Regulatory Effects of NAD⁺ Metabolic Pathways on Sirtuin Activity

NAD⁺ acts as a crucial regulator of cell physiology and as an integral participant in cellular metabolism. By virtue of a variety of signaling activities this central metabolite can exert profound effects on organism health status. Thus, while it serves as a well-known metabolic cofactor functioning as a redox-active substrate, it can also function as a substrate for signaling enzymes, such as sirtuins, poly (ADP-ribosyl) polymerases, mono (ADP-ribosyl) transferases, and CD38. Sirtuins function as NAD⁺-dependent protein deacetylases (deacylases) and catalyze the reaction of NAD⁺ with acyllysine groups to remove the acyl modification from substrate proteins. This deacetylation provides a regulatory function and integrates cellular NAD⁺ metabolism into a large spectrum of cellular processes and outcomes, such as cell metabolism, cell survival, cell cycle, apoptosis, DNA repair, mitochondrial homeostasis and mitochondrial biogenesis, and even lifespan. Increased attention to how regulated and pharmacologic changes in NAD⁺ concentrations can impact sirtuin activities has motivated openings of new areas of research, including investigations of how NAD⁺ levels are regulated at the subcellular level, and searches for more potent NAD⁺ precursors typified by nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN). This review describes current results and thinking of how NAD⁺ metabolic pathways regulate sirtuin activities and how regulated NAD⁺ levels can impact cell physiology. In addition, NAD⁺ precursors are discussed, with attention to how these might be harnessed to generate novel therapeutic options to treat the diseases of aging.