A Prospective Study of High-Density Lipoprotein Cholesterol, Cholesteryl Ester Transfer Protein Gene Variants, and Healthy Aging in Very Old Japanese-American Men

BACKGROUND: High-density lipoprotein cholesterol (HDL-C) and cholesteryl ester transfer protein (CETP) gene deficiency mutations that increase HDL-C levels have been associated with exceptional longevity. However, a recent clinical trial of a promising CETP inhibitor that markedly increases HDL-C was terminated due to increased mortality. In light of this controversy, we examined the relationship among HDL-C, CETP mutations, and longevity phenotypes in the long-lived Japanese-American men of the Honolulu Heart Program (HHP). METHODS: Japanese-American men (n = 3562) were followed for up to 8 years, from average age 78 to average age 84 (maximum age 99), or until death. Total mortality, cause-specific mortality, and healthy survival were evaluated for associations with HDL-C level and CETP genetic variants common in the Japanese population (CD442G and Int 14A). RESULTS: HDL-C was negatively associated with cardiovascular disease (CVD) mortality (p =.002) but not related to non-CVD (p =.147) or total (p =.547) mortality after adjustment for common risk factors. There was a trend for lower mortality for the men with the Int 14A variant. These men also had higher HDL-C levels (p =.047) and were significantly more likely to be healthy survivors (absence of six major age-related diseases and high physical/cognitive function) beyond the age of 90 years (p =.005). CONCLUSIONS: Low HDL-C level is a risk factor for CVD mortality in elderly Japanese-American men. High HDL-C and the Int 14A variant of the CETP gene may increase odds for healthy aging.