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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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#61 stefan_001

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Posted 03 November 2017 - 08:39 PM

It does bother me that the liver seems to filter NR out of the bloodstream so likely has a very brief period it might be effective outside the liver.

But NR does have many proven health benefits, whatever the pathways.

The liver uses NR, it doesnt filter it. So the liver cells, for whatever reason, have need to increase NAD+. So in that sense liver get first pickings to improve its health. I think this somewhat correlates to the studies showing that NAD boosting is good for liver health. That liver NR consumption ofcourse leads to NAM increase.

Edited by stefan_001, 03 November 2017 - 08:42 PM.

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#62 able

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Posted 03 November 2017 - 11:17 PM

 

It does bother me that the liver seems to filter NR out of the bloodstream so likely has a very brief period it might be effective outside the liver.

But NR does have many proven health benefits, whatever the pathways.

The liver uses NR, it doesnt filter it. So the liver cells, for whatever reason, have need to increase NAD+. So in that sense liver get first pickings to improve its health. I think this somewhat correlates to the studies showing that NAD boosting is good for liver health. That liver NR consumption ofcourse leads to NAM increase.

 

 

Yes, clearly boosting of NAD+ is good for liver.  Just wondering if NR is better than NAM and others at boosting it outside the liver.

 

The livers main job is to filter blood.  But I guess it would be more accurate to say the liver filters NR from the bloodstream and metabolizes it, whether that is to NAM, NMN, or whatever.

 

But where does it go so quickly that it is not detectable in blood? 

 

Trammel paper says:

 

"hepatic detection of NR varied and displayed no response to NR administration"

 

and

 

"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"

 

Which I don't quite understand or believe.  

 

If it is phosphorylated (to NMN)  so quickly that it is not detectable in the blood, and doesn't elevate NR levels in the liver, why does it take 4 hours or so before it elevates NAD+, while NMN elevates NAD+ in 30 minutes?

 

That is one of the things that makes me believe Turnbuckle is right and it mostly goes thru NAM. 


Edited by able, 03 November 2017 - 11:22 PM.

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#63 stefan_001

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Posted 04 November 2017 - 06:41 PM

Again the Trammel study only measured the metabolites after 1 hour in the mouse study. The blood measurements taken from Brenner who consumed NR in table 5.1 are more interesting. It shows a more than doubling of NAD+ and almost tripling of NMN in the blood at the first measurement point which was 20 minutes (best would have been if they had measured at 1,5,15,20 minutes) . At that point NAM had risen by 50%. At the next measurement point at 36 minutes NAM peaks and NMN and NAD+ have fallen back. From then onwards there is some form of "oscillation" which could be secondary, tertiary etc waves of the consequence of the NR oral "injection" via the salvage pathways.

 


Edited by stefan_001, 04 November 2017 - 06:49 PM.


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#64 able

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Posted 04 November 2017 - 07:59 PM

Yes.  

 

It does look like there is a smaller spike in NMN and NAD+ at 20 minutes.

 

Then nothing until 4 hours.

 

To me, the best explanation is some NR does make it thru digestion intact and quickly metabolized to NMN and then NAD+ in the liver.

 

After than,  NAD+ drops back down and doesn't see the majority of its increase until 4 hours, exactly how long NAM takes to digest and elevate NAD+ in the liver.

 

That looks like 75% or so of the NR was digested to NAM and at 4 hours is then acting to elevate NAD+.

 

Remember, the NR was not detectable in liver or blood at all.  

 

So I don't see any way that all the NR acts at 20 minutes, then is just "hanging  around" somewhere and suddenly appears to elevate NAD+ at 4 hour point.

 

To me, that also explains how NR has a lot of overlap with NAM in the benefits, but is more effective in some situations.

 

Although the data isn't really clean for that explanation either, as the NMN remains elevated throughout.  So some NR might convert to NMN at 20 minutes to boost NAD, then the NMN remains elevated throughout, but doesn't explain the sudden jump in NAM and NAD at 4 hours.

 

Of course, that is all assuming the data is accurate, which is risky considering it was a n=1 experiment.

 

I do notice that chart is in Trammels thesis, but is not in the paper they later published here.

 

So I don't know if they considered n=1 experiment not good enough proof, or because it was  not positive for NR.

 

 

 

 

 

 

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Edited by able, 04 November 2017 - 08:44 PM.

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#65 stefan_001

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Posted 04 November 2017 - 08:43 PM

That you cannot find NR is no different than when administrating NMN. In the NMN study here:

 

https://www.ncbi.nlm...pubmed/28068222

 

you will find that NMN gets into blood circulation within 2–3 min and is also cleared from blood circulation within 15 min. It doesnt mean that the liver takes all but its simply absorbed by the body.

 

What is interesting is that NR triggers clearly different outcomes than NAM, see for example 5.2a that shows a strong NMN upswing. Interestingly the blood measurement in Brenner shows something similar at 4h (3x jump) so we could speculate that NAM would similarly not cause this upswing of NMN in circulating blood. My "hypothesis" is that by consuming NR (and I think similarly NMN even if we have no measurements) you trigger a different metabolic oscillation that has a more favorable outcome.


Edited by stefan_001, 04 November 2017 - 08:52 PM.


#66 Turnbuckle

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Posted 04 November 2017 - 08:49 PM

 

 

you will find that NMN gets into blood circulation within 2–3 min and is also cleared from blood circulation within 15 min. It doesnt mean that the liver takes all but its simply absorbed by the body.

 

 

Obviously this must be absorption through the oral cavity, esophagus, or stomach, but once it gets into the intestines, previous work shows that it is broken down.



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#67 able

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Posted 04 November 2017 - 09:17 PM

That you cannot find NR is no different than when administrating NMN. In the NMN study here:

 

https://www.ncbi.nlm...pubmed/28068222

 

you will find that NMN gets into blood circulation within 2–3 min and is also cleared from blood circulation within 15 min. It doesnt mean that the liver takes all but its simply absorbed by the body.

 

What is interesting is that NR triggers clearly different outcomes than NAM, see for example 5.2a that shows a strong NMN upswing. Interestingly the blood measurement in Brenner shows something similar at 4h (3x jump) so we could speculate that NAM would similarly not cause this upswing of NMN in circulating blood. My "hypothesis" is that by consuming NR (and I think similarly NMN even if we have no measurements) you trigger a different metabolic oscillation that has a more favorable outcome.

 

 

The behavior certainly seems different to me.

 
NMN is always detectable in blood, but there is large increase that is quickly cleared and returns to baseline levels,and soon thereafter appears as increase in NAD+ in many tissues.  It seems to be quickly utilized and then gone.
 
There is no mysterious second spike 4 hours later.  
 
NR shows the small initial increase at 20 minutes, then nothing until 4 hours later.  Some of the NR is likely to have been phosphorylated to NMN and maybe hanging around as such.  But the relatively small increase in NMN (and speed at which NMN acts) doesn't explain the much later spike in NAD+.
 
I've long thought the slow, time release increase in NAD+ was a great feature of NR, and still think it might be.  But Just would like to know why it happens, and if it is just acting as NAM, or delayed for some reason I haven't seen explained.
 
Maybe some other intermediate like NAAD, or some combination of things, but I just haven't seen something clear on that.

Edited by able, 04 November 2017 - 09:22 PM.


#68 stefan_001

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Posted 04 November 2017 - 09:21 PM

 

That you cannot find NR is no different than when administrating NMN. In the NMN study here:

 

https://www.ncbi.nlm...pubmed/28068222

 

you will find that NMN gets into blood circulation within 2–3 min and is also cleared from blood circulation within 15 min. It doesnt mean that the liver takes all but its simply absorbed by the body.

 

What is interesting is that NR triggers clearly different outcomes than NAM, see for example 5.2a that shows a strong NMN upswing. Interestingly the blood measurement in Brenner shows something similar at 4h (3x jump) so we could speculate that NAM would similarly not cause this upswing of NMN in circulating blood. My "hypothesis" is that by consuming NR (and I think similarly NMN even if we have no measurements) you trigger a different metabolic oscillation that has a more favorable outcome.

 

 

The behavior certainly seems different to me.

 
NMN is always detectable in blood, but there is large increase that is quickly cleared and returns to baseline levels,and soon thereafter appears as increase in NAD+ in many tissues.  It seems to be quickly utilized.
 
There is no mysterious second spike 4 hours later.  
 
NR shows the initial increase at 20 minutes, then nothing until 4 hours later.  Some of the NR is likely to have been phosphorylated to NMN.  But the relatively small increase in NMN (and speed at which NMN acts) doesn't explain the much later spike in NAD+.
 
I've long thought the slow, time release increase in NAD+ was a great feature of NR, and still think it might be.  But Just would like to know why it happens, and if it is just acting as NAM, or delayed for some reason I haven't seen explained.

 

 

So why is there no spike with NAM administration after 4 hours?


 



#69 able

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Posted 04 November 2017 - 09:26 PM

There is.  NAM peaks from 4-8 hours when  supplementation is   NAM or NR.

 

With NR (black) note the big spike in NAM around 6 hours, just before the spike in NAD+ at 8 hours.

 

With NAM (green), NAM is elevated throughout up to around 8 hours before dropping. 

 

That is what Turnbuckle is always pointing out about NR and NAM.   That a lot of NR is just slow release NAM.  

 

Not sure I go that far, but the slow response is most definately different than NMN.

 

 

 

 

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Edited by able, 04 November 2017 - 09:39 PM.


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#70 stefan_001

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Posted 04 November 2017 - 09:48 PM

..

Edited by stefan_001, 04 November 2017 - 09:50 PM.


#71 Michael

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Posted 04 November 2017 - 09:51 PM

Yes.  
 
It does look like there is a smaller spike in NMN and NAD+ at 20 minutes.
 
Then nothing until 4 hours.
 
To me, the best explanation is some NR does make it thru digestion intact and quickly metabolized to NMN and then NAD+ in the liver. ...
 
Remember, the NR was not detectable in liver or blood at all.

 

I wouldn't take that non-finding too literally. As I've mentioned a couple of times, it seems agreed that NR is quite difficult to detect in biological fluids. Trammel's thesis says that "At present, NR has not been detected in the blood cell fraction nor in plasma due to difficulty in its extraction. As it stands, we have measured that NR is absorbed and circulates in a “shadowy” manner" (meaning, by implication of its labeled metabolites). When Imai, whose work is focused on NMN rather than NR, started working on it back in 2009, "we were able to detect nicotinamide, NMN, and nicotinamide riboside (NR) in human plasma samples (Figure 1A). Because of the matrix effects, the development of a quantitative measurement method for these NAD-related chemicals was quite challenging. Nonetheless, we found appropriate column and buffer conditions to obtain linear standard curves of NMN and nicotinamide using human plasma samples spiked with these compounds (Figure 1B)" (2011 grant report). He's of course gone on to further develop the NMN method and actually look for it in mouse and human experiments, while he's unfortunately not done so with NR. And even with those challenges, Frederick & Baur PMID 27508874 do detect it "at trace levels in blood" with LC-MS, and the bulk of it is M+2 (intact):

 

gr6.jpg

 

Presumably improved methods working up from Imai's work would detect it at higher levels, although it's safe to assume it's not going to be orders of magnitude.

 

I do notice that chart is in Trammels thesis, but is not in the paper they later published here.
 
So I don't know if they considered n=1 experiment not good enough proof, or because it was  not positive for NR.

 

It's in the supplemental information.

 

 

you will find that NMN gets into blood circulation within 2–3 min and is also cleared from blood circulation within 15 min. It doesnt mean that the liver takes all but its simply absorbed by the body.

 
Obviously this must be absorption through the oral cavity, esophagus, or stomach, but once it gets into the intestines, previous work shows that it is broken down.

 

(As discussed near the beginning of the thread, Turnbuckle is here insisting on relying entirely on Gross & Henderson PMID 6218262 from 1983, which was based on singly-labeled, secondarily-derived NR, and ignoring subsequent research).


Edited by Michael, 04 November 2017 - 09:52 PM.

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#72 able

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Posted 04 November 2017 - 11:26 PM

Thanks for the clarifications Michael.

 

I had seen that it was difficult to detect, and that it had finally been detected at trace levels. 

 

With all the scrutiny of NR over the last several years, and all the money Chromadex is spending on research , you'd think that is a top priority and should have been solved by now.  

 

They are developing the ability to detect NR as evidenced by the finding at Trace levels.

 

I took this to indicate it only exists in small quantities for short period of time in the bloodstream and is quickly metabolized in the liver.

 

Perhaps that is not the case, and it does exist in larger quantities but is still too difficult to detect.  But it doesn't seem there is evidence to say it exist at more than trace levels for a brief period. 

 

I will certainly feel a lot better about NR when they can detect it at higher levels.

 

 

 

 


Edited by able, 04 November 2017 - 11:49 PM.


#73 Turnbuckle

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Posted 04 November 2017 - 11:37 PM

 

 

 

 

you will find that NMN gets into blood circulation within 2–3 min and is also cleared from blood circulation within 15 min. It doesnt mean that the liver takes all but its simply absorbed by the body.

 
Obviously this must be absorption through the oral cavity, esophagus, or stomach, but once it gets into the intestines, previous work shows that it is broken down.

 

 

(As discussed near the beginning of the thread, Turnbuckle is here insisting on relying entirely on Gross & Henderson PMID 6218262 from 1983, which was based on singly-labeled, secondarily-derived NR, and ignoring subsequent research).

 

 

 

Hardly, the older research was by direct delivery to the intestines, and found no absorption without breakdown. Here  the NMN (dissolved in drinking water) entering circulation in just minutes, and then disappears. This points to absorption prior to entering the intestines, as the residence time in the stomach is longer than a few minutes, and the most likely route is sublingual.


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#74 able

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Posted 05 November 2017 - 12:12 AM

 

 

 

 

 

you will find that NMN gets into blood circulation within 2–3 min and is also cleared from blood circulation within 15 min. It doesnt mean that the liver takes all but its simply absorbed by the body.

 
Obviously this must be absorption through the oral cavity, esophagus, or stomach, but once it gets into the intestines, previous work shows that it is broken down.

 

 

(As discussed near the beginning of the thread, Turnbuckle is here insisting on relying entirely on Gross & Henderson PMID 6218262 from 1983, which was based on singly-labeled, secondarily-derived NR, and ignoring subsequent research).

 

 

 

Hardly, the older research was by direct delivery to the intestines, and found no absorption without breakdown. Here  the NMN (dissolved in drinking water) entering circulation in just minutes, and then disappears. This points to absorption prior to entering the intestines, as the residence time in the stomach is longer than a few minutes, and the most likely route is sublingual.

 

 

Interesting idea.  I hadn't thought about the NMN being absorbed sublingual, which would explain the speed of absorption.

 

If so it revives that discussion about best delivery method for NMN or NR.

 

However, I  don't know that there is any evidence it "disappears".  As the NMN levels drop, NAD+ increases.  Is that what you mean by "disappear" or do you believe it is broken down to NAM also?  I haven't noticed any evidence for that.



#75 Michael

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Posted 05 November 2017 - 03:36 AM

They are developing the ability to detect NR as evidenced by the finding at Trace levels.
 
I took this to indicate it only exists in small quantities for short period of time in the bloodstream and is quickly metabolized in the liver.
 
Perhaps that is not the case, and it does exist in larger quantities but is still too difficult to detect.  But it doesn't seem there is evidence to say it exist at more than trace levels for a brief period. 
 
I will certainly feel a lot better about NR when they can detect it at higher levels.

 
 What is certainly happening is that a lot of it is being utilized in the liver, in no small part because it gets there first via the portal circulation. I have no doubt that very little actually circulates as intact NR, and what NR is formed is rapidly metabolized — not just in the liver, but in every perfused organ along the way. I'll say again that it's a separate question as to which NAD+ precursor actually raises NAD+ more, that it will vary by tissue and by time — and that elevating NAD+ does not, in itself, constitute a health benefit.
 
You quoted the Trammel paper  that "hepatic detection of NR varied and displayed no response to NR administration" and "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", and said you found those statements difficult to understand or believe. Aside from the fact that it would be even harder to detect NR in tissue than blood, rapid phosphorylation is a quite plausible explanation for not finding the stuff — what don't you understand about this?
 

 

 

Obviously this must be absorption through the oral cavity, esophagus, or stomach, but once it gets into the intestines, previous work shows that it is broken down.

 
(As discussed near the beginning of the thread, Turnbuckle is here insisting on relying entirely on Gross & Henderson PMID 6218262 from 1983, which was based on singly-labeled, secondarily-derived NR, and ignoring subsequent research).
 
Hardly, the older research was by direct delivery to the intestines, and found no absorption without breakdown. Here  the NMN (dissolved in drinking water) entering circulation in just minutes, and then disappears. This points to absorption prior to entering the intestines, as the residence time in the stomach is longer than a few minutes, and the most likely route is sublingual.

Both the Brenner-NR and Imai-NMN mouse PK studies have administered their respective precursors by gavage: there's no opportunity for sublingual absorption. I don't see any particular reason to think it's gastric either: all the other B vitamins are predominantly absorbed in the intestine, including NAM and NA. We have microvilii for a reason. And, of course, the human studies have used capsules.

 

IAC, if the debate is now reduced to gastric vs. intestinal absorption, I'd say the question is moot.



#76 able

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Posted 05 November 2017 - 04:27 AM

 

They are developing the ability to detect NR as evidenced by the finding at Trace levels.
 
I took this to indicate it only exists in small quantities for short period of time in the bloodstream and is quickly metabolized in the liver.
 
Perhaps that is not the case, and it does exist in larger quantities but is still too difficult to detect.  But it doesn't seem there is evidence to say it exist at more than trace levels for a brief period. 
 
I will certainly feel a lot better about NR when they can detect it at higher levels.

 
 What is certainly happening is that a lot of it is being utilized in the liver, in no small part because it gets there first via the portal circulation. I have no doubt that very little actually circulates as intact NR, and what NR is formed is rapidly metabolized — not just in the liver, but in every perfused organ along the way. I'll say again that it's a separate question as to which NAD+ precursor actually raises NAD+ more, that it will vary by tissue and by time — and that elevating NAD+ does not, in itself, constitute a health benefit.
 
You quoted the Trammel paper  that "hepatic detection of NR varied and displayed no response to NR administration" and "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", and said you found those statements difficult to understand or believe. Aside from the fact that it would be even harder to detect NR in tissue than blood, rapid phosphorylation is a quite plausible explanation for not finding the stuff — what don't you understand about this?


 

 

I certainly believe that rapid phosphorylation is a quite plausible explanation. Makes perfect sense to me.

 

What I have trouble with is that they propose: 

 

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

 

NMN seems to have a very short delay before elevating NAD+

 

Why does most of the NR have a 4-8 hour delay.  Why isn't it detectable in those 4-8 hours?  It has elevated NAD+ some, and there is some elevation of NMN.  

 

But then the big spike at 4-8 hours just seems strange.  And the fact it occurs in unison with large increase in NAM.

 

I guess some NR could be absorbed quickly through portal circulation as you say, and the majority takes 4-6 hours to make it through digestion, and then is also phosphorylated to NMN too rapidly to be detected in blood.   

 

So that implies that NR never really circulates outside the liver in quantity, but can be more effective than NAM because it is rapidly converted to NMN and either circulates as NMN or NAD+


Edited by able, 05 November 2017 - 04:47 AM.


#77 Turnbuckle

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Posted 05 November 2017 - 12:01 PM

 

Both the Brenner-NR and Imai-NMN mouse PK studies have administered their respective precursors by gavage: there's no opportunity for sublingual absorption. I don't see any particular reason to think it's gastric either: all the other B vitamins are predominantly absorbed in the intestine, including NAM and NA. We have microvilii for a reason. And, of course, the human studies have used capsules.

 

IAC, if the debate is now reduced to gastric vs. intestinal absorption, I'd say the question is moot.

 

 

Then the next most likely absorption is in the stomach. After it passes into the intestines, expect absorption to stop. Drugs are known to be absorbed by the stomach--

 

The human stomach is capable of absorbing most acidic drugs and the very weakly basic drugs. Salicylic acid, aspirin, thiopental, secobarbital and antipyrine, which are undissociated in the acidic gastric contents, were readily absorbed. Phenol red, quinine, ephedrine and aminopyrine, which are almost completely ionized in acid solution were not absorbed. These results are compatible with the hypothesis that drugs are absorbed by passive diffusion of their lipid soluble undissociated form. Many drugs may be absorbed by the human stomach as rapidly or more rapidly than ethyl alcohol.

http://jpet.aspetjou...ntent/120/4/540

 

 

If this is what happened here, dissolving it in water and taking it on an empty stomach might work. And lying on one's left side to increase the residence time.


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#78 able

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Posted 05 November 2017 - 03:18 PM

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.  

 

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. 

 

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.  

 

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.

 

I do really like NR and don't have a problem with other studies.  I just find this particular study makes too many exaggerated or unsubstantiated claims like that which makes me suspicious they are letting monetary considerations bias their interpretation too much.

 

 

 

 

 

 

 


Edited by able, 05 November 2017 - 03:46 PM.

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#79 stefan_001

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Posted 05 November 2017 - 05:07 PM

 

 

Both the Brenner-NR and Imai-NMN mouse PK studies have administered their respective precursors by gavage: there's no opportunity for sublingual absorption. I don't see any particular reason to think it's gastric either: all the other B vitamins are predominantly absorbed in the intestine, including NAM and NA. We have microvilii for a reason. And, of course, the human studies have used capsules.

 

IAC, if the debate is now reduced to gastric vs. intestinal absorption, I'd say the question is moot.

 

 

Then the next most likely absorption is in the stomach. After it passes into the intestines, expect absorption to stop. Drugs are known to be absorbed by the stomach--

 

The human stomach is capable of absorbing most acidic drugs and the very weakly basic drugs. Salicylic acid, aspirin, thiopental, secobarbital and antipyrine, which are undissociated in the acidic gastric contents, were readily absorbed. Phenol red, quinine, ephedrine and aminopyrine, which are almost completely ionized in acid solution were not absorbed. These results are compatible with the hypothesis that drugs are absorbed by passive diffusion of their lipid soluble undissociated form. Many drugs may be absorbed by the human stomach as rapidly or more rapidly than ethyl alcohol.

http://jpet.aspetjou...ntent/120/4/540

 

 

If this is what happened here, dissolving it in water and taking it on an empty stomach might work. And lying on one's left side to increase the residence time.

 

 

What is interesting is whether there could be absorption methods that allows us to "steer" NR to certain tissues so they do not need to compete with the liver:

- for skin dermal application ?

- lungs inhaling (note certain fillers can be damaging) ?

- eyes, eye drops?

- brain, eye drops, nasal spray?

 

Anybody knows a source of NR/Niagen without filler?

 

 


Edited by stefan_001, 05 November 2017 - 05:09 PM.

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#80 Nate-2004

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Posted 05 November 2017 - 08:04 PM

Stefan, given the current formulation it's only stable in water up to 6 hrs before it breaks down (I assume it breaks down into NAM+R?). So the best method is to either mix the relevant amount in a small amount of water or DMSO or saline or something then put it wherever is best. Sublingual could work fine but not sure how long it takes to absorb there.



#81 able

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Posted 05 November 2017 - 08:29 PM

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.

 

 



#82 stefan_001

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Posted 06 November 2017 - 06:44 AM

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.


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#83 stefan_001

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Posted 06 November 2017 - 07:46 AM

Stefan, given the current formulation it's only stable in water up to 6 hrs before it breaks down (I assume it breaks down into NAM+R?). So the best method is to either mix the relevant amount in a small amount of water or DMSO or saline or something then put it wherever is best. Sublingual could work fine but not sure how long it takes to absorb there.

 

Okay then need to make solutions every day, which takes a couple minutes but doable. For anything else than dermal e.g. nasal spray probably need the stuff without filler.


Edited by stefan_001, 06 November 2017 - 07:47 AM.


#84 Turnbuckle

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Posted 06 November 2017 - 10:25 AM

Stefan, given the current formulation it's only stable in water up to 6 hrs before it breaks down (I assume it breaks down into NAM+R?). So the best method is to either mix the relevant amount in a small amount of water or DMSO or saline or something then put it wherever is best. Sublingual could work fine but not sure how long it takes to absorb there.

 

The non-chloride version of NR might work better sublingually. The paper below lists several factors. For instance--

 

Lipophilicity of drug: For a drug to be absorbed completely through sublingual route, the drug must have slightly higher lipid solubility than that required for GI absorption is necessary for passive permeation

 

pH and pKa of the saliva: As the mean pH of the saliva is 6.0, this pH favors the absorption of drugs which remain unionized. Also, the absorption of the drugs through the oral mucosa occurs if the pKa is greater than 2 for an acid and less than 10 for a base.

 

http://www.ijddr.in/...on.php?aid=5669

 

 


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#85 Nate-2004

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Posted 06 November 2017 - 01:29 PM

Who makes it without the chloride and how? I didn't think it was possible to make and stabilize without the chloride salt.



#86 Michael

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Posted 06 November 2017 - 11:48 PM

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:
 

gr1.jpg



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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#87 stefan_001

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Posted 07 November 2017 - 06:50 AM

 

 

Improving the availability to cells other than liver does seem likely to yield better, or at least different, results. ...

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: ...

The same point is made in multiple reviews, such as PMIDs 28899755 and 28784597. ...

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 ...

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).

 
I agree on covering the bases. With NR (and I see NMN pretty much as "doing the same") the discussion in future will shift to what else to add. For ABN I dont understand the product. To get 250mg of NMN you need to consume 700mg of a non specified combination of Trypto, NA, NAM. The whole fact that they dont split it out in in mg per compound points for me to an uncontrolled process or sloppyness. The 700mg might as well be 699mg of NAM and whats the point in taking that?


Edited by Michael, 07 November 2017 - 06:04 PM.
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#88 stefan_001

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Posted 07 November 2017 - 04:07 PM

Ha another ill informed rating. Can the person who gave that then in addition post the composition of the ABN capsule broken down in the 4 compounds?


Edited by stefan_001, 07 November 2017 - 04:12 PM.

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#89 able

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Posted 07 November 2017 - 04:49 PM

Someone stated  on another thread that they had a severe Niacin flush from the mixed NMN product.

 

I don't know how much mg it takes for that to occur, but pretty sure it's more than the 1 mg you hypothesize may be in the product.

 

I actually agree with you about the product - I don't want  a mix, and even if I did, would want to see the mg of each product shown.

 

But I do see that manufacturers use that approach quite a bit.  I'm not a marketing guy, so don't really know why, but I've always thought it could be to:

 

  • Keep competitors from knowing/duplicating their "secret sauce"

 

  • Imply to more gullible consumers that they have a "secret sauce"

 

Whatever the reason in this case, I would agree it is a mistake and would hope they would come out with the details in future versions of this product.


Edited by able, 07 November 2017 - 05:05 PM.

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