Among the advantages of this study are its large number of participants, its longitudinal design, strong pheno- typing, and a relatively homogeneous population. The HHP/HAAS is among the most comprehensive and largest studies of aging men and thus provides a valuable oppor- tunity to assess aging- and longevity-related phenotypes and genotypes.

The epidemiological promise of CETP inhibition for increasing HDL levels and lowering CVD risk has been deemed sufficient enough to initiate clinical trials, but, surprisingly, a recent clinical trial of a promising CETP inhibitor that markedly increases HDL-C (.50%) was terminated due to increased mortality (9). The reasons are unknown, but one possibility is that findings may have been due to higher BP in the intervention group and may have little to do with CETP. However, it raises the important issue of assessing multiple age-related end points, including all-cause mortality.

Disadvantages, as mentioned, include the small numbers of participants with one or more copies of the CETP gene variants of interest and limited statistical power. There is also the possibility that the protective effect for healthy aging is a false-positive finding. It should be replicated in other population samples. Another drawback if the finding is confirmed in other populations is that the mechanism may not necessarily be due to the blood level of CETP. Further work should attempt to correlate blood levels of CETP to healthy aging. Many such genetic findings may be population specific. For example, the gene variants that we studied are prevalent in 2%–7% the Japanese population (11) but are rare in other populations. Finally, another limitation of this study is that we are studying elderly individuals who have already survived, and survival factors may differ at younger ages.

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Despite these hypothetical explanations for the contra- dictory findings, the reasons for such conflicting results are perplexing. It is possible that the focus on CETP inhibition leading to higher total plasma HDL levels and larger HDL particle size, the two most commonly touted protective mechanisms, may be overly simplistic. Recent work sug- gests that CETP inhibition does more than just raise HDL or alter HDL particle size. CETP also plays an important role as a modulator of HDL metabolism and affects its composi- tion and properties (31). That is, CETP can alter the distribution and apolipoprotein make-up of HDL particles. Gene variants, such as I405V or Int 14A, which cause CETP deficiency, may cause the apoA-I in these particles to associate with apoA-II and other HDL apolipoproteins (except apoA-IV) forming HDL that differs in apolipopro- tein composition and function.

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 non- agenarians 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 ¼ 67) sample of elderly (.80 years) Japanese participants in

Conclusion

The current study adds further epidemiologic support for a role of HDL-C and CETP genotype in an ethnic Japanese population for phenotypes related to healthy aging and