Mitochondrial Drivers of Aging: An Integrative Bioenergetic and Genomic Framework for Healthspan Regulation

Mitochondrial dysfunction is increasingly recognized as a central, integrative driver of biological aging and a convergent mechanism underlying multiple age-associated pathologies. This review synthesizes current evidence identifying a coordinated network of mitochondrial “drivers of aging” that collectively erode cellular homeostasis and organismal resilience. Core processes include decline in ATP production, impaired electron transport chain efficiency and supercomplex assembly, excessive reactive oxygen species generation, accumulation of mitochondrial DNA damage and mutations, rising heteroplasmy, reduced DNA repair capacity, and progressive loss of mitochondrial DNA copy number. These genomic and bioenergetic failures are compounded by dysregulated mitochondrial dynamics, diminished biogenesis, and defective mitophagy, leading to the persistence of dysfunctional organelles and amplification of inflammatory and senescence-associated signaling. We propose a conceptual mitochondrial lifespan clock model in which the cumulative imbalance among these interdependent mechanisms accelerates functional decline across tissues, particularly in post-mitotic systems such as muscle, heart, and brain. Importantly, multiple drivers remain plastic and responsive to metabolic, genetic, and pharmacological interventions, highlighting mitochondria not only as biomarkers but as actionable targets for extending healthspan. Understanding the hierarchy, interaction, and reversibility of these mitochondrial determinants provides a unifying framework for translational strategies aimed at delaying aging and mitigating age-related disease.