Sex Difference and Interaction of SIRT1 and FOXO3 Candidate Longevity Genes on Life Expectancy: A 10-Year Prospective Longitudinal Cohort Study

SIRT1 and FOXO3 are both associated with longevity. Molecular biology research in many organisms (yeast, nematode worm Caenorhabditis elegans, and mice mammalian models) shows SIRT1 acts on the FOXO family of forkhead transcription factors to respond to oxidative stress better, shifting processes away from cell death toward stress resistance. Human population studies need epidemiologic evidence. We used an open cohort of 3 166 community-dwelling participants in China with follow-up from 2008 to 2018. The mean age at baseline was 84.6 years. In 16 375 person-years of follow-up, there were 1 968 mortality events. SIRT1 and FOXO3 exhibited Mendelian randomization as there was no correlation with each other and with baseline study population characteristics. Some SIRT1 and FOXO3 single-nucleotide polymorphisms showed protective effects for mortality risk. The FOXO3 protective effect was stronger in females, and the SIRT1 protective effect was stronger in male study participants. We did not see evidence of a synergistic effect of being carriers of both SIRT1 and FOXO3 advantageous alleles.