Randi Chen

FOXO3A genotype is strongly associated with human longevity

Human longevity is a complex phenotype with a significant familial component, yet little is known about its genetic antecedents. Increasing evidence from animal models suggests that the insulin/IGF-1 signaling (IIS) pathway is an important, evolutionarily conserved biological pathway that influences aging and longevity. However, to date human data have been scarce. Studies have been hampered by small sample sizes, lack of precise phenotyping, and population stratification, among other challenges. Therefore, to more precisely assess potential genetic contributions to human longevity from genes linked to IIS signaling, we chose a large, homogeneous, long-lived population of men well-characterized for aging phenotypes, and we performed a nested-case control study of 5 candidate longevity genes. Genetic variation within the FOXO3A gene was strongly associated with human longevity. The OR for homozygous minor vs. homozygous major alleles between the cases and controls was 2.75 (P = 0.00009; adjusted P = 0.00135). Long-lived men also presented several additional phenotypes linked to healthy aging, including lower prevalence of cancer and cardiovascular disease, better self-reported health, and high physical and cognitive function, despite significantly older ages than controls. Several of these aging phenotypes were associated with FOXO3A genotype. Long-lived men also exhibited several biological markers indicative of greater insulin sensitivity and this was associated with homozygosity for the FOXO3A GG genotype. Further exploration of the FOXO3A gene, human longevity and other aging phenotypes is warranted in other populations.

Cholesterol and all-cause mortality in elderly people from the Honolulu Heart Program: a cohort study

BACKGROUND A generally held belief is that cholesterol concentrations should be kept low to lessen the risk of cardiovascular disease. However, studies of the relation between serum cholesterol and all-cause mortality in elderly people have shown contrasting results. To investigate these discrepancies, we did a longitudinal assessment of changes in both lipid and serum cholesterol concentrations over 20 years, and compared them with mortality. METHODS Lipid and serum cholesterol concentrations were measured in 3572 Japanese/American men (aged 71-93 years) as part of the Honolulu Heart Program. We compared changes in these concentrations over 20 years with all-cause mortality using three different Cox proportional hazards models. FINDINGS Mean cholesterol fell significantly with increasing age. Age-adjusted mortality rates were 68.3, 48.9, 41.1, and 43.3 for the first to fourth quartiles of cholesterol concentrations, respectively. Relative risks for mortality were 0.72 (95% CI 0.60-0.87), 0.60 (0.49-0.74), and 0.65 (0.53-0.80), in the second, third, and fourth quartiles, respectively, with quartile 1 as reference. A Cox proportional hazard model assessed changes in cholesterol concentrations between examinations three and four. Only the group with low cholesterol concentration at both examinations had a significant association with mortality (risk ratio 1.64, 95% CI 1.13-2.36). INTERPRETATION We have been unable to explain our results. These data cast doubt on the scientific justification for lowering cholesterol to very low concentrations (<4.65 mmol/L) in elderly people.

Performance-based measures of physical function for high-function populations

OBJECTIVES: To improve and broaden the applicability of performance‐based measures of function for use in clinical and research settings.

Low Serum Cholesterol and Mortality Which Is the Cause and Which Is the Effect

BACKGROUND Many studies have reported an association between a low or lowered blood total cholesterol (TC) level and subsequent nonatherosclerotic disease incidence or death. The question of whether low TC is a true risk factor or alternatively a consequence of occult disease at the time of TC measurement remains unsettled. To shed new light onto this problem, we analyzed TC change over a 6- year period (from exam 1 in 1965 through 1968 to exam 3 in 1971 through 1974) in relation to subsequent 16-year mortality in a cohort of Japanese American men. METHODS AND RESULTS The study was based on 5941 men 45 to 68 years of age without prior history of coronary heart disease, stroke, cancer, or gastrointestinal-liver disease at exam 1 who also participated in exam 3 of the Honolulu Heart Program. The association of TC change with mortality end points was investigated with two different approaches (continuous and categorical TC change) with standard survival analysis techniques. Falling TC level was accompanied by a subsequent increased risk of death caused by some cancers (hemopoietic, esophageal, and prostate), noncardiovascular noncancer causes (particularly liver disease), and all causes. The risk-factor-adjusted rate of all-cause mortality was 30% higher (relative risk, 1.30; 95% CI, 1.06 to 1.59) among persons with a decline from middle (180 to 239 mg/dL) to low (< 180 mg/dL) TC than in persons remaining at a stable middle level. By contrast, there was no significant increase in all-cause mortality risk among cohort men with stable low TC levels. Nonillness mortality (deaths caused by trauma and suicide) was not related to either TC change or the average of TC levels in exams 1 and 3. CONCLUSIONS These results add strength to the reverse-causality proposition that catabolic diseases cause TC to decrease.

Peripheral Artery Disease and Cardiovascular Risk Factors in the Elderly The Honolulu Heart Program

Peripheral vascular disease as measured by the ankle/brachial blood pressure index (ABI) is associated with increased risk of mortality and morbidity. Few sources of data on the relationship of risk factors to ABI are available for the elderly, especially those > 80 years of age, and minority populations. ABI measurements from the Honolulu Heart Programs fourth reexamination of 3450 ambulatory, elderly Japanese American men indicate that the prevalence of an abnormal ABI, defined as a ratio of < 0.9, was 13.6%, increasing from 8.0% in those 71 to 74 years of age to 27.4% in those 85 to 93 years. Associations that were U or J shaped were present for a number or risk factors (higher rates of abnormality [ABI < 0.9] in those in the lowest and highest risk factor quintiles) in a cross-sectional analysis. Risk factors measured at baseline were also predictive of an abnormal ABI 25 years later, even after adjustment for multiple risk factors. The odds ratio (OR) for an ABI < 0.9 at the 80th percentile of cholesterol compared with that at the 20th percentile was 1.4; the OR for 1-hour postload glucose was 1.3, and for alcohol intake 1.2. The OR associated with hypertension was 1.8 and that for smoking, 2.9 (P < .05 for all ORs). These findings are consistent with ABI being a marker for generalized atherosclerotic disease in old and very old Japanese American men.

Elevated Blood Pressure in HIV-Infected Individuals Receiving Highly Active Antiretroviral Therapy

Abstract Objective: We examined the effects of antiretroviral regimens on blood pressure (BP). Method: This retrospective study examined systolic and diastolic BP (SBP and DBP) measurements among participants of a State of Hawaii Department of Health program from January 1995 to July 2003. The change in BP during four consecutive 6-month visits was estimated using linear regression and was interpreted as the change in BP per year. BP changes among the antiretroviral treatment groups were compared to untreated controls. Results: Of 1,601 patients identified, 286 met the criteria for inclusion. After adjustment for baseline age, BP, and CD4+ count, there was an increase in SBP by 4.71 mmHg/year (p = .005) and DBP by 2.26 mmHg/year (p = .076) among patients initiating HAART. Among these patients, an increase of 4.75 mmHg/year in SBP (p = .002) and 1.96 mmHg/year in DBP (p = .042) was seen with HAART regimens containing a protease inhibitor (PI) but no nonnucleoside reverse transcriptase inhibitor (NNRTI). In NNRTI-containing HAART regimens without PIs, an increase of 3.21 mmHg/year in SBP (p = .011) and 2.62 mmHg/year in DBP (p = .050) was observed. No significant BP changes were noted with patients on regimens containing only nucleoside reverse transcriptase inhibitors (NRTIs). Conclusion: The use of NNRTI- or PI-containing HAART is associated with elevation of both SBP and DBP in HIV-infected individuals.

Plasma Fibrinogen as a Predictor of Total and Cause-Specific Mortality in Elderly Japanese-American Men

Abstract—The relation between plasma fibrinogen and total and cause-specific mortality was investigated in a cohort of 3571 Japanese-American men aged 71 to 93 years during a median follow-up of 4.4 years. There were a total of 728 deaths, of which 37% were accounted for by cardiovascular disease and 27% by cancer. The age-adjusted relative risk (RR) for total mortality in the top quintile of fibrinogen (>3.51 g/L) compared with the bottom quintile (<2.57 g/L) was 4.3 (P <0.0001) in the first year of follow-up. RR was reduced to 1.7 in the second year but remained significantly and slightly increased in subsequent years. After adjustment for age and confounding risk factors, the RRs (and 95% confidence intervals) associated with a 1-SD increment of fibrinogen (0.64 g/L) for all-cause, cardiovascular disease, cancer, and other-cause mortality were 1.3 (1.2 to 1.4), 1.2 (1.1 to 1.4), 1.3 (1.2 to 1.5), and 1.3 (1.2 to 1.5), respectively. Preexisting diseases did not influence the significant association of fibrinogen with mortality. There was a significant interaction of fibrinogen with white blood cell count but not with cigarette smoking. We conclude that plasma fibrinogen is an independent risk factor for mortality from a broad spectrum of diseases in elderly men and that this universal effect of fibrinogen on mortality may be mediated partly through inflammation.

The Relationship of Psychosocial Factors to Total Mortality Among Older Japanese‐American Men: The Honolulu Heart Program

OBJECTIVE: To examine the predictive value of psychosocial factors as risk factors for all‐cause mortality.

Shorter Men Live Longer: Association of Height with Longevity and FOXO3 Genotype in American Men of Japanese Ancestry

Objectives To determine the relation between height, FOXO3 genotype and age of death in humans. Methods Observational study of 8,003 American men of Japanese ancestry from the Honolulu Heart Program/Honolulu-Asia Aging Study (HHP/HAAS), a genetically and culturally homogeneous cohort followed for over 40 years. A Cox regression model with age as the time scale, stratified by year of birth, was used to estimate the effect of baseline height on mortality during follow-up. An analysis of height and longevity-associated variants of the key regulatory gene in the insulin/IGF-1 signaling (IIS) pathway, FOXO3, was performed in a HHP-HAAS subpopulation. A study of fasting insulin level and height was conducted in another HHP-HAAS subpopulation. Results A positive association was found between baseline height and all-cause mortality (RR = 1.007; 95% CI 1.003–1.011; P = 0.002) over the follow-up period. Adjustments for possible confounding variables reduced this association only slightly (RR = 1.006; 95% CI 1.002–1.010; P = 0.007). In addition, height was positively associated with all cancer mortality and mortality from cancer unrelated to smoking. A Cox regression model with time-dependent covariates showed that relative risk for baseline height on mortality increased as the population aged. Comparison of genotypes of a longevity-associated single nucleotide polymorphism in FOXO3 showed that the longevity allele was inversely associated with height. This finding was consistent with prior findings in model organisms of aging. Height was also positively associated with fasting blood insulin level, a risk factor for mortality. Regression analysis of fasting insulin level (mIU/L) on height (cm) adjusting for the age both data were collected yielded a regression coefficient of 0.26 (95% CI 0.10–0.42; P = 0.001). Conclusion Height in mid-life is positively associated with mortality, with shorter stature predicting longer lifespan. Height was, moreover, associated with fasting insulin level and the longevity genotype of FOXO3, consistent with a mechanistic role for the IIS pathway.

Relationship between depressive symptoms and diabetes among native Hawaiians

Increased prevalence of depression has been reported among diabetes patients. We examined this association between diabetes and depressive symptoms in a population-based study where glucose tolerance status was determined with World Health Organization (WHO) criteria. Fasting plasma glucose (FPG) was determined from blood collected from 574 native Hawaiians. The Centers for Epidemiological Studies-Depression (CES-D) scale was used to assess depressive symptoms in association with diabetes history and hemoglobin A1c (HbA1c). A significant association was observed between depressive symptoms and HBA1c that persisted after adjusting for age, BMI, gender, education, and after exclusion of participants reporting a history of diabetes. Diabetes history was no longer associated with CES-D depressive symptoms after adjusting for HbA1c. These results support the hypothesis that depressive symptoms associated with diabetes may be partially explained by a shared neuroendocrinological disturbance.