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Charles Brenner: everyone buying the NMN story is being hoodwinked

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#1 Iporuru

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Posted 14 January 2020 - 10:34 AM


A series of tweets which I coalesced into one text: https://twitter.com/...861180964327425

 

 

"There is so much disinformation going around about NMN, it's time for a tweetorial

 

Before you dismiss me as biased because I developed the NR patents @Dartmouth, consider that I've been working on nucleosides and nucleotides since 1993 when I began my postdoc @BrandeisU -- I've continued on the forefront of nucleoside/nucleotide research to this day

 

My primary motivation is for people not to be harmed. I also think it is horrible for people to be fooled or hoodwinked

 

We don't how many people have been harmed by taking NMN because we don't know what's in the bottles produced by so many suppliers. It is certain that everyone buying the NMN story is being hoodwinked. If they are buying NMN, their cells are getting either NR or nicotinamide

 

I will explain all, starting with the basic chemistry

 

What are nucleosides and nucleotides? Let's start with examples and then I will teach you the general principles. NR and adenosine are nucleosides. NMN, NAD and ATP are nucleotides. Nucleosides don't have phosphates. Nucleotides have one or more phosphates

 

Nucleosides are molecules with a base linked to a sugar. When the base is adenine (abbreviated A) and the sugar is ribose, you have adenosine. When the base is nicotinamide and the sugar is ribose, you have NR

 

Nucleosides circulate in the body and are taken up by cells through nucleoside transporters. Inside cells, nucleoside kinases add a phosphate to turn nucleosides into nucleotides. Adenosine kinase converts adenosine into AMP, which can then be converted to ADP and ATP

 

NR also circulates, though it is difficult to detect. When we draw blood, an enzyme that is normally inside cells spills out and breaks the NR into nicotinamide plus ribose. We know NR circulates because every cell has NR kinase (some cells have NR kinase 1 and 2)

 

Moreover, cells with NAD problems, such as those in a failing heart, turn up expression of their NR kinases so that when NR becomes available, NR kinases convert the NR to NMN. In a healthy cell, the NMN is then converted to NAD+, NADH, NADP+ and NADPH. That's how NR works

 

What NMN advocates are saying is that NMN is closer to NAD+ than NR is. They are saying that NR has to be converted to NMN and then to NAD+ and this makes NMN more powerful than NR because it is already has one of the phosphates on it toward rebuilding cellular NAD+

 

If NMN were to get into cells, this would be true but NMN does not get into cells. In fact, no nucleotide has ever been shown to get into cells. NAD+ can be exported from cells through Cx43 and NMN was proposed to enter cells through Slc12a8 but NMN does not enter cells

 

If NMN entered cells as NMN, then it would not need NR kinase to elevate NAD+. We knocked out NR kinase. As expected, NR could not be used by cells from these mice to make NAD+. We and others showed that NMN loses its phosphate outside cells, becoming NR

 

The NMN proponents predicted that NMN would still work as NMN in cells that don't have NR kinase but we and others showed that when NR kinase is knocked out, NMN can only raise NAD+ by acting as nicotinamide. That's because NMN works by conversion to NR and needs NR kinase

 

NMN proponents further claimed that sodium channel Slc12a8 is an NMN transporter. Their data did not show this. Their data showed that there is no cellular increase in NMN after extensive incubation with NMN. Remarkably, their false paper has been cited more than 20 times

 

The fact that NMN is not transported and that NMN and NAD+ have to be made inside cells is not surprising. The 1988 Nobel Prize to Elion, Hitchings and Black for work done since the 1960s showed that you can't deliver nucleotides to cells, only bases or nucleosides

 

@davidasinclair also knows this. That's why his company modified the phosphate on NMN to make it cellularly available. Everything in this thread is supported by public data

 

But guess what happens when the NMN phosphate is modified so that you can load cells up with NMN? https://doi.org/10.1...sci.2019.05.001 Eternal life?

 

No. SARM1 protein is turned on by NMN to produce cADPribose that leads to cell death. Remember when I said that in a healthy cell, NMN is converted to NAD+, NADH, NADP+ and NADPH? In a damaged neuron, NMN cannot be converted to NAD+ and is a death signal

 

Modified NMN will not be a drug for health or longevity. Mark my words. It will be unethical to test it in people because it will produce SARM1-dependent damage in animals

 

Is this why I think that NMN is potentially dangerous as a supplement? No

 

Pure NMN can only deliver NR or nicotinamide to cells (just as NR can only deliver NR or nicotinamide to cells). So NMN itself cannot load up any damaged cell with hazardous levels of NMN

 

The problem is you literally have no idea what you are getting when you buy NMN. I would bet that there's caffeine in most NMN supplements. There is likely a large amount of nicotinamide and residual solvents. There's been no NDI on any NMN source. There are no safety data

 

With NR, if you buy from the company holding the patents, you know you are getting material that has been safety reviewed. There's public information about another seller of NR showing acetamide and toluene in their material

 

What keeps me up at night is the idea that someone will be hurt by taking NR. Safety first. People taking NMN are not been safe. And they've also been hoodwinked by the people asserting that it's closer to NAD+ than NR"


Edited by Iporuru, 14 January 2020 - 10:35 AM.

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#2 able

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Posted 14 January 2020 - 05:02 PM

The sinking stock price of Chromadex is making Dr Brenner  a delusional old man, lashing out and lecturing  Dr Sinclair, Elysium, NMN sellers as if they are biology students in his classroom.

 

He claims the published research on Cx43 and  Slc12a8 is wrong.

 

He ignores recent research that show NMN and NAD+ placed outside cells are able to restore NAD+ inside cells just fine - in fact, NMN was more effective than NR (image below).

 

He ignores  that same research (and others) show NR is  quickly degraded to NAM in water or blood, whereas NMN and NAD+ are stable, which is why they are found in blood.

 

His own study found that taking 1,000 mg of NR does not increase NR in the blood beyond the trace levels.  It is not bioavailable.

 

He acts concerned that NMN is unsafe because it does not have NDI or gras, but was fine with selling NR for a year or more before they had NDI and gras.

 

It’s also comical how he continues to claim, with no evidence, that NMN suppliers are adding caffeine to their product, even though most now post 3rd party test results proving purity. I guess it really bothers him that users consistently report more stimulating effect from NMN as opposed to NR.

 

Dr Sinclair is far too classy to get down in the mud like this,  but it would be good if someone on twitter would refute some of this bs.

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Edited by able, 14 January 2020 - 05:03 PM.

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#3 Oakman

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Posted 14 January 2020 - 05:37 PM

So to summarize, in a perfect world where NR is NR and NMN is NMN without adulterations...

 

"Pure NMN can only deliver NR or nicotinamide to cells (just as NR can only deliver NR or nicotinamide to cells)."

 

In essence to a consumer who believes NAD+ is important to supplement, "Is NR or NMN a cheaper way to produce NAD+ in cells?"

 

An example: 6 mo supply NR is 54 grams (300 mg/day) @$180 or $3.33/g  < TruNiagen

                      3 tubs 15 g NMN = 45 grams (~250 mg/day) @$231 or $5.10/g   < ProHealth         

 

Other NMN suppliers may differ in cost a bit, but not a lot. So the 'winner' is NR price wise and certainly from a studies viewpoint if anyone is in doubt about NMN at all.      

 

The only question I have about it all is, "Why do I think I feel better results from NMN than NR supplementation?"



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#4 able

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Posted 14 January 2020 - 06:11 PM

So to summarize, in a perfect world where NR is NR and NMN is NMN without adulterations...

 

"Pure NMN can only deliver NR or nicotinamide to cells (just as NR can only deliver NR or nicotinamide to cells)."

 

In essence to a consumer who believes NAD+ is important to supplement, "Is NR or NMN a cheaper way to produce NAD+ in cells?"

 

An example: 6 mo supply NR is 54 grams (300 mg/day) @$180 or $3.33/g  < TruNiagen

                      3 tubs 15 g NMN = 45 grams (~250 mg/day) @$231 or $5.10/g   < ProHealth         

 

Other NMN suppliers may differ in cost a bit, but not a lot. So the 'winner' is NR price wise and certainly from a studies viewpoint if anyone is in doubt about NMN at all.      

 

The only question I have about it all is, "Why do I think I feel better results from NMN than NR supplementation?"

 

 

Both NR and NMN are severely degraded in digestion, which is why I favor sublingual delivery.  There is no sublingual option for NR.

 

Ignoring the digestion - Any portion of  NR or NMN supplement that actually makes it to the bloodstream and reach a cell in need, are equally adept at entering the cell to restore NAD+ as shown in the chart.

 

The problem for NR is that it is not stable and very quickly degraded to NAM.  So it is unable to reach most cells as NR.  Multiple studies have shown this.

 

So NR does cost less per mg, but is not found in bloodstream, and unable to do much in tissues beyond the liver.

 

We may feel more effect from NMN as it is found in the bloodstream and reaches the hypothalamus, which is the master regulator of energy metabolism, while NR does not.

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Edited by able, 14 January 2020 - 06:14 PM.

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#5 Harkijn

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Posted 15 January 2020 - 08:05 AM

Thanks for posting Iporuru. I genuinely hope that all NMN users take a second look at how little research has come available about safety and effectiveness of NMN.


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#6 Turnbuckle

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Posted 15 January 2020 - 10:51 AM

Brenner: It is certain that everyone buying the NMN story is being hoodwinked. 

 

 

And NR as well. As Brenner's own work showed, nicotinamide elevated NAD+ almost as much as NR, even though he was only dosing with half as much nicotinamide by weight--a fact you have to dig out of the paper as it is hidden in the phrase mole equivalent doses. One mole of NR weights twice as much as one mole of nicotinamide. And you get faster action with plain nicotinamide (also seen in his paper) because NR has to be digested first. I've found that the "digested" product (nicotinamide + ribose) works better than plain nicotinamide or any of these expensive products being sold. Cells synthesize ribose slowly, so providing it will get quicker action.
 
See Fig. 5B of Brenner's paper. Nicotinamide boosts NAD+ faster and the area under the curve is nearly the same for nicotinamide as for NR, even though only half as much nicotinamide was used. The NAD+ peak is higher for NR, but that is because NR is providing the ribose, and the cells don't have to make it.
 

 

 

 


Edited by Turnbuckle, 15 January 2020 - 10:55 AM.

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#7 MikeDC

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Posted 15 January 2020 - 11:13 AM

It is quite true that NAM is just as effective as NR and NMN in increasing NAD+. The problem is NAM inhibit NAD+ consumption. The increased NAD+ does not result in increased NAD+ consumption. The Trammell paper shows in mice liver NR was able to increase NAd+ consumptions after 4 and 1/2 hours.

Another advantage of NR over NAM as demonstrated by the Nestlé paper is that some cells in the liver depends on NR when under stress.
Since endogenous NR level was extremely low, a little NR that gets into cells can make a big difference.

As Sinclair’s said NMN is not stable in room temperature similar to NR. But Niagen is crystalline NRCL and very stable at room temperature.
It has been shown to be stable in stomach and intestine fluid as well.

Edited by MikeDC, 15 January 2020 - 11:53 AM.

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#8 p75213

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Posted 15 January 2020 - 06:44 PM

It is quite true that NAM is just as effective as NR and NMN in increasing NAD+. The problem is NAM inhibit NAD+ consumption. The increased NAD+ does not result in increased NAD+ consumption. The Trammell paper shows in mice liver NR was able to increase NAd+ consumptions after 4 and 1/2 hours.

Another advantage of NR over NAM as demonstrated by the Nestlé paper is that some cells in the liver depends on NR when under stress.
Since endogenous NR level was extremely low, a little NR that gets into cells can make a big difference.

As Sinclair’s said NMN is not stable in room temperature similar to NR. But Niagen is crystalline NRCL and very stable at room temperature.
It has been shown to be stable in stomach and intestine fluid as well.


As far as I'm aware there has been no studies supplementing with NAM while at the same time activating NAMPT. That would be a worthwhile study.

#9 MikeDC

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Posted 16 January 2020 - 12:29 AM

As far as I'm aware there has been no studies supplementing with NAM while at the same time activating NAMPT. That would be a worthwhile study.


But a similar study was done by Sinclair. He used NMN and NaH2S. NaHS is precursor to H2S which activate NAMPT. Using both together increased NAD+ Additional 50% compared to NMN alone. A lot of people are using Taurine as a replacement for NaHS. We know that probably over 90% of NMN is degraded to NAM. So a NMN study is not that much different from a NAM study.
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#10 able

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Posted 16 January 2020 - 12:49 AM

But a similar study was done by Sinclair. He used NMN and NaH2S. NaHS is precursor to H2S which activate NAMPT. Using both together increased NAD+ Additional 50% compared to NMN alone. A lot of people are using Taurine as a replacement for NaHS. We know that probably over 90% of NMN is degraded to NAM. So a NMN study is not that much different from a NAM study.

 

You have no idea how much NMN can utilize slc12a8.  It may be 1%, or 50%.

 

Dr Brenner wants us to believe it is zero.  But that doesn't really make sense, as there have been numerous studies that show some NMN makes it to bloodstream in a few minutes.

 

I don't believe there are any studies that show such rapid uptake with NR.  Please correct me if there are.

 

Based on the vastly different speed of uptake it seems beyond doubt that some NMN  makes it to bloodstream via a pathway that NR does not access.  We just don't know how much.

 

Claiming 90% of NMN is degraded to NAM is pure speculation with no research behind it.


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#11 MikeDC

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Posted 16 January 2020 - 01:59 AM

Every time you feel like pumping NMN you should look at this chart. I believe this study was done by a research group that is very close to Sinclair.

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#12 able

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Posted 16 January 2020 - 02:20 AM

I guess you are referring to the finding that NR and NMN are almost totally degraded to NAM before leaving the liver?

 

How is that beneficial to NR?

 

The research on slc12a8 shows some NMN goes direct to NAD+ in intestines, but slc12a8 is mostly expressed in older mice.  Likely a response to help compensate for low NAD+.  That pathway wouldn't show on the Rabinowitz study as they used young mice.  Also, Rabinowitz didn't check NAD+ levels in intestine.  Any NMN that used Slc12a8 to NAD+ would obviously not show in blood plasma.

 

How do you explain the numerous studies that show NMN increases blood plasma NMN in minutes?  

 

NR shows up in blood at trace levels.  Brenner study shows 1,000 mg NR a day still does not increase levels of NR in blood.  It is NOT bioavailable.

 

 

 

 


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#13 MikeDC

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Posted 16 January 2020 - 03:14 AM

The chart I posted shows NR is more bioavailable than NMN. The NMN transporter is a joke.
It doesn’t exist.
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#14 jocko6889

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Posted 16 January 2020 - 02:24 PM

Actually, there is a lot of disinformation in Brenner's tweets.

Recent studies have shown oral NR is unstable and breaks down in the bloodstream. It arrives in the tissues as NAM (nicotinamide) and must then get through the NAMPT bottleneck in the salvage pathway to get upconverted to NMN and then NAD+. This is a wasteful and highly inefficient way to get NAD+.

By contrast, NMN (and NAD+) are much more stable and arrive at the tissue mostly intact. Whether you believe Brenner's claim that Slc12a8 doesn't escort NMN directly into certain cell types or not (studies show it does), the fact remains that after NMN arrives at the tissues intact, it is easily broken down into NR in order to pass through the cell membrane where it gets upconverted back to NMN, then to NAD+.

It sounds like Brenner is a paid NR spokesperson.
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#15 Harkijn

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Posted 16 January 2020 - 04:27 PM

It sounds like Brenner is a paid NR spokesperson.

By this conclusion you undermine your own assertions preceeding it. You don't seem to agree with dr. Brenner but that is no reason to accuse him of duplicity. Dr. Brenner, dr. Sinclair, Guarente, Imai and others are quite open about their commercial interests and affiliations.


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#16 Kentavr

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Posted 16 January 2020 - 07:47 PM

I think the advantage of NMN is provided by that phosphate group. When you take NMN, the cell does not need to look for phosphate, which means that the cell cannot reduce the production of NAD + by limiting the availability of the phosphate group (even assuming that NMN breaks down into NR and a phosphate group to enter the cell).
It makes no difference to me what happens in the process if the result is better than from NR.

Elk (scientist): "It's impossible! It is impossible for carrots to fall from the sky in the form of rain!"

Rabbit: ”You don’t understand: I’m not interested in WHY this can’t happen if I get the desired result."

I want to hear an explanation why NMN allows you to create more NAD + molecules than NR, and why there are no negative effects from it.
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#17 p75213

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Posted 16 January 2020 - 11:11 PM

But a similar study was done by Sinclair. He used NMN and NaH2S. NaHS is precursor to H2S which activate NAMPT. Using both together increased NAD+ Additional 50% compared to NMN alone. A lot of people are using Taurine as a replacement for NaHS. We know that probably over 90% of NMN is degraded to NAM. So a NMN study is not that much different from a NAM study.


Taurine reads good so I've just ordered some. Should fit in well with my current stack. Have to do some research on ribose. Turnbuckle mentioned ribose and nam as being a viable alternative to the more expensive precursors and he seems to be quite knowledgeable about these things.

#18 MikeDC

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Posted 17 January 2020 - 12:04 AM

Taurine reads good so I've just ordered some. Should fit in well with my current stack. Have to do some research on ribose. Turnbuckle mentioned ribose and nam as being a viable alternative to the more expensive precursors and he seems to be quite knowledgeable about these things.


Turnbuckle sounds knowledgeable, but he is deadly wrong on NAM+Ribose = NR and NMN

Both NAM and Niacin increases insulin resistance. But NR reduces insulin resistance in mice and no effect on humans so far.
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#19 MikeDC

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Posted 17 January 2020 - 02:18 AM

I think the advantage of NMN is provided by that phosphate group. When you take NMN, the cell does not need to look for phosphate, which means that the cell cannot reduce the production of NAD + by limiting the availability of the phosphate group (even assuming that NMN breaks down into NR and a phosphate group to enter the cell).
It makes no difference to me what happens in the process if the result is better than from NR.

Elk (scientist): "It's impossible! It is impossible for carrots to fall from the sky in the form of rain!"

Rabbit: ”You don’t understand: I’m not interested in WHY this can’t happen if I get the desired result."

I want to hear an explanation why NMN allows you to create more NAD + molecules than NR, and why there are no negative effects from it.


There is plenty of phosphate in the body. High levels of phosphate is actually harmful. NMN loses to Niagen even before you take it because NMN is not stable in room temperature. Between the time it was manufactured to the time you receive it, it may have degraded to NAM already.
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#20 Kentavr

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Posted 18 January 2020 - 05:06 AM

There is plenty of phosphate in the body. High levels of phosphate is actually harmful. NMN loses to Niagen even before you take it because NMN is not stable in room temperature. Between the time it was manufactured to the time you receive it, it may have degraded to NAM already.

 

MIikeDC, I am beginning to doubt your ability to adequately evaluate studies.
 
At first
 
Phrase: “There is plenty of phosphate in the body - this is a general phrase that does not mean anything. There is a significant difference between phosphate, which is very far in the cell in another form, and phosphate, which is nearby in the desired form.
Read at least books on the kinetics of chemical reactions, which indicate how the rate of formation of chemical reaction products depends on concentration.
 
Secondly
 
When you made the argument that NR is cheaper than NMN, I didn’t even answer you. I am writing here.
Yes, maybe NR is cheaper than NMN. However, sublingual absorption is better than through the intestines. NR in sublingual administration tastes disgusting.
For this reason, it’s more profitable to buy NMN. Note that I do not even consider the fact that NMN increases NAD + more than NR, which makes NMN even more profitable.
 
Additionally: the arguments that NMN can break down in the intestines are not relevant for those who take it sublingually.
 
Thirdly
 
So that you do not evade, I will mark my question in red:
 
Why does NAD + increase more with NMN than with NR?

 


Edited by Kentavr, 18 January 2020 - 05:33 AM.

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#21 Kentavr

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Posted 18 January 2020 - 10:56 AM

MikeDC,
 
Fourth
 
NMN decomposes very slowly at room temperature if they are in a crystalline state. Alivebynature sells crystalline form of NMN
 
"Our pure NMN is bioengineered to have thermostability and pH stability. This stable form of NMN retains 98% potency for three months and over 97% potency for six months at temperatures ranging from 39.2 to 110 degrees Fahrenheit. Testing performed after two years of storage at room temperature found a purity of 93%.
 
NMN products not ingested for 3 months or longer may be refrigerated to ensure they maintain full potency. "
 
 
I think this is very good.
 
Fifthly
 
If you think that NMN is too expensive, soon its price will drop significantly, since the Chinese company GENE HARBOR (HONG KONG) BIOTECHNOLOGIES LTD has invested in the construction of a huge plant for the production of NMN to make it cheaper.
 
 
If you doubt their qualifications, then I can tell you that this is a high-tech company that has invested a huge amount of money in the development of enzyme technologies. Since 2007, it has been located in a science park in Hong Kong.
 
 
Here is the website of this company: http://www.nmn-health.com/
Here is her other site: http://www.geneharbortech.com.hk/
 
If you think the product is unsafe, be aware that this is the only NMN manufacturer to have a GRAS certificate.

 


Edited by Kentavr, 18 January 2020 - 11:10 AM.

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#22 MikeDC

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Posted 18 January 2020 - 01:19 PM

I searched for NMN GRAS on the FDA site and could not find anything. Share a link if you have one. I don’t believe anything alivebynature says.
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#23 MikeDC

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Posted 18 January 2020 - 01:44 PM

I found only one GRAS for Nutraland. But it is not NMN.
On the Chinese article they posted a certificate which is fake because FDA only send a letter. You can find the format of the letter on the following link. So there is no GRAS on NMN.

https://www.accessda...SNotices&id=701
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#24 Oakman

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Posted 18 January 2020 - 02:15 PM

I found only one GRAS for Nutraland. But it is not NMN.
On the Chinese article they posted a certificate which is fake because FDA only send a letter. You can find the format of the letter on the following link. So there is no GRAS on NMN.

https://www.accessda...SNotices&id=701

 

https://www.newhope....med-gras-status

The principle of 'generally recognized as safe' for food additives has been in existence since 1958. The rules of the game changed significantly in 1997, however, when the FDA launched the self-affirmation GRAS process, and the voluntary notification process. Under the new procedure, a company can have a safety dossier prepared and have an independent panel of experts evaluate whether a given food additive is safe. But the company is not required to publish that information and submit it to the FDA to review. It is believed that only a small percentage of the total self-affirmed GRAS determinations are ever submitted to the FDA.

Self-affirmed GRAS for NMN  > https://img1.wsimg.c...r=1569708071385



#25 MikeDC

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Posted 18 January 2020 - 02:18 PM

This certificate is undersigned by Susan Cho who works for Nutra Source the company
That helped Nutrland to obtain GRAS on a different ingredient.
I don’t know who is fooling who here. Could be Nutra Source tryjng to fool
Nutraland.

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#26 Kentavr

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Posted 18 January 2020 - 03:47 PM

about-us-01.jpg

 

https://www.nmn-health.com/about/

 



#27 MikeDC

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Posted 18 January 2020 - 04:44 PM

https://www.newhope....med-gras-status
The principle of 'generally recognized as safe' for food additives has been in existence since 1958. The rules of the game changed significantly in 1997, however, when the FDA launched the self-affirmation GRAS process, and the voluntary notification process. Under the new procedure, a company can have a safety dossier prepared and have an independent panel of experts evaluate whether a given food additive is safe. But the company is not required to publish that information and submit it to the FDA to review. It is believed that only a small percentage of the total self-affirmed GRAS determinations are ever submitted to the FDA.

Self-affirmed GRAS for NMN > https://img1.wsimg.c...r=1569708071385


So Nutrland filed Self Affirmed GRAS on one ingredient and choose not to file on NMN. Why?
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#28 MikeDC

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Posted 18 January 2020 - 04:47 PM

about-us-01.jpg

https://www.nmn-health.com/about/


$182 per month.

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#29 Kentavr

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Posted 18 January 2020 - 05:09 PM

$182 per month.

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Of course. Excitement. You would sell too. There are 50 positive reviews on jd.com and not one negative.

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#30 Oakman

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Posted 18 January 2020 - 05:17 PM

So Nutrland filed Self Affirmed GRAS on one ingredient and choose not to file on NMN. Why?

 

Read the story, most don't file. Why? Why should they if they don't have to? They followed the rules.







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