Genetic and Environmental Determinants of Healthy Aging

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

1 1 1 1,2 Tanya A. Koropatnick, Jennifer Kimbell, Randi Chen, John S. Grove, 1,2,3 1,2,3 1,2,3 Timothy A. Donlon, Kamal H. Masaki, Beatriz L. Rodriguez, 1,2,3 1 1,2,3 Bradley J. Willcox, Katsuhiko Yano, and J. David Curb

1Pacific Health Research Institute, Honolulu, Hawaii. 2John A. Burns School of Medicine, University of Hawaii at Manoa. 3Kuakini Medical Center, Honolulu, Hawaii.

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 (n¼3562) 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 ¼ .002) but not related to non-CVD (p ¼ .147) or total (p ¼ .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 (p¼.047) 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 ¼ .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.

Key Words: High-density lipoprotein cholesterol (HDL-C)—Cholesteryl ester transfer protein Americans—Cardiovascular disease—Longevity—Healthy aging.

CARDIOVASCULAR disease (CVD) is a leading cause of death in the Western world, and some data suggest that individuals gifted with exceptional longevity are able to avoid CVD and other major age-associated diseases (1,2). Despite efforts to reduce CVD risk factors, such as cholesterol, smoking, and hypertension, coronary heart disease (CHD)-related mortality remains much higher in the United States than in some non-Western countries such as Japan, whose population is among the longest lived and healthiest in the world (3).

to exceptional longevity (4–6). One of these is the cholesteryl ester transfer protein (CETP) gene, which codes for a carrier in reverse cholesterol transport that mediates the transfer of cholesteryl esters from HDL to LDLs and triglyceride (TG)-rich lipoproteins (7). Several naturally occurring mutations in the CETP gene lead to dramatic reductions in plasma CETP levels and a significant increase in HDL-cholesterol (HDL-C) levels. The most common missense variation (I405V) is known to be over-represented in Ashkenazi Jewish centenarians and their offspring (4). Centenarians and their offspring had an approximate 2- to 3-fold increased frequency of homozygosity for the codon 405 isoleucine to valine (I405V) gene variant of CETP (VV genotype).

Recent findings suggest that a favorable lipoprotein profile, including high levels of high-density lipoprotein (HDL) and low levels of low-density lipoprotein (LDL), is predictive of exceptional longevity, likely due in part to reduction in CVD risk (4). Certain variants in genes involved in lipoprotein metabolism have also been linked

Given that a reduction in CETP level leads to dramatic increases in HDL-C, a new class of CETP inhibitor drugs

only five men could not be traced for mortality information (14). Written informed consent has been obtained from all study participants. Procedures used in the HHP are performed in accordance with institutional guidelines, are approved by an institutional review board, and are described in detail elsewhere (15).

was developed for use in combination with LDL-C-lowering statins to improve lipoprotein profiles and decrease CVD risk in patients with dyslipidemia (8). However, in late 2006, a clinical trial of the CETP inhibitor torcetrapib was halted due to increased mortality in persons taking the drug (9). This development underscores the need for further investigation into the relationship among CETP, HDL-C levels, and health outcomes.