Evolution in health and medicine Sackler colloquium: Genetic variation in human telomerase is associated with telomere length in Ashkenazi centenarians.

Telomere length in humans is emerging as a biomarker of aging because its shortening is associated with aging-related diseases and early mortality. However, genetic mechanisms responsible for these associations are not known. Here, in a cohort of Ashkenazi Jewish centenarians, their offspring, and offspring-matched controls, we studied the inheritance and maintenance of telomere length and variations in two major genes associated with telomerase enzyme activity, hTERT and hTERC. We demonstrated that centenarians and their offspring maintain longer telomeres compared with controls with advancing age and that longer telomeres are associated with protection from age-related diseases, better cognitive function, and lipid profiles of healthy aging. Sequence analysis of hTERT and hTERC showed overrepresentation of synonymous and intronic mutations among centenarians relative to controls. Moreover, we identified a common hTERT haplotype that is associated with both exceptional longevity and longer telomere length. Thus, variations in human telomerase gene that are associated with better maintenance of telomere length may confer healthy aging and exceptional longevity in humans.

Adiponectin levels and genotype: a potential regulator of life span in humans.

Although caloric restriction in numerous models extends life, longevity in humans is suggested to be limited by the increased prevalence of obesity. Adiponectin, a fat-derived peptide, has a protective role against age-related disease, and thus is an excellent candidate gene for longevity. We studied adiponectin levels in centenarians (n = 118), their offspring (n = 228), and unrelated participants <95 (n = 78). Adiponectin levels were significantly greater in participants older than 95 years (p =.01), an effect that was independent of sex and body mass index (BMI). Adiponectin levels in the offspring were higher (following adjustment for age, sex, and BMI) compared to controls (p =.02), suggesting that inherited factors play a role in determining adiponectin levels. Over-representation of two common variants in Adiponectin gene (ADIPOQ) in male long-lived individuals combined with their independent association with elevated plasma adiponectin levels (in men and women) suggests that their presence may promote increased life span through the regulation of adiponectin production and/or secretion.

Individuals with exceptional longevity manifest a delayed association between vitamin D insufficiency and cognitive impairment.

OBJECTIVES: To define vitamin D levels and their association with cognition in subjects with exceptional longevity. DESIGN: Cross-sectional. SETTING: Community and long-term care facilities. PARTICIPANTS: Ashkenazi Jewish subjects (n = 253) with exceptional longevity, with comparison made to the Third National Health and Nutrition Examination Survey (NHANES III) participants aged 70 and older. MEASUREMENTS: Serum 25-hydroxyvitamin D levels were measured using liquid chromatography/tandem mass spectrometry analysis. Cognitive function was assessed using the Mini-Mental State Examination (MMSE) and clock drawing test (CDT: command and copy). RESULTS: The median age of the Ashkenazi subjects was 97 (interquartile range (IQR) 95-104). Age-associated rise in the prevalence of vitamin D insufficiency, defined as a serum vitamin D level of less than 30 ng/mL, was noted in NHANES III (P = .001). In the Ashkenazi group with longevity, the rate of vitamin D insufficiency was comparable with that of the NHANES III participants, who were up to 25 years younger. In the cohort with exceptional longevity, 49% demonstrated cognitive impairment as assessed according to MMSE score (impaired cognition, median 9.5 IQR 0-24); normal cognition, median 29 (IQR 18-30) P < .001). Vitamin D insufficiency was more prevalent in those with impaired cognition, defined according to the MMSE (71.8% vs 57.7%, P = .02) and the CDT copy (84.6% vs. 50.6%, P = .02), than in those with normal cognition. This association remained significant after multivariable adjustment in logistic regression models for cognitive assessments made using the MMSE (odds ratio (OR) = 3.2, 95% confidence interval (CI) = 1.1-9.29, P = .03) and the CDT copy (OR = 8.96, 95% CI = 1.08-74.69, P = .04). CONCLUSION: Higher vitamin D levels may be a marker of delayed aging, because they are associated with better cognitive function in people achieving exceptional longevity.