Collecting this large number of centenarians has allowed us to relate a biological phenotype to a functional one. We hypothesized that high plasma HDL levels are protective on cognitive function among centenarians. We tested cognitive capability by minimental score test (MMSE) and indeed, the HDL plasma levels were highly positively correlated with the MMSE test score. Strict analysis of the MMSE distribution compared to HDL levels revealed that subjects with higher HDL plasma levels were significantly differentiated in MMSE score compared to subjects with low HDL levels, both in men and women (Atzmon et al., 2002). Statistical adjustment for gender, triglyceride levels, nutrients, BMI, LDL levels, albumin, and apolipoprotein (APO-A1) did not affect the association strength between HDL levels and cognitive function. Thus, HDL is a strong independent predictor of cognitive function in this population with very old brains (Atzmon et al., 2002).

The mechanisms of extending life or its components are still unknown. We believe that we have established some insight into the understanding of exceptional longevity and its complexity through the connection between favorable lipid profiles and being spared from age-related diseases. Because such a large percentage of centenarians and offspring have large lipoprotein particle size, we suggest that a favorable lipoprotein profile is necessary but may not be sufficient for exceptional longevity. Indeed, these subjects had to survive the childhood infection epidemic of the beginning of the last century; they avoided cancer and other age-related diseases. Interestingly, 15% of our population has or had a variety of tumors, and the distribution of tumors amongst those with and without CETP genotype is similar. However, we found that centenarians have the same cancer type distribution compared to a common population, but it occurs 20 years later and in mild condition. This data was not associated with any genotype or phenotype described earlier and further illustrates the complexity in elucidating factors involved in longevity. Nevertheless, association analysis of the CETP gene polymorphism demonstrating a causal connection to a favorable lipid profile leads us to conclude that CETP may be the first gene implicated in longevity. Hopefully, this line of research will lead us to establish which genotype is necessary or/and sufficient for lipoprotein metabolism and exceptional longevity (Barzilai et al., 2003).

Of special note is our approach for phenotype. We have realized that a phenotype that could have sustained our subjects throughout life may not be determined any longer because they are near the end of their life. At this age, phenotypic changes that are seen with longevity may be attenuated as in the examples of BMI and HDL levels. In addition, centenarians do not have the appropriate control group, consisting of subjects who died decades ago. Therefore, our study is unique in setting a control group of offspring of centenarians and their age-matched spouse or neighbors. We have shown that the offspring are healthier than the control, supporting the transfer of genetics from their prolong-lived parents. It is this group that allowed us to conclude that lipoprotein particle size is inherited and led us to focus on candidate genes.

In recent years, the strong component of inheritance of longevity among the oldest old became well-established. Increased odds ratios between 4- and 17-fold from appropriate control have been demonstrated amongst siblings and parents of subjects with exceptional longevity (Atzmon et al., 2004; Perls et al., 1998). However, approaches that led to implication of genetic/biological pathway for longevity have been discovered very recently (Barzilai et al., 2003; Geesaman et al., 2003). The two approaches have been a result of identifying a specific intermediate phenotype leading to a candidate gene approach; furthermore,