Note: SNP ¼ single nucleotide polymorphism; SE ¼ standard error; BMI ¼ body mass index.

lowing adjustment for age, sex, and BMI, we found that offspring of exceptionally long-lived individuals (defined in this case as 95 years old or older), some of whom will also live to exceptionally old age, have significantly higher serum adiponectin levels than do controls without a family history of exceptional longevity. A caveat is that modeling assumptions were necessary to detect this difference, but another way to state the observation is that unadjusted mean adiponectin levels were similar between offspring and controls (12.8 vs 12.5 lg/mL, respectively), whereas higher levels would have been expected in controls given their significantly higher mean age. Furthermore, exceptionally long-lived individuals have higher levels of serum adipo- nectin compared to younger persons. An association between higher adiponectin levels and age has been reported pre- viously (14), but we extend these findings to exceptional old age. Lacking an age-matched control group, it is not pos- sible to know if the extremely high levels seen in probands are purely a consequence or in part a cause of exceptional longevity, but the higher adjusted levels seen in their offspring lend support to the latter hypothesis.

expanded set of 748 participants. Frequencies were not significantly different between probands and controls (Table 4). However, given sex differences in survival to excep- tional longevity (34) and the differences in sex ratios in cases versus controls, we stratified the sample by sex and found that the frequencies of two SNPs, rs17300539 and APM1þ2019, both associated with adiponectin levels, were significantly different in frequency in male probands versus controls but not female probands versus controls. For promoter SNP rs17300539, 31% of male probands versus 16% of male controls had at least one copy of the minor (A) allele (p ¼ .04). Male offspring had an intermediate A allele carrier frequency of 26% (p ¼ .04 vs controls). For SNP þ2019, 38% of male probands versus 19% of male controls had the del/del genotype (p ¼ .01) (offspring frequency ¼ 25%, p ¼ .25 vs controls; Table 4); an additive effect was also observed (p ¼ .03). The equivalent analyses in women revealed that 19% of probands versus 29% of controls carried the rs17300539 A allele (p ¼ .08) and 22% of probands versus 23% of controls had the þ2019 del/del genotype (p ¼ .89). The interaction between sex and genotype was significant in both probands versus control cases (p ¼ .007 for rs17300539 and p ¼ .03 for þ2019 by Breslow–Day test for homogeneity of the odds ratios). However, as shown in Table 3, raw significant differences were no longer statistically significant after adjustment for multiple comparisons.

are major risk factors for cardiovascular morbidity and mortality, our findings support the hypothesis that the mechanism whereby higher adiponectin levels may contrib- ute to longevity is through its anti-atherogenic (5,6) and anti-inflammatory (5,7,8) effects. As in the case of HDL levels, adiponectin levels are consistently higher in women than in men, probably due to variations in fat distribution that contribute to adiponectin secretion (14,36). These sex differences in adiponectin levels are consistent with lower CVD incidence rates and greater life expectancy observed in women in our population.

D ISCUSSION

Living to 100 years is a rare phenotype, with prevalence in the general population of 1 in 10,000 individuals (35). Although we have recruited numerous participants at this age, they are rare survivors, and if genetics helps them attain such longevity they should be enriched for specific favor- able genotypes and their corresponding phenotypes. Fol-

The observation that offspring of long-lived probands have higher BMI-, age-, and sex- adjusted adiponectin levels than do spouse controls is suggestive of a genetic mech-

Table 4. Prevalence of Genotypes (%) Associated With High Adiponectin Levels in Probands, Offspring, and Controls

All (N ¼ 653–748) Men (N ¼ 267–298) Women (N ¼ 386–450) Genotype Probands Offspring Controls Probands Offspring Controls Probands Offspring Controls rs17300539 G/A or A/A 22.3 25.2 23.5 30.8*,y 26.7*,y 15.7 19.0 23.9 28.9 APM1þ2019 A/– or –/– 80.8 74.9 80.6 86.7 75.8 81.8 78.7 74.2 79.7 APMþ2019 –/– only 26.2 24.4 21.5 37.8*,y 25.0 19.0 22.1 23.8 23.3

Notes: *p , .05 vs controls. yp , .05 for homogeneity of the odds ratios vs women.

group; offspring of centenarians had an intermediate (21%) frequency (20). Furthermore, lipoprotein particle size was found to be an independent heritable predictor of longevity and was also associated with the CETP VV genotype. We now find that lipoprotein particle size is related to levels of adiponectin (Tables 1 and 2), thus leading us to consider the relationship between adiponectin levels and polymorphisms of CETP. We found no association between the 405 CETP genotype and adiponectin levels, suggesting that the effect of the CETP VV genotype on lipoprotein particle size is not mediated via adiponectin levels (data not shown).