With nicotinamide mononucleotide (NMN) now banned in the US by the FDA, the central question for consumers and regulators is whether nicotinamide riboside (NR) is an adequate substitute. And that question, in turn, depends upon whether NMN is doing something other than delivering NR to cells?
Most people do not understand the strength of the scientific consensus that says NMN cannot enter cells, and must be converted to NR outside the cell before it can replenish NAD+ inside the cell.
Here is how UCLA's Dr. Anthony Covarrubias describes it:
“The research overwhelmingly demonstrates that NMN obtained from the diet or supplementation is a precursor to NR as NMN cannot efficiently cross the cell membrane and suggests NR is more efficient at increasing NAD+ levels."
And here are 18 studies that all say exactly that. The co-authors of these studies include the world's leading NAD researchers, such as Dr. Charles Brenner and Dr. Carles Canto. And the 11th study is co-authored by Dr. David Sinclair. They all agree: NMN must be converted to NR outside the cell before it can replenish NAD+ inside the cell.
Here it is in their words:
1. NMN dephosphorylation to NR constitutes a critical step in order to act as an exogenous NAD+ precursor ...These data...provide compelling evidence for the extracellular conversion of NMN to NR...
2. We also showed that extracellular cleavage of NAD+ and NMN to NR is a prerequisite for using these nucleotides to maintain intracellular NAD contents….The degradation of NAD+ and NMN to NR or Nam is essential for these nucleotides to act as extracellular precursors of intracellular NAD.
3. These observations strongly support the conclusion that both NAD+ and NMN need to be degraded to NR outside the cell to serve as precursors of intracellular NAD+
4. A study using stable isotope-labeled NR and NMN revealed that NMN is dephosphorylated into NR extracellularly. These results suggest that NMN is incorporated into cells after extracellular conversion to NR.
5. The administration of NMN was able to revert the endothelial dysfunction and inflammation by extracellular conversion to NR through CD73
6. In contrast to NR, NMN has a worse bioavailability, as extracellular NMN is unable to pass the endothelial membrane without prior dephosphorylation by CD73 (ecto-5′-nucleotidase) to NR or prior to metabolism to nicotinamide by extracellular CD38
7. We demonstrate that endogenous CD73 enables...the utilization of extracellular NMN as a precursor for intracellular NAD+ biosynthesis in human cells by converting NMN to NR.
8. The very similar actions of both compounds [NR and NMN] might be explained by data indicating that NMN needs to be extracellularly converted to NR to be taken up by the cells.
9. Extracellular sources of NMN do not efficiently cross the endothelial membrane and require previous dephosphorylation by CD73 (ecto-5′-nucleotidase) to generate NR or must be extracellularly metabolized to NAM by CD38
10. NRK1 deficiency, inhibition of CD73 (the cell surface protein thought to convert extracellular NMN to NR), and inhibition of ENTs all prevented NAD+ generation from exogenous NMN, providing evidence for conversion of NMN to NR before cellular uptake.
11. We also conclude that NMN cellular uptake most likely occurs following its dephosphorylation into NR.
12. Unlike nicotinamide mononucleotide, nicotinamide riboside can be freely transported across the cell membrane.
13. The conversion of NMN to NR is essential for it to act as extracellular precursor of intracellular NAD + in HEK293 cells. The extra step in cellular entrance for NMN might be the reason of its less efficient DNA damage protection [compared to NR].
14. Mice primarily rely on the nicotinamide and NR salvage pathways to generate NAD+ from NMN, while the uptake of intact NMN plays a minimal role.
15. NMN has been recently discovered to be converted extracellularly to NR, which is transported into cells.
16. Unlike nicotinamide mononucleotide, nicotinamide riboside can be freely transported across the cell membrane.
17. Most previous studies have shown that exogenous NMN cannot be directly used by cells and needs to be decomposed into NAM and NR.... In our study, the results were in accordance with those of previous studies...
18. From a biochemist's perspective, NR holds an edge over NMN since cells cannot directly absorb NMN, and NMN must be converted to NR before entering cells.
All of these statements are referring to either (1) the general principle that a nucleotide cannot cross the cell membrane (and the addition of a phosphate group to NR not only makes it NMN, but also makes it a polar or charged nucleotide, rather than an uncharged nucleoside), or (2) experimental evidence showing that when researchers blocked the effectiveness of NR, it also blocked the effectiveness of NMN.
Here is the general principle:
Phosphates cannot cross cell membranes through simple diffusion...Thus organisms from the smallest single-celled to the largest multiorgan being have developed transporters to both sense and take up phosphate from the environment.
But could there be such a transporter, one that would transport NMN directly across the cell membrane and allow direct replenishing of NAD from NMN?
Scientists were very excited when one group of researchers reported that they had discovered exactly such an NMN transporter, called Slc12a8, which could provide direct transport to NMN, rather than indirect transport into the cell by first degrading to NR.
The discovery was immediately controversial. Dr. Charles Brenner, a world-leading NAD expert, published a response titled, "Absence of evidence that Slc12a8 encodes an NMN Transporter." In the article, Dr. Brenner wrote, "The analytical methods, transport data, and interpretation underlying this assignment are not sound and do not support transport of NMN by Slc12a8...It would be prudent to continue to consider that Slc12a8 encodes a salt transporter and not a transporter of NMN."
The scientific community has taken a wait-and-see attitude, sometimes referring to the proposed role for Slc12a8 as raising "controversy" or suggesting the need for further studies to clarify.
However controversial and exciting to scientists it might be to propose Slc12a8 as an NMN transporter, it should be much less interesting to consumers of health supplements. That's because Slc12a8 isn't highly expressed in all tissue types, or even most tissue types.
The authors of the study who purported to discover the NMN transporter said, "We find that Slc12a8 is highly expressed and regulated by NAD+ in the mouse small intestine." The same group subsequently found SLC12a8 in a small part of the brain, "mainly localized in the lateral hypothalamus."
People who supplement with NR in hopes of seeing an anti-aging effect are looking for that anti-aging effect across their whole body -- kidney, liver, heart, eyes, ears, skin, muscle, bones, pancreas, and everywhere else. They are not interested in a supplement that is only effective in their small intestine or their lateral hypothalamus.
So the possibility of an NMN transporter isn't an important consideration for supplement consumers unless the transporter is well-expressed in most or all tissue types, which Slc12a8 does not appear to be.
However, there is another reason to doubt whether Slc12a8 even works in the mouse small intestine.
In a preprint (not yet peer-reviewed-and-published) paper posted last fall and co-authored by Dr. David A. Sinclair, the researchers sought to determine the role of the gut microbiome in metabolizing NMN. They labeled NMN with isotopes so they could track the fate of the different parts of the NMN molecule. The place they were looking was in the mouse intestine, and one of the things they were specifically attempting to measure was whether NMN was experiencing direct transport (via Slc12a8) or indirect transport (by first being converted to NR). What they observed was indirect transport, not direct transport:
The inability of exogenous NMN to displace the endogenous NMN pool, combined with the surge of labelled NR, suggests that NMN uptake bypasses direct transport, and would instead support the dephosphorylation of NMN into NR to facilitate its intestinal absorption. If direct transport of NMN does occur, its metabolism is mediated by the microbiome...NMN cellular uptake most likely occurs following its dephosphorylation into NR.
That's not a published, peer-reviewed study (yet), but it is signed by David Sinclair, who knows a lot about NMN, and it casts significant doubt on the direct transport theory, concluding that NMN "most likely" works by first getting converted to NR.
Conclusion
One of the joys and privileges of being a health supplement consumer is that you get to believe whatever you want, for a reason that is whimsical, irrational, or superstitious, or for no reason at all.
But for those who would invoke science as a justification for their beliefs, the science is quite clear that NMN works by being converted to NR. In other words, NMN is a way of delivering NR to cells. Scientists know exactly why this is true, they have lots of studies that demonstrate it, and they have said it over and over. The commentary of responsible health influencers should take this into account.
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