## 4 Nicotinamide Riboside for Healthy Aging and Longevity  
### Nicotinamide Riboside for Healthy Aging  
NAD\({}^{+}\) metabolism and homeostasis are important in aging and disease [174; 175]. Declining NAD\({}^{+}\) levels induce the augmentation of hypoxia-inducible factor-lalpha (HIF-1\(\alpha\)) and a pseudohypoxic state disrupting PGC-1\(\alpha\)/-1\(\beta\)-independent nuclear-MT communication during aging [176]. Thus, in recent preclinical studies, managing NAD\({}^{+}\) deficits with NAM, NA, NR, and NMN provided healthy aging [177]. In the Caco-2 cell line and NIAAA mouse model, NAD\({}^{+}\) supplementation by NR alleviated intestinal barrier injury induced by ethanol via protecting epithelial MT function [178]. NRS increased the formation of human leukocytes from hCD34+ progenitors in the immunodeficient mice model. Thus, through increased MT clearance, NR potently stimulated the hematopoiesis [179] and the lymphoid potential of Atm\({}^{-/-}\) and old mice HSCs [180; 181]. Moreover, NMN can be used to activate SIRT1 and improve the pathophysiology of diet- and age-induced diabetes in mice [182]. Likewise, reduced NMN is a newly analyzed and potent NAD\({}^{+}\) precursor in mammalian cells and mice blood and internal organs [183]. In randomized, double-blind, PLA-controlled clinical trials in healthy middle-aged and older adults, chronic NRS (500 mg twice daily) is safe and well tolerated, and it is recommended for (i) increasing NAD\({}^{+}\) level [8] and (ii) treating elevated systolic blood pressure (SBP) and arterial stiffness having initial above-normal (120-159 mmHg) SBP [184]. In aging and disease, a close connection relates NAD\({}^{+}\) levels and the activation of SIRTs, as seen in murine models: (i) NR alleviates CPT-induced peripheral neuropathy (CIPN) and neuronal death via SIRT2 activation and enhancement of nucleotide excision repair in Lewis lung carcinoma model [185]; (ii) SIRT3 is required for regeneration of WT or mutant liver but not for the beneficial effect of NR [186]; (iii) SIRT3 deficiency aggravates contrast-induced acute kidney injury (CIAKI) in vitro (HK-2 cells) and in vivo (WT and SIRT3 KO mice) [187]; (iv) NR attenuates inflammation and OXS by activation of SIRT1 and normalization of NAD\({}^{+}\)/NADH ratio in alcohol-stimulated RAW 264.7 macrophages and in mouse bone marrow-derived macrophages [188]. NRS could be a missing piece in the puzzle of exercise therapy for older adults. Short-term oral NR treatment, 300 mg/kg or 600 mg/kg daily, improves muscle quality and function in middle-aged male C57 BL/6] mice and increases cellular energetics and differentiating capacity of myogenic progenitors [189]. A randomized, PLA-controlled trial of safe and well-tolerated daily NRPT supplementation (1 g NR and 0.2 g PT) improved skeletal muscle regeneration after experimental muscle injury in 23 elderly individuals (55-80 years) [190]. Moreover, in a double-blind, crossover study, acute NRS improved redox homeostasis and exercise performance in 12 old individuals compared with the same number of young men [191]. Recent studies have highlighted that sentiotherapeutic NRS could contribute to healthy aging and longevity. As a sample of results: (i) the effects of sentiolytic drugs, including NR, were tested on human mesenchymal stromal cells (MSCs) with no significant action on molecular markers for replicative senescence [192]; (ii) the sentiotherapeutic NR triflate improved the NAD\({}^{+}\) levels of buffy coat-derived platelet concentrates, but cannot prevent storage lesion for 23 days [193]; (iii) 17-\(\alpha\)-estradiol late in life extends lifespan in aging UM-HET3 heterogeneous male mice, but NRS does not affect lifespan in either sex [194]. In this regard, NAD\({}^{+}\) supplementation (NR, NAM, NA) exhibited emerging roles in replicative and chronological aging in fungi and mammals. For example: (i) _Saccharomyces cerevisiae YOR071C_ gene encodes the high-affinity NR transporter Nrt1 polypeptide [195]; (ii) _S.