Advisor(s)
Liou Sun
Committee Member(s)
Chad Hunter
Kirk Habegger
Steven Austad
Thane Wibbels
School
College of Arts and Sciences
Document Type
Dissertation
Department (new version)
Biology
Date of Award
9-11-2025
Abstract
In developed nations the average lifespan has nearly doubled over the last 200 years, and the proportion of humans living into old age is ever increasing. While this is certainly a testament to the effectiveness of modern medicine and infrastructure, it presents a unique challenge to public health. Gains to health have not necessarily kept pace with the gains in lifespan, and the expanding aged population positions age-associated diseases to reach unprecedented prevalence. In light of this challenge, a mechanistic understanding of the aging process is necessary to identify factors that control longevity and to ultimately develop strategies for healthy aging. In service of this we begin by leveraging a mouse model of extreme longevity, the growth hormone-releasing hormone knockout (GHRH-KO) mouse, and identify a differential response to glucagon in these mice. Through assessments of whole-body metabolism, protein expression, and gene expression we reveal that long-lived GHRH-KO mice display reduced glucose production in response to an acute glucagon challenge. Consistent with this, we found that gene expression of the glucagon receptor and protein markers of glucagon receptor activity were dramatically less abundant in the livers of GHRH-KO mice. To directly investigate the impact of interrupted glucagon receptor signaling on health and aging, we employed a mouse model of liver-specific glucagon receptor knockout (LKO) and evaluated survival as well as organismal physiology through advanced age. While our LKO mice displayed significantly reduced adiposity, improved glucose tolerance, and enhanced insulin sensitivity through adulthood, features commonly associated with improved health, we observed no lifespan difference in males and significantly reduced lifespans in female LKO mice. Transcriptomic analysis in these mice revealed a unique activation of inflammatory genes, defined by NFκB and cGAS-STING signaling, which was completely absent in males. Together, the work described in this dissertation identifies a new functional role for the glucagon receptor regulating lifespan and implicates glucagon action in the sex-specific differences in mammalian lifespan.
ProQuest ID
Recommended Citation
Lasher, Alexander Tate, "The Hepatic Glucagon Receptor As A Novel Regulator Of Lifespan" (2025). All ETDs from UAB. 7372.
https://digitalcommons.library.uab.edu/etd-collection/7372
