[Rhonda]: The next point of concern is the bioavailability of either nicotinamide riboside
or nicotinamide mononucleotide.
The important point to address is whether nicotinamide riboside or nicotinamide mononucleotide
can reach other tissues intact and directly form NAD+ without going through that NAD+
recycling pathway that I mentioned earlier called the salvage pathway.
The salvage pathway would mean that nicotinamide riboside or nicotinamide mononucleotide were
first metabolized into nicotinamide before forming NAD+ instead of just directly forming
NAD+.
This is an important point because NAD+ produced from the salvage pathway is subject to feedback
inhibition and therefore cannot raise NAD+ levels in tissues above a certain level.
So let's talk about some details.
An animal study using isotope tracers allowed the NAD+ made directly from nicotinamide riboside
or directly from nicotinamide mononucleotide versus NAD+ made from nicotinamide via the
salvage pathway.
What the study found was that a low oral dose (50 mg/kg/bw) of either nicotinamide riboside
or nicotinamide mononucleotide produced very low levels of NAD+ made directly from the
precursors only in the liver but not other tissues.
Low levels of nicotinamide-derived NAD+, on the other hand, were found in the kidneys,
and very low levels of nicotinamide-derived NAD+ were found in the muscles, and brain.
The human equivalent dose of 50mg/kg bw is roughly 4.07mg/kg bw.
So for a 180 lb person that is is approximately 332 mg of either nicotinamide riboside or
nicotinamide mononucleotide.
That is a pretty doable dose but very little increases in NAD+ were found at least in animals
at that dose.
A higher oral dose was also done but only for nicotinamide riboside.
A dose of 200 mg/kg/bw of nicotinamide riboside showed no difference compared to a low dose
in terms of making NAD+ direct from nicotinamide riboside in any tissues other than the liver.
However, more of the NAD+ derived from the salvage pathway was found in the kidney, muscle,
and brain than at a lower dose.
200 mg/kg bw translates to a human equivalent dose of about 16.3mg/kg bw.
Which, for a 180 lb person is about 1330 mg or 1.3 g which is pretty high.
When nicotinamide riboside or nicotinamide mononucleotide were given intravenously at
varying doses (50 mg/kg/bw and 500 mg/kg/bw), directly-produced NAD+ was found in the liver,
kidney, and muscle in a dose-dependent manner.
However, the only NAD+ detected in the brain was that which was salvaged from nicotinamide,
suggesting that neither nicotinamide riboside nor nicotinamide mononucleotide crosses the
blood-brain barrier.
It is noteworthy that a head-to-head comparison of identical doses of injected nicotinamide
riboside and nicotinamide mononucleotide produced more NAD+ made directly from nicotinamide
riboside in the liver, kidney, and particularly in the muscle compared to nicotinamide mononucleotide.
So what does this all mean and should we care?
What this data from the isotope tracer studies means is that even at very high oral doses,
neither nicotinamide riboside and nicotinamide mononucleotide appeared to be directly transported
into tissues other than the liver at the oral doses measured.
However, nicotinamide riboside and nicotinamide mononucleotide were converted into nicotinamide
which was transported to other tissues where some of it was converted into NAD+.
At the end of the day, isn't raising cellular NAD+ levels what is most important anyway?
The other animal studies I previously mentioned that showed positive health benefits in tissues
like the muscle or brain were at very high oral doses of nicotinamide riboside and nicotinamide
mononucleotide.
In fact they were double the high dose that was used in the isotope tracer study.
So it's possible that nicotinamide riboside and nicotinamide mononucleotide can be transported
to tissues other than the liver at a very, very high oral dose...or it's also possible
that the NAD+ derived from the salvage pathway was high enough to do something beneficial.
The isotope data also suggests that if nicotinamide riboside or nicotinamide mononucleotide is
administered intravenously, both nicotinamide riboside and nicotinamide mononucleotide can
be transported to other tissues and directly form NAD+ and not be subject to feedback inhibition.
This also raises NAD+ levels in multiple tissues to a much higher concentration than otherwise
would be.
Of course, IV injection of these NAD+ boosters is very challenging to translate to humans.
You may be wondering why all the messing around with NAD+ boosters like nicotinamide riboside
and nicotinamide mononucleotide in the first place?
The reason nicotinamide riboside and nicotinamide mononucleotide are popular is because they
can be transported into multiple tissue types including the liver, kidney, muscle, and heart.
The brain is the exception.
Neither nicotinamide riboside nor nicotinamide mononucleotide seems to be able to directly
cross the blood-brain barrier but both form nicotinamide which can be transported into
all tissues types including the brain where it can then form NAD+.
So why not just go to the source and take or inject NAD+?
NAD+ has poor bioavailability.
Animal studies have shown that upon ingestion, oral NAD+ is primarily digested into the precursor
nicotinamide but also to nicotinamide riboside and nicotinamide mononucleotide before being
absorbed.
While oral bioavailability of NAD+ is low, the hope is that intravenous NAD+ infusion
may be used to bypass the digestive system.
The problem is that no mammalian NAD+ transporter has been identified and with the exception
of the brain and the heart, extracellular NAD+ has not been shown to be taken up into
tissues.
When NAD+ was injected into the abdominal region of mice it was able to raise NAD+ in
some brain regions.
Similarly, mice injected with a high dose of NAD+ had increased levels in the heart
and protection from cardiac hypertrophy.
Suggesting that direct injection of NAD+ may be doing something beneficial.
Also, just because no data exists that does not mean that NAD+ delivered intravenously
can not raise NAD+ levels in other tissues other than the brain or heart.
It's possible that extracellular NAD+ could be metabolized to nicotinamide (as NAD+ delivered
orally is) which can be transported into other tissues like the muscle and brain.
While there is very little preclinical data and zero clinical data on direct IV injection
of NAD+...it does seem like this may also be a good area to explore as a potential way
to boost NAD+ levels in tissues.