Table 1.

Effects of NMN and NR using in preclinical and clinical studies

NAD+ precursor	Experimental model	Treatment	Outcomes	Reference
NMN	Cerebromicrovascular endothelial cells (CMVECs) isolated from 3- and 24-month-old male F344xBN rats	Cultured primary CMVECs were treated NMN (5 × 10−4 mol/L) for 1 to 5 days	Restoration of angiogenic capacity (formation of capillary-like structures, proliferative, and migratory capability) and attenuation of oxidative stress in aged CMVECs	[140]
	Young (3 months) and aged (24 months) male C57BL/6 mice	Intraperitoneal injections of 500 mg NMN/kg body weight per day for 14 days	Reverse the aging-induced cerebrovascular endothelial dysfunction. Rescued the neurovascular coupling responses associated with an improved cognitive performance by increasing endothelial NO-mediated vasodilation	[141]
	Male Sprague–Dawley rats (12 weeks old)	Intraperitoneal administration of 100 mg/kg on alternate days for a period of 3 months	Prevented neuronal loss and rescued the memory deficits in diabetic rats. Increased brain NAD+ levels, normalized the diabetes-induced decrease in both SIRT1 and PGC-1α, preserving protein deacetylation, and hippocampal biochemical and mitochondrial respiration	[26]
	12- and 14-month-old females C57BL6/JAusb mice	2 g/L in drinking water for 4 weeks	Increased NAD(P)H levels and rejuvenated oocyte quality, leading to fertility restoration and reversal of the adverse effect of maternal age on embryo development	[142]
	Model of isoproterenol-induced cardiac fibrosis in male C57/B6 mice (8–10 weeks old)	Intraperitoneal injections of 500 mg/kg every 3 days before and after isoproterenol injection	Prevention of cardiac dysfunction and attenuation of cardiac hypertrophy. The NAD+ levels and SIRT1 activity were restored, inhibiting oxidative stress, and Smad3 acetylation	[143]
	Model aging mice (male C57BL/6 mice 24-month-old)	Intraperitoneal injections of 500 mg NMN/kg body weight per day for 2 weeks	Anti-aging changes in pro-inflammatory and pro-atherogenic miRNA expression profile in the aorta. Rescue of vascular function and attenuation of oxidative stress	[144]
	24-month-old C57BL/6 mice	Intraperitoneal injections of 500 mg/kg body weight per day for 2 weeks	Reversion of age-related changes in neurovascular mRNA expression profile, leading to the rescue of youthful neurovascular phenotype and to the improvement of cerebromicrovascular endothelial function. Induction of genes involved in mitochondrial rejuvenation, anti-inflammatory, and anti-apoptotic effects, such as SIRT1-mediated upregulation of PGC-1α, FOXO3- and FOXO4-	[145]
	Eight healthy men 45–60 years old	Oral NMN (300 mg/day) after 30 min of breakfast for 90 days	Elongating telomere length in peripheral blood mononuclear cells (PBMC)
NR	Humans 10 twin pairs	Escalating dose of NR supplementation (250 to 1000 mg/day) for 5 months	DNA methylation and modulation epigenetic control of gene expression in muscle and adipose tissue. Reprogramming of tissue NAD+ and mitochondrial metabolism and muscle stem cell identity	[47•]
	Alzheimer’s disease mouse model	NR treatment (12 mM given in their drinking water for 3 months before the tests)	It normalized reduced cerebral NAD+/NADH ratio, lessened phosphorylated Tau, DNA damage, neuroinflammation, and apoptosis of hippocampal neurons	[24]
	8-week-old specific pathogen-free male C57BL/6 J mice	Gavage of NR (400 mg/kg body weight/day) + 50% (v/v) ethanol	NR alleviated the alcohol-induced liver injury. It inhibited the activation of the PP1 pathway, improving serum and liver triglyceride levels and lipid accumulation. Also, NR intervention changed the gut microflora structure and restored the abundance of gut microflora to a level similar to those in normal mice (control). It restored the reduction of bile acid levels in mice feces induced by alcohol exposure, which was correlated with gut microflora	[8]
	C57BL/6 J and Fndc5 knockout (Fndc5−/−) mice with non-alcoholic fatty liver disease (NAFLD) induced by high-fat or methionine/choline-deficient diet	Diet of pellets with NR 400 mg/kg/day for 12–16 weeks. Or intraperitoneal injections 400 mg/kg/day during 2 weeks	Reversion of NAFLD by regulating SIRT2-deppendent Fndc5 deacetylation and deubiquitination, which stimulates the “exerkine” Fndc5/irisin	[146]
	4-week-old male C57BLKS/J db/db mice (transgenic diabetic model) and age-matched C57BL/6 J mice (control)	NR-supplemented food (approximately 400 mg/kg/day) for 12 weeks	Accelerated diabetic wound healing and angiogenesis. Reversion of the reduced NAD concentration in BM-EPCs. It raised the number of EPCs and elevated the tube formation and adhesion ability of BM-EPCs in vitro. NR upregulated Sirt1 expression modulating acetylated PGC-1α expression, and increased p-AMPK/AMPK and VEGF. Furthermore, prevented the accumulation of subcutaneous fat and serum insulin and increasing serum adiponectin levels	[147]
	6-week-old male Balb/c mice for C26 Adenocarcinoma–induced cancer cachexia model	Diet supplemented with NR at 200 or 400 mg/kg daily for 3 weeks	Prevention C26 adenocarcinoma–induced muscle atrophy and weight loss. It restored cachexia-induced fat loss, reverting the epididymal lipolysis and inhibiting the adipose triglyceride lipase gene. NR diet decreased the cytokines TNF-α and IL-6. Increased SIRT1 and mitogen-activated protein kinases (ERK1/2 and JNK) were inactivated. Also, it inhibited muscle-specific ubiquitin–proteasome ligases, such as atrogin-1 and MuRF-1. Genes implicated in muscle atrophy and degradation, Pax7 and mitofusin-2 respectively, were attenuated. PCG-1α, a marker for muscle regeneration, was restored	[148]
	15-months-old male C57BL/6 J mice	Chow supplemented to provide NR at 300 mg or 600 mg/kg/day for 4 weeks	Enhancement of treadmill endurance and open-field activity in middle-aged mice NR increased the size of aerobic muscle fibers, enlarging the slow-twitch fibers In addition, it boosted aerobic and anaerobic, basal and maximal respiration of both mice- and human-derived myogenic progenitors in vitro. The differentiation of human myogenic progenitors toward multinucleated skeletal muscle myotubes was improved along with greater myofiber size, fusion index, and expression of differentiation markers	[149]