Longevity research has matured to the point where significantly postponing age-related decline in physical and mental function is now achievable in the laboratory and foreseeable in the clinic. The most promising strategies involve rejuvenation, i.e. reducing biological age, not merely slowing its progression. We discuss therapeutic strategies for rejuvenation and results achieved thus far, with a focus on in vivo studies. We discuss the implications of interventions which act on mean or maximum lifespan and those showing effects in accelerated disease models. While the focus is on work conducted in mice, we also highlight notable insights in the field from studies in other model organisms. Rejuvenation was originally proposed as easier than slowing aging because it targets initially inert changes to tissue structure and composition, rather than trying to disentangle processes that both create aging damage and maintain life. While recent studies support this hypothesis, a true test requires a panel of rejuvenation interventions targeting multiple damage categories simultaneously. Considerations of cost, profitability and academic significance have dampened enthusiasm for such work, but it is vital. Now is the time for the field to take this key step toward the medical control of aging.

Mitochondria are intracellular organelles that utilize nutrients to generate energy in the form of ATP by oxidative phosphorylation. Mitochondrial DNA (mtDNA) in humans is a 16,569 base pair double-stranded circular DNA that encodes for 13 vital proteins of the electron transport chain. Our understanding of the mitochondrial genome’s transcription, translation, and maintenance is still emerging, and human pathologies caused by mtDNA dysfunction are widely observed. Additionally, a correlation between declining mitochondrial DNA quality and copy number with organelle dysfunction in aging is well-documented in the literature. Despite tremendous advancements in nuclear gene-editing technologies and their value in translational avenues, our ability to edit mitochondrial DNA is still limited. In this review, we discuss the current therapeutic landscape in addressing the various pathologies that result from mtDNA mutations. We further evaluate existing gene therapy efforts, particularly allotopic expression and its potential to become an indispensable tool for restoring mitochondrial health in disease and aging.