Bruner Kassandra R, Byington Isabella R, Marx Tyler J, Vasileva Anastasiia, Fletcher Temara, Ghimire Susma, Zappia India J, Shaju Yashika, Zeng Janan, Wachsmuth Hallie R, Carlyon Thadeus W, Besselsen David G, Drucker Daniel J, Duca Frank A, Stern Jennifer H
bioRxiv. 2025 May 17:2025.05.13.653849. doi: 10.1101/2025.05.13.653849.
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. These lifespan shortening effects are more robust in diet-induced obese mice (54%). 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 (Gcgr ). 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 Gcgr 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.
肥胖和2型糖尿病会加速衰老，缩短健康期的时长。相反，长期热量限制（CR）可延长健康期。旨在了解CR延缓衰老机制的研究主要聚焦于胰岛素及下游信号级联反应。胰高血糖素是一种可对抗调节胰岛素的激素，通常也会受到这些相同干预措施的影响。为了研究胰高血糖素在衰老中的作用，我们采用了饮食调控、全身性和肝脏特异性胰高血糖素受体敲除以及胰高血糖素受体的药理学激活方法。我们发现，在瘦小鼠中，全身性消除胰高血糖素受体信号（Gcgr基因敲除）会使中位寿命缩短35%。在饮食诱导的肥胖小鼠中，这些寿命缩短效应更为显著（54%）。将这些发现扩展至代谢健康方面，我们发现胰高血糖素受体信号对于年轻和老年小鼠对长期热量限制的代谢反应必不可少。虽然热量限制可降低野生型小鼠的肝脏脂肪、血清甘油三酯和血清胆固醇，但在Gcgr基因敲除小鼠中却没有这些代谢益处。与这些观察结果一致，我们发现已知可改善衰老的关键营养感应通路在肝脏中缺乏胰高血糖素受体信号的小鼠（Gcgr基因敲除小鼠）中失调。无论饮食如何，肝脏特异性缺失胰高血糖素受体都会降低衰老小鼠肝脏中的AMP激酶活性。此外，热量限制可降低野生型小鼠肝脏中的mTOR活性，但在Gcgr基因敲除小鼠中却不会。总之，这些发现表明胰高血糖素信号在正常衰老以及热量限制驱动的寿命和健康期延长中均起着关键作用。
