Mitochondrial DNA leakage in aging: Mechanisms, pathological effects, and therapeutic horizons

Cellular senescence is a form of stable growth arrest that contributes to aging and age-related diseases, in part through the senescence-associated secretory phenotype (SASP). Emerging evidence has demonstrated that mitochondrial DNA (mtDNA) leakage is prevalent in senescent cells and acts as a key regulator of the SASP. mtDNA leaks from the mitochondrial matrix into the cytoplasm through multiple pathways and serves as a potent damage-associated molecular pattern (DAMP). It interacts with innate immune sensors, including the cGAS–STING, TLR9, and the NLRP3 inflammasome, thereby amplifying the SASP and accelerating tissue degeneration. Accordingly, mtDNA leakage represents a promising therapeutic target for extending health span and ameliorating age-related diseases. Herein, we classify the therapeutic strategies into two categories: "blocking the source and enhancing clearance" and "inhibiting downstream sensing pathways". We propose that although downstream inhibitors exert remarkable efficacy, therapeutic interventions targeting the upstream sources of mtDNA leakage provide a safer translational avenue for anti-senescence therapies and the amelioration of age-related diseases, while preserving essential innate immune defense functions.