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Whats the TRUTH about Nicotinamide Riboside (NIAGEN)

01
May

NAD+ is the key for Healthy Aging

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+ is a key Co-enzyme used by our mitochondria for energy production in all our cells. Higher NAD+ levels are needed for our cells to function at their best.

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

Nicotinamide Riboside (NR) and Nicotinamide Mononucleotide (NMN) are precursors used by the body to create more NAD+. Oral supplementation with NR and NMN can increase NAD+ levels.

Elevating NAD+ with Supplements

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).

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.

HUMAN NAD+ METABOLISM

NAD+ is constantly being consumed and replenished through the Salvage Pathway, with approximately 3g of NAM metabolized to NMN and then to NAD+ 2-4 times per day (14).

  • The salvage pathway sustains 85% or more of our NAD+ (14)
  • Nampt is the rate-limiting step in the salvage process (97).
  • As we age, Nampt enzyme activity is lower, resulting in less NAM recycling, less NAD+, more disease and aging (97, 101).

NR AND NMN BYPASS THE NAMPT BOTTLENECK

NMN is the immediate precursor to NAD+, and is after Nampt in the salvage process, so NMN bypasses the Nampt bottleck

In 2004 Dr Charles Brenner published a paper showing that the enzyme Nrk1 can catalyze Nicotinamide Riboside directly to Nicotinamide Mononucleotide (100), which means that any NR that makes it’s way into the bloodstream can theoretically bypass the NAMPT bottleneck.

Although NR is unstable by itself, Dartmouth University has patented production methods that combine it with Chloride which makes it stable outside the body

Chromadex has licensed this technology and has been selling Nicotinamide Riboside 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.

Digested 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. This quote below is from the most recent review of Therapeutic Potential of NMN and NR.

Substantial fraction of orally administered NR is likely converted into nicotinamide by first-pass metabolism in the liver or by hydrolysis in the blood circulation before its uptake into other tissues (102)

For more info on how NR is converted to NAM in the body.

Not found in bloodstream

In both mice and humans, studies repeatedly failed to find any NR in the bloodstream at any time, even after very high dosages of NR (97, 98, 99).

The following quote from this Dr Brenner study also did not find NR in bloodstream after oral supplements, but was found in trace amounts after Injection

NR varied and displayed no response to NR administration… but was detected after IP of double labeled NR

A small fraction makes it intact to muscle
and other tissues outside Liver

The charts at left are from this 2016 study which used mice that have had the gene for Nampt ‘knocked out’ in quadricep muscle, so are unable to process NAM. As a result, the NAD+ levels drop to 15% of normal.

These mice were fed double labelled NR to track the movement of the NR through the body.

Any NR that makes it through digestion intact would be incorporated as double labelled NAD (M+2). NR that has been metabolized to NAM loses 1 heavy tracking molecule and would be found as M+1.

Chart D shows both single and double labelled NAD+ (green and red) are abundant in roughly equal amounts in the liver.

Chart C shows quite a lot of single labelled NAD+ in the muscle which is from NR that has been metabolized to NAM and then NMN.

We know this NAD+ was metabolized as NAM and then NMN because these mice lacked Nampt in muscle, so can not process NAM.

At the same time, there is only a tiny fraction of double labelled NAD+ in the muscle.

This demonstrates that NMN, but not NR was readily available for use in the Salvage Pathway inside the muscle.

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.

NMN Bioavailability Summary

  • Make their way intact thru the digestive system (22)
  • Quickly elevates levels of NMN in the bloodstream for use throughout the body (22)
  • Quickly elevates levels of NMN in tissues throughout the body (22)
  • Quickly raises levels of NAD+ in blood, liver and tissues through the body (22, 23)
  • Remain elevated longer than NAM, NA, or NR (18)

NAD+ levels decrease throughout the body as we age, contributing to disease and aging. Restoring NAD+ levels can ameliorate many age released health issues.

A large percentage of NR is first digested to NAM, so it cannot bypass the Nampt bottleneck in many tissues. NR is effective at elevating NAD+ in the Liver, but is not stable in the body and not normally found in the bloodstream, which limits it’s effectiveness.

NMN is the only precursor that is stable and available to cells through the bloodstream, and can bypass the Nampt bottleneck to quickly restore NAD+ throughout the body.

REFERENCES:

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