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Metabolomics and Gene Discoveries Reveal Interrelationships between Glucose, Phosphate and NAD Metabolism

Early models that sought to explain how calorie restriction may alter NAD metabolism were formulated prior to the identification of all of the NAD metabolites and the enzymes that interconvert these metabolites. We have recently identified nicotinamide riboside and nicotinic acid riboside as metabolites and have identified roles for nicotinamide riboside kinase, uridine hydrolase, purine nucleoside phosphorylase, and two multifunctional 5′‐nucleotidases in yeast NAD metabolism. A metabolomic method has quantified the yeast NAD metabolome. Data from yeast cells whose lifespan is extended with vitamin provision or glucose restriction indicate that, while increasing net NAD synthesis is a mechanism for lifespan extension, it is not the mechanism that applies for glucose restriction, nor is a change in the NAD:nicotinamide or NAD:NADH ratio. Some of the same pathways that respond to glucose restriction are also regulated by phosphate restriction and the availability of vitamins. Thus, the calorie restricted metabolome appears to involve a large number of small changes that effect multiple targets rather than a small number of large changes that exclusively target sirtuins.