This new research, published March 22 in Cell, identifies the key cellular mechanisms behind vascular aging and the key role it plays on muscle health.

Scientists at Harvard Medical School, Massachusetts Institute of Technology (MIT) and the University of New South Wales tested NMN, and MIB-626, which is a patent pending product developed by Metrobiotech that combines H2s with Nicotinamide Mononucleotide (NMN) to increase the effectiveness.

These researchers fed 400 mg/kg of NMN per day to 20-month-old mice, an age comparable to 70 years in people. After two months, the mice had increased muscular blood flow, enhanced physical performance and endurance and the old mice became as fit and strong as young mice.

AGING ARTERIES

We are as old as our arteries, the adage goes, so could reversing the aging of blood vessels hold the key to restoring youthful vitality?

In this study, the answer appears to be yes, at least in mice.

“We’ve discovered a way to reverse vascular aging by boosting the presence of naturally occurring molecules in the body that augment the physiological response to exercise,” said study senior investigator David Sinclair, Professor in the Department of Genetics and co-Director of the Paul F. Glenn Center for the Biology of Aging at Harvard Medical School.

As we grow old, we become weak and frail. A constellation of physiological changes—some subtle, some dramatic — precipitate this inevitable decline.

As we age, our tiniest blood vessels wither and die, causing reduced blood flow and compromises oxygenation of organs and tissues. Vascular aging is responsible for a myriad of disorders, such as cardiac and neurological conditions, muscle loss, impaired wound healing and overall frailty.

Scientists have known that loss of blood flow to organs and tissues leads to the build-up of toxins and low oxygen levels. Endothelial cells — which line blood vessels — are essential for the growth of new blood vessels that supply oxygen-rich and nutrient-loaded blood to organs and tissues.

But as these endothelial cells age, blood vessels atrophy, new blood vessels fail to form and blood flow to most parts of the body gradually diminishes. This dynamic is particularly striking in skeletal muscle, which is highly vascularized and depends on a robust blood supply to function.

REDUCED BLOOD FLOW TO MUSCLES

Muscles begin to shrivel and grow weaker with age, a condition known as sarcopenia. The process can be slowed down with regular exercise, but even exercise becomes ineffective.

Sinclair and team wondered: What precisely curtails blood flow and precipitates this unavoidable decline? Why does even exercise lose its protective power to sustain muscle vitality? Is this process reversible?

In a series of experiments, the team found that reduced blood flow develops as endothelial cells start to lose a critical protein known as sirtuin1, or SIRT1. Supplementation with NMN boosts NAD+, stimulates SIRT1 and restores growth of endothelial cells.

RESULTS

After two months of receiving NMN, new blood vessels sprouted within the skeletal muscles of old mice. Capillary density increased and matched the capillary growth of young mice.

Remarkably, blood flow increased and the animals’ endurance (measured by how long they could run on a treadmill before before exhausting) was 56%-80% greater than that of untreated old mice: 1,400 feet compared to 780 feet.

Treated mice received the benefits of exercise just as mice half their age. In young animals, exercise spurs the creation of new blood vessels (neovascularization) and boosts muscle mass, which declines with age in both people and mice.

• NMN restored the vascular system of old mice to that of young mice
• Mice treated with NMN had a 1.6-fold increase in time and distance runs compared to untreated mice
• In young, sedentary animals, NMN did not alter the capillarity or exercise capacity
• In young animals, NMN + exercise resulted in 70% more capillaries than untreated, sedentary mice

NMN restored the blood-vessel- and muscle-boosting effects of a good treadmill run, basically “reversing vascular aging in the mice,” said study co-leader, David Sinclair of Harvard Medical School.

With exercise, the effect is even more dramatic: 32-month-old mice (equivalent to a 90-year-old human) were able to run on average TWICE as far as untreated mice.

The benefits of exercise diminish with time as decreased blood flow and muscle deterioration prevents adequate recovery. It is truly amazing that elderly animals were able to make such dramatic physiological improvements.

NMN BOOSTS NAD+

NMN is found in certain foods and effectively stimulates NAD+ metabolism, a coenzyme the mitochondria depend on to fuel all basic functions within cells. (3,4)

One function of NAD+ is to facilitate communication between the cell nucleus and the mitochondria that power all activity in our cells. (5,6,7)

In previous studies, scientists confirmed a direct link between falling NAD+ levels and aging in both animal and in human subjects and are learning that NAD+ precursors — NMN and NR — can restore NAD+ levels to prevent and even reverse aspects of aging.

NOT THE FIRST BIG NEWS FOR NMN OR DR SINCLAIR

This is not the first time NMN made headlines in anti-aging circles. The lead author for this study, Dr. David Sinclair, published research in 2013 that demonstrating:

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 2013 study prompted more research on the benefits and safety of NMN, including this 2016 study, in which mice were treated with NMN for 12 months. The results showed:

NMN was able to mitigate most age-associated physiological decline in mice

Treatment of old mice with NMN reversed all of the biochemical aspects of aging

In a paper published in Science in 2017, Dr. Sinclair identified that the metabolite NAD+, which is naturally present in every cell of our body, has a key role as a regulator in protein-to-protein interactions that control DNA repair. Treating old mice with NMN improved their cells’ ability to repair DNA.

WHY THIS STUDY STANDS OUT

The potential of NMN has been known for over 5 years now, but this most recent study stands out because it:

1. Shows NEW growth (Angiogenesis) of blood vessels in OLD animals, which is very different than improvement in some metabolic markers that may be temporary.
2. Is the first time we have seen such a significant improvement in physical performance that actually allowed very old animals to perform as they did when young.
3. Renewed capillary growth and increased blood flow “reversed vascular aging” and may help reverse heart and neurological problems in addition to sarcopenia.

Remember, as we age, our arteries harden and atrophy resulting in decreased endurance and muscle loss.

Here, the process was not just halted, but REVERSED, with new growth. The number and density of capillaries was the same as in young animals. This is not a temporary phenomenon that might disappear as the body adjusts and homeostasis kicks in.

According to Dr. Sinclair, the same mechanism could also spur the creation of blood vessels in the brain, where “the lack of oxygen and buildup of waste products” (resulting from capillary loss) “sets off a downward spiral of disease and disability,” such as Parkinson’s and Alzheimer’s. This may be why studies with NMN and NR have proven effective in early studies of such neurological diseases.

Sinclair and his team are now studying whether increasing NAD+ levels will also spur the creation of blood vessels in the brain.

“Anything that contributes to muscle health through vascular health is likely to be quite important,” said the Buck Institute’s Verdin, who takes a daily NAD+ precursor.

There is great interest in anything that can improve angiogenesis and treat heart disease. Pharmaceutical companies have spent BILLIONS over the last 10 years testing various products. So far, all have failed. It’s interesting that the FDA insists any such medication must improve exercise performance in patients. It’s easy to see why Dr. Sinclair has plans for gaining approval for NMN as a pharmaceutical drug.

WHY WE THINK THESE RESULTS WILL BE REPLICATED IN HUMAN TESTING

Both NMN and NR boost NAD+ and have overlapping effects in studies. At least four clinical studies with humans given NMN supplements are ongoing or completed but not yet published. There have been three human studies published with NR that show results in humans that are similar to experiments in mice (r,r,r).

A study conducted by Elysium Health in 2017 using their product, Basis (NR + Pterostilbene), found improvements in mobility. 120 individuals aged 60-80 were given 250 mg or 500 mg of Basis daily for eight weeks. Those receiving the larger dose experienced:  “7.8% improvement in chair stand and 7.5% improvement in distance walked.”

I wrote at the time that it is nice, but not overwhelming, especially since we don’t know if this increased mobility is at a plateau or may improve. Now, with these results from Dr. Sinclair’s latest research in mice over two months old, we see increased endurance on a much larger scale.

However, the improved capillary growth and blood flow behind the increased endurance would not occur quickly. Two months is a long time to a mouse that live around three years.

As humans live 30-40 times longer than mice, two months in mice time is like six years or so in humans.

We are awaiting results that show NMN works the same in humans, but we do have research that makes it plausible NMN could restore blood flow and physical performance as it does with mice.

Completed or in process human studies with NMN:

• Keio University  study with 100 mg and 200 mg per day
• Dr. Sinclair company Metrobio study completed late 2017, with Phase 2 trials late 2018 (more below)
• University of Washington

CONCERNS

Neovascularization—the formation of new blood vessels—should be treated with caution, the researchers say, because increased blood supply could inadvertently fuel tumor growth.

“The last thing you want to do is provide extra blood and nourishment to a tumor if you already have one,” said study co-author Lindsay Wu, at the University of New South Wales School of Medical Sciences.

Sinclair and Wu point out that experiments done provide no evidence treatment with NMN stimulated tumor development in animals treated with the compound.

MAXIMIZE BIOAVAILABILITY OF NMN

We do not believe the best answer is large dosages of oral supplements (capsules), but rather taking Sublingual NMN, as it is a more direct route to the blood and avoids the “first pass” metabolism (stomach, intestines, liver) that degrade a very large percentage of NMN and NR supplements.

From studies on sublingual absorption rates on other molecules, we are convinced sublingual NMN is much more effective, but it is difficult to assign a percentage to how much more.

There is no data on how much more effective NMN is in sublingual form. It’s also difficult to study sublingual absorption with mice as they don’t cooperate when trying to put substances under their tongue.

<!–– the problem with capsules ––>

THE PROBLEM with CAPSULES – DIGESTED IN STOMACH

It has also long been suspected that most NR is digested to NAM in the Gastro-Intestinal tract (r).

More recently, this research published in 2018 confirms that most oral supplements of NMN and NR are digested to NAM in the GI tract or the liver.

Future pharmacological and nutraceutical efforts to boost NAD will need to take into account the minimal oral bioavailability of NR and NMN (R)

We also showed that intravenous, but not oral administration of NR or NMN delivered intact molecules to multiple tissues (R)

Unlike in cell culture where NR and NMN are readily incorporated into NAD, oral administration fails to deliver NR or NMN to tissues (R)

Interestingly, we found that neither compound was able to enter the circulation intact in substantial quantities when delivered orally (R)

The most recent studies showing tremendous health benefits with NMN were accomplished by feeding mice very large dosages of NMN in water (r). However the dosage of 300-400 mg per kg of bodyweight used in many of these studies would equate to approximately 2,000 Mg per day for a 70 kg human. A more effective delivery method is needed !

<!–– NMN bioavailibity ––>

SUBLINGUAL CAN BE MORE BIOAVAILABLE THAN INJECTION !

With intraperitoneal injection, the primary route of absorption is via the mesenteric vessels, which drain into the portal vein and pass through the liver before reaching the bloodstream.

This means, IP avoids the GI tract, but is still sent directly to the Liver, where much of it is converted to NAD+. Elevated NAD+ in the liver is good, but its far better to reach the bloodstream with intact NMN.

Sublingual delivery is not filtered by the Liver and can reach systemic circulation intact, so can actually result in greater bioavailability that direct injection! Some examples are:

• A sublingual formulation of zol… exhibited a faster rate of absorption and higher drug exposure as compared to subcutaneous injection (r)
• sublingually administered epin… results in more rapid absorption and a higher peak plasma concentration compared to injected epin… .(r)
• 40mg of sublingually administered pir.. was found to be as effective as a 75 mg intramuscular injection of dicl… (r)

<!–– when to take sublingual NMN ? ––>

CONCLUSION

According to Dr Wu:
“If these findings translate from mouse to human, we could have a revolutionary impact on the quality of life of older people, and not to mention the benefits of avoiding diseases of aging.”

“This new study adds to the body of work showing that the restoration of NAD+ in mammals can delay and reverse many of the effects of aging.”

Even Dr. Sinclair takes NMN to boost NAD+ levels. “In someone my age [49], it’s probably harder to see immediate benefits,” he said, though he said he feels sharper and younger from it. After his 78-year-old father began taking NMN, “he started climbing mountains and going whitewater rafting and looking forward to the next five years.”

There have been numerous studies documenting improvements from NMN and NR for a wide range of age-related issues, but this is the FIRST evidence that shows actual NEW GROWTH in OLD ANIMALS. NMN enabled them to perform as they did when young.

We are excited about the massive benefits this could bring to hundreds of millions of people. NMN is available now in sublingual tablets, and in powder form, which is perfect for what we believe is the more effective sublingual delivery method.

NMN PRODUCTS

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PURE NMN Sublingual Powder (12 grams)

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NMN’s – 30 ct Sublingual Tablets

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NMN’s – 240 ct Sublingual Tablets

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NAD+ PRODUCTS

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PURE NAD+ 240 ct Sublingual Tablets – 125 mg each

$129.95

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Liquid NAD+ Drops (Sublingual) 30 servings, 125 mg pure NAD+

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PURE NAD+ Powder – 12 Grams Nicotinamide Adenine Dinucleotide

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Pure NAD+ Nasal Spray – Nicotinamide Adenine Dinucleotide

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PURE NAD+ Powder – 25 Grams Nicotinamide Adenine Dinucleotide

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PURE NAD+ Sublingual Tablets in Convenient Tins – 125 mg x 60

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NAD+ OPTIMIZER PRODUCTS

These products do not contain NMN or NAD+. They are designed to maximize NAD+ levels by stimulating internal AMPK production (NAD+/AMPD ACTIVATOR), minimize excessive NAD+ consumption from chronic inflammation (NAD+ DEFENDER), or increase H2S and Nitric Oxide levels in the bloodstream (NAD+ ENERGIZER)

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NAD+Optimizer Series – Protect, Restore, and Energize NAD+ levels

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NAD+/AMPK Activator – 60 Capsules

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NAD+ DEFENDER – Advanced Anti-Inflammatory – 120 Capsules

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NAD+ ENERGIZER – H2S, Nitric Oxide stimulator- 60 Capsules

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The post NMN product shows increased endurance and new blood vessel growth in mice appeared first on Alivebynature - All about NAD+.

As we age, our levels of the Co-enzyme Nicotinamide Adenine Dinucleotide NAD+ drop significantly in multiple organs in mice and humans  (5,8,10).

NAD+ decrease is described as a trigger in age-associated decline(23), and perhaps even the key factor in why we age (5).

In 2013, research published by Dr David Sinclair demonstrated that short term supplementation with Nicotinamide MonoNucleotide (NMN) replenished NAD+ and reversed many aspects of aging, making the cells of old mice resemble those of much younger mice, and greatly improving their health (8).

The quotes below are directly from that research:

NMN was able to mitigate most age-associated physiological declines in mice”

“treatment of old mice with NMN reversed all of these biochemical aspects of aging”

Since Dr Sinclairs landmark 2013 study, dozens of others have been published investigating the efficacy of supplementation with NMN and Nicotinamide Riboside (NR) in treatment and prevention of a wide range of disease including cancer, cardiovascular disease, diabetes, Alzheimers, Parkinsons, and more (5,6,7,9,10,11,13,14,15,16).

According to Dr Sinclair:

“enhancing NAD+ biosynthesis by using NAD+ intermediates, such as NMN and NR, is expected to ameliorate age-associated physiological decline”

WHAT IS NR

Nicotinamide Riboside (NR) and NMN are precursors that are used by our bodies to replenish NAD+ levels.

In 2004 Dr Charles Brenner published a paper showing that the enzyme Nrk1 can catalyze NR directly to NMN (100) which might make it a much more effective precursor to NAD+.  Although NR is unstable by itself, Dartmouth University has patented production methods that combine it with Chloride which makes it stable.

Chromadex has licensed this technology and has been selling NR commercially since 2014 under the brand name “Niagen”.

Tru Niagen is the brand name used by Dr Brenner’s company ProHealthSpan to market their Niagen product.

WHAT IS NAD+

NAD+ is a key co-enzyme that the mitochondria in every cell of our bodies depend on to fuel all basic functions. (3,4)

NAD+ play a key role in communicating between our cells nucleus and the Mitochondria that power all activity in our cells (5,6,7)

NAD+ LEVELS DECREASE WITH AGE

As we age, our bodies produce less NAD+ and the communication between the Mitochondria and cell nucleus is impaired. (5,8,10).

Over time,  decreasing NAD+ impairs the cell’s ability to make energy, which leads to aging and disease (8, 5) and perhaps even the key factor in why we age (5).

NAD+ METABOLISM IN HUMANS

NAD+ is synthesized in humans by several different molecules (precursors), thru 2 different pathways:
De Novo Pathway

• Tryptophan
• Nicotinic Acid (NA)

Salvage Pathway

• NAM – Nicotinamide
• NR – Nicotinamide Riboside
• NMN – Nicotinamide MonoNucleotide

The NAD+ supply is not stagnant – it is constantly being consumed and replenished, with the entire NAD+ pool being turned over 2-4 times per day (14).

This recycling is through the salvage pathway, where the enzyme Nampt catalyzes NAM to NMN, which is then metabolized to NAD+.

Nampt is the rate-limiting step in the salvage process (97).

Many studies have confirmed the importance of Nampt in maintaining sufficient NAD+ levels, such as the quote below from a 2016 study that used mice lacking Nampt in muscle fiber:

“NAD content of muscle was decreased by ~85% confirmed the prevailing view that the salvage route of NAD synthesis from NAM sustains the vast majority of the NAD” (97)

These mice exhibited normal muscle strength and endurance while young, but deteriorated rapidly as they aged which confirmed Nampt is critical to maintaining NAD+ levels.

NMN and NR SUPPLEMENTS CAN BYPASS NAMPT

NR had been known for decades, but was not thought to be that important until 2004 when Dr. Charles Brenner discovered the enzyme NRK1 can phosphorylate NR directly to NMN, bypassing NAM and the Nampt limiting step (100).

This newly discovered “shortcut” in the NAD+ salvage pathway found that NR can be metabolized directly to NMN to boost NAD+ levels more effectively than the already well known precursors  NA, NAM or Tryptophan.

SOME NR IS METABOLIZED TO NAM

When taken orally as a supplement, most NR does not make it through the digestive system intact, but is broken down to NAM (97,98,99).

Even when taken at very high dosages, NR has not been detected in the bloodstream in any research (97,98,99).

“This evidence indicates that NR is converted to NAM before absorption occurs and that this reaction is the rate-limiting step ” (98)

“NR has been shown be converted to Nam before being absorbed or reaching tissues” (99)

“we were surprised to find that NR exerts only a subtle influence on the steady state concentration of NAD in muscles. Our tracer studies suggest that this is largely attributable to breakdown of orally delivered NR into NAM prior to reaching the muscle. ” (97)

HUMAN STUDY ON NR BIOAVAILABILITY

The following five charts are all from the thesis published by Samuel Alan Trammell in 2016 under supervision by Dr Brenner:

Nicotinamide riboside is uniquely and orally bioavailable in mice and humans

This chart above shows the impact on NAD+ metabolites over time for a 52 year old human after ingesting 1000mg of NR daily for 7 days.

NAD+ levels begin to rise at 4.1 hours, and peak at 8.1 hours.

NAM levels double at .6 hours and have a second peak at 7.7 hours, long before NAD+ levels are elevated.

This chart a left shows impact of NR, NA, and NAM supplementation on blood plasma NAD+ (b), and NAM  (d) levels in 12 human subjects.

The red line at 2 hours shows NR supplementation increases NAM perhaps 3x (d), but has not yet elevated NAD+(b).

The 2 hour mark also is the point at which NAM supplementation begins to increase NAD+ levels (b).

The blue line at 8 hours is when both NR (b) and NAM (d) supplementation reach peak NAD+ increase.

Lastly, the green bar and black bar in chart b show that NAM elevates NAD+ slightly less than NR.

NR elevated NAD+ slightly more than NAM, but is much slower acting

MOUSE STUDIES ON NR BIOAVAILABILITY

The chart above shows the result on NAD+ metabolism of 15 mice fed NR by oral gavage at a dose of 185 mg/kg of bodyweight.

The NR was synthesized with heavy atoms of deuterium at the ribosyl C2 and 13C on the Nam side, to allow tracking.

The measurement at 2 hours shows 54% of the NAD+ has the single heavy molecule (white bar, M+1). This 54% was likely broken down to NAM first, losing the second labelled heavy atom.

At the same time point, 5% of the NAD+ had both labels (Grey bar, M+2).

This 5% of NR made it through the digestive tract intact and was metabolized through the shortcut from NR -> NMN -> NAD+, vs 54% that had been through NR -> NAM -> NMN -> NAD+.

The chart above shows the impact of the same double labeled NR on mouse liver, but this time after IP (Intraperitoneal) Injection.

Note the dramatic difference in the ratio of labelled M+2 over M+1. IP results in much higher levels of intact NR (M+2) being metabolized to NAD+, whereas Oral NR shows far more M+1 labelled NR to NAD+.

This different behavior in IP vs oral NR supplementation also implies oral NR is partially metabolized to NAM before conversion to NAD+.

The above chart shows the resultant increase in select NAD+ metabolites of mice fed NR (unlabeled) at 185 mg/kg of bodyweight.

As noted by the authors, NR and NAR are the only NAD+ precursors tested that did NOT result in elevated levels of the precursor in the liver.

Here is one last quote in discussion section from the Trammell thesis:

“NR has not been detected in the blood cell fraction nor in plasma …NR varied and displayed no response to NR administration … but was detected after IP of double labeled NR in liver (Figure 5.7) and muscle (Figure 5.9), revealing NR does circulate”

They are saying that NR is found in small quantities in the liver, but is not detectable in bloodstream.  Oral supplementation with NR did not show any increase in NR in the body.  However, Injection (IP) of NR does result in a detectable increase of NR in muscle and Liver. So NR does circulate in the bloodstream when injected, but has not yet been detected upon oral supplementation.

The timing and amplitude of the increases in metabolites noted above imply that oral NR does not result in a large increase of NR, and that  a significant fraction of the increase in NAD+ is due to NR->NAM->NAD+.

NMN QUICKLY RAISES NAD+ IN LIVER AND BLOOD

In this 2016 study, mice were given a single dose of  NMN in water.

NMN  levels in blood showed it is quickly absorbed from the gut into blood circulation within 2–3 min and then cleared from blood circulation into tissues within 15 min

The chart at right shows levels of a double labeled NAD+ (C13-d-nad+) in liver and soleus muscle at 10 and 30 minutes after oral administration of double labeled NMN.

This clearly shows that NMN makes its way through the liver, into muscle, and is metabolized to NAD+ in 30 minutes (23) .

Orally administered NMN is quickly absorbed, efficiently transported into blood circulation, and immediately converted to NAD+in major metabolic tissues (23).

NMN INCREASES NAD+ and SIRT1 DRAMATICALLY IN ORGANS

In this 2017 study, NMN supplementation for 4 days significantly elevated NAD+ and SIRT1, which protected the mice from Kidney damage.

NAD+ and SIRT1 levels were HIGHER in OLD Mice than in YOUNG Mice that did not receive NMN.

LONG TERM SUPPLEMENTATION WITH NMN

In a long-term experiment documented in the 2016 study (23) , mice were given 2 different doses of NMN over 12 months.

Testing revealed that NMN  prevents some aspects of  physiological decline in mice, noting these changes:

• Decreased body weight and fat
• Increased lean muscle mass
• Increased energy and mobility
• Improved visual acuity
• Improved bone density
• Is well-tolerated with no obvious bad side effects
• Increased oxygen consumption and respiratory capacity
• Improved insulin sensitivity and blood plasma lipid profile

Here are some quotes from  the  study:

NMN effectively mitigates age-associated physiological decline in mice

NMN suppressed age-associated body weight gain, enhanced energy metabolism, promoted physical activity, improved insulin sensitivity and plasma lipid profile, and ameliorated eye function and other pathophysiologies

NMN-administered mice switched their main energy source from glucose to fatty acids

these results strongly suggest that NMN has significant preventive effects against age-associated impairment in energy metabolism

LOWER FAT AND INCREASED LEAN MUSCLE MASS

Researchers found that NMN administration suppressed body weight gain by 4% and 9% in the 100 and 300 mg/kg/day groups.

Analyses of  blood chemistry panels and urine did not detect any sign of toxicity from NMN.

Although health span was clearly improved, there was no difference in maximum lifespan observed.

These results suggest that NMN administration can significantly suppress body weight gain without side effects

INCREASED OXYGEN CONSUMPTION AND RESPIRATORY CAPACITY

Oxygen consumption significantly increased in both 100 and 300 mg/kg/day groups during both light and dark periods (Figure 3A).

Energy expenditure also showed significant increases  (Figure 3B).

Respiratory quotient significantly decreased in both groups during both light and dark periods (Figure 3C),

This suggests that NMN-administered mice switched their main energy source from glucose to fatty acids.

The mice that had been receiving NMN for 12 months exhibited energy levels, food and water consumption equivalent to the mice in the control group that were 6 months younger.

NMN administration has significant preventive effects against age associated physical impairment

The first clinical trial of NMN in humans is currently underway by an international collaborative team between Keio University School of Medicine in Tokyo and Washington University School of Medicine (37).

References:

1. Detection and pharmacological modulation of nicotinamide mononucleotide (NMN) in vitro and in vivo (Formentini, 2009)
2. AMPK regulates energy expenditure by modulating NAD+ metabolism and SIRT1 activity (Cato, 2009)
3. A possibility of nutriceuticals as an anti-aging intervention: activation of sirtuins by promoting mammalian NAD biosynthesis (Imai, 2010)
4. NAD blocks high glucose induced mesangial hypertrophy via activation of the sirtuins-AMPK-mTOR pathway (Zhuo, 2011)
5. Nicotinamide Mononucleotide, a Key NAD+ Intermediate, Treats the Pathophysiology of Diet- and Age-Induced Diabetes in Mice (Yoshino, 2011)
6. The NAD (+) precursor nicotinamide riboside enhances oxidative metabolism and protects against high-fat diet-induced obesity(Canto, 2012 )
7. NAD⁺ repletion improves mitochondrial and stem cell function and enhances life span in mice. (Zhang, 2016)
8. Declining NAD+ Induces a Pseudohypoxic State Disrupting Nuclear-Mitochondrial Communication during Aging (Gomes, Sinclair,2013)
9. Nicotinamide mononucleotide, an intermediate of NAD+ synthesis, protects the heart from ischemia and repercussion (Yamamoto, 2014)
10. NAD+ and sirtuins in aging and disease (Imai, 2014)
11. Effective treatment of mitochondrial myopathy by nicotinamide riboside, a vitamin B3 (Khan, 2014)
12. Effect of nicotinamide mononucleotide on brain mitochondrial respiratory deficits in an Alzheimer’s disease-relevant murine model (Long, 2015)
13. NAD+ metabolism and the control of energy homeostasis – a balancing act between mitochondria and the nucleus (Canto, 2015)
14. NAD+ metabolism: Bioenergetics, signaling and manipulation for therapy (Yang, 2016)
15. NAD+ replenishment improves lifespan and healthspan in ataxia telangiectasia models via mitophagy and DNA repair( Fang, 2016 )
16. Nicotinamide riboside is uniquely and orally bioavailable in mice and humans(Trammell, 2016a )
17. Nicotinamide riboside opposes type 2 diabetes and neuropathy in mice(Trammell, 2016b )
18. β-Nicotinamide Mononucleotide, an Anti-Aging Candidate Compound, Is Retained in the Body for Longer than Nicotinamide in Rats (Kawamura, 2016)
19. The first human clinical study for NMN has started in Japan (Tsubota, 2016)
20. Nicotinamide mononucleotide protects against β-amyloid oligomer-induced cognitive impairment and neuronal death (Wang, 2016)
21. Head to Head Comparison of Short-Term Treatment with the NAD(+) Precursor Nicotinamide Mononucleotide (NMN) and 6 Weeks of Exercise in Obese Female Mice (Uddin, 2016)
22. Long-Term Administration of Nicotinamide Mononucleotide Mitigates Age-Associated Physiological Decline in Mice (Mills, 2016)
23. Nicotinamide mononucleotide supplementation reverses vascular dysfunction and oxidative stress with aging in mice (de Picciotto, 2016)
24. Nicotinamide mononucleotide inhibits JNK activation to reverse Alzheimer disease (Yao, 2017)
25. Nicotinamide mononucleotide requires SIRT3 to improve cardiac function and bioenergetics in a Friedreich’s ataxia cardiomyopathy model (Martin, 2017)
26. Nicotinamide Mononucleotide, an NAD+ Precursor, Rescues Age-Associated Susceptibility to AKI in a Sirtuin 1-Dependent Manner (Guan, 2017)
27. Nicotinamide mononucleotide attenuates brain injury after intracerebral hemorrhage by activating Nrf2/HO-1 signaling pathway (Wei, 2017)
28. Short-term administration of Nicotinamide Mononucleotide preserves cardiac mitochondrial homeostasis and prevents heart failure (Zhang, 2017)
29. Modulating NAD+ metabolism, from bench to bedside (Auwerx, 2017)
30. Aspects of Tryptophan and Nicotinamide Adenine Dinucleotide in Immunity: A New Twist in an Old Tale. (Rodriguez, 2017)
31. Vitamin B3 modulates mitochondrial vulnerability and prevents glaucoma in aged mice (Williams, 2017)
32. NAMPT-mediated NAD biosynthesis as the internal timing mechanism: In NAD+ World, time is running in its own way (Poljsak, 2017)
33. Effect of “Nicotinamide Mononucleotide” (NMN) on Cardiometabolic Function (NMN)
34. The dynamic regulation of NAD metabolism in mitochondria (Stein, 2012)
35. Novel NAD+ metabolomic technologies and their applications to Nicotinamide Riboside interventions (Trammel, 2016)
36. Long-term moderate calorie restriction inhibits inflammation without impairing cell-mediated immunity: a randomized controlled trial in non-obese humans (Meydayni, 2016)
37. A high-fat, ketogenic diet induces a unique metabolic state in mice. (Kennedy, 2007)
38. Ketone body metabolism and cardiovascular disease.(Cotter, 2013)
39. Ketone bodies as signaling metabolites(Newman, 2014)
40. The ketone metabolite β-hydroxybutyrate blocks NLRP3 inflammasome–mediated inflammatory disease(Youm, 2015)
41. The effect of the Spanish Ketogenic Mediterranean Diet on nonalcoholic fatty liver disease: a pilot study.(Guisado, 2011)
42. β-Hydroxybutyrate: A Signaling Metabolite in starvation response(Morales, 2016)
43. Physiological roles of ketone bodies as substrates and signals in mammalian tissues(Robinson, 1980)
44. Ketone bodies mimic the life span extending properties of caloric restriction (Veech, 2017)
45. Novel ketone diet enhances physical and cognitive performance(Murray, 2016)
46. Mitochondrial biogenesis and increased uncoupling protein 1 in brown adipose tissue of mice fed a ketone ester diet.
47. Nutritional Ketosis Alters Fuel Preference and Thereby Endurance Performance in Athletes(Cox, 2013)
48. Neuroendocrine Factors in the Regulation of Inflammation: Excessive Adiposity and Calorie Restriction (Fontana, 2009)
49. Beta-adrenergic receptors are critical for weight loss but not for other metabolic adaptations to the consumption of a ketogenic diet in male mice(August, 2017)
50. A randomized trial of a low-carbohydrate diet for obesity(Foster, 2003)
51. β-Hydroxybutyrate suppresses inflammasome formation by ameliorating endoplasmic reticulum stress via AMPK activation(Bae, 2016)
52. The neuroprotective properties of calorie restriction, the ketogenic diet, and ketone bodies. (Maalouf, 2009)
53. AMPK activation protects cells from oxidative stress‐induced senescence via autophagic flux restoration and intracellular NAD + elevation (Han, 2016)
54. Regulation of AMP-activated protein kinase by natural and synthetic activators (Hardie, 2015)
55. Effects of Exhaustive Aerobic Exercise on Tryptophan-Kynurenine Metabolism in Trained Athletes (Strasser, 2016)
56. PARP-1 inhibition increases mitochondrial metabolism through SIRT1 activation(Bai, 2011)
57. Carbohydrate restriction regulates the adaptive response to fasting (Klein, 1992)
58. Interventions to Slow Aging in Humans: Are We Ready? (longo, 2015)
59. Extending healthy life span–from yeast to humans (longo, 2010)
60. Dietary restriction with and without caloric restriction for healthy aging (Lee, 2016)
61. A Periodic Diet that Mimics Fasting Promotes Multi-System Regeneration, Enhanced Cognitive Performance, and Healthspan (Longo, 2015)
62. Diet mimicking fasting promotes regeneration and reduces autoimmunity and multiple sclerosis symptoms (Longo, 2016
63. Resistance Exercise Training Alters Mitochondrial Function in Human Skeletal Muscle (Porter, 2015)
64. Ketogenic Diet Reduces Midlife Mortality and Improves Memory in Aging Mice (Newman, 2017)
65. The NAD(+)/sirtuin pathway modulates longevity through activation of mitochondrial UPR and FOXO signaling.  (Mouchiroud, 2013)
66. NAMPT- mediated NAD(+) biosynthesis is essential for vision in mice  (Lin, 2016)
67. NAD+ replenishment improves lifespan and healthspan in ataxia telangiectasia models via mitophagy and DNA repair( Fang, 2016 )
68. Inhibiting poly ADP-ribosylation increases fatty acid oxidation and protects against fatty liver disease (Gariani, 2017 )
69. Interdependence of AMPK and SIRT1 for metabolic adaptation to fasting and exercise in skeletal muscle(Canto, 2010)
70. The NAD (+) precursor nicotinamide riboside enhances oxidative metabolism and protects against high-fat diet-induced obesity(Canto, 2012 )
71. Nicotinamide riboside is uniquely and orally bioavailable in mice and humans(Trammell, 2016a )
72. Nicotinamide riboside opposes type 2 diabetes and neuropathy in mice(Trammell, 2016b )
73. Dietary leucine stimulates SIRT1 signaling through activation of AMPK (Hongliang, 2012)
74. Effective treatment of mitochondrial myopathy by nicotinamide riboside, a vitamin B3 (Khan, 2014)
75. NAD blocks high glucose induced mesangial hypertrophy via activation of the sirtuins-AMPK-mTOR pathway (Zhuo, 2011)
76. The effect of different exercise regimens on mitochondrial biogenesis and performance (Philander, 2014)
77. Dietary proanthocyanidins boost hepatic NAD+ metabolism and SIRT1 expression and activity in a dose-dependent manner in healthy rats (Aragon’s, 2016)
78. NAD+ Deficits in Age-Related Diseases and Cancer (Garrido, 2017)
79. Anti-diabetic and anti-lipidemic effects of chlorogenic acid are mediated by ampk activation (Ong, 2013)
80. Chlorogenic Acid Improves Late Diabetes through Adiponectin Receptor Signaling Pathways in db/db Mice (Chang, 2015)
81. Adenosine Monophosphate (AMP)-Activated Protein Kinase: A New Target for Nutraceutical Compounds (Marin-Aguilar, 2017)
82. The Effects of Ramadan Fasting on Body Composition, Blood Pressure, Glucose Metabolism, and Markers of Inflammation in NAFLD Patients: An Observational Trial (Mazidi, 2014)
83. Comparative effects of carbohydrate versus fat restriction on metabolic profiles, biomarkers of inflammation and oxidative stress in overweight patients with Type 2 diabetic and coronary heart disease: A randomized clinical trial. (Raygan, 2016)
84. Normal fasting plasma glucose and risk of type 2 diabetes diagnosis (Nichols, 2008)
85. Are We All Pre-Diabetic? (Stokel,2016)
86. Hepatic NAD⁺ deficiency as a therapeutic target for non-alcoholic fatty liver disease in aging (Zhou, 2016)
87. Effect of exercise intensity on post-exercise oxygen consumption and heart rate recovery (Mann,2014)
88. A 45-minute vigorous exercise bout increases metabolic rate for 14 hours (Knab,2011)
89. Effects of high-intensity resistance training on untrained older men. II. Muscle fiber characteristics and nuclei-cytoplasmic relationships (Gerontol, 2000)
90. Ketogenic Diet Reduces Midlife Mortality and Improves Memory in Aging Mice (Newman, 2017)
91. A Ketogenic Diet Extends Longevity and Healthspan in Adult Mice (Roberts, 2017)
92. NK cells link obesity-induced adipose stress to inflammation (Wensveen, 2015)
93. The “Big Bang” in obese fat: Events initiating obesity-induced adipose tissue inflammation (Wensveen, 2015)
94. The impact of the Standard American Diet in rats: Effects on behavior, physiology and recovery from inflammatory injury(Totsch, 2017)
95. Bioenergetic state regulates innate inflammatory responses through the transcriptional co-repressor CtBP (Shen, 2017)
96. The Ketogenic Diet as a Treatment Paradigm for Diverse Neurological Disorders (Stafstrom, 2012)
97. Loss of NAD Homeostasis Leads to Progressive and Reversible Degeneration of Skeletal Muscle (Fredrick 2016)
98. Digestion and absorption of NAD by the small intestine of the rat (Henderson, 1983)
99. Effects of a wide range of dietary nicotinamide riboside (NR) concentrations on metabolic flexibility and white adipose tissue (WAT) of mice fed a mildly obesogenic diet(Shi, 2017)
100. Discoveries of nicotinamide riboside as a nutrient and conserved NRK genes establish a Preiss-Handler independent route to NAD+ in fungi and humans (Brenner, 2004)
101. Nampt Expression Decreases Age-Related Senescence in Rat Bone Marrow Mesenchymal Stem Cells by Targeting Sirt1 (Ma, 2017)
102. NAD+ Intermediates: The Biology and Therapeutic Potential of NMN and NR (Yoshino, 2017)

This new research examines what happens to NR, NMN and other metabolites of NAD+ in the bloodstream and how they effect intracellular NAD+ levels in peripheral tissues.

Degradation of Extracellular NAD+ Intermediates in Cultures of Human HEK293 Cells(Nikiforov, dec 2019)

When added to the serum outside of cells, all NAD+ metabolites were effective at restoring the NAD+ levels and metabolic activity INSIDE the cells. NMN was the most effective.

NMN is not impeded at crossing the cell membrane, and is more effective at restoring intracellular NAD+ levels

Proponents of NR often point to studies that show NMN and NAD+ must be partially degraded to NR to cross the membrane of some cells, and claim this makes NR a better choice for supplementation.

The faster speed and effectiveness of NMN supplements has always made this position suspect. This research shows crossing the cellular membrane is not an impediment.

This research looked at kidney cells where NMN and NAD+ must be degraded to NR before crossing the cellular membrane.

Interestingly, the conversion does not seem to impact the ability to enter the cells.

They found that enzymes on the outside of the cells themselves (ecto-enzymes) perform this conversion and are ubiquitous.

For example, the ecto-enzyme CD73 can cleave NAD⁺ to NMN and AMP, and also dephosphorylate the NMN to NR and adenosine.

Researchers introduced various NAD+ metabolites to the serum outside of cells.

As shown in the chart above, adding NAD+ or it’s metabolites to the serum OUTSIDE the cells were all effective at restoring the NAD+ levels and metabolic activity INSIDE the cells.

In fact, NMN was by far the most effective at restoring metabolic activity INSIDE the cells.

This was in cells that NMN was supposedly disadvantaged by needing conversion to NR before crossing the cell membrane.

According to the authors:

Interestingly, exogenous nucleotides including NMN, NAMN, NAD+ and NAAD can support the maintenance of intracellular NAD pools as well as the nucleoside NR.

Moreover, the human ecto-enzyme CD73 has been described to catalyze both the cleavage of NAD+ to NMN and AMP as well as the subsequent dephosphorylation of the mononucleotides to the corresponding nucleosides, NR and adenosine.

NMN IS TAKEN UP AND UTILIZED BY CELLS IN MINUTES

Other studies such as the 2013 long term study by Mills show that in mice, NMN is taken up by cells throughout the body within 15 minutes.

The chart at left is from this 2019 study by Kristian.

It shows that NMN given to mice raise levels of NMN and NAD+ found in the blood plasma within 5 minutes, and reaches the hippocampus within 15 minutes.

Conclusion

NMN is quickly and efficiently utilized in all cells and tissues throughout the body.

Crossing the cellular membrane does not impede NMN.

NMN is more effective than other metabolites at restoring NAD+ levels inside of cells.

* The following is a case study, not a clinical trial. There are no human trials that prove effectiveness of any NAD+ boosting supplements for preventing or curing COVID-19. We are merely informing our readers of recent research that indicates increasing NAD+ levels could potentially be effective in the battle against COVID-19.

Growing evidence is pointing to supplementation with NAD+ boosters may be an effective tool in preventing the “cytokine storm” in response to excessive inflammation from COVID-19 (2,3).

Dramatic Cytokine Storm Reversal with an Over the Counter NMN Cocktail⁽¹⁾

This case study (1) published April 20, 2020 by Dr. Robert Huizenga reports a remarkable clinical turnaround against COVID-19 upon providing an oral nicotinamide mononucleotide (NMN) cocktail to a COVID-19 positive patient, who presented with such gravely elevated inflammation levels, that a fatal outcome seemed eminent.

Not only did the NMN mixture lead to a surprisingly rapid and thorough reversal of COVID-19, but it has been widely used for over 2 years now for general health and anti-aging advocates, with no known adverse effects.

Dr. Huizenga, also known as Dr. H on the television show The Biggest Loser, is a former team physician for the Los Angeles Raiders, and author of a book about his experience that was the inspiration for Oliver Stone’s film “Any Given Sunday.”

According to Dr. Huizenga:

A strong causal relationship is established between an oral boosted NMN and the clinical improvement seen with the below described COVID-19 patient. Oral NMN with boosters warrant further examination in COVID-19 related cytokine storm.

COVID-19 complications may be reversible by NAD+ repletion

Given the uncertainty currently circulating about the effectiveness of numerous pharmacological treatments for COVID-19, this case study detailing the progression of COVID-19 in a 55-yr old female patient is quite compelling.

Similar to SARS, Ebola and Dengue Fever, and Septic shock, disease fatality associated with COVID-19 can often be linked to an exaggerated pro-inflammatory response which overwhelms the immune system suddenly such as in this study. Further down, we summarize other research that indicates NMN may help fight the “cytokine storm” which leads to the excessive inflammation and death in COVID-19.

Below is a partial chronology of the events:

Day 1 – A 55 yr old female with typical symptoms tests positive for Covid-19

Initially, the patient tests positive for COVID-19 with standard symptoms.

“A 55-year-old white female presented on 3/16/2020 with one day history of body aches, choking cough and fever to 100.2ºF. The SARS-CoV-2 test was positive. She was treated with Tylenol as needed for fevers”

Day 7 – Bedridden with trouble breathing

Symptoms become more severe and patient becomes bedridden.  Fever increases while oxygen levels decrease.

” bedridden with chest pain, shortness of breath, cough and high fevers (Tmax 102º F). Her room air (RA) O2 % sat was 93-95. A CXR was normal”

Day 8 – Hydroxychloquine, Zithromax, and Zinc treatment initiated

The popular mix of Hydroxychloroquine, Zithromax, and Zinc is administered.  Hydroxychloroquine has been classified as an anti-malarial drug and is useful in treating several forms of malaria as well as lupus and has been used as a possible treatment for COVID-19 but is as yet unproven.

“fever increased to 102.5º F. She was prescribed Zithromax, Hydroxychloroquine and Zinc.”

Day 11 – Patient admitted to hospital with symptoms strongly indicative of fatal outcome

Patient admitted into Cedars Sinai Medical Center complaining of shortness of breath, body aches.  Patient unable to breath without assistance.  CRP levels become alarmingly high.

CRP (C-Reactive Protein) is the most commonly used marker of inflammation levels, and indicates inflammation levels in the body. Very high CRP levels indicate extreme distress as the body fights disease or infection such as virus. Her high CRP levels and other severe symptoms strongly predicted a fatal outcome.

“her temp rose to 103º F with shortness of breath and debilitating body aches. Admission labs were notable for astronomically elevated CRP (217 mg/L), Il-6 (56 pg/mL), TNF-alpha (7.4 ng/mL) and myoglobin (>500 ng/mL) with absolute lymphopenia (490cells/μL).”

Day 12 – Trouble breathing, increasing inflammation leads to “cytokine storm”

Cytokines play an important part in normal immune responses, however a large amount of them released in the body all at once can be harmful. Cytokine storms are a common complication of not only covid-19 but of other respiratory diseases caused by coronaviruses.

A cytokine storm is an overproduction of immune cells and cytokines which can cause fluid buildup and inflammation, leading to an increased risk of mortality due to the shutdown of multiple organs.

Cytokine storm is now considered as the likely major cause of death during the 1918-20 Spanish flu outbreak, which killed more than 50 million people as well as the more recent H1N1 “swine flu” and H5N1 “bird flu” – and now COVID-19.

“On day 12 and 13 the patient further clinically deteriorated; she subjectively felt she was unable to breathe. Her RA oxygenation worsened and increased bilateral pneumonia was noted on CXR.”

“Her deterioration was therefore felt to be the result of cytokine storm.”

Day 13 – Treatment with NMN cocktail initiated

The patient began an over the counter (OTC) NMN cocktail comprised of nicotinamide mononucleotide (NMN), betaine, and NaClon.

“She therefore agreed to begin over the counter (OTC) nicotinamide mononucleotide (NMN) with betaine and NaCl”

Day 14, 15 – Dramatic Improvment begins 12 hours after treament initiated, continuing

After only 12 hours her immune system rebounded and after 36 hours the patient’s fever began to subside and rapid improvement continued.

“after two weeks of continuous fever, the patient turned afebrile. On day 15-17, her clinical signs (shortness of breath, body aches, RA oxygenation, CXR) and prognostic laboratory markers (CRP and absolute lymphocyte count) rapidly and dramatically improved.”​

Day 17 – Patient discharged home, continuing NMN cocktail treatments

The patient was discharged home, continued NMN cocktail treatments, and experienced near normal breathing.

“she was discharged home on oral NMN/betaine/NaCl/Zinc BID with near normal oxygenation despite residual (improving) bilateral pneumonias”

Day 20 – Third day home walking multiple times per day, no sign of virus in nasal test

The patient continued to gain strength and after a few days was walking multiple times per day.

“she felt stronger and was walking multiple times a day. Her nasopharyngeal SARS-CoV-2 test was negative. Her CRP and IL-6 decreased to 7.4 and 3.2 respectively.”​

Day 23 – Patient experiences complete recovery, is asymptomatic and completely virus free

After further testing, the patient was deemed completey virus free.

“she was asymptomatic; her COVID-19 IgG/IgM rapid serology was positive for both IgG and IgM. Her CXR revealed a small amount of residual bilateral pneumonia”

More patients experience similar positive results

After positive outcome of this patient, the NMN cocktail was tried on 2 other elderly COVID positive outpatients after or concurrent with the triple therapy using hydroxychloroquine. Again, dramatic improvements were seen rapidly within 36 to 48 hours in fever, chest pressure, cough, headaches, and low energy.

Evidence of the effectiveness of NAD+ boosters in strengthening immunological response

Other positive assessments of NMN from this study include:

“NMN an OTC NAD-boosting compound with remarkable abilities to mitigate age-associated tissue and organ decline in mice, including an increase in immunity, blood flow, and protection of the kidney, liver and brain from disease and injury.

The compound, a precursor of NAD+, in Phase I and II clinical trials, is safe and well tolerated in humans and has been documented to raise NAD+ levels in whole blood .”​

“The rapidity and thoroughness of the improvement – suggests an OTC NMN cocktail may play a role in reversing potentially fatal cytokine storm.”

“Oral nicotinamide mononucleotide with boosters may naturally trigger anti-inflammation immune systems able to arrest and reverse cytokine storm. This case exhibits a compelling temporal relationship between NMN cocktail use and improvement from deteriorating COVID19 bilateral pneumonias – more remarkably this case documents an unusually rapid and thorough clinical turnaround. Oral NMN with boosters deserve further study in COVID-19 associated cytokine storm.”

“COVID-19 complications may be reversible by NAD+ repletion.”

“Five often cited contributors to COVID-19 morbidity and mortality – the renin–angiotensin (RAS) signaling pathway, oxidative stress, reduced perfusion, endothelial dysfunction and cytokine storm – all involve NAD depletion.”

” NAD+ repletion enhances PARP activity – enzymes directly involved in antiviral (and presumably anti- SARSCoV-2) activities. “

Other studies also point to NAD+ effectiveness in boosting immunity and survival rates

“The molecular story of COVID-19; NAD+ depletion addresses all questions in this infection” ⁽²⁾

This review published Mar 23, 2020 by Isfahan University of Medical Sciences provides evidence that low NAD+ levels could be tied to higher severity and morbidity rates in the COVID-19 pandemic.

Among the findings are that large amounts of NAD+ are used in fighting infections.  Viral infections cause free radicals to form and these free radicals cause DNA damage.  DNA breaks activate the enzyme PARP-1, a DNA base repair enzyme. In order to repair DNA, PARP-1 must have access to large amounts of NAD+.

“In the depicted molecular pathology pathway of COVID-19, almost all procedures lead to or originate from NAD+ depletion. Consumption of NAD in large amounts to repair DNA decreases ATP levels leading to impairment of all activities and integrity of the cell.”

“Taking NAD or Vitamin B3 plus L-tryptophan could replenish NAD and serotonin and recover the body toward hemostasis.”

Research shows that those health issues resulting in increased mortality rates with Covid, such as diabetes and cardiovascular disease also result in decreased NAD+ levels.

We cover more about this research here.

Therapeutic potential of NAD+ in septic shock

New research completed at Brigham and Women’s Hospital at Harvard Medical School, entitled “NAD+ prevents septic shock by non-canonical inflammasome blockade and IL-10”⁽³⁾ shows that modulating NAD+ sensing enzymes controls multiple processes involving cell survival and energy metabolism and supplementation with NAD+ may represent a therapeutic opportunity for aging and for associated disorders, increasing health span and longevity in humans.

According to the authors:

“Inflammasome activation has been pointed out as the major driver of septic shock”

“NAD+ protects mice against septic via inflammasome blockade“

“NAD+ protects against septic shock by blocking the non-canonical inflammasome specifically and via a systemic production of IL-10 cytokine”

We cover more about this research here.

Inflammation activity depletes NAD+

The condition quickly worsens when the innate immune activation fails to clear the source of the pathogen, causing an overwhelming pro-inflammatory reaction, leading to multiple organ damage. The worst cases of septic shock present as refractory hypotension or life-threatening low blood pressure.

It is important to note that during the proinflammatory state or ‘cytokine storm’ in the onset of sepsis, the state of NAD+ levels are further depleted.

In an article entitled “What is the Link Between NAD+ and Your Cells’ Innate Immune Response?”⁽⁴⁾ it states:

“Just like our planet is mustering up the resources to fight the ongoing COVID-19 (Coronavirus) pandemic, so too do our cells need energy to support cellular repair. NAD+ may hold the key to supporting cellular resilience in the face of immune stress, like viral infections.”

“Maintaining your health in the face of a virus like COVID-19 is hard work on your cells which require the energy to help repair the damage caused by free radicals (Filomeni 2015). NAD+ is essential to every step of this process, powering repair enzymes called sirtuins and PARPs.”​

“In order to mount a powerful response when first faced with the new COVID-19 virus, data suggests that strategies to maintain cellular NAD levels, either by increasing its production or inhibiting its depletion may benefit your cells, but further study is required. COVID-19 seems to target high energy expenditure organs, like lungs, kidneys and intestines (Kouhpayeh 2020)—organs that need all the NAD+ they can get.”​

References:

1. Dramatic Cytokine Storm Reversal with an Over the Counter NMN Cocktail
2. The Molecular Story of COVID-19; NAD+ Depletion Addresses All Questions in this Infection
3. NAD+ prevents septic shock by non-canonical inflammasome blockade and IL-10
4. What is the Link Between NAD+ and Your Cells’ Innate Immune Response?

1. https://papers.ssrn.com/sol3/papers.cfm?abstract_id=3581388
2. https://alivebynature.com/could-nad-change-the-trajectory-of-the-covid-19-pandemic%E2%80%8B/
3. https://alivebynature.com/new-research-shows-nad-treatment-may-ward-off-septic-shock/
4. https://www.preprints.org/manuscript/202003.0346/v1
5. https://www.nature.com/articles/s41467-019-13172-8
6. Shirin Kouhpayeh et al. The molecular story of COVID-19; NAD+ depletion addresses all questions in this infection. Pre-Press
7. Das, A … Sinclair, D. Impairment of an Endothelial NAD+-H2S Signaling Network Is a Reversible Cause of Vascular Aging. Cell, Volume 173, Issue 1, 22 March 2018, Pages 74-89.e20
8. Koyuncu E, Budayeva HG, Cristea IM. Sirtuins are evolutionarily conserved viral restriction factors. 2014mBio 5(6): e02249-14.)
9. Matthew E. Grunewald et al. The coronavirus macrodomain is required to prevent PARP-mediated inhibition of virus replication and enhancement of IFN expression Plos Pathog 2019 15 (5): e1007756
10. Kawahara et al. SIRT6 controls NF-kB dependent gene expression and organismal lifespan. Cell 2009; 136:62-74
11. HeY et al. SIRT6 inhibits TNF-alpha induced inflammation of vascular adventitial fibroblasts. Exp Cell Res 2017; 357 188-97.
12. https://www.businesswire.com/news/home/20200420005265/en/ChromaDex-Commits-COVID-19-Research-Promising-Initial-Preclinical

Recently published research shows that a small dose of NMN in the drinking water was able to improve the quality of eggs in older mice and reverse infertility.

Researchers at the Universities of Queensland and New South Wales  led by Dr. Lindsay Wu found that as mice age, levels of nicotinamide adenine dinucleotide (NAD+) decline, which affects the quality of eggs, leading to fertility problems in older female mice.

The research team gave older mice oral doses of the NAD+ precursor compound called nicotinamide mononucleotide (NMN) to increase NAD+ levels.

“Quality eggs are essential for pregnancy success because they provide virtually all the building blocks required by an embryo,” says Professor Hayden Homer, lead researcher on the study. “We treated the mice with low doses of NMN in their drinking water over four weeks, and we were able to dramatically restore egg quality and increase live births during a breeding trial.”

“Our findings suggest there is an opportunity to restore egg quality and in turn female reproductive function using oral administration of NAD-boosting agents – which would be far less invasive than IVF.”

If the results translate to humans, it could open up a new option for couples looking to improve their chances of conception.

Surprisingly, a daily dose 400% higher had no significant effect on live births.

Important implications for dosage of NAD+ precursors

Researchers tested two different dosages of NMN in the drinking water of the mice, using either  0.5g/L  or 2 g/L.  After scaling for the size and increased metabolic rate of mice, this equates to approximately 350 mg or 1,400 mg for a 50 kg human.

The mice were 14-16 months old, which is near the limit of fertility in the breed of mice used.

You can see from the charts above that the smaller dose had a dramatic effect on the live births, while the larger dose had no significant effect.

If these results also apply to humans, it would seem that a dose between 350 mg and 1,400 mg per day would be best for fertility in humans.

Why LESS NMN could be better in some cases—too much Nicotinamide?

Many studies implicate there is an upper limit, after which there is no clear benefit to further dose increases.

This particular study implies smaller doses of NMN may be more effective than larger doses.

This could be related to an upper limit to NMN tolerability or the increased formation of the NMN degradation product nicotinamide, which is a sirtuin inhibitor (Bitterman et al., 2002)

The Rabinowitz research shows that oral delivery of NR and NMN is nearly entirely metabolized to nicotinamide (NAM) in the liver.

The Trammel/Brenner research on nicotinamide riboside (NR) and other studies have shown that taking 1,000 mg of NR in a single dose results in a huge increase of NAM, which the body quickly methylates to MeNAM and excretes from the body.

Why scientists believe excess NAM is harmful

Supplementation with NAM shows some positive benefits in mice and humans, however, there are two reasons scientists believe that
providing excess NAM can be counterproductive:

• Depletes Methyl groups. Excess NAM is methylated to MeNAM for excretion in urine.  This can deplete methyl groups which results in increased homocysteine in the bloodstream. Some research indicates that long term or high doses of NAM are detrimental, because they lead to reductions in available methyl groups.
• Inhibits sirtuins. NAM has been shown in research to inhibit sirtuins. Increasing NAD+ levels activates sirtuins, which is thought to be the pathway that provides positive benefits.

How to avoid excess NAM for best results

If excess NAM is the reason for the upper limit on effectiveness as suggested by the authors in this current study, it is apparent that supplementing NMN while avoiding overproduction of NAM is critical.

The Rabinowitz research shows that oral supplements of NR and NMN are almost completely metabolized to NAM in the liver.

Taking smaller quantities, or spreading it out among several smaller dosages may help, but better delivery methods are needed.

Sublingual and Lipsomal delivery can bypass the liver and avoid excess NAM

Sublingual
Systemic delivery through the sublingual route has emerged from the desire to provide immediate onset of a pharmacological effect. Sublingual administration means placement under the tongue for immediate uptake into the bloodstream through the ventral surface of the tongue and floor of the mouth. NMN or other actives are rapidly absorbed into the reticulated vein which lies underneath the oral mucosa and transported through the facial veins, internal jugular vein and braciocephalic vein and then drained in to systemic circulation.

The main mechanism for the absorption into oral mucosa is via passive diffusion into the lipoidal membrane. The absorption of NMN through the sublingual route is 3 to 10 times greater than the oral route and is only surpassed by hypodermic injection.

Liposomal
Liposomal delivery may further improve upon bioavailability, as liposomes enclose the active in a “cocoon” to protect it from the harsh environment of the stomach and deliver the payload intact to circulation, resulting in minimal loss. They can also be taken sublingually.

Conclusion

This study found NMN restored fertility in older mice, a promising result which has not been achieved with any drug or surgery.

They found this benefit at a relatively small dosage equivalent to 350 mg per day in a 50 kg human.

Much larger doses – equivalent to 1,400 mg per day – did not show the benefit, suggesting an optimal dose is between 350 mg and 1,500 mg per day for humans.

Supplementing with NAD+ precursors in capsules will result in a large increase in NAM.

Large doses may increase NAM enough to inhibit sirtuin function significantly and outweigh any benefit.

Bypassing the liver with sublingual delivery directly to the bloodstream will greatly minimize the NAM produced.