Association of centenarian polygenic score with disability-free survival and its modification effects on aging outcomes

Centenarians exhibit remarkable longevity, and exploring the genetic components associated with this longevity is crucial for understanding the mechanisms underlying human aging. We investigated genetic factors in Japanese centenarians, healthy agers aged 85–89 years, and controls. A genome-wide association study (GWAS) identified longevity-associated variants in APOE and a novel Japanese-specific variant in EYS. Genetic correlation and polygenic risk score analyses revealed favorable genetic profiles related to blood pressure, cardiovascular disease, type 2 diabetes, and liver metabolism in centenarians and healthy individuals. A Centenarian Polygenic Score (CentPGS) was developed using 8,534 single-nucleotide variations (SNVs) from centenarian GWAS, distinguishing centenarians and healthy agers from controls. We calculated disability-free survival (DFS) as a complementary endpoint to lifespan using electronic insurance claims. CentPGS was enriched in older individuals maintaining DFS beyond 95 years. High CentPGS mitigated the negative effects of several risk factors, including cognitive impairment, lower education, and economic hardship, on both lifespan and DFS, suggesting potential interventional targets. Our findings indicate that centenarians possess genetic components that modify the effects of age-related risk factors and contribute to an extended healthspan in the general older adult population, offering insights into interventions that promote healthy aging, even for those with low CentPGS.