15 replies to this topic

[recon]

Hi,

Forgive me if I get anything wrong. I'm new into these NAD+, NR, NMN business.

So, I have been following the news about NAD+ and NR.
If I am correct, NAD+ is naturally occurring in our body and will decline as we age.

Therefore, my question is, if we are young and the NAD+ levels are high, then will supplementation with external NMN or NR to stimulate NAD+ reduce natural NAD+ production in the body?

My idea is that NAD+ is produced naturally in the body and as we age, the levels decline so supplementation when we age is a good move. However, if we are still young and the levels are high, then wouldn't, by negative feedback, that the natural production be impeded? Wouldn't the body reduce production because we have sufficient from exogenous source?

Then, shouldn't NR or NMN only be taken by the aging and not the young? And, wouldn't that also means that if we were to stop, then we will have a period when we have reduced levels due to undercompensation when the levels are greater than natural?

Thank you for your time. I have sent this question to a few manufacturers to get an answer as well.

[able]

Of course older, sicker, fatter humans are going to have lower NAD+ levels and benefit more from NR, but it likely has some benefit for those that are healthy and under 40 - just a matter of is it worth the cost.

 

This study I just posted about here, showed some improvement in metabolic flexibility (better able to burn fat), in younger mice that weren't sick or fat, at a very low dose of NR.

 

The 12 month mouse study with NMN showed significant improvement in a wide range of metabolic health, at a much higher dosage.

 

NMN in water at 100 or 300mg/kg, from 5-17 months resulted in 4 or 9% less weight gain, even on same exact calories.  Thats like teenage to middle age in humans. If humans had 9% weight gain, our health care cost would be reduced astronomically.

 

(oops, edited to remove reference about test subject being overfed - they were on regular chow diet.  Might be even more effective on humans considering the average american diet)

 

 

Edited by able, 12 October 2017 - 07:57 PM.

[recon]

Of course older, sicker, fatter humans are going to have lower NAD+ levels and benefit more from NR, but it likely has some benefit for those that are healthy and under 40 - just a matter of is it worth the cost.

This study I just posted about here, showed some improvement in metabolic flexibility (better able to burn fat), in younger mice that weren't sick or fat, at a very low dose of NR.

The 12 month mouse study with NMN showed significant improvement in a wide range of metabolic health, at a much higher dosage.

NMN in water at 100 or 300mg/kg, from 5-17 months resulted in 4 or 9% less weight gain, even on same exact calories. Thats like teenage to middle age in humans. If humans had 9% weight gain, our health care cost would be reduced astronomically.

(oops, edited to remove reference about test subject being overfed - they were on regular chow diet. Might be even more effective on humans considering the average american diet)

Thanks for the reply. Yeah, I agree with you about that.

However, the second part of my questions bothers me.
If NAD+ is produced naturally by our body, will taking an external substance to stimulate its production eventually reduces the natural driving factor by some sort of a negative feedback mechanism?

As in, if a young healthy person with already high NAD+ production takes an external substance to further stimulate the production of NAD+ (say, NR or NMN, assuming that they work), will the body then reduces its own natural driving factor such that when there is no longer that stimulant, the body do not produce as much?
If so, then, will abruptedly stopping those stimulants (NR/NMN) after taking them for a long time then see a sudden drop in NAD+ levels lower than original levels because the body reduces the natural production since there was a lot of NAD+ than usual?

I'm sorry if I'm being confusing with my question. I think I'm missing some jargon here. Probably "downregulate"?

Thanks in advance.

[recon]

Additionally, in the thread "Study on different dosages of NR using mice with intact NNT gene" it is shown that NR not only works less in those with already elevated NAD+ levels but may be "harmful".

 

So with my hypothesis, the exogenous stimulant of NAD+ will (downregulate?) the production of NAD+ in those with already high enough. In other words, your body reduces the production of that it considers too much from what it considers sufficient.

[Nate-2004]

Forgive me if I get anything wrong. I'm new into these NAD+, NR, NMN business.

So, I have been following the news about NAD+ and NR.
If I am correct, NAD+ is naturally occurring in our body and will decline as we age.

Therefore, my question is, if we are young and the NAD+ levels are high, then will supplementation with external NMN or NR to stimulate NAD+ reduce natural NAD+ production in the body?

My idea is that NAD+ is produced naturally in the body and as we age, the levels decline so supplementation when we age is a good move. However, if we are still young and the levels are high, then wouldn't, by negative feedback, that the natural production be impeded? Wouldn't the body reduce production because we have sufficient from exogenous source?

Then, shouldn't NR or NMN only be taken by the aging and not the young? And, wouldn't that also means that if we were to stop, then we will have a period when we have reduced levels due to undercompensation when the levels are greater than natural?

Thank you for your time. I have sent this question to a few manufacturers to get an answer as well.

 

Short answer, no.

 

Long answer, NR is a precursor to NAD+. We're not stimulating hormone production we are merely providing our bodies with a small molecule that is just a couple of steps away from NAD+ and can enter the cell. This isn't exogenous NAD+.

 

I can understand the concern given that there are many instances where we're taking exogenous hormones, antioxidants or stimulating neurotransmitter production can often down regulate our own endogenous production of these chemicals. However, I don't think in cases where we are taking precursors or that it could be the case with the production of a coenzyme like NAD+.

[recon]

Hi,

Assuming NR will effectively raise NAD+, wouldn’t as the result of greater NAD+, NAMPT will be downregulared?

What then can be supplemented to keep NAMPT up and running to convert the eventual byproduct NAM back into NAD?

I heard that resveratrol is one, but I’m not so sure about pterostilbene.

[Michael]

 

If I am correct, NAD+ is naturally occurring in our body and will decline as we age.[/size]

Therefore, my question is, if we are young and the NAD+ levels are high, then will supplementation with external NMN or NR to stimulate NAD+ reduce natural NAD+ production in the body?[/size]

 
Short answer, no.
 
Long answer, NR is a precursor to NAD+. We're not stimulating hormone production we are merely providing our bodies with a small molecule that is just a couple of steps away from NAD+ and can enter the cell. This isn't exogenous NAD+.

 
That would biologically be very strange. No biochemical reaction proceeds simply on the basis of substrate availability: it's normal for pathways to be down- or counterregulated by an abundance of their product, either by simple product inhibition, or as a via regulation (to avoid imbalances (in this case, possibly an overly oxidative redox tone) or simply to conserve resources (note eg. that NMN-->NAD+ consumes ATP)).
 
This textbook says that NAMPT is inhibited by NAD, and Shibata cites his own PMID 16802695 to the same effect. Frederick and Baur  PMID 25411251 , a study attempting to boost muscle NAD by increasing muscle-specific NAMPT expression,
 

achieved a relative elevation of skeletal muscle NAD greater than or equal to those reported for small molecule precursor supplementation ([with NR or NMN]), exercise (3, 4), or deletion of either PARP-1 (18) or PARP-2 (19). Because increased NAD was achieved via supraphysiological levels of NAMPT protein expression and was not further enhanced by supplementing NAM, it is possible that negative feedback maintains the steady-state NAD concentration in our model at or near a theoretical limit for salvage-mediated synthesis. These observations are consistent with reports that the K_m of NAMPT for NAM in the presence of ATP is well below our observed tissue concentrations of NAM and that physiological levels of pyridine nucleotides can inhibit NAMPT activity in rat liver extracts.

 
The same authors ruminate a bit further here (= here):
 

We wondered of Nampt overexpression cause any effect on redpx indices (NADH, Fp, and redox ratio). However, we found no significant difference between the Nampt transgenic group and the control group, consistent with the equilibration of mitochondrial NAD+/NADH identified in this model using [MS]. Although Nampt functions importantly in salvaging NAD+, other mechanisms likely resist changes in NAD+ levels, including enhanced activity of NAD-dependent enzymes and feedback inhibition of Nampt. Despite the lack of major changes in middle-aged mice, increased capacity for NAD synthesis may help maintain stable NAD levels and redox status at more advanced ages, when NAD normally fails.

The same point was made by Sinclair in this paper (discussed in this thread):
 

NAMPT enzyme activity in skeletal muscle was 7-fold higher in NamptTg mice versus WT mice.  ... NMN, the product of NAMPT activity, was ∼2-fold higher  ... There was a concomitant 1.6-fold elevation of skeletal muscle NAD+ ... This relatively modest increase of NAD⁺ is comparable to other published studies that used various strategies to boost tissue NAD⁺ levels [27-30]. Activation of NAD⁺ consuming pathways or the contribution of other homeostatic mechanisms probably serves to place a ceiling on the maximal NAD⁺ level. [That's consistent also with the larger effect on NMN vs. NAD⁺-MR]. For instance, physiological levels of NAD⁺ can inhibit NAMPT activity, thus posing a powerful feedback inhibition loop that blunts the impact of elevated NAMPT activity [31]. ...

recon: your question here (and certainly my reply!) are so closely tied in to the question in one of your other threads (WIll NR downregulate NAMPT?) — which so far has no takers — as to seem redundant; what would you think of my merging the two threads?

[Nate-2004]

On a related note. This post references a study showing NAMPT can be upregulated by HSF1, which is activated by a number means, such as heat stress or sulforaphane. Maybe the best time to take NMN (or NR?) is before using the sauna?

Edited by Nate-2004, 12 November 2017 - 12:01 AM.

[recon]

recon: your question here (and certainly my reply!) are so closely tied in to the question in one of your other threads (WIll NR downregulate NAMPT?) — which so far has no takers — as to seem redundant; what would you think of my merging the two threads?

Sure thing, Michael! This thread was originally made when I was still largely ignorant of the specific biochemical processes surrounding NAD. The subsequent one was when I wanted to stimulate a conversation on a hypothesis regarding a specific enzyme.

Thanks to you and Nate for answering. I’m quite curious as to why aren’t there more takers to my questions. I think they’re quite relevant to understanding NAD+ processes rather than gourging huge amount of precursors and downregulating everything back to baseline. Or maybe I’m wrong in my direction in all of this.

Edited by recon, 12 November 2017 - 12:15 AM.

[recon]

On a related note. This post references a study showing NAMPT can be upregulated by HSF1, which is activated by a number means, such as heat stress or sulforaphane. Maybe the best time to take NMN (or NR?) is before using the sauna?

Stilbenoids such as resveratrol also upregulates NAMPT. I wonder if pterostilbene, the supposedly more powerful cousin, does that to a greater degree.

Exercise also upregulates NAMPT.

[recon]

We’d want to maximise NAD+ for it to be used by genes such as PARP-1 and the Sirtuins. For now we need to make sure there’s much entry into NAD+ and that they are used by the genes we want them to and to upregulate the enzymes towards NAD+ and to downregulate the enzymes away from NAD+.

So, my tasks are to find substances/actions that:

Correctly uses NAD+ by:
1) activate the Sirtuins.
2) activate PARP-1.

Upregulate towards NAD+ by:
3) upregulates NAMPRT (aka NAMPT)
4) upregulates NMNAT (very important!)
5) upregulates NRK
(salvage pathway)
6) upregulates NAPRT
7) upregulates NADS
(de novo pathway)

Downregulate away from NAD+ by:
8) downregulates NNMT
9) downregulates ACMSD

Increase precursor concentration to prevent reverse catalysis by enzymes via:
10) precursors for salvage pathway
11) precursors for de novo pathway

We must make sure that every enzymes towards NAD+ be upregulated because the increase in NAD+ pool may downregulate them to maintain homeostasis. This goes the same for the exit enzymes away from NAD+ should be downregulated.

There’s a reason why they decrease as we age and it’s not the lack of precursors for sure. So if anyone wants to chip in to find each of the 11 above, feel free.

Edited by recon, 12 November 2017 - 12:45 AM.

[HaplogroupW]

(note eg. that NMN-->NAD+ consumes ATP)

 

 

 

 

I wonder if the decrease of NAD+ with age isn't merely due to loss of mitochondrial membrane potential, not because we are supplying the substrate. To the extent that NR or nicotinamide rescue NAD+ levels, perhaps it's due to their induction of fragmentation/fission, leading to better mitophagy of diseased mt. 

Edited by HaplogroupW, 12 November 2017 - 08:33 AM.

[MikeDC]

The NR + Pterostilbene chart says so. But the NR chart says no. Both study are for a period of 8 weeks.
Did Pterostilbene in the Elysium study influence the curve?

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Edited by MikeDC, 28 November 2018 - 08:24 PM.

[Michael]

The decline in the Elysium study is from a peak at the 30 day mark; there is no corresponding data point in what you call "the NR chart" (please identify this study). So it's entirely possible that that NAD+ levels in the patients studied in what you call "the NR chart" were even higher at the 30 day point, and declined back to a level similar to the tw0-week point at 60 days due to negative feedback.

[MikeDC]

You have a good point.

[Michael]

All:
 
Another study noting a surprising negative feedback effect, most obviously consistent with findings and speculation in Frederick and Baur  PMID 25411251 (which attempted to boost muscle NAD by increasing muscle-specific NAMPT expression):
 

Quantitative analysis of the effects of nicotinamide phosphoribosyltransferase induction on the rates of NAD⁺ synthesis and breakdown in mammalian cells using stable isotope-labeling combined with mass spectrometry

Nobumasa Hara , Harumi Osago, Mineyoshi Hiyoshi, Mikiko Kobayashi-Miura, Mikako Tsuchiya
Published: March 15, 2019
https://doi.org/10.1...al.pone.0214000

Although increased expression of Nampt might be a promising intervention for healthy aging, forced expression of Nampt gene, inducing more than 10-fold increases in the enzyme protein level, has been reported to elevate NAD⁺ levels only 40–60% in mammalian cells [citing their references [11–14], which are several studies by Frederick and Baur and by Sinclair's group — MR]. Mechanisms underlying the limited increases in NAD⁺ levels remain to be determined. Here we show that Nampt is inhibited in cells and that enhanced expression of Nampt activates NAD⁺ breakdown. Combined with the measurement of each cell’s volume, we determined absolute values (μM/h) of the rates of NAD⁺ synthesis (R_S) and breakdown (R_B) using a flux assay with a ²H (D)-labeled Nam, together with the absolute NAD⁺ concentrations in various mammalian cells including primary cultured cardiomyocytes under the physiological conditions ... NAD⁺ concentration was maintained within a narrow range (400–700 μM) in the cells. R_S was much smaller than the total Nampt activity, indicating that NAD⁺ synthesis from Nam in the cells is suppressed. Forced expression of Nampt leading to 6-fold increase in total Nampt activity induced only a 1.6-fold increase in cellular NAD⁺ concentration. Under the conditions, R_S increased by 2-fold, while 2-fold increase in R_B was also observed. .... Our findings suggest that cellular NAD⁺ concentrations do not vary dramatically by the physiological fluctuation of Nampt expression and show the tight link between the NAD⁺ synthesis and its breakdown.