A new study led by researchers at the University of Arizona College of Medicine – Tucson sheds light on how calorie restriction and fasting influence the aging process and how glucagon, a naturally occurring hormone, may hold the key to healthier, longer lives.

Scientists have long known obesity shortens both lifespan and “healthspan” – the years lived free from chronic disease. In contrast, limiting calories has consistently extended life.

Aging research has often focused on insulin, which helps tissues clear glucose from the bloodstream. A team led by Jennifer Stern, assistant professor in the Division of Endocrinology, Diabetes and Metabolism, discovered that glucagon, which counteracts insulin, is also essential.

“My group has shown for the first time that the glucagon is critical for the healthspan improvements stimulated by calorie restriction,” Stern said. “And not just that, but glucagon signaling is crucial for normal aging.”

The paper was published in GeroScience, the journal of the American Aging Association. 

During the study, the research team observed that mice lacking the glucagon receptor have a shorter lifespan compared with mice with normal glucagon signaling.

They studied how mice lacking the glucagon receptor responded to calorie restriction versus mice with an intact glucagon receptor and found that calorie restriction failed to improve metabolic function in mice lacking the receptor. Those mice also didn’t have an extended lifespan.

“Calorie restriction is the one tried-and-true, nongenetic, nonpharmacologic intervention that increases lifespan and also increases healthspan in a huge range of species,” said Stern, who is a member of the BIO5 Institute.

“Although glucagon was discovered over 100 years ago, we’re still discovering new functions of this hormone.”

Moving forward, Stern’s group is testing long-acting glucagon agonists – compounds that boost glucagon activity – in aging mice.

“We have promising data showing that glucagon agonism in aging mice suppresses pathways that have been established to accelerate aging,” she said.

Glucagon agonists are currently being tested in human clinical trials as part of new combination drugs for obesity, diabetes and fatty liver disease.

“These drugs that are close to market could serve a dual purpose,” Stern said. “Not only could they treat metabolic disease, but they also might help to slow aging and minimize age-related disease.”

While work remains before glucagon-based therapies reach patients, Stern believes her team’s findings could shift how scientists and clinicians approach aging.

“The aging field uses calorie restriction as an intervention to identify new pathways and new signaling molecules that can be pharmacologically targeted, as a treatment to slow aging and prevent age-related disease,” she said. “Our glucagon agonism studies are aimed at identifying if we can target the glucagon receptor to affect aging. Could this treatment be used to slow aging in humans? I think that’s what is most exciting.”

The research reported on in this story was supported by the National Institute on Aging, a division of the National Institutes of Health, under award numbers R01AG079924, R56AG079924 and R21AG086805. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.