Valijon, Turnbuckle: as far as I can see, ... there is no actual evidence that nicotinamide + D-ribose elevates NAD+levels any more than nicotinamide alone — let alone that it does so across the set of tissues deferentially accessed by NR ... let alone that the combination provides health benefits in vivo more than nicotinamide alone. As far as I can see, this is purely an hypothesis put forward by Turnbuckle, with zero empirical evidence to support it.
Am I wrong? Can either of you point to any study showing that nicotinamide + D-ribose does any of the above in vivo, after oral administration, more than NAM alone?
The hypothesis that NR has more benefit than nicotinamide + ribose is unproven, as far as I know. Do you have any evidence for it?
Well, first, you will note that I have not made a habit of claiming that NR has any benefit in humans, let alone that it has more benefit than NAM in either man or mouse (let alone that it does so more than NAM + ribose, though I'd generally advise against the latter because ribose is a highly glycating sugar) — and less so yet that NR has more benefit than a higher dose of the cheaper and better-understood NAM. Indeed, I've repeatedly urged caution on all of these questions.
By contrast, you (and now Valijon) are very confidently asserting that NAM+R is better than NR at raising tissue NAD, with (as far as I can see) no supporting evidence. The burden of proof lies with the person making the positive claim.
That said, there certainly is some evidence — albeit a lot less than I would like to see — that NR raises NAD+ in vivo modestly more than an isomolar dose of NAM in mice: this was reported in the liver by Trammel and Brenner PMID 27721479 (Figure 5D).
One paper that has been posted here shows that NR must be broken down before it can be absorbed. That is in rats, but there is no reason to believe it is not true in humans. Thus taking the predigested form of NR ought to act faster than NR, and given a greater than a stoichiometric dose of ribose, ought to produce a larger NR level in the blood for a given nicotinamide content.
Perfused or intact intestine rapidly hydrolyzed NMN to nicotinamide riboside, which accumulated, but was not absorbed. It was slowly cleaved by an enzyme associated with the mucosal cells to nicotinamide, which was the major if not the only labeled compound absorbed.
http://nadh.wiki/wp-...-of-the-Rat.pdf
Contrary to what you would predict from the perfusion study you cite, Cantó and Auwerx PMID 22682224 report that NR (and, notably, nicotinic acid) raise hepatic and muscle NAD+ more than isomolar NMN.
If NR had to be broken down into NMN and then NAM before absorption, and if this made NAM as good or better than NR at raising tissue NAD (as you assert), then you'd certainly have to predict that NMN itself would raise NAD+ in both tissues at least as much if not more than NR.
The study you cite is interesting, and would have been good evidence 5 years ago, but the part of which on which you're relying is a perfusate study, and they only used a single tracer label throughout, whereas the above studies trace of NAD+ itself using dual tracers in intact animals' target organs after oral administration.
So, if you have data showing that NR is actually absorbed as NR, I'd like to see it.
Note that one doesn't actually have to prove — or even believe — that NR is absorbed intact as NR to prove — or believe — that NR raises NAD+ more than NAM, let alone that it delivers more health benefits: we don't know nearly enough about its ADME yet. However, Frederick and Baur PMID 27508874 report that in mice with NAMPT knocked out in their muscle cells (thus, unable to use NAM to synthesize NMN and thence NAD+ in their muscles, but still able to do so normally elsewhere), NR raises liver NAD+ much more than NAM, which makes no obvious sense if you believe all the NR is first broken down to NAM before absorption; moreover, they report tracer data showing it happens largely without breakdown to NAM — and they also find intact NR in the liver, which makes the speculation on this front moot.
They also find that NR raises NAD+ significantly more in the muscle than does NAM (Supplemental Fig. 5I), which is as you'd expect because muscle NAMPT is knocked out — except that they find that NR largely does first get broken down into NAM somewhere between the liver and the muscle before being turned into muscle NAD+. "[O]ral NR dosing increased circulating NAM ≈40-fold, while NMN remained unchanged and NR was detected only at trace levels in the blood. Thus, the majority of the orally administered NR that reaches the muscle appears to enter in the form of liberated NAM or as NMN (Figures 6G and 6H)."
They also find NR improves muscle performance in the knockout mice more than an isomolar dose of NAM, even though they find muscle NAD+ to be only very modestly elevated in any case, and (again) that most of that elevation does involve initial breakdown to NAM.
In light of its potent phenotypic effects in mNKO mice, we were surprised to find that NR exerts only a subtle influence on the steady-state concentration of NAD in muscles. Our tracer studies suggest that this is largely attributable to breakdown of orally delivered NR into NAM prior to reaching the muscle. Nonetheless, our results indicate that NR is more effective than NAM for reversing mNKO phenotypes (Figure S5). The correlation between the NAD content and the respiratory capacity of isolated mitochondria, even in cultured myotubes (Figure 4), supports the model that subtle changes in NAD can disproportionately modulate aerobic metabolism. It is important to note that NAD turnover may vary independently from NAD concentration and that small changes in average tissue concentration might reflect larger changes in specific cells or subcellular compartments. It is also possible that intramuscular conversion of NAD into secondary messengers potently influences calcium homeostasis, which is both essential to muscle contraction and can independently modulate mitochondrial respiration (Ca´rdenas et al., 2010).
Our results leave open the possibility that some of the functional improvements in NR-treated mNKO muscles are secondary to effects in other cell types. Because necrosis was decreased by both NR and NAM at the time point examined in our study, the net effect on the regenerative capacity of satellite cells is not clear and will be an important focus of future work. The observation that NAM treatment was sufficient to confer a partial effect in mNKO muscle supports the model that effects outside of differentiated fibers contribute to the benefits of NR. Such indirect activities may help to explain how oral NR administration clearly mitigates the severity of insults to a growing list of tissues in which robust NAD decrements were not observed before treatment (Brown et al., 2014; Cerutti et al., 2014; Khan et al., 2014; Xu et al., 2015). We also cannot exclude the possibility that NAM contributes slightly to the NAD pool in mNKO myofibers by inhibition of NAM-sensitive NAD consumers or via residual Nampt activity in fibers or fusing myoblasts.
So this can all be a lot more complicated than one might think. Again, the study you cite is interesting, and would have been good evidence 5 years ago, but the part of which on which you're relying is a perfusate study, and they only used a single tracer label throughout, whereas the above studies trace of NAD+ itself using dual tracers in intact animals' target organs after oral administration.
Edited by Michael, 13 May 2017 - 12:36 AM.
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