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.gene ͉ insulin ͉ healthy aging ͉ disease ͉ disability

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Context-Prediction models to identify healthy individuals at high risk of cardiovascular disease have limited accuracy. A low ankle brachial index is an indicator of atherosclerosis and has the potential to improve prediction.Objective-To determine if the ankle brachial index provides information on the risk of cardiovascular events and mortality independently of the Framingham Risk Score and can improve risk prediction.

Findings indicate that infrequent bowel movements are associated with an elevated risk of future PD. Further study is needed to determine whether constipation is part of early PD processes or is a marker of susceptibility or environmental factors that may cause PD.

Impaired olfaction can predate clinical PD in men by at least 4 years and may be a useful screening tool to detect those at high risk for development of PD in later life.

Inflammatory responses are associated with cardiovascular disease and may be associated with dementing disease. We evaluated the long-term prospective association between dementia and high-sensitivity C-reactive protein, a nonspecific marker of inflammation. Data are from the cohort of Japanese American men who were seen in the second examination of the Honolulu Heart Program (1968-1970) and subsequently were reexamined 25 years later for dementia in the Honolulu-Asia Aging Study (1991-1996). In a random subsample of 1,050 Honolulu-Asia Aging Study cases and noncases, high-sensitivity C-reactive protein concentrations were measured from serum taken at the second examination; dementia was assessed in a clinical examination that included neuroimaging and neuropsychological testing and was evaluated using international criteria. Compared with men in the lowest quartile (<0.34mg/L) of high-sensitivity C-reactive protein, men in the upper three quartiles had a 3-fold significantly increased risk for all dementias combined, Alzheimer's disease, and vascular dementia. For vascular dementia, the risk increased with increasing quartile. These relations were independent of cardiovascular risk factors and disease. These data support the view that inflammatory markers may reflect not only peripheral disease, but also cerebral disease mechanisms related to dementia, and that these processes are measurable long before clinical symptoms appear.

Background: The course of weight loss associated with dementia is unclear, particularly prior to and around the onset of the clinical syndrome.Objective: To compare the natural history of weight change from mid to late life in men with and without dementia in late life. Design and Setting:The Honolulu-Asia Aging Study, a 32-year, prospective, population-based study of Japanese American men who had been weighed on 6 occasions between 1965 and 1999 and who had been screened for dementia 3 times between 1991 and 1999.Participants: Of 1890 men (aged 77-98 years), 112 with incident dementia were compared with 1778 without dementia at the sixth examination (1997)(1998)(1999).Main Outcome Measure: Weight change up to and including the sixth examination was treated as the dependent variable and estimated using a repeated measures analysis.Results: Groups with and without dementia did not differ with respect to baseline weight or change in weight from mid to late life (first 26 years' follow-up). In the latelife examinations (final 6 years), mean age-and educationadjusted weight loss was −0.22 kg/y (95% confidence intervals, −0.26 to −0.18) in participants without dementia. Men with incident dementia at the same examination had an additional yearly weight loss of −0.36 kg (95% confidence interval, −0.53 to −0.19). This was not changed substantially with adjustment for risk factors for vascular disease or functional impairment and was significant for both Alzheimer disease and vascular dementia subtypes.Conclusions: Dementia-associated weight loss begins before the onset of the clinical syndrome and accelerates by the time of diagnosis. The potential impact on prognosis should be considered in the case of elderly persons at risk for dementia.

In healthy middle-aged men, long-term mortality risk was associated with grip strength at baseline, independent of BMI. The possible interpretation of the finding is that early life influences on muscle strength may have long-term implications for mortality. Additionally, higher strength itself may provide greater physiologic and functional reserve that protects against mortality.