Table 2.
Aging-related pathways & conditions affected by NAD+ precursors.
| NAD+ precursor | Models | Aging-related pathways and conditions | References |
|---|---|---|---|
| NR, NMN | Worm | Activates sirtuins, which in turn deacetylate and trigger transcription factors PGC-1α, FOXOs and others, linked to aging. | [14, 60] |
| NMN | Mice | Mitigates age-associated body weight gain, improved energy metabolism, stimulated physical activity, improved insulin sensitivity and plasma lipid profile, and ameliorated eye function and other pathophysiologies. | [54] |
| NR | Worm | Restored muscle, melanocyte stem cell pools and neuronal function through initiation of the UPRmt and prohibitin protein synthesis. | [55] |
| NR | Worm, Mice, Yeast | Activate the UPRmt, causing FOXO transcription factor translocation, triggering antioxidant defenses in worms and mice, and delaying lifespan and health. In yeast model, triggering of the UPRmt has also been observed. In mice, NR treatment increased NAD+ levels and PGC-1α-mediated degradation of Bace1 leading to reduce Aβ production. |
[19, 54, 61-63] |
| NMN | Mice | Triggered NAD+ and restored mitochondrial homeostasis through Sirt1-PGC-1α activation. | [24] |
| NR, NMN | Mice, Worm | NR treatment inhibited high-fat DIO by stimulating Sirt1 activity and increasing NAD+ levels. NMN in diabetes mouse model enhanced glucose intolerance, and increased hepatic insulin sensitivity or through restoring NAD+ levels. NR/NMN in a high-fat diet fed mice increased the use of lipids as substrates, improved insulin sensitivity, and increased energy expenditure. |
[14, 24, 60, 64] |
| NR | HEK293 cells, Rats | Inhibits noise-persuaded hearing loss and leads to regeneration of neurite ganglia mediated by NAD+-dependent Sirt3 activity. Increased level of NAD+ directed Sirt1 activity and slows axon degeneration. | [65, 66] |
| NMN | Mice, Rho0 cells | Reverses age-associated genes expression changes linked to inflammation, partly by inducing Sirt1 activity. CD38 KO mice, NNMT KO mice and Parp1 KO mice demonstrate upregulation of NAD+ levels and Sirt1 activation. | [24, 67] |
| NR | Mice | Decreased senescence in neuronal and melanocyte stem cells. Enhanced mitochondrial function, dependent on Sirt1 function. | [68] |
| NMN | Human, Mice | Elongates telomere length of PBMC in mice and humans. Significantly increased the abundance of Helicobacter, Mucispirillum, and Faecalibacterium, and reduced Akkermansia richness related with nicotinamide metabolism. |
[69] |
| NMN, NR | Mice, WRN-KD cells, Worm | Enhanced aging in Werner syndrome is mediated by impaired mitochondrial function and mitophagy, and that bolstering cellular NAD+ levels stabilize Werner syndrome phenotypes. Through DCT-1 and ULK-1-dependent mitophagy, NAD+ repletion helps restore NAD+ metabolic profiles and enhances mitochondrial quality. |
[70] |
| NAM | Mice | Prevents diet-induced hepatosteatosis. Improving redox status and glucose metabolism in livers of HFD-fed mice. Reducing oxidative stress and inflammation. |
[71] |
| TRP | - | Beneficial in numerous neurological disorders especially insomnia and depression. TRP supplement may exacerbate inflammation due to increased production of numerous reactive metabolites including the putative excitotoxin and N-methyl-D-aspartate (NMDA) receptor agonist quinolinic acid or QUIN. |
[72, 73] |
| NAM, NMN, NR, NA | - | Preservation of cognitive function in many health contexts. Promising treatment strategy for various conditions; mainly, age-associated cognitive decline (including Alzheimer’s disease and vascular dementia), but also stroke, diabetes, and traumatic brain injury. |
[74] |
| NMN | Mice, IPEC-J2 cells | Ameliorating the structural and functional deterioration in the intestine during aging. Enhanced the total antioxidant capacity, cell viability and reduced the reactive oxygen species level of senescent IPEC-J2 cells. |
[75] |
| NMN,NR | BMMCs, Mice | Significantly mitigated IgE-mediated anaphylactic responses. Inhibits mast cell degranulation and anaphylaxis, however Sirt6 was required to attain these improvements. |
[76] |
NR, Nicotinamide riboside; NMN, Nicotinamide mononucleotide; PGC-1α, Peroxisome proliferator-activated receptor-gamma coactivator (PGC)-1alpha; FOXO, Forkhead box O; UPRmt, Mitochondrial unfolded protein response; PBMC, Peripheral blood mononuclear cell; NAM, Nicotinamide; TRP, Tryptophan; IPEC-J2, Intestinal porcine epithelial cell line J2; NA, Nicotinic acid; BMMC, Bone marrow mononuclear cells