Hypothesis

Aged dendritic cells sustain chronic activation of the cGAS‑STING pathway due to leakage of nuclear DNA into the cytosol. This persistent signaling drives NF‑κB hyperactivation, PARP1‑mediated NAD+ consumption, and a type I interferon milieu that together exacerbate mitochondrial dysfunction, telomere attrition, senescence, and dysbiosis. Consequently, cGAS‑STING functions as an upstream controller that synchronizes multiple hallmarks of aging.

Mechanistic basis

• Cytosolic DNA accumulates in aged DCs from inefficient clearance of apoptotic nuclei and increased mitochondrial DNA release 23.
• cGAS binds this DNA, synthesizes 2’3’‑cGAMP, and activates STING, leading to TBK1‑IRF3 phosphorylation and robust IFN‑β production.
• STING signaling also engages the IKK complex, amplifying NF‑κB activity and promoting PARP1 activation as a downstream effect of oxidative stress 1.
• PARP1 consumes NAD+, lowering SIRT1/3 activity, which further impairs mitochondrial oxidative phosphorylation and increases ROS, creating a feed‑forward loop that damages telomeres and drives senescence.
• The interferon milieu conditions hematopoietic stem cells toward a myeloid‑biased output, perpetuating the supply of DCs with the same defective phenotype 4.

Testable predictions

• Pharmacological inhibition of cGAS (e.g., with RU.521) or STING (e.g., with C-176) in aged mice will reduce basal NF‑κB and IFN‑β levels in DCs, restore TLR‑dependent cytokine production, and improve mitochondrial respiration.
• Genetic deletion of cGAS specifically in the DC lineage (using CD11c‑Cre) should attenuate age‑related increases in serum IL‑6, type I IFN, and senescence markers, while extending healthspan without affecting acute infection responses.
• Rescue experiments: delivering exogenous NAD+ or a PARP1 inhibitor to cGAS‑STING‑deficient aged DCs will not further improve phenotypes, indicating that the pathway acts upstream of NAD+ depletion.
• Correlative readouts: in human peripheral blood DCs from young vs. old donors, cytosolic DNA accumulation, cGAS activation (phospho‑cGAS), and STING signaling will positively correlate with NF‑κB activity, PARP1 levels, and inversely with TLR‑induced cytokine output.

If inhibition of cGAS‑STING fails to dampen the inflammatory baseline or to rescue TLR responsiveness, the hypothesis would be falsified, supporting the view that aging hallmarks arise from parallel, non‑hierarchical damage accumulation rather than a single upstream controller.