Hypothesis

Senescents immune cells release mitochondrial DNA into the cytosol, activating the cGAS‑STING pathway and triggering chronic type‑I interferon production. This interferon milieu drives paracrine senescence in neighboring non‑immune cells while simultaneously impairing phagocytic clearance, creating a self‑reinforcing loop that drives organismal aging.

Mechanistic Basis

Aged hematopoietic lineages accumulate mitochondrial damage owing to reduced TFAM expression and heightened ROS. Leaked mtDNA engages cytosolic cGAS, stimulating STING‑TBK1‑IRF3 signaling and sustained IFN‑β secretion. IFN‑β activates JAK‑STAT1 in stromal fibroblasts and epithelial cells, upregulating p21^CIP1^ and SASP components. Simultaneously, IFN‑α/β signaling downregulates MerTK and AXL on macrophages, diminishing efferocytosis of senescent cells. The resulting rise in extracellular mtDNA further fuels cGAS‑STING activation in neighboring immune cells, closing the loop.

Testable Predictions

1. Genetic ablation of STING specifically in hematopoietic cells will delay the onset of senescent cell accumulation in liver, kidney and brain of naturally aged mice.
2. Administering a STING inhibitor (e.g., H‑151) to aged mice will reduce circulating IFN‑β, lower SASP markers in tissues, and improve frailty scores without altering lymphocyte counts.
3. Transfer of wild‑type bone marrow into STING‑deficient aged recipients will not transmit premature senescence, whereas transfer of STING‑sufficient marrow into young recipients will induce early tissue senescence.

Potential Experiments

• Generate Vav‑Cre; Sting^fl/fl^ mice and compare senescence‑associated β‑galactosidase, p16^Ink4a^ levels, and frailty index at 18 months versus littermate controls.
• Treat 20‑month‑old C57BL/6 mice with H‑151 (10 mg/kg i.p. twice weekly) for 8 weeks; measure plasma IFN‑β by ELISA, hepatic COL1A1 expression, and grip strength.
• Perform bone‑marrow transplants: WT → young, WT → aged Sting^−/−^, Sting^+/+ → aged Sting^−/−^, and Sting^+/+ → young; assess donor chimerism and recipient tissue senescence at 4 weeks post‑transplant.
• In vitro, co‑culture mtDNA‑treated macrophages with fibroblasts; block IFN‑β receptor to test whether fibroblast p21 induction is interferon‑dependent.