FOXO3A genotype is strongly associated with human longevity. Bradley J. Willcox*, Timothy A. Donlon*, Qimei He*, Randi Chen*, John S. Grove*, Katsuhiko Kamal H. Masaki*, D. Craig Willcox*,**, Beatriz Rodriguez*, and J. David Curb* conducted a study to assess the potential genetic contributions to human longevity from genes linked to IIS signaling. The insulin/IGF-1 signaling (IIS) pathway, an important evolutionarily conserved biological pathway that influences aging and longevity, has been studied in animal models. However, human data has been limited due to small sample sizes, lack of precise phenotyping, and population stratification, among other challenges. The researchers chose a large, homogeneous, long-lived population of men well-characterized for aging phenotypes and performed a nested-case control study of 5 candidate longevity genes.

Genetic variation within the FOXO3A gene was strongly associated with human longevity. 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, which was associated with homozygosity for the FOXO3A GG genotype.

The basic molecular pathway of insulin signaling is conserved through evolution, evidence of which can be seen in yeast, flies, worms, rodents, and humans. A key regulator of this pathway in worms is the transcription factor DAF-16, which is required for the large lifespan extension produced in C. elegans by inhibiting insulin/IGF-1 signaling. Homologues of DAF-16 in several species have been linked to aging phenotypes and longevity.

Human longevity is a complex phenotype with multiple determinants, including genetic differences. Several studies suggest that about 25% of the variation in human lifespan in average-lived populations can be explained by genetic factors. However, studies of candidate longevity-associated genes in humans have generally been disappointing, with few replications observed across populations.

In contrast, there have been several robust genetic findings in model organisms of aging. For example, variation in single genes can result in substantial differences in lifespan in model organisms, particularly with genes that are considered part of the insulin/IGF-1 (IIS) signaling pathway. Mutations that increase SIR-2 activity or that decrease IGF-1 signaling both increase the lifespan of C. elegans by the DAF-16/FOXO protein.

The researchers conclude that further exploration of the FOXO3A gene, human longevity and other aging phenotypes is warranted in other populations. The article is a PNAS Direct Submission.19.48 0100 78.54 13.85 1298 0.1088 Variables at baseline examination. *Cases (longevity phenotype) consisted of all HHP/HAAS participants with DNA samples (living and dead) who had reached the age of 95 years by Aug. 2007: Gp1: Alive, n=37, mean age 98.7, range 97-106 years; Gp2: dead, n=166, mean death age 97.5, range 95-106 years). P value from Student's t-test for continuous variables and χ2 for categorical variables. Log transformation performed for variables not normally distributed. MAF, minor allele frequency; CASI, cognitive abilities screening instrument. Characteristics, general health status, disease prevalence, and functional status are presented (33), and although not yet universally accepted, supportive evidence has accumulated over the years (34, 35). Thus, FOXO may provide a potential forkhead or bridge between insulin signaling, free radicals, and human aging/longevity. From this 1991-1993 baseline population, we selected all participants who, by 2007, had survived to the age of 95 years or more as Phy longevity cases (n=213). We then selected all participants who died before the age of 81 years as average-lived controls (n=402). Baseline characteristics of the cases and controls are presented in Table 1. In terms of biological characteristics, the long-lived cases were older, leaner (lower waist:hip ratio), had lower triglycerides (borderline), lower glucose, lower insulin levels, and a higher prevalence of the FOXO3A3 allele at the baseline examination. The cases also had better self-rated health and a lower prevalence of cardiovascular disease [coronary heart disease (CHD) and stroke] and cancer. Functionally, they appeared better able to walk but had lower grip strength. There was no difference.

There has been some prior work linking genes in the IIS pathway to human longevity (36, 37), including an interesting recent report by Suh et al. (38), which links functionally significant IGF-1 receptor mutations to exceptional longevity, but we have not found any published reports of association between FOXO genes and human longevity. Prior studies have found links between FOXO genes and other aging phenotypes, including 4-year survival and stroke risk (39), as well as premature menopause (40).