14 replies to this topic

[Michael]

All:
 

Dollerup OL, Chubanava S, Agerholm M, Søndergård SD, Altıntaş A, Møller AB, Høyer KF, Ringgaard S, Stødkilde-Jørgensen H, Lavery GG, Barrès R, Larsen S, Prats C, Jessen N, Treebak JT.
Nicotinamide riboside does not alter mitochondrial respiration, content or morphology in skeletal muscle from obese and insulin resistant men.
J Physiol. 2019 Nov 11. doi: 10.1113/JP278752. [Epub ahead of print] PubMed PMID: 31710095.
 
Key points

• •This is the first long‐term human clinical trial to report on effects of NR on skeletal muscle mitochondrial function, content and morphology
• •NR supplementation decreases NAMPT protein abundance in skeletal muscle
• •NR supplementation do not affect NAD metabolite concentrations in skeletal muscle
• •Respiration, distribution, and quantity of muscle mitochondria are unaffected by NR
• •NAMPT in skeletal muscle correlates positively with OXPHOS Complex I, SIRT3, and SDH

Abstract
Preclinical evidence suggest that ... (NR) boosts NAD⁺ levels and improves diseases associated with mitochondrial dysfunction. ... In a randomized, placebo‐controlled clinical trial, 40 [middle‐aged, obese, insulin‐resistant men] received 1,000 mg NR or placebo twice daily for 12 weeks. ...
 
Protein levels of nicotinamide phosphoribosyltransferase (NAMPT), an essential NAD⁺ biosynthetic enzyme in skeletal muscle, decreased 14% with NR. However, steady‐state NAD⁺ levels as well as gene expression and protein abundance of other NAD⁺ biosynthetic enzymes remained unchanged.
 
Neither respiratory capacity of skeletal muscle mitochondria nor abundance of mitochondrial associated proteins were affected by NR. Moreover, no changes in mitochondrial fractional area or network morphology were observed [in a subset of the participants (placebo n = 8; NR n = 8)] ...
 
Our data do not support the hypothesis that dietary NR supplementation has significant impact on skeletal muscle mitochondria in obese and insulin‐resistant men. Future studies on the effects of NR on human skeletal muscle may include both genders and potentially provide comparisons between young and older people.

 

 
This is a much longer-term trial than Brenner's report on NR and the NAD+ metabolome in aged, modestly overweight men (PMID 31278280, discussed here).   The lack of an effect of NR on muscle NAD+ is consistent between the two reports; OTOH, the lack of even an effect on the NAD+ metabolome in this longer-term study sounds on its face to be contradictory, and would be much more surprising (I haven't yet seen the full text).
 
The suppression of NAMPT is something we've speculated about for a long time, as part of homeostatic adaptation to NAD+ precursor supplementation, and is here confirmed in human muscle. Despite this, there was no effect on NAD+ in muscle — presumably because NAMPT downregulation was tuned to maintain NAD+ in steady-state. It would be interesting to see if there were a time-course, though this is much different from the elevation with some modest decline seen in blood fractions.
 
It's surprising that while NR suppressed NAMPT in skeletal muscle (as anticipated), and that NAMPT level "correlates positively with OXPHOS Complex I, SIRT3, and SDH" (which seems to indicate that NR also suppressed these mitochondrial genes, and would also make sense), — yet despite this, there was no net effect on skeletal muscle respiratory capacity. Again, I'd like to see details and discussion from the full text.

This is obviously quite different from what's been reported in mouse liver, and seems quite different from the mouse data on exercise. The effect if any on actual muscle NAD+ has always seemed pretty modest, even in mice. And the lack of effect on metabolism — particularly glycemia — from NR that has been consistently reported in all NR studies (and most notably the lack of such effects in the previous report from this trial) is highly contradictory.
 
This may indeed be a straight-up species different. Certainly the lack of an effect on blood flow, fat or carbohydrate utilisation, or grip strength in the Brenner trial seems consistent with the lack of effect on NAD+ in both studies and the lack of effect on mito respiration here, and contradictory to the rodent studies (though those have looked at endurance running, and not at strength to my recollection). It may be significant that Exercise Boosts NAMPT Levels in Humans, Especially in Older People (PMID: 31207144), and that "There are conflicting results in both animal and human studies as to whether or not exercise increases or decreases NAD+, NADH, and the NAD+/NADH ratio."

Edited by Michael, 14 November 2019 - 03:03 AM.

[Fredrik]

Thank you Michael. Very interesting. And also disappointing.

 

The authors conclude:

 

"Limited tissue bioavailability of orally-supplemented NR may explain the lack of effects in skeletal muscle, and the pharmacokinetic properties of NR in humans require further investigation. While our study provides evidence suggesting that orally-consumed NR affects the NAD + biosynthesis in human skeletal muscle, this effect does not change the steady-state NAD + levels and appears to entail no other functional consequences in this population."

Edited by Fredrik, 12 November 2019 - 08:32 PM.

[LawrenceW]

Question for the guys that understand this better than I do:

 

Is this study saying that NR raises NAD+ levels in blood and that is about all it does?

Edited by LawrenceW, 14 November 2019 - 02:35 PM.

[Fredrik]

Question for the guys that understand this better than I do:

 

Is this study saying that NR raises NAD+ levels in blood and that is about all it does?

 

Did you read the conclusion? It didn´t affect muscles in obese and insulin-resistant men. What else NR do or doesn´t do has to be answered by other studies.

 

"Our data do not support the hypothesis that dietary NR supplementation has significant impact on skeletal muscle mitochondria in obese and insulin‐resistant men. Future studies on the effects of NR on human skeletal muscle may include both genders and potentially provide comparisons between young and older people."

Edited by Fredrik, 14 November 2019 - 03:45 PM.

[joesixpack]

Did you read the conclusion? It didn´t affect muscles in obese and insulin-resistant men. What else NR do or doesn´t do has to be answered by other studies.

 

"Our data do not support the hypothesis that dietary NR supplementation has significant impact on skeletal muscle mitochondria in obese and insulin‐resistant men. Future studies on the effects of NR on human skeletal muscle may include both genders and potentially provide comparisons between young and older people."

We seem to be confused by the conclusions.

 

Does this mean that if we are not obese, and insulin resistant, that it works?

[Fredrik]

We seem to be confused by the conclusions.

 

Does this mean that if we are not obese, and insulin resistant, that it works?

 

Works for what?

 

NR was given to older slightly overweight subjects in another study and it downregulated some mitochondrial gene transcription in muscle:

 

"Twelve aged (median age of 75 years) and marginally overweight (median BMI of 26.6 kg/m2; range 21–30), but otherwise healthy, men were recruited and orally supplemented with 1-g NR per day for 21 days.

 

"Muscle RNA sequencing revealed NR-mediated downregulation of energy metabolism and mitochondria pathways, without altering mitochondrial bioenergetics."

 

 

https://www.scienced...211124719309404

 

 

Edited by Fredrik, 15 November 2019 - 05:15 AM.

[Fredrik]

Question for the guys that understand this better than I do:

 

Is this study saying that NR raises NAD+ levels in blood and that is about all it does?

 

 

...but you´re right LawrenceW, so far dephosphorylated NMN hasn´t amounted to much in human studies.

 

We´ll see if NMN (NR with an added phosphate group) will do better.

 

SPOT THE DIFFERENCE?

 

 Screenshot 2019-11-11 at 23.07.57.png   50.02KB   2 downloads

 

 

Edited by Fredrik, 15 November 2019 - 05:53 AM.

[Tom Andre F. (ex shinobi)]

There is great chance that NMN does exact same tbh..

 

Since a long time I was a believer of NA instead of NR or NMN...

 

Anyway, is it possible that we have similar effect with niaciamide ? I dont think this effect is due to the fact the body modulates, but rather than it "uses" the nampt too much. We know niacinamide uses nampt but decrease sirtuins.

[tunt01]

Surprise, surprise.  There is no free lunch in an NR/NMN supplement.  Better stick with more hormetic interventions.

[p75213]

Time+ from Nuchido takes the approach of activating NAMPT. I'll have a look for an article on neuro hacker which explains the significance of NAMPT and the salvage pathway (for those not familiar - me).

Anyway I'm thinking you could include a supplement which activates AMPK which in turn activates NAMPT. Maybe Jiaogulan (southern ginseng) or the extract - activAMP.

Doing a search for nampt activators on Google, I notice there are a few molecules. However I guess they're not ready for mainstream use yet.

Edited by p75213, 27 November 2019 - 07:57 PM.

[p75213]

Time+ from Nuchido takes the approach of activating NAMPT. I'll have a look for an article on neuro hacker which explains the significance of NAMPT and the salvage pathway (for those not familiar - me).

Anyway I'm thinking you could include a supplement which activates AMPK which in turn activates NAMPT. Maybe Jiaogulan (southern ginseng) or the extract - activAMP.

Doing a search for nampt activators on Google, I notice there are a few molecules. However I guess they're not ready for mainstream use yet.

 

Here's the article from Neuro Hacker explaining nampt and the salvage pathway: https://neurohacker....salvage-pathway

[brundall]

That was an informative read for me. Summarizing...but correct me if I'm wrong

 

1. Taking moderate amounts of a variety of NAD+ precursors is far better than large doses of one kind.

2. ATP is critical for making NAD+ in the salvage pathways

3. Supporting NAMPT is important to effectively salvage NAD+ molecules after they have been converted back to NAM

4. NAMPT support should be adopted in the morning or early afternoon to match circadian driven activity

5. Support methylation to eliminate NAM metabolites 

 

Therefore an effective supplement strategy might be 

 

1. Take NA, NAM and maybe NR or NMN together in small to moderate doses

2. Take Q10 , Creatine and magnesium for ATP production and support

3. Take grape seed extract (proanthocyanidins) and ampk promoters like hesperidin in the am

4. Take methylation support B12, TMG etc

 

[p75213]

That was an informative read for me. Summarizing...but correct me if I'm wrong

 

1. Taking moderate amounts of a variety of NAD+ precursors is far better than large doses of one kind.

2. ATP is critical for making NAD+ in the salvage pathways

3. Supporting NAMPT is important to effectively salvage NAD+ molecules after they have been converted back to NAM

4. NAMPT support should be adopted in the morning or early afternoon to match circadian driven activity

5. Support methylation to eliminate NAM metabolites 

 

Therefore an effective supplement strategy might be 

 

1. Take NA, NAM and maybe NR or NMN together in small to moderate doses

2. Take Q10 , Creatine and magnesium for ATP production and support

3. Take grape seed extract (proanthocyanidins) and ampk promoters like hesperidin in the am

4. Take methylation support B12, TMG etc

 

Jiaogulan activates AMPK which in turn activates Nampt. Activated AMPK also enhances conversion of food into ATP. So you might be able to kill two birds with the one stone. So I'm thinking of the following:

Take NA, NAM and maybe NR or NMN together in small to moderate doses

2. Take jiaogulan , Creatine and magnesium for ATP production and support

3. Take grape seed extract (proanthocyanidins) and ampk promoters like jiaogulan in the am

4. Take methylation support B12, TMG etc

[MikeDC]

The lack of clear clinical benefits from NR and probably from NMN as well is due to the low bioavailability of both NR and NMN. But anecdotal evidence is very strong that NR improves health much more than NAM and NA. How long will it take for someone to design a trial that can prove NR’s beneficial effects?

[Ken Mark]

How long will it take for someone to design a trial that can prove NR’s beneficial effects?

Designing a trial to prove anything is easy but they don't even need to do that until word of mouth publicity (aka anecdotes) is helping them sell their stuff in tons.

I see no other reason to not do a trial.