Notes: ‘‘Healthy aging’’ was defined as survival to age 90 years with an absence of six major chronic diseases (coronary heart disease, stroke, cancer, chronic obstructive pulmonary disease, Parkinson’s disease, diabetes), high physical function (could walk . ½ mile), and high cognitive function (Cognitive Abilities Screening Instrument score .74) in participants who were healthy at the baseline examination.

baseline (free of six major chronic diseases and with high physical/cognitive function; n ¼ 1495), the men who possessed at least one copy of the Int 14A variant (n ¼ 9) were significantly more likely to remain healthy until at least 90 years of age (p ¼ .025; Table 4). One hundred seventy- three men had the D442G missense mutation, but no association was found between this variant and mortality (p ¼ .38).

*Values were taken at baseline (Honolulu Heart Program Exam:

–

eterozygous or homozygous. HDL-C ¼ high-density lipoprotein cholesterol; NA ¼ not applicable.

primarily Caucasian men and women from New York found that low HDL-C levels were significantly associated with all-cause mortality in men, but not women (25), and an 11-year study that followed 1211 Chinese retirees (92% men) from average age 70 to average age 80 years found that CHD-related deaths decreased with increasing HDL-C levels (24).

D ISCUSSION

A strong inverse association exists between blood levels of HDL-C and the risk of CVD in middle-aged individuals (20,21). However, the influence of HDL-C on survival and aging phenotypes in the elderly population is more ambiguous, and few studies have focused on elderly minority populations (12,22–25). Previous reports on the Japanese-American men of the HHP were among the first to demonstrate the inverse relationship between HDL-C and CHD (21) in middle-aged persons, and more recent findings suggest that plasma HDL-C level is also inversely asso- ciated with CHD incidence in elderly persons (12).

The current long-term follow-up study provides further evidence for an inverse relationship between HDL-C and CVD mortality in one of the largest studies (n ¼ 3562) of oldest-old men (average age 84 years at study’s end and maximum age 99 years). In addition, this study provides evidence that higher levels of HDL-C promote a healthy aging advantage for elderly men. Healthy survival as a phenotype (absence of six major age-related diseases with concomitant high physical and cognitive function) has never been studied with regard to HDL-C and CETP gene variants, so this is important and novel information. We found that Japanese-American men of the HHP with the relatively rare Int 14A mutation in the CETP gene were significantly more likely to be healthy beyond 90 years of age. Additionally, a large difference in mortality (reduced by half) between participants with and without the Int 14A mutation suggests an overall survival advantage for men

adjusted HDL-C levels are negatively associated with CVD- related mortality, but not total mortality, in this elderly population. Age-adjusted HDL-C levels were also positively associated with non-CVD mortality; however, this trend was lost with further adjustments for selected CVD risk factors. A healthy aging advantage was found for individuals with higher levels of HDL-C and for individuals with the Int 14A variant in the CETP gene. Furthermore, a nonsignificant trend indicated that men with the Int 14A variant may also have an overall survival advantage. Taken together, these data support prior findings that gene variants that affect HDL-C levels may contribute to exceptional longevity, and they extend such findings to a healthy aging phenotype and to a Japanese population.

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Importantly, more work needs to be done in this area because the influence of HDL-C on mortality has not been clearly established for very old persons. For example, a population-based study of 997 elderly (average age 79 years) men and women from Connecticut found that risk factor-adjusted HDL-C levels were not associated with CHD-related mortality (23). However, a follow-up to this report included the same participants in a much larger collaborative study of 3904 elderly men and women of similar age, and found that low HDL-C levels predicted CHD mortality in both sexes, suggesting that the prior study may have lacked sufficient power (22). A 10-year longitudinal study of 350 elderly (75- to 80-year-old),

Figure 1. Age-adjusted all-cause mortality for men with (þ) and without ((cid:4)) the Int 14A variant of the cholesteryl ester transfer protein (CETP) gene. PY ¼ person years. p ¼ .20.

with this variant; however, this trend was not statistically significant. Like other studies of CETP mutations in this group (10,12), the relatively small number of study par- ticipants with mutations in the CETP gene and the limited number of CVD events resulted in lack of statistical power, thus making it difficult to detect an association between specific CETP genetic variants and longevity.

comparison with younger participants suggesting increased mortality risk with the variant (30). One cross-sectional study of the HHP cohort reported an excess of CHD in individuals with both a CETP mutation and moderate levels of HDL-C (10), which was contrary to expectations. However, cross-sectional studies are open to survival bias among prevalent cases and caution must be applied when interpreting their results. For example, a more recent longitudinal study of the HHP could not confirm those findings, and instead reported a trend for lower CHD incidence rates in men with a CETP mutation (12).