Genetic architecture of human aging and longevity: Insights from genome-wide association studies

Aging represents a fundamental evolutionary feature shared across all living organisms, intrinsically coupled with development and lifespan. It is orchestrated by a complex polygenic architecture involving numerous small-effect variants distributed across diverse biological pathways, giving rise to striking interindividual variation in aging trajectories and lifespan. Over the past decade and a half, genome-wide association studies (GWAS) have uncovered multiple loci associated with lifespan, healthspan, exceptional longevity, and aging, converging on key biological processes such as lipid metabolism, inflammation, insulin/IGF signaling, and DNA repair. These discoveries have illuminated conserved molecular networks underlying the regulation of aging and longevity. Nevertheless, the identified variants collectively account for only a modest fraction of heritability, underscoring that aging and longevity arise from the cumulative and coordinated actions of myriad common alleles within complex biological networks. In this minireview, we synthesize major genetic insights from GWAS of aging and longevity, delineate recurrent pathways and molecular themes, and discuss how these findings refine our understanding of the genomic foundations of lifespan variation. We further highlight outstanding challenges, including phenotypic heterogeneity, ancestry-specific effects, and the limited predictive power of current models, and propose conceptual directions for future research aimed at establishing a more comprehensive and mechanistic framework for the genetic architecture of human aging and healthy longevity.