NR vs NMN

Key Takeaways

• Nicotinamide Riboside (NR) and Nicotinamide Mononucleotide (NMN)  are both NAD+ precursor vitamins
• NAD+ is an essential coenzyme involved in energy metabolism, DNA repair, and epigenetic regulation.
• NR in 2023 was approved by the TGA for use in supplements whereas NMN is not approved for use in supplements in Australia. 
• Studies have confirmed that measurable, biological effects on NAD+ levels can be achieved by chronic oral NR supplementation. 

NAD+, also known as nicotinamide adenine dinucleotide, is an essential coenzyme and plays a role in some seriously important body-related processes, like energy metabolism, DNA repair and epigenetic homeostasis.^1,2  As we age, NAD+ production slows but NAD+ utilization and demand increases. This is thought to be one of the key mechanisms of aging. This discovery prompted scientists to explore the benefits of NAD+ supplementation. 

Supplementing with NAD+ 

NAD+ as a molecule is not bioavailable when taken as a supplement. NAD+ precursors have better absorption and bioavailability, and support increased levels of NAD+. ²

These are some common types of NAD+ supplements:

1. Nicotinamide riboside (NR): NR is a direct precursor to NAD+ and is commonly used as a dietary supplement to increase NAD+ levels in the body. It is converted into NAD+ through a series of enzymatic reactions. NR supplements are available in capsule or powder form.²
2. Nicotinamide mononucleotide (NMN): NMN is another precursor to NAD+ and has gained attention for its potential benefits in supporting cellular energy metabolism and healthy aging. Like NR, NMN is converted into NAD+ within cells. NMN supplements are typically available in capsule form, but not in Australia.²
3. Nicotinamide (NAM): Nicotinamide is another form of vitamin B3 that can be converted into NAD+. It is often used as a supplement for its potential benefits on skin health and cellular metabolism. Nicotinamide supplements are available in various forms, including tablets, capsules, and creams.²
4. NAD+ boosters: In addition to direct NAD+ precursors, some supplements contain compounds that can indirectly support NAD+ levels by enhancing NAD+ biosynthesis or preventing NAD+ degradation. These compounds include tryptophan, niacin², resveratrol, pterostilbene, quercetin, and other polyphenols. NAD+ booster supplements often combine these ingredients to provide comprehensive support for NAD+ metabolism.

Comparison of NR and NMN: 

Key Functions of NAD+:

1. Mitochondrial function: NAD+ plays a crucial role in cellular energy metabolism, particularly in the mitochondria, which are the powerhouses of cells. By supporting mitochondrial function, NAD+ may promote optimal energy production and cellular function. ⁴
2. Oxidative stress and DNA repair: NAD+ is involved in maintaining redox balance within cells and activating enzymes called sirtuins, which have antioxidant properties. Oxidative stress, resulting from an imbalance between reactive oxygen species (ROS) and antioxidant defenses, including DNA. NAD+ may contribute to the regulation of oxidative stress and DNA repair mechanisms, thereby protecting cells including oocytes, sperm, and embryos from oxidative damage and promoting reproductive health. ⁴
3. Epigenetic regulation: NAD+ is involved in epigenetic processes, which refer to modifications to DNA and associated proteins that can influence gene expression patterns without changing the DNA sequence itself. Epigenetic modifications play a critical role in reproductive processes, including oocyte and sperm development,⁶ fertilization, and early embryo development. NAD+ dependent enzymes, such as sirtuins and poly (ADP-ribose) polymerases (PARPs), are involved in epigenetic regulation and may contribute to the maintenance of proper gene expression patterns during reproductive events.⁴
4. Cellular signaling and metabolism: NAD+ is an essential cofactor for enzymes involved in cellular signaling pathways and metabolic processes. These pathways can influence reproductive-related events, including folliculogenesis, ovulation, sperm capacitation, and embryo implantation. By modulating cellular signaling and metabolism, NAD+ may affect key processes involved reproductive success.^1,4

Pharmacokinetics

NR is orally bioavailable and studies have shown that it is efficiently absorbed in both animal models and humans. Studies have shown that NR has higher bioavailability compared to other forms of vitamin B3, such as nicotinamide and nicotinic acid. Best of all, NR doesn’t cause flushing which is a side effect observed in other NAD+ precursor supplements.²

NR has been found to efficiently increase NAD+ levels in various tissues, including skeletal muscle, liver, and brain.²

After absorption, NR is distributed throughout the body. It enters cells and tissues, where it serves as a precursor for the synthesis of NAD+.²

Inside the cell, NR undergoes a series of enzymatic reactions to convert into NAD+. The key enzymatic step in NR metabolism is the phosphorylation of NR to nicotinamide mononucleotide (NMN) by nicotinamide riboside kinases (NRKs). NMN is further converted to NAD+ through other enzymatic reactions. It is important to note that NR is the only NAD+ precursor that can directly cross the cell without active transport. ²

Within the cell, NAD+ serves as a coenzyme involved in numerous cellular processes and is essential for energy metabolism, DNA repair, and cellular signaling.²

NR and its metabolites are excreted from the body primarily through urine. The exact elimination pathways and rates of NR and its metabolites have not been extensively studied and may vary.²

Pharmacodynamics

1. NAD+ synthesis: NR supplementation has been shown to increase NAD+ levels in cells and tissues. By providing a source of NR, the exogenous supply can augment the intracellular availability of NAD+. This increase in NAD+ levels can influence cellular metabolism, redox balance, DNA repair, and signaling pathways.²
2. Sirtuin activation: NAD+ serves as a crucial cofactor for sirtuin enzymes, a class of proteins involved in regulating cellular metabolism, stress responses, and aging processes. Adequate NAD+ levels are necessary for the enzymatic activity of sirtuins, and by promoting NAD+ synthesis, NR supplementation may enhance sirtuin function and activation.⁴
3. PARP activation: Poly(ADP-ribose) polymerases (PARPs) are another class of enzymes that utilize NAD+ as a substrate. They are involved in DNA repair processes and cellular stress responses. Increased NAD+ availability through NR supplementation can support PARP activity, potentially enhancing DNA repair mechanisms.⁴

Dosage, Safety and Side Effects 

Studies have confirmed that measurable, biological effects on NAD+ levels can be achieved by chronic oral NR supplementation.² In humans, a non randomized 8-week placebo-controlled trial with three different doses (up to 1g) in overweight and healthy adults reported NR as safe and orally available.⁵ In animal models, the lowest observed adverse effect level was 1000 mg/ kg/day.² The Therapeutic Goods Administration (TGA) limits the maximum daily oral dose for NR supplements to 300 mg per day and 230 mg for pregnant women.¹⁰ NR has GRAS (generally regarded as safe) status.² 

References

1. Bertoldo, Michael J., Dave R. Listijono, Wing-Hong Jonathan Ho, Angelique H. Riepsamen, Dale M. Goss, Dulama Richani, Xing L. Jin et al. "NAD+ repletion rescues female ***** during reproductive ****." Cell reports 30, no. 6 (2020): 1670-1681. 
2. Mehmel, Mario, Nina Jovanović, and Urs Spitz. "Nicotinamide riboside—the current state of research and therapeutic uses." Nutrients 12, no. 6 (2020): 1616. 
3. Li, Hui, Huan Wang, Jianmin Xu, Xinxin Zeng, Yingpu Sun, and Qingling Yang. "Nicotinamide riboside supplementation ameliorated post-***** quality decline." Reproduction 165, no. 1 (2023): 103-111.
4. Xie, N., Zhang, L., Gao, W. et al. NAD+ metabolism: pathophysiologic mechanisms and therapeutic potential. Sig Transduct Target Ther 5, 227 (2020). https://doi.org/10.1038/s41392-020-00311-7
5. Airhart, Sophia E., Laura M. Shireman, Linda J. Risler, Gail D. Anderson, G. A. Nagana Gowda, Daniel Raftery, Rong Tian, Danny D. Shen, and Kevin D. O’Brien. "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 12, no. 12 (2017): e0186459.
6. Meyer-Ficca, M. L., Zwerdling, A. E., Swanson, C. A., Tucker, A. G., Lopez, S. A., Wandersee, M. K., Warner, G. M., Thompson, K. L., Chini, C. C. S., Chen, H., Chini, E. N., & Meyer, R. G. (2022). Low NAD+Levels Are Associated With a Decline of ***** in Transgenic ANDY and Aging Mice. Frontiers in endocrinology, 13, 896356. https://doi.org/10.3389/fendo.2022.896356
7. Bai, X., Wang, P. Relationship between sperm NAD + concentration and ****** men:A Cohort study. BMC Urol 22, 159 (2022). https://doi.org/10.1186/s12894-022-01107-3
8. ​​Yang, L., Shen, J., Liu, C. et al. Nicotine rebalances NAD+ homeostasis and improves aging-related symptoms in male mice by enhancing NAMPT activity. Nat Commun 14, 900 (2023). https://doi.org/10.1038/s41467-023-36543-8
9. Podolak, Amira, Izabela Woclawek-Potocka, and Krzysztof Lukaszuk. "The Role of Mitochondria in Human ****** and Early Embryo Development: What Can We Learn for Clinical Application of Assessing and Improving Mitochondrial DNA?." Cells 11, no. 5 (2022): 797. 
10. McRae, Cheryl. “Therapeutic Goods (Permissible Ingredients) Determination (No. 2) 2023.” Therapeutic Goods (Permissible Ingredients) Determination (No. 2) 2023, April 14, 2023. https://www.legislation.gov.au/Details/F2023L00455/Html/Volume_4.