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Does NR Get Broken Down into N+R or Is It Stable?

nicotinamide riboside niagen d-ribose nicotinamaide

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#1 Nate-2004

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Posted 06 September 2017 - 08:57 PM


This study found linked in Turnbuckle's thread on manipulating mitochondrial dynamics suggests that NR is broken down in the gut (cleaved by an enzyme). However, it also is a study on orally ingested NMN, not the patented, Chromadex version known as Niagen. 

 

So what is the truth on this? Is it broken down into N+R and does taking Nicotinamide and D-Ribose result in the same effect, or does it not? Is there evidence to the contrary?

 

I've seen this study which talks about effects on NAD+, but not necessarily plasma levels of NR specifically. Any Google search I try on Nicotinamide Riboside or Niagen and blood plasma levels simply leads back to that study. What's the deal?

 

If this study has any carryover to humans and proves true, then neither NMN nor NR are going to be useful if taken orally.

 

 


Edited by Nate-2004, 06 September 2017 - 08:59 PM.

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#2 able

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Posted 07 September 2017 - 12:17 AM

"However, it also is a study on orally ingested NMN"

 

sure you meant Nicotinamide Riboside, not NMN...

 

I've been waiting/searchig for answer on that myself.  Have seen multiple contractictory reference.  

 

I THINK some NR does get cleaved to NAM, but maybe/probably not all.  Need to research more closely, or wait for more research to know.

 

Anyways, don't search on google, but on pubmed

 

https://www.ncbi.nlm.nih.gov/pubmed

 

 


Edited by able, 07 September 2017 - 12:21 AM.


#3 Nate-2004

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Posted 07 September 2017 - 01:49 AM

"However, it also is a study on orally ingested NMN"

 

sure you meant Nicotinamide Riboside, not NMN...

 

I've been waiting/searchig for answer on that myself.  Have seen multiple contractictory reference.  

 

I THINK some NR does get cleaved to NAM, but maybe/probably not all.  Need to research more closely, or wait for more research to know.

 

Anyways, don't search on google, but on pubmed

 

https://www.ncbi.nlm.nih.gov/pubmed

 

 

I'm not sure exactly, but it talks about NMN being reduced to NR, then to NAM. The methods section however talks about giving it NAD. I know you can buy NAD supplements that are basically useless because NAD is too big to enter the cell.

 

 


ABSTRACT A number of preparations of varying complexity have been used in an effort to elucidate the reactions by which NAD is hydrolyzed to nicotinamide during intestinal digestion. NAD labeled with 14Cin the adenine or pyridine moiety was the substrate used with perfused rat intestine, live rats, perfused live rats, with collection of portal flow, intestinal contents, mucosa! tissue, or pancreatic juice. The conclusions reached are that a pyrophosphatase present in the intestinal juice and to a much lesser extent in the pancreatic juice releases 5'-AMP and nicotinamide ribonucleotide. The 5'- AMP was rapidly converted to adenosine then to inosine by bacteria-free intestinal contents. 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.

 

And here:

 

 

 

A series of 15-minute, live-animal experiments was done to determine the sequence of appearance of products from carboxamide-labeled NAD in the lumen of the intestinal segment. Samples of contents (0.1 ml) were withdrawn at times between 0.5 and 15 minutes by inserting a 24-gauge needle through the intestinal wall.

Edited by Nate-2004, 07 September 2017 - 01:57 AM.


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#4 Michael

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Posted 07 September 2017 - 02:57 AM

This study found linked in Turnbuckle's thread on manipulating mitochondrial dynamics suggests that NR is broken down in the gut (cleaved by an enzyme). However, it also is a study on orally ingested NMN, not the patented, Chromadex version known as Niagen.

So what is the truth on this? Is it broken down into N+R and does taking Nicotinamide and D-Ribose result in the same effect, or does it not? Is there evidence to the contrary?


That is evidently not the case, as I explained previously here and in several other places. The cited study (Gross & Henderson PMID 6218262) started with singly-labeled NMN, degraded that into singly-labeled NR (along with singly-labeled NAM and NMN), and then used the resulting singly-labeled NR to do their study. (This is the confusion over NMN vs. NR between your description of the study, Nate, and Able's response). It's not clear to me that they can say with certainty that the "NR" they administered is actually pure NR, rather than a mixture that still contains NMN-derivatived labeled NAM and/or NMN. In any case, because this NR was only labeled at its carbonyl group, they could not trace the fate of the ribosyl moiety, and they also didn't track its fate in target tissues.

Both Frederick & Baur PMID 27508874 and Trammell & Brenner PMID 27721479, using doubly-labeled NR (with deuterium at the ribosyl C2 and 13C at the NAM carbonyl group), find that at least in the liver, a small amount of ingested NR is utilized intact. As reported by Trammell & Brenner PMID 27721479:


54% of the NAD+ and 32% of the NADP+ contained at least one heavy atom, while 5% of the NAD+ and 6% of the NADP+ incorporated both heavy atoms. Because >50% of hepatic NAD+ incorporates label before a rise in NAD+ accumulation, it is clear that the NAD+ pool is dynamic. As shown in Fig. 7c,d, the majority of hepatic Nam and MeNam following gavage of double-labelled NR incorporated a heavy atom, necessarily the 13C in Nam. Because NR drives increased NAD+ synthesis and ADPR production (Fig. 5), the liberated singly labelled Nam becomes incorporated into NMN and NAD+in competition with double labelled NR, thereby limiting subsequent incorporation of both labels into the NAD+ pool.


As I've indicated previously, it does appear likely that additional NR is broken down into NAM prior to entering the systemic circulation. None the less, both Trammell (in his thesis project — see Chapter 5, and especially Figures 5.8 and 5.9) and Frederick & Baur op cit both find doubly-labeled (intact NR-derived) NAD+ in the muscles after gavage and oral administration, respectively. (Note, in Fig. 5. 8, that more of the rise in NAD+ is accounted for by singly-labeled M+1 NAD+ (derived from NAM via salvage pathway after breakdown to NAM) than by doubly-labeled M+2 NAD+ (derived from intact NR); it looks as if a somewhat higher percentage is derived from intact NR after injection (Fig. 5.9), perhaps because it bypasses the intestine and the liver).

Moreover, the elevation in muscle NAD+ in Frederick & Baur PMID 27508874 can't come from uptake of circulating NAM, whether it's derived from broken-down NR or not, because these mice have their muscle NAMPT enzymes knocked out, and therefore can't make NAD+ from NAM — only from NMN or NR.

In any case, direct use of that small amount of circulating NR as an NAD+ precursor and NR-derived NAM may not be the full story on the ultimate effect on tissue NAD+ levels either: as Frederick & Baur PMID 27508874 report, despite only "minute" amounts of intact NR being incorporated into muscle NAD+, and despite their animals' muscles being unable to use NAM to synthesize NAD+,


To test whether NAM itself might account for some of the beneficial effects of NR treatment, we performed an additional experiment that included 3 weeks of NAM treatment. NAM-treated mice exhibited To test whether NAM itself might account for some of the beneficial effects of NR treatment, we performed an additional experiment that included 3 weeks of NAM treatment. NAM-treated mice exhibited intermediate phenotypes with regard to muscle performance and NAD+ levels [as compared with NR-supplemented and vehicle-treated animals] (Figures S5A–S5I).


Indeed, to a rough approximation the effects of NAM are here about half those of NR.

Now, I hasten to add that this can't be extrapolated to indicate the relative effects of NAM vs. NR in normal mice or humans: these were mice with the gene for NAMPT knocked out in their muscles, so they couldn't synthesize NAD+ from NAM directly in their muscles.

Resynthesis from NAM + R is unlikely to be the main explanation, first on a sheer stoichiometry and volume of distribution basis, but also because it's not clear the body even can synthesize NR from NAM + R: very little is known about NR biosynthesis, but the main known route is via the breakdown of NMN, not de novo biosynthesis. Indeed, in their paper on the discovery of the two known enzymes responsible for the production of NR and nicotinic acid riboside, the authors wrote:
 

We set out to determine the enzymes responsible for NR and NAR production. Because there is no biological precedent for nucleoside synthesis de novo and because NR and NAR accumulation appear to occur at the expense of NAD+ (Figs. 1 and 2), we considered the mechanisms by which NAD+ and related compounds could be broken down to NR.


Frederick and Baur propose several possible mechanisms in addition to direct muscle use of intact NR:
 

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 (Cárdenas 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. ... 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.


I will myself note that effects on NADP(H) in C57BL/6 mice could also "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"

 

 

a


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#5 Nate-2004

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Posted 07 September 2017 - 04:48 PM

Michael, thanks for the time spent on answering this. Is it not possible to detect NR (Niagen NR) in the blood plasma after ingestion to verify proper, intact bioavailability?


Edited by Nate-2004, 07 September 2017 - 04:49 PM.


#6 Turnbuckle

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Posted 07 September 2017 - 04:55 PM

There are good reasons for no-conflict-of-interest statements in research, because when there is a conflict as there is in the NR paper that got people interested in taking this stuff, important information gets left off, such as comparing N+R to NR. That is an obvious comparison, but Including such information could cost the researcher/vendors millions, for as the papers Michael quoted above clearly show, very little NR makes it into general circulation, and N by itself provides half the benefit of NR, while the cost of NR is 70 times that of the same amount of N. 


Edited by Turnbuckle, 07 September 2017 - 05:04 PM.

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#7 Nate-2004

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Posted 07 September 2017 - 05:03 PM

as the papers Michael quoted above clearly show, very little NR makes it into general circulation

 

This wasn't clear to me in what Michael posted. Can you quote where this was clear for you?



#8 Turnbuckle

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Posted 07 September 2017 - 05:12 PM

 

as the papers Michael quoted above clearly show, very little NR makes it into general circulation

 

This wasn't clear to me in what Michael posted. Can you quote where this was clear for you?

 

 

 

Where it says this: 54% of the NAD+ and 32% of the NADP+ contained at least one heavy atom, while 5% of the NAD+ and 6% of the NADP+ incorporated both heavy atoms.

 

If NR is absorbed without breaking down then essentially none of the NAD+ and NADP+ would contain one heavy atom, and the amount having both would be much higher. In fact, the low result of approximately 5% having both heavy atoms is consistent with a very high level of breakdown and then reassembly, with some by chance getting both heavy atoms.


Edited by Turnbuckle, 07 September 2017 - 05:14 PM.

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#9 able

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Posted 07 September 2017 - 05:59 PM

 

Where it says this: 54% of the NAD+ and 32% of the NADP+ contained at least one heavy atom, while 5% of the NAD+ and 6% of the NADP+ incorporated both heavy atoms.

 

If NR is absorbed without breaking down then essentially none of the NAD+ and NADP+ would contain one heavy atom, and the amount having both would be much higher. In fact, the low result of approximately 5% having both heavy atoms is consistent with a very high level of breakdown and then reassembly, with some by chance getting both heavy atoms.

 

 

Does that imply that approximately 11% of the NR was found to be absorbed intact (5 NAD+ plus 6 NADP+), and the remainder likely cleaved to NAM?

 

That sounds like a poor percentage, but if 11% quickly makes its way into cells where it's needed, it may still be quicker or more effective than dumping 10x as much NAM, NA, NMN into the bloodstream.

 

 -  oops, just noticed that quote was referring to NAD+ and NADP+ in the Liver ONLY, not in other organs.  So 11% might convert to NAD or NADP in the LIVER, the remainder cleaved to NAM before converting to NAD  in the LIVER ?

 


Edited by able, 07 September 2017 - 06:46 PM.


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#10 Turnbuckle

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Posted 07 September 2017 - 06:37 PM

 

 

Where it says this: 54% of the NAD+ and 32% of the NADP+ contained at least one heavy atom, while 5% of the NAD+ and 6% of the NADP+ incorporated both heavy atoms.

 

If NR is absorbed without breaking down then essentially none of the NAD+ and NADP+ would contain one heavy atom, and the amount having both would be much higher. In fact, the low result of approximately 5% having both heavy atoms is consistent with a very high level of breakdown and then reassembly, with some by chance getting both heavy atoms.

 

 

Does that imply that approximately 11% of the NR was found to be absorbed intact (5 NAD+ plus 6 NADP+), and the remainder likely cleaved to NAM?

 

That sounds like a poor percentage, but if 11% quickly makes its way into cells where it's needed, it may still be quicker or more effective than dumping 10x as much NAM, NA, NMN into the bloodstream.

 

 

This was in the liver only. The rest of the body did see a much increased NAD+. See Fig 6-b and 6-c of the paper, where liver tissue is compared to heart tissue.



#11 Nate-2004

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Posted 07 September 2017 - 09:38 PM

So in the end there's more proof that NR arrives intact to cells whereas there is no proof that NAM + R is synthesized as NR before arriving at the cell. Thus NR results in a proper increase in NAD+ without a consequential inhibition of SIRT1. Am I drawing the right conclusion here? Most of NR does not get broken down into NAM+R.


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#12 able

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Posted 07 September 2017 - 10:10 PM

I believe that study indicates that 11% of the NR processed by the LIVER is direct NR-> NAD+.    

 

The remaining that is processed by the LIVER is FIRST cleaved to NAM (and R).

 

Other tissues also saw an increase in NAD, but the liver is the primary source.

 

As for NAM inhibiting Sirt1 - That is way overblown.  

 

I believe Michael referenced this before.  And I know Dr Sinclair said much the same.  

 

 

 
This study points out some flaws in earlier studies that found NAM inhibits Sirt1, and points out any inhibition is temporary.
 
"However, once administered to cells, NAM is rapidly converted to NAD+ and, therefore, the cellular concentration of NAM decreases rapidly while that of NAD+ increases.  The result would be an inhibition of SIRT1 for a limited duration, followed by an increase in the activity."
 

 

 


Edited by able, 07 September 2017 - 10:23 PM.

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#13 Turnbuckle

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Posted 07 September 2017 - 11:16 PM

 

I believe that study indicates that 11% of the NR processed by the LIVER is direct NR-> NAD+.    

 

The remaining that is processed by the LIVER is FIRST cleaved to NAM (and R).

 

 

 

 

That isn't what it means.



#14 able

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Posted 07 September 2017 - 11:28 PM

Ok.  Can you explain please?

 



#15 Turnbuckle

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Posted 08 September 2017 - 05:59 PM

Ok.  Can you explain please?

 

'

Let's keep things simple and just look at N, R, and NAD. And let's say you have a gram of N+R available in cells and you add a gram of N'R' orally (where N' and R' are labeled with a deuterium atom or C13 atom). So when the cells finish their work, they have 50% NAD+ and 50% NAD''+. That is, half have no label and half are double labeled, while none are single labeled. But this isn't what they saw.

 

What actually happened was that roughly half the NAD+ was single labeled and 5% was double labeled. So it can't be that N'R' was absorbed without breaking down as there would have been 50% doubled labeled, not 5%.

 

Far more likely is that all the oral N'R' is all broken down into N' + R' before being absorbed. Then you have equal amounts of--

 

N

R

N'

R'

 

in the cells. These can be combined in 4 ways--

 

NR -- 25% no label

N'R' -- 25% double labeled

N'R -- 25% single labeled

NR' -- 25% single labeled

 

So a total of 50% is single labeled and 25% is double labeled, even though all of the oral dose was broken down before absorption. (The NAD made from it should show the same percentages.) This isn't far off from the actual results for single labeled NAD, but still higher than the actual results for doubled labeled NAD. The most likely explanation is that some of the oral R' is burned for energy before it can be combined into N'R' and thence into NAD''+. And this is why taking R in a stoichiometric excess should improve results.


Edited by Turnbuckle, 08 September 2017 - 06:46 PM.

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#16 Nate-2004

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Posted 08 September 2017 - 06:09 PM

NR -- 25% no label

N'R' -- 25% double labeled

N'R -- 25% single labeled

NR' -- 25% single labeled

 

So a total of 50% is single labeled and 25% is double labeled, even though all of the oral dose was broken down before absorption. (The NAD made from it should show the same percentages.) This isn't far off from the actual results for single labeled NAD, but still higher than the actual results for doubled labeled NAD. The most likely explanation is that some of the oral R' is burned for energy before it can be combined into N'R' and thence into NAD''+. And this is why taking R in a stoichiometric excess should improve results.

 

 

I think where I'm getting lost on this is on what "no label", "single labeled" and "double labeled" mean. I also don't know what the apostrophes indicate.


Edited by Nate-2004, 08 September 2017 - 06:10 PM.


#17 Turnbuckle

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Posted 08 September 2017 - 06:45 PM

 

NR -- 25% no label

N'R' -- 25% double labeled

N'R -- 25% single labeled

NR' -- 25% single labeled

 

So a total of 50% is single labeled and 25% is double labeled, even though all of the oral dose was broken down before absorption. (The NAD made from it should show the same percentages.) This isn't far off from the actual results for single labeled NAD, but still higher than the actual results for doubled labeled NAD. The most likely explanation is that some of the oral R' is burned for energy before it can be combined into N'R' and thence into NAD''+. And this is why taking R in a stoichiometric excess should improve results.

 

 

I think where I'm getting lost on this is on what "no label", "single labeled" and "double labeled" mean. I also don't know what the apostrophes indicate.

 

 

N' and R' are N and R labeled with a single deuterium atom in place of a hydrogen atom or a 13C atom in place of 12C atom. This raises the molecular mass by one mass atomic unit in each case, and by two for N'R'. "No label" means no deuterium or 13C. Thus with mass spectrometry it is possible to distinguish NAD from NAD' or from NAD'', as they have different masses.

 

 

To test whether NR is incorporated into the peak of NAAD that appears after NR gavage, we synthesized NR with incorporation of deuterium at the ribosyl C2 and 13C into the carbonyl of the Nam moiety. This double-labelled NR was provided to 15 mice by oral gavage...

 

Another indication of the breakdown of the oral dose of N'R' is the appearance of a 45 fold increase of NAAD. That should have been nearly 100% double labeled if there was no breakdown, but in fact it was far short of that, only 8%--

 

 These data indicate that blood cellular NAD+ rose 2.7-fold after one dose of NR and that NA adenine dinucleotide (NAAD) unexpectedly increased 45-fold....As shown in Fig. 7, NR stimulates appearance of double-labelled NAAD (8% of total) at the same time...

 

 


Edited by Turnbuckle, 08 September 2017 - 07:02 PM.

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#18 Nate-2004

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Posted 09 September 2017 - 06:03 PM

So then the follow up question is do we even know if N+R also gets that 8% increase in double-labelled NAAD or would it be even less if any?


Edited by Nate-2004, 09 September 2017 - 06:04 PM.


#19 Turnbuckle

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Posted 09 September 2017 - 06:31 PM

So then the follow up question is do we even know if N+R also gets that 8% increase in double-labelled NAAD or would it be even less if any?

 

 

The researchers did not compare N'R' with N'+R' (that we know about), but if they had, I expect they would have seen more double-labeled NAAD with N'+R', for the simple reason that N'+R' is essentially "predigested." Thus it would have been absorbed more quickly, with less time for R' to be burned for energy.


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#20 Michael

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Posted 09 September 2017 - 07:39 PM

 

Ok.  Can you explain please?

 

'

Let's keep things simple and just look at N, R, and NAD. And let's say you have a gram of N+R available in cells and you add a gram of N'R' orally (where N' and R' are labeled with a deuterium atom or C13 atom). So when the cells finish their work, they have 50% NAD+ and 50% NAD''+. That is, half have no label and half are double labeled, while none are single labeled. But this isn't what they saw.

 

Your analysis here only makes sense in isolated cells, and with a static NAD+ pool. Rather, some NR is passing through the liver on its way to to other sites, and present in the cell at any moment as other parts of the "NAD+ metabolome," as they document: some is still present as NR in the cell; all NR that is eventually incorporated intact into NAD+ has to first pass through NMN; some will pass back from NMN to NR; and all of it that is present in NADP(H) was present previously in NAD+. Moreover, simple hydrolysis of NR as the sole source of single-labeled NAM ignores its production by enzymatic breakdown from NAD+ into NAM+ ADPR.

 

You are also still assuming that NR is synthesized de novo in mammals from NAM + R, for which there is currently no evidence. As far as we know now, the only way NR is present in mammalian cells is from the diet/supplements or from NMN breakdown. It's not even known how it's produced in yeast, and the most likely pathway is as part of a fermentative biosynthetic reaction, which isn't likely to translate to mammalian cells.


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#21 Turnbuckle

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Posted 20 October 2017 - 10:16 AM

 

 

Ok.  Can you explain please?

 

'

Let's keep things simple and just look at N, R, and NAD. And let's say you have a gram of N+R available in cells and you add a gram of N'R' orally (where N' and R' are labeled with a deuterium atom or C13 atom). So when the cells finish their work, they have 50% NAD+ and 50% NAD''+. That is, half have no label and half are double labeled, while none are single labeled. But this isn't what they saw.

 

Your analysis here only makes sense in isolated cells, and with a static NAD+ pool. Rather, some NR is passing through the liver on its way to to other sites, and present in the cell at any moment as other parts of the "NAD+ metabolome," as they document: some is still present as NR in the cell; all NR that is eventually incorporated intact into NAD+ has to first pass through NMN; some will pass back from NMN to NR; and all of it that is present in NADP(H) was present previously in NAD+. Moreover, simple hydrolysis of NR as the sole source of single-labeled NAM ignores its production by enzymatic breakdown from NAD+ into NAM+ ADPR.

 

You are also still assuming that NR is synthesized de novo in mammals from NAM + R, for which there is currently no evidence. As far as we know now, the only way NR is present in mammalian cells is from the diet/supplements or from NMN breakdown. It's not even known how it's produced in yeast, and the most likely pathway is as part of a fermentative biosynthetic reaction, which isn't likely to translate to mammalian cells.

 

 

 

You have attempted to muddy the waters, but the bottom line is that the data do not show that labeled NR is absorbed intact as the authors claim. In fact, Fig. 5d shows that the peak of plasma NAM is far greater with NR than with NAM by itself (which is likely because the NAM peak from NAM dosing was very sharp and they didn't catch the peak). This is consistent with slow digestion of NR to NAM + ribose. Worse for the argument that NR is better than N+R is Fig. 5b which shows the AUC for NAM produced NAD+ is only about 10% less than for NR (and not significantly different). The authors have not made a case that the peak is more important than the average level, so the difference between NR and NAM appears to be trivial (especially considering that they are likely using twice as much NR by weight as NAM). Now if one were to add ribose to NAM to properly compare NR to N+R on a weight basis, that would be a logical and fair trial that would demonstrate clearly if NR was orally available, but the authors did not do it...or at least did not report it. Nor did they find enough NR in the blood to bother with a plot of NR vs time, which should be a giveaway that the title of their paper--Nicotinamide riboside is uniquely and orally bioavailable in mice and humans--is pure fantasy.

 

Also, if NR is digested to N+R, then claims on another thread that ribose has negative health effects applies both to NR and N+R. 


Edited by Turnbuckle, 20 October 2017 - 10:36 AM.

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#22 Advocatus Diaboli

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Posted 20 October 2017 - 03:36 PM

If nicotinamide alone doesn't produce the beneficial effects of either NR or of N+R then wouldn't it be the case that the R in NR and in N+R is utilized in such a manner that in the presence of N it doesn't participate in the advancement of glycation, but is utilized in some different reactive manner avoiding the glycation pitfall? Of course, "To measure is to know".


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#23 able

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Posted 20 October 2017 - 04:08 PM

Turnbuckle - I noticed alivebynature seems to agree with much of what you say about NR.

 

http://alivebynature.com/nmn-or-nr-whats-the-best-nad-booster/

They show some of the charts you mentioned about NR/NAM bioavailability and seems to make a good case that most NR does indeed end up as NAM. 

 

- Big increase in NAM before NAD is elevated

- NO NR increase in liver

- NO NR found in bloodstream

- NAM supplements increase NAD+ faster, and almost as much as NR

- 5% double labeled NAD+ from supplement

- much faster, and more double labeled NAD+ from IP vs supplement

 

I still think some NR makes it through intact, and that is the reason it is clearly more effective than NAM in studies.  

 

But I do agree a lot of the conclusions made in the Trammell paper are unsupported or contrary to some of the evidence, or greatly exaggerated.

 

I see that the 1000mg dose that brenner used shows a 10x increase of NAM in urine.  But I don’t know if that is a significant quantity or not.   

 

Does that mean that large doses of N + R would also just get pissed away?

 

 

 

 

 


Edited by able, 20 October 2017 - 04:20 PM.


#24 Turnbuckle

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Posted 20 October 2017 - 06:05 PM

 

I still think some NR makes it through intact, and that is the reason it is clearly more effective than NAM in studies.  

 

 

 

In which studies is it clearly more effective? In the reference above, the average NAD+ level over time is not statistically different between NAM and NR (the right hand plot of Fig. 5b--area under the curve AUC). Most of the other differences can be put down to the slow digestion/absorption of NR, and/or the lack of ribose with the NAM animals. Ribose is a rare commodity in cells and likely has to be manufactured for NAM to be properly utilized. As for NR getting through intact, a study from 1983 showed that this doesn't happen in the rat--

 

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

 

 

 

The Brenner NR paper claims the opposite, but does not cite this paper or show any data of NR blood levels.


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#25 able

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Posted 21 October 2017 - 11:07 PM

 

 

In which studies is it clearly more effective? In the reference above, the average NAD+ level over time is not statistically different between NAM and NR (the right hand plot of Fig. 5b--area under the curve AUC). Most of the other differences can be put down to the slow digestion/absorption of NR, and/or the lack of ribose with the NAM animals. Ribose is a rare commodity in cells and likely has to be manufactured for NAM to be properly utilized. As for NR getting through intact, a study from 1983 showed that this doesn't happen in the rat--

 

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

 

 

 

The Brenner NR paper claims the opposite, but does not cite this paper or show any data of NR blood levels.

 

 

 

 
I really think I have seen more studies where NAM was not effective and NR was, but I don’t save notes well, and have terrible memory.  Here’s one though, with somewhat conflicting findings:
 
 
 
They used mice with knockout for NAMPT in muscle, which resulted in 85% less NAD+ and deteriorating muscle endurance.  
 
NR and NAM supplements both helped, but NR was more effective.
 
It is one of the studies that made me think that some small amount of NR does make its way direct to tissues besides liver, and may make it a little more effective than NR.
 
 
 
"Mice beginning at age 5.5 months received the treatment continuously for 6 weeks. Intriguingly, this intervention appeared to completely prevent the development of exercise intolerance observed in 7-month-old mNKO mice and reversed lactic acidosis at the point of exhaustion"
 
"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"
 
 
"We found that 100 minutes after oral administration, M+2 NAD was detectable in the liver, whereas the small fraction of NAD labeled in muscle was largely M+1 (Figure 6C, D). "
 
"Accordingly, labeled NR was readily detectable in liver, but not in skeletal muscle (Figure 6E, F)." 
 
"Unlabeled NR was also detectable in both tissues and notably suppressed in mutant muscles, suggesting the existence of a naturally occurring pool capable of interconverting with NMN, perhaps mediated by 5’-nucleotidases (Grozio et al., 2013; Kulikova et al., 2015). "
 
"The minute amount of dual-labeled NAD observed in muscle indicates that direct utilization of NR by the muscle does occur. "
 
"However, oral 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"

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#26 Turnbuckle

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Posted 22 October 2017 - 12:05 AM

Interesting paper, able. It does appear that the NR reaching muscle tissue without being broken down is very close to zero. Thus using N+R over NR is indicated both for cost and for immediacy of effect.


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#27 Nate-2004

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Posted 22 October 2017 - 01:11 PM

I'm a bit more convinced about N+R over NR at the moment. My main concern about N+R right now is the D-ribose and glycation. Perhaps if I just kept the dosage low, like 1g or 2g, perhaps a 1:1 ratio with the NAM, would that be enough?



#28 Turnbuckle

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Posted 22 October 2017 - 01:30 PM

I'm a bit more convinced about N+R over NR at the moment. My main concern about N+R right now is the D-ribose and glycation. Perhaps if I just kept the dosage low, like 1g or 2g, perhaps a 1:1 ratio with the NAM, would that be enough?

 

 

Sure. I cut that down to a little more than stoichiometric a while back. But even if you are below stoichiometric, cells will manufacture the needed ribose. It will just take longer. Prior to adding ribose, I never liked nicotinamide as I felt off taking it. Now I suspect that was the drain on the body's meager ribose reserves.

 

If you look at the rodent results of NAM vs NR, the AUC NAD+ results are about the same, but the peak of NR is higher, likely because the ribose is supplied at the same time and cells don't have to manufacture it. With N+R the peak should be far higher and quicker, as there is no time delay compared to NR, which is something of a slow release product.


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#29 Nate-2004

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Posted 22 October 2017 - 01:38 PM

What is most stoichiometric ratio for N+R? I assume it wouldn't be exactly 1:1.



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#30 Turnbuckle

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Posted 22 October 2017 - 01:46 PM

The MW of nicotinamide is 122 and ribose is 150, so you will need 1 part nicotinamide to 1.23 parts ribose by weight. No need to be precise, I expect.


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