Genetic architecture of human aging and longevity: Insights from genome-wide association studies
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Aging represents a fundamental evolutionary feature sharedacross all living organisms, intrinsically coupled with developmentand lifespan. It is orchestrated by a complex polygenicarchitecture involving numerous small-effect variants distributedacross diverse biological pathways, giving rise to strikinginterindividual variation in aging trajectories and lifespan. Over the past decade and a half, genome-wide associationstudies (GWAS) have uncovered multiple loci associated withlifespan, healthspan, exceptional longevity, and aging, convergingon key biological processes such as lipid metabolism,inflammation, insulin/IGF signaling, and DNA repair. Thesediscoveries have illuminated conserved molecular networksunderlying the regulation of aging and longevity. Nevertheless,the identified variants collectively account for only a modestfraction of heritability, underscoring that aging and longevityarise from the cumulative and coordinated actions of myriadcommon alleles within complex biological networks. In thisminireview, we synthesize major genetic insights from GWASof aging and longevity, delineate recurrent pathways andmolecular themes, and discuss how these findings refine ourunderstanding of the genomic foundations of lifespan variation. We further highlight outstanding challenges, includingphenotypic heterogeneity, ancestry-specific effects, and thelimited predictive power of current models, and proposeconceptual directions for future research aimed at establishinga more comprehensive and mechanistic framework for thegenetic architecture of human aging and healthy longevity.
Abstract
Aging represents a fundamental evolutionary feature sharedacross all living organisms, intrinsically coupled with developmentand lifespan. It is orchestrated by a complex polygenicarchitecture involving numerous small-effect variants distributedacross diverse biological pathways, giving rise to strikinginterindividual variation in aging trajectories and lifespan. Over the past decade and a half, genome-wide associationstudies (GWAS) have uncovered multiple loci associated withlifespan, healthspan, exceptional longevity, and aging, convergingon key biological processes such as lipid metabolism,inflammation, insulin/IGF signaling, and DNA repair. Thesediscoveries have illuminated conserved molecular networksunderlying the regulation of aging and longevity. Nevertheless,the identified variants collectively account for only a modestfraction of heritability, underscoring that aging and longevityarise from the cumulative and coordinated actions of myriadcommon alleles within complex biological networks. In thisminireview, we synthesize major genetic insights from GWASof aging and longevity, delineate recurrent pathways andmolecular themes, and discuss how these findings refine ourunderstanding of the genomic foundations of lifespan variation. We further highlight outstanding challenges, includingphenotypic heterogeneity, ancestry-specific effects, and thelimited predictive power of current models, and proposeconceptual directions for future research aimed at establishinga more comprehensive and mechanistic framework for thegenetic architecture of human aging and healthy longevity.