NAD⁺ Precursors

NAD⁺ is a critical coenzyme required by every living cell in your body to support cellular energy production, as well as cellular repair and defense processes. To produce NAD⁺, cells use building blocks often termed “NAD⁺ precursors.” A precursor is a smaller building block used to create a larger molecule. These precursors undergo a set of chemical conversions that result in the production of NAD⁺. Dietary NAD⁺ precursors such as niacin, nicotinamide, and nicotinamide riboside are the building blocks that cells use to create more NAD⁺. Although the names and structures of these NAD⁺ precursors are slightly similar to the drug nicotine found in tobacco, these molecules are significantly different and produce different effects in the body [1]. More specifically, their differences make one toxic and the others essential.

Established NAD⁺ Precursors

NA Nicotinic Acid

NA
Nicotinic Acid

Nicotinic Acid/Niacin (NA)

Nicotinic acid, more commonly known as niacin, is a form of vitamin B3 that was discovered in the late 1930s. Niacin was found to cure the disease pellagra, which is the late stage of severe niacin deficiency. Pellagra was common in the southern U.S. during the early 1900s where income was low and corn products were a major dietary staple [1, 2]. The disease is characterized by diarrhea, dementia, dermatitis, and eventually death [3]. Niacin can be found in foods such as yeast, meat, fish, milk, eggs, green vegetables, beans, and cereal grains [4]. There is a recommended daily allowance (RDA) of NA at the rate of 14 niacin equivalents (NE) for women and 16 NE for men (1 mg NE = 60 mg of tryptophan = 1 mg niacin). The RDA was established as the necessary dose to prevent Pellagra [5].

Of the B3 vitamins, niacin is the most commonly recognized due to its long history of use as a treatment for elevated cholesterol [6]. Often taken in combination with statins, multiple studies have shown niacin’s positive effect on “good” high-density lipoprotein (HDL) cholesterol [7], with a lesser effect on “bad” low-density lipoprotein (LDL) cholesterol [8]. However, along with its favorable effects on cholesterol, niacin is known to cause an uncomfortable side effect called ‘flushing.’ Often observed in clinical trials, this flushing effect is what deters many from consistent niacin supplementation [9]. However, the development of extended release niacin has reduced flushing for some consumers [9], but long-term use of these at high doses has been linked to hepatotoxicity [5].

Niacin utilizes a three-step pathway, known as the Preiss-Handler pathway, through the cell to convert into NAD⁺ [10].

(NAM) Nicotinamide

(NAM)
Nicotinamide

Nicotinamide/Niacinamide (NAM)

Nicotinamide, also known as niacinamide, is a form of vitamin B3 that was discovered in the late 1930s, around the same time as niacin. However, nicotinamide became the more favorable vitamin B3, more commonly used in nutritional supplements and food fortification [1], as it does not cause flushing [11]. Although nicotinamide is better tolerated than niacin, in higher doses, nicotinamide is known to inhibit important longevity promoting proteins within cells called sirtuins [12]. Sirtuins are important NAD-dependent enzymes critical in cellular metabolism and cellular repair processes, overall helping to maintain and regulate cellular homeostasis [13].

Nicotinamide can be converted into NAD⁺ through a two-step process via the salvage pathway [10].

NR-CI Nicotinamide Riboside Chloride

NR-CI
Nicotinamide Riboside Chloride

Nicotinamide Riboside (NR)

Nicotinamide riboside is the third form of vitamin B3 that was discovered in the 1940s. However, it was not until 2004 that its ability to increase levels of NAD⁺ was discovered [14]. Concurrently, the same group of researchers that discovered NR’s NAD⁺ boosting ability, also identified that NR is found in trace amounts in milk [14]. Although it falls under the vitamin B3 category, NR has unique properties that differentiate it from both niacin and nicotinamide. Unlike niacin, NR does not cause flushing—even at high doses, NR has been shown to be safe in human studies at doses as high as 2000mg/day [15-18] and does not inhibit sirtuins like nicotinamide. In fact, NR has been shown to activate sirtuins in multiple preclinical studies [17, 19, 20]. Furthermore, a preclinical study published in Nature Communications, demonstrated that when all three forms of vitamin B3 (niacin, nicotinamide, and NR) were tested head-to-head, NR was not only the most effective at increasing NAD⁺ levels, but it was also the most effective at activating sirtuins [17].

Tryptophan

Tryptophan

Tryptophan (TRYP)

Tryptophan is a naturally occurring essential amino acid (building blocks that make proteins). It is consumed in the diet from protein rich foods, such as eggs, meat, and seeds. Once consumed, tryptophan can be used to make new proteins, serotonin (a molecule that works in the brain), and the hormone melatonin. In addition, it can be converted to NAD⁺ through a complex, multistep de novo (seven-step) pathway. Because of its many uses, it is safe to assume that all tryptophan consumed does not go towards creating NAD⁺ [21]. Calculations done to determine “niacin equivalents” have revealed that 60 mg of tryptophan may have the same NAD⁺ raising ability as 1 mg of a B3 vitamin (niacin), but these calculations may vary depending on the nutritional state of the consumer [22-24].

Tryptophan can also be converted to niacin within the body, although the efficiency of conversion is low and requires multiple steps [1].

NMN Nicotinamide Mononucleotide

NMN
Nicotinamide Mononucleotide

Nicotinamide mononucleotide (NMN)

Nicotinamide mononucleotide is not a form of vitamin B3, however, it is an intermediate molecule made in the conversion of both nicotinamide and NR to NAD⁺ [21, 25]. It is a type of molecule called a nucleotide, which is very similar to the building blocks of DNA. As a nucleotide, any NMN consumed through the diet or supplementation must be converted to NR prior to entering the cell [10, 25-33]. Once in the cell, the NR is converted back to NMN and subsequently to NAD⁺ [21, 25, 27-29, 32-34]. NMN has not been clinically demonstrated to be safe or effective at boosting NAD⁺ in humans to date.

NAD.png

Same Goal, Different Pathways

While each of these very similar sounding compounds, niacin, nicotinamide, and nicotinamide riboside, all belong to the vitamin B3 family, each molecule is structurally unique, and therefore processed in different ways by the body. These differences contribute to the varying safety and efficacy of each in supporting different aspects of our health. Preclinical studies have proven that there are significant differences in each of the B3 molecules’ ability to effectively support our body’s longevity promoting mechanisms, as well as increase cellular energy production.

When it comes to cellular energy production in the body, our desire is to maximize it. However, herein lies a caveat.  The very processes that make the machinery required for energy generation, as well as the energy generation process itself, use up a portion of our coveted energy. That is why maximizing efficiency in these processes is key.

A key example of this is the production of NAD⁺ in the cell. NAD⁺ is an essential part of the cell’s machinery that produces energy, and it needs to be made by the cell in order to support maximal energy production. Most of a cell’s NAD⁺ is made from three different starting materials or building blocks—each of them a member of the vitamin B3 family. All three forms of vitamin B3 have the ability to boost NAD⁺ in the body to varying degrees. However, the way each unique molecule is metabolized in the body can have a significant impact on each molecule’s NAD⁺ boosting ability.

An analogy of the three different pathways these three building blocks follow to convert into NAD⁺ are illustrated in the graphic below. This graphic is an oversimplification of the actual cellular processes and pathways that are undertaken by each vitamin form to produce NAD⁺. However, as seen below, it demonstrates how the three different pathways from each vitamin form have varying degrees of complexity that require more work by the cell to reach the shared end goal of NAD⁺ production. NA and NAM both reach the top of the mountain (successfully produce NAD⁺), however, the paths are winding, and the path for NAM includes inefficiencies in the form of obstacles. Traveling these paths takes more time and energy, which ideally, we would like to conserve in efforts to maximize energy production. The path of NR to NAD⁺ is analogous to the ease of using a ski lift to reach the top of a mountain. It is much more direct, saving both time and energy--ultimately resulting in the greatest increase in cellular energy production. This concept is further supported by both preclinical and clinical research that suggest NR is the most efficient and effective form of vitamin B3 at boosting NAD⁺ levels [15, 17].

 

References

  1. Higdon, J., et al. Niacin. 2000 8/10/2018; Available from: https://lpi.oregonstate.edu/mic/vitamins/niacin.

  2. Meyer-Ficca, M. and J.B. Kirkland, Niacin. Adv Nutr, 2016. 7(3): p. 556-8.

  3. Hegyi, J., R.A. Schwartz, and V. Hegyi, Pellagra: dermatitis, dementia, and diarrhea. Int J Dermatol, 2004. 43(1): p. 1-5.

  4. EFSA Panel on Dietetic Products, N.a.A.N., Scientific Opinion on Dietary Reference Values for Niacin. EFSA J, 2014. 12(7): p. 3759.

  5. Niacin - Fact Sheet for Health Professionals. 2020 June 3, 2020.

  6. Song, W.L. and G.A. FitzGerald, Niacin, an old drug with a new twist. J Lipid Res, 2013. 54(10): p. 2586-94.

  7. Villines, T.C., et al., Niacin: the evidence, clinical use, and future directions. Curr Atheroscler Rep, 2012. 14(1): p. 49-59.

  8. Ratini, M. Niacin (Vitamin B3) : Benefits, Dosage, Sources, Risks. 2020 March 26, 2020; Available from: https://www.webmd.com/diet/supplement-guide-niacin#1.

  9. Kamanna, V.S., S.H. Ganji, and M.L. Kashyap, The mechanism and mitigation of niacin-induced flushing. Int J Clin Pract, 2009. 63(9): p. 1369-77.

  10. Fang, E.F., et al., NAD(+) in Aging: Molecular Mechanisms and Translational Implications. Trends Mol Med, 2017. 23(10): p. 899-916.

  11. MacKay, D., J. Hathcock, and E. Guarneri, Niacin: chemical forms, bioavailability, and health effects. Nutr Rev, 2012. 70(6): p. 357-66.

  12. Hwang, E.S. and S.B. Song, Possible Adverse Effects of High-Dose Nicotinamide: Mechanisms and Safety Assessment. Biomolecules, 2020. 10(5).

  13. Kupis, W., et al., The role of sirtuins in cellular homeostasis. J Physiol Biochem, 2016. 72(3): p. 371-80.

  14. Bieganowski, P. and C. Brenner, Discoveries of nicotinamide riboside as a nutrient and conserved NRK genes establish a Preiss-Handler independent route to NAD⁺ in fungi and humans. Cell, 2004. 117(4): p. 495-502.

  15. Conze, D., C. Brenner, and C.L. Kruger, Safety and Metabolism of Long-term Administration of NIAGEN (Nicotinamide Riboside Chloride) in a Randomized, Double-Blind, Placebo-controlled Clinical Trial of Healthy Overweight Adults. Sci Rep, 2019. 9(1): p. 9772.

  16. Dollerup, O.L., et al., A randomized placebo-controlled clinical trial of nicotinamide riboside in obese men: safety, insulin-sensitivity, and lipid-mobilizing effects. Am J Clin Nutr, 2018.

  17. Trammell, S.A., et al., Nicotinamide riboside is uniquely and orally bioavailable in mice and humans. Nat Commun, 2016. 7: p. 12948.

  18. Airhart, S.E., et al., An open-label, non-randomized study of the pharmacokinetics of the nutritional supplement nicotinamide riboside (NR) and its effects on blood NAD⁺ levels in healthy volunteers. PLoS One, 2017. 12(12): p. e0186459.

  19. Canto, C., et al., The NAD(+) precursor nicotinamide riboside enhances oxidative metabolism and protects against high-fat diet-induced obesity. Cell Metab, 2012. 15(6): p. 838-47.

  20. Gariani, K., et al., Eliciting the mitochondrial unfolded protein response by nicotinamide adenine dinucleotide repletion reverses fatty liver disease in mice. Hepatology, 2016. 63(4): p. 1190-204.

  21. Canto, C., K.J. Menzies, and J. Auwerx, NAD(+) Metabolism and the Control of Energy Homeostasis: A Balancing Act between Mitochondria and the Nucleus. Cell Metab, 2015. 22(1): p. 31-53.

  22. Canto, C. and J. Auwerx, NAD⁺ as a signaling molecule modulating metabolism. Cold Spring Harb Symp Quant Biol, 2011. 76: p. 291-8.

  23. Bogan, K.L. and C. Brenner, Nicotinic acid, nicotinamide, and nicotinamide riboside: a molecular evaluation of NAD⁺ precursor vitamins in human nutrition. Annu Rev Nutr, 2008. 28: p. 115-30.

  24. Canto, C., A.A. Sauve, and P. Bai, Crosstalk between poly(ADP-ribose) polymerase and sirtuin enzymes. Mol Aspects Med, 2013. 34(6): p. 1168-201.

  25. Garrido, A. and N. Djouder, NAD(+) Deficits in Age-Related Diseases and Cancer. Trends Cancer, 2017. 3(8): p. 593-610.

  26. Camacho-Pereira, J., et al., CD38 Dictates Age-Related NAD Decline and Mitochondrial Dysfunction through an SIRT3-Dependent Mechanism. Cell Metab, 2016. 23(6): p. 1127-1139.

  27. Diguet, N., et al., Nicotinamide Riboside Preserves Cardiac Function in a Mouse Model of Dilated Cardiomyopathy. Circulation, 2017.

  28. Ratajczak, J., et al., NRK1 controls nicotinamide mononucleotide and nicotinamide riboside metabolism in mammalian cells. Nat Commun, 2016. 7: p. 13103.

  29. Vaur, P., et al., Nicotinamide riboside, a form of vitamin B3, protects against excitotoxicity-induced axonal degeneration. FASEB J, 2017. 31(12): p. 5440-5452.

  30. Grozio, A., et al., CD73 protein as a source of extracellular precursors for sustained NAD⁺ biosynthesis in FK866-treated tumor cells. J Biol Chem, 2013. 288(36): p. 25938-49.

  31. Kato, M. and S.J. Lin, Regulation of NAD⁺ metabolism, signaling and compartmentalization in the yeast Saccharomyces cerevisiae. DNA Repair (Amst), 2014. 23: p. 49-58.

  32. Sociali, G., et al., Antitumor effect of combined NAMPT and CD73 inhibition in an ovarian cancer model. Oncotarget, 2016. 7(3): p. 2968-84.

  33. Yoshino, J., et al., Nicotinamide mononucleotide, a key NAD(+) intermediate, treats the pathophysiology of diet- and age-induced diabetes in mice. Cell Metab, 2011. 14(4): p. 528-36.

  34. Imai, S. and L. Guarente, NAD⁺ and sirtuins in aging and disease. Trends Cell Biol, 2014. 24(8): p. 464-71.