DNA is best known as the blueprint of life and is normally confined within the nucleus and mitochondria. During aging, oxidative stress or tissue injury, however, nuclear DNA or mitochondrial DNA (mtDNA) can become damaged and escape into the cytoplasm. Once in the wrong place, self-DNA can shift from a carrier of genetic information to an immune danger signal. In a new review, the team led by Professors Ying Mao and Hui Yang at Huashan Hospital, Fudan University, examines how this transition may contribute to inflammaging and neurological disease.
The ability of nucleic acids to stimulate immunity was recognized decades ago, but how cells detect cytosolic DNA remained unclear for nearly half a century. In 2012-2013, the discovery of the DNA sensor cGAS and its second messenger cGAMP established the core DNA-cGAS-cGAMP-STING-type I interferon pathway. cGAS detects cytoplasmic double-stranded DNA and produces cGAMP, which activates STING and promotes its trafficking from the endoplasmic reticulum to the Golgi apparatus, triggering type I interferon and inflammatory signaling.
The team's earlier studies in PNAS and Nature further showed that cGAS-STING links DNA damage to cellular senescence and can trigger autophagy to clear cytosolic DNA, underscoring its dual roles in immune activation and cellular homeostasis. This duality is central to the review. Short-lived cGAS-STING activation helps defend against infection and remove cellular damage. By contrast, during aging, when self-DNA continues to accumulate, clearance becomes impaired or STING signaling fails to switch off, a protective response can develop into persistent inflammation. The biological outcome therefore depends not simply on whether the pathway is active, but on the source and location of the DNA, the responding cell type, the duration of signaling and whether the response is terminated in time.
The authors organize current evidence along two connected dimensions: how cGAS-STING signaling changes over time during aging, and how the signal is sensed and transmitted among different cell types in the central nervous system.
From a temporal perspective, aging creates conditions that favor persistent signaling. Genomic instability and mitochondrial damage increase the supply of cytosolic DNA, while declining autophagy-lysosomal clearance makes abnormal DNA and activated signaling harder to remove. The key pathological change may therefore be the loss of reversibility: an acute response that should resolve instead becomes chronic, low-grade inflammation.
Mitochondrial DNA is especially important in this process. Mitochondria are not only cellular powerhouses but also immune-regulatory organelles. Because mtDNA is present at high copy number, lies close to sites of reactive oxygen species production and is vulnerable to oxidative damage, mitochondrial stress can release mtDNA into the cytoplasm or extracellular space. Misplaced or oxidized mtDNA can activate cGAS-STING in microglia, astrocytes, neurons and brain endothelial cells, linking metabolic dysfunction to glial activation, blood-brain barrier injury and neuronal damage.
Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis/frontotemporal dementia and ischemic stroke begin with different insults, yet all can involve nuclear DNA damage, mitochondrial dysfunction or mtDNA leakage. Alpha-synuclein pathology, amyloid-beta and Tau abnormalities, C9orf72 and TDP-43-associated organelle stress, and oxidized mtDNA released after ischemia-reperfusion may all converge on cGAS-STING. The pathway is therefore unlikely to be the sole initiator of these diseases; rather, it acts as a key hub that converts diverse forms of cellular injury into sustained neuroinflammation.
This framework also suggests a more precise therapeutic strategy. Instead of broadly suppressing immunity, intervention could target different steps in the disease process: reducing the generation or leakage of inflammatory self-DNA, restoring mitochondrial and autophagic clearance, limiting intercellular cGAMP transmission, or selectively modulating cGAS-STING in particular cell types and disease stages. The goal is not to shut down the pathway completely, but to selectively restrain pathological signaling while preserving its essential roles in antimicrobial defense and immune surveillance. Achieving this balance will require defining the dominant DNA sources, key responding cell types, and optimal therapeutic windows.
By integrating evidence from molecular regulation, cellular senescence, intercellular communication and major neurological diseases, the review presents a unified framework linking endogenous DNA damage to persistent neuroinflammation. The Huashan Hospital team has long studied nucleic acid immunity and metabolic regulation, including how IDH-associated metabolic reprogramming, 2-hydroxyglutarate, alpha-ketoglutarate, aspartate and cGAS-STING shape immune responses and disease progression. The authors propose that future studies should integrate genome stability, mitochondrial homeostasis, metabolism, immune microenvironments and cell-cell communication to identify disease- and stage-specific therapeutic opportunities.
Science China Life Sciences
Literature review