cGAS-STING Signalling Drives Age-Related Chronic Inflammation
The reaction of the innate immune system to damage characteristic of aging biology drives a great deal of age-related chronic inflammation. For example, mislocalized mitochondrial DNA arises as a consequence of age-related mitochondrial dysfunction, and can trigger innate immune sensors that evolved to detect bacterial DNA. Here, researchers look more closely at one of the important signaling pathways involved in the maladaptive innate immune response to damage and dysfunction in aging cells.
Low-grade inflammation is a hallmark of old age and a central driver of ageing-associated impairment and disease. Multiple factors can contribute to ageing-associated inflammation; however, the molecular pathways that transduce aberrant inflammatory signalling and their impact in natural ageing remain unclear. Here we show that the cGAS-STING signalling pathway, which mediates immune sensing of DNA, is a critical driver of chronic inflammation and functional decline during ageing.
Blockade of STING suppresses the inflammatory phenotypes of senescent human cells and tissues, attenuates ageing-related inflammation in multiple peripheral organs and the brain in mice, and leads to an improvement in tissue function. Focusing on the ageing brain, we reveal that activation of STING triggers reactive microglial transcriptional states, neurodegeneration, and cognitive decline. Cytosolic DNA released from perturbed mitochondria elicits cGAS activity in old microglia, defining a mechanism by which cGAS-STING signalling is engaged in the ageing brain. Single-nucleus RNA-sequencing analysis of microglia and hippocampi of a cGAS gain-of-function mouse model demonstrates that engagement of cGAS in microglia is sufficient to direct ageing-associated transcriptional microglial states leading to bystander cell inflammation, neurotoxicity, and impaired memory capacity.
Our findings establish the cGAS-STING pathway as a driver of ageing-related inflammation in peripheral organs and the brain, and reveal blockade of cGAS-STING signalling as a potential strategy to halt neurodegenerative processes during old age.
cGAS-STING is part of our innate anti-viral defense and that it is activated probably just indicates our accumulated viral and microbial burden in old age. Also senses transposable elements which pick up speed in old age. It senses foreign DNA and RNA.
Everybody has at least one chronic viral infection: herpes, Epstein Barr, hepatitis a b c, human cytomegalovirus etc.
Blocking cGAS sounds naive. The body is trying to tell you something and these guys are trying to suppress a major defense mechanism.
Why not try anti-microbial/ antiviral therapy on old humans for an extended period and see is cGAS is less activated after therapy? If it is you reduced burden.
Great work from Switzerland (EPFL) where I live ;-)
So much reporting mentions "low grade" inflammation as the result of "inflamaging". Does anyone have a test number range that indicates if you have low grade inflamation? And what test do you use? C-reactive protien or high sensitivity C-reactive protien? Or something else?
Thanks for any answers to this.