# Nicotinamide Riboside--The Current State of Research and Therapeutic Uses
## 1 Introduction  
In recent years, interest in NAD\({}^{+}\) biology has been gaining momentum, revealing critical insights into its roles in numerous physiological processes and underlining the beneficial effects of supplementation with its precursors. Moreover, accumulating evidence indicates that a decrease in NAD\({}^{+}\) levels contributes to the development of age-associated pathophysiology [1; 2; 3]. The systemic NAD\({}^{+}\) decrease is caused by both lowered rates of biosynthesis and increased use of NAD\({}^{+}\). The immense demand for NAD\({}^{+}\) is caused by its importance in cellular oxidation-reduction reactions, including the majority of catabolic and anabolic reactions, such as glycolysis, fatty acid \(\beta\)-oxidation, tricarboxylic acid cycle, synthesis of fatty acids, cholesterol, steroids, etc. [4; 5; 6]. Additionally, NAD\({}^{+}\)-consuming enzymes, such as sirtuins, poly-ADP-ribose polymerases (PARPs), cADP-ribose synthases (CD38/157 cetoenzymes) [7; 8; 9] and mono-ADP-ribose transferases (ARTs) contribute to an overall depletion of NAD\({}^{+}\). Biosynthesis can compensate somewhat to the depleted levels of NAD\({}^{+}\) via de novo synthesis from tryptophan (Trp) or in the salvage pathways from four other precursors,nicotinamide (NAM), nicotinic acid (NA), nicotinamide riboside, and nicotinamide mononucleotide (NMN). While de novo synthesis from Trp is carried out in an eight-step pathway, the salvageable precursors NA and NAM require only three (Preiss-Handler pathway) and two steps, respectively (Figure 1). Nicotinamide riboside (NR) is an additional salvageable NAD\({}^{+}\) precursor with a two-step [10] or three-step pathway [11] to form NAD\({}^{+}\) (Figure 1). In mammals, the most common precursor is NAM, which can further be used to form NMN by the rate-limiting enzyme, phosphoribosyltransferase (NAMPT) [12]. In the final step, NMN is converted to NAD\({}^{+}\) by NMN/NaMN adenylyltransferases (NMNATs) [13; 14]. As a function of the aging process and/or overnutrition, NAD\({}^{+}\) content and NAMPT expression are found to decline in multiple tissues [3; 15; 16; 17], while the maintenance of NAD\({}^{+}\) levels relies on diverse biosynthetic routes and precursors in different tissues [18; 19]. Nevertheless, the decreased expression of NAMPT enzyme is one of the major causes of the NAD\({}^{+}\) decline over age [15; 20]. The requirement of this enzyme can be bypassed with the direct conversion of NR to NMN by two nicotinamide ribose kinases, NMRK1 and NMRK2 (also known as NRK1 and NRK2) [10]. This also circumvents the requirement of energetically costly PRPP (phosphoribosyl pyrophosphate. Figure 2) and the feedback inhibition by NAD\({}^{+}\)[21]. Alternatively, NR can be turned into NAM by purine nucleoside phosphorylase (NP), which is subsequently converted to NAD\({}^{+}\) via NMN by NMNAT (Figure 1). Hence, the utilization of NR depends on the expression of either the Nrk pathway or NP combined with the NAMPt pathway. The importance of NAD\({}^{+}\) is reflected through the activity of NAD\({}^{+}\)-depleting enzymes, the mediators of aging, which are mostly induced by stress factors, such as DNA damage, oxidative stress, and inflammation. The major downstream mediators are sirtunis, the NAD\({}^{+}\)-dependent deacetylases/deacylases. Sirtunis are conserved regulators of aging and longevity in diverse organisms, and regarded as the master switches of metabolism [22] due to their numerous regulatory functions in metabolism, DNA repair, stress response, chromatin remodeling and circadian rhythm. (Table 1) [2; 23]. Together with sirtunis, PARPs use NAD\({}^{+}\) to produce a chain of ADP-ribose (ADPR) molecules. PARP1 and PARP2 respond to DNA breaks in the nucleus and facilitate the process of DNA repair [23]. As DNA damage accumulates over time, the activation of PARPs increase, which in turn, lowers the activity of SIRT1 due to both substrate competition and PARP2's ability to bind to the promoter of Sirt1 and repress its expression [24].