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AimMarinesco bodies (MB) are intranuclear inclusions in pigmented neurons of the substantia nigra (SN). While rare in children, frequency increases with normal ageing and is high in Alzheimer's disease, dementia with Lewy bodies and other neurodegenerative disorders. Coinciding with the age-related rise in MB frequency is initiation of cell death among SN neurons. Whether MB have a role in this process is unknown. Our aim is to examine the association of MB with SN neuron density in Parkinson's disease (PD) in the Honolulu-Asia Aging Study.MethodsData on MB and neuron density were measured in SN transverse sections in 131 autopsied men aged 73-99 years at the time of death from 1992 to 2007.ResultsMarinesco body frequency was low in the presence vs. absence of PD (2.3% vs. 6.6%, P < 0.001). After PD onset, MB frequency declined as duration of PD increased (P = 0.006). Similar patterns were observed for SN neuron density. When MB frequency was low, neuron density was noticeably reduced in the SN ventrolateral quadrant, the region most vulnerable to PD neurodegeneration. Low MB frequency was unique to PD as its high frequency in non-PD cases was unrelated to parkinsonian signs and incidental Lewy bodies. Frequency was high in the presence of Alzheimer's disease and apolipoprotein ε4 alleles.ConclusionsWhile findings confirm that MB frequency is low in PD, declines in MB frequency continue with PD duration. The extent to which MB have a distinct relationship with PD warrants clarification. Further studies of MB could be important in understanding PD processes.

BackgroundThe ankle brachial index (ABI) is related to risk of cardiovascular events independent of the Framingham risk score (FRS). The aim of this study was to develop and evaluate a risk model for cardiovascular events incorporating the ABI and FRS.DesignAn analysis of participant data from 18 cohorts in which 24,375 men and 20,377 women free of coronary heart disease had ABI measured and were followed up for events.MethodsSubjects were divided into a development and internal validation dataset and an external validation dataset. Two models, comprising FRS and FRS + ABI, were fitted for the primary outcome of major coronary events.ResultsIn predicting events in the external validation dataset, C-index for the FRS was 0.672 (95% CI 0.599 to 0.737) in men and 0.578 (95% CI 0.492 to 0.661) in women. The FRS + ABI led to a small increase in C-index in men to 0.685 (95% CI 0.612 to 0.749) and large increase in women to 0.690 (95% CI 0.605 to 0.764) with net reclassification improvement (NRI) of 4.3% (95% CI 0.0 to 7.6%, p = 0.050) and 9.6% (95% CI 6.1 to 16.4%, p

While animal data suggest a protective effect of caffeine on cognition, studies in humans remain inconsistent. We examined associations of coffee and caffeine intake in midlife with risk of dementia, its neuropathologic correlates, and cognitive impairment among 3494 men in the Honolulu-Asia Aging Study (mean age 52 at cohort entry, 1965-1968) examined for dementia in 1991-1993, including 418 decedents (1992-2004) who underwent brain autopsy. Caffeine intake was determined according to self-reported coffee, tea, and cola consumption at baseline. Logistic regression was used to calculate odds ratios (OR) and 95% confidence intervals (CI) for overall dementia, Alzheimer's disease (AD), vascular dementia (VaD), cognitive impairment (Cognitive Abilities Screening Instrument score <74), and neuropathologic lesions at death (Alzheimer lesions, microvascular ischemic lesions, cortical Lewy bodies, hippocampal sclerosis, generalized atrophy), according to coffee and caffeine intake. Dementia was diagnosed in 226 men (including 118 AD, 80 VaD), and cognitive impairment in 347. There were no significant associations between coffee or caffeine intake and risk of cognitive impairment, overall dementia, AD, VaD, or moderate/high levels of the individual neuropathologic lesion types. However, men in the highest quartile of caffeine intake (>/=411.0 mg/d) [corrected] were less likely than men in the lowest quartile (

Background: Although evidence is accumulating for a protective effect of late life physical activity on the risk of dementia, the findings are inconsistent, especially in men. We examined the association of late life physical activity and the modifying effect of physical function with future risk of dementia in a well-characterized cohort of elderly men participating in the Honolulu-Asia Aging Study (HAAS).Methods: Physical activity by self-report and performance-based physical function was assessed in 2263 men aged 71-92 years without dementia at the baseline examination of the HAAS in 1991-1993. Follow-up for incident dementia occurred at repeat examinations conducted in 1994-1996 and 1997-1999. Analyses were based on Cox proportional hazards models with adjustment for potential confounders, including age, baseline cognitive function, education, and apolipoprotein E genotype.Results: There were 173 incident cases of dementia with a mean follow-up of 6.1 years. Although the incidence of dementia tended to decline with increasing physical activity and function, there was a significant interaction between the latter two factors on dementia risk (p =.022). For men with low physical function, high levels of physical activity were associated with half the risk of dementia versus men who were the least active (hazard ratio [HR], 0.50; 95% confidence interval [CI], 0.28-0.89), with a moderate level of physical activity also providing a protective effect (HR, 0.57; 95% CI, 0.32-0.99). Risk of dementia and Alzheimer's disease declined significantly with increasing physical activity. Findings persisted after age and risk factor adjustment. Similar associations were absent in men with moderate and high physical function.Conclusions: In elderly men with poor physical function, increasing general physical activity may potentially confer a protective effect or delay the onset for dementia. [ABSTRACT FROM AUTHOR]

We redesigned our medical school's Problem-Based Learning (PBL) curriculum to include a substantial increase in required geriatrics content. Innovations included new PBL health care problems and standardized patients (SPs) throughout the first three years and a new required four-week, fourth-year rotation. We used data from the AAMC Medical School Graduation Questionnaire, the UCLA Geriatrics Knowledge Test and Attitudes Survey and a Geriatrics SP Examination to measure self-efficacy, geriatrics specific knowledge, attitudes and clinical skills before and after these curricular changes. Positive effects on students' self-efficacy, knowledge and skills were demonstrated. Scores on the attitude scale were high before and after implementation. The demonstration of improved educational outcomes will help to validate our curricular changes and guide their future development. doi:10.1300/ J021v28n03_04. [ABSTRACT FROM AUTHOR]

Some, but not all, observational studies have suggested that moderate levels of alcohol intake may be associated with improved cognitive function and reduced risk of cognitive decline and dementia. The authors of this 1996-2002 study used data from the Women's Health Initiative Memory Study of postmenopausal combination hormone therapy to assess cross-sectional and prospective associations of self-reported alcohol intake with cognitive function. Across 39 US academic medical centers, 4,461 community-dwelling women aged 65-79 years were followed an average of 4.2 years with annual Modified Mini-Mental State Examinations and standardized protocols for detecting mild cognitive impairment and probable dementia. Compared with no intake, intake of > or =1 drink per day was associated with higher baseline Modified Mini-Mental State Examination scores (p < 0.001) and a covariate-adjusted odds ratio of 0.40 (95% confidence interval: 0.28, 0.99) for significant declines in cognitive function. Associations with incident probable dementia and mild cognitive impairment were of similar magnitude but were not statistically significant after covariate adjustment. Associations with intakes of <1 drink per day were intermediate. Moderate levels of alcohol intake may be associated with better cognition and reduced risk of significant cognitive decline; however, confounding associations with unmeasured factors cannot be ruled out. [ABSTRACT FROM AUTHOR]

Energy restriction extends life span and lowers mortality from age-related diseases in many species, but the effects in humans are unknown. We prospectively examined this relationship in a large epidemiological study of Japanese-American men. We followed 1915 healthy nonsmokers, aged 45-68 years at study onset, for 36 years. Twenty-four-hour recall of diet was recorded at baseline, and follow-up was for all-cause mortality. After adjustment for age and other confounders, there was a trend toward lower mortality in the second quintile of energy intake, suggesting that men who consumed 15% below the group mean were at the lowest risk for all-cause mortality. Increased mortality was seen with intakes below 50% of group mean. Thus, we observed trends between low energy intake and reduced risk for all-cause mortality in humans until energy intake fell to less than half the group mean, consistent with previous findings in other species. [ABSTRACT FROM AUTHOR]

High density lipoprotein (HDL) cholesterol has been inversely associated with coronary heart disease. Associations with stroke are less clear, particularly among the elderly. In this study, the authors examined the relation between HDL cholesterol levels and the risk of stroke in elderly men. Levels of HDL cholesterol were measured in 2,444 Honolulu Heart Program men aged 71-93 years at the 1991-1993 examinations. The participants, who were free of prevalent stroke, coronary heart disease, and cancer at baseline, were followed to the end of 1998 for thromboembolic and hemorrhagic stroke. While HDL cholesterol was unrelated to hemorrhagic events, incidence of thromboembolic stroke declined consistently with increasing HDL cholesterol level (p = 0.003). There was a nearly threefold excess of thromboembolic stroke in men with low HDL cholesterol levels (<1.0 mmol/liter (<40 mg/dl)) compared with men with high levels (> or =1.6 mmol/liter (> or =60 mg/dl)) (10.6/1,000 person-years vs. 3.6/1,000 person-years; p = 0.001). Adjustment for other risk factors had little effect on these findings, although associations appeared strongest in elderly men with 'desirable' total cholesterol levels, hypertension, or diabetes mellitus. These findings suggest that HDL cholesterol level is inversely related to the risk of thromboembolic stroke in elderly men. Whether HDL cholesterol alters the effect of other factors on stroke risk in elderly men warrants further study. [ABSTRACT FROM AUTHOR]

Antioxidants have been hypothesized to protect against Alzheimer's disease, but studies conducted in late life have been inconsistent. Risk factors measured in midlife may better predict dementia in late life because they are less affected by the disease process. The authors examined the association of midlife dietary intake of antioxidants to late-life dementia and its subtypes. Data were obtained from the Honolulu-Asia Aging Study, a prospective community-based study of Japanese-American men who were aged 45-68 years in 1965-1968, when a 24-hour dietary recall was administered. The analysis included 2,459 men with complete dietary data who were dementia-free at the first assessment in 1991-1993 and were examined up to two times for dementia between 1991 and 1999. The sample included 235 incident cases of dementia (102 cases of Alzheimer's disease, 38 cases of Alzheimer's disease with contributing cerebrovascular disease, and 44 cases of vascular dementia). Relative risks by quartile of intake were calculated using Cox proportional hazards models with age as the time scale, after adjustment for sociodemographic and lifestyle factors, cardiovascular risk factors, other dietary constituents, and apolipoprotein E e4. Intakes of beta-carotene, flavonoids, and vitamins E and C were not associated with the risk of dementia or its subtypes. This analysis suggests that midlife dietary intake of antioxidants does not modify the risk of late-life dementia or its most prevalent subtypes. [ABSTRACT FROM AUTHOR]

Objective: To determine the frequency of unrecognized dementia in a group of men found to have dementia by population survey, and to identify factors associated with the failure of a family informant to recognize significant memory impairment.Design and Setting: The Honolulu-Asia Aging Study, a population-based study of dementia among elderly Japanese-American men living on the island of Oahu, Hawaii. Data for this study were from the dementia prevalence survey, 1991-1993.Study Participants: A total of 191 noninstitutionalized men with dementia who had a reliable family informant.Main Outcome Measures: Failure of family informants to recognize a problem with thinking or memory in subjects with dementia.Results: A total of 21% of family informants failed to recognize a problem with memory among subjects subsequently found to have dementia. Among subjects with very mild dementia, 52% of family informants failed to recognize a significant memory problem compared with 13% among more severely demented subjects. Of the subjects with dementia whose family informants did recognize a memory problem, 53% failed to receive a medical evaluation for this problem. For all family informants, increasing age, fewer years of education, less severe dementia, fewer behavioral complications, fewer functional disabilities, and better performance on certain tests of memory and language were significantly associated with the family informant's failure to recognize a problem with memory. When the family informants were wives living with husbands, less severe dementia, fewer behavioral complications, fewer functional disabilities, and intact remote memory were associated with unrecognized dementia.Conclusions: Unrecognized dementia was common in our population, especially among mild cases. Cognitive screening programs for the elderly and public education policies designed to increase awareness of early signs of dementia are needed if interventions for individuals with potentially treatable dementias are to be implemented. [ABSTRACT FROM AUTHOR]

Magnesium (Mg) deficiency is believed to have adverse cardiovascular consequences that are broad and complex, although an association between dietary Mg intake and the risk of coronary heart disease (CHD) has not been clearly identified. The purpose of this study is to examine the relation between dietary Mg intake and future risk of CHD. Reported findings are based on dietary Mg intake in 7,172 men in the Honolulu Heart Program. Intake of Mg was recorded at baseline examinations that took place from 1965 to 1968 when the men were aged 45 to 68 years. In 30 years of follow-up, 1,431 incident cases of CHD were identified. Within 15 years after dietary assessment, the age-adjusted incidence decreased significantly from 7.3 to 4.0 per 1,000 person-years in the lowest (50.3 to 186 mg/day) versus highest (340 to 1,183 mg/day) quintiles of Mg intake (p <0.001). When adjustments were made for age and other nutrients (singly or combined), there was a 1.7- to 2.1-fold excess in the risk of CHD in the lowest versus highest quintiles (p <0.001). The excess risk ranged from 1.5- to 1.8-fold after further adjustment for other cardiovascular risk factors (p <0.05). Associations between dietary Mg and coronary events occurring after 15 years of follow-up were modest. We conclude that the intake of dietary Mg is associated with a reduced risk of CHD. Whether increases in dietary Mg intake can alter the future risk of disease warrants further study. [ABSTRACT FROM AUTHOR]

Purpose: The purpose of this report is to examine the potential for risk factor effects on the incidence of CHD to change over a broad range of ages from middle adulthood to late-life.Methods: Findings are based on repeated risk factor measurements at four examinations over a 26-year period in men enrolled in the Honolulu Heart Program. After each examination, six years of follow-up were available to assess risk factor effects as the cohort aged from 45 to 93 years.Results: Based on 18,456 person intervals of follow-up, 677 men developed CHD (3.7%). After risk factor adjustment, a positive relation between hypertension and CHD declined significantly with age (p = 0.013), primarily due to a large increase in the risk of CHD in elderly men (75 to 93) without hypertension. Effects of total cholesterol on CHD also seemed to decline with advancing age, although changes were not statistically significant. In contrast, men with diabetes had a consistent 2-fold excess risk of CHD across all age groups, while a positive association with body mass index in younger men (45 to 54) became negative in those who were the oldest (75 to 93). Due to infrequent smoking in the elderly, associations between smoking and CHD weakened with age. In the oldest men (75 to 93), alcohol intake was unrelated to CHD, while effects of sedentary life-styles on promoting CHD appeared stronger than in those who were younger.Conclusion: Findings suggest that changes in risk factor effects on the incidence of CHD with advancing age may require updated strategies for CHD prevention as aging occurs. [ABSTRACT FROM AUTHOR]

Low ankle/brachial blood pressure index (ABI) is a marker of generalized atherosclerosis in the elderly, although its association with coronary heart disease (CHD) has not been well established. The purpose of this report is to examine the relation between ABI and the risk of CHD in a sample of elderly men. Findings are based on the ABI that was measured in 2,863 Japanese-American men aged 71 to 93 years at an examination that occurred from 1991 to 1993 in the Honolulu Heart Program. All men were free of total CHD at that time and followed for nonfatal myocardial infarction and death from CHD over a 3- to 6-year period. During follow-up, 186 had a coronary event. Age-adjusted incidence declined significantly from 15.3% in men with an ABI <0.8 to 5.4% in men with an ABI >/=1.0 (p <0.001). The effect of ABI on disease was similar across a variety of risk factor strata, although it seemed strongest in the presence of hypertension and in past and current cigarette smokers. Adjustment for other risk factors failed to diminish the relation between ABI and CHD. We conclude that a low ABI increases the risk of CHD in elderly men. If findings can be extended to other elderly population segments, simple measurement of ABI in an outpatient setting could be an important tool for assessing the risk of CHD in the elderly. [ABSTRACT FROM AUTHOR]

This study tested whether carriage of the longevity-associated G-allele of FOXO3 SNP rs2802292 (TG/GG) protects against incident coronary artery disease (CAD) in men with hypertension. Subjects were American men residing on Oahu having Japanese (n=5415) or Okinawan (n=897) ancestry and free of CAD at baseline (1965-1968) when aged 45-68 years. During follow-up there were 1,629 incident CAD cases. Adjusting for age and cardiovascular disease risk factors, the main effect Cox model showed that in men of Japanese ancestry, hypertension was a strong predictor of CAD (HR 1.61; 95% CI 1.44-1.80), P<0.0001), but TG/GG genotype was not associated with CAD (HR 0.92; 95% CI = 0.82-1.02; p=0.11). A full Cox model showed the interaction of TG/GG with hypertension was significant (β = -0.23, p=0.038). Stratified by hypertension status, TG/GG genotype TG/GG had a protective effect against CAD in each group (HR 0.83; 95% CI 0.71-0.96; p=0.021 in men of Japanese heritage, and HR 0.66; 95% CI 0.43-1.01; p=0.054 in men of Okinawan heritage). No association with CAD was seen in normotensive men having either Japanese (HR 1.04; 95% CI 0.89-1.22; p=0.61) or Okinawan (HR 0.95; 95% CI 0.66-1.38; p=0.79) heritage. The present prospective study found longevity associated FOXO3 genotype did not independently affect risk of CAD in all men. Rather, it was associated with protection against incident CAD in men with hypertension. Hypertensive middle-aged men with FOXO3 TT genotype may merit particular attention in CAD prevention programs., (© The Author(s) 2024. Published by Oxford University Press on behalf of The Gerontological Society of America.)

Objective: To test whether genetic variants of the growth hormone receptor gene (GHR) modulate the effect of lifestyle variables on lung cancer (LC) risk., Materials and Methods: This population-based cohort study involved 6,439 men from the Japan-Hawaii Cancer study drawn from the Kuakini Honolulu Heart Program who were cancer-free at baseline examination (1965-1968; age 45-68 years) and followed-up until December 1999. We determined the association of GHR SNP rs4130113 genotypes GHR-AA (common allele A homozygotes) and GHR-G (minor allele G carriage) with alcohol drinking, BMI, physical activity and cigarette smoking in relation to LC and non-small cell LC (NSCLC). Results were expressed as hazard ratios and 95 % CIs estimated from Cox proportional hazard models., Results: Over mean 26.7 ± 7.4 SD years follow-up, 190 LC cases, including 133 NSCLC cases, were diagnosed. After adjusting for age, education, alcohol intake, BMI, physical activity, cigarette smoking, green tea consumption and dietary saturated fat, main-effect Cox models showed that compared with GHR-AA, GHR-G was associated with protection against LC: HR = 0.75 (95 % CI, 0.56-1.00). Full Cox models showed GHR-G interacted with alcohol intake only (β = 1.171; p = 0.0003; drinks per week: β = 0.279; P = 0.0024). Stratified analyses showed that for GHR-AA, drinkers had reduced LC risk (HR = 0.54; 95 % CI, 0.35-0.85), and that <2 drinks/week had the strongest protection (HR = 0.38; 95 % CI, 0.18-0.83). In contrast, for GHR-G, alcohol drinkers had increased LC risk (HR = 1.70; 95 % CI, 1.07-2.69) which was dose-dependent (P for trend = 0.005). Results for NSCLC were similar., Conclusion: In men with the GHR-AA genotype, alcohol drinking at a low dose poses significantly less risk of LC compared with non-drinkers and higher alcohol consumption., the overall relationship being U-shaped. In contrast, in GHR minor allele carriers, alcohol posed a progressively greater risk of LC as amount consumed increased., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Objective: The G -allele of FOXO3 SNP rs2802292 , which is associated with human resilience and longevity, has been shown to attenuate the impact of hypertension on the risk of intracerebral hemorrhage (ICH). We sought to determine whether the FOXO3 G -allele similarly attenuates the impact of hypertension on the risk of cerebral microinfarcts (CMI)., Methods: From a prospective population-based cohort of American men of Japanese ancestry from the Kuakini Honolulu Heart Program (KHHP) and Kuakini Honolulu-Asia Aging Study (KHAAS) that had brain autopsy data, age-adjusted prevalence of any CMI on brain autopsy was assessed. Logistic regression models, adjusted for age at death, cardiovascular risk factors, FOXO3 and APOE-ε4 genotypes, were utilized to determine the predictors of any CMI. Interaction of FOXO3 genotype and hypertension was analyzed., Results: Among 809 men with complete data, 511 (63.2%) participants had evidence of CMI. A full multivariable model demonstrated that BMI [odds ratio (OR) 1.07, 95% confidence interval (CI) 1.01-1.14, P  = 0.015) was the only predictor of CMI, while hypertension was a borderline predictor (OR 1.44, 95% CI 1.00-2.08, P  = 0.052). However, a significant interaction between FOXO3 G -allele carriage and hypertension was observed ( P  = 0.020). In the stratified analyses, among the participants without the longevity-associated FOXO3 G -allele, hypertension was a strong predictor of CMI (OR 2.25, 95% CI 1.34-3.77, P  = 0.002), while among those with the longevity-associated FOXO3 G -allele, hypertension was not a predictor of CMI (OR 0.88, 95% CI 0.51-1.54, P  = 0.66)., Conclusion: The longevity-associated FOXO3 G -allele mitigates the impact of hypertension on the risk of CMI., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

FOXO3 is a ubiquitous transcription factor expressed in response to cellular stress caused by nutrient deprivation, inflammatory cytokines, reactive oxygen species, radiation, hypoxia, and other factors. We showed previously that the association of inherited FOXO3 variants with longevity was the result of partial protection against mortality risk posed by aging-related life-long stressors, particularly cardiometabolic disease. We then referred to the longevity-associated genotypes as conferring "mortality resilience." Serum proteins whose levels change with aging and are associated with mortality risk may be considered as "stress proteins." They may serve as indirect measures of life-long stress. Our aims were to (1) identify stress proteins that increase with aging and are associated with an increased risk of mortality, and (2) to determine if FOXO3 longevity/resilience genotype dampens the expected increase in mortality risk they pose. A total of 4500 serum protein aptamers were quantified using the Somalogic SomaScan proteomics platform in the current study of 975 men aged 71-83 years. Stress proteins associated with mortality were identified. We then used age-adjusted multivariable Cox models to investigate the interaction of stress protein with FOXO3 longevity-associated rs12212067 genotypes. For all the analyses, the p values were corrected for multiple comparisons by false discovery rate. This led to the identification of 44 stress proteins influencing the association of FOXO3 genotype with reduced mortality. Biological pathways were identified for these proteins. Our results suggest that the FOXO3 resilience genotype functions by reducing mortality in pathways related to innate immunity, bone morphogenetic protein signaling, leukocyte migration, and growth factor response., (© 2023. The Author(s).)

Longevity is written into the genes. While many so-called "longevity genes" have been identified, the reason why particular genetic variants are associated with longer lifespan has proven to be elusive. The aim of the present study was to test the hypothesis that the strongest of 3 adjacent longevity-associated single nucleotide polymorphisms - rs3794396 - of the vascular endothelial growth factor receptor 1 gene, FLT1 , may confer greater lifespan by protecting against mortality risk from one or more adverse medical conditions of aging - namely, hypertension, coronary heart disease (CHD), stroke, and diabetes. In a prospective population-based longitudinal study we followed 3,471 American men of Japanese ancestry living on Oahu, Hawaii, from 1965 until death or to the end of December 2019 by which time 99% had died. Cox proportional hazards models were used to assess the association of FLT1 genotype with longevity for 4 genetic models and the medical conditions. We found that, in major allele recessive and heterozygote disadvantage models, genotype GG ameliorated the risk of mortality posed by hypertension, but not that posed by having CHD, stroke or diabetes. Normotensive subjects lived longest and there was no significant effect of FLT1 genotype on their lifespan. In conclusion, the longevity-associated genotype of FLT1 may confer increased lifespan by protecting against mortality risk posed by hypertension. We suggest that FLT1 expression in individuals with longevity genotype boosts vascular endothelial resilience mechanisms to counteract hypertension-related stress in vital organs and tissues.

Background: We assessed 10-year longitudinal associations between late-life social networks and incidence of all-cause dementia (ACD), Alzheimer's disease (AD), and vascular dementia (VaD) in Japanese-American men., Methods: We prospectively analyzed, from baseline (1991-1993) through 1999-2000, 2636 initially nondemented Kuakini Honolulu-Asia Aging Study participants who remained dementia-free during the first 3 years of follow-up. Global cognition was evaluated by the Cognitive Abilities Screening Instrument (CASI); depressive symptoms by the 11-item Center for Epidemiologic Studies Depression (CES-D) Scale; and social networks by the Lubben Social Network Scale (LSNS). Median split of LSNS scores defined weak/strong social network groups. A panel of neurologists and geriatricians diagnosed and classified dementia; AD and VaD diagnoses comprised cases in which AD or VaD, respectively, were considered the primary cause of dementia., Results: Median (range) baseline age was 77 (71-93) years. Participants with weak (LSNS score ≤29) versus strong (>29) social networks had higher age-adjusted incidence (in person-years) of ACD (12.6 vs. 8.7; p = .014) and AD (6.7 vs. 4.0; p = .007) but not VaD (2.4 vs. 1.4; p = .15). Kaplan-Meier curves showed a lower likelihood of survival free of ACD (log-rank p < .0001) and AD (p = .0006) for men with weak networks. In Cox proportional hazards models adjusting for age, education, APOE ɛ4, prevalent stroke, depressive symptoms, and CASI score (all at baseline), weak networks predicted increased incidence of ACD (hazard ratio [HR] = 1.52, p = .009) and AD (HR = 1.67, p = .014) but not VaD (p > .2)., Conclusion: Weak social networks may heighten the risk of dementia and AD, underscoring the need to promote social connectedness in older adults., (© The Author(s) 2022. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: It is well established that mid-life hypertension increases risk of dementia, whereas the association of late-life hypertension with dementia is unclear., Objective: To determine whether FOXO3 longevity-associated genotype influences the association between late-life hypertension and incident dementia., Methods: Subjects were 2,688 American men of Japanese ancestry (baseline age: 77.0±4.1 years, range 71-93 years) from the Kuakini Honolulu Heart Program. Status was known for FOXO3 rs2802292 genotype, hypertension, and diagnosis of incident dementia to 2012. Association of FOXO3 genotype with late-life hypertension and incident dementia, vascular dementia (VaD) and Alzheimer's disease (AD) was assessed using Cox proportional hazards models., Results: During 21 years of follow-up, 725 men were diagnosed with all-cause dementia, 513 with AD, and 104 with VaD. A multivariable Cox model, adjusting for age, education, APOEɛ4, and cardiovascular risk factors, showed late-life hypertension increased VaD risk only (HR = 1.71, 95% CI = 1.08-2.71, p = 0.022). We found no significant protective effect of FOXO3 longevity genotype on any type of dementia at the population level. However, in a full Cox model adjusting for age, education, APOEɛ4, and other cardiovascular risk factors, there was a significant interaction effect of late-life hypertension and FOXO3 longevity genotype on incident AD (β= -0.52, p = 0.0061). In men with FOXO3 rs2802292 longevity genotype (TG/GG), late-life hypertension showed protection against AD (HR = 0.72; 95% CI = 0.55-0.95, p = 0.021). The non-longevity genotype (TT) (HR = 1.16; 95% CI = 0.90-1.51, p = 0.25) had no protective effect., Conclusion: This longitudinal study found late-life hypertension was associated with lower incident AD in subjects with FOXO3 genotype.

Objective: Since the G allele of forkhead box O3 ( FOXO3 ) single nucleotide polymorphism (SNP) rs2802292 is associated with resilience and longevity, ostensibly by mitigating the adverse effects of chronic cardiometabolic stress on mortality, our aim was to determine the association between the FOXO3 SNP rs2802292 genotype and risk of hypertension-mediated intracerebral haemorrhage (ICH)., Methods: From a prospective population-based cohort of Japanese American men from the Kuakini Honolulu Heart Program (KHHP), age-adjusted prevalence of ICH by hypertension was assessed for the whole cohort after stratifying by FOXO3 genotype. Cox regression models, adjusted for age, cardiovascular risk factors and, FOXO3 and APOE genotypes, were utilized to determine relative risk of hypertension's effect on ICH. All models were created for the whole cohort and stratified by FOXO3 G -allele carriage vs. TT genotype., Results: Among 6469 men free of baseline stroke, FOXO3 G -allele carriage was seen in 3009 (46.5%) participants. Overall, 183 participants developed ICH over the 34-year follow-up period. Age-adjusted ICH incidence was 0.90 vs. 1.32 per 1000 person-years follow-up in those without and with hypertension, respectively ( P  = 0.002). After stratifying by FOXO3 genotype, this association was no longer significant in G allele carriers. In the whole cohort, hypertension was an independent predictor of ICH (relative risk [RR] = 1.70, 95% confidence interval [CI] 1.25, 2.32; P  = 0.0007). In stratified analyses, hypertension remained an independent predictor of ICH among the FOXO3 TT -genotype group (RR = 2.02, 95% CI 1.33, 3.07; P  = 0.001), but not in FOXO3 G -allele carriers (RR = 1.39, 95% CI 0.88, 2.19; P  = 0.15)., Conclusions: The longevity-associated FOXO3   G allele may attenuate the impact of hypertension on ICH risk., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.)

Introduction: Genetic variation in the phosphatidylinositol 3-kinase reregulatory subunit 1 gene (PIK3R1) is associated with longevity., Objective: The aim of the study was to determine whether cardiovascular disease (CVD) affects this association., Methods: We performed a longitudinal study of longevity-associated PIK3R1 single-nucleotide polymorphism rs7709243 genotype by CVD status in 3,584 elderly American men of Japanese ancestry., Results: At baseline (1991-1993), 2,254 subjects had CVD and 1,314 did not. The follow-up until Dec 31, 2019 found that overall, men with a CVD had higher mortality than men without a CVD (p = 1.7 × 10-5). However, survival curves of CVD subjects differed according to PIK3R1 genotype. Those with longevity-associated PIK3R1 TT/CC had survival curves similar to those of subjects without a CVD (p = 0.11 for TT/CC, and p = 0.054 for TC), whereas survival curves for CVD subjects with the CT genotype were significantly attenuated compared with survival curves of subjects without a CVD (p = 0.0000012 compared with TT/CC, and p = 0.0000028 compared with TC). Men without CVD showed no association of longevity-associated genotype with life span (p = 0.58). Compared to subjects without any CVD, hazard ratios for mortality risk were 1.26 (95% CI, 1.14-1.39; p = 0.0000043) for CT subject with CVD and 1.07 (95% CI 0.99-1.17; p = 0.097) for CC/TT subjects with CVD. There was no genotypic effect on life span for 1,007 subjects with diabetes and 486 with cancer., Conclusion: Our study provides novel insights into the basis for PIK3R1 as a longevity gene. We suggest that the PIK3R1 longevity genotype attenuates mortality risk in at-risk individuals by protection against cellular stress caused by CVD., (© 2021 S. Karger AG, Basel.)

The single nucleotide polymorphism (SNP) rs4130113 of the growth hormone receptor gene ( GHR ) is associated with longevity. Here we explored whether longevity-associated genotypes protect against mortality in all individuals, or only in individuals with aging-related diseases. Rs4130113 genotypes were tested for association with mortality in 3,557 elderly American men of Japanese ancestry. At baseline (1991-1993), 1,000 had diabetes, 730 had coronary heart disease (CHD), 1,901 had hypertension, 485 had cancer, and 919 lacked these diseases. The men were followed from baseline until Dec 31, 2019 or death (mean 10.8 ± 6.5 SD years, range 0.01-28.8 years; 99.0% deceased by that date). In a heterozygote disadvantage model, longevity-associated genotypes were associated with significantly lower mortality risk in individuals having hypertension (covariate-adjusted hazard ratio [HR] 0.83 [95% CI: 0.76-0.93, p = 4.3 x10 -4 ]. But in individuals with diabetes, CHD, and cancer there was no genotypic difference in lifespan. As expected, normotensive men outlived men with hypertension ( p = 0.036). There was no effect, however, of genotypic difference on lifespan in normotensive men ( p = 0.11). We found that SNP rs4130113 potentially influenced the binding of transcription factors E2A, MYF, NRSF, TAL1, and TCF12 so as to alter GHR expression. We propose that in individuals with hypertension, longevity-associated genetic variation in GHR enhances cell resilience mechanisms to help protect against cellular stress caused by hypertension. As a result, hypertension-affected men who possess the longevity-associated genetic variant of GHR live as long as normotensive men.

Genetic variants of the kinase signaling gene MAP3K5 are associated with longevity. Here we explore whether the longevity-association involves protection against mortality in all individuals, or only in individuals with aging-related diseases. We tested the strongest longevity associated single nucleotide polymorphism (SNP), rs2076260, for association with mortality in 3,516 elderly American men of Japanese ancestry. At baseline (1991-1993), 2,461 had either diabetes (n=990), coronary heart disease (CHD; n=724), or hypertension (n=1,877), and 1,055 lacked any of these cardiometabolic diseases (CMDs). The men were followed from baseline until Dec 31, 2019. Longevity-associated genotype CC in a major allele homozygote model, and CC + TT in a heterozygote disadvantage model were associated with longer lifespan in individuals having a CMD (covariate-adjusted hazard ratio [HR] 1.23 [95% CI: 1.12-1.35, p= 2.5x10 -5 ] in major allele homozygote model, and 1.22 [95% CI: 1.11-1.33, p= 1.10x10 -5 ] in heterozygote disadvantage model). For diabetes, hypertension and CHD, HR p -values were 0.019, 0.00048, 0.093, and 0.0024, 0.00040, 0.0014, in each respective genetic model. As expected, men without a CMD outlived men with a CMD ( p =1.9x10 -6 ). There was, however, no difference in lifespan by genotype in men without a CMD ( p =0.21 and 0.86, respectively, in each genetic model). In conclusion, we propose that in individuals with a cardiometabolic disease, longevity-associated genetic variation in MAP3K5 enhances resilience mechanisms in cells and tissues to help protect against cardiometabolic stress caused by CMDs. As a result, men with CMD having longevity genotype live as long as all men without a CMD.

FOXO3 is a prominent longevity gene. To date, no-one has examined whether longevity-associated FOXO3 genetic variants protect against mortality in all individuals, or only in those with aging-related diseases. We therefore tested longevity-associated FOXO3 single nucleotide polymorphisms in a haplotype block for association with mortality in 3,584 elderly American men of Japanese ancestry, 2,512 with and 1,072 without a cardiometabolic disease (CMD). At baseline (1991-1993), 1,010 CMD subjects had diabetes, 1,919 had hypertension, and 738 had coronary heart disease (CHD). Follow-up until Dec 31, 2019 found that in CMD-affected individuals, longevity-associated alleles of FOXO3 were associated with significantly longer lifespan: haplotype hazard ratio 0.81 (95% CI 0.72-0.91; diabetes 0.77, hypertension 0.82, CHD 0.83). Overall, men with a CMD had higher mortality than men without a CMD ( P =6x10 -7 ). However, those men with a CMD who had the FOXO3 longevity genotype had similar survival as men without a CMD. In men without a CMD there was no association of longevity-associated alleles of FOXO3 with lifespan. Our study provides novel insights into the basis for the long-established role of FOXO3 as a longevity gene. We suggest that the FOXO3 longevity genotype increases lifespan only in at-risk individuals by protection against cardiometabolic stress.

Background: Parkinson's disease (PD) is a disease of the central nervous system that progressively affects the motor system. Epidemiological studies have provided evidence that exposure to agriculture-related occupations or agrichemicals elevate a person's risk for PD. Here, we sought to examine the possible epigenetic changes associated with working on a plantation on Oahu, HI and/or exposure to organochlorines (OGC) in PD cases., Results: We measured genome-wide DNA methylation using the Illumina Infinium HumanMethylation450K BeadChip array in matched peripheral blood and postmortem brain biospecimens in PD cases (n = 20) assessed for years of plantation work and presence of organochlorines in brain tissue. The comparison of 10+ to 0 years of plantation work exposure detected 7 and 123 differentially methylated loci (DML) in brain and blood DNA, respectively (p < 0.0001). The comparison of cases with 4+ to 0-2 detectable levels of OGCs, identified 8 and 18 DML in brain and blood DNA, respectively (p < 0.0001). Pathway analyses revealed links to key neurotoxic and neuropathologic pathways related to impaired immune and proinflammatory responses as well as impaired clearance of damaged proteins, as found in the predominantly glial cell population in these environmental exposure-related PD cases., Conclusions: These results suggest that distinct DNA methylation biomarker profiles related to environmental exposures in PD cases with previous exposure can be found in both brain and blood.

Objective: While excessive daytime sleepiness (EDS) can predate the clinical diagnosis of Parkinson disease (PD), associations with underlying PD pathogenesis are unknown. Our objective is to determine if EDS is related to brain Lewy pathology (LP), a marker of PD pathogenesis, using clinical assessments of EDS with postmortem follow-up., Methods: Identification of LP was based on staining for α-synuclein in multiple brain regions in a sample of 211 men. Data on EDS were collected at clinical examinations from 1991 to 1999 when participants were aged 72-97 years., Results: Although EDS was more common in the presence vs absence of LP ( p = 0.034), the association became stronger in neocortical regions. When LP was limited to the olfactory bulb, brainstem, and basal forebrain (Braak stages 1-4), frequency of EDS was 10% (4/40) vs 17.5% (20/114) in decedents without LP ( p = 0.258). In contrast, compared to the absence of LP, EDS frequency doubled (36.7% [11/30], p = 0.023) when LP reached the anterior cingulate gyrus, insula mesocortex, and midfrontal, midtemporal, and inferior parietal neocortex (Braak stage 5). With further infiltration into the primary motor and sensory neocortices (Braak stage 6), EDS frequency increased threefold (51.9% [14/27], p < 0.001). Findings were similar across sleep-related features and persisted after adjustment for age and other covariates, including the removal of PD and dementia with Lewy bodies., Conclusions: The association between EDS and PD includes relationships with extensive topographic LP expansion. The neocortex could be especially vulnerable to adverse relationships between sleep disorders and aggregation of misfolded α-synuclein and LP formation., (© 2019 American Academy of Neurology.)

Braak et al.'s 2003 paper detailing the caudo-rostral progression of Lewy body pathology (LP) formed the foundation of current understanding of disease spread in Parkinson's disease (PD); however, its methods are difficult to recreate and consequently multiple new staging systems emerged to recapitulate Braak's staging system using standard neuropathological methods and to account for other patterns of LP. Studies using these systems have documented widely variable rates of cases that 'fail to fit' expected patterns of LP spread. This could be due to population differences, features of individual systems, or may constitute under-recognized patterns of disease. We examined 324 neuropathological cases from the Honolulu Asia Aging Study and applied four different LP staging systems to determine the proportion of cases adhering to different staging methodologies and those that 'fail to fit' expected patterns of LP. Of 141 cases with LP (24: PD, 8: Dementia with Lewy bodies (DLB), 109: Incidental Lewy body disease (ILBD)), our application of Braak et al., 2003 classified 83.7%, Müller et al., 2005 classified 87.9%, Beach et al., 2009 classified 100%, and Leverenz et al., 2008 classified 98.6%. There were significant differences in the cases classifiable by the Leverenz and Beach systems versus the Braak and Müller systems (p < 0.001 for each). In this population-based autopsy cohort with a high prevalence of ILBD, the majority of cases were consistent with the progression characterized by the Braak et al. however, the determination of cases as atypical is highly dependent on the staging system applied., (Published by Elsevier Ltd.)

Background: Organochlorine pesticides are associated with an increased risk of Parkinson's disease. A preliminary analysis from the Honolulu-Asia Aging Study suggested that heptachlor epoxide, a metabolite from an organochlorine pesticide extensively used in Hawaii, may be especially important. This was a cross sectional analysis to evaluate the association of heptachlor epoxide and other organochlorine compounds with Lewy pathology in an expanded survey of brain organochlorine residues from the longitudinal Honolulu-Asia Aging Study., Methods: Organochlorines were measured in frozen occipital or temporal lobes in 705 brains using gas chromatography with mass spectrometry. Lewy pathology was identified using hematoxylin and eosin- and α-synuclein immunochemistry-stained sections from multiple brain regions., Results: The prevalence of Lewy pathology was nearly doubled in the presence versus the absence of heptachlor epoxide (30.1% versus 16.3%, P < 0.001). Although associations with other compounds were weaker, hexachlorobenzene (P = 0.003) and α-chlordane (P = 0.007) were also related to Lewy pathology. Most of the latter associations, however, were a result of confounding from heptachlor epoxide. Neither compound was significantly related to Lewy pathology after adjustment for heptachlor epoxide. In contrast, the association of heptachlor epoxide with Lewy pathology remained significant after adjustments for hexachlorobenzene (P = 0.013) or α-chlordane (P = 0.005). Findings were unchanged after removal of cases of PD and adjustment for age and other characteristics., Conclusions: Organochlorine pesticides are associated with the presence of Lewy pathology in the brain, even after exclusion of PD cases. Although most of the association is through heptachlor epoxide, the role of other organochlorine compounds is in need of clarification. © 2018 International Parkinson and Movement Disorder Society., (© 2018 International Parkinson and Movement Disorder Society.)

Longevity is a polygenic trait in which genetic predisposition is particularly important. We hypothesized that among genes differentially expressed in response to caloric restriction, several may be candidate longevity genes. We tested 459 single-nucleotide polymorphisms (SNPs) in 47 genes differentially expressed in calorically restricted mice and 12 other genes for association with longevity. Subjects were American men of Japanese ancestry, 440 aged ≥95 years and 374 with an average life span. Based on a dominant model of inheritance, an association with longevity at the p < .05 level was seen for SNPs in 13 of the genes. Testing by all possible models increased the number of genes to 18. After correction for multiple testing, four genes retained significance, namely, MAP3K5 (p = .00004), SIRT7 (p = .00004), SIRT5 (p = .0007), and PIK3R1 (p = .01). In a dominant model, association with longevity was seen for multiple adjacent SNPs within two of these genes (MAP3K5 and PIK3R1), as well as in FLT1, consistent with linkage disequilibrium with a causative variant in the vicinity of each respective SNP set. MAP3K5 and FLT1 haplotypes were associated with longevity. In conclusion, the present study implicates variation in MAP3K5, FLT1, PIK3R1, SIRT7, and SIRT5 in human longevity.

Background: Carotid plaque has emerged as a marker of coronary heart disease (CHD) risk. Comparison of carotid plaque burden between different race/ethnic groups may provide a relative estimate of their future CHD risk., Methods: We conducted a population-based study among apparently healthy middle-aged men aged 40-49 years (ERA JUMP study (n = 924)) and recruited 310 Whites in Pittsburgh, US, 313 Japanese in Otsu, Japan, and 301 Koreans in Ansan, South Korea. The number of carotid plaque and CHD risk factors was assessed using a standardized protocol across all centers. The burden of carotid plaque was compared between race/ethnic groups after adjustment for age and BMI, and after multivariable adjustment for other CHD risk factors using marginalized zero-inflated Poisson regression models. Cross-sectional associations of risk factors with plaque were examined., Results: Whites (22.8%) had more than four-fold higher prevalence (p < 0.01) of carotid plaque than Japanese men (4.8%) while the prevalence among Koreans was 10.6%. These differences remained significant after adjustment for age, BMI as well as other risk factors - incidence density ratio (95% confidence interval) for plaque was 0.13 (0.07, 0.24) for Japanese and 0.32 (0.18, 0.58) for Koreans as compared to Whites. Age, hypertension and diabetes were the only risk factors significantly associated with presence of carotid plaque in the overall population., Conclusion: Whites have significantly higher carotid plaque burden than men in Japan and Korea. Lower carotid plaque burden among Japanese and Koreans is independent of traditional CVD risk factors., (Copyright © 2018 Elsevier B.V. All rights reserved.)

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 Americans), different environments with an identical race (Japanese Americans vs. Japanese), and similar races with similar environments (Japanese vs. Koreans). A population-based sample of 1212 men aged 40-49 were analyzed: 307 Caucasians and 300 Japanese Americans in the United States, 310 Japanese in Japan, and 295 Koreans in Korea. We compared the proportion of visceral adipose tissue area to total abdominal adipose tissue area (VAT%) and other factors that can affect abdominal fat distribution (smoking, alcohol use, physical activity levels, and metabolic factors)., Results: VAT% was significantly higher in Japanese and Koreans than in Japanese Americans and Caucasians (50.0, 48.5, 43.2, 41.0%, respectively, P < 0.001). Even after adjustment for possible confounders, the significant VAT% difference remained in comparing groups with identical race but different environments (i.e., Japanese vs. Japanese Americans). In contrast, comparing groups with different races but similar environments (i.e., Caucasians vs. Japanese Americans), VAT% was not significantly different. Comparing groups with similar races and similar environments (i.e., Japanese vs. Koreans), VAT% did not significantly differ., Conclusions: Environmental differences, apart from racial differences, affect the difference in abdominal fat distribution across different groups in middle-aged men.

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, via RNA polymerase II binding chromatin looping, with sites in the FOXO3 promoter, and likely function together as a cis-regulatory unit. The SNPs exhibited a high degree of LD in the Asian population, in which they define a specific longevity haplotype that is relatively common. The haplotype was less frequent in whites and virtually nonexistent in Africans. We identified distant contact points between FOXO3 and 46 neighboring genes, through long-range physical contacts via CCCTC-binding factor zinc finger protein (CTCF) binding sites, over a 7.3 Mb distance on chromosome 6q21. When activated by cellular stress, we visualized movement of FOXO3 toward neighboring genes. FOXO3 resides at the center of this early-replicating and highly conserved syntenic region of chromosome 6. Thus, in addition to its role as a transcription factor regulating gene expression genomewide, FOXO3 may function at the genomic level to help regulate neighboring genes by virtue of its central location in chromatin conformation via topologically associated domains. We believe that the FOXO3 'interactome' on chromosome 6 is a chromatin domain that defines an aging hub. A more thorough understanding of the functions of these neighboring genes may help elucidate the mechanisms through which FOXO3 variants promote longevity and healthy aging., (© 2017 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.)

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 of Japanese ancestry aged ≥95 years and 374 men of average life span revealed association with longevity at the p < .05 level for 2 SNPs in CTGF and 7 in EGFR. Two in CTGF and two in EGFR remained significant after Bonferroni correction. The SNPs of both CTGF and EGFR were in a haplotype block in each respective gene. Haplotype analysis confirmed the suggestive association found by χ2 analysis. We noted an excess of heterozygotes among the longevity cases, consistent with heterozygote advantage in living to extreme old age. No associations of the most significant SNPs were observed in whites or Koreans. In conclusion, the present findings indicate that genetic variation in CTGF and EGFR may contribute to the attainment of extreme old age in Japanese. More research is needed to confirm that genetic variation in CTGF and EGFR contributes to the attainment of extreme old age across human populations., (© The Author 2016. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

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 Honolulu Heart Program cohort and 1,595 White and 1,067 Black elderly individuals from the Health Aging and Body Composition study., Results: Multivariate Cox regression models demonstrated that carriage of the longevity-associated G allele of FOXO3 single nucleotide polymorphisms rs2802292 was a protective factor against CAD mortality in all three populations. In Japanese and Whites, but not in Blacks, the protective effect of the G allele was little changed in models adjusted for other major risk factors. Population-attributable risk (PAR) models found that the nonprotective TT genotype contributed 15%, 9%, and 3% to CAD mortality risk in Japanese, White, and Black Americans, respectively, and was one of the top three contributing factors to CAD mortality. In Japanese, this effect size was comparable with hypertension (15%), but in Whites and Blacks PAR for hypertension was higher (29% and 26%, respectively). G-allele carriers had lower plasma TNF-α than noncarriers, suggesting inflammation as a potential mediating factor for CAD mortality risk., Conclusion: FOXO3 genotype is an important risk factor for CAD mortality in older populations. More research is needed to identify potential mechanisms and targets for intervention., (© The Author 2016. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

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 ancestry drawn from the Family Blood Pressure Program II we genotyped 411 female and 432 male subjects aged 40-79 years and tested for statistical association by contingency table analysis and generalized linear models that included logistic regression adjusting for sibling correlation in the data set. Replication of rs2802292 with EHT was attempted in Japanese SONIC study subjects and of each SNP in a meta-analysis of genome-wide association studies of BP in individuals of European ancestry., Results: In Americans of Japanese ancestry, women homozygous for the longevity-associated (minor) allele of each FOXO3 SNP had 6mm Hg lower systolic BP and 3mm Hg lower diastolic BP compared with major allele homozygotes (Bonferroni corrected P < 0.05 and >0.05, respectively). Frequencies of minor allele homozygotes were 3.3-3.9% in women with EHT compared with 9.5-9.6% in normotensive women ( P = 0.03-0.04; haplotype analysis P = 0.0002). No association with BP or EHT was evident in males. An association with EHT was seen for the minor allele of rs2802292 in the Japanese SONIC cohort ( P = 0.03), while in European subjects the minor allele of each SNP was associated with higher systolic and diastolic BP., Conclusion: Longevity-associated FOXO3 variants may be associated with lower BP and EHT in Japanese women.

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 allele in older Americans of diverse ancestry. It involved a 17-year prospective cohort study of 3584 older American men of Japanese ancestry from the Honolulu Heart Program cohort, followed by a 17-year prospective replication study of 1595 white and 1056 black elderly individuals from the Health Aging and Body Composition cohort. The relation between FOXO3 genotype and cause-specific mortality was ascertained for major causes of death including coronary heart disease (CHD), cancer, and stroke. Age-adjusted and multivariable Cox proportional hazards models were used to compute hazard ratios (HRs) for all-cause and cause-specific mortality. We found G allele carriers had a combined (Japanese, white, and black populations) risk reduction of 10% for total (all-cause) mortality (HR = 0.90; 95% CI, 0.84-0.95; P = 0.001). This effect size was consistent across populations and mostly contributed by 26% lower risk for CHD death (HR = 0.74; 95% CI, 0.64-0.86; P = 0.00004). No other causes of death made a significant contribution to the survival advantage for G allele carriers. In conclusion, at older age, there is a large risk reduction in mortality for G allele carriers, mostly due to lower CHD mortality. The findings support further research on FOXO3 and FoxO3 protein as potential targets for therapeutic intervention in aging-related diseases, particularly cardiovascular disease., (© 2016 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.)

Purpose: Low-carbohydrate diets (LCD) are a popular dietary strategy for weight reduction. The effects of LCD on long-term outcome vary depending on type of LCD, possibly due to the fact that effects on cardiometabolic risk factors may vary with different types of LCD. Accordingly, we studied these relations., Methods: We assessed serum concentrations of high-density lipoprotein cholesterol (HDLc), low-density lipoprotein cholesterol (LDLc), high-sensitivity C-reactive protein (CRP), total cholesterol, glycated hemoglobin, and uric acid, and nutrient intakes by standardized methods in men and women ages 40-59 years from four population samples of Japanese in Japan (553 men and 544 women, combined). For people consuming usual, animal-based, and plant-based LCDs, we calculated LCD scores, based on relative level of fat, protein, and carbohydrate, by modifying the methods of Halton et al. Instead of calculating scores based on animal or vegetable fat, we used saturated fatty acids (SFA) or monounsaturated fatty acids (MUFA) + polyunsaturated fatty acids (PUFA)., Results: In multivariate regression analyses with adjustment for site, age, sex, BMI, smoking, alcohol intake, physical activity, and years of education, all three LCD scores were significantly positively related to HDLc (all P < 0.001), but not to LDLc. The plant-based LCD score was significantly inversely related to log CRP (coefficient = -0.010, P = 0.018)., Conclusions: All three LCD scores were significantly positively related to HDLc. The plant-based LCD score was significantly inversely related to CRP. Carbohydrate intake below 50 % of total energy with higher intakes of vegetable protein and MUFA + PUFA, and lower intakes of SFA may be favorable for reducing cardiometabolic risk factors.