Mitochondrial dysfunction drives chronic inflammation in aging

Mitochondrial dysfunction emerges as a master regulator of aging, integrating not only energy production but also redox control, stem cell renewal, and innate immune signaling. As mitochondria age, their accumulated DNA mutations and eroded quality-control systems allow reactive oxygen species to accumulate and release danger signals that activate inflammation pathways—cGAS-STING and NF-κB chief among them—perpetuating chronic inflammaging. Concurrently, NAD depletion acts as a metabolic bottleneck that weakens sirtuin-dependent resilience and reinforces mitochondrial dysfunction-associated senescence. Emerging therapeutic approaches—NAD repletion, mitophagy enhancers, and precision mitochondrial gene editing with mitoTALENs and mitoZFNs—already show capacity to extend healthspan, though their efficacy depends critically on tissue-specific thresholds and unique biological contexts for each individual.