Age Acceleration and Mortality Risk Constitute Distinct Dimensions of Organ Aging

Organ biological aging is highly heterogeneous, yet existing computational clocks typically model it as a single-rate phenomenon. It remains unclear whether chronological age acceleration and mortality risk are driven by shared or distinct biological programs. Here, we established multi-omics, organ-specific aging clocks for 14 organs across 409,206 UK Biobank participants, integrating nuclear magnetic resonance (NMR) metabolomics, Olink proteomics, and clinical phenotypes. By evaluating age acceleration against both organ-specific mortality and all-cause mortality, we demonstrate that age acceleration and mortality risk are divergent dimensions of organ biology with separable phenotypic, molecular, and genetic architectures. Feature-ablation genome-wide association studies revealed three molecular layers underlying these signatures including NMR-dependent, plasma-protein-direct and clinical-biochemistry-mediated, demonstrating that single-platform designs systematically miss complementary biology. This divergence is highlighted by a prostate paradox, where all-cause mortality training entirely obscures the incident prostate cancer signal that the organ-specific mortality clock powerfully recovers. Finally, applying polygenic scores in a non-overlapping validation cohort of 383,227 individuals alongside bidirectional Mendelian randomization and multi-tier gene prioritization, we prioritized 13 candidate genes underlying these distinct aging dimensions. Our findings establish that multi-omics integration combined with organ-specific training captures vital components of organ aging invisible to conventional single-objective clocks. Crucially, this multi-objective framework enables organ-resolved comorbidity risk assessments that traditional competing-risk models obscure, providing a highly translatable foundation for targeted clinical surveillance and actionable, organ-specific interventions.