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

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 understand the role of glucagon receptor signaling in normal aging, obesity accelerated aging, and the slowed

aging resulting from calorie restriction. We have established that glucagon is integral in extending lifespan in calorie restriction and maintaining lifespan in obesity. We appreciate that insulin plays a key role in aging, but also recognize that pharmacologically targeting insulin signaling is limited because of the key role of insulin in glucose homeostasis. Conversely,

glucagon receptor agonists are safe. In turn, this research provides a unique opportunity to identify a new, therapeutically viable target to extend healthspan and lifespan.