The molecular basis for why certain glucose-lowering interventions extend lifespan has remained elusive until now. This breakthrough reveals how cellular glucose sensors orchestrate the fundamental trade-off between growth and longevity that determines healthy aging. The discovery centers on AXIN protein complexes that function as sophisticated glucose detectors at the lysosomal surface. When glucose levels drop, aldolase enzymes sense the depletion through decreased fructose-1,6-bisphosphate levels. This triggers AXIN:LKB1 complexes to relocate to lysosomes, where they activate AMPK—the cell's master energy sensor—while simultaneously shutting down mTORC1, the growth-promoting pathway. Remarkably, metformin, the diabetes drug known to reduce cancer risk and extend lifespan in multiple species, operates through this identical lysosomal glucose-sensing mechanism. The research further identified lithocholic acid, a bile acid metabolite elevated during calorie restriction, as another activator of this longevity pathway through its receptor TULP3. This bile acid simultaneously boosts sirtuins, increases NAD+ levels, and triggers the same AMPK-mTORC1 regulatory cascade. These findings represent a paradigm shift in understanding metabolic aging control. Rather than viewing glucose regulation and longevity as separate phenomena, this work reveals they share fundamental molecular machinery. The practical implications extend beyond basic biology—the team developed aldometanib, an aldolase inhibitor that mimics glucose starvation effects. In animal studies, this compound not only extended lifespan and improved metabolic health but unexpectedly enhanced immune surveillance against liver cancer, suggesting glucose-sensing pathways coordinate both metabolic and immune aging processes.