are not altered by APOC3 genotype, suggest that the effect of the genotype on the lipoprotein phenotype is mainly mediated by mechanisms that do not involve alterations of these apolipoproteins.

Genetic determinants of human longevity are likely to be multifactorial and polygenic. Thus, polymorphisms in apoli- poproteins and related genes are likely to be only one of several potential pathways in which genetic variants influence longevity. Our approach—to exploit the potent selection of favorable genotypes in exceptionally aged individuals—can be extended to other candidate genes as well as genome-wide analysis. Replications of observed associations of genotypes with longevity, coupled with functional studies to define the mechanisms whereby specific genotypes influence longevity- associated phenotypes, will provide important new under- standings of killing diseases and the aging process. These new understandings could potentially provide insights into preventive and therapeutic interventions for several age- related diseases that impart significant morbidity and mortal- ity among elderly individuals.

We have also shown an association of the APOC3 (cid:1)641 CC genotype with increased insulin sensitivity as measured by homeostatic model assessment. There are known polymor- phisms of the APOC3 promoter within an insulin response element that affect the level of transcription in response to insulin in vitro [29]. In vivo, APOC3 transcription seems to be dependant on insulin, among other factors [30]. Although the (cid:1)641 variant is not located within the insulin response element of the APOC3 gene, the favorable CC genotype was strongly associated with a better insulin sensitivity estimated by the homeostatic model assessment. This can potentially contribute to healthier aging in individuals with the APOC3 (cid:1)641 CC genotype.

exceptional longevity remain largely unknown, pathways involved in lipoprotein metabolism appear to have important influences on longevity in humans. First, the CVD-protective phenotypes of high HDL and large lipoprotein particles sizes are dramatically expressed in our centenarians, and were confirmed in Japanese centenarians [31], and oldest old Italians [32]. Second, a variant in the CETP gene [6] is over- represented in our centenarians, a finding that was confirmed in oldest old Italians [32]. Low CETP levels, which were explained in part by this CETP variant, were observed in our study [6] and in Japanese centenarians [31]. Sequence variants in another lipoprotein gene, the microsomal transfer protein gene, were implicated in another study of centenarians [7]. This study adds APOC3 to the list of lipoprotein genes that may influence exceptional longevity. Interestingly, all these genes are involved in different steps of lipoprotein metab- olism and could potentially be additive in their effects.

Materials and Methods

Study design and participants. In this case-control study, Ashkenazi Jews were recruited as described elsewhere [5,6]. The Ashkenazi population is believed to have descended from a small group of founders based on both historical records and modern genetic evidence. The advantage of using founder populations is that the genetic determinants of a particular disease may be more homoge- neous and easier to define, and false positive results due to population stratification is less likely [39]. Indeed, specific mutations in a number of disease genes (e.g., breast cancer gene 1, breast cancer gene 2, adenomatosis polyposis coli gene, hereditary prostrate cancer gene) have been initially identified in the Ashkenazi population at prevalence rates consistent with a founder effect [40–44]. Stratification in these studies has not been required, and indeed these genes were later implicated in other populations, too [45,46].

Two hundred and thirteen probands with exceptional longevity (157 females and 56 males, age 98.2 (0.36) y [mean (SE)], range 95–107 y; 48% over the age of 100 y) were recruited to participate in the study. The participants’ ages were defined by birth certificates or dates of birth as stated on passports. Probands were required to have been living independently when they were 95 y of age as a reflection of good health, although at the time of recruitment they could be at any level of dependency. In addition, probands were required to have a child who was willing to participate in the study. The offspring group consisted of 122 females and 94 males (age 68.3 [0.45] y, range 51–89 y). The control group included 258 participants derived from two sources: Ashkenazi Jews from the general population recruited by the Einstein Aging Study and spouses of the recruited offspring. The study sample included 183 participants with mean age 71.3 (0.67) y, 57% female [47]. Spouses of offspring included 75 participants with mean age 70.2 (1.17) y, 53% female. These controls as a comparison group similar in age to the offspring are important to overcome the limitation of a cross-sectional sample, because the effects of age on genotype, phenotype (APOC3 levels, lipids etc.), and outcomes (hypertension and longevity) are minimized. Written informed consent was obtained and the study was approved by the Committee on Clinical Investigations of the Albert Einstein College of Medicine.