28 replies to this topic

[Simi]

Abstract:

 

http://science.scien...t/355/6331/1312

 

Articles:

 

http://newatlas.com/...drug-nmn/48584/

 

http://newsroom.unsw...eap-anti-ageing

 

 

 

With a potential supplement on the Horizon:

 

 

"For the past four years, Professor Sinclair and Dr Wu have been working on making NMN into a drug substance with their companies MetroBiotech NSW and MetroBiotech International.  

 

The human trials will begin this year at Brigham and Women’s Hospital, in Boston."

[MikeDC]

If they can make NMN cheaply and stable in water, they might cause some competition in beverage area.

[mrkosh1]

The drug is already out and it is called Nicotinamide Riboside or Niagen.

 

NMN has to be converted to NR before being transported into cells.

 

Any effects seen with NMN will also be witnessed by NR -- probably a tad more so.

 

The good news is that right now NR is an over the counter product.

[Valijon]

This is another question. Right now Chromadex sells NR as a supplement. If you enjoy this product, you do NOT want it being sold as a prescription medication.

[MikeDC]

This is another question. Right now Chromadex sells NR as a supplement. If you enjoy this product, you do NOT want it being sold as a prescription medication.

There will be two forms of NR. One is sold as supplement at cheap price and another sold as drug at higher price.

[Simi]

The drug is already out and it is called Nicotinamide Riboside or Niagen.

 

NMN has to be converted to NR before being transported into cells.

 

Any effects seen with NMN will also be witnessed by NR -- probably a tad more so.

 

The good news is that right now NR is an over the counter product.

 

 

Yes, but I think they are working on a derivation (..it would otherwise be pointless, being already available), one that improves NAD+ generation.

Edited by Simi, 27 March 2017 - 07:04 PM.

[MikeDC]

The drug is already out and it is called Nicotinamide Riboside or Niagen.

NMN has to be converted to NR before being transported into cells.

Any effects seen with NMN will also be witnessed by NR -- probably a tad more so.

The good news is that right now NR is an over the counter product.

Yes, but I think they are working on a derivation (..it would otherwise be pointless, being already available), one that improves NAD+ generation.

I think they are just working on how to synthesize and stablize NMN. Nobody is going to invent a new molecule

[Simi]

True, they could just be trying to find another way to synthesize it - to "defeat" the patent claim by ChromaDex.

 

 

 

EDIT:

 

-Interesting, ChromaDex's IP is synthesizing Nicotinamide Riboside, not Nicotinamide Mononucleotide.

 

 

This one is claiming it as the Mononucleotide variety:

 

https://www.amazon.c...s/dp/B014ESTB7G

 

 

-considering the way supplements are regulated (..they really aren't), my guess is that Fractal Health is shall we say "fibbing"  to their consumers.

 

 

 

Edited by Simi, 27 March 2017 - 10:55 PM.

[PeaceAndProsperity]

^Patent Wars: Modern Business Strategy

[RWhigham]

Vince Giuliano at anti-agingfirewalls.com awhile back obtained a supply of NMN. It raised his NAD+ transiently before homeostasis kicked in. 

 

http://www.anti-agin...-interventions/

"I am now confidence that supplementation with a NAD+ precursor like NMN or NR transiently increased the ratio of NAD+ to NADH (NAD/NADH), but the ratio returns to normal in the course of continued supplementation. "  James Watson

 

Edited by RWhigham, 30 March 2017 - 05:04 PM.

[MikeDC]

Not sure he was speculating or hard data. Even if it is true, it means the ratio is not a determining factor. The absolute value of NAD+ is.

[Simi]

Vince Giuliano at anti-agingfirewalls.com awhile back obtained a supply of NMN. It raised his NAD+ transiently before homeostasis kicked in. 

 

http://www.anti-agin...-interventions/

"I am now confidence that supplementation with a NAD+ precursor like NMN or NR transiently increased the ratio of NAD+ to NADH (NAD/NADH), but the ratio returns to normal in the course of continued supplementation. "  James Watson

 

 

 -really good link, thanks!

 

 

This suggests intermittent use.  

 

..and because much of this research was initiated by looking into a low-calorie diet and its effects, my guess is that you could do an interleaved "on-off" (say every 2 weeks or so) of supplement (normal diet) and then calorie restriction (no supplement) and perhaps achieve a greater level of consistency with the desired result.

[Simi]

The drug is already out and it is called Nicotinamide Riboside or Niagen.

 

NMN has to be converted to NR before being transported into cells.

 

Any effects seen with NMN will also be witnessed by NR -- probably a tad more so.

 

The good news is that right now NR is an over the counter product.

 

 

I looked into this further.

 

 

"..Biosynthesis of NAD+ from NR requires enzyme activities in either of two pathways. In one pathway, specific NR kinases, including human Nrk1 and Nrk2, phosphorylate NR *to* nicotinamide mononucleotide.."

 

 

http://journals.plos...al.pbio.0050263

 

 

 

 

**emphasis added.

[MikeDC]

The drug is already out and it is called Nicotinamide Riboside or Niagen.

NMN has to be converted to NR before being transported into cells.

Any effects seen with NMN will also be witnessed by NR -- probably a tad more so.

The good news is that right now NR is an over the counter product.

I looked into this further.


"..Biosynthesis of NAD+ from NR requires enzyme activities in either of two pathways. In one pathway, specific NR kinases, including human Nrk1 and Nrk2, phosphorylate NR *to* nicotinamide mononucleotide.."


http://journals.plos...al.pbio.0050263




**emphasis added.

This is correct except that NMN can't get through cell membrane. So NMN is converted into NR and get through the membrane. Then NR is converted to NMN with NRK1 and NRK2

[mrkosh1]

 

The drug is already out and it is called Nicotinamide Riboside or Niagen.

 

NMN has to be converted to NR before being transported into cells.

 

Any effects seen with NMN will also be witnessed by NR -- probably a tad more so.

 

The good news is that right now NR is an over the counter product.

 

 

Yes, but I think they are working on a derivation (..it would otherwise be pointless, being already available), one that improves NAD+ generation.

 

 

The most obvious method to improve upon NMN is simply to use NR instead, because NMN must be converted to NR before it can enter a cell.

 

 

[PeaceAndProsperity]

Vince Giuliano at anti-agingfirewalls.com awhile back obtained a supply of NMN. It raised his NAD+ transiently before homeostasis kicked in. 

 

http://www.anti-agin...-interventions/

"I am now confidence that supplementation with a NAD+ precursor like NMN or NR transiently increased the ratio of NAD+ to NADH (NAD/NADH), but the ratio returns to normal in the course of continued supplementation. "  James Watson

So it's simply a waste of time to supplement. Is that the conclusion?
 

[Simi]

"NAD is too large to *cross the cell membrane, but NMN can slip across it easily. Once inside the cell, NMN binds to another NMN molecule to form NAD."

 

 

 

 

 

http://news.harvard....cellular-aging/

 

 

 

*emphasis added.

Edited by Simi, 01 April 2017 - 02:01 AM.

[Valijon]

MikeDC, please divulge any financial interest you may have in Chromadex or any other company distributing or marketing Nicotinamide Riboside.

[mrkosh1]

"NAD is too large to *cross the cell membrane, but NMN can slip across it easily. Once inside the cell, NMN binds to another NMN molecule to form NAD."

 

 

 

 

 

http://news.harvard....cellular-aging/

 

 

 

*emphasis added.

 

This completely contradicts established scientific results. Previous testing showed conclusively that NMN must be converted to NR before passing through the cell membrane. I believe one such test was done in a PhD thesis that was published online. When NMN was added to cell cultures it was transformed extracellularly to NR and then the NR started being transported through the membrane.

 

I don't have the link, but it was discussed on this forum.

 

Do the authors claim to have used some modified form of NMN?

[Simi]

I've done some more reading (..just where did my Friday night go?)  

 

 

-yup, it seems that the middle portion of the cell membrane (periplasm) generally requires striping the phosphate to enter the cell ..at least in yeast (close analog to human cell structure) and bacteria.

 

https://www.ncbi.nlm...9349/figure/F6/

 

 

 

Recent testing has been done on mice, with a focus on NMN.  I'm not sure why it's NMN in favor of NR, and the articles aren't saying why (including the latest one from Harvard) even while referencing multiple supplements including NR.  Maybe it's just a commercial (patent) reason?  Maybe NR is harder on the liver than NMN? Again, don't know

 

-there has to be reason, and I think it's more likely to be a non-commercial reason - but you never know.

 

What I can say is that the dosage on the mice in the recent Harvard study showed no effect with .2 grams, but significant effect with half a gram (of NVM). ..while also mentioning that NR as well as other substances at .2 grams had no effect on mice.

 

As far as the Harvard Gazette, they must have gotten an interview that wasn't as precise at it should have been (..or had taken some liberties with their write-up).

 

 

[MikeDC]

MikeDC, please divulge any financial interest you may have in Chromadex or any other company distributing or marketing Nicotinamide Riboside.

I take Niagen and own the stock like many posters here who are sold on Niagen completely. There is nothing that can come to close to Niagen on anti aging. If you are smart, start taking Niagen. If you are not keep arguing.

[MikeDC]

I think prof. Sinclair is not a true scientist. He intentionally hides the conversion of NMN to Nictinoamide Riboside before entering cell membrane. He is trying to pump NMN. He was not the pioneer on NR so he doesn't want to give any credibility to NR.

[Simi]

Ok, I think I've figured out why NMN (nicotinamide mononucleotide) is preferred vs NR (nicotinamide riboside)..

 

 

 

It's a guess, based on the article below's guess:

 

NAD (specifically the NadR protein) regulates the addition of phosphate to NR (which creates NMN).. so if the cell isn't function great, with lower levels of NadR proteins, then presumably less phosphate binding occurs to NR to create NMN (..which then binds together to create NAD).  

 

-basically a cyclical effect that is decaying. 

 

Dumping more NR into the cell may not substantially increase NMN levels with particularly damaged cells; the NR is there at a much higher supply (due to the supplement) to be converted to NMN, but the NadR protein doesn't have the "demand" to match NR's supply.

 

There are probably cell's in various stages of decline.  The more "healthy" the cell (up to a point), the better the "demand" of NadR matches the supply of NR to produce NMN (..and thereby NAD).  I think this is why NAD levels seem to change in these sorts of studies - some cells (and organisms) are "healthier" overall (..though not "healthy) and just accept NR more readily, showing a rapid increase in NAD - resulting in a "rejuvenated" cell.

 

Now, IF you can bypass this portion of protein signaling (which is likely not working particularly well in the really "UNhealthy" cells), then you should end-up with higher levels of NAD within those really "UNhealthy" cells - hopefully precluding further decline/mutation.

 

 

My guess is that this sort of "supplement" isn't required on a typical "supplemental" basis.  Basically intermittent (monthly, 3 months, 6 months?) short-period (maybe a few days, or even a week?) "dosing" to get cells to better accept an NR supplement (with enough NadR protein to now "demand" that added supply).  The occasional "booster" shot (..or series of injections).

 

 

 

 

Again, it's a guess.

 

 

 

btw, there are mutations (transporter mutations) that allow NMN to pass into the cell without conversion into NR due to the cell membrane's periplasmic acid phosphatase process.

 

My guess is that the corporate-side of this research is focused on synthesizing a particularly beneficial transporter mutation (at a reasonable cost) that accomplishes this process better than the natural acid phosphatase process imposes on "standard" NMN (..which is NMN to NR - to get into the cell). 

 

 

 

-as for why the cell membrane's periplasimic layer acts as a gate-keeper with respect to NMN blocking transportation to the cell, it's function apparently has more to due with keeping NMN from LEAVING the cell (..so it can bind together to create NAD).

 

 

http://jb.asm.org/co...87/13/4521.full

 

 

 

 

 

Edited by Simi, 01 April 2017 - 09:31 PM.

[PeaceAndProsperity]

I think prof. Sinclair is not a true scientist. He intentionally hides the conversion of NMN to Nictinoamide Riboside before entering cell membrane. He is trying to pump NMN. He was not the pioneer on NR so he doesn't want to give any credibility to NR.

How funny, I thought Sinclair was making money off both products? Anyway, I would oddly agree that he is not a credible guy.

 

[Quattro64]

According to Alivebynature website the NMN doesn't get stuck in the liver the same way that NR seems to, so it moves into the blood and enters tissues thru out the body. NR seems to help a great deal with metabolism and healing/rejuvenating the liver. If they are correct then buying NMN is the way to go. IF NR is form needed to enter cells then maybe there is future for it in skin cream? Don't know how pure their NMN product is but it is the cheapest right now. Will be getting some in a day or two.

[sensei]

Put NMN or NR inside liposomes -- that way they will be transported directly to the cellular cytoplasm through the lipid membrane

 

I take 12 grams of liposomal vitamin C at one time without a fart, or diarrhea  -- because it passes through the gut, and is delivered directly to tissue (via the cell membrane -- directly to cytoplasm

[Turnbuckle]

Put NMN or NR inside liposomes -- that way they will be transported directly to the cellular cytoplasm through the lipid membrane

 

I take 12 grams of liposomal vitamin C at one time without a fart, or diarrhea  -- because it passes through the gut, and is delivered directly to tissue (via the cell membrane -- directly to cytoplasm

 

 

Good idea--

 

NIAGENIX™, our latest weight loss formula, combines NIAGEN® with other state-of-the-art ingredients to help you fight the effects of aging, lose stubborn body fat and increase your metabolism... These ingredients are delivered to your cells faster and more efficiently thanks to our one-of-a-kind Liposomal Matrix Delivery System™, which bypasses the destructive elements of the gastric system to optimize absorption rates and oral bioavailability.

 

https://bpisports.com/blog/niagen/

 

 

 

But NR seems to be a minor ingredient as they don't disclose how much is in it. I expect that chromadex will not directly supply a liposomal NR anytime soon--not NR alone, anyway--as it would be difficult to market it without admitting NR is not as orally available as they say it is.

Edited by Turnbuckle, 23 December 2017 - 11:06 AM.

[ekaitz]

Would rectal administration be more bioavailable than oral for the NR?

Edited by ekaitz, 23 December 2017 - 01:58 PM.

[sensei]

Would rectal administration be more bioavailable than oral for the NR?

 

rectal and sublingual bypass the first-pass liver metabolism to a degree -- don't know about bioavailability