Since mid 2016, we’ve been noticing that Research with Nicotinamide Mononucleotide (NMN) seemed to have more dramatic results than studies using Nicotinamide Riboside (NR), and wondered why.
Recently published research with NMN and NR are good examples of the difference.
In Dr Sinclairs latest study, the 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).
In Nov 2017 Elysium Health published a study using Basis on 60-80 year old humans that showed a 7% improvement in endurance with NR after 60 days. Not bad at all – but a long way from near 100% improvement in the Sinclair study using NMN.
In looking at the details from these 2 studies we notice another stark difference.
The NAD+ increase measured in the liver using Basis started out over 90%, but dropped to 40-55% by the end of the trial. It appears that Homeostasis is limiting the long term increase of NAD+ using NR.
The Single dose of 250 Mg NR results in 40% NAD+ increase at 60 days. With the double dose of 500 Mg NR, NAD+ increase is 55% at 60 days, and is likely to continue dropping down to the 40% level.
Older humans such as those in this study generally have about half the NAD+ they did when young, so would need to see around 100% increase to return to youthful levels.
In contrast, the Sinclair study shows NAD+ increase is over 500% at 60 days – homeostasis is NOT limiting the effectiveness of NMN in restoring NAD+ levels.
This may be the reason NMN is effective in this long term (12 month) study.
* Note: There have been NO similar studies with NR longer than 3 months
40-55% NAD+ increase with NR
A single dose of NR has been shown to increase NAD+ by 270%. However, homeostasis soon kicks in and this declines after a few weeks. Increasing the dosage of NR does not provide any further benefit.
The chart at left shows this increase of 270% combined with data from this study by Elysium Health published in 2017.
OVER 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).
We doubt that other studies will confirm a 500% increase as this study shows, but whatever the true value is, it does seems that the HUGE increase in liver indicates homeostasis is not limiting the NAD+ increase from NMN supplementation in this study.
FAR more increase of NAD+ from NMN
Homeostasis refers to the ability of the body or a cell to seek and maintain a condition of equilibrium or stability within its internal environment when dealing with external changes.
Although NR and NMN are very similar in their effect on NAD+ levels from a single dose, homeostasis appears to impact NR much more quickly than NMN, impacting its ability to maintain increased levels of NAD+.
NMN is effective at much higher dosages for much longer than NR.
ANTI-AGING RESULTS WITH NMN
Dozens of research studies have been published showing benefits of NR and NMN supplementation in various disease and illness, with much overlap in their effects (5,6,7,9,10,11,13,14,15,16).
However, the most dramatic results have been those showing old mice that look and perform the same as young mice.
Below are the three studies that made the biggest splash’s about the potential for reversing aging by restoring NAD+ to youthful levels.
These have ALL been accomplished using NMN
Their have been NO studies with NR showing comparable improvements in strength, endurance, vascularity, and muscle growth, with normal, healthy subjects (There are successful studies with NR where mice are genetically modified to replicate disease models).
We don’t believe that is a coincidence, but a result of the homeostasis effect with NR that limits its long term effectiveness.
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)
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.
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
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
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.
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
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
NMN treatment reduces brain cell death and oxidative stress These results further support the neuroprotection of NMN/NAD+
We now demonstrate that mitochondrial respiratory function was restored
NMN could restore cognition in AD model rats
NMN Treatment Rescues Cognitive impairments
Nicotinamide mononucleotide inhibits JNK activation to reverse Alzheimer disease (Yao, 2017)
NMN significantly increased the level of NAD+ in the heart
NMN protected the heart from I/R injury
NMN reduces vascular oxidative stress
NMN treatment normalizes aortic stiffness in old mice
NMN represents a novel strategy for combating arterial aging
NMN can reduce myocardial inflammation NMN thus can cut off the initial inflammatory signal, leading to reduced myocardial inflammation
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
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
- 2016 Keio University Study – UMIN000021309
- 2017 Keio University Study – UMIN000030609 Phase 2, 8 weeks, 30 subjects
- 2017 Hiroshima University Study – UMIN000025739 24 weeks, 20 subjects, 100 & 200mg
- 2017 University of Washington Study – 8 weeks, 50 subjects
- 2017 Sinclair Metrobio study – Phase 1
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.
Very Fast to Liver and muscle tissue
After oral NMN supplementation, levels of NMN in the bloodstream are quickly elevated and remain high longer than NAM, NA, or NR (18, 22, 97, 98, 99)
The chart at left 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 it way through the liver intact, through the bloodstream, into muscle, and is metabolized to NAD+ in 30 minutes (22).
Orally administered NMN is quickly absorbed, efficiently transported into blood circulation, and immediately converted to NAD+in major metabolic tissues (22).
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.
REFERENCES:
- Detection and pharmacological modulation of nicotinamide mononucleotide (NMN) in vitro and in vivo (Formentini, 2009)
- AMPK regulates energy expenditure by modulating NAD+ metabolism and SIRT1 activity (Cato, 2009)
- A possibility of nutriceuticals as an anti-aging intervention: activation of sirtuins by promoting mammalian NAD biosynthesis (Imai, 2010)
- NAD blocks high glucose induced mesangial hypertrophy via activation of the sirtuins-AMPK-mTOR pathway (Zhuo, 2011)
- Nicotinamide Mononucleotide, a Key NAD+ Intermediate, Treats the Pathophysiology of Diet- and Age-Induced Diabetes in Mice (Yoshino, 2011)
- The NAD (+) precursor nicotinamide riboside enhances oxidative metabolism and protects against high-fat diet-induced obesity(Canto, 2012 )
- NAD⁺ repletion improves mitochondrial and stem cell function and enhances life span in mice. (Zhang, 2016)
- Declining NAD+ Induces a Pseudohypoxic State Disrupting Nuclear-Mitochondrial Communication during Aging (Gomes, Sinclair,2013)
- Nicotinamide mononucleotide, an intermediate of NAD+ synthesis, protects the heart from ischemia and repercussion (Yamamoto, 2014)
- NAD+ and sirtuins in aging and disease (Imai, 2014)
- Effective treatment of mitochondrial myopathy by nicotinamide riboside, a vitamin B3 (Khan, 2014)
- Effect of nicotinamide mononucleotide on brain mitochondrial respiratory deficits in an Alzheimer’s disease-relevant murine model (Long, 2015)
- NAD+ metabolism and the control of energy homeostasis – a balancing act between mitochondria and the nucleus (Canto, 2015)
- NAD+ metabolism: Bioenergetics, signaling and manipulation for therapy (Yang, 2016)
- NAD+ replenishment improves lifespan and healthspan in ataxia telangiectasia models via mitophagy and DNA repair( Fang, 2016 )
- Nicotinamide riboside is uniquely and orally bioavailable in mice and humans(Trammell, 2016a )
- Nicotinamide riboside opposes type 2 diabetes and neuropathy in mice(Trammell, 2016b )
- β-Nicotinamide Mononucleotide, an Anti-Aging Candidate Compound, Is Retained in the Body for Longer than Nicotinamide in Rats (Kawamura, 2016)
- The first human clinical study for NMN has started in Japan (Tsubota, 2016)
- Nicotinamide mononucleotide protects against β-amyloid oligomer-induced cognitive impairment and neuronal death (Wang, 2016)
- 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)
- Long-Term Administration of Nicotinamide Mononucleotide Mitigates Age-Associated Physiological Decline in Mice (Mills, 2016)
- Nicotinamide mononucleotide supplementation reverses vascular dysfunction and oxidative stress with aging in mice (de Picciotto, 2016)
- Nicotinamide mononucleotide inhibits JNK activation to reverse Alzheimer disease (Yao, 2017)
- Nicotinamide mononucleotide requires SIRT3 to improve cardiac function and bioenergetics in a Friedreich’s ataxia cardiomyopathy model (Martin, 2017)
- Nicotinamide Mononucleotide, an NAD+ Precursor, Rescues Age-Associated Susceptibility to AKI in a Sirtuin 1-Dependent Manner (Guan, 2017)
- Nicotinamide mononucleotide attenuates brain injury after intracerebral hemorrhage by activating Nrf2/HO-1 signaling pathway (Wei, 2017)
- Short-term administration of Nicotinamide Mononucleotide preserves cardiac mitochondrial homeostasis and prevents heart failure (Zhang, 2017)
- Modulating NAD+ metabolism, from bench to bedside (Auwerx, 2017)
- Aspects of Tryptophan and Nicotinamide Adenine Dinucleotide in Immunity: A New Twist in an Old Tale. (Rodriguez, 2017)
- Vitamin B3 modulates mitochondrial vulnerability and prevents glaucoma in aged mice (Williams, 2017)
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- Effect of “Nicotinamide Mononucleotide” (NMN) on Cardiometabolic Function (NMN)
- The dynamic regulation of NAD metabolism in mitochondria (Stein, 2012)
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- Long-term moderate calorie restriction inhibits inflammation without impairing cell-mediated immunity: a randomized controlled trial in non-obese humans (Meydayni, 2016)
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- Ketone bodies as signaling metabolites(Newman, 2014)
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- β-Hydroxybutyrate: A Signaling Metabolite in starvation response(Morales, 2016)
- Physiological roles of ketone bodies as substrates and signals in mammalian tissues(Robinson, 1980)
- Ketone bodies mimic the life span extending properties of caloric restriction (Veech, 2017)
- Novel ketone diet enhances physical and cognitive performance(Murray, 2016)
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- Nutritional Ketosis Alters Fuel Preference and Thereby Endurance Performance in Athletes(Cox, 2013)
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- 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)
- A randomized trial of a low-carbohydrate diet for obesity(Foster, 2003)
- β-Hydroxybutyrate suppresses inflammasome formation by ameliorating endoplasmic reticulum stress via AMPK activation(Bae, 2016)
- The neuroprotective properties of calorie restriction, the ketogenic diet, and ketone bodies. (Maalouf, 2009)
- AMPK activation protects cells from oxidative stress‐induced senescence via autophagic flux restoration and intracellular NAD + elevation (Han, 2016)
- Regulation of AMP-activated protein kinase by natural and synthetic activators (Hardie, 2015)
- Effects of Exhaustive Aerobic Exercise on Tryptophan-Kynurenine Metabolism in Trained Athletes (Strasser, 2016)
- PARP-1 inhibition increases mitochondrial metabolism through SIRT1 activation(Bai, 2011)
- Carbohydrate restriction regulates the adaptive response to fasting (Klein, 1992)
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- Extending healthy life span–from yeast to humans (longo, 2010)
- Dietary restriction with and without caloric restriction for healthy aging (Lee, 2016)
- A Periodic Diet that Mimics Fasting Promotes Multi-System Regeneration, Enhanced Cognitive Performance, and Healthspan (Longo, 2015)
- Diet mimicking fasting promotes regeneration and reduces autoimmunity and multiple sclerosis symptoms (Longo, 2016
- Resistance Exercise Training Alters Mitochondrial Function in Human Skeletal Muscle (Porter, 2015)
- Ketogenic Diet Reduces Midlife Mortality and Improves Memory in Aging Mice (Newman, 2017)
- The NAD(+)/sirtuin pathway modulates longevity through activation of mitochondrial UPR and FOXO signaling. (Mouchiroud, 2013)
- NAMPT- mediated NAD(+) biosynthesis is essential for vision in mice (Lin, 2016)
- NAD+ replenishment improves lifespan and healthspan in ataxia telangiectasia models via mitophagy and DNA repair( Fang, 2016 )
- Inhibiting poly ADP-ribosylation increases fatty acid oxidation and protects against fatty liver disease (Gariani, 2017 )
- Interdependence of AMPK and SIRT1 for metabolic adaptation to fasting and exercise in skeletal muscle(Canto, 2010)
- The NAD (+) precursor nicotinamide riboside enhances oxidative metabolism and protects against high-fat diet-induced obesity(Canto, 2012 )
- Nicotinamide riboside is uniquely and orally bioavailable in mice and humans(Trammell, 2016a )
- Nicotinamide riboside opposes type 2 diabetes and neuropathy in mice(Trammell, 2016b )
- Dietary leucine stimulates SIRT1 signaling through activation of AMPK (Hongliang, 2012)
- Effective treatment of mitochondrial myopathy by nicotinamide riboside, a vitamin B3 (Khan, 2014)
- NAD blocks high glucose induced mesangial hypertrophy via activation of the sirtuins-AMPK-mTOR pathway (Zhuo, 2011)
- The effect of different exercise regimens on mitochondrial biogenesis and performance (Philander, 2014)
- Dietary proanthocyanidins boost hepatic NAD+ metabolism and SIRT1 expression and activity in a dose-dependent manner in healthy rats (Aragon’s, 2016)
- NAD+ Deficits in Age-Related Diseases and Cancer (Garrido, 2017)
- Anti-diabetic and anti-lipidemic effects of chlorogenic acid are mediated by ampk activation (Ong, 2013)
- Chlorogenic Acid Improves Late Diabetes through Adiponectin Receptor Signaling Pathways in db/db Mice (Chang, 2015)
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- Bioenergetic state regulates innate inflammatory responses through the transcriptional co-repressor CtBP (Shen, 2017)
- The Ketogenic Diet as a Treatment Paradigm for Diverse Neurological Disorders (Stafstrom, 2012)
- Loss of NAD Homeostasis Leads to Progressive and Reversible Degeneration of Skeletal Muscle (Fredrick 2016)
- Digestion and absorption of NAD by the small intestine of the rat (Henderson, 1983)
- 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)
- 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)
- Nampt Expression Decreases Age-Related Senescence in Rat Bone Marrow Mesenchymal Stem Cells by Targeting Sirt1 (Ma, 2017)
- NAD+ Intermediates: The Biology and Therapeutic Potential of NMN and NR (Yoshino, 2017)
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