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Some FACTS about NR and NMN

Chromadex recently published a page (here) listing 16 reasons they think NR is superior to NMN. It’s really more like 2 or 3 points that they restate over and over in slightly different form.

We list those 16 reasons here, and provide a little context (in blue).


1. NMN is not a vitamin

NMN is not yet an established form of vitamin B3 because there are no clinical trials to prove it increases NAD in humans. NMN is also not the type of molecule that would ever be considered as a vitamin because it contains a phosphate.

  • Has absolutely nothing to do with how it works.

2. NR is a vitamin

NR is a proven form of vitamin B3 which is required in small amounts to sustain healthy living. NR is shown in human studies to effectively increase NAD levels.

  • Has absolutely nothing to do with how it works.

Their main argument for the supposed superiority of NR as a NAD+ precursor is repeated in the 4 points below:

3. NMN contains a phosphate
4. NR does not contain a phosphate
5. NMN requires 3 steps to make NAD
6. NR starts making NAD in only 2 steps

In explaining these 4 points, they say:

This phosphate makes it impossible for NMN to get into cells where NAD is created and used

NR is the largest part of NAD that can enter the cell

There are (at least) 4 HUGE problems with this:

  1. This is very much under debate by many very respected researchers in the field, and there is very strong research this is not true, or greatly exaggerated
  2. Even if NMN or NAD+ cannot cross the cellular membrane without some conversion, this is not a bottleneck. That is, it does not impede the uptake of NMN or NAD+ to cells.
  3. NR has seldom been found in the blood, and only at trace levels. Whether NR is able to more easily pass thru the cellular membrane in more tissues than NMN or NAD+ is not relevant if NR is not normally available in the blood stream.
  4. RESULTS MATTER MOST – The health extension and disease fighting benefits have been far more dramatic in research with NMN

Details on these 4 problems with Chromadex arguments are on this page.

7. NMN has 0 published human clinical studies

As of April 2018, NMN’s only published trials are in mice and rats.

  • Clinical Trials with NMN by Dr Sinclair and others have been completed and will be published soon – see below

8. NR has 3 published human clinical studies

NR has completed 5 clinical trials. 3 of them are published and the other 2 are pending publication. All 3 published clinical trials confirm NR is a safe and efficient way of increasing NAD in people.

  • Clinical Trials with NMN by Dr Sinclair and others have been completed and will be published soon – see below

9. NMN is mostly studied by injection

Despite NMN being sold as a pill, NMN is frequently studied through injections in rodents.

  • Not True – Early studies with NMN were done by injection.  Since 2013, most studies with NMN have been done with oral supplements.
  • Studies using oral supplementation with NMN have shown far more dramatic results than those using NR (below)

10. NR is taken orally

In all 5 clinical trials, NR was administered in capsule form, which represents the recommended way of taking NR as a vitamin.

 

  • Clinical Trials with oral supplementation of NMN by Dr Sinclair and others have been completed and will be published soon – see below

11. NMN increases NAD by about 170%

In a 2016 study, NMN and NR were administered to mice in equal doses. NMN increased liver NAD levels by about 170% over baseline.

  • ONLY IN THE LIVER NR elevates NAD+ in the liver slightly more. NMN elevates NAD+ in the kidney slightly more. They have different effects on NAD+ in different cells throughout the body.
  • NAM (another form of B3) in that same study is shown to increase NAD+ in the liver more than NR. MANY supplements increase NAD+ in the liver

12. NR increases NAD by about 220%

In the same study, NR increased NAD levels by about 220% over baseline.

  • ONLY IN THE LIVER NR elevates NAD+ in the liver slightly more. NMN elevates NAD+ in the kidney slightly more. They have different effects on NAD+ in different cells throughout the body.
  • NAM (another form of B3) in that same study is shown to increase NAD+ in the liver more than NR. MANY supplements increase NAD+ in the liver

13. NMN has 0 safety studies in humans

As of April 2018, there are no data available stating whether or not NMN is safe for human consumption.

  • Clinical Trials with NMN by Dr Sinclair and others have been completed and will be published soon – see below

14. NR has 3 published clinical trials confirming it is safe for human consumption

Careful analysis of all the preclinical and clinical information available on NR confirm it is safe and well-tolerated.

  • Clinical Trials with NMN by Dr Sinclair and others have been completed and will be published soon – see below

15. NMN has no known safety status

As of April 2018, NMN has no safety notifications from the United States FDA.

  • Clinical Trials with NMN by Dr Sinclair and others have been completed and will be published soon – see below

16. NR has 2 FDA safety notifications

has twice been successfully reviewed under FDA’s new dietary ingredient (“NDI”) notification program, and has also been successfully notified to the FDA as generally recognized as safe (“GRAS”).

  • Clinical Trials with NMN by Dr Sinclair and others have been completed and will be published soon – see below

SOME FACTS ABOUT NMN

Below are the clinical trial on NMN along with some of the reasons we agree with DR Sinclair that NMN is more effective than NR, with references and direct quotes from some of the research.

DRAMATIC RESULTS WITH NMN IN ENDURANCE AND YOUTHFULLNESS

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)

This third study recently published by Dr Sinclair is a  good example.

Mice that received NMN had nearly 100% increased endurance vs the control mice, and actually grew NEW blood vessels. This was after 60 days, in 20 month old mice (equivalent to 90 year old humans).

Along with the impressive increased endurance, the study shows  NAD+ increase is over 500% at 60 days

RESULTS NOT AS IMPRESSIVE WITH NR

In this 2016 study, 22-24 month old mice were given NR for 6 weeks.

Running distance and duration were improved approximately 20%.

The treatment duration was slightly shorter in this study than with NMN (6 weeks vs 8 weeks), there is a huge difference in the benefit with increased endurance from NMN nearly 100% vs the 20% with NR.

Treating Heart Disease

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)

COMBATTING ALZHEIMERS DISEASE

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)

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.
 

Elevates NAD+ quickly throughout the body

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

Increases NAD+ and Sirt1 Dramatically in organs

The charts at left from 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.

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