Multi-omics perspectives on mitochondrial vulnerability in the aging liver: biological modules and translational implications

Chronological age alone is an incomplete proxy for the biological heterogeneity of the aging liver. Mitochondrial vulnerability may provide a mechanistic link between biological aging and the loss of hepatic resilience under metabolic, toxic, and ischemic stress. Accumulating multi-omics evidence suggests that hepatic aging is best understood as a set of coordinated pathway-level disturbances rather than through isolated biomarkers. Transcriptomic, proteomic, and metabolomic studies converge on five interrelated biological modules: lipid stress, diminished oxidative reserve, proteostatic strain, inflammatory sensitization, and reduced recovery capacity. These modules are interconnected through impaired mitochondrial metabolic flexibility, redox buffering, organelle crosstalk, and quality-control mechanisms. Age-associated changes may remain partly compensated at baseline but become more apparent during metabolic overload, ischemia-reperfusion injury, cold preservation, or ex vivo machine perfusion. Building on cross-species evidence, this Review organizes current findings into a modular framework and examines how mitochondrial vulnerability may connect physiological liver aging with metabolic and ischemic stress. Transplantation and machine perfusion are discussed as stress-exposed settings for evaluating candidate tissue- and fluid-based readouts. Although most omics-derived signals remain insufficiently validated for clinical decision-making, a mitochondrial-centered interpretation may help prioritize biologically coherent mechanisms and improve the translational study of aging-related liver vulnerability.