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Alternating between NR and NMN to avoid negative feedback loop

nr nmn nad nicotinamide riboside negative feedback

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#1 livingguy

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Posted 29 April 2018 - 07:28 AM


Alternating between NR and NMN to avoid negative feedback loop in the production of NAD, could it work in theory? What is the mechanism by which this negative feedback is created and by alternating between the two different precursors could we possibly atleast partially avoid the negative feedback that down regulates the production of NAD and therefore achieve overall higher levels. 


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#2 Michael

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Posted 29 April 2018 - 06:52 PM

No: the best-understood mechanism for negative feedback is from NAD+ itself, which works by inhibiting NAMPT activity; the route by which NAD+ is produced is irrelevant. Additionally, many of the other postulated feedback mechanisms are downstream of NAD+, involving the futile use or metabolism of NAD (by CD38, PARP1, nicotinamide N-Mmthyltransferase, etc).


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#3 livingguy

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Posted 29 April 2018 - 06:59 PM

Thank you Michael for your response, is there any other potential strategy you can think of to overcome the negative feedback loop here. Anything that's worth further investigating in your view for this purpose.

#4 able

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Posted 29 April 2018 - 07:14 PM

No: the best-understood mechanism for negative feedback is from NAD+ itself, which works by inhibiting NAMPT activity; the route by which NAD+ is produced is irrelevant. Additionally, many of the other postulated feedback mechanisms are downstream of NAD+, involving the futile use or metabolism of NAD (by CD38, PARP1, nicotinamide N-Mmthyltransferase, etc).

 

 

I understand that the route  NAD+ is created would be irrelevant to the  negative feedback that limits NAD+ in the liver.

 

And I  have read that the source of most NAD+ throughout the body is from liver, with some references to kidney.

 

But I keep thinking it is  possible the benefits from NR/NMN come from the portion that reaches other tissues throughout the body directly, and is not dependent on maximizing NAD+ in the liver.

 

If that is so, would it be possible that  alternating NR and NMN could benefit other organs or tissues by increasing their NAD+ directly, rather than thru the Liver NAD+/NAM route?


Edited by able, 29 April 2018 - 07:54 PM.


#5 recon

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Posted 29 April 2018 - 08:40 PM

Even if the route of NAD+ creation is relevant, I believe that both NMN and NR, ultimately, is in the same pathway. They’re both in the salvage pathway so the difference between taking NR or NMN is the NAMPT, which is only one of the possible downregulation.

That’s if the route is even relevant in this case. The better postulation is that the feedback loop is not from the route but the pool of NAD+ itself, such as an increased CD38 or PARP1. However, I believe that if this is the case then it’s a bit better.

#6 tunt01

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Posted 29 April 2018 - 09:26 PM

Thank you Michael for your response, is there any other potential strategy you can think of to overcome the negative feedback loop here. Anything that's worth further investigating in your view for this purpose.

 

Why wouldn't you just take breaks from NR or NMN and use it in a pulsatile, intermittent way? 



#7 Michael

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Posted 30 April 2018 - 03:18 AM

I understand that the route  NAD+ is created would be irrelevant to the  negative feedback that limits NAD+ in the liver.

 

And I  have read that the source of most NAD+ throughout the body is from liver, with some references to kidney.

 

But I keep thinking it is  possible the benefits from NR/NMN come from the portion that reaches other tissues throughout the body directly, and is not dependent on maximizing NAD+ in the liver.

 

If that is so, would it be possible that  alternating NR and NMN could benefit other organs or tissues by increasing their NAD+ directly, rather than thru the Liver NAD+/NAM route?

 

No: the same feedback is operant in those other tissues as in the liver. Frederick & Baur are explicit on this in muscle, eg.



#8 MikeDC

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Posted 30 April 2018 - 02:37 PM

It was mentioned in some papers that NAMPT is down regulated when high dose NAM is supplemented. I believe the negative feed back loop for NR and NMN are the same which is

the recycling of NAM. 


Edited by MikeDC, 30 April 2018 - 02:50 PM.


#9 Nate-2004

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Posted 30 April 2018 - 05:45 PM

No: the best-understood mechanism for negative feedback is from NAD+ itself, which works by inhibiting NAMPT activity; the route by which NAD+ is produced is irrelevant. Additionally, many of the other postulated feedback mechanisms are downstream of NAD+, involving the futile use or metabolism of NAD (by CD38, PARP1, nicotinamide N-Mmthyltransferase, etc).

 

It makes even more sense to just ramp up NAMPT via regular, frequent sauna use and to take apigenin or drink chamomile tea. The drop in NAD+ is not the main reason we age anyway. We're still dealing with methylation, telomere attrition, protein misfolds and stem cell depletion... this leads to many problems downstream which result in a loss of immune function which leads to senescent cells which leads to SASP which leads to an increase in CD38 which leads to a loss in NAD+, inflammation and other issues that exacerbate the overall decline... and these are just the end years. I'm mostly concerned about staying young in my 40's and 50's. That's got very little to do with NAD+ or SASP.

 

The sauna use kills a lot of these upstream birds with one stone, it deals with the NAMPT problem (by boosting HSF1),  takes care of the inflammation problem as well as helping to stave off the dysfunctional proteins via a boost in heat shock proteins. Granted that last bit is a study on drosophila (seriously what does it take to measure this same effect in humans?). While all this is going to do is slow things down a little, it's not going to reverse anything. I'm crossing my fingers on the future CRISPR/CAS9 therapies.


Edited by Nate-2004, 30 April 2018 - 05:48 PM.

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#10 MikeDC

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Posted 30 April 2018 - 06:52 PM

It makes even more sense to just ramp up NAMPT via regular, frequent sauna use and to take apigenin or drink chamomile tea. The drop in NAD+ is not the main reason we age anyway. We're still dealing with methylation, telomere attrition, protein misfolds and stem cell depletion... this leads to many problems downstream which result in a loss of immune function which leads to senescent cells which leads to SASP which leads to an increase in CD38 which leads to a loss in NAD+, inflammation and other issues that exacerbate the overall decline... and these are just the end years. I'm mostly concerned about staying young in my 40's and 50's. That's got very little to do with NAD+ or SASP.

 

The sauna use kills a lot of these upstream birds with one stone, it deals with the NAMPT problem (by boosting HSF1),  takes care of the inflammation problem as well as helping to stave off the dysfunctional proteins via a boost in heat shock proteins. Granted that last bit is a study on drosophila (seriously what does it take to measure this same effect in humans?). While all this is going to do is slow things down a little, it's not going to reverse anything. I'm crossing my fingers on the future CRISPR/CAS9 therapies.

 "methylation, telomere attrition, protein misfolds and stem cell depletion" 

These could all be due to NAD+ depletion.  We know NR rejuvenate Stem cells and increase DNA repair capacity. 

 

If would be nice if someone can do a clinical trial comparing Sauna use with NR supplementation.  

 

NAMPT is multifunctional. Too much NAMPT expression may cause off target effects such as inflammation.


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#11 Oakman

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Posted 24 May 2018 - 12:35 AM

No: the best-understood mechanism for negative feedback is from NAD+ itself, which works by inhibiting NAMPT activity; the route by which NAD+ is produced is irrelevant. Additionally, many of the other postulated feedback mechanisms are downstream of NAD+, involving the futile use or metabolism of NAD (by CD38, PARP1, nicotinamide N-Mmthyltransferase, etc).

 

This is an interesting discussion. It's been on my mind, and this piece out of ABN's "NAD+ boosting" discussion caught my eye. It seems to offer a solution. From what they describe, most NR is converted to NAM, before NAMPT converts it to NMN and then finally NAD+.  Therefore, the negative feedback lowers NAD+ production. But NMN is after the NAMPT bottleneck, so there is no way lower NAMPT can lower NMN's ability to become NAD+. This means it can be successful used long term with continued NAD+ elevation - no feedback. Their graphic:

nad-pathways-salvage-300x332.png

 

 

 

You'd think then that NMN was the total answer, sort of, but they continue....

 

However we believe including all four of these NAD+ precursors (NMN, NAM, NA, Tryptophan) makes this far more effective at boosting NAD+ throughout the body as they:

  • utilize different pathways
  • are metabolized at different rates
  • vary in the organs they are effective at raising NAD+

According to Dr. Charles Brenner:

“Not every cell is capable of converting each NAD+ precursor to NAD+ at all times…the precursors are differentially utilized in the gut, brain, blood, and organs” (R).

Which makes sense for total body needs anyway, as they are different compounds, having different pathways and effects, and they do other things beside raise NAD+. Even so, they are saying NMN bypasses the NAMPT bottleneck, yet they still want to use other precursors!? Confusing. Strangely, even though they describe a product containing all this, I can't find that they actually sell it, as the product link goes to NMN PURE.

Thoughts?


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#12 able

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Posted 24 May 2018 - 12:43 AM

This is an interesting discussion. It's been on my mind, and this piece out of ABN's "NAD+ boosting" discussion caught my eye. It seems to offer a solution. From what they describe, most NR is converted to NAM, before NAMPT converts it to NMN and then finally NAD+.  Therefore, the negative feedback lowers NAD+ production. But NMN is after the NAMPT bottleneck, so there is no way lower NAMPT can lower NMN's ability to become NAD+. This means it can be successful used long term with continued NAD+ elevation - no feedback. Their graphic:

nad-pathways-salvage-300x332.png

 

 

 

You'd think then that NMN was the total answer, sort of, but they continue....

 

However we believe including all four of these NAD+ precursors (NMN, NAM, NA, Tryptophan) makes this far more effective at boosting NAD+ throughout the body as they:

  • utilize different pathways
  • are metabolized at different rates
  • vary in the organs they are effective at raising NAD+

According to Dr. Charles Brenner:

“Not every cell is capable of converting each NAD+ precursor to NAD+ at all times…the precursors are differentially utilized in the gut, brain, blood, and organs” (R).

Which makes sense for total body needs anyway, as they are different compounds, having different pathways and effects, and they do other things beside raise NAD+. Even so, they are saying NMN bypasses the NAMPT bottleneck, yet they still want to use other precursors!? Confusing. Strangely, even though they describe a product containing all this, I can't find that they actually sell it, as the product link goes to NMN PURE.

Thoughts?

 

 

They used to sell a product that contained all those precursors.

 

I tried that combination product first, and actually preferred it - but for some reason they switched to just the pure NMN that they sell now.

 

That graphic is obsolete now, as Liu shows that most NMN is also digested to NAM.


Edited by able, 24 May 2018 - 12:45 AM.


#13 MikeDC

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Posted 24 May 2018 - 01:07 AM

Can’t believe some people still saying NMN can get into cells without converting to NR first.
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#14 Oakman

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Posted 24 May 2018 - 02:04 AM

Since you don't list references, you need to convince me. For example, from this Dec14th 2017, Cell Metabolism", it doesn't appear the case is settled. The graphics with the abstract clearly show a NMN > NAD+ direct pathway from food intake in the plasma/extracellular space. Another shows a 'possible' uptake mechanism directly from the blood (as well as thru conversion to NR first). I'd postulate that there is more we don't know about NR and NMN conversions than what we know for sure. Research continues, or.... what am I missing? 

 

NAD+ Intermediates: The Biology and Therapeutic Potential of NMN and NR

 

Research on the biology of NAD+ has been gaining momentum, providing many critical insights into the pathogenesis of age-associated functional decline and diseases. In particular, two key NAD+ intermediates, nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN), have been extensively studied over the past several years. Supplementing these NAD+intermediates has shown preventive and therapeutic effects, ameliorating age-associated pathophysiologies and disease conditions. Although the pharmacokinetics and metabolic fates of NMN and NR are still under intensive investigation, these NAD+ intermediates can exhibit distinct behavior, and their fates appear to depend on the tissue distribution and expression levels of NAD+ biosynthetic enzymes, nucleotidases, and presumptive transporters for each. A comprehensive concept that connects NAD+ metabolism to the control of aging and longevity in mammals has been proposed, and the stage is now set to test whether these exciting preclinical results can be translated to improve human health.

 

Also here, Feb 1st 2018 NAD+ biosynthesis, aging, and disease, "In mammals, a major pathway of NAD + biosynthesis is the salvage pathway from nicotinamide ( Figure 1). Nicotinamide is converted to NMN, a key NAD + intermediate, by nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in this pathway 12. NMNATs then convert NMN into NAD + 1415."


Edited by Oakman, 24 May 2018 - 02:07 AM.

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