A limitation of our cohort was that it only included male participants. Thus, the SNPs tested could be associated with longevity or other aging-related phenotypes in female par- ticipants, as shown for the SNP in EXO1 in female, but not male, German centenarians (21). The longevity-associated allele in the EXO1 promoter, by elevating EXO1 expression, could theoretically have an effect on longevity.

Discussion

To date findings on genetic variants conferring an increase in human life span are limited (23). This reflects, in part, the difficulty of obtaining cohorts of suitable study participants who have attained extreme old age. Therefore, given suffi- cient power, any data, whether positive or negative, may be instructive in deciphering the molecular genetic etiology of human longevity. In the present nested case–control study, after correction for multiple comparisons, none of the SNPs tested were significantly associated with living to the age of 95 years or more. Due to limited resources, not all SNPs that have been discovered in each gene were tested. rather, we tested “tagging SNPs” identified by the HapMap database or, in the case of EXO1, a single functional variant, among seven of potential functional relevance to longevity (21). Thus the SNPs we selected provided maximal coverage of genetic variability across all but EXO1, taking advantage of linkage disequilibrium. We cannot, however, exclude the possibility that one or more polymorphism not in linkage disequilibrium with the SNPs tested, or population-specific

A major advantage of this study is that it employed a nested case–control design. This type of study design selects cases and controls from an ongoing cohort study that involves lon- gitudinally collected data. Consequently, several phenotypes of interest, such as disease prevalence, health status, and functional status, could be obtained by direct clinical exami- nation when the participants were younger, thereby elimi- nating recall bias. recall bias can decrease the reliability of findings from studies of the very old. In this study, major diseases were adjudicated by a morbidity and mortality com- mittee that used performance-based measures of physical and cognitive function to supplement self-reported information.

There are several other strengths to our study. First, the candidate genes selected for analysis were chosen a priori based on hypothesis-driven criteria. Second, not only did the study involve a nested case–control design but it had a high event rate (deaths) during a long period of follow- up. Third, the HHP/HAAS cohort is a highly homogeneous

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