A few weeks ago, a YouTuber named Dr. Brad Stanfield posted a video
in which he explained why he’s decided to stop taking NMN,
one of the most popular supplements in the longevity community.
I watched the video, and decided that I needed to post my own video in reply.
This week, I’m gonna respond to a video that Dr. Brad Stanfield posted on his YouTube channel a few weeks ago.
He posted this video to explain his decision to stop taking NMN.
He feels that the science is new, there too much we don’t know,
and there are some studies that might possibly point to some factors
that contradict taking NAD+ precursors. And I have some thoughts on that.
So, I want to start out by stating that I’m not a doctor, or a scientist, or a researcher.
I’m just a lay person whose passion is longevity science.
Dr. Brad Stanfield on the other hand, is a doctor.
And I’m pretty sure that he’s more qualified than I am to be having any opinion of the subject of NAD,
and NAD+ precursors like NMN or NR.
That said, Dr. Stanfield explained, in great detail, why he’s decided to stop taking NMN.
And he made some pretty good points.
In his video, he referenced some papers that linked NAD+ levels with inflammation,
with SASPs, and with cancer.
So, as I understand it, here’s the case that the papers make, or at least, the conclusions that they came to.
NAD+ metabolism governs the pro-inflammatory effects of
senescent-associated secretory phenotypes, or SASPs. SASPs can cause inflammation
and it’s been discovered that NAD+ can cause this SASP-associated inflammation to become worse.
And what’s driving it is an increase in the ratio between NAD+ and NADH.
NAD is a molecule that transfers electrons,
and as it goes from picking up an electron to dropping one off,
it constantly changes between NAD+ and NADH.
This increase in the ratio of NAD+ to NADH can convert
SASPs with pro-inflammatory factors that are relatively low into highly pro-inflammatory SASPs.
So, NAD+ can make inflammation caused by SASPs worse.
If the ratio of NAD+ to NADH increases.
Now, one of the pro-inflammatory compounds that SASP’s secrete is CD38.
CD38 is found on the surfaces of immune cells, and inflammation causes an increase in macrophages,
which is an immune cell, so this make sense.
CD38 can also act as an enzyme, creating cADP ribose from NAD+.
And CD38 consumes NAD+ at a voracious rate,
consuming 100 molecules of NAD+ for every molecule of cADP ribose that it creates.
So it’s theorized that CD38 acts to limit the harmful impact of NAD+ on SASP-associated inflammation.
One way that NAD+ metabolism is thought to impact both tissue aging and cancer is through NAMPT,
the rate-limiting enzyme that’s part of the salvage pathway in recycling NAD+.
When NAD+ is used by a variety of enzymes, including CD38,
but also by sirtuins and PARPs, which repair DNA, the NAD+ is converted to nicotinamide, or NAM.
NAM is converted into NMN by the enzyme NAMPT
before being further converted back into NAD+.
And like a lot of other things. NAMPT levels go into decline as we age.
And it’s believed that the culprit is inactivity which, in most of us, increases as we grow older.
It’s also thought that NAD+ might increase the risk of cancer.
In mice that had been especially bred to form cancers, NAD+ elevated levels of pre-cancerous markers.
Now, while it did not have the same effect on wild mice,
these cancer-inducing mice might be compared to people who have a family history of cancer. Like me.
So, as we age, we produce more and more senescent cells.
These senescent cells secret pro-inflammatory SASPs.
NAD+ makes this SASP-associated inflammation worse,
and might even increase the risk of cancer.
But these same SASPs also secrete CD38,
possibly in an effort to mitigate the inflammation-heightening effects of NAD+.
So maybe it’s a self-correcting system, trying to balance things out and maintain homeostasis.
So the paper recommends that dietary supplementation of NAD+ precursors,
like NMN and NR, should be administered with precision.
That means that NMN and NR are not supplements that everyone should be taking.
And this seems to be the point that Dr. Stanfield is also making,
and why he’s decided to stop taking NMN.
However, there’s a wealth of other papers that demonstrate several things conclusively.
They’ve demonstrated that as we age, our levels of NAD+ go into serious decline.
They’ve demonstrated that these declining levels of NAD+ can lead to chronic diseases, like cancer.
They’ve demonstrated that the age-related rise in cellular senescence contributes
to this decline in NAD+ levels, as does both declining levels of NAMPT and rising levels of CD38.
OK, we’ve got high levels of NAD+ causing more SASP-associated inflammation to become worse,
but at the same time rising levels of inflammation caused by
cellular senescence causes a decline in NAD+ levels, through the action of CD38 released by SASPs.
So, here that way that I think it works.
When we’re younger, our NAD+ levels are optimal and our NAD+ metabolism is cranking along
tickety-boo.
NAD+ fuels a lot of youth-persevering processes in our bodies.
But apparently it can also fuel SASP-associated inflammation…
which is a bad thing.
But that’s OK.
We’re still young, we don’t have that many senescent cells,
so we don’t have much SASP-associated inflammation.
But as we age, our load of senescent cells get bigger and bigger,
we have more and more of them. And they’re cranking out more and more SASPs.
And suddenly, issue of NAD+ making SASP-associated inflammation worse, is a big deal.
So…CD38 is secreted along with the SASPs, the CD38 consumes NAD+ at a voracious rate,
and it’s no longer a problem.
Added to that is the fact that as we become less and less active, our levels of NAMPT drop.
And so we recycle less and less NAD+.
Unfortunately, while NAD+ is no longer fueling SASP-associated inflammation,
it’s also not fueling repair of our DNA or the activation of sirtuins.
And since repairing damaged DNA and activating sirtuins helps to maintain homeostasis,
homeostasis is lost and we age.
Now, Dr. Stanfield makes the case that while mild activation of sirtuins can lead to a reduction in chronic disease,
over activation can have the opposite effect, leading to a rise in chronic disease.
I’m guessing that this is a correlation of NAD+ making SASP-associated inflammation worse.
But I suspect that the age-related decline in NAD+ levels gets so bad that sirtuin over-activation is no longer a concern.
I think the concern is under-activation.
So, what do we do with this information?
How do we apply it to our longevity strategy?
he first thing to keep in mind is that there’s a lot that we still don’t know.
The research is not very old, and there’s not very much of it.
We need a lot more of it.
We don’t really understand NAD+ metabolism and it’s effect on the aging process.
So anything we do needs to be tempered by this knowledge of what we don’t know.
We don’t want to do anything that we might learn later was a huge mistake.
So, how we apply this information to our longevity strategy kinda depends on how old we are.
My strategy is different now than it would have been when I was in my 20’s or 30’s.
I think the first thing that I would do, at any age, is to try to clear out senescent cells.
Cellular senescence causes chronic inflammation,
and you want to eradicate that as much as possible.
If you can clear out senescent cells, you don’t have as much chronic inflammation.
And you also don’t have as much CD38, which eats into the NAD+ pool.
The next thing that I’d do is start exercising.
Remember earlier when I mentioned that declining levels of NAMPT,
the rate-limiting enzyme of the salvage pathway, is caused by inactivity?
Well, it’s been demonstrated in studies that declining levels of NAMPT can be reversed by exercise.
Aerobic exercise can raise NAMPT levels by 12% and resistance training can raise them by 25%…
in young people.
But in older people, you get an even more pronounced effect,
raising NAMPT levels by 20% with aerobic exercise and 30% with weight training.
I’m guessing that it doesn’t raise the levels as much in younger people because
the levels haven’t gone into as much of a decline.
As I aged, I’d probably start taking CD38 inhibitors like apigenin and quercetin.
There’s a whole lotta science demonstrating that CD38 is inhibited by
both apigenin and quercetin, and that either one of these polyphenols can result in increased levels of NAD+.
I recently did a video on this, and I’ll link to it in the description and in this card up here.
My longevity strategy would start out with trying to plug the hole in my NAD+ pool,
to inhibit or prevent that things that are causing my NAD+ levels to go into decline.
Eliminate CD38, first by eliminating as many senescent cells as I could,
then by inhibiting the effects of CD38.
And by increasing my NAMPT levels so that I was recycling more and more NAD+.
Supplementing with an NAD+ precursor, like MNM or NR,
would be the last type of intervention in my longevity strategy.
So, earlier, I was talking about how one of the papers referenced in Dr. Stanfield’s video
concluded that supplementation with NAD+ precursors should be administered with precision,
and I’d like to revisit that opinion.
That type of precision would require a pretty sound knowledge of my present NAD+ levels.
But NAD+ testing is in it’s infancy.
We would need to constantly monitor our NAD+ levels throughout the day,
because they’re constantly changing throughout the day.
Right now, there’s very few tests available to the consumer that can determine NAD+ levels.
The only one that I know of is offered by BioViva and it costs about $200, although there may be others.
Now, there are some technologies in development that might make it
easier and cheaper to monitor NAD+ levels in the future.
There’s one test that uses liquid chromatography and another that uses a bioluminescent biosensor.
They’re both in development and they both test for NAD+ levels.
But that’s in the future. Which makes that kind of precision kinda difficult.
So, I guess I’d use age as a guide.
If I was younger, I’d wait for the science and technology to catch up
and I’d probably only exercise and maybe try to clear senescent cells.
But as I got older, I’d be more willing to try more aggressive interventions.
But at what age would I be willing to try everything, as aggressively as I could?
Well, I’m 71 and I feel I’m pretty much there.
I don’t know what my NAD+ levels are, but I’m guessing that they’re probably pretty low.
I’m really looking forward to those cheap and easy NAD+ test,
so that I can bring some precision to my strategy.
In the meantime, I’ll guess I’ll try to estimate or test my biological age and us that as a guide.
If any of you guys have a better way of figuring out what your NAD+ levels are,
I’d love to hear about them. Leave me a comment.
That’s it for this video. Check out this playlist of NAD and NAD+ precursors.
I’m outta here, catch ya next week.