The Stern Lab

Glucagon receptor signaling is indispensable for the healthspan effects of caloric restriction in aging male mice - GeroScience Obesity and type 2 diabetes mellitus accelerate aging, shortening the duration of healthspan. Conversely, chronic calorie restriction (CR) extends healthspan. Research aimed at understanding the mechanism by which CR slows aging has focused heavily on insulin and downstream signaling cascades. Glucagon, a hormone that counter-regulates insulin, is commonly affected by these same interventions. To investigate the role of glucagon in aging, we used dietary manipulation, global and liver-specific glucagon receptor knockout, and pharmacological glucagon receptor activation. We found that globally eliminating glucagon receptor signaling (Gcgr KO) decreases median lifespan by 35% in lean mice. Extending these findings to metabolic health, we found that glucagon receptor signaling is indispensable to the metabolic response to chronic CR in young and aged mice. While CR decreased liver fat, serum triglyceride, and serum cholesterol in WT mice, these metabolic benefits were absent in Gcgr KO mice. In line with these observations, we found that critical nutrient-sensing pathways known to improve aging are dysregulated in mice lacking glucagon receptor signaling at the liver (Gcgrhep−/−). Liver-specific deletion of the glucagon receptor decreases hepatic AMP kinase activation in aging mice, regardless of diet. Further, CR decreases hepatic mTOR activity in WT mice but not in Gcgrhep−/− mice. Together, these findings propose that glucagon signaling plays a critical role in both normal aging and the lifespan and healthspan extension driven by caloric restriction. Graphical Abstract

New from Jennifer Stern. A role for the glucagon receptor in the lifespan extending effects of caloric restriction link.springer.com/article/10.1...

Stern Lab had a blast at the Masoro-Barshop Conference on Aging! An exciting weekend learning the latest from leading experts in the aging/metabolism field. Thanks to Barshop Institute for organizing a great meeting and the opportunity to share our research.

Glucagon receptor signaling is indispensable for the healthspan effects of caloric restriction in aging male mice - GeroScience Obesity and type 2 diabetes mellitus accelerate aging, shortening the duration of healthspan. Conversely, chronic calorie restriction (CR) extends healthspan. Research aimed at understanding the mechanism by which CR slows aging has focused heavily on insulin and downstream signaling cascades. Glucagon, a hormone that counter-regulates insulin, is commonly affected by these same interventions. To investigate the role of glucagon in aging, we used dietary manipulation, global and liver-specific glucagon receptor knockout, and pharmacological glucagon receptor activation. We found that globally eliminating glucagon receptor signaling (Gcgr KO) decreases median lifespan by 35% in lean mice. Extending these findings to metabolic health, we found that glucagon receptor signaling is indispensable to the metabolic response to chronic CR in young and aged mice. While CR decreased liver fat, serum triglyceride, and serum cholesterol in WT mice, these metabolic benefits were absent in Gcgr KO mice. In line with these observations, we found that critical nutrient-sensing pathways known to improve aging are dysregulated in mice lacking glucagon receptor signaling at the liver (Gcgrhep−/−). Liver-specific deletion of the glucagon receptor decreases hepatic AMP kinase activation in aging mice, regardless of diet. Further, CR decreases hepatic mTOR activity in WT mice but not in Gcgrhep−/− mice. Together, these findings propose that glucagon signaling plays a critical role in both normal aging and the lifespan and healthspan extension driven by caloric restriction. Graphical Abstract

Excited to share our work establishing a role for glucagon receptor signaling in aging and the healthspan response to caloric restriction. Hot off the press today in GeroScience! @uazbio5.bsky.social @uazbio5.bsky.social @uazhealthsciences.bsky.social
link.springer.com/article/10.1...

Stern lab celebrating Kassie's 1st first author paper 😀. It took a small village to get it done, so proud of you guys!

Stern lab trainees presenting their exciting data today at the ABBS student poster session. Fun afternoon!@uazhealthsciences.bsky.social @uazbio5.bsky.social

A new tragedy for the Endocrine community An outstanding scientist leaves us too soon

ACLY inhibition promotes tumour immunity and suppresses liver cancer - Nature Using metabolic dysfunction-associated steatohepatitis-driven hepatocellular carcinoma mouse models, an ATP citrate lyase inhibitor reduces tumour burden and enhances efficacy of current standards of care.

Nature research paper: ACLY inhibition promotes tumour immunity and suppresses liver cancer

go.nature.com/4l7n4t8

We finished an exciting study today. Obligatory mouse room selfie 🤣

Comprehensive human proteome profiles across a 50-year lifespan reveal aging trajectories and signatures A 50-year multi-tissue proteomic atlas reveals transcriptome-proteome decoupling, proteostasis decline with amyloid accumulation, and asynchronous aging clocks, identifying circulating senoproteins co...

The proteomic blueprint of #aging across 13 human tissues www.cell.com/cell/abstrac...

Systematic profiling reveals betaine as an exercise mimetic for geroprotection Elucidating the multi-faceted health effects of exercise in humans identifies kidney-derived betaine as an exercise mimetic acting as a TBK1 inhibitor with anti-inflammatory and geroprotective activit...

Here studies elucidate the molecular benefits of #exercise and position betaine as an exercise mimetic for healthy #aging www.cell.com/cell/abstrac...

You know you're in sync with your lab mates when everyone accidentally shows up to lab with color coordinated outfits 🤣

Looking forward to attending!

14K views · 1K reactions | These hyperbolic, disingenuous statements by the FDA commissioner are about scoring political points by distorting the conversation around prevention and treatment. The real... These hyperbolic, disingenuous statements by the FDA commissioner are about scoring political points by distorting the conversation around prevention and treatment. The reality is we’re not “putting.....

Yep. This response is spot on
www.facebook.com/reel/2069672...

Glucagon receptor signaling is indispensable for the healthspan effects of caloric restriction in aging male mice Obesity and type 2 diabetes mellitus accelerate aging, shortening the duration of healthspan. Conversely, chronic calorie restriction (CR) extends healthspan. Research aimed at understanding the mecha...

Excited to share our new preprint! www.biorxiv.org/content/10.1...

GLP-1R/GCGR dual agonism dissipates hepatic steatosis to restore insulin sensitivity and rescue pancreatic β-cell function in obese male mice - Nature Communications Early drivers of T2D include ectopic fat accumulation that impairs insulin sensitivity. Here, the authors show that GLP1/GCGR dual agonism provides multimodal benefits in obese male mice by reducing l...

GLP-1R/GCGR dual agonism in mice provides multimodal efficacy to decrease hepatic steatosis and consequently improve insulin sensitivity, in concert with recovery of endogenous β-cell function and reduced insulin demand #diabetes @natcomms.nature.com www.nature.com/articles/s41...

There is no replacement (yet) for animal models in medical research The NIH is “reducing animal use in research.” But there is no replacement for animal models.

It is beyond disturbing when the NIH and HHS Directors do not understand that animal models are essential in research

www.statnews.com/2025/05/19/a...

Congratulations Thadeus and Yashika! Celebrating our awesome UA graduates. So proud of everything you have accomplished in the lab. You will be missed, but we're excited for you to go on and do great things! 🥳 @uazhealthsciences.bsky.social @uazbio5.bsky.social

Top NIH nutrition scientist Kevin Hall says he’s ‘unlikely’ to return to agency Kevin Hall, ultra-processed food expert, says he took retirement after the HHS censored his work and that, despite requests, he's unlikely to return.

An update on renowned nutrition scientist formerly @nih www.statnews.com/2025/05/16/n...

Modeling diabetic alpha cell dysfunction using stem cell-derived alpha cells Shrestha et al. report the development of an in vitro human model of pancreatic alpha cells using pluripotent stem cells (SC-alpha cells). SC-alpha cells recapitulate the gene expression, proglucagon ...

Interrogation of Proglucagon-derived peptide secretion using human stem cell-derived alpha (SC-α) cells www.cell.com/stem-cell-re...

Check out Stern Lab trainees strutting their stuff at today's University of Arizona College of Medicine Research Day poster session. Not at all shy of how proud I am of this crew! 🤩@uazhealthsciences.bsky.social @uazbio5.bsky.social @uarizona.bsky.social

More poster pics!

Super fun evening at the UA Department of Medicine SOAR Research Forum. So proud of all the Stern Lab trainees presenting! @uazhealthsciences.bsky.social @uazbio5.bsky.social

WashU is accepting applications for Postdoctoral Fellowship in Diabetes & Related Metabolic Diseases (T32 DK007120). If you are eligible for T32 support (need to be a US citizen or permanent resident) and are interested in working with stem cell-derived islets, please contact me!

My first graduate student came back to the lab to visit today, in town from med school. I feel like a proud parent. We missed you Tyler! Just like old times, he's got the obligatory selfie arm 🤣

Thank you Dr. Hall, for your contributions to the field of nutrition. This is a huge loss to the scientific community and to the future of human health. We need more scientists like you.

The world of science needs more colleagues like Dr. Kevin Hall. Honesty, integrity and high quality science, answering critical questions with broad implications for improving human health

Harvard University Harvard University is devoted to excellence in teaching, learning, and research, and to developing leaders who make a difference globally.

Harvard redid its whole homepage to push back against the administration’s demands. I mean, this is just a website but I think it’s kind of a great PR move: www.harvard.edu

Research Saves Lives

Without research - at Johns Hopkins and at thousands of other universities, medical schools and research institutions across the nation - scientific breakthroughs suffer and the lifesaving treatments of tomorrow are at risk

www.jhu.edu

ICYMI: New content online: mTORC1 is the central regulator in pancreatic β-cells

How Dismantling DEI Efforts Could Make Clinical Trials Less Representative This Medical News article discusses how the Trump administration’s dismantling of diversity, equity, and inclusion could halt progress made in enrolling clinical trial participants who represent the p...

"Diversity is not just about race and ethnicity. Diversity is about the diversity of the human condition."

This Medical News article discusses how the dismantling of DEI efforts could lead to less representative clinical trials.

#MedSky