Bradley John Willcox

University of Hawaiʻi at Mānoa | UH Manoa · Department of Geriatric Medicine

Background: Calcification of the aorta is a biomarker of atherosclerosis and a predictor of cardiovascular morbidity and mortality. Low mortality from coronary heart disease in Japan cannot be fully explained by genetics or traditional risk factors. Our objective was to compare the progression of aortic calcification (AC) between Japanese in Japan,...

The longevity-associated allele of FOXO3 is associated with a significant reduction in cardiovascular disease (CVD) risk in older adults. We hypothesized that dementia, which shares several risk factors with CVD, might also be related to FOXO3 genotype, particularly vascular dementia (VaD). Therefore, we utilized the Kuakini Honolulu Heart Program/...

We assessed longitudinal associations between social networks and incidence of all-cause dementia, Alzheimer’s disease (AD) and vascular dementia in Kuakini Honolulu-Asia Aging Study participants over a 10-year follow-up period. Median split of Lubben Social Network Scale (LSNS) scores defined weak/strong social networks among 2636 men who were dem...

The longevity-associated FOXO3 G allele of SNP rs2802292 is associated with protection against mortality, however the impact of FOXO3 genotype on the association between hypertension and risk of intracerebral hemorrhage (ICH) has not been assessed. Therefore, we utilized the Kuakini Honolulu Heart Program (KHHP), a prospective population-based coho...

The genetic association of FOXO3 genotypes with human longevity is well established, although the mechanism is not fully understood. We now report on the relationship of the FOXO3 longevity variant rs2802292 with telomere length, telomerase activity, FOXO3 expression and inflammatory cytokine levels in men and women. In agreement with earlier work,...

Kuakini Medical Center (Kuakini) was funded by NIH in late 2019 to create an interdisciplinary Hawai’i-based, Center of Biomedical Research Excellence (COBRE), for translational research on aging. This Center is building upon Kuakini’s five-decades of prior NIH-funded research. These resources include clinical data from the 57-year ongoing Kuakini...

Background Accurate assessment of fat intake is essential to examine relationships between diet and disease risk. However, estimating individual intakes of fat quantity by dietary assessment is difficult. Objective We assessed the association of plasma phospholipid fatty acid levels with dietary intake of fatty acids in the INTERMAP/INTERLIPID stu...

Objectives: The purpose of this study was to evaluate a cross-lagged panel model of general cognition and functional abilities over 13 years. The goal was to determine whether general cognitive abilities predict or precede functional decline versus functional abilities predicting cognitive decline. Methods: The sample included 3508 men (71–93 years...

Human longevity is linked to genetic, cellular, and other complex biological and psychosocial traits. Aging is typically accompanied by gradual brain atrophy and cognitive decline, but the mechanisms are unclear. Cellular aging, characterized by telomere shortening and altered telomerase activity, is related to mortality and brain aging. Decelerate...

Aging demographics in the US, and other industrialized nations, are resulting in rapidly increasing health care costs from age-related diseases. New therapeutic interventions to extend healthspan in older adults requires understanding connections between basic aging biology and human longevity factors. Using clinical samples from the Kuakini Honolu...

Kuakini Medical Center (Kuakini) is creating an interdisciplinary Hawai’i-based Center for translational research on aging. This Center will build upon Kuakini’s five-decades of NIH-funded research, its 420,000-specimen biorepository, and existing strengths in aging research, notably, the 56-year ongoing Kuakini Honolulu Heart Program cohort study...

FOXO3 is among only a few genes that demonstrate a consistently reproducible genetic association with human longevity. We previously demonstrated, in a cross-sectional study of Okinawan Japanese, that the principal longevity variant of FOXO3 (rs 2802292 “G allele”) protects against age-associated attrition of telomere length. We now expand upon thi...

sKuakini Medical Center (Kuakini) is establishing an interdisciplinary Hawai’i-based Center of Biomedical Research Excellence (COBRE) for clinical and translational research on aging. - Specific Aim 1: Create a world class, innovative, interdisciplinary Center for Translational Research on Aging by building on the existing rare and valuable Kuakini...

This study assessed the impact of APOE e2, e4 minor alleles and the FOXO3 longevity-associated genotype (carrier of SNP rs2802292 “G” allele) on 34-year incidence of intracerebral hemorrhage (ICH). Cox regression models were performed to assess the impact of the APOE e2, e4 and FOXO3 G alleles on the incidence of ICH. A total of 6483 participants w...

Environmental signals, including caloric restriction and oxidative stress, trigger FoxO3 to upregulate genes involved in stress resistance, metabolism, cell cycle arrest, and apoptosis that may help mitigate age-related diseases. Activation of FoxO3 has been shown to have a profound life-extending effect on model organisms. Protective SNPs in FOXO3...

Background: Few studies have compared factors related to cognitive function among people with similar genetic backgrounds but different lifestyles. Objective: We aimed to identify factors related to lower cognitive scores among older Japanese men in two genetically similar cohorts exposed to different lifestyle factors. Methods: This cross-sec...

At the end of a very long life, older adults often experience a significant decline in cognitive function. However, there are older adults who have maintained high levels of cognition and physical health. The purpose of this symposium is to illuminate interdisciplinary findings of cognitive engagement with late-life benefits of cognitive functionin...

3,734 Japanese-American male oldest-old (aged 85+ years), from the Kuakini Honolulu Asia Aging Study, were assessed for prevalent cognitive impairment (CI). CI was defined as scoring <74 on the 100-point Cognitive Abilities Screening Instrument (CASI; 80% sensitivity, 90% specificity for dementia). CASI tests from 1991 (Exam 4) to 2012 (Exam 12) id...

Background: Although numerous studies have been published on prognostic factors after a first acute myocardial infarction (AMI) among middle-aged men, little is known about the prognostic factors and genetic determinants for post-AMI elderly patients. Methods: The Kuakini Honolulu Heart Program (KHHP) is a prospective population-based study of card...

Background and aim: Few studies have examined the association of long-chain n-3 polyunsaturated fatty acids (LCn-3PUFAs) with the measures of atherosclerosis in the general population. This study aimed to examine the relationship of total LCn-3PUFAs, eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) with aortic calcification. Methods an...

Background: The number of people with dementia is increasing in the world and it is of great public health concern. Previous observational studies, mainly from western countries, have reported that modifiable factors for development of dementia were cardiometabolic risk factors, related to genetically determined metabolic abilities and lifestyle. T...

Next-generation DNA sequencing has ushered in a new era of genotype-phenotype comparisons that have the potential to elucidate the genetic nature of complex traits. Since such methods rely on short sequence reads and since the human genome is composed largely of repetitive DNA elements larger than these read lengths many results cannot be mapped an...

There are several methods for measuring healthy or “successful” aging utilizing different measures of comorbidity. Each can lead to different conclusions about how “successfully” one is aging. To bring more clarity, we compared 3,741 American men of Japanese ancestry (mean age 77.8 ± 4.7, range 71–93 years) from the 1991–94 exam of the Kuakini Hono...

Here we summarize the latest data on genetic and epigenetic contributions to human aging and longevity. Whereas environmental and lifestyle factors are important at younger ages, the contribution of genetics appears more important in reaching extreme old age. Genome-wide studies have implicated ~57 gene loci in lifespan. Epigenomic changes during a...

Background: Recently, high-density lipoprotein particles (HDL-P) have been found to be more strongly inversely associated with coronary artery disease (CAD) risk than their counterpart, HDL cholesterol (HDL-C). Given that lifestyle is among the first targets in CAD prevention, we compared the associations of HDL-P and HDL-C with selected lifestyle...

Background: Abdominal fat distribution varies across groups with different races or environments. Whether environmental factors, apart from racial differences, affect abdominal fat distribution is unknown. Methods: We compared the abdominal fat distribution of four groups; different races with similar environments (Caucasians vs. Japanese Americ...

The role of fasting glucose, insulin levels, and C-peptide in coronary heart disease (CHD) in non-diabetic individuals remains uncertain. We examined the association between fasting glucose, insulin and C-peptide with the long-term incidence of CHD in Japanese-American men. In 1980–1982, from a random sample of the Honolulu Heart Program men (n = 1...

FOXO3 is one of the most prominent genes demonstrating a consistently reproducible genetic association with human longevity. The mechanisms by which these individual gene variants confer greater organismal lifespan are not well understood. We assessed the effect of longevity-associated FOXO3 alleles on age-related leukocyte telomere dynamics in a c...

Previous studies have shown that walking is associated with increased longevity and a reduced risk of cardiovascular and age-related diseases. Whether walking benefits individuals with diabetes who are at high risk of coronary heart disease (CHD) remains to be determined. The objective of this study is to examine the association between walking and...

Aging is a complex, multifactorial process with significant plasticity. While several biological pathways appear to influence aging, few genes have been identified that are both evolutionarily conserved and have a strong impact on aging and age-related phenotypes. The FoxO3 gene (FOXO3), and its homologs in model organisms, appears especially impor...

Longevity is a polygenic trait in which genetic predisposition is particularly important. We hypothesized that amongst genes differentially expressed in response to caloric restriction, several may be candidate longevity genes. We tested 459 single nucleotide polymorphisms (SNPs) in 46 genes differentially expressed in calorically-restricted mice a...

Background and aims: Several studies have reported a significant inverse association of light to moderate alcohol consumption with coronary heart disease (CHD). However, studies assessing the relationship between alcohol consumption and atherosclerosis have reported inconsistent results. The current study was conducted to determine the relationshi...

Table S1. FOXO3 SNPs evaluated in this study. Table S2. Transcription factors modified by variants. Table S3. Expression patterns of longevity‐associated transcription factors. Table S4. Genes on chromosome 6q21. Table S5. Expression patterns of genes on chromosome 6q21. Table S6. Published GWAS results for chromosome 6q21. Table S7. Amplific...

Fig. S1. Linkage disequilibrium and haplotypes for three populations. Fig. S2. Interactions between potentially functional FOXO3 SNPS and nearby genes on chromosome 6q21. Fig. S3. DNA replication of chromosome 6q21. Fig. S4. Phylogeny of human chromosome 6q21. Fig. S5. FISH experiments to determine the effect of H2O2 stress‐induced activation o...

Objective: The aim of this study was to investigate the association between anthropometric measurements of sarcopenic obesity and all-cause mortality. Methods: The study included 2309 Japanese-American men ages 71 to 93 y. Mortality data were available for up to 24 y of follow-up. Sarcopenic obesity defined by three patterns of obesity indexes (...

FOXO3 has been implicated in longevity in multiple populations. By DNA sequencing in long-lived individuals, we identified all single nucleotide polymorphisms (SNPs) in FOXO3 and showed 41 were associated with longevity. Thirteen of these had predicted alterations in transcription factor binding sites. Those SNPs appeared to be in physical contact,...

Telomere attrition in proliferative tissues is a hallmark feature of human aging. To date, identification of genetic influence on the rate of telomere attrition is poorly understood. The two genes with the most robust effect on human longevity are FOXO3 and APOE. Notably, we discovered a genetic variant of the FOXO3 gene that is strongly associated...

Introduction: Aortic calcification (AC) is an independent predictor of future cardiovascular (CV) events. Marine omega-3 fatty acids (OM3) are reported to have anti-atherogenic properties. Hypothesis: We hypothesized that blood levels of OM3 have a significant inverse association with AC. Methods: ERA JUMP is a population-based study of subclinical...

Introduction: Aortic calcification (AC) is a less widely used measure of atherosclerosis, has been linked to cardiovascular (CV) morbidity and mortality. A J-shaped association of alcohol consumption with CHD has been consistently reported in epidemiological studies. However, scanty literature is available describing the association of alcohol cons...

Arterial stiffness is established as an independent predictor of cardiovascular morbidity and mortality. The objective was to prospectively evaluate association of aortic calcification burden with progression of arterial stiffness in population-based samples of healthy middle-aged men from ERA JUMP cohort (Electron-Beam Computed Tomography and Risk...

A study of elderly Okinawans has been carried out by the Okinawa Centenarian Study (OCS) research group for over four decades. The OCS began in 1975 as a population-based study of centenarians (99-year-olds and older) and other selected elderly persons residing in the main island of the Japanese prefecture of Okinawa. As of 2015, over 1000 centenar...

Objective: A few studies have examined the longitudinal association of blood pressure (BP) with arterial stiffness progression, and the results were inconsistent. The objective of this study was to investigate the roles of initial BP and its longitudinal change on the progression of arterial stiffness measured using brachial-ankle pulse wave veloc...

Introduction: The Canadian Pediatrics Society (CPS) recently released a position statement on early infant (newborn) male circumcision (EIMC). It concluded that since benefits do not exceed risks, circumcision should only be performed on boys in high-risk populations or circumstances. This contradicts recommendations by the American Academy of Pedi...

Introduction: The Canadian Pediatrics Society (CPS) recently released a position statement on early infant (newborn) male circumcision (EIMC). It concluded that since benefits do not exceed risks, circumcision should only be performed on boys in high-risk populations or circumstances. This contradicts recommendations by the American Academy of Ped...

Background We recently reported that protection against coronary artery disease (CAD) mortality is the major contributor to longer life associated with FOXO3 genotype. The present study examined this relation in more detail. Methods We performed a 15-year observational study of 3,584 older American men of Japanese ancestry from the Kuakini Honolul...

Table S1. Serum TNF‐α level by FOXO3 G allele carrier status.

Growth pathways play key roles in longevity. The present study tested single-nucleotide polymorphisms (SNPs) in the connective tissue growth factor gene (CTGF) and the epidermal growth factor receptor gene (EGFR) for association with longevity. Comparison of allele and genotype frequencies of 12 CTGF SNPs and 41 EGFR SNPs between 440 American men o...

Objective: Although a significant positive association of vitamin D deficiency with coronary heart disease has been demonstrated in cross-sectional as well as prospective studies, only a few studies have examined the association of vitamin D deficiency with subclinical atherosclerosis. We examined whether vitamin D deficiency is associated with su...

Nutrition has profound effects on ageing and lifespan. Caloric restriction is the major nutritional intervention that historically has been shown to influence lifespan and/or healthspan in many animal models. Studies have suggested that a reduction in protein intake can also increase lifespan, albeit not as dramatically as caloric restriction. More...

The G allele of the FOXO3 single nucleotide polymorphism (SNP) rs2802292 exhibits a consistently replicated genetic association with longevity in multiple populations worldwide. The aims of this study were to quantify the mortality risk for the longevity-associated genotype and to discover the particular cause(s) of death associated with this allel...

Background: Cross-sectional data suggest that aortic calcification (AC) is independently associated with arterial stiffness, yet no previous study has examined the association prospectively. We hypothesize that increase in AC has a positive association with the progression of arterial stiffness assessed by brachial-ankle pulse-wave velocity (baPWV)...

Background: The minor alleles of 3 FOXO3 single nucleotide polymorphisms (SNPs)-rs2802292, rs2253310, and rs2802288-are associated with human longevity. The aim of the present study was to test these SNPs for association with blood pressure (BP) and essential hypertension (EHT). Methods: In a primary study involving Americans of Japanese ancestr...

Based on the genotypic/phenotypic data from Chinese Longitudinal Healthy Longevity Survey (CLHLS) and Cox proportional hazard model, the present study demonstrates that interactions between carrying FOXO1A-209 genotypes and tea drinking are significantly associated with lower risk of mortality at advanced ages. Such significant association is repli...

The Seven Countries Study in the 1960s showed very low mortality from coronary heart disease (CHD) in Japan, which was attributed to very low levels of total cholesterol. Studies of migrant Japanese to the USA in the 1970s documented increase in CHD rates, thus CHD mortality in Japan was expected to increase as their lifestyle became Westernized, y...

Background C-reactive protein (CRP) and many fatty acids (FAs) have been linked to cardiovascular disease. Associations of serum CRP with FAs in different populations have not been established. Methods Participants were 926 men aged 40–49 (2002–2006) from a population-based sample; 310 Whites from Pennsylvania, U.S., 313 Japanese from Shiga, Japan,...

The gene FOXO3, encoding the transcription factor forkhead box O-3 (FoxO3), is one of only two for which genetic polymorphisms have exhibited consistent associations with longevity in diverse human populations. Here, we review the multitude of actions of FoxO3 that are relevant to health, and thus healthy ageing and longevity. The study involved a...

To study the association between total and differential white blood cell (WBC) count and incident stroke in an older Asian population. Prospective population-based study with 8 years of follow-up. The Honolulu Heart Program, Oahu, Hawaii. Japanese-American men aged 71 to 93 who were free of stroke and had baseline WBC counts measured in 1991-93 (N...

Background: Previous studies have reported an association between total and differential white blood cell (WBC) counts and incident coronary heart disease (CHD), but data from elderly populations are scarce. The purpose of this study was to examine the association between total and differential WBC counts and incident CHD in an elderly Japanese-Ame...

Aim: To examine whether the inflammatory markers C-reactive protein (CRP) and fibrinogen are associated with biomarkers of atherosclerosis [carotid intima-media thickness (IMT) and coronary artery calcification (CAC)] in the general male population, including Asians. Methods: Population-based samples of 310 Japanese, 293 Japanese-American and 29...

Background/objectives: Higher volumes of ectopic cardiovascular fat (ECF) are associated with greater risk of coronary heart disease (CHD). Identifying factors that are associated with ECF volumes may lead to new preventive efforts to reduce risk of CHD. Significant racial/ethnic differences exist for overall and central adiposity measures, which...

Logistic regression analysis based on data from 822 Han Chinese oldest old aged 92+ demonstrated that interactions between carrying FOXO1A-266 or FOXO3-310 or FOXO3-292 and tea drinking at around age 60 or at present time were significantly associated with lower risk of cognitive disability at advanced ages. Associations between tea drinking and re...

Background: The mechanistic target of rapamycin (mTOR) pathway is pivotal for cell growth. Regulatory associated protein of mTOR complex I (Raptor) is a unique component of this pro-growth complex. The present study tested whether variation across the raptor gene (RPTOR) is associated with overweight and hypertension. Methods: We tested 61 commo...

Purpose of the Study: Everyone wants to age successfully; however, the definition and criteria of successful aging remain vague for laypersons, researchers, and policymakers in spite of decades of research on the topic. This paper highlights work of scholars who made significant theoretical contributions to the topic.

To determine the relation between height, FOXO3 genotype and age of death in humans. 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, strat...

Objectives To identify potentially modifiable late-life biological, lifestyle, and sociodemographic factors associated with overall and healthy survival to age 85.DesignProspective longitudinal cohort study with 21 years of follow-up (1991–2012).SettingHawaii Lifespan Study.ParticipantsAmerican men of Japanese ancestry (mean age 75.7, range 71–82)...

Background: Obesity is an established risk factor for hypertension and end stage kidney disease. There is little information on how obesity relates to risk of impaired renal function in apparently healthy individuals. We investigated associations of body mass index (BMI) with timed 24-hour creatinine clearance (Ccr) and glomerular filtration rate (...

Background: Studies have found that HDL particle (HDL-P) concentration is inversely associated with risk of CVD, independent of HDL cholesterol (HDL-C). Dietary factors (such as fatty acid intake) have been found to affect levels of HDL-C and influence risk of CVD. However, little is known about the associations of dietary fatty acid with serum HDL...

Objectives: Mortality from coronary heart disease (CHD) in developed countries started to decline in the late 1960’s and early 1970’s and age-adjusted CHD mortality fell about 50%. This decline is attributed to favorable changes in risk factors in the general population, i.e., total cholesterol, blood pressure, smoking, etc., and improved treatment...

The mechanistic target of rapamycin (mTOR) pathway is crucial for life span determination in model organisms. The aim of the present study was to test tagging single-nucleotide polymorphisms that captured most of the genetic variation across key TOR complex 1 (TORC1) and TOR complex 2 (TORC2) genes MTOR, RPTOR, and RICTOR and the important downstre...

The traditional diet in Okinawa is anchored by root vegetables (principally sweet potatoes), green and yellow vegetables, soybean-based foods, and medicinal plants. Marine foods, lean meats, fruit, medicinal garnishes and spices, tea, alcohol are also moderately consumed. Many characteristics of the traditional Okinawan diet are shared with other h...