Look, NAD is one of the most important molecules in your body.
And the older we get, the more NAD levels decline.
The best way that we know of right now to boost your stores of NAD is by supplementing with NAD precursors.
And that’s what this video is about. So, stick around.
Today we're gonna be talking about nicotinamide adenine dinucleotide, better known as NAD.
More specifically, we're going to be talking about supplemental precursors that you can take
to boost your NAD levels.
But first, let's talk about what NAD is, and the crucial role that NAD plays in aging.
NAD is a molecule that is a derivative of vitamin B3, also known as nicotinamide or niacin.
This molecule is used in over 500 enzymatic reactions,
and it plays a crucial role in metabolism, aging cell death, DNA repair, and gene expression.
More importantly, it's used as a fuel in activating a couple of pathways that are crucial to healthy aging.
One of these is the sirtuin pathway.
Sirtuins, also called the “longevity genes”,
play a critical role in regulating many of the functions that influence the aging process.
They regulate mitochondrial biogenesis, they stimulate apoptosis, they inhibit inflammation,
and they stimulate chemical signaling at the cellular level.
The other pathway that NAD activates is a family of proteins called PARPs, or poly (ADP-ribose) polymerase.
These proteins are involved in cellular processes such as DNA repair, genomics stability,
and programmed cell death.
Both of these pathways are critical to many of the repair processes that go on within the body
and NAD fuels these processes.
Without NAD, these processes don't happen.
Unrepaired damage accumulates and you rapidly grow old and die.
Without making it too complicated, NAD is involved in reduction/oxidation reactions,
and comes in two forms: NAD+ and NADH.
NAD+ takes on electrons and becomes NADH, and NADH gives up electrons and becomes NAD+.
So, an NAD+ molecule accepts an electron from one molecule, becoming NADH,
then goes somewhere else and donates that electron to another molecule, reverting back to NAD+.
Most of the NAD+ in our bodies comes from the recycling of NADH
but some it is lost and it needs to be replaced.
As we age, more and more is lost and more and more needs to be replaced.
And as NAD+ levels drop, many of the processes in our bodies slow down,
including most of the repair processes.
But there's a problem.
The NAD+ molecule is large and bulky, and it doesn't pass across the cellular membrane.
However, there are NAD+ precursors that can cross the cellular membrane
and after they do so they are then converted into NAD+.
There are a lot of pathways for getting to NAD+, and a lot of precursors to NAD+.
And they all start with our diet.
One pathway starts with tryptophan,
but this pathway is really complex, not very efficient, and not a really good source for creating NAD+.
Another pathway starts with nicotinic acid.
But as you’ll see later, that one's also got some problems
and is not a really good candidate for boosting NAD+ levels.
The pathway that were primarily concerned about here is the salvage pathway.
And it starts with either nicotinamide or nicotinamide riboside, both of which can be absorbed through our diet.
Nicotinamide is a water-soluble form of vitamin B3,
and it gets converted into NMN, or nicotinamide mononucleatide, using an enzyme called NAMPT.
But in the salvage pathway, nicotinamide riboside, or NR, can also be converted into NMN.
Either way, NMN gets converted into NAD+.
Now,the final way to get NAD+ is to recycle it from NADH.
OK, so we want to boost our NAD+ levels because they go into decline as we age.
And one of the primary ways that NAD+ levels drop is through an enzyme called CD-38.
This enzyme burns through a lot of NAD+, and levels of CD-38 increase as we age.
In fact they go up by as much as 2 to 3 times.
CD-38 is required for the declines in NAD+ levels and mitochondrial function seen with aging.
As CD-38 levels go up NAD+ levels go down.
CD-38 is an enzyme that breaks down NAD+,
and it’s associated with immune responses and energy metabolism.
Therapies that reduce inflammation, particularly age-related chronic inflammation known as “inflammaging”,
might possibly lower levels of CD-38.
There are other causes of the decline and NAD+ with aging.
PARPs repair damaged DNA.
Now, presumably, damage to DNA goes up as we age.
So PARP activity increases as we age.
Since NAD+ fuel's PARPs, increased PARP activity means increased NAD+ consumption.
So one strategy to boost our NAD+ levels would be to decrease CD-38 activity.
And one way to do that is through the use of flavonoids, particularly a flavonoid called apigenin.
When apigenin was given to mice, it reduced levels of CD-38 by 66% and doubled NAD+ levels.
And really good sources for apigenin are dried parsley, celery and chamomile tea.
Now, you might be tempted to just take it as a supplement,
but pure apigenin is considered to be highly unstable,
so finding pure apigenin as a supplement can be really difficult and really expensive.
You're better off just going with dried parsley and chamomile tea.
The next strategy for boosting NAD+ levels involves the salvage pathway.
When NAD+ levels are depleted a molecule called nicotinamide, or NAM, is created.
As I mentioned earlier, nicotinamide is converted into NAD+ by an enzyme called NAMPT.
But NAMPT is self-limiting and it's also reduced by aging.
Fortunately, there's a couple of things that we can do to boost our supplies of NAMPT.
And one of those things is exercise.
Aerobic training increased NAMPT levels in young individuals by 12% and in older individuals by 28%.
And VO2max proved to be the best indicator of NAMPT levels.
But resistance training is even better.
In young individuals, resistance training increased NAMPT levels by 25%,
and in older individuals, it increased it by 30%.
I haven’t heard how much it might be improved by doing both, but I think it’s worth a shot.
Another way to boost your NAMPT levels is through either calorie restriction, or calorie restriction memetics.
One study showed that giving resveratrol to fish increased their NAMPT levels.
And finally, there's a small molecule called SBI-797812 that has been shown to be an activator of NAMPT.
The effects of this molecule have been demonstrated to turn NAMPT into a "super catalyst"
that more efficiently generates NMN and increases intracellular NAD+.
So we’ll certainly be on the lookout for this.
Our final strategy is what this video’s all about.
Taking NAD+ precursors to boost declining NAD+ levels.
And there's a few different ways that you can achieve this.
The first is by supplementing with niacin.
Now, one study in humans showed that niacin supplementation increased NAD+ levels
by 1.3 times after four months and by 2.3 times after 10 months.
However, there's a couple considerations when taking niacin supplementation.
First off, you want to stay away from the sustained-release form of niacin.
It's been shown to be hepatotoxic, or toxic to the liver.
The instant-release form is much better, but it's got its own drawback.
Instant release niacin can cause a so-called "niacin flush."
This is caused by the dilation of blood vessels
and it can cause skin warmth or reddening and various degrees of itching.
Furthermore, it's been demonstrated that either NMN or NR can raise NAD+ in mice
to higher levels than niacin can.
But, before moving on to NMN & NR, let's take a look at nicotinamide.
Nicotinamide is a water soluble form of vitamin B3, and we can get it through our diet.
But there's been some controversy here.
Nicotinamide, or NAM, has been used in the past as an SIRT1 inhibitor.
It's been shown that nicotinamide stops sirtuin activation after one hour.
Now, after eight hours, when the nicotinamide has been converted into NMN,
there is an activation of the sirtuins.
So, using nicotinamide is still problematic.
During the first 1 to 8 hours nicotinamide is suppressing activation of our sirtuins,
and this is the last thing that we want.
We want our sirtuins to be activated all the time.
So that leaves us with NMN & NR.
But which is best?
Well, both nicotinamide mononucleatide & nicotinamide riboside are on the same pathway,
and either can be utilized to increase NAD+ levels.
We can get NR from our diets, it’s then converted into NMN, and that gets converted into NAD+.
But all that happens inside of the cell.
The problem is getting dietary NMN or NR into the cell, where it can be converted into NAD+.
For a while, it was thought that taking NR was is the best way to boost NAD+.
This was because researchers believed that the NMN molecule was too large
to be transported through the cell membrane into the cell.
Not so with NR.
NR can pass through the cell wall where it’s then converted into NMN.
But a recent study seems to disproved this.
In April of this year, a study was published that showed that a specific transporter of NMN
is highly expressed in the small intestine.
And as we age, this transporter becomes even more highly expressed,
as a response to ever-decreasing levels of NAD+.
And the study showed that this transporter can get the NMN molecule into our cells.
So instead of the NMN molecule having to be converted into a molecule of NR, being absorbed back into the cell,
and then converted back into NMN…
it's been demonstrated that the NMN molecule can be taken up directly into the cell by this transporter.
Now, there's some controversy surrounding this.
Responding to the study, another group of researchers commented
that the “analytical methods, transport data and interpretation underlying this assignment
are not sound and do not support the transport of NMN.”
In response to this, the original researchers replied that this claim of "absence of evidence"
has no concrete foundation and “the data in our article strongly support our conclusion
that this transporter is an NMN transporter.”
So I guess the jury is still out.
Here's the reality.
Research into NAD+, NMN, NR and nicotinamide is still in its infancy.
There haven't been that many studies that have been conducted, and a lot of them are contradictory.
There's a study that shows that both NMN & NR are converted into nicotinamide first,
before eventually being converted into NAD+.
And other studies that show them being converted directly into NAD+.
There's controversy surrounding the NMN transporter.
There's only a single human study of NMN,
and all that study shows is that NMN is safe after taking a single dose.
It says nothing about the effect of taking NMN on NAD+ levels.
Now, in contrast, we do have some data that shows that taking NR
in doses of 300 and 1000 mg does raise levels of NAD+ over 56 days by 1.74 and 1.98 times, respectively.
Now, there’s going to be a trial conducted later this year
by a pharmaceutical group in Shanghai called Effipharm
that’s going to examine the effects of NMN on boosting NAD+ levels…for the first time ever.
But it’s only going to be looking at a dose of 300 mg.
They are planning on doing another trial in the future based on a 1 gram dose.
So, we’ll be keeping a close watch on both of those trials.
There's a lot of theories, but there's still so much that needs to be brought to light.
And that means that anyone who is experimenting with this on their own, needs to be really careful,
needs to exhibit a considerable degree of caution.
Particularly in the dosing amount,
and I believe that right now, that should be kept to a maximum dose of 1g per day.
So for me, the evidence thus far seems to suggest that NMN might be better than NR for increasing NAD+ levels.
But the bottom line is that both of them can raise your levels of NAD+.
In my own practice, I tend to use an abundance of caution.
I've taken NR in the past, but currently I'm not taking anything.
However, I think that I will start taking NMN, and for me, the maximum dose that I would take is 1 g per day.
Now, something to keep in mind.
Basically, NMN & NR are forms of niacin, vitamin B3.
And when taking any form of vitamin B3, it's important to take another supplement called TMG in equal amounts.
TMG stands for trimethyl glycine.
Any form of B3 consumes large amounts of methyl groups and interferes with methylation.
TMG is a methyl group donator,
so taking equal amounts of TMG with your NMN or NR should cancel out the methylation interference.
A final concern surrounds an association between boosting NAD+ levels and cancer.
While improving your levels of NAD+ can help prevent cancer,
if you already have an established cancer,
boosting NAD+ levels have been shown to contribute to cancer growth.
Let me say that again,
if you already have cancer, increasing your NAD+ levels may contribute to the growth of that cancer.
But if you don't have cancer, boosting NAD+ can help keep you cancer-free..
And that’s it. Hope you enjoyed this video.
Now, if you’d like to learn more about sirtuins and their effects on aging, check out this video.
Catch ya next week.