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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These data suggest that avoidance of certain risk factors in midlife is associated with the probability of a long and healthy life among men.

Many performance tests used today are not reliable. Only a few discriminate between the most highly functioning individuals and individuals with good function. Thus, a new recommended battery includes unassisted single-leg stand, balance platform "foam pad, eyes closed," elbow flexion and knee extension strength (strength chair), grip strength, timed chair stands, and the 6-minute walk. These simple performance-based tests have good reliability and discrimination across the range of function and can be used in most clinical and research settings to quickly assess global functional level.