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1853AG 810.030.270.184.101.025.309.087.19374.040.227.012.148660.076.279.016.187AA associations with human lifespan in a cohort of elderly Asian women. Replication of nominally significant findings in independent Caucasian cohorts revealed a SNP in AKT1 that was significantly associated with lifespan, and two SNPs in FOXO3A, which were significantly associated with lifespan in women. Overall, the longevity-associated SNPs were associated with the three major categories (cardiovascular, cancer, and cause of death), suggesting that their association with lifespan is due to a general effect rather than to a specific disease (Table 5). Several previous studies have demonstrated associations between variants in other genes in the insulin/IGF1 signaling pathway and human aging phenotypes. Most of these studies investigated only a small number of SNPs or genes, and their results have not been replicated. Our study analyzed 291 SNPs in 30 genes, providing the first comprehensive screen of the insulin/IGF1 signaling pathway in humans.

Association of genetic variation in AKT1 with human lifespan has not been previously reported; however, several studies have reported associations with FOXOand small insertions-deletions. We did not genotype copy number variants or large insertions-deletions and, with the exception of a few amino acid-coding variants, we only evaluated the effects of common variants (minor allele frequency > 0.05). The relative dearth of common SNPs associated with longevity in the genes we analyzed does not exclude the existence of other genetic effects in the pathway. How the variants we identified affect lifespan remains uncertain. All three longevity-associated SNPs that replicated across three independent cohorts are intronic SNPs of no known function, and they do not reside in motifs conserved through evolution. In the case of FOXO3A, the two longevity-associated SNPs are in LD with other variants across an area of approximately 67 kb (Fig. S1). As the LD is so strong in this case, it is unlikely that these SNPs are tagging rare functional variants. To obtain a complete picture of the association of genetic variation in the insulin/IGF1 pathway with longevity phenotypes, discovery of rare variants by re-sequencing of the same set of candidate genes will be necessary.

In summary, we screened the insulin/IGF1 signaling pathway for association with human longevity and identified common variants in two genes, AKT1 and FOXO3A, which are consistently associated with longer lifespan in three independent Caucasian cohorts. Our results extend the remarkably consistent effect of this pathway on lifespan in model organisms to human populations. Although the effects we observed are subtle, they implicate the insulin/IGF1 signaling pathway in human aging, confirming that studies in model organisms can help us gain insights into the biology of human aging.

Despite these limitations, replication among three independent Caucasian samples, including a founder population (AJC), strengthens our findings. It is unlikely that population stratification could lead to false-positive results that would be consistent across a European American/Caucasian American population and the Ashkenazi population, as the patterns of stratification would be different. Any birth cohort effects should be relatively modest, as the differences in birth year were small.

Cardiovascular Health Study (CHS)

Experimental procedures