Multi-omic underpinnings of heterogeneous aging across multiple organ systems

Aging is the main determinant of chronic diseases and mortality, yet organ-specific aging trajectories vary, and the molecular basis underlying this heterogeneity remains unclear. To elucidate this, we integrated genomic, epigenomic, transcriptomic, proteomic, and metabolomic data, employing post-genome-wide association study methodologies to systematically investigate the molecular mechanisms of nine organ-specific aging clocks and four blood-based epigenetic clocks. We uncovered genetic correlations and specific phenotypic clusters among these aging-related traits, identified prioritized genetic drug targets for heterogeneous aging, and elucidated downstream proteomic and metabolomic effects mediated by heterogeneous aging. We constructed a cross-layer molecular interaction network of heterogeneous aging across multiple organ systems and characterized detectable biomarkers of this heterogeneity. Integrating these findings, we developed an R/Shiny-based framework that provides a comprehensive multi-omic molecular landscape of heterogeneous aging, thereby advancing the understanding of aging heterogeneity and informing precision medicine strategies to delay organ-specific aging and prevent or treat its associated chronic diseases.