# Nicotinamide Riboside--The Current State of Research and Therapeutic Uses
## 1 Introduction
Furthermore, the content of the primary NADase in mammals, CD38, increases with age. This enzyme uses NAD\({}^{+}\) to produce and hydrolyze the Ca\({}^{2+}\)-mobilizing  
Figure 1: NAD\({}^{+}\) synthesis pathways. The figure depicts NAD\({}^{+}\) de novo pathway from tryptophan (Trp) through quinolinic acid (QA), Preiss–Handler pathway from nicotinic acid (NA) via nicotinic acid adenine dinucleotide (NAAD) and NAD synthetase (NADS), and “salvage pathways” from nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN) via purine nucleoside phosphorylase (NP) and nicotinamide phosphoribosyltransferase (NAMPT) enzymes or nicotinamide ribose kinases (NRK) and NMN/NaMN adenylyltransferases (NMNAT), respectively. second messenger, cADP-ribose [25; 26; 27]. CD38 can also degrade the NAD\({}^{+}\) intermediates, NR and NMN [28; 29], which further decreases the content of NAD\({}^{+}\)[30]. The effect of CD38 on NAD\({}^{+}\) content was demonstrated in CD38-deficient mice, whose NAD\({}^{+}\) levels remain high. This preserves mitochondrial respiration and metabolic function with age [31]. Moreover, the inhibition of CD38 can increase NAD\({}^{+}\) levels and improve glucose and lipid metabolism [32]. Apart from the ectoenzymes CD38 and CD157, SARM1 (sterile alpha and Toll/interleukin-1 receptor motif-containing 1) is an additional NAD\({}^{+}\)-depleting enzyme that uses NAD\({}^{+}\) to promote axonal degeneration after injury and thereby decreases its overall content [33]. The immense involvement of NAD\({}^{+}\) in all these processes suggests a significant potential for the treatment of various pathophysiological conditions with supplementation of NAD\({}^{+}\) precursors. However, multiple options exist for supplementation, and the optimal precursor and dosage are still unclear with regard to the specific condition. For the baseline requirements of NAD\({}^{+}\) synthesis, dietary tryptophan or less than 20 mg of niacin (NA, NAM) daily are sufficient. However, growing evidence demonstrates that substantially greater rates of NAD\({}^{+}\) synthesis exhibit numerous beneficial or even therapeutic effects, which can be achieved by supplementation of its intermediat \begin{table}
\begin{tabular}{c c c c} \hline \hline  & **Localization** & **General Function** & **Function** \\ \hline SIRT1 & Nucleus, Cytosol & DNA repair & Glucose metabolism, differentiation, insulin secretion, neuroprotection, vascular protection \\ \hline SIRT2 & Cytosol, Nucleus & Cell cycle & Adipose tissue development and functionality, blood glucose homeostasis, modulation of peripheral myelination \\ \hline SIRT3 & Mitochondria, Nucleus, Cytosol & Mitochondrial metabolism & ATP homeostasis, ROS detoxification, tumor suppression, DNA repair, neuroprotection, apoptosis suppression \\ \hline SIRT4 & Mitochondria & Mitochondrial metabolism & Insulin secretion, DNA repair, apoptosis suppression \\ \hline SIRT5 & Mitochondria, Cytosol, Nucleus & Mitochondrial metabolism & Urea cycle, ketone body formation, nitrogenous waste management, ROS detoxification \\ \hline SIRT6 & Nucleus (Chromatin) & DNA repair & Telomerase protection, genome stability, cholesterol homeostasis, glycolysis and gluconeogenesis \\ \hline SIRT7 & Nucleus (Nucleolus) & rRNA transcription, cell cycle & Cardiac protection \\ \hline \hline \end{tabular}
\end{table} 
Table 1: Central role of sirtunis in DNA repair, cell cycle control and mitochondria function (adapted from [PERSON] et al. [34]). Figure 2: Activation of the NMRK2 pathway represent a common adaptive mechanism in the failing heart where NAD\({}^{+}\) levels are low. NAD\({}^{+}\) synthesis from NR through the NMRK2 pathway may be favored, as the NMN synthesis from NR by NMRK enzymes requires only one ATP molecule while synthesis from NAM by NAMPT requires at least three ATP equivalents. are found in a wide variety of foods, including meat, eggs, dairy, certain vegetables and whole wheat [35; 36].