392 replies to this topic

[Forever21]

Is there a Reddit-style sidebar here? Do you know of a blog post that writes in-depth on the difference between these and what's the best to get?

[MikeDC]

NAD+ is a coenzyme in all your cells that regulate hundreds of biological processes, especially in regulating longevity genes and energy production. All the others are precursors that gets converted to NAD+ when taken orally. Niagen is a trade name of NR (Nicotinamide Riboside). It is the only commercially available NAD+ precursor that has been validated by multiple human clinical trials. The Colorado clinical trials publication is eminent. It will show that Niagen lowers blood pressure and many other health benefits. NMN has done well in mice studies. But there is no human clinical trial results available yet. The only pharmacokinetics study of NMN on mice shows that NMN is not an effective NAD+ precursor compared to NR. NAM is the old fashioned vitamin B3 Nicotinamide. A just published paper shows that it has some health benefits, but not a good NAD+ precursor and doesn’t extend lifespan. There are close to half a million people taking Niagen now and it is almost 5 years since launch. No serious side effects have been reported.

[hav]

This post covers the difference between NAD+, NM, NMN, NR:

 

http://tonglab.biolo...earch/nad.shtml

 

Which to get?  Practical choices are only between NR and NMN.  Depends on how you want to take it.  Sinclair injected mice with NMN, probably because it's more water soluble than NR and thus more suitable for injection.  Orally, it may solely be a decision based on price.  NMN gets converted to NR by gut flora in the intestinal tract but neither are absorbed directly. NR is the only one of the two to get cleaved, however, by an intestinal enzyme allowing the resulting metabolite to be absorbed. So it might not matter which you take orally (assuming your gut is not probiotic deficient) but taking NR does save one step. There may be some difference in survival chances on the trip through the stomach but I don't know that's been proven yet.  I have heard some talk of applying an enteric coating which could make a difference.

 

Howard

[Forever21]

NAD+ is a coenzyme in all your cells that regulate hundreds of biological processes, especially in regulating longevity genes and energy production. All the others are precursors that gets converted to NAD+ when taken orally. Niagen is a trade name of NR (Nicotinamide Riboside). It is the only commercially available NAD+ precursor that has been validated by multiple human clinical trials. The Colorado clinical trials publication is eminent. It will show that Niagen lowers blood pressure and many other health benefits. NMN has done well in mice studies. But there is no human clinical trial results available yet. The only pharmacokinetics study of NMN on mice shows that NMN is not an effective NAD+ precursor compared to NR. NAM is the old fashioned vitamin B3 Nicotinamide. A just published paper shows that it has some health benefits, but not a good NAD+ precursor and doesn’t extend lifespan. There are close to half a million people taking Niagen now and it is almost 5 years since launch. No serious side effects have been reported.

 

 

I would appreciate it if those who downvoted this guy for this comment to come out and make a proper retort to his bold assertions.

[MikeDC]

This post covers the difference between NAD+, NM, NMN, NR:

http://tonglab.biolo...earch/nad.shtml

Which to get? Practical choices are only between NR and NMN. Depends on how you want to take it. Sinclair injected mice with NMN, probably because it's more water soluble than NR and thus more suitable for injection. Orally, it may solely be a decision based on price. NMN gets converted to NR by gut flora in the intestinal tract but neither are absorbed directly. NR is the only one of the two to get cleaved, however, by an intestinal enzyme allowing the resulting metabolite to be absorbed. So it might not matter which you take orally (assuming your gut is not probiotic deficient) but taking NR does save one step. There may be some difference in survival chances on the trip through the stomach but I don't know that's been proven yet. I have heard some talk of applying an enteric coating which could make a difference.

Howard

NMN is definitely not converted to NR in the intestines. It is mostly absorbed intact. It gets converted to NR outside cells. But the conversion rate is very small. So a majority of NMN is washed out in the urine. To get the same NAD+ increase as from 250mg NR, you will need 5,000mg NMN. The clinical results from NR is so much better than NAM means that NR is not cleaved either in the intestines.

NAD+ is a coenzyme in all your cells that regulate hundreds of biological processes, especially in regulating longevity genes and energy production. All the others are precursors that gets converted to NAD+ when taken orally. Niagen is a trade name of NR (Nicotinamide Riboside). It is the only commercially available NAD+ precursor that has been validated by multiple human clinical trials. The Colorado clinical trials publication is eminent. It will show that Niagen lowers blood pressure and many other health benefits. NMN has done well in mice studies. But there is no human clinical trial results available yet. The only pharmacokinetics study of NMN on mice shows that NMN is not an effective NAD+ precursor compared to NR. NAM is the old fashioned vitamin B3 Nicotinamide. A just published paper shows that it has some health benefits, but not a good NAD+ precursor and doesn’t extend lifespan. There are close to half a million people taking Niagen now and it is almost 5 years since launch. No serious side effects have been reported.

I would appreciate it if those who downvoted this guy for this comment to come out and make a proper retort to his bold assertions.

A lot of people posting here are not into finding the best way to extend life span. Either they have agenda or just ignorant.

[TMNMK]

Be sure to listen to this great find by @bluemoon: http://www.longecity...d-master-aging/

 

It very lightly touches on some differences between supplements (nicotinic acid or niacin, nicotinamide, and tryptophan) although I don't think Dr. Brenner discusses NMN in the interview. There is a lot of discussion on the various benefits of supplements here on these forums at longecity, unfortunately some of it is entirely uninformed so my advice is go straight to the source. Read the hundreds of studies that are out there on NR, NMN, and the NAD+ cycle and put a far greater weight on the information in the studies more than anything anyone says here. I do feel that this forum needs a library, perhaps pinned to the top of links to studies (even if they are behind paywalls) so that newcomers can quickly get the list, but barring that, google scholar is not too bad.

Edited by TMNMK, 12 March 2018 - 02:00 PM.

[Forever21]

Be sure to listen to this great find by @bluemoon: http://www.longecity...d-master-aging/

 

It very lightly touches on some differences between supplements (nicotinic acid or niacin, nicotinamide, and tryptophan) although I don't think Dr. Brenner discusses NMN in the interview. There is a lot of discussion on the various benefits of supplements here on these forums at longecity, unfortunately some of it is entirely uninformed so my advice is go straight to the source. Read the hundreds of studies that are out there on NR, NMN, and the NAD+ cycle and put a far greater weight on the information in the studies more than anything anyone says here. I do feel that this forum needs a library, perhaps pinned to the top of links to studies (even if they are behind paywalls) so that newcomers can quickly get the list, but barring that, google scholar is not too bad.

 

 

 

Look no more than Reddit's sidebar. A place where newcomers can learn the basics, intros, and such perpetually asking the forums.

[hav]

NMN is definitely not converted to NR in the intestines. It is mostly absorbed intact. It gets converted to NR outside cells. But the conversion rate is very small. So a majority of NMN is washed out in the urine. To get the same NAD+ increase as from 250mg NR, you will need 5,000mg NMN. The clinical results from NR is so much better than NAM means that NR is not cleaved either in the intestines.

 

I think this is one of the source studies on the subject that followed up and confirmed earlier research by John Hopkins Univ.

 

https://www.ncbi.nlm.../pubmed/6218262

 

... intestine rapidly hydrolyzed NMN to nicotinamide riboside, which accumulated, but was not absorbed. It was slowly cleaved by an enzyme associated with the mucosal cells to nicotinamide, which was the major if not the only labeled compound absorbed.

 

Howard

[MikeDC]

NMN is definitely not converted to NR in the intestines. It is mostly absorbed intact. It gets converted to NR outside cells. But the conversion rate is very small. So a majority of NMN is washed out in the urine. To get the same NAD+ increase as from 250mg NR, you will need 5,000mg NMN. The clinical results from NR is so much better than NAM means that NR is not cleaved either in the intestines.

I think this is one of the source studies on the subject that followed up and confirmed earlier research by John Hopkins Univ.

https://www.ncbi.nlm.../pubmed/6218262

... intestine rapidly hydrolyzed NMN to nicotinamide riboside, which accumulated, but was not absorbed. It was slowly cleaved by an enzyme associated with the mucosal cells to nicotinamide, which was the major if not the only labeled compound absorbed.

Howard

Many studies turn out to be wrong. This one is probably wrong.

[Forever21]

This post covers the difference between NAD+, NM, NMN, NR:

 

http://tonglab.biolo...earch/nad.shtml

 

Which to get?  Practical choices are only between NR and NMN.  Depends on how you want to take it.  Sinclair injected mice with NMN, probably because it's more water soluble than NR and thus more suitable for injection.  Orally, it may solely be a decision based on price.  NMN gets converted to NR by gut flora in the intestinal tract but neither are absorbed directly. NR is the only one of the two to get cleaved, however, by an intestinal enzyme allowing the resulting metabolite to be absorbed. So it might not matter which you take orally (assuming your gut is not probiotic deficient) but taking NR does save one step. There may be some difference in survival chances on the trip through the stomach but I don't know that's been proven yet.  I have heard some talk of applying an enteric coating which could make a difference.

 

Howard

 

 

I know RevGenetics and ALIVE sell NMN now. But who sells NR? What's the most popular purchase here at Longecity?

[TMNMK]

NR is produced by a company called Chromadex using patents licensed from Dartmouth and some other institutions. They have their own brand Tru Niagen. HPN and Life Extension sell re-labeled Chromadex NR. Many companies that used to sell NR no longer do as a result of Chromadex going straight to consumer with their Tru Niagen brand. There is also a company called Elysium that sells NR (with pterostilbene - you can also get pterostilbene from Chromadex) but Elysium's NR is not sourced from Chromadex and there is ongoing litigation regarding that. Personally, I feel it is safe to purchase NR from either HPN or Life Extension but when you can buy it directly from Chromadex I'm not sure why one would, although I haven't looked at the pricing lately from the resellers. I would shy away from Elysium as that whole situation is a bit caustic and I'd rather go with a company that has a good reputation than one that behaves in the fashion that Elysium has, but that's just me. I wouldn't blame anyone for any choice they made in that regard though, I'm a "don't tread on me" kinda guy.

Edited by TMNMK, 25 March 2018 - 01:26 PM.

[hav]

Have been source checking references listed on one of the NMN sites and while one of their references seems to be a mistake or mix-up (and it's referenced in 4 out of 5 of their talking points!), another referenced study may be significant.  It's a 2016 study that found different results regarding NMN absorption in mice compared to the rat studies I referenced earlier which found no direct NMN absorption.  This 2016 mouse study found:

 

 

We next administered NMN at a dose of 300 mg/kg body weight to mice by oral gavage and measured plasma NMN and hepatic NAD⁺ levels over 30 min. Plasma NMN levels exhibited a steep increase at 2.5 min, further increases from 5 to 10 min, and then went back to original levels at 15 min (Figure 1A), implicating very fast absorption in the gut. Consistent with this notion, hepatic NAD⁺ levels showed a steady increase from 15 to 30 min (Figure 1A). We also measured tissue NAD⁺ levels 60 min after oral gavage of NMN. Although differences did not reach statistical significance at this particular dose, relatively small increases in NAD⁺ levels were observed in the liver, skeletal muscle, and cortex of the brain, but not in WAT or brown adipose tissue

 

This mouse study doesn't shed any light on relative amounts of NAD⁺ generated by MNM conversion in the bloodstream/cells compared to NAD⁺ created in the digestive tract before absorption into the bloodstream.  It's also unknown whether human's would be more like rats or mice in this instance.  Fwiw, the 300 mg/kg oral dosage in mice corresponds to a 2gm/day dose for an 80 kg human assuming 12:1 mouse to human allometric scaling.  Sinclaire's most recent NMN mouse study employs similar oral administration at 400 mg/kg.

 

Howard

Edited by hav, 25 March 2018 - 02:23 PM.

[LawrenceW]

In humans, NR is converted to NMN by NRK1 (Bieganowski & Brenner, 2004; Tempel et al., 2007). 

 

 

[hav]

In humans, NR is converted to NMN by NRK1 (Bieganowski & Brenner, 2004; Tempel et al., 2007). 

 

Those are both in vitro studies. Not sure it directly relates to oral oral ingestion of nr if it gets cleaved before absorption in the digestive tract. Relates more to the metabolic processes of NAD+ transitions at the cellular level. But it does suggest a method of making nmn out of nr using nrk1 yeast.  Maybe there's a remote possibility of some advantage in ingesting a probiotic along with nr but I don't know of one that contains nrk1 yeast specifically.
 

Howard

[Harkijn]

 

 

 Maybe there's a remote possibility of some advantage in ingesting a probiotic along with nr but I don't know of one that contains nrk1 yeast specifically.

 

 

That's an interesting side thought. Are you thinking of good old baker's yeast?

https://www.uniprot.org/uniprot/P53915

[LawrenceW]

I was taking 500 mg twice per day of Niagen.  My understanding of the Niagen patent is that NR by itself is unstable and the patent is for attaching NR to a salt to stabilize it. At a 500 mg dose of Niagen, how much of the salt am I ingesting?

[TMNMK]

I was taking 500 mg twice per day of Niagen.  My understanding of the Niagen patent is that NR by itself is unstable and the patent is for attaching NR to a salt to stabilize it. At a 500 mg dose of Niagen, how much of the salt am I ingesting?

 

You can read it in the wikipedia page on NR or for future reference the way you would do this is you would count the elements in the molecule (don't forget hidden hydrogens) or look up the CAS (1341-23-7) and find that it has a formula of C11H15N2O5 and then add a chloride anion making it C11H15N2O5Cl

 

Use a periodic table, for example: https://www.ptable.com/ and find the atomic weight of each element and multiply by the number of that element in the formula. So we have

 

C11H15N2O5Cl

 

(12.011)*11 + (1.008)*15 + (14.007)*2 + (15.999)*5 + (35.450)*1

 

132.121 + 15.120 + 28.014 + 79.995 + 35.450

 

290.700 g/mol is therefore the molar mass of NR+ Cl- salt and therefore NR+ has molar mass of 255.250 g/mol (simply subtract 35.450 molar mass of chloride anion you looked up on the periodic table from the 290.700 you got previously for the formula for C11H15N2O5Cl).

 

Ok, so now its just some algebra:

 

255.250 g/mol        x mg

-------------------- =  ------------

290.700 g/mol        500 mg

 

And you get for 500mg of NR+ Cl- salt  you get 439.026mg of NR.

 

So if you were using wikipedia numbers and simply multiplying 88 by 5, you'd be off by about a milligram.

Edited by TMNMK, 27 March 2018 - 02:55 PM.

[TMNMK]

Also note that the reason this molecule is able to form a salt is that the nitrogen in the NR nucleoside is a quaternary ammonium cation so has a positive charge. So normally with nitrogen you get 3 bonds to play with for a neutral nitrogen. For example you can have primary amines, secondary amines, and tertiary amines, but you can also form as in this case a quaternary ammonium cation due the lone electron pair available on nitrogen at that point as in the pyridine ring here. And you can get diquats too, two quaternary ammonium cations in different positions on the ring! You might have heard of quaternary ammonium salts being used as surfactants (in detergents and whatnot) or as phase transfer catalysts, those are examples also of this situation we have here.

Edited by TMNMK, 27 March 2018 - 04:14 PM.

[LawrenceW]

TNMNK

 

Thanks for taking the time to provide such a detailed answer.

[hav]

 

Maybe there's a remote possibility of some advantage in ingesting a probiotic along with nr but I don't know of one that contains nrk1 yeast specifically.

That's an interesting side thought. Are you thinking of good old baker's yeast?

https://www.uniprot.org/uniprot/P53915

 

 

Saccharomyces cerevisiae is used in both bakers and brewers yeast and gets mentioned from time to time in NR and NMN papers. More recently Tryptone and nrk1 yeasts are also coming up and it just makes me wonder if other probiotics might also be helpful. 
 

Howard

[stefan_001]

@TMNMK, that was a great educational session! 

[TMNMK]

@TMNMK, that was a great educational session! 

 

Thanks, glad you enjoyed, I realized I should clarify - primary, secondary, and tertiary amines confer basicity due to the lone pair of electrons (pyridine is basic for example), instead of "neutral nitrogen" I should have said "nitrogen with a formal charge of zero", but ammonium cations have a fourth bond using that lone pair and therefore have a formal charge of one and thus confer acidity. Ignore that "neutral nitrogen" part, that's just confusing. So often amines as the "free base" are oils which makes delivering them as salts much more convenient (α-methylphenethylamine.HCl salt as those with ADHD may know). Whereas the ammonium cation in NR having a formal charge of one on that group and therefore being acidic forms salt with a base such as the chloride anion. Anyway, just to clarify. 

Edited by TMNMK, 27 March 2018 - 09:49 PM.

[Forever21]

In humans, NR is converted to NMN by NRK1 (Bieganowski & Brenner, 2004; Tempel et al., 2007). 

 

 

I'm confused.

 

NMN gets converted to NR - Hav (Howard)

 

NMN is definitely not converted to NR - MikeDC

 

NR is converted to NMN - LawrenceW

 

Which one do most of you get? The science talks here are beyond my intellect capabilities. I just want to buy the best one.

[hav]

I'm confused.

 

NMN gets converted to NR - Hav (Howard)

 

NMN is definitely not converted to NR - MikeDC

 

NR is converted to NMN - LawrenceW

 

Which one do most of you get? The science talks here are beyond my intellect capabilities. I just want to buy the best one.

 

We're all right... depending on location. What I mentioned refers to studies of what happens to orally taken NR and NMN in the digestive tract.  Other things happen if NR or NMN get injected into the bloodstream. And other things again at the cellular level like in muscles.

 

If you're going to take it orally, it might not make a difference which you take, though taking NR might have an efficiency edge over NMN because that 1st conversion step (NMN -> NR) has already been done for you.  Also NMN molecules are a bit heavier meaning, all other things being equal, it costs more per molecule unless it's cheaper per mg than NR.  There's a monopoly on NR so there's an inclination to price it higher.  NMN competition will hopefully counter that.

 

We've had a group buy on NR here for some time so I suspect that's what most here are taking.  That's what I've been taking.  But if I can get NMN for 30% or less than the NR price, I plan on trying it.  There are at least 2 respectable sources of pure NMN I know of and that also interests me.

 

Howard

[LawrenceW]

If you need 30% more NMN to equalize the molecular weight between NR and NMN, then why don't you get a 30% increase in NAD+ from using NR? There must be something else going on that we don't understand yet.

 

[LawrenceW]

If as Brenner and MikeDC theorize that step #1 is for the NMN to convert into NR, then from that point forward shouldn't all NAD+ percentage increases in all organs be the same for both NMN and NR supplementations? If their theory is correct, then there should be no difference in the percentage increase of NAD+ in liver versus kidney.

[TMNMK]

If as Brenner and MikeDC theorize that step #1 is for the NMN to convert into NR, then from that point forward shouldn't all NAD+ percentage increases in all organs be the same for both NMN and NR supplementations? If their theory is correct, then there should be no difference in the percentage increase of NAD+ in liver versus kidney.

 

It's not that simple, especially in-vivo, not like a mathematical proof. Very rarely is a reaction, enzymatically catalyzed or not, 100% efficient which is why yields are so important for each step of a multi-stage reaction. Lets take an example in a controlled environment, say you had a quantity of an initial molecule A and you wanted to convert that to B and then further to C. 

 

Lets say A->B could be achieved at 90% yield (that's pretty good for most reactions) and B->C could be achieved at 90% yield as well (great, right?). You are now left with an 81% yield, in borosilicate erlenmeyer flasks, in a controlled laboratory, at controlled temperatures, and with reagents from Sigma-Aldrich.

 

That is not going to happen in-vivo, it will be much less efficient, it is far too complex of an environment. That our biochemical machinery functions in a fashion that allows us to compose these hypothesis at all is astonishing.

 

EDIT: Someone asked for references via a tag on the post, fair question but also not a simple answer, I guess the best I can do is refer to some places to start:

 

For ochem stuff:

 

Brown/Foote/Iverson - Organic Chemistry

Vollhardt/Schore - Organic Chemistry

C.F.Wilcox - Experimental Organic Chemistry - A Small Scale Approach

Petrucci/Harwood - General Chemistry: Principles and Modern Application

Organic Chemistry" by Clayden, Greeves, Warren and Wothers (Oxford University Press)

 

These are pretty good too:

 

https://open.umn.edu....aspx?bookId=69

https://www.amazon.c...ganic chemistry

 

and last but not least: https://www.amazon.c...y/dp/0582462363

 

But if the references needed were more regarding efficiency of enzymatic catalysis, well I just googled this, maybe a starting point:

 

https://chem.librete...ency_of_Enzymes

 

Edited by TMNMK, 01 April 2018 - 03:31 PM.

[LawrenceW]

Thanks for the quick reply TMNMK

 

Instead of using a theoretical molecule A and molecule B.  Let's start with the theory that upon entering the body NMN turns into NR.  Molecular weight of NR is 255.247. Molecular weight of NMN is 335.229.  Under that ratio and by a 100% efficient method of conversion, 1,000 mg of NMN would at best be converted into 750 mg of NR. Then how do an equal weight of NMN and NR increase the NAD+ in the Kidney an almost equal amount? After all if the NMN converting to NR theory were correct there would be 25% less NR derived from NMN acting on the kidney and therefore you would expect the NAD+ increase from NMN supplementation to also be at least 25% less. As this is not the case, does it not suggest that NMN and NR enter the body under a different and not yet understood mechanism? 

 

 

[TMNMK]

Ah I see what you are saying now. I am also not convinced yet that the only way for NMN to enter every type of cell is via CD73 conversion to NR and then for NR to enter via nucleoside transporter. There very well may be another mechanism, at least in some types of cells. Perhaps in kidney there is an expression of this putative alternative pathway more so than in other organs although we do have some studies that suggest that CD73 is a primary route for a number of different cell lines: 

 

https://www.nature.c...les/ncomms13103

https://www.ncbi.nlm...les/PMC3764798/

https://www.ncbi.nlm...les/PMC4823084/

https://www.ncbi.nlm...les/PMC5508210/

 

 

Edited by TMNMK, 01 April 2018 - 04:42 PM.

[MikeDC]

I think my explanation in another thread made the most sense why NMN generated more NAD+ in the kidney while NR generates more NAD+ in all other tissues. We know that Ling Liu’s Dissertation shows that NMN disappears from blood quickly even after IV supplementation. NMN is much less bioavailable than NR in the blood. The proposed reason for this is NMN is stuck in the kidney tissue when blood is filtered at kidney. This concentrated NMN generated more NAD+ in the kidney. This doesn’t mean NMN can get into cells without converting to NR first in kidney cells. Sinclair’s mention of NMN and NR behave differently in different cells is just pumping NMN without any solid evidence. So far there is no data that shows NMN can get into cells while all data shows NR can get into all cells tested. NAD+ can actually get into cells without converting to NR first. The discussion of NR and NMN supplementation starts at page 32.

 

  https://dataspace.pr...0181D_12390.pdf

 

Another issue with NMN is not all NMN are converted to NR, a lot of NMN are metablized and flushed out in the urine.

Edited by MikeDC, 02 April 2018 - 01:04 PM.