The baseline examination for this study was HHP Exam 4, which was carried out between 1991 and 1994 on the surviving HHP participants as part of the Honolulu Asia Aging Study (HAAS), a study of cognitive aging (mean baseline age 78 years, range 71–93 years). The measure- ments taken at this examination provide the baseline clinical data for this study. There are two follow-up periods: total mortality data are available until 2005, which provide 11– 14 years of follow-up. For cause-specific mortality, which is updated less frequently due to its adjudication by a morbidity and mortality committee, the follow-up is 5–8 years. Risk factors measured at baseline included body mass index (BMI), alcohol consumption, smoking habits (pack years), physical activity [as measured by the physical activity index (16)], hypertension, systolic blood pressure (BP), diabetes, and fasting levels of serum glucose, total serum cholesterol, TG, and HDL-C. A diagnosis of hypertension was made when either systolic BP was (cid:2)140 mmHg or diastolic BP was (cid:2)90 mmHg or when the participant was taking medication for high BP. Diabetes was defined on the basis of medical history or the use of insulin or oral hypoglycemic agents. Diabetes was also considered present when fasting glucose concentrations were .125 mg/dL or when glucose levels were (cid:2)200 mg/dL 2 hours after ingestion of 75-g glucose.

Previously we reported that 5.6% of the Japanese- American men of the Honolulu Heart Program (HHP) have either the D442G (5.1%) or the Int 14A (0.51%) mutation in the CETP gene (10). These variants are common in the general Japanese population and appear to explain a signif- icant portion of the variation in HDL-C levels (11). In our prior work these mutations were associated with a 35% decrease in plasma CETP levels and a significant (p , .001) increase in HDL-C levels. More recently, a 7-year follow-up study of the now elderly HHP participants (71–93 years) revealed that the relative risk of CHD incidence is signifi- cantly (p , .05) lower for men with high (.60 mg/dL) HDL-C levels (12). A trend also suggested that men with either the D442G or Int 14A CETP mutations have a lower incidence of CHD.

disease, but fewer protect against multiple age-related dis- eases and disability. HDL has been proposed as a protector against both CVD and dementia, two phenotypes important for healthy aging. However, little is known about how HDL and gene variants that affect HDL might affect other pheno- types that represent healthy aging and longevity. Therefore, the current study investigates the relationship of HDL-C level and CETP mutations to several aging- and longevity- related phenotypes including total mortality, CVD mortality, non-CVD mortality, and a novel phenotype of healthy aging that incorporates multiple diseases, physical function, and cognitive function. This novel phenotype is defined by exceptional survival to age 90 years or more while remaining free of six major chronic diseases and main- taining high physical and cognitive function.

Healthy aging was defined as survival beyond the age of 90 years with the absence of six major age-related diseases (CHD, stroke, cancer, chronic obstructive pulmonary disease, Parkinson’s disease, and type 2 diabetes mellitus), ability to walk half a mile, and absence of cognitive dis- ability as determined by a Cognitive Abilities Screening Instrument (CASI) score . 74 (17).

Participants were excluded from analyses if serum cholesterol levels or CETP genotyping data were not available, resulting in a total study population of 3562 participants for HDL-C level comparisons, and 3448 par- ticipants for the CETP association analysis. For the healthy aging analysis, to achieve a true incidence study, all par- ticipants who were determined to be unhealthy at base- line (prevalence of any one of six major diseases, could not walk a half mile, or had CASI score (cid:3)74) were excluded from the sample, and the remaining 1643 healthy partici- pants were followed until they reached age 90 years or more or died.

M ETHODS

Participants and General Procedures

study of heart disease, stroke, and other diseases in a sample of 8006 men of Japanese ancestry in Hawaii. These men were recruited from 9877 men (all ethnic Japanese men with valid contact information), who were born between 1900 and 1999, and lived on the island of Oahu (13). Participants received comprehensive examinations at the time of enrollment, when they were 45–68 years old (mean age 54 years). Since that time, participants have undergone nine repeat examinations during which phenotypic information has been obtained by physical and cognitive examinations and cross-checked with medical records and self report. Follow-up of all hospital discharges, death certificates, and autopsy records for morbidity and mortality due to CHD, cancer, and stroke has been performed for all participants. A follow-up survey for HHP Exam 4 (1991–1993) found that

Laboratory Analyses

Methods for preparing blood samples for analysis followed the guidelines of the Lipid Standardization Laboratory of the Centers for Disease Control and Pre- vention. Blood samples were collected after an overnight fast of at least 12 hours. Blood was centrifuged within 30 minutes of collection at 3000 3 g for 10 minutes at 48C, and the plasma was frozen at(cid:4)708C for up to 2 months. Samples were shipped to the University of Vermont, where HDL-C

Table 1. Demographics and Clinical Data by Age Group (HHP Exam: 1991–1994)