Uncertainty redefines biological age

Biological aging clocks usually compress complex biological profiles into a single age estimate, leaving unclear how uncertain those estimates are and whether that uncertainty is biologically meaningful. This study developed a probabilistic framework to derive biological age gap (BAG) and biological age uncertainty (BAU) from the mean and width of predicted-age distributions in more than 450,000 UK Biobank participants.

The researchers evaluated prospective associations with aging-related outcomes and characterized BAU through cross-omic profiling, genome-wide association studies, and tissue and functional mapping. BAU was weakly correlated with BAG and increased with age-signal disagreement across individual molecules and discrete organs, linking uncertainty to reduced coherence of aging biological systems. Higher BAU was associated with mortality, loss of healthspan, and multimorbidity independently of BAG, with mortality hazard ratios of 1.24 (95% CI, 1.23-1.26) and 1.40 (95% CI, 1.37-1.43) per standard deviation for NMR-derived and proteomic-derived BAU, respectively. Longitudinal increases in NMR-derived BAU were associated with subsequent health decline, and mortality associations were replicated using routine-blood-derived BAU in three independent external cohorts.

Cross-omic analyses linked BAU to inflammation, metabolic regulation, and tissue remodelling. Genetic analyses revealed overlapping but distinct architectures of BAU and BAG, and tissue and functional mapping further implicated immune and lipid-metabolic processes.

The study establishes a framework for characterizing biological age through both its mean deviation and uncertainty, defining BAU as a new dimension of human aging that links the coherence of aging signals to future health vulnerability.