NAD+ Precursor
NAD+ precursors are molecules that can be converted into NAD+, a vital coenzyme found in all living cells, crucial for energy production, cellular repair, and longevity. Taking NAD+ directly is generally considered inefficient due to its inability to enter cells directly due to its large size and polar nature, making it unable to cross the cell membrane effectively. Thus, NAD+ precursors like NMN, NR, and NA, which are smaller and can enter cells more easily, are used to increase cellular NAD+ levels, as they can be converted into NAD+ once inside the cells. These precursors are therefore preferred for supplementation to boost NAD+ levels efficiently within the body.
- Nicotinamide Mononucleotide (NMN): A prominent NAD+ precursor, NMN, is involved in the biosynthesis of NAD+. NMN enters cells via specific transporters and is converted to NAD+ through a series of enzymatic reactions.
- Nicotinamide Riboside (NR): Another significant precursor, NR, is converted into NMN before participating in NAD+ synthesis. NR can enter cells through unique transporters and is phosphorylated to NMN by the enzyme NR kinase.
- Nicotinamide (NAM): NAM, a form of vitamin B3, is also a precursor of NAD+, contributing to its synthesis through the salvage pathway. NAM is converted to NMN by the enzyme nicotinamide phosphoribosyltransferase (NAMPT).
- Nicotinic Acid (NA): NA, another form of vitamin B3, serves as a precursor of NAD+ through the Preiss-Handler pathway. NA is converted to NAD+ via a series of enzymatic reactions, first to nicotinic acid mononucleotide (NAMN), then to nicotinic acid adenine dinucleotide (NAAD), and finally to NAD+.
- Reduced Nicotinamide Mononucleotide (NMNH): A new and efficient NAD+ precursor, NMNH operates via a novel metabolic pathway that is independent of the enzymes NRK (Nicotinamide Riboside Kinase) and NAMPT (Nicotinamide Phosphoribosyltransferase).
Comparision
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| Precursor | Nicotinamide Mononucleotide (NMN) | Nicotinamide Riboside (NR) | Nicotinamide (NAM) | Nicotinic Acid (NA) |
|---|---|---|---|---|
| Structure | 
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| Description | A vital NAD+ precursor involved in the biosynthesis of NAD+. NMN enters cells via specific transporters. | A significant precursor that is converted into NMN before participating in NAD+ synthesis. NR can enter cells through unique transporters. | A form of vitamin B3 and a precursor of NAD+, contributing to its synthesis through the salvage pathway. | Another form of vitamin B3 serving as a precursor of NAD+. |
| Pathway | NAD+ salvage pathway | NAD+ salvage pathway | Salvage Pathway | Preiss-Handler Pathway |
| Conversion Process | Converted directly to NAD+ through a series of enzymatic reactions. | Phosphorylated to NMN by the enzyme NR kinase, then converted to NAD+. | Converted to NMN by the enzyme nicotinamide phosphoribosyltransferase (NAMPT), then to NAD+. | Converted to NAD+ via a series of enzymatic reactions: NA → NAMN → NAAD → NAD+. |
| Molecular Weight | 334.22 g/mol | 255.25 g/mol | 122.13 g/mol | 123.11 g/mol |
| Bioavailability | Currently under investigation, but shows promise in preliminary studies | Good bioavailability when taken orally | Lower bioavailability compared to NMN and NR | Well-established bioavailability |
| Safety and Toxicity | Considered safe at moderate doses; long-term effects still under investigation | Generally regarded as safe; high doses may cause mild side effects | Generally safe; excessive amounts may cause flushing and other side effects | Safe at recommended doses; high doses may cause flushing |
| Natural Sources | Not found in significant amounts in food | Found in trace amounts in milk | Found in meat, fish, and grains | Found in meat, fish, and grains |
| Research Status | Extensively studied in animals; human research is ongoing | Well-studied in both animals and humans | Extensively researched | Extensively researched |
| Cost and Accessibility | Relatively expensive; widely available as a supplement | Moderate cost; widely available as a supplement | Less expensive; widely available in both food and supplement form | Least expensive; widely available in both food and supplement form |
| Half-Life | Not well-established; more research needed | Short, around 2.7 hours in humans | Longer than NMN and NR | Long, around 5.6 hours in humans |
| Clinical Trials | Several ongoing to determine efficacy and safety in humans | Numerous completed and ongoing, showing promising results for various health conditions | Extensively studied, with numerous trials completed | Extensively studied, with numerous trials completed |
See also
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References
- ↑ Li X et al.: The acute effect of different NAD+ precursors included in the combined metabolic activators. Free Radic Biol Med 2023. (PMID 37271226) [PubMed] [DOI] NAD+ and glutathione precursors are currently used as metabolic modulators for improving the metabolic conditions associated with various human diseases, including non-alcoholic fatty liver disease, neurodegenerative diseases, mitochondrial myopathy, and age-induced diabetes. Here, we performed a one-day double blinded, placebo-controlled human clinical study to assess the safety and acute effects of six different Combined Metabolic Activators (CMAs) with 1 g of different NAD+ precursors based on global metabolomics analysis. Our integrative analysis showed that the NAD+ salvage pathway is the main source for boosting the NAD+ levels with the administration of CMAs without NAD+ precursors. We observed that incorporation of nicotinamide (Nam) in the CMAs can boost the NAD+ products, followed by niacin (NA), nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN), but not flush free niacin (FFN). In addition, the NA administration led to a flushing reaction, accompanied by decreased phospholipids and increased bilirubin and bilirubin derivatives, which could be potentially risky. In conclusion, this study provided a plasma metabolomic landscape of different CMA formulations, and proposed that CMAs with Nam, NMN as well as NR can be administered for boosting NAD+ levels to improve altered metabolic conditions.
- ↑ She J et al.: Pharmacology and Potential Implications of Nicotinamide Adenine Dinucleotide Precursors. Aging Dis 2021. (PMID 34881075) [PubMed] [DOI] [Full text] Coenzyme I (nicotinamide adenine dinucleotide, NAD+/NADH) and coenzyme II (nicotinamide adenine dinucleotide phosphate, NADP+/NADPH) are involved in various biological processes in mammalian cells. NAD+ is synthesised through the de novo and salvage pathways, whereas coenzyme II cannot be synthesised de novo. NAD+ is a precursor of coenzyme II. Although NAD+ is synthesised in sufficient amounts under normal conditions, shortage in its supply due to over consumption and its decreased synthesis has been observed with increasing age and under certain disease conditions. Several studies have proved that in a wide range of tissues, such as liver, skin, muscle, pancreas, and fat, the level of NAD+ decreases with age. However, in the brain tissue, the level of NADH gradually increases and that of NAD+ decreases in aged people. The ratio of NAD+/NADH indicates the cellular redox state. A decrease in this ratio affects the cellular anaerobic glycolysis and oxidative phosphorylation functions, which reduces the ability of cells to produce ATP. Therefore, increasing the exogenous NAD+ supply under certain disease conditions or in elderly people may be beneficial. Precursors of NAD+ have been extensively explored and have been reported to effectively increase NAD+ levels and possess a broad range of functions. In this review article, we discuss the pharmacokinetics and pharmacodynamics of NAD+ precursors.