high levels and increased size of HDL. This discrepancy may be explained by other variants in CETP or in other genes that modulate lipoprotein particle con- centrations and size. Other single nucleotide polymorphisms in the CETP genes did not differ in frequency be- tween our groups. Moreover, we ana- lyzed regulatory domains of hepatic li- pase, which also regulates lipoprotein size, and failed to note any increased fre- quency of any of the variants we found. Recently, Arai et al43 investigated more than 200 Japanese centenarians for as- sociation between a CETP TaqI poly- morphism (but not the I405V polymor- phism) as well as hepatic lipase polymorphisms, and did not demon- strate an increase in frequency in this population.BecauseCETPdeficiencyhas not been previously associated with in- creased LDL size, additional genes that modulateLDLsizeorenvironmentalfac- tors are likely to be involved in the regu- lation of LDL particle sizes and may be necessary to enhance the probability of exceptional longevity. Whether lipo- proteinparticlesizeandtheI405VCETP polymorphism are important predic- tors of longevity in other populations re- mains to be determined.

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

Funding/Support: Thisworkwassupportedbygrants fromthePaulBeesonPhysicianFacultyScholarinAg- ing Award, the Ellison Medical Foundation Senior Scholar Award (RO1 AG-18728-01A1), the General Clinical Research Center (MO1-RR12248) and Dia- betesResearchandTrainingCenter(DK20541)atthe Albert Einstein College of Medicine, and the Balti- more Veterans Affairs Geriatric Research and Educa- tion Clinical Center. Roche Molecular Systems devel- oped genotyping reagents for research use and

Acknowledgment: WethankWilliamGreiner,Debo- rahDavidson,DavidRosen,ReenaGotesman,Pegah Rabizadah, and Carmel Schahar for their contribu- tions to this study; Harry Shamoon, MD, Norman Fleischer, MD, Ilan Gabriely, MD, and Luciano Ros- setti, 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 grate- fultothefollowinginstitutionsthatassistedinrecruit- ment:TheHebrewHomefortheAging,Riverdale,NY; Kittay House, Bronx, NY; the Hebrew Home Hospi- tal, 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, Wash- ington, DC.

nrecentyears,certaingeneticmanipu- lationsinlowerspecieshavebeenshown to extend life-span by mechanisms that seemunlikelytoberelevantinhumans.1 Our endeavor to study exceptional lon- gevity in Ashkenazi Jews was based on evidence for strong inheritance of this phenotype.1-4However,thelackofgood biological markers, which might pro- vide mechanistic insights into excep- tional longevity, has hampered system- atic genetic analysis. The important findings of this work suggest pleiotro- pic vascular effects of lipoproteins with large particle sizes that are health pro- moting. Striking association of excep- tional longevity with homozygosity for thevaline405alleleofCETPmayexplain inpartthelinkbetweenlipoproteinpar- ticlesizeandexceptionallongevity.Fur- ther elucidation of the genetic and bio- logical mechanisms that determine lipoprotein particle sizes may provide key insights into preventive and thera- peutic interventions for several age- related diseases that impart significant morbidity and mortality to elderly indi- viduals.

REFERENCES

1. BarzilaiN,ShuldinerAR.Searchingforhumanlon- gevity 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 cente- narians. Proc Natl Acad Sci U S A. 2002;99:8442-

Case-control studies are subject to problems that sometimes limit their va- lidity. However, in the case of genetic studies, these limitations are fre- quently overcome. A major problem af- fecting case-control studies is biased- recall ascertainment of exposure status. When the exposure is a genotype, how- ever, this problem cannot arise. Simi- larly, the use of prevalent cases and control groups entails length-biased sampling; but with longevity as the out- come, once again the problem is nul- lified. Case-control studies cannot by themselves establish a causal relation- ship but with a genotype exposure, at least the possibility of reverse causal- ity is entirely excluded and the expo- sure is unequivocally known to pre- cede the outcome. The recruitment of cases and control groups from sepa- rate population groups is another com- mon source of bias in case-control stud- ies. In our situation, the controls were

Atzmon G, Schechter C, Greiner W, et al. Clinical

4. Puca AA, Daly MJ, Brewster SJ, et al. A genome- wide scan for linkage to human exceptional longev- ityidentifiesalocusonchromosome4.ProcNatlAcad

7. AtzmonG,GabrielyI,GreinerW,etal.PlasmaHDL levelshighlycorrelatewithcognitivefunctioninexcep- tional longevity. J Gerontol. 2002;57:M712-M715. 8. LancasterJM,CarneyME,FutrealPA.BRCA1and 2: a genetic link to familial breast and ovarian cancer.

10. ExpertPanelonDetection,Evaluation,andTreat- ment of High Blood Cholesterol in Adults. Executive Summary of The Third Report of The National Cho- lesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood CholesterolinAdults(AdultTreatmentPanelIII).JAMA. 2001;285:2486-2497.

Author Contributions: Study concept and design: Barzilai. Acquisitionofdata:Barzilai,Atzmon,Schaefer,Lipton, Cheng. Analysisandinterpretationofdata:Barzilai,Atzmon, Schechter, Cupples, Lipton, Cheng, Shuldiner. Draftingofthemanuscript:Barzilai,Atzmon,Schechter, Cheng. Critical revision of the manuscript for important in