is known regarding its link with poor decision making that often entails being overly impatient. Here we investigate the relationship between LTL and the degree of impatience, which is measured in the laboratory using an incentivized delay discounting task. In a sample of 1,158 Han Chinese undergraduates, we observe that steeper delay discounting, indexing higher degree of impatience, is negatively associated with LTL. The relationship is robust after controlling for health-related variables, as well as risk attitude-another important determinant of decision making. LTL in females is more sensitive to impatience than in males. We then asked if genes possibly modulate the effect of impatient behavior on LTL. The oxytocin receptor gene (OXTR) polymorphism rs53576, which has figured prominently in investigations of social cognition and psychological resources, and the estrogen receptor β gene (ESR2) polymorphism rs2978381, one of two gonadal sex hormone genes, significantly mitigate the negative effect of impatience on cellular aging in females. The current results contribute to understanding the relationship between preferences in decision making, particularly impatience, and cellular aging, for the first time to our knowledge. Notably, oxytocin and estrogen receptor polymorphisms temper accelerated cellular aging in young females who tend to make impatient choices.

  5. Telomere length is not associated with frailty in older Chinese elderly: Cross-sectional and longitudinal analysis.

    PubMed

    Yu, Ruby; Tang, Nelson; Leung, Jason; Woo, Jean

    2015-12-01

    Telomere shortening has been associated with biological age and several chronic degenerative diseases. However, less is known about telomere length and frailty, which is an indicator of biological age. This study examines the association between telomere length and frailty in a prospective study over five years of 2006 men and women aged 65 years and older living in the community. The frailty status was determined by the Fried's criteria. Telomere length in leukocytes was measured using the quantitative polymerase chain reaction. Logistic regression was used to examine the association between telomere length and incidence of frailty. Among 2006 subjects (mean age 72.4±5.1 years, 51.3% women), the mean telomere length at baseline was 9.1±2.0kb and the frailty phenotype was detected in 127 subjects (6.3%). Male gender was related to shorter telomere length, with increased years of age related to a shortened telomere length (P<0.05). In both men and women, no statistically significant difference of telomere length and the frailty phenotype was observed at baseline. After 4 years of follow-up, 116 cases of frailty were identified. There was no association between telomere length and incident frailty. In conclusion, telomere length was not associated with frailty in this study population.

  6. Change in Leukocyte Telomere Length Predicts Mortality in Patients with Stable Coronary Heart Disease from the Heart and Soul Study

    PubMed Central

    Goglin, Sarah E.; Farzaneh-Far, Ramin; Epel, Elissa S.; Lin, Jue; Blackburn, Elizabeth H.

    2016-01-01

    Background Short telomere length independently predicts mortality in patients with coronary heart disease. Whether 5-year change in telomere length predicts subsequent mortality in patients with coronary heart disease has not been evaluated. Methods In a prospective cohort study of 608 individuals with stable coronary artery disease, we measured leukocyte telomere length at baseline and after five years of follow-up. We divided the sample into tertiles of telomere change: shortened, maintained or lengthened. We used Cox survival models to evaluate 5-year change in telomere length as a predictor of mortality. Results During an average of 4.2 years follow-up, there were 149 deaths. Change in telomere length was inversely predictive of all-cause mortality. Using the continuous variable of telomere length change, each standard deviation (325 base pair) greater increase in telomere length was associated with a 24% reduction in mortality (HR 0.76, 95% CI 0.61–0.94; p = 0.01), adjusted for age, sex, waist to hip ratio, exercise capacity, LV ejection fraction, serum creatinine, and year 5 telomere length. Mortality occurred in 39% (79/203) of patients who experienced telomere shortening, 22% (45/203) of patients whose telomere length was maintained, and 12% (25/202) of patients who experienced telomere lengthening (p<0.001). As compared with patients whose telomere length was maintained, those who experienced telomere lengthening were 56% less likely to die (HR 0.44, 95% CI, 0.23–0.87). Conclusions In patients with coronary heart disease, an increase in leukocyte telomere length over 5 years is associated with decreased mortality. PMID:27783614

  7. Oxidative Stress-induced Telomere Length Shortening of Circulating Leukocyte in Patients with Obstructive Sleep Apnea

    PubMed Central

    Kim, Kyung Soo; Kwak, Jin Wook; Lim, Su Jin; Park, Yong Kyun; Yang, Hoon Shik; Kim, Hyun Jik

    2016-01-01

    The main mechanism of pathogenesis which causes systemic complications in obstructive sleep apnea (OSA) patients is believed to be intermittent hypoxia-induced intermediary effect and it depends on the burden of oxidative stress during sleep. We aimed to search the predictive markers which reflect the burden of systemic oxidative stress in patients with OSA and whether excessive telomere length shortening is a characteristic feature that can assess oxidative stress levels. We used quantitative PCR to measure telomere length using peripheral blood genomic DNA. Telomere lengths were compared in an age- and body mass index (BMI)-dependent manner in 34 healthy volunteers and 43 OSA subjects. We also performed reactive oxygen species assay to measure the concentration of hydrogen peroxide in the peripheral blood of healthy volunteers and OSA subjects. We found that the serum concentration of hydrogen peroxide was considerably higher in OSA patients, and that this was closely related with the severity of OSA. Significantly shortened telomere length was observed in the circulating leukocytes of the peripheral blood of OSA patients, and telomere length shortening was aggravated more acutely in an age- and BMI-dependent manner. An inverse correlation was observed between the concentration of hydrogen peroxide and the telomere length of OSA patients and excessive telomere length shortening was also linked to severity of OSA. The results provided evidence that telomere length shortening or excessive cellular aging might be distinctive in circulating leukocyte of OSA patients and may be an predictive biomarker for reflect the burden of oxidative stress in the peripheral blood of OSA patients. PMID:27699083

  8. Oxidative Stress-induced Telomere Length Shortening of Circulating Leukocyte in Patients with Obstructive Sleep Apnea

    PubMed Central

    Kim, Kyung Soo; Kwak, Jin Wook; Lim, Su Jin; Park, Yong Kyun; Yang, Hoon Shik; Kim, Hyun Jik

    2016-01-01

    The main mechanism of pathogenesis which causes systemic complications in obstructive sleep apnea (OSA) patients is believed to be intermittent hypoxia-induced intermediary effect and it depends on the burden of oxidative stress during sleep. We aimed to search the predictive markers which reflect the burden of systemic oxidative stress in patients with OSA and whether excessive telomere length shortening is a characteristic feature that can assess oxidative stress levels. We used quantitative PCR to measure telomere length using peripheral blood genomic DNA. Telomere lengths were compared in an age- and body mass index (BMI)-dependent manner in 34 healthy volunteers and 43 OSA subjects. We also performed reactive oxygen species assay to measure the concentration of hydrogen peroxide in the peripheral blood of healthy volunteers and OSA subjects. We found that the serum concentration of hydrogen peroxide was considerably higher in OSA patients, and that this was closely related with the severity of OSA. Significantly shortened telomere length was observed in the circulating leukocytes of the peripheral blood of OSA patients, and telomere length shortening was aggravated more acutely in an age- and BMI-dependent manner. An inverse correlation was observed between the concentration of hydrogen peroxide and the telomere length of OSA patients and excessive telomere length shortening was also linked to severity of OSA. The results provided evidence that telomere length shortening or excessive cellular aging might be distinctive in circulating leukocyte of OSA patients and may be an predictive biomarker for reflect the burden of oxidative stress in the peripheral blood of OSA patients.

  9. Age-adjusted recipient pretransplantation telomere length and treatment-related mortality after hematopoietic stem cell transplantation

    PubMed Central

    Calado, Rodrigo T.; Busson, Marc; Abrams, Jeffrey; Adoui, Nadir; Robin, Marie; Larghero, Jérôme; Dhedin, Nathalie; Xhaard, Alienor; Clave, Emmanuel; Charron, Dominique; Toubert, Antoine; Loiseau, Pascale; Socié, Gérard; Young, Neal S.

    2012-01-01

    Telomere attrition induces cell senescence and apoptosis. We hypothesized that age-adjusted pretransplantation telomere length might predict treatment-related mortality (TRM) after hematopoietic stem cell transplantation (HSCT). Between 2000 and 2005, 178 consecutive patients underwent HSCT from HLA-identical sibling donors after myeloablative conditioning regimens, mainly for hematologic malignancies (n = 153). Blood lymphocytes' telomere length was measured by real-time quantitative PCR before HSCT. Age-adjusted pretransplantation telomere lengths were analyzed for correlation with clinical outcomes. After age adjustment, patients' telomere-length distribution was similar among all 4 quartiles except for disease stage. There was no correlation between telomere length and engraftment, GVHD, or relapse. The overall survival was 62% at 5 years (95% confidence interval [CI], 54-70). After a median follow-up of 51 months (range, 1-121 months), 43 patients died because of TRM. The TRM rate inversely correlated with telomere length. TRM in patients in the first (lowest telomere length) quartile was significantly higher than in patients with longer telomeres (P = .017). In multivariate analysis, recipients' age (hazard ratio, 1.1; 95% CI, .0-1.1; P = .0001) and age-adjusted telomere length (hazard ratio, 0.4; 95% CI; 0.2-0.8; P = .01) were independently associated with TRM. In conclusion, age-adjusted recipients' telomere length is an independent biologic marker of TRM after HSCT. PMID:22948043

  10. Strong association between long and heterogeneous telomere length in blood lymphocytes and bladder cancer risk in Egyptian.

    PubMed

    Wang, Hongkun; Wang, Ying; Kota, Krishna K; Kallakury, Bhaskar; Mikhail, Nabiel N; Sayed, Douaa; Mokhtar, Ahmed; Maximous, Doaa; Yassin, Etemad H; Gouda, Iman; Sobitan, Adebiyi; Sun, Bing; Loffredo, Christopher A; Zheng, Yun-Ling

    2015-11-01

    Although it is widely recognized that telomere dysfunction plays an important role in cancer, the relationship between telomere function and bladder cancer risk is not well defined. In a case-control study of bladder cancer in Egypt, we examined relationships between two telomere features and bladder cancer risk. Telomere fluorescent in situ hybridization was used to measure telomere features using short-term cultured blood lymphocytes. Logistic regression was used to estimate the strength of association between telomere features and the risk of urothelial carcinoma of the bladder. High telomere length variation (TLV) across all chromosomal ends was significantly associated with an increased risk of bladder cancer [adjusted odds ratios (OR) = 2.22, 95% confidence interval (CI) = 1.48-3.35], as was long average telomere length (OR = 3.19, 95% CI = 2.07, 4.91). Further, TLV and average telomere length jointly affected bladder cancer risk: when comparing individuals with long telomere length and high TLV to those with short telomere length and low TLV, the adjusted OR was 14.68 (95% CI: 6.74-31.98). These associations were stronger among individuals who are 60 years of age or younger. In summary, long and heterogeneous telomere length in blood lymphocytes was strongly associated with an increased bladder cancer risk in Egyptian and the association was modulated by age.

  11. Stress Responsive Biochemical Anabolic/Catabolic Ratio and Telomere Length in Older Adults

    PubMed Central

    Vasunilashorn, Sarinnapha; Cohen, Alan A.

    2014-01-01

    It has been hypothesized that chronic psychological stress is associated with shorter telomere length; however, the mechanisms that link stress and telomere length are not well understood. To examine the interplay between biochemical factors related to stress arousal and cellular aging, we investigate the association between anabolic/catabolic (A/C) imbalance and leukocyte telomere length (LTL) in the Social Environment and Biomarkers of Aging Study (SEBAS) in Taiwan (N=925). SEBAS participants age 54 and older (mean age 68.3) with values for two anabolic hormones (serum dehydroepiandrosterone sulfate [DHEAS] and insulin growth factor [IGF]-1), four catabolic hormones (cortisol, epinephrine, norepinephrine, and interleukin-6 [IL-6]), and leukocyte telomere length were examined. We found that high IL-6 was associated with short LTL (≤0.88 T/S ratio; odds ratio [OR] 1.41, 95% confidence interval [CI] 1.04–1.92). Neither DHEAS/cortisol nor IGF-1/cortisol ratio was associated with telomere length; however, a high A/C imbalance summary score was associated with a greater odds of having a short LTL relative to long LTL (OR 1.19, 95% CI 1.05–1.35). These results indicate that our A/C imbalance score, defined by several anabolic and catabolic biochemical factors, may be one mechanism through which psychological stress is associated with short leukocyte telomere length and possibly cellular senescence. PMID:25343365

  12. Minishelterins separate telomere length regulation and end protection in fission yeast.

    PubMed

    Pan, Lili; Hildebrand, Katie; Stutz, Cian; Thomä, Nicolas; Baumann, Peter

    2015-06-01

    The conserved shelterin complex is critical for chromosome capping and maintaining telomere length homeostasis. In fission yeast, shelterin is comprised of five proteins. Taz1, Rap1, and Poz1 function as negative regulators of telomere elongation, whereas Pot1 and Tpz1 are critical for end capping and telomerase recruitment. How the five proteins work together to safeguard chromosome ends and promote telomere length homeostasis is a matter of great interest. Using a combination of deletions, fusions, and tethers, we define key elements of shelterin important for telomere length regulation. Surprisingly, deletion of the entire Rap1 and Poz1 proteins does not impair telomere length regulation as long as a static bridge is provided between Taz1 and Tpz1. Cells harboring minishelterin display wild-type telomere length and intact subtelomeric silencing. However, protection against end fusions in G1 is compromised in the absence of Rap1. Our data reveal a remarkable plasticity in shelterin architecture and separate functions in length regulation and end protection.

  13. The effect of chemotherapeutic agents on telomere length maintenance in breast cancer cell lines.

    PubMed

    Motevalli, Azadeh; Yasaei, Hemad; Virmouni, Sara Anjomani; Slijepcevic, Predrag; Roberts, Terry

    2014-06-01

    Mammalian telomeric DNA consists of tandem repeats of the sequence TTAGGG associated with a specialized set of proteins, known collectively as Shelterin. These telosomal proteins protect the ends of chromosomes against end-to-end fusion and degradation. Short telomeres in breast cancer cells confer telomere dysfunction and this can be related to Shelterin proteins and their level of expression in breast cancer cell lines. This study investigates whether expression of Shelterin and Shelterin-associated proteins are altered, and influence the protection and maintenance of telomeres, in breast cancer cells. 5-aza-2'-deoxycytidine (5-aza-CdR) and trichostatin A (TSA) were used in an attempt to reactivate the expression of silenced genes. Our studies have shown that Shelterin and Shelterin-associated genes were down-regulated in breast cancer cell lines; this may be due to epigenetic modification of DNA as the promoter region of POT1 was found to be partially methylated. Shelterin genes expression was up-regulated upon treatment of 21NT breast cancer cells with 5-aza-CdR and TSA. The telomere length of treated 21NT cells was measured by q-PCR showed an increase in telomere length at different time points. Our studies have shown that down-regulation of Shelterin genes is partially due to methylation in some epithelial breast cancer cell lines. Removal of epigenetic silencing results in up-regulation of Shelterin and Shelterin-associated genes which can then lead to telomere length elongation and stability. PMID:24807106

  14. Heritability of Telomere Length in a Study of Long-Lived Families

    PubMed Central

    Honig, Lawrence S.; Kang, Min Suk; Cheng, Rong; Eckfeldt, John H.; Thyagarajan, Bharat; Leiendecker-Foster, Catherine; Province, Michael A.; Sanders, Jason L.; Perls, Thomas; Christensen, Kaare; Lee, Joseph H.; Mayeux, Richard P.; Schupf, Nicole

    2015-01-01

    Chromosomal telomere length shortens with repeated cell divisions. Human leukocyte DNA telomere length (LTL) determined has been shown to shorten during aging. LTL shortening has correlated with decreased longevity, dementia, and other age-associated processes. Since LTL varies widely between individuals in a given age group, it has been hypothesized to be a marker of biological aging. However, the principal basis for the variation of human LTL has not been established, although various studies have reported heritability. Here we use a family-based study of longevity to study heritability of LTL in 3037 individuals. We show that LTL is shorter in older individuals, and in males, and has a high heritability (overall h2 = 0.54). In the offspring generation, who are in middle-life, we find an ordinal relationship: persons more-closely-related to elderly probands have longer LTL than persons less-closely-related, who nonetheless have longer LTL than unrelated spouses of the offspring generation. These results support a prominent genetic underpinning of LTL. Elucidation of such genetic bases may provide avenues for intervening in the aging process. PMID:26239175

  15. Nutrients, foods, dietary patterns and telomere length: Update of epidemiological studies and randomized trials.

    PubMed

    Freitas-Simoes, Tania-Marisa; Ros, Emilio; Sala-Vila, Aleix

    2016-04-01

    Identifying simple strategies to prevent or delay age-associated pathologies is a major public health concern. Attrition of telomeres, chromatin structures that help maintain genome stability, leads to cell death or senescence. Thus telomere length is a reliable hallmark of biological aging and the risk of developing age-related chronic diseases through common oxidation and inflammation mechanisms. Variability in telomere shortening that is independent of chronological age suggests that it is a modifiable factor, which may be explained in part by lifestyle variables such as smoking, adiposity, physical exercise, and diet. Here we summarize data from published studies focused on nutrition (nutrients, foods, and dietary patterns) and telomere length. Research on the topic is incipient and most data comes from epidemiologic studies, often cross-sectional in design. Consistent with well-known evidence of benefit or harm for chronic age-related diseases, dietary antioxidants and consumption of antioxidant-rich, plant-derived foods help maintain telomere length. In contrast, total and saturated fat intake and consumption of refined flour cereals, meat and meat products, and sugar-sweetened beverages relate to shorter telomeres. Data on alcohol and dairy products is controversial. There is evidence that adherence to the Mediterranean diet is associated with longer telomeres. Randomized clinical trials are limited to seafood-derived long-chain n-3 polyunsaturated fatty acids, with promising results. To fill the many gaps in our knowledge of the aging process and confirm nutrition as a useful tool to counteract biological aging more research is warranted, particularly observational studies using repeated measurements of telomere length and randomized trials of foods and dietary patterns with sequential telomere analyses. PMID:26975532

  16. Nutrients, foods, dietary patterns and telomere length: Update of epidemiological studies and randomized trials.

    PubMed

    Freitas-Simoes, Tania-Marisa; Ros, Emilio; Sala-Vila, Aleix

    2016-04-01

    Identifying simple strategies to prevent or delay age-associated pathologies is a major public health concern. Attrition of telomeres, chromatin structures that help maintain genome stability, leads to cell death or senescence. Thus telomere length is a reliable hallmark of biological aging and the risk of developing age-related chronic diseases through common oxidation and inflammation mechanisms. Variability in telomere shortening that is independent of chronological age suggests that it is a modifiable factor, which may be explained in part by lifestyle variables such as smoking, adiposity, physical exercise, and diet. Here we summarize data from published studies focused on nutrition (nutrients, foods, and dietary patterns) and telomere length. Research on the topic is incipient and most data comes from epidemiologic studies, often cross-sectional in design. Consistent with well-known evidence of benefit or harm for chronic age-related diseases, dietary antioxidants and consumption of antioxidant-rich, plant-derived foods help maintain telomere length. In contrast, total and saturated fat intake and consumption of refined flour cereals, meat and meat products, and sugar-sweetened beverages relate to shorter telomeres. Data on alcohol and dairy products is controversial. There is evidence that adherence to the Mediterranean diet is associated with longer telomeres. Randomized clinical trials are limited to seafood-derived long-chain n-3 polyunsaturated fatty acids, with promising results. To fill the many gaps in our knowledge of the aging process and confirm nutrition as a useful tool to counteract biological aging more research is warranted, particularly observational studies using repeated measurements of telomere length and randomized trials of foods and dietary patterns with sequential telomere analyses.

  17. Telomere Length Variation in Juvenile Acute Myocardial Infarction

    PubMed Central

    Fornengo, Cristina; Di Gaetano, Cornelia; Ricceri, Fulvio; Guarrera, Simonetta; Critelli, Rossana; Anselmino, Matteo; Piazza, Alberto; Gaita, Fiorenzo; Bergerone, Serena; Matullo, Giuseppe

    2012-01-01

    Leukocyte telomere length (LTL) provides a potential marker of biological age, closely related to the endothelial dysfunction and consequently to the atherosclerotic process. To investigate the relationship between the LTL and the risk of premature acute myocardial infarction and to evaluate the predictive value of LTL on the onset of major cardiovascular events, 199 patients from 18 to 48 years old with first diagnosis of acute myocardial infarction were enrolled and were matched with 190 controls for sex and age (±1 year). Clinical data and coronary artery disease were evaluated at enrollment and at follow up. LTL was measured at enrollment using a quantitative PCR-based method. No significant differences were observed in LTL between cases and controls (p = 0.20) and with the presence of coronary artery disease in patients (p = 0.47). Hypercholesterolemic cases presented LTL significantly longer than cases without hypercholesterolemia (t/s: 0.82±0.16 p = 0.79 and t/s norm: 0.79±0.19 p = 0.01), as confirmed in multivariate regression analysis (p = 0.005, β = 0.09). Furthermore, multivariate regression analysis showed LTL significantly shorter in hypertensive cases than in normotensive cases (p = 0.04, β = −0.07). One hundred seventy-one cases (86%) ended the average follow up of 9±5 years, 92 (54%) presented a major cardiovascular event. At multivariate regression analysis the LTL detected at enrollment did not represent a predictive factor of major cardiovascular events nor it significantly impacted with cumulative events. Based on present cohort of young Italian patients, the LTL did not represent a marker of acute myocardial infarction nor had a predictive role at medium term follow up. PMID:23145125

  18. Replication Timing of Human Telomeres is Conserved during Immortalization and Influenced by Respective Subtelomeres.

    PubMed

    Piqueret-Stephan, Laure; Ricoul, Michelle; Hempel, William M; Sabatier, Laure

    2016-01-01

    Telomeres are specific structures that protect chromosome ends and act as a biological clock, preventing normal cells from replicating indefinitely. Mammalian telomeres are replicated throughout S-phase in a predetermined order. However, the mechanism of this regulation is still unknown. We wished to investigate this phenomenon under physiological conditions in a changing environment, such as the immortalization process to better understand the mechanism for its control. We thus examined the timing of human telomere replication in normal and SV40 immortalized cells, which are cytogenetically very similar to cancer cells. We found that the timing of telomere replication was globally conserved under different conditions during the immortalization process. The timing of telomere replication was conserved despite changes in telomere length due to endogenous telomerase reactivation, in duplicated homologous chromosomes, and in rearranged chromosomes. Importantly, translocated telomeres, possessing their initial subtelomere, retained the replication timing of their homolog, independently of the proportion of the translocated arm, even when the remaining flanking DNA is restricted to its subtelomere, the closest chromosome-specific sequences (inferior to 500 kb). Our observations support the notion that subtelomere regions strongly influence the replication timing of the associated telomere. PMID:27587191

  19. Replication Timing of Human Telomeres is Conserved during Immortalization and Influenced by Respective Subtelomeres

    PubMed Central

    Piqueret-Stephan, Laure; Ricoul, Michelle; Hempel, William M.; Sabatier, Laure

    2016-01-01

    Telomeres are specific structures that protect chromosome ends and act as a biological clock, preventing normal cells from replicating indefinitely. Mammalian telomeres are replicated throughout S-phase in a predetermined order. However, the mechanism of this regulation is still unknown. We wished to investigate this phenomenon under physiological conditions in a changing environment, such as the immortalization process to better understand the mechanism for its control. We thus examined the timing of human telomere replication in normal and SV40 immortalized cells, which are cytogenetically very similar to cancer cells. We found that the timing of telomere replication was globally conserved under different conditions during the immortalization process. The timing of telomere replication was conserved despite changes in telomere length due to endogenous telomerase reactivation, in duplicated homologous chromosomes, and in rearranged chromosomes. Importantly, translocated telomeres, possessing their initial subtelomere, retained the replication timing of their homolog, independently of the proportion of the translocated arm, even when the remaining flanking DNA is restricted to its subtelomere, the closest chromosome-specific sequences (inferior to 500 kb). Our observations support the notion that subtelomere regions strongly influence the replication timing of the associated telomere. PMID:27587191

  20. Protocol for a systematic review of the association between chronic stress during the life course and telomere length

    PubMed Central

    2014-01-01

    Background The effects of stress on ill health have become evident in recent years. Under acute stress situations, a cascade of physiological events helps the body mount an appropriate adaptive response. However, under chronic stress situations, this physiological response may lead to wear and tear on the body that accelerates the decline in physiological functioning and increases the risk of chronic conditions. Recent evidence for social stress experienced during childhood suggests serious consequences many years later, even later life. Telomere length, a marker of cell aging, may provide a link between chronic social stress and age-associated physical and mental decline and risk of chronic conditions. This study examines whether chronic social stress is associated with telomere length throughout the life course. Methods/Design We will perform a systematic review of the literature on the relationship between chronic social stress, for example, due to violence, extreme poverty, or caregiving of people with disabling conditions (exposure), and telomere length (outcome) by searching electronic databases in MEDLINE (PubMed interface), EMBASE (OVID interface), Cochrane Central (OVID interface) and gray literature from their start date onwards. We will limit the search to studies performed on human populations. Two reviewers will conduct standardized screening, eligibility assessment, data abstraction, and scientific quality assessment. All study designs investigating the association between chronic social stress and telomere length in healthy or diseased adults and children will be eligible for inclusion in the review. We will extract individual demographic and socioeconomic characteristics, research setting, method of measuring telomere length, reported outcome, and determinants of interest. Studies will also be stratified by 1) age into 3 groups: childhood (0 to 18 years), adulthood (19 to 64 years) and late life (65+); 2) cell type; 3) study design; and 4

  1. Long telomere length and a TERT-CLPTM1 locus polymorphism association with melanoma risk.

    PubMed

    Llorca-Cardeñosa, Marta J; Peña-Chilet, Maria; Mayor, Matias; Gomez-Fernandez, Cristina; Casado, Beatriz; Martin-Gonzalez, Manuel; Carretero, Gregorio; Lluch, Ana; Martinez-Cadenas, Conrado; Ibarrola-Villava, Maider; Ribas, Gloria

    2014-12-01

    Telomere length has been associated with the development of cancer. Studies have shown that shorter telomere length may be related to a decreased risk of cutaneous melanoma. Furthermore, deregulation of the telomere-maintaining gene complexes, has been related to this oncogenic process. Some variants in these genes seem to be correlated with a change in telomerase expression. We examined the effect of 10 single nucleotide polymorphisms (SNPs) in the TERT gene (encoding telomerase), one SNP in the related TERT-CLPTM1L locus and one SNP in the TRF1 gene with telomere length, and its influence on melanoma risk in 970 Spanish cases and 733 Spanish controls. Genotypes were determined using KASP technology, and telomere length was measured by quantitative polymerase chain reaction (PCR) on DNA extracted from peripheral blood leucocytes. Our results demonstrate that shorter telomere length is associated with a decreased risk of melanoma in our population (global p-value, 2.69×10(-11)), which may be caused by a diminution of proliferative potential of nevi (melanoma precursor cells). We also obtained significant results when we tested the association between rs401681 variant (TERT-CLPTM1L locus) with melanoma risk (Odds ratio, OR; 95% confidence interval, CI=1.24 (1.08-1.43); p-value, 3×10(-3)). This is the largest telomere-related study undertaken in a Spanish population to date. Furthermore, this study represents a comprehensive analysis of some of the most relevant telomere pathway genes in relation to cutaneous melanoma susceptibility.

  2. The association between leukocyte telomere length and cigarette smoking, dietary and physical variables, and risk of prostate cancer.

    PubMed

    Mirabello, Lisa; Huang, Wen-Yi; Wong, Jason Y Y; Chatterjee, Nilanjan; Reding, Douglas; Crawford, E David; De Vivo, Immaculata; Hayes, Richard B; Savage, Sharon A

    2009-08-01

    Telomeres consist of nucleotide repeats and a protein complex at chromosome ends that are essential to maintaining chromosomal integrity. Several studies have suggested that subjects with shorter telomeres are at increased risk of bladder and lung cancer. In comparison to normal tissues, telomeres are shorter in high-grade intraepithelial neoplasia and prostate cancer. We examined prostate cancer risk associated with relative telomere length as determined by quantitative PCR on prediagnostic buffy coat DNA isolated from 612 advanced prostate cancer cases and 1049 age-matched, cancer-free controls from the PLCO Cancer Screening Trial. Telomere length was analyzed as both a continuous and a categorical variable with adjustment for potential confounders. Statistically significant inverse correlations between telomere length, age and smoking status were observed in cases and controls. Telomere length was not associated with prostate cancer risk (at the median, OR = 0.85, 95% CI: 0.67, 1.08); associations were similar when telomere length was evaluated as a continuous variable or by quartiles. The relationships between telomere length and inflammation-related factors, diet, exercise, body mass index, and other lifestyle variables were explored since many of these have previously been associated with shorter telomeres. Healthy lifestyle factors (i.e., lower BMI, more exercise, tobacco abstinence, diets high in fruit and vegetables) tended to be associated with greater telomere length. This study found no statistically significant association between leukocyte telomere length and advanced prostate cancer risk. However, correlations of telomere length with healthy lifestyles were noted, suggesting the role of these factors in telomere biology maintenance and potentially impacting overall health status.

  3. Genomics, Telomere Length, Epigenetics, and Metabolomics in the Nurses’ Health Studies

    PubMed Central

    Aschard, Hugues; De Vivo, Immaculata; Michels, Karin B.; Kraft, Peter

    2016-01-01

    Objectives. To review the contribution of the Nurses’ Health Study (NHS) and NHS II to genomics, epigenetics, and metabolomics research. Methods. We performed a narrative review of the publications of the NHS and NHS II between 1990 and 2016 based on biospecimens, including blood and tumor tissue, collected from participants. Results. The NHS has contributed to the discovery of genetic loci influencing more than 45 complex human phenotypes, including cancers, diabetes, cardiovascular disease, reproductive characteristics, and anthropometric traits. The combination of genomewide genotype data with extensive exposure and lifestyle data has enabled the evaluation of gene–environment interactions. Furthermore, data suggest that longer telomere length increases risk of cancers not related to smoking, and that modifiable factors (e.g., diet) may have an impact on telomere length. “Omics” research in the NHS continues to expand, with epigenetics and metabolomics becoming greater areas of focus. Conclusions. The combination of prospective biomarker data and broad exposure information has enabled the NHS to participate in a variety of “omics” research, contributing to understanding of the epidemiology and biology of multiple complex diseases. PMID:27459442

  4. Telomeres and marrow failure.

    PubMed

    Calado, Rodrigo T

    2009-01-01

    Telomeres, repeat sequences at the ends of chromosomes, are protective chromosomal structures highly conserved from primitive organisms to humans. Telomeres inevitably shorten with every cell cycle, and telomere attrition has been hypothesized to be fundamental to normal senescence of cells, tissues, and organisms. Molecular mechanisms have evolved to maintain their length and protective function; telomerase (TERT) is a reverse transcriptase enzyme that uses an RNA molecule (TERC) as the template to elongate the 3' ends of telomeres. Shelterin is a collection of DNA-binding proteins that cover and protect telomeres. The recent discovery of inherited mutations in genes that function to repair telomeres as etiologic in a range of human diseases, which have clinical manifestations in diverse tissues, including the hematopoietic tissue, suggests that defects in telomere repair and protection can cause organ failure. Dyskeratosis congenita is the prototype of telomere diseases; it is characterized by bone marrow failure, mucocutaneous abnormalities, pulmonary fibrosis, liver cirrhosis, and increased susceptibility to cancer, including acute myeloid leukemia. Aplastic anemia, acute myeloid leukemia, and idiopathic pulmonary fibrosis also are associated with inherited mutations in telomere repair or protection genes. Additionally, telomere defects associate with predisposition to hematologic malignancy and epithelial tumors. Telomere erosion is abnormally rapid in patients with mutations in telomerase genes but also after hematopoietic stem cell transplant, and telomeres are naturally shorter in older individuals-all conditions associated with higher rates of malignant diseases. In human tissue culture, short telomeres produce end-to-end chromosome fusion, nonreciprocal translocations, and aneuploidy.

  5. Complete sequence analysis of mitochondrial DNA and telomere length in aplastic anemia.

    PubMed

    Cui, Xing; Wang, Junqiang; Cai, Zhiguo; Wang, Jingyi; Liu, Kui; Cui, Siyuan; Zhang, Jie; Luo, Yaqin; Wang, Xin; Li, Weiwei; Jing, Jingyan

    2014-11-01

    The present study was primarily undertaken to examine the hypothesis that mitochondrial DNA (mtDNA) mutations and telomere length may be associated with aplastic anemia (AA). Our study included a single institution analysis of 40 patients presenting with AA first diagnosed at the Affiliated Hospital of Shandong, University of Traditional Chinese Medicine between 2010 and 2013. Bone marrow and oral epithelial samples were collected from patients with AA (n=40) for mtDNA mutation and telomere length determinations. Bone marrow specimens were collected from 40 healthy volunteers as controls for the examination of telomere length. The mitochondrial genome was amplified by polymerase chain reaction (PCR), and the products were used for sequencing and analysis. We detected 146 heteroplasmic mutations in 18 genes from 40 patients with AA, including 39 silent mutations and 28 frameshift mutations. We used the gamma globin gene (HBG) as the control gene in real-time PCR to survey the relative telomere length measurements of the patients with AA and the healthy volunteers. Telomere length was expressed as the relative T/S value. We observed a negative correlation between the mtDNA non-silent mutation and the white blood cell (WBC) count, hemoglobin and platelet count. Of note, there was a positive correlation between the relative T/S value and WBC count, hemoglobin and platelet count, and a negative correlation between the non-silent mutation and the relative T/S value. We conclude that the functional impairment of the mitochondrial respiratory chain induced by mutation and telomere length shortening may play an important role in the process of hematopoietic failure in patients with AA. Additionally, mtDNA mutations and telomere length shortening influenced each other.

  6. Paroxysmal nocturnal hemoglobinuria and telomere length predicts response to immunosuppressive therapy in pediatric aplastic anemia.

    PubMed

    Narita, Atsushi; Muramatsu, Hideki; Sekiya, Yuko; Okuno, Yusuke; Sakaguchi, Hirotoshi; Nishio, Nobuhiro; Yoshida, Nao; Wang, Xinan; Xu, Yinyan; Kawashima, Nozomu; Doisaki, Sayoko; Hama, Asahito; Takahashi, Yoshiyuki; Kudo, Kazuko; Moritake, Hiroshi; Kobayashi, Masao; Kobayashi, Ryoji; Ito, Etsuro; Yabe, Hiromasa; Ohga, Shouichi; Ohara, Akira; Kojima, Seiji

    2015-12-01

    Acquired aplastic anemia is an immune-mediated disease characterized by severe defects in stem cell number resulting in hypocellular marrow and peripheral blood cytopenias. Minor paroxysmal nocturnal hemoglobinuria populations and a short telomere length were identified as predictive biomarkers of immunosuppressive therapy responsiveness in aplastic anemia. We enrolled 113 aplastic anemia patients (63 boys and 50 girls) in this study to evaluate their response to immunosuppressive therapy. The paroxysmal nocturnal hemoglobinuria populations and telomere length were detected by flow cytometry. Forty-seven patients (42%) carried a minor paroxysmal nocturnal hemoglobinuria population. The median telomere length of aplastic anemia patients was -0.99 standard deviation (SD) (range -4.01-+3.01 SD). Overall, 60 patients (53%) responded to immunosuppressive therapy after six months. Multivariate logistic regression analysis identified the absence of a paroxysmal nocturnal hemoglobinuria population and a shorter telomere length as independent unfavorable predictors of immunosuppressive therapy response at six months. The cohort was stratified into a group of poor prognosis (paroxysmal nocturnal hemoglobinuria negative and shorter telomere length; 37 patients) and good prognosis (paroxysmal nocturnal hemoglobinuria positive and/or longer telomere length; 76 patients), respectively. The response rates of the poor prognosis and good prognosis groups at six months were 19% and 70%, respectively (P<0.001). The combined absence of a minor paroxysmal nocturnal hemoglobinuria population and a short telomere length is an efficient predictor of poor immunosuppressive therapy response, which should be considered while deciding treatment options: immunosuppressive therapy or first-line hematopoietic stem cell transplantation. The trial was registered in www.umin.ac.jp with number UMIN000017972.

  7. The epigenetic clock and telomere length are independently associated with chronological age and mortality

    PubMed Central

    Marioni, Riccardo E; Harris, Sarah E; Shah, Sonia; McRae, Allan F; von Zglinicki, Thomas; Martin-Ruiz, Carmen; Wray, Naomi R; Visscher, Peter M; Deary, Ian J

    2016-01-01

    Background: Telomere length and DNA methylation have been proposed as biological clock measures that track chronological age. Whether they change in tandem, or contribute independently to the prediction of chronological age, is not known. Methods: We address these points using data from two Scottish cohorts: the Lothian Birth Cohorts of 1921 (LBC1921) and 1936 (LBC1936). Telomere length and epigenetic clock estimates from DNA methylation were measured in 920 LBC1936 participants (ages 70, 73 and 76 years) and in 414 LBC1921 participants (ages 79, 87 and 90 years). Results: The epigenetic clock changed over time at roughly the same rate as chronological age in both cohorts. Telomere length decreased at 48–67 base pairs per year on average. Weak, non-significant correlations were found between epigenetic clock estimates and telomere length. Telomere length explained 6.6% of the variance in age in LBC1921, the epigenetic clock explained 10.0%, and combined they explained 17.3% (all P < 1 × 10−7). Corresponding figures for the LBC1936 cohort were 14.3%, 11.7% and 19.5% (all P < 1 × 10−12). In a combined cohorts analysis, the respective estimates were 2.8%, 28.5% and 29.5%. Also in a combined cohorts analysis, a one standard deviation increase in baseline epigenetic age was linked to a 22% increased mortality risk (P = 2.6 × 10−4) whereas, in the same model, a one standard deviation increase in baseline telomere length was independently linked to an 11% decreased mortality risk (P = 0.06). Conclusions: These results suggest that telomere length and epigenetic clock estimates are independent predictors of chronological age and mortality risk. PMID:27075770

  8. Replication Timing of Human Telomeres Is Chromosome Arm–Specific, Influenced by Subtelomeric Structures and Connected to Nuclear Localization

    PubMed Central

    Arnoult, Nausica; Schluth-Bolard, Caroline; Letessier, Anne; Drascovic, Irena; Bouarich-Bourimi, Rachida; Campisi, Judith; Kim, Sahn-ho; Boussouar, Amina; Ottaviani, Alexandre; Magdinier, Frédérique; Gilson, Eric; Londoño-Vallejo, Arturo

    2010-01-01

    The mechanisms governing telomere replication in humans are still poorly understood. To fill this gap, we investigated the timing of replication of single telomeres in human cells. Using in situ hybridization techniques, we have found that specific telomeres have preferential time windows for replication during the S-phase and that these intervals do not depend upon telomere length and are largely conserved between homologous chromosomes and between individuals, even in the presence of large subtelomeric segmental polymorphisms. Importantly, we show that one copy of the 3.3 kb macrosatellite repeat D4Z4, present in the subtelomeric region of the late replicating 4q35 telomere, is sufficient to confer both a more peripheral localization and a later-replicating property to a de novo formed telomere. Also, the presence of β-satellite repeats next to a newly created telomere is sufficient to delay its replication timing. Remarkably, several native, non-D4Z4–associated, late-replicating telomeres show a preferential localization toward the nuclear periphery, while several early-replicating telomeres are associated with the inner nuclear volume. We propose that, in humans, chromosome arm–specific subtelomeric sequences may influence both the spatial distribution of telomeres in the nucleus and their replication timing. PMID:20421929

  9. Development of a new method for synthesis of tandem hairpin pyrrole-imidazole polyamide probes targeting human telomeres.

    PubMed

    Kawamoto, Yusuke; Bando, Toshikazu; Kamada, Fukumi; Li, Yue; Hashiya, Kaori; Maeshima, Kazuhiro; Sugiyama, Hiroshi

    2013-11-01

    Pyrrole–imidazole (PI) polyamides bind to the minor groove of DNA in a sequence-specific manner without causing denaturation of DNA. To visualize telomeres specifically, tandem hairpin PI polyamides conjugated with a fluorescent dye have been synthesized, but the study of telomeres using these PI polyamides has not been reported because of difficulties synthesizing these tandem hairpin PI polyamides. To synthesize tandem hairpin PI polyamides more easily, we have developed new PI polyamide fragments and have used them as units in Fmoc solid-phase peptide synthesis. Using this new method, we synthesized four fluorescent polyamide probes for the human telomeric repeat TTAGGG, and we examined the binding affinities and specificities of the tandem hairpin PI polyamides, the UV–vis absorption and fluorescence spectra of the fluorescent polyamide probes, and telomere staining in mouse MC12 and human HeLa cells. The polyamides synthesized using the new method successfully targeted to human and mouse telomeres under mild conditions and allow easier labeling of telomeres in the cells while maintaining the telomere structure. Using the fluorescent polyamides, we demonstrated that the telomere length at a single telomere level is related to the abundance of TRF1 protein, a shelterin complex component in the telomere.

  10. The Association Between Global DNA Methylation and Telomere Length in a Longitudinal Study of Boilermakers

    PubMed Central

    Wong, Jason Y.Y.; De Vivo, Immaculata; Lin, Xihong; Grashow, Rachel; Cavallari, Jennifer; Christiani, David C.

    2014-01-01

    The objectives of this study were to determine if global DNA methylation, as reflected in LINE-1 and Alu elements, is associated with telomere length and whether it modifies the rate of telomeric change. A repeated-measures longitudinal study was performed with a panel of 87 boilermaker subjects. The follow-up period was 29 months. LINE-1 and Alu methylation was determined using pyrosequencing. Leukocyte relative telomere length was assessed via real-time qPCR. Linear-mixed models were used to estimate the association between DNA methylation and telomere length. A structural equation model (SEM) was used to explore the hypothesized relationship between DNA methylation, proxies of particulate matter exposure, and telomere length at baseline. There appeared to be a positive association between both LINE-1 and Alu methylation levels, and telomere length. For every incremental increase in LINE-1 methylation, there was a statistically significant 1.0 × 10−1 (95% CI: 4.6 × 10−2, 1.5 × 10−1, P < 0.01) unit increase in relative telomere length, controlling for age at baseline, current and past smoking status, work history, BMI (log kg/m2) and leukocyte differentials. Furthermore, for every incremental increase in Alu methylation, there was a statistically significant 6.2 × 10−2 (95% CI: 1.0 × 10−2, 1.1 × 10−1, P = 0.02) unit increase in relative telomere length. The interaction between LINE-1 methylation and follow-up time was statistically significant with an estimate −9.8 × 10−3 (95% CI: −1.8 × 10−2, −1.9 × 10−3, P = 0.02); suggesting that the rate of telomeric change was modified by the degree of LINE-1 methylation. No statistically significant association was found between the cumulative PM exposure construct, with global DNA methylation and telomere length at baseline. PMID:24616077

  11. Longitudinal telomere length shortening and cognitive and physical decline in later life: The Lothian Birth Cohorts 1936 and 1921

    PubMed Central

    Harris, Sarah E.; Marioni, Riccardo E.; Martin-Ruiz, Carmen; Pattie, Alison; Gow, Alan J.; Cox, Simon R.; Corley, Janie; von Zglinicki, Thomas; Starr, John M.; Deary, Ian J.

    2016-01-01

    Telomere length is hypothesised to be a biological marker of both cognitive and physical ageing. Here we measure telomere length, and cognitive and physical abilities at mean ages 70, 73 and 76 years in the Lothian Birth Cohort 1936 (LBC1936), and at mean ages 79, 87, 90 and 92 years in the Lothian Birth Cohort 1921 (LBC1921). We investigate whether telomere length change predicts change in cognitive and physical abilities. In LBC1936 telomere length decreased by an average of 65 base pairs per year and in LBC1921 by 69 base pairs per year. However, change in telomere length did not predict change in cognitive or physical abilities. This study shows that, although cognitive ability, walking speed, lung function and grip strength all decline with age, they do so independently of telomere length shortening. PMID:26876762

  12. Longitudinal telomere length shortening and cognitive and physical decline in later life: The Lothian Birth Cohorts 1936 and 1921.

    PubMed

    Harris, Sarah E; Marioni, Riccardo E; Martin-Ruiz, Carmen; Pattie, Alison; Gow, Alan J; Cox, Simon R; Corley, Janie; von Zglinicki, Thomas; Starr, John M; Deary, Ian J

    2016-03-01

    Telomere length is hypothesised to be a biological marker of both cognitive and physical ageing. Here we measure telomere length, and cognitive and physical abilities at mean ages 70, 73 and 76 years in the Lothian Birth Cohort 1936 (LBC1936), and at mean ages 79, 87, 90 and 92 years in the Lothian Birth Cohort 1921 (LBC1921). We investigate whether telomere length change predicts change in cognitive and physical abilities. In LBC1936 telomere length decreased by an average of 65 base pairs per year and in LBC1921 by 69 base pairs per year. However, change in telomere length did not predict change in cognitive or physical abilities. This study shows that, although cognitive ability, walking speed, lung function and grip strength all decline with age, they do so independently of telomere length shortening.

  13. Genetic variants within telomere-associated genes, leukocyte telomere length and the risk of acute coronary syndrome in Czech women.

    PubMed

    Dlouha, Dana; Pitha, Jan; Mesanyova, Jana; Mrazkova, Jolana; Fellnerova, Adela; Stanek, Vladimir; Lanska, Vera; Hubacek, Jaroslav A

    2016-02-15

    The association between leukocyte telomere length (LTL) and cardiovascular disease (CVD) has been published in many reports, although almost exclusively in men. In our study we analysed the association between LTL and five selected variants within three candidate genes (TERC rs12696304; TERF2IP rs3784929 and rs8053257; UCP2 rs659366 and rs622064), which are not only involved in telomere-length maintenance but also potentially associated with higher risk of acute coronary syndrome (ACS) in Czech women (505 cases and 642 controls). We detected significantly shorter LTL in women with ACS (P<0.001), but the difference disappeared after multiple adjustments. We did not find any significant associations between analysed variants and LTL, except for rs622064 within the UCP2 gene, in which case AA homozygotes had a higher LTL (P<0.04). Genotype frequencies of the analysed SNPs did not differ between controls and women with ACS. Variants within UCP2 (rs622064; CC vs. A allele carriers OR=1.61; 95% CI: 1.21-2.15, P<0.002) and within TERF2IP (rs8053257; A allele carriers vs. GG, OR=1.78; 95% CI: 1.07-3.18, P<0.03) were associated with increased risk of type 2 diabetes mellitus (T2DM). Analysed polymorphisms were not major determinants of telomere length or ACS risk in Czech females.

  14. Telomerase gene therapy rescues telomere length, bone marrow aplasia, and survival in mice with aplastic anemia.

    PubMed

    Bär, Christian; Povedano, Juan Manuel; Serrano, Rosa; Benitez-Buelga, Carlos; Popkes, Miriam; Formentini, Ivan; Bobadilla, Maria; Bosch, Fatima; Blasco, Maria A

    2016-04-01

    Aplastic anemia is a fatal bone marrow disorder characterized by peripheral pancytopenia and marrow hypoplasia. The disease can be hereditary or acquired and develops at any stage of life. A subgroup of the inherited form is caused by replicative impairment of hematopoietic stem and progenitor cells due to very short telomeres as a result of mutations in telomerase and other telomere components. Abnormal telomere shortening is also described in cases of acquired aplastic anemia, most likely secondary to increased turnover of bone marrow stem and progenitor cells. Here, we test the therapeutic efficacy of telomerase activation by using adeno-associated virus (AAV)9 gene therapy vectors carrying the telomerase Tert gene in 2 independent mouse models of aplastic anemia due to short telomeres (Trf1- and Tert-deficient mice). We find that a high dose of AAV9-Tert targets the bone marrow compartment, including hematopoietic stem cells. AAV9-Tert treatment after telomere attrition in bone marrow cells rescues aplastic anemia and mouse survival compared with mice treated with the empty vector. Improved survival is associated with a significant increase in telomere length in peripheral blood and bone marrow cells, as well as improved blood counts. These findings indicate that telomerase gene therapy represents a novel therapeutic strategy to treat aplastic anemia provoked or associated with short telomeres.

  15. Skin pentosidine and telomere length do not covary with age in a long-lived seabird.

    PubMed

    Rattiste, Kalev; Klandorf, Hillar; Urvik, Janek; Sepp, Tuul; Asghar, Muhammad; Hasselquist, Dennis; Cooey, Crissa; Hõrak, Peeter

    2015-08-01

    The questions about why and how senescence occurs in the wild are among the most pertinent ones in evolutionary ecology. Telomere length is a commonly used marker for aging, while other biomarkers of aging have received considerably less attention. Here we studied how another potent indicator of aging-skin pentosidine concentration-relates to age and blood telomere length in a long-lived seabird with well-documented reproductive senescence. We found no associations between telomere length, skin pentosidine and chronological age in male common gulls (Larus canus), aging from 2 to 30 years. However, the variance in telomere length was 4.6 times higher among the birds older than 13 years, which hints at relaxed selection on telomere length among the birds that have passed their prime age of reproduction. These results suggest that physiological and chronological ages may be largely uncoupled in our study system. Furthermore, our findings do not support a hypothesis about the presence of a common physiological factor (e.g., such as oxidative stress) that would cause covariation between two independent markers of aging.

  16. CUMULATIVE PM2.5 EXPOSURE AND TELOMERE LENGTH IN WORKERS EXPOSED TO WELDING FUMES

    PubMed Central

    Wong, Jason Y. Y.; De Vivo, Immaculata; Lin, Xihong; Christiani, David C.

    2014-01-01

    Telomeres are genomic structures that reflect both mitotic history and biochemical trauma to the genome. Metals inherent in fine particulate matter (PM2.5) were shown to be genotoxic via oxidative damage. However, few studies investigated the induction time of cumulative PM2.5 exposure on telomere length in a longitudinal setting. Therefore, the purpose of this study was to assess the association between occupational PM2.5 exposure in various time windows and telomere length. The study population consisted of 48 boilermakers and the follow-up period was 8 yr. The main exposures were cumulative occupational PM2.5 in the month, year, and career prior to each blood draw, assessed via work history questionnaires and area air measures. Repeated telomere length measurements from leukocytes were assessed via real-time quantitative polymerase chain reaction (qPCR). Analysis was performed using linear mixed models controlling for confounders and white blood cell differentials. Cumulative PM2.5 exposure was treated continuously and categorized into quartiles, in separate analyses. At any follow-up time, for each milligram per cubic meter per hour increase in cumulative PM2.5 exposure in the prior month, there was a statistically significant decrease in relative telomere length of −0.04 units. When categorizing the exposure into quartiles, there was a significant negative association between telomere length and highest quartile of cumulative PM2.5 exposure in the prior month (−0.16). These findings suggest that genomic trauma to leukocyte telomeres was more consistent with recent occupational PM2.5 exposure, as opposed to cumulative exposure extending into the distant past. PMID:24627998

  17. The Relationship between Inflammatory Biomarkers and Telomere Length in an Occupational Prospective Cohort Study

    PubMed Central

    Wong, Jason Y. Y.; De Vivo, Immaculata; Lin, Xihong; Fang, Shona C.; Christiani, David C.

    2014-01-01

    Background Chronic inflammation from recurring trauma is an underlying pathophysiological basis of numerous diseases. Furthermore, it may result in cell death, scarring, fibrosis, and loss of tissue function. In states of inflammation, subsequent increases in oxidative stress and cellular division may lead to the accelerated erosion of telomeres, crucial genomic structures which protect chromosomes from decay. However, the association between plasma inflammatory marker concentrations and telomere length has been inconsistent in previous studies. Objective The purpose of this study was to determine the longitudinal association between telomere length and plasma inflammatory biomarker concentrations including: CRP, SAA, sICAM-1, sVCAM-1, VEGF, TNF-α, IL-1β, IL-2, IL-6, IL-8, and IL-10. Methods The longitudinal study population consisted of 87 subjects. The follow-up period was approximately 2 years. Plasma inflammatory biomarker concentrations were assessed using highly sensitive electrochemiluminescent assays. Leukocyte relative telomere length was assessed using Real-Time qPCR. Linear mixed effects regression models were used to analyze the association between repeated-measurements of relative telomere length as the outcome and each inflammatory biomarker concentration as continuous exposures separately. The analyses controlled for major potential confounders and white blood cell differentials. Results At any follow-up time, each incremental ng/mL increase in plasma CRP concentration was associated with a decrease in telomere length of −2.6×10−2 (95%CI: −4.3×10−2, −8.2×10−3, p = 0.004) units. Similarly, the estimate for the negative linear association between SAA and telomere length was −2.6×10−2 (95%CI:−4.5×10−2, −6.1×10−3, p = 0.011). No statistically significant associations were observed between telomere length and plasma concentrations of pro-inflammatory interleukins, TNF-α, and VEGF. Conclusions Findings from this

  18. HIV Infection Is Associated with Shortened Telomere Length in Ugandans with Suspected Tuberculosis

    PubMed Central

    Auld, Elizabeth; Lin, Jue; Chang, Emily; Byanyima, Patrick; Ayakaka, Irene; Musisi, Emmanuel; Worodria, William; Davis, J. Lucian; Segal, Mark; Blackburn, Elizabeth; Huang, Laurence

    2016-01-01

    Introduction HIV infection is a risk factor for opportunistic pneumonias such as tuberculosis (TB) and for age-associated health complications. Short telomeres, markers of biological aging, are also associated with an increased risk of age-associated diseases and mortality. Our goals were to use a single cohort of HIV-infected and HIV-uninfected individuals hospitalized with pneumonia to assess whether shortened telomere length was associated with HIV infection, TB diagnosis, and 2-month mortality. Methods This was a sub-study of the IHOP Study, a prospective observational study. Participants consisted of 184 adults admitted to Mulago Hospital in Kampala, Uganda who underwent evaluation for suspected TB and were followed for 2 months. Standardized questionnaires were administered to collect demographic and clinical data. PBMCs were isolated and analyzed using quantitative PCR to determine telomere length. The association between HIV infection, demographic and clinical characteristics, and telomere length was assessed, as were the associations between telomere length, TB diagnosis and 2-month mortality. Variables with a P≤0.2 in bivariate analysis were included in multivariate models. Results No significant demographic or clinical differences were observed between the HIV-infected and HIV-uninfected subjects. Older age (P<0.0001), male gender (P = 0.04), total pack-years smoked (P<0.001), alcohol consumption in the past year (P = 0.12), and asthma (P = 0.08) were all associated (P≤0.2) with shorter telomere length in bivariate analysis. In multivariate analysis adjusting for these five variables, HIV-positive participants had significantly shorter telomeres than HIV-negative participants (β = -0.0621, 95% CI -0.113 to -0.011, P = 0.02). Shortened telomeres were not associated with TB or short-term mortality. Conclusions The association between HIV infection and shorter telomeres suggests that HIV may play a role in cellular senescence and biological aging and

  19. Functional variants in CYP1B1, KRAS and MTHFR genes are associated with shorter telomere length in postmenopausal women.

    PubMed

    Cerne, Jasmina Z; Pohar-Perme, Maja; Cerkovnik, Petra; Gersak, Ksenija; Novakovic, Srdjan

    2015-07-01

    Estrogens and antioxidants indirectly alleviate telomere attrition. However, available clinical data on the association between hormone exposure and telomere length are inconclusive. In the present study, we examined the effects of exogenous estrogen use and of some genetic factors implicated in estrogen metabolism and oxidative stress response on mean leukocyte telomere length. We studied 259 postmenopausal women. Genotyping was conducted for CYP1B1 (rs1056836), COMT (rs4680), GSTP1 (rs1695), MnSOD (rs4880), KRAS (rs61764370), and MTHFR (rs1801133 and rs1801131) polymorphisms. Mean leukocyte telomere length was measured using a quantitative real-time PCR assay. In multivariate analysis we found no association between oral contraceptives or hormone replacement therapy (HRT) and mean leukocyte telomere length. The presence of variant alleles in CYP1B1, KRAS and MTHFR genes was statistically significantly associated with shorter mean leukocyte telomere length. Further, the data provided evidence for the effect modification of the association between HRT and mean leukocyte telomere length by the CYP1B1, KRAS and MTHFR genotypes. Our findings suggest that functionally relevant genetic variants within estrogen and folate metabolic pathways may influence telomere length. We propose these genetic factors should be taken into consideration when interpreting associations between hormone exposure and telomere length.

  20. Functional variants in CYP1B1, KRAS and MTHFR genes are associated with shorter telomere length in postmenopausal women.

    PubMed

    Cerne, Jasmina Z; Pohar-Perme, Maja; Cerkovnik, Petra; Gersak, Ksenija; Novakovic, Srdjan

    2015-07-01

    Estrogens and antioxidants indirectly alleviate telomere attrition. However, available clinical data on the association between hormone exposure and telomere length are inconclusive. In the present study, we examined the effects of exogenous estrogen use and of some genetic factors implicated in estrogen metabolism and oxidative stress response on mean leukocyte telomere length. We studied 259 postmenopausal women. Genotyping was conducted for CYP1B1 (rs1056836), COMT (rs4680), GSTP1 (rs1695), MnSOD (rs4880), KRAS (rs61764370), and MTHFR (rs1801133 and rs1801131) polymorphisms. Mean leukocyte telomere length was measured using a quantitative real-time PCR assay. In multivariate analysis we found no association between oral contraceptives or hormone replacement therapy (HRT) and mean leukocyte telomere length. The presence of variant alleles in CYP1B1, KRAS and MTHFR genes was statistically significantly associated with shorter mean leukocyte telomere length. Further, the data provided evidence for the effect modification of the association between HRT and mean leukocyte telomere length by the CYP1B1, KRAS and MTHFR genotypes. Our findings suggest that functionally relevant genetic variants within estrogen and folate metabolic pathways may influence telomere length. We propose these genetic factors should be taken into consideration when interpreting associations between hormone exposure and telomere length. PMID:25987236

  1. hTERT cancer risk genotypes are associated with telomere length.

    PubMed

    Melin, Beatrice S; Nordfjäll, Katarina; Andersson, Ulrika; Roos, Göran

    2012-05-01

    Telomere biology is associated with cancer initiation and prognosis. Collected data suggest that blood cell telomere length (TL) can change over time, which may be related to development of common disorders, such as cardiovascular diseases and cancer. Recently, single nucleotide polymorphisms in the region of the human telomerase reverse transcriptase (hTERT) gene were associated with various malignancies, including glioma, lung and urinary bladder cancer, and telomerase RNA gene hTERC genotypes were recently linked to TL. In the present study a hypothetical association between identified genotypes in hTERT and hTERC genes and TL were investigated. We analyzed 21 polymorphisms, covering 90% of the genetic variance, in the hTERT gene, two genetic variants in hTERC, and relative TL(RTL) at average age 50 and 60 in 959 individuals with repeated blood samples. Mean RTL at age 60 was associated with four genetic variants of the hTERT gene (rs2736100, rs2853672, rs2853677, and rs2853676), two of which reported to be associated with cancer risk. Two alleles (rs12696304, rs16847897) near the hTERC gene were confirmed as also being associated with RTL at age 60. Our data suggest that hTERT and hTERC genotypes have an impact on TL of potential relevance and detectable first at higher ages, which gives us further insight to the complex regulation of TL.

  2. Effects of physical activity in telomere length: Systematic review and meta-analysis.

    PubMed

    Mundstock, Eduardo; Zatti, Helen; Louzada, Fernanda Mattos; Oliveira, Suelen Goecks; Guma, Fátima T C R; Paris, Mariana Migliorini; Rueda, Angélica Barba; Machado, Denise Greff; Stein, Renato T; Jones, Marcus Herbert; Sarria, Edgar E; Barbé-Tuana, Florencia M; Mattiello, Rita

    2015-07-01

    The aim of this systematic review is to assess the effects of exercise on telomeres length. We searched the following databases: MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library), Scopus, LILACS, SPORTDiscus and Web of Science from inception to August 2014. All articles that assessed the effects of exercise in telomere length were included in this review. The search strategy used the following combinations of terms: telomere AND "motor activity" OR exercise OR "physical activity". Two reviewers, working independently, screened all titles and abstracts to identify studies that could meet inclusion criteria. Whenever possible, and if appropriate, we performed a random-effect meta-analysis of study outcomes. Thirty-seven original studies were included in this systematic review, including 41,230 participants. Twenty articles did not find statistically significant association, whereas 15 described a positive association. Two papers found an inverted "U" correlation. There is a tendency toward demonstrating an effect of exercise on telomere length. Few prospective studies were found, many studies did not reach statistical significance and there was an important methodological diversity. For this reason, a possible significant association between physical activity and telomere length remains an open question.

  3. Synaptonemal complex extension from clustered telomeres mediates full-length chromosome pairing in Schmidtea mediterranea

    PubMed Central

    Xiang, Youbin; Miller, Danny E.; Ross, Eric J.; Sánchez Alvarado, Alejandro; Hawley, R. Scott

    2014-01-01

    In the 1920s, József Gelei proposed that chromosome pairing in flatworms resulted from the formation of a telomere bouquet followed by the extension of synapsis from telomeres at the base of the bouquet, thus facilitating homolog pairing in a processive manner. A modern interpretation of Gelei’s model postulates that the synaptonemal complex (SC) is nucleated close to the telomeres and then extends progressively along the full length of chromosome arms. We used the easily visible meiotic chromosomes, a well-characterized genome, and RNAi in the sexual biotype of the planarian Schmidtea mediterranea to test that hypothesis. By identifying and characterizing S. mediterranea homologs of genes encoding synaptonemal complex protein 1 (SYCP1), the topoisomerase-like protein SPO11, and RAD51, a key player in homologous recombination, we confirmed that SC formation begins near the telomeres and progresses along chromosome arms during zygotene. Although distal regions pair at the time of bouquet formation, pairing of a unique interstitial locus is not observed until the formation of full-length SC at pachytene. Moreover, neither full extension of the SC nor homologous pairing is dependent on the formation of double-strand breaks. These findings validate Gelei’s speculation that full-length pairing of homologous chromosomes is mediated by the extension of the SC formed near the telomeres. S. mediterranea thus becomes the first organism described (to our knowledge) that forms a canonical telomere bouquet but does not require double-strand breaks for synapsis between homologous chromosomes. However, the initiation of SC formation at the base of the telomere bouquet, which then is followed by full-length homologous pairing in planarian spermatocytes, is not observed in other species and may not be conserved. PMID:25404302

  4. Telomere length in Chernobyl accident recovery workers in the late period after the disaster

    PubMed Central

    Reste, Jelena; Zvigule, Gunda; Zvagule, Tija; Kurjane, Natalja; Eglite, Maija; Gabruseva, Natalija; Berzina, Dace; Plonis, Juris; Miklasevics, Edvins

    2014-01-01

    The outcome of the Chernobyl nuclear power plant (CNPP) accident was that a huge number of people were exposed to ionizing radiation. Previous studies of CNPP clean-up workers from Latvia revealed a high occurrence of age-associated degenerative diseases and cancer in young adults, as well as a high mortality as a result of cardiovascular disorders at age 45–54 years. DNA tandem repeats that cap chromosome ends, known as telomeres, are sensitive to oxidative damage and exposure to ionizing radiation. Telomeres are important in aging processes and carcinogenesis. The aim of this study was to investigate the long-term effect of protracted ionizing radiation exposure on telomere length in CNPP clean-up workers. Relative telomere length (RTL) was measured in peripheral blood leukocytes of 595 CNPP clean-up workers and 236 gender- and age-matched controls using real-time quantitative polymerase chain reaction (q-PCR). Close attention was paid to participation year and tasks performed during the worker's stay in Chernobyl, health status, and RTL differences between subgroups. Telomere shortening was not found in CNPP clean-up workers; on the contrary, their RTL was slightly greater than in controls (P = 0.001). Longer telomeres were found in people who worked during 1986, in those undertaking ‘dirty’ tasks (digging and deactivation), and in people with cancer. Shorter telomeres appeared frequently in those with cataract, osteoporosis, atherosclerosis, or coronary heart disease. We conclude that the longer telomeres revealed in people more heavily exposed to ionizing radiation probably indicate activation of telomerase as a chromosome healing mechanism following damage, and reflect defects in telomerase regulation that could potentiate carcinogenesis. PMID:25015931

  5. Telomere length in Chernobyl accident recovery workers in the late period after the disaster.

    PubMed

    Reste, Jelena; Zvigule, Gunda; Zvagule, Tija; Kurjane, Natalja; Eglite, Maija; Gabruseva, Natalija; Berzina, Dace; Plonis, Juris; Miklasevics, Edvins

    2014-11-01

    The outcome of the Chernobyl nuclear power plant (CNPP) accident was that a huge number of people were exposed to ionizing radiation. Previous studies of CNPP clean-up workers from Latvia revealed a high occurrence of age-associated degenerative diseases and cancer in young adults, as well as a high mortality as a result of cardiovascular disorders at age 45-54 years. DNA tandem repeats that cap chromosome ends, known as telomeres, are sensitive to oxidative damage and exposure to ionizing radiation. Telomeres are important in aging processes and carcinogenesis. The aim of this study was to investigate the long-term effect of protracted ionizing radiation exposure on telomere length in CNPP clean-up workers. Relative telomere length (RTL) was measured in peripheral blood leukocytes of 595 CNPP clean-up workers and 236 gender- and age-matched controls using real-time quantitative polymerase chain reaction (q-PCR). Close attention was paid to participation year and tasks performed during the worker's stay in Chernobyl, health status, and RTL differences between subgroups. Telomere shortening was not found in CNPP clean-up workers; on the contrary, their RTL was slightly greater than in controls (P = 0.001). Longer telomeres were found in people who worked during 1986, in those undertaking 'dirty' tasks (digging and deactivation), and in people with cancer. Shorter telomeres appeared frequently in those with cataract, osteoporosis, atherosclerosis, or coronary heart disease. We conclude that the longer telomeres revealed in people more heavily exposed to ionizing radiation probably indicate activation of telomerase as a chromosome healing mechanism following damage, and reflect defects in telomerase regulation that could potentiate carcinogenesis.

  6. Human CST has independent functions during telomere duplex replication and C-strand fill-in

    PubMed Central

    Wang, Feng; Stewart, Jason A.; Kasbek, Christopher; Zhao, Yong; Wright, Woodring E.; Price, Carolyn M.

    2012-01-01

    Summary Human CST (CTC1-STN1-TEN1) is an RPA-like complex that is needed for efficient replication through the telomere duplex and genome-wide replication restart after fork stalling. Here we show that STN1/CST has a second function in telomere replication during G-overhang maturation. Analysis of overhang structure after STN1 depletion revealed normal kinetics for telomerase-mediated extension in S-phase but a delay in subsequent overhang shortening. This delay resulted from a defect in C-strand fill-in. Short telomeres exhibited the fill-in defect but normal telomere duplex replication, indicating that STN1/CST functions independently in these processes. Our work also indicates that the requirement for STN1/CST in telomere duplex replication correlates with increasing telomere length and replication stress. Our results provide the first direct evidence that STN1/CST participates in C-strand fill-in. They also demonstrate that STN1/CST participates in two mechanistically separate steps during telomere replication and identify CST as a novel replication factor that solves diverse replication-associated problems. PMID:23142664

  7. A correlation study of telomere length in peripheral blood leukocytes and kidney function with age.

    PubMed

    Zhang, Wei-Guang; Wang, Yong; Hou, Kai; Jia, Lin-Pei; Ma, Jie; Zhao, De-Long; Zhu, Shu-Ying; Bai, Xiao-Juan; Cai, Guang-Yan; Wang, Yan-Ping; Sun, Xue-Feng; Chen, Xiang-Mei

    2015-06-01

    The current study aimed to investigate the association between telomere length in peripheral blood leukocytes and kidney function in various age groups of a healthy population. A total of 139 healthy individuals were divided into five groups according to their age: 35‑44, 45‑54, 55‑64, 65‑74 and >75 years old. Peripheral blood leukocytes were obtained and the telomere restriction fragment (TRF) length was assayed using a digoxigenin‑labeled hybridization probe in Southern blot assays. Laboratory assays of kidney function were also performed. A correlation was observed between TRF length and age (r=‑0.314, P<0.001), with the telomere length of the individuals >75 years group being significantly shorter than the telomere length of the 35‑44, 45‑54 and 55‑64 years age groups (P<0.05). By contrast, the TRF length for males versus females did not differ for any of the age groups, while a correlation was observed between TRF length and serum levels of cystatin C (r=‑0.195, P<0.05). There was also a correlation between TRF length and glomerular filtration rate (r=‑0.184, P<0.05). The current study demonstrated that in this cohort, leukocyte telomere length reduced with age and was correlated with serum levels of cystatin C and glomerular filtration rate. Therefore, TRF length is associated with kidney function and may serve as a marker of aging.

  8. Significant Correlation of Species Longevity with DNA Double Strand Break-Recognition but not with Telomere Length

    PubMed Central

    Lorenzini, Antonello; Johnson, F. Brad; Oliver, Anthony; Tresini, Maria; Smith, Jasmine S.; Hdeib, Mona; Sell, Christian; Cristofalo, Vincent J.; Stamato, Thomas D.

    2009-01-01

    Summary The identification of the cellular mechanisms responsible for the wide differences in species lifespan remains one of the major unsolved problems of the biology of aging. We measured the capacity of nuclear protein to recognize DNA double strand breaks (DSB) and telomere length of skin fibroblasts derived from mammalian species that exhibit wide differences in longevity. Our results indicate DNA DSB recognition increases exponentially with longevity. Further, an analysis of the level of Ku80 protein in human, cow, and mouse suggests that Ku levels vary dramatically between species and these levels are strongly correlated with longevity. In contrast mean telomere length appears to decrease with increasing longevity of the species, although not significantly. These findings suggest that an enhanced ability to bind to DNA-ends may be important for longevity. A number of possible roles for increased levels of Ku and DNA-PKcs are discussed. PMID:19896964

  9. Telomere length of tumor tissues and survival in patients with early stage non-small cell lung cancer.

    PubMed

    Jeon, Hyo-Sung; Choi, Yi Young; Choi, Jin Eun; Lee, Won Kee; Lee, Eungbae; Yoo, Seung Soo; Lee, Shin Yup; Lee, Jaehee; Cha, Seung Ick; Kim, Chang Ho; Park, Jae Yong

    2014-04-01

    Telomere shortening leads to genomic instability that drives oncogenesis through the activation of telomerase and the generation of other mutations necessary for tumor progression. This study was conducted to determine the impact of telomere shortening on the survival of patients with early stage non-small cell lung cancer (NSCLC). Relative telomere length in tumor tissues was measured by quantitative polymerase chain reaction in 164 patients with surgically resected NSCLC. The association between telomere length and overall survival (OS) and disease-free survival (DFS) was analyzed. When the patients were categorized into quartiles based on telomere length, those patients with the 1st quartile (shortest) of telomere length had a significantly worse OS and DFS compared to patients with the 2nd to the 4th quartiles of telomere length (adjusted hazard ratio for OS = 2.67, 95% confidence interval = 1.50-4.75, P = 0.001; and adjusted hazard ratio for DFS = 1.92, 95% confidence interval = 1.17-3.14, P = 0.01). An association between telomere length and survival outcome was more pronounced in squamous cell carcinomas than adenocarcinomas (P-value of test for homogeneity for OS and DFS = 0.05 and 0.02, respectively). Telomere length of tumor tissues is an independent prognostic factor in patients with surgically resected early stage NSCLC.

  10. Predicting Survival from Telomere Length versus Conventional Predictors: A Multinational Population-Based Cohort Study.

    PubMed

    Glei, Dana A; Goldman, Noreen; Risques, Rosa Ana; Rehkopf, David H; Dow, William H; Rosero-Bixby, Luis; Weinstein, Maxine

    2016-01-01

    Telomere length has generated substantial interest as a potential predictor of aging-related diseases and mortality. Some studies have reported significant associations, but few have tested its ability to discriminate between decedents and survivors compared with a broad range of well-established predictors that include both biomarkers and commonly collected self-reported data. Our aim here was to quantify the prognostic value of leukocyte telomere length relative to age, sex, and 19 other variables for predicting five-year mortality among older persons in three countries. We used data from nationally representative surveys in Costa Rica (N = 923, aged 61+), Taiwan (N = 976, aged 54+), and the U.S. (N = 2672, aged 60+). Our study used a prospective cohort design with all-cause mortality during five years post-exam as the outcome. We fit Cox hazards models separately by country, and assessed the discriminatory ability of each predictor. Age was, by far, the single best predictor of all-cause mortality, whereas leukocyte telomere length was only somewhat better than random chance in terms of discriminating between decedents and survivors. After adjustment for age and sex, telomere length ranked between 15th and 17th (out of 20), and its incremental contribution was small; nine self-reported variables (e.g., mobility, global self-assessed health status, limitations with activities of daily living, smoking status), a cognitive assessment, and three biological markers (C-reactive protein, serum creatinine, and glycosylated hemoglobin) were more powerful predictors of mortality in all three countries. Results were similar for cause-specific models (i.e., mortality from cardiovascular disease, cancer, and all other causes combined). Leukocyte telomere length had a statistically discernible, but weak, association with mortality, but it did not predict survival as well as age or many other self-reported variables. Although telomere length may eventually help scientists

  11. Predicting Survival from Telomere Length versus Conventional Predictors: A Multinational Population-Based Cohort Study.

    PubMed

    Glei, Dana A; Goldman, Noreen; Risques, Rosa Ana; Rehkopf, David H; Dow, William H; Rosero-Bixby, Luis; Weinstein, Maxine

    2016-01-01

    Telomere length has generated substantial interest as a potential predictor of aging-related diseases and mortality. Some studies have reported significant associations, but few have tested its ability to discriminate between decedents and survivors compared with a broad range of well-established predictors that include both biomarkers and commonly collected self-reported data. Our aim here was to quantify the prognostic value of leukocyte telomere length relative to age, sex, and 19 other variables for predicting five-year mortality among older persons in three countries. We used data from nationally representative surveys in Costa Rica (N = 923, aged 61+), Taiwan (N = 976, aged 54+), and the U.S. (N = 2672, aged 60+). Our study used a prospective cohort design with all-cause mortality during five years post-exam as the outcome. We fit Cox hazards models separately by country, and assessed the discriminatory ability of each predictor. Age was, by far, the single best predictor of all-cause mortality, whereas leukocyte telomere length was only somewhat better than random chance in terms of discriminating between decedents and survivors. After adjustment for age and sex, telomere length ranked between 15th and 17th (out of 20), and its incremental contribution was small; nine self-reported variables (e.g., mobility, global self-assessed health status, limitations with activities of daily living, smoking status), a cognitive assessment, and three biological markers (C-reactive protein, serum creatinine, and glycosylated hemoglobin) were more powerful predictors of mortality in all three countries. Results were similar for cause-specific models (i.e., mortality from cardiovascular disease, cancer, and all other causes combined). Leukocyte telomere length had a statistically discernible, but weak, association with mortality, but it did not predict survival as well as age or many other self-reported variables. Although telomere length may eventually help scientists

  12. Work-Related Exhaustion and Telomere Length: A Population-Based Study

    PubMed Central

    Ahola, Kirsi; Sirén, Ilari; Kivimäki, Mika; Ripatti, Samuli; Aromaa, Arpo; Lönnqvist, Jouko; Hovatta, Iiris

    2012-01-01

    Background Psychological stress is suggested to accelerate the rate of biological aging. We investigated whether work-related exhaustion, an indicator of prolonged work stress, is associated with accelerated biological aging, as indicated by shorter leukocyte telomeres, that is, the DNA-protein complexes that cap chromosomal ends in cells. Methods We used data from a representative sample of the Finnish working-age population, the Health 2000 Study. Our sample consisted of 2911 men and women aged 30–64. Work-related exhaustion was assessed using the Maslach Burnout Inventory - General Survey. We determined relative leukocyte telomere length using a quantitative real-time polymerase chain reaction (PCR) -based method. Results After adjustment for age and sex, individuals with severe exhaustion had leukocyte telomeres on average 0.043 relative units shorter (standard error of the mean 0.016) than those with no exhaustion (p = 0.009). The association between exhaustion and relative telomere length remained significant after additional adjustment for marital and socioeconomic status, smoking, body mass index, and morbidities (adjusted difference 0.044 relative units, standard error of the mean 0.017, p = 0.008). Conclusions These data suggest that work-related exhaustion is related to the acceleration of the rate of biological aging. This hypothesis awaits confirmation in a prospective study measuring changes in relative telomere length over time. PMID:22808115

  13. Telomere Length and Pulse Pressure in Newly Diagnosed, Antipsychotic-Naive Patients With Nonaffective Psychosis

    PubMed Central

    Fernandez-Egea, Emilio; Bernardo, Miguel; Heaphy, Christopher M.; Griffith, Jeffrey K.; Parellada, Eduard; Esmatjes, Enric; Conget, Ignacio; Nguyen, Linh; George, Varghese; Stöppler, Hubert; Kirkpatrick, Brian

    2009-01-01

    Introduction: Recent studies suggest that in addition to factors such as treatment side effects, suicide, and poor health habits, people with schizophrenia may have an increased risk of diabetes prior to antipsychotic treatment. Diabetes is associated with an increased pulse pressure (PP) and a shortened telomere. We tested the hypothesis that prior to antipsychotic treatment, schizophrenia and related disorders are associated with a shortened telomere, as well as an increased PP. Methods: Telomere content (which is highly correlated with telomere length) and PP were measured in newly diagnosed, antipsychotic-naive patients with schizophrenia and related disorders on first clinical contact and in matched control subjects. Both groups were also administered an oral glucose tolerance test. Results: Compared with control subjects, the patients with psychosis had decreased telomere content and an increased PP. As previously reported, they also had increased glucose concentrations at 2 hours. These differences could not be attributed to differences in age, ethnicity, smoking, gender, body mass index, neighborhood of residence, socioeconomic status, aerobic conditioning, or an increased cortisol concentration in the psychotic subjects. Discussion: These results suggest that prior to antipsychotic use, nonaffective psychosis is associated with reduced telomere content and increased PP, indices that have been linked to an increased risk of diabetes and hypertension. PMID:19279086

  14. Shortened telomere length in white matter oligodendrocytes in major depression: potential role of oxidative stress.

    PubMed

    Szebeni, Attila; Szebeni, Katalin; DiPeri, Timothy; Chandley, Michelle J; Crawford, Jessica D; Stockmeier, Craig A; Ordway, Gregory A

    2014-10-01

    Telomere shortening is observed in peripheral mononuclear cells from patients with major depressive disorder (MDD). Whether this finding and its biological causes impact the health of the brain in MDD is unknown. Brain cells have differing vulnerabilities to biological mechanisms known to play a role in accelerating telomere shortening. Here, two glia cell populations (oligodendrocytes and astrocytes) known to have different vulnerabilities to a key mediator of telomere shortening, oxidative stress, were studied. The two cell populations were separately collected by laser capture micro-dissection of two white matter regions shown previously to demonstrate pathology in MDD patients. Cells were collected from brain donors with MDD at the time of death and age-matched psychiatrically normal control donors (N = 12 donor pairs). Relative telomere lengths in white matter oligodendrocytes, but not astrocytes, from both brain regions were significantly shorter for MDD donors as compared to matched control donors. Gene expression levels of telomerase reverse transcriptase were significantly lower in white matter oligodendrocytes from MDD as compared to control donors. Likewise, the gene expression of oxidative defence enzymes superoxide dismutases (SOD1 and SOD2), catalase (CAT) and glutathione peroxidase (GPX1) were significantly lower in oligodendrocytes from MDD as compared to control donors. No such gene expression changes were observed in astrocytes from MDD donors. These findings suggest that attenuated oxidative stress defence and deficient telomerase contribute to telomere shortening in oligodendrocytes in MDD, and suggest an aetiological link between telomere shortening and white matter abnormalities previously described in MDD.

  15. Telomere Restriction Fragment (TRF) Analysis

    PubMed Central

    Mender, Ilgen; Shay, Jerry W.

    2016-01-01

    While telomerase is expressed in ~90% of primary human tumors, most somatic tissue cells except transiently proliferating stem-like cells do not have detectable telomerase activity (Shay and Wright, 1996; Shay and Wright, 2001). Telomeres progressively shorten with each cell division in normal cells, including proliferating stem-like cells, due to the end replication (lagging strand synthesis) problem and other causes such as oxidative damage, therefore all somatic cells have limited cell proliferation capacity (Hayflick limit) (Hayflick and Moorhead, 1961; Olovnikov, 1973). The progressive telomere shortening eventually leads to growth arrest in normal cells, which is known as replicative senescence (Shay et al., 1991). Once telomerase is activated in cancer cells, telomere length is stabilized by the addition of TTAGGG repeats to the end of chromosomes, thus enabling the limitless continuation of cell division (Shay and Wright, 1996; Shay and Wright, 2001). Therefore, the link between aging and cancer can be partially explained by telomere biology. There are many rapid and convenient methods to study telomere biology such as Telomere Restriction Fragment (TRF), Telomere Repeat Amplification Protocol (TRAP) (Mender and Shay, 2015b) and Telomere dysfunction Induced Foci (TIF) analysis (Mender and Shay, 2015a). In this protocol paper we describe Telomere Restriction Fragment (TRF) analysis to determine average telomeric length of cells. Telomeric length can be indirectly measured by a technique called Telomere Restriction Fragment analysis (TRF). This technique is a modified Southern blot, which measures the heterogeneous range of telomere lengths in a cell population using the length distribution of the terminal restriction fragments (Harley et al., 1990; Ouellette et al., 2000). This method can be used in eukaryotic cells. The description below focuses on the measurement of human cancer cells telomere length. The principle of this method relies on the lack of

  16. Association of telomere length and mitochondrial DNA copy number in a community sample of healthy adults.

    PubMed

    Tyrka, Audrey R; Carpenter, Linda L; Kao, Hung-Teh; Porton, Barbara; Philip, Noah S; Ridout, Samuel J; Ridout, Kathryn K; Price, Lawrence H

    2015-06-01

    Cellular aging plays a role in longevity and senescence, and has been implicated in medical and psychiatric conditions, including heart disease, cancer, major depression and posttraumatic stress disorder. Telomere shortening and mitochondrial dysfunction are thought to be central to the cellular aging process. The present study examined the association between mitochondrial DNA (mtDNA) copy number and telomere length in a sample of medically healthy adults. Participants (total n=392) were divided into 4 groups based on the presence or absence of early life adversity and lifetime psychopathology: No Adversity/No Disorder, n=136; Adversity/No Disorder, n=91; No Adversity/Disorder, n=46; Adversity/Disorder, n=119. Telomere length and mtDNA copy number were measured using quantitative polymerase chain reaction. There was a positive correlation between mtDNA and telomere length in the entire sample (r=0.120, p<0.001) and in each of the four groups of participants (No Adversity/No Disorder, r=0.291, p=0.001; Adversity/No Disorder r=0.279, p=0.007; No Adversity/Disorder r=0.449, p=0.002; Adversity/Disorder, r=0.558, p<0.001). These correlations remained significant when controlling for age, smoking, and body mass index and establish an association between mtDNA and telomere length in a large group of women and men both with and without early adversity and psychopathology, suggesting co-regulation of telomeres and mitochondrial function. The mechanisms underlying this association may be important in the pathophysiology of age-related medical conditions, such as heart disease and cancer, as well as for stress-associated psychiatric disorders.

  17. Cdc13 N-Terminal Dimerization DNA Binding and Telomere Length Regulation

    SciTech Connect

    M Mitchell; J Smith; M Mason; S Harper; D Speicher; F Johnson; E Skordalakes

    2011-12-31

    The essential yeast protein Cdc13 facilitates chromosome end replication by recruiting telomerase to telomeres, and together with its interacting partners Stn1 and Ten1, it protects chromosome ends from nucleolytic attack, thus contributing to genome integrity. Although Cdc13 has been studied extensively, the precise role of its N-terminal domain (Cdc13N) in telomere length regulation remains unclear. Here we present a structural, biochemical, and functional characterization of Cdc13N. The structure reveals that this domain comprises an oligonucleotide/oligosaccharide binding (OB) fold and is involved in Cdc13 dimerization. Biochemical data show that Cdc13N weakly binds long, single-stranded, telomeric DNA in a fashion that is directly dependent on domain oligomerization. When introduced into full-length Cdc13 in vivo, point mutations that prevented Cdc13N dimerization or DNA binding caused telomere shortening or lengthening, respectively. The multiple DNA binding domains and dimeric nature of Cdc13 offer unique insights into how it coordinates the recruitment and regulation of telomerase access to the telomeres.

  18. Cdc13 N-Terminal Dimerization, DNA Binding, and Telomere Length Regulation ▿ †

    PubMed Central

    Mitchell, Meghan T.; Smith, Jasmine S.; Mason, Mark; Harper, Sandy; Speicher, David W.; Johnson, F. Brad; Skordalakes, Emmanuel

    2010-01-01

    The essential yeast protein Cdc13 facilitates chromosome end replication by recruiting telomerase to telomeres, and together with its interacting partners Stn1 and Ten1, it protects chromosome ends from nucleolytic attack, thus contributing to genome integrity. Although Cdc13 has been studied extensively, the precise role of its N-terminal domain (Cdc13N) in telomere length regulation remains unclear. Here we present a structural, biochemical, and functional characterization of Cdc13N. The structure reveals that this domain comprises an oligonucleotide/oligosaccharide binding (OB) fold and is involved in Cdc13 dimerization. Biochemical data show that Cdc13N weakly binds long, single-stranded, telomeric DNA in a fashion that is directly dependent on domain oligomerization. When introduced into full-length Cdc13 in vivo, point mutations that prevented Cdc13N dimerization or DNA binding caused telomere shortening or lengthening, respectively. The multiple DNA binding domains and dimeric nature of Cdc13 offer unique insights into how it coordinates the recruitment and regulation of telomerase access to the telomeres. PMID:20837709

  19. Alterations of telomere length and DNA methylation in hairdressers: A cross-sectional study.

    PubMed

    Li, Huiqi; Åkerman, Gabriella; Lidén, Carola; Alhamdow, Ayman; Wojdacz, Tomasz K; Broberg, Karin; Albin, Maria

    2016-03-01

    Working as hairdressers has been associated with increased risk for cancer, particularly bladder cancer. To evaluate if current hairdressers have elevated risks of adverse health effects, we measured several biomarkers related to cancer-related DNA alterations. We enrolled 295 hairdressers and 92 non-hairdressers (all female non-smokers) from Stockholm and southern Sweden. Questionnaire data were collected for each participant, including work tasks for the hairdressers. We measured telomere length in peripheral blood leucocytes using quantitative PCR and DNA methylation status of genes relevant for bladder cancer using methylation sensitive high resolution melting analysis. The hairdressers had shorter telomeres (β = -0.069, P = 0.019) compared with non-hairdressers. Shorter telomeres were found in hairdressers up to 32 years old performing hair waving more than once per week as compared with hairdressers in the same age group performing hair waving less often (β = -0.12, P = 0.037). Hair waving was associated with less frequent CDKN2A methylation (odds ratio, OR = 0.19, P = 0.033). Shorter telomeres in hairdressers may indicate a genotoxic effect. Performing hair waving was associated with short telomere length, although the effect was only observed in young hairdressers. No clear patterns were discerned with regard to DNA methylation of bladder cancer-related genes. The observed changes of methylation were not all in the expected direction and warrant further investigation. PMID:26637967

  20. Genetic determination of telomere size in humans: A twin study of three age groups

    SciTech Connect

    Slagboom, P.E.; Droog, S.; Boomsma, D.I.

    1994-11-01

    Reduction of telomere length has been postulated to be a casual factor in cellular aging. Human telomeres terminate in tandemly arranged repeat arrays consisting of the (TTAGGG) motif. The length of these arrays in cells from human mitotic tissues is inversely related to the age of the donor, indicating telomere reduction with age. In addition to telemore length differences between different age cohorts, considerable variation is present among individuals of the same age. To investigate whether this variation can be ascribed to genetic influences, we have measured the size of terminal restriction fragments (TRFs) in HaeIII-digested genomic DNA from 123 human MZ and DZ twin pairs 2-95 years of age. The average rate of telomere shortening was 31 bp/year, which is similar to that observed by others. Statistical analysis in 115 pairs 2-63 years of age indicates a 78% heritability for mean TRF length in this age cohort. The individual differences in mean TRF length in blood, therefore, seem to a large extent to be genetically determined. 24 refs., 4 figs., 2 tabs.

  1. Chromatin Structure in Telomere Dynamics

    PubMed Central

    Galati, Alessandra; Micheli, Emanuela; Cacchione, Stefano

    2013-01-01

    The establishment of a specific nucleoprotein structure, the telomere, is required to ensure the protection of chromosome ends from being recognized as DNA damage sites. Telomere shortening below a critical length triggers a DNA damage response that leads to replicative senescence. In normal human somatic cells, characterized by telomere shortening with each cell division, telomere uncapping is a regulated process associated with cell turnover. Nevertheless, telomere dysfunction has also been associated with genomic instability, cell transformation, and cancer. Despite the essential role telomeres play in chromosome protection and in tumorigenesis, our knowledge of the chromatin structure involved in telomere maintenance is still limited. Here we review the recent findings on chromatin modifications associated with the dynamic changes of telomeres from protected to deprotected state and their role in telomere functions. PMID:23471416

  2. Life stress, emotional health, and mean telomere length in the European Prospective Investigation into Cancer (EPIC)-Norfolk population study.

    PubMed

    Surtees, Paul G; Wainwright, Nicholas W J; Pooley, Karen A; Luben, Robert N; Khaw, Kay-Tee; Easton, Douglas F; Dunning, Alison M

    2011-11-01

    We investigated the association between psychological stress, emotional health, and relative mean telomere length in an ethnically homogeneous population of 4,441 women, aged 41-80 years. Mean telomere length was measured using high-throughput quantitative real-time polymerase chain reaction. Social adversity exposure and emotional health were assessed through questionnaire and covariates through direct measurement and questionnaire. This study found evidence that adverse experiences during childhood may be associated with shorter telomere length. This finding remained after covariate adjustment and showed evidence of a dose-response relationship with increasing number of reported childhood difficulties associated with decreasing relative mean telomere length. No associations were observed for any of the other summary measures of social adversity and emotional health considered. These results extend and provide support for some previous findings concerning the association of adverse experience and emotional health histories with shorter telomere length in adulthood. Replication of these findings in longitudinal studies is now essential.

  3. The use of telomere length as a predictive biomarker for injury prognosis in juvenile rats following a concussion/mild traumatic brain injury.

    PubMed

    Hehar, Harleen; Mychasiuk, Richelle

    2016-03-01

    Telomeres were originally believed to be passive players in cellular replication, but recent research has highlighted their more active role in epigenetic patterning and promotion of cellular growth and survival. Furthermore, literature demonstrates that telomere length (TL) is responsive to environmental manipulations such as prenatal stress and dietary programming. As the search for a prognostic biomarker of concussion has had limited success, this study sought to examine whether or not telomere length (TL) could be an efficacious predictor of symptom severity in juvenile rats following concussion. Rats from four distinct experimental groups (caloric restriction (CR), high fat diet (HFD), exercise (EX), and standard controls (STD)) received a mild traumatic brain injury (mTBI)/concussion and were then subjected to a behavioural test battery. The test battery was scored and the animals were categorized as poor, average, or good, based on their performance on the 6 tests examined. Skin cells (from ear notch samples) were taken 17days post-injury and DNA was extracted for telomere length analysis. Ear notch skin cell TL was highly correlated with brain tissue TL for a given individual. Animals in the CR and EX cohorts had significantly longer telomeres, while animals in the HFD cohort had significantly shorter telomeres, when compared to controls. The mTBI/concussion reduced TL in all cohorts except the EX group. A significant linear relationship was found between TL and performance on the behavioural test battery, whereby shorter telomeres were associated with poorer performance and longer telomeres with better performance. As performance on the test battery is linked to symptom severity, this study found TL to be a reasonable tool for concussion prognosis. Future studies with human populations should examine the validity of TL in peripheral cells, as a predictor of concussion pathology.

  4. Apollo, an Artemis-related nuclease, interacts with TRF2 and protects human telomeres in S phase.

    PubMed

    van Overbeek, Megan; de Lange, Titia

    2006-07-11

    Human chromosome ends are protected by shelterin, an abundant six-subunit protein complex that binds specifically to the telomeric-repeat sequences, regulates telomere length, and ensures that chromosome ends do not elicit a DNA-damage response (reviewed in). Using mass spectrometry of proteins associated with the shelterin component Rap1, we identified an SMN1/PSO2 nuclease family member that is closely related to Artemis. We refer to this protein as Apollo and report that Apollo has the ability to localize to telomeres through an interaction with the shelterin component TRF2. Although its low abundance at telomeres indicates that Apollo is not a core component of shelterin, Apollo knockdown with RNAi resulted in senescence and the activation of a DNA-damage signal at telomeres as evidenced by telomere-dysfunction-induced foci (TIFs). The TIFs occurred primarily in S phase, suggesting that Apollo contributes to a processing step associated with the replication of chromosome ends. Furthermore, some of the metaphase chromosomes showed two telomeric signals at single-chromatid ends, suggesting an aberrant telomere structure. We propose that the Artemis-like nuclease Apollo is a shelterin accessory factor required for the protection of telomeres during or after their replication.

  5. Telomere length in children environmentally exposed to low-to-moderate levels of lead

    SciTech Connect

    Pawlas, Natalia; Płachetka, Anna; Kozłowska, Agnieszka; Broberg, Karin; Kasperczyk, Sławomir

    2015-09-01

    Shorter relative telomere length in peripheral blood is a risk marker for some types of cancers and cardiovascular diseases. Several environmental hazards appear to shorten telomeres, and this shortening may predispose individuals to disease. The aim of the present cross-sectional study was to assess the effect of environmental exposure to lead on relative telomere length (rTL) in children. A cohort of 99 8-year-old children was enrolled from 2007–2010. Blood lead concentrations (B-Pb) were measured by graphite furnace atomic absorption spectrometry, and blood rTL was measured by quantitative PCR. The geometric mean of B-Pb was 3.28 μg/dl (range: 0.90–14.2), and the geometric mean of rTL was 1.08 (range: 0.49–2.09). B-Pb was significantly inversely associated with rTL in the children (r{sub S} = − 0.25, p = 0.013; in further analyses both log-transformed-univariate regression analysis β = − 0.13, p = 0.026, and R{sup 2}adj 4%; and β = − 0.12, p = 0.056 when adjusting for mothers' smoking during pregnancy, Apgar score, mother's and father's ages at delivery, sex and mother's education, R{sup 2}adj 12%, p = 0.011). The effect of lead remained significant in children without prenatal tobacco exposure (N = 87, r{sub S} = − 0.24, p = 0.024; in further analyses, β = − 0.13, p = 0.029, and R{sup 2}adj 4%). rTL was not affected by sex, the concentrations of other elements in the blood (i.e., cadmium and selenium concentrations), or oxidative injury parameters (total antioxidant status, 8-hydroxydeoxyguanosine and thiobarbituric acid-reactive substances). Lead exposure in childhood appears to be associated with shorter telomeres, which might contribute to diseases, such as cardiovascular disease. The inverse association between blood lead level and the telomeres in children emphasizes the importance of further reducing lead levels in the environment. - Highlights: • This cross-sectional study analyzes the association between environmental lead exposure

  6. Telomere length and associations with somatic mutations and clinical outcomes in acute myeloid leukemia.

    PubMed

    Watts, Justin M; Dumitriu, Bogdan; Hilden, Patrick; Kishtagari, Ashwin; Rapaport, Franck; Chen, Christina; Ahn, Jihae; Devlin, Sean M; Stein, Eytan M; Rampal, Raajit; Levine, Ross L; Young, Neal; Tallman, Martin S

    2016-10-01

    We examined the genetic implications and clinical impact of telomere length (TL) in 67 patients with acute myeloid leukemia (AML). There was a trend toward improved survival at 6 months in patients with longer TL. We found that patients with activating mutations, such as FLT3-ITD, had shorter TL, while those with mutations in epigenetic modifying enzymes, particularly IDH1 and IDH2, had longer TL. These are intriguing findings that warrant further investigation in larger cohorts. Our data show the potential of TL as a predictive biomarker in AML and identify genetic subsets that may be particularly vulnerable to telomere-targeted therapies.

  7. PBMC telomerase activity, but not leukocyte telomere length, correlates with hippocampal volume in major depression

    PubMed Central

    Wolkowitz, Owen M.; Mellon, Synthia H.; Lindqvist, Daniel; Epel, Elissa S.; Blackburn, Elizabeth H.; Lin, Jue; Reus, Victor I.; Burke, Heather; Rosser, Rebecca; Mahan, Laura; Mackin, Scott; Yang, Tony; Weiner, Michael; Mueller, Susanne

    2015-01-01

    Accelerated cell aging, indexed in peripheral leukocytes by telomere length and in peripheral blood mononuclear cells (PBMCs) by telomerase activity, has been reported in several studies of major depressive disorder (MDD). However, the relevance of these peripheral measures for brain indices that are presumably more directly related to MDD pathophysiology is unknown. In this study, we explored the relationship between PBMC telomerase activity and leukocyte telomere length and magnetic resonance imaging-estimated hippocampal volume in un-medicated depressed individuals and healthy controls. We predicted that, to the extent peripheral and central telomerase activity are directly related, PBMC telomerase activity would be positively correlated with hippocampal volume, perhaps due to hippocampal telomerase-associated neurogenesis, neuroprotection or neurotrophic facilitation, and that this effect would be clearer in individuals with increased PBMC telomerase activity, as previously reported in un-medicated MDD. We did not have specific hypotheses regarding the relationship between leukocyte telomere length and hippocampal volume, due to conflicting reports in the published literature. We found, in 25 un-medicated MDD subjects, that PBMC telomerase activity was significantly positively correlated with hippocampal volume; this relationship was not observed in 18 healthy controls. Leukocyte telomere length was not significantly related to hippocampal volume in either group (19 unmedicated MDD subjects and 17 healthy controls). Although the nature of the relationship between peripheral telomerase activity and telomere length and the hippocampus is unclear, these preliminary data are consistent with the possibility that PBMC telomerase activity indexes, and may provide a novel window into, hippocampal neuroprotection and/or neurogenesis in MDD. PMID:25773002

  8. Childhood socioeconomic status, telomere length, and susceptibility to upper respiratory infection.

    PubMed

    Cohen, Sheldon; Janicki-Deverts, Denise; Turner, Ronald B; Marsland, Anna L; Casselbrant, Margaretha L; Li-Korotky, Ha-Sheng; Epel, Elissa S; Doyle, William J

    2013-11-01

    Low socioeconomic status (SES) during childhood and adolescence has been found to predict greater susceptibility to common cold viruses in adults. Here, we test whether low childhood SES is associated with shorter leukocyte telomere length in adulthood, and whether telomere length mediates the association between childhood SES and susceptibility to acute upper respiratory disease in adulthood. At baseline, 196 healthy volunteers reported whether they currently owned their home and, for each year of their childhood, whether their parents owned the family home. Volunteers also had blood drawn for assessment of specific antibody to the challenge virus, and for CD8+ CD28- T-lymphocyte telomere length (in a subset, n=135). They were subsequently quarantined in a hotel, exposed to a virus (rhinovirus [RV] 39) that causes a common cold and followed for infection and illness (clinical cold) over five post-exposure days. Lower childhood SES as measured by fewer years of parental home ownership was associated with shorter adult CD8+ CD28- telomere length and with an increased probability of developing infection and clinical illness when exposed to a common cold virus in adulthood. These associations were independent of adult SES, age, sex, race, body mass, neuroticism, and childhood family characteristics. Associations with infections and colds were also independent of pre-challenge viral-specific antibody and season. Further analyses do not support mediating roles for smoking, alcohol consumption or physical activity but suggest that CD8+ CD28- cell telomere length may act as a partial mediator of the associations between childhood SES and infection and childhood SES and colds.

  9. Effect of Intensive Exercise in Early Adult Life on Telomere Length in Later Life in Men

    PubMed Central

    Laine, Merja K.; Eriksson, Johan G.; Kujala, Urho M.; Raj, Rahul; Kaprio, Jaakko; Bäckmand, Heli M.; Peltonen, Markku; Sarna, Seppo

    2015-01-01

    A career as an elite-class male athlete seems to improve metabolic heath in later life and is also associated with longer life expectancy. Telomere length is a biomarker of biological cellular ageing and could thus predict morbidity and mortality. The main aim of this study was to assess the association between vigorous elite-class physical activity during young adulthood on later life leukocyte telomere length (LTL). The study participants consist of former male Finnish elite athletes (n = 392) and their age-matched controls (n = 207). Relative telomere length was determined from peripheral blood leukocytes by quantitative real-time polymerase chain reaction. Volume of leisure-time physical activity (LTPA) was self-reported and expressed in metabolic equivalent hours. No significant difference in mean age-adjusted LTL in late life (p = 0.845) was observed when comparing former male elite athletes and their age-matched controls. Current volume of LTPA had no marked influence on mean age-adjusted LTL (p for trend 0.788). LTL was inversely associated with age (p = 0.004).Our study findings suggest that a former elite athlete career is not associated with LTL later in life. Key points A career as an elite-class athlete is associated with improved metabolic health in late life and is associated with longer life expectancy. A career as an elite-class athlete during young adulthood was not associated with leukocyte telomere length in later life. Current volume of leisure-time physical activity did not influence telomere length in later life. PMID:25983570

  10. Frailty and telomere length: cross-sectional analysis in 3537 older adults from the ESTHER cohort.

    PubMed

    Saum, Kai-Uwe; Dieffenbach, Aida Karina; Müezzinler, Aysel; Müller, Heiko; Holleczek, Bernd; Stegmaier, Christa; Butterbach, Katja; Schick, Matthias; Canzian, Federico; Stammer, Hermann; Boukamp, Petra; Hauer, Klaus; Brenner, Hermann

    2014-10-01

    Both telomere length and frailty were observed to be associated with aging. Whether and to what extent telomere length is related to frailty is essentially unknown. In this cross-sectional analysis of baseline data of 3537 community-dwelling adults aged 50 to 75 years of a large German cohort study, we assessed the hypothesis that shorter telomere length might be a biological marker for frailty. Using whole blood DNA we examined mean telomere repeat copy to single gene copy number (T/S ratio) using quantitative PCR. Construction of a frailty index (FI) was based on a deficit accumulation approach, which quantifies frailty as ratio of the deficits present divided by the total number of deficits considered. Mean FI was determined according to age by tertiles of T/S ratio. Furthermore, we used correlation analyses stratified for gender and age groups to examine the association of the T/S ratio with frailty. Mean FI value was similar across tertiles of the T/S ratio (0.24±0.14, 0.24±0.14 and 0.23±0.14, respectively (p=0.09)), and FI and the T/S ratio were uncorrelated in gender- and age-specific analyses. In conclusion, T/S ratio and frailty were unrelated in this large sample of older adults. T/S ratio may therefore not be a meaningful biological marker for frailty.

  11. Systematic review of the association between chronic social stress and telomere length: A life course perspective.

    PubMed

    Oliveira, Bruna Silva; Zunzunegui, Maria Victoria; Quinlan, Jacklyn; Fahmi, Hassan; Tu, Mai Thanh; Guerra, Ricardo Oliveira

    2016-03-01

    Our aim was to examine whether chronic social stress is associated with telomere length throughout the life course, following our protocol published in 2014. Structured searches were conducted in MEDLINE (PubMed interface), EMBASE (OVID interface), Cochrane Central (OVID interface) and grey from their start date onwards. Reference lists of retrieved citations were hand searched for relevant studies. Eighteen studies published until May 1, 2015 investigating the association between chronic social stress (as defined by poverty, exposure to violence, or family caregiving) and telomere length in healthy or diseased adults and children were independently selected by 2 reviewers. Sixteen of those studies were cross-sectional and two had a longitudinal design. Studies differed in type of stress exposure, method to measure telomere length and cell type. As meta-analysis could not be conducted, the data were synthesized as a narrative review. Based on this comprehensive review, chronic social stress accompanies telomere shortening in both early and adult exposures, with most eligible studies showing a significant relationship. We discuss the significance of chronic stress of social origin and the potential for social interventions through public policies and we recommend methodological improvements that would allow for future meta-analysis. PMID:26732034

  12. Association between telomere length and chromosome 21 nondisjunction in the oocyte.

    PubMed

    Albizua, I; Rambo-Martin, B L; Allen, E G; He, W; Amin, A S; Sherman, S L

    2015-11-01

    Chromosome 21 nondisjunction in oocytes is the most common cause of trisomy 21, the primary chromosomal abnormality responsible for Down syndrome (DS). This specific type of error is estimated to account for over 90 % of live births with DS, with maternal age being the best known risk factor for chromosome 21 nondisjunction. The loss of telomere length and the concomitant shortening of chromosomes are considered a biological marker for aging. Thus, we tested the hypothesis that mothers who had a maternal nondisjunction error leading to a live birth with DS (n = 404) have shorter telomeres than mothers with live births without DS (n = 42). In effect, our hypothesis suggests that mothers of children with DS will appear "biologically older" as compared to the mothers of euploid children. We applied a quantitative PCR assay to measure the genome-wide relative telomere length to test this hypothesis. The results of our study support the hypothesis that young mothers of DS babies are "biologically older" than mothers of euploid babies in the same age group and supports telomere length as a biomarker of age and hence risk for chromosome nondisjunction. PMID:26407969

  13. Depression, anxiety and telomere length in young adults: evidence from the National Health and Nutrition Examination Survey.

    PubMed

    Needham, B L; Mezuk, B; Bareis, N; Lin, J; Blackburn, E H; Epel, E S

    2015-04-01

    Telomere length has been hypothesized to be a marker of cumulative exposure to stress, and stress is an established cause of depression and anxiety disorders. The aim of this study was to examine the relationship between depression, anxiety and telomere length, and to assess whether this relationship is moderated by race/ethnicity, gender and/or antidepressant use. Data were from the 1999-2002 National Health and Nutrition Examination Survey. Telomere length was assessed using the quantitative PCR method of telomere length relative to standard reference DNA. Past-year major depression (MD), generalized anxiety disorder (GAD) and panic disorder (PD), as well as depressed affect and anxious affect, were assessed using the Composite International Diagnostic Inventory (N=1290). Multiple linear regression was used to assess the relationship between depression and anxiety disorders and telomere length. Among women, those with GAD or PD had shorter telomeres than those with no anxious affect (β: -0.07, P<0.01), but there was no relationship among men (β: 0.08, P>0.05). Among respondents currently taking an antidepressant, those with MD had shorter telomeres than those without (β: -0.26, P<0.05), but there was no association between MD and telomere length among those not using antidepressants (β: -0.00, P>0.05). Neither depressive nor anxiety disorders were directly associated with telomere length in young adults. There was suggestive evidence that pharmacologically treated MD is associated with shorter telomere length, likely reflecting the more severe nature of MD that has come to clinical attention.

  14. Mapping Genetic Loci That Determine Leukocyte Telomere Length in a Large Sample of Unselected Female Sibling Pairs

    PubMed Central

    Andrew, Toby; Aviv, Abraham; Falchi, Mario; Surdulescu, Gabriela L.; Gardner, Jeffrey P.; Lu, Xiaobin; Kimura, Masayuki; Kato, Bernet S.; Valdes, Ana M.; Spector, Tim D.

    2006-01-01

    Telomeres play a central role in cellular senescence and cancer pathobiology and are associated with age-related diseases such as atherosclerosis and dementia. Telomere length varies between individuals of the same age, is influenced by DNA-damaging factors such as oxidative stress, and is heritable. We performed a quantitative-trait linkage analysis using an ∼10-cM genomewide map for mean leukocyte terminal-restriction fragment (TRF) lengths measured by Southern blotting, in 2,050 unselected women aged 18–80 years, comprising 1,025 complete dizygotic twin pairs. Heritability of mean batch-adjusted TRF was 36% (95% confidence interval [CI] 18%–48%), with a large common environmental effect of 49% (95% CI 40%–58%). Significant linkage was observed on chromosome 14 (LOD 3.9) at 14q23.2, and suggestive linkage at 10q26.13 (LOD 2.4) and 3p26.1 (LOD 2.7). This is the first report of loci, mapped in a sample of healthy individuals, that influence mean telomere variation in humans. PMID:16400618

  15. Telomeres in cancer and ageing

    PubMed Central

    Donate, Luis E.; Blasco, Maria A.

    2011-01-01

    Telomeres protect the chromosome ends from unscheduled DNA repair and degradation. Telomeres are heterochromatic domains composed of repetitive DNA (TTAGGG repeats) bound to an array of specialized proteins. The length of telomere repeats and the integrity of telomere-binding proteins are both important for telomere protection. Furthermore, telomere length and integrity are regulated by a number of epigenetic modifications, thus pointing to higher order control of telomere function. In this regard, we have recently discovered that telomeres are transcribed generating long, non-coding RNAs, which remain associated with the telomeric chromatin and are likely to have important roles in telomere regulation. In the past, we showed that telomere length and the catalytic component of telomerase, Tert, are critical determinants for the mobilization of stem cells. These effects of telomerase and telomere length on stem cell behaviour anticipate the premature ageing and cancer phenotypes of telomerase mutant mice. Recently, we have demonstrated the anti-ageing activity of telomerase by forcing telomerase expression in mice with augmented cancer resistance. Shelterin is the major protein complex bound to mammalian telomeres; however, its potential relevance for cancer and ageing remained unaddressed to date. To this end, we have generated mice conditionally deleted for the shelterin proteins TRF1, TPP1 and Rap1. The study of these mice demonstrates that telomere dysfunction, even if telomeres are of a normal length, is sufficient to produce premature tissue degeneration, acquisition of chromosomal aberrations and initiation of neoplastic lesions. These new mouse models, together with the telomerase-deficient mouse model, are valuable tools for understanding human pathologies produced by telomere dysfunction. PMID:21115533

  16. Exposure to Persistent Organic Pollutants Predicts Telomere Length in Older Age: Results from the Helsinki Birth Cohort Study

    PubMed Central

    Guzzardi, Maria Angela; Iozzo, Patricia; Salonen, Minna K.; Kajantie, Eero; Airaksinen, Riikka; Kiviranta, Hannu; Rantakokko, Panu; Eriksson, Johan Gunnar

    2016-01-01

    As the population ages, the occurrence of chronic pathologies becomes more common. Leukocyte telomere shortening associates to ageing and age-related diseases. Recent studies suggest that environmental chemicals can affect telomere length. Persistent organic pollutants (POPs) are most relevant, since they are ingested with foods, and accumulate in the body for a long time. This longitudinal study was undertaken to test if circulating POPs predict telomere length and shortening in elderly people. We studied 1082 subjects belonging to the Helsinki Birth Cohort Study (born 1934-1944), undergoing two visits (2001-2004 and 2011-2014). POPs (oxychlordane, trans-nonachlor, p, p’-DDE, PCB 153, BDE 47, BDE 153) were analysed at baseline. Relative telomere length was measured twice, ’10 years apart, by quantitative real-time PCR. Oxychlordane, trans-nonachlor and PCB-153 levels were significant predictors of telomere length and shortening. In men, we did not find a linear relationship between POPs exposure and telomere shortening. In women, a significant reduction across quartiles categories of oxychlordane and trans-nonachlor exposure was observed. Baseline characteristics of subjects in the highest POPs categories included higher levels of C-reactive protein and fasting glucose, and lower body fat percentage. This is one of few studies combining POPs and telomere length. Our results indicate that exposure to oxychlordane, trans-nonachlor and PCB 153 predicts telomere attrition. This finding is important because concentrations of POPs observed here occur in contemporary younger people, and may contribute to an accelerated ageing.

  17. Lymphocyte telomere length is long in BRCA1 and BRCA2 mutation carriers regardless of cancer-affected status

    PubMed Central

    McGuffog, Lesley; Barrowdale, Daniel; Frost, Debra; Ellis, Steve D.; Platte, Radka; Fineberg, Elena; Izatt, Louise; Adlard, Julian; Bardwell, Julian; Brewer, Carole; Cole, Trevor; Cook, Jackie; Davidson, Rosemary; Donaldson, Alan; Dorkins, Huw; Douglas, Fiona; Eason, Jacqueline; Houghton, Catherine; Kennedy, M. John; McCann, Emma; Miedzybrobzka, Zosia; Murray, Alex; Porteous, Mary E.; Rogers, Mark T.; Side, Lucy E.; Tischkowitz, Marc; Walker, Lisa; Hodgson, Shirley; Eccles, Diana M.; Morrison, Patrick J.; Evans, D. Gareth; Eeles, Rosalind A.; Antoniou, Antonis C.; Easton, Douglas F.

    2014-01-01

    Background Telomere length has been linked to risk of common diseases, including cancer, and has previously been proposed as a biomarker for cancer risk. Germline BRCA1 and BRCA2 mutations predispose to breast, ovarian and other cancer types. Methods We investigated telomere length in BRCA mutation carriers and their non-carrier relatives and further examined whether telomere length is a modifier of cancer risk in mutation carriers. We measured mean telomere length in DNA extracted from whole blood using high-throughput Q-PCR. Participants were from the EMBRACE study in the UK and Eire (n=4,822) and comprised BRCA1 (n=1,628) and BRCA2 (n=1,506) mutation carriers and their non-carrier relatives (n=1,688). Results We find no significant evidence that mean telomere length is associated with breast or ovarian cancer risk in BRCA mutation carriers. However, we find mutation carriers to have longer mean telomere length than their non-carrier relatives (all carriers vs. non-carriers, P-trend=0.0018), particularly in families with BRCA2 mutations (BRCA2 mutation carriers vs. all non-carriers, P-trend=0.0016). Our findings lend little support to the hypothesis that short mean telomere length predisposes to cancer. Conversely, our main and unexpected finding is that BRCA mutation carriers (regardless of cancer status) have longer telomeres than their non-mutation carrier, non-cancer-affected relatives. The longer telomere length in BRCA2 mutation carriers is consistent with its role in DNA damage response. Conclusions Overall, it appears that increased telomere length may be a consequence of these mutations, but is not itself directly related to the increased cancer risk in carriers. Impact The finding that mutation carriers to have longer mean telomere lengths than their non-carrier relatives is unexpected but biologically plausible and could open up new lines of research into the functions of the BRCA proteins. To our knowledge, this is the largest study of telomere length

  18. A Common Variant in the Telomerase RNA Component Is Associated with Short Telomere Length

    PubMed Central

    Njajou, Omer T.; Blackburn, Elizabeth H.; Pawlikowska, Ludmila; Mangino, Massimo; Damcott, Coleen M.; Kwok, Pui-Yan; Spector, Timothy D.; Newman, Anne B.; Harris, Tamara B.; Cummings, Steven R.; Cawthon, Richard M.; Shuldiner, Alan R.; Valdes, Ana M.; Hsueh, Wen-Chi

    2010-01-01

    Background Telomeres shorten as cells divide. This shortening is compensated by the enzyme telomerase. We evaluated the effect of common variants in the telomerase RNA component (TERC) gene on telomere length (TL) in the population-based Health Aging and Body Composition (Health ABC) Study and in two replication samples (the TwinsUK Study and the Amish Family Osteoporosis Study, AFOS). Methodology Five variants were identified in the TERC region by sequence analysis and only one SNP was common (rs2293607, G/A). The frequency of the G allele was 0.26 and 0.07 in white and black, respectively. Testing for association between TL and rs2293607 was performed using linear regression models or variance component analysis conditioning on relatedness among subjects. Results The adjusted mean TL was significantly shorter in 665 white carriers of the G allele compared to 887 non-carriers from the Health ABC Study (4.69±0.05 kbp vs. 4.86±0.04 kbp, measured by quantitative PCR, p = 0.005). This association was replicated in another white sample from the TwinsUK Study (6.90±0.03 kbp in 301 carriers compared to 7.06±0.03 kbp in 395 non-carriers, measured by Southern blots, p = 0.009). A similar pattern of association was observed in whites from the family-based AFOS and blacks from the Health ABC cohort, although not statistically significant, possibly due to the lower allele frequency in these populations. Combined analysis using 2,953 white subjects from 3 studies showed a significant association between TL and rs2293607 (β = −0.19±0.04 kbp, p = 0.001). Conclusion Our study shows a significant association between a common variant in TERC and TL in humans, suggesting that TERC may play a role in telomere homeostasis. PMID:20885959

  19. Human telomeric G-quadruplex: thermodynamic and kinetic studies of telomeric quadruplex stability

    PubMed Central

    Chaires, Jonathan B.

    2010-01-01

    Summary Thermodynamic and kinetic studies complement high-resolution structures of G-quadruplexes. Such studies are essential for a thorough understanding of the mechanisms that govern quadruplex folding and conformational changes in quadruplexes. This perspective article reviews representative thermodynamic and kinetic studies of the folding of human telomeric quadruplex structures. Published thermodynamic data vary widely and are inconsistent. Possible reasons for these inconsistencies are discussed. The key issue of whether or not such folding reactions are a simple two-state process is examined. A tentative energy balance for the folding of telomeric quadruplexes in Na+ and K+ solution, and for conformational transition between these forms will be presented. PMID:19951355

  20. Omega-3 Fatty Acids, Oxidative Stress, and Leukocyte Telomere Length: A Randomized Controlled Trial

    PubMed Central

    Kiecolt-Glaser, Janice K.; Epel, Elissa S.; Belury, Martha A.; Andridge, Rebecca; Lin, Jue; Glaser, Ronald; Malarkey, William B.; Hwang, Beom Seuk; Blackburn, Elizabeth

    2012-01-01

    Shorter telomeres have been associated with poor health behaviors, age-related diseases, and early mortality. Telomere length is regulated by the enzyme telomerase, and is linked to exposure to proinflammatory cytokines and oxidative stress. In our recent randomized controlled trial, omega-3 (n-3) polyunsaturated fatty acid (PUFA) supplementation lowered the concentration of serum proinflammatory cytokines. This study assessed whether n-3 PUFA supplementation also affected leukocyte telomere length, telomerase, and oxidative stress. In addition to testing for group differences, changes in the continuous n-6:n-3 PUFA ratio were assessed to account for individual differences in adherence, absorption, and metabolism. The double-blind 4-month trial included 106 healthy sedentary overweight middle-aged and older adults who received (1) 2.5 g/day n-3 PUFAs, (2) l.25 g/day n-3 PUFAs, or (3) placebo capsules that mirrored the proportions of fatty acids in the typical American diet. Supplementation significantly lowered oxidative stress as measured by F2-isoprostanes (p=0.02). The estimated geometric mean log-F2-isoprostanes values were 15% lower in the two supplemented groups compared to placebo. Although group differences for telomerase and telomere length were nonsignificant, changes in the n-6:n-3 PUFA plasma ratios helped clarify the intervention’s impact: telomere length increased with decreasing n-6:n-3 ratios, p=0.02. The data suggest that lower n-6:n-3 PUFA ratios can impact cell aging. The triad of inflammation, oxidative stress, and immune cell aging represents important pre-disease mechanisms that may be ameliorated through nutritional interventions. This translational research broadens our understanding of the potential impact of the n-6:n-3 PUFA balance. ClinicalTrials.gov identifier: NCT00385723 PMID:23010452

  1. Childhood Adversities Are Associated with Shorter Telomere Length at Adult Age both in Individuals with an Anxiety Disorder and Controls

    PubMed Central

    Kananen, Laura; Surakka, Ida; Pirkola, Sami; Suvisaari, Jaana; Lönnqvist, Jouko; Peltonen, Leena; Ripatti, Samuli; Hovatta, Iiris

    2010-01-01

    Accelerated leukocyte telomere shortening has been previously associated to self-perceived stress and psychiatric disorders, including schizophrenia and mood disorders. We set out to investigate whether telomere length is affected in patients with anxiety disorders in which stress is a known risk factor. We also studied the effects of childhood and recent psychological distress on telomere length. We utilized samples from the nationally representative population-based Health 2000 Survey that was carried out between 2000–2001 in Finland to assess major public health problems and their determinants. We measured the relative telomere length of the peripheral blood cells by quantitative real-time PCR from 321 individuals with DSM-IV anxiety disorder or subthreshold diagnosis and 653 matched controls aged 30–87 years, who all had undergone the Composite International Diagnostic Interview. While telomere length did not differ significantly between cases and controls in the entire cohort, the older half of the anxiety disorder patients (48–87 years) exhibited significantly shorter telomeres than healthy controls of the same age (P = 0.013). Interestingly, shorter telomere length was also associated with a greater number of reported childhood adverse life events, among both the anxiety disorder cases and controls (P = 0.005). Childhood chronic or serious illness was the most significantly associated single event affecting telomere length at the adult age (P = 0.004). Self-reported current psychological distress did not affect telomere length. Our results suggest that childhood stress might lead to accelerated telomere shortening seen at the adult age. This finding has potentially important implications supporting the view that childhood adversities might have a considerable impact on well being later in life. PMID:20520834

  2. Effect of the anatomical site on telomere length and pref-1 gene expression in bovine adipose tissues

    SciTech Connect

    Yamada, Tomoya Higuchi, Mikito; Nakanishi, Naoto

    2015-08-07

    Adipose tissue growth is associated with preadipocyte proliferation and differentiation. Telomere length is a biological marker for cell proliferation. Preadipocyte factor-1 (pref-1) is specifically expressed in preadipocytes and acts as a molecular gatekeeper of adipogenesis. In the present study, we investigated the fat depot-specific differences in telomere length and pref-1 gene expression in various anatomical sites (subcutaneous, intramuscular and visceral) of fattening Wagyu cattle. Visceral adipose tissue expressed higher pref-1 mRNA than did subcutaneous and intramuscular adipose tissues. The telomere length in visceral adipose tissue tended to be longer than that of subcutaneous and intramuscular adipose tissues. The telomere length of adipose tissue was not associated with adipocyte size from three anatomical sites. No significant correlation was found between the pref-1 mRNA level and the subcutaneous adipocyte size. In contrast, the pref-1 mRNA level was negatively correlated with the intramuscular and visceral adipocyte size. These results suggest that anatomical sites of adipose tissue affect the telomere length and expression pattern of the pref-1 gene in a fat depot-specific manner. - Highlights: • Visceral adipose tissue express higher pref-1 mRNA than other anatomical sites. • Telomere length in visceral adipose tissue is longer than other anatomical sites. • Telomere length of adipose tissue is not associated with adipocyte size. • Pref-1 mRNA is negatively correlated with intramuscular and visceral adipocyte size.

  3. Telomeres and the ethics of human cloning.

    PubMed

    Allhoff, Fritz

    2004-01-01

    In search of a potential problem with cloning, I investigate the phenomenon of telomere shortening which is caused by cell replication; clones created from somatic cells will have shortened telomeres and therefore reach a state of senescence more rapidly. While genetic intervention might fix this problem at some point in the future, I ask whether, absent technological advances, this biological phenomenon undermines the moral permissibility of cloning.

  4. Telomere length shortening is associated with treatment-free remission in chronic myeloid leukemia patients.

    PubMed

    Caocci, Giovanni; Greco, Marianna; Delogu, Giuseppe; Secchi, Christian; Martino, Bruno; Labate, Claudia; Abruzzese, Elisabetta; Trawinska, Malgorzata Monika; Galimberti, Sara; Orru, Federica; Fozza, Claudio; Gambacorti Passerini, Carlo; Galimi, Francesco; La Nasa, Giorgio

    2016-01-01

    We studied telomere length in 32 CML patients who discontinued imatinib after achieving complete molecular remission and 32 age-sex-matched controls. The relative telomere length (RTL) was determined by q-PCR as the telomere to single copy gene (36B4) ratio normalized to a reference sample (K-562 DNA). Age-corrected RTL (acRTL) was also obtained. The 36-month probability of treatment-free remission (TFR) was 59.4 %. TFR patients showed shorter acRTL compared to relapsed (mean ± SD = 0.01 ± 0.14 vs 0.20 ± 0.21; p = 0.01). TFR was significantly higher in CML patients with acRTL ≤0.09 (78.9 vs 30.8 %, p = 0.002). CML stem cells harboring longer telomeres possibly maintain a proliferative potential after treatment discontinuation. PMID:27473052

  5. A prospective study of leukocyte telomere length and risk of phobic anxiety among women.

    PubMed

    Ramin, Cody; Wang, Wei; Prescott, Jennifer; Rosner, Bernard; Simon, Naomi M; De Vivo, Immaculata; Okereke, Olivia I

    2015-12-15

    We prospectively examined the relation of relative telomere lengths (RTLs), a marker of biological aging, to phobic anxiety in later-life. RTLs in peripheral blood leukocytes were measured among 3194 women in the Nurses' Health Study who provided blood samples in 1989/90. The Crown-Crisp Phobic Index (CCI, range=0–16) was assessed in 1988 and 2004. Only participants with CCI≤3 (consistent with no meaningful anxiety symptoms) in 1988 were included. We related baseline RTLs to odds ratios (ORs) of incident high phobic anxiety symptoms (CCI≥6). To enhance clinical relevance, we used finite mixture modeling (FMM) to relate baseline RTLs to latent classes of CCI in 2004. RTLs were not significantly associated with high phobic anxiety symptoms after 16 years of follow-up. However, FMM identified 3 groups of phobic symptoms in later-life: severe, minimal/intermediate, and non-anxious. The severe group had non-significantly shorter multivariable-adjusted mean RTLs than the minimal/intermediate and non-anxious groups. Women with shorter telomeres vs. longest telomeres had non-significantly higher likelihood of being in the severe vs. non-anxious group. Overall, there was no significant association between RTLs and incident phobic anxiety symptoms. Further work is required to explore potential connections of telomere length and emergence of severe phobic anxiety symptoms during later-life.

  6. A prospective study of leukocyte telomere length and risk of phobic anxiety among women.

    PubMed

    Ramin, Cody; Wang, Wei; Prescott, Jennifer; Rosner, Bernard; Simon, Naomi M; De Vivo, Immaculata; Okereke, Olivia I

    2015-12-15

    We prospectively examined the relation of relative telomere lengths (RTLs), a marker of biological aging, to phobic anxiety in later-life. RTLs in peripheral blood leukocytes were measured among 3194 women in the Nurses' Health Study who provided blood samples in 1989/90. The Crown-Crisp Phobic Index (CCI, range=0–16) was assessed in 1988 and 2004. Only participants with CCI≤3 (consistent with no meaningful anxiety symptoms) in 1988 were included. We related baseline RTLs to odds ratios (ORs) of incident high phobic anxiety symptoms (CCI≥6). To enhance clinical relevance, we used finite mixture modeling (FMM) to relate baseline RTLs to latent classes of CCI in 2004. RTLs were not significantly associated with high phobic anxiety symptoms after 16 years of follow-up. However, FMM identified 3 groups of phobic symptoms in later-life: severe, minimal/intermediate, and non-anxious. The severe group had non-significantly shorter multivariable-adjusted mean RTLs than the minimal/intermediate and non-anxious groups. Women with shorter telomeres vs. longest telomeres had non-significantly higher likelihood of being in the severe vs. non-anxious group. Overall, there was no significant association between RTLs and incident phobic anxiety symptoms. Further work is required to explore potential connections of telomere length and emergence of severe phobic anxiety symptoms during later-life. PMID:26603336

  7. Pre-diagnostic obesity and physical inactivity are associated with shorter telomere length in prostate stromal cells

    PubMed Central

    Joshu, Corinne E; Peskoe, Sarah B; Heaphy, Christopher M; Kenfield, Stacey A; Van Blarigan, Erin L; Mucci, Lorelei A; Giovannucci, Edward L; Stampfer, Meir J; Yun, GhilSuk; Lee, Thomas K; Hicks, Jessica L; De Marzo, Angelo M; Meeker, Alan K; Platz, Elizabeth A

    2015-01-01

    Obesity and inactivity have been with associated advanced stage prostate cancer, and poor prostate cancer outcomes, though the underlying mechanism(s) is unknown. To determine if telomere shortening, which has been associated with lethal prostate cancer, may be a potential underlying mechanism, we prospectively evaluated the association between measures of adiposity, physical activity and telomere length in 596 participants in the Health Professionals Follow-up Study, who were surgically treated for prostate cancer. Using tissue microarrays, we measured telomere length in cancer and benign cells using a telomere-specific fluorescence in situ hybridization assay. Adiposity and activity were assessed via questionnaire within 2 years of diagnosis. Adjusting for age, pathologic stage and grade, the median and standard deviation of the per cell telomere signals were determined for each man for stromal cells and cancer cells by adiposity and activity categories. Overweight/obese men (54%) were similar to normal weight men on most factors, but had higher Gleason sum and lower activity levels. Overweight/obese men had 7.4% shorter telomeres in stromal cells than normal weight men (P=0.06). The least active men had shorter telomeres in stromal cells than more active men (P-trend=0.002). Men who were overweight/obese and the least active had the shortest telomeres in stromal cells (20.7% shorter; P=0.0005) compared to normal weight men who were the most active. Cancer cell telomere length and telomere length variability did not differ by measures of adiposity or activity. Telomere shortening in prostate cells may be one mechanism through which lifestyle influences prostate cancer risk and outcomes. PMID:25990087

  8. CpG-island promoters drive transcription of human telomeres

    PubMed Central

    Nergadze, Solomon G.; Farnung, Benjamin O.; Wischnewski, Harry; Khoriauli, Lela; Vitelli, Valerio; Chawla, Raghav; Giulotto, Elena; Azzalin, Claus M.

    2009-01-01

    The longstanding dogma that telomeres, the heterochromatic extremities of linear eukaryotic chromosomes, are transcriptionally silent was overturned by the discovery that DNA-dependent RNA polymerase II (RNAPII) transcribes telomeric DNA into telomeric repeat-containing RNA (TERRA). Here, we show that CpG dinucleotide-rich DNA islands, shared among multiple human chromosome ends, promote transcription of TERRA molecules. TERRA promoters sustain cellular expression of reporter genes, are located immediately upstream of TERRA transcription start sites, and are bound by active RNAPII in vivo. Finally, the identified promoter CpG dinucleotides are methylated in vivo, and cytosine methylation negatively regulates TERRA abundance. The existence of subtelomeric promoters, driving TERRA transcription from independent chromosome ends, supports the idea that TERRA exerts fundamental functions in the context of telomere biology. PMID:19850908

  9. Telomeres, stem cells, and hematology

    PubMed Central

    2008-01-01

    Telomeres are highly dynamic structures that adjust the cellular response to stress and growth stimulation based on previous cell divisions. This critical function is accomplished by progressive telomere shortening and DNA damage responses activated by chromosome ends without sufficient telomere repeats. Repair of critically short telomeres by telomerase or recombination is limited in most somatic cells, and apoptosis or cellular senescence is triggered when too many uncapped telomeres accumulate. The chance of the latter increases as the average telomere length decreases. The average telomere length is set and maintained in cells of the germ line that typically express high levels of telomerase. In somatic cells, the telomere length typically declines with age, posing a barrier to tumor growth but also contributing to loss of cells with age. Loss of (stem) cells via telomere attrition provides strong selection for abnormal cells in which malignant progression is facilitated by genome instability resulting from uncapped telomeres. The critical role of telomeres in cell proliferation and aging is illustrated in patients with 50% of normal telomerase levels resulting from a mutation in one of the telomerase genes. Here, the role of telomeres and telomerase in human biology is reviewed from a personal historical perspective. PMID:18263784

  10. Telomere length change plateaus at 4 years of age in Latino children: associations with baseline length and maternal change.

    PubMed

    Wojcicki, Janet M; Shiboski, Stephen; Heyman, Melvin B; Elwan, Deena; Lin, Jue; Blackburn, Elizabeth; Epel, Elissa

    2016-06-01

    Telomeres are the protective complexes at the end of chromosomes, required for genomic stability. Little is known about predictors of attrition in young children or the relationship between parental and child patterns of telomere change. Telomere length was assessed twice over one year, at 4 and at 5 years of age, in Latino preschool children (n = 77) and their mothers (n = 70) in whole blood leukocytes. Maternal and child rates of attrition during the same time period were compared in 70 mother-child pairs. More children showed lengthened telomeres over one year compared to their mothers and very few children showed attrition (2.6 %). Approximately 31 % of children and 16 % of mothers displayed lengthening over one year while 66 % of children showed maintenance in contrast with 74 % of mothers. The strongest predictor for child telomere length change was child's baseline telomere length (r = -0.61, p < 0.01). Maternal rate of change was associated with child rate of change (r = 0.33, p < 0.01). After controlling for child baseline telomere length, the relationship between child and maternal rate of change trended towards significance (Coeff = 0.20, 95 % CI -0.03 to 0.43; p = 0.08). We found primarily maintenance and lengthening from 4 to 5 years of age in children, with minimal telomere attrition, indicating that most of the telomere loss happens in the first 4 years, plateauing by age 4. Lastly, we found close to 10 % of the variance in rate of change in children shared by mothers. While some of this shared variance is genetic, there are likely environmental factors that need to be further identified that impact rate of telomere length change. PMID:26965507

  11. Urinary Phthalates and Leukocyte Telomere Length: An Analysis of NHANES 1999-2002.

    PubMed

    Scinicariello, Franco; Feroe, Aliya G; Attanasio, Roberta

    2016-04-01

    The International Agency for Research on Cancer classified the di-2-ethylhexyl phthalate (DEHP) as "possibly carcinogenic to humans". In vitro studies reported that phthalate exposure resulted in induction of several nuclear transcription factors that are activators of telomerase reverse transcriptase (TERT) and telomerase activity of the human telomerase complex. The objective of this study was to determine whether there is an association between urinary phthalate metabolites [mono-ethyl phthalate (MEP), mono-butyl phthalate (MBP), mono-(2-ethyl)-hexyl phthalate (MEHP), and mono-benzyl phthalate (MBzP) and leukocyte telomere length (LTL) in the adult population of the National Health and Nutrition Examination Survey (NHANES) 1999-2002 (n=2472). After adjustment for potential confounders, participants in the 3rd and 4th quartiles of urinary MEHP had statistically significantly longer LTL (5.34%, 95% CI: 1.31, 9.53; and 7.14%, 95% CI: 2.94, 11.63; respectively) compared to the lowest quartile, with evidence of a dose-response relationship (p-trend=0.01). The association remained when the analyses were stratified by age groups (20-39years, 40-59years, and 60years and older), and sex. Furthermore, MBP and MBzP were associated with higher LTL in older participants. The age independent association between longer LTL and MEHP (a metabolite of DEHP) might suggest a possible role of MEHP as tumor promoter. PMID:27211552

  12. Urinary Phthalates and Leukocyte Telomere Length: An Analysis of NHANES 1999-2002.

    PubMed

    Scinicariello, Franco; Feroe, Aliya G; Attanasio, Roberta

    2016-04-01

    The International Agency for Research on Cancer classified the di-2-ethylhexyl phthalate (DEHP) as "possibly carcinogenic to humans". In vitro studies reported that phthalate exposure resulted in induction of several nuclear transcription factors that are activators of telomerase reverse transcriptase (TERT) and telomerase activity of the human telomerase complex. The objective of this study was to determine whether there is an association between urinary phthalate metabolites [mono-ethyl phthalate (MEP), mono-butyl phthalate (MBP), mono-(2-ethyl)-hexyl phthalate (MEHP), and mono-benzyl phthalate (MBzP) and leukocyte telomere length (LTL) in the adult population of the National Health and Nutrition Examination Survey (NHANES) 1999-2002 (n=2472). After adjustment for potential confounders, participants in the 3rd and 4th quartiles of urinary MEHP had statistically significantly longer LTL (5.34%, 95% CI: 1.31, 9.53; and 7.14%, 95% CI: 2.94, 11.63; respectively) compared to the lowest quartile, with evidence of a dose-response relationship (p-trend=0.01). The association remained when the analyses were stratified by age groups (20-39years, 40-59years, and 60years and older), and sex. Furthermore, MBP and MBzP were associated with higher LTL in older participants. The age independent association between longer LTL and MEHP (a metabolite of DEHP) might suggest a possible role of MEHP as tumor promoter.

  13. Association between Maternal Symptoms of Sleep Disordered Breathing and Fetal Telomere Length

    PubMed Central

    Salihu, Hamisu M.; King, Lindsey; Patel, Priyanshi; Paothong, Arnut; Pradhan, Anupam; Louis, Judette; Naik, Eknath; Marty, Phillip J.; Whiteman, Valerie

    2015-01-01

    Study Objectives: Our investigation aims to assess the impact of symptoms of maternal sleep-disordered breathing, specifically sleep apnea risk and daytime sleepiness, on fetal leukocyte telomere length. Participants and Setting: Pregnant women were recruited upon hospital delivery admission. Interventions: Sleep exposure outcomes were measured using the Berlin Questionnaire to quantify sleep apnea and the Epworth Sleepiness Scale to measure daytime sleepiness. Participants were classified as “High Risk” or “Low Risk” for sleep apnea based on responses to the Berlin, while “Normal” or “Abnormal” daytime sleepiness was determined based on responses to the Epworth. Design: Neonatal umbilical cord blood samples (N = 67) were collected and genomic DNA was isolated from cord blood leukocytes using Quantitative PCR. A ratio of relative telomere length was derived by telomere repeat copy number and single copy gene copy number (T/S ratio) and used to compare telomere lengths. Bootstrap and ANOVA statistical procedures were employed. Measurements and Results: On the Berlin, 68.7% of participants were classified as Low Risk while 31.3% were classified as High Risk for sleep apnea. According to the Epworth scale, 80.6% were determined to have Normal daytime sleepiness, and 19.4% were found to have Abnormal daytime sleepiness. The T/S ratio among pregnant women at High Risk for sleep apnea was significantly shorter than for those at Low Risk (P value < 0.05), and the T/S ratio among habitual snorers was significantly shorter than among non-habitual snorers (P value < 0.05). Although those with Normal Sleepiness had a longer T/S ratio than those with Abnormal Sleepiness, the difference was not statistically significant. Conclusion: Our results provide the first evidence demonstrating shortened telomere length among fetuses exposed to maternal symptoms of sleep disordered breathing during pregnancy, and suggest sleep disordered breathing as a possible mechanism

  14. Telomere length in peripheral blood leukocytes and lung cancer risk: a large case-control study in Caucasians.

    PubMed

    Sanchez-Espiridion, Beatriz; Chen, Meng; Chang, Joe Y; Lu, Charles; Chang, David W; Roth, Jack A; Wu, Xifeng; Gu, Jian

    2014-05-01

    Telomere dysfunction is a crucial event in malignant transformation and tumorigenesis. Telomere length in peripheral blood leukocytes has been associated with lung cancer risk, but the relationship has remained controversial. In this study, we investigated whether the association might be confounded by study of different histological subtypes of lung cancer. We measured relative telomere lengths in patients in a large case-control study of lung cancer and performed stratified analyses according to the two major histologic subtypes [adenocarcinoma and squamous cell carcinoma (SCC)]. Notably, patients with adenocarcinoma had longer telomeres than controls, whereas patients with SCC had shorter telomeres compared with controls. Long telomeres were associated with increased risk of adenocarcinoma, with the highest risk associated with female sex, younger age (<60 years), and lighter smoking (<30 pack-years). In contrast, long telomeres were protective against SCC, particularly in male patients. Our results extend the concept that telomere length affects risk of lung cancer in a manner that differs with histologic subtype.

  15. Telomere shortening and cell senescence induced by perylene derivatives in A549 human lung cancer cells.

    PubMed

    Taka, Thanachai; Huang, Liming; Wongnoppavich, Ariyaphong; Tam-Chang, Suk-Wah; Lee, T Randall; Tuntiwechapikul, Wirote

    2013-02-15

    Cancer cells evade replicative senescence by re-expressing telomerase, which maintains telomere length and hence chromosomal integrity. Telomerase inhibition would lead cancer cells to senesce and therefore prevent cancer cells from growing indefinitely. G-quadruplex ligands can attenuate telomerase activity by inducing G-quadruplex formation at the 3'-overhang of telomere and at the human telomerase reverse transcriptase (hTERT) promoter; the former prevents telomerase from accessing the telomere, and the latter acts as a transcriptional silencer. The present investigation found that perylene derivatives PM2 and PIPER induced G-quadruplex formation from both telomeric DNA and the hTERT promoter region in vitro. Further, TRAP assay showed that these compounds inhibited telomerase in a dose-dependent manner. When A549 human lung cancer cells were treated with these compounds, hTERT expression was down-regulated. Moreover, the crude protein extract from these treated cells exhibited less telomerase activity. In the long-term treatment of A549 lung cancer cells with sub-cytotoxic dose of these perylenes, telomere shortening, reduction of cell proliferation and tumorigenicity, and cell senescence were observed. The results of this study indicate that perylene derivatives warrant further consideration as effective agents for cancer therapy.

  16. Multiplex time-reducing quantitative polymerase chain reaction assay for determination of telomere length in blood and tissue DNA.

    PubMed

    Jiao, Jingjing; Kang, Jing X; Tan, Rui; Wang, Jingdong; Zhang, Yu

    2012-04-01

    In this paper we describe a multiplex time-reducing quantitative polymerase chain reaction (qPCR) method for determination of telomere length. This multiplex qPCR assay enables two pairs of primers to simultaneously amplify telomere and single copy gene (albumin) templates, thus reducing analysis time and labor compared with the previously established singleplex assay. The chemical composition of the master mix and primers for the telomere and albumin were systematically optimized. The thermal cycling program was designed to ensure complete separation of the melting processes of the telomere and albumin. Semi-log standard curves of DNA concentration versus cycle threshold (C (t)) were established, with a linear relationship over an 81-fold DNA concentration range. The well-performed intra-assay (RSD range 2.4-4.7%) and inter-assay (RSD range: 3.1-5.0%) reproducibility were demonstrated to ensure measurement stability. Using wild-type, Lewis lung carcinoma and H22 liver carcinoma C57BL/6 mouse models, significantly different telomere lengths among different DNA samples were not observed in wild-type mice. However, the relative telomere lengths of the tumor DNA in the two strains of tumor-bearing mice were significantly shorter than the lengths in the surrounding non-tumor DNA of tumor-bearing mice and the tissue DNA of wild-type mice. These results suggest that the shortening of telomere lengths may be regarded as an important indicator for cancer control and prevention. Quantification of telomere lengths was further confirmed by the traditional Southern blotting method. This method could be successfully used to reduce the time needed for rapid, precise measurement of telomere lengths in biological samples.

  17. Covalent ligation studies on the human telomere quadruplex

    PubMed Central

    Qi, Jianying; Shafer, Richard H.

    2005-01-01

    Recent X-ray crystallographic studies on the human telomere sequence d[AGGG(TTAGGG)3] revealed a unimolecular, parallel quadruplex structure in the presence of potassium ions, while earlier NMR results in the presence of sodium ions indicated a unimolecular, antiparallel quadruplex. In an effort to identify and isolate the parallel form in solution, we have successfully ligated into circular products the single-stranded human telomere and several modified human telomere sequences in potassium-containing solutions. Using these sequences with one or two terminal phosphates, we have made chemically ligated products via creation of an additional loop. Circular products have been identified by polyacrylamide gel electrophoresis, enzymatic digestion with exonuclease VII and electrospray mass spectrometry in negative ion mode. Optimum pH for the ligation reaction of the human telomere sequence ranges from 4.5 to 6.0. Several buffers were also examined, with MES yielding the greatest ligation efficiency. Human telomere sequences with two phosphate groups, one each at the 3′ and 5′ ends, were more efficient at ligation, via pyrophosphate bond formation, than the corresponding sequences with only one phosphate group, at the 5′ end. Circular dichroism spectra showed that the ligation product was derived from an antiparallel, single-stranded guanine quadruplex rather than a parallel single-stranded guanine quadruplex structure. PMID:15933211

  18. Telomere length is a prognostic biomarker in elderly advanced ovarian cancer patients: a multicenter GINECO study

    PubMed Central

    Falandry, Claire; Horard, Béatrice; Bruyas, Amandine; Legouffe, Eric; Cretin, Jacques; Meunier, Jérôme; Alexandre, Jérôme; Delecroix, Valérie; Fabbro, Michel; Certain, Marie-Noëlle; Maraval-Gaget, Raymonde; Pujade-Lauraine, Eric; Gilson, Eric; Freyer, Gilles

    2015-01-01

    Purpose Age induces a progressive decline in functional reserve and impacts cancer treatments. Telomere attrition leads to tissue senescence. We tested the hypothesis that telomere length (TL) could predict patient vulnerability and outcome with cancer treatment. Patients and methods An ancillary study in the Elderly Women GINECO Trial 3 was performed to evaluate the impact of geriatric covariates on survival in elderly advanced ovarian cancer patients receiving six cycles of carboplatin. TL was estimated from peripheral blood at inclusion using standard procedures. Results TL (in base pairs) was estimated for 109/111 patients (median 6.1 kb; range [4.5-8.3 kb]). With a cut-off of 5.77 kb, TL discriminated two patient groups, long telomere (LT) and short telomeres (ST), with significantly different treatment completion rates of 0.80 (95%CI [0.71-0.89]) and 0.59 (95%CI [0.41-0.76]), respectively (odds ratio [OR]=2.8, p=0.02). ST patients were at higher risk of serious adverse events (SAE, OR=2.7; p=0.02) and had more unplanned hospital admissions (OR=2.1; p=0.08). After adjustment on FIGO stage, TL shorter than 6 kb was a risk factor of premature death (HR=1.57; p=0.06). Conclusion This exploratory study identifies TL as predictive factor of decreased treatment completion, SAE risk, unplanned hospital admissions and OS after adjustment on FIGO stage. PMID:26638179

  19. Telomere attrition and Chk2 activation in human heart failure

    PubMed Central

    Oh, Hidemasa; Wang, Sam C.; Prahash, Arun; Sano, Motoaki; Moravec, Christine S.; Taffet, George E.; Michael, Lloyd H.; Youker, Keith A.; Entman, Mark L.; Schneider, Michael D.

    2003-01-01

    The “postmitotic” phenotype in adult cardiac muscle exhibits similarities to replicative senescence more generally and constitutes a barrier to effective restorative growth in heart disease. Telomere dysfunction is implicated in senescence and apoptotic signaling but its potential role in heart disorders is unknown. Here, we report that cardiac apoptosis in human heart failure is associated specifically with defective expression of the telomere repeat- binding factor TRF2, telomere shortening, and activation of the DNA damage checkpoint kinase, Chk2. In cultured cardiomyocytes, interference with either TRF2 function or expression triggered telomere erosion and apoptosis, indicating that cell death can occur via this pathway even in postmitotic, noncycling cells; conversely, exogenous TRF2 conferred protection from oxidative stress. In vivo, mechanical stress was sufficient to down-regulate TRF2, shorten telomeres, and activate Chk2 in mouse myocardium, and transgenic expression of telomerase reverse transcriptase conferred protection from all three responses. Together, these data suggest that apoptosis in chronic heart failure is mediated in part by telomere dysfunction and suggest an essential role for TRF2 even in postmitotic cells. PMID:12702777

  20. Telomere Length in Peripheral Blood Mononuclear Cells of Patients on Chronic Hemodialysis Is Related With Telomerase Activity and Treatment Duration.

    PubMed

    Stefanidis, Ioannis; Voliotis, Georgios; Papanikolaou, Vassilios; Chronopoulou, Ioanna; Eleftheriadis, Theodoros; Kowald, Axel; Zintzaras, Elias; Tsezou, Aspasia

    2015-09-01

    Telomere shortening to a critical limit is associated with replicative senescence. This process is prevented by the enzyme telomerase. Oxidative stress and chronic inflammation are factors accelerating telomere loss. Chronic hemodialysis, typically accompanied by oxidative stress and inflammation, may be also associated with replicative senescence. To test this hypothesis, we determined telomere length and telomerase activity in peripheral blood mononuclear cells (PBMCs) in a cross-sectional study. Hemodialysis patients at the University Hospital Larissa and healthy controls were studied. Telomere length was determined by the TeloTAGGG Telomere Length Assay and telomerase activity by Telomerase PCR-ELISA (Roche Diagnostics GmbH, Mannheim, Germany). We enrolled 43 hemodialysis patients (17 females; age 65.0 ± 12.7 years) and 23 controls (six females; age 62.1 ± 15.7 years). Between the two groups, there was no difference in telomere length (6.95 ± 3.25 vs. 7.31 ± 1.96 kb; P = 0.244) or in telomerase activity (1.82 ± 2.91 vs. 2.71 ± 3.0; P = 0.085). Telomere length correlated inversely with vintage of hemodialysis (r = -0.332, P = 0.030). In hemodialysis patients, positive telomerase activity correlated with telomere length (r = 0.443, P = 0.030). Only age, and neither telomere length nor telomerase activity, was an independent survival predictor (hazard ratio 1.116, 95% confidence interval 1.009-1.234, P = 0.033). In this study, telomere length and telomerase activity in PBMCs are not altered in hemodialysis patients compared with healthy controls. Long duration of hemodialysis treatment is associated with telomere shortening and positive telomerase activity with an increased telomere length in PBMCs of hemodialysis patients. The underlying mechanism and clinical implications of our findings require further investigation.

  1. Production efficiency and telomere length of the cloned pigs following serial somatic cell nuclear transfer.

    PubMed

    Kurome, Mayuko; Hisatomi, Hisashi; Matsumoto, Shirou; Tomii, Ryo; Ueno, Satoshi; Hiruma, Katsumi; Saito, Hitoshi; Nakamura, Kimitoshi; Okumura, Kenji; Matsumoto, Mitsuhito; Kaji, Yuji; Endo, Fumio; Nagashima, Hiroshi

    2008-08-01

    The aim of the present study was to examine the production efficiency of cloned pigs by serial somatic cell nuclear transfer (SCNT) and to ascertain any changes in the telomere lengths of multiple generations of pigs. Using fetal fibroblasts as the starting nuclear donor cells, porcine salivary gland progenitor cells were collected from the resultant first-generation cloned pigs to successively produce second- and third-generation clones, with no significant differences in production efficiency, which ranged from 1.4% (2/140) to 3.3% (13/391) among the 3 generations. The average telomere lengths (terminal restriction fragment values) for the first, second and third generation clones were 16.3, 18.1 and 20.5 kb, respectively, and were comparable to those in age-matched controls. These findings suggest that third-generation cloned pigs can be produced by serial somatic cell cloning without compromising production efficiency and that the telomere lengths of cloned pigs from the first to third generations are normal. PMID:18490858

  2. [Interspecific variability of telomeric DNA length in some Siberian and endemic Baĭkal planarians (Plathelminthes, Tricladida)].

    PubMed

    Koroleva, A G; Kiril'chik, S V; Timoshkin, O A

    2010-09-01

    The length of the telomeric DNA in nine species of planarians inhabiting Lake Baikal and one Siberian species from Baikal rivers was determined using Southern hybridization. According to preliminary estimations, it varied in the range of 25-30 kb (Rimacephalus arecepta, Rimacephalus pulvinar, Sorocelis hepatizon, Sorocelis nigrofasciata, Protocotylus sp., Baikalobia guttata, Bdellocephala baikalensis, Phagocata sibirica) and 50 kb (Baikaloplana valida, Baikalobia copulatrix). It is the first estimation of the values of telomeric region lengths for Baikal free-living flat worms.

  3. Leukocyte telomere length in relation to the risk of Barrett's esophagus and esophageal adenocarcinoma.

    PubMed

    Wennerström, E Christina M; Risques, Rosa A; Prunkard, Donna; Giffen, Carol; Corley, Douglas A; Murray, Liam J; Whiteman, David C; Wu, Anna H; Bernstein, Leslie; Ye, Weimin; Chow, Wong-Ho; Vaughan, Thomas L; Liao, Linda M

    2016-09-01

    Chronic inflammation and oxidative damage caused by obesity, cigarette smoking, and chronic gastroesophageal reflux disease (GERD) are major risk factors associated with Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC). EAC has been increasing the past few decades, and early discovery and treatment are crucial for survival. Telomere shortening due to cell division and oxidative damage may reflect the impact of chronic inflammation and could possibly be used as predictor for disease development. We examined the prevalence of shorter leukocyte telomere length (LTL) among individuals with GERD, BE, or EAC using a pooled analysis of studies from the Barrett's and Esophageal Adenocarcinoma Consortium (BEACON). Telomere length was measured in leukocyte DNA samples by Q-PCR. Participants included 1173 patients (386 with GERD, 384 with EAC, 403 with BE) and 736 population-based controls. The association of LTL (in tertiles) along the continuum of disease progression from GERD to BE to EAC was calculated using study-specific odds ratios (ORs) and 95% confidence intervals (CIs) from logistic regression models adjusted for potential confounders. Shorter LTL were less prevalent among GERD patients (OR 0.57; 95% CI: 0.35-0.93), compared to population-based controls. No statistically significant increased prevalence of short/long LTL among individuals with BE or EAC was observed. In contrast to some earlier reports, our findings add to the evidence that leukocyte telomere length is not a biomarker of risk related to the etiology of EAC. The findings do not suggest a relationship between LTL and BE or EAC. PMID:27384379

  4. [Telomere length and transrenal DNA isolated from transplanted kidney recipients' urine].

    PubMed

    Kłoda, Karolina; Drozd, Arleta; Borowiecka, Ewa; Domański, Leszek

    2015-05-17

    Transplantation is the preferred method of end stage renal insufficiency treatment due to better quality of life and extended life of transplanted patients. Currently a non-invasive test, which evaluates the risk of acute or chronic rejection or deterioration of the transplanted organ's function, is being sought. An increase of the transrenal DNA concentration in the urine of urinary tract infection patients and in renal graft recipients during an episode of acute rejection was observed. There were also reports on shortening of telomeres in transplanted organ chromosomes, as the result of accelerated aging of cells, and its connection with the onset of chronic allograft nephropathy and the degree of its completion, and thus the deterioration of kidney function. The aim of this paper is to describe the urine genetic analysis through determining the length of the telomeres and the content of transrenal DNA to monitor kidney function and to evaluate the prevalence of acute and chronic rejection in patients after kidney transplantation. The genetic analysis of the biological material collected from patients relies on the determination of transrenal DNA content and length of DNA telomeres isolated from the urine of kidney recipients. The presented methods assume that the genetic profile of the transplanted organ recipient as well as kidney donor can be determined, so the source of the genetic material in the urine of the patient can be identified. A measurable effect of these methods' use would be to complement the evaluation of the prevalence of acute and chronic rejection and transplanted kidney function with a modern, non-invasive method, which is the analysis of telomere length from sediment of urine and the content of transrenal DNA in the urine.

  5. Leukocyte telomere length in relation to the risk of Barrett's esophagus and esophageal adenocarcinoma.

    PubMed

    Wennerström, E Christina M; Risques, Rosa A; Prunkard, Donna; Giffen, Carol; Corley, Douglas A; Murray, Liam J; Whiteman, David C; Wu, Anna H; Bernstein, Leslie; Ye, Weimin; Chow, Wong-Ho; Vaughan, Thomas L; Liao, Linda M

    2016-09-01

    Chronic inflammation and oxidative damage caused by obesity, cigarette smoking, and chronic gastroesophageal reflux disease (GERD) are major risk factors associated with Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC). EAC has been increasing the past few decades, and early discovery and treatment are crucial for survival. Telomere shortening due to cell division and oxidative damage may reflect the impact of chronic inflammation and could possibly be used as predictor for disease development. We examined the prevalence of shorter leukocyte telomere length (LTL) among individuals with GERD, BE, or EAC using a pooled analysis of studies from the Barrett's and Esophageal Adenocarcinoma Consortium (BEACON). Telomere length was measured in leukocyte DNA samples by Q-PCR. Participants included 1173 patients (386 with GERD, 384 with EAC, 403 with BE) and 736 population-based controls. The association of LTL (in tertiles) along the continuum of disease progression from GERD to BE to EAC was calculated using study-specific odds ratios (ORs) and 95% confidence intervals (CIs) from logistic regression models adjusted for potential confounders. Shorter LTL were less prevalent among GERD patients (OR 0.57; 95% CI: 0.35-0.93), compared to population-based controls. No statistically significant increased prevalence of short/long LTL among individuals with BE or EAC was observed. In contrast to some earlier reports, our findings add to the evidence that leukocyte telomere length is not a biomarker of risk related to the etiology of EAC. The findings do not suggest a relationship between LTL and BE or EAC.

  6. Number of Children and Telomere Length in Women: A Prospective, Longitudinal Evaluation.

    PubMed

    Barha, Cindy K; Hanna, Courtney W; Salvante, Katrina G; Wilson, Samantha L; Robinson, Wendy P; Altman, Rachel M; Nepomnaschy, Pablo A

    2016-01-01

    Life history theory (LHT) predicts a trade-off between reproductive effort and the pace of biological aging. Energy invested in reproduction is not available for tissue maintenance, thus having more offspring is expected to lead to accelerated senescence. Studies conducted in a variety of non-human species are consistent with this LHT prediction. Here we investigate the relationship between the number of surviving children born to a woman and telomere length (TL, a marker of cellular aging) over 13 years in a group of 75 Kaqchikel Mayan women. Contrary to LHT's prediction, women who had fewer children exhibited shorter TLs than those who had more children (p = 0.045) after controlling for TL at the onset of the 13-year study period. An "ultimate" explanation for this apparently protective effect of having more children may lay with human's cooperative-breeding strategy. In a number of socio-economic and cultural contexts, having more chilren appears to be linked to an increase in social support for mothers (e.g., allomaternal care). Higher social support, has been argued to reduce the costs of further reproduction. Lower reproductive costs may make more metabolic energy available for tissue maintenance, resulting in a slower pace of cellular aging. At a "proximate" level, mechanisms involved may include the actions of the gonadal steroid estradiol, which increases dramatically during pregnancy. Estradiol is known to protect TL from the effects of oxidative stress as well as increase telomerase activity, an enzyme that maintains TL. Future research should explore the potential role of social support as well as that of estradiol and other potential biological pathways in the trade-offs between reproductive effort and the pace of cellular aging within and among human as well as in non-human populations. PMID:26731744

  7. Age and Heat Stress as Determinants of Telomere Length in a Long-Lived Fish, the Siberian Sturgeon.

    PubMed

    Simide, Rémy; Angelier, Frédéric; Gaillard, Sandrine; Stier, Antoine

    2016-01-01

    Telomeres shorten at each cell division due to the end-replication problem but also in response to oxidative stress. Consequently, telomeres shorten with age in many endotherms, and this shortening is accelerated under stressful environmental conditions. Data in ectotherm vertebrates remain scarce so far, so our goal was to review existing data for fish and to test the influence of age and stress on telomere length in a very long-lived fish, the Siberian sturgeon (Acipenser baerii). Our review of the literature revealed age-related telomere shortening in approximately half of the published studies. In the Siberian sturgeon, we found a significant telomere shortening with age, both at the intraindividual level using red blood cells (-12.5% in 16 mo) and at the interindividual level using cross-sectional samples of fin over an age range of 8 yr. We also found that heat stress (30°C) significantly reduced telomere length by 15.0% after only 1 mo of exposure. Our results highlight that both age and stressful environmental conditions might be important determinants of telomere length in fish. PMID:27617363

  8. Age and Heat Stress as Determinants of Telomere Length in a Long-Lived Fish, the Siberian Sturgeon.

    PubMed

    Simide, Rémy; Angelier, Frédéric; Gaillard, Sandrine; Stier, Antoine

    2016-01-01

    Telomeres shorten at each cell division due to the end-replication problem but also in response to oxidative stress. Consequently, telomeres shorten with age in many endotherms, and this shortening is accelerated under stressful environmental conditions. Data in ectotherm vertebrates remain scarce so far, so our goal was to review existing data for fish and to test the influence of age and stress on telomere length in a very long-lived fish, the Siberian sturgeon (Acipenser baerii). Our review of the literature revealed age-related telomere shortening in approximately half of the published studies. In the Siberian sturgeon, we found a significant telomere shortening with age, both at the intraindividual level using red blood cells (-12.5% in 16 mo) and at the interindividual level using cross-sectional samples of fin over an age range of 8 yr. We also found that heat stress (30°C) significantly reduced telomere length by 15.0% after only 1 mo of exposure. Our results highlight that both age and stressful environmental conditions might be important determinants of telomere length in fish.

  9. Embryonic and postnatal telomere length decrease with ovulation order within clutches

    PubMed Central

    Noguera, José C.; Metcalfe, Neil B.; Reichert, Sophie; Monaghan, Pat

    2016-01-01

    Telomere length (TL) in early life has been found to be predictive of subsequent lifespan. Factors such as parental TL, parental age and environmental conditions during development have been shown to contribute to the observed variation in TL among individuals. One factor that has not hitherto been considered is ovulation order, although it is well established that the last hatched/born offspring in a brood or litter often show relatively poor subsequent performance. We examined the within- and across-clutch effect of ovulation order on TL in embryos of zebra finches experiencing the same controlled incubation conditions (N = 151), and tested whether any such ovulation order effects remained detectable in adults (N = 122). Irrespective of clutch and egg size, TL in early-stage embryos (72 h incubation) markedly decreased with within-clutch ovulation order; the difference in TL of first and last-laid embryos was equivalent to the average within-individual telomere loss over the entire period of nestling and juvenile life. This ovulation-order effect occurred only within but not across clutches, and was still evident in adults. Given that TL in early life predicts lifespan, our results suggest that parental effects on telomere length could contribute to the known poor performance of later-ovulated family members. PMID:27174767

  10. Psychological Profiles in the Prediction of Leukocyte Telomere Length in Healthy Individuals

    PubMed Central

    Starnino, Louisia; Busque, Lambert; Tardif, Jean-Claude

    2016-01-01

    Background Shorter telomere length (TL) may signal premature cellular aging and increased risk for disease. While depression and psychosocial stress have been associated with shorter telomeres, other psychological risk factors for cardiovascular disease have received less attention. Purpose To evaluate the association between TL and psychological risk factors (symptoms of anxiety and depression, hostility and defensiveness traits) for heart disease, and to examine whether chronological age and sex moderate the associations observed. Methods 132 healthy men and women (Mage = 45.34 years) completed the Marlowe-Crowne Social Desirability Scale, the Beck Depression Inventory II, The Beck Anxiety Inventory and the Cook-Medley Hostility Scale. Relative TL was measured by quantitative polymerase chain reaction (PCR) of total genomic DNA samples. A series of hierarchical linear regressions were performed controlling for pertinent covariates. Results Shorter TL was observed among individuals high in defensiveness (β = -.221) and depressive symptoms (β = -.213), as well as in those with less hostility (β =.256) and anxiety (β =.220)(all Ps<.05). Psychological variables explained 19% of the variance over and above that explained by covariates (age, sex, exercise, alcohol consumption, systemic inflammation, and 24-hr mean arterial pressure). Age moderated the relation between TL and defensiveness (β =.179, p =.03). Sex did not influence any of the relations. Conclusions Telomere length is associated with psychological burden though the direction of effect differs depending on the psychological variables under study. Further research is needed to determine the reasons for and implications of these seemingly contradictory findings. PMID:27788238

  11. Human telomere biology: A contributory and interactive factor in aging, disease risks, and protection.

    PubMed

    Blackburn, Elizabeth H; Epel, Elissa S; Lin, Jue

    2015-12-01

    Telomeres are the protective end-complexes at the termini of eukaryotic chromosomes. Telomere attrition can lead to potentially maladaptive cellular changes, block cell division, and interfere with tissue replenishment. Recent advances in the understanding of human disease processes have clarified the roles of telomere biology, especially in diseases of human aging and in some aging-related processes. Greater overall telomere attrition predicts mortality and aging-related diseases in inherited telomere syndrome patients, and also in general human cohorts. However, genetically caused variations in telomere maintenance either raise or lower risks and progression of cancers, in a highly cancer type-specific fashion. Telomere maintenance is determined by genetic factors and is also cumulatively shaped by nongenetic influences throughout human life; both can interact. These and other recent findings highlight both causal and potentiating roles for telomere attrition in human diseases.

  12. Number of Children and Telomere Length in Women: A Prospective, Longitudinal Evaluation

    PubMed Central

    Barha, Cindy K.; Hanna, Courtney W.; Salvante, Katrina G.; Wilson, Samantha L.; Robinson, Wendy P.; Altman, Rachel M.; Nepomnaschy, Pablo A.

    2016-01-01

    Life history theory (LHT) predicts a trade-off between reproductive effort and the pace of biological aging. Energy invested in reproduction is not available for tissue maintenance, thus having more offspring is expected to lead to accelerated senescence. Studies conducted in a variety of non-human species are consistent with this LHT prediction. Here we investigate the relationship between the number of surviving children born to a woman and telomere length (TL, a marker of cellular aging) over 13 years in a group of 75 Kaqchikel Mayan women. Contrary to LHT’s prediction, women who had fewer children exhibited shorter TLs than those who had more children (p = 0.045) after controlling for TL at the onset of the 13-year study period. An “ultimate” explanation for this apparently protective effect of having more children may lay with human’s cooperative-breeding strategy. In a number of socio-economic and cultural contexts, having more chilren appears to be linked to an increase in social support for mothers (e.g., allomaternal care). Higher social support, has been argued to reduce the costs of further reproduction. Lower reproductive costs may make more metabolic energy available for tissue maintenance, resulting in a slower pace of cellular aging. At a “proximate” level, mechanisms involved may include the actions of the gonadal steroid estradiol, which increases dramatically during pregnancy. Estradiol is known to protect TL from the effects of oxidative stress as well as increase telomerase activity, an enzyme that maintains TL. Future research should explore the potential role of social support as well as that of estradiol and other potential biological pathways in the trade-offs between reproductive effort and the pace of cellular aging within and among human as well as in non-human populations. PMID:26731744

  13. Longer telomeres in chronic, moderate, unconjugated hyperbilirubinaemia: insights from a human study on Gilbert’s Syndrome

    PubMed Central

    Tosevska, Anela; Moelzer, Christine; Wallner, Marlies; Janosec, Milan; Schwarz, Ursula; Kern, Carina; Marculescu, Rodrig; Doberer, Daniel; Weckwerth, Wolfram; Wagner, Karl-Heinz

    2016-01-01

    Bilirubin (BR) is a natural endogenous compound with a potent bioactivity. Gilbert’s Syndrome (GS) is a benign hereditary condition of increased unconjugated bilirubin (UCB) in serum and serves as a convenient model for studying the effects of BR in humans. In absence of liver disease, increased UCB levels are inversely associated to all-cause mortality risk, especially from cardiovascular diseases (CVDs). On the other hand, telomere malfunction is linked to a higher risk of CVDs. To our knowledge, there is no data on whether UCB is linked to telomere length in healthy or diseased individuals In the present study we have observed a relationship between mildly increased serum UCB and telomere length. We used an in vivo approach, assessing telomere length in PBMCs from individuals with GS (n = 60) and matched healthy controls (n = 60). An occurrence of longer telomeres was observed in male individuals chronically exposed to increased UCB, as well as in Gunn rats, an animal model of unconjugated hyperbilirubinaemia. Previously identified differences in immunomodulation and redox parameters in individuals with GS, such as IL-6, IL-1β and ferric reducing ability of plasma, were confirmed and proposed as possible contributors to the occurrence of longer telomeres in GS. PMID:26926838

  14. Exposure to Persistent Organic Pollutants Predicts Telomere Length in Older Age: Results from the Helsinki Birth Cohort Study

    PubMed Central

    Guzzardi, Maria Angela; Iozzo, Patricia; Salonen, Minna K.; Kajantie, Eero; Airaksinen, Riikka; Kiviranta, Hannu; Rantakokko, Panu; Eriksson, Johan Gunnar

    2016-01-01

    As the population ages, the occurrence of chronic pathologies becomes more common. Leukocyte telomere shortening associates to ageing and age-related diseases. Recent studies suggest that environmental chemicals can affect telomere length. Persistent organic pollutants (POPs) are most relevant, since they are ingested with foods, and accumulate in the body for a long time. This longitudinal study was undertaken to test if circulating POPs predict telomere length and shortening in elderly people. We studied 1082 subjects belonging to the Helsinki Birth Cohort Study (born 1934-1944), undergoing two visits (2001-2004 and 2011-2014). POPs (oxychlordane, trans-nonachlor, p, p’-DDE, PCB 153, BDE 47, BDE 153) were analysed at baseline. Relative telomere length was measured twice, ’10 years apart, by quantitative real-time PCR. Oxychlordane, trans-nonachlor and PCB-153 levels were significant predictors of telomere length and shortening. In men, we did not find a linear relationship between POPs exposure and telomere shortening. In women, a significant reduction across quartiles categories of oxychlordane and trans-nonachlor exposure was observed. Baseline characteristics of subjects in the highest POPs categories included higher levels of C-reactive protein and fasting glucose, and lower body fat percentage. This is one of few studies combining POPs and telomere length. Our results indicate that exposure to oxychlordane, trans-nonachlor and PCB 153 predicts telomere attrition. This finding is important because concentrations of POPs observed here occur in contemporary younger people, and may contribute to an accelerated ageing. PMID:27699078

  15. Regulation of Telomere Length Requires a Conserved N-Terminal Domain of Rif2 in Saccharomyces cerevisiae.

    PubMed

    Kaizer, Hannah; Connelly, Carla J; Bettridge, Kelsey; Viggiani, Christopher; Greider, Carol W

    2015-10-01

    The regulation of telomere length equilibrium is essential for cell growth and survival since critically short telomeres signal DNA damage and cell cycle arrest. While the broad principles of length regulation are well established, the molecular mechanism of how these steps occur is not fully understood. We mutagenized the RIF2 gene in Saccharomyces cerevisiae to understand how this protein blocks excess telomere elongation. We identified an N-terminal domain in Rif2 that is essential for length regulation, which we have termed BAT domain for Blocks Addition of Telomeres. Tethering this BAT domain to Rap1 blocked telomere elongation not only in rif2Δ mutants but also in rif1Δ and rap1C-terminal deletion mutants. Mutation of a single amino acid in the BAT domain, phenylalanine at position 8 to alanine, recapitulated the rif2Δ mutant phenotype. Substitution of F8 with tryptophan mimicked the wild-type phenylalanine, suggesting the aromatic amino acid represents a protein interaction site that is essential for telomere length regulation.

  16. PSYCHIATRIC DISORDERS AND LEUKOCYTE TELOMERE LENGTH: UNDERLYING MECHANISMS LINKING MENTAL ILLNESS WITH CELLULAR AGING

    PubMed Central

    Lindqvist, Daniel; Epel, Elissa S.; Mellon, Synthia H.; Penninx, Brenda W.; Révész, Dóra; Verhoeven, Josine E.; Reus, Victor I.; Lin, Jue; Mahan, Laura; Hough, Christina M.; Rosser, Rebecca; Bersani, F. Saverio; Blackburn, Elizabeth H.; Wolkowitz, Owen M.

    2015-01-01

    Many psychiatric illnesses are associated with early mortality and with an increased risk of developing physical diseases that are more typically seen in the elderly. Moreover, certain psychiatric illnesses may be associated with accelerated cellular aging, evidenced by shortened leukocyte telomere length (LTL), which could underlie this association. Shortened LTL reflects a cell’s mitotic history and cumulative exposure to inflammation and oxidation as well as the availability of telomerase, a telomere-lengthening enzyme. Critically short telomeres can cause cells to undergo senescence, apoptosis or genomic instability, and shorter LTL correlates with poorer health and predicts mortality. Emerging data suggest that LTL may be reduced in certain psychiatric illnesses, perhaps in proportion to exposure to the psychiatric illnesses, although conflicting data exist. Telomerase has been less well characterized in psychiatric illnesses, but a role in depression and in antidepressant and neurotrophic effects has been suggested by preclinical and clinical studies. In this article, studies on LTL and telomerase activity in psychiatric illnesses are critically reviewed, potential mediators are discussed, and future directions are suggested. A deeper understanding of cellular aging in psychiatric illnesses could lead to re-conceptualizing them as systemic illnesses with manifestations inside and outside the brain and could identify new treatment targets. PMID:25999120

  17. Telomere length in white blood cell DNA and lung cancer: a pooled analysis of three prospective cohorts.

    PubMed

    Seow, Wei Jie; Cawthon, Richard M; Purdue, Mark P; Hu, Wei; Gao, Yu-Tang; Huang, Wen-Yi; Weinstein, Stephanie J; Ji, Bu-Tian; Virtamo, Jarmo; Hosgood, H Dean; Bassig, Bryan A; Shu, Xiao-Ou; Cai, Qiuyin; Xiang, Yong-Bing; Min, Shen; Chow, Wong-Ho; Berndt, Sonja I; Kim, Christopher; Lim, Unhee; Albanes, Demetrius; Caporaso, Neil E; Chanock, Stephen; Zheng, Wei; Rothman, Nathaniel; Lan, Qing

    2014-08-01

    We investigated the relationship between telomere length and lung cancer in a pooled analysis from three prospective cohort studies: the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial, conducted among men and women in the United States, and previously published data from the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Trial conducted among male smokers in Finland, and the Shanghai Women's Health Study (SWHS), which is comprised primarily of never-smokers. The pooled population included 847 cases and 847 controls matched by study, age, and sex. Leukocyte telomere length was measured by a monochrome multiplex qPCR assay. We used conditional logistic regression models to calculate ORs and their 95% confidence intervals (CI) for the association between telomere length and lung cancer risk, adjusted for age and pack-years of smoking. Longer telomere length was associated with increased lung cancer risk in the pooled analysis [OR (95% CI) by quartile: 1.00; 1.24 (0.90-1.71); 1.27 (0.91-1.78); and 1.86 (1.33-2.62); P trend = 0.000022]. Findings were consistent across the three cohorts and strongest for subjects with very long telomere length, i.e., lung cancer risks for telomere length [OR (95% CI)] in the upper half of the fourth quartile were 2.41 (1.28-4.52), 2.16 (1.11-4.23), and 3.02(1.39-6.58) for the PLCO trial, the ATBC trial, and the SWHS, respectively. In addition, the association persisted among cases diagnosed more than 6 years after blood collection and was particularly evident for female adenocarcinoma cases. Telomere length in white blood cell DNA may be a biomarker of future increased risk of lung cancer in diverse populations.

  18. Automated Assay of Telomere Length Measurement and Informatics for 100,000 Subjects in the Genetic Epidemiology Research on Adult Health and Aging (GERA) Cohort

    PubMed Central

    Lapham, Kyle; Kvale, Mark N.; Lin, Jue; Connell, Sheryl; Croen, Lisa A.; Dispensa, Brad P.; Fang, Lynn; Hesselson, Stephanie; Hoffmann, Thomas J.; Iribarren, Carlos; Jorgenson, Eric; Kushi, Lawrence H.; Ludwig, Dana; Matsuguchi, Tetsuya; McGuire, William B.; Miles, Sunita; Quesenberry, Charles P.; Rowell, Sarah; Sadler, Marianne; Sakoda, Lori C.; Smethurst, David; Somkin, Carol P.; Van Den Eeden, Stephen K.; Walter, Lawrence; Whitmer, Rachel A.; Kwok, Pui-Yan; Risch, Neil; Schaefer, Catherine; Blackburn, Elizabeth H.

    2015-01-01

    The Kaiser Permanente Research Program on Genes, Environment, and Health (RPGEH) Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort includes DNA specimens extracted from saliva samples of 110,266 individuals. Because of its relationship to aging, telomere length measurement was considered an important biomarker to develop on these subjects. To assay relative telomere length (TL) on this large cohort over a short time period, we created a novel high throughput robotic system for TL analysis and informatics. Samples were run in triplicate, along with control samples, in a randomized design. As part of quality control, we determined the within-sample variability and employed thresholds for the elimination of outlying measurements. Of 106,902 samples assayed, 105,539 (98.7%) passed all quality control (QC) measures. As expected, TL in general showed a decline with age and a sex difference. While telomeres showed a negative correlation with age up to 75 years, in those older than 75 years, age positively correlated with longer telomeres, indicative of an association of longer telomeres with more years of survival in those older than 75. Furthermore, while females in general had longer telomeres than males, this difference was significant only for those older than age 50. An additional novel finding was that the variance of TL between individuals increased with age. This study establishes reliable assay and analysis methodologies for measurement of TL in large, population-based human studies. The GERA cohort represents the largest currently available such resource, linked to comprehensive electronic health and genotype data for analysis. PMID:26092717

  19. Telomere length is a biomarker of cumulative oxidative stress, biologic age, and an independent predictor of survival and therapeutic treatment requirement associated with smoking behavior.

    PubMed

    Babizhayev, Mark A; Savel'yeva, Ekaterina L; Moskvina, Svetlana N; Yegorov, Yegor E

    2011-11-01

    Globally, tobacco use is associated with 5 million deaths per annum and is regarded as one of the leading causes of premature death. Major chronic disorders associated with smoking include cardiovascular diseases, several types of cancer, and chronic obstructive pulmonary disease (lung problems). Cigarette smoking (CS) generates a cumulative oxidative stress, which may contribute to the pathogenesis of chronic diseases. Mainstream and side stream gas-phase smoke each have about the same concentration of reactive free radical species, about 1 × 10(16) radicals per cigarette (or 5 × 10(14) per puff). This effect is critical in understanding the biologic effects of smoke. Several lines of evidence suggest that cigarette smoke constituents can directly activate vascular reactive oxygen species production. In this work we present multiple evidence that CS provide the important risk factors in many age-related diseases, and is associated with increased cumulative and systemic oxidative stress and inflammation. The cited processes are marked by increased white blood cell (leucocytes, WBCs) turnover. The data suggest an alteration of the circulating WBCs by CS, resulting in increased adherence to endothelial cells. Telomeres are complex DNA-protein structures located at the end of eukaryotic chromosomes. Telomere length shortens with biologic age in all replicating somatic cells. It has been shown that tobacco smoking enhances telomere shortening in circulating human WBCs. Telomere attrition (expressed in WBCs) can serve as a biomarker of the cumulative oxidative stress and inflammation induced by smoking and, consequently, show the pace of biologic aging. We originally propose that patented specific oral formulations of nonhydrolized carnosine and carcinine provide a powerful tool for targeted therapeutic inhibition of cumulative oxidative stress and inflammation and protection of telomere attrition associated with smoking. The longitudinal studies of the clinical

  20. Finding a human telomere DNA-RNA hybrid G-quadruplex formed by human telomeric 6-mer RNA and 16-mer DNA using click chemistry: a protective structure for telomere end.

    PubMed

    Xu, Yan; Suzuki, Yuta; Ishizuka, Takumi; Xiao, Chao-Da; Liu, Xiao; Hayashi, Tetsuya; Komiyama, Makoto

    2014-08-15

    Telomeric repeat-containing RNA is a non-coding RNA molecule newly found in mammalian cells. The telomere RNA has been found to localize to the telomere DNA, but how the newly discovered RNA molecule interacts with telomere DNA is less known. In this study, using the click chemistry we successfully found that a 6-mer human telomere RNA and 16-mer human telomere DNA sequence can form a DNA-RNA hybrid type G-quadruplex structure. Detection of the click-reaction products directly probes DNA-RNA G-quadruplex structures in a complicated solution, whereas traditional methods such as NMR and crystallography may not be suitable. Importantly, we found that formation of DNA-RNA G-quadruplex induced an exonuclease resistance for telomere DNA, indicating that such structures might be important for protecting telomeric DNA from enzyme digestion to avoid telomere DNA shortening. These results provide the direct evidence for formation of DNA-RNA hybrid G-quadruplex structure by human telomere DNA and RNA sequence, suggesting DNA-RNA hybrid G-quadruplex structure associated between telomere DNA and RNA may respond to chromosome end protection and/or present a valuable target for drug design.

  1. Tiptoeing to chromosome tips: facts, promises and perils of today's human telomere biology.

    PubMed Central

    Fajkus, J; Simícková, M; Maláska, J

    2002-01-01

    The past decade has witnessed an explosion of knowledge concerning the structure and function of chromosome terminal structures-telomeres. Today's telomere research has advanced from a pure descriptive approach of DNA and protein components to an elementary understanding of telomere metabolism, and now to promising applications in medicine. These applications include 'passive' ones, among which the use of analysis of telomeres and telomerase (a cellular reverse transcriptase that synthesizes telomeres) for cancer diagnostics is the best known. The 'active' applications involve targeted downregulation or upregulation of telomere synthesis, either to mortalize immortal cancer cells, or to rejuvenate mortal somatic cells and tissues for cellular transplantations, respectively. This article reviews the basic data on structure and function of human telomeres and telomerase, as well as both passive and active applications of human telomere biology. PMID:12028791

  2. Urinary Phthalates and Leukocyte Telomere Length: An Analysis of NHANES 1999–2002

    PubMed Central

    Scinicariello, Franco; Feroe, Aliya G.; Attanasio, Roberta

    2016-01-01

    The International Agency for Research on Cancer classified the di-2-ethylhexyl phthalate (DEHP) as “possibly carcinogenic to humans”. In vitro studies reported that phthalate exposure resulted in induction of several nuclear transcription factors that are activators of telomerase reverse transcriptase (TERT) and telomerase activity of the human telomerase complex. The objective of this study was to determine whether there is an association between urinary phthalate metabolites [mono-ethyl phthalate (MEP), mono-butyl phthalate (MBP), mono-(2-ethyl)-hexyl phthalate (MEHP), and mono-benzyl phthalate (MBzP) and leukocyte telomere length (LTL) in the adult population of the National Health and Nutrition Examination Survey (NHANES) 1999–2002 (n = 2472). After adjustment for potential confounders, participants in the 3rd and 4th quartiles of urinary MEHP had statistically significantly longer LTL (5.34%, 95% CI: 1.31, 9.53; and 7.14%, 95% CI: 2.94, 11.63; respectively) compared to the lowest quartile, with evidence of a dose–response relationship (p-trend = 0.01). The association remained when the analyses were stratified by age groups (20–39 years, 40–59 years, and 60 years and older), and sex. Furthermore, MBP and MBzP were associated with higher LTL in older participants. The age independent association between longer LTL and MEHP (a metabolite of DEHP) might suggest a possible role of MEHP as tumor promoter. PMID:27211552

  3. Preanalytical Conditions and DNA Isolation Methods Affect Telomere Length Quantification in Whole Blood

    PubMed Central

    Tolios, Alexander; Teupser, Daniel; Holdt, Lesca M.

    2015-01-01

    Telomeres are located at chromosome ends and their length (TL) has been associated with aging and human diseases such as cancer. Whole blood DNA is frequently used for TL measurements but the influence of preanalytical conditions and DNA isolation methods on TL quantification has not been thoroughly investigated. To evaluate potential preanalytical as well as methodological bias on TL, anonymized leftover EDTA-whole blood samples were pooled according to leukocyte counts and were incubated with and without actinomycin D to induce apoptosis as a prototype of sample degradation. DNA was isolated from fresh blood pools and after freezing at -80°C. Commercially available kits using beads (Invitrogen), spin columns (Qiagen, Macherey-Nagel and 5prime) or precipitation (Stratec/Invisorb) and a published isopropanol precipitation protocol (IPP) were used for DNA isolation. TL was assessed by qPCR, and normalized to the single copy reference gene 36B4 using two established single-plex and a new multiplex protocol. We show that the method of DNA isolation significantly affected TL (e.g. 1.86-fold longer TL when comparing IPP vs. Invitrogen). Sample degradation led to an average TL decrease of 22% when using all except for one DNA isolation method (5prime). Preanalytical storage conditions did not affect TL with exception of samples that were isolated with the 5prime kit, where a 27% increase in TL was observed after freezing. Finally, performance of the multiplex qPCR protocol was comparable to the single-plex assays, but showed superior time- and cost-effectiveness and required > 80% less DNA. Findings of the current study highlight the need for standardization of whole blood processing and DNA isolation in clinical study settings to avoid preanalytical bias of TL quantification and show that multiplex assays may improve TL/SCG measurements. PMID:26636575

  4. Effect of the anatomical site on telomere length and pref-1 gene expression in bovine adipose tissues.

    PubMed

    Yamada, Tomoya; Higuchi, Mikito; Nakanishi, Naoto

    2015-08-01

    Adipose tissue growth is associated with preadipocyte proliferation and differentiation. Telomere length is a biological marker for cell proliferation. Preadipocyte factor-1 (pref-1) is specifically expressed in preadipocytes and acts as a molecular gatekeeper of adipogenesis. In the present study, we investigated the fat depot-specific differences in telomere length and pref-1 gene expression in various anatomical sites (subcutaneous, intramuscular and visceral) of fattening Wagyu cattle. Visceral adipose tissue expressed higher pref-1 mRNA than did subcutaneous and intramuscular adipose tissues. The telomere length in visceral adipose tissue tended to be longer than that of subcutaneous and intramuscular adipose tissues. The telomere length of adipose tissue was not associated with adipocyte size from three anatomical sites. No significant correlation was found between the pref-1 mRNA level and the subcutaneous adipocyte size. In contrast, the pref-1 mRNA level was negatively correlated with the intramuscular and visceral adipocyte size. These results suggest that anatomical sites of adipose tissue affect the telomere length and expression pattern of the pref-1 gene in a fat depot-specific manner.

  5. Unusual telomeric DNAs in human telomerase-negative immortalized cells.

    PubMed

    Nabetani, Akira; Ishikawa, Fuyuki

    2009-02-01

    A significant fraction of human cancer cells and immortalized cells maintain telomeres in a telomerase-independent manner called alternative lengthening of telomeres (ALT). It has been suggested that ALT involves homologous recombination that is expected to generate unique intermediate DNAs. However, the precise molecular mechanism of ALT is not known. To gain insight into how telomeric DNAs (T-DNAs) are maintained in ALT, we examined the physical structures of T-DNAs in ALT cells. We found abundant single-stranded regions in both G and C strands of T-DNAs. Moreover, two-dimensional gel electrophoreses and native in-gel hybridization analyses revealed novel ALT-specific single-stranded T-DNAs, in addition to previously reported t-circles. These newly identified ALT-specific T-DNAs include (i) the t-complex, which consists of highly branched T-DNAs with large numbers of internal single-stranded portions; (ii) ss-G, which consists of mostly linear single-G-strand T-DNAs; and (iii) ss-C, which consists of most likely circular single-C-strand T-DNAs. Cellular-DNA fractionation by the Hirt protocol revealed that t-circles and ss-G exist in ALT cells as extrachromosomal and chromatin-associated DNAs. We propose that such ALT-specific T-DNAs are produced by telomere metabolism specific to ALT, namely, homologous recombination and the rolling-circle replication mechanism.

  6. Inflammation, But Not Telomere Length, Predicts Successful Ageing at Extreme Old Age: A Longitudinal Study of Semi-supercentenarians.

    PubMed

    Arai, Yasumichi; Martin-Ruiz, Carmen M; Takayama, Michiyo; Abe, Yukiko; Takebayashi, Toru; Koyasu, Shigeo; Suematsu, Makoto; Hirose, Nobuyoshi; von Zglinicki, Thomas

    2015-10-01

    To determine the most important drivers of successful ageing at extreme old age, we combined community-based prospective cohorts: Tokyo Oldest Old Survey on Total Health (TOOTH), Tokyo Centenarians Study (TCS) and Japanese Semi-Supercentenarians Study (JSS) comprising 1554 individuals including 684 centenarians and (semi-)supercentenarians, 167 pairs of centenarian offspring and spouses, and 536 community-living very old (85 to 99 years). We combined z scores from multiple biomarkers to describe haematopoiesis, inflammation, lipid and glucose metabolism, liver function, renal function, and cellular senescence domains. In Cox proportional hazard models, inflammation predicted all-cause mortality with hazard ratios (95% CI) 1.89 (1.21 to 2.95) and 1.36 (1.05 to 1.78) in the very old and (semi-)supercentenarians, respectively. In linear forward stepwise models, inflammation predicted capability (10.8% variance explained) and cognition (8(.)6% variance explained) in (semi-)supercentenarians better than chronologic age or gender. The inflammation score was also lower in centenarian offspring compared to age-matched controls with Δ (95% CI) = - 0.795 (- 1.436 to - 0.154). Centenarians and their offspring were able to maintain long telomeres, but telomere length was not a predictor of successful ageing in centenarians and semi-supercentenarians. We conclude that inflammation is an important malleable driver of ageing up to extreme old age in humans.

  7. Influence of DNA extraction methods on relative telomere length measurements and its impact on epidemiological studies

    PubMed Central

    Raschenberger, Julia; Lamina, Claudia; Haun, Margot; Kollerits, Barbara; Coassin, Stefan; Boes, Eva; Kedenko, Ludmilla; Köttgen, Anna; Kronenberg, Florian

    2016-01-01

    Measurement of telomere length is widely used in epidemiologic studies. Insufficient standardization of the measurements processes has, however, complicated the comparison of results between studies. We aimed to investigate whether DNA extraction methods have an influence on measured values of relative telomere length (RTL) and whether this has consequences for epidemiological studies. We performed four experiments with RTL measurement in quadruplicate by qPCR using DNA extracted with different methods: 1) a standardized validation experiment including three extraction methods (magnetic-particle-method EZ1, salting-out-method INV, phenol-chloroform-isoamyl-alcohol PCI) each in the same 20 samples demonstrated pronounced differences in RTL with lowest values with EZ1 followed by INV and PCI-isolated DNA; 2) a comparison of 307 samples from an epidemiological study showing EZ1-measurements 40% lower than INV-measurements; 3) a matching-approach of two similar non-diseased control groups including 143 pairs of subjects revealed significantly shorter RTL in EZ1 than INV-extracted DNA (0.844 ± 0.157 vs. 1.357 ± 0.242); 4) an association analysis of RTL with prevalent cardiovascular disease detected a stronger association with INV than with EZ1-extracted DNA. In summary, DNA extraction methods have a pronounced influence on the measured RTL-values. This might result in spurious or lost associations in epidemiological studies under certain circumstances. PMID:27138987

  8. Telomere length shows no association with BRCA1 and BRCA2 mutation status.

    PubMed

    Killick, Emma; Tymrakiewicz, Malgorzata; Cieza-Borrella, Clara; Smith, Paula; Thompson, Deborah J; Pooley, Karen A; Easton, Doug F; Bancroft, Elizabeth; Page, Elizabeth; Leongamornlert, Daniel; Kote-Jarai, Zsofia; Eeles, Rosalind A

    2014-01-01

    This study aimed to determine whether telomere length (TL) is a marker of cancer risk or genetic status amongst two cohorts of BRCA1 and BRCA2 mutation carriers and controls. The first group was a prospective set of 665 male BRCA1/2 mutation carriers and controls (mean age 53 years), all healthy at time of enrollment and blood donation, 21 of whom have developed prostate cancer whilst on study. The second group consisted of 283 female BRCA1/2 mutation carriers and controls (mean age 48 years), half of whom had been diagnosed with breast cancer prior to enrollment. TL was quantified by qPCR from DNA extracted from peripheral blood lymphocytes. Weighted and unweighted Cox regressions and linear regression analyses were used to assess whether TL was associated with BRCA1/2 mutation status or cancer risk. We found no evidence for association between developing cancer or being a BRCA1 or BRCA2 mutation carrier and telomere length. It is the first study investigating TL in a cohort of genetically predisposed males and although TL and BRCA status was previously studied in females our results don't support the previous finding of association between hereditary breast cancer and shorter TL. PMID:24489760

  9. Influence of DNA extraction methods on relative telomere length measurements and its impact on epidemiological studies.

    PubMed

    Raschenberger, Julia; Lamina, Claudia; Haun, Margot; Kollerits, Barbara; Coassin, Stefan; Boes, Eva; Kedenko, Ludmilla; Köttgen, Anna; Kronenberg, Florian

    2016-01-01

    Measurement of telomere length is widely used in epidemiologic studies. Insufficient standardization of the measurements processes has, however, complicated the comparison of results between studies. We aimed to investigate whether DNA extraction methods have an influence on measured values of relative telomere length (RTL) and whether this has consequences for epidemiological studies. We performed four experiments with RTL measurement in quadruplicate by qPCR using DNA extracted with different methods: 1) a standardized validation experiment including three extraction methods (magnetic-particle-method EZ1, salting-out-method INV, phenol-chloroform-isoamyl-alcohol PCI) each in the same 20 samples demonstrated pronounced differences in RTL with lowest values with EZ1 followed by INV and PCI-isolated DNA; 2) a comparison of 307 samples from an epidemiological study showing EZ1-measurements 40% lower than INV-measurements; 3) a matching-approach of two similar non-diseased control groups including 143 pairs of subjects revealed significantly shorter RTL in EZ1 than INV-extracted DNA (0.844 ± 0.157 vs. 1.357 ± 0.242); 4) an association analysis of RTL with prevalent cardiovascular disease detected a stronger association with INV than with EZ1-extracted DNA. In summary, DNA extraction methods have a pronounced influence on the measured RTL-values. This might result in spurious or lost associations in epidemiological studies under certain circumstances. PMID:27138987

  10. Longer genotypically-estimated leukocyte telomere length is associated with increased adult glioma risk.

    PubMed

    Walsh, Kyle M; Codd, Veryan; Rice, Terri; Nelson, Christopher P; Smirnov, Ivan V; McCoy, Lucie S; Hansen, Helen M; Elhauge, Edward; Ojha, Juhi; Francis, Stephen S; Madsen, Nils R; Bracci, Paige M; Pico, Alexander R; Molinaro, Annette M; Tihan, Tarik; Berger, Mitchel S; Chang, Susan M; Prados, Michael D; Jenkins, Robert B; Wiemels, Joseph L; Samani, Nilesh J; Wiencke, John K; Wrensch, Margaret R

    2015-12-15

    Telomere maintenance has emerged as an important molecular feature with impacts on adult glioma susceptibility and prognosis. Whether longer or shorter leukocyte telomere length (LTL) is associated with glioma risk remains elusive and is often confounded by the effects of age and patient treatment. We sought to determine if genotypically-estimated LTL is associated with glioma risk and if inherited single nucleotide polymorphisms (SNPs) that are associated with LTL are glioma risk factors. Using a Mendelian randomization approach, we assessed differences in genotypically-estimated relative LTL in two independent glioma case-control datasets from the UCSF Adult Glioma Study (652 patients and 3735 controls) and The Cancer Genome Atlas (478 non-overlapping patients and 2559 controls). LTL estimates were based on a weighted linear combination of subject genotype at eight SNPs, previously associated with LTL in the ENGAGE Consortium Telomere Project. Mean estimated LTL was 31bp (5.7%) longer in glioma patients than controls in discovery analyses (P = 7.82x10-8) and 27bp (5.0%) longer in glioma patients than controls in replication analyses (1.48x10-3). Glioma risk increased monotonically with each increasing septile of LTL (O.R.=1.12; P = 3.83x10-12). Four LTL-associated SNPs were significantly associated with glioma risk in pooled analyses, including those in the telomerase component genes TERC (O.R.=1.14; 95% C.I.=1.03-1.28) and TERT (O.R.=1.39; 95% C.I.=1.27-1.52), and those in the CST complex genes OBFC1 (O.R.=1.18; 95% C.I.=1.05-1.33) and CTC1 (O.R.=1.14; 95% C.I.=1.02-1.28). Future work is needed to characterize the role of the CST complex in gliomagenesis and further elucidate the complex balance between ageing, telomere length, and molecular carcinogenesis.

  11. Longer genotypically-estimated leukocyte telomere length is associated with increased adult glioma risk

    PubMed Central

    Walsh, Kyle M.; Codd, Veryan; Rice, Terri; Nelson, Christopher P.; Smirnov, Ivan V.; McCoy, Lucie S.; Hansen, Helen M.; Elhauge, Edward; Ojha, Juhi; Francis, Stephen S.; Madsen, Nils R.; Bracci, Paige M.; Pico, Alexander R.; Molinaro, Annette M.; Tihan, Tarik; Berger, Mitchel S.; Chang, Susan M.; Prados, Michael D.; Jenkins, Robert B.; Wiemels, Joseph L.; Samani, Nilesh J.; Wiencke, John K.; Wrensch, Margaret R.

    2015-01-01

    Telomere maintenance has emerged as an important molecular feature with impacts on adult glioma susceptibility and prognosis. Whether longer or shorter leukocyte telomere length (LTL) is associated with glioma risk remains elusive and is often confounded by the effects of age and patient treatment. We sought to determine if genotypically-estimated LTL is associated with glioma risk and if inherited single nucleotide polymorphisms (SNPs) that are associated with LTL are glioma risk factors. Using a Mendelian randomization approach, we assessed differences in genotypically-estimated relative LTL in two independent glioma case-control datasets from the UCSF Adult Glioma Study (652 patients and 3735 controls) and The Cancer Genome Atlas (478 non-overlapping patients and 2559 controls). LTL estimates were based on a weighted linear combination of subject genotype at eight SNPs, previously associated with LTL in the ENGAGE Consortium Telomere Project. Mean estimated LTL was 31bp (5.7%) longer in glioma patients than controls in discovery analyses (P = 7.82×10-8) and 27bp (5.0%) longer in glioma patients than controls in replication analyses (1.48×10-3). Glioma risk increased monotonically with each increasing septile of LTL (O.R.=1.12; P = 3.83×10-12). Four LTL-associated SNPs were significantly associated with glioma risk in pooled analyses, including those in the telomerase component genes TERC (O.R.=1.14; 95% C.I.=1.03-1.28) and TERT (O.R.=1.39; 95% C.I.=1.27-1.52), and those in the CST complex genes OBFC1 (O.R.=1.18; 95% C.I.=1.05-1.33) and CTC1 (O.R.=1.14; 95% C.I.=1.02-1.28). Future work is needed to characterize the role of the CST complex in gliomagenesis and further elucidate the complex balance between ageing, telomere length, and molecular carcinogenesis. PMID:26646793

  12. Suppression of OsKu80 results in defects in developmental growth and increased telomere length in rice (Oryza sativa L.).

    PubMed

    Byun, Mi Young; Cui, Li Hua; Kim, Woo Taek

    2015-12-25

    The Ku70-Ku80 heterodimer plays a critical role in the maintenance of genomic stability in humans and yeasts. In this report, we identified and characterized OsKu80 in rice, a model monocot crop. OsKu80 forms a heterodimer with OsKu70 in yeast and plant cells, as demonstrated by yeast two-hybrid, in vivo co-immunoprecipitation, and bimolecular fluorescence complementation assays. RNAi-mediated knock-down T3 transgenic rice plants (Ubi:RNAi-OsKu80) displayed a retarded growth phenotype at the post-germination stage. In addition, the Ubi:RNAi-OsKu80 knock-down progeny exhibited noticeably increased telomere length as compared to wild-type rice. These results are discussed with the idea that OsKu80 plays a role in developmental growth and telomere length regulation in rice plants.

  13. Leukocyte telomere length and prevalence of age-related diseases in semisupercentenarians, centenarians and centenarians' offspring.

    PubMed

    Tedone, Enzo; Arosio, Beatrice; Gussago, Cristina; Casati, Martina; Ferri, Evelyn; Ogliari, Giulia; Ronchetti, Francesco; Porta, Alessandra; Massariello, Francesca; Nicolini, Paola; Mari, Daniela

    2014-10-01

    Centenarians and their offspring are increasingly considered a useful model to study and characterize the mechanisms underlying healthy aging and longevity. The aim of this project is to compare the prevalence of age-related diseases and telomere length (TL), a marker of biological age and mortality, across five groups of subjects: semisupercentenarians (SSCENT) (105-109years old), centenarians (CENT) (100-104years old), centenarians' offspring (CO), age- and gender-matched offspring of parents who both died at an age in line with life expectancy (CT) and age- and gender-matched offspring of both non-long-lived parents (NLO). Information was collected on lifestyle, past and current diseases, medical history and medication use. SSCENT displayed a lower prevalence of acute myocardial infarction (p=0.027), angina (p=0.016) and depression (p=0.021) relative to CENT. CO appeared to be healthier compared to CT who, in turn, displayed a lower prevalence of both arrhythmia (p=0.034) and hypertension (p=0.046) than NLO, characterized by the lowest parental longevity. Interestingly, CO and SSCENT exhibited the longest (p<0.001) and the shortest (p<0.001) telomeres respectively while CENT showed no difference in TL compared to the younger CT and NLO. Our results strengthen the hypothesis that the longevity of parents may influence the health status of their offspring. Moreover, our data also suggest that both CENT and their offspring may be characterized by a better TL maintenance which, in turn, may contribute to their longevity and healthy aging. The observation that SSCENT showed considerable shorter telomeres compared to CENT may suggest a progressive impairment of TL maintenance mechanisms over the transition from centenarian to semisupercentenarian age.

  14. Polychlorinated Biphenyls and Leukocyte Telomere Length: An Analysis of NHANES 1999–2002

    PubMed Central

    Scinicariello, Franco; Buser, Melanie C.

    2015-01-01

    Polychlorinated biphenyls (PCBs) induce the expression of the proto-oncogene c-myc which has a role in cellular growth and proliferation programs. The c-myc up-regulates the telomerase reverse transcriptase which adds the telomeres repeating sequences to the chromosomal ends to compensate for the progressive loss of telomeric sequence. We performed multivariate linear regression to analyze the association of PCBs, polychlorinated dibenzo-p-dioxins, and 1,2,3,4,6,7,8-heptachlorodibenzofuran with leukocyte telomere length (LTL) in the adult population (n = 2413) of the National Health and Nutrition Examination Survey 1999–2002. LTL was natural log-transformed and the results were re-transformed and presented as percent differences. Individuals in the 3rd and 4th quartiles of the sum of PCBs were associated with 8.33% (95% CI: 4.08–13.88) and 11.63% (95% CI: 6.18–17.35) longer LTLs, respectively, compared with the lowest quartile, with evidence of a dose–response relationship (p-trend < 0.01). The association of the sum PCBs with longer LTL was found in both sexes. Additionally, 1,2,3,4,6,7,8-heptachlorodibenzofuran and 1,2,3,6,7,8-hexachlorodibenzo-p-dioxin were associated with longer LTL. The age independent association between longer LTL and environmental exposures to PCBs, 1,2,3,4,6,7,8-heptachlorodibenzofuran and 1,2,3,6,7,8-hexachlorodibenzo-p-dioxin may support a role as tumor promoter of these compounds. Further studies to evaluate the effect of these compounds on LTL are needed to more fully understand the implications of our finding. PMID:26844276

  15. Reduced telomere length in subjects with dementia and diabetes mellitus type 2 is independent of apolipoprotein E4 genotype.

    PubMed

    Kota, Lakshmi Narayanan; Bharath, Srikala; Purushottam, Meera; Paul, Pradip; Sivakumar, Palanimuthu Thangaraju; Varghese, Mathew; Jain, Sanjeev

    2014-12-01

    Apolipoprotein E4 gene is associated with increased risk of dementia with comorbid diabetes mellitus. Both dementia and diabetes mellitus type 2 are independently associated with telomere shortening. We assessed relative telomere length and apolipoprotein E genotype in subjects with dementia (n=70) and cognitively normal control groups (n=55) with and without comorbid diabetes mellitus type 2. Relative telomere length was highest in the control group (Q2=0.91) followed by dementia (Q2=0.48) and dementia with comorbid diabetes mellitus type 2 (Q2=0.39). Apolipoprotein E4 allele frequency was highest in dementia with comorbid diabetes mellitus type 2 (0.26). Apolipoprotein E4 allele was not significantly associated with telomere attrition in both dementia and cognitively normal group irrespective of comorbid diabetes mellitus type 2 (P>0.05). The findings suggest that relative telomere length is unrelated to apolipoprotein E4 genotype in dementia and cognitive normal subjects with or without comorbid diabetes mellitus type 2.

  16. Telomerase inhibitor imetelstat has preclinical activity across the spectrum of non-small cell lung cancer oncogenotypes in a telomere length dependent manner.

    PubMed

    Frink, Robin E; Peyton, Michael; Schiller, Joan H; Gazdar, Adi F; Shay, Jerry W; Minna, John D

    2016-05-31

    Telomerase was evaluated as a therapeutic oncotarget by studying the efficacy of the telomerase inhibitor imetelstat in non-small cell lung cancer (NSCLC) cell lines to determine the range of response phenotypes and identify potential biomarkers of response. A panel of 63 NSCLC cell lines was studied for telomere length and imetelstat efficacy in inhibiting colony formation and no correlation was found with patient characteristics, tumor histology, and oncogenotypes. While there was no overall correlation between imetelstat efficacy with initial telomere length (ranging from 1.5 to 20 kb), the quartile of NSCLC lines with the shortest telomeres was more sensitive than the quartile with the longest telomeres. Continuous long-term treatment with imetelstat resulted in sustained telomerase inhibition, progressive telomere shortening and eventual growth inhibition in a telomere-length dependent manner. Cessation of imetelstat therapy before growth inhibition was followed by telomere regrowth. Likewise, in vivo imetelstat treatment caused tumor xenograft growth inhibition in a telomere-length dependent manner. We conclude from these preclinical studies of telomerase as an oncotarget tested by imetelstat response that imetelstat has efficacy across the entire oncogenotype spectrum of NSCLC, continuous therapy is necessary to prevent telomere regrowth, and short telomeres appears to be the best treatment biomarker.

  17. Prevention Effects Ameliorate the Prospective Association Between Nonsupportive Parenting and Diminished Telomere Length

    PubMed Central

    Yu, Tianyi; Beach, Steven R. H.; Philibert, Robert A.

    2014-01-01

    Telomere length (TL) is an indicator of general systemic aging, with diminished TL associated with several chronic diseases of aging and with heightened mortality risk. Research has begun to focus on the ways in which stress contributes to telomere attrition. The purposes of this study were (a) to establish whether exposure to nonsupportive parenting, defined as high levels of conflict and rancor with low levels of warmth and emotional support, at age 17 would forecast TL 5 years later; and (b) to determine whether participation in an efficacious family-centered prevention program could ameliorate any associations that emerged. Rural African American adolescents participated in the Adults in the Making (AIM) program or a control condition. Primary caregivers provided data on nonsupportive parenting during a pretest when adolescents were age 17. Adolescents provided data on anger at the pretest and at a posttest administered 7 months later. When the youths were age 22, TL was assayed from a blood draw. The results indicated that heightened nonsupportive parenting forecast diminished TL among young adults in the control condition but not among those who participated in AIM; socioeconomic status risk, life stress, and the use of alcohol and cigarettes at age 17, and blood pressure and body mass index at age 22, were controlled. Subsequent exploratory analyses suggested that AIM-induced reductions in adolescents’ anger served as a mediator connecting group assignment to TL. The results suggest that the cellular-level sequelae of nonsupportive parenting and stress are not immutable. PMID:24599483

  18. Prevention effects ameliorate the prospective association between nonsupportive parenting and diminished telomere length.

    PubMed

    Brody, Gene H; Yu, Tianyi; Beach, Steven R H; Philibert, Robert A

    2015-02-01

    Telomere length (TL) is an indicator of general systemic aging, with diminished TL associated with several chronic diseases of aging and with heightened mortality risk. Research has begun to focus on the ways in which stress contributes to telomere attrition. The purposes of this study were (a) to establish whether exposure to nonsupportive parenting, defined as high levels of conflict and rancor with low levels of warmth and emotional support, at age 17 would forecast TL 5 years later; and (b) to determine whether participation in an efficacious family-centered prevention program could ameliorate any associations that emerged. Rural African American adolescents participated in the Adults in the Making (AIM) program or a control condition. Primary caregivers provided data on nonsupportive parenting during a pretest when adolescents were age 17. Adolescents provided data on anger at the pretest and at a posttest administered 7 months later. When the youths were age 22, TL was assayed from a blood draw. The results indicated that heightened nonsupportive parenting forecast diminished TL among young adults in the control condition but not among those who participated in AIM; socioeconomic status risk, life stress, and the use of alcohol and cigarettes at age 17, and blood pressure and body mass index at age 22, were controlled. Subsequent exploratory analyses suggested that AIM-induced reductions in adolescents' anger served as a mediator connecting group assignment to TL. The results suggest that the cellular-level sequelae of nonsupportive parenting and stress are not immutable.

  19. Daily torpor is associated with telomere length change over winter in Djungarian hamsters.

    PubMed

    Turbill, Christopher; Smith, Steve; Deimel, Caroline; Ruf, Thomas

    2012-04-23

    Ageing can progress at different rates according to an individual's physiological state. Natural hypothermia, including torpor and hibernation, is a common adaptation of small mammals to survive intermittent or seasonal declines in environmental conditions. In addition to allowing energy savings, hypothermia and torpor have been associated with retarded ageing and increased longevity. We tested the hypothesis that torpor use slows ageing by measuring changes in the relative telomere length (RTL) of Djungarian hamsters, Phodopus sungorus, a highly seasonal rodent using spontaneous daily torpor, over 180 days of exposure to a short-day photoperiod and warm (approx. 20°C) or cold (approx. 9°C) air temperatures. Multi-model inference showed that change in RTL within individuals was best explained by positive effects of frequency of torpor use, particularly at low body temperatures, as well as the change in body mass and initial RTL. Telomere dynamics have been linked to future survival and proposed as an index of rates of biological ageing. Our results therefore support the hypothesis that daily torpor is associated with physiological changes that increase somatic maintenance and slow the processes of ageing. PMID:21920955

  20. Daily torpor is associated with telomere length change over winter in Djungarian hamsters.

    PubMed

    Turbill, Christopher; Smith, Steve; Deimel, Caroline; Ruf, Thomas

    2012-04-23

    Ageing can progress at different rates according to an individual's physiological state. Natural hypothermia, including torpor and hibernation, is a common adaptation of small mammals to survive intermittent or seasonal declines in environmental conditions. In addition to allowing energy savings, hypothermia and torpor have been associated with retarded ageing and increased longevity. We tested the hypothesis that torpor use slows ageing by measuring changes in the relative telomere length (RTL) of Djungarian hamsters, Phodopus sungorus, a highly seasonal rodent using spontaneous daily torpor, over 180 days of exposure to a short-day photoperiod and warm (approx. 20°C) or cold (approx. 9°C) air temperatures. Multi-model inference showed that change in RTL within individuals was best explained by positive effects of frequency of torpor use, particularly at low body temperatures, as well as the change in body mass and initial RTL. Telomere dynamics have been linked to future survival and proposed as an index of rates of biological ageing. Our results therefore support the hypothesis that daily torpor is associated with physiological changes that increase somatic maintenance and slow the processes of ageing.

  1. Modulation of telomere shelterin by TRF1 [corrected] and TRF2 interacts with telomerase to maintain the telomere length in non-small cell lung cancer.

    PubMed

    Hsu, Chung-Ping; Ko, Jiunn-Liang; Shai, Sen-Ei; Lee, Li-Wen

    2007-12-01

    Our previous report demonstrated good correlations between the expressions of h-TERT and its associated genes, such as c-Myc, TRF1 and TRF2. To observe the interaction between telomerase activity and expression of its associated genes in regulation of the telomere restriction fragment length (TRFL) in non-small cell lung cancer (NSCLC), 79 NSCLC specimens were examined. Telomerase activity, h-TERT, TRF1 and TRF2 genes expression were observed in 60.8, 66.7, 74.7, and 83.5% of the tumour tissues, respectively. The TRFL were shorter in both tumour tissues and telomerase positive tissues, as compared to their counterparts. The t/n-TRFLR (tumour-to-normal TRFL ratio) was also lower in telomerase positive tissues. When telomerase was negative, the t/n-TRFLR was lower in both TRF1 positive and TFR2 positive. However, when telomerase was positive, the t/n-TRFLR was only lower in the TFR2 positive group. When t/n-TRFLR level was equal to or less than 75%, the majority of the specimens became TRF1 and TRF2 positive. To explain these findings, our hypothesis is that when the TRF length becomes shorter during tumour progression, the tumour cells can sustain a better tolerance to shorter telomere with the help of both TRF1 and TRF2, but without immediate activation of the telomerase. However, when the TRF length reaches a critical level, changing the telomere shelterin by persistent expression of the TRF2, which in combination with telomerase activation reverses the telomere shortening.

  2. The OB-fold domain 1 of human POT1 recognizes both telomeric and non-telomeric DNA motifs

    PubMed Central

    Kolar, Carol; Yan, Ying; Borgstahl, Gloria E.O.; Ouellette, Michel M.

    2015-01-01

    The POT1 protein plays a critical role in telomere protection and telomerase regulation. POT1 binds single-stranded 5’-TTAGGGTTAG-3’ and forms a dimer with the TPP1 protein. The dimer is recruited to telomeres, either directly or as part of the Shelterin complex. Human POT1 contains two Oligonucleotide/Oligosaccharide Binding (OB) fold domains, OB1 and OB2, which make physical contact with the DNA. OB1 recognizes 5’-TTAGGG whereas OB2 binds to the downstream TTAG-3’. Studies of POT1 proteins from other species have shown that some of these proteins are able to recognize a broader variety of DNA ligands than expected. To explore this possibility in humans, we have used SELEX to reexamine the sequence-specificity of the protein. Using human POT1 as a selection matrix, high-affinity DNA ligands were selected from a pool of randomized single-stranded oligonucleotides. After six successive rounds of selection, two classes of high-affinity targets were obtained. The first class was composed of oligonucleotides containing a cognate POT1 binding sites (5’-TTAGGGTTAG-3’). The second and more abundant class was made of molecules that carried a novel non-telomeric consensus: 5’-TNCANNAGKKKTTAGG-3’ (where K=G/T and N=any base). Binding studies showed that these non-telomeric sites were made of an OB1-binding motif (TTAGG) and a non-telomeric motif (NT motif), with the two motifs recognized by distinct regions of the OB1 domain. POT1 interacted with these non-telomeric binding sites with high affinity and specificity, even when bound to its dimerization partner TPP1. This intrinsic ability of POT1 to recognize NT motifs raises the possibility that the protein may fulfill additional functions at certain non-telomeric locations of the genome, in perhaps gene transcription, replication, or repair. PMID:25934589

  3. Race-Ethnicity, Poverty, Urban Stressors, and Telomere Length in a Detroit Community-based Sample.

    PubMed

    Geronimus, Arline T; Pearson, Jay A; Linnenbringer, Erin; Schulz, Amy J; Reyes, Angela G; Epel, Elissa S; Lin, Jue; Blackburn, Elizabeth H

    2015-06-01

    Residents of distressed urban areas suffer early aging-related disease and excess mortality. Using a community-based participatory research approach in a collaboration between social researchers and cellular biologists, we collected a unique data set of 239 black, white, or Mexican adults from a stratified, multistage probability sample of three Detroit neighborhoods. We drew venous blood and measured telomere length (TL), an indicator of stress-mediated biological aging, linking respondents' TL to their community survey responses. We regressed TL on socioeconomic, psychosocial, neighborhood, and behavioral stressors, hypothesizing and finding an interaction between poverty and racial-ethnic group. Poor whites had shorter TL than nonpoor whites; poor and nonpoor blacks had equivalent TL; and poor Mexicans had longer TL than nonpoor Mexicans. Findings suggest unobserved heterogeneity bias is an important threat to the validity of estimates of TL differences by race-ethnicity. They point to health impacts of social identity as contingent, the products of structurally rooted biopsychosocial processes.

  4. Association Between Leukocyte Telomere Length and Plasma Homocysteine in a Singapore Chinese Population

    PubMed Central

    Rane, Grishma; Koh, Woon-Puay; Kanchi, Madhu Mathi; Wang, Renwei; Yuan, Jian-Min

    2015-01-01

    Abstract Rationale: Leukocyte telomere length (LTL) and plasma homocysteine (HCY) have been independently associated with cardiovascular disease (CVD) morbidity and mortality. However, few studies have investigated the association between LTL and HCY levels. Objective: This study investigated the association of LTL with CVD risk factors, including HCY, in an overt CVD-free Singapore Chinese population comprised of middle aged and elderly, the age group at risk of developing CVD. Approach: The association of plasma HCY and other CVD biomarkers with LTL were assessed in 100 samples drawn from the Singapore Chinese Health Study (SCHS). SCHS, a population-based cohort, recruited Chinese individuals, aged 45–74 years, between 1993 and 1998. Questionnaire data were collected via face-to-face interviews. Known CVD biomarkers were measured from the blood collected at the time of recruitment, and LTL was measured using the conventional Southern blot method. Results: After adjustment for age, gender, smoking status, education, and dialect, LTL was found to be inversely associated with plasma HCY levels (p for trend=0.014). Serum urate showed a weak association (p for trend=0.056). Other CVD risk factors and nutrients, namely total cholesterol, low-density lipoprotein (LDL), triglycerides and creatinine, high-density lipoprotein (HDL), folate, and vitamin B6 showed the expected trend with LTL, but did not reach statistical significance. Conclusion: LTL displayed an inverse association with plasma HCY. This LTL–HCY inverse association in subjects lacking obvious cardiovascular events suggests that telomere length may be an intermediary in the biological mechanism by which elevated HCY leads to CVD. PMID:25546508

  5. Pesticide Use and Relative Leukocyte Telomere Length in the Agricultural Health Study.

    PubMed

    Andreotti, Gabriella; Hoppin, Jane A; Hou, Lifang; Koutros, Stella; Gadalla, Shahinaz M; Savage, Sharon A; Lubin, Jay; Blair, Aaron; Hoxha, Mirjam; Baccarelli, Andrea; Sandler, Dale; Alavanja, Michael; Beane Freeman, Laura E

    2015-01-01

    Some studies suggest that telomere length (TL) may be influenced by environmental exposures, including pesticides. We examined associations between occupational pesticide use reported at three time points and relative telomere length (RTL) in the Agricultural Health Study (AHS), a prospective cohort study of pesticide applicators in Iowa and North Carolina. RTL was measured by qPCR using leukocyte DNA from 568 cancer-free male AHS participants aged 31-94 years with blood samples collected between 2006 and 2008. Self-reported information, including pesticide use, was collected at three time points: enrollment (1993-1997) and two follow-up questionnaires (1998-2003, 2005-2008). For each pesticide, we evaluated cumulative use (using data from all three questionnaires), and more recent use (using data from the last follow-up questionnaire). Multivariable linear regression was used to examine the associations between pesticide use (ever, lifetime days, intensity-weighted lifetime days (lifetime days*intensity score)) and RTL, adjusting for age at blood draw and use of other pesticides. Of the 57 pesticides evaluated with cumulative use, increasing lifetime days of 2,4-D (p-trend=0.001), diazinon (p-trend=0.002), and butylate (p-trend=0.01) were significantly associated with shorter RTL, while increasing lifetime days of alachlor was significantly associated with longer RTL (p-trend=0.03). Only the association with 2,4-D was significant after adjustment for multiple comparisons. Of the 40 pesticides evaluated for recent use, malathion was associated with shorter RTL (p=0.03), and alachlor with longer RTL (p=0.03). Our findings suggest that leukocyte TL may be impacted by cumulative use and recent use of certain pesticides.

  6. Low estrogen levels and obesity are associated with shorter telomere lengths in pre- and postmenopausal women

    PubMed Central

    Shin, Yun-A; Lee, Kyoung-Young

    2016-01-01

    The aim of this study was to determine whether there is an association between leukocyte telomere length (LTL), and estrogen level, oxidative stress, cardiovascular disease (CVD) risk factors, and cardiorespiratory fitness (CRF) in pre- and postmenopausal obese women. Fifty-four obese women (premenopausal, n=25; postmenopausal, n=29) were selected to participate in this study. The outcome measurements in the pre- and postmenopausal groups were compared using independent t-tests and Pearson correlation analysis. The estrogen level (P<0.001), LTL (P<0.05), high-density lipoprotein level (P<0.05), and CRF (P<0.001) were higher in premenopausal women than in postmenopausal women. The body fat percentage (P<0.05) and triglyceride concentration (P<0.05) were lower in premenopausal women than in postmenopausal women. There were no significant associations between LTL, CVD risk, CRF, and oxidative stress and antioxidant enzyme activity in pre-menopausal women. The body mass index (BMI) and body fat percent-age in postmenopausal women were negatively associated with LTL (P<0.05). When all women were considered (i.e., both pre- and post-menopause), the BMI, percentage of fat, and waist circumference had a negative association with LTL (P<0.05), and estrogen levels were positively associated with LTL (P<0.05). Decreased estrogen levels after menopause, a pivotal factor in the biology of aging, and obesity were more associated with shorter telomere lengths in pre- and postmenopausal women than aerobic capacity and other CVD risk factors. PMID:27419121

  7. Low estrogen levels and obesity are associated with shorter telomere lengths in pre- and postmenopausal women.

    PubMed

    Shin, Yun-A; Lee, Kyoung-Young

    2016-06-01

    The aim of this study was to determine whether there is an association between leukocyte telomere length (LTL), and estrogen level, oxidative stress, cardiovascular disease (CVD) risk factors, and cardiorespiratory fitness (CRF) in pre- and postmenopausal obese women. Fifty-four obese women (premenopausal, n=25; postmenopausal, n=29) were selected to participate in this study. The outcome measurements in the pre- and postmenopausal groups were compared using independent t-tests and Pearson correlation analysis. The estrogen level (P<0.001), LTL (P<0.05), high-density lipoprotein level (P<0.05), and CRF (P<0.001) were higher in premenopausal women than in postmenopausal women. The body fat percentage (P<0.05) and triglyceride concentration (P<0.05) were lower in premenopausal women than in postmenopausal women. There were no significant associations between LTL, CVD risk, CRF, and oxidative stress and antioxidant enzyme activity in pre-menopausal women. The body mass index (BMI) and body fat percent-age in postmenopausal women were negatively associated with LTL (P<0.05). When all women were considered (i.e., both pre- and post-menopause), the BMI, percentage of fat, and waist circumference had a negative association with LTL (P<0.05), and estrogen levels were positively associated with LTL (P<0.05). Decreased estrogen levels after menopause, a pivotal factor in the biology of aging, and obesity were more associated with shorter telomere lengths in pre- and postmenopausal women than aerobic capacity and other CVD risk factors. PMID:27419121

  8. Pesticide Use and Relative Leukocyte Telomere Length in the Agricultural Health Study.

    PubMed

    Andreotti, Gabriella; Hoppin, Jane A; Hou, Lifang; Koutros, Stella; Gadalla, Shahinaz M; Savage, Sharon A; Lubin, Jay; Blair, Aaron; Hoxha, Mirjam; Baccarelli, Andrea; Sandler, Dale; Alavanja, Michael; Beane Freeman, Laura E

    2015-01-01

    Some studies suggest that telomere length (TL) may be influenced by environmental exposures, including pesticides. We examined associations between occupational pesticide use reported at three time points and relative telomere length (RTL) in the Agricultural Health Study (AHS), a prospective cohort study of pesticide applicators in Iowa and North Carolina. RTL was measured by qPCR using leukocyte DNA from 568 cancer-free male AHS participants aged 31-94 years with blood samples collected between 2006 and 2008. Self-reported information, including pesticide use, was collected at three time points: enrollment (1993-1997) and two follow-up questionnaires (1998-2003, 2005-2008). For each pesticide, we evaluated cumulative use (using data from all three questionnaires), and more recent use (using data from the last follow-up questionnaire). Multivariable linear regression was used to examine the associations between pesticide use (ever, lifetime days, intensity-weighted lifetime days (lifetime days*intensity score)) and RTL, adjusting for age at blood draw and use of other pesticides. Of the 57 pesticides evaluated with cumulative use, increasing lifetime days of 2,4-D (p-trend=0.001), diazinon (p-trend=0.002), and butylate (p-trend=0.01) were significantly associated with shorter RTL, while increasing lifetime days of alachlor was significantly associated with longer RTL (p-trend=0.03). Only the association with 2,4-D was significant after adjustment for multiple comparisons. Of the 40 pesticides evaluated for recent use, malathion was associated with shorter RTL (p=0.03), and alachlor with longer RTL (p=0.03). Our findings suggest that leukocyte TL may be impacted by cumulative use and recent use of certain pesticides. PMID:26196902

  9. Segregating YKU80 and TLC1 alleles underlying natural variation in telomere properties in wild yeast.

    PubMed

    Liti, Gianni; Haricharan, Svasti; Cubillos, Francisco A; Tierney, Anna L; Sharp, Sarah; Bertuch, Alison A; Parts, Leopold; Bailes, Elizabeth; Louis, Edward J

    2009-09-01

    In yeast, as in humans, telomere length varies among individuals and is controlled by multiple loci. In a quest to define the extent of variation in telomere length, we screened 112 wild-type Saccharomyces sensu stricto isolates. We found extensive telomere length variation in S. paradoxus isolates. This phenotype correlated with their geographic origin: European strains were observed to have extremely short telomeres (<150 bp), whereas American isolates had telomeres approximately three times as long (>400 bp). Insertions of a URA3 gene near telomeres allowed accurate analysis of individual telomere lengths and telomere position effect (TPE). Crossing the American and European strains resulted in F1 spores with a continuum of telomere lengths consistent with what would be predicted if many quantitative trait loci (QTLs) were involved in length maintenance. Variation in TPE is similarly quantitative but only weakly correlated with telomere length. Genotyping F1 segregants indicated several QTLs associated with telomere length and silencing variation. These QTLs include likely candidate genes but also map to regions where there are no known genes involved in telomeric properties. We detected transgressive segregation for both phenotypes. We validated by reciprocal hemizygosity that YKU80 and TLC1 are telomere-length QTLs in the two S. paradoxus subpopulations. Furthermore, we propose that sequence divergence within the Ku heterodimer generates negative epistasis within one of the allelic combinations (American-YKU70 and European-YKU80) resulting in very short telomeres. PMID:19763176

  10. Organization and Evolution of Drosophila Terminin: Similarities and Differences between Drosophila and Human Telomeres.

    PubMed

    Raffa, Grazia D; Cenci, Giovanni; Ciapponi, Laura; Gatti, Maurizio

    2013-01-01

    Drosophila lacks telomerase and fly telomeres are elongated by occasional transposition of three specialized retroelements. Drosophila telomeres do not terminate with GC-rich repeats and are assembled independently of the sequence of chromosome ends. Recent work has shown that Drosophila telomeres are capped by the terminin complex, which includes the fast-evolving proteins HOAP, HipHop, Moi, and Ver. These proteins, which are not conserved outside Drosophilidae and closely related Diptera, localize and function exclusively at telomeres, protecting them from fusion events. Other proteins required to prevent end-to-end fusion in flies include HP1, Eff/UbcD1, ATM, the components of the Mre11-Rad50-Nbs (MRN) complex, and the Woc transcription factor. These proteins do not share the terminin properties; they are evolutionarily conserved non-fast-evolving proteins that do not accumulate only at telomeres and do not serve telomere-specific functions. We propose that following telomerase loss, Drosophila rapidly evolved terminin to bind chromosome ends in a sequence-independent manner. This hypothesis suggests that terminin is the functional analog of the shelterin complex that protects human telomeres. The non-terminin proteins are instead likely to correspond to ancestral telomere-associated proteins that did not evolve as rapidly as terminin because of the functional constraints imposed by their involvement in diverse cellular processes. Thus, it appears that the main difference between Drosophila and human telomeres is in the protective complexes that specifically associate with the DNA termini. We believe that Drosophila telomeres offer excellent opportunities for investigations on human telomere biology. The identification of additional Drosophila genes encoding non-terminin proteins involved in telomere protection might lead to the discovery of novel components of human telomeres. PMID:23675571

  11. Organization and Evolution of Drosophila Terminin: Similarities and Differences between Drosophila and Human Telomeres

    PubMed Central

    Raffa, Grazia D.; Cenci, Giovanni; Ciapponi, Laura; Gatti, Maurizio

    2013-01-01

    Drosophila lacks telomerase and fly telomeres are elongated by occasional transposition of three specialized retroelements. Drosophila telomeres do not terminate with GC-rich repeats and are assembled independently of the sequence of chromosome ends. Recent work has shown that Drosophila telomeres are capped by the terminin complex, which includes the fast-evolving proteins HOAP, HipHop, Moi, and Ver. These proteins, which are not conserved outside Drosophilidae and closely related Diptera, localize and function exclusively at telomeres, protecting them from fusion events. Other proteins required to prevent end-to-end fusion in flies include HP1, Eff/UbcD1, ATM, the components of the Mre11-Rad50-Nbs (MRN) complex, and the Woc transcription factor. These proteins do not share the terminin properties; they are evolutionarily conserved non-fast-evolving proteins that do not accumulate only at telomeres and do not serve telomere-specific functions. We propose that following telomerase loss, Drosophila rapidly evolved terminin to bind chromosome ends in a sequence-independent manner. This hypothesis suggests that terminin is the functional analog of the shelterin complex that protects human telomeres. The non-terminin proteins are instead likely to correspond to ancestral telomere-associated proteins that did not evolve as rapidly as terminin because of the functional constraints imposed by their involvement in diverse cellular processes. Thus, it appears that the main difference between Drosophila and human telomeres is in the protective complexes that specifically associate with the DNA termini. We believe that Drosophila telomeres offer excellent opportunities for investigations on human telomere biology. The identification of additional Drosophila genes encoding non-terminin proteins involved in telomere protection might lead to the discovery of novel components of human telomeres. PMID:23675571

  12. Organization and Evolution of Drosophila Terminin: Similarities and Differences between Drosophila and Human Telomeres.

    PubMed

    Raffa, Grazia D; Cenci, Giovanni; Ciapponi, Laura; Gatti, Maurizio

    2013-01-01

    Drosophila lacks telomerase and fly telomeres are elongated by occasional transposition of three specialized retroelements. Drosophila telomeres do not terminate with GC-rich repeats and are assembled independently of the sequence of chromosome ends. Recent work has shown that Drosophila telomeres are capped by the terminin complex, which includes the fast-evolving proteins HOAP, HipHop, Moi, and Ver. These proteins, which are not conserved outside Drosophilidae and closely related Diptera, localize and function exclusively at telomeres, protecting them from fusion events. Other proteins required to prevent end-to-end fusion in flies include HP1, Eff/UbcD1, ATM, the components of the Mre11-Rad50-Nbs (MRN) complex, and the Woc transcription factor. These proteins do not share the terminin properties; they are evolutionarily conserved non-fast-evolving proteins that do not accumulate only at telomeres and do not serve telomere-specific functions. We propose that following telomerase loss, Drosophila rapidly evolved terminin to bind chromosome ends in a sequence-independent manner. This hypothesis suggests that terminin is the functional analog of the shelterin complex that protects human telomeres. The non-terminin proteins are instead likely to correspond to ancestral telomere-associated proteins that did not evolve as rapidly as terminin because of the functional constraints imposed by their involvement in diverse cellular processes. Thus, it appears that the main difference between Drosophila and human telomeres is in the protective complexes that specifically associate with the DNA termini. We believe that Drosophila telomeres offer excellent opportunities for investigations on human telomere biology. The identification of additional Drosophila genes encoding non-terminin proteins involved in telomere protection might lead to the discovery of novel components of human telomeres.

  13. Moderate and intense exercise lifestyles attenuate the effects of aging on telomere length and the survival and composition of T cell subpopulations.

    PubMed

    Silva, Léia Cristina Rodrigues; de Araújo, Adriana Ladeira; Fernandes, Juliana Ruiz; Matias, Manuella de Sousa Toledo; Silva, Paulo Roberto; Duarte, Alberto J S; Garcez Leme, Luiz Eugênio; Benard, Gil

    2016-02-01

    Studies indicate that exercise might delay human biological aging, but the effects of long-term exercise on T cell function are not well known. We tested the hypothesis that moderate or intense exercise lifestyle may attenuate the effects of aging on the telomere length and the survival and composition of T cell subpopulations. Elderly (65-85 years) with intense training lifestyle (IT, n = 15), moderate training lifestyle (MT, n = 16), and who never trained (NT, n = 15) were studied. Although the three groups presented the age-associated contraction of the TCD4(+)/TCD8(+) naïve compartments and expansion of the memory compartments, both training modalities were associated with lower proportion of terminally differentiated (CD45RA(+)CCR7(neg)) TCD4(+) and TCD8(+) cells, although among the latter cells, the reduction reached statistical significance only with IT. MT was associated with higher proportion of central memory TCD4(+) cells, while IT was associated with higher proportion of effector memory TCD8(+) cells. However, both training lifestyles were unable to modify the proportion of senescent (CD28(neg)) TCD8(+) cells. Telomeres were longer in T cells in both training groups; with IT, telomere length increased mainly in TCD8(+) cells, whereas with MT, a modest increase in telomere length was observed in both TCD8(+) and TCD4(+) cells. Reduced commitment to apoptosis of resting T cells, as assessed by caspase-3 and Bcl-2 expression, was seen predominantly with IT. Measurement of pro-inflammatory cytokines in serum and peripheral blood mononuclear cell (PBMC)'s supernatants did not show chronic low-grade inflammation in any of the groups. In conclusion, MT and IT lifestyles attenuated some of the effects of aging on the immune system.

  14. Multiple independent variants at the TERT locus are associated with telomere length and risks of breast and ovarian cancer

    PubMed Central

    Bojesen, Stig E; Pooley, Karen A; Johnatty, Sharon E; Beesley, Jonathan; Michailidou, Kyriaki; Tyrer, Jonathan P; Edwards, Stacey L; Pickett, Hilda A; Shen, Howard C; Smart, Chanel E; Hillman, Kristine M; Mai, Phuong L; Lawrenson, Kate; Stutz, Michael D; Lu, Yi; Karevan, Rod; Woods, Nicholas; Johnston, Rebecca L; French, Juliet D; Chen, Xiaoqing; Weischer, Maren; Nielsen, Sune F; Maranian, Melanie J; Ghoussaini, Maya; Ahmed, Shahana; Baynes, Caroline; Bolla, Manjeet K; Wang, Qin; Dennis, Joe; McGuffog, Lesley; Barrowdale, Daniel; Lee, Andrew; Healey, Sue; Lush, Michael; Tessier, Daniel C; Vincent, Daniel; Bacot, Françis; Vergote, Ignace; Lambrechts, Sandrina; Despierre, Evelyn; Risch, Harvey A; González-Neira, Anna; Rossing, Mary Anne; Pita, Guillermo; Doherty, Jennifer A; Álvarez, Nuria; Larson, Melissa C; Fridley, Brooke L; Schoof, Nils; Chang-Claude, Jenny; Cicek, Mine S; Peto, Julian; Kalli, Kimberly R; Broeks, Annegien; Armasu, Sebastian M; Schmidt, Marjanka K; Braaf, Linde M; Winterhoff, Boris; Nevanlinna, Heli; Konecny, Gottfried E; Lambrechts, Diether; Rogmann, Lisa; Guénel, Pascal; Teoman, Attila; Milne, Roger L; Garcia, Joaquin J; Cox, Angela; Shridhar, Vijayalakshmi; Burwinkel, Barbara; Marme, Frederik; Hein, Rebecca; Sawyer, Elinor J; Haiman, Christopher A; Wang-Gohrke, Shan; Andrulis, Irene L; Moysich, Kirsten B; Hopper, John L; Odunsi, Kunle; Lindblom, Annika; Giles, Graham G; Brenner, Hermann; Simard, Jacques; Lurie, Galina; Fasching, Peter A; Carney, Michael E; Radice, Paolo; Wilkens, Lynne R; Swerdlow, Anthony; Goodman, Marc T; Brauch, Hiltrud; García-Closas, Montserrat; Hillemanns, Peter; Winqvist, Robert; Dürst, Matthias; Devilee, Peter; Runnebaum, Ingo; Jakubowska, Anna; Lubinski, Jan; Mannermaa, Arto; Butzow, Ralf; Bogdanova, Natalia V; Dörk, Thilo; Pelttari, Liisa M; Zheng, Wei; Leminen, Arto; Anton-Culver, Hoda; Bunker, Clareann H; Kristensen, Vessela; Ness, Roberta B; Muir, Kenneth; Edwards, Robert; Meindl, Alfons; Heitz, Florian; Matsuo, Keitaro; du Bois, Andreas; Wu, Anna H; Harter, Philipp; Teo, Soo-Hwang; Schwaab, Ira; Shu, Xiao-Ou; Blot, William; Hosono, Satoyo; Kang, Daehee; Nakanishi, Toru; Hartman, Mikael; Yatabe, Yasushi; Hamann, Ute; Karlan, Beth Y; Sangrajrang, Suleeporn; Kjaer, Susanne Krüger; Gaborieau, Valerie; Jensen, Allan; Eccles, Diana; Høgdall, Estrid; Shen, Chen-Yang; Brown, Judith; Woo, Yin Ling; Shah, Mitul; Azmi, Mat Adenan Noor; Luben, Robert; Omar, Siti Zawiah; Czene, Kamila; Vierkant, Robert A; Nordestgaard, Børge G; Flyger, Henrik; Vachon, Celine; Olson, Janet E; Wang, Xianshu; Levine, Douglas A; Rudolph, Anja; Weber, Rachel Palmieri; Flesch-Janys, Dieter; Iversen, Edwin; Nickels, Stefan; Schildkraut, Joellen M; Silva, Isabel Dos Santos; Cramer, Daniel W; Gibson, Lorna; Terry, Kathryn L; Fletcher, Olivia; Vitonis, Allison F; van der Schoot, C Ellen; Poole, Elizabeth M; Hogervorst, Frans B L; Tworoger, Shelley S; Liu, Jianjun; Bandera, Elisa V; Li, Jingmei; Olson, Sara H; Humphreys, Keith; Orlow, Irene; Blomqvist, Carl; Rodriguez-Rodriguez, Lorna; Aittomäki, Kristiina; Salvesen, Helga B; Muranen, Taru A; Wik, Elisabeth; Brouwers, Barbara; Krakstad, Camilla; Wauters, Els; Halle, Mari K; Wildiers, Hans; Kiemeney, Lambertus A; Mulot, Claire; Aben, Katja K; Laurent-Puig, Pierre; van Altena, Anne M; Truong, Thérèse; Massuger, Leon F A G; Benitez, Javier; Pejovic, Tanja; Perez, Jose Ignacio Arias; Hoatlin, Maureen; Zamora, M Pilar; Cook, Linda S; Balasubramanian, Sabapathy P; Kelemen, Linda E; Schneeweiss, Andreas; Le, Nhu D; Sohn, Christof; Brooks-Wilson, Angela; Tomlinson, Ian; Kerin, Michael J; Miller, Nicola; Cybulski, Cezary; Henderson, Brian E; Menkiszak, Janusz; Schumacher, Fredrick; Wentzensen, Nicolas; Marchand, Loic Le; Yang, Hannah P; Mulligan, Anna Marie; Glendon, Gord; Engelholm, Svend Aage; Knight, Julia A; Høgdall, Claus K; Apicella, Carmel; Gore, Martin; Tsimiklis, Helen; Song, Honglin; Southey, Melissa C; Jager, Agnes; van den Ouweland, Ans M W; Brown, Robert; Martens, John W M; Flanagan, James M; Kriege, Mieke; Paul, James; Margolin, Sara; Siddiqui, Nadeem; Severi, Gianluca; Whittemore, Alice S; Baglietto, Laura; McGuire, Valerie; Stegmaier, Christa; Sieh, Weiva; Müller, Heiko; Arndt, Volker; Labrèche, France; Gao, Yu-Tang; Goldberg, Mark S; Yang, Gong; Dumont, Martine; McLaughlin, John R; Hartmann, Arndt; Ekici, Arif B; Beckmann, Matthias W; Phelan, Catherine M; Lux, Michael P; Permuth-Wey, Jenny; Peissel, Bernard; Sellers, Thomas A; Ficarazzi, Filomena; Barile, Monica; Ziogas, Argyrios; Ashworth, Alan; Gentry-Maharaj, Aleksandra; Jones, Michael; Ramus, Susan J; Orr, Nick; Menon, Usha; Pearce, Celeste L; Brüning, Thomas; Pike, Malcolm C; Ko, Yon-Dschun; Lissowska, Jolanta; Figueroa, Jonine; Kupryjanczyk, Jolanta; Chanock, Stephen J; Dansonka-Mieszkowska, Agnieszka; Jukkola-Vuorinen, Arja; Rzepecka, Iwona K; Pylkäs, Katri; Bidzinski, Mariusz; Kauppila, Saila; Hollestelle, Antoinette; Seynaeve, Caroline; Tollenaar, Rob A E M; Durda, Katarzyna; Jaworska, Katarzyna; Hartikainen, Jaana M; Kosma, Veli-Matti; Kataja, Vesa; Antonenkova, Natalia N; Long, Jirong; Shrubsole, Martha; Deming-Halverson, Sandra; Lophatananon, Artitaya; Siriwanarangsan, Pornthep; Stewart-Brown, Sarah; Ditsch, Nina; Lichtner, Peter; Schmutzler, Rita K; Ito, Hidemi; Iwata, Hiroji; Tajima, Kazuo; Tseng, Chiu-Chen; Stram, Daniel O; van den Berg, David; Yip, Cheng Har; Ikram, M Kamran; Teh, Yew-Ching; Cai, Hui; Lu, Wei; Signorello, Lisa B; Cai, Qiuyin; Noh, Dong-Young; Yoo, Keun-Young; Miao, Hui; Iau, Philip Tsau-Choong; Teo, Yik Ying; McKay, James; Shapiro, Charles; Ademuyiwa, Foluso; Fountzilas, George; Hsiung, Chia-Ni; Yu, Jyh-Cherng; Hou, Ming-Feng; Healey, Catherine S; Luccarini, Craig; Peock, Susan; Stoppa-Lyonnet, Dominique; Peterlongo, Paolo; Rebbeck, Timothy R; Piedmonte, Marion; Singer, Christian F; Friedman, Eitan; Thomassen, Mads; Offit, Kenneth; Hansen, Thomas V O; Neuhausen, Susan L; Szabo, Csilla I; Blanco, Ignacio; Garber, Judy; Narod, Steven A; Weitzel, Jeffrey N; Montagna, Marco; Olah, Edith; Godwin, Andrew K; Yannoukakos, Drakoulis; Goldgar, David E; Caldes, Trinidad; Imyanitov, Evgeny N; Tihomirova, Laima; Arun, Banu K; Campbell, Ian; Mensenkamp, Arjen R; van Asperen, Christi J; van Roozendaal, Kees E P; Meijers-Heijboer, Hanne; Collée, J Margriet; Oosterwijk, Jan C; Hooning, Maartje J; Rookus, Matti A; van der Luijt, Rob B; van Os, Theo A M; Evans, D Gareth; Frost, Debra; Fineberg, Elena; Barwell, Julian; Walker, Lisa; Kennedy, M John; Platte, Radka; Davidson, Rosemarie; Ellis, Steve D; Cole, Trevor; Paillerets, Brigitte Bressac-de; Buecher, Bruno; Damiola, Francesca; Faivre, Laurence; Frenay, Marc; Sinilnikova, Olga M; Caron, Olivier; Giraud, Sophie; Mazoyer, Sylvie; Bonadona, Valérie; Caux-Moncoutier, Virginie; Toloczko-Grabarek, Aleksandra; Gronwald, Jacek; Byrski, Tomasz; Spurdle, Amanda B; Bonanni, Bernardo; Zaffaroni, Daniela; Giannini, Giuseppe; Bernard, Loris; Dolcetti, Riccardo; Manoukian, Siranoush; Arnold, Norbert; Engel, Christoph; Deissler, Helmut; Rhiem, Kerstin; Niederacher, Dieter; Plendl, Hansjoerg; Sutter, Christian; Wappenschmidt, Barbara; Borg, Åke; Melin, Beatrice; Rantala, Johanna; Soller, Maria; Nathanson, Katherine L; Domchek, Susan M; Rodriguez, Gustavo C; Salani, Ritu; Kaulich, Daphne Gschwantler; Tea, Muy-Kheng; Paluch, Shani Shimon; Laitman, Yael; Skytte, Anne-Bine; Kruse, Torben A; Jensen, Uffe Birk; Robson, Mark; Gerdes, Anne-Marie; Ejlertsen, Bent; Foretova, Lenka; Savage, Sharon A; Lester, Jenny; Soucy, Penny; Kuchenbaecker, Karoline B; Olswold, Curtis; Cunningham, Julie M; Slager, Susan; Pankratz, Vernon S; Dicks, Ed; Lakhani, Sunil R; Couch, Fergus J; Hall, Per; Monteiro, Alvaro N A; Gayther, Simon A; Pharoah, Paul D P; Reddel, Roger R; Goode, Ellen L; Greene, Mark H; Easton, Douglas F; Berchuck, Andrew; Antoniou, Antonis C; Chenevix-Trench, Georgia; Dunning, Alison M

    2013-01-01

    TERT-locus single nucleotide polymorphisms (SNPs) and leucocyte telomere measures are reportedly associated with risks of multiple cancers. Using the iCOGs chip, we analysed ~480 TERT-locus SNPs in breast (n=103,991), ovarian (n=39,774) and BRCA1 mutation carrier (11,705) cancer cases and controls. 53,724 participants have leucocyte telomere measures. Most associations cluster into three independent peaks. Peak 1 SNP rs2736108 minor allele associates with longer telomeres (P=5.8×10−7), reduced estrogen receptor negative (ER-negative) (P=1.0×10−8) and BRCA1 mutation carrier (P=1.1×10−5) breast cancer risks, and altered promoter-assay signal. Peak 2 SNP rs7705526 minor allele associates with longer telomeres (P=2.3×10−14), increased low malignant potential ovarian cancer risk (P=1.3×10−15) and increased promoter activity. Peak 3 SNPs rs10069690 and rs2242652 minor alleles increase ER-negative (P=1.2×10−12) and BRCA1 mutation carrier (P=1.6×10−14) breast and invasive ovarian (P=1.3×10−11) cancer risks, but not via altered telomere length. The cancer-risk alleles of rs2242652 and rs10069690 respectively increase silencing and generate a truncated TERT splice-variant. PMID:23535731

  15. Are the leukocyte telomere length attrition and telomerase activity alteration potential predictor biomarkers for sporadic TAA in aged individuals?

    PubMed

    Balistreri, Carmela R; Pisano, Calogera; Martorana, Adriana; Triolo, Oreste F; Lio, Domenico; Candore, Giuseppina; Ruvolo, Giovanni

    2014-01-01

    A large variability in occurrence, complications, and age/gender manifestations characterizes individual susceptibility of sporadic thoracic aortic aneurysms (TAA), even in subjects with the same risk factor profiles. The reasons are poorly understood. On the other hand, TAA pathophysiology mechanisms remain unclear than those involved in abdominal aorta aneurysms. However, recent evidence is suggesting a crucial role of biological ageing in inter-individual risk variation of cardiovascular diseases, including sporadic TAA. Biological age rather than chronological age is a better predictor of vascular risk. Relevant assumptions support this concept. In confirming this evidence and our preliminary data, the mean of blood leukocyte telomere length, through use of terminal restriction fragment assay and in blood samples from sporadic TAA patients and controls, was examined. Telomerase activity was also analyzed in two groups. In addition, we verified the weight of genetic inflammatory variants and the major TAA risk factors in telomere/telomerase impairment. Aorta histopathological abnormalities and systemic inflammatory mediators were ultimately correlated with telomere/telomerase impairment. Data obtained demonstrated shorter telomeres and a reduced telomerase activity in TAA patients significantly associated with a genetic inflammatory risk profile, age, gender, smoking, hypertension, a histopathological phenotype, and higher levels of systemic inflammatory mediators than controls. In conclusion, telomere and telomerase activity's detection might be used as predictor biomarkers of sporadic TAA. Their impairment also suggests a strong role of vascular ageing in sporadic TAA, evocated by both environmental and genetic inflammatory factors.

  16. Effects of Unpredictable Variable Prenatal Stress (UVPS) on Bdnf DNA Methylation and Telomere Length in the Adult Rat Brain

    NASA Technical Reports Server (NTRS)

    Blaze, Jennifer; Asok, A.; Moyer, E. L.; Roth, T. L.; Ronca, A. E.

    2015-01-01

    In utero exposure to stress can shape neurobiological and behavioral outcomes in offspring, producing vulnerability to psychopathology later in life. Animal models of prenatal stress likewise have demonstrated long-­-term alterations in brain function and behavioral deficits in offspring. For example, using a rodent model of unpredictable variable prenatal stress (UVPS), in which dams are exposed to unpredictable, variable stress across pregnancy, we have found increased body weight and anxiety-­-like behavior in adult male, but not female, offspring. DNA methylation (addition of methyl groups to cytosines which normally represses gene transcription) and changes in telomere length (TTAGGG repeats on the ends of chromosomes) are two molecular modifications that result from stress and could be responsible for the long-­-term effects of UVPS. Here, we measured methylation of brain-­-derived neurotrophic factor (bdnf), a gene important in development and plasticity, and telomere length in the brains of adult offspring from the UVPS model. Results indicate that prenatally stressed adult males have greater methylation in the medial prefrontal cortex (mPFC) compared to non-­-stressed controls, while females have greater methylation in the ventral hippocampus compared to controls. Further, prenatally stressed males had shorter telomeres than controls in the mPFC. These findings demonstrate the ability of UVPS to produce epigenetic alterations and changes in telomere length across behaviorally-­-relevant brain regions, which may have linkages to the phenotypic outcomes.

  17. The Association between Telomere Length and Cancer Prognosis: Evidence from a Meta-Analysis

    PubMed Central

    Li, Lu; Zhou, Ying; Wang, Chao; Hou, Shuxun

    2015-01-01

    Background Telomeres are essential for chromosomal integrity and stability. Shortened telomere length (TL) has been associated with risk of cancers and aging-related diseases. Several studies have explored associations between TL and cancer prognosis, but the results are conflicting. Methods Prospective studies on the relationship between TL and cancer survival were identified by a search of PubMed up to May 25, 2015. There were no restrictions on the cancer type or DNA source. The quality of the included studies was assessed using the Newcastle-Ottawa Scale. Meta-analysis approaches were conducted to determine pooled relative risks and 95% confidence intervals. Results Thirty-three articles containing forty-five independent studies were ultimately involved in our meta-analysis, of which twenty-seven were about overall cancer survival and eighteen were about cancer progression. Short TL was associated with increased cancer mortality risk (RR = 1.30, 95%CI: 1.06–1.59) and poor cancer progression (RR = 1.44, 95%CI: 1.10–1.88), both with high levels of heterogeneity (I2 = 83.5%, P = 0.012for overall survival and I2 = 75.4%, P = 0.008 for progression). TL was an independent predictor of overall cancer survival and progression in chronic lymphocytic leukemia. Besides, short telomeres were also associated with increased colorectal cancer mortality and decreased overall survival of esophageal cancer, but not in other cancers. Cancer progression was associated with TL in Asian and America populations and short TL predicted poor cancer survival in older populations. Compared with tumor tissue cells, TL in blood lymphocyte cells was better for prediction. In addition, the associations remained significant when restricted to studies with adjustments for age, with larger sample sizes, measuring TL using southern blotting or estimating risk effects by hazard ratios. Conclusion Short TL demonstrated a significant association with poor cancer survival, suggesting the

  18. Genetic determinants of telomere length and risk of common cancers: a Mendelian randomization study.

    PubMed

    Zhang, Chenan; Doherty, Jennifer A; Burgess, Stephen; Hung, Rayjean J; Lindström, Sara; Kraft, Peter; Gong, Jian; Amos, Christopher I; Sellers, Thomas A; Monteiro, Alvaro N A; Chenevix-Trench, Georgia; Bickeböller, Heike; Risch, Angela; Brennan, Paul; Mckay, James D; Houlston, Richard S; Landi, Maria Teresa; Timofeeva, Maria N; Wang, Yufei; Heinrich, Joachim; Kote-Jarai, Zsofia; Eeles, Rosalind A; Muir, Ken; Wiklund, Fredrik; Grönberg, Henrik; Berndt, Sonja I; Chanock, Stephen J; Schumacher, Fredrick; Haiman, Christopher A; Henderson, Brian E; Amin Al Olama, Ali; Andrulis, Irene L; Hopper, John L; Chang-Claude, Jenny; John, Esther M; Malone, Kathleen E; Gammon, Marilie D; Ursin, Giske; Whittemore, Alice S; Hunter, David J; Gruber, Stephen B; Knight, Julia A; Hou, Lifang; Le Marchand, Loic; Newcomb, Polly A; Hudson, Thomas J; Chan, Andrew T; Li, Li; Woods, Michael O; Ahsan, Habibul; Pierce, Brandon L

    2015-09-15

    Epidemiological studies have reported inconsistent associations between telomere length (TL) and risk for various cancers. These inconsistencies are likely attributable, in part, to biases that arise due to post-diagnostic and post-treatment TL measurement. To avoid such biases, we used a Mendelian randomization approach and estimated associations between nine TL-associated SNPs and risk for five common cancer types (breast, lung, colorectal, ovarian and prostate cancer, including subtypes) using data on 51 725 cases and 62 035 controls. We then used an inverse-variance weighted average of the SNP-specific associations to estimate the association between a genetic score representing long TL and cancer risk. The long TL genetic score was significantly associated with increased risk of lung adenocarcinoma (P = 6.3 × 10(-15)), even after exclusion of a SNP residing in a known lung cancer susceptibility region (TERT-CLPTM1L) P = 6.6 × 10(-6)). Under Mendelian randomization assumptions, the association estimate [odds ratio (OR) = 2.78] is interpreted as the OR for lung adenocarcinoma corresponding to a 1000 bp increase in TL. The weighted TL SNP score was not associated with other cancer types or subtypes. Our finding that genetic determinants of long TL increase lung adenocarcinoma risk avoids issues with reverse causality and residual confounding that arise in observational studies of TL and disease risk. Under Mendelian randomization assumptions, our finding suggests that longer TL increases lung adenocarcinoma risk. However, caution regarding this causal interpretation is warranted in light of the potential issue of pleiotropy, and a more general interpretation is that SNPs influencing telomere biology are also implicated in lung adenocarcinoma risk.

  19. Association of Leukocyte Telomere Length with Oxidative Stress in Yoga Practitioners

    PubMed Central

    Keerthi, Gorantla Shravya; Kumar, Chintala Kiran; Reddy, Natham Mallikarjuna

    2015-01-01

    Objective: Yoga is a mind-body modulation technique that has been shown to have beneficial effects on various diseases related to various systems in the body. However, the molecular basis of mechanism of action is not clear. Hence, this study was designed to study the leukocyte telomere biology and its relation with homocysteine and oxidative stress in yoga practitioners. Materials and Methods: This is a prospective case-control study involving Yoga practitioners aged 30–40 y with minimum of two years yoga practice (Yoga group) and age, gender and body mass index matched sedentary healthy general population with no medical problems (Control group). Leukocyte telomere length (LTL) was measured by using quantitative PCR (qPCR), fasting plasma homocysteine was measured by a rapid high-performance liquid chromatography assay and the oxidative stress was assessed with total antioxidant status (TAOS), malondialdehyde (MDA) measured by calorimetry. Results: The LTL was shorter in control group than in yoga group (p<0.001). The TAOS was more in yoga group when compared to control group (p=0.008), MDA and homocysteine was high in control group when compared to Yoga group (p<0.001). Further, the LTL was positively correlated with TAOS (r=0.841, p<0.001) and negatively correlated with MDA (r=-0.931, p<0.001) and Homocysteine (r=-0.756, p<0.001). Conclusion: The LTL is well-preserved in people who practice Yoga regularly with lower systemic oxidative stress compared to those who have a relatively sedentary lifestyle despite lack of any medical disorders. The habitual yoga practice seems to inhibit replicative cellular senescence. PMID:25954614

  20. Employment and work schedule are related to telomere length in women

    PubMed Central

    Parks, C G; DeRoo, L A; Miller, D B; McCanlies, E C; Cawthon, R M; Sandler, D P

    2011-01-01

    Objectives To examine the association of employment and work schedule with shorter DNA telomeres, a marker of cellular ageing and disease risk factor, and consider whether differences were related to health, behaviours and sociodemographic factors, or varied by stress levels or menopausal status. Methods This cross-sectional analysis of 608 women aged 35–74 in the Sister Study examined determinants of relative telomere length (rTL) measured by quantitative PCR in leucocyte DNA. Age-adjusted regression models estimated base pair (bp) rTL differences for current and lifetime schedule characteristics (ie, part-time, full-time or overtime hours; multiple jobs; irregular hours; shiftwork; work at night). Covariates included race, smoking, perceived stress, sleep, physical activity, health and menopausal status, education, marital status, live births, children under 18, measured body mass index and urinary stress hormones. Results Compared with non-employed women with moderate or substantial past work histories (n=190), those currently working full-time (n=247; median 40 h/week) had a shorter rTL, an age-adjusted difference of −329 bp (95% CI −110 to −548). Longer-duration full-time work was also associated with shorter rTL (age-adjusted difference of −472 bp, 95% CI −786 to −158 for 20+ vs 1–5 years). Findings were not explained by health and demographic covariates. However, rTL differences for working at least full-time were greater in women with higher stress and epinephrine levels. Conclusions Current and long-term full-time work were associated with shorter rTL, with differences of similar magnitude to smoking and history of heart disease or diabetes. Longitudinal data with specific stress measures are needed to further evaluate the impact of work schedule on rTL. PMID:21540175

  1. Genetic determinants of telomere length and risk of common cancers: a Mendelian randomization study

    PubMed Central

    Zhang, Chenan; Doherty, Jennifer A.; Burgess, Stephen; Hung, Rayjean J.; Lindström, Sara; Kraft, Peter; Gong, Jian; Amos, Christopher I.; Sellers, Thomas A.; Monteiro, Alvaro N.A.; Chenevix-Trench, Georgia; Bickeböller, Heike; Risch, Angela; Brennan, Paul; Mckay, James D.; Houlston, Richard S.; Landi, Maria Teresa; Timofeeva, Maria N.; Wang, Yufei; Heinrich, Joachim; Kote-Jarai, Zsofia; Eeles, Rosalind A.; Muir, Ken; Wiklund, Fredrik; Grönberg, Henrik; Berndt, Sonja I.; Chanock, Stephen J.; Schumacher, Fredrick; Haiman, Christopher A.; Henderson, Brian E.; Amin Al Olama, Ali; Andrulis, Irene L.; Hopper, John L.; Chang-Claude, Jenny; John, Esther M.; Malone, Kathleen E.; Gammon, Marilie D.; Ursin, Giske; Whittemore, Alice S.; Hunter, David J.; Gruber, Stephen B.; Knight, Julia A.; Hou, Lifang; Le Marchand, Loic; Newcomb, Polly A.; Hudson, Thomas J.; Chan, Andrew T.; Li, Li; Woods, Michael O.; Ahsan, Habibul; Pierce, Brandon L.

    2015-01-01

    Epidemiological studies have reported inconsistent associations between telomere length (TL) and risk for various cancers. These inconsistencies are likely attributable, in part, to biases that arise due to post-diagnostic and post-treatment TL measurement. To avoid such biases, we used a Mendelian randomization approach and estimated associations between nine TL-associated SNPs and risk for five common cancer types (breast, lung, colorectal, ovarian and prostate cancer, including subtypes) using data on 51 725 cases and 62 035 controls. We then used an inverse-variance weighted average of the SNP-specific associations to estimate the association between a genetic score representing long TL and cancer risk. The long TL genetic score was significantly associated with increased risk of lung adenocarcinoma (P = 6.3 × 10−15), even after exclusion of a SNP residing in a known lung cancer susceptibility region (TERT-CLPTM1L) P = 6.6 × 10−6). Under Mendelian randomization assumptions, the association estimate [odds ratio (OR) = 2.78] is interpreted as the OR for lung adenocarcinoma corresponding to a 1000 bp increase in TL. The weighted TL SNP score was not associated with other cancer types or subtypes. Our finding that genetic determinants of long TL increase lung adenocarcinoma risk avoids issues with reverse causality and residual confounding that arise in observational studies of TL and disease risk. Under Mendelian randomization assumptions, our finding suggests that longer TL increases lung adenocarcinoma risk. However, caution regarding this causal interpretation is warranted in light of the potential issue of pleiotropy, and a more general interpretation is that SNPs influencing telomere biology are also implicated in lung adenocarcinoma risk. PMID:26138067

  2. Genetic determinants of telomere length and risk of common cancers: a Mendelian randomization study.

    PubMed

    Zhang, Chenan; Doherty, Jennifer A; Burgess, Stephen; Hung, Rayjean J; Lindström, Sara; Kraft, Peter; Gong, Jian; Amos, Christopher I; Sellers, Thomas A; Monteiro, Alvaro N A; Chenevix-Trench, Georgia; Bickeböller, Heike; Risch, Angela; Brennan, Paul; Mckay, James D; Houlston, Richard S; Landi, Maria Teresa; Timofeeva, Maria N; Wang, Yufei; Heinrich, Joachim; Kote-Jarai, Zsofia; Eeles, Rosalind A; Muir, Ken; Wiklund, Fredrik; Grönberg, Henrik; Berndt, Sonja I; Chanock, Stephen J; Schumacher, Fredrick; Haiman, Christopher A; Henderson, Brian E; Amin Al Olama, Ali; Andrulis, Irene L; Hopper, John L; Chang-Claude, Jenny; John, Esther M; Malone, Kathleen E; Gammon, Marilie D; Ursin, Giske; Whittemore, Alice S; Hunter, David J; Gruber, Stephen B; Knight, Julia A; Hou, Lifang; Le Marchand, Loic; Newcomb, Polly A; Hudson, Thomas J; Chan, Andrew T; Li, Li; Woods, Michael O; Ahsan, Habibul; Pierce, Brandon L

    2015-09-15

    Epidemiological studies have reported inconsistent associations between telomere length (TL) and risk for various cancers. These inconsistencies are likely attributable, in part, to biases that arise due to post-diagnostic and post-treatment TL measurement. To avoid such biases, we used a Mendelian randomization approach and estimated associations between nine TL-associated SNPs and risk for five common cancer types (breast, lung, colorectal, ovarian and prostate cancer, including subtypes) using data on 51 725 cases and 62 035 controls. We then used an inverse-variance weighted average of the SNP-specific associations to estimate the association between a genetic score representing long TL and cancer risk. The long TL genetic score was significantly associated with increased risk of lung adenocarcinoma (P = 6.3 × 10(-15)), even after exclusion of a SNP residing in a known lung cancer susceptibility region (TERT-CLPTM1L) P = 6.6 × 10(-6)). Under Mendelian randomization assumptions, the association estimate [odds ratio (OR) = 2.78] is interpreted as the OR for lung adenocarcinoma corresponding to a 1000 bp increase in TL. The weighted TL SNP score was not associated with other cancer types or subtypes. Our finding that genetic determinants of long TL increase lung adenocarcinoma risk avoids issues with reverse causality and residual confounding that arise in observational studies of TL and disease risk. Under Mendelian randomization assumptions, our finding suggests that longer TL increases lung adenocarcinoma risk. However, caution regarding this causal interpretation is warranted in light of the potential issue of pleiotropy, and a more general interpretation is that SNPs influencing telomere biology are also implicated in lung adenocarcinoma risk. PMID:26138067

  3. Effect of vegetable consumption on the association between peripheral leucocyte telomere length and hypertension: a case–control study

    PubMed Central

    Lian, Fuzhi; Wang, Jinquan; Huang, Xianhong; Wu, Yinyin; Cao, Yifei; Tan, Xiaohua; Xu, Xianrong; Hong, Yu; Yang, Lei; Gao, Xiang

    2015-01-01

    Objectives Peripheral leucocyte telomere length has been suggested to be inversely associated with hypertension risk. Both telomere length and hypertension risk can be modified by certain dietary factors, such as fruit and vegetables. This study was to examine the potential effect of these dietary factors on the association between telomere length and hypertension risk. Study design A community-based case–control study. Participants 271 hypertensive patients and 455 normotensive controls aged 40–70 years and living in Yinzhou, Zhejiang Province, China. Outcome measures Peripheral leucocyte relative telomere length (RTL) was measured using quantitative real-time PCR. Dietary intake was assessed by a brief semiquantitative food frequency questionnaire. The association between RTL and hypertension risk was analysed using logistic regression, and the modulatory effect of dietary intake on RTL-related hypertension risk was analysed using likelihood ratio tests. Results Among controls, longer age-adjusted RTL was associated with higher vegetable intake (p=0.01). Individuals with longer age-adjusted RTL (based on median value) were 30% less likely to have hypertension (OR=0.70, 95% CI 0.52 to 0.96; p=0.03). The observed RTL-hypertension relationship appeared to be modified by vegetable intake—longer RTL was significantly associated with lower hypertension risk only in those with greater vegetable consumption (OR=0.28, 95% CI 0.14 to 0.57; p<0.001), but not in those with lower vegetable intake (P-interaction=0.008). Conclusions Certain dietary factors might modify telomere-related hypertension risk. PMID:26560064

  4. Mechanochemical properties of individual human telomeric RNA (TERRA) G-quadruplexes.

    PubMed

    Yangyuoru, Philip M; Zhang, Amy Y Q; Shi, Zhe; Koirala, Deepak; Balasubramanian, Shankar; Mao, Hanbin

    2013-10-11

    Potential functions: By following the unfolding and refolding of individual human RNA telomeric (TERRA) G-quadruplexes (GQs) in laser tweezers, the mechanical stability and transition kinetics of RNA GQs are obtained. Comparison between TERRA and DNA GQs suggests their different regulatory capacities for processes associated with human telomeres.

  5. Empirical evaluation of humpback whale telomere length estimates; quality control and factors causing variability in the singleplex and multiplex qPCR methods

    PubMed Central

    2012-01-01

    Background Telomeres, the protective cap of chromosomes, have emerged as powerful markers of biological age and life history in model and non-model species. The qPCR method for telomere length estimation is one of the most common methods for telomere length estimation, but has received recent critique for being too error-prone and yielding unreliable results. This critique coincides with an increasing awareness of the potentials and limitations of the qPCR technique in general and the proposal of a general set of guidelines (MIQE) for standardization of experimental, analytical, and reporting steps of qPCR. In order to evaluate the utility of the qPCR method for telomere length estimation in non-model species, we carried out four different qPCR assays directed at humpback whale telomeres, and subsequently performed a rigorous quality control to evaluate the performance of each assay. Results Performance differed substantially among assays and only one assay was found useful for telomere length estimation in humpback whales. The most notable factors causing these inter-assay differences were primer design and choice of using singleplex or multiplex assays. Inferred amplification efficiencies differed by up to 40% depending on assay and quantification method, however this variation only affected telomere length estimates in the worst performing assays. Conclusion Our results suggest that seemingly well performing qPCR assays may contain biases that will only be detected by extensive quality control. Moreover, we show that the qPCR method for telomere length estimation can be highly precise and accurate, and thus suitable for telomere measurement in non-model species, if effort is devoted to optimization at all experimental and analytical steps. We conclude by highlighting a set of quality controls which may serve for further standardization of the qPCR method for telomere length estimation, and discuss some of the factors that may cause variation in qPCR experiments

  6. TERRA, hnRNP A1, and DNA-PKcs Interactions at Human Telomeres.

    PubMed

    Le, Phuong N; Maranon, David G; Altina, Noelia H; Battaglia, Christine L R; Bailey, Susan M

    2013-01-01

    Maintenance of telomeres, repetitive elements at eukaryotic chromosomal termini, and the end-capping structure and function they provide, are imperative for preserving genome integrity and stability. The discovery that telomeres are transcribed into telomere repeat containing RNA (TERRA) has revolutionized our view of this repetitive, rather unappreciated region of the genome. We have previously shown that the non-homologous end-joining, shelterin associated DNA dependent protein kinase catalytic subunit (DNA-PKcs) participates in mammalian telomeric end-capping, exclusively at telomeres created by leading-strand synthesis. Here, we explore potential roles of DNA-PKcs and its phosphorylation target heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) in the localization of TERRA at human telomeres. Evaluation of co-localized foci utilizing RNA-FISH and three-dimensional (3D) reconstruction strategies provided evidence that both inhibition of DNA-PKcs kinase activity and siRNA depletion of hnRNP A1 result in accumulation of TERRA at individual telomeres; depletion of hnRNP A1 also resulted in increased frequencies of fragile telomeres. These observations are consistent with previous demonstrations that decreased levels of the nonsense RNA-mediated decay factors SMG1 and UPF1 increase TERRA at telomeres and interfere with replication of leading-strand telomeres. We propose that hTR mediated stimulation of DNA-PKcs and subsequent phosphorylation of hnRNP A1 influences the cell cycle dependent distribution of TERRA at telomeres by contributing to the removal of TERRA from telomeres, an action important for progression of S-phase, and thereby facilitating efficient telomere replication and end-capping.

  7. Evaluation of Initial Telomere Length and Changes after Transplantation in Adult Double-Unit Cord Blood Transplant Recipients.

    PubMed

    Ashbridge, Beth; Zehir, Ahmet; Lubin, Marissa; Barker, Juliet N; Moore, Malcolm A S

    2015-07-01

    Cord blood (CB) leukocytes have inherent telomere length (TL) variation, and CB hematopoietic stem cells (HSC) can maintain high telomerase levels preventing telomere attrition in vitro. We evaluated TL changes in 13 adult double-unit CB transplant (CBT) recipients. In the 26 units, we observed a marked variation in CB TL at thaw (median, 9.99 kilobases [kb]; range, 6.85 to 13.5). All 13 patients engrafted. Of 11 engrafting with 1 unit, there was no correlation between unit dominance and TL (mean dominant unit TL, 8.84 kb ± 1.76; mean nonengrafting unit TL, 10.3 kb ± 1.81; P = .77). Serial measurements of TL up to 1 year after CBT demonstrated an overall mean 3.04 kb ± .16 TL decrease with only 1 patient exhibiting telomere maintenance. In summary, initial TL does not predict CB unit dominance. Moreover, our analysis suggests neonatal hematopoiesis makes a transition to an HSC characterized by changes in average TL and potentially low telomerase asymmetric cell division in adult CBT recipients. Further investigation of alterations in telomere length and its clinical implications after transplantation of this observation are indicated.

  8. Exposure to Inorganic Arsenic Is Associated with Increased Mitochondrial DNA Copy Number and Longer Telomere Length in Peripheral Blood

    PubMed Central

    Ameer, Syeda S.; Xu, YiYi; Engström, Karin; Li, Huiqi; Tallving, Pia; Nermell, Barbro; Boemo, Analia; Parada, Luis A.; Peñaloza, Lidia G.; Concha, Gabriela; Harari, Florencia; Vahter, Marie; Broberg, Karin

    2016-01-01

    Background: Exposure to inorganic arsenic (iAs) through drinking water causes cancer. Alterations in mitochondrial DNA copy number (mtDNAcn) and telomere length in blood have been associated with cancer risk. We elucidated if arsenic exposure alters mtDNAcn and telomere length in individuals with different arsenic metabolizing capacity. Methods: We studied two groups in the Salta province, Argentina, one in the Puna area of the Andes (N = 264, 89% females) and one in Chaco (N = 169, 75% females). We assessed arsenic exposure as the sum of arsenic metabolites [iAs, methylarsonic acid (MMA), dimethylarsinic acid (DMA)] in urine (U-As) using high-performance liquid chromatography coupled with hydride generation and inductively coupled plasma mass spectrometry. Efficiency of arsenic metabolism was expressed as percentage of urinary metabolites. MtDNAcn and telomere length were determined in blood by real-time PCR. Results: Median U-As was 196 (5–95 percentile: 21–537) μg/L in Andes and 80 (5–95 percentile: 15–1637) μg/L in Chaco. The latter study group had less-efficient metabolism, with higher %iAs and %MMA in urine compared with the Andean group. U-As was significantly associated with increased mtDNAcn (log2 transformed to improve linearity) in Chaco (β = 0.027 per 100 μg/L, p = 0.0085; adjusted for age and sex), but not in Andes (β = 0.025, p = 0.24). U-As was also associated with longer telomere length in Chaco (β = 0.016, p = 0.0066) and Andes (β = 0.0075, p = 0.029). In both populations, individuals with above median %iAs showed significantly higher mtDNAcn and telomere length compared with individuals with below median %iAs. Conclusions: Arsenic was associated with increased mtDNAcn and telomere length, particularly in individuals with less-efficient arsenic metabolism, a group who may have increased risk for arsenic-related cancer.

  9. Exposure to Inorganic Arsenic Is Associated with Increased Mitochondrial DNA Copy Number and Longer Telomere Length in Peripheral Blood

    PubMed Central

    Ameer, Syeda S.; Xu, YiYi; Engström, Karin; Li, Huiqi; Tallving, Pia; Nermell, Barbro; Boemo, Analia; Parada, Luis A.; Peñaloza, Lidia G.; Concha, Gabriela; Harari, Florencia; Vahter, Marie; Broberg, Karin

    2016-01-01

    Background: Exposure to inorganic arsenic (iAs) through drinking water causes cancer. Alterations in mitochondrial DNA copy number (mtDNAcn) and telomere length in blood have been associated with cancer risk. We elucidated if arsenic exposure alters mtDNAcn and telomere length in individuals with different arsenic metabolizing capacity. Methods: We studied two groups in the Salta province, Argentina, one in the Puna area of the Andes (N = 264, 89% females) and one in Chaco (N = 169, 75% females). We assessed arsenic exposure as the sum of arsenic metabolites [iAs, methylarsonic acid (MMA), dimethylarsinic acid (DMA)] in urine (U-As) using high-performance liquid chromatography coupled with hydride generation and inductively coupled plasma mass spectrometry. Efficiency of arsenic metabolism was expressed as percentage of urinary metabolites. MtDNAcn and telomere length were determined in blood by real-time PCR. Results: Median U-As was 196 (5–95 percentile: 21–537) μg/L in Andes and 80 (5–95 percentile: 15–1637) μg/L in Chaco. The latter study group had less-efficient metabolism, with higher %iAs and %MMA in urine compared with the Andean group. U-As was significantly associated with increased mtDNAcn (log2 transformed to improve linearity) in Chaco (β = 0.027 per 100 μg/L, p = 0.0085; adjusted for age and sex), but not in Andes (β = 0.025, p = 0.24). U-As was also associated with longer telomere length in Chaco (β = 0.016, p = 0.0066) and Andes (β = 0.0075, p = 0.029). In both populations, individuals with above median %iAs showed significantly higher mtDNAcn and telomere length compared with individuals with below median %iAs. Conclusions: Arsenic was associated with increased mtDNAcn and telomere length, particularly in individuals with less-efficient arsenic metabolism, a group who may have increased risk for arsenic-related cancer. PMID:27597942

  10. Conservation of the human telomere sequence (TTAGGG)n among vertebrates.

    PubMed Central

    Meyne, J; Ratliff, R L; Moyzis, R K

    1989-01-01

    To determine the evolutionary origin of the human telomere sequence (TTAGGG)n, biotinylated oligodeoxynucleotides of this sequence were hybridized to metaphase spreads from 91 different species, including representative orders of bony fish, reptiles, amphibians, birds, and mammals. Under stringent hybridization conditions, fluorescent signals were detected at the telomeres of all chromosomes, in all 91 species. The conservation of the (TTAGGG)n sequence and its telomeric location, in species thought to share a common ancestor over 400 million years ago, strongly suggest that this sequence is the functional vertebrate telomere. Images PMID:2780561

  11. Race, Ethnicity, Psychosocial Factors, and Telomere Length in a Multicenter Setting

    PubMed Central

    Mitra, Nandita; Ravichandran, Krithika; Branas, Charles; Spangler, Elaine; Zhou, Wenting; Paskett, Electra D.; Gehlert, Sarah; DeGraffinreid, Cecilia

    2016-01-01

    Background Leukocyte telomere length(LTL) has been associated with age, self-reported race/ethnicity, gender, education, and psychosocial factors, including perceived stress, and depression. However, inconsistencies in associations of LTL with disease and other phenotypes exist across studies. Population characteristics, including race/ethnicity, laboratory methods, and statistical approaches in LTL have not been comprehensively studied and could explain inconsistent LTL associations. Methods LTL was measured using Southern Blot in 1510 participants from a multi-ethnic, multi-center study combining data from 3 centers with different population characteristics and laboratory processing methods. Main associations between LTL and psychosocial factors and LTL and race/ethnicity were evaluated and then compared across generalized estimating equations(GEE) and linear regression models. Statistical models were adjusted for factors typically associated with LTL(age, gender, cancer status) and also accounted for factors related to center differences, including laboratory methods(i.e., DNA extraction). Associations between LTL and psychosocial factors were also evaluated within race/ethnicity subgroups (Non-hispanic Whites, African Americans, and Hispanics). Results Beyond adjustment for age, gender, and cancer status, additional adjustments for DNA extraction and clustering by center were needed given their effects on LTL measurements. In adjusted GEE models, longer LTL was associated with African American race (Beta(β)(standard error(SE)) = 0.09(0.04), p-value = 0.04) and Hispanic ethnicity (β(SE) = 0.06(0.01), p-value = 0.02) compared to Non-Hispanic Whites. Longer LTL was also associated with less than a high school education compared to having greater than a high school education (β(SE) = 0.06(0.02), p-value = 0.04). LTL was inversely related to perceived stress (β(SE) = -0.02(0.003), p<0.001). In subgroup analyses, there was a negative association with LTL in

  12. Systemic lupus erythematosus and vitamin D deficiency are associated with shorter telomere length among African Americans: a case-control study.

    PubMed

    Hoffecker, Brett M; Raffield, Laura M; Kamen, Diane L; Nowling, Tamara K

    2013-01-01

    Systemic lupus erythematosus (SLE) is a chronic systemic autoimmune disease that disproportionately affects African American females. The causes of SLE are unknown but postulated to be a combination of genetic predisposition and environmental triggers. Vitamin D deficiency is one of the possible environmental triggers. In this study we evaluated relationships between vitamin D status, cellular aging (telomere length) and anti-telomere antibodies among African American Gullah women with SLE. The study population included African American female SLE patients and unaffected controls from the Sea Island region of South Carolina. Serum 25-hydroxyvitamin D levels were measured using a nonchromatographic radioimmunoassay. Telomere length was measured in genomic DNA of peripheral blood mononuclear cells (PBMCs) by monochrome multiplex quantitative PCR. Anti-telomere antibody levels were measured by enzyme-linked immunosorbent assay (ELISA). Patients with SLE had significantly shorter telomeres and higher anti-telomere antibody titers compared to age- and gender-matched unaffected controls. There was a positive correlation between anti-telomere antibody levels and disease activity among patients and a significant correlation of shorter telomeres with lower 25-hydroxyvitamin D levels in both patients and controls. In follow-up examination of a subset of the patients, the patients who remained vitamin D deficient tended to have shorter telomeres than those patients whose 25-hydroxyvitamin D levels were repleted. Increasing 25-hydroxyvitamin D levels in African American patients with SLE may be beneficial in maintaining telomere length and preventing cellular aging. Moreover, anti-telomere antibody levels may be a promising biomarker of SLE status and disease activity.

  13. Current employment status, occupational category, occupational hazard exposure, and job stress in relation to telomere length: The Multiethnic Study of Atherosclerosis (MESA)

    PubMed Central

    Fujishiro, Kaori; Diez-Roux, Ana V; Landsbergis, Paul; Jenny, Nancy Swords; Seeman, Teresa

    2014-01-01

    Objective Telomere length has been proposed as a biomarker of cell senescence, which is associated with a wide array of adverse health outcomes. While work is a major determinant of health, few studies have investigated the association of telomere length with various dimensions of occupation. Accelerated cellular aging could be a common pathway linking occupational exposure to several health outcomes. Methods Leukocyte telomere length was assessed using quantitative polymerase chain reaction (Q-PCR) in a community-based sample of 981 individuals (age: 45–84 years old). Questionnaires were used to collect information on current employment status, current or main occupation before retirement, and job strain. The O*NET (Occupational Resource Network) database was linked to the questionnaire data to create 5 exposure measures: physical activity on the job, physical hazard exposure, interpersonal stressors, job control, and job demands. Linear regression was used to estimate associations of occupational characteristics with telomere lengths after adjustment for age, sex, race, socioeconomic position, and several behavioral risk factors. Results There were no mean differences in telomere lengths across current employment status, occupational category, job strain categories or levels of most O*NET exposure measures. There was also no evidence that being in lower status occupational categories or being exposed to higher levels of adverse physical or psychosocial exposures accelerated the association between age and telomere shortening. Conclusions Cellular aging as reflected by shorter telomeres does not appear to be an important pathway linking occupation to various health outcomes. PMID:23686115

  14. Race-Ethnicity, Poverty, Urban Stressors, and Telomere Length in a Detroit Community-based Sample.

    PubMed

    Geronimus, Arline T; Pearson, Jay A; Linnenbringer, Erin; Schulz, Amy J; Reyes, Angela G; Epel, Elissa S; Lin, Jue; Blackburn, Elizabeth H

    2015-06-01

    Residents of distressed urban areas suffer early aging-related disease and excess mortality. Using a community-based participatory research approach in a collaboration between social researchers and cellular biologists, we collected a unique data set of 239 black, white, or Mexican adults from a stratified, multistage probability sample of three Detroit neighborhoods. We drew venous blood and measured telomere length (TL), an indicator of stress-mediated biological aging, linking respondents' TL to their community survey responses. We regressed TL on socioeconomic, psychosocial, neighborhood, and behavioral stressors, hypothesizing and finding an interaction between poverty and racial-ethnic group. Poor whites had shorter TL than nonpoor whites; poor and nonpoor blacks had equivalent TL; and poor Mexicans had longer TL than nonpoor Mexicans. Findings suggest unobserved heterogeneity bias is an important threat to the validity of estimates of TL differences by race-ethnicity. They point to health impacts of social identity as contingent, the products of structurally rooted biopsychosocial processes. PMID:25930147

  15. Race/Ethnicity, Poverty, Urban Stressors and Telomere Length in a Detroit Community-Based Sample

    PubMed Central

    Geronimus, Arline T.; Pearson, Jay A.; Linnenbringer, Erin; Schulz, Amy J.; Reyes, Angela G.; Epel, Elissa S.; Lin, Jue; Blackburn, Elizabeth H.

    2015-01-01

    Residents of distressed urban areas suffer early aging-related disease and excess mortality. Using a community-based participatory research approach in a collaboration between social researchers and cellular biologists, we collected a unique data set of 239 black, white, or Mexican adults from a stratified, multi-stage probability sample of three Detroit neighborhoods. We drew venous blood and measured Telomere Length (TL), an indicator of stress-mediated biological aging, linking respondents’ TL to their community survey responses. We regressed TL on socioeconomic, psychosocial, neighborhood, and behavioral stressors, hypothesizing and finding an interaction between poverty and racial/ethnic group. Poor whites had shorter TL than nonpoor whites; poor and nonpoor blacks had equivalent TL; poor Mexicans had longer TL than nonpoor Mexicans. Findings suggest unobserved heterogeneity bias is an important threat to the validity of estimates of TL differences by race/ethnicity. They point to health impacts of social identity as contingent, the products of structurally-rooted biopsychosocial processes. PMID:25930147

  16. Discrimination, mental health, and leukocyte telomere length among African American men.

    PubMed

    Chae, David H; Epel, Elissa S; Nuru-Jeter, Amani M; Lincoln, Karen D; Taylor, Robert Joseph; Lin, Jue; Blackburn, Elizabeth H; Thomas, Stephen B

    2016-01-01

    African American men in the US experience disparities across multiple health outcomes. A common mechanism underlying premature declines in health may be accelerated biological aging, as reflected by leukocyte telomere length (LTL). Racial discrimination, a qualitatively unique source of social stress reported by African American men, in tandem with poor mental health, may negatively impact LTL in this population. The current study examined cross-sectional associations between LTL, self-reported racial discrimination, and symptoms of depression and anxiety among 92 African American men 30-50 years of age. LTL was measured in kilobase pairs using quantitative polymerase chain reaction assay. Controlling for sociodemographic factors, greater anxiety symptoms were associated with shorter LTL (b=-0.029, standard error [SE]=0.014; p<0.05). There were no main effects of racial discrimination or depressive symptoms on LTL, but we found evidence for a significant interaction between the two (b=0.011, SE=0.005; p<0.05). Racial discrimination was associated with shorter LTL among those with lower levels of depressive symptoms. Findings from this study highlight the role of social stressors and individual-level psychological factors for physiologic deterioration among African American men. Consistent with research on other populations, greater anxiety may reflect elevated stress associated with shorter LTL. Racial discrimination may represent an additional source of social stress among African American men that has detrimental consequences for cellular aging among those with lower levels of depression.

  17. Alterations in leukocyte telomere length in workers occupationally exposed to benzene.

    PubMed

    Bassig, Bryan A; Zhang, Luoping; Cawthon, Richard M; Smith, Martyn T; Yin, Songnian; Li, Guilan; Hu, Wei; Shen, Min; Rappaport, Stephen; Barone-Adesi, Francesco; Rothman, Nathaniel; Vermeulen, Roel; Lan, Qing

    2014-10-01

    Exposure to benzene, a known leukemogen and probable lymphomagen, has been demonstrated to result in oxidative stress, which has previously been associated with altered telomere length (TL). TL specifically has been associated with several health outcomes in epidemiologic studies, including cancer risk, and has been demonstrated to be altered following exposure to a variety of chemical agents. To evaluate the association between benzene exposure and TL, we measured TL by monochrome multiplex quantitative PCR in 43 workers exposed to high levels of benzene and 43 age and sex-matched unexposed workers in Shanghai, China. Benzene exposure levels were monitored using organic vapor passive dosimetry badges before phlebotomy. The median benzene exposure level in exposed workers was 31 ppm. The mean TL in controls, workers exposed to levels of benzene below the median (≤31 ppm), and above the median (>31 ppm) was 1.26 ± 0.17, 1.25 ± 0.16, and 1.37 ± 0.23, respectively. Mean TL was significantly elevated in workers exposed to >31 ppm of benzene compared with controls (P = 0.03). Our findings provide evidence that high levels of occupational benzene exposure are associated with TL. Environ.

  18. Diurnal and stress-reactive dehydroepiandrosterone levels and telomere length in youth.

    PubMed

    Dismukes, Andrew R; Meyer, Vanessa J; Shirtcliff, Elizabeth A; Theall, Katherine P; Esteves, Kyle C; Drury, Stacy S

    2016-05-01

    The current investigation examined the association between the aging-related biomarkers dehydroepiandrosterone (DHEA) and telomere length (TL) in community-recruited African-American youth. The examination of DHEA included stress reactive, basal and diurnal sampling, in order to elucidate the underlying physiological process that may overlap with TL. One hundred and two participants completed the Trier Social Stressor Test for children (TSST-C). TL was obtained from all youth from buccal swabs on the same day as the TSST-C. Saliva samples from 83 participants were obtained over the course of two additional days to measure waking and diurnal levels of DHEA. DHEA diurnal slope was a robust predictor of TL (B=0.516, P<0.05), while other DHEA values were not significantly associated with TL. This study is one of the first studies to examine basal, diurnal and reactivity measurements of DHEA in youth. Furthermore, this is the first study, to our knowledge, to demonstrate a positive association between DHEA, a putative anti-aging hormone, and TL, an indicator of cellular aging. PMID:27221260

  19. Urban environment shortens telomere length in nestling great tits, Parus major.

    PubMed

    Salmón, P; Nilsson, J F; Nord, A; Bensch, S; Isaksson, C

    2016-06-01

    Urban environments are expanding rapidly, and with urbanization come both challenges and opportunities for wildlife. Challenges include combating the anthropogenic disturbances such as light, noise and air pollution and lower availability of natural food sources. The benefits are many, including the availability of anthropogenic food sources, breeding boxes and warmer temperatures. Thus, depending on the context, urbanization can have both positive and negative effects on fitness related traits. It is well known that early-life conditions can have lifelong implications on fitness; little is however known about development in urban environments. We reciprocally cross-fostered urban and rural nestling great tits (Parus major L.) to study how growing up in an urban versus rural habitat affected telomere length (TL)-a suggested biomarker of longevity. We show, for the first time, that growing up in an urban environment significantly shortens TL, independently of natal origin (i.e. urban or rural). This implies that the urban environment imposes a challenge to developing birds, with potentially irreversible effects on lifespan. PMID:27303051

  20. Diurnal and stress-reactive dehydroepiandrosterone levels and telomere length in youth

    PubMed Central

    Dismukes, Andrew R; Meyer, Vanessa J; Shirtcliff, Elizabeth A; Theall, Katherine P; Esteves, Kyle C

    2016-01-01

    The current investigation examined the association between the aging-related biomarkers dehydroepiandrosterone (DHEA) and telomere length (TL) in community-recruited African-American youth. The examination of DHEA included stress reactive, basal and diurnal sampling, in order to elucidate the underlying physiological process that may overlap with TL. One hundred and two participants completed the Trier Social Stressor Test for children (TSST-C). TL was obtained from all youth from buccal swabs on the same day as the TSST-C. Saliva samples from 83 participants were obtained over the course of two additional days to measure waking and diurnal levels of DHEA. DHEA diurnal slope was a robust predictor of TL (B=0.516, P<0.05), while other DHEA values were not significantly associated with TL. This study is one of the first studies to examine basal, diurnal and reactivity measurements of DHEA in youth. Furthermore, this is the first study, to our knowledge, to demonstrate a positive association between DHEA, a putative anti-aging hormone, and TL, an indicator of cellular aging. PMID:27221260

  1. Prognostic significance of telomeric repeat length alterations in pathological stage I-IIIA non-small cell lung cancer.

    PubMed

    Hirashima, T; Komiya, T; Nitta, T; Takada, Y; Kobayashi, M; Masuda, N; Matui, K; Takada, M; Kikui, M; Yasumitu, T; Ohno, A; Nakagawa, K; Fukuoka, M; Kawase, I

    2000-01-01

    This study was performed to evaluate the prognostic significance of alteration in telomere length in pathological stage (p-stage) I-IIIA non-small cell lung cancer (NSCLC). Paired cancer and normal lung tissues were obtained from 72 patients with histologically confirmed p-stage I-IIIA NSCLC. Terminal restriction fragment (TRF) length, which indicates telomere length, was measured by Southern blot analysis. Tumor telomerase activity was also assayed by non-radioactive PCR-ELISA in 55 patients. TRF length (mean +/- SD) in normal tissue was 6.2 +/- 1.1 Kb. Therefore, upper and lower limits of normal range in TRF length was set at 8.4 (mean + 2SD) Kb and 4.0 (mean-2SD) Kb, respectively. A tumor showing TRF length over normal range was defined as positive for the alteration. In 72 patients, 25 (34.7%) with alteration in TRF length had significantly shorter survival durations than those of the others. Telomerase activity did not correlate with survival duration. In multivariate analysis, alteration in TRF length (P = 0.0033) was second to p-stage (P = 0.0004) in importance among the various parameters.

  2. Longitudinal changes of telomere length and epigenetic age related to traumatic stress and post-traumatic stress disorder.

    PubMed

    Boks, Marco P; van Mierlo, Hans C; Rutten, Bart P F; Radstake, Timothy R D J; De Witte, Lot; Geuze, Elbert; Horvath, Steve; Schalkwyk, Leonard C; Vinkers, Christiaan H; Broen, Jasper C A; Vermetten, Eric

    2015-01-01

    Several studies have reported an association between traumatic stress and telomere length suggesting that traumatic stress has an impact on ageing at the cellular level. A newly derived tool provides an additional means to investigate cellular ageing by estimating epigenetic age based on DNA methylation profiles. We therefore hypothesise that in a longitudinal study of traumatic stress both indicators of cellular ageing will show increased ageing. We expect that particularly in individuals that developed symptoms of post-traumatic stress disorder (PTSD) increases in these ageing parameters would stand out. From an existing longitudinal cohort study, ninety-six male soldiers were selected based on trauma exposure and the presence of symptoms of PTSD. All military personnel were deployed in a combat zone in Afghanistan and assessed before and 6 months after deployment. The Self-Rating Inventory for PTSD was used to measure the presence of PTSD symptoms, while exposure to combat trauma during deployment was measured with a 19-item deployment experiences checklist. These groups did not differ for age, gender, alcohol consumption, cigarette smoking, military rank, length, weight, or medication use. In DNA from whole blood telomere length was measured and DNA methylation levels were assessed using the Illumina 450K DNA methylation arrays. Epigenetic ageing was estimated using the DNAm age estimator procedure. The association of trauma with telomere length was in the expected direction but not significant (B=-10.2, p=0.52). However, contrary to our expectations, development of PTSD symptoms was associated with the reverse process, telomere lengthening (B=1.91, p=0.018). In concordance, trauma significantly accelerated epigenetic ageing (B=1.97, p=0.032) and similar to the findings in telomeres, development of PTSD symptoms was inversely associated with epigenetic ageing (B=-0.10, p=0.044). Blood cell count, medication and premorbid early life trauma exposure did not

  3. Where You Live May Make You Old: The Association between Perceived Poor Neighborhood Quality and Leukocyte Telomere Length

    PubMed Central

    Park, Mijung; Verhoeven, Josine E.; Cuijpers, Pim; Reynolds III, Charles F.; Penninx, Brenda W. J. H.

    2015-01-01

    Background Strong evidence supports that living in disadvantaged neighborhoods has direct unfavorable impact on mental and physical health. However, whether it also has direct impact on cellular health is largely unknown. Thus we examined whether neighborhood quality was associated with leukocyte telomere length, an indicator of cellular aging. Methods In May 2014, we extracted and analyzed baseline data from the Netherlands Study of Depression and Anxiety (NESDA), a large epidemiological study of individuals age between 18–65 years (n=2902). Telomere length was determined using quantitative polymerase chain reaction. Neighborhood quality was assessed using modified measures of perceived neighborhood disorder, fear of crime, and noise. We used multivariable linear regression models to examine association between perceived neighborhood quality and telomere length with comprehensive adjustment for individual and community characteristics related to socioeconomic and demographic status, urbanization level, mental and physical health, and lifestyle. Results Compared to individuals who reported good neighborhood quality, the mean telomere length of those who reported moderate neighborhood quality was approximately 69 base pair shorter (β =-69.33, 95% CI: -119.49, -19.17, p= 0.007), and that of those who reported poor neighborhood quality were 174 base pair shorter (β =-173.80, 95% CI: -298.80, -49.01, p=0.006). For illustrative purposes, one could extrapolate these outcomes to 8.7 and 11.9 years in chronological age, respectively. Conclusion We have established an association between perceived neighborhood quality and cellular aging over and above a range of individual attributes. Biological aging processes may be impacted by socioeconomic milieu. PMID:26083263

  4. Telomere position effect: regulation of gene expression with progressive telomere shortening over long distances

    PubMed Central

    Robin, Jérôme D.; Ludlow, Andrew T.; Batten, Kimberly; Magdinier, Frédérique; Stadler, Guido; Wagner, Kathyrin R.; Wright, Woodring E.

    2014-01-01

    While global chromatin conformation studies are emerging, very little is known about the chromatin conformation of human telomeres. Most studies have focused on the role of telomeres as a tumor suppressor mechanism. Here we describe how telomere length regulates gene expression long before telomeres become short enough to produce a DNA damage response (senescence). We directly mapped the interactions adjacent to specific telomere ends using a Hi-C (chromosome capture followed by high-throughput sequencing) technique modified to enrich for specific genomic regions. We demonstrate that chromosome looping brings the telomere close to genes up to 10 Mb away from the telomere when telomeres are long and that the same loci become separated when telomeres are short. Furthermore, expression array analysis reveals that many loci, including noncoding RNAs, may be regulated by telomere length. We report three genes (ISG15 [interferon-stimulated gene 15 kd], DSP [Desmoplakin], and C1S [complement component 1s subcomplement]) located at three different subtelomeric ends (1p, 6p, and 12p) whose expressions are altered with telomere length. Additionally, we confirmed by in situ analysis (3D-FISH [three-dimensional fluorescence in situ hybridization]) that chromosomal looping occurs between the loci of those genes and their respective telomere ends. We term this process TPE-OLD for “telomere position effect over long distances.” Our results suggest a potential novel mechanism for how telomere shortening could contribute to aging and disease initiation/progression in human cells long before the induction of a critical DNA damage response. PMID:25403178

  5. 25-Hydroxyvitamin D Concentration and Leukocyte Telomere Length in Young Adults: Findings From the Northern Finland Birth Cohort 1966.

    PubMed

    Williams, Dylan M; Palaniswamy, Saranya; Sebert, Sylvain; Buxton, Jessica L; Blakemore, Alexandra I F; Hyppönen, Elina; Jarvelin, Marjo-Riitta

    2016-02-01

    Higher vitamin D status, lower adiposity, and longer telomere length are each reportedly associated with lower risk of several chronic diseases and all-cause mortality. However, direct relationships between vitamin D status (measured by circulating 25-hydroxyvitamin D (25(OH)D) concentration), adiposity, and telomere length are not well established. We conducted a cross-sectional analysis of associations of 25(OH)D and body mass index (BMI; weight (kg)/height (m)(2)) with mean relative leukocyte telomere length (LTL) using data gathered on 5,096 participants from Northern Finland Birth Cohort 1966 at age 31 years (1997). 25(OH)D was not associated with LTL in either basic or confounder/mediator-adjusted models. BMI was inversely associated with LTL after adjustment for potential confounding by age, sex, socioeconomic position, physical activity, diet, smoking, alcohol intake, and use of oral contraceptives (per 1-unit increase in BMI, mean difference in LTL = -0.4%, 95% confidence interval: -0.6, -0.2). The BMI-LTL association was also independent of 25(OH)D and was attenuated slightly, but remained, after adjustment for C-reactive protein, a marker of low-grade inflammation (mean difference in LTL = -0.3%, 95% confidence interval -0.6, -0.1). These findings suggest that vitamin D status is unlikely to be an important determinant of LTL, at least by young adulthood. Inflammation may partly mediate associations of adiposity with LTL.

  6. Multiple independent variants at the TERT locus are associated with telomere length and risks of breast and ovarian cancer.

    PubMed

    Bojesen, Stig E; Pooley, Karen A; Johnatty, Sharon E; Beesley, Jonathan; Michailidou, Kyriaki; Tyrer, Jonathan P; Edwards, Stacey L; Pickett, Hilda A; Shen, Howard C; Smart, Chanel E; Hillman, Kristine M; Mai, Phuong L; Lawrenson, Kate; Stutz, Michael D; Lu, Yi; Karevan, Rod; Woods, Nicholas; Johnston, Rebecca L; French, Juliet D; Chen, Xiaoqing; Weischer, Maren; Nielsen, Sune F; Maranian, Melanie J; Ghoussaini, Maya; Ahmed, Shahana; Baynes, Caroline; Bolla, Manjeet K; Wang, Qin; Dennis, Joe; McGuffog, Lesley; Barrowdale, Daniel; Lee, Andrew; Healey, Sue; Lush, Michael; Tessier, Daniel C; Vincent, Daniel; Bacot, Françis; Vergote, Ignace; Lambrechts, Sandrina; Despierre, Evelyn; Risch, Harvey A; González-Neira, Anna; Rossing, Mary Anne; Pita, Guillermo; Doherty, Jennifer A; Alvarez, Nuria; Larson, Melissa C; Fridley, Brooke L; Schoof, Nils; Chang-Claude, Jenny; Cicek, Mine S; Peto, Julian; Kalli, Kimberly R; Broeks, Annegien; Armasu, Sebastian M; Schmidt, Marjanka K; Braaf, Linde M; Winterhoff, Boris; Nevanlinna, Heli; Konecny, Gottfried E; Lambrechts, Diether; Rogmann, Lisa; Guénel, Pascal; Teoman, Attila; Milne, Roger L; Garcia, Joaquin J; Cox, Angela; Shridhar, Vijayalakshmi; Burwinkel, Barbara; Marme, Frederik; Hein, Rebecca; Sawyer, Elinor J; Haiman, Christopher A; Wang-Gohrke, Shan; Andrulis, Irene L; Moysich, Kirsten B; Hopper, John L; Odunsi, Kunle; Lindblom, Annika; Giles, Graham G; Brenner, Hermann; Simard, Jacques; Lurie, Galina; Fasching, Peter A; Carney, Michael E; Radice, Paolo; Wilkens, Lynne R; Swerdlow, Anthony; Goodman, Marc T; Brauch, Hiltrud; Garcia-Closas, Montserrat; Hillemanns, Peter; Winqvist, Robert; Dürst, Matthias; Devilee, Peter; Runnebaum, Ingo; Jakubowska, Anna; Lubinski, Jan; Mannermaa, Arto; Butzow, Ralf; Bogdanova, Natalia V; Dörk, Thilo; Pelttari, Liisa M; Zheng, Wei; Leminen, Arto; Anton-Culver, Hoda; Bunker, Clareann H; Kristensen, Vessela; Ness, Roberta B; Muir, Kenneth; Edwards, Robert; Meindl, Alfons; Heitz, Florian; Matsuo, Keitaro; du Bois, Andreas; Wu, Anna H; Harter, Philipp; Teo, Soo-Hwang; Schwaab, Ira; Shu, Xiao-Ou; Blot, William; Hosono, Satoyo; Kang, Daehee; Nakanishi, Toru; Hartman, Mikael; Yatabe, Yasushi; Hamann, Ute; Karlan, Beth Y; Sangrajrang, Suleeporn; Kjaer, Susanne Krüger; Gaborieau, Valerie; Jensen, Allan; Eccles, Diana; Høgdall, Estrid; Shen, Chen-Yang; Brown, Judith; Woo, Yin Ling; Shah, Mitul; Azmi, Mat Adenan Noor; Luben, Robert; Omar, Siti Zawiah; Czene, Kamila; Vierkant, Robert A; Nordestgaard, Børge G; Flyger, Henrik; Vachon, Celine; Olson, Janet E; Wang, Xianshu; Levine, Douglas A; Rudolph, Anja; Weber, Rachel Palmieri; Flesch-Janys, Dieter; Iversen, Edwin; Nickels, Stefan; Schildkraut, Joellen M; Silva, Isabel Dos Santos; Cramer, Daniel W; Gibson, Lorna; Terry, Kathryn L; Fletcher, Olivia; Vitonis, Allison F; van der Schoot, C Ellen; Poole, Elizabeth M; Hogervorst, Frans B L; Tworoger, Shelley S; Liu, Jianjun; Bandera, Elisa V; Li, Jingmei; Olson, Sara H; Humphreys, Keith; Orlow, Irene; Blomqvist, Carl; Rodriguez-Rodriguez, Lorna; Aittomäki, Kristiina; Salvesen, Helga B; Muranen, Taru A; Wik, Elisabeth; Brouwers, Barbara; Krakstad, Camilla; Wauters, Els; Halle, Mari K; Wildiers, Hans; Kiemeney, Lambertus A; Mulot, Claire; Aben, Katja K; Laurent-Puig, Pierre; Altena, Anne Mvan; Truong, Thérèse; Massuger, Leon F A G; Benitez, Javier; Pejovic, Tanja; Perez, Jose Ignacio Arias; Hoatlin, Maureen; Zamora, M Pilar; Cook, Linda S; Balasubramanian, Sabapathy P; Kelemen, Linda E; Schneeweiss, Andreas; Le, Nhu D; Sohn, Christof; Brooks-Wilson, Angela; Tomlinson, Ian; Kerin, Michael J; Miller, Nicola; Cybulski, Cezary; Henderson, Brian E; Menkiszak, Janusz; Schumacher, Fredrick; Wentzensen, Nicolas; Le Marchand, Loic; Yang, Hannah P; Mulligan, Anna Marie; Glendon, Gord; Engelholm, Svend Aage; Knight, Julia A; Høgdall, Claus K; Apicella, Carmel; Gore, Martin; Tsimiklis, Helen; Song, Honglin; Southey, Melissa C; Jager, Agnes; den Ouweland, Ans M Wvan; Brown, Robert; Martens, John W M; Flanagan, James M; Kriege, Mieke; Paul, James; Margolin, Sara; Siddiqui, Nadeem; Severi, Gianluca; Whittemore, Alice S; Baglietto, Laura; McGuire, Valerie; Stegmaier, Christa; Sieh, Weiva; Müller, Heiko; Arndt, Volker; Labrèche, France; Gao, Yu-Tang; Goldberg, Mark S; Yang, Gong; Dumont, Martine; McLaughlin, John R; Hartmann, Arndt; Ekici, Arif B; Beckmann, Matthias W; Phelan, Catherine M; Lux, Michael P; Permuth-Wey, Jenny; Peissel, Bernard; Sellers, Thomas A; Ficarazzi, Filomena; Barile, Monica; Ziogas, Argyrios; Ashworth, Alan; Gentry-Maharaj, Aleksandra; Jones, Michael; Ramus, Susan J; Orr, Nick; Menon, Usha; Pearce, Celeste L; Brüning, Thomas; Pike, Malcolm C; Ko, Yon-Dschun; Lissowska, Jolanta; Figueroa, Jonine; Kupryjanczyk, Jolanta; Chanock, Stephen J; Dansonka-Mieszkowska, Agnieszka; Jukkola-Vuorinen, Arja; Rzepecka, Iwona K; Pylkäs, Katri; Bidzinski, Mariusz; Kauppila, Saila; Hollestelle, Antoinette; Seynaeve, Caroline; Tollenaar, Rob A E M; Durda, Katarzyna; Jaworska, Katarzyna; Hartikainen, Jaana M; Kosma, Veli-Matti; Kataja, Vesa; Antonenkova, Natalia N; Long, Jirong; Shrubsole, Martha; Deming-Halverson, Sandra; Lophatananon, Artitaya; Siriwanarangsan, Pornthep; Stewart-Brown, Sarah; Ditsch, Nina; Lichtner, Peter; Schmutzler, Rita K; Ito, Hidemi; Iwata, Hiroji; Tajima, Kazuo; Tseng, Chiu-Chen; Stram, Daniel O; van den Berg, David; Yip, Cheng Har; Ikram, M Kamran; Teh, Yew-Ching; Cai, Hui; Lu, Wei; Signorello, Lisa B; Cai, Qiuyin; Noh, Dong-Young; Yoo, Keun-Young; Miao, Hui; Iau, Philip Tsau-Choong; Teo, Yik Ying; McKay, James; Shapiro, Charles; Ademuyiwa, Foluso; Fountzilas, George; Hsiung, Chia-Ni; Yu, Jyh-Cherng; Hou, Ming-Feng; Healey, Catherine S; Luccarini, Craig; Peock, Susan; Stoppa-Lyonnet, Dominique; Peterlongo, Paolo; Rebbeck, Timothy R; Piedmonte, Marion; Singer, Christian F; Friedman, Eitan; Thomassen, Mads; Offit, Kenneth; Hansen, Thomas V O; Neuhausen, Susan L; Szabo, Csilla I; Blanco, Ignacio; Garber, Judy; Narod, Steven A; Weitzel, Jeffrey N; Montagna, Marco; Olah, Edith; Godwin, Andrew K; Yannoukakos, Drakoulis; Goldgar, David E; Caldes, Trinidad; Imyanitov, Evgeny N; Tihomirova, Laima; Arun, Banu K; Campbell, Ian; Mensenkamp, Arjen R; van Asperen, Christi J; van Roozendaal, Kees E P; Meijers-Heijboer, Hanne; Collée, J Margriet; Oosterwijk, Jan C; Hooning, Maartje J; Rookus, Matti A; van der Luijt, Rob B; Os, Theo A Mvan; Evans, D Gareth; Frost, Debra; Fineberg, Elena; Barwell, Julian; Walker, Lisa; Kennedy, M John; Platte, Radka; Davidson, Rosemarie; Ellis, Steve D; Cole, Trevor; Bressac-de Paillerets, Brigitte; Buecher, Bruno; Damiola, Francesca; Faivre, Laurence; Frenay, Marc; Sinilnikova, Olga M; Caron, Olivier; Giraud, Sophie; Mazoyer, Sylvie; Bonadona, Valérie; Caux-Moncoutier, Virginie; Toloczko-Grabarek, Aleksandra; Gronwald, Jacek; Byrski, Tomasz; Spurdle, Amanda B; Bonanni, Bernardo; Zaffaroni, Daniela; Giannini, Giuseppe; Bernard, Loris; Dolcetti, Riccardo; Manoukian, Siranoush; Arnold, Norbert; Engel, Christoph; Deissler, Helmut; Rhiem, Kerstin; Niederacher, Dieter; Plendl, Hansjoerg; Sutter, Christian; Wappenschmidt, Barbara; Borg, Ake; Melin, Beatrice; Rantala, Johanna; Soller, Maria; Nathanson, Katherine L; Domchek, Susan M; Rodriguez, Gustavo C; Salani, Ritu; Kaulich, Daphne Gschwantler; Tea, Muy-Kheng; Paluch, Shani Shimon; Laitman, Yael; Skytte, Anne-Bine; Kruse, Torben A; Jensen, Uffe Birk; Robson, Mark; Gerdes, Anne-Marie; Ejlertsen, Bent; Foretova, Lenka; Savage, Sharon A; Lester, Jenny; Soucy, Penny; Kuchenbaecker, Karoline B; Olswold, Curtis; Cunningham, Julie M; Slager, Susan; Pankratz, Vernon S; Dicks, Ed; Lakhani, Sunil R; Couch, Fergus J; Hall, Per; Monteiro, Alvaro N A; Gayther, Simon A; Pharoah, Paul D P; Reddel, Roger R; Goode, Ellen L; Greene, Mark H; Easton, Douglas F; Berchuck, Andrew; Antoniou, Antonis C; Chenevix-Trench, Georgia; Dunning, Alison M

    2013-04-01

    TERT-locus SNPs and leukocyte telomere measures are reportedly associated with risks of multiple cancers. Using the Illumina custom genotyping array iCOGs, we analyzed ∼480 SNPs at the TERT locus in breast (n = 103,991), ovarian (n = 39,774) and BRCA1 mutation carrier (n = 11,705) cancer cases and controls. Leukocyte telomere measurements were also available for 53,724 participants. Most associations cluster into three independent peaks. The minor allele at the peak 1 SNP rs2736108 associates with longer telomeres (P = 5.8 × 10(-7)), lower risks for estrogen receptor (ER)-negative (P = 1.0 × 10(-8)) and BRCA1 mutation carrier (P = 1.1 × 10(-5)) breast cancers and altered promoter assay signal. The minor allele at the peak 2 SNP rs7705526 associates with longer telomeres (P = 2.3 × 10(-14)), higher risk of low-malignant-potential ovarian cancer (P = 1.3 × 10(-15)) and greater promoter activity. The minor alleles at the peak 3 SNPs rs10069690 and rs2242652 increase ER-negative (P = 1.2 × 10(-12)) and BRCA1 mutation carrier (P = 1.6 × 10(-14)) breast and invasive ovarian (P = 1.3 × 10(-11)) cancer risks but not via altered telomere length. The cancer risk alleles of rs2242652 and rs10069690, respectively, increase silencing and generate a truncated TERT splice variant. PMID:23535731

  7. Leukocyte telomere length is associated with advanced age-related macular degeneration in the Han Chinese population.

    PubMed

    Weng, Xiaoling; Zhang, Hong; Kan, Mengyuan; Ye, Junyi; Liu, Fatao; Wang, Ting; Deng, Jiaying; Tan, Yanfang; He, Lin; Liu, Yun

    2015-09-01

    Telomeres located at the ends of chromosomes are involved in genomic stability and play a key role in various cancers and age-related diseases. Age-related macular degeneration (AMD) is a late-onset, age-associated progressive neurodegenerative disease, which includes the geographic atrophy (GA) subtype and the choroidal neovascularization (CNV) subtype. To better understand how leukocyte telomere length (LTL) is related to AMD, we conducted an association study in 197 AMD patients and 259 healthy controls using the established quantitative PCR technique. Logistic regression was performed to evaluate the association of LTL and AMD with the age-adjusted ratio of the telomere length to the copy number of a single-copy gene (T/S). Notably, we found a significant association between AMD and LTL (OR=2.24; 95% CI=1.68-3.07; P=0.0001) after adjusting for age and sex. Furthermore, the results showed a strongly significant association between the GA subtype and the LTL (OR=4.81; 95% CI=3.15-7.82; P=0.0001) after adjusting for age and sex. Our findings provide evidence of the role that LTL plays in the pathological mechanisms of AMD, mainly in the GA subgroup but not the CNV subgroup.

  8. Shorter telomere length in peripheral blood lymphocytes of workers exposed to polycyclic aromatic hydrocarbons.

    PubMed

    Pavanello, Sofia; Pesatori, Angela-C; Dioni, Laura; Hoxha, Mirjam; Bollati, Valentina; Siwinska, Ewa; Mielzyńska, Danuta; Bolognesi, Claudia; Bertazzi, Pier-Alberto; Baccarelli, Andrea

    2010-02-01

    Shorter telomere length (TL) in peripheral blood lymphocytes (PBLs) is predictive of lung cancer risk. Polycyclic aromatic hydrocarbons (PAHs) are established lung carcinogens that cause chromosome instability. Whether PAH exposure and its molecular effects are linked with shorter TL has never been evaluated. In the present study, we investigated the effect of chronic exposure to PAHs on TL measured in PBLs of Polish male non-current smoking cokeoven workers and matched controls. PAH exposure and molecular effects were characterized using measures of internal dose (urinary 1-pyrenol), effective dose [anti-benzo[a]pyrene diolepoxide (anti-BPDE)-DNA adduct], genetic instability (micronuclei, MN) and DNA methylation [p53 promoter and Alu and long interspersed nuclear element-1 (LINE-1) repetitive elements, as surrogate measures of global methylation] in PBLs. TL was measured by real-time polymerase chain reaction. Cokeoven workers were heavily exposed to PAHs (79% exceeded the urinary 1-pyrenol biological exposure index) and exhibited lower TL (P = 0.038) than controls, as well as higher levels of genetic and chromosomal alterations [i.e. anti-BPDE-DNA adduct and MN (P < 0.0001)] and epigenetic changes [i.e. p53 gene-specific promoter and global methylation (P

  9. Effects of cigarette smoking and nicotine metabolite ratio on leukocyte telomere length.

    PubMed

    Verde, Zoraida; Reinoso-Barbero, Luis; Chicharro, Luis; Garatachea, Nuria; Resano, Pilar; Sánchez-Hernández, Ignacio; Rodríguez González-Moro, Jose Miguel; Bandrés, Fernando; Santiago, Catalina; Gómez-Gallego, Félix

    2015-07-01

    Studies of the effects of smoking on leukocyte telomere length (LTL) using cigarettes smoked per day or pack years smoked (PYS) present limitations. Reported high levels of smoking may not increase toxin exposure levels proportionally. Nicotine metabolism ratio (NMR) predicts total cigarette puff volume and overall exposure based on total N-nitrosamines, is highly reproducible and independent of time since the last cigarette. We hypothesized that smokers with higher NMRs will exhibit increased total puff volume, reflecting efforts to extract more nicotine from their cigarettes and increasing toxin exposure. In addition, higher levels of smoking could cause a gross damage in LTL. The urinary cotinine, 3-OH cotinine and nicotine levels of 147 smokers were analyzed using a LC/MS system Triple-Q6410. LTL and CYP2A6 genotype was determined by PCR in blood samples. We found a significant association between NMR and CYP2A6 genotype. Reduction in LTL was seen in relation to accumulated tobacco consumption and years smoking when we adjusted for age and gender. However, there were no significant differences between NMR values and LTL. In our study the higher exposure was associated with lower number of PYS. Smokers with reduced cigarette consumption may exhibit compensatory smoking behavior that results in no reduced tobacco toxin exposure. Our results suggest that lifetime accumulated smoking exposure could cause a gross damage in LTL rather than NMR or PYS. Nevertheless, a combination of smoking topography (NMR) and consumption (PYS) measures may provide useful information about smoking effects on health outcomes.

  10. Telomere length is associated with oppositional defiant behavior and maternal clinical depression in Latino preschool children.

    PubMed

    Wojcicki, J M; Heyman, M B; Elwan, D; Shiboski, S; Lin, J; Blackburn, E; Epel, E

    2015-06-16

    Exposure to psychological stress and depression are associated with shorter white blood cell telomere length (TL) in adults, possibly via associated lifelong oxidative stressors. Exposure to maternal depression increases risk for future depression and behavior problems in children, and Latino youth are at high risk. Few studies have evaluated the role of exposure to maternal depression or child behavior in relation to TL in children. We assessed early-childhood exposures to maternal depression from birth to the age of 5 years and child behavior from ages 3-5 years in a cohort of Latino children in relation to child leukocyte TL at ages 4 and 5 years. Children who had oppositional defiant behavior at 3, 4 or 5 years had shorter TL than those without by ~450 base pairs (P < 0.01). In multivariate analyses, independent predictors for shorter TL at 4 and 5 years of age included oppositional defiant disorder at 3, 4 or 5 years (β = -359.25, 95% CI -633.84 to 84.66; P = 0.01), exposure to maternal clinical depression at 3 years of age (β = -363.99, 95% CI -651.24 to 764.74; P = 0.01), shorter maternal TL (β = 502.92, 95% CI 189.21-816.63) and younger paternal age at the child's birth (β = 24.63, 95% CI 1.14-48.12). Thus, exposure to maternal clinical depression (versus depressive symptoms) in early childhood was associated with deleterious consequences on child cellular health as indicated by shorter TL at 4 and 5 years of age. Similarly, children with oppositional defiant behavior also had shorter TL, possibly related to early exposures to maternal clinical depression. Our study is the first to link maternal clinical depression and oppositional defiant behavior with shorter TL in the preschool years in a relatively homogenous population of low-income Latino children.

  11. p53 binds human telomeric G-quadruplex in vitro.

    PubMed

    Adámik, Matej; Kejnovská, Iva; Bažantová, Pavla; Petr, Marek; Renčiuk, Daniel; Vorlíčková, Michaela; Brázdová, Marie

    2016-01-01

    The tumor suppressor protein p53 is a key factor in genome stability and one of the most studied of DNA binding proteins. This is the first study on the interaction of wild-type p53 with guanine quadruplexes formed by the human telomere sequence. Using electromobility shift assay and ELISA, we show that p53 binding to telomeric G-quadruplexes increases with the number of telomeric repeats. Further, p53 strongly favors G-quadruplexes folded in potassium over those formed in sodium, thus indicating the telomeric G-quadruplex conformational selectivity of p53. The presence of the quadruplex-stabilizing ligand, N-methyl mesoporphyrin IX (NMM), increases p53 recognition of G-quadruplexes in potassium. Using deletion mutants and selective p53 core domain oxidation, both p53 DNA binding domains are shown to be crucial for telomeric G-quadruplex recognition.

  12. DNA damage-induced phosphorylation of the human telomere-associated protein TRF2

    PubMed Central

    Tanaka, Hiromi; Mendonca, Marc S.; Bradshaw, Paul S.; Hoelz, Derek J.; Malkas, Linda H.; Meyn, M. Stephen; Gilley, David

    2005-01-01

    Several protein kinases from diverse eukaryotes known to perform important roles in DNA repair have also been shown to play critical roles in telomere maintenance. Here, we report that the human telomere-associated protein TRF2 is rapidly phosphorylated in response to DNA damage. We find that the phosphorylated form of TRF2 is not bound to telomeric DNA, as is the ground form of TRF2, and is rapidly localized to damage sites. Our results suggest that the ataxia-telangiectasia-mutated (ATM) protein kinase signal-transduction pathway is primarily responsible for the DNA damage-induced phosphorylation of TRF2. Unlike DNA damage-induced phosphorylation of other ATM targets, the phosphorylated form of TRF2 is transient, being detected rapidly at DNA damage sites postirradiation, but largely dissipated by 2 hours. In addition, we report that the phosphorylated form of TRF2 is present at telomeres in cell types undergoing telomere-based crisis and a recombination-driven, telomerase-independent, alternative lengthening of telomeres (ALT) pathway, likely as a consequence of a telomere-based DNA damage response. Our results link the induction of TRF2 phosphorylation to the DNA damage-response system, providing an example of direct cross-talk via a signaling pathway between these two major cellular processes essential for genomic stability, telomere maintenance, and DNA repair. PMID:16223874

  13. A prospective analysis of telomere length and pancreatic cancer in the alpha-tocopherol beta-carotene cancer (ATBC) prevention study.

    PubMed

    Lynch, Shannon M; Major, Jacqueline M; Cawthon, Richard; Weinstein, Stephanie J; Virtamo, Jarmo; Lan, Qing; Rothman, Nathaniel; Albanes, Demetrius; Stolzenberg-Solomon, Rachael Z

    2013-12-01

    Smoking and diabetes, consistent risk factors for pancreatic cancer, are also factors that influence telomere length maintenance. To test whether telomere length is associated with pancreatic cancer risk, we conducted a nested case-control study in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study cohort of male smokers, aged 50-69 years at baseline. Between 1992 and 2004, 193 incident cases of pancreatic adenocarcinoma occurred (mean follow-up from blood draw: 6.3 years) among participants with whole blood samples available for telomere length assays. For these cases and 660 controls, we calculated odds ratios (OR) and 95% confidence intervals using unconditional logistic regression, adjusting for age, number of years smoked regularly, and history of diabetes mellitus. Telomere length was categorized into quartiles (shortest to longest) and analyzed as both a categorical and a continuous normal variable (reported per 0.2 unit increase in telomere length). All statistical tests were two-sided. Longer telomere length was significantly associated with increased pancreatic cancer risk (continuous OR = 1.26 95% CI = 1.09-1.46; highest quartile compared to lowest, OR = 1.57, 95% CI = 1.01-2.43, p-trend = 0.007). This association remained for subjects diagnosed within the first five years of blood draw (continuous OR = 1.46, 95% CI = 1.19-1.79 highest quartile OR = 2.92, 95% CI = 1.47-5.77, p-trend = 0.002), but not those diagnosed greater than five years after blood draw (continuous OR = 1.03, 95% CI = 0.85-1.22; highest quartile OR = 1.04, 95% CI = 0.60-1.79). This is the first prospective study to suggest an association between longer blood leukocyte telomere length and increased pancreatic cancer risk.

  14. Telomere length is highly inherited and associated with hyperactivity-impulsivity in children with attention deficit/hyperactivity disorder

    PubMed Central

    Costa, Danielle de Souza; Rosa, Daniela Valadão Freitas; Barros, Alexandre Guimarães Almeida; Romano-Silva, Marco Aurélio; Malloy-Diniz, Leandro Fernandes; Mattos, Paulo; de Miranda, Débora Marques

    2015-01-01

    Telomere length (TL) is highly heritable, and a shorter telomere at birth may increase the risk of age-related problems. Additionally, a shorter TL may represent a biomarker of chronic stress and has been associated with psychiatric disorders. However, no study has explored whether there is an association between TL and the symptoms of one of the most common neurodevelopmental disorders in childhood: Attention Deficit/Hyperactive Disorder (ADHD). We evaluated 61 (range, 6–16 years) ADHD children and their parents between 2012 and 2014. TL was measured with a quantitative polymerase chain reaction method with telomere signal normalized to the signal from a single copy gene (36B4) to generate a T/S ratio. Family data was processed through a generalized estimated equations (GEE) model to determine the effect of parental TL on children TL. Inattentive and hyperactive-impulsive symptoms were also evaluated in relation to TL. For the first time, we found general heritability to be the major mechanism explaining interindividual TL variation in ADHD (father-child: 95% CI = 0.35/0.91, p < 0.001; mother-child: 95% CI = 0.38/0.74, p < 0.001). The hyperactive-impulsive dimension of ADHD was related with children’s TL (r = −339, p = 0.008) and maternal TL (r = −264, p = 0.047), but not with paternal TL (p > 0.05). The ADHD inattentive dimension was not significant associated with TL in this study (p > 0.05). TL was shown to be a potential biomarker of the ADHD symptoms burden in families affected by this neurodevelopmental disorder. However, it is crucial that future studies investigating the rate of telomere attrition in relation to psychiatric problems to consider the strong determination of TL at birth by inheritance. PMID:26217174

  15. 25-Hydroxyvitamin D Concentration and Leukocyte Telomere Length in Young Adults: Findings From the Northern Finland Birth Cohort 1966

    PubMed Central

    Williams, Dylan M.; Palaniswamy, Saranya; Sebert, Sylvain; Buxton, Jessica L.; Blakemore, Alexandra I. F.; Hyppönen, Elina; Jarvelin, Marjo-Riitta

    2016-01-01

    Higher vitamin D status, lower adiposity, and longer telomere length are each reportedly associated with lower risk of several chronic diseases and all-cause mortality. However, direct relationships between vitamin D status (measured by circulating 25-hydroxyvitamin D (25(OH)D) concentration), adiposity, and telomere length are not well established. We conducted a cross-sectional analysis of associations of 25(OH)D and body mass index (BMI; weight (kg)/height (m)2) with mean relative leukocyte telomere length (LTL) using data gathered on 5,096 participants from Northern Finland Birth Cohort 1966 at age 31 years (1997). 25(OH)D was not associated with LTL in either basic or confounder/mediator-adjusted models. BMI was inversely associated with LTL after adjustment for potential confounding by age, sex, socioeconomic position, physical activity, diet, smoking, alcohol intake, and use of oral contraceptives (per 1-unit increase in BMI, mean difference in LTL = −0.4%, 95% confidence interval: −0.6, −0.2). The BMI-LTL association was also independent of 25(OH)D and was attenuated slightly, but remained, after adjustment for C-reactive protein, a marker of low-grade inflammation (mean difference in LTL = −0.3%, 95% confidence interval −0.6, −0.1). These findings suggest that vitamin D status is unlikely to be an important determinant of LTL, at least by young adulthood. Inflammation may partly mediate associations of adiposity with LTL. PMID:26797572

  16. The Truncated Human Telomeric Sequence forms a Hybrid-Type Intramolecular Mixed Parallel/antiparallel G-quadruplex Structure in K(+) Solution.

    PubMed

    Liu, Yuxia; Cheng, Dengfeng; Ge, Min; Lin, Weizhen

    2016-07-01

    In 80-90% tumor cells, telomerase becomes active and stabilizes the length of telomeres. The formation and stabilization of G-quadruplexes formed from human telomeric sequences have been proved able to inhibit the activity of telomerase, thus human telomeric G-quadruplex structure has become a potential target for the development of cancer therapy. Hence, structure of G-quadruplex formed in K(+) solution has been an attractive hotspot for further studies. However, the exact structure of human telomeric G-quadruplex in K(+) is extremely controversial, this study provides information for the understanding of different G-quadruplexes. Here, we report that 22nt and 24nt human telomeric sequences form unimolecular hybrid-type mixed parallel/antiparallel G-quadruplex in K(+) solution elucidated utilizing Circular Dichroism, Differential Scanning Calorimetry, and gel electrophoresis. Moreover, individual configuration of these two sequences was speculated in this study. The detailed structure information of the G-quadruplex formed under physiologically relevant condition is necessary for structure-based rational drug design.

  17. The Truncated Human Telomeric Sequence forms a Hybrid-Type Intramolecular Mixed Parallel/antiparallel G-quadruplex Structure in K(+) Solution.

    PubMed

    Liu, Yuxia; Cheng, Dengfeng; Ge, Min; Lin, Weizhen

    2016-07-01

    In 80-90% tumor cells, telomerase becomes active and stabilizes the length of telomeres. The formation and stabilization of G-quadruplexes formed from human telomeric sequences have been proved able to inhibit the activity of telomerase, thus human telomeric G-quadruplex structure has become a potential target for the development of cancer therapy. Hence, structure of G-quadruplex formed in K(+) solution has been an attractive hotspot for further studies. However, the exact structure of human telomeric G-quadruplex in K(+) is extremely controversial, this study provides information for the understanding of different G-quadruplexes. Here, we report that 22nt and 24nt human telomeric sequences form unimolecular hybrid-type mixed parallel/antiparallel G-quadruplex in K(+) solution elucidated utilizing Circular Dichroism, Differential Scanning Calorimetry, and gel electrophoresis. Moreover, individual configuration of these two sequences was speculated in this study. The detailed structure information of the G-quadruplex formed under physiologically relevant condition is necessary for structure-based rational drug design. PMID:26867976

  18. TELOMERE AND TELOMERASE MODULATION BY BERGAMOT POLYPHENOLIC FRACTION IN EXPERIMENTAL PHOTOAGEING IN HUMAN KERATINOCYTES.

    PubMed

    Nisticò, S; Ehrlich, J; Gliozzi, M; Maiuolo, J; Del Duca, E; Muscoli, C; Mollace, V

    2015-01-01

    Photoageing represents the addition of extrinsic chronic ultraviolet radiation-induced damage on intrinsic ageing and accounts for most age-associated changes in skin appearance. In this study, we evaluated the effect of 38% BPF, a highly concentrated extract of the bergamot fruit (Citrus bergamia) on UVB-induced photoageing by examining inflammatory cytokine expression, telomere length/telomerase alterations and cellular viability in human immortalized HaCaT keratinocytes. Our results suggest that 38% BPF protects HaCaT cells against UVB-induced oxidative stress and markers of photoageing in a dose-dependent manner and could be a useful supplement in skin care products. Together with antioxidant properties, BPF, a highly concentrated extract of the bergamot fruit, appears to modulate basic cellular signal transduction pathways leading to anti-proliferative, anti-aging and immune modulating responses.

  19. TELOMERE AND TELOMERASE MODULATION BY BERGAMOT POLYPHENOLIC FRACTION IN EXPERIMENTAL PHOTOAGEING IN HUMAN KERATINOCYTES.

    PubMed

    Nisticò, S; Ehrlich, J; Gliozzi, M; Maiuolo, J; Del Duca, E; Muscoli, C; Mollace, V

    2015-01-01

    Photoageing represents the addition of extrinsic chronic ultraviolet radiation-induced damage on intrinsic ageing and accounts for most age-associated changes in skin appearance. In this study, we evaluated the effect of 38% BPF, a highly concentrated extract of the bergamot fruit (Citrus bergamia) on UVB-induced photoageing by examining inflammatory cytokine expression, telomere length/telomerase alterations and cellular viability in human immortalized HaCaT keratinocytes. Our results suggest that 38% BPF protects HaCaT cells against UVB-induced oxidative stress and markers of photoageing in a dose-dependent manner and could be a useful supplement in skin care products. Together with antioxidant properties, BPF, a highly concentrated extract of the bergamot fruit, appears to modulate basic cellular signal transduction pathways leading to anti-proliferative, anti-aging and immune modulating responses. PMID:26403416

  20. Telomere-surrounding regions are transcription-permissive 3D nuclear compartments in human cells

    SciTech Connect

    Quina, Ana Sofia; Parreira, Leonor . E-mail: lparreir@igc.gulbenkian.pt

    2005-07-01

    Positioning of genes relative to nuclear heterochromatic compartments is thought to help regulate their transcriptional activity. Given that human subtelomeric regions are rich in highly expressed genes, we asked whether human telomeres are related to transcription-permissive nuclear compartments. To address this question, we investigated in the nuclei of normal human lymphocytes the spatial relations of two constitutively expressed genes (ACTB and RARA) and three nuclear transcripts (ACTB, IL2RA and TCRB) to telomeres and centromeres, as a function of gene activity and transcription levels. We observed that genes and gene transcripts locate close to telomere clusters and away from chromocenters upon activation of transcription. These findings, together with the observation that SC35 domains, which are enriched in pre-mRNA processing factors, are in close proximity to telomeres, indicate that telomere-neighboring regions are permissive to gene expression in human cells. Therefore, the associations of telomeres observed in the interphase nucleus might contribute, as opposed to chromocenters, for the establishment of transcription-permissive 3D nuclear compartments.