Is nicotinamide riboside (NR) broken down into nicotinamide (NAM) before it's absorbed?

Is nicotinamide riboside (NR) broken down into nicotinamide mononucleotide (NMN) before it's absorbed? More accurately niacinamide (NAM) http://jn.nutrition..../2/412.full.pdf

 

This is the continuation of a question raised on the group buy thread. Posts 179-184

Edited by Bryan_S, 30 June 2014 - 08:21 AM.

So it looks like NMN is broken down to NR, and NR is broken down to NAM, in the intestine prior to absorption. So I think the title of the thread should have been 

Is nicotinamide riboside (NR) broken down into nicotinamide (NAM) before it's absorbed?

 

To get NR to reach the various tissues (muscles, brain, etc) one might have to use some sort of liposomal delivery, or infusion, or transdermal

 

correct it was 3am

Or possibility, the conversion of NR to NAM can be swamped by a higher dosage, so NR might be directly absorbed into the blood at high enough doses.  Sinclair I believe applied NR to his rodents via gavage, so it would have had to pass through the intestinal mucosa if he was to obtain results with NR that he claims differ from NAM.  I hope this gets cleared up before long.

I was in the middle of a group buy when Primal brought this up so I was a bit reluctant to divert my energies to research this. Plus this topic was filling up the other thread so we initiated this one. I don't have it all in front of me and its late but NR appears to be absorbed by the mucosa (don't know how much) and it also appears to be cleaved into NAM. In the end the NAM is converted back into NR. So the question is what the advantage of taking NR if its broken down into NAM anyway? Primal raised a valid point from the 1983 data. What we need is other comparative studies.

 

We have some pretty smart people around here and should be able to settle this.

Or possibility, the conversion of NR to NAM can be swamped by a higher dosage, so NR might be directly absorbed into the blood at high enough doses.  Sinclair I believe applied NR to his rodents via gavage, so it would have had to pass through the intestinal mucosa if he was to obtain results with NR that he claims differ from NAM.  I hope this gets cleared up before long.

 

In this paper, they present evidence that the conversion of NR to NAM is saturable.  If Sinclair et al. used gavage, then oral dosing clearly works.  The question then becomes is NAM an adequate substitute for NR.  This review suggests that it's not.

Main questions to me are

 

1) how much oral NR needs to be taken in one sitting to saturate the hydrolysis/phosphorylysis of NR in the intestine

2) what happens to additional oral NR, is it broken down to something other than niacinamide, or does it passively diffuse through the intestine, or whatnot.

3) If it diffuse through the intestine as is, does it survive the liver first past metabolism?

4) If it does, does the high level of NR in blood translate into levels of NAD in cells higher that can reasonably be obtained from niacin. For example this study doesnt look too good for NR (against niacin) - eg looking at graph D in figure 1

5) If significant NR reach the blood, does its metabolism require methyl groups (like that of niacin and niacinamide)

6) If oral NR does not beat niacin, is there other delivery methods that works better. It looks like many people here use sublingual niagen.

 

Depending on the answers to those questions, an efficient strategy to take NR might be to take a very high dose once a week or once a month, instead of taking it daily. Or daily sublingual. Or infusions. And similar to niacin and niacinamide, making sure one's methylation is working well. 

 

Btw what do we know about the experiment in which Sinclair used gavage? Did it find that "oral dosing clearly works"?

 

 

 

 

Or possibility, the conversion of NR to NAM can be swamped by a higher dosage, so NR might be directly absorbed into the blood at high enough doses.  Sinclair I believe applied NR to his rodents via gavage, so it would have had to pass through the intestinal mucosa if he was to obtain results with NR that he claims differ from NAM.  I hope this gets cleared up before long.

 

Is this the NR study referred to?  It's not by Sinclair. I thought Sinclair did the one where NMN was delivered by IP injection.  Looks like this one just mixed the NR into food pellets that the researchers made:

 

The NAD+ precursor nicotinamide riboside enhances oxidative metabolism and protects against high-fat diet induced obesity

 

 

We fed 10-week-old male C57Bl/6J mice with either chow (CD) or high-fat diet (HFD), supplemented or not with NR at 400 mg/kg/day. While NR had no effect on the body weight (BW) on CD, HFD-induced body weight gain was significantly attenuated by NR (Fig.3A), due to reduced fat mass (Fig.3B). This was visibly translated into a significant lower weight of the epididymal depot in NR-fed mice (Fig.S2A). Importantly, this was not due to redistribution of lipids to other tissues (Fig.S2A), most notably to liver, which actually contained 40% less triglycerides (Fig.S2B).

...

8 weeks-old male C57Bl/6J mice were purchased from Charles River and powder chow (D12450B) and high fat (D12492) diets were from Research Diets Inc (New Brunswick, NJ, USA). 80 ml of water per kg of powder CD were used to make food pellets. 40 ml of water per kg of powder HFD were used to make food pellets. For NR, NMN and NA supplemented diets, the appropriate amount of these compounds was added to the water used to create the pellets, taking into account the differences in the daily intake of each diet. Mice were housed separately, had ad libitum access to water and food and were kept under a 12h dark-light cycle. Mice were fed with homemade pellets from 10 weeks of age. To make the pellets, the powder food was mixed with water (vehicle) or with NR.

...

In conclusion, our work shows that NR is a powerful supplement to boost NAD⁺ levels, activate sirtuin signalling and improve mitochondrial function, suggesting that this vitamin could be used to prevent and treat the mitochondrial decline that is a hallmark of many diseases associated with aging.

 

In any event, the dosage of NR above was in fact delivered through the digestive tract and seemed to have measured effects which included enhanced mitochondrial function.

 

Howard

Howard that was a great study. Where I find most of these studies lacking is in the 1983 study they worked with live dissected tissues and could measure the NAD precursor levels during conversion and absorption. If we feed oral NR to a mouse and in a given periods of time take a blood or tissue biopsies and measured NAD levels we'll expect to see increased levels. Now I think where this research falls apart is we don't know how much of the oral NR is absorbed naturally through the mucosa and how much of it is being converted to (NAM) before it's absorbed in the intestine. If I remember correctly (NAM) is 3 steps away from NAD.

 

 

Here was one of the best arguments for NR in the study you cited: http://www.ncbi.nlm....les/PMC3616313/

 

We also tested whether the increase in NAD+ would be concomitant to changes in other NAD+ metabolites. Strikingly, NADH and nicotinamide (NAM) levels were largely diminished in muscles from NR-fed mice (Fig.5B), indicating that NR specifically increases NAD+, but not necessarily other by-products of NAD+ metabolism. We analyzed in vivo whether the activity of major NAD+ degrading enzymes or the levels of Nampt could also contribute to the increase in NAD+ after chronic NR supplementation. As previously observed in HEK293T cells (Fig.1G-H), PARP-1 levels and global PARylation were similar in muscle (Fig.5C) and livers (Fig.S4D) from NR- and vehicle-fed mice, indicating that the enhanced NAD+ content cannot be explained by differential NAD+ consumption through PARP activity. Nampt mRNA (Fig.5D) and protein (Fig.5C, Fig.S4E and data not shown) levels were also similar in NR and vehicle fed mice, suggesting that NAD+ salvage pathways do not explain the differences in NAD+ levels. We furthermore could not detect differences in mRNA expression of the different NMN adenylyltransferase (NMNAT) enzymes (Fig.5D). Altogether, these results reinforce the notion that the higher NAD+ levels observed in tissues from NR-fed mice is consequent to an increase in direct NAD+ synthesis from NR.

 

So this was a great study but does it go far enough and which other studies make the same conclusions?

 

Bryan

 

In any event, the dosage of NR above was in fact delivered through the digestive tract and seemed to have measured effects which included enhanced mitochondrial function.

 

Howard

 

 

in some experiments NAM was shown to do that as well, so it doesnt answer our questions

 If I remember correctly (NAM) is 3 steps away from NAD.

 

 

 

 

2 steps, as can be seen in the picture you posted. Also potentially in 1 step in a reaction that requires ATP 

ATP + nicotinamide ribonucleotide  diphosphate + NAD⁺

 

 

Edited by Primal, 01 July 2014 - 10:44 PM.

Here is what I'd expect if NR is the preferred precursor, 2nd only to NMN and we are keeping up with demand with our supplementation. NAM levels should be building up in excess in the tissues and eventually excreted in the urine. Where is it going and why isn't it being treated like mega doses of Na and NAM which are being dumped in the urine.

 

So we're sort of saying the same thing.

 

That Chart does indicate 2 steps like NR or NAM could enter the cycle at that exact position. I read somewhere NAM was being converted to NR so thats where I remembered 3 steps.

Edited by Bryan_S, 02 July 2014 - 12:01 AM.

Here is what I'd expect if NR is the preferred precursor, 2nd only to NMN and we are keeping up with demand with our supplementation. NAM levels should be building up in excess in the tissues and eventually excreted in the urine. Where is it going and why isn't it being treated like mega doses of Na and NAM which are being dumped in the urine.

 

How do we know it isn't being excreted as NAM?

 

 

In any event, the dosage of NR above was in fact delivered through the digestive tract and seemed to have measured effects which included enhanced mitochondrial function.

 

Howard

 

 

in some experiments NAM was shown to do that as well, so it doesnt answer our questions

 

 

Sorry, I was responding to Maxwat's comment focusing on NR conversion possibly being swamped.  Thought OP's question was rhetorical since the answer was in the 1983 Gross & Henderson study he posted.  It indicates NAD converts to NMN and 5-AMP and then the NMN portion converts to NR in the intestine which then converts to NAM which is absorbed:

 

 

Dietary NAD was hydrolyzed primarily in the small intestine of the rat. The initial step was shown to be cleavage to NMN and 5'-AMP

...

Increasing the dosage of NAD caused a decrease in the percentage of labeled products removed from the intestine and a decrease in the percentage of NR that was converted to NAm. The uptake of [14C]-carboxamide-labeled NAD was relatively slow (24% in 15 minutes) compared to the uptake of [HC]NAm (80% in 15 minutes), shown previously to be a nonsaturable process (10). This evidence indicates that NR is converted to NAm before absorption occurs and that this reaction is the rate-limiting step.

 

Which also begs the question of what might show greatest or quickest absorption.  Looks like NAD is slower on the uptake, some of it gets diverted into 5-AMP, and increasing dosage is counterproductive which sounds like the swamping Maxwatt referred to. NMN is really expensive but its higher water solubility makes it more practical for injection which is probably why Sinclair chose it.  NR and NAM both look pretty good but I'd expect NAM to absorb faster and maybe more efficiently since it would skip the NR to NAM conversion step.  Note that this study did not administer NR directly and that the observed swamping of the NR to NAM conversion step was for increasing dosages of NAD.  Nothing like that was mentioned in the NR study I posted.  Suggesting the rate limiting might be caused by the 5-AMP byproduct.

 

Howard

 

Edited by hav, 02 July 2014 - 07:26 PM.

So given the question about absorption , conversion and or relative efficacy of the different forms of niacin's ability to raise NAD levels....why not take all three or some combination thereof ?
I currently take 500 mg of NR in the am. I'm considering adding 1-200 mg of NA later in the day. The flushing side effect is difficult for me.

Edited by Kevnzworld, 03 July 2014 - 04:00 AM.

"The possibility exists that NR may be absorbed without further cleavage."

 

Who said that, the 1983 Gross & Henderson study said that. In fact it was already posted once before. Some doubt must have existed because they made this statement at the very top of the paper.

 

http://jn.nutrition..../2/412.full.pdf

 

The radiochemical NAD was purchased and the precursors were their own products derived from the initial NAD. It's not like they could order radioactive NR back in 1982 to track its absorption and transport. They made the stuff themselves and we are looking at so many variables.

 

You guys kick this around awhile longer but as far as I can find this study has not been duplicated. I need to see data that either confirms or denies their conclusions.

 

I'm pretty convinced much of the NR is being absorbed through the mucosa anyway but if you guys can find something concrete to change my mind I'll listen.

 

Primal you may be asking a question that we cant find adequate data to support either way.

 

I'd be interested in seeing papers from:

DARTMOUTH, CORNELL DR. ANTHONY SAUVE WASHINGTON UNIVERSITY ST. LOUIS, MIT DR LEONARD GUARENTE, THE UNIVERSITY OF IOWA DR CHARLES BRENNER just to name a few.

I was in the middle of a group buy when Primal brought this up so I was a bit reluctant to divert my energies to research this. Plus this topic was filling up the other thread so we initiated this one. I don't have it all in front of me and its late but NR appears to be absorbed by the mucosa (don't know how much) and it also appears to be cleaved into NAM. In the end the NAM is converted back into NR. So the question is what the advantage of taking NR if its broken down into NAM anyway? Primal raised a valid point from the 1983 data. What we need is other comparative studies.

 

We have some pretty smart people around here and should be able to settle this.

 

Do we know what NAM% converts back to NR or NMN?   Because nicotinamide is said to inhibit sirtuin function, iirc.

 

 Because nicotinamide is said to inhibit sirtuin function, iirc.

 

 

too many people here taking sentences out of context from studies. NR, NA, NMN, tryptophan all convert to NAM in vivo. NAM inhibit sirtuins. Thus all these NAD+ precursors inhibit sirtuins. right? of course its not that simple. These things are dynamic systems that depends on concentrations of each and regulators and demands and ROS etc oversimplifying can lead to much misunderstanding

 

Unless I'm missing well done studies, preferably with humans, that show that 2-4g/day oral NAM inhibit sirtuins in many tissues while same dose oral niacin boost their activity?

Edited by Phoenicis, 11 July 2014 - 12:59 AM.

 

Edited by Phoenicis, 11 July 2014 - 01:08 AM.

 

 

 Because nicotinamide is said to inhibit sirtuin function, iirc.

 

 

too many people here taking sentences out of context from studies. NR, NA, NMN, tryptophan all convert to NAM in vivo. NAM inhibit sirtuins. Thus all these NAD+ precursors inhibit sirtuins. right? of course its not that simple. These things are dynamic systems that depends on concentrations of each and regulators and demands and ROS etc oversimplifying can lead to much misunderstanding

 

Unless I'm missing well done studies, preferably with humans, that show that 2-4g/day oral NAM inhibit sirtuins in many tissues while same dose oral niacin boost their activity?

 

It's not sentences from studies out of context, it is direct comments from lead researchers about concerns regarding high dose nicotinamide supplementation

 

 

One of the immediate implications of the work is that it emphasizes the functional difference between nicotinamide and nicotinic acid. Nicotinic acid (niacin) is a known anticholesterol treatment, while nicotinamide (or niacinimide) is sometimes touted for anti-aging abilities and is in clinical trials as a therapy for diabetes and cancer. However, the two substances are sometimes sold interchangeably as supplements under the name vitamin B3. "Our study raises the concern of taking high doses of nicotinamide," Sinclair said, because nicotinamide puts a damper on Sir2's actions in the cell.-sd

ChromaDex Initiates First Human Clinical Study to Confirm ChromaDex's NIAGEN™ Nicotinamide Riboside Will Increase NAD+

 

I'm on the road but noticed this PR was just released about a PK study on Nicotinamide Riboside to be performed by Dr. Charles Brenner who is is credited with discovery of NR as a vitamin in organisms from yeast to people as published in Cell in 2004.

 

 

"The human clinical study is designed to determine the pharmacokinetics (PK) and bioavailability of NIAGEN™ as well as provide information about an effective NR dose range in humans. Most importantly, this study aims to confirm earlier animal studies conducted by various universities and research institutes, which showed that oral dosing of the compound results in an increased level of nicotinamide adenine dinucleotide (NAD+) and NAD+ metabolites in the body."

Source:

http://investors.chromadex.com/phoenix.zhtml?c=212121&p=irol-newsarticle

 

Ask and you shall receive. From this Dr. Brenner should arrive at an effective dosage of (NR) for humans, as this will be one of the studies objectives. We should be able to pull up the full clinical study objectives shortly. At the moment they do not appear to be published.

I have gotten some lab results of an analysis of Niagen, which is the on form of nicotinamide riboside most of us have access to:  exclusive of fillers and excipients, it is abount 90% NR, and 10% niacinamide, plus a trace, around 0.05% methylnicotinate.

 

What effect this has, good or bad, on the metabolism of NR I don't know.

 

"The human clinical study is designed to determine the pharmacokinetics (PK) and bioavailability of NIAGEN™ as well as provide information about an effective NR dose range in humans.

 

If they find that NR is mostly broken down to NAM in the intestine hopefully they will say it even if that would completely kill their blockbuster 

I have gotten some lab results of an analysis of Niagen, which is the on form of nicotinamide riboside most of us have access to:  exclusive of fillers and excipients, it is abount 90% NR, and 10% niacinamide, plus a trace, around 0.05% methylnicotinate.

 

What effect this has, good or bad, on the metabolism of NR I don't know.

 

so you sent some niagen to a 3rd party testing lab? interesting. Did you also test for fillers, excipients, residual solvents, heavy metals, bacteries/yeast/fungi ? if so would you mind posting the full results?

 

I'm looking for a testing lab for a bulk purchase I'm about to make (not NR)

A third party tested it, and only included what he considered to be the active ingredients in the report I saw.  I am assuming bacterials and heavy metals were negligable.  You can try American Analytic Lab Corp in Chicago for testing. As long as they have an NR reference standard, you are good to go.

 

 

"The human clinical study is designed to determine the pharmacokinetics (PK) and bioavailability of NIAGEN™ as well as provide information about an effective NR dose range in humans.

 

If they find that NR is mostly broken down to NAM in the intestine hopefully they will say it even if that would completely kill their blockbuster 

 

 

 

Primal, Have you read The NAD+ Precursor Nicotinamide Riboside Enhances Oxidative Metabolism and Protects against High-Fat Diet-Induced Obesity  Volume 15, Issue 6, 6 June 2012

 

As we examine the possible pathways and precursors to the Mitochondria to produce NAD+ (NR) seems to be the most direct path without activating the GPR109A receptor or involving a conversion in the liver or liver complications such as Na. They infer in this study (NMN) needs to be converted to (NR) for uptake into the cell, so if this is the case why inject (NMN) as in the Sinclair study? No direct mention was made about (NAM) in this study pertaining to your question. At any rate it's looking like (NR) might be the best vehicular NAD+ precursor from mouth to cell, at least in this study. See the Discussion section.

 

So far out of all the orally administered NAD+ precursors (NA, NAM and NR) NR seems to be the one generating the most interest in all the recent studies. I would like to see a study specific to NAM or a direct comparison of mucosal absorption and ultimately cell uptake of both but I don't think a study has been conducted to frame this comparison. However I do remember something to the effect that NR raised NAD levels in more tissues throughout the body than (NAM). Missing a direct reference

 

So far I'm leaning to (NR) as the best and most potent path because the researchers arrived here before NIAGEN was ever produced or the ChromaDex marketing machine began working.  I've reached out to one of the (NR) researchers and the only comment I've generated to date is "We have results in animals in which NR has different and often superior activities than Nam." Research is ongoing and I expect we will hear more as all the benefits are documented and the dosage is nailed down.

 

I look forward to the pharmacokinetics data as it becomes available.

 

maxwatt thanks for the NIAGEN™ testing data. All benchmarks help!

Edited by Bryan_S, 18 July 2014 - 07:21 PM.

If they find that NR is mostly broken down to NAM in the intestine hopefully they will say it even if that would completely kill their blockbuster

Primal, Have you read The NAD+ Precursor Nicotinamide Riboside Enhances Oxidative Metabolism and Protects against High-Fat Diet-Induced Obesity Volume 15, Issue 6, 6 June 2012

As we examine the possible pathways and precursors to the Mitochondria to produce NAD+ (NR) seems to be the most direct path without activating the GPR109A receptor or involving a conversion in the liver or liver complications such as Na.

I agree on the GPR109A activation (good for the heart and I like it) with NA, but I think most liver issues were caused with the extended release formula of NA, not the immediate release which has been used in high doses to treat schizophrenia for more than 70 years. I have heard (correct me if I'm wrong) that most people will not experience liver issues at 1.5g / day which would be extremely expensive with Niagen. I do think that 3g doses are excessive for healthy individuals. I am interested in NR, but it's priced so high and some of it may be getting converting into Nam before it even becomes NAD+. When you read books like 'Niacin: the Real Story' its clear that nicotinic acid has been pioneered as an NAD+ precursor by doctors with some decent results, but drug candidates based on it have mostly failed. I wonder what the future holds for these new NAD+ precursors, all I can say for now: 100 x 250mg Niacin capsules for $5, whereas 30 x 250mg NR cost $47.99 (!).

Edited by Michael, 14 May 2017 - 03:43 PM.
trim quotes

First off let me say I'm not an expert on Niacin toxicity. But I believe its fair to say NA vs NR isn't really an even race. Niacin is metabolized in the liver to niacinamide and this is the step that makes a difference. Once niacin enters the liver, it is metabolized by either conjugation or amidation. The hepatotoxicity is an overload condition reached by a slow saturation and accumulation in the system and is eventually rate limited by the liver when it cant cope from a processing standpoint.

 

 

We can safely avoid that with a direct path with NR. Plus from a flushing standpoint I'd never get my wife to take Niacin approaching anything resembling therapeutic levels as with NR. There is more but that's what first comes to mind.

Edited by Bryan_S, 21 July 2014 - 04:13 PM.

Which is why NA has been documented as an effective NAD+ precursor for ages. You must really dislike that flush? Let's keep this on topic guys!

 

This all seems to depend on the expression of Nrk1 in tissues, if that isn't present, or is inhibited, then nucleoside splitting and Nam salvage may take place: http://www.jbc.org/c...8.full.pdf html

 

I believe I read somewhere that Nrk1 is expressed in some tissues more than others, but I can't find the reference.

Edited by LexLux, 21 July 2014 - 04:15 PM.