Advisor(s)

Liou Sun

Committee Member(s)

Jason Heaton
Thane Wibbels

Document Type

Thesis

Date of Award

1-27-2026

Degree Name

Master of Science (MS)

School

College of Arts and Sciences

Department

Biology

Abstract

Chronic sterile inflammation (inflammaging) is a core pillar of aging, and the cGAS-STING innate immune pathway has emerged as a key driver of this process. However, how this pathway intersects with systemic endocrine signaling remains poorly understood. Here, we investigated the intersection of endocrine signaling and cGAS-STING activation using two complementary mouse models with opposing lifespan phenotypes: a short-lived, liver-specific glucagon receptor knockout (LKO) mouse and a long-lived growth hormone-releasing hormone knockout (GHRH-KO) mouse. We demonstrate that despite presenting with a metabolically healthy phenotype, female LKO mice exhibited a significantly reduced lifespan. We link this premature mortality to a sex specific activation of the cGAS-STING pathway. This inflammation, which was absent in male LKO mice, correlates with systemic pathology, including significant NFκB activation, inflammatory gene expression, and tissue damage in the kidney. In contrast, the long-lived GHRH-KO mice showed a suppression of the cGAS-STING pathway. This was characterized by a significant, tissue-specific reduction in STING protein in the liver, a protective effect that was maintained even under the inflammatory challenge of a high-fat diet. Taken together, our findings identify the glucagon and growth hormone endocrine axes as important influences on cGAS-STING activity. These results reinforce the link between metabolism and inflammaging and highlight the cGAS-STING pathway as a promising therapeutic target for promoting healthy aging.

Keywords

Aging;Biology;Endocrinology;Inflammation

ProQuest Publication Number

32286067

ISBN

9798273382190

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