71 replies to this topic

[MikeDC]

So both NR and NMN need to be formulated for lymphatic delivery. That will improve bioavailability considerably. ChromaDex is obviously in denial of this need. Lysosomal formulation of NMN might appear first。

https://www.scienced...818087613000135

[able]

This study was misleading. It gaves you the impression that most NMN were absorbed within 35 mins. The data from Ling Liu’s Paper showed that most of the absorption of NMN and NR is after 45 mins. To reconcile the two studies, initially small amounts of NMN were absorbed intact through the lymphatic system and enter blood stream. The majority of NMN were absorbed later and most are hydrolysed into NAM before entering liver.

 

Ok, so now you admit that some NMN clearly make it to liver and beyond, intact and very quickly, and not all is converted to NAM, as you were cherry picking from the Liu study.

 

Still waiting for your reference to any study  showing more benefit with NR vs NMN, to justify your claim it is clearly superior.

[joesixpack]

Hi guys, I am one of the people that struggle with taking high doses of NR and NMN. I get the racing heart, heavy chest, dizzy thing.  Also, an afib fluttering that is very disconcerting. So I backed off from 250 mg a day NR after three days. It was too much. I tried both of them. Went to 125 mg NR every other day and was fine. After a month of that, I am at 125 mg NR a day at 2 months. I have experienced positive effects. I suffered from vertigo at heights, or driving through mountains at height a year ago, it is much better now. The vertigo was a recent development in the last few years, so an improvement was noticed quickly. I also have better mental acuity. No scientific results, just anecdotal, but it is real. I smoke, and drink. I also exercise on a regular basis and use the sauna. 69 years old, generally good heath, the usual hypertension drugs. Pulse has dropped from 90 resting, to 80 in the last month. Blood pressure is controlled at 117/78. Also on thyroid replacement therapy.

 

I am considering adding 125 mg NMN to the mix, or adding 125 mg NR. I also take pterostilbene, and TMG, magnesium, D3. The TMG came from an article that indicated NR robs methyl molecules and you should take TMG to deal with it. I think that it helps me tolerate the NR, or NMN, which gives me the same issues.

 

That is my experience, I would be interested to hear any thoughts on it. 

 

Anyone have a positive result with such a low dose? It appears that you can acclimate yourself to take it, if you have an over reaction to a normal dose, like I did.

 

 

[Joe Garma]

I'm not sure what you mean.

 

NR by itself is not stable.  They add CL to make it stable enough to store and sell it.  Adding it to water breaks the bond with the CL, and it is not stable.  I doubt a cheap, pure NR will be stable enough to work in a water delivery form.   Likewise, once in the bloodstream it is not stable, once the NR -CL bond is broken.

 

Which form is least likely to be detrimental?  I don't know of any evidence of negative side effects from any of the forms you mention

 

Which form is most likely to be most beneficial in most ways?  I doubt anyone really knows for sure  yet.  Dr Sinclair says we will likely find they have unique benefits. I hope we will start to see comparison research for specific disease/illness, so we might know if one is better for heart disease, another good for blood sugar, etc.  

 

Of course the manufacturers are also biased, but I do learn some from the  marketing  info produced by ABN and Chromadex.  

 

NAD+ for the brain & metabolism, NMN for the body

 

8 Key Differences Between NMN & NR

 

[Joe Garma]

I've been reading every study about NAD+ precursors, NR and NMN being the most prominent. Doing this not only for my own edification and longevity program (been taking NR for two years now), but also for a client, Prohealth, who has been selling a sublingual form of NMN and expanding its NMN product line, including a bulk powder offering that will dramatically reduce the price.  This is sorely needed, because if you're going to consume the amount of NMN that it's leading investigator, Dr. David Sinclair, does at 1 gram/day, you either have to be affluent or get it in bulk.

 

The research on which precursor, NAD or NMN, is better is inconclusive, as is bioavailability.  My takeaway from what I've read is that:

 

• The NAD+ molecule consumed directly is to large to enter the cells of most tissues in the body
• NMN and NR does boost NAD+ but it's unclear which is better
• Bioavailability might be enhanced for most tissues if the precursor is taken sublingually

 

I've written about this. For those interested:

 

• Read about Elysium Health's NR product (Basis) here: https://www.garmaonh...ke-you-younger/
• Read a comparison of NR and NMN and sirutin activation here: https://www.garmaonh...mn-young-again/

 

 

 

 

[George2]

Nothing is clear about the NR, NMN, NAD, NA, NAM controversy. I have tried NA, NR, NMN (the latter for only the last 20 days). For 3 years I was on 1 gm NA (despite the flushing) and last 6 months on NR (250 mg). I see some effect on endurance (I don't get tired while cycling -- even ultra-endurance rides - 1000 km or longer). My personal experience is that NA seems to have improved my endurance, and it is too early to report on NR or NMN even though I have been taking NR for 6 months. However, I have not seen a decline in endurance after switching to NR from NA. Based on the reading of the scientific literature which seems colored by commercial interests, these compounds seems to have different efficacy in different tissues. Until someone undertakes a comprehensive study of these compounds administered by various routes in similar animals and at the minimum NAD concentrations in various tissues and tissue-types carefully analyzed, it will be impossible to compare various studies by various groups and we will not be able to draw any specific conclusions. However, in terms of health-benefits, oral NMN administration seems to produce some benefits in mice even if the debate roars on whether orally-administered NMN and NR is destroyed in the gut and the liver or whether NMN can cross the plasma membrane. Ultimately, what matters is the health benefit that one can derive from these molecules. NR clearly increases NAD levels in plasma in humans, but they have not shown any significant health benefits (in fact none other than some increase in ability to do sit-ups from a chair). Perhaps it is best to take a cocktail of NMN, NR, NAD (latter by sublingual route) at lower concentrations than focus on one molecule. 

[George2]

Its true that Dr Brenner says only NR can enter cells, but more and more research is showing otherwise, such as this one from October 2018:

 

The Plasma NAD+ Metabolome Is Dysregulated in “Normal” Aging

 

"While it is thought that NAD+ is predominantly an intracellular nucleotide, emerging evidence suggests that extracellular NAD+ crosses the plasma membrane and replenishes intracellular NAD+.21"

 

ABN does a nice job reviewing some research published in August  that proves  NAD+ rapidly enter hypothalamus directly, but that NR and NMN cannot, and from September, the  importance of increased NAD+ in hypothalamus.

 

I have long found it curious that Elysium measured the success of their first study by how much basis increased levels of NAD+ IN THE BLOOD.  If the cell membrane is some impenetrable barrier that stops NAD+ from entering, why would they say increased levels of NAD+ in the blood is the goal?  

 

NAD+ may not readily enter all cells intact, but it certainly seems increased NAD+ in the bloodstream has benefit

 

I think this new findings by Grozio et al published in Nature Communications may give an answer to the controversy. https://www.nature.c...55-018-0015-6. They have discovered a new NMN transporter on cells -- Slc12a8 -- which transport NMN to the cells. Of course, some NMN can get converted to NR, but clearly there is active uptake. What the NMN cannot enter cells proponents probably missed was this active transport and only noticed the fraction of NMN getting converted to NR. THIS IS GOING TO BE A BIG BLOW FOR CHROMADEX WHO HAS TRIED VERY HARD TO KNOCK-DOWN NMN. There was always this unanswered discrepancy that MNN produced better results on a variety of health parameters in mice (more than NR) while Brenner and others claimed that NMN must get converted to NR before it can enter the cell, in which case NR should have shown better physiological results, which it hasn't. Of course, the authors observed a huge difference in expression of Slc12a8 in various organs with intestine having the highest expression and brain having low expression. Also, they are not discounting the NMN dephosphorylation pathway (to NR) and both of these are happening simultaneously. It is likely that in some tissues NMN mostly gets converted to NR and gets absorbed while in others direct uptake of NMN may be the primary mode. 

Edited by George2, 16 February 2019 - 07:34 PM.

[MikeDC]

Nothing has changed by the discovery of the so called NMN transporter. As the author has pointed out, the NMN transporter is only expressed in a meaningful way in intestine only. In other cells, the expression is extremely small and will not make any difference. Virtually all NMN still need to convert to NR before entering cells. As the author also pointed out the NMN transport in the intestine is also very small and get saturated in a few minutes. The total NMN transported by this transporter is only a few percent at most. As the Ling Liu’s Paper shows NMN’s bioavailability is no better than NR.

[able]

Nothing has changed by the discovery of the so called NMN transporter. As the author has pointed out, the NMN transporter is only expressed in a meaningful way in intestine only. In other cells, the expression is extremely small and will not make any difference. Virtually all NMN still need to convert to NR before entering cells. As the author also pointed out the NMN transport in the intestine is also very small and get saturated in a few minutes. The total NMN transported by this transporter is only a few percent at most. As the Ling Liu’s Paper shows NMN’s bioavailability is no better than NR.

 

Why do you have a problem with  it being called the "so called NMN transporter"?  It is very specific for transporting NMN, not NR, NAM, or other similar molecules.

 

As you know, the study found Slc12a8 is increased in older, sicker animals, in response to low NAD+ levels. It is a mechanism the body uses to try and make up for insufficient NAD+

 

You have absolutely no idea how much percent of NMN can utilize the Slc12a8 transporter.  None.  

 

They found it is not expressed at all in young, healthy animals, which is precisely what the Liu study used. So of course, no NMN utilized Slc12a8 transport in the Liu research.

 

It might be a very small amount of NMN that can utilize this new transporter, or it might be significant.  You don't know, so please don't go making things up that are not in the research.

 

It might not matter that much, or, it might prove a big advantage for NMN, and explain why research consistently shows better results with NMN in sicker animals.

 

One thing it does prove very conclusively, is that Dr Brenner was flat wrong when he keeps saying all NMN must go thru NR to enter cells.  And Dr Imai and Sinclair were right when they keep saying there must be a transporter.   

Edited by able, 20 February 2019 - 01:16 AM.

[MikeDC]

Why do you have a problem with it being called the "so called NMN transporter"? It is very specific for transporting NMN, not NR, NAM, or other similar molecules.

As you know, the study found Slc12a8 is increased in older, sicker animals, in response to low NAD+ levels. It is a mechanism the body uses to try and make up for insufficient NAD+

You have absolutely no idea how much percent of NMN can utilize the Slc12a8 transporter. None.

They found it is not expressed at all in young, healthy animals, which is precisely what the Liu study used. So of course, no NMN utilized Slc12a8 transport in the Liu research.

It might be a very small amount of NMN that can utilize this new transporter, or it might be significant. You don't know, so please don't go making things up that are not in the research.

It might not matter that much, or, it might prove a big advantage for NMN, and explain why research consistently shows better results with NMN in sicker animals.

One thing it does prove very conclusively, is that Dr Brenner was flat wrong when he keeps saying all NMN must go thru NR to enter cells. And Dr Imai and Sinclair were right when they keep saying there must be a transporter.

Until you can show study results that NMN can increase NAD+ significantly without NRK1, previous study results still stand. NRK1 has been shown to be greatly expressed during injury so obviously the cells uses NR as precursor rather than NMN. Ling liu’s Paper also shows baseline NR is much higher than NMN. It tells you which precursor the body uses naturally.

[able]

Until you can show study results that NMN can increase NAD+ significantly without NRK1, previous study results still stand. NRK1 has been shown to be greatly expressed during injury so obviously the cells uses NR as precursor rather than NMN. Ling liu’s Paper also shows baseline NR is much higher than NMN. It tells you which precursor the body uses naturally.

 

There you go again.  Lose one argument, so you jump to another.

 

YOU brought up the Slc12a8 transporter.

 

It was so nice being able to discuss things rationally. while you were banned.

Edited by able, 20 February 2019 - 01:41 AM.

[MikeDC]

There you go again. Lose one argument, so you jump to another.

YOU brought up the Slc12a8 transporter.

It was so nice being able to discuss things rationally. while you were banned.

LawrenceW was able to fool the board members with the NMN transporter pump. I just injected reality into the argument. Nothing has changed. NMN transport is neglible compared to NR transport.