The most essential tool of the immune system is the detection of foreign DNA. In mammalian cells, this task is solved by the cGAS-STING signaling pathway.

Usually, DNA is found in the cell nucleus and mitochondria. cGAS-STING is needed to detect DNA contained in the cytosol because DNA in the cytosol is a sign of cell damage or infection. Upon detection of cytosolic DNA, the cGAS-STING pathway is activated, triggering inflammatory gene expression and an immune response. Activation of the cGAS-STING pathway results in the production of type I interferons (IFN-I) and the manifestation of interferon-stimulated genes (ISGs) responsible for antiviral functions.

cGAS-STING Causes Age-Related Inflammation and Neurodegeneration

Aging is associated with a decrease in bodily functions and an increase in susceptibility to various diseases. Chronic inflammation leads to age-related decline in functions. Drugs that reduce chronic inflammation can slow aging and delay cancer, cardiovascular disease, and neurodegeneration.

Senescent cells secrete inflammatory proteins, collectively called the aging-associated secretory phenotype (SASP). Activation of the cGAS-STING pathway contributes to aging. The cGAS enzyme recognizes cytosolic DNA in senescent cells, which leads to the activation of the IFN-I response, which triggers the production of SASP proteins, promoting aging of neighboring cells.

STING causes age-related inflammation

Swiss scientists have shown that suppression of STING in human cells and tissues can block the inflammatory response of aging cells. The STING inhibitor H-151 suppressed the activation of several pro-inflammatory genes and ISG without affecting other, non-inflammatory features of aging cells. H-151 suppressed the release of pro-inflammatory signals from aging cells at the tissue level.

When the scientists injected the STING inhibitor into ancient mice, the mice had reduced activation of immune system genes associated with aging. The production of inflammatory cytokines also decreased, and the accumulation of inflammatory cells in the kidneys decreased, accompanied by a decrease in the level of markers of kidney damage (creatinine, urea) and a decline in the number of macrophages in white adipose tissue.

The STING inhibitor improved physical and cognitive function in older mice by suppressing inflammation. Mice treated with H-151 increased muscle strength and physical endurance and enhanced spatial and associative memory.

cGAS-STING Affects Brain Aging

In the brains of old mice, an increase in activated microglia, resident macrophages of the central nervous system, was observed. The STING inhibitor reduced microglial activation and the immunoreactivity of astrocytes in the hippocampus. The STING inhibitor protected mice from loss of hippocampal neurons and increased synapse activity.

Age-Related Neurodegeneration Is Linked to Microglia

The scientists examined how genes expressed in the hippocampus of young and old mice differ. In aged mice, many genes have been implicated in innate immunity, including genes associated with IFN-I signaling and microglia function. The STING inhibitor reduced the expression of some of these genes.

The neurodegenerative effects of STING on brain aging are linked to microglia. The microglia of old mice showed increased expression of innate immunity genes. When the scientists examined the hippocampi of old and young mice, they found that the aging hippocampus had elevated levels of the STING protein, with most of the STING derived from microglia. STING is upregulated in the microglia of aged mice, triggering an innate immune response in the aging brain.

Mitochondrial DNA Activates cGAS in Senescent Microglia

Mitochondrial DNA (mtDNA) is the primary activator of cGAS-STING signaling, and impaired mitochondrial homeostasis is a sign of aging and neurodegenerative diseases.

Physiologically significant stress accompanying many diseases and aging promotes mtDNA release into the cytosol, activating cGAS-STING signaling. In old microglia, mitochondria are deformed and do not have a characteristic internal structure. Unlike young microglia, mtDNA accumulates in the cytosol of aged microglia. mtDNA stimulates inflammatory responses of old microglia and activates cGAS-STING.

Activation of Microglial cGAS Promotes Aging of Brain Cells

Activation of cGAS is sufficient to promote the transition of microglia into various states of activation associated with aging and disease. Microglial cGAS activation changes RNA molecules synthesized by other brain cells – oligodendrocytes and astrocytes but has almost no effect on neurons. Oligodendrocytes express several genes that are associated with aging and neurodegeneration.

Activation of cGAS Leads to Neurodegeneration

The scientists experimented on mice with activated microglia that expressed cGAS (hereinafter, mg-CgasR241E mice). Compared to normal mice, these mice showed cognitive impairment in the Morris water maze test and loss of hippocampal neuronal density. The STING inhibitor H-151 restored learning ability in mice, suggesting that the pro-inflammatory effects of STING impair neuronal function.

Activation of cGAS impairs neuronal survival due to TNF. When scientists cultured mg-CgasR241E mouse microglia with primary neurons from normal mice, cGAS activity contributed to neuronal death. Neurotoxicity is because IFN-I puts microglia into a state where they secrete the pro-inflammatory cytokine TNF. The addition of neutralizing anti-TNF antibodies saved neurons from dying. In contrast, blocking IFN-I signals had no effect.

Conclusion

Due to aging, which is accompanied by mitochondrial dysfunction and inflammation, mtDNA accumulates in the cytosol of senescent cells. mtDNA activates the cGAS-STING signaling pathway, also promoting inflammation and aging.

The cGAS-STING signaling pathway activates an IFN-I response in microglia that promotes aging, neuronal death, and cognitive impairment. In addition to IFN-I, cGAS activation triggers a gene expression program in microglia that is common to many neurodegenerative diseases and aging.

cGAS activation in microglia impairs neuronal survival. The pro-inflammatory cytokine TNF is responsible for neurotoxicity. Other brain cells, activated oligodendrocytes, and astrocytes, contribute to the propagation of neurotoxic signals.

The cGAS-STING pathway drives age-related inflammation in peripheral organs and the brain. Blockade of cGAS-STING signaling can halt neurodegeneration in old age.

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