biostudies-literatureLin JRNIA NIH HHSNHGRI NIH HHS783-794https://www.ebi.ac.uk/biostudies/studies/S-EPMC12434795biostudies-literatureUnknown1(9)Extreme longevity in humans has a strong genetic component, but whether this involves genetic variation in the same longevity pathways as found in model organisms is unclear. Using whole-exome sequences of a large cohort of Ashkenazi Jewish centenarians to examine enrichment for rare coding variants, we found most longevity-associated rare coding variants converge upon conserved insulin/insulin-like growth factor 1 signaling and AMP-activating protein kinase signaling pathways. Centenarians have a number of pathogenic rare coding variants similar to control individuals, suggesting that rare variants detected in the conserved longevity pathways are protective against age-related pathology. Indeed, we detected a pro-longevity effect of rare coding variants in the Wnt signaling pathway on indNature agingRare genetic coding variants associated with human longevity and protection against age-related diseases.PMC12434795P01 AG017242U19 AG056278R01 AG060747R01 HG008153R01 AG057909R01 AG061155Vijg JSin-Chan PNapolioni VNiedernhofer LJBarzilai NGorg SFranke AZhang ZDZhang QLaudes MMitra JSuh YWang ZJabalameli MRNebel ANguyen NShuldiner ARGorbunova VAtzmon GRegeneron Genetics CenterRobbins PDLadiges WCGreicius MDMilman SLin JRTorres GGYe KGao TfalseRare genetic coding variants associated with human longevity and protection against age-related diseases.Extreme longevity in humans has a strong genetic component, but whether this involves genetic variation in the same longevity pathways as found in model organisms is unclear. Using whole-exome sequences of a large cohort of Ashkenazi Jewish centenarians to examine enrichment for rare coding variants, we found most longevity-associated rare coding variants converge upon conserved insulin/insulin-like growth factor 1 signaling and AMP-activating protein kinase signaling pathways. Centenarians have a number of pathogenic rare coding variants similar to control individuals, suggesting that rare variants detected in the conserved longevity pathways are protective against age-related pathology. Indeed, we detected a pro-longevity effect of rare coding variants in the Wnt signaling pathway on ind2021-01-01T00:00:00Z2021 Sep2026-06-02T05:52:09.432Z2026-04-14T03:14:07.011ZS-EPMC124347953711762710.1038/s43587-021-00108-5