WHAT IS NAD+

NAD+ 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)Scientists have now confirmed a direct link between falling NAD+ levels and aging in both animal and in human subjects.

NAD+ DECLINES WITH AGE

As 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).

NAD+ METABOLISM IN HUMANS

NAD+ can be synthesized in humans from several different molecules (precursors), thru  the De Novo  and Salvage Pathways.

The salvage pathway sustains 85% or more of our NAD+ (14), with approximately 3g of NAM metabolized to NMN and then to NAD 2-4 times per day (14).

Nampt is the rate-limiting step in the salvage process (97).

SUBLINGUAL NMN AND NAD+ BYPASS THE LIVER and NAMPT BOTTLENECKS

As we age, Nampt enzyme activity is lower, resulting in less NAM recycling, less NAD+, more disease and aging (97,101).

All NAD+ supplements can restore NAD+ in the Liver but does not solve NAD+ deficiency throughout the body. This research shows that NAD+ in the liver is metabolized by CD38 to NAM, and ONLY NAM is excreted to the rest of the body.

Sublingual administration of NMN or NAD+ supplements bypass the 2 bottlenecks – the liver and NAMPT processing of NAM.

Providing NAD+ or its immediate precursor, NMN, directly to the bloodstream is much more effective than dropping large quantities of NAM or NR into the liver and trying to force it to produce more NMN and NAD to the bloodstream.

In mammals, the entire NAD+ pool is consumed 2-4 times a day and recycled thru the “salvage pathway”, which is responsible for 85% of our NAD+ (14).

In the salvage pathway, Nicotinamide (NAM) and Nicotinamide Riboside (NR) are first converted to NMN, which is then further converted to NAD+ (14).

NMN is more correctly referred to as a NAD+ intermediate because
NMN is the last step before conversion to NAD+

In 2004 Dr Charles Brenner discovered that NR can be phosphorylated to NMN in the body, to increase NAD+ without going thru NAM. This allows it to bypass the “NAMPT bottleneck”.

Chromadex has licensed methods to produce NR and has been selling NR commercially since 2014. Dr Brenner is now the chief scientific advisor for Chromadex.

NMN was prohibitively expensive until 2017, but there are no patents controlling the production of NMN so the prices have been dropping rapidly, and is now about the same as NR. Dr Sinclair is the leading researcher in use of NMN.

The NAD+ molecule itself is too large to make it through the digestive system intact when taken as capsules, which is why  NR and NMN have been used as supplements to increase NAD+ levels in the body.

Recently however, research has shown NMN and NR are also mostly digested by the stomach and liver.  Sublingual delivery of NAD+ and NMN allows them to bypass the GI tract.

 

 

 

Poor Bioavailability from Capsules

NAD+ not effective in drinking water or in capsule form
The NAD+ molecule is twice as large as NR or NMN, and is totally degraded in the Gastro-Intestinal tract, so researchers do not use NAD+ in drinking water of mice and it is not sold in capsule form for humans.

NAD+ in IV or IP injections
Research has been successful using NAD+ injections in mice.

In humans, clinics that provide NAD+ by IV are exploding in popularity, even though they charge over $1,000 a day and require the patient to be hooked up to a drip IV for 8 hours.

NMN and NR poor bioavailability in capsules
NMN and NR capsules are only partially digested in the stomach, but are almost totally metabolized in the liver and excreted as NAM (Liu, 2018).

Sublingual delivery solves the bioavailability problem

Molecules like NMN, NR and NAD+ that have low molecular weight and are hydrophilic can be absorbed through the capillaries under the tongue directly into the bloodstream. This is called Sublingual (under the tongue) delivery.

Sublingual delivery can bypass the stomach and liver.

This solves the bioavailability problem of capsules that get digested in the stomach, so NAD+ can be used instead of NAD+ precursors. It also greatly improves the effectiveness of NMN.