# Investigating the Role of Hepatic Glucagon Receptor Signaling in Healthspan and Aging

> **NIH AG R01** · UNIVERSITY OF ARIZONA · 2026 · $603,657

## Abstract

Project Summary:
 Obesity and type 2 diabetes mellitus accelerate aging shortening the duration of healthspan. Conversely,
chronic calorie restriction extends healthspan. Most research aimed at understanding the mechanism by which
calorie restriction slows aging has focused on insulin and downstream signaling cascades. Similarly, the
accelerated aging in type 2 diabetes is largely attributed to dysfunctional insulin signaling. Glucagon, a hormone
that counter-regulates insulin, is commonly affected by these same interventions.
 We have shown that glucagon receptor deletion decreases median lifespan by 35% in normal weight mice.
Glucagon receptor deletion shortens lifespan to a greater degree in diet induced obese mice and prevents the
extension in lifespan resulting from calorie restriction. This proposes that the hyperglucagonemia in obesity may
be protective against obesity accelerated aging and that glucagon is essential for calorie restriction to extend
lifespan.
 Although the role of glucagon receptor signaling in aging has not been heavily investigated, the rigor of this
work is supported by known effects of glucagon on downstream messengers that extend healthspan. Both
AMPK activity and cyclic AMP are established mediators that extend healthspan. Glucagon activates AMPK
and increases cAMP.
 Highlighting the significance of this proposal, Glucagon receptor agonists are entering the market for the
treatment of diabetes and obesity. To understand the potential impact of these agonists, we propose to study
the role of glucagon receptor signaling in normal aging, the accelerated aging in obesity, and the slowed aging
resulting from calorie restriction.
 We propose 2 aims that focus on genetic (Aim 1) and pharmacological (Aim 2) manipulation to increase
glucagon receptor signaling. We will combine these models with dietary models of obesity and calorie restriction
and with genetic models of normal glucagon receptor signaling and glucagon receptor knockout to better

## Key facts

- **NIH application ID:** 11314613
- **Project number:** 5R01AG079924-03
- **Recipient organization:** UNIVERSITY OF ARIZONA
- **Principal Investigator:** JENNIFER HELENE STERN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** AG
- **Fiscal year:** 2026
- **Award amount:** $603,657
- **Award type:** 5
- **Project period:** 2024-09-15T00:00:00 → 2029-03-31T00:00:00

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11314613

## Citation

> US National Institutes of Health, RePORTER application 11314613, Investigating the Role of Hepatic Glucagon Receptor Signaling in Healthspan and Aging (5R01AG079924-03). Retrieved via AI Analytics 2026-07-12 from https://api.ai-analytics.org/grant/nih/11314613. Licensed CC0.

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