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Sample records for affect telomere length

  1. Specific DNA replication mutations affect telomere length in Saccharomyces cerevisiae.

    PubMed Central

    Adams, A K; Holm, C

    1996-01-01

    To investigate the relationship between the DNA replication apparatus and the control of telomere length, we examined the effects of several DNA replication mutations on telomere length in Saccharomyces cerevisiae. We report that a mutation in the structural gene for the large subunit of DNA replication factor C (cdc44/rfc1) causes striking increases in telomere length. A similar effect is seen with mutations in only one other DNA replication gene: the structural gene for DNA polymerase alpha (cdc17/pol1) (M.J. Carson and L. Hartwell, Cell 42:249-257, 1985). For both genes, the telomere elongation phenotype is allele specific and appears to correlate with the penetrance of the mutations. Furthermore, fluorescence-activated cell sorter analysis reveals that those alleles that cause elongation also exhibit a slowing of DNA replication. To determine whether elongation is mediated by telomerase or by slippage of the DNA polymerase, we created cdc17-1 mutants carrying deletions of the gene encoding the RNA component of telomerase (TLC1). cdc17-1 strains that would normally undergo telomere elongation failed to do so in the absence of telomerase activity. This result implies that telomere elongation in cdc17-1 mutants is mediated by the action of telomerase. Since DNA replication involves transfer of the nascent strand from polymerase alpha to replication factor C (T. Tsurimoto and B. Stillman, J. Biol. Chem. 266:1950-1960, 1991; T. Tsurimoto and B. Stillman, J. Biol. Chem. 266:1961-1968, 1991; S. Waga and B. Stillman, Nature [London] 369:207-212, 1994), one possibility is that this step affects the regulation of telomere length. PMID:8756617

  2. Traffic noise exposure affects telomere length in nestling house sparrows

    PubMed Central

    Meillère, Alizée; Brischoux, François; Ribout, Cécile; Angelier, Frédéric

    2015-01-01

    In a consistently urbanizing world, anthropogenic noise has become almost omnipresent, and there are increasing evidence that high noise levels can have major impacts on wildlife. While the effects of anthropogenic noise exposure on adult animals have been widely studied, surprisingly, there has been little consideration of the effects of noise pollution on developing organisms. Yet, environmental conditions experienced in early life can have dramatic lifelong consequences for fitness. Here, we experimentally manipulated the acoustic environment of free-living house sparrows (Passer domesticus) breeding in nest boxes. We focused on the impact of such disturbance on nestlings’ telomere length and fledging success, as telomeres (the protective ends of chromosomes) appear to be a promising predictor of longevity. We showed that despite the absence of any obvious immediate consequences (growth and fledging success), nestlings reared under traffic noise exposure exhibited reduced telomere lengths compared with their unexposed neighbours. Although the mechanisms responsible for this effect remain to be determined, our results provide the first experimental evidence that noise alone can affect a wild vertebrate's early-life telomere length. This suggests that noise exposure may entail important costs for developing organisms. PMID:26382074

  3. Traffic noise exposure affects telomere length in nestling house sparrows.

    PubMed

    Meillère, Alizée; Brischoux, François; Ribout, Cécile; Angelier, Frédéric

    2015-09-01

    In a consistently urbanizing world, anthropogenic noise has become almost omnipresent, and there are increasing evidence that high noise levels can have major impacts on wildlife. While the effects of anthropogenic noise exposure on adult animals have been widely studied, surprisingly, there has been little consideration of the effects of noise pollution on developing organisms. Yet, environmental conditions experienced in early life can have dramatic lifelong consequences for fitness. Here, we experimentally manipulated the acoustic environment of free-living house sparrows (Passer domesticus) breeding in nest boxes. We focused on the impact of such disturbance on nestlings' telomere length and fledging success, as telomeres (the protective ends of chromosomes) appear to be a promising predictor of longevity. We showed that despite the absence of any obvious immediate consequences (growth and fledging success), nestlings reared under traffic noise exposure exhibited reduced telomere lengths compared with their unexposed neighbours. Although the mechanisms responsible for this effect remain to be determined, our results provide the first experimental evidence that noise alone can affect a wild vertebrate's early-life telomere length. This suggests that noise exposure may entail important costs for developing organisms.

  4. Acculturation Predicts Negative Affect and Shortened Telomere Length.

    PubMed

    Ruiz, R Jeanne; Trzeciakowski, Jerome; Moore, Tiffany; Ayers, Kimberly S; Pickler, Rita H

    2016-10-12

    Chronic stress may accelerate cellular aging. Telomeres, protective "caps" at the end of chromosomes, modulate cellular aging and may be good biomarkers for the effects of chronic stress, including that associated with acculturation. The purpose of this analysis was to examine telomere length (TL) in acculturating Hispanic Mexican American women and to determine the associations among TL, acculturation, and psychological factors. As part of a larger cross-sectional study of 516 pregnant Hispanic Mexican American women, we analyzed DNA in blood samples (N = 56) collected at 22-24 weeks gestation for TL as an exploratory measure using monochrome multiplex quantitative telomere polymerase chain reaction (PCR). We measured acculturation with the Acculturation Rating Scale for Mexican Americans, depression with the Beck Depression Inventory, discrimination with the Experiences of Discrimination Scale, and stress with the Perceived Stress Scale. TL was negatively moderately correlated with two variables of acculturation: Anglo orientation and greater acculturation-level scores. We combined these scores for a latent variable, acculturation, and we combined depression, stress, and discrimination scores in another latent variable, "negative affectivity." Acculturation and negative affectivity were bidirectionally correlated. Acculturation significantly negatively predicted TL. Using structural equation modeling, we found the model had an excellent fit with the root mean square error of approximation estimate = .0001, comparative fit index = 1.0, Tucker-Lewis index = 1.0, and standardized root mean square residual = .05. The negative effects of acculturation on the health of Hispanic women have been previously demonstrated. Findings from this analysis suggest a link between acculturation and TL, which may indicate accelerated cellular aging associated with overall poor health outcomes.

  5. Telomere length affects the frequency and mechanism of antigenic variation in Trypanosoma brucei.

    PubMed

    Hovel-Miner, Galadriel A; Boothroyd, Catharine E; Mugnier, Monica; Dreesen, Oliver; Cross, George A M; Papavasiliou, F Nina

    2012-01-01

    Trypanosoma brucei is a master of antigenic variation and immune response evasion. Utilizing a genomic repertoire of more than 1000 Variant Surface Glycoprotein-encoding genes (VSGs), T. brucei can change its protein coat by "switching" from the expression of one VSG to another. Each active VSG is monoallelically expressed from only one of approximately 15 subtelomeric sites. Switching VSG expression occurs by three predominant mechanisms, arguably the most significant of which is the non-reciprocal exchange of VSG containing DNA by duplicative gene conversion (GC). How T. brucei orchestrates its complex switching mechanisms remains to be elucidated. Recent work has demonstrated that an exogenous DNA break in the active site could initiate a GC based switch, yet the source of the switch-initiating DNA lesion under natural conditions is still unknown. Here we investigated the hypothesis that telomere length directly affects VSG switching. We demonstrate that telomerase deficient strains with short telomeres switch more frequently than genetically identical strains with long telomeres and that, when the telomere is short, switching preferentially occurs by GC. Our data supports the hypothesis that a short telomere at the active VSG expression site results in an increase in subtelomeric DNA breaks, which can initiate GC based switching. In addition to their significance for T. brucei and telomere biology, the findings presented here have implications for the many diverse pathogens that organize their antigenic genes in subtelomeric regions.

  6. 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

  7. [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.

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

    PubMed Central

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

    2014-01-01

    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. PMID:24789893

  9. Telomere length and genetic anticipation in Lynch syndrome.

    PubMed

    Seguí, Nuria; Pineda, Marta; Guinó, Elisabet; Borràs, Ester; Navarro, Matilde; Bellido, Fernando; Moreno, Victor; Lázaro, Conxi; Blanco, Ignacio; Capellá, Gabriel; Valle, Laura

    2013-01-01

    Telomere length variation has been associated with increased risk of several types of tumors, and telomere shortening, with genetic anticipation in a number of genetic diseases including hereditary cancer syndromes. No conclusive studies have been performed for Lynch syndrome, a hereditary colorectal cancer syndrome caused by germline mutations in the DNA mismatch repair genes. Here we evaluate telomere length in Lynch syndrome, both as a cancer risk factor and as a mechanism associated with anticipation in the age of cancer onset observed in successive generations of Lynch syndrome families. Leukocyte telomere length was measured in 244 mismatch repair gene mutation carriers from 96 Lynch syndrome families and in 234 controls using a monochrome multiplex quantitative PCR method. Cancer-affected mutation carriers showed significantly shorter telomeres than cancer-free mutation carriers. In addition, cancer-affected carriers showed the most pronounced shortening of telomere length with age, compared with unaffected carriers. The anticipation in the age of cancer onset observed in successive generations was not associated with telomere shortening, although, interestingly, all mother-son pairs showed telomere shortening. In conclusion, cancer-affected mismatch repair gene mutation carriers have distinct telomere-length pattern and dynamics. However, anticipation in the age of onset is not explained by telomere shortening. Pending further study, our findings suggest that telomere attrition might explain the previously reported dependence of cancer risk on the parent-of-origin of mismatch repair gene mutations.

  10. The known genetic loci for telomere length may be involved in the modification of telomeres length after birth

    PubMed Central

    Weng, Qiao; Du, Jiangbo; Yu, Fei; Huang, Tongtong; Chen, Mengxi; Lv, Hong; Ma, Hongxia; Hu, Zhibin; Jin, Guangfu; Hu, Yali; Shen, Hongbing

    2016-01-01

    Telomere length varies considerably among individuals. It is highly heritable and decreases with ageing or ageing related diseases. Recently, genome-wide association studies (GWAS) have identified several genetic loci associated with telomere length in adults. However, it is unclear whether these loci represent the genetic basis of telomere length or determine the individual susceptibility to shortening during growth process. Using DNA extracted from peripheral and cord blood of 444 mother-newborn pairs from a Chinese population, we measured relative telomere length (RTL) and genotyped eight known telomere length related variants that were initially identified in populations of European descent. We observed the T allele of rs10936599 and the T allele of rs2736100 were norminally associated with shorter RTL (P = 0.041 and 0.046, respectively) in maternal samples. Furthermore, the Weighted genetic score (WGS) of eight variants was significantly associated with RTL in maternal samples (R2 = 0.012, P = 0.025). However, we didn’t detect any significant associations for any individual variant or the combined WGS with RTL in newborns. These findings didn’t support the hypothesis that telomere length related loci may affect telomere length at birth, and we suggested that these loci may play a role in telomere length modification during life course. PMID:27929092

  11. 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

  12. 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

  13. Association between Genetic Variations Affecting Mean Telomere Length and the Prevalence of Hypertension and Coronary Heart Disease in Koreans

    PubMed Central

    2016-01-01

    In this study, we investigated whether the single nucleotide polymorphisms (SNPs) associated with telomere length (TL) were associated with the incidence of hypertension (HTN)/coronary heart disease (CHD) and cardiovascular risk factors in the Korean population. Data from 5,705 (ages 39–70) participants in the Korean Genome Epidemiology Study (rural Ansung and urban Ansan cohorts) were studied. Twelve SNPs known to be associated with telomere biology were tested for an association with HTN/CHD. As results, no significant associations were found between the selected TL-related SNPs and prevalence of HTN and CHD. Among non-alcohol users, subjects with minor alleles in rs1269304 and rs10936601 (TERC and LRRC34, respectively) exhibited a higher rate of CHD occurrence (odds ratio [OR], 1.862; 95% confidence intervals [CIs], 1.137, 3.049; OR, 1.855; 95% CIs, 1.111, 2.985; respectively). However, alcohol users with minor alleles in rs398652 (PELI2) were significantly associated with higher HTN prevalence (OR, 1.179; 95% CIs, 1.040, 1.336). Of the 3 SNPs related to disease outcomes, rs1296304 was significantly associated with increased levels of diastolic blood pressure (β estimate, 0.470; 95% CIs, 0.013, 0.926). The minor allele in rs398652 was significantly associated with higher levels of body mass index (OR, 0.128; 95% CIs, 0.010, 0.246) and γ-glutamyl transpeptidase (OR, 0.013; 95% CIs, 0.001, 0.024). In conclusion, there were no significant associations between the selected TL-related SNPs and the occurrence of HTN/CHD in Koreans. However, the results suggest the presence of a possible interaction between related SNPs and alcohol behavior associated with HTN/CHD occurrence. PMID:27812514

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

    PubMed

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

    2005-11-08

    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.

  15. 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.

  16. Telomere lengths in human oocytes, cleavage stage embryos and blastocysts

    PubMed Central

    Turner, S.; Wong, H.P.; Rai, J.; Hartshorne, G.M.

    2010-01-01

    Telomeres are repeated sequences that protect the ends of chromosomes and harbour DNA repair proteins. Telomeres shorten during each cell division in the absence of telomerase. When telomere length becomes critically short, cell senescence occurs. Telomere length therefore reflects both cellular ageing and capacity for division. We have measured telomere length in human germinal vesicle (GV) oocytes and preimplantation embryos, by quantitative fluorescence in situ hybridization (Q-FISH), providing baseline data towards our hypothesis that telomere length is a marker of embryo quality. The numbers of fluorescent foci suggest that extensive clustering of telomeres occurs in mature GV stage oocytes, and in preimplantation embryos. When calculating average telomere length by assuming that each signal presents one telomere, the calculated telomere length decreased from the oocyte to the cleavage stages, and increased between the cleavage stages and the blastocyst (11.12 versus 8.43 versus 12.22 kb, respectively, P < 0.001). Other methods of calculation, based upon expected maximum and minimum numbers of telomeres, confirm that telomere length in blastocysts is significantly longer than cleavage stages. Individual blastomeres within an embryo showed substantial variation in calculated average telomere length. This study implies that telomere length changes according to the stage of preimplantation embryo development. PMID:20573647

  17. TOR links starvation responses to telomere length maintenance.

    PubMed

    Kupiec, Martin; Weisman, Ronit

    2012-06-15

    Telomeres are nucleoprotein structures that protect the ends of eukaryotic chromosomes and play important roles in ensuring the genome's integrity. Telomere length is maintained by complex mechanisms that ensure length homeostasis. Recent work has linked telomere length maintenance to the Tor protein kinases, which are central regulators of cellular growth. Here we summarize these results, which suggest a link between nutrient availability, telomere length maintenance and chronological lifespan.

  18. Telomere length and telomerase activity in the context of menopause.

    PubMed

    Pines, A

    2013-12-01

    Telomere length is a marker of cell aging, since shorter telomeres and a higher rate of telomere shortening with time are associated with poorer health status and survival. Various factors may determine telomere length and the function of the telomere maintenance system, including the hereditary load and several modifiable variables such as diet and lifestyle. Telomere length and telomerase activity were investigated extensively in a variety of diseases, such as malignancies (i.e. breast and colon cancer), cardiovascular disease and its related metabolic risk factors, cognitive, mental and psychiatric conditions, and many others. Some evidence points at an association between longer endogenous estrogen exposure (length of reproductive years of life) and greater telomere length and lower telomerase activity. However, there is probably no correlation in regard to menopause per se or the use of hormone therapy. Changing the nutrition and implementing healthy lifestyles may improve the telomere/telomerase parameters in postmenopausal women, but better understanding of this system is still needed.

  19. The latent cytomegalovirus decreases telomere length by microcompetition

    PubMed Central

    Javaherian, Adrian

    2015-01-01

    Reduced telomere length has been associated with aging and age-related diseases. Latent infection with the Cytomegalovirus (CMV) induces telomere shortening in the infected cells. Latent CMV infection may cause reduced telomere length via GABP transcription factor deficiency, according to the Microcompetition Theory. Microcompetition and viral-induced transcription factor deficiency is important since most people harbor a latent viral infection.

  20. 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

  1. Extreme telomere length dimorphism in the Tasmanian devil and related marsupials suggests parental control of telomere length.

    PubMed

    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.

  2. Association between Snoring and Leukocyte Telomere Length

    PubMed Central

    Shin, Chol; Yun, Chang-Ho; Yoon, Dae Wui; Baik, Inkyung

    2016-01-01

    Study Objectives: Data on the association between snoring and telomere length, an indicator of biological aging, are very limited. Moreover, no polysomnography (PSG) studies on this association in a general population have been conducted. Our study aimed to evaluate the association between snoring and leukocyte telomere length (LTL) using PSG and a questionnaire. Methods: A cross-sectional PSG study embedded in a population-based cohort from the Korean Genome Epidemiology Study was conducted in 2010–2013. During the same period, questionnaire-based interviews, blood collection, and relative LTL assays were conducted. A total of 887 Korean men and women aged 50–79 y with an apnea-hypopnea index (AHI) < 15 determined in the PSG study were included in the study. Results: We observed that the percentage of time spent snoring during sleep (% time spent snoring) assessed by PSG was inversely associated with LTL even after adjusting for potential risk factors and AHI. In the linear regression association between tertiles of percentage of time spent snoring and log-transformed LTL, coefficient estimates (P value) were −0.076 (< 0.05) for the second tertile and −0.084 (< 0.01) for the third tertile compared with the bottom tertile. When LTL was compared according to snoring status determined using PSG and questionnaire information, both primary snorers and those with mild sleep apnea (5 ≤ AHI < 15) had shorter LTL than nonsnorers. Conclusions: Our findings suggest that snoring may influence telomere attrition independent of sleep apnea. Citation: Shin C, Yun CH, Yoon DW, Baik I. Association between snoring and leukocyte telomere length. SLEEP 2016;39(4):767–772. PMID:26715224

  3. Physical activity and telomere length: Impact of aging and potential mechanisms of action.

    PubMed

    Arsenis, Nicole C; You, Tongjian; Ogawa, Elisa F; Tinsley, Grant M; Zuo, Li

    2017-03-30

    Telomeres protect the integrity of information-carrying DNA by serving as caps on the terminal portions of chromosomes. Telomere length decreases with aging, and this contributes to cell senescence. Recent evidence supports that telomere length of leukocytes and skeletal muscle cells may be positively associated with healthy living and inversely correlated with the risk of several age-related diseases, including cancer, cardiovascular disease, obesity, diabetes, chronic pain, and stress. In observational studies, higher levels of physical activity or exercise are related to longer telomere lengths in various populations, and athletes tend to have longer telomere lengths than non-athletes. This relationship is particularly evident in older individuals, suggesting a role of physical activity in combating the typical age-induced decrements in telomere length. To date, a small number of exercise interventions have been executed to examine the potential influence of chronic exercise on telomere length, but these studies have not fully established such relationship. Several potential mechanisms through which physical activity or exercise could affect telomere length are discussed, including changes in telomerase activity, oxidative stress, inflammation, and decreased skeletal muscle satellite cell content. Future research is needed to mechanistically examine the effects of various modalities of exercise on telomere length in middle-aged and older adults, as well as in specific clinical populations.

  4. 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.

  5. 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.

  6. Uncoupling of longevity and telomere length in C. elegans.

    PubMed

    Raices, Marcela; Maruyama, Hugo; Dillin, Andrew; Karlseder, Jan

    2005-09-01

    The nematode Caenorhabditis elegans, after completing its developmental stages and a brief reproductive period, spends the remainder of its adult life as an organism consisting exclusively of post-mitotic cells. Here we show that telomere length varies considerably in clonal populations of wild-type worms, and that these length differences are conserved over at least ten generations, suggesting a length regulation mechanism in cis. This observation is strengthened by the finding that the bulk telomere length in different worm strains varies considerably. Despite the close correlation of telomere length and clonal cellular senescence in mammalian cells, nematodes with long telomeres were neither long lived, nor did worm populations with comparably short telomeres exhibit a shorter life span. Conversely, long-lived daf-2 and short-lived daf-16 mutant animals can have either long or short telomeres. Telomere length of post-mitotic cells did not change during the aging process, and the response of animals to stress was found independent of telomere length. Collectively, our data indicate that telomere length and life span can be uncoupled in a post-mitotic setting, suggesting separate pathways for replication-dependent and -independent aging.

  7. Telomere Length of Individual Chromosomes in Patients with Rheumatoid Arthritis.

    PubMed

    Blinova, E A; Zinnatova, E V; Barkovskaya, M Sh; Borisov, V I; Sizikov, A E; Kozhevnikov, V S; Rubtsov, N B; Kozlov, V A

    2016-04-01

    We analyzed telomere length of individual chromosomes in peripheral blood lymphocytes of healthy individuals and patients with rheumatoid arthritis. Quantitative fluorescent in situ hybridization and subsequent computer analysis of metaphase chromosomes showed that distribution of telomere length on individual chromosomes is different under normal and pathological conditions. Patients with rheumatoid arthritis had significantly shorter chromosome 4p telomeres, which can be essential for pathogenesis of this multifactorial disease. Additionally, disease activity inversely correlated with telomere length on chromosome 10p carrying genes involved in T cell differentiation and proliferation.

  8. Telomere length and periodontal attachment loss: a prospective cohort study

    PubMed Central

    Thomson, WM; Zeng, J; Broadbent, JM; Foster Page, LA; Shalev, I; Moffitt, TE; Caspi, A; Williams, SM; Braithwaite, AW; Robertson, SP; Poulton, R

    2016-01-01

    Aim To examine the association between telomere erosion and periodontitis in a longstanding prospective cohort study of New Zealand adults. Specific hypotheses tested were: (1) that exposure to periodontitis at ages 26 and 38 was associated with accelerated leucocyte telomere erosion; and (2) that accelerated leucocyte telomere erosion was associated with higher rates of periodontitis by ages 26 and 38. Materials and Methods Periodontal attachment loss data were collected at ages 26 and 38. Blood samples taken at the same ages were analysed to obtain estimates of leucocyte telomere length and erosion over a 12-year period. Results Overall, mean telomere length reduced by 0.15 T/S ratio (adjusted) from age 26 to 38 among the 661 participants reported on here. During the same period, the mean attachment loss increased by 10%, after adjusting for sex, socio-economic status and smoking. Regression models showed that attachment loss did not predict telomere length, and that telomere erosion did not predict attachment loss. Conclusions Although both periodontitis and telomere length are age-dependent, they do not appear to be linked, suggesting that determination of leucocyte telomere length may not be a promising clinical approach at this age for identifying people who are at risk for periodontitis. PMID:26713854

  9. 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.

  10. 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.

  11. 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.

  12. 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.

  13. 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.

  14. Prostate Cancer Cell Telomere Length Variability and Stromal Cell Telomere Length as Prognostic Markers for Metastasis and Death

    PubMed Central

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

    2013-01-01

    Current prognostic indicators are imperfect predictors of outcome in men with clinicallylocalized prostate cancer. Thus, tissue-based markers are urgently needed to improve treatment and surveillance decision-making. Given that shortened telomeres enhance chromosomal instability and such instability is a hallmark of metastatic lesions, we hypothesized that alterations in telomere length in the primary cancer would predict risk of progression to metastasis and prostate cancer death. To test this hypothesis, we conducted a prospective cohort study of 596 surgically treated men who participated in the ongoing Health Professionals Follow-up Study. Men who had the combination of more variable telomere length among prostate cancer cells (cell-to-cell) and shorter telomere length in prostate cancer-associated stromal cells were substantially more likely to progress to metastasis or die of their prostate cancer. These findings point to the translational potential of this telomere biomarker for prognostication and risk stratification for individualized therapeutic and surveillance strategies. PMID:23779129

  15. Alterations of telomere length in human brain tumors.

    PubMed

    Kheirollahi, Majid; Mehrazin, Masoud; Kamalian, Naser; Mehdipour, Parvin

    2011-09-01

    Telomeres at the ends of human chromosomes consist of tandem hexametric (TTAGGG)n repeats, which protect them from degradation. At each cycle of cell division, most normal somatic cells lose approximately 50-100 bp of the terminal telomeric repeat DNA. Precise prediction of growth and estimation of the malignant potential of brain tumors require additional markers. DNA extraction was performed from the 51 frozen tissues, and a non-radioactive chemiluminescent assay was used for Southern blotting. One sample t-test shows highly significant difference in telomere length in meningioma and astrocytoma with normal range. According to our results, higher grades of meningioma and astrocytoma tumors show more heterogeneity in telomere length, and also it seems shortening process of telomeres is an early event in brain tumors.

  16. Telomere length and cardiovascular aging: the means to the ends?

    PubMed

    De Meyer, Tim; Rietzschel, Ernst R; De Buyzere, Marc L; Van Criekinge, Wim; Bekaert, Sofie

    2011-04-01

    Epidemiologic and other evidence clearly indicates that peripheral blood leukocyte telomere length, a systemic marker for biological aging, can be useful as a cardiovascular aging biomarker. Although telomere biology might yield new insights into the underlying molecular biology of vascular aging and even radically improve current cardiovascular risk stratification, the specific nature of the association between telomere length and cardiovascular disease still remains to be elucidated. Here, we review several candidate hypotheses and critically review supporting and contesting scientific evidence for the underlying theories. For each hypothesis, we discuss the potential implications. We conclude that the most promising theory is based on an acceleration of the telomere attrition rate due to cardiovascular aging related factors, possibly complemented by telomere mediated hematopoietic senescence.

  17. 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

  18. 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.

  19. 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.

  20. 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.

  1. Estimating telomere length from whole genome sequence data.

    PubMed

    Ding, Zhihao; Mangino, Massimo; Aviv, Abraham; Spector, Tim; Durbin, Richard

    2014-05-01

    Telomeres play a key role in replicative ageing and undergo age-dependent attrition in vivo. Here, we report a novel method, TelSeq, to measure average telomere length from whole genome or exome shotgun sequence data. In 260 leukocyte samples, we show that TelSeq results correlate with Southern blot measurements of the mean length of terminal restriction fragments (mTRFs) and display age-dependent attrition comparably well as mTRFs.

  2. Estimating telomere length from whole genome sequence data

    PubMed Central

    Ding, Zhihao; Mangino, Massimo; Aviv, Abraham; Spector, Tim; Durbin, Richard

    2014-01-01

    Telomeres play a key role in replicative ageing and undergo age-dependent attrition in vivo. Here, we report a novel method, TelSeq, to measure average telomere length from whole genome or exome shotgun sequence data. In 260 leukocyte samples, we show that TelSeq results correlate with Southern blot measurements of the mean length of terminal restriction fragments (mTRFs) and display age-dependent attrition comparably well as mTRFs. PMID:24609383

  3. 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

  4. 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

  5. Telomere Length Is a Determinant of Emphysema Susceptibility

    PubMed Central

    Alder, Jonathan K.; Guo, Nini; Kembou, Frant; Parry, Erin M.; Anderson, Collin J.; Gorgy, Amany I.; Walsh, Michael F.; Sussan, Thomas; Biswal, Shyam; Mitzner, Wayne; Tuder, Rubin M.

    2011-01-01

    Rationale: Germline mutations in the enzyme telomerase cause telomere shortening, and have their most common clinical manifestation in age-related lung disease that manifests as idiopathic pulmonary fibrosis. Short telomeres are also a unique heritable trait that is acquired with age. Objectives: We sought to understand the mechanisms by which telomerase deficiency contributes to lung disease. Methods: We studied telomerase null mice with short telomeres. Measurements and Main Results: Although they have no baseline histologic defects, when mice with short telomeres are exposed to chronic cigarette smoke, in contrast with controls, they develop emphysematous air space enlargement. The emphysema susceptibility did not depend on circulating cell genotype, because mice with short telomeres developed emphysema even when transplanted with wild-type bone marrow. In lung epithelium, cigarette smoke exposure caused additive DNA damage to telomere dysfunction, which limited their proliferative recovery, and coincided with a failure to down-regulate p21, a mediator of cellular senescence, and we show here, a determinant of alveolar epithelial cell cycle progression. We also report early onset of emphysema, in addition to pulmonary fibrosis, in a family with a germline deletion in the Box H domain of the RNA component of telomerase. Conclusions: Our data indicate that short telomeres lower the threshold of cigarette smoke–induced damage, and implicate telomere length as a genetic susceptibility factor in emphysema, potentially contributing to its age-related onset in humans. PMID:21757622

  6. 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

  7. 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

  8. 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...

  9. 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.

  10. 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

  11. Inositol pyrophosphates modulate cell cycle independently of alteration in telomere length.

    PubMed

    Banfic, Hrvoje; Crljen, Vladiana; Lukinovic-Skudar, Vesna; Dembitz, Vilma; Lalic, Hrvoje; Bedalov, Antonio; Visnjic, Dora

    2016-01-01

    Synthesis of inositol pyrophosphates through activation of Kcs1 plays an important role in the signalling response required for cell cycle progression after mating pheromone arrest. Overexpression of Kcs1 doubled the level of inositol pyrophosphates when compared to wild type cells and 30 min following the release from α-factor block further increase in inositol pyrophosphates was observed, which resulted that cells overexpressing Kcs1 reached G2/M phase earlier than wild type cells. Similar effect was observed in ipk1Δ cells, which are unable to synthesize IP6-derived inositol pyrophosphates (IP7 and IP8) but will synthesize IP5-derived inositol pyrophosphates (PP-IP4 and (PP)2-IP3). Although ipk1Δ cells have shorter telomeres than wild type cells, overexpression of Kcs1 in both strains have similar effect on cell cycle progression. As it is known that PP-IP4 regulates telomere length through Tel1, inositol polyphosphates, cell cycle and telomere length were determined in tel1Δ cells. The release of the cells from α-factor block and overexpression of Kcs1 in tel1Δ cells produced similar effects on inositol pyrophosphates level and cell cycle progression when compared to wild type cells, although tel1Δ cells possesses shorter telomeres than wild type cells. It can be concluded that telomere length does not affect cell cycle progression, since cells with short telomeres (ipk1Δ and tel1Δ) progress through cell cycle in a similar manner as wild type cells and that overexpression of Kcs1 in cells with either short or normal telomeres will increase S phase progression without affecting telomere length. Furthermore, IP5-derived inositol pyrophosphates can compensate for the loss of IP6-derived inositol pyrophosphates, in modulating S phase progression of the cell cycle.

  12. Developmental control of telomere lengths and telomerase activity in plants.

    PubMed Central

    Riha, K; Fajkus, J; Siroky, J; Vyskot, B

    1998-01-01

    Telomere lengths and telomerase activity were studied during the development of a model dioecious plant, Melandrium album (syn Silene latifolia). Telomeric DNA consisted of Arabidopsis-type TTTAGGG tandem repeats. The terminal positions of these repeats were confirmed by both Bal31 exonuclease degradation and in situ hybridization. Analysis of terminal restriction fragments in different tissues and ontogenetic stages showed that telomere lengths are stabilized precisely and do not change during plant growth and development. Telomerase activity tested by using a semiquantitative telomerase repeat amplification protocol correlated with cell proliferation in the tissues analyzed. Highest activity was found in germinating seedlings and root tips, whereas we observed a 100-fold decrease in telomerase activity in leaves and no activity in quiescent seeds. Telomerase also was found in mature pollen grains. Telomerase activity in tissues containing dividing cells and telomere length stability during development suggest their precise control during plant ontogenesis; however, the telomere length regulation mechanism could be unbalanced during in vitro dedifferentiation. PMID:9761795

  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. 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.

  15. Childhood adversities are associated with shorter telomere length at adult age both in individuals with an anxiety disorder and controls.

    PubMed

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

    2010-05-25

    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.

  16. Test anxiety and telomere length: Academic stress in adolescents may not cause rapid telomere erosion.

    PubMed

    Zou, Yaru; Leong, Waiian; Yao, Mingling; Hu, Xuefei; Lu, Sixiao; Zhu, Xiaowei; Chen, Lianxiang; Tong, Jianjing; Shi, Jingyi; Gilson, Eric; Ye, Jing; Lu, Yiming

    2017-01-22

    Academic stress (AS) is one of the most important health problems experienced by students, but no biomarker of the potential psychological or physical problems associated with AS has yet been identified. As several cross-sectional studies have shown that psychiatric conditions accelerate aging and shorten telomere length (TL), we explored whether AS affected TL.Between June 2014 and July 2014, we recruited 200 junior high school students with imminent final examinations for participation in this study. The students were divided into three subgroups (mild, moderate, and severe anxiety) using the Sarason Test Anxiety Scale (TAS). Saliva samples were collected for TL measurement via quantitative polymerase chain reaction (qPCR).Students from both a specialized and a general school suffered from anxiety (p > 0.05). A total 35% had severe anxiety (score: 26.09±3.87), 33% had moderate anxiety (16.98±2.64), and 32% had mild anxiety (7.89±1.92). The TAS values differed significantly (p < 0.05) among the three subgroups, but the TLs of saliva cells differed only slightly (p > 0.05): 1.14±0.46 for those with severe anxiety, 1.02±0.40 for those with moderate anxiety, and 1.12±0.45 for those with mild anxiety.Previous reports have found that AS is very common in Asian adolescents. We found no immediate telomere shortening in adolescents with AS. Longitudinal observations are required to determine if TL is affected by AS.

  17. 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.

  18. A Biobehavioral Perspective on Telomere Length and the Exposome

    PubMed Central

    Lyon, Debra E.; Starkweather, Angela R.; Montpetit, Alison; Menzies, Victoria; Jallo, Nancy

    2017-01-01

    A major objective of biobehavioral research is defining the mechanisms that underlie linkages among behavior, biology, health, and disease. The genomic revolution has demonstrated the importance of studying the role of the environment in (epi)genetic mechanisms. The idea that interactions between environment and genetics influence health outcomes is a central concept of the exposome, a measure of environmental exposures throughout a lifetime. Research suggests that telomere length (TL) and biologic factors involved in telomere stability may provide an understanding of the effects of gene–environment interaction on disease risk. Telomeres, thus, have become important biomarkers for aging as well as for stress-related disease. However, incorporating telomeres into biobehavioral research requires consideration of several aspects of the exposome. Internal and external modifiable and nonmodifiable exposures have the potential to influence TL. Future research utilizing the concept of the exposome will provide meaningful findings related to exposure sources as well as dosage and duration across the life span that influence telomere biology and disease occurrence. Such findings can be translated into clinical practice and may provide a basis for personalized disease prevention and treatment approaches. PMID:25199652

  19. 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

  20. Chronic and acute effects of endurance training on telomere length.

    PubMed

    Borghini, Andrea; Giardini, Guido; Tonacci, Alessandro; Mastorci, Francesca; Mercuri, Antonella; Mrakic-Sposta, Simona; Sposta, Simona Mrakic; Moretti, Sarah; Andreassi, Maria Grazia; Pratali, Lorenza

    2015-09-01

    Telomere shortening is considered a cellular marker of health status and biological ageing. Exercise may influence the health and lifespan of an individual by affecting telomere length (TL). However, it is unclear whether different endurance exercise levels may have beneficial or detrimental effects on biological aging. The aims of the study were to assess both chronic and acute effects of endurance training on TL after an exceptional and extreme trail race. TL was assessed in 20 endurance athletes (17 males; age = 45.4 ± 9.2 years) and 42 age- and gender-matched sedentary controls (32 males; age = 45.9 ± 9.5 years) with quantitative real-time PCR at baseline conditions. Of the 20 runners enrolled in the 'Tor des Géants ®' ultra-distance trail race, 15 athletes (12 males; age = 47.2 ± 8.5 years) were re-evaluated at the intermediate point and 14 athletes (11 males; age = 47.1 ± 8.8 years) completed the competition and were analysed at the final point. Comparison between the two groups (endurance athletes vs. sedentary controls) revealed a significant difference in TL (1.28 ± 0.4 vs. 1.02 ± 0.3, P = 0.005). TL was better preserved in elder endurance runners compared with the same age control group (1.3 ± 0.27 vs. 0.91 ± 0.21, P = 0.003). TL was significantly reduced at the intermediate (0.88 ± 0.36 vs. 1.11 ± 0.34, P = 0.002) and final point compared with baseline measurements (0.86 ± 0.4 vs. 1.11 ± 0.34, P = 0.0006) for athletes engaged in the ultra-marathon race. Our data suggest that chronic endurance training may provide protective effects on TL attenuating biological aging. Conversely, acute exposure to an ultra-distance endurance trail race implies telomere shortening probably caused by oxidative DNA damage.

  1. 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.

  2. Shorter leukocyte telomere length in patients at ultra high risk for psychosis.

    PubMed

    Maurya, Pawan Kumar; Rizzo, Lucas Bortolotto; Xavier, Gabriela; Tempaku, Priscila Farias; Zeni-Graiff, Maiara; Santoro, Marcos L; Mazzotti, Diego Robles; Zugman, André; Pan, Pedro; Noto, Cristiano; Maes, Michael; Asevedo, Elson; Mansur, Rodrigo B; Cunha, Graccielle R; Gadelha, Ary; Bressan, Rodrigo A; Belangero, Sintia Iole; Brietzke, Elisa

    2017-03-05

    Telomere length attrition has been demonstrated in schizophrenia but not in individuals in ultra high risk (UHR) for psychosis. The present study aimed to compare the leukocyte telomere length (TL) between patients at UHR for psychosis and healthy controls (HC). Twenty-two participants with UHR and 88 HC were enrolled in this study. Telomere lengths were determined using a multiplex qPCR assay. After adjustment for age, sex, ethnicity, and education, patients in UHR, compared with HC groups, had shorter telomere length (RR: 0.929, p=0.031). Shorter leukocyte telomere length in UHR could represent early signs of accelerated aging in this population.

  3. Impact of Dehydroepiandrosterone Sulfate on Newborn Leukocyte Telomere Length

    PubMed Central

    Liu, Han; Zhou, Guangdi; Chen, Qian; Ouyang, Fengxiu; Little, Julian; Zhang, Jun; Chen, Dan

    2017-01-01

    The newborn setting of leukocyte telomere length (LTL) likely has important implications for telomere dynamics over the lifespan. However, its determinants are poorly understood. Hormones play an important role during pregnancy and delivery. We hypothesized that exposure to hormones may impact the fetal telomere biology system. To test this hypothesis, cortisol, estradiol, dehydroepiandrosterone sulfate (DHEAS) and reactive oxygen species (ROS) were measured in cord blood of 821 newborns from a prospective study. After accounting for the effects of potential determinants of newborn LTL, a 10-fold increase in DHEAS concentration was associated with a 0.021 increase in T/S ratio of newborn LTL (95% confidence interval: 0.009–0.034, P = 0.0008). For newborns who fell in the lowest quartile of DHEAS level, the mean newborn LTL was estimated to be approximately 2.0% shorter than the newborns in the highest DHEAS concentration quartile (P = 0.0014). However, no association was found between newborn LTL and cortisol or estradiol. As expected, newborns with higher ROS level (ROS > 260 mol/L) had lower LTL compared to that with lower ROS level (ROS ≤ 260 mol/L) (P = 0.007). There was also an inverse relationship between DHEAS and ROS (P < 1×10−4). Our findings suggest that exposure to DHEAS may exert a “programming” effect on the newborn telomere biology system. PMID:28186106

  4. Telomere Length as a Predictor of Aggressive Prostate Cancer

    DTIC Science & Technology

    2008-11-01

    tissue microarrays. We used FISH to conduct relative quantitation of telomere length in ~4000 digitally-imaged spots equating to ~40,000 records . For...intake, obesity, physical inactivity b) Oxidative stress – antioxidants ( lycopene , selenium, vitamin E) and oxidants (cigarette smoking) 4...the TMAs by the Harvard investigators was 663, which is greater than the 400 samples we had proposed to investigate. Efficiency in the use of TMAs

  5. Telomere length and incident atrial fibrillation – data of the PREVEND cohort

    PubMed Central

    Siland, Joylene E.; Geelhoed, Bastiaan; van Gelder, Isabelle C.; van der Harst, Pim; Rienstra, Michiel

    2017-01-01

    Background The incidence of atrial fibrillation (AF) increases with age. Telomere length is considered a marker of biological ageing. We investigated the association between leukocyte telomere length and incident AF in the Dutch Prevention of Renal and Vascular End-stage Disease (PREVEND) study. Methods We included 7775 individuals without prevalent AF, and with leukocyte telomere length measured. Mean telomere length was determined by a monochrome multiplex quantitative polymerase chain reaction-based assay. Results Mean age of our cohort was 49±13 years, and 50% were men. During a mean follow-up of 11.4±2.9 years incident AF was detected in 367 (4.7%) individuals. Telomere length was shorter in individuals developing incident AF compared to those without AF (p = 0.013). Incident AF was inversely related to the telomere length. In the quartile with the longest telomere length 68 (3.5%) individuals developed AF, in the shortest telomere length quartile 100 (5.1%) individuals (p = 0.032). Telomere length was associated with incident AF in the second shortest telomere length quartile using the longest telomere length quartile as reference (hazard ratio 1.64; 95% CI 1.02–2.66; p = 0.043). After including age or AF risk factors, the relation between telomere length and incident AF was no longer significant. We found a significant interaction of age, male sex, systolic blood pressure, BMI, heart failure, and myocardial infarction with telomere length for the association with incident AF. Conclusions We found that shorter leukocyte telomere length is not independently associated with incident AF in a community-based cohort. PMID:28158257

  6. 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.

  7. How Do Growth and Sibling Competition Affect Telomere Dynamics in the First Month of Life of Long-Lived Seabird?

    PubMed Central

    Mizutani, Yuichi; Niizuma, Yasuaki; Yoda, Ken

    2016-01-01

    Telomeres are nucleotide sequences located at the ends of chromosomes that promote genome stability. Changes in telomere length (dynamics) are related to fitness or life expectancy, and telomere dynamics during the development phase are likely to be affected by growth and stress factors. Here, we examined telomere dynamics of black-tailed gull chicks (Larus crassirostris) in nests with and without siblings. We found that the initial telomere lengths of singletons at hatching were longer than those of siblings, indicating that singletons are higher-quality chicks than siblings in terms of telomere length. Other factors likely affecting individual quality (i.e., sex, laying date, laying order of eggs, and clutch size) were not related to telomere lengths. Within broods, initial telomere lengths were longer in older chicks than in younger chicks, suggesting that maternal effects, which vary with laying sequence, influence the initial lengths. Additionally, telomeres of chicks with a sibling showed more attrition between hatching and fledging than those of singleton chicks, suggesting that being raised with siblings can cause a sustained competitive environment that leads to telomere loss. High growth rates were associated with a low degree of telomere shortening observed in older siblings, perhaps because slower growth reflects higher food stress and/or higher aerobic metabolism from increased begging effort. Our results show that developmental telomere attrition was an inevitable consequence in two-chick nests in the pre- and post-hatching microenvironments due to the combination of social stress within the nest and maternal effects. The results of our study shed light on telomere dynamics in early life, which may represent an important physiological undercurrent of life-history traits. PMID:27902754

  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. 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

  10. 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.

  11. Measuring telomere length and telomere dynamics in evolutionary biology and ecology

    PubMed Central

    Nussey, Daniel H; Baird, Duncan; Barrett, Emma; Boner, Winnie; Fairlie, Jennifer; Gemmell, Neil; Hartmann, Nils; Horn, Thorsten; Haussmann, Mark; Olsson, Mats; Turbill, Chris; Verhulst, Simon; Zahn, Sandrine; Monaghan, Pat

    2014-01-01

    Telomeres play a fundamental role in the protection of chromosomal DNA and in the regulation of cellular senescence. Recent work in human epidemiology and evolutionary ecology suggests adult telomere length (TL) may reflect past physiological stress and predict subsequent morbidity and mortality, independent of chronological age. Several different methods have been developed to measure TL, each offering its own technical challenges. The aim of this review is to provide an overview of the advantages and drawbacks of each method for researchers, with a particular focus on issues that are likely to face ecologists and evolutionary biologists collecting samples in the field or in organisms that may never have been studied in this context before. We discuss the key issues to consider and wherever possible try to provide current consensus view regarding best practice with regard to sample collection and storage, DNA extraction and storage, and the five main methods currently available to measure TL. Decisions regarding which tissues to sample, how to store them, how to extract DNA, and which TL measurement method to use cannot be prescribed, and are dependent on the biological question addressed and the constraints imposed by the study system. What is essential for future studies of telomere dynamics in evolution and ecology is that researchers publish full details of their methods and the quality control thresholds they employ. PMID:25834722

  12. Clinical Associations of Leukocyte Telomere Length in a Cohort of Repatriated Prisoners of War

    DTIC Science & Technology

    2014-07-01

    to 01-07-2014 4 . TITLE AND SUBTITLE Clinical Associations of Leukocyte Telomere Length in a Cohort of Repatriated Prisoners of War 5a. CONTRACT...biomarker of aging and disease ( 4 ). However, these commercially available blood tests utilize the readily accessible leukocyte telomere length (LTL...added LTL measurements to its laboratory panel in 2011. This preliminary study was undertaken to determine if a commercial 4 RPW TELOMERE LENGTH LTL

  13. 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.

  14. Investigation of telomere lengths measurement by quantitative real-time PCR to predict age.

    PubMed

    Hewakapuge, Sudinna; van Oorschot, Roland A H; Lewandowski, Paul; Baindur-Hudson, Swati

    2008-09-01

    Currently DNA profiling methods only compare a suspect's DNA with DNA left at the crime scene. When there is no suspect, it would be useful for the police to be able to predict what the person of interest looks like by analysing the DNA left behind in a crime scene. Determination of the age of the suspect is an important factor in creating an identikit. Human somatic cells gradually lose telomeric repeats with age. This study investigated if one could use a correlation between telomere length and age, to predict the age of an individual from their DNA. Telomere length, in buccal cells, of 167 individuals aged between 1 and 96 years old was measured using real-time quantitative PCR. Telomere length decreased with age (r=-0.185, P<0.05) and the age of an individual could be roughly determined by the following formula: (age=relative telomere length -1.5/-0.005). The regression (R(2)) value between telomere length and age was approximately 0.04, which is too low to be use for forensics. The causes for the presence of large variation in telomere lengths in the population were further investigated. The age prediction accuracies were low even after dividing samples into non-related Caucasians, males and females (5%, 9% and 1%, respectively). Mean telomere lengths of eight age groups representing each decade of life showed non-linear decrease in telomere length with age. There were variations in telomere lengths even among similarly aged individuals aged 26 years old (n=10) and age 54 years old (n=9). Therefore, telomere length measurement by real-time quantitative PCR cannot be used to predict age of a person, due to the presence of large inter-individual variations in telomere lengths.

  15. 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

  16. 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

    2016-08-11

    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.

  17. On being the right size: increased body size is associated with reduced telomere length under natural conditions.

    PubMed

    Ringsby, Thor Harald; Jensen, Henrik; Pärn, Henrik; Kvalnes, Thomas; Boner, Winnie; Gillespie, Robert; Holand, Håkon; Hagen, Ingerid Julie; Rønning, Bernt; Sæther, Bernt-Erik; Monaghan, Pat

    2015-12-07

    Evolution of body size is likely to involve trade-offs between body size, growth rate and longevity. Within species, larger body size is associated with faster growth and ageing, and reduced longevity, but the cellular processes driving these relationships are poorly understood. One mechanism that might play a key role in determining optimal body size is the relationship between body size and telomere dynamics. However, we know little about how telomere length is affected when selection for larger size is imposed in natural populations. We report here on the relationship between structural body size and telomere length in wild house sparrows at the beginning and end of a selection regime for larger parent size that was imposed for 4 years in an isolated population of house sparrows. A negative relationship between fledgling size and telomere length was present at the start of the selection; this was extended when fledgling size increased under the selection regime, demonstrating a persistent covariance between structural size and telomere length. Changes in telomere dynamics, either as a correlated trait or a consequence of larger size, could reduce potential longevity and the consequent trade-offs could thereby play an important role in the evolution of optimal body size.

  18. 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

  19. Setting the Trajectory: Racial Disparities in Newborn Telomere Length

    PubMed Central

    Drury, Stacy S.; Esteves, Kyle; Hatch, Virginia; Woodbury, Margaret; Borne, Sophie; Adamski, Alys; Theall, Katherine P.

    2015-01-01

    Objective To explore racial differences in newborn telomere length (TL) and the effect moderation of the sex of the infant while establishing the methodology for the use of newborn blood spots for telomere length analyses. Study design Pregnant mothers were recruited from the Greater New Orleans area. TL was determined using MMQ-PCR on DNA extracted from infant blood spots. Demographic data and other covariates were obtained via maternal report prior to infant birth. Birth outcome data were obtained from medical records and maternal report. Results Black infants weighed significantly less than white infants at birth, and had significantly longer TL than White infants (p=0.0134), with the strongest effect observed in Black female infants. No significant differences in gestational age were present. Conclusions Significant racial differences in TL were present at birth in this sample, even after controlling for a range of birth outcomes and demographic factors. As longer initial TL is predictive of more rapid TL attrition across the life course, these findings provide evidence that, even at birth, biological vulnerability to early life stress may differ by race and sex. PMID:25681203

  20. 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.

  1. Surface Enhanced Raman Scattering Based in Situ Hybridization Strategy for Telomere Length Assessment.

    PubMed

    Zong, Shenfei; Chen, Chen; Wang, Zhuyuan; Zhang, Yizhi; Cui, Yiping

    2016-02-23

    Assessing telomere length is of vital importance since telomere length is closely related with several fatal diseases such as atherosclerosis and cancer. Here, we present a strategy to assess/measure telomere length, that is, surface enhanced Raman scattering (SERS) based in situ hybridization (SISH). The SISH method uses two kinds of SERS nanoprobes to hybridize in situ with telomeres and centromeres, respectively. The telomere specific SERS nanoprobe is called the Telo-probe, while the centromere specific SERS nanoprobe is called the Centro-probe. They are composed of metal nanoparticles (NPs), Raman reporter molecules and specially designed DNA strands. With longer telomeres, more Telo-probes will hybridize with them, resulting in a stronger SERS signal. To exclude possible influence of the SERS intensity by external factors (such as the nanoprobe concentration, the cell number or different batches of nanoprobes), centromeres are used as the inner control, which can be recognized by Centro-probes. Telomere length is evaluated using a redefined telomere-to-centromere ratio (T/C ratio). The calculation method for T/C ratio in SISH method is more reliable than that in fluorescent in situ hybridization (FISH). In addition, unlike FISH method, the SISH method is insensitive to autofluorescence. Moreover, SISH method can be used to analyze single telomeres. These features make SISH an excellent alternative strategy for telomere length measurement.

  2. Common genetic variants associated with telomere length confer risk for neuroblastoma and other childhood cancers.

    PubMed

    Walsh, Kyle M; Whitehead, Todd P; de Smith, Adam J; Smirnov, Ivan V; Park, Minsun; Endicott, Alyson A; Francis, Stephen S; Codd, Veryan; Samani, Nilesh J; Metayer, Catherine; Wiemels, Joseph L

    2016-06-01

    Aberrant telomere lengthening is an important feature of cancer cells in adults and children. In addition to somatic mutations, germline polymorphisms in telomere maintenance genes impact telomere length. Whether these telomere-associated polymorphisms affect risk of childhood malignancies remains largely unexplored. We collected genome-wide data from three groups with pediatric malignancies [neuroblastoma (N = 1516), acute lymphoblastic leukemia (ALL) (N = 958) and osteosarcoma (N = 660)] and three control populations (N = 6892). Using case-control comparisons, we analyzed eight single nucleotide polymorphisms (SNPs) in genes definitively associated with interindividual variation in leukocyte telomere length (LTL) in prior genome-wide association studies: ACYP2, TERC, NAF1, TERT, OBFC1, CTC1, ZNF208 and RTEL1 Six of these SNPs were associated (P < 0.05) with neuroblastoma risk, one with leukemia risk and one with osteosarcoma risk. The allele associated with longer LTL increased cancer risk for all these significantly associated SNPs. Using a weighted linear combination of the eight LTL-associated SNPs, we observed that neuroblastoma patients were predisposed to longer LTL than controls, with each standard deviation increase in genotypically estimated LTL associated with a 1.15-fold increased odds of neuroblastoma (95%CI = 1.09-1.22; P = 7.9×10(-7)). This effect was more pronounced in adolescent-onset neuroblastoma patients (OR = 1.46; 95%CI = 1.03-2.08). A one standard deviation increase in genotypically estimated LTL was more weakly associated with osteosarcoma risk (OR = 1.10; 95%CI = 1.01-1.19; P = 0.017) and leukemia risk (OR = 1.07; 95%CI = 1.00-1.14; P = 0.044), specifically for leukemia patients who relapsed (OR = 1.19; 95%CI = 1.01-1.40; P = 0.043). These results indicate that genetic predisposition to longer LTL is a newly identified risk factor for neuroblastoma and potentially for other cancers of childhood.

  3. 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.

  4. 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.

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

    PubMed

    Yamada, Tomoya; Higuchi, Mikito; Nakanishi, Naoto

    2015-08-07

    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.

  6. QTL Mapping and Candidate Gene Analysis of Telomere Length Control Factors in Maize (Zea mays L.)

    PubMed Central

    Brown, Amber N.; Lauter, Nick; Vera, Daniel L.; McLaughlin-Large, Karen A.; Steele, Tace M.; Fredette, Natalie C.; Bass, Hank W.

    2011-01-01

    Telomere length is a quantitative trait important for many cellular functions. Failure to regulate telomere length contributes to genomic instability, cellular senescence, cancer, and apoptosis in humans, but the functional significance of telomere regulation in plants is much less well understood. To gain a better understanding of telomere biology in plants, we used quantitative trait locus (QTL) mapping to identify genetic elements that control telomere length variation in maize (Zea mays L.). For this purpose, we measured the median and mean telomere lengths from 178 recombinant inbred lines of the IBM mapping population and found multiple regions that collectively accounted for 33–38% of the variation in telomere length. Two-way analysis of variance revealed interaction between the quantitative trait loci at genetic bin positions 2.09 and 5.04. Candidate genes within these and other significant QTL intervals, along with select genes known a priori to regulate telomere length, were tested for correlations between expression levels and telomere length in the IBM population and diverse inbred lines by quantitative real-time PCR. A slight but significant positive correlation between expression levels and telomere length was observed for many of the candidate genes, but Ibp2 was a notable exception, showing instead a negative correlation. A rad51-like protein (TEL-MD_5.04) was strongly supported as a candidate gene by several lines of evidence. Our results highlight the value of QTL mapping plus candidate gene expression analysis in a genetically diverse model system for telomere research. PMID:22384354

  7. The Effect on Melanoma Risk of Genes Previously Associated With Telomere Length

    PubMed Central

    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.

    2014-01-01

    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

  8. 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.

  9. Realizing the Translational Potential of Telomere Length Variation as a Tissue-Based Prognostic Marker for Prostate Cancer

    DTIC Science & Technology

    2014-10-01

    Telomere Length Variation as a Tissue- Based Prognostic Marker for Prostate Cancer PRINCIPAL INVESTIGATOR: Elizabeth A. Platz CONTRACTING...Translational Potential of Telomere Length Variation as a Tissue- Based Prognostic Marker for Prostate Cancer 5b. GRANT NUMBER W81XWH-12-1-0545 5c...combination of telomere length variability in prostate cancer cells and short telomere length in cancer -associated stromal cells is an independent

  10. 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

  11. 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

  12. 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

  13. n-3 Fatty Acid Supplementation and Leukocyte Telomere Length in Patients with Chronic Kidney Disease.

    PubMed

    Barden, Anne; O'Callaghan, Nathan; Burke, Valerie; Mas, Emile; Beilin, Lawrence J; Fenech, Michael; Irish, Ashley B; Watts, Gerald F; Puddey, Ian B; Huang, Rae-Chi; Mori, Trevor A

    2016-03-19

    DNA telomere shortening associates with the age-related increase cardiovascular disease (CVD) risk. Reducing oxidative stress, could modify telomere erosion during cell replication, and CVD risk in patients with chronic kidney disease (CKD). The effect of n-3 fatty acids and coenzyme Q10 (CoQ) on telomere length was studied in a double-blind placebo-controlled trial in CKD. Eighty-five CKD patients were randomized to: n-3 fatty acids (4 g); CoQ (200 mg); both supplements; or control (4 g olive oil), daily for 8 weeks. Telomere length was measured in neutrophils and peripheral blood mononuclear cells (PBMC) at baseline and 8 weeks, with and without correction for cell counts. Main and interactive effects of n-3 fatty acids and CoQ on telomere length were assessed adjusting for baseline values. F₂-isoprostanes were measured as markers of oxidative stress. There was no effect of n-3 fatty acids or CoQ on neutrophil or PBMC telomere length. However, telomere length corrected for neutrophil count was increased after n-3 fatty acids (p = 0.015). Post-intervention plasma F₂-isoprostanes were negative predictors of post-intervention telomere length corrected for neutrophil count (p = 0.025).The effect of n-3 fatty acids to increased telomere length corrected for neutrophil count may relate to reduced oxidative stress and increased clearance of neutrophils with shorter telomeres from the circulation. This may be a novel mechanism of modifying CVD risk in CKD patients.

  14. 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

  15. Clinicopathological characteristics of TERT promoter mutation and telomere length in hepatocellular carcinoma

    PubMed Central

    Lee, Hye Won; Park, Tae In; Jang, Se Young; Park, Soo Young; Park, Won-Jin; Jung, Soo-Jung; Lee, Jae-Ho

    2017-01-01

    Abstract Promoter mutations in telomerase reverse transcriptase (TERT) and telomere length have been studied in various tumors. In the present study, the frequency and clinical characteristics of TERT promoter mutation and telomere length were studied in hepatocellular carcinoma (HCC). TERT promoter mutation and telomere length were analyzed in 162 tumor samples of the patients with HCC by sequencing and real-time PCR, respectively. The TERT promoter mutation rate was 28.8% (46/160) in HCC and was associated with males (P = 0.027). The telomere length was not significantly different in the presence of a TERT promoter mutation but was shorter in high-grade tumor stages (P = 0.048). Survival analyses showed that poor overall survival was associated with longer telomere length (P = 0.013). However, the TERT promoter mutation did not have a prognostic value for HCC. Multivariate survival analyses demonstrated that the telomere length was an independent prognostic marker for poor overall survival (hazard ratio = 1.75, 95% confidence interval: 1.046–2.913, P = 0.033). These data demonstrated that TERT promoter mutation is a frequent event in HCC; however, telomere length, but not the presence of a TERT promoter mutation, might have potential value as a prognostic indicator of HCC. PMID:28151853

  16. Clinicopathological characteristics of TERT promoter mutation and telomere length in hepatocellular carcinoma.

    PubMed

    Lee, Hye Won; Park, Tae In; Jang, Se Young; Park, Soo Young; Park, Won-Jin; Jung, Soo-Jung; Lee, Jae-Ho

    2017-02-01

    Promoter mutations in telomerase reverse transcriptase (TERT) and telomere length have been studied in various tumors. In the present study, the frequency and clinical characteristics of TERT promoter mutation and telomere length were studied in hepatocellular carcinoma (HCC). TERT promoter mutation and telomere length were analyzed in 162 tumor samples of the patients with HCC by sequencing and real-time PCR, respectively. The TERT promoter mutation rate was 28.8% (46/160) in HCC and was associated with males (P = 0.027). The telomere length was not significantly different in the presence of a TERT promoter mutation but was shorter in high-grade tumor stages (P = 0.048). Survival analyses showed that poor overall survival was associated with longer telomere length (P = 0.013). However, the TERT promoter mutation did not have a prognostic value for HCC. Multivariate survival analyses demonstrated that the telomere length was an independent prognostic marker for poor overall survival (hazard ratio = 1.75, 95% confidence interval: 1.046-2.913, P = 0.033). These data demonstrated that TERT promoter mutation is a frequent event in HCC; however, telomere length, but not the presence of a TERT promoter mutation, might have potential value as a prognostic indicator of HCC.

  17. 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.

  18. Lack of correlation between telomere length and telomerase activity and expression in leukemic cells.

    PubMed

    Januszkiewicz, Danuta; Wysoki, Jacek; Lewandowski, Krzysztof; Pernak, Monika; Nowicka, Karina; Rembowska, Jolanta; Nowak, Jerzy

    2003-12-01

    The expression of three components of telomerase complex (hTR, hTERT, TP1) along with telomerase activity and telomere length in leukemic cells was investigated. Cells were isolated from peripheral blood and/or bone marrow of children with acute lymphoblastic (ALL) and non-lymphoblastic (ANLL) leukemia. Expression of three components of telomerase as well as telomerase activity was found in all leukemic cells. Chemiluminescent detection of terminal restriction fragments (TRF) from DNA isolated from ALL cells showed variable patterns expressing considerable heterogeneity of telomere length. The ALL cells appeared to have both long and short telomere lengths, in contrast to normal peripheral lymphocytes, which produced limited pattern of TRF. The ANLL cells produced predominantly short telomere pattern despite high telomerase activity and expression. It can be concluded that high telomerase activity and expression in leukemic cells is not always correlated with long telomeres (TRF pattern).

  19. 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.

  20. 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

  1. Telomere Length and Survival of Patients with Hepatocellular Carcinoma in the United States

    PubMed Central

    Yang, Baiyu; Shebl, Fatma M.; Sternberg, Lawrence R.; Warner, Andrew C.; Kleiner, David E.; Edelman, Daniel C.; Gomez, Allison; Dagnall, Casey L.; Hicks, Belynda D.; Altekruse, Sean F.; Hernandez, Brenda Y.; Lynch, Charles F.; Meltzer, Paul S.; McGlynn, Katherine A.

    2016-01-01

    Background Telomere shortening is an important molecular event in hepatocellular carcinoma (HCC) initiation; however, its role in HCC progression and prognosis is less clear. Our study aimed to examine the association of telomere length with survival of patients with HCC. Methods We measured telomere length in tumor and adjacent non-tumor tissues from 126 persons with HCC in the United States (U.S.) who were followed for mortality outcomes. Relative telomere length (RTL) was measured by a monochrome multiplex quantitative polymerase chain reaction assay. Multivariable Cox proportional hazards modeling was used to calculate hazard ratios (HRs) and 95% CIs for the association between telomere length and all-cause mortality. We also examined associations between telomere length and patient characteristics using multiple linear regression. Results During a mean follow-up of 6.0 years, 79 deaths occurred among 114 individuals for whom survival data were available. The ratio of RTL in tumor relative to non-tumor tissue was greater for individuals with regional or distant stage tumors (0.97) than localized stage tumors (0.77), and for individuals with grade III or IV tumors (0.95) than grade II (0.88) or grade I (0.67) tumors. An RTL ratio ≥1 was not associated with survival (HR 0.92, 95% CI 0.55, 1.55) compared to a ratio <1, after adjusting for age at diagnosis, sex, tumor stage and tumor size. Similarly, RTL in the tumor and non-tumor tissue, respectively, were not associated with survival. Conclusions This U.S. based study found that telomeres may be longer in more aggressive HCCs. There was no evidence, however, that telomere length was associated with survival of patients with HCC. Future investigations are warranted to clarify the role of telomere length in HCC prognosis. PMID:27880792

  2. Telomere length and age-at-menopause in the US

    PubMed Central

    Shenassa, Edmond D.; Rossen, Lauren M.

    2015-01-01

    Objectives Age-at-menopause and leukocyte telomere length (LTL) are both associated with biologic aging. Therefore, it would be reasonable to hypothesize that LTL may also serve as a marker for reproductive aging as shorter LTL may be associated with earlier age-at-menopause. Methods We analyzed data from 799 post-menopausal (ages 41–85) participants in the National Health and Nutrition Examination Survey (1999–2002), a nationally representative sample of U.S. women. Results Controlling for behavioral, socio-demographic, and health-related determinants of menopause, we found that among non-Hispanic white women, an increase of one standard deviation in LTL was associated with a 0.43 year higher reported age-at-menopause. Among Mexican–Americans, an increase of one standard deviation in LTL was associated with a 1.56 year earlier menopause. There was no significant association between LTL and age-at-menopause among non-Hispanic black women. Conclusions Our main finding is evidence of a strong interaction by race/ethnicity in the association between LTL and age-at-menopause. This evidence does not support the hypothesis that shorter LTL is a predictor of earlier age-at-menopause, as the magnitude and direction of the associations between LTL and age-at-menopause varied across racial/ethnic groups. PMID:26297686

  3. 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

    2016-03-08

    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.

  4. 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

  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. The Est1 subunit of Saccharomyces cerevisiae telomerase makes multiple contributions to telomere length maintenance.

    PubMed Central

    Evans, Sara K; Lundblad, Victoria

    2002-01-01

    The telomerase-associated Est1 protein of Saccharomyces cerevisiae mediates enzyme access by bridging the interaction between the catalytic core of telomerase and the telomere-binding protein Cdc13. In addition to recruiting telomerase, Est1 may act as a positive regulator of telomerase once the enzyme has been brought to the telomere, as previously suggested by the inability of a Cdc13-Est2 fusion protein to promote extensive telomere elongation in an est1-Delta strain. We report here three classes of mutant Est1 proteins that retain association with the telomerase enzyme but confer different in vivo consequences. Class 1 mutants display a telomere replication defect but are capable of promoting extensive telomere elongation in the presence of a Cdc13-Est2 fusion protein, consistent with a defect in telomerase recruitment. Class 2 mutants fail to elongate telomeres even in the presence of the Cdc13-Est2 fusion, which is the phenotype predicted for a defect in the proposed second regulatory function of EST1. A third class of mutants impairs an activity of Est1 that is potentially required for the Ku-mediated pathway of telomere length maintenance. The isolation of mutations that perturb separate functions of Est1 demonstrates that a telomerase holoenzyme subunit can contribute multiple regulatory roles to telomere length maintenance. PMID:12454059

  8. Dietary patterns, food groups and telomere length: a systematic review of current studies.

    PubMed

    Rafie, N; Golpour Hamedani, S; Barak, F; Safavi, S M; Miraghajani, M

    2017-02-01

    Telomere length (TL) is recognized as a biomarker of aging and shorter telomeres are linked with shorter lifespan. Inter-individual variability in telomere length is highly heritable. However, there has been a resurgence of interest in the controversial relationship between diet and TL. Evaluating the impact of diet at the food group and dietary pattern level will provide greater insight into the effect of diet on TL dynamics, which are of significant importance in health and longevity. This article reports the first systematic review of the relation between food groups, dietary patterns and TL in human populations based on PRISMA guidelines.

  9. Telomere Length Polymorphisms: A Potential Factor Underlying Increased Risk of Prostate Cancer in African American Men and Familial Prostate Cancer

    DTIC Science & Technology

    2008-12-01

    Defective chromosome segregation and telomere dysfunction in aggressive Wilms ’ tumors . Clinical Cancer Research. 13:6593-6602. 2007. 5. Bechan GI...cell tumors reveals evidence of telomere length heterogeneity and non-telomerase mediated telomere maintenance in tumor subsets. Modern Pathology 20...163A-163A 739 Suppl. 2 Mar. 2007. 4. Meeker AK, Bova GS, Hicks JL, De Marzo AM. Direct in situ analysis of telomere lengths in primary tumors and

  10. 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

  11. 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.

  12. Influence of exposure to pesticides on telomere length in tobacco farmers: A biology system approach.

    PubMed

    Kahl, Vivian Francília Silva; da Silva, Juliana; da Silva, Fernanda Rabaioli

    Various pesticides in the form of mixtures must be used to keep tobacco crops pest-free. Recent studies have shown a link between occupational exposure to pesticides in tobacco crops and increased damage to the DNA, mononuclei, nuclear buds and binucleated cells in buccal cells as well as micronuclei in lymphocytes. Furthermore, pesticides used specifically for tobacco crops shorten telomere length (TL) significantly. However, the molecular mechanism of pesticide action on telomere length is not fully understood. Our study evaluated the interaction between a complex mixture of chemical compounds (tobacco cultivation pesticides plus nicotine) and proteins associated with maintaining TL, as well as the biological processes involved in this exposure by System Biology tools to provide insight regarding the influence of pesticide exposure on TL maintenance in tobacco farmers. Our analysis showed that one cluster was associated with TL proteins that act in bioprocesses such as (i) telomere maintenance via telomere lengthening; (ii) senescence; (iii) age-dependent telomere shortening; (iv) DNA repair (v) cellular response to stress and (vi) regulation of proteasome ubiquitin-dependent protein catabolic process. We also describe how pesticides and nicotine regulate telomere length. In addition, pesticides inhibit the ubiquitin proteasome system (UPS) and consequently increase proteins of the shelterin complex, avoiding the access of telomerase in telomere and, nicotine activates UPS mechanisms and promotes the degradation of human telomerase reverse transcriptase (hTERT), decreasing telomerase activity.

  13. 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.

  14. Effect of tissue fixatives on telomere length determination by quantitative PCR.

    PubMed

    Koppelstaetter, Christian; Jennings, Paul; Hochegger, Kathrin; Perco, Paul; Ischia, Rudolf; Karkoszka, Henryk; Mayer, Gert

    2005-12-01

    Telomere length is a well established marker of cellular senescence and thus biological age. Quantitative PCR allows the determination even from very low amounts of tissue by using telomere specific and single copy gene primers. Comparing a directly processed tissue sample to a 4% formaldehyde fixed one showed a significantly reduced efficiency of PCR reactions (mainly in single copy gene experiments) in a storage time-dependent manner resulting in an artificial increase in reported relative telomere length. This effect was not seen when the tissue was stored in RNA later solution. In summary, telomere length determination from formaldehyde fixed material by quantitative PCR is not a reliable method. Unfortunately therefore, many easily accessible tissue samples from pathology laboratories are unsuitable for this technique.

  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.

  16. The impact of voluntary exercise on relative telomere length in a rat model of developmental stress

    PubMed Central

    2012-01-01

    Background Exposure to early adverse events can result in the development of later psychopathology, and is often associated with cognitive impairment. This may be due to accelerated cell aging, which can be catalogued by attritioned telomeres. Exercise enhances neurogenesis and has been proposed to buffer the effect of psychological stress on telomere length. This study aimed to investigate the impact of early developmental stress and voluntary exercise on telomere length in the ventral hippocampus (VH) and prefrontal cortex (PFC) of the rat. Forty-five male Sprague–Dawley rats were categorised into four groups: maternally separated runners (MSR), maternally separated non-runners (MSnR), non-maternally separated runners (nMSR) and non-maternally separated non-runners (nMSnR). Behavioural analyses were conducted to assess anxiety-like behaviour and memory performance in the rats, after which relative telomere length was measured using qPCR. Results Maternally separated (MS) rats exhibited no significant differences in either anxiety levels or memory performance on the elevated-plus maze and the open field compared to non-maternally separated rats at 49 days of age. Exercised rats displayed increased levels of anxiety on the day that they were removed from the cages with attached running wheels, as well as improved spatial learning and temporal recognition memory compared to non-exercised rats. Exploratory post-hoc analyses revealed that maternally separated non-exercised rats exhibited significantly longer telomere length in the VH compared to those who were not maternally separated; however, exercise appeared to cancel this effect since there was no difference in VH telomere length between maternally separated and non-maternally separated runners. Conclusions The increased telomere length in the VH of maternally separated non-exercised rats may be indicative of reduced cellular proliferation, which could, in turn, indicate hippocampal dysfunction. This effect on

  17. Cognitive Change during the Life Course and Leukocyte Telomere Length in Late Middle-Aged Men

    PubMed Central

    Rask, Lene; Bendix, Laila; Harbo, Maria; Fagerlund, Birgitte; Mortensen, Erik L.; Lauritzen, Martin J.; Osler, Merete

    2016-01-01

    Importance: Cognitive skills are known to decline through the lifespan with large individual differences. The molecular mechanisms for this decline are incompletely understood. Although leukocyte telomere length provides an index of cellular age that predicts the incidence of age-related diseases, it is unclear whether there is an association between cognitive decline and leukocyte telomere length. Objective: To examine the association between changes in cognitive function during adult life and leukocyte telomere length after adjusting for confounding factors such as education, mental health and life style. Design, Setting, and Participants: Two groups of men with negative (n = 97) and positive (n = 93) change in cognitive performance were selected from a birth cohort of 1985 Danish men born in 1953. Cognitive performance of each individual was assessed at age ~20 and 56 years. Leukocyte telomere length at age ~58 was measured using qPCR. Linear regression models were used to investigate the association between cognitive function and leukocyte telomere length. Results: Men with negative change in cognitive performance during adult life had significantly shorter mean leukocyte telomere length than men with positive change in cognitive performance (unadjusted difference β = −0.09, 95% CI −0.16 to −0.02, p = 0.02). This association remained significant after adjusting for smoking, alcohol consumption, leisure time activity, body mass index (BMI) and cholesterol (adjusted difference β = −0.09, 95% CI −0.17 to −0.01, p = 0.02) but was non-significant after adjusting for smoking, alcohol consumption, leisure time activity, BMI, cholesterol, current cognitive function, depression and education (adjusted difference β = −0.07, 95% CI −0.16 to −0.01, p = 0.08). Conclusion and Relevance: Preclinical cognitive changes may be associated with leukocyte telomere length. PMID:28018213

  18. 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

  19. 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.

  20. 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

  1. Extended Interferon-Alpha Therapy Accelerates Telomere Length Loss in Human Peripheral Blood T Lymphocytes

    PubMed Central

    O'Bryan, Joel M.; Potts, James A.; Bonkovsky, Herbert L.; Mathew, Anuja; Rothman, Alan L.

    2011-01-01

    Background Type I interferons have pleiotropic effects on host cells, including inhibiting telomerase in lymphocytes and antiviral activity. We tested the hypothesis that long-term interferon treatment would result in significant reduction in average telomere length in peripheral blood T lymphocytes. Methods/Principal Findings Using a flow cytometry-based telomere length assay on peripheral blood mononuclear cell samples from the Hepatitis-C Antiviral Long-term Treatment against Cirrhosis (HALT-C) study, we measured T cell telomere lengths at screening and at months 21 and 45 in 29 Hepatitis-C virus infected subjects. These subjects had failed to achieve a sustained virologic response following 24 weeks of pegylated-interferon-alpha plus ribavirin treatment and were subsequently randomized to either a no additional therapy group or a maintenance dose pegylated-IFNα group for an additional 3.5 years. Significant telomere loss in naïve T cells occurred in the first 21 months in the interferon-alpha group. Telomere losses were similar in both groups during the final two years. Expansion of CD8+CD45RA+CD57+ memory T cells and an inverse correlation of alanine aminotransferase levels with naïve CD8+ T cell telomere loss were observed in the control group but not in the interferon-alpha group. Telomere length at screening inversely correlated with Hepatitis-C viral load and body mass index. Conclusions/Significance Sustained interferon-alpha treatment increased telomere loss in naïve T cells, and inhibited the accumulation of T cell memory expansions. The durability of this effect and consequences for immune senescence need to be defined. PMID:21829595

  2. 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.

  3. No association between mean telomere length and life stress observed in a 30 year birth cohort.

    PubMed

    Jodczyk, Sarah; Fergusson, David M; Horwood, L John; Pearson, John F; Kennedy, Martin A

    2014-01-01

    Telomeres are specialised structures that cap the ends of chromosomes. They shorten with each cell division and have been proposed as a marker of cellular aging. Previous studies suggest that early life stressors increase the rate of telomere shortening with potential impact on disease states and mortality later in life. This study examined the associations between telomere length and exposure to a number of stressors that arise during development from the antenatal/perinatal period through to young adulthood. Participants were from the Christchurch Health and Development Study (CHDS), a New Zealand longitudinal birth cohort which has followed participants from birth until age 30. Telomere length was obtained on DNA from peripheral blood samples collected from consenting participants (n = 677) at age 28-30, using a quantitative PCR assay. These data were assessed for associations with 26 measures of life course adversity or stress which occurred prior to 25 years of age. No associations were found between telomere length measured at age 28-30 years and life course adversity or stress for specific measures and for the summary risk scores for each developmental domain. The correlations were very small ranging from -0.06 to 0.06 with a median of 0.01, and none were statistically significant. Our results in this well-studied birth cohort do not support prior reports of such associations, and underscore the need for more extensive replication of proposed links between stress and telomere biology in larger cohorts with appropriate phenotypic data.

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

    PubMed

    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 24days, 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.

  5. PCB153 reduces Telomerase Activity and Telomere Length in Immortalized Human Skin Kerantinocytes (HaCaT) but not in Human Foreskin Keratinocytes (NFK)

    PubMed Central

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

    2012-01-01

    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. PMID:22210444

  6. Telomeric overhang length determines structural dynamics and accessibility to telomerase and ALT associated proteins

    PubMed Central

    Hwang, Helen; Kreig, Alex; Calvert, Jacob; Lormand, Justin; Kwon, Yongho; Daley, James M.; Sung, Patrick; Opresko, Patricia L.; Myong, Sua

    2014-01-01

    The G-rich single stranded DNA at the 3′ end of human telomeres can self-fold into G-quaduplex (GQ). However, telomere lengthening by telomerase or the recombination-based alternative lengthening of telomere (ALT) mechanism requires protein loading on the overhang. Using single molecule fluorescence spectroscopy we discovered that lengthening the telomeric overhang also increased the rate of dynamic exchanges between structural conformations. Overhangs with five to seven TTAGGG repeats, compared to four repeats, showed much greater dynamics and accessibility to telomerase binding and activity, and loading of the ALT-associated proteins RAD51, WRN and BLM. Although the eight repeats are highly dynamic, they can fold into two GQs, which limited protein accessibility. In contrast, the telomere-specific protein, POT1 is unique in that it binds independently of repeat number. Our results suggest that the telomeric overhang length and dynamics may contribute to the regulation of telomere extension via telomerase action and the ALT mechanism. PMID:24836024

  7. 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

    2016-04-07

    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.

  8. 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.

  9. 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

  10. 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

  11. 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

  12. Sphingolipids regulate telomere clustering by affecting the transcription of genes involved in telomere homeostasis.

    PubMed

    Ikeda, Atsuko; Muneoka, Tetsuya; Murakami, Suguru; Hirota, Ayaka; Yabuki, Yukari; Karashima, Takefumi; Nakazono, Kota; Tsuruno, Masahiro; Pichler, Harald; Shirahige, Katsuhiko; Kodama, Yukiko; Shimamoto, Toshi; Mizuta, Keiko; Funato, Kouichi

    2015-07-15

    In eukaryotic organisms, including mammals, nematodes and yeasts, the ends of chromosomes, telomeres are clustered at the nuclear periphery. Telomere clustering is assumed to be functionally important because proper organization of chromosomes is necessary for proper genome function and stability. However, the mechanisms and physiological roles of telomere clustering remain poorly understood. In this study, we demonstrate a role for sphingolipids in telomere clustering in the budding yeast Saccharomyces cerevisiae. Because abnormal sphingolipid metabolism causes downregulation of expression levels of genes involved in telomere organization, sphingolipids appear to control telomere clustering at the transcriptional level. In addition, the data presented here provide evidence that telomere clustering is required to protect chromosome ends from DNA-damage checkpoint signaling. As sphingolipids are found in all eukaryotes, we speculate that sphingolipid-based regulation of telomere clustering and the protective role of telomere clusters in maintaining genome stability might be conserved in eukaryotes.

  13. The JIL-1 Kinase Affects Telomere Expression in the Different Telomere Domains of Drosophila

    PubMed Central

    Silva-Sousa, Rute; Casacuberta, Elena

    2013-01-01

    In Drosophila, the non-LTR retrotransposons HeT-A, TART and TAHRE build a head-to-tail array of repetitions that constitute the telomere domain by targeted transposition at the end of the chromosome whenever needed. As a consequence, Drosophila telomeres have the peculiarity to harbor the genes in charge of telomere elongation. Understanding telomere expression is important in Drosophila since telomere homeostasis depends in part on the expression of this genomic compartment. We have recently shown that the essential kinase JIL-1 is the first positive regulator of the telomere retrotransposons. JIL-1 mediates chromatin changes at the promoter of the HeT-A retrotransposon that are necessary to obtain wild type levels of expression of these telomere transposons. With the present study, we show how JIL-1 is also needed for the expression of a reporter gene embedded in the telomere domain. Our analysis, using different reporter lines from the telomere and subtelomere domains of different chromosomes, indicates that JIL-1 likely acts protecting the telomere domain from the spreading of repressive chromatin from the adjacent subtelomere domain. Moreover, the analysis of the 4R telomere suggests a slightly different chromatin structure at this telomere. In summary, our results strongly suggest that the action of JIL-1 depends on which telomere domain, which chromosome and which promoter is embedded in the telomere chromatin. PMID:24244743

  14. 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.

  15. 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

  16. 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.

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

    PubMed Central

    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

  18. Emotions and Family Interactions in Childhood: Associations with Leukocyte Telomere Length

    PubMed Central

    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 links between children's affective responses and daily family interactions may have implications for telomere length. PMID:26551267

  19. 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

  20. 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.

  1. 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

  2. Telomere length in epidemiology: a biomarker of aging, age-related disease, both, or neither?

    PubMed

    Sanders, Jason L; Newman, Anne B

    2013-01-01

    Telomeres are nucleoprotein caps flanking DNA. They are shortened by cell division and oxidative stress and are lengthened by the enzyme telomerase and DNA exchange during mitosis. Short telomeres induce cellular senescence. As an indicator of oxidative stress and senescence (2 processes thought to be fundamental to aging), telomere length is hypothesized to be a biomarker of aging. This hypothesis has been tested for more than a decade with epidemiologic study methods. In cross-sectional studies, researchers have investigated whether leukocyte telomere length (LTL) is associated with demographic, behavioral, and health variables. In prospective studies, baseline LTL has been used to predict mortality and occasionally other adverse health outcomes. Conflicting data have generated heated debate about the value of LTL as a biomarker of overall aging. In this review, we address the epidemiologic data on LTL and demonstrate that shorter LTL is associated with older age, male gender, Caucasian race, and possibly atherosclerosis; associations with other markers of health are equivocal. We discuss the reasons for discrepancy across studies, including a detailed review of methods for measuring telomere length as they apply to epidemiology. Finally, we conclude with questions about LTL as a biomarker of aging and how epidemiology can be used to answer these questions.

  3. Brood size moderates associations between relative size, telomere length, and immune development in European starling nestlings.

    PubMed

    Nettle, Daniel; Andrews, Clare; Reichert, Sophie; Bedford, Tom; Gott, Annie; Parker, Craig; Kolenda, Claire; Martin-Ruiz, Carmen; Monaghan, Pat; Bateson, Melissa

    2016-11-01

    For young birds in a nest, body size may have implications for other aspects of development such as telomere length and immune function. However, it is possible to predict associations in either direction. On the one hand, there may be trade-offs between growth and telomere maintenance, and growth and investment in immune function, suggesting there will be negative correlations. On the other hand, relatively larger individuals might be advantaged in competition with their nest-mates, allowing them to garner more resources overall, leading to positive correlations. We studied development over the nestling period in 34 nests of wild European starlings, Sturnus vulgaris. Intrabrood competition is typically more intense in larger broods. Hence, we predicted that body size should become an increasingly positive predictor of telomere length and immune functioning as brood size increases. In partial support of our prediction, there were significant interactions between brood size and body size in predicting both erythrocyte telomere length change and plasma levels of the cytokine interleukin-6. The associations between body size and these outcomes went from negative in the smallest broods to positive in the largest. A further immune marker, high-sensitivity C-reactive protein, showed no systematic patterning with body size or brood size. Our results confirm that the size to which a nestling grows is important for telomere dynamics and the development of the immune system, but the phenotypic associations are moderated by the competitive context.

  4. Telomere Length in Elderly Caucasians Weakly Correlates with Blood Cell Counts

    PubMed Central

    Witecka, Joanna; Koscinska-Marczewska, Justyna; Szwed, Malgorzata; Owczarz, Magdalena; Mossakowska, Malgorzata; Milewicz, Andrzej; Zejda, Jan; Wiecek, Andrzej

    2013-01-01

    Background. Age-related decrease in bone marrow erythropoietic capacity is often accompanied by the telomere length shortening in peripheral white blood cells. However, limited and conflicting data hamper the conclusive opinion regarding this relationship. Therefore, the aim of this study was to assess an association between telomere length and peripheral blood cell count parameters in the Polish elderly population. Material and Methods. The substudy included 1573 of 4981 subjects aged 65 years or over, participants of the population-based PolSenior study. High-molecular-weight DNA was isolated from blood mononuclear cells. Telomere length (TL) was measured by QRT-PCR as abundance of telomere template versus a single gene copy encoding acidic ribosomal phosphoprotein P0. Results. Only white blood count (WBC) was significantly different in TL tertile subgroups in all subjects (P = 0.02) and in men (P = 0.01), but not in women. Merely in men significant but weak positive correlations were found between TL and WBC (r = 0.11, P < 0.05) and RBC (r = 0.08, P < 0.05). The multiple regression analysis models confirmed a weak, independent contribution of TL to both RBC and WBC. Conclusions. In the elderly, telomere shortening limits hematopoiesis capacity to a very limited extent. PMID:24453794

  5. 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.

  6. 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

  7. Alterations of Mitochondrial DNA Copy Number and Telomere Length with Early Adversity and Psychopathology

    PubMed Central

    Tyrka, Audrey R.; Parade, Stephanie H.; Price, Lawrence H.; Kao, Hung-Teh; Porton, Barbara; Philip, Noah S.; Welch, Emma S.; Carpenter, Linda L.

    2015-01-01

    Background Telomere shortening and alterations of mitochondrial biogenesis are involved in cellular aging. Childhood adversity is associated with telomere shortening, and several investigations have shown short telomeres in psychiatric disorders. Recent studies have examined whether mitochondria might be involved in neuropsychiatric conditions; findings are limited and no prior work has examined this in relation to stress exposure. Methods Two-hundred and ninety healthy adults provided information on childhood parental loss and maltreatment and completed diagnostic interviews. Participants were categorized into four groups based upon the presence or absence of childhood adversity and the presence or absence of lifetime psychopathology (depressive, anxiety, and substance use disorders). Telomere length and mtDNA copy number were measured from leukocyte DNA by qPCR. Results Childhood adversity and lifetime psychopathology were each associated with shorter telomeres (p < .01) and higher mtDNA copy numbers (p < .001). Significantly higher mtDNA copy numbers and shorter telomeres were seen in individuals with major depression, depressive disorders, and anxiety disorders, as well as those with parental loss and childhood maltreatment. A history of substance disorders was also associated with significantly higher mtDNA copy numbers. Conclusion This study provides the first evidence of an alteration of mitochondrial biogenesis with early life stress and with anxiety and substance use disorders. We replicate prior work on telomere length and psychopathology, and show that this effect is not secondary to medication use or comorbid medical illness. Finally, we show that early life stress and psychopathology are each associated with these markers of cellular aging. PMID:25749099

  8. 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.

  9. Effects of axotomy on telomere length, telomerase activity, and protein in activated microglia.

    PubMed

    Flanary, Barry E; Streit, Wolfgang J

    2005-10-15

    The adult central nervous system (CNS) is generally thought of as a postmitotic organ. However, DNA labeling studies have shown that one major population of nonneuronal cells, called microglia, retain significant mitotic potential. Microglial cell division is prominent during acute CNS injury involving neuronal damage or death. Prior work from this laboratory has shown that purified microglia maintained in vitro with continual mitogenic stimulation exhibit telomere shortening before entering senescence. In the current study, we sought to investigate whether telomere shortening occurs in dividing microglia in vivo. For this purpose, we used a nerve injury model that is known to trigger localized microglial proliferation in a well-defined CNS region, the facial motor nucleus. Adult Sprague-Dawley rats underwent facial nerve axotomy, and facial motor nuclei were microdissected after 1, 4, 7, and 10 days. Whole tissue samples were subjected to measurements of telomere length, telomerase activity, and telomerase protein. Results revealed a tendency for all of these parameters to be increased in lesioned samples. In addition, microglial cells isolated directly from axotomized facial nuclei with fluorescence-activated cell sorting (FACS) showed increased telomerase activity relative to unoperated controls, suggesting that microglia are the primary cell type responsible for the increases observed in whole tissue samples. Overall, the results show that microglia activated by injury are capable of maintaining telomere length via telomerase during periods of high proliferation in vivo. We conclude that molecular mechanisms pertaining to telomere maintenance are active in the injured CNS.

  10. 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.

  11. 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.

  12. Short telomere length in blood leucocytes contributes to the presence of atherothrombotic stroke and haemorrhagic stroke and risk of post-stroke death.

    PubMed

    Zhang, Weili; Chen, Yu; Wang, Yuyao; Liu, Peng; Zhang, Mei; Zhang, Channa; Hu, Frank B; Hui, Rutai

    2013-03-13

    Inter-individual differences in biological aging could affect susceptibility to stroke. To date, the relationship between stroke and telomere shortening remain inconclusive; and sparse data are available for haemorrhagic stroke. A Chinese case-control study was conducted, comprising 1756 cases (767 atherothrombosis, 503 lacunar infarction and 486 haemorrhagic strokes) and 1801 controls. Stroke patients were prospectively followed up for a median of 4.5 (range, 0.1-6.0) years. Individuals with shorter telomere length had a higher presence of atherothrombotic stroke {multivariate OR (odds ratio) 1.37 [95% CI (confidence interval), 1.06-1.77]; P=0.015} or haemorrhagic stroke [multivariate OR 1.48 (95% CI, 1.08-2.02); P=0.016] in comparison of the lowest to highest tertile of telomere length. Particularly, in subjects with a family history of stroke, there was a significant 2.55-fold increased presence of atherothrombotic stroke (95% CI, 1.87-3.48; Ptrend<0.0001) and a 2.33-fold increased presence of haemorrhagic stroke (95% CI, 1.62-3.36; Ptrend<0.0001). During the follow-up, 338 recurrent strokes and 312 deaths (181 from stroke or coronary heart disease and 131 from other causes) were documented. Associations with stroke recurrence were not observed in the follow-up patients, whereas atherothrombotic stroke cases with shorter telomeres had 69% increased risk of post-stroke death [relative risk, 1.69 (95% CI, 1.07-2.67); P=0.02]. Finally, we compared telomere lengths in 12 paired samples of circulating leucocytes and carotid atherosclerotic plaques from patients undergoing carotid endarterectomy; there was a positive correlation between vessel wall tissue and leucocyte telomere length. In conclusion, shorter telomere length may serve as a potential marker for the presence of atherothrombotic and haemorrhagic stroke and for the risk of post-stroke death.

  13. U-shaped association between telomere length and esophageal squamous cell carcinoma risk: a case-control study in Chinese population.

    PubMed

    Du, Jiangbo; Xue, Wenjie; Ji, Yong; Zhu, Xun; Gu, Yayun; Zhu, Meng; Wang, Cheng; Gao, Yong; Dai, Juncheng; Ma, Hongxia; Jiang, Yue; Chen, Jiaping; Hu, Zhibin; Jin, Guangfu; Shen, Hongbing

    2015-12-01

    Telomeres play a critical role in biological ageing by maintaining chromosomal integrity and preventing chromosome ends fusion. Epidemiological studies have suggested that inter-individual differences of telomere length could affect predisposition to multiple cancers, but evidence regarding esophageal squamous cell carcinoma (ESCC) was still uncertain. Several telomere length-related single nucleotide polymorphisms (TLSNPs) in Caucasians have been reported in genome-wide association studies. However, the effects of telomere length and TL-SNPs on ESCC development are unclear. Therefore, we conducted a case-control study (1045 ESCC cases and 1433 controls) to evaluate the associations between telomere length, TL-SNPs, and ESCC risk in Chinese population. As a result, ESCC cases showed overall shorter relative telomere length (RTL) (median: 1.34) than controls (median: 1.50, P < 0.001). More interestingly, an evident nonlinear U-shaped association was observed between RTL and ESCC risk (P < 0.001), with odds ratios (95% confidence interval) equal to 2.40 (1.84-3.14), 1.36 (1.03-1.79), 1.01 (0.76-1.35), and 1.37 (1.03-1.82) for individuals in the 1st (the shortest), 2nd, 3rd, and 5th (the longest) quintile, respectively, compared with those in the 4th quintile as reference group. No significant associations were observed between the eight reported TL-SNPs and ESCC susceptibility. These findings suggest that either short or extremely long telomeres may be risk factors for ESCC in the Chinese population.

  14. The association between intelligence and telomere length: a longitudinal population based study.

    PubMed

    Kingma, Eva M; de Jonge, Peter; van der Harst, Pim; Ormel, Johan; Rosmalen, Judith G M

    2012-01-01

    Low intelligence has been associated with poor health and mortality, but underlying mechanisms remain obscure. We hypothesized that low intelligence is associated with accelerated biological ageing as reflected by telomere length; we suggested potential mediation of this association by unhealthy behaviors and low socioeconomic position. The study was performed in a longitudinal population-based cohort study of 895 participants (46.8% males). Intelligence was measured with the Generalized Aptitude-Test Battery at mean age 52.8 years (33-79 years, SD=11.3). Leukocyte telomere length was measured by PCR. Lifestyle and socioeconomic factors were assessed using written self-report measures. Linear regression analyses, adjusted for age, sex, and telomere length measured at the first assessment wave (T1), showed that low intelligence was associated with shorter leukocyte telomere length at approximately 2 years follow-up (beta= .081, t=2.160, p= .031). Nearly 40% of this association was explained by an unhealthy lifestyle, while low socioeconomic position did not add any significant mediation. Low intelligence may be a risk factor for accelerated biological ageing, thereby providing an explanation for its association with poor health and mortality.

  15. Leukocyte Telomere Length in Healthy White and Black Adolescents: Relations to Race, Sex, Adiposity, Adipokines and Physical Activity

    PubMed Central

    Zhu, Haidong; Wang, Xiaoling; Gutin, Bernard; Davis, Catherine L.; Keeton, Daniel; Thomas, Jeffrey; Stallmann-Jorgensen, Inger; Mooken, Grace; Bundy, Vanessa; Snieder, Harold; van der Harst, Pim; Dong, Yanbin

    2010-01-01

    Objectives To examine the relations of race, sex, adiposity, adipokines and physical activity to telomere length in adolescents. Study design Leukocyte telomere length (T/S ratio) was assessed cross-sectionally in 667 adolescents (aged 14–18 years, 48% blacks, 51% girls) using a quantitative PCR method. Generalized Estimating Equations analyses were performed. Results Black adolescents had longer telomeres than white adolescents (age and sex adjusted T/S ratio ± SE: 1.32 ± 0.01 vs. 1.27 ± 0.01, p=0.014) and girls had longer telomeres than boys (age and race adjusted T/S ratio ± SE: 1.31 ± 0.01 vs. 1.27 ± 0.01, p=0.007). None of the adiposity or adipokine measures explained a significant proportion of the variance in telomere length. Vigorous physical activity was positively associated with telomere length (adjusted R2=0.019, p=0.009) and accounted for 1.9% of the total variance only in girls. Conclusion This study, conducted in a biracial adolescent cohort, demonstrated that: (1) race and sex differences in telomere length have already emerged during adolescence; (2) adiposity and adipokines are not associated with telomere length at this age; and (3) the anti-aging effect of vigorous physical activity may begin in youth especially in girls. PMID:20855079

  16. Telomere length shortening in gastric mucosa is a field effect associated with increased risk of gastric cancer.

    PubMed

    Tahara, Tomomitsu; Shibata, Tomoyuki; Kawamura, Tomohiko; Horiguchi, Noriyuki; Okubo, Masaaki; Nakano, Naoko; Ishizuka, Takamitsu; Nagasaka, Mitsuo; Nakagawa, Yoshihito; Ohmiya, Naoki

    2016-07-01

    Telomere shortening occurs in many organs and tissues and is accelerated by oxidative injury and rapid cell turnover. Short telomeres initiate chromosomal instability and may eventually contribute to tumorigenesis. To evaluate telomere length as potential biomarker for gastric cancer (GC) risk, we measured average telomere length using quantitative real-time PCR in GC tissues and in non-neoplastic mucosa from patients with GC and without GC. We obtained of 217 GC patients matched biopsies from the GC and adjacent tissues as well as gastric biopsies of 102 subjects without GC. Relative telomere length was measured in genomic DNA by real-time PCR. Relative telomere length decreased gradually in Helicobacter pylori (H. pylori) negative and positive gastric mucosa of GC free subjects compared with adjacent mucosa and cancer tissue from GC patients (4.03 ± 0.3 vs. 2.82 ± 0.19 vs. 0.82 ± 0.07 vs. 0.29 ± 0.09, P < 0.0001). In non-neoplastic mucosa of GC patients, shorter telomeres were found significantly more often than in that of GC free subjects (age, sex, and H. pylori adjusted odds ratio = 7.81, 95 % confidence interval = 4.71-12.9, P < 0.0001). Telomere shortening in non-neoplastic mucosa was associated with chronic inflammation (P = 0.0018) and intestinal metaplasia (P < 0.0001). No significant associations were found between relative telomere length and clinicopathological features of GC and overall survival. Telomere shortening in gastric mucosa reflects a field effect in an early stage of carcinogenesis and is associated with an increased risk of GC. Telomere length in GC is not associated with clinicopathological features or prognosis.

  17. Telomere Length Assessment for Prediction of Organ Transplantation Outcome. Future or Failure: A Review of the Literature

    PubMed Central

    Kłoda, Karolina; Domański, Leszek; Mierzecki, Artur

    2017-01-01

    Telomeres are located at each end of eukaryotic chromosomes. Their functional role is genomic stability maintenance. The protective role of telomeres depends on various factors, including number of nucleotides repeats, telomere-binding proteins, and telomerase activity. Organ transplantation is the preferred replacement therapy in the case of chronic kidney disease and the only possibility of sustaining recipients’ life in the case of advanced liver failure. While the prevalence of acute rejection is constantly decreasing, prevention of transplanted organ long-term function loss is still challenging. It has been demonstrated that post-transplant stressors accelerate aging of the allografts manifested through telomere shortening. The aim of this paper was to evaluate the importance of telomere length assessment for prediction of organ transplantation outcome. Literature review included the 10 most important studies regarding linkage between allograft function and telomere erosion, including 2 of our own reports. Telomere length assessment is useful to predict organ transplantation outcome. The importance of telomere length as a prediction marker depends on the analyzed material. To obtain reliable results, both graft cells (donor material) and lymphocytes (recipient material) should be examined. In the case of kidney transplantation, assessment of telomere length in the early post-transplant period allows prediction of the long-term function of the transplanted organ. To increase the accuracy of transplantation outcome prediction, telomere length assessment should be combined with evaluation of other aging biomarkers, like CDKN2A (p16). Large-scale clinical studies regarding telomere length measurement, including genome wide association analysis introducing relevant genetic factors, are needed for the future. PMID:28076340

  18. 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.

  19. Leukocyte telomere length predicts SSRI response in major depressive disorder: A preliminary report.

    PubMed

    Hough, Christina M; Bersani, F Saverio; Mellon, Synthia H; Epel, Elissa S; Reus, Victor I; Lindqvist, Daniel; Lin, Jue; Mahan, Laura; Rosser, Rebecca; Burke, Heather; Coetzee, John; Nelson, J Craig; Blackburn, Elizabeth H; Wolkowitz, Owen M

    2016-07-01

    Short leukocyte telomere length (LTL) may be associated with several psychiatric disorders, including major depressive disorder (MDD). Short LTL has previously been associated with poor response to psychiatric medications in bipolar disorder and schizophrenia, but no studies have prospectively assessed the relationship of LTL to SSRI response in MDD. We assessed pre-treatment LTL, depression severity (using the Hamilton Depression Rating Scale [HDRS]), and self-reported positive and negative affect in 27 healthy, unmedicated adults with MDD. Subjects then underwent open-label treatment with a selective serotonin reuptake inhibitor (SSRI) antidepressant for eight weeks, after which clinical ratings were repeated. Analyses were corrected for age, sex and BMI. "Non-responders" to treatment (HDRS improvement <50%) had significantly shorter pre-treatment LTL, compared to "Responders" (p=0.037). Further, shorter pre-treatment LTL was associated with less improvement in negative affect (p<0.010) but not with changes in positive affect (p=0.356). This preliminary study is the first to assess the relationship between LTL and SSRI response in MDD and among the first to prospectively assess its relationship to treatment outcome in any psychiatric illness. Our data suggest that short LTL may serve as a vulnerability index of poorer response to SSRI treatment, but this needs examination in larger samples.

  20. QTL mapping of leukocyte telomere length in American Indians: The Strong Heart Family Study

    PubMed Central

    Lin, Jue; Matsuguchi, Tet; Blackburn, Elizabeth; Best, Lyle G.; Lee, Elisa T.; MacCluer, Jean W.; Cole, Shelley A.; Zhao, Jinying

    2013-01-01

    Telomeres play a central role in cellular senescence and are associated with a variety of age-related disorders such as dementia, Alzheimer's disease and atherosclerosis. Telomere length varies greatly among individuals of the same age, and is heritable. Here we performed a genome-wide linkage scan to identify quantitative trait loci (QTL) influencing leukocyte telomere length (LTL) measured by quantitative PCR in 3,665 American Indians (aged 14 – 93 years) from 94 large, multi-generational families. All participants were recruited by the Strong Heart Family Study (SHFS), a prospective study to identify genetic factors for cardiovascular disease and its risk factors in American Indians residing in Oklahoma, Arizona and Dakota. LTL heritability was estimated to be between 51% and 62%, suggesting a strong genetic predisposition to interindividual variation of LTL in this population. Significant QTLs were localized to chromosome 13 (Logarithm of odds score (LOD) = 3.9) at 13q12.11, to 18q22.2 (LOD = 3.2) and to 3p14.1 (LOD = 3.0) for Oklahoma. This is the first study to identify susceptibility loci influencing leukocyte telomere variation in American Indians, a minority group suffering from a disproportionately high rate of type 2 diabetes and other age-related disorders. PMID:24036517

  1. 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.

  2. Telomerase contributes to tumorigenesis by a telomere length-independent mechanism

    PubMed Central

    Stewart, Sheila A.; Hahn, William C.; O'Connor, Benjamin F.; Banner, Elisa N.; Lundberg, Ante S.; Modha, Poonam; Mizuno, Hana; Brooks, Mary W.; Fleming, Mark; Zimonjic, Drazen B.; Popescu, Nicholas C.; Weinberg, Robert A.

    2002-01-01

    Once immortalized, human cells are susceptible to transformation by introduction of an oncogene such as ras. Several lines of evidence now suggest that the maintenance of telomere length is a major determinant of replicative lifespan in human cells and thus of the immortalized state. The majority of human tumor cells acquire immortality through expression of the catalytic subunit of telomerase (hTERT), whereas others activate an alternative mechanism of telomere maintenance (ALT) that does not depend on the actions of telomerase. We have examined whether ALT could substitute for telomerase in the processes of transformation in vitro and tumorigenesis in vivo. Expression of oncogenic H-Ras in the immortal ALT cell line GM847 did not result in their transformation. However, subsequent ectopic expression of hTERT in these cells imparted a tumorigenic phenotype. Indeed, this outcome was also observed after introduction of a mutant hTERT that retained catalytic activity but was incapable of maintaining telomere length. These studies indicate that hTERT confers an additional function that is required for tumorigenesis but does not depend on its ability to maintain telomeres. PMID:12193655

  3. The role of telomere length modulation in delayed chromosome instability induced by ionizing radiation in human primary fibroblasts.

    PubMed

    Berardinelli, Francesco; Antoccia, Antonio; Buonsante, Rossella; Gerardi, Silvia; Cherubini, Roberto; De Nadal, Viviana; Tanzarella, Caterina; Sgura, Antonella

    2013-04-01

    Telomere integrity is important for chromosome stability. The main objective of our study was to investigate the relationship between telomere length modulation and mitotic chromosome segregation induced by ionizing radiation in human primary fibroblasts. We used X-rays and low-energy protons because of their ability to induce different telomeric responses. Samples irradiated with 4 Gy were fixed at different times up to 6 days from exposure and telomere length, anaphase abnormalities, and chromosome aberrations were analyzed. We observed that X-rays induced telomere shortening in cells harvested at 96 hrs, whereas protons induced a significant increase in telomere length at short as well as at long harvesting times (24 and 96 hrs). Consistent with this, the analysis of anaphase bridges at 96 hrs showed a fourfold increase in X-ray- compared with proton-irradiated samples, suggesting a correlation between telomere length/dysfunction and chromosome missegregation. In line with these findings, the frequency of dicentrics and rings decreased with time for protons whereas it remained stable after X-rays irradiation. Telomeric FISH staining on anaphases revealed a higher percentage of bridges with telomere signals in X-ray-treated samples than that observed after proton irradiation, thus suggesting that the aberrations observed after X-ray irradiation originated from telomere attrition and consequent chromosome end-to-end fusion. This study shows that, beside an expected "early" chromosome instability induced shortly after irradiation, a delayed one occurs as a result of alterations in telomere metabolism and that this mechanism may play an important role in genomic stability.

  4. 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

  5. Increased telomere length and proliferative potential in peripheral blood mononuclear cells of adults of different ages stimulated with concanavalin A

    PubMed Central

    2013-01-01

    Background Recently, a direct correlation with telomere length, proliferative potential and telomerase activity has been found in the process of aging in peripheral blood cells. The objective of the study was to evaluate telomere length and proliferative potential in peripheral blood mononuclear cells (PBMCs) after stimulation with Concanavalin A (ConA) of young adults compared with older adults. Methods Blood samples were obtained from 20 healthy young males (20–25 years old) (group Y) and 20 males (60–65 years old) (group O). We compared PBMC proliferation before and after stimulation with ConA. DNA was isolated from cells separated before and after culture with ConA for telomeric measurement by real-time polymerase chain reaction. Results In vitro stimulation of PBMCs from young subjects induced an increase of telomere length as well as a higher replicative capacity of cell proliferation. Samples from older adults showed higher loss of telomeric DNA (p = 0.03) and higher levels of senescent (≤6.2 kb) telomeric DNA (p = 0.02) and displayed a marked decrease of proliferation capacity. Viability cell counts and CFSE tracking in 72-h-old cell cultures indicated that group O PBMCs (CD8+ and CD4+ T cells) underwent fewer mitotic cycles and had shorter telomeres than group Y (p = 0.04). Conclusions Our findings confirm that telomere length in older-age adults is shorter than in younger subjects. After stimulation with ConA, cells are not restored to the previous telomere length and undergo replicative senescence. This is in sharp contrast to the response observed in young adults after ConA stimulation where cells increase in telomere length and replicative capacity. The mechanisms involved in this phenomenon are not yet clear and merit further investigation. PMID:24063536

  6. Association between shortened telomere length and systemic lupus erythematosus: a meta-analysis.

    PubMed

    Lee, Y H; Jung, J H; Seo, Y H; Kim, J-H; Choi, S J; Ji, J D; Song, G G

    2017-03-01

    Objective We aimed to evaluate the relationship between telomere length and systemic lupus erythematosus (SLE). Methods PUBMED and EMBASE databases were searched; meta-analyses were performed comparing telomere length in SLE patients and healthy controls, and on SLE patients in subgroups based on ethnicity, sample type, assay method and data type. Results Eight studies including 472 SLE patients and 365 controls were ultimately selected which showed that telomere length was significantly shorter in the SLE group than in the control group (standardized mean difference (SMD) = -0.835, 95% confidence interval (CI) = -1.291 to -0.380, p = 3.3 × 10(-4)). Stratification by ethnicity showed significantly shortened telomere length in the SLE group in Caucasian, Asian and mixed populations (SMD = -0.455, 95% CI = -0.763 to -0.147, p = 0.004; SMD = -0.887, 95% CI = -1.261 to -0.513, p = 3.4 × 10(-4); SMD = -0.535, 95% CI = -0.923 to -0.147, p = 0.007; respectively). Furthermore, telomere length was significantly shorter in the SLE group than in the control group in whole blood and peripheral blood mononuclear cell groups (SMD = -0.361, 95% CI = -0.553 to -0.169, p = 2.3 × 10(-4); SMD = -1.546, 95% CI = -2.583 to -0.510, p = 0.003; respectively); a similar trend was observed in leukocyte groups (SMD = -0.699, 95% CI = -1.511 to -0.114, p = 0.092). Meta-analyses based on assay method or data type revealed similar associations. Conclusions Our meta-analysis demonstrated that telomere length was significantly shorter in patients with SLE, regardless of ethnicity, sample type or assay method evaluated.

  7. 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.

  8. mtDNA haplogroup J Modulates telomere length and Nitric Oxide production

    PubMed Central

    2011-01-01

    Background Oxidative stress due to the overproduction of nitric oxide (NO) and other oxygen reactive species (ROS), play a main role in the initiation and progression of the OA disease and leads to the degeneration of mitochondria. Therefore, the goal of this work is to describe the difference in telomere length of peripheral blood leukocytes (PBLs) and Nitric Oxide (NO) production between mitochondrial DNA (mtDNA) haplogroup J and non-J carriers, as indirect approaches of oxidative stress. Methods The telomere length of PBL was analyzed in DNA samples from 166 healthy controls (114 J and 52 non-J) and 79 OA patients (41 J and 38 non-J) by means of a validated qPCR method. The NO production was assessed in 7 carriers of the haplogroup J and 27 non-J carriers, by means of the colorimetric reaction of the Griess reagent in supernatants of cultured chondrocytes. Inducible nitric oxide synthase (iNOS) mRNA from these samples was analyzed by qPCR. Appropiated statistical analyses were performed Results Carriers of the haplogroup J showed a significantly longer telomere length of PBLs than non-J carriers, regardless of age, gender and diagnosis (p = 0.025). Cultured chondrocytes carrying the mtDNA haplogroup J also showed a lower NO production than non-J carriers (p = 0.043). No significant correlations between age and telomore length of PBLs were detected neither for carriers of the haplogroup J nor for non-J carriers. A strong positive correlation between NO production and iNOS expression was also observed (correlation coefficient = 0.791, p < 0.001). Conclusion The protective effect of the mtDNA haplogroup J in the OA disease arise from a lower oxidative stress in carriers of this haplogroup, since this haplogroup is related to lower NO production and hence longer telomere length of PBLs too. PMID:22171676

  9. Reduction of leucocyte telomere length in radiographic hand osteoarthritis: a population‐based study

    PubMed Central

    Zhai, G; Aviv, A; Hunter, D J; Hart, D J; Gardner, J P; Kimura, M; Lu, X; Valdes, A M; Spector, T D

    2006-01-01

    Background Although age is the strongest predictor of osteoarthritis, the exact mechanism underlying this disorder remains elusive. Objective To examine the association between leucocyte telomere length (LTL), a bio‐indicator of ageing, and radiographic hand osteoarthritis. Methods An unselected, predominantly female sample from the TwinsUK Adult Twin Registry (Twin Research and Genetic Epidemiology Unit, St Thomas Hospital, London, UK) was studied. Radiographs of both hands were obtained with a standard posteroanterior view and assessed for radiographic osteoarthritis according to the Kellgren/Lawrence (K/L) score. Individual radiographic features including osteophytes and joint space narrowing (JSN) were also assessed on a four‐point scale using a standard atlas. Hand osteoarthritis was defined radiographically as having ⩾3 osteoarthritis‐affected joints of both hands (K/L score⩾2). Severity of hand osteoarthritis was indicated semiquantitatively by total K/L scores, osteophytes, JSN scores and proportion of joints affected. Mean LTL was measured by the terminal restriction fragment length using the Southern blot. Results A total of 1086 Caucasian subjects (mean (SD) age 55 (8.0) years) were studied. LTL was 6.95 (0.64) kb and was inversely correlated with age. After adjustment for age, sex, body mass index and smoking, LTL was significantly shorter by 178 bp in subjects with hand osteoarthritis (n = 160) than in those without (n = 926; p = 0.04). LTL was also significantly associated with semicontinuous measures of osteoarthritis (eg, total K/L score, JSN score, osteophyte score and proportion of joints affected) after adjustment (all p⩽0.02) in a dose–response fashion. Conclusion Shorter LTL equivalent to around 11 years of annual loss in normal people is associated with radiographic hand osteoarthritis and disease severity, suggesting potential shared mechanisms between osteoarthritis and ageing, and implicating oxidative

  10. Short communication: Ovine leukocyte telomere length is associated with variation in the cortisol response to systemic bacterial endotoxin challenge.

    PubMed

    Yip, L; Oh, S Y; Li, Z; You, Q; Quinton, V M; Gilchrist, G C; Karrow, N A

    2016-04-01

    Stress has been associated with biological aging and numerous age-related diseases. This may be due, in part, to accelerated shortening of telomeres, which are critical genomic structures that cap and protect chromosomal ends. Dysfunction of the hypothalamic-pituitary-adrenal axis may indirectly contribute to telomere shortening if an animal reacts too strongly or weakly to a stressor, leading to accelerated biological aging. In this study, outbred Rideau-Arcott sheep were stress challenged with Escherichia coli endotoxin and classified as high, middle, or low cortisol responders to investigate a potential relationship between cortisol response and age, and telomere length. In the present study, no association was found between age and telomere length. The study, however, revealed shorter telomeres in high and low cortisol responders compared with the middle cortisol responders, which suggests that health and longevity may be compromised in extreme high- and low-stress-responding sheep.

  11. Significant correlation of species longevity with DNA double strand break recognition but not with telomere length.

    PubMed

    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

    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 (DSBs) 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.

  12. 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

  13. 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

  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. Investigating the associations between adiposity, life course overweight trajectories, and telomere length

    PubMed Central

    Wulaningsih, Wahyu; Watkins, Johnathan; Matsuguchi, Tetsuya; Hardy, Rebecca

    2016-01-01

    Obesity may accelerate ageing through chronic inflammation. To further examine this association, we assessed current adiposity, adiposity at early adulthood and life course overweight trajectories in relation to leukocyte telomere length (LTL). We included a total of 7,008 nationally representative U.S. residents and collected information on objectively measured body mass index (BMI), waist circumference and percent body fat. BMI at age 25 and overweight trajectories were assessed using self-reported history. Leukocyte telomere length (LTL) relative to a standard DNA reference (T/S ratio) was quantified by polymerase chain reaction (PCR). Linear regression models were used to examine the difference in LTL across adiposity measures at examination, BMI at age 25, and overweight trajectories. A 0.2% decrease in telomere length (95% CI:−0.3 to −0.07%) was observed for every kg/m2 increase in BMI, whereas a unit increase in waist circumference (cm) and percent body fat contributed to a 0.09% and 0.01% decrease in LTL, respectively. Higher BMI and being obese at age 25 contributed to lower LTL at older ages. Associations between weight loss through life course and LTL were observed, which further marked the importance of life course adiposity dynamics as a determinant of ageing. PMID:27650676

  16. Associations of Leukocyte Telomere Length With Aerobic and Muscular Fitness in Young Adults.

    PubMed

    Williams, Dylan M; Buxton, Jessica L; Kantomaa, Marko T; Tammelin, Tuija H; Blakemore, Alexandra I F; Järvelin, Marjo-Riitta

    2017-03-01

    Decline in both telomere length and physical fitness over the life course may contribute to increased risk of several chronic diseases. The relationship between telomere length and aerobic and muscular fitness is not well characterized. We examined whether there are cross-sectional associations of mean relative leukocyte telomere length (LTL) with objective measures of aerobic fitness, muscle strength, and muscle endurance, using data on 31-year-old participants of the Northern Finland Birth Cohort 1966 (n = 4,952-5,205, varying by exposure-outcome analysis). Aerobic fitness was assessed by means of heart rate measurement following a standardized submaximal step test; muscular fitness was assessed by means of a maximal isometric handgrip strength test and a test of lower-back trunk muscle endurance. Longer LTL was associated with higher aerobic fitness and better trunk muscle endurance in models including adjustment for age, sex, body mass index, socioeconomic position, diet, smoking, alcohol consumption, physical activity level, and C-reactive protein. In a sex-stratified analysis, LTL was not associated with handgrip strength in either men or women. LTL may relate to aspects of physical fitness in young adulthood, but replication of these findings is required, along with further studies to help assess directions and causality in these associations.

  17. Investigating the associations between adiposity, life course overweight trajectories, and telomere length.

    PubMed

    Wulaningsih, Wahyu; Watkins, Johnathan; Matsuguchi, Tetsuya; Hardy, Rebecca

    2016-09-18

    Obesity may accelerate ageing through chronic inflammation. To further examine this association, we assessed current adiposity, adiposity at early adulthood and life course overweight trajectories in relation to leukocyte telomere length (LTL). We included a total of 7,008 nationally representative U.S. residents and collected information on objectively measured body mass index (BMI), waist circumference and percent body fat. BMI at age 25 and overweight trajectories were assessed using self-reported history. Leukocyte telomere length (LTL) relative to a standard DNA reference (T/S ratio) was quantified by polymerase chain reaction (PCR). Linear regression models were used to examine the difference in LTL across adiposity measures at examination, BMI at age 25, and overweight trajectories. A 0.2% decrease in telomere length (95% CI: -0.3 to -0.07%) was observed for every kg/m2 increase in BMI, whereas a unit increase in waist circumference (cm) and percent body fat contributed to a 0.09% and 0.01% decrease in LTL, respectively. Higher BMI and being obese at age 25 contributed to lower LTL at older ages. Associations between weight loss through life course and LTL were observed, which further marked the importance of life course adiposity dynamics as a determinant of ageing.

  18. 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.

  19. Key Immune Cell Cytokines Affects the Telomere Activity of Cord Blood Cells In vitro

    PubMed Central

    Brazvan, Balal; Farahzadi, Raheleh; Mohammadi, Seyede Momeneh; Montazer Saheb, Soheila; Shanehbandi, Dariush; Schmied, Laurent; Soleimani Rad, Jafar; Darabi, Masoud; Nozad Charoudeh, Hojjatollah

    2016-01-01

    Purpose: Telomere is a nucleoprotein complex at the end of eukaryotic chromosomes and its length is regulated by telomerase. The number of DNA repeat sequence (TTAGGG)n is reduced with each cell division in differentiated cells. The aim of this study was to evaluate the effect of SCF (Stem Cell Factor), Flt3 (Fms- Like tyrosine kinase-3), Interleukin-2, 7 and 15 on telomere length and hTERT gene expression in mononuclear and umbilical cord blood stem cells (CD34+ cells) during development to lymphoid cells. Methods: The mononuclear cells were isolated from umbilical cord blood by Ficoll-Paque density gradient. Then cells were cultured for 21 days in the presence of different cytokines. Telomere length and hTERT gene expression were evaluated in freshly isolated cells, 7, 14 and 21 days of culture by real-time PCR. The same condition had been done for CD34+ cells but telomere length and hTERT gene expression were measured at initial and day 21 of the experiment. Results: Highest hTERT gene expression and maximum telomere length were measured at day14 of MNCs in the presence of IL-7 and IL-15. Also, there was a significant correlation between telomere length and telomerase gene expression in MNCs at 14 days in a combination of IL-7 and IL-15 (r = 0.998, p =0.04). In contrast, IL-2 showed no distinct effect on telomere length and hTERT gene expression in cells. Conclusion: Taken together, IL-7 and IL-15 increased telomere length and hTERT gene expression at 14 day of the experiment. In conclusion, it seems likely that cells maintain naïve phenotype due to prolonged exposure of IL-7 and IL-15. PMID:27478776

  20. Measurement of Telomere length: a new assay using QuantiGene chemistry on a Luminex platform

    PubMed Central

    Kibriya, Muhammad G.; Jasmine, Farzana; Roy, Shantanu; Ahsan, Habibul; Pierce, Brandon

    2014-01-01

    Background Telomeres are tandem repeats of sequences present at the end of the chromosomes that maintain chromosomal integrity. After repeated cell division, telomeres shorten to a critical level, triggering replicative senescence or apoptosis, which is a key determinant of cellular ageing. Short telomeres also contribute to genome instability and are a hallmark of many cancers. There are several methods for estimating telomere length (TL) from extracted DNA samples. Southern blot is accurate but requires a large quantity of DNA and is expensive. qPCR is cost-effective and requires a small quantity of DNA and is therefore widely used for large-scale epidemiological studies; however, typically requires triplicates. We describe a novel multiplexed probe-based non-PCR method for TL measurement. Methods A small amount of DNA (∼50ng) is hybridized to telomere repeat sequence-specific probes (T) and a reference single gene probes (R). T and R signals are detected from a single reaction well containing the same input DNA. Branching DNA technology is used to amplify the signal which is detected by Luminex technology. Results The intra- and inter-assay CV (∼3% and ∼5% respectively) shows the precision of the new assay and the measurements from single well correlated well with traditional single-plex qPCR run in triplicate (r=0.7 to 0.8). The assay was also validated in an independent set of samples using Southern blot (r=0.74). Conclusion We describe a novel assay for TL assessment using Luminex platform. Impact This may offer an alternative cost-efficient way to study TL in extracted DNA samples. PMID:25472675

  1. Semen preparation methods and sperm telomere length: density gradient centrifugation versus the swim up procedure

    PubMed Central

    Zhao, Feifei; Yang, Qingling; Shi, Senlin; Luo, Xiaoyan; Sun, Yingpu

    2016-01-01

    Previous studies have shown that both density gradient centrifugation (DGC) and swim up (SU) procedures can select spermatozoa with longer telomeres for assisted reproduction techniques (ART). However, it is unknown which approach is more effective. The aim of the present study was to compare the effects of these two methods on sperm telomere length (STL). A total of 150 normozoospermic subjects were recruited. STL, DNA fragmentation index (DFI), reactive oxygen species (ROS) content and progressive motility of semen samples were detected before and after the procedures of DGC and SU. When compared to raw semen, the average length of sperm telomeres was significantly longer after the two sperm preparation methods. However, no significant difference was found between the DGC and SU procedures. We also found that semen prepared by the two methods had lower DNA fragmentation, ROS content and sperm progressive motility. However, no significant difference was found in those parameters between the two procedures. This is the first study that compares the effects of the DGC and SU procedures on STL, and the results show that both methods can recover a sperm population with longer STL and better DNA integrity for ART. PMID:27958357

  2. Select aging biomarkers based on telomere length and chronological age to build a biological age equation.

    PubMed

    Zhang, Wei-Guang; Zhu, Shu-Ying; Bai, Xiao-Juan; Zhao, De-Long; Jian, Shi-Min; Li, Juan; Li, Zuo-Xiang; Fu, Bo; Cai, Guang-Yan; Sun, Xue-Feng; Chen, Xiang-Mei

    2014-06-01

    The purpose of this study is to build a biological age (BA) equation combining telomere length with chronological age (CA) and associated aging biomarkers. In total, 139 healthy volunteers were recruited from a Chinese Han cohort in Beijing. A genetic index, renal function indices, cardiovascular function indices, brain function indices, and oxidative stress and inflammation indices (C-reactive protein [CRP]) were measured and analyzed. A BA equation was proposed based on selected parameters, with terminal telomere restriction fragment (TRF) and CA as the two principal components. The selected aging markers included mitral annulus peak E anterior wall (MVEA), intima-media thickness (IMT), cystatin C (CYSC), D-dimer (DD), and digital symbol test (DST). The BA equation was: BA = −2.281TRF + 26.321CYSC + 0.025DD − 104.419MVEA + 34.863IMT − 0.265DST + 0.305CA + 26.346. To conclude, telomere length and CA as double benchmarks may be a new method to build a BA.

  3. 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

  4. 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

  5. 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.

  6. Telomere length in the gastric mucosa after Helicobacter pylori eradication and its potential role in the gastric carcinogenesis.

    PubMed

    Tahara, Tomomitsu; Tahara, Sayumi; Tuskamoto, Tetsuya; Horiguchi, Noriyuki; Kawamura, Tomohiko; Okubo, Masaaki; Ishizuka, Takamitsu; Nagasaka, Mitsuo; Nakagawa, Yoshihito; Shibata, Tomoyuki; Kuroda, Makoto; Ohmiya, Naoki

    2017-02-14

    The molecular mechanisms of gastric carcinogenesis after Helicobacter pylori (H. pylori) eradication remain unclear. We examined the telomere length of gastric mucosa samples after successful H. pylori eradication in patients without and those with gastric cancer. Telomere length was measured by the real-time PCR among four different groups of biopsies: gastric body from subjects without history of H. pylori infection (Hp-: n = 23), gastric body from cancer-free subjects after H. pylori eradication (cancer-free body: n = 24), gastric body from early gastric cancer patients diagnosed after H. pylori eradication (EGC body: n = 35) and its paired samples from adjacent mucosa of cancerous area (EGC ADJ: n = 35). The Hp-group presented the longest telomeres among the all groups (Hp- vs. all others, all P < 0.05). Samples from EGC body group showed shorter telomere length than the samples from cancer-free body groups (P < 0.05). Conversely, samples from EGC ADJ group showed rather longer telomere length compared to the EGC body group (P < 0.05), which was also confirmed by the comparison of 35 matched samples (P = 0.0007). Among the samples after H. pylori eradication, shorter telomere length was associated with higher expression of IL-1B and NF-kB (P < 0.0001, 0.0006, respectively). Longer telomere length was also associated with higher expression of TNF-A (P = 0.01). Telomere shortening seems to be important initial steps in gastric cancer predisposition after H. pylori eradication, while it might shift to lengthening to acquire more aggressive pathway to develop cancer.

  7. Long leukocyte telomere length in prostate cancer patients at diagnosis is associated with poor metastasis-free and cancer-specific survival.

    PubMed

    Svenson, Ulrika; Roos, Göran; Wikström, Pernilla

    2017-02-01

    Previous studies have suggested that leukocyte telomere length is associated with risk of developing prostate cancer. Investigations of leukocyte telomere length as a prognostic factor in prostate cancer are, however, lacking. In this study, leukocyte telomere length was investigated both as a risk marker, comparing control subjects and patient risk groups (based on serum levels of prostate-specific antigen, tumor differentiation, and tumor stage), and as a prognostic marker for metastasis-free and cancer-specific survival. Relative telomere length was measured by a well-established quantitative polymerase chain reaction method in 415 consecutively sampled individuals. Statistical evaluation included 162 control subjects without cancer development during follow-up and 110 untreated patients with newly diagnosed localized prostate cancer at the time of blood draw. Leukocyte telomere length did not differ significantly between control subjects and patients, or between patient risk groups. Interestingly, however, and in line with our previous results in breast and kidney cancer patients, relative telomere length at diagnosis was an independent prognostic factor. Patients with long leukocyte telomeres (⩾median) had a significantly worse prostate cancer-specific and metastasis-free survival compared to patients with short telomere length. In contrast, for patients who died of other causes than prostate cancer, long relative telomere length was not coupled to shorter survival time. To our knowledge, these results are novel and give further strength to our hypothesis that leukocyte telomere length might be used as a prognostic marker in malignancy.

  8. The study on telomere length for age estimation in a Thai population.

    PubMed

    Srettabunjong, Supawon; Satitsri, Saravut; Thongnoppakhun, Wanna; Tirawanchai, Nednapis

    2014-06-01

    Age is one of the key parameters in establishing a physical characteristic profile of an individual. For biological evidence left in crime scenes such as blood, saliva, hair, etc, the evidence owner's age can be determined only by DNA extracted from these materials. Previous researches have found that there are certain DNA regions with specialized characteristic and function called telomere being able to predict age. The present study was to determine the correlation between telomere length and age as well as the effect of sex on the correlation and to create linear regression equation for age estimation in Thai population for forensic purposes. Blood samples obtained from unrelated healthy Thai fresh cadavers without anatomical organ abnormalities were used in this study. All cadaver subjects underwent the postmortem examination in jurisdiction of the Department of Forensic Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, and Institute of Forensic Medicine, Police General Hospital. Fifty blood samples from both sexes of all ages divided into 6 groups for equal age distribution (0-11, 12-23, 24-35, 36-47, 48-59, and 60 years old and older) were collected for a total of 100 samples. The extracted genomic DNA samples were then subjected to telomere length estimation by terminal restriction fragment (TRF) assay. The results showed that the mean TRF length was inversely correlated with age (r = -0.625), and sex did not have a statistically significant influence on the association between age and mean TRF length (P > 0.05). The obtained linear regression equation was y = 113.538 ± 9.604 - 0.012 × (R = 0.391; P < 0.001). However, the correlation was too low to be used for age estimation with high certainty and a possible reason for this in part would be the postmortem DNA degradation at some level, even using fresh cadaver blood, and other biological factors such as ethnicity and DNA sources. Roughly, those individuals who had a mean TRF length

  9. Long term effects of radiation exposure on telomere lengths of leukocytes and its associated biomarkers among atomic-bomb survivors

    PubMed Central

    Lustig, Ana; Shterev, Ivo; Geyer, Susan; Shi, Alvin; Hu, Yiqun; Morishita, Yukari; Nagamura, Hiroko; Sasaki, Keiko; Maki, Mayumi; Hayashi, Ikue; Furukawa, Kyoji; Yoshida, Kengo; Kajimura, Junko; Kyoizumi, Seishi; Kusunoki, Yoichiro; Ohishi, Waka; Nakachi, Kei; Weng, Nan-ping; Hayashi, Tomonori

    2016-01-01

    Ionizing radiation (IR) is a major source of cellular damage and the immediate cellular response to IR has been well characterized. But the long-term impact of IR on cell function and its relationship with aging are not known. Here, we examined the IR effects on telomere length and other biomarkers 50 to 68 years post-exposure (two time points per person) in survivors of the atomic bombing at Hiroshima during WWII. We found that telomere length of leukocytes was inversely correlated with the dose of IR (p=0.008), and this effect was primarily found in survivors who were exposed at younger ages; specifically those <12 years old (p=0.0004). Although a dose-related retardation of telomere shortening with age was observed in the cross-sectional data, longitudinal follow-up after 11 years did not show IR exposure-related alteration of the rate of telomere shortening with age. In addition, IR diminished the associations between telomere length and selected aging biomarkers that were observed in survivors with no dose. These included uric acid metabolism, cytokines, and blood T cell counts. These findings showed long-lasting detrimental effects of IR on telomere length of leukocytes in both dose- and age-at-exposure dependent manner, and on alterations of biomarkers with aging. PMID:27102155

  10. 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

  11. Psychiatric disorders and leukocyte telomere length: Underlying mechanisms linking mental illness with cellular aging.

    PubMed

    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

    2015-08-01

    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.

  12. The effect of the severity of obstructive sleep apnea syndrome on telomere length.

    PubMed

    Tempaku, Priscila Farias; Mazzotti, Diego Robles; Hirotsu, Camila; Andersen, Monica Levy; Xavier, Gabriela; Maurya, Pawan Kumar; Rizzo, Lucas Bortolotto; Brietzke, Elisa; Belangero, Sintia Iole; Bittencourt, Lia; Tufik, Sergio

    2016-10-25

    Aging is associated with an increase in the prevalence of obstructive sleep apnea syndrome (OSAS) as well as the shortening of telomeres. It is known that OSAS-related factors are stimuli that can contribute to the acceleration of cellular senescence. Thus, the present study aimed to compare the leukocyte telomere length (LTL) between OSAS patients and controls, as well as to verify the correlation between LTL and sleep parameters. We used DNA extracted of 928 individuals from EPISONO to measure the LTL by the quantitative real-time polymerase chain reaction. All individuals were subjected to one full-night polysomnography. LTL was significantly shorter in OSAS patients compared to controls. The results showed negative correlations between LTL and the following variables: apnea-hypopnea index, respiratory disturbance index, desaturation index and wake after sleep onset. LTL was positively correlated with sleep efficiency, total sleep time, basal, minimum and maximum oxygen saturation. Lastly, it was observed that OSAS severity was associated with shorter LTL even after adjusting for sex, age, years of schooling, body mass index, diabetes, stroke and heart attack. In conclusion, our study indicates the presence of an association between LTL and OSAS and a significant impact of severity of OSAS in telomeres shortening.

  13. The effect of the severity of obstructive sleep apnea syndrome on telomere length

    PubMed Central

    Tempaku, Priscila Farias; Mazzotti, Diego Robles; Hirotsu, Camila; Andersen, Monica Levy; Xavier, Gabriela; Maurya, Pawan Kumar; Rizzo, Lucas Bortolotto; Brietzke, Elisa; Belangero, Sintia Iole; Bittencourt, Lia; Tufik, Sergio

    2016-01-01

    Aging is associated with an increase in the prevalence of obstructive sleep apnea syndrome (OSAS) as well as the shortening of telomeres. It is known that OSAS-related factors are stimuli that can contribute to the acceleration of cellular senescence. Thus, the present study aimed to compare the leukocyte telomere length (LTL) between OSAS patients and controls, as well as to verify the correlation between LTL and sleep parameters. We used DNA extracted of 928 individuals from EPISONO to measure the LTL by the quantitative real-time polymerase chain reaction. All individuals were subjected to one full-night polysomnography. LTL was significantly shorter in OSAS patients compared to controls. The results showed negative correlations between LTL and the following variables: apnea-hypopnea index, respiratory disturbance index, desaturation index and wake after sleep onset. LTL was positively correlated with sleep efficiency, total sleep time, basal, minimum and maximum oxygen saturation. Lastly, it was observed that OSAS severity was associated with shorter LTL even after adjusting for sex, age, years of schooling, body mass index, diabetes, stroke and heart attack. In conclusion, our study indicates the presence of an association between LTL and OSAS and a significant impact of severity of OSAS in telomeres shortening. PMID:27690344

  14. Leukocyte Telomere Length in the Neonatal Offspring of Mothers with Gestational and Pre-Gestational Diabetes

    PubMed Central

    Gilfillan, Christopher; Naidu, Pratyusha; Gunawan, Florence; Hassan, Fadwa; Tian, Pei; Elwood, Ngaire

    2016-01-01

    Aims Telomeres undergo shortening with cell division, accelerated by increased oxidative stress. We aimed to demonstrate shortened telomeres in the offspring of mothers who have diabetes as a consequence of exposure to increased oxidative stress during intrauterine development. Methods We examined the level of glycaemia (glucose, HbA1c, fructosamine), oxidative stress (lipid peroxidation) and the levels of antioxidant enzymes (Superoxide dismutase (SOD) and Selenium dependent glutathione peroxidase) and correlate these findings with mean telomere length (TL) in maternal and foetal blood in groups of pregnant women with pre-gestational diabetes (PGD), gestational diabetes (GD) and a euglycaemic control group. Results Foetal and maternal glucose, maternal HbA1c, and foetal insulin and C-peptide were higher in the PGD group with the GD group being intermediate. Markers of oxidative stress did not vary between groups with the exception of foetal SOD activity that was highest in the GD group. There were no detectable differences in maternal or foetal TL between study groups. An exploratory analysis looking at correlations between glycaemic and oxidative stress parameters and TL revealed a negative correlation between maternal and foetal glucose and TL across the whole study population. This relationship held for the short-term marker of glycaemic control, fructosamine. Conclusions We were unable to show significant telomere shortening in the offspring of mothers with PGD or GD. Exploratory analysis revealed a relationship between foetal TL and short-term glycaemia particularly in PGD. It is possible that increased telomerase activity can compensate for long-term increased oxidative stress but not for short-term dysglycaemia. PMID:27736899

  15. Telomere length in subjects with schizophrenia, their unaffected siblings and healthy controls: Evidence of accelerated aging.

    PubMed

    Czepielewski, Leticia Sanguinetti; Massuda, Raffael; Panizzutti, Bruna; da Rosa, Eduarda Dias; de Lucena, David; Macêdo, Danielle; Grun, Lucas Kich; Barbé-Tuana, Florencia María; Gama, Clarissa Severino

    2016-07-01

    Schizophrenia (SZ) is associated with broad burden. The clinical manifestations of SZ are related to pathophysiological alterations similar to what is seen in normal aging. Our aim was to evaluate the differences in telomere length (TL), a biomarker of cellular aging, in subjects with SZ (n=36), unaffected siblings (SB, n=36) and healthy controls (HC, n=47). SZ had shorter TL compared to HC, but no difference was found in SB comparing to SZ. These findings indicate that a pathological accelerated aging profile could be present in the course of SZ and further studies are needed to confirm TL as potential endophenotype, especially in at risk populations.

  16. Association between telomere length and CYP19 TTTA repetition polymorphism in healthy and breast cancer-diagnosed women

    PubMed Central

    Murillo-Ortiz, Blanca; Martínez-Garza, Sandra; Suárez García, David; Castillo Valenzuela, Rosa del Carmen; García Regalado, Juan Francisco; Cano Velázquez, Gerardo

    2017-01-01

    Introduction Several studies have reported an increase in breast cancer (BC) risk when patients are carriers of the CYP19 TTA polymorphism with ≥10 repeats; moreover, it has been reported that telomere length is associated with a higher susceptibility of developing cancer. Objective The objective of this study was to understand the relationship between CYP19 TTTA repetition polymorphism and telomere length and its effects on serum estradiol, estrone and follicle-stimulating hormone (FSH). Materials and methods A total of 180 postmenopausal healthy and 70 BC-diagnosed women were included. Telomere length was determined through real-time quantitative polymerase chain reaction, and aromatase polymorphism was analyzed through DNA; both samples were obtained from circulating leukocytes. Serum estrone, estradiol and FSH were determined by enzyme-linked immunosorbent assay. Results Patients with a BC diagnosis showed >10 repetitions more frequently, compared with that of healthy women (50% vs 23%, χ2 = 11.44, p = 0.0007). A significant difference in telomere length between healthy and BC women was observed (5,042.7 vs 2,256.7 pb, Z = 4.88, p < 0.001). CYP19 TTTA repeat polymorphism was associated with serum levels of estradiol and estrone in both groups, being higher in those with >10 repeats. Moreover, telomere length showed an inverse relationship with the number of repeats of the aromatase polymorphism in healthy women (R2 = 0.04, r = −0.24); in contrast, BC patients did not display this relationship. In addition, telomere length presented an inverse relationship with serum levels of estradiol and estrone in BC patients (p = 0.02). Conclusion Telomere length is shorter in BC patients than in healthy patients. The CYP19 TTTA repeat polymorphism is associated with serum levels of estradiol and estrone in both healthy women and BC patients, being higher in those with polymorphism carriers >10 repeats. Telomere length has an inverse correlation with the number of

  17. Telomere-driven diseases and telomere-targeting therapies.

    PubMed

    Martínez, Paula; Blasco, Maria A

    2017-04-03

    Telomeres, the protective ends of linear chromosomes, shorten throughout an individual's lifetime. Telomere shortening is proposed to be a primary molecular cause of aging. Short telomeres block the proliferative capacity of stem cells, affecting their potential to regenerate tissues, and trigger the development of age-associated diseases. Mutations in telomere maintenance genes are associated with pathologies referred to as telomere syndromes, including Hoyeraal-Hreidarsson syndrome, dyskeratosis congenita, pulmonary fibrosis, aplastic anemia, and liver fibrosis. Telomere shortening induces chromosomal instability that, in the absence of functional tumor suppressor genes, can contribute to tumorigenesis. In addition, mutations in telomere length maintenance genes and in shelterin components, the protein complex that protects telomeres, have been found to be associated with different types of cancer. These observations have encouraged the development of therapeutic strategies to treat and prevent telomere-associated diseases, namely aging-related diseases, including cancer. Here we review the molecular mechanisms underlying telomere-driven diseases and highlight recent advances in the preclinical development of telomere-targeted therapies using mouse models.

  18. Influence of In Utero Maternal and Neonate Factors on Cord Blood Leukocyte Telomere Length: Clues to the Racial Disparity in Prostate Cancer?

    PubMed Central

    Weber, Kari A.; Heaphy, Christopher M.; Rohrmann, Sabine; Gonzalez, Beverly; Bienstock, Jessica L.; Agurs-Collins, Tanya; Platz, Elizabeth A.

    2016-01-01

    Background. Modifiable factors in adulthood that explain the racial disparity in prostate cancer have not been identified. Because racial differences in utero that may account for this disparity are understudied, we investigated the association of maternal and neonate factors with cord blood telomere length, as a cumulative marker of cell proliferation and oxidative damage, by race. Further, we evaluated whether cord blood telomere length differs by race. Methods. We measured venous umbilical cord blood leukocyte relative telomere length by qPCR in 38 black and 38 white full-term male neonates. Using linear regression, we estimated geometric mean relative telomere length and tested for differences by race. Results. Black mothers were younger and had higher parity and black neonates had lower birth and placental weights. These factors were not associated with relative telomere length, even after adjusting for or stratifying by race. Relative telomere length in black (2.72) and white (2.73) neonates did not differ, even after adjusting for maternal or neonate factors (all p > 0.9). Conclusions. Maternal and neonate factors were not associated with cord blood telomere length, and telomere length did not differ by race. These findings suggest that telomere length at birth does not explain the prostate cancer racial disparity. PMID:28070423

  19. The age‐dependent association between aortic pulse wave velocity and telomere length

    PubMed Central

    Yasmin; Butcher, Lee; Cockcroft, John R.; Wilkinson, Ian B.; Erusalimsky, Jorge D.; McEniery, Carmel M.

    2017-01-01

    Key points Age significantly modifies the relationship between aortic pulse wave velocity and telomere length.The differential relationships observed between aortic pulse wave velocity and telomere length in younger and older individuals suggest that the links between cellular and vascular ageing reflect a complex interaction between genetic and environmental factors acting over the life‐course. Abstract Ageing is associated with marked large artery stiffening. Telomere shortening, a marker of cellular ageing, is linked with arterial stiffening. However, the results of existing studies are inconsistent, possibly because of the confounding influence of variable exposure to cardiovascular risk factors. Therefore, we investigated the relationship between telomere length (TL) and aortic stiffness in well‐characterized, younger and older healthy adults, who were pre‐selected on the basis of having either low or high aortic pulse wave velocity (aPWV), a robust measure of aortic stiffness. Demographic, haemodynamic and biochemical data were drawn from participants in the Anglo‐Cardiff Collaborative Trial. Two age groups with an equal sex ratio were examined: those aged <30 years (younger) or >50 years (older). Separately for each age group and sex, DNA samples representing the highest (n = 125) and lowest (n = 125) extremes of aPWV (adjusted for blood pressure) were selected for analysis of leukocyte TL. Ultimately, this yielded complete phenotypic data on 904 individuals. In younger subjects, TL was significantly shorter in those with high aPWV vs. those with low aPWV (P = 0.017). By contrast, in older subjects, TL was significantly longer in those with high aPWV (P = 0.001). Age significantly modified the relationship between aPWV and TL (P < 0.001). Differential relationships are observed between aPWV and TL, with an inverse association in younger individuals and a positive association in older individuals. The links between cellular and vascular

  20. 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

  1. 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

    2016-05-03

    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.

  2. Risky family processes prospectively forecast shorter telomere length mediated through negative emotions.

    PubMed

    Brody, Gene H; Yu, Tianyi; Shalev, Idan

    2016-11-10

    Objective: This study was designed to examine prospective associations of risky family environments with subsequent levels of negative emotions and peripheral blood mononuclear cell telomere length (TL), a marker of cellular aging. A second purpose was to determine whether negative emotions mediate the hypothesized link between risky family processes and diminished telomere length. Method: Participants were 293 adolescents (age 17 years at the first assessment) and their primary caregivers. Caregivers provided data on risky family processes when the youths were age 17 years, youths reported their negative emotions at age 18 years, and youths' TL was assayed from a blood sample at age 22 years. Results: The results revealed that (a) risky family processes forecast heightened negative emotions (β = .316, p < .001) and diminished TL (β = -.199, p = .003) among youths, (b) higher levels of negative emotions forecast shorter TL (β = -.187, p = .012), and (c) negative emotions served as a mediator connecting risky family processes with diminished TL (indirect effect = -0.012, 95% CI [-0.036, -0.002]). Conclusions: These findings are consistent with the hypothesis that risky family processes presage premature cellular aging through effects on negative emotions, with potential implications for lifelong health. (PsycINFO Database Record

  3. Corticosterone, inflammation, immune status and telomere length in frigatebird nestlings facing a severe herpesvirus infection

    PubMed Central

    Sebastiano, Manrico; Eens, Marcel; Angelier, Frederic; Pineau, Kévin; Chastel, Olivier; Costantini, David

    2017-01-01

    Herpesvirus outbreaks are common in natural animal populations, but little is known about factors that favour the infection and its consequences for the organism. In this study, we examined the pathophysiological consequences of a disease probably attributable to herpesvirus infection for several markers of immune function, corticosterone, telomere length and inflammation. In addition, we assessed whether any markers used in this study might be associated with the occurrence of visible clinical signs of the disease and its impact on short-term survival perspectives. To address our questions, in spring 2015, we collected blood samples from nestlings of the magnificent frigatebird (Fregata magnificens) that were free of any clinical signs or showed visible signs of the disease. We found that the plasma concentration of haptoglobin was strongly associated with the infection status and could predict probabilities of survival. We also found that nestlings with clinical signs had lower baseline corticosterone concentrations and similar telomere length compared with healthy nestlings, whereas we did not find any association of the infection status with innate immune defenses or with nitric oxide concentration. Overall, our results suggest that the plasma concentration of haptoglobin might be a valuable tool to assess survival probabilities of frigatebird nestlings facing a herpesvirus outbreak. PMID:28070333

  4. 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

  5. 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

  6. 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.

  7. Estimating Telomere Length Heritability in an Unrelated Sample of Adults: Is Heritability of Telomere Length Modified by Life Course Socioeconomic Status?

    PubMed Central

    Faul, Jessica D.; Mitchell, Colter M.; Smith, Jennifer A.; Zhao, Wei

    2016-01-01

    Telomere length (TL) is a widely used marker of biological aging and is associated with an increased risk of morbidity and mortality. Recently, there has been evidence for an association between socioeconomic status (SES) and TL, particularly with measures of education and childhood SES. Individual differences in TL are also influenced by genetic factors, with heritability estimates from twin and sibling studies ranging from 34 to 82 percent. Yet unknown is the additive heritability of TL due to measured genetic variations and the extent that heritability is modified by SES. Data from the Health and Retirement Study, a nationally-representative cohort of older adults (mean 69 years), were used to provide the first estimates of molecular-based heritability of TL using genome-wide complex trait analysis (GCTA). We found that additive genetic variance contributed 28 percent (p=0.012) of total phenotypic variance of TL in the European American sample (n=3290). Estimation using the GCTA and KING Robust relationship inference methods did not differ significantly in this sample. None of the variance from the gene-by-SES interactions examined contributed significantly to the total TL variance. Estimation of heritability and genetic interaction with SES in the African American sample (n=442) was too unstable to provide reliable estimates. PMID:27050034

  8. 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.

  9. Polychlorinated Biphenyls and Leukocyte Telomere Length: An Analysis of NHANES 1999-2002.

    PubMed

    Scinicariello, Franco; Buser, Melanie C

    2015-12-01

    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.

  10. 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

  11. 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

  12. Telomerase inhibitor imetelstat has preclinical activity across the spectrum of non-small cell lung cancer oncogenotypes in a telomere length dependent manner

    PubMed Central

    Frink, Robin E.; Peyton, Michael; Schiller, Joan H.; Gazdar, Adi F.; Shay, Jerry W.; Minna, John D.

    2016-01-01

    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. PMID:27192120

  13. 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

  14. Leukocyte telomere length and mortality among U.S. adults: Effect modification by physical activity behaviour.

    PubMed

    Loprinzi, Paul D; Loenneke, Jeremy P

    2017-02-17

    The purpose of this study was to examine the association between leukocyte telomere length (LTL) and mortality (outcome variable), with consideration by physical activity behaviour. Data from the 1999-2002 National Health and Nutrition Examination Survey were employed (N = 6,611; 20-85 yrs), with follow-up mortality assessment through 31 December 2006. DNA was extracted from whole blood to assess LTL via quantitative polymerase chain reaction. Compared to those in the first LTL tertile, the adjusted hazard ratio for all-cause mortality for those in the 2(nd) and 3(rd) LTL tertiles, respectively, was 0.82 (95% CI: 0.60-1.12; P = .22) and 0.76 (95% CI: 0.50-1.14; P = .18). However, after adjustments, LTL tertile 3 (vs. 1) was associated with all-cause mortality (HR = 0.37; 95% CI: 0.14-0.93; P = .03) for those who engaged in moderate-intensity exercise. Similarly, LTL was associated with CVD-specific mortality for those who engaged in moderate-intensity exercise (HR = 0.17; 95% CI: 0.04-0.73; P = .02). Longer telomeres are associated with increased survival, particularly among men and those who are active, underscoring the importance of promotion of physical activity behaviour.

  15. Paroxysmal nocturnal haemoglobinuria phenotype cells and leucocyte subset telomere length in childhood acquired aplastic anaemia.

    PubMed

    Tutelman, Perri R; Aubert, Geraldine; Milner, Ruth A; Dalal, Bakul I; Schultz, Kirk R; Deyell, Rebecca J

    2014-03-01

    The significance of paroxysmal nocturnal haemoglobinuria (PNH(pos) ) cells and leucocyte subset telomere lengths in paediatric aplastic anaemia (AA) is unknown. Among 22 children receiving immunosuppressive therapy (IST) for AA, 73% (16/22) were PNH(pos) , of whom 94% achieved at least a partial response (PR) to IST; 11/16 (69%) achieved complete response (CR). Only 2/6 (33%) PNH(neg) patients achieved PR. PNH(pos) patients were less likely to fail IST compared to PNH(neg) patients (odds ratio 0·033; 95% confidence interval 0·002-0·468; P = 0·012). Children with AA had short granulocyte (P = 7·8 × 10(-9) ), natural killer cell (P = 6·0 × 10(-4) ), naïve T lymphocyte (P = 0·002) and B lymphocyte (P = 0·005) telomeres compared to age-matched normative data.

  16. Sugary beverage and food consumption, and leukocyte telomere length maintenance in pregnant women.

    PubMed

    Leung, C W; Laraia, B A; Coleman-Phox, K; Bush, N R; Lin, J; Blackburn, E H; Adler, N E; Epel, E S

    2016-09-01

    Leukocyte telomere length (LTL) has been inversely associated with sugar-sweetened beverage (SSB) consumption in cross-sectional studies, but no studies have examined whether dietary intake influences LTL over time. This study examined longitudinal associations between sugary foods and beverages and LTL. Participants were 65 overweight and obese pregnant women, aged 18-45 years, from a mindfulness intervention study conducted from early pregnancy (⩽16 weeks gestation) and followed through 9 months postpartum. During pregnancy and postpartum, dietary intake was measured with 24-h diet recalls, and LTL was assessed using quantitative PCR. Adjusting for sociodemographic and health characteristics, decreased SSB consumption from baseline to 9 months postpartum was associated with greater concurrent LTL lengthening (β=-0.102, 95% confidence interval (CI) -0.192, -0.013). No associations between sugary foods and LTL were found in either period. The finding that reduced SSB consumption is associated with increased LTL warrants investigation in large cohort studies.

  17. 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.

  18. Pesticide Use and Relative Leukocyte Telomere Length in the Agricultural Health Study

    PubMed Central

    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

  19. 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.

  20. 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

  1. 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

  2. Relative telomere lengths in tumor and normal mucosa are related to disease progression and chromosome instability profiles in colorectal cancer

    PubMed Central

    Jorissen, Robert N.; Hampson, Debbie; Ghosh, Anil; Sengupta, Neel; Thaha, Mohamed; Ahmed, Shafi; Kirwan, Michael; Aleva, Floor; Propper, David; Feakins, Roger M.; Vulliamy, Tom; Elwood, Ngaire J.; Tian, Pei; Ward, Robyn L.; Hawkins, Nicholas J.; Xu, Zheng-Zhou; Molloy, Peter L.; Jones, Ian T.; Croxford, Matthew; Gibbs, Peter; Silver, Andrew; Sieber, Oliver M.

    2016-01-01

    Telomeric dysfunction is linked to colorectal cancer (CRC) initiation. However, the relationship of normal tissue and tumor telomere lengths with CRC progression, molecular features and prognosis is unclear. Here, we measured relative telomere length (RTL) by real-time quantitative PCR in 90 adenomas (aRTL), 419 stage I-IV CRCs (cRTL) and adjacent normal mucosa (nRTL). Age-adjusted RTL was analyzed against germline variants in telomere biology genes, chromosome instability (CIN), microsatellite instability (MSI), CpG island methylator phenotype (CIMP), TP53, KRAS, BRAF mutations and clinical outcomes. In 509 adenoma or CRC patients, nRTL decreased with advancing age. Female gender, proximal location and the TERT rs2736100 G allele were independently associated with longer age-adjusted nRTL. Adenomas and carcinomas exhibited telomere shortening in 79% and 67% and lengthening in 7% and 15% of cases. Age-adjusted nRTL and cRTL were independently associated with tumor stage, decreasing from adenoma to stage III and leveling out or increasing from stage III to IV, respectively. Cancer MSI, CIMP, TP53, KRAS and BRAF status were not related to nRTL or cRTL. Near-tetraploid CRCs exhibited significantly longer cRTLs than CIN- and aneuploidy CRCs, while cRTL was significantly shorter in CRCs with larger numbers of chromosome breaks. Age-adjusted nRTL, cRTL or cRTL:nRTL ratios were not associated with disease-free or overall survival in stage II/III CRC. Taken together, our data show that both normal mucosa and tumor RTL are independently associated with CRC progression, and highlight divergent associations of CRC telomere length with tumor CIN profiles. PMID:27167335

  3. Relative telomere lengths in tumor and normal mucosa are related to disease progression and chromosome instability profiles in colorectal cancer.

    PubMed

    Suraweera, Nirosha; Mouradov, Dmitri; Li, Shan; Jorissen, Robert N; Hampson, Debbie; Ghosh, Anil; Sengupta, Neel; Thaha, Mohamed; Ahmed, Shafi; Kirwan, Michael; Aleva, Floor; Propper, David; Feakins, Roger M; Vulliamy, Tom; Elwood, Ngaire J; Tian, Pei; Ward, Robyn L; Hawkins, Nicholas J; Xu, Zheng-Zhou; Molloy, Peter L; Jones, Ian T; Croxford, Matthew; Gibbs, Peter; Silver, Andrew; Sieber, Oliver M

    2016-06-14

    Telomeric dysfunction is linked to colorectal cancer (CRC) initiation. However, the relationship of normal tissue and tumor telomere lengths with CRC progression, molecular features and prognosis is unclear. Here, we measured relative telomere length (RTL) by real-time quantitative PCR in 90 adenomas (aRTL), 419 stage I-IV CRCs (cRTL) and adjacent normal mucosa (nRTL). Age-adjusted RTL was analyzed against germline variants in telomere biology genes, chromosome instability (CIN), microsatellite instability (MSI), CpG island methylator phenotype (CIMP), TP53, KRAS, BRAF mutations and clinical outcomes. In 509 adenoma or CRC patients, nRTL decreased with advancing age. Female gender, proximal location and the TERT rs2736100 G allele were independently associated with longer age-adjusted nRTL. Adenomas and carcinomas exhibited telomere shortening in 79% and 67% and lengthening in 7% and 15% of cases. Age-adjusted nRTL and cRTL were independently associated with tumor stage, decreasing from adenoma to stage III and leveling out or increasing from stage III to IV, respectively. Cancer MSI, CIMP, TP53, KRAS and BRAF status were not related to nRTL or cRTL. Near-tetraploid CRCs exhibited significantly longer cRTLs than CIN- and aneuploidy CRCs, while cRTL was significantly shorter in CRCs with larger numbers of chromosome breaks. Age-adjusted nRTL, cRTL or cRTL:nRTL ratios were not associated with disease-free or overall survival in stage II/III CRC. Taken together, our data show that both normal mucosa and tumor RTL are independently associated with CRC progression, and highlight divergent associations of CRC telomere length with tumor CIN profiles.

  4. 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

  5. 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

  6. Telomere length and cardiovascular risk factors in a middle-aged population free of overt cardiovascular disease.

    PubMed

    Bekaert, Sofie; De Meyer, Tim; Rietzschel, Ernst R; De Buyzere, Marc L; De Bacquer, Dirk; Langlois, Michel; Segers, Patrick; Cooman, Luc; Van Damme, Piet; Cassiman, Peter; Van Criekinge, Wim; Verdonck, Pascal; De Backer, Guy G; Gillebert, Thierry C; Van Oostveldt, Patrick

    2007-10-01

    Evidence assembled over the last decade shows that average telomere length (TL) acts as a biomarker for biological aging and cardiovascular disease (CVD) in particular. Although essential for a more profound understanding of the underlying mechanisms, little reference information is available on TL. We therefore sought to provide baseline TL information and assess the association of prevalent CVD risk factors with TL in subjects free of overt CVD within a small age range. We measured mean telomere restriction fragment length of peripheral blood leukocytes in a large, representative Asklepios study cohort of 2509 community-dwelling, Caucasian female and male volunteers aged approximately 35-55 years and free of overt CVD. We found a manifest age-dependent telomere attrition, at a significantly faster rate in men as compared to women. No significant associations were established with classical CVD risk factors such as cholesterol status and blood pressure, yet shorter TL was associated with increased levels of several inflammation and oxidative stress markers. Importantly, shorter telomere length was associated with an increasingly unhealthy lifestyle, particularly in men. All findings were age and gender adjusted where appropriate. With these cross-sectional results we show that TL of peripheral blood leukocytes primarily reflects the burden of increased oxidative stress and inflammation, whether or not determined by an increasingly unhealthy lifestyle, while the association with classical CVD risk factors is limited. This further clarifies the added value of TL as a biomarker for biological aging and might improve our understanding of how TL is associated with CVD.

  7. 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.

  8. 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

  9. 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.

  10. 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

  11. Low Birth Weight in MZ Twins Discordant for Birth Weight is Associated with Shorter Telomere Length and lower IQ, but not Anxiety/Depression in Later Life.

    PubMed

    Strohmaier, Jana; van Dongen, Jenny; Willemsen, Gonneke; Nyholt, Dale R; Zhu, Gu; Codd, Veryan; Novakovic, Boris; Hansell, Narelle; Wright, Margaret J; Rietschel, Liz; Streit, Fabian; Henders, Anjali K; Montgomery, Grant W; Samani, Nilesh J; Gillespie, Nathan A; Hickie, Ian B; Craig, Jeffrey M; Saffery, Richard; Boomsma, Dorret I; Rietschel, Marcella; Martin, Nicholas G

    2015-04-01

    Shorter telomere length (TL) has found to be associated with lower birth weight and with lower cognitive ability and psychiatric disorders. However, the direction of causation of these associations and the extent to which they are genetically or environmentally mediated are unclear. Within-pair comparisons of monozygotic (MZ) and dizygotic (DZ) twins can throw light on these questions. We investigated correlations of within pair differences in telomere length, IQ, and anxiety/depression in an initial sample from Brisbane (242 MZ pairs, 245 DZ same sex (DZSS) pairs) and in replication samples from Amsterdam (514 MZ pairs, 233 DZSS pairs) and Melbourne (19 pairs selected for extreme high or low birth weight difference). Intra-pair differences of birth weight and telomere length were significantly correlated in MZ twins, but not in DZSS twins. Greater intra-pair differences of telomere length were observed in the 10% of MZ twins with the greatest difference in birth weight compared to the bottom 90% in both samples and also in the Melbourne sample. Intra-pair differences of telomere length and IQ, but not of TL and anxiety/depression, were correlated in MZ twins, and to a smaller extent in DZSS twins. Our findings suggest that the same prenatal effects that reduce birth weight also influence telomere length in MZ twins. The association between telomere length and IQ is partly driven by the same prenatal effects that decrease birth weight.

  12. Mild hyperoxia limits hTR levels, telomerase activity, and telomere length maintenance in hTERT-transduced bone marrow endothelial cells.

    PubMed

    Napier, Christine E; Veas, Laura A; Kan, Chin-Yi; Taylor, Lisa M; Yuan, Jun; Wen, Victoria W; James, Alexander; O'Brien, Tracey A; Lock, Richard B; MacKenzie, Karen L

    2010-10-01

    Reactivation of telomerase in endothelial cells (ECs) may be an effective approach to the treatment of vascular disorders associated with telomere attrition and EC senescence. However, overexpression of human telomerase reverse transcriptase (hTERT) does not prevent net telomere loss in ECs grown in standard culture medium with exposure to atmospheric oxygen (21% O(2)). Since these culture conditions are hyperoxic relative to normal tissue in vivo, where oxygen tension is estimated to be 1%-6%, we examined the effects of reduced exposure to oxidative stress (OS) on telomere length maintenance in hTERT-transduced bone marrow endothelial (BMhTERT) cells. Propagation of BMhTERT cells in the free radical scavenger, tert-butylhydroxylamine (tBN), and/or in 5% O(2) increased telomerase enzyme activity and facilitated telomere length maintenance. The enhancement of telomerase activity correlated with higher levels of the telomerase RNA component (hTR). We also investigated the role of the telomere binding protein, TRF1, in telomere length regulation under alternate OS conditions. Inhibition of TRF1 function had no effect on telomere length in BMhTERT cells grown under standard culture conditions. However, alleviation of OS by growth in tBN plus 5% O(2), elevated hTR levels, enhanced telomerase enzyme activity, and enabled progressive telomere lengthening. The direct impact of hTR levels on telomerase-mediated telomere lengthening was demonstrated by overexpression of hTR. BMhTERT cells transduced with hTR exhibited very high telomerase enzyme activity and underwent dramatic telomere lengthening under standard culture conditions. Overall, these results demonstrate that hTR levels are reduced by mild hyperoxia and limit telomerase-mediated telomere lengthening in hTERT-transduced ECs.

  13. Long-Term Effects of Radiation Exposure and Metabolic Status on Telomere Length of Peripheral Blood T Cells in Atomic Bomb Survivors.

    PubMed

    Yoshida, Kengo; Misumi, Munechika; Kubo, Yoshiko; Yamaoka, Mika; Kyoizumi, Seishi; Ohishi, Waka; Hayashi, Tomonori; Kusunoki, Yoichiro

    2016-10-01

    In a series of studies of atomic bomb survivors, radiation-dose-dependent alterations in peripheral T-cell populations have been reported. For example, reduced size in naïve T-cell pools and impaired proliferation ability of T cells were observed. Because these alterations are also generally observed with human aging, we hypothesized that radiation exposure may accelerate the aging process of the T-cell immune system. To further test this hypothesis, we conducted cross-sectional analyses of telomere length, a hallmark of cellular aging, of naïve and memory CD4 T cells and total CD8 T cells in the peripheral blood of 620 atomic bomb survivors as it relates to age and radiation dose, using fluorescence in situ hybridization with flow cytometry. Since telomere shortening has been recently demonstrated in obesity-related metabolic abnormalities and diseases, the modifying effects of metabolic status were also examined. Our results indicated nonlinear relationships between T-cell telomere length and prior radiation exposure, i.e., longer telomeres with lower dose exposure and a decreasing trend of telomere length with individuals exposed to doses higher than 0.5 Gy. There were associations between shorter T-cell telomeres and higher hemoglobin Alc levels or fatty liver development. In naïve and memory CD4 T cells, radiation dose and high-density lipoprotein (HDL) cholesterol were found to positively interact with telomere length, suggesting that the decreasing trend of telomere length from a higher radiation dose was less conspicuous in individuals with a higher HDL cholesterol. It is therefore likely that radiation exposure perturbs T-cell homeostasis involving telomere length maintenance by multiple biological mechanisms, depending on dose, and that long-term-radiation-induced effects on the maintenance of T-cell telomeres may be modified by the subsequent metabolic conditions of individuals.

  14. 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

  15. Effects of size at birth, childhood growth patterns and growth hormone treatment on leukocyte telomere length

    PubMed Central

    Smeets, Carolina C. J.; Codd, Veryan; Denniff, Matthew; Samani, Nilesh J.; Hokken-Koelega, Anita C. S.

    2017-01-01

    Background Small size at birth and rapid growth in early life are associated with increased risk of cardiovascular disease in later life. Short children born small for gestational age (SGA) are treated with growth hormone (GH), inducing catch-up in length. Leukocyte telomere length (LTL) is a marker of biological age and shorter LTL is associated with increased risk of cardiovascular disease. Objectives To investigate whether LTL is influenced by birth size, childhood growth and long-term GH treatment. Methods We analyzed LTL in 545 young adults with differences in birth size and childhood growth patterns. Previously GH-treated young adults born SGA (SGA-GH) were compared to untreated short SGA (SGA-S), SGA with spontaneous catch-up to a normal body size (SGA-CU), and appropriate for gestational age with a normal body size (AGA-NS). LTL was measured using a quantitative PCR assay. Results We found a positive association between birth length and LTL (p = 0.04), and a trend towards a positive association between birth weight and LTL (p = 0.08), after adjustments for gender, age, gestational age and adult body size. Weight gain during infancy and childhood and fat mass percentage were not associated with LTL. Female gender and gestational age were positively associated with LTL, and smoking negatively. After adjustments for gender, age and gestational age, SGA-GH had a similar LTL as SGA-S (p = 0.11), SGA-CU (p = 0.80), and AGA-NS (p = 0.30). Conclusions Larger size at birth is positively associated with LTL in young adulthood. Growth patterns during infancy and childhood are not associated with LTL. Previously GH-treated young adults born SGA have similar LTL as untreated short SGA, SGA with spontaneous catch-up and AGA born controls, indicating no adverse effects of GH-induced catch-up in height on LTL. PMID:28178350

  16. Soda and Cell Aging: Associations Between Sugar-Sweetened Beverage Consumption and Leukocyte Telomere Length in Healthy Adults From the National Health and Nutrition Examination Surveys

    PubMed Central

    Laraia, Barbara A.; Needham, Belinda L.; Rehkopf, David H.; Adler, Nancy E.; Lin, Jue; Blackburn, Elizabeth H.

    2014-01-01

    Objectives. We tested whether leukocyte telomere length maintenance, which underlies healthy cellular aging, provides a link between sugar-sweetened beverage (SSB) consumption and the risk of cardiometabolic disease. Methods. We examined cross-sectional associations between the consumption of SSBs, diet soda, and fruit juice and telomere length in a nationally representative sample of healthy adults. The study population included 5309 US adults, aged 20 to 65 years, with no history of diabetes or cardiovascular disease, from the 1999 to 2002 National Health and Nutrition Examination Surveys. Leukocyte telomere length was assayed from DNA specimens. Diet was assessed using 24-hour dietary recalls. Associations were examined using multivariate linear regression for the outcome of log-transformed telomere length. Results. After adjustment for sociodemographic and health-related characteristics, sugar-sweetened soda consumption was associated with shorter telomeres (b = –0.010; 95% confidence interval [CI] = −0.020, −0.001; P = .04). Consumption of 100% fruit juice was marginally associated with longer telomeres (b = 0.016; 95% CI = −0.000, 0.033; P = .05). No significant associations were observed between consumption of diet sodas or noncarbonated SSBs and telomere length. Conclusions. Regular consumption of sugar-sweetened sodas might influence metabolic disease development through accelerated cell aging. PMID:25322305

  17. Social isolation shortens telomeres in African Grey parrots (Psittacus erithacus erithacus).

    PubMed

    Aydinonat, Denise; Penn, Dustin J; Smith, Steve; Moodley, Yoshan; Hoelzl, Franz; Knauer, Felix; Schwarzenberger, Franz

    2014-01-01

    Telomeres, the caps of eukaryotic chromosomes, control chromosome stability and cellular senescence, but aging and exposure to chronic stress are suspected to cause attrition of telomere length. We investigated the effect of social isolation on telomere length in the highly social and intelligent African Grey parrot (Psittacus erithacus erithacus). Our study population consisted of single-housed (n = 26) and pair-housed (n = 19) captive individuals between 0.75 to 45 years of age. Relative telomere length of erythrocyte DNA was measured by quantitative real-time PCR. We found that telomere length declined with age (p<0.001), and socially isolated parrots had significantly shorter telomeres compared to pair-housed birds (p<0.001) - even among birds of similar ages. Our findings provide the first evidence that social isolation affects telomere length, which supports the hypothesis that telomeres provide a biomarker indicating exposure to chronic stress.

  18. 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.

  19. 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

  20. Leukocyte telomere length in Hispanic schizophrenia patients under treatment with olanzapine.

    PubMed

    Monroy-Jaramillo, Nancy; Rodríguez-Agudelo, Yaneth; Aviña-Cervantes, Luis Carlos; Roberts, David L; Velligan, Dawn I; Walss-Bass, Consuelo

    2017-02-10

    Different lines of evidence indicate that patients with schizophrenia (SZ) exhibit accelerated aging. Leukocyte telomere length (TL), an aging marker, is associated with age-related and chronic pathologies, including schizophrenia. We analyzed leukocyte TL in 170 SZ patients of Hispanic ancestry grouped based on antipsychotic treatment, compared to 126 matched controls. The group under treatment with atypical antipsychotics was further subdivided according to the risk of medication to cause metabolic syndrome (MetS). Our results show significant erosion in the TL of SZ patients under treatment with the atypical antipsychotics clozapine and olanzapine, which cause high-risk for MetS, compared to healthy controls and patients under treatment with medium and low-risk antipsychotics. However, when the analysis was done separately for clozapine and olanzapine, a significant difference remained only for olanzapine. These findings suggest that atypical antipsychotics that cause high-risk for MetS, particularly olanzapine, may modulate leukocyte TL in SZ patients. Future research is required to elucidate if in fact atypical antipsychotics are involved in TL maintenance in SZ subjects and the mechanism by which this occurs.

  1. 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.

  2. Sedentary behavior, physical activity and cardiorespiratory fitness on leukocyte telomere length

    PubMed Central

    Edwards, Meghan K.; Loprinzi, Paul D.

    2017-01-01

    Background: Emerging work is starting to investigate the cumulative effects of moderate-to-vigorous physical activity (MVPA), sedentary behavior and cardiorespiratory fitness on health. The objective of this study was to examine the cumulative and independent associations of MVPA, sedentary behavior and cardiorespiratory fitness on leukocyte telomere length (LTL). Methods: Data from the 1999-2002 National Health and Nutrition Examination Survey (NHANES) were used (N = 1868 adults 20+ years); analyzed in 2016. Sedentary behavior and MVPA were subjectively assessed with cardiorespiratory fitness determined from a submaximal treadmill-based test; participants were classified as above or below the median values for each of these three parameters. A blood sample was obtained from each participant to assess LTL via quantitative polymerase chain reaction, with participants grouped into LTL tertiles. Results: Participants who engaged in higher MVPA, sat less and had higher cardiorespiratory fitness had an increased odds (ranging from 85% to 105%) of being in LTL tertile 3 (vs. 1). In an extended adjusted multinomial logistic regression model, only MVPA was positively associated with LTL (odds ration [OR] = 1.37; 95% CI: 0.99-1.90; P = 0.05). Conclusion: All three behavior characteristics, but particularly MVPA, may be important in preserving LTLs. PMID:28058238

  3. Sedentary behavior, physical activity and cardiorespiratory fitness on leukocyte telomere length.

    PubMed

    Edwards, Meghan K; Loprinzi, Paul D

    2017-01-01

    Background: Emerging work is starting to investigate the cumulative effects of moderate-to-vigorous physical activity (MVPA), sedentary behavior and cardiorespiratory fitness on health. The objective of this study was to examine the cumulative and independent associations of MVPA, sedentary behavior and cardiorespiratory fitness on leukocyte telomere length (LTL). Methods: Data from the 1999-2002 National Health and Nutrition Examination Survey (NHANES) were used (N = 1868 adults 20+ years); analyzed in 2016. Sedentary behavior and MVPA were subjectively assessed with cardiorespiratory fitness determined from a submaximal treadmill-based test; participants were classified as above or below the median values for each of these three parameters. A blood sample was obtained from each participant to assess LTL via quantitative polymerase chain reaction, with participants grouped into LTL tertiles. Results: Participants who engaged in higher MVPA, sat less and had higher cardiorespiratory fitness had an increased odds (ranging from 85% to 105%) of being in LTL tertile 3 (vs. 1). In an extended adjusted multinomial logistic regression model, only MVPA was positively associated with LTL (odds ration [OR] = 1.37; 95% CI: 0.99-1.90; P = 0.05). Conclusion: All three behavior characteristics, but particularly MVPA, may be important in preserving LTLs.

  4. Effects of PCB126 and PCB153 on telomerase activity and telomere length in undifferentiated and differentiated HL-60 cells.

    PubMed

    Xin, Xing; Senthilkumar, P K; Schnoor, Jerald L; Ludewig, Gabriele

    2016-02-01

    PCBs are persistent organic pollutants that are carcinogenic and immunotoxic and have developmental toxicity. This suggests that they may interfere with normal cell maturation. Cancer and stem/progenitor cells have telomerase activity to maintain and protect the chromosome ends, but lose this activity during differentiation. We hypothesized that PCBs interfere with telomerase activity and the telomere complex, thereby disturbing cell differentiation and stem/progenitor cell function. HL-60 cells are cancer cells that can differentiated into granulocytes and monocytes. We exposed HL-60 cells to PCB126 (dioxin-like) and PCB153 (nondioxin-like) 6 days before and during 3 days of differentiation. The differentiated cells showed G0/G1 phase arrest and very low telomerase activity. hTERT and hTR, two telomerase-related genes, were downregulated. The telomere shelterins TRF1, TRF2, and POT1 were upregulated in granulocytes, and TRF2 was upregulated and POT1 downregulated in monocytes. Both PCBs further reduced telomerase activity in differentiated cells, but had only small effects on the differentiation and telomere-related genes. Treatment of undifferentiated HL-60 cells for 30 days with PCB126 produced a downregulation of telomerase activity and a decrease of hTERT, hTR, TRF1, and POT1 gene expression. With PCB153, the effects were less pronounced and some shelterin genes were increased after 30 days of exposure. With each PCB, no differentiation of cells was observed and cells continued to proliferate despite reduced telomerase activity, resulting in shortened telomeres after 30 days of exposure. These results indicate cell-type and PCB congener-specific effects on telomere/telomerase-related genes. Although PCBs do not seem to strongly affect differentiation, they may influence stem or progenitor cells through telomere attrition with potential long-term consequences for health.

  5. Effects of PCB126 and PCB153 on telomerase activity and telomere length in undifferentiated and differentiated HL-60 cells

    PubMed Central

    Xin, Xing; Senthilkumar, PK; Schnoor, Jerald L.; Ludewig, Gabriele

    2015-01-01

    PCBs are persistent organic pollutants with carcinogenic, immune- and developmental toxicity. This suggests that they may interfere with normal cell maturation. Cancer and stem/progenitor cells have telomerase activity to maintain and protect the chromosome ends, but lose this activity during differentiation. We hypothesized that PCBs interfere with telomerase activity and the telomere complex thereby disturbing cell differentiation and stem/progenitor cell function. HL-60 cells are cancer cells that can differentiate to granulocytes and monocytes. We exposed HL-60 cells to the PCB126 (dioxin-like) and PCB153 (non-dioxin-like) 6 days before and during 3 days of differentiation. The differentiated cells showed G0/G1 phase arrest and very low telomerase activity. hTERT and hTR, two telomerase-related genes, were down-regulated. The telomere shelterins TRF1, TRF2, and POT were upregulated in granulocytes, TRF2 was up- and POT1 downregulated in monocytes. Both PCBs reduced telomerase activity in undifferentiated cells and further reduced telomerase activity in differentiated cells, but had only small effects on the differentiation and telomere-related genes. Long term treatment of undifferentiated HL-60 cells with PCB126 produced a downregulation of telomerase activity and decrease of hTERT, hTR, TRF1, and POT1 gene expression. With PCB153 the effects were less pronounced and some shelterin genes were increased after 30 days exposure. With each PCB no differentiation of cells was observed and cells continued to proliferate despite reduced telomerase activity, resulting in shortened telomeres after 30 days of exposure. These results indicate cell type and PCB congener specific effects on telomeres/telomerase-related genes and, although PCBs do not seem to strongly affect differentiation, they could influence the longevity of stem or progenitor cells through telomere attrition with potential long-term consequences for health. PMID:26330309

  6. Mediterranean diet and leukocyte telomere length in a multi-ethnic elderly population.

    PubMed

    Gu, Yian; Honig, Lawrence S; Schupf, Nicole; Lee, Joseph H; Luchsinger, Jose A; Stern, Yaakov; Scarmeas, Nikolaos

    2015-01-01

    Leukocyte telomere length (LTL) is considered as the marker of biological aging and may be related to environmental factors. The current study aimed to examine the relation between Mediterranean-type diet and LTL. We used a cross-sectional study of 1743 multi-ethnic community residents of New York aged 65 years or older. Mediterranean-type diet (MeDi) was calculated from dietary information collected using a food frequency questionnaire. LTL was measured from leukocyte DNA using a real-time PCR method to measure T/S ratio, the ratio of telomere (T) to single-copy gene (S) sequence. Regression analysis showed that the MeDi score was not associated with LTL in the overall study population (β = 12.5; p = 0.32) after adjusting for age, sex, education, ethnicity, caloric intake, smoking, and physical and leisure activities. However, we found a significant association between MeDi and LTL among non-Hispanic whites (β = 48.3; p = 0.05), and the results held after excluding dementia subjects (β = 49.6; p = 0.05). We further found that, in the whole population, vegetable and cereal consumption above the sex-specific population median was associated with longer LTL (β = 89.1, p = 0.04) and shorter LTL (β = -93.5; p = 0.03), respectively. Among non-Hispanic whites, intake of meat or dairy below sex-specific population medians was associated with longer LTL (β = 154.7, p = 0.05; β = 240.5, p < 0.001, respectively). We found that higher adherence to a MeDi was associated with longer LTL among whites but not among African Americans and Hispanics. Additionally, a diet high in vegetables but low in cereal, meat, and dairy might be associated with longer LTL among healthy elderly.

  7. 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

  8. Peripheral blood lymphocyte telomere length as a predictor of response to immunosuppressive therapy in childhood aplastic anemia.

    PubMed

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

    2014-08-01

    Predicting the response to immunosuppressive therapy could provide useful information to help the clinician define treatment strategies for patients with aplastic anemia. In our current study, we evaluated the relationship between telomere length of lymphocytes at diagnosis and the response to immunosuppressive therapy in 64 children with aplastic anemia, using flow fluorescence in situ hybridization. Median age of patients was ten years (range 1.5-16.2 years). Severity of the disease was classified as very severe in 23, severe in 21, and moderate in 20 patients. All patients were enrolled in multicenter studies using antithymocyte globulin and cyclosporine. The response rate to immunosuppressive therapy at six months was 52% (33 of 64). The probability of 5-year failure-free survival and overall survival were 56% (95% confidence interval (CI): 41-69%) and 97% (95%CI: 87-99%), respectively. Median telomere length in responders was -0.4 standard deviation (SD) (-2.7 to +3.0 SD) and -1.5 SD (-4.0 to +1.6 (SD)) in non-responders (P<0.001). Multivariate analysis showed that telomere length shorter than -1.0 SD (hazard ratio (HR): 22.0; 95%CI: 4.19-115; P<0.001), platelet count at diagnosis less than 25×10(9)/L (HR: 13.9; 95%CI: 2.00-96.1; P=0.008), and interval from diagnosis to immunosuppressive therapy longer than 25 days (HR: 4.81; 95%CI: 1.15-20.1; P=0.031) were the significant variables for poor response to immunosuppressive therapy. Conversely to what has been found in adult patients, measurement of the telomere length of lymphocytes at diagnosis is a promising assay in predicting the response to immunosuppressive therapy in children with aplastic anemia.

  9. 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.

  10. Relationships of survival time, productivity and cause of death with telomere lengths of cows produced by somatic cell nuclear transfer.

    PubMed

    Konishi, Kazuyuki; Yonai, Miharu; Kaneyama, Kanako; Ito, Satoshi; Matsuda, Hideo; Yoshioka, Hajime; Nagai, Takashi; Imai, Kei

    2011-10-01

    The reproductive ability, milk-producing capacity, survival time and relationships of these parameters with telomere length were investigated in 4 groups of cows produced by somatic cell nuclear transfer (SCNT). Each group was produced using the same donor cells (6 Holstein (1H), 3 Holstein (2H), 4 Jersey (1J) and 5 Japanese Black (1B) cows). As controls, 47 Holstein cows produced by artificial insemination were used. The SCNT cows were artificially inseminated, and multiple deliveries were performed after successive rounds of breeding and conception. No correlation was observed between the telomere length and survival time in the SCNT cows. Causes of death of SCNT cows included accidents, accident-associated infections, inappropriate management, acute mastitis and hypocalcemia. The lifetime productivity of SCNT cows was superior to those of the controls and cell donor cows. All SCNT beef cows with a relatively light burden of lactation remained alive and showed significantly prolonged survival time compared with the cows in the SCNT dairy breeds. These results suggest that the lifetime productivity of SCNT cows was favorable, and their survival time was more strongly influenced by environmental burdens, such as pregnancy, delivery, lactation and feeding management, than by the telomere length.

  11. Direct comparison of flow-FISH and qPCR as diagnostic tests for telomere length measurement in humans.

    PubMed

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

    2014-01-01

    Telomere length measurement is an essential test for the diagnosis of telomeropathies, which are caused by excessive telomere erosion. Commonly used methods are terminal restriction fragment (TRF) analysis by Southern blot, fluorescence in situ hybridization coupled with flow cytometry (flow-FISH), and quantitative PCR (qPCR). Although these methods have been used in the clinic, they have not been comprehensively compared. Here, we directly compared the performance of flow-FISH and qPCR to measure leukocytes' telomere length of healthy individuals and patients evaluated for telomeropathies, using TRF as standard. TRF and flow-FISH showed good agreement and correlation in the analysis of healthy subjects (R(2) = 0.60; p<0.0001) and patients (R(2) = 0.51; p<0.0001). In contrast, the comparison between TRF and qPCR yielded modest correlation for the analysis of samples of healthy individuals (R(2) = 0.35; p<0.0001) and low correlation for patients (R(2) = 0.20; p = 0.001); Bland-Altman analysis showed poor agreement between the two methods for both patients and controls. Quantitative PCR and flow-FISH modestly correlated in the analysis of healthy individuals (R(2) = 0.33; p<0.0001) and did not correlate in the comparison of patients' samples (R(2) = 0.1, p = 0.08). Intra-assay coefficient of variation (CV) was similar for flow-FISH (10.8 ± 7.1%) and qPCR (9.5 ± 7.4%; p = 0.35), but the inter-assay CV was lower for flow-FISH (9.6 ± 7.6% vs. 16 ± 19.5%; p = 0.02). Bland-Altman analysis indicated that flow-FISH was more precise and reproducible than qPCR. Flow-FISH and qPCR were sensitive (both 100%) and specific (93% and 89%, respectively) to distinguish very short telomeres. However, qPCR sensitivity (40%) and specificity (63%) to detect telomeres below the tenth percentile were lower compared to flow-FISH (80% sensitivity and 85% specificity). In the clinical setting, flow-FISH was more accurate, reproducible, sensitive, and specific in the measurement of human

  12. 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

    Telomere length measurement is an essential test for the diagnosis of telomeropathies, which are caused by excessive telomere erosion. Commonly used methods are terminal restriction fragment (TRF) analysis by Southern blot, fluorescence in situ hybridization coupled with flow cytometry (flow-FISH), and quantitative PCR (qPCR). Although these methods have been used in the clinic, they have not been comprehensively compared. Here, we directly compared the performance of flow-FISH and qPCR to measure leukocytes' telomere length of healthy individuals and patients evaluated for telomeropathies, using TRF as standard. TRF and flow-FISH showed good agreement and correlation in the analysis of healthy subjects (R2 = 0.60; p<0.0001) and patients (R2 = 0.51; p<0.0001). In contrast, the comparison between TRF and qPCR yielded modest correlation for the analysis of samples of healthy individuals (R2 = 0.35; p<0.0001) and low correlation for patients (R2 = 0.20; p = 0.001); Bland-Altman analysis showed poor agreement between the two methods for both patients and controls. Quantitative PCR and flow-FISH modestly correlated in the analysis of healthy individuals (R2 = 0.33; p<0.0001) and did not correlate in the comparison of patients' samples (R2 = 0.1, p = 0.08). Intra-assay coefficient of variation (CV) was similar for flow-FISH (10.8±7.1%) and qPCR (9.5±7.4%; p = 0.35), but the inter-assay CV was lower for flow-FISH (9.6±7.6% vs. 16±19.5%; p = 0.02). Bland-Altman analysis indicated that flow-FISH was more precise and reproducible than qPCR. Flow-FISH and qPCR were sensitive (both 100%) and specific (93% and 89%, respectively) to distinguish very short telomeres. However, qPCR sensitivity (40%) and specificity (63%) to detect telomeres below the tenth percentile were lower compared to flow-FISH (80% sensitivity and 85% specificity). In the clinical setting, flow-FISH was more accurate, reproducible, sensitive, and specific in the

  13. Smoking, second-hand smoke exposure and smoking cessation in relation to leukocyte telomere length and mortality

    PubMed Central

    Wulaningsih, Wahyu; Serrano, Fidel Emmanuel C.; Utarini, Adi; Matsuguchi, Tetsuya; Watkins, Johnathan

    2016-01-01

    Objectives To investigate the link between smoking exposure, telomere length and mortality, with emphasis on second-hand smoke (SHS) exposure and the duration of smoking cessation. Results A total of 1,018 participants died during follow-up (mean: 10.3 years). A 50 base-pair decrease in LTL was shown among cotinine-confirmed current versus never smokers. The 90th quantile of LTL decreased with increasing cotinine among never smokers, indicating a role of SHS. Longer telomeres with smoking cessation were indicated but limited to a 3-16 year period of abstaining smoking. When assessing mortality, we observed a lower risk of all-cause death for the second quintile compared to the first among never smokers (HR: 0.67, 95% CI: 0.52-0.87), and a higher risk was found among current smokers (HR: 1.89, 1.19-2.92). MATERIALS AND METHODS We studied 6,456 nationally representative U.S. respondents with mortality follow-up through to 31 December 2011. Smoking status was assessed by interviews and cotinine levels. Relative leukocyte telomere length (LTL) was quantified by polymerase chain reaction (PCR). Multivariable linear regression was performed to examine LTL by smoking exposure, adjusted for age, sex, race/ethnicity, socioeconomic status, education, body mass index, alcohol consumption, and physical activity. We further estimated the association of LTL with cotinine levels using quantile regression, and with smoking cessation dynamics. Cox regression was used to estimate mortality by smoking status and LTL. Conclusion Our findings indicated a complex association between smoking, telomere length, and mortality. LTL alterations with SHS and smoking cessation warrant further investigation for translation to public health measures. PMID:27509177

  14. Telomere length in the two extremes of abnormal fetal growth and the programming effect of maternal arterial hypertension.

    PubMed

    Tellechea, Mariana; Gianotti, Tomas Fernandéz; Alvariñas, Jorge; González, Claudio D; Sookoian, Silvia; Pirola, Carlos J

    2015-01-19

    We tested the hypothesis that leukocyte telomere length (LTL) is associated with birth weight in both extremes of abnormal fetal growth: small (SGA) and large for gestational age newborns (LGA). Clinical and laboratory variables of the mothers and the neonates were explored; 45 newborns with appropriate weight for gestational age (AGA), 12 SGA and 12 LGA were included. Whether the differences might be explained by variation in OBFC1 (rs9419958) and CTC1 (rs3027234) genes associated with LTL was determined. A significant association between birth weight and LTL was observed; LTL was significantly shorter in LGA newborns (1.01 ± 0.12) compared with SGA (1.73 ± 0.19) p < 0.005, mean ± SE. Maternal (Spearman R = -0.6, p = 0.03) and neonatal LTL (R = -0.25, p = 0.03) were significantly and inversely correlated with maternal history of arterial hypertension in previous gestations. Neonatal LTL was not significantly associated with either rs9419950 or rs3027234, suggesting that the association between neonatal LTL and birth weight is not influenced by genetic variation in genes that modify the interindividual LTL. In conclusion, telomere biology seems to be modulated by abnormal fetal growth; modifications in telomere length might be programmed by an adverse environment in utero.

  15. Telomere length, genetic variants and risk of squamous cell carcinoma of the head and neck in Southeast Chinese

    PubMed Central

    Gu, Yayun; Yu, Chengxiao; Miao, Limin; Wang, Lihua; Xu, Chongquan; Xue, Wenjie; Du, Jiangbo; Yuan, Hua; Dai, Juncheng; Jin, Guangfu; Hu, Zhibin; Ma, Hongxia; Shen, Hongbing

    2016-01-01

    Telomere dysfunction participates in malignant transformation and tumorigenesis. Previous studies have explored the associations between telomere length (TL) and cancer susceptibility; however, the findings are inconclusive. The associations between genetic variants and TL have been verified by quite a few genome-wide association studies (GWAS). Yet, to date, there was no published study on the relationship between TL, related genetic variants and susceptibility to squamous cell carcinoma of the head and neck (SCCHN) in Chinese. Hence, we detected relative telomere length (RTL) by using quantitative PCR and genotyped seven selected single nucleotide polymorphisms by TaqMan allelic discrimination assay in 510 SCCHN cases and 913 controls in southeast Chinese. The results showed that RTL was significantly associated with SCCHN risk [(adjusted odds ratio (OR) = 1.19, 95% confidence interval (CI) = 1.08–1.32, P = 0.001]. Furthermore, among seven selected SNPs, only G allele of rs2736100 related to RTL in Caucasians was significantly associated with both the decreased RTL (P = 0.002) and the increased susceptibility to SCCHN in Chinese (additive model: adjusted OR = 1.17, 95%CI = 1.00–1.38, P = 0.049). These findings provide evidence that shortened TL is a risk factor for SCCHN, and genetic variants can contribute to both TL and the susceptibility to SCCHN in southeast Chinese population. PMID:26857734

  16. 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.

  17. Telomere Length and Neighborhood Circumstances: Evaluating Biological Response to Unfavorable Exposures.

    PubMed

    Lynch, Shannon M; Mitra, Nandita; Ravichandran, Krithika; Mitchell, Jonathan; Spangler, Elaine; Zhou, Wenting; Paskett, Electra D; Gehlert, Sarah; DeGraffinreid, Cecilia; Stowe, Raymond; Dubowitz, Tamara; Riethman, Harold; Branas, Charles C; Peek, M K; Rebbeck, Timothy R

    2017-04-01

    Background: Multilevel frameworks suggest neighborhood circumstances influence biology; however, this relationship is not well studied. Telomere length (TL) shortening has been associated with individual-level and neighborhood-level exposures and disease and may provide insights into underlying biologic mechanisms linking neighborhood with biology. To support neighborhood-biology investigations, we sought to determine the independent effect of neighborhood exposures on TL using standard multilevel linear regression models and quantile regression, a nonlinear, social science method applicable for testing the biologic hypothesis that extremes of the TL distribution are related to poor outcomes.Methods: In a multicenter, cross-sectional study, blood TL was measured in 1,488 individuals from 127 census tracts in three U.S. regions using terminal restriction fragment assays. Multilevel linear and quantile regression models were adjusted for individual-level race, education, perceived stress, and depression. Neighborhood exposures included population density, urban/residential crowding, residential stability/mobility, and socioeconomic status.Results: TL was not associated with any neighborhood variable using linear models, but quantile regression revealed inverse associations between population density and urban crowding at the lower tails of the TL distribution [5th (population density P = 0.03; urban crowding P = 0.002), 50th (both P < 0.001), 75th percentiles (both P < 0.001)]. TL was related to residential stability at the upper tail (95th percentile P = 0.006).Conclusions: Findings support the use of nonlinear statistical methods in TL research and suggest that neighborhood exposures can result in biological effects.Impact: TL may serve as an underlying example of a biologic mechanism that can link neighborhood with biology, thus supporting multilevel investigations in future studies. Cancer Epidemiol Biomarkers Prev; 26(4); 553-60. ©2017 AACRSee all the articles

  18. 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.

  19. 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

  20. 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.

  1. CHILDHOOD TRAUMA ASSOCIATED WITH SHORT LEUKOCYTE TELOMERE LENGTH IN POST-TRAUMATIC STRESS DISORDER

    PubMed Central

    O’Donovan, Aoife; Epel, Elissa; Lin, Jue; Wolkowitz, Owen; Cohen, Beth; Maguen, Shira; Metzler, Thomas; Lenoci, Maryann; Blackburn, Elizabeth; Neylan, Thomas C

    2011-01-01

    Background Post-traumatic stress disorder (PTSD) is associated with increased risk for age-related diseases and early mortality. An accelerated rate of biological aging could contribute to this increased risk. To investigate, we assessed leukocyte telomere length (LTL), an emerging marker of biological age, in men and women with and without PTSD. We also examined childhood trauma, a risk factor for both PTSD and short LTL, as a potential contributor to short LTL in PTSD. Methods Participants included 43 adults with chronic PTSD (n=18 with multiple categories of childhood trauma) and 47 controls (none with multiple categories of childhood trauma) (M age = 30.55, SD = 7.44). Exclusion criteria included physical illness, medication use, obesity, alcohol or substance abuse, and pregnancy. Structured clinical interviews were conducted to assess PTSD and other psychiatric disorders and childhood trauma exposure. LTL was measured with quantitative polymerase chain reaction. Results As predicted, participants with PTSD had shorter age-adjusted LTL than controls. Exposure to childhood trauma was also associated with short LTL. In fact, childhood trauma appeared to account for the PTSD group difference in LTL; only participants with PTSD and exposure to multiple categories of childhood trauma had significantly shorter LTL than controls. Conclusions Childhood trauma is associated with short LTL in individuals with PTSD. Chronic exposure to the psychobiological sequelae of childhood trauma could increase risk for PTSD and short LTL. Thus, the lasting psychological impact of exposure to trauma in childhood may be accompanied by equally enduring changes at the molecular level. PMID:21489410

  2. Leukocyte Telomere Length Is Associated With Disability In Older U.S. Population

    PubMed Central

    Risques, Rosa Ana; Arbeev, Konstantin G.; Yashin, Anatoli I.; Ukraintseva, Svetlana V.; Martin, George M.; Rabinovitch, Peter S.; Oshima, Junko

    2010-01-01

    OBJECTIVES To determine whether the mean leukocyte telomere length (LTL) serves as a biomarker of disability assessed by Activities of Daily Living (ADL) and what factors may modify this relationship. DESIGN Retrospective cross-sectional study. SETTING A subset of the National Long Term Care Survey (NTLCS), a Medicare-based U.S. population longitudinal study focused on trends of overall health and functional status in the elderly. PARTICIPANTS Six hundred and twenty four individuals from the 1999 wave of the NTLCS cohort. MEASUREMENTS Relative LTL determined by quantitative PCR. LTL has previously been shown to correlate with common age-related disorders and mortality, as well as with socioeconomical status. RESULTS We observed gender difference of LTL, but not age-dependent shortening or association with socio-economical status. Importantly, LTL was associated with disability and functional status assessed by ADL. The association between ADL and LTL was more significant among non-diabetic subjects, while associations were not seen when diabetic subjects only were analyzed. Associations of LTL with cardiovascular diseases and cancer were also present in the non-diabetic group, but not in the diabetic group. CONCLUSION Our findings support the concept that LTL is a biomarker of overall well-being that is predictive of disability of older individuals in the US population. Diabetes plays an important role as a modifier of the association of LTL with disability, cardiovascular diseases, and cancer. These associations have obvious clinical implications due to the potential predictive value of LTL and deserve further investigation. PMID:20579170

  3. Telomere maintenance and the etiology of adult glioma.

    PubMed

    Walsh, Kyle M; Wiencke, John K; Lachance, Daniel H; Wiemels, Joseph L; Molinaro, Annette M; Eckel-Passow, Jeanette E; Jenkins, Robert B; Wrensch, Margaret R

    2015-11-01

    A growing body of epidemiologic and tumor genomic research has identified an important role for telomere maintenance in glioma susceptibility, initiation, and prognosis. Telomere length has long been investigated in relation to cancer, but whether longer or shorter telomere length might be associated with glioma risk has remained elusive. Recent data address this question and are reviewed here. Common inherited variants near the telomerase-component genes TERC and TERT are associated both with longer telomere length and increased risk of glioma. Exome sequencing of glioma patients from families with multiple affected members has identified rare inherited mutations in POT1 (protection of telomeres protein 1) as high-penetrance glioma risk factors. These heritable POT1 mutations are also associated with increased telomere length in leukocytes. Tumor sequencing studies further indicate that acquired somatic mutations of TERT and ATRX are among the most frequent alterations found in adult gliomas. These mutations facilitate telomere lengthening, thus bypassing a critical mechanism of apoptosis. Although future research is needed, mounting evidence suggests that glioma is, at least in part, a disease of telomere dysregulation. Specifically, several inherited and acquired variants underlying gliomagenesis affect telomere pathways and are also associated with increased telomere length.

  4. Telomere neurobiology.

    PubMed

    Mattson, Mark P; Zhang, Peisu; Cheng, Aiwu

    2008-01-01

    The ends of chromosomes consist of a hexanucleotide DNA repeat sequence and specialized DNA-binding and telomere-associated proteins. An enzyme activity called telomerase maintains telomere length by using an RNA template (TR) and a reverse transcriptase (TERT) to add the hexanucleotide sequence to the free chromosome end. The structure of telomeres is maintained and modified by telomere repeat-binding factors (TRF1 and TRF2) and proteins known for their role in DNA damage responses, including poly(ADP-ribose) polymerase-1, Werner, and ATM. Telomerase activity can be quantified using a telomere repeat amplification protocol (TRAP) assay, and levels of TERT and telomere-associated proteins are evaluated by immunoblot and immunocytochemical methods. Levels of TERT and telomere-associated proteins can be overexpressed or knocked down using viral vector-based methods. Using the kinds of approaches described here, evidence has been obtained suggesting that telomeres play important roles in regulating neural stem cell proliferation, neuronal differentiation, senescence of glial cells, and apoptosis and DNA damage responses of neural cells.

  5. Intake of small-to-medium-chain saturated fatty acids is associated with peripheral leukocyte telomere length in postmenopausal women.

    PubMed

    Song, Yan; You, Nai-Chieh Y; Song, Yiqing; Kang, Mo K; Hou, Lifang; Wallace, Robert; Eaton, Charles B; Tinker, Lesley F; Liu, Simin

    2013-06-01

    Dietary factors, including dietary fat, may affect the biological aging process, as reflected by the shortening of telomere length (TL), by affecting levels of oxidative stress and inflammatory responses. We examined the direct relations of total and types of dietary fats and fat-rich foods to peripheral leukocyte TL. In 4029 apparently healthy postmenopausal women who participated in the Women's Health Initiative, intakes of total fat, individual fatty acids, and fat-rich foods were assessed by a questionnaire. TL was measured by quantitative polymerase chain reaction. Intake of short-to-medium-chain saturated fatty acids (SMSFAs; aliphatic tails of ≤ 12 carbons) was inversely associated with TL. Compared with participants in other quartiles of SMSFA intake, women who were in the highest quartile (median: 1.29% of energy) had shorter TLs [mean: 4.00 kb (95% CI: 3.89, 4.11 kb)], whereas women in the lowest quartile of intake (median: 0.29% of energy) had longer TLs [mean: 4.13 kb (95% CI: 4.03, 4.24 kb); P-trend = 0.046]. Except for lauric acid, all other individual SMSFAs were inversely associated with TL (P < 0.05). In isoenergetic substitution models, the substitution of 1% of energy from SMSFAs with any other energy source was associated with 119 bp longer TLs (95% CI: 21, 216 bp). Intakes of nonskim milk, butter, and whole-milk cheese (major sources of SMSFAs) were all inversely associated with TL. No significant associations were found with long-chain saturated fatty acids, monounsaturated fatty acids, and polyunsaturated fatty acids. In conclusion, we found that higher intakes of SMSFAs and SMSFA-rich foods were associated with shorter peripheral leukocyte TL among postmenopausal women. These findings suggest the potential roles of SMSFAs in the rate of biological aging.

  6. SUMOylation regulates telomere length by targeting the shelterin subunit Tpz1Tpp1 to modulate shelterin–Stn1 interaction in fission yeast

    PubMed Central

    Miyagawa, Keisuke; Low, Ross S.; Santosa, Venny; Tsuji, Hiroki; Moser, Bettina A.; Fujisawa, Shiho; Harland, Jennifer L.; Raguimova, Olga N.; Go, Andrew; Ueno, Masaru; Matsuyama, Akihisa; Yoshida, Minoru; Nakamura, Toru M.; Tanaka, Katsunori

    2014-01-01

    Telomeres protect DNA ends of linear eukaryotic chromosomes from degradation and fusion, and ensure complete replication of the terminal DNA through recruitment of telomerase. The regulation of telomerase is a critical area of telomere research and includes cis regulation by the shelterin complex in mammals and fission yeast. We have identified a key component of this regulatory pathway as the SUMOylation [the covalent attachment of a small ubiquitin-like modifier (SUMO) to target proteins] of a shelterin subunit in fission yeast. SUMOylation is known to be involved in the negative regulation of telomere extension by telomerase; however, how SUMOylation limits the action of telomerase was unknown until now. We show that SUMOylation of the shelterin subunit TPP1 homolog in Schizosaccharomyces pombe (Tpz1) on lysine 242 is important for telomere length homeostasis. Furthermore, we establish that Tpz1 SUMOylation prevents telomerase accumulation at telomeres by promoting recruitment of Stn1-Ten1 to telomeres. Our findings provide major mechanistic insights into how the SUMOylation pathway collaborates with shelterin and Stn1-Ten1 complexes to regulate telomere length. PMID:24711392

  7. The role of telomere dynamics in aging and cancer

    NASA Astrophysics Data System (ADS)

    Blagoev, Krastan; Goodwin, Edwin

    2006-03-01

    Telomere length changes are far more dynamic than previously thought. In addition to a gradual loss of ˜100 base pairs per telomere in each cell division, losses as well as gains may occur within a single cell cycle. We are investigating how telomere exchange, extension, and deletion affect the proliferative potential of telomerase-negative somatic cells. Experimental techniques are being devised to detect dynamic telomere processes and quantify both the frequency and length changes of each. In parallel, a ``dynamic telomere model'' is being used that incorporates telomere dynamics to study how the telomere size distribution evolves with time. This is an essential step towards understanding the role that telomere dynamics play in the normal aging of tissues and organisms. The model casts light on relationships not otherwise easily explained by a deterministic ``mitotic clock,'' or to what extent the shortest initial telomere determines the onset of senescence. We also expect to identify biomarkers that will correlate with aging better than average telomere length and to shed light on the transition to unlimited growth found in telomerase-negative tumor cells having the ALT (alternative lengthening of telomeres) phenotype, and to evaluate strategies to suppress the growth of these tumors.

  8. 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

  9. Dietary inflammatory index and telomere length in subjects with a high cardiovascular disease risk from the PREDIMED-NAVARRA study: cross-sectional and longitudinal analyses over 5 y1

    PubMed Central

    García-Calzón, Sonia; Zalba, Guillermo; Ruiz-Canela, Miguel; Shivappa, Nitin; Hébert, James R; Martínez, J Alfredo; Fitó, Montserrat; Gómez-Gracia, Enrique; Martínez-González, Miguel A; Marti, Amelia

    2015-01-01

    Background: Dietary factors can affect telomere length (TL), a biomarker of aging, through oxidation and inflammation-related mechanisms. A Dietary Inflammatory Index (DII) could help to understand the effect of the inflammatory potential of the diet on telomere shortening. Objective: This study aimed to determine the association of the DII with TL and to examine whether diet-associated inflammation could modify the telomere attrition rate after a 5-y follow-up of a Mediterranean dietary intervention. Design: This was a prospective study of 520 participants at high cardiovascular disease risk (mean ± SD age: 67.0 ± 6.0 y, 45% males) from the PREDIMED-NAVARRA (PREvención con DIeta MEDiterránea-NAVARRA) trial. Leukocyte TL was measured by quantitative real-time polymerase chain reaction at baseline and after 5 y of follow-up. The DII was calculated from self-reported data by using a validated 137-item food-frequency questionnaire. Results: Longer telomeres at baseline were found in participants who had a more anti-inflammatory diet (lowest DII score) (P-trend = 0.012). Longitudinal analyses further showed that a greater anti-inflammatory potential of the diet (i.e., a decrease in the DII) could significantly slow down the rate of telomere shortening. Moreover, the multivariable-adjusted OR for short telomeres (z score ≤20th percentile) was 1.80 (95% CI: 1.03, 3.17) in a comparison between the highest (proinflammatory) and the lowest (anti-inflammatory) DII tertiles. Similarly, a greater DII (greatest proinflammatory values) after a 5-y follow-up was associated with almost a 2-fold higher risk of accelerated telomere attrition compared with the highest decrease in DII (greatest anti-inflammatory values) during this period (P-trend = 0.025). Conclusions: This study showed both cross-sectional and longitudinal associations between the inflammatory potential of the diet and telomere shortening in subjects with a high cardiovascular disease risk. Our findings are

  10. Telomere shortening in leukocyte subpopulations in depression

    PubMed Central

    2014-01-01

    Background Telomere shortening is a normal age-related process. However, premature shortening of telomeres in leukocytes – as has been reported in depression – may increase the risk for age-related diseases. While previous studies investigated telomere length in peripheral blood mononuclear cells (PBMCs) as a whole, this study investigated specific changes in the clonal composition of white blood cells of the adaptive immune system (CD4+ helper and CD8+ cytotoxic T lymphocytes, and CD20+ B lymphocytes). Methods Forty-four females with a history of unipolar depression were investigated and compared to fifty age-matched female controls. Telomere lengths were compared between three groups: 1) individuals with a history of depression but currently no clinically relevant depressive symptoms, 2) individuals with a history of depression with relevant symptoms of depression, and 3) healthy age-matched controls. Telomere length was assessed using quantitative fluorescence in situ hybridization (qFISH). Results Both groups with a history of unipolar depression (with and without current depressive symptoms) showed significantly shorter telomeres in all three lymphocyte subpopulations. The effect was stronger in CD8+ and CD20+ cells than in CD4+ cells. Individuals with a history of depression and with (without) current symptoms exhibited a CD8+ telomere length shortening corresponding to an age differential of 27.9 (25.3) years. Conclusions A history of depression is associated with shortened telomeres in the main effector populations of the adaptive immune system. Shorter telomeres seem to persist in individuals with lifetime depression independently of the severity of depressive symptoms. CD8+ cytotoxic T cells and CD20+ B cells seem to be particularly affected in depression. The total number of depressive episodes did not influence telomere length in the investigated adaptive immune cell populations. PMID:24996455

  11. A test of biological and behavioral explanations for gender differences in telomere length: the multi-ethnic study of atherosclerosis.

    PubMed

    Needham, Belinda L; Diez Roux, Ana V; Bird, Chloe E; Bradley, Ryan; Fitzpatrick, Annette L; Jacobs, David R; Ouyang, Pamela; Seeman, Teresa E; Thurston, Rebecca C; Vaidya, Dhananjay; Wang, Steven

    2014-01-01

    The purpose of this study was to examine biological and behavioral explanations for gender differences in leukocyte telomere length (LTL), a biomarker of cell aging that has been hypothesized to contribute to women's greater longevity. Data are from a subsample (n = 851) of the Multi-Ethnic Study of Atherosclerosis, a population-based study of women and men aged 45 to 84. Mediation models were used to examine study hypotheses. We found that women had longer LTL than men, but the gender difference was smaller at older ages. Gender differences in smoking and processed meat consumption partially mediated gender differences in telomere length, whereas gender differences in estradiol, total testosterone, oxidative stress, and body mass index did not. Neither behavioral nor biological factors explained why the gender difference in LTL was smaller at older ages. Longitudinal studies are needed to assess gender differences in the rate of change in LTL over time; to identify the biological, behavioral, and psychosocial factors that contribute to these differences throughout the life course; and to determine whether gender differences in LTL explain the gender gap in longevity.

  12. In vitro aging of rat lung cells. Downregulation of telomerase activity and continuous decrease of telomere length are not incompatible with malignant transformation.

    PubMed

    Petitot, Fabrice; Lebeau, Jérôme; Dano, Laurent; Lectard, Bruno; Altmeyer, Sandrine; Levalois, Céline; Chevillard, Sylvie

    2003-05-15

    Most normal mammalian somatic cells cultivated in vitro enter replicative senescence after a finite number of divisions, as a consequence of the progressive shortening of telomeres during proliferation that reflects one aspect of organism/cellular aging. The situation appears more complex in rodent cells due to physiological telomerase expression in most somatic normal tissues, great telomere length, and the difficulties of finding suitable in vitro culture conditions. To study in vitro aging of rat lung epithelial cells, we have developed primary culture conditions adapted to rat fresh lung explants and have studied for 1 year (50 passages) the changes in cellular proliferation and mortality, genetic instability, telomerase activity, telomere length, and tumorigenic potential. We have observed an absence of senescence and/or crisis, a transient genetic instability, the persistence of a differentiated Clara cell phenotype, a steady decrease in telomerase activity followed by a low residual activity together with a continuous decrease in telomere length, a constant rate of proliferation, and the acquisition of tumorigenic potential. The bypass of the growth arrest and the acquisition of long-term growth properties could be explained by the loss of p16(INK4a) expression, the ARF/p53 pathway not being altered. In conclusion, these results clearly indicate that, in rat lung epithelial cells, in vitro transformation and acquisition of tumorigenic properties can occur even if the telomere length is still decreasing and telomerase activity remains downregulated.

  13. Telomere and telomerase biology.

    PubMed

    Giardini, Miriam Aparecida; Segatto, Marcela; da Silva, Marcelo Santos; Nunes, Vinícius Santana; Cano, Maria Isabel Nogueira

    2014-01-01

    Telomeres are the physical ends of eukaryotic linear chromosomes. Telomeres form special structures that cap chromosome ends to prevent degradation by nucleolytic attack and to distinguish chromosome termini from DNA double-strand breaks. With few exceptions, telomeres are composed primarily of repetitive DNA associated with proteins that interact specifically with double- or single-stranded telomeric DNA or with each other, forming highly ordered and dynamic complexes involved in telomere maintenance and length regulation. In proliferative cells and unicellular organisms, telomeric DNA is replicated by the actions of telomerase, a specialized reverse transcriptase. In the absence of telomerase, some cells employ a recombination-based DNA replication pathway known as alternative lengthening of telomeres. However, mammalian somatic cells that naturally lack telomerase activity show telomere shortening with increasing age leading to cell cycle arrest and senescence. In another way, mutations or deletions of telomerase components can lead to inherited genetic disorders, and the depletion of telomeric proteins can elicit the action of distinct kinases-dependent DNA damage response, culminating in chromosomal abnormalities that are incompatible with life. In addition to the intricate network formed by the interrelationships among telomeric proteins, long noncoding RNAs that arise from subtelomeric regions, named telomeric repeat-containing RNA, are also implicated in telomerase regulation and telomere maintenance. The goal for the next years is to increase our knowledge about the mechanisms that regulate telomere homeostasis and the means by which their absence or defect can elicit telomere dysfunction, which generally results in gross genomic instability and genetic diseases.

  14. [Telomere length and phylogenetic relationship of Baikal and Siberian planarians (Turbellaria, Tricladida)].

    PubMed

    Koroleva, A G; Evtushenko, E V; Timoshkin, O A; Vershinin, A V; Kiril'chik, S V

    2013-01-01

    Dynamics of the telomeric DNA (tDNA) and the phylogeny of the Baikal and Siberian planarians have been studied based on the analysis of the 18S rDNA and beta-actin gene fragments. A relationship between tDNA and the planarians size has been demonstrated. Giant planarians with a minor exception have longer tDNA than little planarians. Phylogenetic affinity between the species that have the stretched tracks of tDNA, big size and similar habitats may indicate possible role of tDNA in the development of the indefinite regenerative capacity of planarians.

  15. 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.

  16. Polymorphisms in Telomere Length Associated TERC and TERT predispose for Ischemic Stroke in a Chinese Han population

    PubMed Central

    Zhang, Shuo; Ji, Guofa; Liang, Yiqian; Zhang, Rui; Shi, Puyu; Guo, Dangshe; Li, Chunqi; Feng, Jing; Liu, Feng; Peng, Rong; Chen, Mingwei

    2017-01-01

    The role of telomere in genomic stability is an established fact. Variation in leukocyte telomere length (LTL) has been considered a crucial factor that associated with age-associated diseases. To elucidate the association between LTL variation and ischemic stroke (IS) risk, we selected ten single nucleotide polymorphisms (SNPs) in three genes (TERC, TERT and RTEL1) that previously reported link to LTL, and genotyped SNPs of these genes in a case-control study. The association between polymorphisms and IS risk were tested by Chi squared test and haplotype analysis. In allele association analysis, allele “C” in rs10936599 of TERC gene and allele “G” in rs2853677 of TERT gene were found to have an increased risk of IS when compared with allele “T” and “A”, respectively. Model association analysis showed that genotype “G/A” in the overdominant model and genotypes “G/A” and “A/A” in the dominant model of rs2242652 presented a more likelihood to have IS. Another TERT locus (rs2853677) with genotype “G” was also found IS-related risky in the log-additive model. Taken together, our results suggest a potential association between LTL related TERC, TERT gene variants and ischemic stroke risk. PMID:28057933

  17. Embryonic exposure to corticosterone modifies the juvenile stress response, oxidative stress and telomere length

    PubMed Central

    Haussmann, Mark F.; Longenecker, Andrew S.; Marchetto, Nicole M.; Juliano, Steven A.; Bowden, Rachel M.

    2012-01-01

    Early embryonic exposure to maternal glucocorticoids can broadly impact physiology and behaviour across phylogenetically diverse taxa. The transfer of maternal glucocorticoids to offspring may be an inevitable cost associated with poor environmental conditions, or serve as a maternal effect that alters offspring phenotype in preparation for a stressful environment. Regardless, maternal glucocorticoids are likely to have both costs and benefits that are paid and collected over different developmental time periods. We manipulated yolk corticosterone (cort) in domestic chickens (Gallus domesticus) to examine the potential impacts of embryonic exposure to maternal stress on the juvenile stress response and cellular ageing. Here, we report that juveniles exposed to experimentally increased cort in ovo had a protracted decline in cort during the recovery phase of the stress response. All birds, regardless of treatment group, shifted to oxidative stress during an acute stress response. In addition, embryonic exposure to cort resulted in higher levels of reactive oxygen metabolites and an over-representation of short telomeres compared with the control birds. In many species, individuals with higher levels of oxidative stress and shorter telomeres have the poorest survival prospects. Given this, long-term costs of glucocorticoid-induced phenotypes may include accelerated ageing and increased mortality. PMID:22072607

  18. Sports and Exercise at Different Ages and Leukocyte Telomere Length in Later Life – Data from the Berlin Aging Study II (BASE-II)

    PubMed Central

    Saßenroth, Denise; Meyer, Antje; Salewsky, Bastian; Kroh, Martin; Norman, Kristina; Steinhagen-Thiessen, Elisabeth; Demuth, Ilja

    2015-01-01

    Physical activity and sports have repeatedly been reported to be associated with telomere length. We studied the association of different types of sports across different stages of life on relative leukocyte telomere length (rLTL) in advanced age.815 participants (397 men) from the Berlin Aging Study II aged over 61 years were included in the analysis. rLTL was measured by real time PCR and physical activity was determined retrospectively by questionnaire, assessing type and duration of sports in the past as well as currently. Five separate multiple linear regression models adjusted for various control variables were performed. 67.3% of participants exercised currently, whereas 19.4% performed sports only between the age of 20 and 30. rLTL was higher in subjects who stated to exercise currently (N = 456), and in subjects who engaged in endurance (N = 138) or intensive activity sports (N = 32). Current physical activity was positively associated with rLTL in the risk factor adjusted regression model (β = 0.26, p < 0.001) and practicing sports for a minimum of 10 years preceding the assessment had a significant effect on rLTL (β = 0.39, p = 0.011). The highest impact was seen for intensive activity sports (β = 0.79, p < 0.001) and physical activity since at least 42 years (β = 0.47, p = 0.001). However, physical activity only between 20 and 30 years of age did not affect rLTL in old age when compared to no sports at all (β = -0.16, p = 0.21). Physical activity is clearly associated with longer rLTL. The effect is seen with longer periods of physical activity (at least 10 years), with intensive sports activities having the greatest impact on rLTL. Our data suggest that regular physical activity for at least 10 years is necessary to achieve a sustained effect on rLTL. PMID:26630493

  19. Sports and Exercise at Different Ages and Leukocyte Telomere Length in Later Life--Data from the Berlin Aging Study II (BASE-II).

    PubMed

    Saßenroth, Denise; Meyer, Antje; Salewsky, Bastian; Kroh, Martin; Norman, Kristina; Steinhagen-Thiessen, Elisabeth; Demuth, Ilja

    2015-01-01

    Physical activity and sports have repeatedly been reported to be associated with telomere length. We studied the association of different types of sports across different stages of life on relative leukocyte telomere length (rLTL) in advanced age.815 participants (397 men) from the Berlin Aging Study II aged over 61 years were included in the analysis. rLTL was measured by real time PCR and physical activity was determined retrospectively by questionnaire, assessing type and duration of sports in the past as well as currently. Five separate multiple linear regression models adjusted for various control variables were performed. 67.3% of participants exercised currently, whereas 19.4% performed sports only between the age of 20 and 30. rLTL was higher in subjects who stated to exercise currently (N = 456), and in subjects who engaged in endurance (N = 138) or intensive activity sports (N = 32). Current physical activity was positively associated with rLTL in the risk factor adjusted regression model (β = 0.26, p < 0.001) and practicing sports for a minimum of 10 years preceding the assessment had a significant effect on rLTL (β = 0.39, p = 0.011). The highest impact was seen for intensive activity sports (β = 0.79, p < 0.001) and physical activity since at least 42 years (β = 0.47, p = 0.001). However, physical activity only between 20 and 30 years of age did not affect rLTL in old age when compared to no sports at all (β = -0.16, p = 0.21). Physical activity is clearly associated with longer rLTL. The effect is seen with longer periods of physical activity (at least 10 years), with intensive sports activities having the greatest impact on rLTL. Our data suggest that regular physical activity for at least 10 years is necessary to achieve a sustained effect on rLTL.

  20. Telomerase RNA stem terminus element affects template boundary element function, telomere sequence, and shelterin binding.

    PubMed

    Webb, Christopher J; Zakian, Virginia A

    2015-09-08

    The stem terminus element (STE), which was discovered 13 y ago in human telomerase RNA, is required for telomerase activity, yet its mode of action is unknown. We report that the Schizosaccharomyces pombe telomerase RNA, TER1 (telomerase RNA 1), also contains a STE, which is essential for telomere maintenance. Cells expressing a partial loss-of-function TER1 STE allele maintained short stable telomeres by a recombination-independent mechanism. Remarkably, the mutant telomere sequence was different from that of wild-type cells. Generation of the altered sequence is explained by reverse transcription into the template boundary element, demonstrating that the STE helps maintain template boundary element function. The altered telomeres bound less Pot1 (protection of telomeres 1) and Taz1 (telomere-associated in Schizosaccharomyces pombe 1) in vivo. Thus, the S. pombe STE, although distant from the template, ensures proper telomere sequence, which in turn promotes proper assembly of the shelterin complex.

  1. Predictors of telomere content in dragon lizards

    NASA Astrophysics Data System (ADS)

    Ballen, Cissy; Healey, Mo; Wilson, Mark; Tobler, Michael; Olsson, Mats

    2012-08-01

    Telomeres shorten as a consequence of DNA replication, in particular in cells with low production of telomerase and perhaps in response to physiological stress from exposure to reactive oxygen species, such as superoxide. This process of telomere attrition is countered by innate antioxidation, such as via the production of superoxide dismutase. We studied the inheritance of telomere length in the Australian painted dragon lizard ( Ctenophorus pictus) and the extent to which telomere length covaries with mass-corrected maternal reproductive investment, which reflects the level of circulating yolk precursor and antioxidant, vitellogenin. Our predictors of offspring telomere length explained 72 % of telomere variation (including interstitial telomeres if such are present). Maternal telomere length and reproductive investment were positively influencing offspring telomere length in our analyses, whereas flow cytometry-estimated superoxide level was negatively impacting offspring telomere length. We suggest that the effects of superoxide on hatchling telomere shortening may be partly balanced by transgenerational effects of vitellogenin antioxidation.

  2. Shorter Telomere Length - A Potential Susceptibility Factor for HIV-Associated Neurocognitive Impairments in South African Woman

    PubMed Central

    Malan-Müller, Stefanie; Hemmings, Sîan Megan Joanna; Spies, Georgina; Kidd, Martin; Fennema-Notestine, Christine; Seedat, Soraya

    2013-01-01

    The neuropathogenesis of the human immunodeficiency virus (HIV) may manifest as various neurocognitive impairments (NCI). HIV-positive individuals also have significantly shorter telomere length (TL) in peripheral blood mononuclear cells (PBMCs) and CD8+ T cells compared to HIV-negative individuals. Additionally, reduced TL has been found to be associated with chronic psychological stress. This study focused on the effects of HIV-infection and chronic stress associated with childhood trauma on telomere length, and investigated whether leukocyte TL (LTL), in particular, represents a risk factor for NCI. Eighty-three HIV-positive and 45 HIV-negative women were assessed for childhood trauma and were subjected to detailed neurocognitive testing. Blood from each participant was used to extract Deoxyribonucleic acid (DNA). Relative LTL were determined by performing real time quantitative PCR reactions as described by Cawthon et al. (2002). As expected, relative LTL in the HIV-positive individuals was significantly shorter than that of HIV-negative individuals (F = 51.56, p = <0.01). Notably, a significant positive correlation was evident between relative LTL and learning performance in the HIV-positive group. In addition, a significant negative correlation was observed between relative LTL and verbal fluency, but this association was only evident in HIV-positive individuals who had experienced trauma. Our results suggest that reduced LTL is associated with worse learning performance in HIV-positive individuals, indicating that TL could act as a susceptibility factor in increasing neurocognitive decline in HIV-infected individuals. PMID:23472184

  3. Telomeres and immune competency.

    PubMed

    Weng, Nan-ping

    2012-08-01

    Telomeres are essential for the integrity of chromosomes and for cellular replication. Attrition of telomeres occurs during DNA replication owing to the inability of conventional DNA polymerase to replicate chromosomal termini and the insufficient compensation for telomere loss by telomerase, an enzyme that synthesizes telomeric DNA. A number of genetic defects have been described in humans and in animal models that cause accelerated telomere attrition, in turn leading to severe phenotypes of hematopoietic and other proliferating cells. Telomere length, most frequently measured as an average value in heterogeneous peripheral blood leukocyte populations in humans, has been associated with a wide range of health conditions and diseases of immune and non-immune cells. Here, I review recent studies of telomere length dynamics with particular relevance to immune function.

  4. Population mixture model for nonlinear telomere dynamics

    NASA Astrophysics Data System (ADS)

    Itzkovitz, Shalev; Shlush, Liran I.; Gluck, Dan; Skorecki, Karl

    2008-12-01

    Telomeres are DNA repeats protecting chromosomal ends which shorten with each cell division, eventually leading to cessation of cell growth. We present a population mixture model that predicts an exponential decrease in telomere length with time. We analytically solve the dynamics of the telomere length distribution. The model provides an excellent fit to available telomere data and accounts for the previously unexplained observation of telomere elongation following stress and bone marrow transplantation, thereby providing insight into the nature of the telomere clock.

  5. Role of the ESCRT Complexes in Telomere Biology

    PubMed Central

    Dieckmann, Anna K.; Babin, Vera; Harari, Yaniv; Eils, Roland; König, Rainer

    2016-01-01

    ABSTRACT Eukaryotic chromosomal ends are protected by telomeres from fusion, degradation, and unwanted double-strand break repair events. Therefore, telomeres preserve genome stability and integrity. Telomere length can be maintained by telomerase, which is expressed in most human primary tumors but is not expressed in the majority of somatic cells. Thus, telomerase may be a highly relevant anticancer drug target. Genome-wide studies in the yeast Saccharomyces cerevisiae identified a set of genes associated with telomere length maintenance (TLM genes). Among the tlm mutants with short telomeres, we found a strong enrichment for those affecting vacuolar and endosomal traffic (particularly the endosomal sorting complex required for transport [ESCRT] pathway). Here, we present our results from investigating the surprising link between telomere shortening and the ESCRT machinery. Our data show that the whole ESCRT system is required to safeguard proper telomere length maintenance. We propose a model of impaired end resection resulting in too little telomeric overhang, such that Cdc13 binding is prevented, precluding either telomerase recruitment or telomeric overhang protection. PMID:27834202

  6. Role of the ESCRT Complexes in Telomere Biology.

    PubMed

    Dieckmann, Anna K; Babin, Vera; Harari, Yaniv; Eils, Roland; König, Rainer; Luke, Brian; Kupiec, Martin

    2016-11-08

    Eukaryotic chromosomal ends are protected by telomeres from fusion, degradation, and unwanted double-strand break repair events. Therefore, telomeres preserve genome stability and integrity. Telomere length can be maintained by telomerase, which is expressed in most human primary tumors but is not expressed in the majority of somatic cells. Thus, telomerase may be a highly relevant anticancer drug target. Genome-wide studies in the yeast Saccharomyces cerevisiae identified a set of genes associated with telomere length maintenance (TLM genes). Among the tlm mutants with short telomeres, we found a strong enrichment for those affecting vacuolar and endosomal traffic (particularly the endosomal sorting complex required for transport [ESCRT] pathway). Here, we present our results from investigating the surprising link between telomere shortening and the ESCRT machinery. Our data show that the whole ESCRT system is required to safeguard proper telomere length maintenance. We propose a model of impaired end resection resulting in too little telomeric overhang, such that Cdc13 binding is prevented, precluding either telomerase recruitment or telomeric overhang protection.

  7. Abnormal Glucose Tolerance, White Blood Cell Count, and Telomere Length in Newly Diagnosed, Antidepressant-Naïve Patients with Depression

    PubMed Central

    Garcia-Rizo, Clemente; Fernandez-Egea, Emilio; Miller, Brian J.; Oliveira, Cristina; Justicia, Azucena; Griffith, Jeffrey K.; Heaphy, Christopher M.; Bernardo, Miguel; Kirkpatrick, Brian

    2012-01-01

    Chronic mood disorders have been associated with a shortened telomere, a marker of increased mortality rate and ageing, and impaired cellular immunity. However, treatment may confound these relationships. We examined the relationship of glucose tolerance, white blood cell count and telomere length to depression in newly diagnosed, antidepressant-naïve patients. Subjects with major depression (n=15), and matched healthy control subjects (n=70) underwent a two-hour oral glucose tolerance test and evaluation of blood cell count and telomere content. The depression group had significantly higher two-hour glucose concentrations and a lower lymphocyte count than control subjects (respective means [SD] for two-hour glucose were 125.0 mg/dL [67.9] vs 84.6 [25.6] (p<.001); for lymphocyte count 2.1 × 109/L [0.6] vs. 2.5 ×109/L [0.7] p=.028).Telomere content was significantly shortened in the depression group (87.9 [7.6]) compared to control subjects (101.0 [14.3]; p<0.01). Abnormal glucose tolerance, lymphopenia and a shortened telomere are present early in the course of depression independently of the confounding effect of antidepressant treatment, supporting the concept of major depression as an accelerated ageing disease. PMID:23207109

  8. 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

    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

    2015-08-01

    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.

  9. 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

  10. Method Specific Calibration Corrects for DNA Extraction Method Effects on Relative Telomere Length Measurements by Quantitative PCR.

    PubMed

    Seeker, Luise A; Holland, Rebecca; Underwood, Sarah; Fairlie, Jennifer; Psifidi, Androniki; Ilska, Joanna J; Bagnall, Ainsley; Whitelaw, Bruce; Coffey, Mike; Banos, Georgios; Nussey, Daniel H

    2016-01-01

    Telomere length (TL) is increasingly being used as a biomarker in epidemiological, biomedical and ecological studies. A wide range of DNA extraction techniques have been used in telomere experiments and recent quantitative PCR (qPCR) based studies suggest that the choice of DNA extraction method may influence average relative TL (RTL) measurements. Such extraction method effects may limit the use of historically collected DNA samples extracted with different methods. However, if extraction method effects are systematic an extraction method specific (MS) calibrator might be able to correct for them, because systematic effects would influence the calibrator sample in the same way as all other samples. In the present study we tested whether leukocyte RTL in blood samples from Holstein Friesian cattle and Soay sheep measured by qPCR was influenced by DNA extraction method and whether MS calibration could account for any observed differences. We compared two silica membrane-based DNA extraction kits and a salting out method. All extraction methods were optimized to yield enough high quality DNA for TL measurement. In both species we found that silica membrane-based DNA extraction methods produced shorter RTL measurements than the non-membrane-based method when calibrated against an identical calibrator. However, these differences were not statistically detectable when a MS calibrator was used to calculate RTL. This approach produced RTL measurements that were highly correlated across extraction methods (r > 0.76) and had coefficients of variation lower than 10% across plates of identical samples extracted by different methods. Our results are consistent with previous findings that popular membrane-based DNA extraction methods may lead to shorter RTL measurements than non-membrane-based methods. However, we also demonstrate that these differences can be accounted for by using an extraction method-specific calibrator, offering researchers a simple means of accounting for

  11. Telomerase activity is more significant for predicting the outcome of IVF treatment than telomere length in granulosa cells.

    PubMed

    Wang, Wenjun; Chen, Hong; Li, Ruiqi; Ouyang, Nengyong; Chen, Jinghua; Huang, Lili; Mai, Meiqi; Zhang, Ningfeng; Zhang, Qingxue; Yang, Dongzi

    2014-05-01

    Our previous study has demonstrated that luteinized granulosa cells (GCs) have the potential to proliferate and that the telomerase activity (TA) of luteinized GCs may predict the clinical outcomes of IVF treatment. However, in the field of telomere research, there have always been different opinions regarding the significance of TA and telomere length (TL). Thus, in the present study, we compared the effects of these two parameters on IVF treatment outcomes in the same individuals. TL did not differ significantly between the pregnant group and the non-pregnant group. The TA, number of retrieved oocytes and rate of blastocyst transfer were significantly higher in the pregnant group than in the non-pregnant group (0.8825 OD×mm, 12.75±2.20 and 34.48%, respectively, in the pregnant group vs 0.513 OD×mm, 11.60±0.93 and 14.89%, respectively, in the non-pregnant group (P<0.05)), while basal FSH level was lower in the pregnant group than in the non-pregnant group. The subjects did not differ with regard to ovarian stimulation or other clinical characteristics. A TA increase of 1 OD×mm increased the chance of becoming pregnant 4.769-fold (odds ratio: 5.769, 95% CI: 1.434-23.212, P<0.014). The areas under the receiver operating characteristic curves were 0.576 for TL and 0.674 for TA (P=0.271 and P<0. 012 respectively). The corresponding cut-off points were 4.470 for TL and 0.650 OD×mm for TA. These results demonstrate that TA is a better predictor of pregnancy outcomes following IVF treatment than TL. No other clinical parameters, including age, baseline FSH level or peak oestradiol level, distinguished between the pregnant group and the non-pregnant group as effectively as TA.

  12. Method Specific Calibration Corrects for DNA Extraction Method Effects on Relative Telomere Length Measurements by Quantitative PCR

    PubMed Central

    Holland, Rebecca; Underwood, Sarah; Fairlie, Jennifer; Psifidi, Androniki; Ilska, Joanna J.; Bagnall, Ainsley; Whitelaw, Bruce; Coffey, Mike; Banos, Georgios; Nussey, Daniel H.

    2016-01-01

    Telomere length (TL) is increasingly being used as a biomarker in epidemiological, biomedical and ecological studies. A wide range of DNA extraction techniques have been used in telomere experiments and recent quantitative PCR (qPCR) based studies suggest that the choice of DNA extraction method may influence average relative TL (RTL) measurements. Such extraction method effects may limit the use of historically collected DNA samples extracted with different methods. However, if extraction method effects are systematic an extraction method specific (MS) calibrator might be able to correct for them, because systematic effects would influence the calibrator sample in the same way as all other samples. In the present study we tested whether leukocyte RTL in blood samples from Holstein Friesian cattle and Soay sheep measured by qPCR was influenced by DNA extraction method and whether MS calibration could account for any observed differences. We compared two silica membrane-based DNA extraction kits and a salting out method. All extraction methods were optimized to yield enough high quality DNA for TL measurement. In both species we found that silica membrane-based DNA extraction methods produced shorter RTL measurements than the non-membrane-based method when calibrated against an identical calibrator. However, these differences were not statistically detectable when a MS calibrator was used to calculate RTL. This approach produced RTL measurements that were highly correlated across extraction methods (r > 0.76) and had coefficients of variation lower than 10% across plates of identical samples extracted by different methods. Our results are consistent with previous findings that popular membrane-based DNA extraction methods may lead to shorter RTL measurements than non-membrane-based methods. However, we also demonstrate that these differences can be accounted for by using an extraction method-specific calibrator, offering researchers a simple means of accounting for

  13. Genome-wide studies of telomere biology in budding yeast

    PubMed Central

    Harari, Yaniv; Kupiec, Martin

    2014-01-01

    Telomeres are specialized DNA-protein structures at the ends of eukaryotic chromosomes. Telomeres are essential for chromosomal stability and integrity, as they prevent chromosome ends from being recognized as double strand breaks. In rapidly proliferating cells, telomeric DNA is synthesized by the enzyme telomerase, which copies a short template sequence within its own RNA moiety, thus helping to solve the “end-replication problem”, in which information is lost at the ends of chromosomes with each DNA replication cycle. The basic mechanisms of telomere length, structure and function maintenance are conserved among eukaryotes. Studies in the yeast Saccharomyces cerevisiae have been instrumental in deciphering the basic aspects of telomere biology. In the last decade, technical advances, such as the availability of mutant collections, have allowed carrying out systematic genome-wide screens for mutants affecting various aspects of telomere biology. In this review we summarize these efforts, and the insights that this Systems Biology approach has produced so far.

  14. 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.

  15. Genetic variants associated with longer telomere length are associated with increased lung cancer risk among never-smoking women in Asia: A report from the Female Lung Cancer Consortium in Asia

    PubMed Central

    Machiela, Mitchell J; Hsiung, Chao Agnes; Shu, Xiao-Ou; Seow, Wei Jie; Wang, Zhaoming; Matsuo, Keitaro; Hong, Yun-Chul; Seow, Adeline; Wu, Chen; Hosgood, H Dean; Chen, Kexin; Wang, Jiu-Cun; Wen, Wanqing; Cawthon, Richard; Chatterjee, Nilanjan; Hu, Wei; Caporaso, Neil E; Park, Jae Yong; Chen, Chien-Jen; Kim, Yeul Hong; Kim, Young Tae; Landi, Maria Teresa; Shen, Hongbing; Lawrence, Charles; Burdett, Laurie; Yeager, Meredith; Chang, I-Shou; Mitsudomi, Tetsuya; Kim, Hee Nam; Chang, Gee-Chen; Bassig, Bryan A; Tucker, Margaret; Wei, Fusheng; Yin, Zhihua; An, She-Juan; Qian, Biyun; Lee, Victor Ho Fun; Lu, Daru; Liu, Jianjun; Jeon, Hyo-Sung; Hsiao, Chin-Fu; Sung, Jae Sook; Kim, Jin Hee; Gao, Yu-Tang; Tsai, Ying-Huang; Jung, Yoo Jin; Guo, Huan; Hu, Zhibin; Hutchinson, Amy; Wang, Wen-Chang; Klein, Robert J; Chung, Charles C; Oh, In-Jae; Chen, Kuan-Yu; Berndt, Sonja I; Wu, Wei; Chang, Jiang; Zhang, Xu-Chao; Huang, Ming-Shyan; Zheng, Hong; Wang, Junwen; Zhao, Xueying; Li, Yuqing; Choi, Jin Eun; Su, Wu-Chou; Park, Kyong Hwa; Sung, Sook Whan; Chen, Yuh-Min; Liu, Li; Kang, Chang Hyun; Hu, Lingmin; Chen, Chung-Hsing; Pao, William; Kim, Young-Chul; Yang, Tsung-Ying; Xu, Jun; Guan, Peng; Tan, Wen; Su, Jian; Wang, Chih-Liang; Li, Haixin; Sihoe, Alan Dart Loon; Zhao, Zhenhong; Chen, Ying; Choi, Yi Young; Hung, Jen-Yu; Kim, Jun Suk; Yoon, Ho-Il; Cai, Qiuyin; Lin, Chien-Chung; Park, In Kyu; Xu, Ping; Dong, Jing; Kim, Christopher; He, Qincheng; Perng, Reury-Perng; Kohno, Takashi; Kweon, Sun-Seog; Chen, Chih-Yi; Vermeulen, Roel C H; Wu, Junjie; Lim, Wei-Yen; Chen, Kun-Chieh; Chow, Wong-Ho; Ji, Bu-Tian; Chan, John K C; Chu, Minjie; Li, Yao-Jen; Yokota, Jun; Li, Jihua; Chen, Hongyan; Xiang, Yong-Bing; Yu, Chong-Jen; Kunitoh, Hideo; Wu, Guoping; Jin, Li; Lo, Yen-Li; Shiraishi, Kouya; Chen, Ying-Hsiang; Lin, Hsien-Chih; Wu, Tangchun; Wong, Maria Pik; Wu, Yi-Long; Yang, Pan-Chyr; Zhou, Baosen; Shin, Min-Ho; Fraumeni, Joseph F; Zheng, Wei; Lin, Dongxin; Chanock, Stephen J; Rothman, Nathaniel; Lan, Qing

    2016-01-01

    Recent evidence from several relatively small nested case-control studies in prospective cohorts shows an association between longer telomere length measured phenotypically in peripheral white blood cell (WBC) DNA and increased lung cancer risk. We sought to further explore this relationship by examining a panel of 7 telomere-length associated genetic variants in a large study of 5,457 never-smoking female Asian lung cancer cases and 4,493 never-smoking female Asian controls using data from a previously reported genome-wide association study. Using a group of 1,536 individuals with phenotypically measured telomere length in WBCs in the prospective Shanghai Women’s Health study, we demonstrated the utility of a genetic risk score (GRS) of 7 telomere-length associated variants to predict telomere length in an Asian population. We then found that GRSs used as instrumental variables to predict longer telomere length were associated with increased lung cancer risk (OR = 1.51 (95% CI=1.34–1.69) for upper vs. lower quartile of the weighted GRS, P-value=4.54×10−14) even after removing rs2736100 (P-value=4.81×10−3), a SNP in the TERT locus robustly associated with lung cancer risk in prior association studies. Stratified analyses suggested the effect of the telomere-associated GRS is strongest among younger individuals. We found no difference in GRS effect between adenocarcinoma and squamous cell subtypes. Our results indicate that a genetic background that favors longer telomere length may increase lung cancer risk, which is consistent with earlier prospective studies relating longer telomere length with increased lung cancer risk. PMID:25516442

  16. Genetic variants associated with longer telomere length are associated with increased lung cancer risk among never-smoking women in Asia: a report from the female lung cancer consortium in Asia.

    PubMed

    Machiela, Mitchell J; Hsiung, Chao Agnes; Shu, Xiao-Ou; Seow, Wei Jie; Wang, Zhaoming; Matsuo, Keitaro; Hong, Yun-Chul; Seow, Adeline; Wu, Chen; Hosgood, H Dean; Chen, Kexin; Wang, Jiu-Cun; Wen, Wanqing; Cawthon, Richard; Chatterjee, Nilanjan; Hu, Wei; Caporaso, Neil E; Park, Jae Yong; Chen, Chien-Jen; Kim, Yeul Hong; Kim, Young Tae; Landi, Maria Teresa; Shen, Hongbing; Lawrence, Charles; Burdett, Laurie; Yeager, Meredith; Chang, I-Shou; Mitsudomi, Tetsuya; Kim, Hee Nam; Chang, Gee-Chen; Bassig, Bryan A; Tucker, Margaret; Wei, Fusheng; Yin, Zhihua; An, She-Juan; Qian, Biyun; Lee, Victor Ho Fun; Lu, Daru; Liu, Jianjun; Jeon, Hyo-Sung; Hsiao, Chin-Fu; Sung, Jae Sook; Kim, Jin Hee; Gao, Yu-Tang; Tsai, Ying-Huang; Jung, Yoo Jin; Guo, Huan; Hu, Zhibin; Hutchinson, Amy; Wang, Wen-Chang; Klein, Robert J; Chung, Charles C; Oh, In-Jae; Chen, Kuan-Yu; Berndt, Sonja I; Wu, Wei; Chang, Jiang; Zhang, Xu-Chao; Huang, Ming-Shyan; Zheng, Hong; Wang, Junwen; Zhao, Xueying; Li, Yuqing; Choi, Jin Eun; Su, Wu-Chou; Park, Kyong Hwa; Sung, Sook Whan; Chen, Yuh-Min; Liu, Li; Kang, Chang Hyun; Hu, Lingmin; Chen, Chung-Hsing; Pao, William; Kim, Young-Chul; Yang, Tsung-Ying; Xu, Jun; Guan, Peng; Tan, Wen; Su, Jian; Wang, Chih-Liang; Li, Haixin; Sihoe, Alan Dart Loon; Zhao, Zhenhong; Chen, Ying; Choi, Yi Young; Hung, Jen-Yu; Kim, Jun Suk; Yoon, Ho-Il; Cai, Qiuyin; Lin, Chien-Chung; Park, In Kyu; Xu, Ping; Dong, Jing; Kim, Christopher; He, Qincheng; Perng, Reury-Perng; Kohno, Takashi; Kweon, Sun-Seog; Chen, Chih-Yi; Vermeulen, Roel C H; Wu, Junjie; Lim, Wei-Yen; Chen, Kun-Chieh; Chow, Wong-Ho; Ji, Bu-Tian; Chan, John K C; Chu, Minjie; Li, Yao-Jen; Yokota, Jun; Li, Jihua; Chen, Hongyan; Xiang, Yong-Bing; Yu, Chong-Jen; Kunitoh, Hideo; Wu, Guoping; Jin, Li; Lo, Yen-Li; Shiraishi, Kouya; Chen, Ying-Hsiang; Lin, Hsien-Chih; Wu, Tangchun; Wong, Maria Pik; Wu, Yi-Long; Yang, Pan-Chyr; Zhou, Baosen; Shin, Min-Ho; Fraumeni, Joseph F; Zheng, Wei; Lin, Dongxin; Chanock, Stephen J; Rothman, Nathaniel; Lan, Qing

    2015-07-15

    Recent evidence from several relatively small nested case-control studies in prospective cohorts shows an association between longer telomere length measured phenotypically in peripheral white blood cell (WBC) DNA and increased lung cancer risk. We sought to further explore this relationship by examining a panel of seven telomere-length associated genetic variants in a large study of 5,457 never-smoking female Asian lung cancer cases and 4,493 never-smoking female Asian controls using data from a previously reported genome-wide association study. Using a group of 1,536 individuals with phenotypically measured telomere length in WBCs in the prospective Shanghai Women's Health study, we demonstrated the utility of a genetic risk score (GRS) of seven telomere-length associated variants to predict telomere length in an Asian population. We then found that GRSs used as instrumental variables to predict longer telomere length were associated with increased lung cancer risk (OR = 1.51 (95% CI = 1.34-1.69) for upper vs. lower quartile of the weighted GRS, p value = 4.54 × 10(-14) ) even after removing rs2736100 (p value = 4.81 × 10(-3) ), a SNP in the TERT locus robustly associated with lung cancer risk in prior association studies. Stratified analyses suggested the effect of the telomere-associated GRS is strongest among younger individuals. We found no difference in GRS effect between adenocarcinoma and squamous cell subtypes. Our results indicate that a genetic background that favors longer telomere length may increase lung cancer risk, which is consistent with earlier prospective studies relating longer telomere length with increased lung cancer risk.

  17. Telomeres and human health.

    PubMed

    Bojesen, S E

    2013-11-01

    Telomeres are the tips of chromosomes and consist of proteins and hexanucleotide tandem repeats of DNA. The DNA repeats are shortened at each mitotic division of normal cells, and the telomere length chronicles how many divisions the cell has undergone. Thus, telomere length is a marker of fundamental biological pathways. It has been possible to measure telomere length for more than 20 years, and it has been established that telomere length is associated with age, sex and lifestyle factors. Here, the current knowledge of telomere length as a biomarker of disease susceptibility and mortality will be reviewed. In addition, technical difficulties and the reasons why measurement of telomeres has still not been introduced into routine clinical practice will be discussed. Findings from recent studies conducted in many thousands of individuals indicate that telomere length is not-or at best only marginally-independently associated with risk of common disorders such as cardiovascular, pulmonary and neoplastic diseases. However, in sufficiently powered studies, short telomeres are repeatedly and independently found to be associated with increased risk of early death in the general population or in subsets of individuals. This indicates that measurement of telomeres could be a valuable prognostic biomarker in many clinical settings. However, whether short telomeres are a causal factor for or simply a marker of increased risk of early death must be determined. Finally, how Mendelian randomization studies could clarify this issue, and which clinical studies might be carried out to refine this very promising biomarker for routine clinical use will be considered.

  18. Consequences of telomere shortening at an active VSG expression site in telomerase-deficient Trypanosoma brucei.

    PubMed

    Dreesen, Oliver; Cross, George A M

    2006-12-01

    Trypanosoma brucei evades the host immune response by sequential expression of a large family of variant surface glycoproteins (VSG) from one of approximately 20 subtelomeric expression sites (ES). VSG transcription is monoallelic, and little is known about the regulation of antigenic switching. To explore whether telomere length could affect antigenic switching, we created a telomerase-deficient cell line, in which telomeres shortened at a rate of 3 to 6 bp at each cell division. Upon reaching a critical length, short silent ES telomeres were stabilized by a telomerase-independent mechanism. The active ES telomere progressively shortened and frequently broke. Upon reaching a critical length, the short active ES telomere stabilized, but the transcribed VSG was gradually lost from the population and replaced by a new VSG through duplicative gene conversion. We propose a model in which subtelomeric-break-induced replication-mediated repair at a short ES telomere leads to duplicative gene conversion and expression of a new VSG.

  19. Associations of Accelerometer-Measured and Self-Reported Sedentary Time With Leukocyte Telomere Length in Older Women.

    PubMed

    Shadyab, Aladdin H; Macera, Caroline A; Shaffer, Richard A; Jain, Sonia; Gallo, Linda C; LaMonte, Michael J; Reiner, Alexander P; Kooperberg, Charles; Carty, Cara L; Di, Chongzhi; Manini, Todd M; Hou, Lifang; LaCroix, Andrea Z

    2017-01-18

    Few studies have assessed the association of sedentary time with leukocyte telomere length (LTL). In a cross-sectional study conducted in 2012-2013, we examined associations of accelerometer-measured and self-reported sedentary time with LTL in a sample of 1,481 older white and African-American women from the Women's Health Initiative and determined whether associations varied by level of moderate- to vigorous-intensity physical activity (MVPA). The association between sedentary time and LTL was evaluated using multiple linear regression models. Women were aged 79.2 (standard deviation, 6.7) years, on average. Self-reported sedentary time was not associated with LTL. In a model adjusting for demographic characteristics, lifestyle behaviors, and health-related factors, among women at or below the median level of accelerometer-measured MVPA, those in the highest quartile of accelerometer-measured sedentary time had significantly shorter LTL than those in the lowest quartile, with an average difference of 170 base pairs (95% confidence interval: 4, 340). Accelerometer-measured sedentary time was not associated with LTL in women above the median level of MVPA. Findings suggest that, on the basis of accelerometer measurements, higher sedentary time may be associated with shorter LTL among less physically active women.

  20. Childhood Conscientiousness and Leukocyte Telomere Length 40 Years Later in Adult Women—Preliminary Findings of a Prospective Association

    PubMed Central

    Edmonds, Grant W.; Côté, Hélène C. F.; Hampson, Sarah E.

    2015-01-01

    Leukocyte telomere length (LTL) shortens with age, and is a prospective marker of mortality related to cardiovascular disease. Many health behaviors and social environmental factors have been found to be associated with LTL. Several of these are also associated with conscientiousness, a dispositional personality trait. Conscientiousness is a propensity to be planful, adhere to social norms, and inhibit pre-potent responses. Like LTL, conscientiousness is prospectively related to mortality, possibly through cumulative effects on health over the life course via multiple pathways. As a result, we hypothesized that childhood levels of conscientiousness would predict LTL prospectively in adulthood. We selected a sample of 60 women in the Hawaii Personality and Health Cohort; 30 described by their teachers as high on conscientiousness in childhood and 30 described as low on the trait. Dried blood spot samples collected in adulthood 40 years later were used as sources of DNA for the LTL assay. Conscientiousness was associated with longer LTL (p = .02). Controlling for age did not account for this association. Controlling for education and physiological dysregulation partially attenuated the association, and the effect remained significant when accounting for differences in LTL across cultural groups. These results represent the first evidence that childhood personality prospectively predicts LTL 40 years later in adulthood. Our findings would be consistent with a mediation hypothesis whereby conscientiousness predicts life paths and trajectories of health that are reflected in rates of LTL erosion across the lifespan. PMID:26218760

  1. Age-related declines in immune response in a wild mammal are unrelated to immune cell telomere length

    PubMed Central

    Waring, Laura; McDonald, Robbie A.; Delahay, Richard; Young, Andrew

    2016-01-01

    Senescence has been hypothesized to arise in part from age-related declines in immune performance, but the patterns and drivers of within-individual age-related changes in immunity remain virtually unexplored in natural populations. Here, using a long-term epidemiological study of wild European badgers (Meles meles), we (i) present evidence of a within-individual age-related decline in the response of a key immune-signalling cytokine, interferon-gamma (IFNγ), to ex vivo lymphocyte stimulation, and (ii) investigate three putative drivers of individual variation in the rate of this decline (sex, disease and immune cell telomere length; ICTL). That the within-individual rate of age-related decline markedly exceeded that at the population level suggests that individuals with weaker IFNγ responses are selectively lost from this population. IFNγ responses appeared to decrease with the progression of bovine tuberculosis infection (independent of age) and were weaker among males than females. However, neither sex nor disease influenced the rate of age-related decline in IFNγ response. Similarly, while ICTL also declines with age, variation in ICTL predicted neither among- nor within-individual variation in IFNγ response. Our findings provide evidence of within-individual age-related declines in immune performance in a wild mammal and highlight the likely complexity of the mechanisms that generate them. PMID:26888036

  2. Depressive symptoms are associated with leukocyte telomere length in American Indians: findings from the Strong Heart Family Study

    PubMed Central

    Zhao, Qi; Zhu, Yun; Yeh, Fawn; Lin, Jue; Lee, Elisa T.; Cole, Shelley A.; Calhoun, Darren; Zhao, Jinying

    2016-01-01

    Patients with depression have an increased risk for many aging-related disorders, but the biological mechanisms underlying this link remain to be determined. Here we examined the association between depressive symptoms and leukocyte telomere length (LTL), a marker of biological aging, among 2,175 American Indians participating in the Strong Heart Family Study. Depressive symptoms were assessed by the Center for Epidemiologic Studies of Depression Scale (CES-D), which was categorized into four levels: none (< 10), mild (10-15), moderate (16-24), and severe (> 24). LTL (T/S ratio) was quantified by qPCR. The association between depressive symptoms and LTL was examined by multivariate generalized estimating equation models, adjusting for sociodemographic factors, lifestyle factors, and chronic conditions. Results showed that individuals with a higher level of depressive symptoms had shorter LTL. Specifically, LTL in participants reporting none, mild, moderate, and severe depressive symptoms were 1.000, 0.999, 0.988, and 0.966, respectively (P for trend = 0.0278). Moreover, gender appears to modulate the effect of reported depressive symptoms that fall in the severe range (CES-D > 24) on LTL (P for interaction = 0.0346). Our results suggest that depressive symptoms may accelerate biological aging through pathways beyond traditional risk factors in American Indians. PMID:27870638

  3. Age-related declines in immune response in a wild mammal are unrelated to immune cell telomere length.

    PubMed

    Beirne, Christopher; Waring, Laura; McDonald, Robbie A; Delahay, Richard; Young, Andrew

    2016-02-24

    Senescence has been hypothesized to arise in part from age-related declines in immune performance, but the patterns and drivers of within-individual age-related changes in immunity remain virtually unexplored in natural populations. Here, using a long-term epidemiological study of wild European badgers (Meles meles), we (i) present evidence of a within-individual age-related decline in the response of a key immune-signalling cytokine, interferon-gamma (IFNγ), to ex vivo lymphocyte stimulation, and (ii) investigate three putative drivers of individual variation in the rate of this decline (sex, disease and immune cell telomere length; ICTL). That the within-individual rate of age-related decline markedly exceeded that at the population level suggests that individuals with weaker IFNγ responses are selectively lost from this population. IFNγ responses appeared to decrease with the progression of bovine tuberculosis infection (independent of age) and were weaker among males than females. However, neither sex nor disease influenced the rate of age-related decline in IFNγ response. Similarly, while ICTL also declines with age, variation in ICTL predicted neither among- nor within-individual variation in IFNγ response. Our findings provide evidence of within-individual age-related declines in immune performance in a wild mammal and highlight the likely complexity of the mechanisms that generate them.

  4. Childhood Conscientiousness and Leukocyte Telomere Length 40 Years Later in Adult Women--Preliminary Findings of a Prospective Association.

    PubMed

    Edmonds, Grant W; Côté, Hélène C F; Hampson, Sarah E

    2015-01-01

    Leukocyte telomere length (LTL) shortens with age, and is a prospective marker of mortality related to cardiovascular disease. Many health behaviors and social environmental factors have been found to be associated with LTL. Several of these are also associated with conscientiousness, a dispositional personality trait. Conscientiousness is a propensity to be planful, adhere to social norms, and inhibit pre-potent responses. Like LTL, conscientiousness is prospectively related to mortality, possibly through cumulative effects on health over the life course via multiple pathways. As a result, we hypothesized that childhood levels of conscientiousness would predict LTL prospectively in adulthood. We selected a sample of 60 women in the Hawaii Personality and Health Cohort; 30 described by their teachers as high on conscientiousness in childhood and 30 described as low on the trait. Dried blood spot samples collected in adulthood 40 years later were used as sources of DNA for the LTL assay. Conscientiousness was associated with longer LTL (p = .02). Controlling for age did not account for this association. Controlling for education and physiological dysregulation partially attenuated the association, and the effect remained significant when accounting for differences in LTL across cultural groups. These results represent the first evidence that childhood personality prospectively predicts LTL 40 years later in adulthood. Our findings would be consistent with a mediation hypothesis whereby conscientiousness predicts life paths and trajectories of health that are reflected in rates of LTL erosion across the lifespan.

  5. Association of adiponectin and leptin with relative telomere length in seven independent cohorts including 11,448 participants.

    PubMed

    Broer, Linda; Raschenberger, Julia; Deelen, Joris; Mangino, Massimo; Codd, Veryan; Pietiläinen, Kirsi H; Albrecht, Eva; Amin, Najaf; Beekman, Marian; de Craen, Anton J M; Gieger, Christian; Haun, Margot; Henneman, Peter; Herder, Christian; Hovatta, Iiris; Laser, Annika; Kedenko, Lyudmyla; Koenig, Wolfgang; Kollerits, Barbara; Moilanen, Eeva; Oostra, Ben A; Paulweber, Bernhard; Quaye, Lydia; Rissanen, Aila; Roden, Michael; Surakka, Ida; Valdes, Ana M; Vuolteenaho, Katriina; Thorand, Barbara; van Dijk, Ko Willems; Kaprio, Jaakko; Spector, Tim D; Slagboom, P Eline; Samani, Nilesh J; Kronenberg, Florian; van Duijn, Cornelia M; Ladwig, Karl-Heinz

    2014-09-01

    Oxidative stress and inflammation are major contributors to accelerated age-related relative telomere length (RTL) shortening. Both conditions are strongly linked to leptin and adiponectin, the most prominent adipocyte-derived protein hormones. As high leptin levels and low levels of adiponectin have been implicated in inflammation, one expects adiponectin to be positively associated with RTL while leptin should be negatively associated. Within the ENGAGE consortium, we investigated the association of RTL with adiponectin and leptin in seven independent cohorts with a total of 11,448 participants. We performed partial correlation analysis on Z-transformed RTL and LN-transformed leptin/adiponectin, adjusting for age and sex. In extended models we adjusted for body mass index (BMI) and C-reactive protein (CRP). Adiponectin showed a borderline significant association with RTL. This appeared to be determined by a single study and when the outlier study was removed, this association disappeared. The association between RTL and leptin was highly significant (r = -0.05; p = 1.81 × 10(-7)). Additional adjustment for BMI or CRP did not change the results. Sex-stratified analysis revealed no difference between men and women. Our study suggests that high leptin levels are associated with short RTL.

  6. Telomere profiles and tumor-associated macrophages with different immune signatures affect prognosis in glioblastoma.

    PubMed

    Hung, Noelyn A; Eiholzer, Ramona A; Kirs, Stenar; Zhou, Jean; Ward-Hartstonge, Kirsten; Wiles, Anna K; Frampton, Chris M; Taha, Ahmad; Royds, Janice A; Slatter, Tania L

    2016-03-01

    Telomere maintenance is a hallmark of cancer and likely to be targeted in future treatments. In glioblastoma established methods of identifying telomerase and alternative lengthening of telomeres leave a significant proportion of tumors with no defined telomere maintenance mechanism. This study investigated the composition of these tumors using RNA-Seq. Glioblastomas with an indeterminate telomere maintenance mechanism had an increased immune signature compared with alternative lengthening of telomeres and telomerase-positive tumors. Immunohistochemistry for CD163 confirmed that the majority (80%) of tumors with an indeterminate telomere maintenance mechanism had a high presence of tumor-associated macrophages. The RNA-Seq and immunostaining data separated tumors with no defined telomere maintenance mechanism into three subgroups: alternative lengthening of telomeres like tumors with a high presence of tumor-associated macrophages and telomerase like tumors with a high presence of tumor-associated macrophages. The third subgroup had no increase in tumor-associated macrophages and may represent a distinct category. The presence of tumor-associated macrophages conferred a worse prognosis with reduced patient survival times (alternative lengthening of telomeres with and without macrophages P=0.0004, and telomerase with and without macrophages P=0.013). The immune signatures obtained from RNA-Seq were significantly different between telomere maintenance mechanisms. Alternative lengthening of telomeres like tumors with macrophages had increased expression of interferon-induced proteins with tetratricopeptide repeats (IFIT1-3). Telomerase-positive tumors with macrophages had increased expression of macrophage receptor with collagenous structure (MARCO), CXCL12 and sushi-repeat containing protein x-linked 2 (SRPX2). Telomerase-positive tumors with macrophages were also associated with a reduced frequency of total/near total resections (44% vs >76% for all other subtypes

  7. 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.

  8. Posttraumatic Stress Disorder, Adverse Childhood Events, and Buccal Cell Telomere Length in Elderly Swiss Former Indentured Child Laborers.

    PubMed

    Küffer, Andreas Lorenz; O'Donovan, Aoife; Burri, Andrea; Maercker, Andreas

    2016-01-01

    Posttraumatic stress disorder (PTSD) is associated with increased risk for age-related diseases and early mortality. Accelerated biological aging could contribute to this elevated risk. The aim of the present study was to assess buccal cell telomere length (BTL) - a proposed marker of biological age - in men and women with and without PTSD. The role of childhood trauma was assessed as a potential additional risk factor for shorter telomere length. The sample included 62 former indentured Swiss child laborers (age: M = 76.19, SD = 6.18) and 58 healthy controls (age: M = 71.85, SD = 5.97). Structured clinical interviews were conducted to screen for PTSD and other psychiatric disorders. The Childhood Trauma Questionnaire (CTQ) was used to assess childhood trauma exposure. Quantitative polymerase chain reaction was used to measure BTL. Covariates include age, sex, years of education, self-evaluated financial situation, depression, and mental and physical functioning. Forty-eight (77.42%) of the former indentured child laborers screened positive for childhood trauma, and 21 (33.87%) had partial or full-blown PTSD. Results did not support our hypotheses that PTSD and childhood trauma would be associated with shorter BTL. In fact, results revealed a trend toward longer BTL in participants with partial or full PTSD [F(2,109) = 3.27, p = 0.04, η(2) = 0.06], and longer BTL was marginally associated with higher CTQ scores (age adjusted: β = 0.17 [95% CI: -0.01 to 0.35], t = 1.90, p = 0.06). Furthermore, within-group analyses indicated no significant association between BTL and CTQ scores. To the best of our knowledge, this is the first study exploring the association between childhood trauma and BTL in older individuals with and without PTSD. Contrary to predictions, there were no significant differences in BTL between participants with and without PTSD in our adjusted analyses, and childhood adversity was not associated with BTL

  9. Posttraumatic Stress Disorder, Adverse Childhood Events, and Buccal Cell Telomere Length in Elderly Swiss Former Indentured Child Laborers

    PubMed Central

    Küffer, Andreas Lorenz; O’Donovan, Aoife; Burri, Andrea; Maercker, Andreas

    2016-01-01

    Posttraumatic stress disorder (PTSD) is associated with increased risk for age-related diseases and early mortality. Accelerated biological aging could contribute to this elevated risk. The aim of the present study was to assess buccal cell telomere length (BTL) – a proposed marker of biological age – in men and women with and without PTSD. The role of childhood trauma was assessed as a potential additional risk factor for shorter telomere length. The sample included 62 former indentured Swiss child laborers (age: M = 76.19, SD = 6.18) and 58 healthy controls (age: M = 71.85, SD = 5.97). Structured clinical interviews were conducted to screen for PTSD and other psychiatric disorders. The Childhood Trauma Questionnaire (CTQ) was used to assess childhood trauma exposure. Quantitative polymerase chain reaction was used to measure BTL. Covariates include age, sex, years of education, self-evaluated financial situation, depression, and mental and physical functioning. Forty-eight (77.42%) of the former indentured child laborers screened positive for childhood trauma, and 21 (33.87%) had partial or full-blown PTSD. Results did not support our hypotheses that PTSD and childhood trauma would be associated with shorter BTL. In fact, results revealed a trend toward longer BTL in participants with partial or full PTSD [F(2,109) = 3.27, p = 0.04, η2 = 0.06], and longer BTL was marginally associated with higher CTQ scores (age adjusted: β = 0.17 [95% CI: −0.01 to 0.35], t = 1.90, p = 0.06). Furthermore, within-group analyses indicated no significant association between BTL and CTQ scores. To the best of our knowledge, this is the first study exploring the association between childhood trauma and BTL in older individuals with and without PTSD. Contrary to predictions, there were no significant differences in BTL between participants with and without PTSD in our adjusted analyses, and childhood adversity was not associated with

  10. 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

  11. Smoking and perceived stress in relation to short salivary telomere length among caregivers of children with disabilities.

    PubMed

    Chen, Xiaoli; Velez, Juan Carlos; Barbosa, Clarita; Pepper, Micah; Andrade, Asterio; Stoner, Lee; De Vivo, Immaculata; Gelaye, Bizu; Williams, Michelle A

    2015-01-01

    Telomere length (TL), the length of repeated DNA sequence that forms protective caps at the end of chromosomes, has emerged as a novel biomarker of cell aging and oxidative stress. There is increasing research exploring the associations of smoking and perceived stress with TL, and the results are inconsistent. This study aimed to examine whether smoking and perceived stress were associated with shortened salivary TL among primary caregivers of children with disabilities. Using a quantitative polymerase chain reaction method, salivary TL was assessed among 89 caregivers aged 19-69 years (87% were women) who took care of disabled children in the Patagonia Region, Chile. Interviewer-administered questionnaires were used to collect information on sociodemographic and lifestyle factors. The 14-item Perceived Stress Scale was used to assess perceived stress. Mean relative TL was 0.92 (standard error = 0.03). Smokers had age-adjusted mean TL that was 0.07 units lower (β = -0.07, standard error = 0.03; p = 0.012) than non-smokers. Smokers were 2.17 times more likely to have shorter TL ( < 0.73, the lowest quartile of TL) than non-smokers (odds ratio = 3.17; 95% confidence interval = 1.05-9.52) with adjustment for age and perceived stress. Caregivers with higher perceived stress were 2.13 times more likely to have shorter TL (odds ratio = 3.13; 95% confidence interval = 1.03-9.55) than caregivers with lower perceived stress after adjustment for age and smoking. This study provides the first evidence of strong associations between smoking and perceived stress and shortened salivary TL among caregivers of children with disabilities. Larger studies with detailed information on smoking status are warranted to confirm our findings.

  12. Telomere dysfunction and chromothripsis.

    PubMed

    Ernst, Aurélie; Jones, David T W; Maass, Kendra K; Rode, Agata; Deeg, Katharina I; Jebaraj, Billy Michael Chelliah; Korshunov, Andrey; Hovestadt, Volker; Tainsky, Michael A; Pajtler, Kristian W; Bender, Sebastian; Brabetz, Sebastian; Gröbner, Susanne; Kool, Marcel; Devens, Frauke; Edelmann, Jennifer; Zhang, Cindy; Castelo-Branco, Pedro; Tabori, Uri; Malkin, David; Rippe, Karsten; Stilgenbauer, Stephan; Pfister, Stefan M; Zapatka, Marc; Lichter, Peter

    2016-06-15

    Chromothripsis is a recently discovered form of genomic instability, characterized by tens to hundreds of clustered DNA rearrangements resulting from a single dramatic event. Telomere dysfunction has been suggested to play a role in the initiation of this phenomenon, which occurs in a large number of tumor entities. Here, we show that telomere attrition can indeed lead to catastrophic genomic events, and that telomere patterns differ between cells analyzed before and after such genomic catastrophes. Telomere length and telomere stabilization mechanisms diverge between samples with and without chromothripsis in a given tumor subtype. Longitudinal analyses of the evolution of chromothriptic patterns identify either stable patterns between matched primary and relapsed tumors, or loss of the chromothriptic clone in the relapsed specimen. The absence of additional chromothriptic events occurring between the initial tumor and the relapsed tumor sample points to telomere stabilization after the initial chromothriptic event which prevents further shattering of the genome.

  13. Short-term inhibition of TERT induces telomere length-independent cell cycle arrest and apoptotic response in EBV-immortalized and transformed B cells

    PubMed Central

    Celeghin, Andrea; Giunco, Silvia; Freguja, Riccardo; Zangrossi, Manuela; Nalio, Silvia; Dolcetti, Riccardo; De Rossi, Anita

    2016-01-01

    Besides its canonical role in stabilizing telomeres, telomerase reverse transcriptase (TERT) may promote tumorigenesis through extra-telomeric functions. The possible therapeutic effects of BIBR1532 (BIBR), a powerful TERT inhibitor, have been evaluated in different cellular backgrounds, but no data are currently available regarding Epstein–Barr virus (EBV)-driven B-cell malignancies. Our aim was to characterize the biological effects of TERT inhibition by BIBR on EBV-immortalized lymphoblastoid cell lines (LCLs) and fully transformed Burkitt's lymphoma (BL) cell lines. We found that BIBR selectively inhibits telomerase activity in TERT-positive 4134/Late and 4134/TERT+ LCLs and EBV-negative BL41 and EBV-positive BL41/B95.8 BL cell lines. TERT inhibition led to decreased cell proliferation, accumulation of cells in the S-phase and ultimately to increased apoptosis, compared with mock-treated control cells. All these effects occurred within 72 h and were not observed in BIBR-treated TERT-negative 4134/TERT- and U2OS cells. The cell cycle arrest and apoptosis, consequent upon short-term TERT inhibition, were associated with and likely dependent on the activation of the DNA damage response (DDR), highlighted by the increased levels of γH2AX and activation of ATM and ATR pathways. Analyses of the mean and range of telomere lengths and telomere dysfunction-induced foci indicated that DDR after short-term TERT inhibition was not related to telomere dysfunction, thus suggesting that TERT, besides stabilizing telomere, may protect DNA via telomere-independent mechanisms. Notably, TERT-positive LCLs treated with BIBR in combination with fludarabine or cyclophosphamide showed a significant increase in the number of apoptotic cells with respect to those treated with chemotherapeutic agents alone. In conclusion, TERT inhibition impairs cell cycle progression and enhances the pro-apoptotic effects of chemotherapeutic agents in TERT-positive cells. These results support new

  14. Focal Length Affects Depicted Shape and Perception of Facial Images.

    PubMed

    Třebický, Vít; Fialová, Jitka; Kleisner, Karel; Havlíček, Jan

    2016-01-01

    Static photographs are currently the most often employed stimuli in research on social perception. The method of photograph acquisition might affect the depicted subject's facial appearance and thus also the impression of such stimuli. An important factor influencing the resulting photograph is focal length, as different focal lengths produce various levels of image distortion. Here we tested whether different focal lengths (50, 85, 105 mm) affect depicted shape and perception of female and male faces. We collected three portrait photographs of 45 (22 females, 23 males) participants under standardized conditions and camera setting varying only in the focal length. Subsequently, the three photographs from each individual were shown on screen in a randomized order using a 3-alternative forced-choice paradigm. The images were judged for attractiveness, dominance, and femininity/masculinity by 369 raters (193 females, 176 males). Facial width-to-height ratio (fWHR) was measured from each photograph and overall facial shape was analysed employing geometric morphometric methods (GMM). Our results showed that photographs taken with 50 mm focal length were rated as significantly less feminine/masculine, attractive, and dominant compared to the images taken with longer focal lengths. Further, shorter focal lengths produced faces with smaller fWHR. Subsequent GMM revealed focal length significantly affected overall facial shape of the photographed subjects. Thus methodology of photograph acquisition, focal length in this case, can significantly affect results of studies using photographic stimuli perhaps due to different levels of perspective distortion that influence shapes and proportions of morphological traits.

  15. 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

  16. Association of relative telomere length with progression of chronic kidney disease in two cohorts: effect modification by smoking and diabetes.

    PubMed

    Raschenberger, Julia; Kollerits, Barbara; Ritchie, James; Lane, Beverley; Kalra, Philip A; Ritz, Eberhard; Kronenberg, Florian

    2015-07-07

    Chronic kidney disease (CKD) is a highly progressive disease. We studied the association between relative telomere length (RTL) and CKD progression and tested whether this association is modified by smoking and diabetes mellitus. RTL was measured by qPCR in two prospective cohort studies, the MMKD-Study (n = 166) and the CRISIS-Study (n = 889) with a median follow-up of 4.5 and 2.8 years, respectively. Progression was defined as doubling of baseline serum creatinine (MMKD-Study) and/or end stage renal disease (both studies). 59 and 105 of the patients from MMKD and CRISIS experienced a progression of CKD. Mean standardized pooled RTL was 0.74 ± 0.29. In the meta-analysis shorter RTL at baseline showed a borderline association with CKD progression (HR = 1.07 [95%CI 1.00-1.15]; p = 0.06). We observed an effect modification of RTL and CKD progression by smoking and diabetes (p-values of interaction p = 0.02 and p = 0.09, respectively). Each 0.1 unit shorter RTL was significantly associated with an increased hazard for CKD progression in active-smokers by 44% (HR = 1.44 [1.16-1.81]; p = 0.001) and in patients with diabetes mellitus by 16% (HR = 1.16 [1.01-1.34]; p = 0.03). Estimates were adjusted for baseline age, sex, proteinuria and GFR. This study in two independent cohorts reinforces that RTL is a marker and potentially a pathogenetic factor for CKD progression.

  17. Association of relative telomere length with progression of chronic kidney disease in two cohorts: effect modification by smoking and diabetes

    PubMed Central

    Raschenberger, Julia; Kollerits, Barbara; Ritchie, James; Lane, Beverley; Kalra, Philip A.; Ritz, Eberhard; Kronenberg, Florian

    2015-01-01

    Chronic kidney disease (CKD) is a highly progressive disease. We studied the association between relative telomere length (RTL) and CKD progression and tested whether this association is modified by smoking and diabetes mellitus. RTL was measured by qPCR in two prospective cohort studies, the MMKD-Study (n = 166) and the CRISIS-Study (n = 889) with a median follow-up of 4.5 and 2.8 years, respectively. Progression was defined as doubling of baseline serum creatinine (MMKD-Study) and/or end stage renal disease (both studies). 59 and 105 of the patients from MMKD and CRISIS experienced a progression of CKD. Mean standardized pooled RTL was 0.74 ± 0.29. In the meta-analysis shorter RTL at baseline showed a borderline association with CKD progression (HR = 1.07 [95%CI 1.00–1.15]; p = 0.06). We observed an effect modification of RTL and CKD progression by smoking and diabetes (p-values of interaction p = 0.02 and p = 0.09, respectively). Each 0.1 unit shorter RTL was significantly associated with an increased hazard for CKD progression in active-smokers by 44% (HR = 1.44 [1.16–1.81]; p = 0.001) and in patients with diabetes mellitus by 16% (HR = 1.16 [1.01–1.34]; p = 0.03). Estimates were adjusted for baseline age, sex, proteinuria and GFR. This study in two independent cohorts reinforces that RTL is a marker and potentially a pathogenetic factor for CKD progression. PMID:26149682

  18. Leukocyte Telomere Length-Related rs621559 and rs398652 Genetic Variants Influence Risk of HBV-Related Hepatocellular Carcinoma

    PubMed Central

    Shi, Juan; Lu, Chao; Wei, Jinyu; Li, Lichao; Zhou, Changchun; Yuan, Qipeng; Zhou, Liqing; Yang, Ming

    2014-01-01

    Recent genome-wide association studies (GWAS) have identified eleven leukocyte telomere length (LTL)-related single nucleotide polymorphisms (SNPs). Since LTL has been associated with risk of many malignancies, LTL-related SNPs may contribute to cancer susceptibility. To test this hypothesis in hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC), we genotyped these eleven LTL-related SNPs in a case-control set including 1186 HBV-related HCC cases, 508 chronic HBV carriers and 1308 healthy controls at the discovery stage. The associations of HCC risk with these SNPs were further confirmed in an independent case-control set. We found that 1p34.2 rs621559 and 14q21 rs398652 were significantly associated with HBV-related HCC risk (both P<0.005 after Bonferroni corrections). There was no significant difference of either rs621559 or rs398652 genotypes between chronic HBV carriers and healthy controls, demonstrating that the association was not due to predisposition to HBV infection. In the pooled analyses (1806 HBV-related HCC cases and 1954 controls), we observed a decreased HCC risk, 0.72-times, associated with the 1p34.2 rs621559 AA genotype compared to the GG genotype (P = 1.6×10−6). Additionally, there was an increased HCC risk, 1.27-fold, associated with the rs398652 GG genotype (P = 3.3×10−6). A statistical joint effect between the rs621559 GG and rs398652 GG genotypes may exist in elevating risk of HBV-related HCC. We show, for the first time, that rs398652 and rs621559 might be marker genetic variants for risk of HBV-related HCC in the Chinese population. PMID:25365256

  19. Different TP53 mutations are associated with specific chromosomal rearrangements, telomere length changes, and remodeling of the nuclear architecture of telomeres.

    PubMed

    Samassekou, Oumar; Bastien, Nathalie; Lichtensztejn, Daniel; Yan, Ju; Mai, Sabine; Drouin, Régen

    2014-11-01

    TP53 mutations are the most common mutations in human cancers, and TP53-R175H and TP53-R273H are the most frequent. The impact of these mutations on genomic instability after tumor initiation is still uncovered. To gain insight into this, we studied the effects of three specific TP53 mutants (TP53-V143A, TP53-R175H, and TP53-R273H) on genomic instability using four isogenic lines of LoVo cells. Multicolor fluorescence in situ hybridization (FISH), three-dimensional (3D) quantitative FISH (Q-FISH) on interphase and Q-FISH on metaphases were used to investigate genomic instability. We found that LoVo cells expressing mutant TP53-R175H displayed the highest level of chromosomal instability among the LoVo cell lines. Furthermore, we observed that mutant TP53-R175H and TP53-V143A showed more alterations in their 3D nuclear architecture of telomeres than the mutant TP53-R273H and the wild type. Moreover, we noted an association between some chromosomal abnormalities and telomere elongation in the mutant TP53-R175H. Taken together, our results indicate that the mutation TP53-R175H is more likely to cause higher levels of genomic instability than the other TP53 mutations. We proposed that the type of TP53 mutations and the genetic background of a cancer cell are major determinants of the TP53-dependent genomic instability.

  20. Methods of Combinatorial Optimization to Reveal Factors Affecting Gene Length

    PubMed Central

    Bolshoy, Alexander; Tatarinova, Tatiana

    2012-01-01

    In this paper we present a novel method for genome ranking according to gene lengths. The main outcomes described in this paper are the following: the formulation of the genome ranking problem, presentation of relevant approaches to solve it, and the demonstration of preliminary results from prokaryotic genomes ordering. Using a subset of prokaryotic genomes, we attempted to uncover factors affecting gene length. We have demonstrated that hyperthermophilic species have shorter genes as compared with mesophilic organisms, which probably means that environmental factors affect gene length. Moreover, these preliminary results show that environmental factors group together in ranking evolutionary distant species. PMID:23300345

  1. Methods of combinatorial optimization to reveal factors affecting gene length.

    PubMed

    Bolshoy, Alexander; Tatarinova, Tatiana

    2012-01-01

    In this paper we present a novel method for genome ranking according to gene lengths. The main outcomes described in this paper are the following: the formulation of the genome ranking problem, presentation of relevant approaches to solve it, and the demonstration of preliminary results from prokaryotic genomes ordering. Using a subset of prokaryotic genomes, we attempted to uncover factors affecting gene length. We have demonstrated that hyperthermophilic species have shorter genes as compared with mesophilic organisms, which probably means that environmental factors affect gene length. Moreover, these preliminary results show that environmental factors group together in ranking evolutionary distant species.

  2. Focal Length Affects Depicted Shape and Perception of Facial Images

    PubMed Central

    Třebický, Vít; Fialová, Jitka; Kleisner, Karel; Havlíček, Jan

    2016-01-01

    Static photographs are currently the most often employed stimuli in research on social perception. The method of photograph acquisition might affect the depicted subject’s facial appearance and thus also the impression of such stimuli. An important factor influencing the resulting photograph is focal length, as different focal lengths produce various levels of image distortion. Here we tested whether different focal lengths (50, 85, 105 mm) affect depicted shape and perception of female and male faces. We collected three portrait photographs of 45 (22 females, 23 males) participants under standardized conditions and camera setting varying only in the focal length. Subsequently, the three photographs from each individual were shown on screen in a randomized order using a 3-alternative forced-choice paradigm. The images were judged for attractiveness, dominance, and femininity/masculinity by 369 raters (193 females, 176 males). Facial width-to-height ratio (fWHR) was measured from each photograph and overall facial shape was analysed employing geometric morphometric methods (GMM). Our results showed that photographs taken with 50 mm focal length were rated as significantly less feminine/masculine, attractive, and dominant compared to the images taken with longer focal lengths. Further, shorter focal lengths produced faces with smaller fWHR. Subsequent GMM revealed focal length significantly affected overall facial shape of the photographed subjects. Thus methodology of photograph acquisition, focal length in this case, can significantly affect results of studies using photographic stimuli perhaps due to different levels of perspective distortion that influence shapes and proportions of morphological traits. PMID:26894832

  3. Serum 25-Hydroxyvitamin D Has a Modest Positive Association with Leukocyte Telomere Length in Middle-Aged US Adults.

    PubMed

    Beilfuss, Julia; Camargo, Carlos A; Kamycheva, Elena

    2017-04-01

    Background: Vitamin D deficiency has been linked to all-cause mortality and cancer. However, the biological plausibility of these associations is not well established. Leukocyte telomere length (LTL) shortening is associated with aging and is a hallmark of genomic instability and carcinogenesis.Objective: We aimed to investigate the association between serum 25-hydroxyvitamin D [25(OH)D] concentrations and LTL in the general US population.Methods: We analyzed data from the US NHANES 2001-2002. The study population comprised 1542 younger adults (aged 20-39 y), 1336 middle-aged adults (aged 40-59 y), and 1382 older adults (aged ≥60 y). LTL was measured by using quantitative polymerase chain reaction. Serum 25(OH)D concentrations ≥50 nmol/L were considered optimal. Linear regression, adjusted for age, sex, race/ethnicity, body mass index (BMI), total energy and sugar intakes, calcium intake, socioeconomic status, milk and dietary supplement consumption, and physical activity, was applied to investigate the association between serum 25(OH)D and LTL.Results: In the total population, age, sex, BMI, and non-Hispanic black race/ethnicity were significant predictors of LTL. In the participants aged 40-59 y, an increment in serum 25(OH)D of 10 nmol/L was associated with a 0.03- ± 0.01-kbp longer LTL, adjusted for age, sex, race/ethnicity, and other factors (P = 0.001). In the same age group, 25(OH)D concentrations ≥50 nmol/L were associated with a 0.13- ± 0.04-kbp longer LTL than those for 25(OH)D concentrations <50 nmol/L (P = 0.01). The association was independent of age, sex, race/ethnicity, BMI, and other factors.Conclusions: In a nationally representative population of adults, serum 25(OH)D was positively associated with LTL in middle-aged participants (aged 40-59 y), independently of other factors. These findings suggest that decreased 25(OH)D concentrations are associated with genomic instability, although the clinical impact of this observation remains

  4. Associations of ghrelin with eating behaviors, stress, metabolic factors, and telomere length among overweight and obese women: preliminary evidence of attenuated ghrelin effects in obesity?

    PubMed

    Buss, Julia; Havel, Peter J; Epel, Elissa; Lin, Jue; Blackburn, Elizabeth; Daubenmier, Jennifer

    2014-05-01

    Ghrelin regulates homeostatic food intake, hedonic eating, and is a mediator in the stress response. In addition, ghrelin has metabolic, cardiovascular, and anti-aging effects. This cross-sectional study examined associations between total plasma ghrelin, caloric intake based on 3day diet diaries, hedonic eating attitudes, stress-related and metabolic factors, and leukocyte telomere length in overweight (n=25) and obese women (n=22). We hypothesized associations between total plasma ghrelin and eating behaviors, stress, metabolic, cardiovascular, and cell aging factors among overweight women, but not among obese women due to lower circulating ghrelin levels and/or central resistance to ghrelin. Confirming previous studies demonstrating lowered plasma ghrelin in obesity, ghrelin levels were lower in the obese compared with overweight women. Among the overweight, ghrelin was positively correlated with caloric intake, giving in to cravings for highly palatable foods, and a flatter diurnal cortisol slope across 3days. These relationships were non-significant among the obese group. Among overweight women, ghrelin was negatively correlated with insulin resistance, systolic blood pressure, and heart rate, and positively correlated with telomere length. Among the obese subjects, plasma ghrelin concentrations were negatively correlated with insulin resistance, but were not significantly correlated with blood pressure, heart rate or telomere length. Total plasma ghrelin and its associations with food intake, hedonic eating, and stress are decreased in obesity, providing evidence consistent with the theory that central resistance to ghrelin develops in obesity and ghrelin's function in appetite regulation may have evolved to prevent starvation in food scarcity rather than cope with modern food excess. Furthermore, ghrelin is associated with metabolic and cardiovascular health, and may have anti-aging effects, but these effects may be attenuated in obesity.

  5. Shorter sperm telomere length in association with exposure to polycyclic aromatic hydrocarbons: Results from the MARHCS cohort study in Chongqing, China and in vivo animal experiments.

    PubMed

    Ling, Xi; Zhang, Guowei; Chen, Qing; Yang, Huan; Sun, Lei; Zhou, Niya; Wang, Zhi; Zou, Peng; Wang, Xiaogang; Cui, Zhihong; Liu, Jinyi; Ao, Lin; Cao, Jia

    2016-10-01

    It has been well demonstrated that polycyclic aromatic hydrocarbons (PAHs) can cause reproductive toxicity, and shorter telomere length in sperm may be one of the factors causing male infertility. However, whether exposure to PAHs is associated with sperm telomere length (STL) has never been evaluated. The present study aimed to assess the potential association between PAHs exposure and STL, and to explore potential biomarkers that may predict the effects of low-level exposure to PAHs on human sperm. Questionnaires and biological samples were collected from 666 volunteers participating in the Male Reproductive Health in Chongqing College Students (MARHCS) cohort study in 2014. Semen parameters were measured for 656 participants, while urinary PAH metabolites, STL and sperm apoptosis were successfully measured for 492, 444 and 628 participants, respectively. The linear regression analysis revealed that increased levels of urinary 1-hydroxypyrene (1-OHPyr) and 1-hydroxynapthalene (1-OHNap) were associated with decreased STL (-0.385; 95% CI, -0.749, -0.021 for 1-OHPyr; and -0.079; 95% CI, -0.146, -0.011 for 1-OHNap). The significant negative associations remained after adjusting for potential confounders. However, no significant associations were observed between urinary PAH metabolites and semen quality or sperm apoptosis. We also administrated rats with benzo[a]pyrene (B[a]P; 0, 1, 5, and 10mg/kg) for 4weeks and found shorter STL and decreased telomerase expression in germ cells in a dose-dependent manner. In conclusion, environmental exposure to some PAHs may be associated with decreased human STL, and the in vivo animal results also demonstrate the adverse effects of B[a]P on telomere of male germ cells.

  6. Interaction of Berberine derivative with protein POT1 affect telomere function in cancer cells

    SciTech Connect

    Xiao, Nannan; Chen, Siqi; Ma, Yan; Qiu, Jun; Tan, Jia-Heng; Ou, Tian-Miao; Gu, Lian-Quan; Huang, Zhi-Shu; Li, Ding

    2012-03-16

    Highlights: Black-Right-Pointing-Pointer The protein POT1 plays an important role in telomere protection. Black-Right-Pointing-Pointer Functional POT1 was overexpressed in Escherichia coli for the first time, and purified. Black-Right-Pointing-Pointer Compound Sysu-00692 was found to be the first POT1-binding ligand. Black-Right-Pointing-Pointer Sysu-00692 could interfere with the binding activity of POT1 in vivo. Black-Right-Pointing-Pointer Sysu-00692 had inhibition on telomerase and cell proliferation. -- Abstract: The protein POT1 plays an important role in telomere protection, which is related with telomere elongation and cell immortality. The protein has been recognized as a promising drug target for cancer treatment. In the present study, we cloned, overexpressed in Escherichia coli for the first time, and purified recombinant human POT1. The protein was proved to be active through filter binding assay, FRET and CD experiments. In the initial screening for protein binding ligands using SPR, compound Sysu-00692 was found to bind well with the POT1, which was confirmed with EMSA. Its in vivo activity study showed that compound Sysu-00692 could interfere with the binding between human POT1 and the telomeric DNA through chromatin immunoprecipitation. Besides, the compound showed mild inhibition on telomerase and cell proliferation. As we know, compound Sysu-00692 is the first reported POT1-binding ligand, which could serve as a lead compound for further improvement. This work offered a potentially new approach for drug design for the treatment of cancers.

  7. Realizing the Translational Potential of Telomere Length Variation as a Tissue-Based Prognostic Marker for Prostate Cancer

    DTIC Science & Technology

    2015-10-01

    DATE: October 2015 TYPE OF REPORT: Annual PREPARED FOR: U.S. Army Medical Research and Materiel Command Fort Detrick, Maryland 21702-5012...NAME(S) AND ADDRESS(ES) 10. SPONSOR/MONITOR’S ACRONYM(S) U.S. Army Medical Research and Materiel Command Fort Detrick, Maryland 21702-5012 11...and analyze an entire prostate TMA. We demonstrated our ability to quantitate the telomere signals on a per nucleus basis in both the cancer and

  8. How current ginning processes affect fiber length uniformity index

    Technology Transfer Automated Retrieval System (TEKTRAN)

    There is a need to develop cotton ginning methods that improve fiber characteristics that are compatible with the newer and more efficient spinning technologies. A literature search produced recent studies that described how current ginning processes affect HVI fiber length uniformity index. Resul...

  9. Telomere longitudinal shortening as a biomarker for dementia status of adults with Down syndrome.

    PubMed

    Jenkins, Edmund C; Ye, Lingling; Krinsky-McHale, Sharon J; Zigman, Warren B; Schupf, Nicole; Silverman, Wayne P

    2016-03-01

    Previous studies have suggested that Alzheimer's disease (AD) causes an accelerated shortening of telomeres, the ends of chromosomes consisting of highly conserved TTAGGG repeats that, because of unidirectional 5'-3' DNA synthesis, lose end point material with each cell division. Our own previous work suggested that telomere length of T-lymphocytes might be a remarkably accurate biomarker for "mild cognitive impairment" in adults with Down syndrome (MCI-DS), a population at dramatically high risk for AD. To verify that the progression of cognitive and functional losses due to AD produced this observed telomere shortening, we have now examined sequential changes in telomere length in five individuals with Down syndrome (3F, 2M) as they transitioned from preclinical AD to MCI-DS (N = 4) or dementia (N = 1). As in our previous studies, we used PNA (peptide nucleic acid) probes for telomeres and the chromosome 2 centromere (as an "internal standard" expected to be unaffected by aging or dementia status), with samples from the same individuals now collected prior to and following development of MCI-DS or dementia. Consistent shortening of telomere length was observed over time. Further comparisons with our previous cross-sectional findings indicated that telomere lengths prior to clinical decline were similar to those of other adults with Down syndrome (DS) who have not experienced clinical decline while telomere lengths following transition to MCI-DS or dementia in the current study were comparable to those of other adults with DS who have developed MCI-DS or dementia. Taken together, findings indicate that telomere length has significant promise as a biomarker of clinical progression of AD for adults with DS, and further longitudinal studies of a larger sample of individuals with DS are clearly warranted to validate these findings and determine if and how factors affecting AD risk also influence these measures of telomere length.

  10. Leukocyte Telomere Length in Relation to 17 Biomarkers of Cardiovascular Disease Risk: A Cross-Sectional Study of US Adults

    PubMed Central

    Rehkopf, David H.; Needham, Belinda L.; Lin, Jue; Blackburn, Elizabeth H.; Zota, Ami R.; Wojcicki, Janet M.

    2016-01-01

    Background Leukocyte telomere length (LTL) is a putative biological marker of immune system age, and there are demonstrated associations between LTL and cardiovascular disease. This may be due in part to the relationship of LTL with other biomarkers associated with cardiovascular disease risk. However, the strength of associations between LTL and adiposity, metabolic, proinflammatory, and cardiovascular biomarkers has not been systematically evaluated in a United States nationally representative population. Methods and Findings We examined associations between LTL and 17 cardiovascular biomarkers, including lipoproteins, blood sugar, circulatory pressure, proinflammatory markers, kidney function, and adiposity measures, in adults ages 20 to 84 from the cross-sectional US nationally representative 1999–2002 National Health and Nutrition Examination Survey (NHANES) (n = 7,252), statistically adjusting for immune cell type distributions. We also examine whether these associations differed systematically by age, race/ethnicity, gender, education, and income. We found that a one unit difference in the following biomarkers were associated with kilobase pair differences in LTL: BMI -0.00478 (95% CI -0.00749–-0.00206), waist circumference -0.00211 (95% CI -0.00325–-0.000969), percentage of body fat -0.00516 (95% CI -0.00761–-0.0027), high density lipoprotein (HDL) cholesterol 0.00179 (95% CI 0.000571–0.00301), triglycerides -0.000285 (95% CI -0.000555–-0.0000158), pulse rate -0.00194 (95% CI -0.00317–-0.000705), C-reactive protein -0.0363 (95% CI 0.0601–-0.0124), cystatin C -0.0391 (95% CI -0.0772–-0.00107). When using clinical cut-points we additionally found associations between LTL and insulin resistance -0.0412 (95% CI -0.0685–-0.0139), systolic blood pressure 0.0455 (95% CI 0.00137–0.0897), and diastolic blood pressure -0.0674 (95% CI -0.126–-0.00889). These associations were 10%–15% greater without controlling for leukocyte cell types. There

  11. Leucocyte Telomere Length and Risk of Type 2 Diabetes Mellitus: New Prospective Cohort Study and Literature-Based Meta-Analysis

    PubMed Central

    Heydon, Emma E.; Tsimikas, Sotirios; Haun, Margot; Mayr, Agnes; Weger, Siegfried; Witztum, Joseph L.; Butterworth, Adam S.; Willeit, Johann; Kronenberg, Florian; Kiechl, Stefan

    2014-01-01

    Background Short telomeres have been linked to various age-related diseases. We aimed to assess the association of telomere length with incident type 2 diabetes mellitus (T2DM) in prospective cohort studies. Methods Leucocyte relative telomere length (RTL) was measured using quantitative polymerase chain reaction in 684 participants of the prospective population-based Bruneck Study (1995 baseline), with repeat RTL measurements performed in 2005 (n = 558) and 2010 (n = 479). Hazard ratios for T2DM were calculated across quartiles of baseline RTL using Cox regression models adjusted for age, sex, body-mass index, smoking, socio-economic status, physical activity, alcohol consumption, high-density lipoprotein cholesterol, log high-sensitivity C-reactive protein, and waist-hip ratio. Separate analyses corrected hazard ratios for within-person variability using multivariate regression calibration of repeated measurements. To contextualise findings, we systematically sought PubMed, Web of Science and EMBASE for relevant articles and pooled results using random-effects meta-analysis. Results Over 15 years of follow-up, 44 out of 606 participants free of diabetes at baseline developed incident T2DM. The adjusted hazard ratio for T2DM comparing the bottom vs. the top quartile of baseline RTL (i.e. shortest vs. longest) was 2.00 (95% confidence interval: 0.90 to 4.49; P = 0.091), and 2.31 comparing the bottom quartile vs. the remainder (1.21 to 4.41; P = 0.011). The corresponding hazard ratios corrected for within-person RTL variability were 3.22 (1.27 to 8.14; P = 0.014) and 2.86 (1.45 to 5.65; P = 0.003). In a random-effects meta-analysis of three prospective cohort studies involving 6,991 participants and 2,011 incident T2DM events, the pooled relative risk was 1.31 (1.07 to 1.60; P = 0.010; I2 = 69%). Conclusions/Interpretation Low RTL is independently associated with the risk of incident T2DM. To avoid regression dilution biases in

  12. Lengths of Orthologous Prokaryotic Proteins Are Affected by Evolutionary Factors

    PubMed Central

    Tatarinova, Tatiana; Dien Bard, Jennifer; Cohen, Irit

    2015-01-01

    Proteins of the same functional family (for example, kinases) may have significantly different lengths. It is an open question whether such variation in length is random or it appears as a response to some unknown evolutionary driving factors. The main purpose of this paper is to demonstrate existence of factors affecting prokaryotic gene lengths. We believe that the ranking of genomes according to lengths of their genes, followed by the calculation of coefficients of association between genome rank and genome property, is a reasonable approach in revealing such evolutionary driving factors. As we demonstrated earlier, our chosen approach, Bubble-sort, combines stability, accuracy, and computational efficiency as compared to other ranking methods. Application of Bubble Sort to the set of 1390 prokaryotic genomes confirmed that genes of Archaeal species are generally shorter than Bacterial ones. We observed that gene lengths are affected by various factors: within each domain, different phyla have preferences for short or long genes; thermophiles tend to have shorter genes than the soil-dwellers; halophiles tend to have longer genes. We also found that species with overrepresentation of cytosines and guanines in the third position of the codon (GC3 content) tend to have longer genes than species with low GC3 content. PMID:26114113

  13. Lengths of Orthologous Prokaryotic Proteins Are Affected by Evolutionary Factors.

    PubMed

    Tatarinova, Tatiana; Salih, Bilal; Dien Bard, Jennifer; Cohen, Irit; Bolshoy, Alexander

    2015-01-01

    Proteins of the same functional family (for example, kinases) may have significantly different lengths. It is an open question whether such variation in length is random or it appears as a response to some unknown evolutionary driving factors. The main purpose of this paper is to demonstrate existence of factors affecting prokaryotic gene lengths. We believe that the ranking of genomes according to lengths of their genes, followed by the calculation of coefficients of association between genome rank and genome property, is a reasonable approach in revealing such evolutionary driving factors. As we demonstrated earlier, our chosen approach, Bubble-sort, combines stability, accuracy, and computational efficiency as compared to other ranking methods. Application of Bubble Sort to the set of 1390 prokaryotic genomes confirmed that genes of Archaeal species are generally shorter than Bacterial ones. We observed that gene lengths are affected by various factors: within each domain, different phyla have preferences for short or long genes; thermophiles tend to have shorter genes than the soil-dwellers; halophiles tend to have longer genes. We also found that species with overrepresentation of cytosines and guanines in the third position of the codon (GC3 content) tend to have longer genes than species with low GC3 content.

  14. Nuclear envelope attachment is not necessary for telomere function in fission yeast.

    PubMed

    Chikashige, Yuji; Haraguchi, Tokuko; Hiraoka, Yasushi

    2010-01-01

    Inner nuclear membrane (INM) proteins can be important for positioning chromosomes within the nucleus. Little is known about INM proteins in the fission yeast Schizossacharomayces pombe. Telomeres are the most obvious chromosomal sites that are anchored to the nuclear envelope in this organism. A group of proteins that tether telomeres to the spindle-pole body (SPB) during meiotic prophase, such as Bqt1, Bqt2 and Sad1, has been identified previously, but proteins for anchoring telomeres to the nuclear envelope in vegetative cells have not been identified until recently. A recent report demonstrates that Bqt3 and Bqt4 are INM proteins that affect nuclear positioning of telomeres in vegetative cells, and consequently affect the telomere clustering in meiotic prophase. Interestingly, in the absence of Bqt4, telomeres are separated from the nuclear envelope but telomere silencing and telomere length are properly regulated. An important implication of these results is that the functional integrity of telomeres is maintained independently of their connection to the nuclear envelope.

  15. Telomere-interactive agents affect proliferation rates and induce chromosomal destabilization in sea urchin embryos.

    PubMed

    Izbicka, E; Nishioka, D; Marcell, V; Raymond, E; Davidson, K K; Lawrence, R A; Wheelhouse, R T; Hurley, L H; Wu, R S; Von Hoff, D D

    1999-08-01

    Cationic porphyrins, which interact with guanine quadruplex (G4) telomeric folds, inhibit telomerase activity in human tumor cells. In this study, we have further examined effects of porphyrins and other telomere- and telomerase-interactive agents on proliferation rates and chromosome stability in a novel in vivo model, developing sea urchin embryos. We studied two porphyrins: (i) TMPyP4, a potent telomerase inhibitor; and (ii) TMPyP2, an isomer of TMPyP4 and an inefficient telomerase inhibitor, azidothymine (AZT), the reverse transcriptase inhibitor, antisense phosphorothioate oligonucleotide to telomerase RNA (TAG6) and a control scrambled sequence (ODN). TMPyP4, AZT and TAG6 (but not TMPyP2 or ODN) decreased the rates of cell proliferation and increased the percentage of cells trapped in mitosis. Nuclear localization of TAG6, but not of ODN, was demonstrated with 5'-fluoresceinated analogs of TAG6 and ODN. Formation of elongated chromosomes incapable of separating in anaphase, induced by TMPyP4, AZT and TAG6, closely resembled phenotypes resulting from telomerase template mutation or dominant negative TRF2 allele. Our data suggest that G4-interactive agents exert their antiproliferative effects via chromosomal destabilization and warrant their further development as valuable anticancer tools.

  16. Telomere Length Is Not Related to Established Cardiovascular Risk Factors but Does Correlate with Red and White Blood Cell Counts in a German Blood Donor Population

    PubMed Central

    Kelsch, Reinhard; Jäger, Kathrin; Brüggmann, Nina; van der Harst, Pim; Walter, Michael

    2015-01-01

    Telomere length (TL) is considered a marker of biological aging and has been associated with the presence of various coronary risk factors in patients. Much less is known about the relationships between TL and classic coronary risk factors in other populations. We measured TL in peripheral blood leukocytes of 343 middle-aged blood donors (mean age 40.2 ± 12.4 years; 201 men, 142 women) using quantitative polymerase chain reaction. Median TL was 0.86 (range: 0.48–1.85) relative TL units. In linear regression analyses with natural log-transformed T to S ratio as the dependent variable, there was a significant association with age (per year: beta = -0.007, p<0.001) and sex (males vs. females: beta = 0.075, p = 0.007) with longer telomeres in men. After adjusting for these two variables, we observed no association of TL with classic coronary risk factors including cholesterol (p = 0.36), triglyceride (p = 0.09), HDL-cholesterol (p = 0.26), LDL-cholesterol (p = 0.36), smoking (p = 0.97), and personal (p = 0.46) or family history (p = 0.63) of cardiovascular disease. However, we did find a significant positive association with white (p = 0.011) and red blood cell count (p = 0.031), hemoglobin (p = 0.014) and hematocrit (p = 0.013); we also found a borderline positive association with thrombocytes (p = 0.074). Positive associations remained significant for hemoglobin (p = 0.017), hematocrit (p = 0.023), and leukocytes (p = 0.009) in a subgroup with no reported vascular disease; associations were of borderline significance for erythrocytes (p = 0.053) and thrombocytes (p = 0.088) in this subgroup. The data do not support the concept that classic coronary risk factors contribute to telomere attrition in a blood donor population. However, telomere attrition may be a marker for reduced proliferation reserve in hematopoietic progenitor cells. PMID:26445269

  17. The functional polymorphism rs73598374:G>A (p.Asp8Asn) of the ADA gene is associated with telomerase activity and leukocyte telomere length.

    PubMed

    Concetti, Fabio; Carpi, Francesco M; Nabissi, Massimo; Picciolini, Matteo; Santoni, Giorgio; Napolioni, Valerio

    2015-02-01

    Recent evidence demonstrated a relevant role of adenosine deaminase (ADA) in replicative senescence of T cells through its capacity to modulate telomerase activity (TA). Herein, we tested the impact of the functional polymorphism ADA rs73598374:G>A (c.22G>A, p.Asp8Asn) on telomere biology, by measuring TA and leukocyte telomere length (LTL) in healthy subjects selected according to rs73598374 genotype. rs73598374-A carriers showed lower TA (P=0.019) and shorter LTL (P=0.003), respectively, compared to G/G carriers. rs73598374-A carriers showed a stronger cross-sectional age reduction of LTL (r=-0.314, P=0.005) compared to G/G carriers (r=-0.243, P=0.022). The reduced ADA activity associated to rs73598374-A variant predisposes those carriers to display higher levels of adenosine compared to G/G carriers. Consequently, it may lead to an accelerated process of replicative senescence, causing a stronger reduction of TA and in turn shorter LTL. In conclusion, the crucial role played by replicative senescence of the immune system in several human diseases and in the aging process underscores the relevance of the present findings and also spurs interest into the possible involvement of rs73598374 in shaping the susceptibility to several age-related diseases.

  18. Childhood Personality, Betrayal Trauma, and Leukocyte Telomere Length in Adulthood: A Lifespan Perspective on Conscientiousness and Betrayal Traumas as Predictors of a Biomarker of Cellular Aging.

    PubMed

    Edmonds, Grant W; Hampson, Sarah E; Côté, Hélène C F; Hill, Patrick L; Klest, Bridget

    2016-01-01

    Conscientiousness is associated with longevity. As such, identifying the biological pathways linking personality to mortality is important. This study employs longitudinal data spanning >40 years to test prospective associations with Leukocyte Telomere Length (LTL), a potential marker of cellular aging. Because telomeres shorten over time, and are sensitive to oxidative stress, shorter LTL may reflect cumulative damage associated with negative health behaviors and past stressful events. We investigated childhood conscientiousness as a protective factor, expecting an association with longer LTL in adulthood, possibly reflecting slower LTL shortening. Potential lifespan pathways involving childhood trauma, smoking behaviors, and Body Mass Index (BMI) were explored. Childhood conscientiousness showed a small raw association with LTL (r = .08, p = .04), although this effect did not persist when controlling for age and sex. Despite this lack of a direct effect on LTL, we detected an indirect effect operating jointly through BMI and smoking. Higher rates of childhood betrayal trauma were associated with shorter LTL. Contrary to our hypothesis that conscientiousness would buffer this effect, we found evidence for an interaction with childhood betrayal traumas where the association between childhood betrayal traumas and LTL was larger for those higher on conscientiousness in childhood.

  19. Telomere dynamics in parasitic great spotted cuckoos and their magpie hosts.

    PubMed

    Soler, J J; Ruiz Castellano, C; Martínez-de la Puente, J; Tomás, G; Ruiz-Rodríguez, M; Figuerola, J

    2015-09-01

    Although little is known on the impact of environment on telomere length dynamics, it has been suggested to be affected by stress, lifestyle and/or life-history strategies of animals. We here compared telomere dynamics in erythrocytes of hatchlings and fledglings of the brood parasite great spotted cuckoos (Clamator glandarius) and of magpies (Pica pica), their main host in Europe. In magpie chicks, telomere length decreased from hatching to fledging, whereas no significant change in telomere length of great spotted cuckoo chicks was found. Moreover, we found interspecific differences in the association between laying date and telomere shortening. Interspecific differences in telomere shortening were interpreted as a consequence of differences in lifestyle and life-history characteristics of magpies and great spotted cuckoos. In comparison with magpies, cuckoos experience reduced sibling competition and higher access to resources and, consequently, lower stressful environmental conditions during the nestling phase. These characteristics also explain the associations between telomere attrition and environmental conditions (i.e. laying date) for magpies and the absence of association for great spotted cuckoos. These results therefore fit expectations on telomere dynamics derived from interspecific differences in lifestyle and life history of brood parasites and their bird hosts.

  20. Realizing the Translational Potential of Telomere Length Variation as a Tissue-Based Prognostic Marker for Prostate Cancer

    DTIC Science & Technology

    2013-10-01

    References…………………………………………………………………………….2 Appendices……………………………………………………………………………2 1 INTRODUCTION: Currently used clinico ...prostate cancer recurrence nested case -control study (Brady study; in part with prior DOD funding to Dr. Platz at Hopkins) and associated tissue...524 cases and 524 controls) and cut and mounted the sections (Task 4b completed) for staining for telomere-specific FISH, cytokeratin 903

  1. Leukocyte Telomere Length is Associated With Serum Vitamin B12 and Homocysteine Levels in Older Adults With the Presence of Systemic Inflammation.

    PubMed

    Shin, Chol; Baik, Inkyung

    2016-01-01

    Folate, vitamin B12, and homocysteine (HCY) are involved in the metabolism of nucleic acid precursors and it has been hypothesized that they also influence telomere length, a biomarker of aging. However, previous studies have reported inconsistent findings, and data for older adults are limited. Our study aimed to evaluate associations between leukocyte telomere length (LTL) and serum folate, vitamin B12, and HCY levels among adults aged 55 years and over. In a cross-sectional study in 798 men and women aged 55-79 years, serum folate, vitamin B12, and HCY levels were measured using chemiluminescent immunometric assays, and relative LTL was assessed using quantitative real-time polymerase chain reaction. To evaluate associations between LTL and serum folate, vitamin B12, and HCY levels, multiple linear regression models were used. In multiple models adjusted for age, sex, serum high sensitive C-reactive protein (hs-CRP) levels, and other potential confounding factors, we found no association between LTL and serum folate, vitamin B12, and HCY levels. However, we did find a significant inverse association between HCY levels and LTL in participants with serum hs-CRP levels of ≥ 2 mg/L (p < 0.05). Moreover, there was a trend toward an association between HCY and vitamin B12 levels in these individuals (p = 0.08). In those with serum hs-CRP levels of < 2 mg/L, HCY was inversely associated with vitamin B12 levels (p < 0.001) and had no association with LTL. Our findings suggest that increased serum HCY levels, when combined with the presence of systemic inflammation, may play a role in accelerating biological aging.

  2. Cellular Aging and Restorative Processes: Subjective Sleep Quality and Duration Moderate the Association between Age and Telomere Length in a Sample of Middle-Aged and Older Adults

    PubMed Central

    Cribbet, Matthew R.; Carlisle, McKenzie; Cawthon, Richard M.; Uchino, Bert N.; Williams, Paula G.; Smith, Timothy W.; Gunn, Heather E.; Light, Kathleen C.

    2014-01-01

    Study Objectives: To examine whether subjective sleep quality and sleep duration moderate the association between age and telomere length (TL). Design: Participants completed a demographic and sleep quality questionnaire, followed by a blood draw. Setting: Social Neuroscience Laboratory. Participants: One hundred fifty-four middle-aged to older adults (age 45-77 y) participated. Participants were excluded if they were on immunosuppressive treatment and/or had a disease with a clear immunologic (e.g., cancer) component. Interventions: N/A. Measurements and Results: Subjective sleep quality and sleep duration were assessed using the Pittsburgh Sleep Quality Index (PSQI) and TL was determined using peripheral blood mononuclear cells (PBMCs). There was a significant first-order negative association between age and TL. Age was also negatively associated with the self-reported sleep quality item and sleep duration component of the PSQI. A significant age × self-reported sleep quality interaction revealed that age was more strongly related to TL among poor sleepers, and that good sleep quality attenuated the association between age and TL. Moreover, adequate subjective sleep duration among older adults (i.e. greater than 7 h per night) was associated with TL comparable to that in middle-aged adults, whereas sleep duration was unrelated to TL for the middle-aged adults in our study. Conclusions: The current study provides evidence for an association between sleep quality, sleep duration, and cellular aging. Among older adults, better subjective sleep quality was associated with the extent of cellular aging, suggesting that sleep duration and sleep quality may be added to a growing list of modifiable behaviors associated with the adverse effects of aging. Citation: Cribbet MR; Carlisle M; Cawthon RM; Uchino BN; Williams PG; Smith TW; Gunn HE; Light KC. Cellular aging and restorative processes: subjective sleep quality and duration moderate the association between age and

  3. Telomere attrition and diabetes mellitus.

    PubMed

    Tamura, Yoshiaki; Takubo, Kaiyo; Aida, Junko; Araki, Atsushi; Ito, Hideki

    2016-03-01

    Type 2 diabetes mellitus (DM) is a disease characterized by dysfunction of various organs. Recent studies have shown a close relationship between DM and telomere attrition in leukocytes. In patients with DM or impaired glucose tolerance, excessive oxidative stress induces damage to telomeres and shortens their length. Furthermore, it is suggested that telomere length is a good surrogate marker for mortality and diabetic complications in DM patients. We recently found that telomere length in pancreatic β-cells is also shortened in DM patients, potentially leading to an impaired capacity for proliferation and insulin secretion, and accelerated cell death. In contrast, leukocyte telomere length has also been reported in patients with obesity or insulin resistance, both of which are frequently associated with type 2 DM. In an animal model, it has been shown that telomere attrition in adipose tissue induces insulin resistance. Taken together, the available data suggest that hyperglycemia, oxidative stress, and telomere attrition in pancreatic β-cells and adipocytes create a vicious cycle that underlies the pathophysiology of type 2 DM. Inhibition of telomere attrition in various organs, including pancreatic β-cells, could be a new approach for preventing the progression of DM and its complications.

  4. Super-telomeres in transformed human fibroblasts.

    PubMed

    Chiodi, Ilaria; Belgiovine, Cristina; Zongaro, Samantha; Ricotti, Roberta; Horard, Beatrice; Lossani, Andrea; Focher, Federico; Gilson, Eric; Giulotto, Elena; Mondello, Chiara

    2013-08-01

    Telomere length maintenance is critical for organisms' long-term survival and cancer cell proliferation. Telomeres are kept within species-specific length ranges by the interplay between telomerase activity and telomeric chromatin organization. In this paper, we exploited telomerase immortalized human fibroblasts (cen3tel) that gradually underwent neoplastic transformation during culture propagation to study telomere composition and length regulation during the transformation process. Just after telomerase catalytic subunit (hTERT) expression, cen3tel telomeres shortened despite the presence of telomerase activity. At a later stage and concomitantly with transformation, cells started elongating telomeres, which reached a mean length greater than 100kb in about 900 population doublings. Super-telomeres were stable and compatible with cell growth and tumorigenesis. Telomere extension was associated with increasing levels of telomerase activity that were linked to the deregulation of endogenous telomerase RNA (hTERC) and exogenous telomerase reverse transcriptase (hTERT) expression. Notably, the increase in hTERC levels paralleled the increase in telomerase activity, suggesting that this subunit plays a role in regulating enzyme activity. Telomeres ranging in length between 10 and more than 100kb were maintained in an extendible state although TRF1 and TRF2 binding increased with telomere length. Super-telomeres neither influenced subtelomeric region global methylation nor the expression of the subtelomeric gene FRG1, attesting the lack of a clear-cut relationship between telomere length, subtelomeric DNA methylation and expression in human cells. The cellular levels of the telomeric proteins hTERT, TRF1, TRF2 and Hsp90 rose with transformation and were independent of telomere length, pointing to a role of these proteins in tumorigenesis.

  5. Longer telomeres are associated with cancer risk in MMR-proficient hereditary non-polyposis colorectal cancer.

    PubMed

    Seguí, Nuria; Guinó, Elisabet; Pineda, Marta; Navarro, Matilde; Bellido, Fernando; Lázaro, Conxi; Blanco, Ignacio; Moreno, Victor; Capellá, Gabriel; Valle, Laura

    2014-01-01

    Aberrant telomere length measured in blood has been associated with increased risk of several cancer types. In the field of hereditary non-polyposis colorectal cancer (CRC), and more particularly in Lynch syndrome, caused by germline mutations in the mismatch repair (MMR) genes, we recently found that cancer-affected MMR gene mutation carriers had shorter telomeres and more pronounced shortening of telomere length with age than controls and unaffected MMR gene mutation carriers. Here we evaluate blood telomere length in MMR-proficient hereditary non-polyposis CRC, i.e. familial CRC type X (fCRC-X). A total of 57 cancer-affected and 57 cancer-free individuals from 34 Amsterdam-positive fCRC-X families were analyzed and compared to the data previously published on 144 cancer-affected and 100 cancer-free MMR gene mutation carriers, and 234 controls. Relative telomere length was measured using a monochrome multiplex quantitative PCR method, following strict measures to avoid sources of bias and adjusting by age. Despite the retrospective nature of our study, the results show that longer telomeres associate with cancer risk in fCRC-X, thus identifying different patterns of telomere length according to the status of the MMR system.

  6. Exposure to oxychlordane is associated with shorter telomeres in arctic breeding kittiwakes.

    PubMed

    Blévin, Pierre; Angelier, Frédéric; Tartu, Sabrina; Ruault, Stéphanie; Bustamante, Paco; Herzke, Dorte; Moe, Børge; Bech, Claus; Gabrielsen, Geir Wing; Bustnes, Jan Ove; Chastel, Olivier

    2016-09-01

    Telomeres are DNA-protein complexes located at the end of chromosomes, which play an important role in maintaining the genomic integrity. Telomeres shorten at each cell division and previous studies have shown that telomere length is related to health and lifespan and can be affected by a wide range of environmental factors. Among them, some persistent organic pollutants (POPs) have the potential to damage DNA. However, the effect of POPs on telomeres is poorly known for wildlife. Here, we investigated the relationships between some legacy POPs (organochlorine pesticides and polychlorobiphenyls) and telomere length in breeding adult black-legged kittiwakes (Rissa tridactyla), an arctic seabird species. Our results show that among legacy POPs, only blood concentration of oxychlordane, the major metabolite of chlordane mixture, is associated with shorter telomere length in females but not in males. This suggests that female kittiwakes could be more sensitive to oxychlordane, potentially explaining the previously reported lower survival rate in most oxychlordane-contaminated kittiwakes from the same population. This study is the first to report a significant and negative relationship between POPs and telomere length in a free-living bird and highlights sex-related susceptibility to banned pesticides.

  7. Associations of cadmium and lead exposure with leukocyte telomere length: findings from National Health and Nutrition Examination Survey, 1999-2002.

    PubMed

    Zota, Ami R; Needham, Belinda L; Blackburn, Elizabeth H; Lin, Jue; Park, Sung Kyun; Rehkopf, David H; Epel, Elissa S

    2015-01-15

    Cadmium and lead are ubiquitous environmental contaminants that might increase risks of cardiovascular disease and other aging-related diseases, but their relationships with leukocyte telomere length (LTL), a marker of cellular aging, are poorly understood. In experimental studies, they have been shown to induce telomere shortening, but no epidemiologic study to date has examined their associations with LTL in the general population. We examined associations of blood lead and cadmium (n = 6,796) and urine cadmium (n = 2,093) levels with LTL among a nationally representative sample of US adults from the National Health and Nutrition Examination Survey (1999-2002). The study population geometric mean concentrations were 1.67 µg/dL (95% confidence interval (CI): 1.63, 1.70) for blood lead, 0.44 µg/L (95% CI: 0.42, 0.47) for blood cadmium, and 0.28 µg/L (95% CI: 0.27, 0.30) for urine cadmium. After adjustment for potential confounders, the highest (versus lowest) quartiles of blood and urine cadmium were associated with -5.54% (95% CI: -8.70, -2.37) and -4.50% (95% CI: -8.79, -0.20) shorter LTLs, respectively, with evidence of dose-response relationship (P for trend < 0.05). There was no association between blood lead concentration and LTL. These findings provide further evidence of physiological impacts of cadmium at environmental levels and might provide insight into biological pathways underlying cadmium toxicity and chronic disease risks.

  8. Telomeres, aging, and plants: from weeds to Methuselah - a mini-review.

    PubMed

    Watson, J Mathew; Riha, Karel

    2011-01-01

    The process of aging affects most, if not all, living creatures, from single celled yeast to multi-cellular mammals and plants. The DNA end-replication problem along with the tissue-limited expression of telomerase led to the telomere hypothesis of aging, where limits on cellular proliferation are genetically encoded in the lengths of a cell's telomeres. Support for this hypothesis has been found in several organisms, from worms to mice to humans. While development, and therefore the process of aging, is quite different between plants and animals, telomere biology between these organisms is fundamentally the same. Do telomeres, then, also play the role of a molecular clock in plants? In this review, we explore the current knowledge of the relationship between telomeres and aging in plants in three specific cases: leaf senescence, aging of perennials and seed longevity.

  9. Therapeutic inhibition of TRF1 impairs the growth of p53-deficient K-RasG12V-induced lung cancer by induction of telomeric DNA damage.

    PubMed

    García-Beccaria, María; Martínez, Paula; Méndez-Pertuz, Marinela; Martínez, Sonia; Blanco-Aparicio, Carmen; Cañamero, Marta; Mulero, Francisca; Ambrogio, Chiara; Flores, Juana M; Megias, Diego; Barbacid, Mariano; Pastor, Joaquín; Blasco, Maria A

    2015-07-01

    Telomeres are considered anti-cancer targets, as telomere maintenance above a minimum length is necessary for cancer growth. Telomerase abrogation in cancer-prone mouse models, however, only decreased tumor growth after several mouse generations when telomeres reach a critically short length, and this effect was lost upon p53 mutation. Here, we address whether induction of telomere uncapping by inhibition of the TRF1 shelterin protein can effectively block cancer growth independently of telomere length. We show that genetic Trf1 ablation impairs the growth of p53-null K-Ras(G12V)-induced lung carcinomas and increases mouse survival independently of telomere length. This is accompanied by induction of telomeric DNA damage, apoptosis, decreased proliferation, and G2 arrest. Long-term whole-body Trf1 deletion in adult mice did not impact on mouse survival and viability, although some mice showed a moderately decreased cellularity in bone marrow and blood. Importantly, inhibition of TRF1 binding to telomeres by small molecules blocks the growth of already established lung carcinomas without affecting mouse survival or tissue function. Thus, induction of acute telomere uncapping emerges as a potential new therapeutic target for lung cancer.

  10. Factors affecting intrauterine contraceptive device performance. I. Endometrial cavity length.

    PubMed

    Hasson, H M; Berger, G S; Edelman, D A

    1976-12-15

    The relationship of endometrial cavity length to intrauterine contraceptive device (IUD) performance was evaluated in 319 patients wearing three types of devices. The rate of events, defined as pregnancy, expulsion, or medical removal, increased significantly when the length of the IUD was equal to, exceeded, or was shorter by two or more centimeters than the length of the endometrial cavity. Total uterine length was found to be a less accurate prognostic indicator of IUD performance than endometrial cavity length alone.

  11. Cinnamaldehyde and eugenol change the expression folds of AKT1 and DKC1 genes and decrease the telomere length of human adipose-derived stem cells (hASCs): An experimental and in silico study

    PubMed Central

    Absalan, Abdorrahim; Mesbah-Namin, Seyed Alireza; Tiraihi, Taki; Taheri, Taher

    2017-01-01

    Objective(s): To investigate the effect of cinnamaldehyde and eugenol on the telomere-dependent senescence of stem cells. In addition, to search the probable targets of mentioned phytochemicals between human telomere interacting proteins (TIPs) using in silico studies. Materials and Methods: Human adipose derived stem cells (hASCs) were studied under treatments with 2.5 µM/ml cinnamaldehyde, 0.1 µg/ml eugenol, 0.01% DMSO or any additive. The expression of TERT, AKT1 and DKC1 genes and the telomere length were assessed over 48-hr treatment. In addition, docking study was conducted to show probable ways through which phytochemicals interact with TIPs. Results: Treated and untreated hASCs had undetectable TERT expression, but they had different AKT1 and DKC1 expression levels (CI=0.95; P<0.05). The telomere lengths were reduced in phytochemicals treated with hASCs when compared with the untreated cells (P<0.05). Docking results showed that the TIPs might be the proper targets for cinnamaldehyde and eugenol. Data mining showed there are many targets for cinnamaldehyde and eugenol in the intracellular environment. Conclusion: The general effect of cinnamaldehyde and eugenol is their induction of stem cell senescence. Therefore, they could be applicable as chemo-preventive or antineoplastic agents. PMID:28392905

  12. 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

  13. Telomere Length, Long-Term Black Carbon Exposure, and Cognitive Function in a Cohort of Older Men: The VA Normative Aging Study

    PubMed Central

    Colicino, Elena; Wilson, Ander; Frisardi, Maria Chiara; Prada, Diddier; Power, Melinda C.; Hoxha, Mirjam; Dioni, Laura; Spiro, Avron; Vokonas, Pantel S.; Weisskopf, Marc G.; Schwartz, Joel D.; Baccarelli, Andrea A.

    2016-01-01

    Background: Long-term air pollution exposure has been associated with age-related cognitive impairment, possibly because of enhanced inflammation. Leukocytes with longer telomere length (TL) are more responsive to inflammatory stimuli, yet TL has not been evaluated in relation to air pollution and cognition. Objectives: We assessed whether TL modifies the association of 1-year exposure to black carbon (BC), a marker of traffic-related air pollution, with cognitive function in older men, and we examined whether this modification is independent of age and of C-reactive protein (CRP), a marker of inflammation. Methods: Between 1999 and 2007, we conducted 1–3 cognitive examinations of 428 older men in the Veterans Affairs (VA) Normative Aging Study. We used covariate-adjusted repeated-measure logistic regression to estimate associations of 1-year BC exposure with relative odds of being a low scorer (≤ 25) on the Mini-Mental State Examination (MMSE), which is a proxy of poor cognition. Confounders included age, CRP, and lifestyle and sociodemographic factors. Results: Each doubling in BC level was associated with 1.57 (95% CI: 1.20, 2.05) times higher odds of low MMSE scores. The BC-MMSE association was greater only among individuals with longer blood TL (5th quintile) (OR = 3.23; 95% CI: 1.37, 7.59; p = 0.04 for BC-by-TL-interaction). TL and CRP were associated neither with each other nor with MMSE. However, CRP modified the BC-MMSE relationship, with stronger associations only at higher CRP (5th quintile) and reference TL level (1st quintile) (OR = 2.68; 95% CI: 1.06, 6.79; p = 0.04 for BC-by-CRP-interaction). Conclusions: TL and CRP levels may help predict the impact of BC exposure on cognitive function in older men. Citation: Colicino E, Wilson A, Frisardi MC, Prada D, Power MC, Hoxha M, Dioni L, Spiro A III, Vokonas PS, Weisskopf MG, Schwartz JD, Baccarelli AA. 2017. Telomere length, long-term black carbon exposure, and cognitive function in a cohort of older

  14. Cross-sectional Associations between Exposure to Persistent Organic Pollutants and Leukocyte Telomere Length among U.S. Adults in NHANES, 2001–2002

    PubMed Central

    Mitro, Susanna D.; Birnbaum, Linda S.; Needham, Belinda L.; Zota, Ami R.

    2015-01-01

    Background: Exposure to persistent organic pollutants (POPs) such as dioxins, furans, and polychlorinated biphenyls (PCBs) may influence leukocyte telomere length (LTL), a biomarker associated with chronic disease. In vitro research suggests dioxins may bind to the aryl hydrocarbon receptor (AhR) and induce telomerase activity, which elongates LTL. However, few epidemiologic studies have investigated associations between POPs and LTL. Objectives: We examined the association between 18 PCBs, 7 dioxins, and 9 furans and LTL among 1,330 U.S. adults from NHANES 2001–2002. Methods: We created three summed POP metrics based on toxic equivalency factor (TEF), a potency measure including affinity for the AhR: a) non–dioxin-like PCBs (composed of 10 non–dioxin-like PCBs; no AhR affinity and no TEF); b) non-ortho PCBs (composed of 2 non–ortho-substituted PCBs with high TEFs); and c) toxic equivalency (TEQ) (composed of 7 dioxins, 9 furans, 2 non–ortho-substituted PCBs, and 6 mono–ortho-substituted PCBs; weighted by TEF). We tested the association between each metric and LTL using linear regression, adjusting for demographics, blood cell count and distribution, and another metric with a different TEF (i.e., non-ortho PCBs and TEQ adjusted for non–dioxin-like PCBs; non–dioxin-like PCBs adjusted for non-ortho PCBs). Results: In adjusted models, each doubling of serum concentrations of non-ortho PCBs and TEQ was associated with 3.74% (95% CI: 2.10, 5.40) and 5.29% (95% CI: 1.66, 9.05) longer LTLs, respectively. Compared with the lowest quartile, the highest quartile of exposure was associated with 9.16% (95% CI: 2.96, 15.73) and 7.84% (95% CI: –0.53, 16.92) longer LTLs, respectively. Non–dioxin-like PCBs were not associated with LTL. Conclusions: POPs with high TEFs and AhR affinity were associated with longer LTL. Because many dioxin-associated cancers are also associated with longer LTL, these results may provide insight into the mechanisms underlying PCB

  15. Telomeres and Telomerase in Cardiovascular Diseases

    PubMed Central

    Yeh, Jih-Kai; Wang, Chao-Yung

    2016-01-01

    Telomeres are tandem repeat DNA sequences present at the ends of each eukaryotic chromosome to stabilize the genome structure integrity. Telomere lengths progressively shorten with each cell division. Inflammation and oxidative stress, which are implicated as major mechanisms underlying cardiovascular diseases, increase the rate of telomere shortening and lead to cellular senescence. In clinical studies, cardiovascular risk factors such as smoking, obesity, sedentary lifestyle, and hypertension have been associated with short leukocyte telomere length. In addition, low telomerase activity and short leukocyte telomere length have been observed in atherosclerotic plaque and associated with plaque instability, thus stroke or acute myocardial infarction. The aging myocardium with telomere shortening and accumulation of senescent cells limits the tissue regenerative capacity, contributing to systolic or diastolic heart failure. In addition, patients with ion-channel defects might have genetic imbalance caused by oxidative stress-related accelerated telomere shortening, which may subsequently cause sudden cardiac death. Telomere length can serve as a marker for the biological status of previous cell divisions and DNA damage with inflammation and oxidative stress. It can be integrated into current risk prediction and stratification models for cardiovascular diseases and can be used in precise personalized treatments. In this review, we summarize the current understanding of telomeres and telomerase in the aging process and their association with cardiovascular diseases. In addition, we discuss therapeutic interventions targeting the telomere system in cardiovascular disease treatments. PMID:27598203

  16. Telomeres, A Busy Platform for Cell Signaling

    PubMed Central

    Gardano, Laura; Pucci, Fabio; Christian, Larissa; Le Bihan, Thierry; Harrington, Lea

    2013-01-01

    Telomeres are the terminal structures at the ends of linear chromosomes that represent a solution to the end replication problem. Specific binding of the six-protein subunit complex shelterin to telomeric, repetitive TTAGGG DNA sequences contributes to the stable architecture and maintenance of telomeres. Proteins involved in the DNA damage response are also localized at telomeres, and play a role in the surveillance and maintenance of telomere integrity. The enzyme responsible for telomere extension is telomerase, a ribonucleoprotein with reverse transcriptase activity. In the absence of telomerase, telomeres shorten to a length threshold that triggers the DNA damage response and replicative senescence. Here, we will summarize the latest findings concerning vertebrate telomere structure and epigenetics, and we present data regarding the impact of short telomeres upon cell signaling. In particular, in murine embryonic stem cells lacking telomerase, we found that distribution of cytosolic/nuclear β-catenin, a key component of the Wnt signaling pathway, changes when telomeres become critically short. We discuss implications and future perspectives of the effect of epigenetic modifications and/or conformational changes of telomeres on cell metabolism and signaling networks. Such an analysis may unveil potential therapeutic targets for pathologies like cancer, where the integrity of telomeres is altered. PMID:23772418

  17. Telomere Length and CCL11 Levels are Associated With Gray Matter Volume and Episodic Memory Performance in Schizophrenia: Evidence of Pathological Accelerated Aging.

    PubMed

    Czepielewski, Leticia Sanguinetti; Massuda, Raffael; Panizzutti, Bruna; Grun, Lucas Kich; Barbé-Tuana, Florencia María; Teixeira, Antonio Lucio; Barch, Deanna M; Gama, Clarissa S

    2017-02-22

    Schizophrenia (SZ) is associated with increased somatic morbidity and mortality, in addition to cognitive impairments similar to those seen in normal aging, which may suggest that pathological accelerated aging occurs in SZ. Therefore, we aim to evaluate the relationships of age, telomere length (TL), and CCL11 (aging and inflammatory biomarkers, respectively), gray matter (GM) volume and episodic memory performance in individuals with SZ compared to healthy controls (HC). One hundred twelve participants (48 SZ and 64 HC) underwent clinical and memory assessments, structural MRI, and had their peripheral blood drawn for biomarkers analysis. Comparisons of group means and correlations were performed. Participants with SZ had decreased TL and GM volume, increased CCL11, and worse memory performance compared to HC. In SZ, shorter TL was related to increased CCL11, and both biomarkers were related to reduced GM volume, all of which were related to worse memory performance. Older age was only associated with reduced GM, but longer duration of illness was related with all the aforementioned variables. Younger age of disease onset was associated with increased CCL11 levels and worse memory performance. In HC, there were no significant correlations except between memory and GM. Our results are consistent with the hypothesis of accelerated aging in SZ. These results may indicate that it is not age itself, but the impact of the disease associated with a pathological accelerated aging that leads to impaired outcomes in SZ.

  18. Socioeconomic Factors and Leukocyte Telomere Length In A Multi-Ethnic Sample: Findings From The Multi-Ethnic Study of Atherosclerosis (MESA)

    PubMed Central

    Carroll, Judith E.; Diez-Roux, Ana V.; Adler, Nancy E.; Seeman, Teresa E.

    2012-01-01

    Previous findings have linked lower socioeconomic status (SES) with elevated morbidity and mortality. Leukocyte telomere length (LTL), which also has been associated with age-related disease morbidity and mortality, is a marker of aging at the cellular level, making it a valuable early biomarker of risk and an indicator of biological age. It is hypothesized that SES will be associated with LTL, indicating that SES influences disease risk by accelerating biological aging. In the present sample we test for associations of childhood SES and adult SES (i.e. education, income, home ownership) with LTL, and examine whether these associations vary by racial/ethnic group. Analyses on 963 subjects (18.7% White, 53% Hispanics, and 28.5% African American) from the Stress ancillary study of the Multi-Ethnic Study of Atherosclerosis revealed a significant difference in LTL between home owners and renters in Hispanic and White participants (p < .05), but not amongst African Americans (p = .98). There were no linear associations of adult education or family income with LTL, however, there was an inverse association between father’s education and LTL (p = .03). These findings suggest that for Whites and Hispanics renting vs. owning a home is associated with an older biological age; however we did not replicate previous findings linking education with LTL. PMID:23142704

  19. Prolonged exposure of naïve CD8+ T cells to interleukin-7 or interleukin-15 stimulates proliferation without differentiation or loss of telomere length

    PubMed Central

    Wallace, Diana L; Bérard, Marion; Soares, Maria V D; Oldham, Janine; Cook, Joanne E; Akbar, Arne N; Tough, David F; Beverley, Peter C L

    2006-01-01

    Interleukin (IL)-7 and IL-15 are cytokines implicated in homeostatic control of the peripheral CD8 T-cell pool. We compared the effects of IL-7 and IL-15 on survival and proliferation of purified human CD8+ T-cell subsets. Low concentrations of either cytokine reduced the spontaneous apoptosis of all subsets, and enhancement of survival corresponded to the extent of Bcl-2 up-regulation. Surprisingly, although minimal proliferation of naïve CD8+ T cells was observed during the first week of culture with cytokines, a marked expansion of these cells occurred at later time points, particularly in response to IL-15. This occurred largely without phenotypic change or acquisition of effector function, indicating a dissociation of differentiation from proliferation. Notably, progression of naïve CD8+ T cells through several cell divisions resulted in up-regulation of telomerase and the maintenance of telomere length. These data show that IL-7 and IL-15 induce cell proliferation and rescue from apoptosis in a concentration, time and subset-dependent manner, and have implications for the homeostatic expansion of the naïve CD8+ T-cell pool. PMID:17005004

  20. Circulating cell-free DNA, telomere length and bilirubin in the Vienna Active Ageing Study: exploratory analysis of a randomized, controlled trial

    PubMed Central

    Tosevska, Anela; Franzke, Bernhard; Hofmann, Marlene; Vierheilig, Immina; Schober-Halper, Barbara; Oesen, Stefan; Neubauer, Oliver; Wessner, Barbara; Wagner, Karl-Heinz

    2016-01-01

    Telomere length (TL) in blood cells is widely used in human studies as a molecular marker of ageing. Circulating cell-free DNA (cfDNA) as well as unconjugated bilirubin (UCB) are dynamic blood constituents whose involvement in age-associated diseases is largely unexplored. To our knowledge, there are no published studies integrating all three parameters, especially in individuals of advanced age. Here we present a secondary analysis from the Vienna Active Aging Study (VAAS), a randomized controlled intervention trial in institutionalized elderly individuals (n = 101). Using an exploratory approach we combine three blood-based molecular markers (TL, UCB and cfDNA) with a range of primary and secondary outcomes from the intervention. We further look at the changes occurring in these parameters after 6-month resistance exercise training with or without supplementation. A correlation between UCB and TL was evident at baseline (p < 0.05), and both were associated with increased chromosomal anomalies such as nucleoplasmatic bridges and nuclear buds (p < 0.05). Of the three main markers explored in this paper, only cfDNA decreased significantly (p < 0.05) after 6-month training and dietary intervention. No clear relationship could be established between cfDNA and either UCB or TL. The trial was registered at ClinicalTrials.gov (NCT01775111). PMID:27905522

  1. Schizosaccharomyces pombe mst2+ Encodes a MYST Family Histone Acetyltransferase That Negatively Regulates Telomere Silencing†

    PubMed Central

    Gómez, Eliana B.; Espinosa, Joaquín M.; Forsburg, Susan L.

    2005-01-01

    Histone acetylation and deacetylation are associated with transcriptional activity and the formation of constitutively silent heterochromatin. Increasingly, histone acetylation is also implicated in other chromosome transactions, including replication and segregation. We have cloned the only Schizosaccharomyces pombe MYST family histone acetyltransferase genes, mst1+ and mst2+. Mst1p, but not Mst2p, is essential for viability. Both proteins are localized to the nucleus and bound to chromatin throughout the cell cycle. Δmst2 genetically interacts with mutants that affect heterochromatin, cohesion, and telomere structure. Mst2p is a negative regulator of silencing at the telomere but does not affect silencing in the centromere or mating type region. We generated a census of proteins and histone modifications at wild-type telomeres. A histone acetylation gradient at the telomeres is lost in Δmst2 cells without affecting the distribution of Taz1p, Swi6p, Rad21p, or Sir2p. We propose that the increased telomeric silencing is caused by histone hypoacetylation and/or an increase in the ratio of methylated to acetylated histones. Although telomere length is normal, meiosis is aberrant in Δmst2 diploid homozygote mutants, suggesting that telomeric histone acetylation contributes to normal meiotic progression. PMID:16199868

  2. Telomere shortening and metabolic compromise underlie dystrophic cardiomyopathy

    PubMed Central

    Chang, Alex Chia Yu; Ong, Sang-Ging; LaGory, Edward L.; Kraft, Peggy E.; Giaccia, Amato J.; Wu, Joseph C.; Blau, Helen M.

    2016-01-01

    Duchenne muscular dystrophy (DMD) is an incurable X-linked genetic disease that is caused by a mutation in the dystrophin gene and affects one in every 3,600 boys. We previously showed that long telomeres protect mice from the lethal cardiac disease seen in humans with the same genetic defect, dystrophin deficiency. By generating the mdx4cv/mTRG2 mouse model with “humanized” telomere lengths, the devastating dilated cardiomyopathy phenotype seen in patients with DMD was recapitulated. Here, we analyze the degenerative sequelae that culminate in heart failure and death in this mouse model. We report progressive telomere shortening in developing mouse cardiomyocytes after postnatal week 1, a time when the cells are no longer dividing. This proliferation-independent telomere shortening is accompanied by an induction of a DNA damage response, evident by p53 activation and increased expression of its target gene p21 in isolated cardiomyocytes. The consequent repression of Pgc1α/β leads to impaired mitochondrial biogenesis, which, in conjunction with the high demands of contraction, leads to increased oxidative stress and decreased mitochondrial membrane potential. As a result, cardiomyocyte respiration and ATP output are severely compromised. Importantly, treatment with a mitochondrial-specific antioxidant before the onset of cardiac dysfunction rescues the metabolic defects. These findings provide evidence for a link between short telomere length and metabolic compromise in the etiology of dilated cardiomyopathy in DMD and identify a window of opportunity for preventive interventions. PMID:27799523

  3. Innate sexuality determines the mechanisms of telomere maintenance.

    PubMed

    Tasaka, Kenta; Yokoyama, Naoki; Nodono, Hanae; Hoshi, Motonori; Matsumoto, Midori

    2013-01-01

    Recently, telomere length has been shown to be differentially regulated in asexually and sexually reproducing planarians. In addition, it was found that asexual worms maintain telomere length somatically during reproduction by fission or when regeneration is induced by amputation, whereas sexual worms only achieve telomere elongation through sexual reproduction. We have established an experimental bioassay system to induce switching from asexual to sexual reproduction in planarians, that is, sexualization. In this study, the relationship between the reproductive mode and telomere maintenance was investigated using innate asexually reproducing worms, innate sexually reproducing worms, and experimentally sexualized worms. Here, we show that innate asexual planarians maintain telomere length during cell division and that innate sexual planarians exhibit telomere shortening. However, experimental sexualized worms maintain telomere length during cell division. These results indicate that innate sexuality is linked to the mechanism of telomere maintenance.

  4. Altered Telomere Nuclear Matrix Interactions and Nucleosomal Periodicity in Ataxia Telangiectasia Cells before and after Ionizing Radiation Treatment

    PubMed Central

    Smilenov, Lubomir B.; Dhar, Sonu; Pandita, Tej K.

    1999-01-01

    Cells derived from ataxia telangiectasia (A-T) patients show a prominent defect at chromosome ends in the form of chromosome end-to-end associations, also known as telomeric associations, seen at G1, G2, and metaphase. Recently, we have shown that the ATM gene product, which is defective in the cancer-prone disorder A-T, influences chromosome end associations and telomere length. A possible hypothesis explaining these results is that the defective telomere metabolism in A-T cells are due to altered interactions between the telomeres and the nuclear matrix. We examined these interactions in nuclear matrix halos before and after radiation treatment. A difference was observed in the ratio of soluble versus matrix-associated telomeric DNA between cells derived from A-T and normal individuals. Ionizing radiation treatment affected the ratio of soluble versus matrix-associated telomeric DNA only in the A-T cells. To test the hypothesis that the ATM gene product is involved in interactions between telomeres and the nuclear matrix, we examined such interactions in human cells expressing either a dominant-negative effect or complementation of the ATM gene. The phenotype of RKO colorectal tumor cells expressing ATM fragments containing a leucine zipper motif mimics the altered interactions of telomere and nuclear matrix similar to that of A-T cells. A-T fibroblasts transfected with wild-type ATM gene had corrected telomere-nuclear matrix interactions. Further, we found that A-T cells had different micrococcal nuclease digestion patterns compared to normal cells before and after irradiation, indicating differences in nucleosomal periodicity in telomeres. These results suggest that the ATM gene influences the interactions between telomeres and the nuclear matrix, and alterations in telomere chromatin could be at least partly responsible for the pleiotropic phenotypes of the ATM gene. PMID:10490633

  5. Distinct Responses of Stem Cells to Telomere Uncapping-A Potential Strategy to Improve the Safety of Cell Therapy.

    PubMed

    Liu, Chang Ching; Ma, Dong Liang; Yan, Ting-Dong; Fan, XiuBo; Poon, Zhiyong; Poon, Lai-Fong; Goh, Su-Ann; Rozen, Steve G; Hwang, William Ying Khee; Tergaonkar, Vinay; Tan, Patrick; Ghosh, Sujoy; Virshup, David M; Goh, Eyleen L K; Li, Shang

    2016-10-01

    In most human somatic cells, the lack of telomerase activity results in progressive telomere shortening during each cell division. Eventually, DNA damage responses triggered by critically short telomeres induce an irreversible cell cycle arrest termed replicative senescence. However, the cellular responses of human pluripotent stem cells to telomere uncapping remain unknown. We generated telomerase knockout human embryonic stem (ES) cells through gene targeting. Telomerase inactivation in ES cells results in progressive telomere shortening. Telomere DNA damage in ES cells and neural progenitor cells induces rapid apoptosis when telomeres are uncapped, in contrast to fibroblast cells that enter a state of replicative senescence. Significantly, telomerase inactivation limits the proliferation capacity of human ES cells without affecting their pluripotency. By targeting telomerase activity, we can functionally separate the two unique properties of human pluripotent stem cells, namely unlimited self-renewal and pluripotency. We show that the potential of ES cells to form teratomas in vivo is dictated by their telomere length. By controlling telomere length of ES cells through telomerase inactivation, we can inhibit teratoma formation and potentially improve the safety of cell therapies involving terminally differentiated cells as well as specific progenitor cells that do not require sustained cellular proliferation in vivo, and thus sustained telomerase activity. Stem Cells 2016;34:2471-2484.

  6. Factors affecting gestation length in the Thoroughbred mare.

    PubMed

    Davies Morel, M C G; Newcombe, J R; Holland, S J

    2002-12-16

    In order to assist in the accurate prediction of the timing of parturition in the mare true gestation length, along with the potential effect of a number of factors, was investigated. Data from 433 Thoroughbred foal pregnancies were used. Sequential ultrasonic scanning allowed the true gestation length (fertilisation-parturition) to be ascertained, as apposed to previous work, which used the mating-parturition interval. An average gestation length of 344.1 +/- 0.49 days was evident. Colt foal pregnancies were significantly (P < 0.001) longer (346.2 +/- 0.72) than fillies (342.4 +/- 0.65). Month of birth had a significant effect on gestation length in all foals (P < 0.001). With foals born in January having the shortest gestation lengths and those born in April the longest. Mare age, year of birth, stallion age, stud farm and the interval between ovulation and mating had no significant effect. It is concluded that (i) the gestation length range (315-388 days), all resulting in viable foals is noteworthy and of clinical importance when considering the classification of dysmaturity in foals, (ii) mares carrying colt foals due to be born in the middle of the breeding season (April) are likely to have the longer gestation lengths.

  7. Runaway telomere elongation caused by telomerase RNA gene mutations.

    PubMed

    McEachern, M J; Blackburn, E H

    1995-08-03

    The ribonucleoprotein enzyme telomerase adds telomeric DNA onto chromosome ends and is normally regulated so that telomeric DNA lengths are kept within defined bounds. In the telomerase RNA gene from the yeast Kluyveromyces lactis, specific mutations that alter telomeric DNA sequences result in telomeres elongating to up to 100 times their normal length and impair cell growth. Some mutations cause immediate elongation whereas others behave like genetic time bombs, causing elongation only after a latent period of hundreds of generations.

  8. Cellular Consequences of Telomere Shortening in Histologically Normal Breast Tissues

    DTIC Science & Technology

    2013-09-01

    prognostic and/or risk biomarker [2]. Dysfunctional telomeres cause genomic instability via chromosomal breakage-fusion-bridge cycles. In the...invited to write a review article describing “The potential utility of telomere-related markers for cancer diagnosis” [7]. In alignment with his...De Marzo, E.A. Platz, and A.K. Meeker. Prostate cancer cell telomere length variability and stromal cell telomere length as prognostic markers for

  9. Pot1 and Telomere Maintenance

    PubMed Central

    Baumann, Peter; Price, Carolyn

    2010-01-01

    Proteins that specifically bind the single stranded overhang at the ends of telomeres have been identified in a wide range of eukaryotes and play pivotal roles in chromosome end protection and telomere length regulation. Here we summarize recent findings regarding the functions of POT1 proteins in vertebrates and discuss the functional evolution of POT1 proteins following gene duplication in protozoa, plants, nematodes and mice. PMID:20493859

  10. Select Neurocognitive Impairment in HIV-Infected Women: Associations with HIV Viral Load, Hepatitis C Virus, and Depression, but Not Leukocyte Telomere Length

    PubMed Central

    Giesbrecht, Chantelle J.; Thornton, Allen E.; Hall-Patch, Clare; Maan, Evelyn J.; Côté, Hélène C. F.; Money, Deborah M.; Murray, Melanie; Pick, Neora

    2014-01-01

    Background Through implementation of combination antiretroviral therapy (cART) remarkable gains have been achieved in the management of HIV infection; nonetheless, the neurocognitive consequences of infection remain a pivotal concern in the cART era. Research has often employed norm-referenced neuropsychological scores, derived from healthy populations (excluding many seronegative individuals at high risk for HIV infection), to characterize impairments in predominately male HIV-infected populations. Methods Using matched-group methodology, we assessed 81 HIV-seropositive (HIV+) women with established neuropsychological measures validated for detection of HIV-related impairments, as well as additional detailed tests of executive function and decision-making from the Cambridge Neuropsychological Test Automated Battery (CANTAB). Results On validated tests, the HIV+ women exhibited impairments that were limited to significantly slower information processing speed when compared with 45 HIV-seronegative (HIV−) women with very similar demographic backgrounds and illness comorbidities. Additionally, select executive impairments in shifting attention (i.e., reversal learning) and in decision-making quality were revealed in HIV+ participants. Modifiers of neurocognition in HIV-infected women included detectable HIV plasma viral load, active hepatitis C virus co-infection, and self-reported depression symptoms. In contrast, leukocyte telomere length (LTL), a marker of cellular aging, did not significantly differ between HIV+ and HIV− women, nor was LTL associated with overall neurocognition in the HIV+ group. Conclusions The findings suggest that well-managed HIV infection may entail a more circumscribed neurocognitive deficit pattern than that reported in many norm-referenced studies, and that common comorbidities make a secondary contribution to HIV-related neurocognitive impairments. PMID:24595021

  11. The hnRNP A1 homolog Hrb87F/Hrp36 is important for telomere maintenance in Drosophila melanogaster.

    PubMed

    Singh, Anand K; Lakhotia, Subhash C

    2016-06-01

    Unlike the telomerase-dependent mammalian telomeres, HeT-A, TART, and TAHRE (HTT) retroposon arrays regulate Drosophila telomere length. Cap prevents telomeric associations (TAs) and telomeric fusions (TFs). Our results suggest important roles of Hrb87F in telomeric HTT array and cap maintenance in Drosophila. All chromosome arms, except 2L, in Df(3R)Hrb87F homozygotes (Hrb87F-null) displayed significantly elongated telomeres with amplified HTT arrays and high TAs, all of which resolved without damage. Presence of FLAG-tagged Hrb87F (FLAG-Hrb87F) on cap and subtelomeric regions following hsFLAG-Hrb87F transgene expression in Df(3R)Hrb87F homozygotes suppressed TAs without affecting telomere length. A normal X-chromosome telomere expanded within five generations in Hrb87F-null background and displayed high TAs, but not when hsFLAG-Hrb87F was co-expressed. Tel (1) /Gaiano line or HP1 loss-of-function mutant-derived expanded telomeres carry Hrb87F on cap and HTT arrays while Hrb87F-null telomeres have HP1 and HOAP on caps and expanded HTT arrays. ISWI, seen only on cap on normal telomeres, was abundant on Hrb87F-null expanded HTT arrays. Extended telomeres derived from Tel (1) (Gaiano) or HP1-null mutation background interact with those from Hrb87F-null, since while the end association frequency was negligible in Df(3R)Hrb87F/+ nuclei, it increased significantly in co-presence of Tel (1) or HP1-null-based expanded telomere/s. Together, these suggest complex interactions between members of the proteome of telomere so that absence of any key member leads to telomere expansion and/or enhanced TAs/TFs. HTT expansion in Hrb87F-null condition is not developmental but a germline event presumably because absence of Hrb87F in germline may deregulate HTT retroposition/replication leading to telomere elongation.

  12. Increased expression of telomere-regulating genes in endurance athletes with long leukocyte telomeres.

    PubMed

    Denham, Joshua; O'Brien, Brendan J; Prestes, Priscilla R; Brown, Nicholas J; Charchar, Fadi J

    2016-01-15

    Leukocyte telomeres shorten with age, and excessive shortening is associated with age-related cardiometabolic diseases. Exercise training may prevent disease through telomere length maintenance although the optimal amount of exercise that attenuates telomere attrition is unknown. Furthermore, the underlying molecular mechanisms responsible for the enhanced telomere maintenance observed in endurance athletes is poorly understood. We quantified the leukocyte telomere length and analyzed the expression of telomere-regulating genes in endurance athletes and healthy controls (both n = 61), using quantitative PCR. We found endurance athletes have significantly longer (7.1%, 208-416 nt) leukocyte telomeres and upregulated TERT (2.0-fold) and TPP1 (1.3-fold) mRNA expression compared with controls in age-adjusted analysis. The telomere length and telomere-regulating gene expression differences were no longer statistically significant after adjustment for resting heart rate and relative V̇O(2 max) (all P > 0.05). Resting heart rate emerged as an independent predictor of leukocyte telomere length and TERT and TPP1 mRNA expression in stepwise regression models. To gauge whether volume of exercise was associated with leukocyte telomere length, we divided subjects into running and cycling tertiles (distance covered per week) and found individuals in the middle and highest tertiles had longer telomeres than individuals in the lowest tertile. These data emphasize the importance of cardiorespiratory fitness and exercise training in the prevention of biological aging. They also support the concept that moderate amounts of exercise training protects against biological aging, while higher amounts may not elicit additional benefits.

  13. End Joining at Caenorhabditis elegans Telomeres

    PubMed Central

    Lowden, Mia Rochelle; Meier, Bettina; Lee, Teresa Wei-sy; Hall, Julie; Ahmed, Shawn

    2008-01-01

    Critically shortened telomeres can be subjected to DNA repair events that generate end-to-end chromosome fusions. The resulting dicentric chromosomes can enter breakage–fusion–bridge cycles, thereby impeding elucidation of the structures of the initial fusion events and a mechanistic understanding of their genesis. Current models for the molecular basis of fusion of critically shortened, uncapped telomeres rely on PCR assays that typically capture fusion breakpoints created by direct ligation of chromosome ends. Here we use independent approaches that rely on distinctive features of Caenorhabditis elegans to study the frequency of direct end-to-end chromosome fusion in telomerase mutants: (1) holocentric chromosomes that allow for genetic isolation of stable end-to-end fusions and (2) unique subtelomeric sequences that allow for thorough PCR analysis of samples of genomic DNA harboring multiple end-to-end fusions. Surprisingly, only a minority of end-to-end fusion events resulted from direct end joining with no additional genome rearrangements. We also demonstrate that deficiency for the C. elegans Ku DNA repair heterodimer does not affect telomere length or cause synthetic effects in the absence of telomerase. PMID:18780750

  14. Rapid telomere motions in live human cells analyzed by highly time-resolved microscopy

    PubMed Central

    Wang, Xueying; Kam, Zvi; Carlton, Peter M; Xu, Lifeng; Sedat, John W; Blackburn, Elizabeth H

    2008-01-01

    Background Telomeres cap chromosome ends and protect the genome. We studied individual telomeres in live human cancer cells. In capturing telomere motions using quantitative imaging to acquire complete high-resolution three-dimensional datasets every second for 200 seconds, telomere dynamics were systematically analyzed. Results The motility of individual telomeres within the same cancer cell nucleus was widely heterogeneous. One class of internal heterochromatic regions of chromosomes analyzed moved more uniformly and showed less motion and heterogeneity than telomeres. The single telomere analyses in cancer cells revealed that shorter telomeres showed more motion, and the more rapid telomere motions were energy dependent. Experimentally increasing bulk telomere length dampened telomere motion. In contrast, telomere uncapping, but not a DNA damaging agent, methyl methanesulfonate, significantly increased telomere motion. Conclusion New methods for seconds-scale, four-dimensional, live cell microscopic imaging and data analysis, allowing systematic tracking of individual telomeres in live cells, have defined a previously undescribed form of telomere behavior in human cells, in which the degree of telomere motion was dependent upon telomere length and functionality. PMID:19014413

  15. Targeted DNA damage at individual telomeres disrupts their integrity and triggers cell death

    PubMed Central

    Sun, Luxi; Tan, Rong; Xu, Jianquan; LaFace, Justin; Gao, Ying; Xiao, Yanchun; Attar, Myriam; Neumann, Carola; Li, Guo-Min; Su, Bing; Liu, Yang; Nakajima, Satoshi; Levine, Arthur S.; Lan, Li

    2015-01-01

    Cellular DNA is organized into chromosomes and capped by a unique nucleoprotein structure, the telomere. Both oxidative stress and telomere shortening/dysfunction cause aging-related degenerative pathologies and increase cancer risk. However, a direct connection between oxidative damage to telomeric DNA, comprising <1% of the genome, and telomere dysfunction has not been established. By fusing the KillerRed chromophore with the telomere repeat binding factor 1, TRF1, we developed a novel approach to generate localized damage to telomere DNA and to monitor the real time damage response at the single telomere level. We found that DNA damage at long telomeres in U2OS cells is not repaired efficiently compared to DNA damage in non-telomeric regions of the same length in heterochromatin. Telomeric DNA damage shortens the average length of telomeres and leads to cell senescence in HeLa cells and cell death in HeLa, U2OS and IMR90 cells, when DNA damage at non-telomeric regions is undetectable. Telomere-specific damage induces chromosomal aberrations, including chromatid telomere loss and telomere associations, distinct from the damage induced by ionizing irradiation. Taken together, our results demonstrate that oxidative damage induces telomere dysfunction and underline the importance of maintaining telomere integrity upon oxidative damage. PMID:26082495

  16. Yeast hnRNP-related proteins contribute to the maintenance of telomeres

    SciTech Connect

    Lee-Soety, Julia Y.; Jones, Jennifer; MacGibeny, Margaret A.; Remaly, Erin C.; Daniels, Lynsey; Ito, Andrea; Jean, Jessica; Radecki, Hannah; Spencer, Shannon

    2012-09-14

    Highlights: Black-Right-Pointing-Pointer Yeast hnRNP-related proteins are able to prevent faster senescence in telomerase-null cells. Black-Right-Pointing-Pointer The conserved RRMs in Npl3 are important for telomere maintenance. Black-Right-Pointing-Pointer Human hnRNP A1 is unable to complement the lack of NPL3 in yeast. Black-Right-Pointing-Pointer Npl3 and Cbc2 may work as telomere capping proteins. -- Abstract: Telomeres protect the ends of linear chromosomes, which if eroded to a critical length can become uncapped and lead to replicative senescence. Telomerase maintains telomere length in some cells, but inappropriate expression facilitates the immortality of cancer cells. Recently, proteins involved in RNA processing and ribosome assembly, such as hnRNP (heterogeneous nuclear ribonucleoprotein) A1, have been found to participate in telomere maintenance in mammals. The Saccharomyces cerevisiae protein Npl3 shares significant amino acid sequence similarities with hnRNP A1. We found that deleting NPL3 accelerated the senescence of telomerase null cells. The highly conserved RNA recognition motifs (RRM) in Npl3 appear to be important for preventing faster senescence. Npl3 preferentially binds telomere sequences in vitro, suggesting that Npl3 may affect telomeres directly. Despite similarities between the two proteins, human hnRNP A1 is unable to complement the lack of Npl3 to rescue accelerated senescence in tlc1 npl3 cells. Deletion of CBC2, which encodes another hnRNP-related protein that associates with Npl3, also accelerates senescence. Potential mechanisms by which hnRNP-related proteins maintain telomeres are discussed.

  17. Acacetin and Chrysin, Two Polyphenolic Compounds, Alleviate Telomeric Position Effect in Human Cells

    PubMed Central

    Boussouar, Amina; Barette, Caroline; Nadon, Robert; Saint-Léger, Adelaïde; Broucqsault, Natacha; Ottaviani, Alexandre; Firozhoussen, Arva; Lu, Yiming; Lafanechère, Laurence; Gilson, Eric; Magdinier, Frédérique; Ye, Jing

    2013-01-01

    We took advantage of the ability of human telomeres to silence neighboring genes (telomere position effect or TPE) to design a high-throughput screening assay for drugs altering telomeres. We identified, for the first time, that two dietary flavones, acacetin and chrysin, are able to specifically alleviate TPE in human cells. We further investigated their influence on telomere integrity and showed that both drugs drastically deprotect telomeres against DNA damage response. However, telomere deprotection triggered by shelterin dysfunction does not affect TPE, indicating that acacetin and chrysin target several functions of telomeres. These results show that TPE-based screening assays represent valuable methods to discover new compounds targeting telomeres. PMID:23962900

  18. Dynamics of telomeric DNA turnover in yeast.

    PubMed Central

    McEachern, Michael J; Underwood, Dana Hager; Blackburn, Elizabeth H

    2002-01-01

    Telomerase adds telomeric DNA repeats to telomeric termini using a sequence within its RNA subunit as a template. We characterized two mutations in the Kluyveromyces lactis telomerase RNA gene (TER1) template. Each initially produced normally regulated telomeres. One mutation, ter1-AA, had a cryptic defect in length regulation that was apparent only if the mutant gene was transformed into a TER1 deletion strain to permit extensive replacement of basal wild-type repeats with mutant repeats. This mutant differs from previously studied delayed elongation mutants in a number of properties. The second mutation, TER1-Bcl, which generates a BclI restriction site in newly synthesized telomeric repeats, was indistinguishable from wild type in all phenotypes assayed: cell growth, telomere length, and in vivo telomerase fidelity. TER1-Bcl cells demonstrated that the outer halves of the telomeric repeat tracts turn over within a few hundred cell divisions, while the innermost few repeats typically resisted turnover for at least 3000 cell divisions. Similarly deep but incomplete turnover was also observed in two other TER1 template mutants with highly elongated telomeres. These results indicate that most DNA turnover in functionally normal telomeres is due to gradual replicative sequence loss and additions by telomerase but that there are other processes that also contribute to turnover. PMID:11805045

  19. Telomere dynamics in wild brown trout: effects of compensatory growth and early growth investment.

    PubMed

    Näslund, Joacim; Pauliny, Angela; Blomqvist, Donald; Johnsson, Jörgen I

    2015-04-01

    After a period of food deprivation, animals often respond with a period of faster than normal growth. Such responses have been suggested to result in decreased chromosomal maintenance, which in turn may affect the future fitness of an individual. Here, we present a field experiment in which a food deprivation period of 24 days was enforced on fish from a natural population of juvenile brown trout (Salmo trutta) at the start of the high-growth season in spring. The growth of the food-deprived fish and a non-deprived control group was then monitored in the wild during 1 year. Fin tissue samples were taken at the start of the experiment and 1 year after food deprivation to monitor the telomere dynamics, using reduced telomere length as an indicator of maintenance cost. The food-deprived fish showed partial compensatory growth in both mass and length relative to the control group. However, we found no treatment effects on telomere dynamics, suggesting that growth-compensating brown trout juveniles are able to maintain their telomeres during their second year in the stream. However, body size at the start of the experiment, reflecting growth rate during their first year of life, was negatively correlated with change in telomere length over the following year. This result raises the possibility that rapid growth early in life induces delayed costs in cellular maintenance.

  20. Single-molecule choreography between telomere proteins and G quadruplexes.

    PubMed

    Hopfner, Karl-Peter

    2014-06-10

    Telomeric DNA binds proteins to protect chromosome ends, but it also adopts G quadruplex (GQ) structures. Two new studies by Hwang and colleagues (in this issue of Structure) and Ray and colleagues (published elsewhere) use single molecule imaging to reveal how GQs affect the binding of different telomere associated proteins. The data suggest that GQs play important roles in regulating accessibility of telomeres.

  1. SORBS2 transcription is activated by telomere position effect–over long distance upon telomere shortening in muscle cells from patients with facioscapulohumeral dystrophy

    PubMed Central

    Robin, Jérôme D.; Ludlow, Andrew T.; Batten, Kimberly; Gaillard, Marie-Cécile; Stadler, Guido; Magdinier, Frédérique; Wright, Woodring E.; Shay, Jerry W.

    2015-01-01

    DNA is organized into complex three-dimensional chromatin structures, but how this spatial organization regulates gene expression remains a central question. These DNA/chromatin looping structures can range in size from 10–20 kb (enhancers/repressors) to many megabases during intra- and inter-chromosomal interactions. Recently, the influence of telomere length on chromatin organization prior to senescence has revealed the existence of long-distance chromatin loops that dictate the expression of genes located up to 10 Mb from the telomeres (Telomere Position Effect–Over Long Distances [TPE-OLD]). Here, we demonstrate the existence of a telomere loop at the 4q35 locus involving the sorbin and SH3 domain-containing protein 2 gene, SORBS2, a skeletal muscle protein using a modification of the chromosome conformation capture method. The loop reveals a cis-acting mechanism modifying SORBS2 transcription. The expression of this gene is altered by TPE-OLD in myoblasts from patients affected with the age-associated genetic disease, facioscapulohumeral muscular dystrophy (FSHD1A, MIM 158900). SORBS2 is expressed in FSHD myoblasts with short telomeres, while not detectable in FSHD myoblasts with long telomeres or in healthy myoblasts regardless of telomere length. This indicates that TPE-OLD may modify the regulation of the 4q35 locus in a pathogenic context. Upon differentiation, both FSHD and healthy myotubes express SORBS2, suggesting that SORBS2 is normally up-regulated by maturation/differentiation of skeletal muscle and is misregulated by TPE-OLD-dependent variegation in FSHD myoblasts. These findings provide additional insights for the complexity and age-related symptoms of FSHD. PMID:26359233

  2. SORBS2 transcription is activated by telomere position effect-over long distance upon telomere shortening in muscle cells from patients with facioscapulohumeral dystrophy.

    PubMed

    Robin, Jérôme D; Ludlow, Andrew T; Batten, Kimberly; Gaillard, Marie-Cécile; Stadler, Guido; Magdinier, Frédérique; Wright, Woodring E; Shay, Jerry W

    2015-12-01

    DNA is organized into complex three-dimensional chromatin structures, but how this spatial organization regulates gene expression remains a central question. These DNA/chromatin looping structures can range in size from 10-20 kb (enhancers/repressors) to many megabases during intra- and inter-chromosomal interactions. Recently, the influence of telomere length on chromatin organization prior to senescence has revealed the existence of long-distance chromatin loops that dictate the expression of genes located up to 10 Mb from the telomeres (Telomere Position Effect-Over Long Distances [TPE-OLD]). Here, we demonstrate the existence of a telomere loop at the 4q35 locus involving the sorbin and SH3 domain-containing protein 2 gene, SORBS2, a skeletal muscle protein using a modification of the chromosome conformation capture method. The loop reveals a cis-acting mechanism modifying SORBS2 transcription. The expression of this gene is altered by TPE-OLD in myoblasts from patients affected with the age-associated genetic disease, facioscapulohumeral muscular dystrophy (FSHD1A, MIM 158900). SORBS2 is expressed in FSHD myoblasts with short telomeres, while not detectable in FSHD myoblasts with long telomeres or in healthy myoblasts regardless of telomere length. This indicates that TPE-OLD may modify the regulation of the 4q35 locus in a pathogenic context. Upon differentiation, both FSHD and healthy myotubes express SORBS2, suggesting that SORBS2 is normally up-regulated by maturation/differentiation of skeletal muscle and is misregulated by TPE-OLD-dependent variegation in FSHD myoblasts. These findings provide additional insights for the complexity and age-related symptoms of FSHD.

  3. Changes of telomere status with aging: An update.

    PubMed

    Ishikawa, Naoshi; Nakamura, Ken-Ichi; Izumiyama-Shimomura, Naotaka; Aida, Junko; Matsuda, Yoko; Arai, Tomio; Takubo, Kaiyo

    2016-03-01

    Accumulated data have shown that most human somatic cells or tissues show irreversible telomere shortening with age, and that there are strong associations between telomere attrition and aging-related diseases, including cancers, diabetes and cognitive disorders. Although it has been largely accepted that telomere attrition is one of the major causes of aging-related disorders, critical aspects of telomere biology remain unresolved, especially the lack of standardized methodology for quantification of telomere length. Another frustrating issue is that no potentially promising methods for safe prevention of telomere erosion, or for telomere elongation, have been devised. Here, we review several methods for quantification of telomere length currently utilized worldwide, considering their advantages and drawbacks. We also summarize the results of our recent studies of human cells and tissues, mainly using quantitative fluorescence in situ hybridization and Southern blotting, including those derived from patients with progeria-prone Werner syndrome and trisomy 21, and several strains of induced pluripotent stem cells. We discuss the possible merits of using telomere shortness as an indicator, or a new marker, for diagnosis of precancerous states and aging-related disorders. In addition, we describe newly found factors that are thought to impact telomere dynamics, providing a new avenue for examining the unsolved issues related to telomere restoration and maintenance.

  4. Telomere elongation (Tel), a new mutation in Drosophila melanogaster that produces long telomeres.

    PubMed Central

    Siriaco, Giorgia M; Cenci, Giovanni; Haoudi, Abdelali; Champion, Larry E; Zhou, Chun; Gatti, Maurizio; Mason, James M

    2002-01-01

    In most eukaryotes telomeres are extended by telomerase. Drosophila melanogaster, however, lacks telomerase, and telomere-specific non-LTR retrotransposons, HeT-A and TART, transpose specifically to chromosome ends. A Drosophila strain, Gaiano, that has long telomeres has been identified. We extracted the major Gaiano chromosomes into an Oregon-R genetic background and examined the resulting stocks after 60 generations. In situ hybridization using HeT-A and TART sequences showed that, in stocks carrying either the X or the second chromosome from Gaiano, only the Gaiano-derived chromosomes display long telomeres. However, in stocks carrying the Gaiano third chromosome, all telomeres are substantially elongated, indicating that the Gaiano chromosome 3 carries a factor that increases HeT-A and TART addition to the telomeres. We show that this factor, termed Telomere elongation (Tel), is dominant and localizes as a single unit to 69 on the genetic map. The long telomeres tend to associate with each other in both polytene and mitotic cells. These associations depend on telomere length rather than the presence of Tel. Associations between metaphase chromosomes are resolved during anaphase, suggesting that they are mediated by either proteinaceous links or DNA hydrogen bonding, rather than covalent DNA-DNA bonds. PMID:11805059

  5. Telomeres, Age and Reproduction in a Long-Lived Reptile

    PubMed Central

    Plot, Virginie; Criscuolo, François; Zahn, Sandrine; Georges, Jean-Yves

    2012-01-01

    A major interest has recently emerged in understanding how telomere shortening, mechanism triggering cell senescence, is linked to organism ageing and life history traits in wild species. However, the links between telomere length and key history traits such as reproductive performances have received little attention and remain unclear to date. The leatherback turtle Dermochelys coriacea is a long-lived species showing rapid growth at early stages of life, one of the highest reproductive outputs observed in vertebrates and a dichotomised reproductive pattern related to migrations lasting 2 or 3 years, supposedly associated with different environmental conditions. Here we tested the prediction of blood telomere shortening with age in this species and investigated the relationship between blood telomere length and reproductive performances in leatherback turtles nesting in French Guiana. We found that blood telomere length did not differ between hatchlings and adults. The absence of blood telomere shortening with age may be related to an early high telomerase activity. This telomere-restoring enzyme was formerly suggested to be involved in preventing early telomere attrition in early fast-growing and long-lived species, including squamate reptiles. We found that within one nesting cycle, adult females having performed shorter migrations prior to the considered nesting season had shorter blood telomeres and lower reproductive output. We propose that shorter blood telomeres may result from higher oxidative stress in individuals breeding more frequently (i.e., higher costs of reproduction) and/or restoring more quickly their body reserves in cooler feeding areas during preceding migration (i.e., higher foraging costs). This first study on telomeres in the giant leatherback turtle suggests that blood telomere length predicts not only survival chances, but also reproductive performances. Telomeres may therefore be a promising new tool to evaluate individual reproductive

  6. Short Telomeres in Key Tissues Initiate Local and Systemic Aging in Zebrafish

    PubMed Central

    Carneiro, Madalena C.; Ferreira, Tânia; Carvalho, Tânia; Ferreira, Miguel Godinho

    2016-01-01

    Telomeres shorten with each cell division and telomere dysfunction is a recognized hallmark of aging. Tissue proliferation is expected to dictate the rate at which telomeres shorten. We set out to test whether proliferative tissues age faster than non-proliferative due to telomere shortening during zebrafish aging. We performed a prospective study linking telomere length to tissue pathology and disease. Contrary to expectations, we show that telomeres shorten to critical lengths only in specific tissues and independently of their proliferation rate. Short telomeres accumulate in the gut but not in other highly proliferative tissues such as the blood and gonads. Notably, the muscle, a low proliferative tissue, accumulates short telomeres and DNA damage at the same rate as the gut. Together, our work shows that telomere shortening and DNA damage in key tissues triggers not only local dysfunction but also anticipates the onset of age-associated diseases in other tissues, including cancer. PMID:26789415

  7. The asymmetry of telomere replication contributes to replicative senescence heterogeneity

    PubMed Central

    Bourgeron, Thibault; Xu, Zhou; Doumic, Marie; Teresa Teixeira, Maria

    2015-01-01

    In eukaryotes, the absence of telomerase results in telomere shortening, eventually leading to replicative senescence, an arrested state that prevents further cell divisions. While replicative senescence is mainly controlled by telomere length, the heterogeneity of its onset is not well understood. This study proposes a mathematical model based on the molecular mechanisms of telomere replication and shortening to decipher the causes of this heterogeneity. Using simulations fitted on experimental data obtained from individual lineages of senescent Saccharomyces cerevisiae cells, we decompose the sources of senescence heterogeneity into interclonal and intraclonal components, and show that the latter is based on the asymmetry of the telomere replication mechanism. We also evidence telomere rank-switching events with distinct frequencies in short-lived versus long-lived lineages, revealing that telomere shortening dynamics display important variations. Thus, the intrinsic heterogeneity of replicative senescence and its consequences find their roots in the asymmetric structure of telomeres. PMID:26468778

  8. Finding a place in the SUN: telomere maintenance in a diverse nuclear landscape.

    PubMed

    Ebrahimi, Hani; Cooper, Julia Promisel

    2016-06-01

    Telomeres function in the context of a complex nuclear milieu in which telomeres tend to occupy distinct subnuclear regions. Indeed, regulation of the subnuclear positioning of telomeres is conserved from yeast to human, raising the age-old question: to what extent is location important for function? In mitotically dividing cells, the positioning of telomeres affects their epigenetic state and influences telomere processing and synthesis. In meiotic cells, telomere location is important for homologue pairing, centromere assembly and spindle formation. Here we focus on recent insights into the functions of telomere positioning in maintaining genome integrity.

  9. Air Pollution Stress and the Aging Phenotype: The Telomere Connection.

    PubMed

    Martens, Dries S; Nawrot, Tim S

    2016-09-01

    Aging is a complex physiological phenomenon. The question why some subjects grow old while remaining free from disease whereas others prematurely die remains largely unanswered. We focus here on the role of air pollution in biological aging. Hallmarks of aging can be grouped into three main categories: genomic instability, telomere attrition, and epigenetic alterations leading to altered mitochondrial function and cellular senescence. At birth, the initial telomere length of a person is largely determined by environmental factors. Telomere length shortens with each cell division and exposure to air pollution as well as low residential greens space exposure is associated with shorter telomere length. Recent studies show that the estimated effects of particulate air pollution exposure on the telomere mitochondrial axis of aging may play an important role in chronic health effects of air pollution. The exposome encompasses all exposures over an entire life. As telomeres can be considered as the cellular memories of exposure to oxidative stress and inflammation, telomere maintenance may be a proxy for assessing the "exposome". If telomeres are causally related to the aging phenotype and environmental air pollution is an important determinant of telomere length, this might provide new avenues for future preventive strategies.

  10. Telomere homeostasis in mammalian germ cells: a review.

    PubMed

    Reig-Viader, Rita; Garcia-Caldés, Montserrat; Ruiz-Herrera, Aurora

    2016-06-01

    Telomeres protect against genome instability and participate in chromosomal movements during gametogenesis, especially in meiosis. Thus, maintaining telomere structure and telomeric length is essential to both cell integrity and the production of germ cells. As a result, alteration of telomere homeostasis in the germ line may result in the generation of aneuploid gametes or gametogenesis disruption, triggering fertility problems. In this work, we provide an overview on fundamental aspects of the literature regarding the organization of telomeres in mammalian germ cells, paying special attention to telomere structure and function, as well as the maintenance of telomeric length during gametogenesis. Moreover, we discuss the different roles recently described for telomerase and TERRA in maintaining telomere functionality. Finally, we review how new findings in the field of reproductive biology underscore the role of telomere homeostasis as a potential biomarker for infertility. Overall, we anticipate that the study of telomere stability and equilibrium will contribute to improve diagnoses of patients; assess the risk of infertility in the offspring; and in turn, find new treatments.

  11. Telomeric transcriptome from Chironomus riparius (Diptera), a species with noncanonical telomeres.

    PubMed

    Martínez-Guitarte, J L; de la Fuente, M; Morcillo, G

    2014-06-01

    Although there are alternative telomere structures, most telomeres contain DNA arrays of short repeats (6-26 bp) maintained by telomerase. Like other diptera, Chironomus riparius has noncanonical telomeres and three subfamilies, TsA, TsB and TsC, of longer sequences (176 bp) are found at their chromosomal ends. Reverse transcription PCR was used to show that different RNAs are transcribed from these sequences. Only one strand from TsA sequences seems to render a noncoding RNA (named CriTER-A); transcripts from both TsB strands were found (CriTER-B and αCriTER-B) but no TsC transcripts were detected. Interestingly, these sequences showed a differential transcriptional response upon heat shock, and they were also differentially affected by inhibitors of RNA polymerase II and RNA polymerase III. A computer search for transcription factor binding sites revealed putative regulatory cis-elements within the transcribed sequence, reinforcing the experimental evidence which suggests that the telomeric repeat might function as a promoter. This work describes the telomeric transcriptome of an insect with non-telomerase telomeres, confirming the evolutionary conservation of telomere transcription. Our data reveal differences in the regulation of telomeric transcripts between control and stressful environmental conditions, supporting the idea that telomeric RNAs could have a relevant role in cellular metabolism in insect cells.

  12. Arc Deflection Length Affected by Transverse Rotating Magnetic Field with Lateral Gas

    NASA Astrophysics Data System (ADS)

    Shiino, Toru; Ishii, Yoko; Yamamoto, Shinji; Iwao, Toru; High Current Energy Laboratory (HiCEL) Team

    2016-10-01

    Gas metal arc welding using shielding gas is often used in the welding industry. However, the arc deflection affected by lateral gas is problem because of inappropriate heat transfer. Shielding gas is used in order to prevent the instability affected by the arc deflection. However, the shielding gas causes turbulence, then blowhole of weld defect occurs because the arc affected by the instability is contaminated by the air. Thus, the magnetic field is applied to the arc in order to stabilize the arc using low amount of shielding gas. The method of applying the transverse rotating magnetic field (RMF) to the arc is one of the methods to prevent the arc instability. The RMF drives the arc because of electromagnetic force. The driven arc is considered to be prevented to arc deflection of lateral gas because the arc is restrained by the magnetic field because of the driven arc. In addition, it is assume the RMF prevented to the arc deflection of lateral gas from the multiple directions. In this paper, the arc deflection length affected by the RMF with lateral gas was elucidated in order to know the effect of the RMF for arc stabilization. Specifically, the arc deflection length affected by the magnetic frequency and the magnetic flux density is measured by high speed video camera. As a result, the arc deflection length decreases with increasing magnetic frequency, and the arc deflection length increases with increasing the magnetic flux density.

  13. Transcription and activation under environmental stress of the complex telomeric repeats of Chironomus thummi.

    PubMed

    Martínez-Guitarte, J L; Díez, J L; Morcillo, G

    2008-01-01

    In contrast to their traditional role, telomeres seem to behave as transcriptionally active regions. RNAs complementary to the short DNA repeats characteristic of telomerase-maintained telomeres have recently been identified in various mammalian cell lines, representing a new and unexpected element in telomere architecture. Here, we report the existence of transcripts complementary to telomeric sequences characteristic of Chironomus thummi telomeres. As in other Diptera, the non-canonical telomeres of chironomids lack the simple telomerase repeats and have instead more complex repetitive sequences. Northern blots of total RNA hybridized with telomere probes and RT-PCR with telomere-specific tailed primers confirm the existence of small non-coding RNAs of around 200 bp, the size of the DNA repeated telomeric unit. Telomere transcripts are heterogeneous in length, and they appear as a ladder pattern that probably corresponds to multimers of the repeat. Moreover, telomeres are activated under conditions of environmental stress, such as heat shock, appearing highly decondensed and densely labelled with acetylated H4 histone, as well as with RNA polymerase II antibodies, both marks of transcriptional activity. Changes in the expression levels of telomeric RNA were detected after heat shock. These findings provide evidence that transcriptional activity of the repetitive telomere sequences is an evolutionarily conserved feature, not limited to telomerase telomeres. The functional significance of this non-coding RNA as a new additional element in the context of telomere biology remains to be explained.

  14. Danazol Treatment for Telomere Diseases

    PubMed Central

    Townsley, Danielle M.; Dumitriu, Bogdan; Liu, Delong; Biancotto, Angélique; Weinstein, Barbara; Chen, Christina; Hardy, Nathan; Mihalek, Andrew D.; Lingala, Shilpa; Kim, Yun Ju; Yao, Jianhua; Jones, Elizabeth; Gochuico, Bernadette R.; Heller, Theo; Wu, Colin O.; Calado, Rodrigo T.; Scheinberg, Phillip; Young, Neal S.

    2016-01-01

    BACKGROUND Genetic defects in telomere maintenance and repair cause bone marrow failure, liver cirrhosis, and pulmonary fibrosis, and they increase susceptibility to cancer. Historically, androgens have been useful as treatment for marrow failure syndromes. In tissue culture and animal models, sex hormones regulate expression of the telomerase gene. METHODS In a phase 1–2 prospective study involving patients with telomere diseases, we administered the synthetic sex hormone danazol orally at a dose of 800 mg per day for a total of 24 months. The goal of treatment was the attenuation of accelerated telomere attrition, and the primary efficacy end point was a 20% reduction in the annual rate of telomere attrition measured at 24 months. The occurrence of toxic effects of treatment was the primary safety end point. Hematologic response to treatment at various time points was the secondary efficacy end point. RESULTS After 27 patients were enrolled, the study was halted early, because telomere attrition was reduced in all 12 patients who could be evaluated for the primary end point; in the intention-to-treat analysis, 12 of 27 patients (44%; 95% confidence interval [CI], 26 to 64) met the primary efficacy end point. Unexpectedly, almost all the patients (11 of 12, 92%) had a gain in telomere length at 24 months as compared with baseline (mean increase, 386 bp [95% CI, 178 to 593]); in exploratory analyses, similar increases were observed at 6 months (16 of 21 patients; mean increase, 175 bp [95% CI, 79 to 271]) and 12 months (16 of 18 patients; mean increase, 360 bp [95% CI, 209 to 512]). Hematologic responses occurred in 19 of 24 patients (79%) who could be evaluated at 3 months and in 10 of 12 patients (83%) who could be evaluated at 24 months. Known adverse effects of danazol — elevated liver-enzyme levels and muscle cramps — of grade 2 or less occurred in 41% and 33% of the patients, respectively. CONCLUSIONS In our study, treatment with danazol led to telomere

  15. In situ analysis of changes in telomere size during replicative aging and cell transformation

    PubMed Central

    1996-01-01

    Telomeres have been shown to gradually shorten during replicative aging in human somatic cells by Southern analysis. This study examines telomere shortening at the single cell level by fluorescence in situ hybridization (FISH). FISH and confocal microscopy of interphase human diploid fibroblasts (HDFs) demonstrate that telomeres are distributed throughout the nucleus with an interchromosomal heterogeneity in size. Analysis of HDFs at increasing population doubling levels shows a gradual increase in spot size, intensity, and detectability of telomeric signal. FISH of metaphase chromosomes prepared from young and old HDFs shows a heterogeneity in detection frequency for telomeres on chromosomes 1, 9, 15, and Y. The interchromosomal distribution of detection frequencies was similar for cells at early and late passage. The telomeric detection frequency for metaphase chromosomes also decreased with age. These observations suggest that telomeres shorten at similar rates in normal human somatic cels. T-antigen transformed HDFs near crisis contained telomere signals that were low compared to nontransformed HDFs. A large intracellular heterogeneity in telomere lengths was detected in two telomerase-negative cell lines compared to normal somatic cells and the telomerase-positive 293 cell line. Many telomerase-negative immortal cells had telomeric signals stronger than those in young HDFs, suggesting a different mechanism for telomere length regulation in telomerase-negative immortal cells. These studies provide an in situ demonstration of interchromosomal heterogeneity in telomere lengths. Furthermore, FISH is a reliable and sensitive method for detecting changes in telomere size at the single cell level. PMID:8698806

  16. cDNA Library Screening Identifies Protein Interactors Potentially Involved in Non-Telomeric Roles of Arabidopsis Telomerase.

    PubMed

    Dokládal, Ladislav; Honys, David; Rana, Rajiv; Lee, Lan-Ying; Gelvin, Stanton B; Sýkorová, Eva

    2015-01-01

    Telomerase-reverse transcriptase (TERT) plays an essential catalytic role in maintaining telomeres. However, in animal systems telomerase plays additional non-telomeric functional roles. We previously screened an Arabidopsis cDNA library for proteins that interact with the C-terminal extension (CTE) TERT domain and identified a nuclear-localized protein that contains an RNA recognition motif (RRM). This RRM-protein forms homodimers in both plants and yeast. Mutation of the gene encoding the RRM-protein had no detectable effect on plant growth and development, nor did it affect telomerase activity or telomere length in vivo, suggesting a non-telomeric role for TERT/RRM-protein complexes. The gene encoding the RRM-protein is highly expressed in leaf and reproductive tissues. We further screened an Arabidopsis cDNA library for proteins that interact with the RRM-protein and identified five interactors. These proteins are involved in numerous non-telomere-associated cellular activities. In plants, the RRM-protein, both alone and in a complex with its interactors, localizes to nuclear speckles. Transcriptional analyses in wild-type and rrm mutant plants, as well as transcriptional co-analyses, suggest that TERT, the RRM-protein, and the RRM-protein interactors may play important roles in non-telomeric cellular functions.

  17. Unique C. elegans telomeric overhang structures reveal the evolutionarily conserved properties of telomeric DNA

    PubMed Central

    Školáková, Petra; Foldynová-Trantírková, Silvie; Bednářová, Klára; Fiala, Radovan; Vorlíčková, Michaela; Trantírek, Lukáš

    2015-01-01

    There are two basic mechanisms that are associated with the maintenance of the telomere length, which endows cancer cells with unlimited proliferative potential. One mechanism, referred to as alternative lengthening of telomeres (ALT), accounts for approximately 10–15% of all human cancers. Tumours engaged in the ALT pathway are characterised by the presence of the single stranded 5′-C-rich telomeric overhang (C-overhang). This recently identified hallmark of ALT cancers distinguishes them from healthy tissues and renders the C-overhang as a clear target for anticancer therapy. We analysed structures of the 5′-C-rich and 3′-G-rich telomeric overhangs from human and Caenorhabditis elegans, the recently established multicellular in vivo model of ALT tumours. We show that the telomeric DNA from C. elegans and humans forms fundamentally different secondary structures. The unique structural characteristics of C. elegans telomeric DNA that are distinct not only from those of humans but also from those of other multicellular eukaryotes allowed us to identify evolutionarily conserved properties of telomeric DNA. Differences in structural organisation of the telomeric DNA between the C. elegans and human impose limitations on the use of the C. elegans as an ALT tumour model. PMID:25855805

  18. Sustained telomere erosion due to increased stem cell turnover during triple autologous hematopoietic stem cell transplantation.

    PubMed

    Widmann, Thomas; Kneer, Harald; König, Jochem; Herrmann, Markus; Pfreundschuh, Michael

    2008-01-01

    Telomeres cap chromosomal ends and are shortened throughout a lifetime. Additional telomere erosion has been documented during conventional chemotherapy or hematopoietic stem cell transplantation. Previous studies of stem cell transplantation reported variable amounts of telomere shortening with inconsistent results regarding the persistence of telomere shortening. Here we have prospectively studied telomere length and proliferation kinetics of hematopoietic cells in aggressive non-Hodgkin lymphoma patients who underwent a four-course high-dose chemotherapy protocol combined with triple autologous stem cell transplantation. We observed sustained telomere shortening in hematopoietic cells after triple stem cell transplantation with prolonged stem cell replication during the first year after stem cell transplantation.

  19. Telomere attrition and restoration in the normal teleost Oryzias latipes are linked to growth rate and telomerase activity at each life stage.

    PubMed

    Hatakeyama, Hitoshi; Yamazaki, Hiromi; Nakamura, Ken-Ichi; Izumiyama-Shimomura, Naotaka; Aida, Junko; Suzuki, Hiroetsu; Tsuchida, Shuichi; Matsuura, Masaaki; Takubo, Kaiyo; Ishikawa, Naoshi

    2016-01-01

    Telomere shortening occurs when cells divide, both in vitro and in vivo. On the other hand, telomerase is able to maintain telomere length in cells by adding TTAGGG repeats to the ends of telomeres. However, the interrelationships existing among telomere length, telomerase activity and growth in vertebrates remain to be clarified. In the present study we measured telomere length (terminal restriction fragment length), telomerase activity and body growth of Oryzias latipes from the embryo stage until senescence. During the rapid growth stage (age 0-7 months), telomeres shortened in parallel with decreasing telomerase activity. Then, during adolescence (age 7 months - 1 year), telomeres lengthened quickly as growth slowed and telomerase activity increased. In the adult stage (age 1-4 years) characterized by little growth, telomerase activity decreased gradually and telomeres shortened. Our data indicate that telomere attrition and restoration are linked to growth and telomerase activity, and suggest that critical loss of telomere homeostasis is associated with mortality in this animal.

  20. An experimental demonstration that early-life competitive disadvantage accelerates telomere loss.

    PubMed

    Nettle, Daniel; Monaghan, Pat; Gillespie, Robert; Brilot, Ben; Bedford, Thomas; Bateson, Melissa

    2015-01-07

    Adverse experiences in early life can exert powerful delayed effects on adult survival and health. Telomere attrition is a potentially important mechanism in such effects. One source of early-life adversity is the stress caused by competitive disadvantage. Although previous avian experiments suggest that competitive disadvantage may accelerate telomere attrition, they do not clearly isolate the effects of competitive disadvantage from other sources of variation. Here, we present data from an experiment in European starlings (Sturnus vulgaris) that used cross-fostering to expose siblings to divergent early experience. Birds were assigned either to competitive advantage (being larger than their brood competitors) or competitive disadvantage (being smaller than their brood competitors) between days 3 and 12 post-hatching. Disadvantage did not affect weight gain, but it increased telomere attrition, leading to shorter telomere length in disadvantaged birds by day 12. There were no effects of disadvantage on oxidative damage as measured by plasma lipid peroxidation. We thus found strong evidence that early-life competitive disadvantage can accelerate telomere loss. This could lead to faster age-related deterioration and poorer health in later life.

  1. 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.

  2. Telomere profiling: toward glioblastoma personalized medicine.

    PubMed

    Ferrandon, Sylvain; Saultier, Paul; Carras, Julien; Battiston-Montagne, Priscillia; Alphonse, Gersende; Beuve, Michael; Malleval, Céline; Honnorat, Jérôme; Slatter, Tania; Hung, Noelyn; Royds, Janice; Rodriguez-Lafrasse, Claire; Poncet, Delphine

    2013-02-01

    Despite a standard of care combining surgery, radiotherapy (RT), and temozolomide chemotherapy, the average overall survival (OS) of glioblastoma patients is only 15 months, and even far lower when the patient cannot benefit from this combination. Therefore, there is a strong need for new treatments, such as new irradiation techniques. Against this background, carbon ion hadrontherapy, a new kind of irradiation, leads to a greater biological response of the tumor, while minimizing adverse effects on healthy tissues in comparison with RT. As carbon ion hadrontherapy is restricted to RT-resistant patients, photon irradiation resistance biomarkers are needed. Long telomeres and high telomerase activity have been widely associated with photon radioresistance in other cancers. Moreover, telomere protection, telomere function, and telomere length (TL) also depend on the shelterin protein complex (TRF1, TRF2, TPP1, POT1, TIN2, and hRAP1). We thus decided to evaluate an enlarged telomeric status (TL, telomerase catalytic subunit, and the shelterin component expression level) as a potential radioresistance biomarker in vitro using cellular models and ex vivo using patient tumor biopsies. In addition, nothing was known about the role of telomeres in carbon ion response. We thus evaluated telomeric status after both types of irradiation. We report here a significant correlation between TL and the basal POT1 expression level and photon radioresistance, in vitro, and a significant increase in the OS of patients with long telomeres or a high POT1 level, in vivo. POT1 expression was predictive of patient response irrespective of the TL. Strikingly, these correlations were lost, in vitro, when considering carbon irradiation. We thus propose (1) a model of the implications of telomeric damage in the cell response to both types of irradiation and (2) assessment of the POT1 expression level and TL using patient tumor biopsies to identify radioresistant patients who could benefit from

  3. Treating Cancer by Targeting Telomeres and Telomerase

    PubMed Central

    Ivancich, Marko; Schrank, Zachary; Wojdyla, Luke; Leviskas, Brandon; Kuckovic,