Lin's research reveals a sophisticated glucose-sensing mechanism where the AXIN:LKB1 complex translocates to lysosomal surfaces when aldolase detects low glucose via fructose-1,6-bisphosphate signals. This activates AMPK while inhibiting mTORC1, creating a metabolic switch that extends lifespan. The pathway is activated by metformin and lithocholic acid (LCA), a metabolite enriched in calorie-restricted mice that signals through TULP3 receptors to boost sirtuins and NAD+.
This discovery fundamentally reframes glucose as more than fuel—it's a longevity signaling molecule. The identification of aldometanib, an aldolase inhibitor that mimics glucose starvation, demonstrates therapeutic potential. Beyond metabolic benefits like reversing fatty liver, aldometanib mobilizes CD8+ T cells against hepatocellular carcinomas, suggesting glucose sensing connects metabolism to immune function. This work bridges caloric restriction research with cancer immunotherapy through a unified glucose-sensing paradigm. While promising, the pathway's complexity raises questions about therapeutic targeting without disrupting normal glucose homeostasis, and human validation remains critical.
