FOXO3 longevity variant

FOXO3 encodes a forkhead-box transcription factor that integrates signals from the insulin/IGF-1 and AMPK pathways to regulate stress resistance, autophagy, apoptosis, and antioxidant gene expression. A cluster of intronic single-nucleotide polymorphisms — most prominently rs2802292 — was first associated with exceptional longevity in Hawaiian men of Japanese ancestry (Willcox et al., 2008) and has since been replicated across multiple independent cohorts in Europe, East Asia, and Ashkenazi populations. The protective allele is thought to promote nuclear retention of FOXO3, enhancing expression of downstream targets including GADD45, SOD2, and autophagy regulators. Because FOXO3 sits at the convergence of multiple conserved longevity pathways, it remains one of the most consistently replicated genetic associations with human lifespan.