Fig. 2. Average HDL and LDL particle sizes among probands, offspring, and control groups. ***p < 0.0001.

7. Polymorphism in the CETP gene and the phenotype of exceptional longevity

After the observation that offspring of exceptionally long-lived individuals also have a protective lipoprotein phenotype, we further searched for potential candidate genes. We failed to find any mutations or polymorphism in the promoter of hepatic lipase, a strong determinant of lipoprotein size. We then studied CETP gene, another obvious candidate for it has been shown to modulate HDL and LDL levels and sizes. Our findings showed a significant statistical association between genetic variation in CETP and exceptional longevity (Barzilai et al., 2003). Homo- zygosity for the 405V allele of CETP was at a significantly higher percentage among centenarian and their offspring compared to an Ashkenazi control group (Fig. 3). Further investigation of subjects carrying the VV genotype showed lower serum CETP levels and larger lipoprotein particle sizes. Following reasonable statistical assumption, we calculated that the attributable ‘‘risk’’ of one having the VV genotype to reach exceptional old age is 18.1. We proposed a causal connection between individuals carrying the VV genotype and survival advantage, mediated by decreased levels of CETP that promotes higher lipoprotein sizes and levels which we believe lead to exceptional longevity (Barzilai et al., 2003). This finding along with the recent discovery that a common polymorphism of micro- somal transfer protein (MTP), a protein involved in

6. HDL levels and minimental score

Collecting this large number of centenarians has allowed us to relate a biological phenotype to a functional one. We hypothesized that high plasma HDL level is protective on cognitive function among centenarians. We tested cognitive capability by minimental score test (MMSE) and indeed the HDL plasma levels where 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 differ- entiated in MMSE score compared to subjects with low HDL levels, both in men and women (Atzmon et al., 2002). Statistical adjustment for gender, triglycerides 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 popula- tion with very old brains (Atzmon et al., 2002).

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.

25:20. CETP 405VV genotype percentage       Probands Offspring Ashkenazi Control*p<0.05

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 percent 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 last century; they avoided cancer and other age- related diseases. Interestingly, 15% of our population have or had variety of tumors and the distribution of tumor amongst these 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 a

Fig. 3. Percentage of CETP 405 favorable allele among probands, off- spring, and control groups.*p < 0.05.

lipoprotein metabolism, is associated with exceptional longevity (Geesaman et al., 2003) provides further evidence for a link between genetics and a protective lipoprotein phenotype.

8. Conclusion

In recent years, the strong component of inheritance of longevity among the ‘‘oldest old’’ became well established. Increased odds ratio of 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 result of identifying a specific intermediate phenotype leading to candidate gene approach; furthermore, the second approach was from linkage analysis and ‘industrial’ effort to focus on the site of the initial LOD score (Geesaman et al., 2003). Interestingly, both discov- eries were of known polymorphisms.

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