A metabolite sensor CtBP2 is secreted in response to shifts in cellular energy status to maintain systemic/organismal health

While intracellular metabolic homeostasis is coordinated by metabolite-sensing molecules, intercellular (cell-to-cell) metabolic harmonization remains underexplored. Here we describe an intercellular (cell-to-cell) communication system regulated by a metabolite sensor C-terminal binding protein 2 (CtBP2). CtBP2 is secreted via exosomes in response to reductive metabolism, which is suppressed by excessive oxidative stress. A series of pro-longevity agents, such as metformin, resveratrol and hydrogen sulfide, induce CtBP2 secretion, and administration of exosome CtBP2 extends lifespan in mice. Consistent with these findings, serum CtBP2 concentrations are higher in human subjects from families with a history of longevity and exhibit an age-dependent decline. Healthspan is also improved by exosome CtBP2 as exemplified by protection against frailty in mice and elevated serum CtBP2 levels are associated with less cardiovascular diseases in human. These health benefits could be attributed to the adequate increase of reduction potentials that induces activation of Forkhead box M1 (FoxM1) and AMP-activated protein kinase (AMPK). Our findings illustrate a metabolic system that presents potential as a target for future clinical applications.