The cGAS protein is a sensor for mislocalized DNA in the cell cytoplasm, and responds by triggering STING, a regulator of the inflammatory response to damage and dysfunction. The cGAS-STING interaction produces some fraction of the maladaptive chronic inflammation characteristic of aging, as, among other reasons, mitochondrial dysfunction tends to spill mitochondrial DNA fragments into the cell cytoplasm. Nothing in the cell has only one purpose, however, and cGAS is also involved in the regulation of the DNA damage response in the cell nucleus. It is known to inhibit homologous recombination of double strand breaks, for example.
An examination of cGAS in different species suggests that different variants can aid or hinder late life health via their actions in either the DNA repair context or the chronic inflammation context. Introducing naked mole rat cGAS into mice improves DNA repair and reduces the impact of aging, and a rare lineage of humans exhibits a variant form of cGAS that reduces cGAS-STING activation, and thus late life inflammation.
cGAS does serve a useful purpose, despite producing a maladaptive contribution to degenerative aging. This is demonstrated in today's open access paper, in which disabling cGAS entirely in killifish does not extend life. Benefits are provided by removing its maladaptive activity, and harms are caused by removing its helpful activity. This is characteristic of interventions in the regulation of inflammation: chronic inflammation is harmful, but the normal short term inflammatory response serves a necessary purpose in tissue maintenance, and both run through the same regulatory pathways, making it challenging to intervene in a selective way.
Loss of killifish cGAS attenuates age-related signatures but does not affect organismal life span
A major source of inflammaging stems from chronic activation of the nucleic acid-sensing innate immune pathway cGAS/STING. Cytosolic DNA fragments arising from DNA damage, mitochondrial dysfunction, or infection bind cGAS to stimulate production of 2'3'-cGAMP (cGAMP). Subsequently, cGAMP activates STING, triggering the type I interferon response and inflammatory cytokine production. While this pathway is important for host defense, its chronic stimulation promotes age-related pathology. The cGAS-STING pathway also plays a central role in cellular senescence. Cytosolic DNA in these cells is detected by cGAS, triggering the senescence-associated secretory phenotype (SASP), whose persistence fosters chronic inflammation. Hence, limiting cGAS/STING pathway activity may improve late-life health.
Despite its importance in age-related disease, the effect of cGAS/STING on lifespan itself remains unknown. Here, we elucidated the role of cGAS in the short-lived African turquoise killifish Nothobranchius furzeri, a vertebrate model of aging. In this work, we used CRISPR-engineering to knock out killifish cGAS to examine its impact on senescence and aging. We hypothesized that cGAS loss would improve health and extend life. Although cGAS deficiency reduced senescence markers, attenuated age-related transcriptional changes, and maintained higher proliferative capacity with age, lifespan was unchanged, indicating that cGAS is not limiting for organismal longevity.
View the full article at FightAging
