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Summary The insulin/IGF1 signaling pathways affect lifespan in several model organisms, including worms, flies and mice. To investigate whether common genetic variation in this pathway influences lifespan in humans, we genotyped 291 common variants in 30 genes encoding proteins in the insulin/IGF1 signaling pathway in a cohort of elderly Caucasian women selected from the Study of Osteoporotic Fractures (SOF), including 293 long-lived cases (lifespan ≥ 92 years (y), mean ± standard deviation (SD) = 95.3 ± 2.2y) and 603 average-lifespan controls (lifespan ≤ 79y, mean=75.7 ± 2.6y). Variants were selected for genotyping using a haplotype tagging approach. We found a modest excess of variants nominally associated with longevity. We then replicated nominally significant variants in two additional Caucasian cohorts containing both males and females: the Cardiovascular Health Study (CHS) and Ashkenazi Jewish Centenarians (AJC). An intronic single nucleotide polymorphism (SNP) in AKT1, rs3803304, was significantly associated with lifespan in a meta-analysis across the three cohorts (odds ratio (OR)=0.78 (95% confidence interval (CI)=0.68-0.89), adjusted p=0.043); two intronic SNPs in FOXO3A demonstrated a significant lifespan association among women only (rs1935949, OR=1.35, 95% CI=1.15-1.57, adjusted p=0.0093). Conclusion: common variants in several insulin/IGF1 pathway genes are associated with human lifespan.

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