Genetic and molecular factors underlying human longevity and epigenetic aging.

Abstract

Biological aging is a complex process associated with declining physiological function and increased risk of aging-related diseases. However, its risk factors and molecular mechanisms remain poorly understood. Here, we performed a comprehensive integrative analysis to identify putative risk factors and molecular phenotypes associated with four epigenetic aging acceleration and human longevity. We first investigated the association between aging-related traits and potential risk factors using genome-wide association study (GWAS) data, identifying cholesterol levels, immune cell traits and insulin-like growth factor-1 (IGF1) as associated with longevity. To investigate the molecular mechanisms, we integrated GWAS summary data for epigenetic aging and longevity with five types of molecular QTL (xQTL) datasets, including gene expression (eQTL), splicing (sQTL), alternative polyadenylation (apaQTL), protein (pQTL), and metabolite QTL (mQTL). We identified 30 genes, 11 splicing events, 5 proteins, 3 alternative polyadenylation events, and 39 metabolites associated with aging-related traits, highlighting key regulatory mechanisms that link genetic variants to epigenetic aging and longevity. Drug-target annotation using DrugBank further prioritized therapeutic candidates, including CASP8, PSRC1 and SORT, as potential intervention targets. These findings provide a comprehensive resource for understanding the molecular architecture of aging and highlight potential novel targets for precision interventions in aging-related diseases.