Activation of cGAS-STING signaling in senescent cells promotes the aging process by remodeling the functions of the immune system.

An accumulation of senescent cells within tissues is a hallmark of the aging process. Cellular senescence is associated with an increased level of cytosolic dsDNA which primarily originates from a leakage of mitochondrial DNA (mtDNA) and a loss of genomic DNA integrity. Cytosolic dsDNA is an important alarming factor for cytosolic dsDNA sensors which trigger the remodeling of the immune system through diverse signaling pathways. The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) (cGAS-STING) signaling is a major defence mechanism induced by an accumulation of cytosolic dsDNA in senescent cells. The cGAS-STING pathway stimulates immune responses via the interferon regulatory factor 3 (IRF3) and nuclear factor-κB (NF-κB)-driven pathways. The activation of cGAS-STING signaling in senescent cells generates pleiotropic immune responses in a context-dependent manner. For instance, cGAS-STING signaling induces proinflammatory responses by enhancing the secretion of cytokines, chemokines, and colony-stimulating factors. The secretion of many chemokines and colony-stimulating factors can remodel hematopoiesis and enhance thymic involution with aging. Moreover, cGAS-STING signaling promotes proinflammatory responses by stimulating the NLRP3 inflammasomes. On the other hand, cGAS-STING signaling aids in the resolution of inflammation by recruiting immunosuppressive cells into tissues and suppressing the pathogenic activity of T helper 17 cells. In addition, an increased cGAS-STING signaling in senescent cells stimulates the expression of inhibitory immune checkpoint ligands, such as PD-L1, and thus prevents their elimination by immune cells. Recent studies have clearly revealed that cGAS-STING signaling not only induces cellular senescence but it can also promote the aging process.