44 replies to this topic

[able]

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.

 

 

I don't forget or dismiss the Elysium or Colorado study.  I would however say the health benefits in both of those studies were somewhat disappointing.

 

You're right that there have been no human studies with NMN yet published, so we don't know if NMN works as well in humans. 

 

But if you just compare studies in mice, of which there have been far more done with NR, I still don't see any study that shows the dramatic benefits that we see in these three studies with NMN  (Sinclair, Mills, Sinclair).

[MikeDC]

I don't forget or dismiss the Elysium or Colorado study. I would however say the health benefits in both of those studies were somewhat disappointing.

You're right that there have been no human studies with NMN yet published, so we don't know if NMN works as well in humans.

But if you just compare studies in mice, of which there have been far more done with NR, I still don't see any study that shows the dramatic benefits that we see in these three studies with NMN (Sinclair, Mills, Sinclair).

I don’t see how these studies are more significant than NR studies, especially the clearance of plaques in the mice brain. NR study also extended life span in mice when started late in life. Human studies are ultimately the answer to their effectiveness. Mice studies are just prove of concept.
The Colorado study picked a bunch of very healthy people with perfect cholesterol and glucose. So there was no improvement their. But luckily some of these people have blood pressure between 120 and 139, NR improves blood pressure on these people. The Elysium trial used basis which contains Pterostilbene. Pterostilbene increases cholesterol. So it cancels out the good effect of NR.

[Oakman]

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.

 

"Thus, these data establish that increasing NRK activity by transient overexpression is sufficient to boost NR-driven NAD+synthesis, suggesting a rate-limiting role for NRK1 and/or NRK2 in NR utilization."

 

"By establishing NRK1 as a rate-limiting and essential enzyme for NR and NMN metabolism, we highlight NR and NMN as convergent NR supplementation strategies. "

[MikeDC]

"Thus, these data establish that increasing NRK activity by transient overexpression is sufficient to boost NR-driven NAD+synthesis, suggesting a rate-limiting role for NRK1 and/or NRK2 in NR utilization."

"By establishing NRK1 as a rate-limiting and essential enzyme for NR and NMN metabolism, we highlight NR and NMN as convergent NR supplementation strategies. "

I think the term “rate limiting” is used too loosely. The rate depends on the concentrations of both NR and NRK1. Increasing the concentration of either one will increase NAD+ production.

Edited by MikeDC, 27 May 2018 - 10:24 PM.

[able]

I don’t see how these studies are more significant than NR studies, especially the clearance of plaques in the mice brain. NR study also extended life span in mice when started late in life. Human studies are ultimately the answer to their effectiveness. Mice studies are just prove of concept.
The Colorado study picked a bunch of very healthy people with perfect cholesterol and glucose. So there was no improvement their. But luckily some of these people have blood pressure between 120 and 139, NR improves blood pressure on these people. The Elysium trial used basis which contains Pterostilbene. Pterostilbene increases cholesterol. So it cancels out the good effect of NR.

 

 

Clearance of plaques is good, but not a dramatic anti-aging example imo.  I do agree, the extension in lifespan that was kind of implied in that one study with NR was  encouraging, but there is no detail at all on that.

 

Are there any examples of NR increasing endurance almost 100%?  Promoting NEW blood vessel growth in very old mice?  Making muscle in old mice look identical to young mice?

 

Below are some quotes from the 3 studies I mentioned that show the most dramatic anti-aging effects, plus one other.

 

Can you point to similar with NR?  Again, I'm not talking about improving symptoms in diseased or unhealthy animals, but reversing some aspects of aging in healthy animals.

 

After 6 days of NMN, 22 month old mice  had the muscle capacity, endurance and metabolism of 6 month old  mice (2013 Sinclair)

 

NMN effectively mitigates age-associated physiological decline in mice (2016 Mills)

 

“NAD+ and SIRT1 levels were HIGHER in OLD Mice than in YOUNG Mice that did not receive NMN.” (Hao, 2017)

 

“The old mice became as fit and strong as young mice” (Sinclair, 2018)

Edited by able, 28 May 2018 - 03:13 AM.

[MikeDC]

Clearance of plaques is good, but not a dramatic anti-aging example imo. I do agree, the extension in lifespan that was kind of implied in that one study with NR was encouraging, but there is no detail at all on that.

Are there any examples of NR increasing endurance almost 100%? Promoting NEW blood vessel growth in very old mice? Making muscle in old mice look identical to young mice?

Below are some quotes from the 3 studies I mentioned that show the most dramatic anti-aging effects, plus one other.

Can you point to similar with NR? Again, I'm not talking about improving symptoms in diseased or unhealthy animals, but reversing some aspects of aging in healthy animals.

After 6 days of NMN, 22 month old mice had the muscle capacity, endurance and metabolism of 6 month old mice (2013 Sinclair)

NMN effectively mitigates age-associated physiological decline in mice (2016 Mills)

“NAD+ and SIRT1 levels were HIGHER in OLD Mice than in YOUNG Mice that did not receive NMN.” (Hao, 2017)

“The old mice became as fit and strong as young mice” (Sinclair, 2018)

If you repeat the NMN studies with NR, you will get better results. It is just that Sinclair is focused on aging and NR researchers were focused on diseases. The effects can be translated between NMN and NR on all mice studies. For humans we don’t know yet.

NAM can probably reproduce all the NMN study results as well. NMN doesn’t get into muscles cells even if you inject it. All the effects are from NAM.

Edited by MikeDC, 28 May 2018 - 02:02 PM.

[able]

A few days ago, Dr Sinclair posted on twitter:

 

Just got approval for the next phase of a study of NAD boosters in humans. Lots of work to do, but for now...

 

and 

 

One of my students, just now: "An hour ago, David, I thought I was going to fail." And at this moment, we're looking at results that might be some of the most important work ever to come out of this lab.

 

 

I've seen references to the Phase 1 study that was done with his company, Metrobiotech, and supposedly completed late 2017. So this must be the Phase 2 that they hoped would start in fall 2018.

 

My question is, how/why can they jump to Phase 2 before they even bother to publish Phase 1? And why don't they register their research at clinicaltrials.gov?

 

I guess it is a good sign that they are moving to phase 2 so soon, but just seems not very transparent.  Is that because of who he is, and he is able to do all this in silent mode, to keep the findings quiet?

 

Also curious - are there any Phase 2 trials for NR starting soon?  I don't recall seeing anything on that.

Edited by able, 02 July 2018 - 05:11 AM.

[bluemoon]

 

I've seen references to the Phase 1 study that was done with his company, Metrobiotech, and supposedly completed late 2017. So this must be the Phase 2 that they hoped would start in fall 2018.

.....

.....

 

Also curious - are there any Phase 2 trials for NR starting soon?  I don't recall seeing anything on that.

 

NR doesn't need any trials, let alone a phase 2 trial since it is not trying to get FDA approval as a drug. Elysium's Leonard Guarente said a year ago that it was setting up six new trials for basis but the only one I've seen at clinictrials.gov is one for acute kidney failure. 

 

I still don't understand what Sinclair is doing with NMN since it is obviously already being sold unless he is adding to NMN to turn the new pill into a drug.

[MikeDC]

ChromaDex, Elysium, or Sinclair can’t get an IND before they can solve the bioavailability issue. So Sinclair’s trials are supplement trials. Not Drug trials.

Wonder why Sinclair has not published a lifespan study of NMN on mice? My guess is NMN didn’t extend lifespan so the study was never published.

[Phoebus]

ChromaDex, Elysium, or Sinclair can’t get an IND before they can solve the bioavailability issue. So Sinclair’s trials are supplement trials. Not Drug trials.

Wonder why Sinclair has not published a lifespan study of NMN on mice? My guess is NMN didn’t extend lifespan so the study was never published.

 

 

what bioavailability issue.?

[able]

what bioavailability issue.?

 

 

The fact that nearly all NR and NMN supplements are digested to NAM, according to the Liu research.

 

Hence, the reason for sublingual delivery.

 

Is it not possible to replicate sublingual delivery in mice?   Is that the reason it hasn't been investigated for NR/NMN by researchers?

 

I remember Turnbuckle suggested in another thread that when mice are given NR/NMN in their drinking water, they absorb some of it in their mouths, bypassing the GI tract, which may account for the speed it reaches the blood.    If so, that implies a reason such studies might not  correlate well with humans taking supplements.

[Phoebus]

The fact that nearly all NR and NMN supplements are digested to NAM, according to the Liu research.

 

 

 

 

by the liver? or its broken down by stomach acid? where does this happen? 

[aaaaaaal]

ChromaDex, Elysium, or Sinclair can’t get an IND before they can solve the bioavailability issue. So Sinclair’s trials are supplement trials. Not Drug trials.

Wonder why Sinclair has not published a lifespan study of NMN on mice? My guess is NMN didn’t extend lifespan so the study was never published.

 

"My guess is". Exactly.

[MikeDC]

"My guess is". Exactly.

Sinclair’s headline seeking nature ensured that he has done a lifespan study with NMN. Why hasn’t he published it? He is coauthor of a recent paper showing NAM does not extend lifespan in mice.

[Castiel]

Hmmm, regards chromadex patents aren't they chemical synthesis patents?  Isn't NR also made biologically?  It seems some genetic engineering and you could increase biological production and obtain it that way bypassing the patent.