Regulation of Sirtuins by Systemic NAD+ Biosynthesis

In recent years, nicotinamide adenine dinucleotide (NAD⁺) biology has been increasingly drawing significant attention within the scientific community and providing its vast implication for various age-associated pathophysiologies and disease conditions. Particularly, the role of NAD⁺ in the regulation of sirtuins, an evolutionary conserved family of NAD⁺-dependent deacetylases/deacylases, has been extensively studied. Systemic NAD⁺ biosynthesis mediated by intra- and extracellular nicotinamide phosphoribosyltransferase and sirtuins cooperate to regulate many fundamental biological processes in different tissues and organs and promote physiological resilience in response to nutritional and environmental perturbations. Accumulating lines of evidence suggest that systemic decline in NAD⁺ availability is a critical trigger for age-associated functional decline and disease conditions through the reduction in sirtuin activities in different subcellular compartments. In this chapter, we will discuss the current understanding of the intimate connection between systemic NAD⁺ biosynthesis and sirtuin functions and its implications in aging and longevity control.