Pathway

cGAS-STING Pathway

Last updated Sat May 30 2026 00:00:00 GMT+0000 (Coordinated Universal Time)

Mechanistic— Fast-growing area of aging biology

What it is

Cytosolic DNA is normally a sign of viral infection. cGAS (cyclic GMP-AMP synthase) is a cytosolic enzyme that binds double-stranded DNA and produces the second messenger cGAMP. cGAMP activates STING (stimulator of interferon genes) on the endoplasmic reticulum, which drives TBK1, IRF3, and NF-κB activation → type-I interferons + inflammatory cytokines.

Why it matters in aging

With age, cytosolic DNA accumulates from three sources:

Leaky mitochondria dumping mtDNA into the cytosol (Mitochondrial dysfunction).
Senescent cells with disrupted nuclear envelopes releasing chromatin fragments (cytoplasmic chromatin fragments, CCFs).
De-repressed LINE-1 retrotransposons generating cDNA.

Chronic cGAS–STING signalling is now considered a central upstream driver of "inflammaging" and the SASP, distinct from canonical NLRP3 inflammasome activation.

Why this matters for senolytics

Many SASP factors are downstream of STING. Inhibiting STING blunts the SASP without killing senescent cells — a senomorphic strategy distinct from clearance.

Pharmacology

STING agonists (ADU-S100, MK-1454) are in oncology trials for immune activation.
STING antagonists are in pre-clinical development for autoimmune disease and aging-related inflammation.
Many botanical anti-inflammatories (e.g. astragalus polysaccharides) modulate STING; clinical relevance debated.

Diseases driven by it

Beyond inflammaging, gain-of-function STING mutations cause SAVI (STING-associated vasculopathy with onset in infancy). Aicardi-Goutières syndrome involves over-active cGAS sensing of endogenous nucleic acids.

References

Hopfner, K.-P. & Hornung, V. Molecular mechanisms and cellular functions of cGAS–STING signalling. Nat. Rev. Mol. Cell Biol. 21, 501–521 (2020).