Dissecting systemic control of metabolism and aging in the NAD World: The importance of SIRT1 and NAMPT-mediated NAD biosynthesis

Many countries are facing social and economic problems due to increased elderly demographics. With these demands, it is now critical to understand the fundamental regulatory mechanism for aging and longevity in mammals. Our studies on the mammalian NAD-dependent deacetylase SIRT1 and nicotinamide phosphoribosyltransferase (NAMPT)-mediated systemic NAD biosynthesis led us to propose a comprehensive model for the systemic regulatory network connecting metabolism and aging, termed the “NAD World”. In this article, I will discuss the importance of SIRT1 and NAMPT-mediated NAD biosynthesis in the NAD World and the system dynamics of this hierarchical network for the connection between metabolism and aging.

► This review discusses a systemic regulatory network regulating metabolism and aging.
► SIRT1 functions as a key mediator controlling metabolic responses in various tissues.
► NAMPT functions as a pace maker regulating circadian NAD production and SIRT1.
► Their interplay defines specific tissues as critical frailty points in the NAD World.
► Frailty tissues determine the hierarchical regulatory dynamics of mammalian aging.