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Nicotinamide Mononucleotide (NMN)

NMN, a B-Vitamin derivative, is the most direct and effective way to supplement the game-changing anti-aging agent NAD+.

I rank it among Carbon 60 and SKQ1 as a game-changing anti-aging innovation. 

"NAD will turn out to be one of the greatest advances in medical science since Fleming."

Proclaimed Dr. Philip Milgram of the NAD Treatment Center in San Diego, California.

This article is mostly going to focus on decoding what the human studies are saying about Nicotinamide Mononucleotide and how this squares up with the anecdotal experiences of Biohackers online. For more of my own personal experiences, thoughts, and comparisons please see the written and video reviews in the sidebar.

Scientific Research

History

A B-Vitamin From Space?

NMN - A Bioavailable Source of NAD+

Vs Alzheimer's

Vs Diabetes and Obesity

Vs Aging

Vs Addiction

Vs Ischemic Brain Injury

Sirtuin Biohack

Mitochondrial Biohack

Nicotinamide Riboside vs Nicotinamide Mononucleotide

Sources

Experiential

Cofactors

Usage & Dosage

Side Effects

Risk Grade

Conclusion


Scientific Research

There are over a hundred scientific papers about NMN and 34 items of human research with an active interest in the compound by anti-aging researchers. If you're clever with Pubmed you might note that currently there are no completed NMN clinical trials, there are, however, 25 NAD+ clinical trials which is what NMN metabolizes into so we'll be considering the human data coming out of these trials. Currently, there's at least one NMN human trial going on in Japan, when it's published in 2019 or 2020 we'll have a wealth of clinical data by which to further evaluate NMN,

Colorado Universities collaborated on a 2019 clinical trial which recognized that NMN and Nicotinamide Riboside supplementation is well-tolerated and elevates NAD+...

...the use of NAD+ precursors to augment NAD+ bioavailability has been proposed as a strategy for improving cardiovascular and other physiological functions with aging in humans. Here we provide the evidence in a 2 × 6-week randomized, double-blind, placebo-controlled, crossover clinical trial that chronic supplementation with the NAD+ precursor vitamin, nicotinamide riboside (NR), is well tolerated and effectively stimulates NAD+ metabolism in healthy middle-aged and older adults.

Here David Sinclair, the godfather of NAD research explains its mechanism

[Video Rewinding the clock on aging blood vessels]

  History

  An articulate article appeared in Scientific American, Beyond Resveratrol: The Anti-Aging NAD Fad, that's worth quoting...

The NAD story took off toward the end of 2013 with a high-profile paper by Harvard's David Sinclair and colleagues. Sinclair, recall, achieved fame in the mid-2000s for research on yeast and mice that suggested the red wine ingredient resveratrol mimics anti-aging effects of calorie restriction. This time his lab made headlines by reporting that the mitochondria in muscles of elderly mice were restored to a youthful state after just a week of injections with NMN (nicotinamide mononucleotide)

  A B-Vitamin From Space?

NMN is a form of Vitamin B3. Dr. Lee Know explains in his recent book, Mitochondria and the Future of Medicine...

Back in 2001, NASA scientists found traces of vitamin B3 in meteorites, adding support to the theory that life on Earth was seeded by extraterrestrial sources. Vitamin B3’s importance to life is apparent when we consider that it is the precursor of the biological molecules NAD+ and NADH...

Recently, more biologically efficient forms of vitamin B3 have emerged. For example, nicotinamide riboside currently appears as the most efficient precursor of NAD+ and NADH.

  NMN - A Bioavailable Source of NAD+

The more you research NAD+, the more you'll think to yourself...

This stuff sounds great! Can I take it as a normal supplement? 

The only legitimate way to supplement NAD+ itself is via injection. Which is expensive, entails a visit to a doctor and a needle prick. To supplement your NAD+ levels you'll want to orally supplement either NMN or NR (Nicotinamide Riboside), it's molecular precursors.

  From a 2019 paper, Nicotinamide Mononucleotide: Exploration of Diverse Therapeutic Applications of a Potential Molecule, published in the journal Biomolecules which delves further into the uses and benefits of NMN. 

Due to the unavailability of a suitable transporter, NMN enters inside the mammalian cell in the form of nicotinamide riboside followed by its subsequent conversion to NMN and NAD+. This particular molecule has demonstrated several beneficial pharmacological activities in preclinical studies...

NMN could open up a new horizon in modern therapeutics. This biomolecule has demonstrated numerous beneficial pharmacological activities in several preclinical disease models including myocardial and cerebral ischemia, neurodegenerative disorders like Alzheimer’s disease, and diabetes...

You might be wondering...

So if NMN comes from Vitamin B3 why not just take Vitamin B3?

Firstly, taking Vitamin B3 causes an unpleasant skin flush, which the therapeutic applications paper mentions...

nicotinic acid, and nicotinamide have several disadvantages in terms of their therapeutic application. Nicotinamide may cause hepatotoxicity or flushing...

  Vs Alzheimer's

Animal studies indicate a promising therapeutic application treating Alzheimer’s.

NMN has also shown promising activity in the treatment of Alzheimer’s disease as demonstrated by Long et al. It has the capability to treat underlying causes of Alzheimer’s disease, e.g., morphological abnormalities of mitochondria, decrease in oxygen consumption rates (OCR) and NAD+ content... This finding confirms the previous studies where NMN has been proved for its potential therapeutic application in Alzheimer’s disease.

Furthermore, NMN treatment resulted in significant improvement, measured by a decrease in edema, neuronal death, ROS content, neurological inflammation, expression of intercellular adhesion molecule-1, neutrophil infiltration and microglia activation in the affected area of the brain.

  Vs Diabetes and Obesity

These therapeutic applications have been identified.

NMN has also shown potential to be used as a therapeutic for the treatment of diabetes. The unique characteristic feature of type 2 diabetes which occurs due to oxidative stress, augmented inflammatory response, impaired lipid metabolism- all of which can be ameliorated by NAD+...

And NMN is demonstrated to have a weight loss effect, it resulted in a 4% - 9% decrease in weight.

NMN can reduce age-associated weight gain in a dose-dependent manner, supported by a research on mice... NMN treatment also improved metabolic disorders like glucose intolerance and reduced hepatic citrate synthase activity, similar to that of exercise... In light of the above discussion, it can be inferred that NMN can improve certain metabolic complications associated with obesity...

  Vs Aging

Animal research found that 12-months of NMN dosage reversed a number of symptoms of aging

Ageing is a natural human phenomenon characterized by downregulated energy production by mitochondria, as previously mentioned, owing to the depletion of NAD+ in multiple organs...

Decreasing NAD+ level is also associated with age-related DNA damage. Being the precursor of NAD+, NMN can provide these beneficial effects as well.

As stated earlier, increase in body weight and obesity-related complications like a decrease in energy metabolism and locomotor activity are also associated with ageing. These conditions were reversed by 12-month NMN intervention

  Vs Addiction

The NAD molecule is recognized by researchers and practitioners as a powerful therapeutic intervention in addiction treatment, rehab, and healing.

There are two books, totaling 380 pages, which praise NAD+ precursors as powerfully effective addiction treatments. About the author of Addiction: the Dark Night of the Soul/ Nad+: the Light of Hope

Paula Norris Mestayer, M.Ed., LPC, FAPA, is the groundbreaking therapist who pioneered the development of American protocols for utilizing NAD+ to effectively treat addiction-with minimal withdrawal symptoms and without substituting another narcotic. The founder of Springfield Wellness Center, she has helped thousands of people successfully break the rehab/relapse cycle.

From Ten Days to Recovery: NAD Intravenous Treatment- A breakthrough treatment for addiction, depression and anxiety

NAD IV therapy has been found to safely bring about measurable improvement in a ten-day period of treatment. The treatment is safe, natural, holistic and an effective means of helping the patient begin the  road to recovery. Through years of substance abuse and stress, NAD levels are depleted, which leads to poor cellular function, especially in the brain, resulting in “brain fog” which often prevents effective recovery.

We have treated several patients addicted to alcohol, heroin, opiates, methadone, suboxone, antidepressants and benzodiazepines (brand names such as Valium Lorazepam). Virtually every patient we have treated previously tried other means of recovery, often multiple times... Each had a different but all too familiar path to addiction – some, a motorcycle accident or dental procedure that resulted in opiates being prescribed, and then an eventual spiral into heroin. Some people have had a lifetime of alcohol abuse that eventually became unbearable. The good news is that all of these people have been helped by NAD therapy.

A 2018 paper, The Intertwined Roles of Circadian Rhythms and Neuronal Metabolism Fueling Drug Reward and Addiction, included this diagram showing its mechanism in normalizing award and arousal systems enabling recovery.

To quote Dr. Ross Grant of the University of Sydney, Australia

"When we fully understand the role of NAD+ in overcoming oxidative stress, which is a leading cause of illness and death in developed countries, it will be obvious why it works to treat addiction."

A 2014 clinical study of 60 alcohol and opioid addicts that evaluated self-reported cravings. It followed up with the addicts and assessed the severity of their cravings after 12 and 20 months. It concluded: 

NAD is an effective detox treatment for alcohol and opiate addicts as evidenced by a significant reduction in craving ratings. NAD was effective in reducing and maintaining the number of relapse episodes, as well as severity of drug cravings. NAD shows potential as a long-term therapy in maintaining sobriety through minimizing drug cravings and preventing relapse.

  Vs Ischemic Brain Injury

Animal studies identify a therapeutic application treating cerebral ischemia.

NMN has also shown its therapeutic potential for the treatment of cerebral ischemia in preclinical studies... NAD+ catabolism were reduced and body temperature remained unaffected which proved that NMN treatment was solely responsible for this protective effect against ischemic brain injury... NMN, being a successful entity in preclinical studies, could act as an alternative therapeutic strategy in this disorder.

  Sirtuin Biohack

Sirtuins are genetic switches. They are chemical switches that turn on and off the genes that control metabolism, stress response, susceptibility to chronic disease, immunity, our reproductive impulses and much more.

NAD plays a crucial role in these switches working. Without sufficient NAD your genes get stuck turned on or off.

The NAD findings tie into the ongoing story about enzymes called sirtuins, which Guarente, Sinclair and other researchers have implicated as key players in conferring the longevity and health benefits of calorie restriction... A slew of other health benefits have been attributed to SIRT1 activation in hundreds of studies, including several small human trials.

From the Scientific American article. A sapient biohacker with true self-knowledge knows what genetic black swans are lurking in their genome and takes preventative measures. Check out my deep-drive article on this topic 130 Problematic Gene Alleles predicting Alzheimer's, Parkinson's, Diabetes & other diseases.

[Podcast 130 Problematic Gene Alleles predicting Alzheimer's, Parkinson's, Diabetes & other diseases]

  Mitochondrial Biohack

From the paper on its therapeutic applications...

In human cells, NMN is available as a source of cellular energy. Not long ago, this molecule was only known for its activity as an intermediate in [NAD+] biosynthesis.

From the Scientific American article

Recent research suggests it may be possible to reverse mitochondrial decay with dietary supplements that increase cellular levels of a molecule called NAD (nicotinamide adenine dinucleotide).

NAD is a linchpin of energy metabolism, among other roles, and its diminishing level with age has been implicated in mitochondrial deterioration. Supplements containing nicotinamide riboside, or NR, a precursor to NAD that's found in trace amounts in milk, might be able to boost NAD levels.

In 2000, Guarente's lab reported that NAD fuels the activity of sirtuins, including SIRT1—the more NAD there is in cells, the more SIRT1 does beneficial things. One of those things is to induce formation of new mitochondria. NAD can also activate another sirtuin, SIRT3, which is thought to keep mitochondria running smoothly.

Dave Asprey describes NAD in his mitochondrial manifesto, Head Strong.

...your mitochondria need NAD to complete the Krebs cycle and produce energy. A reduction in NAD causes all of the weaknesses that can stem from a lack of energy in your cells.

[Video Mitochondria are to Genes what Free Will is to Predetermination - Book Review of Head Strong]

  Nicotinamide Riboside vs Nicotinamide Mononucleotide

One of the first questions that probably comes to mind when researching NAD is...

Which precursor is better? NR or NMN?

It's actually hard to say at this stage of scientific discovery. In many ways, we are still in the early days of anti-aging research and in several years more human clinical trials will have been done. Research has proven that NMN activates the Sirtuin SIRT3 while NR does not. I perused a not insignificant number of anecdotal reports from users of both NR and NMN -- the common sentiment seems to be that NMN feels more like a classic Nootropic; it has a more visceral, acute energizing effect. The authors of the therapeutic applications paper throw up their hands and admit...

It is very hard to delineate the borderline between the efficiency of NMN and NR. It is reasonable to conclude that both of them share some overlapping activities, as well as their own positive and negative impacts.

There's a couple of anti-aging researchers that make the case that NR is absorbed a little better since it is a smaller molecule, however, there are no clinical trials comparing the two and interestingly many biohackers who have tried both indicated in a survey and in a multiplicity of anecdotal reports that NMN has a more acute, noticeable effect. I guess it comes down to the old practitioner vs theorist paradigm. If you're a pragmatic practitioner, NMN is the best option. If you have faith in experts' theories, go for NR.

If you can afford it, try both NMN and NR. Give each 12-weeks of dosing to see how they affect you differently. You may find that there's really not much experiential difference between the two.

  Sources

You want to get pure, Pharmaceutical Grade NMN which is over 97% pure NOT Food Grade. Food Grade is less pure and unsurprisingly, cheaper. Whoever you buy it from should supply a COA verifying purity and who explicitly states that it's Pharmaceutical Grade. This does not mean that Food Grade stuff is a total scam, it will still probably do you some good, but smart consumers demand Pharmaceutical Grade.

NMN Product __

Pricing: Fortunately for Biohackers (who aren't millionaires!) NMN no longer costs $1,700 per gram. But it's not cheap. One Biohacker reported:

I've been taking NMN since July 2015 and the only side effect that I have noticed is a rapid slimming of the wallet!

There's a vendor Alive by Nature on Amazon that many anti-aging experimenters order from, in my research I ran across a handful of negative reports about these guys. I would urge you to only order from them if you can verify that they have a valid guarantee policy.

Want to order it wholesale? You'll have to buy at least a kilo which runs about $3000 for 98% pure stuff.

  Experiential

  A pioneering and articulate biohacker, LawrenceW, used NMN for about a year and meticulously reported the effects and subjective experience on Longecity. His first few months on the stuff produced some pretty astounding results...

When I first started taking NMN, I immediately noticed a slight increase in energy. My weight beginning to drop within a couple of days. Within weeks I felt that I was shedding belly fat and noticed a visible flattening of my tummy. At about 3 weeks I noticed that the arthritis in my knuckles had started to clear up.  Within the first month I noticed that I was sleeping much more soundly, sleeping about an hour longer and waking up really refreshed and clear-minded. By 3 months all the arthritis had cleared up body-wide including my shoulder, elbows, knees and right hip... At that time, I also noticed an increase in strength, endurance and muscle size.

About midway through the program, my neighbors were stopping me and commenting that I was looking healthier, younger, more energetic, buff, really good, etc. One of the more interesting comments was that I was moving like a much younger person. After that comment I focused on my walking mechanics. I realized that I was walking with much straighter posture, with shoulders back, chest out and a looser, more fluid and quicker stride, as all my joints were now more flexible and pain free. Physically, I felt like my body did 20 years earlier. I had an interesting conversation with a cosmetic surgeon friend, who said that he could make a 70-year-old look like a 50-year-old, but he couldn’t make them move like a 50-year-old. I now believe that NMN can make one move like a much younger person.

This may strike as a too-good-to-be-true anecdote, but Lawrence's doctor was impressed with the quantified health improvements that blood testing revealed. Notably, BUN, Hgb A1C, Total cholesterol, Triglycerides, Cardiac risk, Testosterone, C-reactive protein, Tumor Necrosis Factor Alpha and Interleukin-6 Plasma numbers had improved.

These last three tests were all measurements of inflammation levels in my body. As increased inflammation is tied to aging and a decrease in general health, I was pleased to see my inflammation levels being reduced. As a chronological 60-year old male, I was pleased to see that my biological age had dropped from 70 to 44.

I found this anecdote especially interesting because after using NMN for a while, he went off it for a year and then back on it at about half the original dosage. He noted that some of the quantifiable health benefits persisted but some did not.

In summary, some of the benefits appeared to be lasting, while others went away after I stopped taking NMN.  Overall, I felt my initial experience with NMN was very positive with no downside risk.

Increased energy, is a frequently reported, and sometimes instantaneous, effect of supplementing NMN. A 59-year-old Texan taking between 500 - 1000 milligrams reported:

The big change was increased endurance in the gym and on my bike. I had more and more “good days”, and found I was increasing the weights I used, and getting better times when I worked hard on the bike... I still have prostate problems, gray hair, and sore joints, - but energy, endurance, physique, and cognition are like I am 20 years younger.

An uptick in physical energy is often noted, it seems to be a real workout performance enhancer. Mikaela on Longecity reported:

I recently added 500mg of NMN sublingualy and have been amazed by the energy boost.  I was able to do extra reps with weights.

An East Coast Biohacker noted that it's a great biohack for joggers:

I do notice that my recovery is excellent. Ran 4+ miles the other day (which is good for me, getting back into the spring swing) and had zero joint pain with barely any soreness the next day.

An Australian Biohacker commented on its taste and aesthetics

First impression: tastes great. A bit like vitamin C crystals, but less acidic. Very easy to take. I dropped half a scoop under my tongue and my mouth immediately filled with saliva. The powder dissolved in seconds.

  Cofactors

Resveratrol and Pterostilbene are identified in the Scientific American article

NAD boosters might work synergistically with supplements like resveratrol to help reinvigorate mitochondria and ward off diseases of aging.

While resveratrol has hogged the anti-aging spotlight over the past decade, unsung researchers in places like Oxford, Miss., have quietly shown that pterostilbene is a kind of extra-potent version of resveratrol. The pterostilbene molecule is nearly identical to resveratrol's except for a couple of differences that make it more "bioavailable"...

[Video Pros vs Cons of Resveratrol - Should Biohackers take it?]

Alpha Lipoic Acid, Anti-Aging researcher Dr. Lee Know explains the synergy between these two supplements...

Another benefit of ALA is its ability to modulate the state of the energy carrier nicotinamide adenine dinucleotide (NAD)... There’s also another way that ALA can modulate the NADH:NAD+ ratio, and even influence the aging process at the cellular level—through the activation of a class of genes known as sirtuins.

Importantly, ALA supplements must be kept cold. Don't just pick up any old ALA supplement found in white plastic bottles on your pharmacy's shelves.

  Usage & Dosage

There's some room for self-experimentation with NMN. There's no universal usage protocol. Biohackers report taking between 250 milligrams and 3 grams daily.

  LawrenceW reported:

I took a 3,400mg of NMN dose twice daily. I took my morning dose at around 7:00am and my evening dose at around 6:30pm.

After 8 months of 3400 milligrams daily, his blood work revealed that his biological age had reduced from 70-years-old to 44-years-old. He maintained this biological age after reducing the daily dosage to 1600 milligrams.

In Dr. David Sinclair's Joe Rogan Interview he revealed that he takes between 500 - 1000 milligrams daily.

[Video Joe Rogan Experience #1234 - David Sinclair]

David Sinclair mixes powdered NMN with yogurt.  Bulgaria, where I live, is home to some of the best organic probiotic yogurts in the world. So I'll be trying this!

  Side Effects

  • Increased appetite is reported in a few places around the internet. Just be sure to stay active and consistent with your exercise while using NMN.
  • Sleep Disruption in the initial few weeks of usage reported by a couple of YouTubers. Apparently, they need less sleep. They find themselves waking up in the middle of the night with the energy to get their day started.

  Risk Grade: A-

NMN is quite safe. It is, after all, a B-Vitamin. It's as safe as any vitamin but doesn't deserve an A+ risk grade because of the lack of human clinical trials.

  • A 2018 placebo-controlled, double-blinded clinical trial of 40 men noted that 12-weeks of NR supplementation (at 2 grams daily) was safe.
  • I combed the Longecity anti-aging forums for any reports of negative side effects and found none. One Biohacker reported: I've taken both NR for about two years and NMN for three months and have had no adverse side-effects, nor has anyone I know who takes them.
  • The therapeutic applications paper concluded Although NMN has shown significant beneficial pharmacological activities in preclinical studies which the scientists have been searching for a long time, it still lacks sufficient clinical and toxicological data.

  Conclusion...

NMN is one of the most promising anti-aging molecules that are exciting practitioners and researchers alike. I rank it among SKQ1 and C60 Fullerenes as a longevity gamechanger to watch and experiment with.

 

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