The best NAD+ precursor, NMN, NR, NA or Trp?

by Nov 30, 2019About NMN

The best NAD+ precursor, NMN, NR, NA or Trp?

There’s no denying that NMN and NR are among the best well-known nicotinamide adenine dinucleotide precursor supplements on the market, followed by Nicotinic Acid (NA), Nicotinamide (Nam), and Tryptophan (Trp). [1] Except tryptophan, all of these precursors are Vitamin B3 derivatives.

Tryptophan is a kind of amino acid that is abundant in various foods. Tryptophan has to proceed through the most complex pathway before transforming into NAD+ and is regarded as the least effective NAD+ precursor.

NAD+ levels in our bodies are maintained by three independent pathways [2]:

  • the Preiss-Handler pathway (dietary NA to NAD+)
  • the De novo synthesis pathway (Tryptophan to NAD+)
  • the Salvage pathway.(NR, NMN to NAD+)

A 2016 study on NR safety and bioavailability tested three precursors of NR and NA in mice, concluding that NR was in the highest levels of circulating NAD+ of the three NAD+ boosters at that time. [3]

Effects of Different Forms of Vitamin B3 on Circulating NAD+ Levels

 

You’ll notice that most authoritative sites and bloggers have been boasting NR as the best NAD supplement since 2015. It might be true 2 or 3 years ago. However, the information is outdated.

It’s the year 2019 now and close to 2020, and people are talking more about NMN.If you use the Google Trends tool to compare the topic NMN and NR, NMN is absolutely far more popular than NR itself from the second half of 2018. (the red line is NMN, and the blue line is NR)
nicotinamide riboside VS nicotinamide mononucleotide

Dr. David Sinclair, a professor at Harvard Medical School, best known for his advocacy for resveratrol as an anti-aging dietary supplement, also recommends NMN and takes NMN every day for DNA-repair, anti-aging, and longevity.

Then, as an NAD+ precursor, is NMN better than NR now?

Frankly speaking, Nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN) have never been examined head to head in any clinical studies to find out whether one produces more NAD+ with less energy than the other. We’ll compare NMN and NR in several ways:

More NMN supplement brands than NR brands

If you search NMN or nicotinamide mononucleotide supplements on Amazon, there are more than 180 NMN supplements from over 30 suppliers, and the number is still on the rise every week. Only two NR supplement brands are available. The NR supplements are using branded NR ingredient Niagen or Tru Niagen, in the form of nicotinamide riboside chloride.

End customers have more choices in buying NMN nutritional products in various forms, such as powder, tablet, capsule, spray, etc. But NR buyers don’t.

NR is a patented NAD+ precursor exclusively from Chromadex.
If you’re a supplement manufacturer and want to buy some NR bulk raw powder from China to use it in your new anti-aging supplement formula, be careful with NR. The bad news is that you may infringe their NR patents worldwide, and are not allowed to sell NR finished dosage formulations anywhere in the world.

Therefore, if you’re a supplement brand supplier or contract manufacturer, be careful when using NR.  In contrast, NMN has no such patent problems. NMN is the most direct NAD+ precursor, just like the air and water to humans. No one is able to patent air or water in the world to stop people from using it. That’s why so many NMN supplements out there.

NMN Molecule is more efficient than NR

NMN is an immediate precursor to NAD+ and it readily and directly converted to NAD+ by the action of the enzyme NMNAT.
NR is an indirect precursor to NAD+.  In order to synthesize NAD+, NR has two routes to follow, either:
(i) NR must first undergo phosphorylation into NMN, which then converts to NAD+, orconversion from NR to NMN to NAD+

(ii) NR must travel through a five-stage pathway to NAD+ synthesis (NR → Nam → NAMN+ → NAAD+ → NAD+) [4]

However, there is a big problem in the second method (the de novo pathway).The de novo pathway is enzymatically rate-limited, meaning that you can take all the B3 or Tryptophan you want and it won’t enhance the NAD+ levels above your baseline.

Supplementing NMN or NR allows NAD+ synthesis via the salvage pathway, which is effectively a backdoor that enables unrestricted NAD+ synthesis to improve your NAD+ levels significantly above your baseline.

As NR has to first transform to NMN before converting to NAD+, it makes sense that NMN is the superior supplement to boost NAD+ levels and it proves that this is typically true.

Unique transporter found for NMN, NOT for NR

NMN is a direct NAD+ precursor and can be utilized efficiently in the cell.

Newly uncovered NMN transporter gene SLC12A8 shows that NMN enters cells directly without turning into NR before entering cells.[5] Actually, NMN has an immediate transportation system that is unique to NMN, NOT NR. It’s reasonable to state that NMN is a more effective NAD supplement and it is more advanced than NR.  Studies discovered that when cells are low in NAD+, they respond by expressing more SLC12A8 transporters, enabling the efficient absorption of NMN from the bloodstream. The SLC12A8 transporter gene is expressed in many tissues and is rich in the small intestines where NMN is quickly absorbed from the gut within 2-3 minutes, converting to NAD+ in 10-30 min (mice research).

NMN is more stable than NR

In both mice and human being studies, NR has been confirmed to be highly unstable and quickly degrade into regular vitamin B3. NR that degrades into B3 which is restricted to the rate-limited de novo pathway can’t increase your NAD+ levels above your baseline.[6]

On the other hand, NMN is highly stable in the body and therefore can better take advantage of the unrestricted salvage pathway and enhance NAD+ levels significantly above your baseline.

Furthermore, NMN is more stable in chemical and physical features than NR. NMN powder at room temperature is stable and good for long time transportation and storage.

To sum up, stability means more NAD.

NMN has higher bioavailability (absorption) than NR

In one mice study, NMN is absorbed through the gut and was detectable in the blood within 2 – 3 minutes. Within 15 minutes, NMN was completely absorbed into cell tissues and subsequently transformed into NAD+ for further use.[7]

NMN in the liver of mice fed with NR detectably increased at approximately 3-4 hours after administration⁠. At 7.7 hours, NAD+ increased by 2.7-fold above baseline concentration in the bloodstream.[3]

Similarly, one human research demonstrated that NR levels in whole blood peaked at around 3 hours after a 1000 mg dose of NR.[8] Therefore it’s possible that NR might need 2 to 3 hours to get absorbed through the gut, or that some NR is degraded into nicotinamide before getting converted into NMN.

It appears that NMN is absorbed through the gut in minutes, whereas NR may take around 3 hours.

NMN enhances endurance while NR doesn’t at 200mg

Rhonda Patrick, Ph.D., had a face-to-face interview with David Sinclair. In this YouTube video, Dr. David Sinclair talked about NMN and NMN advantages over NR. He said that at the same dose of 200mg, NR did not increase endurance, but NMN did.

Matt Kaeberlein, who he mentioned in this interview, works on dog aging now after doing the SIR2 extension lifespan. Matt also has published that, comparing NR and NMN, only NMN worked in his disease model, which was a mitochondrial disease where those animals really need a boost of NAD.

So one of the issues could be that NMN is a better molecule in that regard.

One mice study found that oral NR supplementation (200 mg per kg of body weight) only raised NAD+ levels in the liver, not muscle. [9]

One nicotinamide riboside study on mice published in 2016 in the Journal of the International Society of Sports Nutrition showed that nicotinamide riboside decreases exercise performance in rats by 35 %.[10]

Unlike NR, NMN was shown to increase physical performance, as measured by treadmill run time, by 60% and double exercise endurance to levels that matched or even exceeded that of younger mice. [6]

NMN has more advantages over NR

NMN has quite a few strong advantages of its own.NMN is able to do some things in mice studies that NR isn’t.

While assessing the efficiency to treat Friedreich’s Ataxia (FRDA), a rare inherited childhood heart disease, NMN was found successful where NR treatment failed.[7]

In mouse models of Alzheimer’s, subcutaneous (under the skin) administration of NMN reduced beta-amyloid plaque production. Alzheimer’s disease is widely believed to be driven by the production and deposition of the Beta-amyloid peptide. NMN decreases Beta-amyloid peptide buildup, while NR does not [11]. Although NR reduced neuroinflammation, reduced hippocampal cell death, and improved cognitive function, it did not reduce amyloid plaque production⁠.

NMN is more promising than NR

Currently, NR is much more studied on humans than NMN. However, many NMN clinical studies are being conducted worldwide. The number of pending NMN clinical trials is more than that of NR, and more convincing results will be revealed in 2020.

Currently, the manufacturing cost of NMN is high. But as more NMN bulk powder manufacturers like Effepharm join the NMN supply market, and more NMN demand is for anti-aging supplements and cosmetics, the ultimate unit price for NMN will drop down dramatically due to mass production and fierce market competition in the coming years.

As a novel versatile compound, more beneficial studies on NMN should be done in Alzheimer’s, diabetes, cardiovascular diseases, etc.

References:

  1. Lin, J., Pan, Y. & Wang, J. Quant Biol. NAD+ and its precursors in human longevity. Quantitative Biology. December 2015, Volume 3, Issue 4, pp 193–198 https://doi.org/10.1007/s40484-015-0055-9
  2. Verdin E. NAD⁺in aging, metabolism, and neurodegeneration. Science. 2015;350(6265):1208-13. https://www.ncbi.nlm.nih.gov/pubmed/26785480
  3. Trammell SA, Schmidt MS, Weidemann BJ, et al. Nicotinamide riboside is uniquely and orally bioavailable in mice and humans. Nat Commun. 2016;7:12948. https://www.ncbi.nlm.nih.gov/pubmed/27721479
  4. Denu JM. Vitamins and aging: pathways to NAD+ synthesis. Cell. 2007;129(3):453-4. https://www.ncbi.nlm.nih.gov/pubmed/17482537
  5. Grozio A, Mills KF, Yoshino J, et al. Slc12a8 is a nicotinamide mononucleotide transporter. Nat Metab. 2019;1(1):47-57. https://www.ncbi.nlm.nih.gov/pubmed/31131364
  6. Das A, Huang GX, Bonkowski MS, et al. Impairment of an Endothelial NAD-HS Signaling Network Is a Reversible Cause of Vascular Aging. Cell. 2018;173(1):74-89.e20. https://www.ncbi.nlm.nih.gov/pubmed/29570999
  7. Airhart SE, Shireman LM, Risler LJ, 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):e0186459. https://www.ncbi.nlm.nih.gov/pubmed/29211728
  8. Airhart SE, Shireman LM, Risler LJ, 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):e0186459. https://www.ncbi.nlm.nih.gov/pubmed/29211728
  9. Liu L, Su X, Quinn WJ, et al. Quantitative Analysis of NAD Synthesis-Breakdown Fluxes. Cell Metab. 2018;27(5):1067-1080.e5. https://www.ncbi.nlm.nih.gov/pubmed/29685734
  10. Kourtzidis IA, Stoupas AT, Gioris IS, et al. The NAD(+) precursor nicotinamide riboside decreases exercise performance in rats. J Int Soc Sports Nutr. 2016;13:32. https://www.ncbi.nlm.nih.gov/pubmed/27489522
  11. Hou Y, Lautrup S, Cordonnier S, et al. NAD supplementation normalizes key Alzheimer’s features and DNA damage responses in a new AD mouse model with introduced DNA repair deficiency. Proc Natl Acad Sci USA. 2018;115(8): E1876-E1885. https://www.ncbi.nlm.nih.gov/pubmed/29432159

 

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