University of Arizona scientist links calorie restriction, glucagon and healthy aging

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

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Her findings appear in a paper published Sept. 25 by GeroScience, the journal of the American Aging Association. Dr. Stern, an assistant professor in the Division of Endocrinology, Diabetes & Metabolism, is senior author. Kassandra Bruner, a research technologist in her lab, is first author on the paper.

Dr. Stern will present those findings Nov. 6 at the Seminar on Translational Medicine in Cardiometabolic Diseases – Emerging Methods and Technologies, hosted in Denmark by the University of Copenhagen. She’s one of only two U.S. scientists invited to speak at this conference.

“Calorie restriction is an intervention studied by the aging field for decades,” she said. “And it’s the one tried and true, non-genetic, non-pharmacologic intervention that increases lifespan and also increases healthspan in a huge range of species, including model organisms — fruit flies, worms, mice, all the way up to non-human primates.”

From calorie restriction to fasting

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.

Dr. Stern noted, however, such interventions are “very difficult to maintain … to convince a human to just decrease your calorie intake and you’ll be healthier and live longer.”

More recent studies suggest extended fasting periods — sometimes referred to as intermittent fasting — can produce similar benefits. Whether that fasting is for eight, 12, 16 hours or longer, the results are positive, she said.

“There isn’t a magic number of hours,” Dr. Stern explained, “but those longer breaks from feeding affect nutrient sensing pathways that regulate aging. Our calorie restriction protocol combines both caloric restriction and intermittent fasting.”

The role of glucagon

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Aging research has often focused on insulin, which helps tissues clear glucose from the bloodstream. But Dr. Stern’s team 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,” Dr. Stern explained. “And not just that, but glucagon signaling is crucial for normal aging. Although it was discovered over 100 years ago, we’re still discovering new functions of this hormone.”

Her research team observed mice lacking the glucagon receptor have a shorter lifespan. Going on to study how mice lacking the glucagon receptor respond to calorie restriction versus mice with an intact glucagon receptor, they found that mice lacking the receptor fail to improve metabolic function. They also don’t have an extended lifespan.

Toward new therapies

Dr. Stern’s group is now testing long-acting glucagon agonists — compounds that boost glucagon signaling — in aging mice. “Thus far, we have promising data showing that glucagon agonism in aging mice suppresses pathways that have been established to accelerate aging,” she said.

Their work links glucagon to mTOR signaling, a signaling pathway known to accelerate aging. Rapamycin, a drug that’s used as an immunosuppressant to prevent organ rejection and treat certain cancers and rare disease, also inhibits mTOR signaling and extends lifespan.

“We’ve now shown that glucagon agonism robustly inhibits the mTOR pathway, too.”

Clinical relevance

Glucagon agonists are being tested already in human clinical trials as part of new combination drugs for obesity, diabetes and fatty liver disease. One such drug is Retatrutide, being developed by Eli Lilly. Her lab is using a long-acting glucagon agonist developed by Novo Nordisk.

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

While a lot of work remains before glucagon-based therapies reach patients, Dr. 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’s 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 Nos. 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.

NOTE: Another, shorter version of this story appears on the U of A Office of Research and Partnership website.