Pioneers: Glucose Sensing and Control of Health-span and Lifespan

Abstract

My independent career started based on a simple doctrine of protein multifunctionality, by intuitively choosing the protein called AXIN, which has turned out to be the protagonist of my scientific life. This led us to discover the sensing pathway for glucose, which links to AMPK and mTORC1, two master metabolic controllers. We found that AXIN binds LKB1, an upstream kinase of AMPK, and that the AXIN:LKB1 complex translocates to the lysosomal surface after the lysosomal aldolase senses low glucose (fructose-1,6-bisphosphate as the direct signal) to activate AMPK and concomitantly inhibit mTORC1. Remarkably, we found that the lysosomal glucose-sensing AMPK pathway is shared by metformin, a glucose-lowering drug known to also extend lifespan and reduce cancer risk. In search of metabolites enriched in calorie-restricted mice and able to activate AMPK via the lysosomal pathway, we identified that lithocholic acid (LCA) as such a factor. We also identified TULP3 as the LCA receptor, which signals to activate sirtuins, increase NAD⁺, activate AMPK and inhibit mTORC1. In translation, we have identified an aldolase inhibitor termed aldometanib, which mimics glucose starvation to activate AMPK. Aldometanib can alleviate fatty liver, lower blood glucose, and extend lifespan in animals. Surprisingly, aldometanib can also mobilize tumoricidal CD8⁺ T cells to infiltrate and contain hepatocellular carcinomas (HCC), enabling HCC-bearing mice to live to ripe ages, the endpoint of cancer therapy. Our work has thus revealed that glucose acts as a messenger that signals through a specialized route to control health-span and lifespan. We will continue to explore the teleological meaning of glucose as a “chosen” molecule.