The NAD World: A New Systemic Regulatory Network for Metabolism and Aging—Sirt1, Systemic NAD Biosynthesis, and Their Importance
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For the past several years, it has been demonstrated that the NAD-dependent protein deacetylase Sirt1 and nicotinamide phosphoribosyltransferase (Nampt)-mediated systemic NAD biosynthesis together play a critical role in the regulation of metabolism and possibly aging in mammals. Based on our recent studies on these two critical components, we have developed a hypothesis of a novel systemic regulatory network, named “NAD World”, for mammalian aging. Conceptually, in the NAD World, systemic NAD biosynthesis mediated by intra- and extracellular Nampt functions as a driver that keeps up the pace of metabolism in multiple tissues/organs, and the NAD-dependent deacetylase Sirt1 serves as a universal mediator that executes metabolic effects in a tissue-dependent manner in response to changes in systemic NAD biosynthesis. This new concept of the NAD World provides important insights into a systemic regulatory mechanism that fundamentally connects metabolism and aging and also conveys the ideas of functional hierarchy and frailty for the regulation of metabolic robustness and aging in mammals.
KeywordsNAD World Metabolism Aging Sirt1 Nampt Systemic NAD biosynthesis Pancreatic β cells Neurons Robustness Frailty
I thank all members of the Imai lab for their helpful discussions and comments. I apologize to those whose work is not cited due to the focus of this review and space limitations. This work was supported by grants from the National Institute on Aging (AG024150), Ellison Medical Foundation, and Longer Life Foundation to S. I.
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