NMN SUPPLEMENTS

WHY SUBLINGUAL?

POOR BIOAVAILABILITY FOR NAD+, NMN, AND NR CAPSULES

All NAD+ supplements can restore NAD+ in the Liver but this does not solve NAD+ deficiency throughout the body.

This research shows that ALL NAD+, NMN and NR are metabolized by CD38 in the liver to NAM, and ONLY NAM is excreted to the rest of the body

“orally delivered NR and NMN are converted into NAM before reaching the systemic circulation“

“we found that neither compound was able to enter the circulation intact in substantial quantities when delivered orally“

“IV administration of either compound results in its detection within the circulation, proving that the route of delivery has a profound effect on the ability of these precursors to reach target tissues”

* the above are direct quotes from the research

Quantitative Analysis of NAD Synthesis-Breakdown Fluxes (Liu, 2018)

Providing NAD+ or its immediate precursor, NMN, directly to the bloodstream is much more effective than dropping large quantities of NAM or NR into the liver and trying to force it to produce more NMN and NAD to the bloodstream.

NMN SUPPLEMENTATION

NMN shows a particular ability to restore vascular growth and benefit tissues such as muscle and heart that haven’t been replicated in studies with NR or NAD+.

Below are the three studies that made the biggest splash’s about the potential for reversing aging by restoring NAD+ to youthful levels that have ALL been accomplished using NMN

After 6 days of NMN, 22 month old mice  had the muscle capacity, endurance and metabolism of 6 month old  mice (2013 Sinclair study)

NMN effectively mitigates age-associated physiological decline in mice (2016 Mills Long Term study)

“The old mice became as fit and strong as young mice” (Sinclair, 2018)

The third study identifies the key cellular mechanisms behind vascular aging and the critical role it plays on muscle health.

Dr Sinclairs team fed NMN to old mice. 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.

NEW BLOOD VESSELS sprouted within the skeletal muscles, capillary density increased and matched the capillary growth of young mice.

  • NMN restored the vascular system of old mice to that of young mice.
  • Mice treated with NMN had  had nearly 100% increased endurance.

Renewed capillary growth and increased blood flow may help reverse heart and neurological problems in addition to sarcopenia.

According to Dr. Sinclair, the same mechanism could spur the creation of blood vessels in the brain, where “the lack of oxygen and buildup of waste products sets off a downward spiral of disease and disability,” such as Parkinson’s and Alzheimer’s.

Sublingual NMN does bypass the liver to send the NMN direct to the bloodstream where it can be used by cells that have their own salvage pathway to increase intercellular NAD+.

In vivo, NMN is found in blood plasma. When added to blood in vitro, it is stable. (Canto,Brenner 2016)

Our results further demonstrate that while NR is spontaneously converted to NAM in cell-free plasma, NMN is more resistant to this process.

On the contrary, NMN is stable in plasma and there is no NAM increase in NMN samples up to 1 h incubation.

 

500% NAD+ increase with NMN ?
The chart at right shows NAD+ increase measured in the liver (and soleus muscle) after 60 days of supplementation with NMN (Sinclair, 2018).

This is the best indication we have to date, but was with mice. With humans, there has been a Japanese clinical study completed, and one by Dr Sinclair, but neither has yet published the results.

We doubt they will show anywhere near this 500% increase, as NMN and NR are so closely related. But this does provide some hope that NMN is not subject to the same limits on the long-term increase of NAD+ levels as have been found with NR (above).

Alzheimer’s disease (AD) pathogenesis is widely believed to be driven by the production and deposition of the β-amyloid peptide (Aβ). Evidence now indicates that the solubility of Aβ, and the quantity of Aβ in different pools is related to disease state (r).Researchers believe that flaws in the processes governing production, accumulation or disposal of beta-amyloid are the primary cause of Alzheimer’s (r).

In studies published in 2017 and 2018 NMN decreased β-amyloid buildup, while NR did not.

“NR lessened pTau pathology in both 3xTgAD and 3xTgAD/Polβ+/− mice but had no impact on amyloid β peptide (Aβ) accumulation”(Hou, 2018)

“NMN decreased β-amyloid production, amyloid plaque burden, synaptic loss, and inflammatory responses in AD-Tg mice” (Yao, 2017)

2 separate studies to treat a form of heart disease called Friedreich’s Ataxia with NR and NMN were published in 2017. Treatment with NMN was successful, while NR did not improve cardiac function.

“Remarkably, NMN administered to FXN-KO mice restores cardiac function to near-normal levels. “(Martin, 2017)

“In conclusion, NAD+ supplementation with NR in the FRDA model of mitochondrial heart disease does not alter SIRT3 activity or improve cardiac function.”(Stram, 2017)

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

Long-Term Administration of Nicotinamide Mononucleotide Mitigates Age-Associated Physiological Decline in Mice (mills, 2016)

Raising NAD+ levels in old mice restores mitochondrial function to that of a young mouse

Restore the mitochondrial homeostasis and key biochemical markers of muscle health in a 22-month-old mouse to levels similar to a 6-month-old mouse

Declining NAD+ Induces a Pseudohypoxic State Disrupting Nuclear-Mitochondrial Communication during Aging (Gomes, Sinclair,2013)

DNA Repair

This study showed supplementation with NMN was able to repair the DNA in cells damaged by radiation

The cells of old mice were indistinguishable from young mice after just one week of treatment.

A conserved NAD+ binding pocket that regulates protein-protein interactions during aging (Sinclair, 2017)

WEIGHT

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

Nicotinamide Mononucleotide, a Key NAD+ Intermediate, Treats the Pathophysiology of Diet- and Age-Induced Diabetes in Mice (Yoshino, 2011)

NAD(+) levels were increased significantly both in muscle and liver by NMN

NMN-supplementation can induce similar reversal of the glucose intolerance

NMN intervention is likely to be increased catabolism of fats NMN-supplementation does mimic exercise

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)

NMN significantly increased the level of NAD+ in the heart

NMN protected the heart from I/R injury

Nicotinamide mononucleotide, an intermediate of NAD+ synthesis, protects the heart from ischemia and repercussion (Yamamoto, 2014)

NMN reduces vascular oxidative stress

NMN treatment normalizes aortic stiffness in old mice

NMN represents a novel strategy for combating arterial aging

Nicotinamide mononucleotide supplementation reverses vascular dysfunction and oxidative stress with aging in mice (de Picciotto, 2016)

NMN can reduce myocardial inflammation NMN thus can cut off the initial inflammatory signal, leading to reduced myocardial inflammation

Short-term administration of Nicotinamide Mononucleotide preserves cardiac mitochondrial homeostasis and prevents heart failure (Zhang, 2017)

ENERGY

Remarkably, NMN administered to FXN-KO mice restores cardiac function to near-normal levels.

Restoration of cardiac function and energy metabolism upon NMN supplementation

Remarkable decrease in whole-body EE and cardiac energy wasting

Nicotinamide mononucleotide requires SIRT3 to improve cardiac function and bioenergetics in a Friedreich’s ataxia cardiomyopathy model

VISION

Exogenous NMN prevents photoreceptor degeneration and restores vision

NMN rescues retinal dysfunction in light-induced degeneration

 

NAMPT-mediated NAD+ biosynthesis is essential for vision in mice (lin, 2016)

Completed and pending publication

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.