We hypothesize that accumulation of mitochondrial DNA (mtDNA) heteroplasmy beyond a tissue-specific threshold (~60-80%) activates cGAS-STING and NLRP3 inflammasome signaling, which drives a feed-forward loop of cellular senescence and inflammaging. In autoimmune/rheumatic disease patients—who already exhibit elevated baseline inflammation—this threshold is reached 10-15 years earlier than in healthy controls, explaining the accelerated biological aging observed in SLE and RA cohorts.

Specifically, heteroplasmic mtDNA mutations in Complex I (particularly m.3243A>G and m.11778G>A) generate excess ROS that oxidize cytosolic mtDNA fragments, converting them into potent cGAS-STING agonists. The resulting IFN-β and IL-18 secretion establishes paracrine senescence in tissue-resident macrophages, measurable as a >0.5 correlation between heteroplasmy burden (ultra-deep mtDNA sequencing) and Horvath/GrimAge epigenetic clock acceleration in paired blood-synovium samples.

Testable prediction: MitoQ (mitochondria-targeted antioxidant reducing oxidized mtDNA fragment release) combined with dasatinib+quercetin will reduce GrimAge acceleration by >2 years over 12 months in RA patients with heteroplasmy >60%, versus <0.5 years in those with heteroplasmy <40%. Testable in a 2-arm stratified pilot (n=40) with serial epigenetic clock measurements at 0, 6, and 12 months.