Table 1 |.

Preclinical studies in mouse models of human diseases using NAD⁺-boosting strategies

Mechanism of action	Compound	Model	Outcome	Refs
NAD+ precursors	Nicotinamide	High-fat diet-fed and standard diet-fed male C57BL/6J wild-type mice	Prevents diet-induced hepatosteatosis and improves glucose metabolism and redox status in liver. Increases pentose phosphate pathway and reduces protein carbonylation. No change in lifespan	200
		Alzheimer disease-relevant 3xTgAD mice	Increases of antioxidant levels, autophagy-lysosome clearance and oxidative stress resistance/mitochondrial function/integrity. Decreases of Aβ peptide and phosphorylated tau levels. Improvements in neuronal plasticity/cognitive function	233
	NMN	Male C57BL/6N wild-type mice	Inhibits age-induced weight gain, increases insulin sensitivity, plasma lipid levels, physical activity and energy expenditure and improves muscle mitochondrial function	199
		C57BL/6J wild-type mice	Enhances skeletal muscle mitochondrial oxidative metabolism in aged mice	201
		Male Long-Evans rats Ischaemia-reperfusion or cisplatin-induced acute kidney injury in Sirt1+/− mice, C57BL/6 mice and 129S2/Sv mice	Improves mitochondrial function, decreases inflammation, improves physiologic reserve and decreases mortality, despite having no major effect on blood pressure or oxidative damage Protects renal function from cisplatin-induced injury in wild-type mice but not in Sirt1+/− mice	202,204
		High-fat diet-induced obese female mice	Improves glucose tolerance and increases liver citrate synthase activity and triglyceride accumulation	203
		Transverse aortic constriction-stressed mice, male conditional knockout mice Male cardiac-specific Fxn-knockout mice (Friedreich ataxia cardiomyopathy model) and male Sirt3-knockout/Fkn-knockout mice	Improves mitochondrial function and protects mice from heart failure Improves cardiac functions and reduces energy waste and improve energy utilization in Fxn-knockout mice but not in Sirt3-knockout/Fkn-knockout mice	205,207
		Rod-specific Namp-knockout mice, light-induced retinal dysfunction (129S1/SvlmJ)	Rescues retinal degeneration and protects the retina from light-induced injury	206
		Alzheimer disease-relevant (AD-Tg) male and female mice	Decreases APP levels and increases mitochondrial function	161
		Male C57BL/6 mice Male C57BL/6 male	Improves carotid artery endothelium-dependent dilation Rescues neurovascular coupling responses by increasing endothelial NO-mediated vasodilation and improves spatial working memory and gait coordination	208,209
		Intracerebroventricular infusion of Aβ1–42 oligomer in male Wister rats APPswe/PS1dE9 transgenic mice (Alzheimer disease model) and wild-type mice	Improves learning and memory Improves cognitive function	176,177
		Cerebral ischaemia in male C57BL/6 mice Collagen-induced intracerebral haemorrhage in male CD1 mice Male tissue plasminogen activator-treated cerebral ischaemia CD1 mice	Reduces cell death of neurons and improves neurologica outcome Reduces brain oedema and cell death and promotes the recovery of body weight and neurological function Decreases mortality, brain infarction, oedema, apoptosis and haemorrhage and protects blood-brain-barrier integrity	234–236
		Male and female Tg(SIRT2);Bubr1H/+ mice	Increases NAD+ levels and restores BubR1 levels	237
	Nicotinamide riboside	C57BL/6 wild-type or muscle-specific Nampt-knockout (male or female) mice Wild-type or mdx mice, and Mdx/Utrn-knockout mice Male C57BL/6 muscle stem cell-specific Sirt1- knockout mice and mdx mice 70–80-year-old men	Restores muscle mass, force generation, endurance and mitochondrial respiratory capacity in Nampt-knockout mice Improves muscle function and reduces heart disease Improves endurance, grip strength and recovery from cardiotoxin-induced muscle injury in aged mice, induces the mitochondria unfolded protein response and delayed senescence in stem cells, and increases lifespan Suppresses specific circulating inflammatory cytokine levels; no change in mitochondrial biogenesis and metabolism	188,197, 198,238
		Male high- fat diet- fed C57BL/6 wild- type, high- fat diet- fed liver- specific Sirt1- knockout and high- fat diet- fed Apoe- knockout KK/HIJ mice Male C57BL/6 wild- type or liver- specific Nampt- knockout mice	Prevents fatty liver and induces the mitochondrial unfolded protein response with diminished effects in Sirt1- knockout mice Improves glucose homeostasis, increases adiponectin level, and lowers hepatic cholesterol level. Improves liver regeneration, reduces hepatic steatosis and reverses the poor regeneration phenotype in liver- specific Nampt- knockout mice	239–241
		Female Sprague Dawley rats Male high-fat diet-fed C57BL/6 wild-type mice	Prevents or reverses paclitaxel-induced hypersensitivity to pain, no change in locomotor activity Improves glucose tolerance, reduces weight gain and hepatic, steatosis and protects against diabetic neuropathy	242,243
		C57BL/6 wild- type or Xpa−/−/Csa−/− mice Male C57BL/6 wild- type and Atm−/− mice Male C57BL/6 wild- type and Csbm/m mice	Lowers mitochondrial membrane potential and reactive oxygen species production Improves motor coordination and behaviour and increases the number of Purkinje cells and Atm−/− mouse Lifespan Improves the function of mitochondria isolated from cerebellum	33,135,244
		3xTgAD and 3xTgAD/Polb+/− mice iPS cell- derived dopaminergic neurons from patients with GBA- related PD	Decreases phosphorylated tau levels, no effect on Aβ levels, increases neurogenesis, LTP and cognitive function, and reduces neuroinflammation (NLRP3, caspase 3) Ameliorates mitochondrial function by increasing the mitochondrial unfolded protein response (HSP60) and increases autophagy and lysosomal function	137,175
		Cisplatin- induced acute kidney failure in C57Bl/6NTac mice	Decreases blood urea nitrogen levels and levels of markers od glomerular dysfunction	211
NAD+ biosynthesis modulators	P7C3	Osteosarcoma cell line U2OS and lung cancer cell line H2122 cells	Protects cultured cells from doxorubicin-mediated toxicity by enhancing NAMPT activity	214
	SBI-797812	Lung carcinoma A549 cells and male C57BL/6J mice	Increases NMN and NAD+ levels by increasing NAMPT activity and modest increase of hepatic NAD+ levels in mice	214,215
	TES-991 and TES-102524	MCD diet- induced non- alcoholic fatty liver disease and ischaemia–reperfusion- induced acute kidney injury in male C57BL/6J wild- type mice	Boosts de novo NAD+ synthesis by inhibiting ACMSD and increases mitochondrial functions in liver, kidney and brain	216
CD38 inhibitors	Apigenin	High-fat diet-fed C57BL/6 wild-type mice	Decreases global protein acetylation and improves glucose and lipid homeostasis	226
	Luteolinidin	Heart ischaemia-reperfusion model in male Sprague Dawley rats	Improves vascular and cardiac contractile function by restoring NADP(H) and NAD(H) pools	228
	78c	Diet- induced obese C57Bl6 wild- type mice C57BL/6 wild-type mice Heart ischaemia–reperfusion model in male C57Bl/6J wild- type mice	Elevates NAD+ levels in liver and muscle Improves glucose tolerance, muscle function, exercise capacity and cardiac function by mitigating mTOR– p70S6K/ERK and telomere- associated DNA damage Pathways Protects against both postischaemic endothelial and cardiac myocyte injury. Enhances preservation of contractile function and coronary flow, and decreases infarction	91,230,231

Aβ, amyloid-β ; ACMSD, α-amino-β-carboxymuconate ε-semialdehyde decarboxylase; APP, amyloid precursor protein; GBA, β-glucocerebrosidase; iPS cell; induced pluripotent stem cell; LTP, long-term potentiation; MCD diet, methionine–choline-deficient diet; NAD⁺, nicotinamide adenine dinucleotide; NMN, nicotinamide mononucleotide; NAMPT, nicotinamide phosphoribosyltransferase; PD, Parkinson disease.