So when Trammel paper says:
"Consistent with rapid phosphorylation of NR and NAR by NR kinases41, the only NAD+ metabolites that do not produce hepatic peaks as a function of gavage of NAD+ precursor vitamins are NR and NAR"
Their point is NR phosphorylates to NMN so quickly it is not detectable in blood.
They also say elsewhere:
"we establish that NR is a superior NAD+ precursor compared to NMN using stable isotope labeling technologies "
This is where they show in some cells in test tube that NMN is de-phosphorylated to NR to enter cells.
These 2 statements seem incompatible.
First, note that there is nothing at all incompatible between the two statements as far as reporting their experimental findings. What you're really pointing to, correctly, is the illogical jump to claiming the superiority of NR as a supplement, based on its ability to enter cells in culture, when it's reasonably clear that the amount of NR per se to which cells in different tissues beyond the liver are actually exposed to in vivo after oral administration is quite low (and doubtless varies from one tissue to another).
I've made this point at least half a dozen times, every time someone says "NR is superior to NMN, because NMN can't enter into cells." See eg. here, here, and here — and here, where you (able) stepped in to make it on my behalf 
.
We're not going to get hard answers on this until someone does massively-parallel experiments testing the effects of different NAD+ precursors on NAD+ levels and redox ratios in different tissues at different timepoints, preferably at different doses and combinations, and examining different subcellular compartments (since mito levels are somewhat independent of cytosolic). And at different ages, too, as presumably the rates and reasons for age-related NAD+ or NAD+:NADH decline with age are also different in different tissues.
And, again, that's properly a separate question from the actual health benefits (if any) of these various supplements.
Able wrote: If they believe NR is not found in the blood because it is so quickly phosphorylated to NMN to circulate, the way NMN enters a cell does not make NR the superior precursor as they claim.
That would be irrelevant, as both would have the same pathway once the NR has become NMN.
But the fact NMN goes thru NR to enter a cell wouldn't make NR superior when they already say NR is not found because it rapidly dephosphorylates to NMN.
Right.
Able wrote: it is phosphorylated to NMN so rapidly that it can't be detected
yet it takes 8 hours before it elevates NAD+ to peak levels
Well, first, they aren't saying it's phosphorylated to NMN so rapidly that it can't be detected at all: they do detect hepatic NR in Supplementary Figure 1, with a small, rapid initial spike followed by a crash, a larger spike, another crash, and then maximum levels at 12 h. They're saying that rapid phosphorylation is the likely expanation for why there's no clear peak. Frederick & Baur PMID 27508874 do report significant doubly-labeled NR in the liver of both WT and muscle-specific NAMPT-KO mice 100 min after oral gavage with 200 mg/kg NR (Fig 6F (in my previous post)), but we don't know what the time-course is.
One thing you're apparently not taking into account is that it will take some time for NR to be absorbed into liver or blood from the GI tract, and for interconversion into different elements of the "NAD+ metabolome" to occur thereafter: we don't know exactly when the highest fractional absorption of NR into liver, plasma, or PBMC levels are, or the time-course of subsequent metabolism. Even the fraction that is instantaneously converted to NMN isn't expected to simply accumulate linearly as NMN: rather, some of it it will flux from NMN through the "NAD+ metabolome," which in turn leads to that fraction of the NR-derived NMN "disappearing." Note the M+1 NR fraction in Frederick & Baur Fig. 6F, which is about half the doubly-labeled value, at 100 minutes, indicating NR that has already converted to NMN and then been retroconverted.
You don't expect NMN levels will rise linearly with onstreaming of NR, as it's converted to NAD+ and NAD+ is metabolized into NAM. NMN may only really start to accumulate once the tissue's ability to further metabolize it into NAD+ is maxed out, leaving it nowhere to go metabolically except enzymatic retroconversion to NR. Certainly the rises in NMN and NAD+ all seem to point in the same direction: in the published Brenner-Trammel PMID 27721479 NMN and NAD+ both peak almost simultaneously at 8 h In the mouse liver (Fig. 5), in PBMC in Brenner's n=1 (Supplementary Table 1), and albeit with a lot of noise, also in PBMC in the pharmacodynamic study in humans (Figure 8). Also note that there's a rapid initial small spike and a fall in both followed by another larger rise in mouse liver, and possibly in human PBMC (magnify the screen for the Figures)
Additionally, in each of these graphs, they're only looking at NAD metabolome members in one place at a time. Some NR and NMN is also moving into plasma, endothelial cells, intestinal cells, or going into the systemic circulation as it comes onstream. And there is the yet-unexplained, surprise rise in NAAD, which clearly plays into this somewhere.
And again, part of the problem is also the difficulty of assaying NR in biological fluids.
Able wrote: NR may be superior as it acts as a "time-release" version of NMN (if it all makes it thru stomach undigested). And less expensive. Or because of all the other metabolites that it increases, which they point out but then say they don't result in increased NAD.
Well, they clearly can't be claiming that. Clearly they are saying that NR goes through NMN to form NAD+ (it has no other route), and they certainly don't say that NR-derived NAM has no effect on NAD+.
Improving the availability to cells other than liver does seem likely to yield better, or at least different, results.
Am guessing that is what Dr Sinclair means when he keeps referring to being 2-3 years out for a product with improved targeting (not sure what words he used). Perhaps that is the goal of his NMN derivative patent.
That also seems to be the goal of the NMN product alivebynature just introduced, although I'm dubious their product actually achieves what they claim.
The formulation of this product is strange and I suspect not driven but science but other factors, the story is written to fit the formulation. In order to get an alleged 125mg NMN you need to take 350mg of other stuff for a combined 475mg pill. I could imagine the 350mg is added to dilute manufacturing compounds or then some other reason. If they could produce 125mg NMN pills without the other additions they would have a winner in their hands, the logical conclusion is they cannot.
I don't agree. I certainly doubt that they can strongly justify the exact doses and ratios of different precursors they've used, but everyone in the field acknowledges that different tissues differential utilize different precursors, as the Alive BN page rightly indicates:
Distinct metabolic routes, starting from various precursors,are known to support NAD+ biosynthesis with tissue/cell-specific efficiencies, probably reflecting differential expression of the corresponding rate-limiting enzymes, i.e. ... Nam phosphoribosyltransferase (NamPRT [= NAMPT], EC 2.4.2.12) and NR kinase (NRK, EC 2.7.1.22), which catalyze NMN formation from Nam and NR, respectively, and quinolinic acid (QA) phosphoribosyltransferase (QAPRT, EC 2.4.2.19) and NA phosphoribosyltransferase (NAPRT, EC 6.3.4.21), which synthesize NAMN from QA and NA, respectively. ... Understanding the contribution of these enzymes to NAD+ levels depending on the tissue/cell type and metabolic status is necessary for the rational design of therapeutic strategies aimed at modulating NAD+ availability" (PMID 25223558).
The same point is made in multiple reviews, such as PMIDs 28899755 and 28784597. Quoting from the latter:
The existence of different pathways leading to NAD+ production raises questions on the relative importance of each pathway and which of them possess the highest potential to boost NAD+ levels. The preferable precursor for NAD+ production within the organism is hence still a matter of debate. There is evidence that NAM possesses a higher NAD+ boosting capability when compared to NA in different organs in mice (Collins & Chaykin, 1971, 1972; Mori et al, 2014; Yang et al, 2014). Additionally, in human plasma, levels of NAM were reported to be fivefold higher than NA levels (Jacobson et al, 1995). However, several other studies claim the opposite: NA is a more effective NAD+ precursor than NAM (Ijichi et al, 1966; Hagino et al, 1968; Lin & Henderson, 1972; Williams et al, 1985; Jackson et al, 1995; Hara et al, 2007).
It is important to mention that in Mori et al (2014) the authors quantified the activity of NMNAT and NADS; therefore, the comparison was rather made between the “deamidated” (e.g., from NA) and “amidated” route, which includes both NAM and NR. And even if the authors of this study claim that NAM is the main precursor for NAD+ synthesis, the possibility of a significant contribution of other precursors using the amidated NAD+ biosynthesis route (e.g., NR) cannot be discounted. In support of this, a very recent study showed that NR has a greater capacity over NA and NAM to boost hepatic NAD+ levels (Trammell et al, 2016a). …
A large number of reviews attribute a marginal role to the de novo NAD+ synthesis pathway. However, a solid support for this claim is lacking. ... Rat primary hepatocytes, treated with NA, NAM, or tryptophan, were reported to use exclusively tryptophan for their NAD+ biosynthesis, even though they were still able to take up NA and NAM from the culture medium (Bender & Olufunwa, 1988). Administration of tryptophan, NA, or NAM to rats showed that tryptophan resulted in the highest hepatic NAD+ concentrations (Bender et al, 1982). Moreover, it has been shown that in rat liver, NA and NAM have a very limited capacity for NAD+ production, probably due to the saturation of the involved phosphoribosyltransferases, whereas no such limitations were detected for the NAD+ synthesis from tryptophan (Williams et al, 1950; Bender et al, 1982; McCreanor & Bender, 1986). [Contrast the Cantó & Auwerx liver NA data above -MR].
As I've mentioned before, note that Cantó and Auwerx PMID 22682224 report that NR raises hepatic and (apparently) muscle NAD+ more than isomolar NMN after oral administration. In fact, nicotinic acid appears to be as good as NR in muscle, and both of them better than NMN, while NA is pretty clearly better than either in liver — this seemingly contra Trammel-Brenner:
One key difference between the two papers: Trammel-Brenner give us data for several time points over 12-15 hours after a single oral adminstration by gavage, while Cantó & Auwerx give us one data point, taken after one week of having it in their chow every day.
There's certainly a rationale, then, for "covering your bases," though I don't think ABN or anyone can strongly justify any specific formulation (which will doubtless vary in any case by tissue, age, and disease state).
Who makes it without the chloride and how? I didn't think it was possible to make and stbilize without the chloride salt.
Even as a salt, some forms are extremely hygroscopic, as discussed in the (GSK?!?) patent. It's been speculated that IAS' product may be free molecular NR (or, more plausibly ISTM, a less stable salt), consistent with its short expiry date. Per the NR patent, most forms of NR prior to the hygroscopic that it would seem hard to imagine anyone could even get it into pills; I personally wouldn't suggest it.
Edited by Michael, 06 November 2017 - 11:50 PM.
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