A modular architecture of human cellular aging across organs and diseases

<jats:p>Aging is a heterogeneous biological process in which different cellular systems undergo molecular remodeling at distinct rates, yet whether human cellular aging follows an organized architecture across organs remains unclear. Here, we integrate a multi-organ human single-cell transcriptomic atlas with plasma proteomic profiles from approximately 50,000 participants to reconstruct cellular aging states at population scale. By projecting cell-type-enriched molecular signatures onto circulating proteins, we characterize aging patterns across 128 organ-cell type pairs and identify 14 cellular aging modules comprising conserved cross-organ programs and organ-specific aging states. These modules reveal cellular identity as a dominant organizing axis of human aging that transcends anatomical boundaries. Module-level aging states uncover substantial inter-individual heterogeneity, with 34% of individuals exhibiting extreme aging deviation in at least one cellular module. Cellular aging modules exhibit distinct temporal trajectories, with structural and tissue-resident modules showing earlier remodeling than immune lineages. The modular organization of cellular aging is reflected in disease susceptibility, with accelerated aging of specific modules, particularly epithelial aging, showing broad associations with disease burden and mortality. Longitudinal analyses further demonstrate the stability and clinical relevance of cellular aging states, whereas lifestyle, metabolic and pharmacological factors show selective relationships with individual aging programs. Together, our study establishes a modular framework for understanding human cellular aging and reveals an organization of biological aging that may help explain individual differences in healthspan.</jats:p>