NAD+ Precursor: Difference between revisions

Latest revision as of 21:50, 18 December 2023

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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NAD+ Precursors
Precursor	Nicotinamide Mononucleotide (NMN)	Nicotinamide Riboside (NR)	Nicotinamide (NAM)	Nicotinic Acid (NA)
Structure
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

Todo

2023, The acute effect of different NAD⁺ precursors included in the combined metabolic activators ^[1]
2021, Pharmacology and Potential Implications of Nicotinamide Adenine Dinucleotide Precursors ^[2]
2022, Supplementation with NAD⁺ and Its Precursors to Prevent Cognitive Decline across Disease Contexts ^[3]
2022, NAD⁺ Precursors: A Questionable Redundancy ^[4]
2021, Precursor comparisons for the upregulation of nicotinamide adenine dinucleotide. Novel approaches for better aging ^[5]

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] Abstract
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] Abstract
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.
↑ Campbell JM: Supplementation with NAD⁺ and Its Precursors to Prevent Cognitive Decline across Disease Contexts. Nutrients 2022. (PMID 35956406) [PubMed] [DOI] [Full text] Abstract
The preservation of cognitive ability by increasing nicotinamide adenine dinucleotide (NAD+) levels through supplementation with NAD+ precursors has been identified as a promising treatment strategy for a number of conditions; principally, age-related cognitive decline (including Alzheimer's disease and vascular dementia), but also diabetes, stroke, and traumatic brain injury. Candidate factors have included NAD+ itself, its reduced form NADH, nicotinamide (NAM), nicotinamide mononucleotide (NMN), nicotinamide riboside (NR), and niacin (or nicotinic acid). This review summarises the research findings for each source of cognitive impairment for which NAD+ precursor supplementation has been investigated as a therapy. The findings are mostly positive but have been made primarily in animal models, with some reports of null or adverse effects. Given the increasing popularity and availability of these factors as nutritional supplements, further properly controlled clinical research is needed to provide definitive answers regarding this strategy's likely impact on human cognitive health when used to address different sources of impairment.
↑ Canto C: NAD⁺ Precursors: A Questionable Redundancy. Metabolites 2022. (PMID 35888754) [PubMed] [DOI] [Full text] Abstract
The last decade has seen a strong proliferation of therapeutic strategies for the treatment of metabolic and age-related diseases based on increasing cellular NAD+ bioavailability. Among them, the dietary supplementation with NAD+ precursors-classically known as vitamin B3-has received most of the attention. Multiple molecules can act as NAD+ precursors through independent biosynthetic routes. Interestingly, eukaryote organisms have conserved a remarkable ability to utilize all of these different molecules, even if some of them are scarcely found in nature. Here, we discuss the possibility that the conservation of all of these biosynthetic pathways through evolution occurred because the different NAD+ precursors might serve specialized purposes.
↑ Palmer RD et al.: Precursor comparisons for the upregulation of nicotinamide adenine dinucleotide. Novel approaches for better aging. Aging Med (Milton) 2021. (PMID 34553119) [PubMed] [DOI] [Full text] Abstract
Nicotinamide adenine dinucleotide (NAD) is a coenzyme found in every human cell and regulates a number of systems across multiple cellular compartments and tissue types via an endogenous and exogenous influence. NAD levels are demonstrated to decline with age and therefore measures to counteract the waning of NAD have been devised. A number of NAD precursor candidates such as nicotinamide riboside (NR), nicotinamide mononucleotide (NMN), the reduced form of nicotinamide mononucleotide (NMNH), nicotinic acid (NA) nicotinamide (NAM), and dihydronicotinamide riboside (DNR) increase NAD levels in vitro and in vivo. This discussion will focus on the precursors NR, NMN, NMNH, and DNR in the upregulation of NAD. There are many publications on NAD precursors as it has become popular for human consumption in recent years due to its vital importance to the general consumer. However, there is no consensus between researchers and this was the aim of this review, to determine and discuss their areas of agreement versus disagreement, to highlight the gaps in research, and to give recommendations for future work. Bioavailability and potency of NR, NMNH, NMN, and DNR is also examined on the light of the most recent literature.

[pmid37271226-1] 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] Abstract
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.

[pmid34881075-2] She J et al.: Pharmacology and Potential Implications of Nicotinamide Adenine Dinucleotide Precursors. Aging Dis 2021. (PMID 34881075) [PubMed] [DOI] [Full text] Abstract
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.

[pmid35956406-3] Campbell JM: Supplementation with NAD⁺ and Its Precursors to Prevent Cognitive Decline across Disease Contexts. Nutrients 2022. (PMID 35956406) [PubMed] [DOI] [Full text] Abstract
The preservation of cognitive ability by increasing nicotinamide adenine dinucleotide (NAD+) levels through supplementation with NAD+ precursors has been identified as a promising treatment strategy for a number of conditions; principally, age-related cognitive decline (including Alzheimer's disease and vascular dementia), but also diabetes, stroke, and traumatic brain injury. Candidate factors have included NAD+ itself, its reduced form NADH, nicotinamide (NAM), nicotinamide mononucleotide (NMN), nicotinamide riboside (NR), and niacin (or nicotinic acid). This review summarises the research findings for each source of cognitive impairment for which NAD+ precursor supplementation has been investigated as a therapy. The findings are mostly positive but have been made primarily in animal models, with some reports of null or adverse effects. Given the increasing popularity and availability of these factors as nutritional supplements, further properly controlled clinical research is needed to provide definitive answers regarding this strategy's likely impact on human cognitive health when used to address different sources of impairment.

[pmid35888754-4] Canto C: NAD⁺ Precursors: A Questionable Redundancy. Metabolites 2022. (PMID 35888754) [PubMed] [DOI] [Full text] Abstract
The last decade has seen a strong proliferation of therapeutic strategies for the treatment of metabolic and age-related diseases based on increasing cellular NAD+ bioavailability. Among them, the dietary supplementation with NAD+ precursors-classically known as vitamin B3-has received most of the attention. Multiple molecules can act as NAD+ precursors through independent biosynthetic routes. Interestingly, eukaryote organisms have conserved a remarkable ability to utilize all of these different molecules, even if some of them are scarcely found in nature. Here, we discuss the possibility that the conservation of all of these biosynthetic pathways through evolution occurred because the different NAD+ precursors might serve specialized purposes.

[pmid34553119-5] Palmer RD et al.: Precursor comparisons for the upregulation of nicotinamide adenine dinucleotide. Novel approaches for better aging. Aging Med (Milton) 2021. (PMID 34553119) [PubMed] [DOI] [Full text] Abstract
Nicotinamide adenine dinucleotide (NAD) is a coenzyme found in every human cell and regulates a number of systems across multiple cellular compartments and tissue types via an endogenous and exogenous influence. NAD levels are demonstrated to decline with age and therefore measures to counteract the waning of NAD have been devised. A number of NAD precursor candidates such as nicotinamide riboside (NR), nicotinamide mononucleotide (NMN), the reduced form of nicotinamide mononucleotide (NMNH), nicotinic acid (NA) nicotinamide (NAM), and dihydronicotinamide riboside (DNR) increase NAD levels in vitro and in vivo. This discussion will focus on the precursors NR, NMN, NMNH, and DNR in the upregulation of NAD. There are many publications on NAD precursors as it has become popular for human consumption in recent years due to its vital importance to the general consumer. However, there is no consensus between researchers and this was the aim of this review, to determine and discuss their areas of agreement versus disagreement, to highlight the gaps in research, and to give recommendations for future work. Bioavailability and potency of NR, NMNH, NMN, and DNR is also examined on the light of the most recent literature.

[1]

[2]

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[5]

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-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 and NR, 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.
+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 ==
+{{Citations Needed}}
+{| class="wikitable"
+|+NAD+ Precursors
+!Precursor
+![[Nicotinamide Mononucleotide (NMN)]]
+![[Nicotinamide Riboside (NR)]]
+![[Nicotinamide (NAM)]]
+![[Nicotinic Acid (NA)]]
+|-
+!Structure
+|[[File:Nicotinamide mononucleotide.svg|200px]]
+|[[File:Nicotinamide riboside.svg|200px]]
+|[[File:Nicotinamid.svg|200px]]
+|[[File:Nicotinic acid.svg|200px]]
+|-
+!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
+|}
-* [[Nicotinamid Mononucleotide (NMN)|Nicotinamide Mononucleotide (NMN)]]: A prominent NAD+ precursor, NMN, is involved in the biosynthesis of NAD+.
+==See also==
-* [[Nicotinamide Riboside (NR)]]: Another significant precursor, NR, is converted into NMN before participating in NAD+ synthesis.
+*[[Nicotinamide Adenine Dinucleotide (NAD)]]
+*[[NAD+ Booster]]
-* [[Nicotinamide (NAM)]]: NAM, a form of vitamin B3, is also a precursor of NAD+, contributing to its synthesis through the salvage pathway.
+== Todo ==
+* {{pmid text|37271226}}
+* {{pmid text|34881075}}
+* {{pmid text|35956406}}
+* {{pmid text|35888754}}
+* {{pmid text|34553119}}
+== References ==
+<references />
 [[Category:Molecular and Cellular Biology]]