Glucagon, a key hormone in maintaining euglycemia during fasting, also exerts broad metabolic effects, including regulation of lipid oxidation, adiposity, insulin sensitivity, and metabolic rate. However, its role in aging and longevity remains largely unexplored, a significant omission given the extensive research on dietary restriction and insulin signaling in lifespan modulation. Here, we investigated the impact of hepatic glucagon receptor (GCGR) signaling on lifespan using a liver-specific GCGR knockout (LKO) mouse model. While male LKO mice exhibited normal lifespan, female LKO mice displayed a significant reduction in survival. Strikingly, and in contrast to prevailing expectations based on metabolic improvements, this shortened lifespan in females occurred despite marked enhancements in metabolic health, including reduced body weight and adiposity, preferential glucose oxidation, elevated metabolic rate, and enhanced glucose tolerance and insulin sensitivity throughout adulthood. Underpinning this detrimental outcome, transcriptomic and biochemical analyses revealed a striking, female-specific activation of pro-inflammatory pathways, notably NF-κB and cGAS-STING signaling, in the liver and kidney of aged LKO mice as well as reduced expression of hepatic xenobiotic metabolism genes. These findings identify a novel, sexually dimorphic role for the hepatic glucagon receptor in regulating lifespan, linking its interruption in females to late-life inflammation and reduced longevity despite an otherwise beneficial metabolic phenotype.
