Since the first discovery of nicotinamide adenine dinucleotide (NAD⁺)-dependent deacetylase activity of the silent information regulator 2 (Sir2) family (‘sirtuins’),¹ the field of sirtuin biology has been evolving rapidly over the past 16 years. Many researchers from different fields have encountered sirtuins in their own research, enriching our knowledge of this fascinating family of enzymes. It is now clear that sirtuins are involved in the regulation of many fundamental biological processes throughout the body.^2,3 Furthermore, it has been revealed that sirtuins possess much broader enzymatic activities, namely, deacylases, including deacetylase, desuccinylase, demaloynylase, deglutarylase, long-chain deacylase, lipoamidase, and ADP-ribosyltransferase.^4,5 All these enzymatic activities specifically require NAD⁺, and the catalytic mechanism of this NAD⁺ dependency has been studied extensively.⁶ Clearly, sirtuins have evolved to respond to the availability of NAD⁺, an essential currency of cellular metabolism and DNA damage repair, and convert this information to many different biological outputs. In this particular review article, we will focus on this intimate connection between sirtuin function, aging/longevity control in particular, and their indispensable co-substrate, NAD⁺.

The origin of the connection between NAD⁺ and sirtuins is ancient. For instance, vibriophage KVP40 possesses a minimal set of genes for NAD⁺ biosynthesis and consumption, namely, the genes encoding two key NAD⁺ biosynthetic enzymes, nicotinamide phosphoribosyltransferase (NAMPT) and nicotinamide/nicotinic acid mononucleotide adenylyltransferase (NMNAT),^2,3 and a sirtuin family protein (Figure 1).⁷ Although why such a minimalistic organism keeps these three genes in its genome remains unclear, one potential explanation is that controlling the host cell’s metabolism and proliferation in a NAD⁺-dependent manner could provide benefits for this particular vibriophage to efficiently produce progeny in the host cell. Such a NAD⁺/sirtuin-mediated virus–host relationship might be a prototype for the much more complex inter-tissue communication mediated by NAMPT and the mammalian sirtuin SIRT1.⁸ As discussed later in this review, NAMPT and SIRT1 comprise multiple layers of feedback regulatory loops inside cells and between tissues and organs, and contribute to the systemic regulation of mammalian aging and longevity.^{9,​10,​11,​12} Another interesting example is the connection between the nicotinamidase Pnc1 and Sir2 proteins in yeast, worms, and flies. Whereas vertebrates and a limited number of bacterial species mainly use NAMPT to synthesize NAD⁺ from nicotinamide, invertebrates and most bacterial species use nicotinamidase to convert nicotinamide to nicotinic acid and synthesize NAD⁺ from nicotinic acid (Figure 1).¹³ Pnc1 regulates NAD⁺ biosynthesis and affects lifespan in those organisms