The NAD+ Precursor Wars!

Many camps here! This is getting fun :-)

Two different supplements: nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN). Both backed by good science & scientists (one camp is shilling supplements while the other camp is selling books, which I don't really care about) (the social media war is, however, hilarious).

Both precursors appear equally effective in the rodent studies and I expect this to cross over when NMN finally has human studies.

BIG difference that nobody is really talking about is TISSUE SPECIFICITY. 



1st problem: commentators were talking about NR/NMN as if it passed from your gullet directly to the liver. NR would be absorbed directly; NMN would be dephosphorylated to NR, absorbed, get re-phosphorylated back to NMN then converted to NAD+.

[insert Slc12a8 image here]

Since NMN and NR cost the same, this doesn't really matter. Right?

Supp manufacturers just thought that since NMN was one step closer to NAD+, it might make a better precursor. But if it's converted to NR prior to absorption, who cares?

And if the liver just releases niacinamide (NAM) to the rest of the body, WHO CARES? 

THE PLOT THICKENS

This becomes relevant with all the different preparations on the market -- intranasal, sublingual, regular oral (NR/NMN), NAD+ directly, and why can't I just save a ton of money and use NAM instead! Relevant, yes. And interesting. I'll summarize...

*in no particular order*

The first thing we encounter is absorption. Did everyone assume NR/NMN automatically pass through the intestinal tract intact? Well, it turns out we have some options: NR absorbed directly, then converted to NMN then NAD+; NMN converted to NR, absorbed then converted back into NMN then NAD+, or more recently (and debated), NMN absorbed directly intact.

Potentially, the same thing happens at the liver.

Advantage of NR/NMN over niacinamide (NAM) is liver can just waste NAM; NR/NMN has to go through NAD+. Other tissues can do nothing with NAM or convert it into NAD+.

Sublingual/intranasal NR/NMN/NAD+ [theoretically] go straight to the bloodstream; aren't neutered by the liver; ergo, other tissues don't really have the option to "do nothing with NAM;" they have to go through NAD+. A forced NAD+ boost in peripheral tissues?

Some speculation going on here, but I like the idea of NR/NMN reaching tissues other than liver, like brain and skeletal muscle. Liver NAD+ is cool, like, to help you metabolize alcohol, but I'm also interested in CNS NAD+.

Some of the basis for this speculation is that NAM is no where near as cool as NR/NMN in animal studies. The latter improves things all throughout the body, supporting that forced NAD+ boost?

This may happen because some NR/NMN slips past the liver with oral dosing, or completely bypasses it altogether with sublingual/nasal delivery (which has NOT been tested; totally hypothetical).

Dosing: more guesswork here. I don't know if it's better to take when NAD+ levels are high to further increase the peak (eg, while fasting, a few hours before your biggest meal) or when they're low, to buffer the trough (eg, while fed, right after your biggest meal).

However, in light of this blog post, I'm thinking once daily, not in divided doses. That's because if absorption/uptake IS transporter-mediated (and assuming we're not taking sublingual/nasal), then a higher dose might have a better chance of saturating the transporters and allowing some NR/NMN into the bloodstream to facilitate NAD+ in peripheral tissues... at least better than NAM would do if NR/NMN went through the liver first.

Another advantage of NR/NMN over NAM is that not all tissues express the enzymes to convert NAM to NAD+; and it seems as though the cells that need more NAD+ increase the expression of NR -> NAD+ enzymes (not NAM -> NAD+ enzymes)...

***interesting mouse study: NAMPT is the enzyme required to convert NAM to NMN and ultimately NAD+. Removing NAMPT from mouse skeletal muscle reduces NAD+ by 80% and basically destroys muscle performance (Frederick et al., 2016) (cool study BTW). 1) This suggests NAMPT is the dominant NAD+ synthesis pathway in mouse skeletal muscle and NAM, not necessarily NR/NMN could do the trick. However, supplementing NR restored muscle performance better than NAM w/o restoring NAD+. Lol.

Obviously a lot of guesswork/moving parts here. What do you think?

Have you tried any of these? Did it work?


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