Whats the TRUTH about Nicotinamide Riboside (NIAGEN)

chromadex niagen

Nicotinamide Riboside (NR) is a recently discovered form of vitamin B3 that can increase levels of Nicotinamide Adenine Dinucleotide (NAD+) levels in humans.

NR was discovered in 2004 by Dr Charles Brenner, and is used in his research.  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+

NR benefits chartNAD+ 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

NAD+ levels decreaseAs 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).

HEALTH ISSUES RELATED TO DECLINING NAD+ LEVELS

  • Neural cognitive dysfunction (9,10,11)
  • Inflammation of vascular systems leading to hypertension, heart attack and stroke( 12,13,14)
  • Increased fat storage in the liver(15,16,17)
  • Increased visceral fat storage – belly fat (18,19)
  • Increased blood sugar levels, Insulin resistance, and metabolic syndrome (20,21,22)
  • Increased fatigue and loss of muscle strength (23,24)
Conclusion: Declining NAD+ levels are implicated in many age related disease and chronic conditions

BENEFITS OF INCREASED NAD+

Below are some of the benefits that have been proven to result from increased NAD+ levels in studies with mice.

  • Reversed indications of aging in muscles
  • Cardiovascular health
  • Improved Energy
  • Decreased Muscle Soreness
  • Improved Memory
  • Better Sleep
  • Improved Hearing and Vision

RESTORING NAD+ LEVELS

In mammals, NAD+ can be created from simple elements present in the body such as Nicotinic Acid or Tryptophan thru the “de novo” pathway.

However the entire NAD+ pool is consumed 2-4 times a day and recycled thru the “salvage pathway”(14).

Nicotinamide or Nicotinamide Riboside are first converted to NMN, which is then further converted to NAD+(14).

It is sometimes referred to as a NAD+ intermediate because NMN is the last step before conversion to NAD+

NAD+ Precursors:

  • Tryptophan
  • NA – Nicotinic Acid
  • NAM – Nicotinamide
  • NR – Nicotinamide Riboside
  • NMN – Nicotinamide Mononucleotide

According to Dr Brenner:
“Not every cell is capable of converting each NAD+ precursor to NAD+ at all times…the precursors are differentially utilized in the gut, brain, blood, and organs” (R).

NICOTINAMIDE MONONUCLEOTIDE

David_Sinclair_solo_mid_0_0_4_1

The  landmark 2013 study by Dr David Sinclair demonstrated that supplementation with NMN  increased levels of NAD+ and  reversed age related degeneration in mice.

After 6 days of NMN, 22 month old mice  had the muscle capacity, endurance and metabolism of 6 month old  mice (25).

That  study generated a lot of interest and currently  NMN is being investigated for use in treatment of a wide range of age related conditions (27,28,29,30,31)

ORAL SUPPLEMENTATION OF NMN QUICKLY RAISES NAD+ IN LIVER AND BLOOD

mouse-single-doseIn 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 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 its way through the liver, into muscle, and is metabolized to NAD+ in 30 minutes (23) .

According to Dr Sinclair, the speed at which the NMN is utilized implies that there may be a transporter that directly uptakes NMN into cells and tissues(8).

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 RESEARCH WITH NMN

mouse-long-term-research

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:

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.

INCREASED OXYGEN CONSUMPTION AND RESPIRATORY CAPACITY

screen-shot-2016-11-04-at-2-22-48-pm

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.

Read more about NMN here

NICOTINAMIDE RIBOSIDE

A 2012 study showed that giving mice supplements of NR is effective in raising NAD+ levels and improved the numbers and function of mitochondria (33).

Those mice that received supplements showed increased energy and improved insulin sensitivity, while protecting the animals from metabolic syndrome. They also showed increased endurance, running 33% farther on treadmill testing vs control mice.

The chart at left is from the 2016 Phd dissertation by Samuel AJ Trammel(39), and shows the effect of NR, NAM, and NA on raising NAD+ levels on mice.

NR is the slowest acting, but achieves the greatest overall boost of NAD+ levels of the three.

HUMAN STUDY #1
Dr Charles Brenner authored the first human study comparing the effect of different dosage on NAD+ levels of humans.

nr_nad_chart

Some people believe NMN must be converted to NR before entering cells.

This seems at odds with the speed at which NMN is utilized in cells as shown in the NMN charts above (15 minutes) compared with NR which takes 8 hours to reach peak levels in both mice and humans.

In this study 6 female and 6 male subjects received 100, 300, or 1,000mg of Nicotinamide Riboside. Blood levels of NAD+ were measured at 1,2,4,8 and 24 hours after supplementation. This was repeated 2 more times, with 7 days between testing.

The chart above shows:

  • NAD+ levels begin to increase at 4 hours, and peak at 8 hours
  • NAD+ levels remain elevate through 24 hours
  • 300mg dose was approximately equal to the 1,000mg dose at 24 hours.
  • NAAD levels increase significantly from Not Measurable (NM) as NAD+ levels peak

These results indicate a “ceiling” to how high supplementation with NR can raise NAD+ levels. Beyond a certain point, any additional NR ends up as NAAD.

HUMAN STUDY #2
A recently completed study of Elysium Healths’ Basis brand of Nicotinamide Riboside is not yet published, but Elysium Health did publish a press release that tells us the primary and secondary endpoints were met, and gives a little guidance on the increase in NAD+ levels achieved with 2 different dosages.

This is a much larger study of 120 elderly subjects tested bi-weekly over 8 weeks.

The press release states that the single dose (125 mg of NIAGEN) resulted in a 40% increase in blood NAD+ levels that was maintained throughout the 8 weeks of the study.

The 250 mg dosage resulted in an increase that was “significantly higher” than the 125 mg dose, and reached 90% at one of the 4 checkpoints (4 weeks).

Since the increase from the 250 mg dosages reached a plateau at 4 weeks, and dropped afterwards, implies that any higher dosage would not be any more effective.

This rather speculative interpretation agrees with the results in Study #1 that the most effective dosage is likely lower than 500 mg per day.

Conclusion: Most people will require less than 500mg of NR per day to realize the maximum possible increase in blood NAD+ levels

SIDE EFFECTS

This safety assesment looked at all current  studies of Nicotinamide Riboside and  found no noticeable side effects at dosages up to 3,000 mg per day.

Of course, this is a very new supplement that doesn’t have years of history, so if you are trying NR out, you should keep informed of ongoing research.

When published, the previously mentioned study of 120 elderly volunteers should be very helpful in determining best therapeutical and maximum recommended dosages.

FINAL THOUGHTS: DOES IT WORK?

  • Recent research answered a basic question by demonstrating that NR DOES raise NAD+ levels in humans.
  • Supplementation of mice with NMN and NR has shown protection from a wide range of metabolic injury and illness

However until the current human studies with NMN are published, we don’t yet know for sure if the benefits seen in studies with mice will also been seen in humans.

WHAT WE RECOMMEND

We believe NR has tremendous health benefits.

However, we also believe that research shows NMN makes it’s way through the liver and is metabolized into tissue more quickly and effectively than NR.

Recently, our manufacturing partner has been able to bring the price down so that we can now offer NMN at a price that is competitive with NR.

Read about the science behind NMN and why we think it will prove to be more effective for health.


ProHealth is currently the best price for Niagen.

The 2 bottles for $119 works out to 30 cents per mg – whereas HPN and others are 33 to 37 cents per mg.

We also like the 333mg capsule size, since that is thought to be the most effective dosage for NR

You can find it here on Amazon

 

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 and insulin resistance (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)