The role of CETP as a longevity gene (a gene that enhances survival to exceptional old age) has also been called into question, and this area clearly requires further study. On the supportive side, a CETP deficiency mutation (I405V) that causes an increase in HDL concentration and larger particle size has been associated with increased odds for exceptional longevity and decreased odds for dementia in studies of Ashkenazi Jewish centenarians and their offspring (4,5). Some long-lived families in Japan also appear to possess a higher prevalence of the Int 14A variant (26), which has similar effects on HDL levels and particle size as the I405V variant. Furthermore, a study of several hundred frail, community-dwelling octogenarians and nonagenarians in Italy also found a protective effect of HDL-C on the risk of all-cause mortality, although the genetic basis of this was not reported (27). These findings suggest that some aspect of the high HDL phenotype may have lifelong protective effects and that this is apparent in multiple ethnic groups. However, until the current study, whether this phenotype is associated with good health in long-lived persons or healthy aging (i.e., low morbidity, high physical and cognitive function as a single phenotype) had not been studied.

Interestingly, some work suggests that heterozygous CETP-deficient patients, who have highly differentiated HDL, especially those with high LpA-I a-1 levels, have more effective reverse cholesterol transport (improved anti-atherogenesis) as compared to homozygotes, who may have very large, undifferentiated HDL particles. Thus CETP heterozygotes may have more effective reverse cholesterol transport and may be at less CVD risk than homozygotes, and we speculate that this might be linked to other phenotypes of healthy aging (32). Therefore, it is plausible that differences in HDL subtype and effectiveness may be one possible explanation for the differential risk seen with different CETP inhibitors and genotypes in clinical and epidemiological studies. These differences might also affect healthy aging and longevity. More research is required in this important area to understand these complexities and to generalize findings between populations.

On the negative side, the epidemiologic data are not universally supportive. For example, prior cross-sectional studies of Japanese and Italian centenarians found that CETP mutations were not associated with exceptional longevity (28,29), and a marked reduction in the prevalence of the Int 14A mutation was found in a small (n = 67) sample of elderly (>80 years) Japanese participants.

Conclusion

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