Peter Attia's interview of biochemist Chris Masterjohn is a must-listen for those following the science around Nicotinamide Riboside (NR), Nicotinamide Mononucleotide (NMN), and Nicotinamide or Niacinamide (NAM). It's pretty amazing.
Here are the three things that impressed me most:
(1) Masterjohn explains why NR is superior to NMN
(2) Masterjohn explains why the long-term effects of NR supplementation are probably better than the early studies are showing
(3) Masterjohn explains why NR is superior to nicotinamide EVEN IF the NR were entirely converted to nicotinamide in the liver, as suggested by the Rabinowitz isotope study.
I will attempt to summarize these three points in lay language, but you'd definitely rather hear it from an M.D. and a Ph.D. than from a J.D., so do head over to Peter Attia's website, or Chris Masterjohn's website.
Why is NR superior to NMN?
Masterjohn says, "I would bet money that oral NMN is not absorbed intact, and that’s because NMN has a charged phosphate group on it, and generally charged phosphates cannot cross cells, and so they are hydrolyzed. And even if it were true that there were transporters in the intestine that could take up NMN intact, it probably still would not be absorbed intact because the phosphatases in the small intestine cleave the phosphates off of everything that you eat non-specifically, because generally phosphates can’t cross cells. So I doubt that the NMN gets in there intact, and if anything maybe it gets cleaved to NR, and the NR does get there intact."
(Read more about the differences between NR and NMN or the other NAD precursors)
Long-Term Effects of NR Supplementation
Masterjohn notes that most of the studies -- including the University of Colorado study that observed a wide range of metabolic functions including motor function, body fat, and insulin regulation -- are 12-16 week studies, which are pretty short. Short-term effects might be observed in parts of the body that see very rapid NAD turnover, like the skin and the intestines, which are exposed to constant insult, and thus are perpetually requiring NAD for repairs. So if you take away this ability to repair, you pretty quickly see negative results in the skin and intestine, as in pellagra, which manifests with dermatitis and diarrhea. So we should expect to see the greatest short term benefits of increasing cellular NAD replenishment in those tissues that have the highest NAD turnover. Over the long-term what you would expect is increased genomic stability, decreased accumulation of DNA damage, and increased telomere length, but there have not yet been attempts to measure these potential long-term benefits in humans, and in the short-term you might not see significant results elsewhere in the body. Therefore, negative results in 12-16 week studies should not be considered conclusive.
What If NR Is Converted to NAM in the Liver?
[My paraphrase of a lengthy discussion]
The 2018 Rabinowitz isotope tracer study shows that very little orally consumed NR makes it directly into muscle tissue, and the vast majority is converted to nicotinamide in the liver. Which would make you think that consuming oral nicotinamide directly would be a superior way of replenishing cellular NAD, but it is not.
In a prior study, Rabinowitz ALSO measured a much lower NAD response in muscle from oral NAM than from oral NR.
Here is how these two apparently contradictory findings can be reconciled.
Nicotinamide is taken up by the cells from the bloodstream, but nicotinamide cannot be stored in the cells, because nicotinamide inhibits sirtuin and PARP enzymes that are performing essential DNA repair functions.
So once the nicotinamide is taken in by the cell, it's a liability, and the cell can't have the nicotinamide hanging around. Instead, the cell makes an immediate decision to turn the nicotinamide into NAD, or to methylate the nicotinamide so that it can be excreted in the urine.
The same dynamic applies in the liver. When the liver encounters nicotinamide, it must immediately convert the nicotinamide to NAD, or methylate it for secretion.
But the liver can only make so much NAD at once, so if the amount of nicotinamide available exceeds what the liver can immediately turn into NAD, then the rest has to be excreted. As a result, you are going to see a lot more waste down the detoxification path if you flood the liver with nicotinamide.
By contrast, if you give the liver NR, instead of nicotinamide, NR poses no threat to sirtuins and PARPs. The NR is not a liability if the liver does not immediately convert it to NAD. The NR does not force the liver to make an immediate decision to convert or detoxify.
In fact, NR can ONLY be used to make NAD before it does anything else. So the liver HAS to turn the NR into NAD before the NR can ever be exposed to the methylation-detoxification pathway, and it can convert the NR now or convert it later.
This matters because the liver is not just making NAD for itself. The liver also carries all of the NAD reserves for the rest of the body. So the liver doesn't only have NAD that is immediately being used in expiration, sirtuins and PARPs. The liver also has a reserve pool of NAD that it holds onto for the specific purpose of a slow release of nicotinamide to the rest of the tissues, which those tissues will take up. And then those tissues will face the immediate decision of whether to detoxify it or to make NAD.
But if the liver can safely hold on to the NR, and have a better ability to make NAD and then release nicotinamide on an as-needed basis, and on a continuous basis, then you have a superior way of ensuring the continuous delivery of nicotinamide optimized to reach the other tissues at a rate that the other tissues can take up and do something useful with.