Telomere length (TL) is emerging as a biomarker for aging and survival. To evaluate factors influencing this trait, we measured TL in a large homogeneous population, estimated the heritability (h 2 ), and tested for parental effects on TL variation. Our sample included 356 men and 551 women, aged 18 -92 years, from large Amish families. Mean TL in leukocytes was measured by quantitative PCR (mean: 6,198 ؎ 1,696 bp). The h 2 of TL was 0.44 ؎ 0.06 (P < 0.001), after adjusting for age, sex, and TL assay batch. As expected, TL was negatively correlated with age (r ‫؍‬ ؊0.40; P < 0.001). There was no significant difference in TL between men and women, consistent with our previous findings that Amish men lived as long as Amish women. There was a stronger and positive correlation and association between TL in the offspring and paternal TL (r ‫؍‬ 0.46, P < 0.001; ␤ ‫؍‬ 0.22, P ‫؍‬ 0.006) than offspring and maternal TL (r ‫؍‬ 0.18, P ‫؍‬ 0.04; ␤ ‫؍‬ ؊0.02, P ‫؍‬ 0.4). Furthermore, we observed a positive correlation and association between daughter's TL and paternal lifespan (r ‫؍‬ 0.20, P < 0.001; ␤ ‫؍‬ 0.21, P ‫؍‬ 0.04), but not between daughter's TL and maternal lifespan (r ‫؍‬ ؊0.01, ␤ ‫؍‬ 0.04; both P ‫؍‬ not significant). Our data, which are based on one of the largest family studies of human TL, support a link between TL and aging and lifespan and suggest a strong genetic influence, possibly via an imprinting mechanism, on TL regulation.heritability ͉ parental effects ͉ sex specific ͉ imprinting ͉ Amish T elomeres are DNA capping structures that protect the ends of eukaryotic chromosomes. In vitro studies in mammalian cells suggest that telomere shortening triggers cellular senescence or apoptosis, depending on cell type (1-4). Studies in humans have shown that telomeres shorten with aging in various mitotic tissues and cell types (5-7). The rate of telomere attrition is slower in long-lived mammals compared with short-lived ones (8). Senescent cells accumulate with increasing age in vivo (9) and are thought to play an important role in organismal aging (10), which is characterized by physiologic and metabolic decline (4) and increasing susceptibility to several diseases associated with death (11). Thus, it is likely that telomere shortening may be mechanistically linked to organismal lifespan.Factors influencing telomere homeostasis are not fully known; however, it is likely that both environmental and biological factors play roles. Among the biological factors, a growing body of evidence suggests that genes play a very important role. Several genes that influence telomere length (TL) have been identified in model organisms (12, 13). In humans, shelterin, the protein complex that shapes and safeguards telomeres is made up of six subunits: TRF1, TRF2, TIN2, Rap1, TPP1, and POT1 (14). Other genes, such as TERT, UP1, Tankyrase, EST1, EST2, and EST3 are known to influence telomere homeostasis, and other genes such as YKU70, SIR4, and RIF2, encode proteins that bind specifically to the telomeres (13). In humans, the re...

Elevated resting heart rate is associated with greater risk of cardiovascular disease and mortality. In a 2-stage meta-analysis of genome-wide association studies in up to 181,171 individuals, we identified 14 new loci associated with heart rate and confirmed associations with all 7 previously established loci. Experimental downregulation of gene expression in Drosophila melanogaster and Danio rerio identified 20 genes at 11 loci that are relevant for heart rate regulation and highlight a role for genes involved in signal transmission, embryonic cardiac development and the pathophysiology of dilated cardiomyopathy, congenital heart failure and/or sudden cardiac death. In addition, genetic susceptibility to increased heart rate is associated with altered cardiac conduction and reduced risk of sick sinus syndrome, and both heart rate–increasing and heart rate–decreasing variants associate with risk of atrial fibrillation. Our findings provide fresh insights into the mechanisms regulating heart rate and identify new therapeutic targets.

Although telomere length (TL) is known to play a critical role in cellular senescence, the relationship of TL to aging and longevity in humans is not well understood. In a large biracial population-based cohort, we tested the hypotheses that elderly persons with shorter TL in peripheral white blood cells have poorer survival, shorter life span, and fewer years of healthy life (YHL). Associations were evaluated using Cox proportional hazard models and linear regression analyses where appropriate. TL (in kilo base pairs) was not associated with overall survival (hazard ratio 1.0; 95% confidence interval 0.9-1.1) or death from any specific underlying cause including infectious diseases, cancer, or cardiac and cerebrovascular diseases. TL, however, was positively associated with more YHL (beta = 0.08 +/- 0.04, p = .03). Findings suggest that TL may not be a strong biomarker of survival in older individuals, but it may be an informative biomarker of healthy aging.

Aims/hypothesis Accumulating evidence suggests a cross-sectional association between oxidative stress and type 2 diabetes (T2D). Systemic oxidative stress, as measured by oxidized LDL (oxLDL), has been correlated with visceral fat. We examined the relationship between oxLDL, and T2D- and obesity-related traits in a bi-racial sample of 2,985 subjects at baseline and after 7 years of follow-up. Methods We examined six T2D-related traits (T2D status, HbA1c, fasting glucose, insulin, adiponectin and HOMA-IR) as well as six obesity-related traits (obesity status, BMI, leptin, % body fat, visceral and subcutaneous fat mass) using logistic and linear regression models. Results In all subjects at baseline, oxLDL was positively associated with T2D (OR=1.3,95% CI:1.1–1.5), fasting glucose (β=0.03±0.006), HbA1c (β=0.02±0.004), fasting insulin (β=0.12±0.02), HOMA-IR (β=0.13±0.02) and negatively with adiponectin (β=−0.16±0.03), (all p<0.001). The strength and magnitude of these associations did not differ much between blacks and whites. In both blacks and whites, oxLDL was also associated with obesity (OR=1.3, 95% CI:1.1–1.4) and 3 of its related traits (β=0.60±0.14 for BMI, β=0.74±0.17 for % body fat, β=0.29±0.06 for visceral fat; all p<0.001). Furthermore, of 4 traits measured after 7 years of follow-up (fasting glucose, HbA1c, BMI and % fat), their relationship with oxLDL were similar to baseline observations. No significant association was found between oxLDL and incident T2D. Interestingly, oxLDL was significantly associated with % change in T2D- and obesity-related traits in whites but not in blacks. Conclusion/interpretation Our data suggest that systemic oxidative stress may be a novel risk factor for T2D and obesity.

Objective Obesity and shorter telomeres are commonly associated with elevated risk for age-related diseases and mortality. Whether telomere length (TL) may be associated with obesity or variations in adiposity is not well established. Therefore, we set out to test the hypothesis that TL may be a risk factor for increased adiposity using data from a large population-based cohort study. Design Levels of adiposity were assessed in 6 ways (obesity status, body mass index or BMI, the percentage of body fat or % body fat, leptin, visceral and subcutaneous fat mass) in 2,721 elderly subjects (42% black and 58% white). Associations between TL measured in leukocytes at baseline and adiposity traits measured at baseline and 3 of these traits after 7 years of follow-up were tested using regression models adjusting for important covariates. Additionally, we look at weight changes and relative changes in BMI and % body fat between baseline and follow-up. Results At baseline, TL was negatively associated with % body fat (β = −0.35 ± 0.09, p = 0.001) and subcutaneous fat (β = −2.66 ± 1.07, p = 0.01), and positively associated with leptin after adjusting for % body fat (β = 0.32 ± 0.14, p = 0.001), but not with obesity, BMI or visceral fat. Prospective analyses showed that longer TL was associated with positive percent change between baseline and 7-year follow-up for both BMI (β = 0.48 ± 0.20, p = 0.01) and % body fat (β = 0.42 ± 0.23, p = 0.05). Conclusion Our study suggests that shorter TL may be a risk factor for increased adiposity. Coupling with previous reports on their reversed roles, the relationship between adiposity and TL may be complicated and warrant more prospective studies.