Program > Browse abstracts by author > Meadow Michael

Aging-associated inflammation, or ‘inflammaging,' is the gradual but significant increase in pro-inflammatory markers in the blood and tissues of aged organisms. This increase in inflammatory markers has been shown to be a hallmark of several age-associated diseases including certain cancers, osteoporosis, arthritis, and kidney disease. Cyclic GMP-AMP Synthase (cGAS) is a cytosolic nucleic acid sensor that functions as a part of the innate immune system to specifically detect double-stranded nucleic acids in the cytoplasm and initiate the proper inflammatory response. While this is intended to target foreign pathogens, endogenous LINE1 (L1) cDNA transcripts, which have been shown to be elevated in aged-mouse models, can also be recognized by cGAS and contribute to misguided pro-inflammatory activity during aging. The unintended consequences of this endogenous immune signaling has led to exploration of cGAS as a potential target to alleviate inflammation and extend healthspan, lifespan, or both. Intriguingly, a significant population of cGAS has also been shown to be stable and inactive when bound to chromatin, but the function of this nuclear localization is largely unknown. Here, we report that cGAS deficiency in vitro and in vivo results in aberrant L1 mRNA transcription, cytoplasmic L1 cDNA formation, and an increase in pro-inflammatory markers. Additionally, we show that cGAS stabilizes proper genomic organization by repressing L1 transcripts. STED microscopy reveals cGAS resides bound to nucleosomes in heterochromatic regions of the genome, suggesting cGAS prevents L1 expression by repressing transcription. Further, loss of cGAS results in increased susceptibility to DNA damage. These results suggest a previously undescribed regulatory role for nuclear cGAS on repressing L1 elements and stabilizing chromatin organization, suggesting other targets in the cGAS pathway, such as STING, or a specific pharmacological target to the cGAMP producing C-terminus, may serve as more beneficial therapeutic targets in combating inflammaging.