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Nicotinamide Riboside [Curated]

nicotinamide riboside nicotinamide nad boosting charles brenner david sinclair leonard guarente niagen niacinamide nicotinamide mononucleotide

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#2101 mikeinnaples

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Posted 26 April 2017 - 04:35 PM

 

For months now there has been a campaign to refute the FACT that NMN must be converted into NR before entering cells. When I've mentioned this, people always claim that I need to provide citations. Well, I found the thesis.

 

http://ir.uiowa.edu/...533&context=etd

 

 

 

This
 

Though the primary breakdown product of NAD+ is Nam and the complete bacterially digested product is NA, nicotinamide riboside (NR) is an additional salvageable precursor that exists intracellularly and in milk (7, 30, 31). The unique NR salvage pathway is via nicotinamide riboside kinases (7). In addition, NR can be split into a Nam moiety and resynthesized to NAD+ via Nam salvage enzymes (32). Nicotinic acid riboside (NAR) is an alternate substrate of nicotinamide riboside kinases (33) and purine nucleoside phosphorylase (13) that has been shown to be an intracellular NAD+ precursor (30) but has not been reported to circulate. Whereas NA is the salvageable precursor of NAD+ that has been exposed to the most digestive enzymes and Nam is the salvageable precursor that is produced by every cell with NAD+ -consuming enzymes

 

 

and this

 

careful examination indicates that extracellular NA, Nam, and NR increase intracellular NAD+ in yeast and vertebrate cells, whereas NMN requires dephosphorylation to NR

 

 

Hmm ...interesting theses.


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#2102 mikeinnaples

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Posted 26 April 2017 - 04:41 PM

Though current data is highly suggestive that NMN utilization requires dephosphorylation by CD73 to NR or hydrolysis to Nam by CD38, these studies do not preclude that nor tested whether NMN and NR are equally efficacious as precursors. The rate of NMN dephosphorylation could be non-rate limiting to its utilization, rendering NMN and NR equivalently efficacious. We sought to directly test efficacy of NMN versus NR as salvageable NAD+ precursors using stable isotope labeling and LC-MS/MS. In so doing, we show direct evidence that NR is a more efficacious precursor and confirm metabolite-metabolite relationships in a human hepatocyte cell line

 

 

 

 

 



#2103 bluemoon

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Posted 26 April 2017 - 07:52 PM

 

My understanding is that NR is far better than NMN because it doesn't get degraded in the gut and can instantly penetrate the cell membrane.  

 

 

 

I'm curious why David Sicnlair is then working on a drug that involves NMN. He could just as easily make one with NR. Keep in mind that what he is working on is a drug, not just trying to manufacture NMN cheaply if I've read that correctly. He is also conducting a six month human trial of just NMN, which is interesting. 



#2104 Bryan_S

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Posted 26 April 2017 - 08:26 PM

Guys I'm going to start removing posts if you all can't get along. I expect "all opinions" to be supported by well researched academic findings. That is the standard I want upheld! I simply have no trouble finding supporting studies pro and con for much of this banter and its about time to begin to offer your fellow LongeCity members the same attention to detail your anchor members provide. If we respond to a someone else's post with only a moments consideration it's likely going to be marked with a: 

 

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comment. The rating system is here for the countless people who want to learn and read our "informed" comments. It's not a contest, it about what our readers deem is good content, on topic and what is not. Let's not over analyze what the rating system is for, lets all do good supporting research either Pro or Con to the ideas being discussed here.

 

As always JMHO


Edited by Bryan_S, 26 April 2017 - 08:27 PM.

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#2105 midas

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Posted 26 April 2017 - 09:44 PM

 

 


 

 

I'm curious why David Sicnlair is then working on a drug that involves NMN.

The NR ship has sailed (Chromadex/Niagen) = $0............The NMN ship has not yet left the harbour = $$$$$$$


Edited by midas, 26 April 2017 - 09:44 PM.

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#2106 bluemoon

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Posted 26 April 2017 - 10:19 PM

  

The NR ship has sailed (Chromadex/Niagen) = $0............The NMN ship has not yet left the harbour = $$$$$$$

 

 

But to my knowledge Sinclair is not trying to sell NMN to compete against NR. That is already out on the market, anyway. Sinclair is developing a drug  that he apparently thinks will be more effective than NR alone or NMN in just vitamin form. Maybe what he is developing could use NR instead of NMN but the fact that he is using NMN is interesting. 

 

Isn't this at least a hint that it isn't clear that NR is far superior to NMN?


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#2107 midas

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Posted 26 April 2017 - 11:03 PM

 

  

The NR ship has sailed (Chromadex/Niagen) = $0............The NMN ship has not yet left the harbour = $$$$$$$

 

 

But to my knowledge Sinclair is not trying to sell NMN to compete against NR. That is already out on the market, anyway. Sinclair is developing a drug  that he apparently thinks will be more effective than NR alone or NMN in just vitamin form. Maybe what he is developing could use NR instead of NMN but the fact that he is using NMN is interesting. 

 

Isn't this at least a hint that it isn't clear that NR is far superior to NMN?

 

 

The way I see it he is going to do something along the same lines as Elysum Health has done with Basis, combining NR with Pterostilbene. But combining NMN with something else and it will probably be something that is already out there. Personally I think Sinclair is in this for the money and what ever he comes up with aint going to be cheap.....There's something about Sinclair, I just cant take to him. 
 


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#2108 Michael

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Posted 26 April 2017 - 11:30 PM

I'm curious why David Sicnlair is then working on a drug that involves NMN. He could just as easily make one with NR. Keep in mind that what he is working on is a drug, not just trying to manufacture NMN cheaply if I've read that correctly.


I'm pretty sure everyone is misunderstanding some of Sinclair's and Wu's statements to the media and the unfortunate wording of an UNSW press release ("developing NMN into a drug substance.") I think that they are merely talking about turning NMN itself into a "drug," in the technical sense. Properly, a "drug" is simply any chemical that causes a therapeutic effect. Thus, any "supplement" that causes a therapeutic effect is a "drug." If you think about it, until relatively recently nearly  all "drugs" were natural products — digitalis, morphine, quinine, reserpine, pilocarpine, lithium, ergot, atropine, etc, etc — and scientists and doctors would routinely speak of "herbal drugs" and "mineral drugs."

 

The notion that a "drug" is by definition an artificial (and preferably patentable) chemical entity and thus wholly distinct from a "dietary supplement" is the product of the public's superstitions around things being "natural," compounded by the early supplement wars of the 1970s leading into the "Proxmire Amendment" and effectively enshrined in US law by DSHEA, both of which (the naturalist fallacy and the legal defense) provide strong incentives for the supplement industry to rigorously insist on the distinction. (Of course, they then want to sneak around it: being forbidden to make "drug" claims, and required to affix the disclaimer "not intended to diagnose, treat, cure, or prevent any disease", they then try to make wording that has the form of a structure-function claim but winks at a drug claim).

 

Thus, when Sinclair says

 

Human trials of NMN therapy will begin within six months.

 

"This is the closest we are to a safe and effective anti-ageing drug that's perhaps only three to five years away from being on the market if the trials go well," says Sinclair, who maintains a lab at UNSW in Sydney.

 

... he's talking about NMN being licensed as a drug. This is made explicit in an answer given by Wu to questions about the UNSW press release from the Australian public broadcaster:

 

 

Q: Why is it realistic to claim that this drug will be on the market in “three to five years”, as has been widely reported in the media and in the UNSW press release?

 

Wu: We’re about to start a clinical trial, which will focus on safety only. This is the first step in the drug development pathway. Depending on whether this is an accelerated or standard approval pathway, this is the time taken to reach the end of phase III clinical trials ... The figure shown in that link is for what is called a “new chemical entity”, which is a molecule that is completely new to science and for which there is no data on what it can do to the human body. The molecule we are using is not a new chemical entity, it is a metabolite that is present inside every cell in the body.

 

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 only aren't 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).


Edited by Michael, 26 April 2017 - 11:34 PM.

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#2109 warner

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Posted 27 April 2017 - 02:01 AM

Guys I'm going to start removing posts if you all can't get along. I expect "all opinions" to be supported by well researched academic findings. That is the standard I want upheld!  ... The rating system is here for the countless people who want to learn and read our "informed" comments. It's not a contest, it about what our readers deem is good content, on topic and what is not. Let's not over analyze what the rating system is for, lets all do good supporting research either Pro or Con to the ideas being discussed here.

imho, the simplistic rating system hands power to the less-informed, less-thoughtful, less-studious, less-mature, less-respectful, etc.  It turns science into an opinion poll/contest.  And the notion that posters can be chastised and trained to be better users of the rating system is unrealistic.  We've already provided good ideas about how the system can be improved (I would get rid of the thing altogether - posters should be expected to explain themselves), but if those suggestions are going to be ignored, then expect to be stuck with the consequences.  It's certainly not our fault that your (LongeCity's) system doesn't work well.  (And yes, I agree this post is an almost complete waste of our time, but you can blame that too on the rating system, which is like an unruly child needing constant attention that someone has let loose on the forum.)


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#2110 bluemoon

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Posted 27 April 2017 - 06:44 AM

 

 

The way I see it he is going to do something along the same lines as Elysum Health has done with Basis, combining NR with Pterostilbene. But combining NMN with something else and it will probably be something that is already out there. Personally I think Sinclair is in this for the money and what ever he comes up with aint going to be cheap.....There's something about Sinclair, I just cant take to him. 
 

 

 

No. Elysium just put two natural compounds, NR and pterostilbine together. Sinclair is making a drug with NMN.  


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#2111 bluemoon

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Posted 27 April 2017 - 06:48 AM

 

I'm curious why David Sicnlair is then working on a drug that involves NMN. He could just as easily make one with NR. Keep in mind that what he is working on is a drug, not just trying to manufacture NMN cheaply if I've read that correctly.


I'm pretty sure everyone is misunderstanding some of Sinclair's and Wu's statements to the media and the unfortunate wording of an UNSW press release ("developing NMN into a drug substance.") I think that they are merely talking about turning NMN itself into a "drug," 

 

There is no basis for thinking this. Sinclair hopes this drug  will be out in 2020. NMN is already on the market, right? How do you turn NMN into a drug??


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#2112 ambivalent

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Posted 27 April 2017 - 01:05 PM

OT: Well I guess we can expect some NR exposure now:

 

https://investorshub...ge_id=130851324


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#2113 Oakman

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Posted 27 April 2017 - 01:38 PM

OT: Well I guess we can expect some NR exposure now:

 

https://investorshub...ge_id=130851324

 

I'm confused (not unusual). How can a public company, supposedly owned by its shareholders, suddenly sell part of itself to a private investor, without consent from the existing shareholders?


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#2114 MikeDC

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Posted 27 April 2017 - 02:20 PM

OT: Well I guess we can expect some NR exposure now:

https://investorshub...ge_id=130851324


I'm confused (not unusual). How can a public company, supposedly owned by its shareholders, suddenly sell part of itself to a private investor, without consent from the existing shareholders?
They don't need shareholder approval for the first two dranches. The last part needs shareholder approval. They can sell shares that have been authorized. They just need to register it.
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#2115 able

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Posted 27 April 2017 - 04:57 PM

Looks like Chromadex share price shot up the last couple days.  

 

Any thoughts if it was this private investment, or perhaps some other recent news out or something about to pop?

 

https://seekingalpha.com/symbol/CDXC



#2116 MikeDC

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Posted 27 April 2017 - 05:15 PM

Looks like Chromadex share price shot up the last couple days.

Any thoughts if it was this private investment, or perhaps some other recent news out or something about to pop?

https://seekingalpha.com/symbol/CDXC

I think today's news was leaked yeaterday. Many good news ahead. The positive result of anti aging effects in humans, the Fortune 500, the costco sales.

#2117 Michael

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Posted 27 April 2017 - 06:51 PM

 

I'm curious why David Sicnlair is then working on a drug that involves NMN.

I'm pretty sure everyone is misunderstanding some of Sinclair's and Wu's statements to the media and the unfortunate wording of an UNSW press release ("developing NMN into a drug substance.") I think that they are merely talking about turning NMN itself into a "drug,"

 
There is no basis for thinking this.

There is certainly a basis for thinking this: I just provided it ;) .
 

Sinclair hopes this drug  will be out in 2020. NMN is already on the market, right? How do you turn NMN into a drug??

 
The same way that BioStratum was going to turn pyridoxamine into a drug (and got AOR's, LEF's, and Jarrow's products pulled off the market — see BioStratum's successful arguments to FDA), that VIATRIS GmbH was going to turn R-lipoic acid into a drug, and indeed that existing drug molecules are given whole new licenses for new indications — which is, in fact, the same process you go through for a new chemical entity, beyond getting to skip some of the earliest steps in the process. See the Wikipedia entry to which Wu pointed in his response quoted above.  The exception under DSHEA is for supplements that were marketed in the United States before 1994. Anything else is fair game for IND status.

 

imho, the simplistic rating system hands power to the less-informed, less-thoughtful, less-studious, less-mature, less-respectful, etc.   ...  We've already provided good ideas about how the system can be improved ...

 
Yes, but you're putting them in the wrong place  ;)  . If anyone has any issues with the Forums, they should be posted in the Forums Issues area, not a thread about NR. (I'm not sure if Registered Users can post there or not; if not, that's readily rectified, and should be, by becoming a Member).


Edited by Michael, 27 April 2017 - 07:09 PM.

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#2118 mrkosh1

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Posted 27 April 2017 - 08:30 PM

 

Sinclair hopes this drug  will be out in 2020. NMN is already on the market, right? How do you turn NMN into a drug??

 
The same way that BioStratum was going to turn pyridoxamine into a drug (and got AOR's, LEF's, and Jarrow's products pulled off the market  [,,]

 
That's what I'm worried about. He might be wanting to get NMN categorized as a drug so that he could sell it at a hundred times what NR costs. Then if someone sees that NR is on the market and is just as potent or slightly more so they may try to turn it into a drug as well.
 
Right now, there is zero reason I'm aware of why anyone would want to take NMN over NR. However, I could see a situation in which NMN as as a drug is sold for $500 dollars a bottle to hundreds of millions of senior citizens across the planet. In such a case NR would obviously be pulled off the market.      
 
If R-Alpha Lipoic Acid is taken off the market, that would be horrible. R-ALA may be highly synergistic with NR.


Edited by Michael, 28 April 2017 - 10:15 AM.
trim quotes


#2119 bluemoon

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Posted 27 April 2017 - 08:53 PM

 

 

Sinclair hopes this drug  will be out in 2020. NMN is already on the market, right? How do you turn NMN into a drug??

 
The same way that BioStratum was going to turn pyridoxamine into a drug (and got AOR's, LEF's, and Jarrow's products pulled off the market — see BioStratum's successful arguments to FDA), that VIATRIS GmbH was going to turn R-lipoic acid into a drug, and indeed that existing drug molecules are given whole new licenses for new indications — which is, in fact, the same process you go through for a new chemical entity, beyond getting to skip some of the earliest steps in the process. See the Wikipedia entry to which Wu pointed in his response quoted above.  The exception under DSHEA is for supplements that were marketed in the United States before 1994. Anything else is fair game for NDI status. 

 

OK, this helps, but I think it is still unclear with NMN, unless you have information not stated in the recent articles. (Edit: the email from Lindsay Wu does make it seem like just NMN)  Chromadex is trying to get FDA approval for NR to be a drug for Cockayne Syndrome. If the FDA approves this would supplement vendors be forced to not sell NR? Also, if Sinclair is trying to market NMN as a drug, what leverage does would he have as BioStratum seemed to have? I guess NMN could be forced off the market as we wait 3 to 5 years for this "new drug" to be sold at a higher price. Well, at least the FDA has no power in China.


Edited by bluemoon, 27 April 2017 - 08:55 PM.

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#2120 able

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Posted 27 April 2017 - 09:15 PM

I read somewhere (on this forum, I believe), that you can get approval to sell a product as a drug, so prescription by doctor means insurance will pay for it.  And it can still be sold OTC as a supplement.  I don't think we have seen anything that indicates some other plan, for nmn or nr, have we?

 


Edited by able, 27 April 2017 - 09:16 PM.

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#2121 MikeDC

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Posted 27 April 2017 - 11:30 PM

I read somewhere (on this forum, I believe), that you can get approval to sell a product as a drug, so prescription by doctor means insurance will pay for it. And it can still be sold OTC as a supplement. I don't think we have seen anything that indicates some other plan, for nmn or nr, have we?


ChromaDex is also trying to make Niagen a drug too. Niacin is a supplement and also a drug.

People taking niacin drug now should all switch to Niagen.
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#2122 VP.

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Posted 28 April 2017 - 01:06 AM

I'm not sure if this has been posted but it's the first I have heard it. Sinclair gives a interview to the Daily Mail (yeah I know) that has some very interesting quotes about NMN.  No one on these boards has reported anything quite like this after taking NR. Is he full of it?

 

Professor Sinclair is so convinced of his pill’s safety that not only has he been taking it himself, so has his 77-year-old father.

The results certainly sound encouraging. Before he started taking a 500mg NMN pill every morning, 47-year-old Professor Sinclair had his blood tested and was told his body had a biological age of 58.

After consuming NMN for three months, he was tested again and his biological age was 32.

As for his father, he’s recently been out-pacing the professor’s younger brother on mountaineering expeditions in their native Australia.

‘He’s as vigorous as he was in his 20s and 30s, and he seems to be getting more energetic,’ says Professor Sinclair.

The manufacturing process of the NMN pill is complicated and expensive, and it currently costs Professor Sinclair more than $1,000 (£797) a month to buy it just for himself.

Large-scale manufacturing would bring the cost down, but he says that ultimately it won’t be cheap. Of course it won’t — if it lives up to the hype, then it really is the long-sought-after elixir of youth.

http://www.dailymail...ixir-youth.html

 

Is this the "blood test" Sinclair is using? http://www.aging-us....cle/100968/text

http://www.aging.ai/

Try it yourself. I am 56 but it says I'm 39 by biological age and I've been taking NR for about a year. I will have to dig my old blood tests to see if anything has changed. 


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#2123 soulprogrammer

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Posted 28 April 2017 - 01:28 AM

"Try it yourself. I am 56 but it says I'm 39 by biological age and I've been taking NR for about a year. I will have to dig my old blood tests to see if anything has changed. "

 

I think you should you post in NR Personal Sharing Experience thread instead.  If you can find your old blood test before taking NR, that will be a nice comparison before and after.


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#2124 MikeDC

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Posted 28 April 2017 - 09:46 AM

https://www.ncbi.nlm...6/?i=1&from=nmn

A few papers indicate high levels of NMN causes degeneration of axon.
So large doses of NMN or NR could cause harm if there is any NMN accumulation.
For people who has the conversion of NMN to NAD+ as rate limiting step,
High doses of NMN and NR can cause serious side effects.
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#2125 soulprogrammer

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Posted 28 April 2017 - 10:09 AM

https://www.ncbi.nlm...6/?i=1&from=nmn

A few papers indicate high levels of NMN causes degeneration of axon.
So large doses of NMN or NR could cause harm if there is any NMN accumulation.
For people who has the conversion of NMN to NAD+ as rate limiting step,
High doses of NMN and NR can cause serious side effects.

 

 

The paper you cited didn't mention NR right? 

 

Full paper here:

http://s000.tinyuplo...687704446118633

 


Edited by soulprogrammer, 28 April 2017 - 10:11 AM.


#2126 Michael

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Posted 28 April 2017 - 10:48 AM

 

https://www.ncbi.nlm...6/?i=1&from=nmn

A few papers indicate high levels of NMN causes degeneration of axon. ...

 

The paper you cited didn't mention NR right? 

 

Full paper here:

http://s000.tinyuplo...687704446118633

 

SP, thanks for this — but while interesting in itself, that is clearly not the paper to which MDC refers and will be of less interest to people following this thread than the one MDC intended. MDC's direct link was to this review/commentary, which in turn refers to this paper. The primary paper is for the moment available free in full text (as is their previous paper PMID 25323584 (full text)); if you also have access to the review/commentary, that would be a further contribution of value. (For what it's worth, the primary paper does not mention NR, though I see no reason to doubt that any implications for NMN would also apply to NR, tho' it's not clear to me as of yet whether there are any implications for either as of yet, having only glanced at it).

 

BTW, there are several notable papers in the hit list that MDC somewhat awkwardly linked: PMID 28386082 (free ull text), PMID 8330719 (paywallled), PMID 28246130 (paywalled — and anyone reading and/or sharing a copy of this paper should also grab the erratum, which is also perversely paywalled).


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#2127 Iporuru

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Posted 28 April 2017 - 01:01 PM

Richest man in Asia invests in Chromadex (Niagen),will own 20% of company:

 

http://www.timelessl...-20-of-company/



#2128 soulprogrammer

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Posted 28 April 2017 - 01:37 PM

I read the paper, it doesn't provide any info on dosage at all.

 

How might NMN accumulation cause axon degeneration? The earlier study by Di Stefano et al. demonstrated that NMN induces a rise in intra-axonal Ca2+, which is dependent on SARM1 [17]. This rise in Ca2+ immediately precedes axon fragmentation. Therefore, one possibility is that NMN binds to a yet unidentified protein, the binding of which causes Ca2+ release from internal stores in axons and subsequent axon degeneration. Another possibility is that NMN inhibits the activity of an NAD+ utilizing enzyme (e.g. PARP, sirtuin) that is required to maintain axon viability. Indeed NMN can inhibit the activity of the bacterial ADP-ribosyltransferase diphtheria toxin [20], which is structurally and functionally related to mammalian PARPs (PARP1-17 in humans). This inhibition is competitive with NAD+ ; therefore, when NAD+ levels decrease following axotomy, inhibition by NMN might be more prominent. Understanding the mechanism by which supraphysiological levels of NMN cause axon degeneration is critical for demonstrating that NMN is indeed a pro-axon degenerative molecule. Lastly, the NMNd mice developed in the current study will be useful for evaluating the potential role of NMN as a pro-axon degenerative molecule in neurological disorders, which could lead to the development of novel therapeutics for these disorders.

 

 

 

Full paper here:

http://s000.tinyuplo...524804686968425



#2129 bluemoon

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Posted 28 April 2017 - 01:44 PM


 

 

 

Professor Sinclair is so convinced of his pill’s safety that not only has he been taking it himself, so has his 77-year-old father.

 

The results certainly sound encouraging. Before he started taking a 500mg NMN pill every morning, 47-year-old Professor Sinclair had his blood tested and was told his body had a biological age of 58.

After consuming NMN for three months, he was tested again and his biological age was 32. 

 

 

Sinclair at 45 and was taking 1000 mg of resveratrol a day and still had a biological age of 58? Sayonara to resveratrol. Yet Sinclair said a year before he told the Washington Post that he was taking 1000 mg a day of resveratrol that "Resveratrol is old technology. We think the NR path is superior." (He didn't say NMN but discussed his 2013 NMN mice experiment.) 

 

He has enough money to take $18 a day of a 500 mg capsule but if NR is superior or equivalent to NMN than why pay 10 times as much?  


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#2130 ceridwen

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Posted 28 April 2017 - 02:12 PM

Going on looks alone. I think Sinclair looks younger than his chronological age.
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