of exceptional longevity. The offspring–control difference in adiponectin levels appears to be stronger in men than in women. In addition, two common ADIPOQ polymorphisms were associated with adiponectin levels, with stronger evidence in men. (This association was not seen in the probands, which may be due to the small sample size and other factors potentially controlling aging- and/or longevity- related increases in adiponectin levels.). To our knowledge, we further demonstrate for the first time that the high adiponectin alleles of these same ADIPOQ polymorphisms are over-represented in exceptionally long-lived men. The rs17300539 A allele and þ2019 del allele were significantly more prevalent in long-lived male probands versus male controls. Thus our data support the hypothesis that genetic variants in ADIPOQ that influence adiponectin levels may contribute to this rare phenotype of exceptional longevity. That this association was seen only in men suggests that polymorphism in ADIPOQ may be a greater determinant of longevity in men than in women. This may be due to the fact that women have higher adiponectin levels compared to men and are protected from cardiovascular morbidity and mortality independent of genotype. Given the drawback of association studies with insufficient statistical power, a recognized limitation of performing multiple comparisons is an inflation of type I error. Indeed, after statistical adjust- ment for multiple comparisons, our raw results were no longer significant. In any case, we are currently following both male and female offspring and controls longitudinally with regard to cardiovascular outcome to test the hypothesis that increased adiponectin levels, particular adiponectin genotypes and other factors inherited from long-lived pro- bands, provide protection from CVD through enhanced

Our endeavor to study exceptional longevity in Ashkenazi Jews was based on the hypothesis that the phenotypic and genotypic characteristics of longevity may be less complex in this relatively genetically homogeneous population. At the same time, findings in this population will likely reflect biologically and genetically relevant pathways present in other populations as well. Indeed, the relationships we observed between adiponectin levels and BMI, sex, and lipoprotein profile are in complete agreement with findings of others in diverse populations (14). Because obesity is associated with low adiponectin, these findings also 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 the promotion of longevity may lead to development of strategies for the delay or prevention of age-related disease.

ACKNOWLEDGMENTS

This work has been supported by grants from the Paul Beeson Physician Faculty Scholar in Aging Award, the Ellison Medical Foundation Senior Scholar Award, the National Institutes of Health (R01 AG18728), the General Clinical Research Center (M01-RR12248), the Diabetes Research and Training Center (DK 20541) at the Albert Einstein College of Medicine, and the Baltimore VA Geriatric Research and Education Clinical Center.

Because we have studied a relatively homogeneous cohort of Ashkenazi Jews residing on the East Coast of the United States, population stratification is an unlikely explanation for the observed associations. Furthermore, the same alleles enriched in male probands were associated with higher adiponectin levels, as previously reported in other populations (13,28). Theþ2019 single nucleotide deletion is present in the 39-untranslated region, and thus it is possible that it could affect protein expression by altering messenger RNA (mRNA) stability or translational efficiency. However, we cannot rule out the possibility that this and the promoter variant may not be causal, but rather in linkage disequilib- rium with functional variants. Functional studies will be required to further define the causal role of these variants on adiponectin levels and the longevity phenotype. Since several comparisons were made and the associations are at a modest level of significance, the replication of previous reports of association with adiponectin levels in the same direction (13,28) supports a true effect on adiponectin levels and enrichment in long-lived probands of the rs17300539 G/A-A/A and APM1þ2019 del/del.

We are indebted to all participants and their families for their commit- ment and enthusiasm. We are also grateful to the following institutions that assisted in recruitment: The Hebrew Home for the Aging, Riverdale, NY; Kittay House, Bronx, NY; the Hebrew Home Hospital, West Hartford, CT; and the Jewish Home for the Aged, New Haven, CT, all under the aegis of the association for the Jewish Aging Services, Washington, DC. We also thank Sandy Ott for performing the genotype analysis.

Drs. Atzmon and Pollin contributed equally to this work.

CORRESPONDENCE

Address correspondence to Nir Barzilai, MD, Institute for Aging Research, Belfer Bldg. #701, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461. E-mail: barzilai@aecom.yu.edu

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