Beyond accelerated aging: Multi-organ aging imbalance predicts adverse health outcomes

Abstract Biological aging varies across organ systems, yet the extent of this cross-organ dispersion and its implications for health remain poorly characterized. We quantified this dispersion as multi-organ aging imbalance, using the within-person standard deviation of standardized biological-age deviations across six organ systems in 221,599 UK Biobank participants. Higher multi-organ aging imbalance was independently associated with all-cause mortality (HR per 1-s.d. increase, 1.11; 95% CI, 1.09–1.13), six incident organ-disease outcomes and three multimorbidity transitions after adjustment for overall biological-age deviation, chronological age and sex. Notably, greater imbalance was associated with elevated mortality risk even among individuals with relatively low overall biological aging (HR, 1.09; 95% CI, 1.03–1.16). Associations with mortality were validated in five external cohorts. In separate analyses restricted to ELSA and CHARLS, higher imbalance was associated with greater frailty burden and incident frailty. Enrichment analysis of proteins associated with imbalance highlighted amino acid and fatty acid metabolism, immune signaling, telomere organization and DNA repair. Associations were robust across alternative imbalance definitions and persisted after excluding organs with extreme age deviations, with similar findings observed using 11 protein-derived organ ages. Together, these findings highlight cross-organ aging dispersion as a complementary dimension of biological aging with implications for health vulnerability.