[Show abstract][Hide abstract] ABSTRACT: Telomere length is a putative biomarker of ageing, morbidity and mortality. Its application is hampered by lack of widely applicable reference ranges and uncertainty regarding the present limits of measurement reproducibility within and between laboratories.
International Journal of Epidemiology 09/2014; · 9.20 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Objective: Social control in the health domain refers to attempts by social network members to get an individual to modify their health behaviors. According to the dual effects model of social control, having one's health behavior controlled by others should be related to healthier behavioral change, but might arouse psychological distress as one may resent being controlled. Despite potential healthy behavior change, the stress of social control may thus be detrimental as interpersonal stress has been related to negative health outcomes. In the present study, the association between perceived social control and telomere length was tested to examine its association to biological outcomes. Method: In this cross-sectional study, a relatively healthy community sample of 140 middle age and older adults completed measures of perceived social control, perceived stress, and health behaviors. Peripheral blood mononuclear cells were used to determine telomere length. Results: Main results showed that higher levels of perceived direct social network control were associated with shorter telomere length. These links were not influenced by statistical controls for medication use, self-rated health, trait hostility, and optimism. Perceived social control was also related to greater perceived stress but not health behaviors overall. However, neither perceived stress nor health behaviors mediated the link between social control and telomere length. Conclusions: Although the study design precludes strong inferences, these results suggest that perceived social control may be associated with cellular aging. These data also highlight the utility of integrating biological outcomes into social control models. (PsycINFO Database Record (c) 2014 APA, all rights reserved).
[Show abstract][Hide abstract] ABSTRACT: 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. Mol. Mutagen., 2014. Published . This article is a U.S. Government work and is in the public domain in the USA.
Environmental and Molecular Mutagenesis 06/2014; · 2.55 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The mitochondria are essential organelles and are the location of cellular respiration, which is responsible for the majority of ATP production. Each cell contains multiple mitochondria, and each mitochondrion contains multiple copies of its own circular genome. The ratio of mitochondrial genomes to nuclear genomes is referred to as mitochondrial copy number. Decreases in mitochondrial copy number are known to occur in many tissues as people age, and in certain diseases. The regulation of mitochondrial copy number by nuclear genes has been studied extensively. While mitochondrial variation has been associated with longevity and some of the diseases known to have reduced mitochondrial copy number, the role that the mitochondrial genome itself has in regulating mitochondrial copy number remains poorly understood.
[Show abstract][Hide abstract] ABSTRACT: We investigated the relationship between telomere length and lung cancer in a pooled analysis from three prospective cohort studies: the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial, conducted among men and women in the United States, and previously published data from the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) trial conducted among male smokers in Finland, and the Shanghai Women's Health Study (SWHS), which is comprised primarily of never-smokers. The pooled population included 847 cases and 847 controls matched by study, age, and sex. Leukocyte telomere length was measured by a monochrome multiplex quantitative PCR assay. We used conditional logistic regression models to calculate odds ratios (OR) and their 95% confidence intervals (CI) for the association between telomere length and lung cancer risk, adjusted for age and pack-years of smoking. Longer telomere length was associated with increased lung cancer risk in the pooled analysis (OR(95% CI) by quartile: 1.00; 1.24(0.90-1.71); 1.27(0.91-1.78); and 1.86(1.33-2.62); P-trend=0.000022). Findings were consistent across the three cohorts and strongest for subjects with very long telomere length, i.e., lung cancer risks for telomere length (OR(95% CI)) in the upper half of the fourth quartile were 2.41(1.28-4.52), 2.16(1.11-4.23) and 3.02(1.39-6.58) for the PLCO trial, the ATBC trial, and the SWHS, respectively. In addition, the association persisted among cases diagnosed more than six years after blood collection and was particularly evident for female adenocarcinoma cases. Telomere length in white blood cell DNA may be a biomarker of future increased risk of lung cancer in diverse populations.
[Show abstract][Hide abstract] ABSTRACT: Telomeres play an essential role in maintaining chromosomal integrity in the face of physiological stressors. Although, the age-related shortening of telomere length (TL) in highly proliferative tissue, is predominantly due to the replication process, the mechanism for telomere shortening in skeletal muscle, which is minimally proliferative, is unclear. By studying TL in both the upper and lower limbs of the young (Y), old-mobile (OM), and old-immobile (OI) and by virtue of the bipedal nature of human locomotion, which declines with age, it may be possible to elucidate the mechanism responsible for cellular aging of skeletal muscle. With this approach, we revealed that TL (~15 kb) in arm skeletal muscle is unaffected by age. In contrast TL fell progressively in the legs across the young (~15 kb), the old mobile (~13 kb), and old immobile (~11 kb). Interestingly, there was a reciprocal rise in leg muscle free radical across these groups that was correlated with TL (r=0.7), with no such relationship in the arm (r=0.09). Our results document that chronologic age, per se, does not affect cellular aging of skeletal muscle, but reveals that physical inactivity, likely mediated by free radicals, has a profound effect upon this process.
[Show abstract][Hide abstract] ABSTRACT: Telomere shortening in arteries could lead to telomere uncapping and cellular senescence, which in turn could promote the development of hypertension.
To assess the novel role of arterial telomere dysfunction in hypertension, we compared mean telomere length (qPCR), telomere uncapping (serine 139 phosphorylated histone γ-H2A.X (γ-H2) localized to telomeres: ChIP), and tumor suppressor protein p53 (P53)/cyclin-dependent kinase inhibitor 1A (P21)-induced senescence (P53 bound to P21 gene promoter: ChIP) in arteries from 55 age-matched hypertensive and nonhypertensive individuals. Arterial mean telomere length was not different in hypertensive patients compared with nonhypertensive individuals (P = 0.29). Arterial telomere uncapping and P53/P21-induced senescence were two-fold greater in hypertensive patients compared with nonhypertensive individuals (P = 0.04 and P = 0.02, respectively). Arterial mean telomere length was not associated with telomere uncapping or P53/P21-induced senescence (r = -0.02, P = 0.44 and r = 0.01, P = 0.50, respectively), but telomere uncapping was a highly influential covariate for the hypertension group difference in P53/P21-induced senescence (r = 0.62, P < 0.001, ηp = 0.35). Finally, telomere uncapping was a significant predictor of hypertension status (P = 0.03), whereas mean telomere length was not (P = 0.68).
Collectively, these findings demonstrate that arterial telomere uncapping and P53/P21-induced senescence are linked to hypertension independently of mean telomere length, and telomere uncapping influences hypertension status more than mean telomere length.
Journal of Hypertension 03/2014; · 4.22 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To examine whether subjective sleep quality and sleep duration moderate the association between age and telomere length (TL).
Participants completed a demographic and sleep quality questionnaire, followed by a blood draw.
Social Neuroscience Laboratory.
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.
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.
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.
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 telomere length in a sample of middle-aged and older adults. SLEEP 2014;37(1):65-70.
[Show abstract][Hide abstract] ABSTRACT: Human age-dependent telomere attrition and telomere shortening are associated with several age-associated diseases and poorer overall survival. The aim of this study was to determine longitudinal leukocyte telomere length dynamics and identify factors associated with temporal changes in telomere length.
Leukocyte telomere length was measured by quantitative polymerase chain reaction in 8074 participants from the Prevention of Renal and Vascular End-stage Disease (PREVEND) study, an ongoing community-based prospective cohort study initiated in 1997. Follow-up data were available at two time points up to 2007. Leukocyte telomere length was measured, on between one and three separate occasions, in a total of 16,783 DNA samples. Multilevel growth models were created to identify the factors that influence leukocyte telomere dynamics.
We observed an average attrition rate of 0.47±0.16 relative telomere length units (RTLUs) per year in the study population aged 48 (range 39 to 60) years at baseline. Annual telomere attrition rate increased with age (P < 0.001), and was faster on average in men than in women (P for interaction 0.043). The major independent factors determining telomere attrition rate were active smoking (approximately tripled the loss of RTLU per year, P < 0.0001) and multiple traits of the metabolic syndrome (waist-hip ratio, P = 0.007; blood glucose level, P = 0.045; and HDL cholesterol level, P < 0.001).
Smoking and variables linked to the metabolic syndrome are modifiable lifestyle factors that accelerate telomere attrition in humans. The higher rate of cellular ageing may mediate the link between smoking and the metabolic syndrome to an increased risk of several age-associated diseases. This article is protected by copyright. All rights reserved.
Journal of Internal Medicine 10/2013; · 5.79 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Arterial telomere dysfunction may contribute to chronic arterial inflammation by inducing cellular senescence and subsequent senescence-associated inflammation. Though 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.
AJP Heart and Circulatory Physiology 05/2013; · 4.01 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: A recent genome-wide association study of lung cancer among never-smoking females in Asia demonstrated that the rs2736100 polymorphism in the TERT-CLPTM1L locus on chromosome 5p15.33 was strongly and significantly associated with risk of adenocarcinoma of the lung. The telomerase gene TERT is a reverse transcriptase that is critical for telomere replication and stabilization by controlling telomere length. We previously found that longer telomere length measured in peripheral white blood cell DNA was associated with increased risk of lung cancer in a prospective cohort study of smoking males in Finland. To follow up on this finding, we carried out a nested case-control study of 215 female lung cancer cases and 215 female controls, 94% of whom were never-smokers, in the prospective Shanghai Women's Health Study cohort. There was a dose-response relationship between tertiles of telomere length and risk of lung cancer (odds ratio (OR), 95% confidence interval [CI]: 1.0, 1.4 [0.8-2.5], and 2.2 [1.2-4.0], respectively; P trend = 0.003). Further, the association was unchanged by the length of time from blood collection to case diagnosis. In addition, the rs2736100 G allele, which we previously have shown to be associated with risk of lung cancer in this cohort, was significantly associated with longer telomere length in these same study subjects (P trend = 0.030). Our findings suggest that individuals with longer telomere length in peripheral white blood cells may have an increased risk of lung cancer, but require replication in additional prospective cohorts and populations.
PLoS ONE 03/2013; 8(3):e59230. · 3.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND: It has been hypothesized that genomic instability related to telomere dysfunction may contribute to carcinogenesis. There is some evidence from case-control studies suggesting that short leukocyte telomere length (TL) may be associated with an increased risk of renal cell carcinoma (RCC); however, this association has not been investigated prospectively. METHODS: We conducted a nested case-control study (209 cases, 410 controls) of RCC risk in relation to pre-diagnostic leukocyte TL in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. Odds ratios (OR) and 95% confidence intervals (CI) were estimated using conditional logistic regression. RESULTS: Leukocyte TL was not significantly associated with future risk of RCC (highest quartile vs. lowest: OR=0.8, 95% CI=0.5-1.5; Ptrend=0.6). Analyses stratified by sex, age, and time from blood collection to RCC diagnosis were similarly null. Conclusions and Impact: The results of this study, to our knowledge the first prospective investigation of its kind, do not support an association between pre-diagnostic leukocyte TL and risk of RCC.
Cancer Epidemiology Biomarkers & Prevention 03/2013; · 4.56 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background
Recent meta-analyses have suggested that short telomere length was associated with increased risk of cancer. We therefore tested the hypotheses that short telomere length was associated with increased risk of cancer and with increased risk of early death after cancer.Methods
We measured leukocyte telomere length in a prospective study of 47 102 Danish general population participants from the Copenhagen City Heart Study and the Copenhagen General Population Study. Patients were followed for up to 20 years for cancer diagnosis and death. Follow-up was 100% complete. All statistical tests were two-sided.ResultsTelomere length decreased linearly with increasing age (P <.001). During follow-up, we observed 3142 first cancers and, among these individuals, 1730 deaths. Decreasing quartiles of telomere length were associated with decreasing survival after cancer (log-rank P <.001). Multivariable-adjusted hazard ratios of early death were 1.31 (95% confidence interval [CI] = 1.14 to 1.52) in individuals in the quartile and 1.43 (95% CI = 1.13 to 1.80) in individuals in the decile with the shortest telomeres vs the longest. Unadjusted hazard ratios of cancer risk were 1.74 (95% CI = 1.58 to 1.93) and 2.00 (95% CI = 1.70 to 2.35) in individuals in the quartile and decile with the shortest vs longest telomeres; however, multivariable adjustment changed these hazard ratios to 0.98 (95% CI = 0.88 to 1.08) and 0.95 (95% CI = 0.80 to 1.11), mainly because of age adjustment.Conclusions
Short telomere length is associated with reduced survival after cancer but not with cancer risk. The latter contrasts with findings from recent meta-analyses.
[Show abstract][Hide abstract] ABSTRACT: Alzheimer's disease (AD) is the most common cause of dementia and AD risk clusters within families. Part of the familial aggregation of AD is accounted for by excess maternal vs. paternal inheritance, a pattern consistent with mitochondrial inheritance. The role of specific mitochondrial DNA (mtDNA) variants and haplogroups in AD risk is uncertain.
We determined the complete mitochondrial genome sequence of 1007 participants in the Cache County Study on Memory in Aging, a population-based prospective cohort study of dementia in northern Utah. AD diagnoses were made with a multi-stage protocol that included clinical examination and review by a panel of clinical experts. We used TreeScanning, a statistically robust approach based on haplotype networks, to analyze the mtDNA sequence data. Participants with major mitochondrial haplotypes H6A1A and H6A1B showed a reduced risk of AD (p = 0.017, corrected for multiple comparisons). The protective haplotypes were defined by three variants: m.3915G>A, m.4727A>G, and m.9380G>A. These three variants characterize two different major haplogroups. Together m.4727A>G and m.9380G>A define H6A1, and it has been suggested m.3915G>A defines H6A. Additional variants differentiate H6A1A and H6A1B; however, none of these variants had a significant relationship with AD case-control status.
Our findings provide evidence of a reduced risk of AD for individuals with mtDNA haplotypes H6A1A and H6A1B. These findings are the results of the largest study to date with complete mtDNA genome sequence data, yet the functional significance of the associated haplotypes remains unknown and replication in others studies is necessary.
PLoS ONE 09/2012; 7(9):e45134. · 3.53 Impact Factor