Correction for multiple comparisons would be considered by many as overly conservative. To our knowledge, there is no other example of a polymorphic allele whose frequency was demonstrated to be so dramatically increased in centenarians and for which there is plausible biological mechanism to explain the association. Although the effect of the valine405 allele on the structure and function of the CETP protein has not been studied, homozygosity for the valine allele has been shown to result in significantly decreased CETP concentrations,34-36 as we demonstrated; and significantly decreased CETP activity,37-39 as confirmed by Boekholdt and Thompson.40 Furthermore, in 2 populations, each with more than 1000 participants, valine 405 homozygosity was associated with a 6.5-mg/dL or approximately 13% increase41 and approximately 4% increase42 in HDL cholesterol.

Although this VV homozygosity appears in less than 20% of the offspring, spouses or neighbors of the offspring, neither of which were enriched with longevity genes, and the cases were the offspring group who were children of the probands. Therefore, differences in environment, social,Explained by other variants in CETP or in other genes that modulate lipoprotein particle concentrations and size. Other single nucleotide polymorphisms in the CETP genes did not differ in frequency between our groups. Moreover, we analyzed regulatory domains of hepatic lipase, which also regulates lipoprotein size, and failed to note any increased frequency of any of the variants we found. Recently, Arai et al. investigated more than 200 Japanese centenarians for association between a CETP TaqI polymorphism (but not the I405V polymorphism) as well as hepatic lipase polymorphisms and did not demonstrate an increase in frequency in this population. Because CETP deficiency has not been previously associated with increased LDL size, additional genes that modulate LDL size or environmental factors are likely to be involved in the regulation of LDL particle sizes and may be necessary to enhance the probability of exceptional longevity. Whether lipoprotein particle size and the I405V CETP polymorphism are important predictors of longevity in other populations remains to be determined.

Statistical expertise: Atzmon, Schechter, Cupples. Obtained funding: Barzilai, Shuldiner. Administrative, technical, or material support: Barzilai, Atzmon, Schaefer, Lipton, Cheng, Shuldiner.

Funding/Support: This work was supported by grants from the Paul Beeson Physician Faculty Scholar in Aging Award, the Ellison Medical Foundation Senior Scholar Award (RO1 AG-18728-01A1), the General Clinical Research Center (MO1-RR12248), and Diabetes Research and Training Center (DK20541) at the Albert Einstein College of Medicine and the Baltimore Veterans Affairs Geriatric Research and Education Clinical Center. Roche Molecular Systems developed genotyping reagents for research use.

Acknowledgment: We thank William Greiner, Deborah Davidson, David Rosen, Reena Gotesman, Pegah Rabizadah, and Carmel Schahar for their contributions to this study; Harry Shamoon, MD, Norman Fleischer, MD, Ilan Gabriely, MD, and Luciano Rossetti, MD, for their support; and David S. Freedman, PhD, for reading and commenting on this article. We are indebted to all participants and their families for their dedication 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, Conn; and the Jewish Home for the Aged, New Haven, Conn., all under the aegis of the association for the Jewish Aging Services, Washington, DC.

In recent years, certain genetic manipulations in lower species have been shown to extend lifespan by mechanisms that seem unlikely to be relevant in humans. Our endeavor to study exceptional longevity in Ashkenazi Jews was based on evidence for strong inheritance of this phenotype. However, the lack of good biological markers that might provide mechanistic insights into exceptional longevity has hampered systematic genetic analysis.

The important findings of this work suggest pleiotropic vascular effects of lipoproteins with large particle sizes that are health-promoting. Striking association of exceptional longevity with homozygosity for the valine 405 allele of CETP may explain in part the link between lipoprotein particle size and exceptional longevity. Further elucidation of the genetic and biological mechanisms that determine lipoprotein particle sizes may provide key insights into preventive and therapeutic interventions for several age-related diseases that impart significant morbidity and mortality to elderly individuals.

REFERENCES

1. Barzilai N., Shuldiner AR. Searching for human longevity genes: the future history of gerontology in the post-genomic era. J Gerontol. 2001;56A:M83-M87.

2. Perls TT, Wilmoth J, Levenson R, et al. Life-long sustained mortality advantage of siblings of centenarians. Proc Natl Acad Sci U S A. 2002;99:8442-

Case-control studies are subject to problems that sometimes limit their validity. However, in the case of genetic studies, these limitations are frequently overcome. A major problem affecting case-control studies is biased-recall ascertainment of exposure status. When the exposure is a genotype, however, this problem cannot arise. Similarly, the use of prevalent cases and control groups entails length-biased sampling; but with longevity as the outcome, once again the problem is nullified.