The phenotypic characteristics of exceptionally long-lived probands, their offspring, and unrelated controls are shown in Table 1. Adiponectin levels are known to be associated with age and BMI (a surrogate for body fat), and these relationships held in our sample (Figure 1 and Table 2). As previously described (31, 32), women had significantly higher adiponectin levels than did men in the combined sample (15.6 ± 0.49 vs. 11.6 ± 0.58 lg/mL; p < .0001, adjusted for age at recruitment and BMI). Furthermore, adiponectin levels were correlated with some serum lipid levels (Table 2); for example, Spearman correlation coefficients for triglycerides and HDL with adiponectin levels were −0.19 (p = .0005) and 0.23 (p < .0001), respectively. Lipoprotein particle sizes were positively correlated, whereas waist circumference was negatively correlated with adiponectin levels (Table 2). Glucose, LDL levels, and blood pressure showed no significant correlation with adiponectin levels.

Low adiponectin levels have been associated with metabolic syndrome (33); this relationship held in our control and offspring groups. The mean difference in adiponectin levels between persons with and without metabolic syndrome was 3.18 lg/mL (p = .011). This difference was observed in both offspring and controls, and the effect size was similar in each group (p = .56 for interaction effect), suggesting that the biological action of adiponectin to protect from metabolic syndrome is similar in offspring (with higher adjusted adiponectin levels) who are expected to be genetically enriched for longevity compared to controls. The relationship between adiponectin levels and metabolic syndrome was significant in both sexes but stronger among men (women: 13.5 ± 1.2 vs. 16.6 ± 0.6, p = .02; men: 7.7 ± 1.2 vs. 11.5 ± 0.5, p = .004).

Before analysis, genotypes were checked for Mendelian consistency where possible by comparing probands-offspring pairs. Mendelian errors were resolved or removed before analysis. Allele frequencies were calculated by gene counting. All SNPs conformed to Hardy-Weinberg expectations. We evaluated the association between SNP genotype and phenotype (adiponectin levels) under the additive and dominant genetic models using multiple regression. Statistical analyses were performed using Stata 9.2 (Stata Corp., College Station, TX) and SAS 9.1 (Cary, NC).

RESULTS

Controls examined unadjusted crude data; and (iii) offspring and controls, where crude data were adjusted for age (except age and sex), sex (except sex), and BMI (except age, sex, BMI, and % fat). Examination was performed as previously described (2, 20, 21). The presence of metabolic syndrome was determined using National Cholesterol Education Program (NCEP), Adult Treatment Panel III (ATP III) criteria (25). Percentage body fat wasJews has yielded interesting findings regarding the role of adiponectin levels and ADIPOQ polymorphisms in this rare phenotype. Our results suggest that higher adiponectin levels may contribute to longevity through its anti-atherogenic and anti-inflammatory effects. We found that offspring of long-lived probands have higher adiponectin levels than spouse controls, supporting a genetic mechanism for exceptional longevity. Two common ADIPOQ polymorphisms were associated with adiponectin levels, with stronger evidence in men. These same polymorphisms were over-represented in exceptionally long-lived men, suggesting that genetic variants in ADIPOQ may contribute to exceptional longevity. However, the association was not significant after statistical adjustment for multiple comparisons. Further longitudinal studies are needed to confirm these findings and determine the role of adiponectin and ADIPOQ polymorphisms in cardiovascular outcomes.The study on Ashkenazi Jews was based on the hypothesis that the characteristics of longevity may be less complex in this relatively homogeneous population. The findings in this population are likely to reflect biologically and genetically relevant pathways present in other populations as well. The relationships observed between adiponectin levels and BMI, sex, and lipoprotein profile are in complete agreement with the findings of others in diverse populations (14). These findings shed light on the biology behind the emerging evidence that human longevity is being threatened by the epidemic of obesity (10). Further mechanistic understanding of the role of adiponectin in promoting longevity may lead to the development of strategies for delaying or preventing age-related diseases. 

ACKNOWLEDGMENTS