How aging unleashes chronic brain inflammation through the cGAS-STING pathway

Mitochondrial dysfunction in aged cells releases DNA fragments into the cytoplasm, activating the cGAS sensor and its adaptor protein STING in a chronic inflammatory response that characterizes aging and neurodegeneration in the central nervous system. This mechanism, originally evolved as a defense against bacterial and viral pathogens, becomes pathological when damaged mitochondria allow mitochondrial DNA to escape into the cytosolic space, particularly in microglia, neurons, and endothelial cells. Alzheimer's disease models demonstrate that mitochondrial DNA leakage is a key trigger of the cGAS-STING cascade, sustaining persistent, low-grade inflammation that accelerates neuronal loss and cognitive decline. Small-molecule cGAS inhibitors and STING antagonists show promising results in preclinical studies, reducing inflammatory responses without complete suppression. The therapeutic challenge lies in selectively modulating this pathway in the brain through context-dependent and time-restricted approaches, preserving systemic antiviral function while dampening neuroinflammatory pathology. For the longevity-conscious biohacker, this implicates that strategies targeting mitochondrial stabilization—through exercise, selective caloric restriction, or mitoprotective compounds—may reduce chronic cGAS activation before it becomes pathological.