Nicotinamide Mononucleotide NMN - Explained, All Research and Overview Contribute

Joey B. Wong | earned $0.94

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I am lead to this chemical from my research on the highly marketed Nicotinamide Riboside after finding out this is the ORIGINAL chemical that was originally used in most of the anti-aging studies regarding NAD+ .

We are here to find out "what happened?", why is Nicotinamide Mononucleutoide (NMN) so much less heard of than Nicotinamide Riboside? Is it really better? Does it work the same way?

I am very enthusiastic about this research because NMN is one of these "conspiracy" chemicals - do we not know much about it simply because big pharma doesn't want us to?

Let's take an unbiased dive at this the best we can.

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Nicotinamide mononucleotide, a key NAD+ intermediate, treats the pathophysiology of diet- and age-induced diabetes in mice

NMN was immediately utilized and converted to NAD+ within 15 min, resulting in significant increases in NAD+ levels over 60 min

Administering NMN, a key NAD+ intermediate, can be an effective intervention to treat the pathophysiology of diet- and age-induced T2D

Surprisingly, just one dose of NMN normalized impaired glucose tolerance

“Improved fat metabolism

Nicotinamide mononucleotide (NMN) supplementation ameliorates the impact of maternal obesity in mice: comparison with exercise.

Both interventions reduced adiposity, and showed a modest improvement in glucose tolerance and improved markers of mitochondrial function. NMN appeared to have stronger effects on liver fat catabolism (Hadh) and synthesis (Fasn) than exercise. The interventions appeared to exert the most global benefit in mice that were most metabolically challenged (HFD-consuming offspring of obese mothers). This work encourages further study to confirm the suitability of NMN for use in reversing metabolic dysfunction linked to programming by maternal obesity.

The Landmark Study That Started It All

David Sinclair is a prominent anti-aging scientist famous for bringing Reservatrol to the scene. Reservatrol turned out to be not so "miracle" as he and his company Sirtris Pharmaceuticals (which has since been sold) purported to be.

I will not go into his profile as he is famous and the information is readily available on Wikipedia and other websites.

Whilst David Sinclair is a big name and a highly persuasive person, in science people do not work alone. David collaborates with many other equally talented scientists before publishing his research.

In 2013 David Sinclair with his team published a important milestone in anti-aging science, this is one of the three keystone studies to look at today in 2018.

The three crucial studies to look at is the original 2013 David Sinclair led study, which wasn't focused on Nicotinamide Mononucleotide, but rather just a chemical used to establish the link between NAD+ increase, mitochondria and sirtuin activity. This was at the time a breakthrough in understanding the link between NAD+ and age.

Raising NAD+ levels in old mice restores mitochondrial function and homeostasis to that of young mice

Key biochemical markers of muscle health in 22-month-old mice returned to levels similar to 6-month-old mice.

- The original 2013 landmark study.

Secondly, the long term study by Mills in 2016, which proved NMN mitigates age-associated physiological decline in mice.

Thirdly, a 2018 Sinclair study that identified key cellular mechaisms behind vascular aging and muscle health, and how NMN kept old mice fit and young via NMN orally. Importantly in this one NMN led to angiogenesis, a restoration of heart tissue in old mice.

It turns out Nicotinamide Mononucleotide (NMN) might be important after all.

 

What is Nicontinamide Mononucleotide (NMN)?

NMN is a nucleotide derived from Ribose and Nicotinamide. NMN is a derivative of Niacin.

Humans naturally have enzymes to generate Nicotinamide Adenine Dinucleotide (NAD+) from NMN.

What is very confusing for a lot of people digging into David Sinclair's team's research is that it often doesn't actually spell out Nicotinamide Mononucleotide (NMN) in the paper titles, nor is it greatly featured in the content and subsequent mainstream media propagation of his team's papers.

There are three possible reasons for this:

  1. NMN was simply seen as a common sense very simple way to raise NAD+. NAD+ was what the studies were about, so the methods to raise NAD+ was not emphasized in the abstract or discussion.
  2. NMN cannot be patented, thus it cannot be monetized (more on this later when we get to Nicotinamide Riboside).
  3. Sinclair's team is trying to discover a molecule that will do the same thing, is patentable and has the benefits of being simpler to produce and introduce to the body. Notable a Sirt1 activator he discovered called SRT1720. The results have not been impressive.

What seemed to have happened was that the NMN results was ASSUMED to be easily REPLICATED by any other NAD+ precursors like Niacin or Nicotinamide Riboside (NR), but as the years piled on it became clearer NMN did something unique, something the original researchers either completely overlooked, or was unsatisfied with due to the non-profitable nature of NMN.

How Does NMN Work?

All SIRT1 activators try to achieve the same thing. They are trying to replicate one of the purported effects of calorie restriction (a well documented anti-aging technique). An important part of this is sirtuins, a group of seven genes that evidence points out to being very important in regulating the aging process.

Sirtuins, a group of seven genes, control a variety of protective processes, scientists do not know everything regarding their exact pathways and how they work, but they figured out it protects chromosomes, protect stem cells being lost and importantly protect cells from becoming senescent.

Sirtuins are activated by changes in lifestyle such as exercise and calorie restriction caused by things like lack of sugar or increase in NAD. (Relation with increasing NAD+ is not a coincidence as the landmark study proved the two are related).

Brief Summary of Mitochondria's Importance in Aging and How This NAD Thing Got Started (link)

As discussed before in the Nicotinamide Riboside article I wrote, like NR, NMN does not work by simply increasing NAD+ . In this very recent study NMN mimics and augments exercise by inhibiting NICD-Notch. NMN is linked to boosting NAD+ thus promoting SIRT1 dependent processes, such as capillary density in muscle creation (angiogenesis).

NMN works by being converted to NAD+ by three NMN adenylyltransferases, NMNAT1-3. It is a 1 step process which makes it the closest precursor possible. NMN may work by activating other pathways too (which seems to be the case).

Since 2013, various studies and the elaborated 2016 study are completely focused on NMN showing a plethora of benefits that they assume are happening with NAD+ increase. There is in fact so much research on NMN providing stunning anti-aging results that it is too much to be covered here. 

NMN reliably increases NAD+ levels when ingested orally in the short term, it is not known currently how much of NMN is metabolized to NAM (Nicotinamide/Niacinamide), however the superb results of NMN likely points to NMN have some indirect effect that is different to NAM or it likely does not all get converted into NAM.

It should be noted that sublingual NMN is highly likely to be more bioavailable, but perhaps with a different path without the first pass metabolism, it is also possible that sublingual NMN or NR may be hydrolyzed in the mouth or metabolized in the mucosal membranes, so sublingual is not a sure bet.

NMN is well tolerated in rats over 12 month trial. 100mg per kg and 300mg per kg. Notably whilst a dose-dependent rise in NAD+ was detected in the liver and BAT (Brown Adipose Tissue), it was NOT detected in skeletal muscles and WAT (White Adipose Tissue).

What is the Difference Between NMN and NR? Is it Superior? Nicotinamide Mononucleotide Vs Nicotinamide Riboside

The reason you hear way more about Nicotinamide Riboside (NR) is pretty simple, money and availability.

When the landmark study in 2013 was released, not only is NMN unpatentable due to it being classed as a common compound (like you can't patent air), NMN was also not ready for mass industrial production.

On the other hand, a company called Chromadex had a patented compound that purported to increase NAD+ reliably and jump in to quickly say NR is almost the same thing. Since NR is patented, it could be sold at a much higher mark-up and licenses can be sold to other supplement companies like Elysium, thus the original compound used in both the 2013 and then 2016 compound was swept under.

Of course, initially, people were drawn to NR, especially since it would be commercially available first, however over time more and more people began to suspect that NMN was better or at least it was just as good.

Why sell you NR (Nicotinamide Riboside)? Apart from the high-profit margins gained from being a patented product (unlike NA/NAM/NMN).  NR is 2 steps away from NAD+ , NR first converts INTO NMN before be converting finally to NAD+.

On the other hand NMN converts to NAD+ directly - meaning it is a 1 step process. NMN is closer to NAD+ than NR. 

Nicotinamide Mononucleotide vs Nicotinamide Riboside

(NR is phosphorylated to NMN by Nicotinamide Riboside Kinases (NRKs).

(Note NMN is also synthesized from Nicotinamide and PRPP by Nicotinamide Phosphoribosyltransferase short as NAMPT).

This means everything becomes NMN before turning into NAD+, NMN is one of the most direct precursors which explains WHY the studies used NMN.

But again, remember NMN is unpatentable meaning there is no money.

The question is does NR work? We answered this question with a conclusive yes in our other research topic.

Next, the question is, is NMN better?

Several things weigh favorably for NMN over NR:

  1. Being 1 step away from being NAD+ puts NMN the closest possible to NAD+. This has bioavailability implications too.
  2. There have been no financial incentives to fund NMN research, this reduces possible bias, yet the results from all the studies involving NMN has been stellar, and personally, I feel superior and more quantifiable than the research has been with NR.
  3. NMN is taken by David Sinclair himself and his family, if the lead scientists takes it, there is a possibility that he understands himself that this is the best compound, but there is no money to be made off selling it. 
  4. It is THE chemical used in the landmark 2013 study and the further elaborate one done in 2016, both studies used NMN not NR. When the media reports miraculous results they refer to these studies and not NR. The most recent study in 2018 by David Sinclair's team also uses NMN and not NR.
  5. NR has been condemned as scientists trying to cash in their credentials.
  6. NMN is stable in blood plasma. In both mice and humans studies have repeatedly failed to find NR in blood plasma at any given time. (R) (R) (R)
  7. NR's effects on NAD+ has been painstakingly proven by human pharmacodynamics trial in University of Washington, it is likely massively converted into NAM (Nicotinamide), which is responsible for the NAD+ increase at lower doses, and leaves NR intact at higher doses because of the liver's limited ability to metabolize it into NAM. (Discussion).

As I have mentioned previously in the NR article, because different NAD+ precursors require different pathways enabled by different gene expression and cell types, it is likely NR, NMN, NAM and NA all work on different pathways, activate different things due to molecular difference and thus do not work exactly the same way metabolically. 

As a calorie restriction mimetic it is likely NEITHER chemicals NR or NMN will alone prolong lifespan, instead it is likely to prolong healthspan.

Furthermore being a non-patented compound NMN is likely to become cheaper and cheaper, since being manufactured NMN prices have already began diving and will likely eventually become cheaper than NR, and NR might become cheaper to compete with NMN.

There is an argument from Chromaxdex (the company behind NR) that NMN may not enter cells directly due to it containing a phosphate.

^ In my opinion,the entire argument from Chromadex is biased, so should be read with skepticism. Results seem to favor NMN over NR.

Subjectively, in my opinion, results from NMN has been more impressive. NMN increased endurance by nearly 100% vs control mice in the 2018 study. It causes new blood vessels to grow in 20 month old mice. NAD+ increase is over 500% at 60 days.

In comparison in this 2016 study, endurance was improved by only 20% with NR bringing it in line with the hypothesis that it is converted to NAM most likely by the first pass metabolism. NMN restores cardiac function to near normal levels for mice with Fridreich's Ataxia (R), whilst NR did not (R) . In studies published in 2017 and 2018 NMN decreased β-amyloid buildup, while NR did not.

^ These studies do not demonstrate conclusively NMN is better, they may be selectively showing tht NMN does SOME things better than NR, there could be things NR does better than NMN, however a lot of research seems to show that NMN simply does anti-aging better than NR.

Would NR alone have caused such excitement in the anti-aging community? Vitamin B3 is not a new supplement, both Niacin and Nicotinamide have been known to increase NAD+ levels for decades.

Human Clinical Trials

Humans clinical trials are currently ongoing, and pending publications:

Beginning 2018

  • 2018 Sinclair Metrobio study – Phase 2

The Phase 1 study by Dr Sinclair has been completed, and they are ready to go forward with the Phase 2 study, so we can conclude there were positive results, and no negative side effects, else they would have to publish those immediately.

In the University of Washington study, participants are 50 healthy women between 55 and 70 years of age with slightly high blood glucose,BMI and triglyceride levels.

Using a dose of 2 capsules of 125mg NMN per day over a period of 8 weeks, researchers are testing for:

  • change in beta-cell function
  • works to control blood sugar
  • blood vessels dilate
  • effects of NMN on blood lipids
  • effects of NMN on body fat
  • markers of cardiovascular and metabolic health

The active supplementation portion of this study has ended, but testing of metabolic parameters will continue for 2 years after supplementation has ended.  So researchers know the immediate effects and  preliminary results are expected to be announced in 2018, with  final results expected in 2020.

Conclusion

After this, I will attach all the research outside of the 3 key studies mentioned already, of which there are tons.

The conclusion I have for NMN is that it like NR conclusively raises NAD+ levels and works perhaps to a higher level than NR. 

In my opinion, it is likely NMN and NR don't work in the same way both in terms of metabolic conversion in the liver and in terms of pathways to NAD+, different cells have different gene expressions meaning the effects of the two of NMN and NR on NAD+ and sirtuin are likely different.

Though not entirely proven, I suspect that NR's effects majorly comes from being converted to NAM at lower doses, with higher doses leaving some NR intact, explaining why NR seems to work better at higher doses. Blood plasma work also points towards NMN reaching plasma after first pass metabolism but not NR, which leads me to think that NMN works better because NMN is actually reaching a lot of tissues.

Another unsettled point is how sublingual delivery would alter the bioavailability of NMN and NR. In general I don't see why a sublingual administration would not be superior to oral ingestion other than the limitations of how much NMN and NR can go through this way. 

Sublingual NR is likely difficult since commercially NR is made with a chloride with stability reasons, this gives it an awful taste making it hard for it to be formed into sublingual tablets compared to NMN.

NR does currently have the advantage in that it does have completed human trials, something NMN cannot claim at the moment as of of mid 2018. I expect that to change by 2020.

If one is unsure about which supplement to go for, the answer may simply to take both as Jansen from lifespan.io has suggested.

 

Potential Downsides to NMN (Needs Work)

It has been suggested that high levels of NAD+ may simply be downregulated, explaining why some people feel amazing effects that disappear in a few weeks. This goes in tandem with the longer term studies which suggested that NAD+ increases are downregulated by homeostasis.

Since NAD+ levels decrease rapidly due to aging, it is likely that supplementing NMN/NR during middle age would raise NAD+ levels to normal and no more.

If this hypothesis is true, then this will be true for both NR and NMN.

Oversupplementation may lead to downregulation of otherwise healthy natural levels of NAD+ thus creating a dependence on exogenous NMN/NR, mean,ing upon sudden withdrawal of NMN/NR NAD+ levels would be far lower than before homeostasis kicks in.



^ I have done a lot of work on opiate drug tolerances and the issue of homeostasis is very complicated and greatly vary from one person to another, downregulation is not a simple issue. For example it is possible for the liver to INCREASE metabolisis of NR to NAM when high levels of NR are continually ingested. Tolerance/homeostasis is a HUGE problem for a lot of exogenous interventions.

Again, homeostasis is
a incredibly difficult topic, and varies greatly from person to person. For example some people can take benzodiazepines for life whilst others develop complete tolerance within a week.

(Copied) Warner on Longecity.org says: About a week ago we replaced 250 mg/d NR with 375 mg/d NMN as ABN sublingual tablets (a little more expensive than the powder), 125 mg morning, aft, and evening. Unlike NR, the NMN is not affecting my (or wife's) sleep. Too early to report results, but nothing negative so far. Would like to see something positive though before upping dose. Bryan Nettles, owner of ABN, reported good results with 3-4 sublingual tablets per day, and increased that to 6-8, and then 10-12...

(Copied) RPG says Amazon.com: “I have taken Niagen prior and read Dr. Sinclair's research on aging whereby he reversed aging in mice with NMN after one week with very high dosages of NMN/kg of weight. So I purchased this product. It is much more "powerful" than Niagen in my option after taking it now for nearly two weeks. Right from the beginning you notice that you have more energy - not a "buzzing" kind of energy and then a crash. Just merely an energy when you ask your body to do something... it is there for you to do it. At 57, I am no longer wanting to take a nap after lunch while I sit at my work desk and I enjoy reading until 11 p.m. until I retire. I think nothing of running to my car when in the park after going for a walk and I am not even someone who exercises. I notice when I run that I am not "huffing and puffing" as before if I would attempt to do it - what stops me is that my heart rate gets up there and I think well I best not have such a high heart rate so I stop running. I am just feeling like I am getting my "youthful" feeling back that I have not felt in years. So all is good and I certainly will continue to take it. “

(Copied from Amazon) Britt Sloan says: I ordered this product along with Co Q10 for the same company for my mother. I decided to go ahead and get myself some too since I have suffered for decades from pain from what's diagnosed as fibromyalgia. Also always feeling tired and fatigued. I have not been able to work out for real for a good year or two. And when I did the pain was absolutely incredible and overwhelming. So I just stopped. I really had not expected the results that I got from taking this. I had extensively read everything I could possibly find on the subject and had come to have some belief in the concept of the product. So for myself I have noticed after about a week of taking it that that pain that I was feeling throughout my body and random places particularly the joints seems to be nonexistent. And the pain that develops when sitting or having pressure up against certain parts of my body doesn't seem to happen. I feel more focused. And I seem like I don't run out of energy as quickly. I do not in any way feel stimulated or as if I have taken caffeine or vitamin B. I just simply can go longer than I did before and normally the times that I would be ready to just sit down on the couch and rest those times are not coming. I have found other benefits as well. For my mother. She is about 74 years old and has gotten to the point where moving from one room to the other in the house has brought her exhaustion. I have hated seeing this. I recently got her some serovital and she saw the benefits from it and has had an improvement in her overall well-being and energy. Although not completely. After taking these supplements NMN, she has been going day after day cleaning going out into the yard and seems to have a Renewed Energy. She noted to me that normally when she gets down on her hands and knees to wash the dog that she can barely get her legs to lift her. But she noted that she was very surprised while she was cleaning the house that for some reason her legs were able to lift her very easily. I also noted this when I decided to go try to work out and when I tried to do the pull-ups they just seemed easier. As if my muscles were all engaging or something. Hard to explain, because it's not like you feel like you have extra energy. It's just that you're not running out of energy. I don't know what this would do for a normal healthy person. But for myself and for my mom I have to say I'm absolutely amazed. I have stuff so many different supplements and pills in my mouth trying to solve some of the problems I have and so far in the short amount of time I am really impressed. I would encourage someone to try it if they have a feeling that they may need it. Who knows if these benefits will last or if it will diminish with time. I pray that it continues to work. This could potentially change my life. Oh and one last thing that I noticed when looking in the mirror I can actually see more definition around my area. I had already been trying to lose weight but always get stuck at a certain point and I actually see some slimming happening in my body. I noted that in some of the studies that I read about. Also I would recommend taking this with Co Q10. However I am not personally of the belief that you would need to buy it from this company. I do however think that this particular product from this company is better when it comes to nmn. Just my opinion but like I said I did a lot of reading.

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