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Nicotinamide Riboside limited by instability in bloodstream

Strategies to restore global NAD+ levels with Nicotinamide Riboside (NR) and Nicotinamide Mononucleotide (NMN) supplementation have garnered much attention, but there are challenges with oral administration.

Research shows that very little of these molecules make it through the gastrointestinal tract tract and liver without being degraded to less effective metabolites. This is why we design our NMN products for sublingual delivery.

However, making it through the GI tract and liver is just the first step. To be effective in tissues throughout the body, they must also be present in the bloodstream.

NR IS NOT STABLE IN THE BLOODSTREAM

Recent research covered below shows that when added to the bloodstream, NR is mostly degraded to nicotinamide (NAM) and is no longer found after one hour.

NAM levels increase initially, but the body regulates NAM levels. Excess NAM is methylated to MeNAM or Me2PY and excreted in the urine.

NR IS NEVER WIDELY AVAILABLE IN THE BLOODSTREAM

The next two charts are derived from the Brenner study published in August 2019.

Nicotinamide Riboside Augments the Aged Human Skeletal Muscle NAD+ Metabolome and Induces Transcriptomic and Anti-inflammatory Signatures (Brenner, August 2019)

Twelve male humans aged 70-80 years old were given 1,000 mg of Nicotinamide Riboside (NR) per day for 3 weeks.

NR supplementation had no effect on levels of NR circulating in the bloodstream.

  • NR was found at trace levels in the blood
  • NR levels were unchanged after supplementation
  • NMN was increased after NR supplementation
  • MeNAM and Me2PY in blood increased far more than NMN

EXCESS NAM IS METHYLATED AND EXCRETED IN URINE

 

Excess NAM is methylated to MeNAM, Me2PY or Me4PY to enable excretion in the urine.

The chart at left shows the massive increase of those metabolites in the blood are excreted in urine.

This study shows that NR is never available in the blood in appreciable quantity.

Supplementation with NR does result in more NMN available in the blood, but the majority is excreted in the urine as Methylated NAM.

 

NMN IS STABLE IN THE BLOOD, NR IS NOT

Degradation of Extracellular NAD+ Intermediates in Cultures of Human HEK293 Cells (Nikiforov, december 2019).

The Nikiforov study examined the stability of NAD+ and its metabolites in blood plasma.

This confirmed prior research that enzymes in human blood readily degrade NAD+, NMN and NR at different rates, with NR being the least stable.

According to the authors:

NMN exhibits a relatively high chemical stability but is partly dephosphorylated to NR by the cells.

Surprisingly, NR was also rather efficiently hydrolyzed to Nam.

 

Loss of NAD homeostasis leads to progressive and reversible degeneration of skeletal muscle (Bauer, 2017).

The chart at left is from the Bauer study and shows the change in NR, NAM and NMN found in blood plasma after oral gavage of NR at 200 mg/kg.

NR was found at trace levels and not increased.

Within minutes, NAM was increased 16x, reaching 40x increase by 100 minutes.

This is a short-term increase in NAM following a single dose of NR, which shows it is degraded to NAM. This increased NAM is temporary, as excess NAM will be methylated and excreted in urine.

According to the authors:

Oral NR dosing increased circulating NAM 40-fold while NMN remained unchanged and NR was detected only at trace levels in the blood.

Orally administered NR that reaches the muscle appears to enter in the form of liberated NAM.

A reduced form of nicotinamide riboside defines a new path for NAD+ biosynthesis and acts as an orally bioavailable NAD+ precursor (Canto, december 2019).

The more recent study by Canto measures the degradation of NR to NAM in blood.

The chart at left shows NAM levels in blood plasma massively increase one hour after oral gavage of 500 mg/kg of NR.

According to the authors:

NR quickly disappears from the bloodstream, and is almost undetectable 1 h after intraperitoneal administration at 500 mg/kg.

Elegant tracer experiments demonstrated that after oral intake, NR was utilized as such by the liver, while it predominantly reached the peripheral tissues as its degradation product, NAM.

 

Extracellular NAM is a weak NAD+ precursor in multiple cells and tissues.

Extracellular NR degradation to NAM could constitute a limitation for its pharmacological efficacy.

 

These recently published studies show:

NMN

  • NMN IS STABLE IN BLOOD
  • NMN IS FOUND IN BLOOD AT 10X THE QUANTITY AS NR AND IS READILY AVAILABLE TO TISSUES THROUGHOUT THE BODY

NR

  • NR IS NOT STABLE IN BLOOD AND DEGRADES WITHIN ONE HOUR
  • NR IS NOT FOUND IN BLOOD AT MORE THAN TRACE LEVELS AND IS NOT AVAILABLE TO TISSUES OUTSIDE THE LIVER
  • SUPPLEMENTATION WITH NR DOES NOT INCREASE AVAILABILITY OF NR IN THE BLOODSTREAM
  • DUE TO LIMITED STABILITY, NR IS DEGRADED TO NAM BEFORE REACHING PERIPHERAL TISSUES

Conclusion

NR is unstable in aqueous liquid, so is not found in the bloodstream at more than trace levels. Any NR that survives the GI tract and makes it to the bloodstream is hydrolyzed to NAM within one hour, greatly limiting availability to peripheral tissues. Excess NAM is methylated and excreted in urine.

NMN is stable in the bloodstream and can be readily increased with supplementation, making it available to cells throughout the body in much greater quantity than NR.