In the goal of improving our daily health, we tend to remember our doctor’s usual recommendations: a healthy diet, physical activity, 7-8 hours of sleep per night, no smoking, limiting alcohol consumption, etc. Yet, according to influencers (Egle Pavyde, 2024), journalists (David Cox, 2024; Emily Dougherty, 2024), and YouTubers (Rhonda Patrick, 2020), there is a broad spectrum of dietary supplements, named “NAD+ precursor supplements”, that could improve our health (Migaud et al., 2024) These precursors mainly refer to nicotinamide mononucleotide (NMN) and nicotinamide riboside (NR).
The NAD+ precursors have been acknowledged to possess multiple benefits on metabolic health, DNA repair, and longevity in different study models, such as in fruit flies (Gabrawy et al., 2024), worms (Mouchiroud et al., 2013), and mice (Fang et al., 2016). Even though the clinical trials failed to reproduce the numerous benefits of the NAD+ precursors observed in the previous studies, they still proved that those molecules may benefit human health. Following the trend, pharmaceutical companies have produced a wide range of products labeled as “NAD+ precursors”. However, there are some “catches” that customers are not necessarily aware of.
Manufacturing mistakes
One major issue is the manufacturing of NAD+ precursors and how some pharmaceutical companies (voluntarily or not) produce supplements with lower concentrations of the sold molecule than labeled. This has been recently highlighted by a research article published in GeroScience (Sandalova et al., 2024). Indeed, the research team investigated 18 different brands of NMN products and assessed the purity of the compounds. The amount of NMN in the samples ranged from not being detected at all in some cases (ND) to being nearly 100% of the sample’s weight in others (shown in the figure below). This implies that some brands sell a product labeled as NMN without containing the actual NMN molecules. While there could be different explanations for this lack of active molecules in the compound (degradation of NMN, additives compromising the NMN molecule stability), the customers are unable to verify the quality of their supplements.
Selling unstable and untested molecules
Another mistake pharmaceutical companies make is to get ahead of science and sell supplements with effects that have not been proven in humans or even properly described by scientific researchers. This is the case with the NAD+ precursor NMNH (Dihydronicotinamide Mononucleotide (NMNH) Supplement | Double Wood Supplements – Double Wood Supplements Intl., n.d.; Probase Nutrition UthpeakTM NMNH NAD Supplement, 250mg Per Serving, 60, n.d.). NMNH is the reduced form of NAD+ and has been demonstrated to have a potency to generate high amounts of NAD+ in mice and in vitro in human kidney and thymic cells (Zapata-Pérez et al., 2021). I have asked a few questions from Pr. Zapata-Pérez, the lead author of the mentioned study on NMNH. He explained that, first, the efficiency of NMNH to generate significantly higher levels of NAD+ compared to NR and NMN could be due to NMNH being metabolized in another pathway or that NMNH is much less degraded to nicotinamide (NAM) than NR or NMN.
“In my opinion, the moment to sell NMNH as a supplement has not come yet. We know just a little bit about pharmacodynamics (remember that NMNH is quickly degraded in acidic conditions) and about the effects that supplementation with NMNH has.”
Ruben Zapata-Pèrez
Second, NMNH is highly unstable (aka sensitive to degradation) in acidic conditions (like in the human stomach). In other words, if a pill containing NMNH would go through the stomach, the molecule would be degraded without any benefit for the body. Finally, Pr. Zapata-Pérez pointed out that we know very little about the mode of action of NMNH and the effects that NMNH supplementation may have on humans, even with the little evidence from mouse studies. Conclusively, why sell NMNH when so little is known about the molecule?
In the last decade, a lot has been discovered about the biology of NAD+, and multiple clinical trials are still ongoing to determine what will be the best treatment for people tomorrow. NAD+ precursors are nonetheless already available for purchase for everyone, but it should not be forgotten that this is an experiment with your health, as science might not be able, today, to provide a proper answer to what is happening when you take that pill.
Author: Thomas Brochard
References:
David Cox. (2024, July 13). Want to live to 100? It might be time to try this new supplement. Https://Www.Telegraph.Co.Uk/Health-Fitness/Diet/Supplements/Nad-Supplement/.
Dihydronicotinamide Mononucleotide (NMNH) Supplement | Double Wood Supplements – Double Wood Supplements Intl. (n.d.). Retrieved August 9, 2024, from https://doublewoodsupplements.store/products/dihydronicotinamide-mononucleotide-nmnh
Egle Pavyde. (2024, May 28). NAD+, NMN and NR: PART 2. Https://Www.Linkedin.Com/Pulse/Nad-Nmn-Nr-Part-2-Egle-Pavyde-Up4ef/.
Emily Dougherty. (2024, February 13). Meet NAD+, the Latest Celebrity Biohacking Trend. Https://Www.Elle.Com/Beauty/Health-Fitness/A46598724/Everything-You-Need-to-Know-Nad/.
Fang, E. F., Kassahun, H., Croteau, D. L., Scheibye-Knudsen, M., Marosi, K., Lu, H., Shamanna, R. A., Kalyanasundaram, S., Bollineni, R. C., Wilson, M. A., Iser, W. B., Wollman, B. N., Morevati, M., Li, J., Kerr, J. S., Lu, Q., Waltz, T. B., Tian, J., Sinclair, D. A., … Bohr, V. A. (2016). NAD+ Replenishment Improves Lifespan and Healthspan in Ataxia Telangiectasia Models via Mitophagy and DNA Repair. Cell Metabolism, 24(4), 566–581. https://doi.org/10.1016/J.CMET.2016.09.004
Gabrawy, M. M., Westbrook, R., King, A., Khosravian, N., Ochaney, N., DeCarvalho, T., Wang, Q., Yu, Y., Huang, Q., Said, A., Abadir, M., Zhang, C., Khare, P., Fairman, J. E., Le, A., Milne, G. L., Vonhoff, F. J., Walston, J. D., & Abadir, P. M. (2024). Dual treatment with kynurenine pathway inhibitors and NAD+ precursors synergistically extends life span in Drosophila. Aging Cell, 23(4). https://doi.org/10.1111/ACEL.14102
Migaud, M. E., Ziegler, M., & Baur, J. A. (2024). Regulation of and challenges in targeting NAD+ metabolism. Nature Reviews Molecular Cell Biology. https://doi.org/10.1038/s41580-024-00752-w
Mouchiroud, L., Houtkooper, R. H., Moullan, N., Katsyuba, E., Ryu, D., Cantó, C., Mottis, A., Jo, Y.-S., Viswanathan, M., Schoonjans, K., Guarente, L., & Auwerx, J. (2013). The NAD+/Sirtuin Pathway Modulates Longevity through Activation of Mitochondrial UPR and FOXO Signaling. Cell, 154(2), 430–441. https://doi.org/10.1016/j.cell.2013.06.016
Probase Nutrition UthpeakTM NMNH NAD Supplement, 250mg Per Serving, 60. (n.d.). Retrieved August 9, 2024, from https://probasenutrition.com/collections/anti-aging/products/probase-nutrition-uthpeakTM-nmnh-nad-supplement-250mg-per-serving-60-count-30-servings-may-be-more-effective-than-nr-or-nmn
Rhonda Patrick. (2020, January 28). NAD+ in Aging: Role of Nicotinamide Riboside and Nicotinamide Mononucleotide. Https://Www.Youtube.Com/Watch?V=hggLOXhFRxc.
Sandalova, E., Li, H., Guan, L., Raj, S. D., Lim, T. G., Tian, E., Kennedy, B. K., & Maier, A. B. (2024). Testing the amount of nicotinamide mononucleotide and urolithin A as compared to the label claim. GeroScience. https://doi.org/10.1007/S11357-024-01257-2
Zapata-Pérez, R., Tammaro, A., Schomakers, B. V., Scantlebery, A. M. L., Denis, S., Elfrink, H. L., Giroud-Gerbetant, J., Cantó, C., López-Leonardo, C., McIntyre, R. L., van Weeghel, M., Sánchez-Ferrer, Á., & Houtkooper, R. H. (2021). Reduced nicotinamide mononucleotide is a new and potent NAD+ precursor in mammalian cells and mice. FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology, 35(4), 1–17. https://doi.org/10.1096/FJ.202001826R
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