44 replies to this topic

[aaaaaaal]

He doesn't seem to pay much attention to NR?

[TMNMK]

NMN is less investigated so my guess is that he feels there is more fruit to be had with regard to publication on NMN.

I would bet that if NMN was presently marketed as a GRAS supplement and there were fewer studies on NR, we would think he had an NR bias. Do a google scholar search for:

"nicotinamide riboside" author:Sinclair

https://scholar.goog...=en&as_sdt=0,22

 

Ultimately his interest is ageing and presently the NAD metabolome in general is capturing his interest, NR and NMN both included.

 

Here's a short article from 2016 where he and Dr. Wu don't even mention NMN, but refer to studies on NR exclusively: https://www.ncbi.nlm...les/PMC5034109/

 

Behind the curtains, I'm willing to bet he's just as impressed with NR as he is with NMN.

Edited by TMNMK, 19 April 2018 - 09:51 AM.

[bluemoon]

Sinclair's initial 2013 study on mice was with NMN and showed muscles reverted to much younger ones. He implies he is working on using NMN to create a patentable drug. In 2014, Sinclair said at a presentation in Australia: "Imagine taking a pill that combined NR with say, metformin." (paraphrase) He did discuss both NR and NMN at the time.  

[LawrenceW]

It seems that the further that Dr. Sinclair gets into his research, the less he talks about NR.

 

October 2016

 

January 2017

 

March 2017

 

June 2017

https://www.youtube.com/watch?v=XSz-rplWaxw

 

July 2017

https://www.youtube.com/watch?v=hgQM9l8RWCw

 

March 2018

https://hms.harvard....rewinding-clock

 

 

[ledgf]

It's the patent fights and lawsuits between Elysium and Chromadex. Sinclair's protege Joe Baur is in court right now testifying for Elysium...

they assume that Chromadex will get control of NR, so the commercial potential for them is in NMN. 

Hopefully more labs will publish on both soon... it's possible that a mix of NR and NMN is best. 

Aarhus study on NR and Type 2 diabetes should publish soon, it complete over a year ago... keep an eye out for it. 

[MikeDC]

Purely related to commercial interests. Sinclair tries very hard to avoid talking about NR. He wants to make money from NMN so NR is his enemy.

[bluemoon]

 

Aarhus study on NR and Type 2 diabetes should publish soon, it complete over a year ago... keep an eye out for it. 

 

Is it possible Chromadex won't try to publish the results of its n=140 perspn trial? Or has that been sent for publication?

[MikeDC]

Is it possible Chromadex won't try to publish the results of its n=140 perspn trial? Or has that been sent for publication?

 

The CEO said they might split up the data into two publications. My guess is the data showed some health benefit that was not the aim of the clinical trial.

Guess the participants were not as healthy as the Colorado trial. The Colorado trial was almost shelved if not for some participants having blood pressure between 120 and 139.

Choosing participants with perfect health and blood markers is a very bad idea to study the benefit of NR. 

[Michael]

It's the patent fights and lawsuits between Elysium and Chromadex. Sinclair's protege Joe Baur is in court right now testifying for Elysium...

they assume that Chromadex will get control of NR, so the commercial potential for them is in NMN. 

Hopefully more labs will publish on both soon... it's possible that a mix of NR and NMN is best. 

Aarhus study on NR and Type 2 diabetes should publish soon, it complete over a year ago... keep an eye out for it. 

 

 

Purely related to commercial interests. Sinclair tries very hard to avoid talking about NR. He wants to make money from NMN so NR is his enemy.

 

As I've written before, I wish people would quit the needless character assassination — especially in the complete absence of any evidence whatsoever. As I've written before:

 

 

As to all the speculation about why Sinclair keeps using NMN instead of NR (and is not doing comparisons with NR): the question, of course, could just as easily be turned around to ask why all the people doing studies with NR aren't all doing comparison studies with NMN — or why both aren't doing comparisons with nicotinic acid or niacinamide. Let's remember that the nicotinic acid elevated NAD+ as well as NR in muscle and did a better job in liver according to Canto et al, contrary to Brenner; let's also remember that nicotinamide has been reported to have many of the effects reported for NR, such as against animal models of diabetic obesity and Alzheimer's.

 

I strongly suspect that the main reasons for most researchers are (a) that they have an existing and often free supply of one agent vs. the other, and (b) it just costs a lot of time and money to do an extra group of mice with a different agent (including the extra time and money to prepare the dosed chow, in oral studies). Science funding is at present miserably, pathetically hard to come by (and the proposed NIH budget cut is a threat to our ability to conquer aging), and you have researchers routinely trying to stick to their miserly budgets by doing studies in way too few mice as it is: the notion that they should increase their numbers by 50% to indulge our curiosity is understandable, but in current circumstances suicidal. (But if you want science done right, push for an expansion of the NIH budget (or your national equivalent), and for goodness' sake, donate to SENS Foundation).

 

Let's also remember that Sinclair's 2013 muscle study was the first  in vivo study showing health effects in  mammals; it's unlikely that NR would be anything but a biochemistry tool without it, and Chromadex would still mostly be an analytical standard business, selling NR on the side to scientists for cellular biochemistry studies.

Edited by Michael, 24 April 2018 - 06:59 PM.

[MikeDC]

“Let's also remember that Sinclair's 2013 muscle study was the first in vivo study showing health effects in mammals; it's unlikely that NR would be anything but a biochemistry tool without it, and Chromadex would still mostly be an analytical standard business, selling NR on the side to scientists for cellular biochemistry studies.”

2013
https://www.ncbi.nlm...namide riboside

2012
https://www.ncbi.nlm...namide riboside

[Michael]

“Let's also remember that Sinclair's 2013 muscle study was the first in vivo study showing health effects in mammals; it's unlikely that NR would be anything but a biochemistry tool without it, and Chromadex would still mostly be an analytical standard business, selling NR on the side to scientists for cellular biochemistry studies.”

2013
https://www.ncbi.nlm...namide riboside

2012
https://www.ncbi.nlm...namide riboside

 

Allow me to correct myself. Let's also remember that Sinclair's 2013 muscle study was the first in vivo study showing health effects in normally-aging mammals, as opposed to high-fat-fed diabesity or cellular biochemistry.

[Oakman]

With all the conspiracy theories here, I'll venture a pseudo-factual quess. I say pseudo because it seems hardly anything is 'fact'....as we know so little about in vivo NAD+ metabolism in humans. We do know a bit about in vivo in lab rodents, et al, and in vitro on various tissues, but that appears to be the extent so far.

 

OK, so I'll suggest the reason there is the focus on NMN currently by some is the theory that NMN is a single step away from NAD+, and so the the shortest possible route to NAD+. But that's not all it has going for it.

 

The theory also goes that NR is converted first 95% to NAM, 5% to NMN and so requires, and is limited to using the rate limiting NAMPT step of going NAM >NAMPT> NMN before being converted to NAD+.

 

Since NAMPT is a major part of the body's feedback loops limiting and/or suppressing NAD+ production to maintain homeostasis, continuous NR supplementation is dampened by reducing production of NAMPT, whereas direct NMN supplementation is not, and so long term NMN supplementation continues to raise NAD+ levels, regardless of negative feedback.

 

My belief is that for best effect of NAD+ boosting in vivo, NR and NMN and NAM and Tryptophan and NA are all valuable. But only NMN presents a possible way around the negative feedback loops limiting long term elevation of NAD+ production. At least that is where the scientific literature is pointing. 

 

IF, and that's a big IF the above is found to be "actually" true, we should all be congratulating this concept, as it provides a way out of the paradox experienced so far in maintaining NAD+ levels above homeostasis, long term.

[MikeDC]

Are you just ignorant or trying to mislead people? NMN needs to convert to NR before getting into cells. Oral NR and NMN are mostly converted to NAM before entering liver. Oral NR increases more NAD+ than NMN except in kidney.

Forget about oral. Look at the IV data. IV NR contributed to direct conversion to NAD+ significantly more than NMN in liver, kidney, and muscles. There is zero direct conversion of NMN to NAD+ in muscles from IV NMN.

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Edited by MikeDC, 24 May 2018 - 06:35 PM.

[LawrenceW]

I ask that everyone cut MikeDC some slack today, as his Chromadex stock is down 6% and it is obviously affecting his mood.

[able]

Are you just ignorant or trying to mislead people? NMN needs to convert to NR before getting into cells. Oral NR and NMN are mostly converted to NAM before entering liver. Oral NR increases more NAD+ than NMN except in kidney.

Forget about oral. Look at the IV data. IV NR contributed to direct conversion to NAD+ significantly more than NMN in liver, kidney, and muscles. There is zero direct conversion of NMN to NAD+ in muscles from IV NMN.

 

"NMN needs to convert to NR before getting into cells"

 

 

Maybe - Brenner demonstrated that is true in one particular type of liver cell, in test tubes.  It may, or may not be true in other cells.  Many researchers like Dr Sinclair believe otherwise (as you know).

 

 

"Oral NR increases more NAD+ than NMN" 

 

Mostly in the liver.  Proving nothing, since NAM increases NAD+ in the liver MUCH more than NR per mg.

 

There is zero direct conversion of NMN to NAD+ in muscles from IV NMN

 

And yet, the 3 studies with most dramatic effect imo, showed significant benefit in muscle - much more than any study of NR has yet shown (Sinclair, Mills, Sinclair)

 

Clearly there is a LOT researchers don't yet understand about how NAD+ benefits health.   As Michael has long said, the increase of NAD+ does not prove a benefit.

 

The most recent study with NR shows  NAD+ was increased, but surprisingly NO benefit to health.

 

 

NAD+ repletion produces no therapeutic effect in mice with respiratory chain complex III deficiency and chronic energy deprivation

Edited by able, 25 May 2018 - 01:17 AM.

[MikeDC]

"NMN needs to convert to NR before getting into cells"


Maybe - Brenner demonstrated that is true in one particular type of liver cell, in test tubes. It may, or may not be true in other cells. Many researchers like Dr Sinclair believe otherwise (as you know).


"Oral NR increases more NAD+ than NMN"

Mostly in the liver. Proving nothing, since NAM increases NAD+ in the liver MUCH more than NR per mg.

There is zero direct conversion of NMN to NAD+ in muscles from IV NMN

And yet, the 3 studies with most dramatic effect imo, showed significant benefit in muscle - much more than any study of NR has yet shown (Sinclair, Mills, Sinclair)

Clearly there is a LOT researchers don't yet understand about how NAD+ benefits health. As Michael has long said, the increase of NAD+ does not prove a benefit.

The most recent study with NR shows NAD+ was increased, but surprisingly NO benefit to health.


NAD+ repletion produces no therapeutic effect in mice with respiratory chain complex III deficiency and chronic energy deprivation

Your points are not even worth arguing. You keep ignoring facts and take speculation as truth. There are other studies that show NMN needs to convert to NR before entering cells. There has not been a single study so far that shows NMN can get into cells directly. This has been tested in many tissues beyond liver.

[able]

Your points are not even worth arguing. You keep ignoring facts and take speculation as truth. There are other studies that show NMN needs to convert to NR before entering cells. There has not been a single study so far that shows NMN can get into cells directly. This has been tested in many tissues beyond liver.

 

You are taking speculation as truth without citing any references.

 

Regardless of the route taken, NMN is very quickly utilized in cells  - within 15 minutes in muscle (mills).

 

Please show me one study where NR showed benefits  as dramatic as the latest Sinclair study  - double the endurance  in normal, healthy mice.

 

I'm not saying NMN is definitely more effective, but there is evidence for that.  You act as if it is an open and shut case that NR is far superior, cherry picking some data and ignoring other, or claiming the data is faulty when it doesn't support your case.

Edited by able, 25 May 2018 - 01:47 AM.

[MikeDC]

You are taking speculation as truth without citing any references.

Regardless of the route taken, NMN is very quickly utilized in cells - within 15 minutes in muscle (mills).

Please show me one study where NR showed benefits as dramatic as the latest Sinclair study - double the endurance in normal, healthy mice.

I'm not saying NMN is definitely more effective, but there is evidence for that. You act as if it is an open and shut case that NR is far superior, cherry picking some data and ignoring other, or claiming the data is faulty when it doesn't support your case.

The references have been cited many many times in many threads. Learn it first before posting.

[bluemoon]

 .   As Michael has long said, the increase of NAD+ does not prove a benefit.

 

The most recent study with NR shows  NAD+ was increased, but surprisingly NO benefit to health.

 

 

The recent mouse study is one of several where others have shown benefits. I realize that Michael thinks the Elysium walking test part where healthy 60 to 80 year olds taking 500 mg of NR with 100 mg of pterostilbine will not hold up under further testing but the U of Colorado study also showed blood pressure benefits and a less hardened aorta, right? 

[MikeDC]

NMN depends on NRK1,2

In muscle

https://www.ncbi.nlm.../?i=2&from=nrk1

In liver, brown adipose, and muscles

https://www.ncbi.nlm...03/#!po=18.5897

This paper shows NRK1 is important in maintaining cell health even without NR supplementation. This is confirmation that our body uses NR for basic metabolism without exogenous NR. Ling LIU’s paper showed baseline NR is much higher than NMN in mice.
https://www.ncbi.nlm...1&from=nrk1 nmn

[MikeDC]

See how extensive the list of tissues that NRK1 gene is expressed.

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[Oakman]

Are you just ignorant or trying to mislead people? NMN needs to convert to NR before getting into cells. Oral NR and NMN are mostly converted to NAM before entering liver. Oral NR increases more NAD+ than NMN except in kidney.

Forget about oral. Look at the IV data. IV NR contributed to direct conversion to NAD+ significantly more than NMN in liver, kidney, and muscles. There is zero direct conversion of NMN to NAD+ in muscles from IV NMN.

 

I'll choose ignorant. Based on the research, primarily NMN > NR > cells.  Now how best to modulate NRK1 expression for maximum NAD+.

[MikeDC]

I'll choose ignorant. Based on the research, primarily NMN > NR > cells. Now how best to modulate NRK1 expression for maximum NAD+.

I read somewhere that NR stimulate NRK1 expression. NRK1 has not been shown to be a bottle neck. The focus of future developments is to increase oral NR bioavailability.

[Phoebus]

 

 

 

The most recent study with NR shows  NAD+ was increased, but surprisingly NO benefit to health.

 

 

NAD+ repletion produces no therapeutic effect in mice with respiratory chain complex III deficiency and chronic energy deprivation

 

 

ugh, this is my fear actually. That I will spend all this time and money on increasing my  NAD+ and in reality it does virtually nothing for my health in the real world. 

[LawrenceW]

Phoebus.

 

My fears also, that is why we are extremely pleased with the real world results that we have achieved by taking NMN.

 

You can read more about it at: https://www.longecit...erience-thread/

 

[able]

ugh, this is my fear actually. That I will spend all this time and money on increasing my  NAD+ and in reality it does virtually nothing for my health in the real world. 

 

 

I didn't reference that study to imply that NR has no health benefits.  

 

I pointed that out to show that its not as simple as. xx% NAD+ increase ->   xx% health benefit.

 

In this particular study, they did see increased NAD+, but no health benefit. 

 

Its fine for researchers to tease out the metabolic pathways to better understand and design new studies, but for US to use is not really confirmation of benefit.

 

Thats why I favor NMN a bit - it just seems the results on health benefits have been more convincingly positive to me.

 

It's a mystery to me that Liu shows no uptake of NMN to muscle, even with injections.  Yet the 3 studies I find most impressive for health benefits in normal mice were mostly about benefits to muscle from NMN.  Something strange about that.

Edited by able, 26 May 2018 - 10:48 PM.

[MikeDC]

ugh, this is my fear actually. That I will spend all this time and money on increasing my NAD+ and in reality it does virtually nothing for my health in the real world.

“We linked this lack of therapeutic effect to NAD+-independent activation of SIRT-1 and -3 via AMPK and cAMP signaling related to the starvation-like metabolic state of Bcs1lp.S78G mice.”

This doesn’t represent normal metabolism.

Edited by MikeDC, 27 May 2018 - 12:39 AM.

[stefan_001]

I ask that everyone cut MikeDC some slack today, as his Chromadex stock is down 6% and it is obviously affecting his mood.

 

Lawrence I am just wondering are you like this in real life too? Collecting people and setting them up against others? I get it that you are a total fan of NMN and you dont like to hear anything about NR in particular of an outspoken NR fan but its only days ago you spewed your "we expected more of you comment" towards me. Frankly I find it appalling and poor character. The same goes to people that encourage this behavior in the ratings.
 

Edited by stefan_001, 27 May 2018 - 07:33 AM.

[MikeDC]

I didn't reference that study to imply that NR has no health benefits.

I pointed that out to show that its not as simple as. xx% NAD+ increase -> xx% health benefit.

In this particular study, they did see increased NAD+, but no health benefit.

Its fine for researchers to tease out the metabolic pathways to better understand and design new studies, but for US to use is not really confirmation of benefit.

Thats why I favor NMN a bit - it just seems the results on health benefits have been more convincingly positive to me.

It's a mystery to me that Liu shows no uptake of NMN to muscle, even with injections. Yet the 3 studies I find most impressive for health benefits in normal mice were mostly about benefits to muscle from NMN. Something strange about that.

NMN benefit muscles through NAM. There is no conflict there.

[bluemoon]

I didn't reference that study to imply that NR has no health benefits.  

 

I pointed that out to show that its not as simple as. xx% NAD+ increase ->   xx% health benefit.

 

In this particular study, they did see increased NAD+, but no health benefit. 

 

 

I don't think anyone here discussing NR (or NMN) has thought it is "as simple as xx% NAD+ increase -> xx% health benefit" in general. I don't understand how one can quickly forget or dismiss the benefits shown in the Elysium study or the Colorado study.  That isn't to say that NMN is not superior to NR but so far there have been no human trials to show that.