Regulation of alanine glutamine asparagine catabolism is common to mouse models that extend lifespan

Previous work has shown that three interventions that extend mouse lifespan (acarbose, canagliflozin, or calorie restricted diet) as well as two genetic models (Snell and GHRKO) down-regulate MEK1-ERK and mTOR signaling and activate chaperone-mediated autophagy. Because of the common signaling and physiological changes seen in these models, we hypothesized that they might also display shared changes affecting glycolysis and energy metabolism, including catabolism of amino acids. Here we show evidence that this set of slow-aging mice downregulate key hepatic enzymes controlling glycolysis, but up-regulate enzymes involved in the catabolism of alanine, glutamine, and asparagine leading to Krebs cycle intermediaries. These results suggest that these models undergo a metabolic shift from glucose to increased amino catabolism in the liver. The same pattern of changes can be reproduced in vivo by trametinib, a drug that extends lifespan through inhibition of the MEK1-ERK-MNK pathway. In vitro models suggested that these changes might be the effects of a secondary hormonal signal(s). Our evidence suggests that this second messenger is likely to be glucagon. A glucagon analog can mimic the declines in glucose utilization and increases in the alanine/glutamine/asparagine catabolic enzymes found in the long-lived mouse models. We also report evidence for enhanced pancreatic production of glucagon in slow-aging mice, which correlates with the enzymatic shifts and lifespan extension. Based on these experimental models, we hypothesize that components of the insulin-glucagon axis are a fundamental regulator of the metabolic shift seen in multiple interventions that extend mouse lifespan.