# Nicotinamide Riboside--The Current State of Research and Therapeutic Uses
## 6 Advantages Compared to Other NAD\({}^{+}\) Precursors  
At the current time, NR is emerging as a leading candidate due to its bioavailability, safety, and strong ability to raise NAD\({}^{+}\) content compared to other precursors [149]. Among diverse NAD\({}^{+}\) precursors, NMN and NR presented better pharmacokinetic and pharmacological properties [156]. The bioavailability between the NAD\({}^{+}\) precursors (NMN, NR, NAM, and NA) was assessed in preclinical studies as the ability to elevate intracellular NAD\({}^{+}\). NR was able to increase NAD\({}^{+}\) levels in the liver of mice, exhibiting greater oral bioavailability than NAM, which was, in turn, more orally bioavailable than NA [149]. In addition, animal studies have reported that equimolar oral NR is superior to NA and NAM in elevating NAD\({}^{+}\) content in the liver [149]. Similarly, the NAD\({}^{+}\) content in muscles could be significantly increased with NR and NA, but not with NMN [149]. The three precursors (NA, NMN, and NR) differed in the degree to which they promote the accumulation of ADPR, the measure of sirtunis activity, and other NAD\({}^{+}\)-consuming activities [149]. Namely, NR was found to increase ADPR \(\sim\)3 more than NAM, which supports NR as a favored NAD\({}^{+}\) precursor to increase NAD\({}^{+}\) and NAD\({}^{+}\)-consuming activities in the liver [149]. Moreover, the activity of sirtunis was stimulated after NR-induced NAD\({}^{+}\) levels increased [37]. Both SIRT1 and SIRT3 activities increased in vitro and in vivo [37], which favors the hypothesis that NR can increase NAD\({}^{+}\) levels in at least mitochondrial and nuclear compartments. NR's ability to increase NAD\({}^{+}\) in different subcellular compartments represents the crucial difference compared to other approaches of increasing intracellular NAD\({}^{+}\) levels. Although all three precursors, NA, NAM, and NR can raise both NAD\({}^{+}\) and NADP\({}^{+}\) levels [149; 157; 14], they all exhibit distinct physiological responses. For example, NA shows lowering effects on blood lipid levels, and it is used to treat dyslipidemia [151]. However, NA is implicated with flushing at doses higher than 50 mg/day [151]. On the contrary, NAM does not affect lipid blood levels, yet it can exhibit sirtun-inhibiting effects at higher doses [116; 149]. Among the three mentioned precursors, only NR could prolong survival and induce hematopoietic stem cell regeneration, as documented in a study with mice treated with irradiation [158]. Furthermore, orally administered NR was found to improve resistance to and reversal of chemotherapeutic neuropathy [159]. This implies advantages of the NR precursor for potential use in cancer patients undergoing chemo- or radiotherapy. The bioavailabilityof NAD\({}^{+}\) precursors can be assessed by measuring NAAD levels. Namely, NAAD represents the most sensitive biomarker of effective NAD\({}^{+}\) supplementation since it is undetectable in the blood prior to supplementation, and the increase of its levels has been observed in the liver after orally administered NAD\({}^{+}\) precursors. NR was found to increase NAAD by at least 45-fold compared to baseline [149]. In addition, NR could significantly elevate NAAD heart content, where the increase of NAD\({}^{+}\) occurs in the absence of a steady-state NAD\({}^{+}\) increase [149]. Surprisingly NA, the only precursor expected to convert to NAD\({}^{+}\) through a NAAD intermediate, produced the least NAAD, while NAM and NR both produced peaks of hepatic NAAD [149]. High availability of NR has been observed in the normal human diet. NR does not require conversion to enter the cell, which could partially explain the high level of availability. On the contrary, NAD\({}^{+}\) and its precursors have to be converted to either NR or NAM before entering the cell [153]. While NAD\({}^{+}\) and NMN are being converted to NR extracellular by CD73 [28], their cellular conversion depends on the NMRK pathway [153; 160].