71 replies to this topic

[smithx]

Now that pure NAD+ powder as well as pure NMN powder are available from AliveByNature (again, if you trust their assays), we should consider what's better to supplement.

 

It seems likely that any supplementation would be sublingual or as liquid drops meant to be absorbed by the tongue, directly into the bloodstream. This also means that other forms of NR which are a lot less expensive than NR-Cl could be used, since the main advantage of NR-Cl ("Niagen" brand) is that it remains in powder form more easily due to being less hygroscopic.

 

So what's the best evidence we have so far of which form is:

 

- Most likely to be beneficial in the greatest number of ways

- Least likely to be detrimental

 

 

[able]

I'm not sure what you mean.

 

NR by itself is not stable.  They add CL to make it stable enough to store and sell it.  Adding it to water breaks the bond with the CL, and it is not stable.  I doubt a cheap, pure NR will be stable enough to work in a water delivery form.   Likewise, once in the bloodstream it is not stable, once the NR -CL bond is broken.

 

Which form is least likely to be detrimental?  I don't know of any evidence of negative side effects from any of the forms you mention

 

Which form is most likely to be most beneficial in most ways?  I doubt anyone really knows for sure  yet.  Dr Sinclair says we will likely find they have unique benefits. I hope we will start to see comparison research for specific disease/illness, so we might know if one is better for heart disease, another good for blood sugar, etc.  

 

Of course the manufacturers are also biased, but I do learn some from the  marketing  info produced by ABN and Chromadex.  

 

NAD+ for the brain & metabolism, NMN for the body

 

8 Key Differences Between NMN & NR

 

 

Edited by able, 11 November 2018 - 03:18 PM.

[smithx]

Pure NR is listed by manufacturers as being stable for 2 years or more, which sounds good if true. What information have you found about NR instability?

 

The bigger issue is that it turns out (which I should have researched before posting) that NR is not very water soluble. So for sublingual or most other applications, NR-Cl seems preferable.

 

What I was trying to get at with this question was, which of these compounds are most likely to be most beneficial and least harmful in terms of:

 

• absorption - do they get into the body unchanged through either oral or sublingual route?
• once in the blood do they get into the cells? Some people have questioned whether NAD+ gets into cells from the blood. If it doesn't then it might not be a good idea to use NAD+ as a supplement.
  • On the other hand, if NAD+ doesn't get into cells, what happens to it? Does it metabolize into something that does get in eventually, and is that better or not as good as what happens with the precursors?
• once absorbed, which ones elevate NAD+ the most for a given oral or sublingual dosage? This is important in terms of dosing and also cost considerations.
• once in the cell, does one form tend to have any negative side effects compared to another form?
  • We've seen reports of NMN perhaps causing axon damage, albeit in the presence of specific medical conditions, but still this is an interesting data point.
  • Does one form or another suppress or otherwise alter NAD+ de-novo synthesis?
  • Does one form or another cause a tolerance response, such that continuing to supplement the same amount initially causes an increase in NAD+ and then drops back to a lower level?
  • Does one form or another create a dependency with continued supplementation such that discontinuing it causes the NAD+ level to fall to a level substantially below its level prior to the start of supplementation

 

I know that many of these are not answerable with the current data, but hope to provoke a discussion to consider these and other potential issues and also to encourage people to post references which may be germane.

 

 

 

 

 

[able]

I'll look for some quotes about NR stability, as a powder and in the blood.   It isn't something I dreamed up, but is very well known and not in doubt.

 

The patents Chromadex licensed from Dartmouth were for process to manufacture Nicotinamide Riboside Chloride.  The Chloride was added specifically to make it stable.

 

Many people and even manufacturers refer to a product as Nicotinamide Riboside, when in reality it is Nicotinamide Riboside Chloride that they all use and sell.

 

I am extremely doubtful there is any actual product on the market containing pure NR - Can you link to one?

 

Edited by able, 12 November 2018 - 05:48 AM.

[Oakman]

These questions reflect the unsettling fact that so little is actually known about the metabolism of these various molecules inside our bodies. Available studies are full of statistics, but definitive conclusions remain in the realm of conjecture. Reason being, getting accurate assays in vivo of either the molecules themselves, or their metabolites (and especially in real human subjects) has proven to be a daunting task. Even noted researchers themselves can't come up with study results that agree about much, and there are competing commercial interest involved besides.

 

The lack of definitive results has left early adopters forced to make (un)educated guesses about dosing, choice of molecules, and cost benefit. For those of us too old to wait, there is no alternative to N=1 efforts. 

• One thing 'seems' obvious; sublingual administration, where possible, holds the most promise because of its bioavailability and convenience, as well as consistent dosing.
• Second, short of definitive studies, a nominal dosing (for safety and cost) of each molecule seems the smart path forward until we know better. 
• Third, the commercialization of each molecule inevitably results in overblown or simply false claims, until proven right or wrong in hindsight.

One thing is for sure. It's an exciting time.

[stefan_001]

Personally I believe in multiple admin routes. A healthy liver is extremely important, so somw oral consumption cannot hurt.

[able]

 

 

• once in the blood do they get into the cells? Some people have questioned whether NAD+ gets into cells from the blood. If it doesn't then it might not be a good idea to use NAD+ as a supplement.

 

Its true that Dr Brenner says only NR can enter cells, but more and more research is showing otherwise, such as this one from October 2018:

 

The Plasma NAD+ Metabolome Is Dysregulated in “Normal” Aging

 

"While it is thought that NAD+ is predominantly an intracellular nucleotide, emerging evidence suggests that extracellular NAD+ crosses the plasma membrane and replenishes intracellular NAD+.21"

 

ABN does a nice job reviewing some research published in August  that proves  NAD+ rapidly enter hypothalamus directly, but that NR and NMN cannot, and from September, the  importance of increased NAD+ in hypothalamus.

 

I have long found it curious that Elysium measured the success of their first study by how much basis increased levels of NAD+ IN THE BLOOD.  If the cell membrane is some impenetrable barrier that stops NAD+ from entering, why would they say increased levels of NAD+ in the blood is the goal?  

 

NAD+ may not readily enter all cells intact, but it certainly seems increased NAD+ in the bloodstream has benefit

 

 

Edited by able, 13 November 2018 - 04:39 AM.

[MikeDC]

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Edited by MikeDC, 14 November 2018 - 10:26 PM.

[MikeDC]

This is from the ChromaDex July presentation. Looks like plasma NAD+ is increased linearly with dose up to 1000mg per day. The little dip at 8 weeks is across all doses including placebo. So it might be measurement inaccuracies.

[able]

This is from the ChromaDex July presentation. Looks like plasma NAD+ is increased linearly with dose up to 1000mg per day. The little dip at 8 weeks is across all doses including placebo. So it might be measurement inaccuracies.

 

Interesting to see that 1,000 mg seems much more effective than 300 mg.  Definitely good to know that many have been underusing.

 

Notice that they use levels of  NAD+ in the blood to demonstrate effectiveness.  

 

So they must now believe the recent research that shows increased NAD+ in the blood is beneficial, contrary to the marketing representations about NAD+ being unable to enter a cell.

Edited by able, 14 November 2018 - 10:31 PM.

[MikeDC]

Its true that Dr Brenner says only NR can enter cells, but more and more research is showing otherwise, such as this one from October 2018:

The Plasma NAD+ Metabolome Is Dysregulated in “Normal” Aging

"While it is thought that NAD+ is predominantly an intracellular nucleotide, emerging evidence suggests that extracellular NAD+ crosses the plasma membrane and replenishes intracellular NAD+.21"

ABN does a nice job reviewing some research published in August that proves NAD+ rapidly enter hypothalamus directly, but that NR and NMN cannot, and from September, the importance of increased NAD+ in hypothalamus.

I have long found it curious that Elysium measured the success of their first study by how much basis increased levels of NAD+ IN THE BLOOD. If the cell membrane is some impenetrable barrier that stops NAD+ from entering, why would they say increased levels of NAD+ in the blood is the goal?

NAD+ may not readily enter all cells intact, but it certainly seems increased NAD+ in the bloodstream has benefit

How is it otherwise? NR has been clearly demonstrated to enter cells. NAD+ and NMN can be broken down to NR before entering cells.

[able]

How is it otherwise? NR has been clearly demonstrated to enter cells. NAD+ and NMN can be broken down to NR before entering cells.

 

Guess you didn't read any of the research I linked to....  Proves NAD+ does enter some cells intact, like hypothalamus and heart.

 

NAD+ rapidly enter hypothalamus directly, but that NR and NMN cannot, and from September, the  importance of increased NAD+ in hypothalamus.

Edited by able, 14 November 2018 - 10:35 PM.

[MikeDC]

Guess you didn't read any of the research I linked to.... Proves NAD+ does enter some cells intact, like hypothalamus and heart.

NAD+ rapidly enter hypothalamus directly, but that NR and NMN cannot, and from September, the importance of increased NAD+ in hypothalamus.

I have known of lituratures that say NAD+ can enter cells. That has nothing to do with NR entering cells.

[MikeDC]

Interesting to see that 1,000 mg seems much more effective than 300 mg. Definitely good to know that many have been underusing.

Notice that they use levels of NAD+ in the blood to demonstrate effectiveness.

So they must now believe the recent research that shows increased NAD+ in the blood is beneficial, contrary to the marketing representations about NAD+ being unable to enter a cell.

NR increased NAD+, NR, and NMN in the plasma. All of them are precursors to NAD+. So NR taken orally doesn’t need to pass liver. The increased NAD+, NR, and NMN in the plasma will have similar effects as NR in the blood stream.

[able]

NR increased NAD+, NR, and NMN in the plasma. All of them are precursors to NAD+. So NR taken orally doesn’t need to pass liver. The increased NAD+, NR, and NMN in the plasma will have similar effects as NR in the blood stream.

 

 

Have they published something that shows increased NR in the blood from this study?  

 

I noticed the Martens study showed a slight increase in NMN in the blood, but again, were unable to detect NR in the blood:

 

"Consistent with the only other report of NR ingestion in humans26, we were unable to detect NR concentrations in PBMCs during either treatment condition, despite using optimized recovery methods."

 

 

As for the increased NAD+  - definitely a nice increase from higher dosage.  But I don't understand how you know that has bypassed the liver.  Liu showed that nearly all oral NR/NMN  is broken down in liver and excreted as NAM.  

 

Is there any indication the increased NAD in the blood is NOT from NR excreted as NAM from the liver?

 

I believe NR is more beneficial than NAM.  But if all they have to show from the study is  NAD+ increase in the blood that  is from NAM excreted by the liver, it doesn't seem to help their case much.  I hope they have positive results from other tests in that study.

Edited by able, 15 November 2018 - 12:11 AM.

[MikeDC]

Have they published something that shows increased NR in the blood from this study?

I noticed the Martens study showed a slight increase in NMN in the blood, but again, were unable to detect NR in the blood:

"Consistent with the only other report of NR ingestion in humans26, we were unable to detect NR concentrations in PBMCs during either treatment condition, despite using optimized recovery methods."


As for the increased NAD+ - definitely a nice increase from higher dosage. But I don't understand how you know that has bypassed the liver. Liu showed that nearly all oral NR/NMN is broken down in liver and excreted as NAM.

Is there any indication the increased NAD in the blood is NOT from NR excreted as NAM from the liver?

I believe NR is more beneficial than NAM. But if all they have to show from the study is NAD+ increase in the blood that is from NAM excreted by the liver, it doesn't seem to help their case much. I hope they have positive results from other tests in that study.

Ling liu’s Paper showed baseline NR is much higher than baseline NMN. She showed majority of NR and NMN were broken down before reaching liver. But it doesn’t exlude small amount of NR reaching liver and blood stream. In the end what count is health benefit. NR has shown more benefit than NAM in both studies and user experiences.

[Harkijn]

In the end the situation is still the same: we simply don't know enough to decide if NR,NMN,NAD is best. Stefan has a point  when he says above that multiple administration is the best practical way forward right now.

I am glad the Martens study still gets some attention. For me the most important point of this research is not so much the data on bioavailibility, but the impressive improvements in health parameters as compared to placebo. Very motivating!

[Fredrik]

...For me the most important point of this research is not so much the data on bioavailibility, but the impressive improvements in health parameters as compared to placebo. Very motivating!

 

 

 What impressive improvements in health parameters by NR supplementation in humans do you refer to? I am impressed with the trials done on mice and rats when it comes to NAD+ precursors NR and NMN. But without an actual effect on human health, increasing NAD+ is just a side effect of taking NR and other NAD+ precursors.

 

The human NR studies so far has been really disappointing (no human NMN studies published by the time of this writing). No glucose- or insulin lowering, no effect on body weight and no cardiovascular benefits. Just a small lowering of liver lipids. Let us hope that future trials show that NR or NMN can have some effect on cognition or muscle wasting at least.

 

According to Martens  et al, the drop in blood pressure was not statistically significant.

 

 

Supplementation with NR tended to lower mean systolic (SBP; mean change = −3.9 mmHg; one-sided 95% CI (−∞, −0.058)) and diastolic (DBP; mean change = −2.0 mmHg; one-sided 95% CI (−∞, −0.26)) blood pressure (BP) in all subjects as a group (Fig. 3a–c); however, these comparisons were not statistically significant after correction for multiple comparisons.

 

 

 

The measure of the stiffness of the aorta that showed a trend towards reduction also was NOT statistically significant according to the researchers themselves.

 

 

We also observed a trend towards a reduction in the mean carotid-femoral pulse wave velocity (PWV) with NR supplementation, the clinical “gold standard” measure of the stiffness of the aorta38, and a strong independent risk factor for incident cardiovascular events with aging and age-related diseases (Fig. 4a; mean change = −41.5 m s−1; one-sided 95% CI (−∞, −4.8)). However, this reduction was not statistically significant after correction for multiple comparisons.

 

 

No effect of NR was observed on ultrasound-determined carotid artery compliance (Fig. 4c) or brachial artery flow-mediated dilation, a measure of vascular endothelial function (Fig. 4d).

 

 

 

The following is list of all things that were NOT affected by NR at all like glucose regulation, insulin, V02max, body weight, percent body fat, overall motor function or exercise performance.

 

 

 

Total energy intake and expenditure, oxidative fuel source (carbohydrate vs. fat), and physical activity patterns were not affected by NR (Supplementary Table 7). Likewise, we observed no difference in body mass, body mass index (BMI) or percent body fat compared with the placebo arm (Supplementary Table 7) and no differences were observed in measures of glucose or insulin regulation (Supplementary Table 7). Finally, there was no effect of the intervention on overall motor function (Supplementary Figure 2), maximal exercise capacity, as assessed by VO2 max and treadmill time to exhaustion (Supplementary Figure 1A, B), or on markers of submaximal exercise performance (Supplementary Figure 1C−F).

 

 

 

What improvement in health parameters in this study from Marten et al on NR in humans did you find impressive?

 

Remember, increasing NAD+ is not a health outcome. It is an interesting observation with the animal data we have. But without an actual effect on health, increasing NAD+ is just a side effect of taking NR.

 

 

1. Martens CR, Denman BA, Mazzo MR, Armstrong ML, Reisdorph N, McQueen MB, Chonchol M, Seals DR. Chronic nicotinamide riboside supplementation is well-tolerated and elevates NAD+ in healthy middle-aged and older adults. Nature communications. 2018 Mar 29;9(1):1286.

Edited by Fredrik, 16 November 2018 - 03:50 PM.

[MikeDC]

These human studies are just for prove of concept. So far they know NR can decrease blood pressure and fatty liver.
Like Brenner said future clinical trials with more participants, more serious symptoms for longer period of time will show NR can reduce blood pressure and fatty liver statistically significantly.

[Fredrik]

These human studies are just for prove of concept. So far they know NR can decrease blood pressure and fatty liver.
Like Brenner said future clinical trials with more participants, more serious symptoms for longer period of time will show NR can reduce blood pressure and fatty liver statistically significantly.

 

No. It was not a "proof of concept"- study. That is what Dr Brenner and Chromadex referred to it as afterwards in a press release. It was an intervention trial to test the efficacy of NR to improve a range of physiological functions in humans and it failed in doing so.

 

The title and description of Chromadex and Martens trial on clinicaltrials.org before they had the disappointing results of NR was as follows:

 

"Safety & Efficacy of Nicotinamide Riboside Supplementation for Improving Physiological Function in Middle-Aged and Older Adults"

 

The purpose of this study is to assess the efficacy of supplementation with the Nicotinamide Adenine Dinucleotide (NAD+) precursor compound, Nicotinamide Riboside (NR), for improving physiological function (vascular, motor, and cognitive) in healthy middle-aged and older adult"

 

 

And they failed to show any significant results. No lowering of blood pressure or improvement of other physiological functions at all.

 

Those "future clinical trials" on NR has not been done so we have no results to discuss. We can only discuss the trials that has published results and so far human supplementation with NR has not shown any impressive benefits.

 

1. Safety & Efficacy of Nicotinamide Riboside Supplementation for Improving Physiological Function in Middle-Aged and Older Adults

 

https://clinicaltria...how/NCT02921659

Edited by Fredrik, 16 November 2018 - 04:36 PM.

[MikeDC]

Yes, they are prove of concepts clinical trials. Subsequent trials will have more participants and focus on One medical condition at a time.

[Harkijn]

 

 

 

 

 

What improvement in health parameters in this study from Marten et al on NR in humans did you find impressive

In a small scale, rather short test period the value of statistics should not be overrated. Take a look at the improvements of specific test persons and you can imagine that they would not agree with you.

Edited by Harkijn, 16 November 2018 - 04:45 PM.

[Fredrik]

Yes, they are prove of concepts clinical trials. Subsequent trials will have more participants and focus on One medical condition at a time.

 

Can you please provide a link to these future trials, as I have done with the current one? I would like to see the published future data so we can discuss it in detail.

 

In the meantime we can only discuss the disappointing human clinical trials and the exciting animal studies on NR that actually has been done.

Edited by Fredrik, 16 November 2018 - 04:47 PM.

[Harkijn]

 

Remember, increasing NAD+ is not a health outcome. It is an interesting observation with the animal data we have. But without an actual effect on health, increasing NAD+ is just a side effect of taking NR.

 

 

 

Also, remember the value of a healthy NAD metabolism. Read up on this in the Auwerx study.

Anyway we all agree that there are too may unknowns and that  it may take up to two years before  a finished research article  is published.

[Fredrik]

Also, remember the value of a healthy NAD metabolism. Read up on this in the Auwerx study.

Anyway we all agree that there are too may unknowns and that  it may take up to two years before  a finished research article  is published.

 

I have read the Auwerx review (was not a study) and if NR is important for a healthy metabolism it would have at least lowered glucose, insulin, LDL, TG and weight. But Nada unfortunately. I hope for some great results in future studies on brain and muscle health. But human NR supplementation so far has produced underwhelming results.

[MikeDC]

The test subject are healthy adults. We don’t expect significant improvement in health markers in these subjects. The dosing periods were very short also.

[Fredrik]

The test subject are healthy adults. We don’t expect significant improvement in health markers in these subjects. The dosing periods were very short also.

They were looking for improvements in physiological function in these healthy adults but NR provided none.

”The purpose of this study is to assess the efficacy of supplementation with the Nicotinamide Adenine Dinucleotide (NAD+) precursor compound, Nicotinamide Riboside (NR), for improving physiological function (vascular, motor, and cognitive) in healthy middle-aged and older adult"

[Harkijn]

I had no expectations about glucose, insulin,LDL,TG, weight in healthy adults so at present I am not so disappointed about the properties of NR. But I agree we are still in sore need of more research data.

[MikeDC]

They were looking for improvements in physiological function in these healthy adults but NR provided none.

”The purpose of this study is to assess the efficacy of supplementation with the Nicotinamide Adenine Dinucleotide (NAD+) precursor compound, Nicotinamide Riboside (NR), for improving physiological function (vascular, motor, and cognitive) in healthy middle-aged and older adult"

If your cholesterol is already at 180, it will not improve. But if your cholesterol is 250, it will improve. All my friends with very high LDL and triglycerides got great improvements.

[ceridwen]

What about 129?
It won't improve?