Mitochondria are power plants, hundreds of these organelles working in every cell to manufacture the adenosine triphosphate (ATP) chemical energy store molecule used to power cell operations. The decline of mitochondrial function with age impacts this supply, with negative consequences, but other equally important issues arise from mitochondrial dysfunction. For example, an important realization in aging research was that dysfunctional mitochondria contribute meaningfully to the chronic inflammation of aging, a topic that is a primary focus of this paper.
Mitochondria are increasingly recognized as master regulators of aging, integrating bioenergetics, redox control, stem cell fate, and innate immune signaling. This review synthesizes evidence that mitochondrial dysfunction is not only a hallmark but also an upstream driver of stem cell exhaustion and inflammaging. We discuss how age-associated mitochondrial DNA (mtDNA) mutations and clonal mosaicism impair respiration and reshape metabolite availability, thereby reprogramming long-lived epigenetic states that govern quiescence, lineage commitment, and regenerative output. In parallel, erosion of mitochondrial quality control (MQC), including fission-fusion balance, mitophagy, and the mitochondrial unfolded protein response (UPRmt), permits the persistence of reactive oxygen species (ROS)-producing organelles and lowers containment of mitochondrial danger signals.
A central advance is that mitochondrial damage can be decoded as inflammation: cytosolic mtDNA and other mitochondrial damage-associated molecular patterns (mtDAMPs) activate cGAS-STING and NF-κB pathways, reinforcing senescence-linked cytokine circuits and chronic inflammatory tone. We further highlight nicotinamide adenine dinucleotide (NAD) depletion as a metabolic bottleneck that compromises sirtuin-dependent resilience and can enforce mitochondrial dysfunction-associated senescence (MiDAS), linking redox collapse to altered senescence phenotypes and regenerative decline.
Finally, we evaluate emerging mitochondria-targeted rejuvenation strategies, NAD repletion, mitophagy enhancers, mitochondrial transplantation/engineering, and precision elimination of mutant mtDNA using mitochondria-targeted transcription activator-like effector nucleases (mitoTALENs) or zinc-finger nucleases (mitoZFNs), emphasizing tissue-specific thresholds and context dependence for effective healthspan extension.
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