Mitochondrial dysfunction is a convergent hallmark of biological aging and a mechanistically attractive target for gerotherapeutic development. Yet translation of mitochondria-focused interventions has been limited by pathway complexity, tissue heterogeneity, and insufficiently harmonized endpoints. This review synthesizes recent original evidence through a unifying mitochondrial quality control (MQC) framework comprising four interdependent modules: removal (mitophagy and mitochondrial-derived vesicles), repair (mitochondrial proteostasis and UPRmt/ISR signaling), remodeling (fission-fusion control and cristae architecture), and renewal (biogenesis coupled to turnover). We map druggable nodes across these modules and organize therapeutic efforts into five pharmacological classes: autophagy/mitophagy enhancers (including pathway-brake inhibitors and emerging mitophagy-targeting chimeras), NAD+ /sirtuin-AMPK-mTOR axis modulators, mitochondria-targeted redox modulators, cristae/mPTP/cardiolipin-directed stabilizers, and mitochondria-targeted delivery platforms. Drawing on recent human studies and late-stage mitochondrial therapeutic programs, we highlight practical lessons on dosing schedules, baseline vulnerability, and the importance of pairing molecular engagement with performance endpoints. We then outline a translational strategy that prioritizes flux-aware readouts and triangulates mechanism with function using in vivo bioenergetics (31P-MRS), blood-based cellular respiration (PBMC/platelet assays and composite indices), and circulating stress/damage signals (cell-free mtDNA species and mitokines). Finally, we discuss key bottlenecks including tissue selective exposure, long term safety for maintenance therapies, and inconsistency in clinical endpoints, and we propose actionable directions such as biomarker guided precision geroscience, intermittent or sequential combination strategies that balance clearance with renewal, and next generation chemical biology approaches to improve target specificity. Collectively, this framework seeks to accelerate the development of pharmacotherapies targeting mitochondrial quality control with clinically interpretable endpoints in aging.
Longevity & Aging