A Novel Caloric Restriction-Like Mimetic Affects Longevity in Yeast by Reprogramming Core Metabolic Pathways

Glucose limitation is a simple intervention that extends yeast replicative lifespan (RLS) via the same pathway(s) thought to mediate the benefits of caloric restriction (CR) in mammals. Here we report on “C1”, a small molecule that mimics key aspects of CR. C1 was identified in a high throughput screen for drug-like molecules that reverse the RLS shortening effect of the sirtuin inhibitor and NAD+ precursor nicotinamide. C1 reduces the cellular dependence on glycolysis and the pentose phosphate pathway, even in the presence of glucose, and compensates by elevating fatty acid -oxidation to maintain acetyl-CoA levels. C1 acts either downstream of Sir2 or in an independent CR pathway. In this regard, chemical-genetic interactions indicate that C1 influences Tor2 signaling via effects on phosphoinositide pools. Key activities of C1 extend to mammals. C1 stimulates -oxidation in mammalian cells, and in mice, reduces levels of triacylglycerides and cholesterol in livers of lean and obese mice. C1 confers oxidative resistance to diamide in both yeast and mammalian cells. In conclusion, C1 induces global changes in metabolism in yeast and mammalian cells that mimic aspects of CR. Future work will be aimed at identifying the cellular target of C1