24 replies to this topic

[MikeDC]

NMN and NR reverses endothelial cell dysfunction. NMN’s effect is abolished when CD73 is deleted or an inhibitor is used.
https://www.scienced...00629522030246X

[able]

So they found if they introduced NMN or NR to one type of endothelial cells, NR and NMN performed the same.

 

Beneficial effects of NMN and NR were comparable and could be both ascribed to NAD- dependent mechanisms, as suggested in previous studies  

 

Then they found in mice they engineered to not have CD73 enzymes, NMN wasn't able to enter the cell.  

 

So, CD73 is important for NMN (and NAD+) entry into cells. 

 

 

I don't know of any research that shows there is a shortage of CD73 when we age.  In fact, I believe it is the opposite.

 

 

It wouldn't be so important if NR was available.

 

Since NR is not bioavailable and is unstable in blood so is very seldom found in the bloodstream, the authors point out the importance of CD73 enzymes to enable NMN inside these cells:

 

These results suggest again that intracellular NAD synthesis by NAMPT  from nicotinamide and extracellular conversion of NMN to NR represents  the two major systems maintaining intracellular NAD in endothelial inflammation. 

 

 

 

Notice they don't mention NR itself being a major source of maintaining NAD+, as it is not available in the bloodstream.  

 

It is important as a transitory molecule to help NMN or NAD to enter to this type of cell.

 

Edited by able, 11 May 2020 - 10:43 PM.

[granth998]

There's no real world scenario where CD73 would be completely eliminated.  It's a very common cellular surface enzyme, so it's rather disingenuous to imply this part of the study is anything but a control to show its relevance.

 

In regards to NMN or NAD+, NR is merely a transient molecule to facilitate passage into the cell.  While NR is useful as a product of the salvage pathway after conversion from NAM, it is miscast in the role of a supplement to enhance levels of NAD+.  Research has shown NR to be far too unstable in the bloodstream, breaking down rather easily into NAM which then has to pass through the NAMPT bottleneck in order to get upconverted back into NR again.  Its only use as a supplement then would be as ordinary, downgraded nicotinamide.

 

Research shows that NMN and NAD+ are far more stable molecules that survive in the bloodstream mostly intact when they arrive at the site of the tissue itself.  As a result, NMN and NAD+ are far superior to NR as a supplement.

Edited by jocko6889, 14 May 2020 - 09:39 PM.

[MikeDC]

There's no real world scenario where CD73 would be completely eliminated. It's a very common cellular surface enzyme, so it's rather disingenuous to imply this part of the study is anything but a control to show its relevance.

In regards to NMN or NAD+, NR is merely a transient molecule to facilitate passage into the cell. While NR is useful as a product of the salvage pathway after conversion from NAM, it is miscast in the role of a supplement to enhance levels of NAD+. Research has shown NR to be far too unstable in the bloodstream, breaking down rather easily into NAM which then has to pass through the NAMPT bottleneck in order to get upconverted back into NR again. Its only use as a supplement then would be as ordinary, downgraded nicotinamide.

Research shows that NMN and NAD+ are far more stable molecules that survive in the bloodstream mostly intact when they arrive at the site of the tissue itself. As a result, NMN and NAD+ are far superior to NR as a supplement.

So far the evidence favors NR over NMN as oral supplement.

[granth998]

So far the evidence favors NR over NMN as oral supplement.

Post any evidence that oral NR survives in the bloodstream and makes it to the tissues as NR and not NAM.  As I said, NR is not stable in the bloodstream.  Facts are facts.

[MikeDC]

Post any evidence that oral NR survives in the bloodstream and makes it to the tissues as NR and not NAM. As I said, NR is not stable in the bloodstream. Facts are facts.

This has been discussed in previous thread. No need to repeat here again. Brenner did a comparison of all NAD+ precursors and will be published soon. It used isotope tracing. That will clarify a lot of things. Did you read the article that even injected NMN didn’t increase nad+ in mice brain?

[granth998]

This has been discussed in previous thread. No need to repeat here again. Brenner did a comparison of all NAD+ precursors and will be published soon. It used isotope tracing. That will clarify a lot of things. Did you read the article that even injected NMN didn’t increase nad+ in mice brain?

Brenner is on the payroll of Chromadex.  No credible scientist would accept money from a company to prove the superiority of its product and then expect others, including peers believe his work was objective.  Contrast this with David Sinclair, a leader in the field of longevity who takes NMN but does not accept money from any company that sells NAD+ boosters.  Credible scientists go to great lengths to avoid funding that might create the perception that their work was biased in any way.

[MikeDC]

Brenner is on the payroll of Chromadex. No credible scientist would accept money from a company to prove the superiority of its product and then expect others, including peers believe his work was objective. Contrast this with David Sinclair, a leader in the field of longevity who takes NMN but does not accept money from any company that sells NAD+ boosters. Credible scientists go to great lengths to avoid funding that might create the perception that their work was biased in any way.

Gates foundation didn’t have a problem funding that study. It may also include NAD and NRH. NRH is much superior to NR and NMN.

Edited by MikeDC, 16 May 2020 - 01:38 PM.

[LawrenceW]

MikeDC

 

Is NRH going to be classified as a dietary supplement or a drug?

[Harkijn]

Many scientists have moved from their university labs into  commercial spin-offs once they made a promising discovery. It's basically the way innovation works....

[MikeDC]

MikeDC

Is NRH going to be classified as a dietary supplement or a drug?

Good question. We have been wondering why ChromaDex is trying very hard to hide NRH. Either they have a secret deal with a big pharma or Brenner don’t want anything better than NR.

[granth998]

Good question. We have been wondering why ChromaDex is trying very hard to hide NRH. Either they have a secret deal with a big pharma or Brenner don’t want anything better than NR.

"We have been wondering why ChromaDex is trying very hard to hide NRH"..... "Brenner don't want anything better than NR"

 

Glad you can at least admit the possibility of corporate influence on his work.  To me, reading his studies it's rather obvious. 

 

NRH is a much more stable molecule in the blood.  Although it needs a lot more research, unlike NR it shows promise of one day competing with NMN and NAD+ as a legitimate NAD+ booster.

[granth998]

Many scientists have moved from their university labs into  commercial spin-offs once they made a promising discovery. It's basically the way innovation works....

Unfortunately, as government funding has dried up more scientists are getting on the payroll of corporations.  Although some legitimate science in that environment can be done, the results rarely conflict with the goals of the corporate sponsors.  "Scientists" working for tobacco companies, artificial sweetener companies, RoundUp weed killer, and on and on are the most obvious examples of scientists used as pawns to sell products with sometimes dangerous results for the public.  To say "it's basically the way innovation works" is an inaccurate, overly broad view.  In order to be objective, science should be insulated from monetary influence as much as possible.

 

"Sit before facts as a child and let them take you wherever they will, even to the darkest abyss" - TH Huxley

[MikeDC]

It is not corporate influence on his work. NR is Brenner’s baby. He is blocking the progress of NRH.

[granth998]

It is not corporate influence on his work. NR is Brenner’s baby. He is blocking the progress of NRH.

If there's no corporate influence on Brenner's work and he's truly an unbiased scientist, then why would he be blocking the progress of NRH?  Would it be because ChromaDex has millions invested in NR and they need to protect their market share?

 

Also, you said, "NR is Brenner's baby".  That's not very scientific.  Science is tentative and subject to change.  You can't be invested in an idea so much that you ignore any evidence against it.  What you're saying only adds to the evidence that Brenner is a paid advocate for NR.

[MikeDC]

Brenner doesn’t need pay to advocate NR. Just like Sinclair doesn’t need pay to advocate NMN. It is professional pride.

[Harkijn]

It is not corporate influence on his work. NR is Brenner’s baby. He is blocking the progress of NRH.

 

Hi MikeDC, you seem to have some latest news or inside knowledge (from Nestle?) about NRH. NRH is an important development ( as readily acknowledged by dr. FrankenBrenner).

If you have any additional info please place it in the NRH thread:

https://www.longecit...er-than-nr-nrh/

Thanks in advance!

[Linux]

What you're saying only adds to the evidence that Brenner is a paid advocate for NR.

 

He is. And you are a paid advocate for NMN since you work for ALIVEBYNATURE -a seller of NMN supplements (you´ve got the same username on Alivebynature´s forum where your official title is "Chief information officer (CIO) for Alivebynature").

 

Alivebynature used to sell and heavily promote NR when they purchased this raw material from Chromadex some years ago. When Chromadex stopped selling it to them ALL the articles praising the "celullar energizer" and "NAD+ booster" NR disappeared from their site. Suddenly the science wasn´t valid anymore. They scrambled to find a new hero ingredient and that was NMN. Now the science had to be twisted and bent to fit their new product line.

 

NMN is now Alivebynature´s baby and they will protect and promote it at all cost, truth and science be damned. FDA had to force Alivebynature to remove all their coronavirus articles where they claimed that NMN could treat and prevent COVID-19.

 

It´s despicable when companies try to cash in on others misery. Using a crisis like this to profit on peoples fear. Thankfully FDA stepped in and put a stop to that campaign of misinformation.

Edited by Linux, 17 May 2020 - 05:53 PM.

[MikeDC]

He is. And you are a paid advocate for NMN since you work for ALIVEBYNATURE -a seller of NMN supplements (you´ve got the same username on Alivebynature´s forum where your official title is "Chief information officer (CIO) for Alivebynature").

Alivebynature used to sell and heavily promote NR when they purchased this raw material from Chromadex some years ago. When Chromadex stopped selling it to them ALL the articles praising the "celullar energizer" and "NAD+ booster" NR disappeared from their site. Suddenly the science wasn´t valid anymore. They scrambled to find a new hero ingredient and that was NMN. Now the science had to be twisted and bent to fit their new product line.

NMN is now Alivebynature´s baby and they will protect and promote it at all cost, truth and science be damned. FDA had to force Alivebynature to remove all their coronavirus articles where they claimed that NMN could treat and prevent COVID-19.

It´s despicable when companies try to cash in on others misery. Using a crisis like this to profit on peoples fear. Thankfully FDA stepped in and put a stop to that campaign of misinformation.

People who work for vendors should make it known. He may not be the only one who work for alivebynature or paid by alivebynature or another company.

[Fredrik]

Post any evidence that oral NR survives in the bloodstream and makes it to the tissues as NR and not NAM.  As I said, NR is not stable in the bloodstream.  Facts are facts.

 

 

How the conversion of NR to NAD+ takes place is still somewhat debated and there´s no data yet on how the conversion of NMN to NAD+ may take place in humans. There´s speculation that the gut microbiome is also involved in converting NR and NMN into NAD+. 

 

NMN is NR with a phosphate group attached to it and that gets cleaved off by the ectoenzymes CD73 outside the cells (extracellularly) so NMN turns into NR and then inside the cell (intracellularly) NR turns back into NMN and then to NAD+.

 

There may be other unknown direct NMN transporters in humans. There´s one, slc12a8, expressed in mouse intestinal and liver cells. It is unknown if humans have that transporter though.

https://www.nature.c...2255-018-0009-4

 

A clinical trial published in Scientific Reports in 2019 concludes NR both safely and effectively increases NAD levels in a dose-dependent manner in healthy overweight adults. The study used an 8-week randomized, double-blind, placebo-controlled trial to conduct its evaluation. After two weeks, the study results are as follows:

•   100 mg of NR increased whole blood NAD+ by 22%
•   300 mg of NR increased whole blood NAD+ by 51%
• 1000 mg of NR increased whole blood NAD+ by 142%.

 

https://www.nature.c...598-019-46120-z

 

Another study published in Nature Communications in 2016 reports that a single dose of NR can elevate human blood NAD+ levels 2.7-fold.

https://www.nature.c...les/ncomms12948

 

And this recent niacin trial increased blood levels of NAD+ by 800% in the dosing range of 750-1000 mg:

 

"We administered an increasing dose of NAD+-booster niacin, a vitamin B3 form (to 750-1,000 mg/day; clinicaltrials.govNCT03973203) for patients and their matched controls for 10 or 4 months, respectively.

 

Blood NAD+ increased in all subjects, up to 8-fold, and muscle NAD+ of patients reached the level of their controls. Some patients showed anemia tendency, while muscle strength and mitochondrial biogenesis increased in all subjects. In patients, muscle metabolome shifted toward controls and liver fat decreased even 50%.

 

Our evidence indicates that blood analysis is useful in identifying NAD+ deficiency and points niacin to be an efficient NAD+ booster for treating mitochondrial myopathy."

 

https://www.ncbi.nlm...pubmed/32386566

 

This human clinical trial of NMN will finally tell us if and how much 300 mg of NMN can raise the serum blood levels of NAD+.

 

https://clinicaltria... ... w=2&rank=2

Edited by Fredrik, 18 May 2020 - 09:02 PM.

[able]

Good explanation Fredrik.

 

I hope we don't have to wait for the effepharm trial that hasn't started yet, to learn how NMN effects NAD+ levels.  The University of Washington study is complete, and Metrobiotech is in Phase 2 already.

 

I do find it strange that the Niacin study uses blood NAD+ levels as primary endpoint for efficacy, yet Chromadex keeps telling us that NAD+ is "too big" to enter cells, and is not useful.

 

Are blood NAD+ levels key, as this study says, or not?

Edited by able, 18 May 2020 - 10:39 PM.

[MikeDC]

Good explanation Fredrik.

I hope we don't have to wait for the effepharm trial that hasn't started yet, to learn how NMN effects NAD+ levels. The University of Washington study is complete, and Metrobiotech is in Phase 2 already.

I do find it strange that the Niacin study uses blood NAD+ levels as primary endpoint for efficacy, yet Chromadex keeps telling us that NAD+ is "too big" to enter cells, and is not useful.

Are blood NAD+ levels key, as this study says, or not?

The NAD+ in the blood are mostly inside cells. NAD+ and NMN are both precursors to NR in tissues. They are converted to NR before entering cells.

[MikeDC]

How the conversion of NR to NAD+ takes place is still somewhat debated and there´s no data yet on how the conversion of NMN to NAD+ may take place in humans. There´s speculation that the gut microbiome is also involved in converting NR and NMN into NAD+.

NMN is NR with a phosphate group attached to it and that gets cleaved off by the ectoenzymes CD73 outside the cells (extracellularly) so NMN turns into NR and then inside the cell (intracellularly) NR turns back into NMN and then to NAD+.

There may be other unknown direct NMN transporters in humans. There´s one, slc12a8, expressed in mouse intestinal and liver cells. It is unknown if humans have that transporter though.
https://www.nature.c...2255-018-0009-4

A clinical trial published in Scientific Reports in 2019 concludes NR both safely and effectively increases NAD levels in a dose-dependent manner in healthy overweight adults. The study used an 8-week randomized, double-blind, placebo-controlled trial to conduct its evaluation. After two weeks, the study results are as follows:

• 100 mg of NR increased whole blood NAD+ by 22%
• 300 mg of NR increased whole blood NAD+ by 51%
• 1000 mg of NR increased whole blood NAD+ by 142%.

https://www.nature.c...598-019-46120-z

Another study published in Nature Communications in 2016 reports that a single dose of NR can elevate human blood NAD+ levels 2.7-fold.
https://www.nature.c...les/ncomms12948

And this recent niacin trial increased blood levels of NAD+ by 800% in the dosing range of 750-1000 mg:

"We administered an increasing dose of NAD+-booster niacin, a vitamin B3 form (to 750-1,000 mg/day; clinicaltrials.govNCT03973203) for patients and their matched controls for 10 or 4 months, respectively.

Blood NAD+ increased in all subjects, up to 8-fold, and muscle NAD+ of patients reached the level of their controls. Some patients showed anemia tendency, while muscle strength and mitochondrial biogenesis increased in all subjects. In patients, muscle metabolome shifted toward controls and liver fat decreased even 50%.

Our evidence indicates that blood analysis is useful in identifying NAD+ deficiency and points niacin to be an efficient NAD+ booster for treating mitochondrial myopathy."

https://www.ncbi.nlm...pubmed/32386566

This human clinical trial of NMN will finally tell us if and how much 300 mg of NMN can raise the serum blood levels of NAD+.

https://clinicaltria... ... w=2&rank=2

There is no debate on how NR converte to NAD+. NRK1 and NRK2 are required.

[able]

The NAD+ in the blood are mostly inside cells. NAD+ and NMN are both precursors to NR in tissues. They are converted to NR before entering cells.

 

 

NAD+ levels in blood were massively increased.  NAD+ in muscle doubled.  Patients had very impressive improvements in muscle strength.

 

NMN was increased about 3x.

 

NR was found at trace levels - about 1/1000 that of NAD+, 1/20 that of NMN, and did not increase significantly.

 

NR does not seem to play a significant role here at all.

 

For that matter, I dont believe any studies show a significant increase in NR levels. The more we learn, it seems the main action of NR is to increase NAD+ levels, but doesn't act as NR at all.  Niacin increases NAD+ at far less cost.

 

Image attached.

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Edited by able, 19 May 2020 - 02:04 AM.

[MikeDC]

NAD+ levels in blood were massively increased. NAD+ in muscle doubled. Patients had very impressive improvements in muscle strength.

NMN was increased about 3x.

NR was found at trace levels - about 1/1000 that of NAD+, 1/20 that of NMN, and did not increase significantly.

NR does not seem to play a significant role here at all.

For that matter, I dont believe any studies show a significant increase in NR levels. The more we learn, it seems the main action of NR is to increase NAD+ levels, but doesn't act as NR at all. Niacin increases NAD+ at far less cost.

Image attached.

NR levels depends on when you measure it. Steady state NR level may not be increased significantly. One Nestlé study shows endogenous NR is indispensable. Even though the bioavailability of NR is low. The amount of NR reaching the cells can still be much much more than the baseline NR or NMN and can make significant impact on health and aging. My opinion is NAR is better than NR because Niacin is better than NAM.

Edited by MikeDC, 19 May 2020 - 11:06 AM.