Genetic determinants of centenarian longevity, as quantified by the 'CentPGS' score, are associated with a lower risk of multiple age-related diseases and a longer healthspan.

Abstract Centenarians exhibit remarkable longevity, and exploring the genetic determinants of that longevity is crucial for understanding the mechanisms of human ageing. Although APOE4 is the most common implicated negative factor in longevity, other genetic factors and their associated phenotypes are not fully understood. We conducted a genome-wide association study (GWAS) of 964 Japanese centenarians (including 173 supercentenarians) and 7,306 controls to identify the genetic components of longevity and the correlated phenotypes. GWAS summary statistics revealed that the genetic components of longevity were negatively associated with the risk of multiple age-related diseases and biometrics. Survival analysis indicated that a polygenic score derived from these summary statistics, called CentPGS, was correlated with healthspan in a cohort of healthy older people. This association was independent of APOE4 genotype and sex, suggesting that CentPGS is a promising genetic indicator of healthspan and may be used in future investigations into healthy longevity.