May 8, 2026 • 45 mins
We track the real biology behind the NAD+ craze, from how cells turn food into energy to why that energy system breaks down with age. We also weigh what NMN and NR actually do in human trials against what marketing claims they do, including the messy roles of CD38 and the gut microbiome.
• NAD+ as an electron carrier that powers ATP production
• Mitochondrial dysfunction as NAD+ declines with age
• Sirtuins as NAD+-dependent regulators of repair and stress responses
• Why “sirtfood” claims collapse on dose and bioavailability
• The failed PARP1 explanation and the disposable soma theory
• CD38 as an NADase that rises with age
• Knockout and overexpression studies that point to causation
• Why oral NAD+ cannot raise intracellular NAD+ directly
• NR and NMN as precursors using salvage pathways and transporters
• CD38 degrading precursors in vivo and acting as an ectoenzyme
• What 2025–2026 human clinical trials show on safety and biomarkers
• Muscle biopsy paradox of unchanged steady-state NAD+
• Metabolic flux, species differences, and why humans are not mice
• Microbiome conversion of NR into niacin and the NAAD signal
• Conflicts of interest, surrogate markers versus real clinical endpoints
• Supplement purity problems and the theoretical cancer-fueling risk
• Why CD38 inhibitors may be a better long-term target than higher dosing
This podcast is created by Ai for educational and entertainment purposes only and does not constitute professional medical or health advice. Please talk to your healthcare team for medical advice.
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Episode Transcript
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SPEAKER_01 (00:00):
I want you to imagine something for a second.
Imagine if your cells.
Uh every single one of thetrillions of microsopic cells
keeping you alive right now hada tiny battery indicator
floating right above them.
SPEAKER_00 (00:13):
Like exactly what you see in the top right corner
of your phone screen.
SPEAKER_01 (00:16):
Yes, exactly like that.
And you know, when you're a kid,that battery is just pegged at
100%.
It is bright solid green.
Right.
You can run around a playgroundall day, scrape your knee,
bounce back the next morning,and your internal machinery just
hums along.
But as you get older, thatlittle battery icon starts
draining.
It drops to 80%, then 50%.
(00:37):
And eventually, somewhere inmiddle age, it starts blinking
that terrifying, anxious,flashing red.
SPEAKER_00 (00:44):
Which is honestly a very visceral way to visualize
chronological aging versusbiological aging.
Trevor Burrus, Jr.
SPEAKER_01 (00:50):
It's the worst feeling when your phone does it,
and it's worse when your bodydoes it.
You know, your energy dips, yourmuscles just don't recover after
a workout, your focus blurs.
The fundamental machinery ofyour body just sort of it grinds
down.
SPEAKER_00 (01:02):
Aaron Powell And that blinking red battery isn't
just a metaphor, it is the exactbiological mechanism we are
unpacking for today's deep dive.
Because that cellular battery ispowered by a very real, very
heavily researched moleculecalled NAD plus Nair.
SPEAKER_01 (01:19):
Right.
NAD plus C, which stands fornicotinamide adenine
dinucleotide.
SPEAKER_00 (01:25):
Right.
You nailed the pronunciation.
SPEAKER_01 (01:26):
Thank you.
I practiced.
But seriously, I mean, I can'teven open my phone lately
without seeing a techbillionaire or some fitness
influencer trying to sell me apill that supposedly boosts this
stuff.
The obsession is justeverywhere.
SPEAKER_00 (01:38):
It really is.
It sits at the absolute centerof the modern anti-aging
industry, but uh moreimportantly, it sits at the
center of the human agingprocess itself.
SPEAKER_01 (01:47):
Yeah.
SPEAKER_00 (01:48):
So today we are going to cut straight through
the marketing campaigns.
We have a massive stack ofscientific literature in front
of us.
SPEAKER_01 (01:53):
Well, it is a mountain of papers.
SPEAKER_00 (01:55):
Literally.
We've got clinical reviews from2025 and 2026, deep cellular
biology studies, metabolicprofiles.
And our mission today is to lookat exactly what happens inside
human cells when that batterydrains.
SPEAKER_01 (02:07):
Because the hype right now is completely
unhinged.
You have entire supplementempires built overnight, people
claiming they've found theliteral cure for aging, and you
know, consumers spendingbillions on NAD plus precursors
like NMN and NR.
SPEAKER_00 (02:20):
Aaron Powell Which is why we need to separate the
genuine, fascinating cellularbiology from the frankly
dangerous commercial hype.
The transition from we reversedaging in a laboratory mouse to
this pill works in complex humanbeings is incredibly fraught.
SPEAKER_01 (02:37):
So fraught.
Let's unpack the actual biologyfirst, because before we can
understand why we're losing ourvitality, we really need to
understand what powers it in thefirst place.
SPEAKER_00 (02:45):
Exactly.
SPEAKER_01 (02:46):
So uh NAD plus gas, the battery fluid, what exactly
is this molecule doing inside ofus?
SPEAKER_00 (02:52):
Aaron Ross Powell Well, at its core, NAD plus is
an essential coenzyme for energyproduction.
You can kind of think of it as abiological shuttle bus.
Aaron Powell A shuttle bus?
For what?
For electrons.
It is absolutely critical forthe fundamental metabolic
processes.
And I'm talking about thefoundational mechanics of
keeping a mammal alive.
Things like glycolysis, thetricarboxylic acid cycle,
(03:13):
oxidative phosphorylation.
SPEAKER_01 (03:14):
Okay, wait, hold on.
Let's not lose anyone in thebiochemistry right out of the
gate.
Let's break those down.
Glycolysis is just, I mean,that's just breaking down sugar,
right?
SPEAKER_00 (03:23):
Basically, yes.
Glycolysis literally meanssplitting sugar.
When you eat a carbohydrate, itenters the cell and an enzymatic
process splits that glucosemolecule to extract energy.
Right.
But to do that, the cell needsto move electrons around.
This involves what we call redoxreactions.
SPEAKER_01 (03:41):
Redox, meaning reduction and oxidation.
SPEAKER_00 (03:44):
Precisely.
Oxidation is when a moleculeloses an electron, and reduction
is when a molecule gains anelectron.
NAD plus is the molecule thatswoops in, grabs those
high-energy electrons from thesugar you ate.
Which reduces the NAD plus itinto a form called NADH, and
then it acts as that shuttlebus, physically carrying those
electrons to the mitochondria.
SPEAKER_01 (04:04):
Aaron Powell, so it's literally like a
microscopic dump truck justmoving energy from my breakfast
into my cellular engines.
SPEAKER_00 (04:10):
Aaron Powell That is exactly what it is.
And once it drops off thoseelectrons at the mitochondria,
it powers that third process Imentioned, oxidative
phosphorylation.
SPEAKER_01 (04:18):
That's a mouthful.
SPEAKER_00 (04:19):
It is, but it's just the actual assembly line inside
your mitochondria where ATP isgenerated.
SPEAKER_01 (04:23):
Aaron Powell And ATP is the energy currency.
SPEAKER_00 (04:25):
Right.
The chemical energy currencyyour body uses to contract
muscles, fire neurons, keep yourheart beating.
SPEAKER_01 (04:30):
So to put it in completely different terms, uh I
want you to imagine your body isthis massive, high-tech, smart
home.
SPEAKER_00 (04:38):
Okay, like this.
SPEAKER_01 (04:39):
Without NAD plus show, it's like the electrical
grid just goes offline.
Right.
Without that physical carriermoving the electrons, the
lights, which are yourmitochondria, they just flicker
and die.
The security system, which wouldbe your DNA repair mechanisms,
it completely shuts down.
The whole house just goes dark.
SPEAKER_00 (04:56):
Aaron Powell That is a highly accurate analogy.
Because in healthy cells, theentire respiration-driving ADP
synthesis relies entirely on theratio between the empty dump
trucks.
And NAD plus NADH.
When your NAD plus levelsdecline, the transport system
halts.
That leads directly tomitochondrial dysfunction.
SPEAKER_01 (05:16):
Which is bad.
SPEAKER_00 (05:16):
It's universally recognized as one of the primary
hallmarks of aging.
Your cells literally suffocatebecause they just can't process
energy.
SPEAKER_01 (05:25):
Dude, that's wild.
And it doesn't stop with justthe mitochondria shutting down
because when we talk about NADplus area, we also have to talk
about the sirtuins.
SPEAKER_00 (05:33):
Ah, yes, the sirtuins.
SPEAKER_01 (05:35):
Which, going back to the smart home thing, those
would be the security guardsrunning the house, right?
SPEAKER_00 (05:40):
The sirtuins are fascinating.
In humans, we have seven ofthem, Sert T1 through CirceRT7.
In the longevity community,you'll hear them constantly
referred to as the longevityproteins.
SPEAKER_01 (05:50):
Right.
SPEAKER_00 (05:51):
Biochemically, they are NAD plus independent
diabetylysis.
SPEAKER_01 (05:56):
Okay, stop right there.
Diacylase explain what thatactually means in plain English,
because that gets thrown arounda lot in these longevity blogs,
and it sounds superintimidating.
SPEAKER_00 (06:05):
Let's break the word down.
A deacetylase is an enzyme thatremoves a specific chemical tag
called an acetyl group fromother proteins.
Think of an acetyl group as aphysical clamp on a piece of
machinery.
When the clamp is on, themachine behaves one way, or
maybe it's turned offcompletely.
SPEAKER_01 (06:21):
So the sirtuin comes along, rips the clamp off, and
suddenly the machine changesbehavior, like flipping a
molecular switch.
SPEAKER_00 (06:28):
Yes, that is the exact mechanism.
And through this deacetylaseactivity, sirtuans manage
immense cellularresponsibilities.
They regulate cellular stressresponses, they initiate DNA
repair when you're exposed toradiation or toxins.
SPEAKER_01 (06:44):
Wow.
SPEAKER_00 (06:45):
And they control mitochondrial biogenesis.
SPEAKER_01 (06:47):
Which means building new mitochondria.
SPEAKER_00 (06:49):
Exactly.
It's the cell's ability to buildbrand new mitochondria when the
old ones wear out.
SPEAKER_01 (06:54):
That's incredible.
So they're just constantlypatrolling the cell, flipping
switches, telling the body, hey,clean up this misfolded protein,
fix that broken strand of DNA,build more engines.
SPEAKER_00 (07:03):
They are the master regulators.
For example, look at Sort3.
Sort 3 is localized specificallyinside the mitochondria.
Its job is to regulate keymetabolic enzymes like IDH2 and
LCAD.
SPEAKER_01 (07:14):
And what do those do?
SPEAKER_00 (07:15):
Well, IDH2 is an enzyme that protects the cell
against severe oxidative stress.
It neutralizes the toxicbyproducts of energy production.
SPEAKER_01 (07:24):
Sort of like cleaning up the exhaust fumes.
SPEAKER_00 (07:26):
Exactly.
And LCAD stands for long-chainacylcoa dehydrogenase.
It's the enzyme that allows yourbody to break down stored fat
for energy instead of justrelying on sugar.
SPEAKER_01 (07:35):
Oh wow.
So Certi3 is basically the bossthat turns on the fat-burning
furnace and the antioxidantdefense shield.
SPEAKER_00 (07:41):
Yes.
But here is the critical,non-negotiable catch in all of
this biology.
Sertuans are strictly dependenton NAD plus Shay.
SPEAKER_01 (07:51):
Right.
The NAD plus a dependent part ofthe name.
If there's no electricity in thesmart home, the security guards
can't do their jobs.
They don't have the fuel.
SPEAKER_00 (07:59):
They are physically incapable of functioning without
it.
When sirtuans remove that acetylplant we talked about, they
actually consume a molecule ofNAD plus in the process.
SPEAKER_01 (08:09):
Oh, they use it up?
SPEAKER_00 (08:10):
Yes.
If NAD plus levels drop below acertain threshold, the sirtuins
just go dormant.
The DNA damage accumulates, themitochondria don't get rebuilt,
and you age.
SPEAKER_01 (08:20):
Okay.
That makes perfect terrifyingsense.
But wait, since we're talkingabout fueling sirtuins, uh, I
have to ask about this.
Because maybe four or five yearsago, the internet completely
lost its mind over cert foods.
SPEAKER_00 (08:30):
The certfood diet, I knew we would end up here.
SPEAKER_01 (08:33):
Dude, people were obsessed.
I mean, the entire pitch wasthat certain foods contain
natural compounds that basicallyforce these sirtuan pathways to
activate.
SPEAKER_00 (08:40):
Yes, I remember.
SPEAKER_01 (08:41):
We're talking drinking green tea for the
catechins, eating bowls ofberries for anthocyanins, red
onions, turmeric for curcumin,and the big one, drinking red
wine and eating dark chocolatefor the resveratrol.
SPEAKER_00 (08:53):
The dream diet.
SPEAKER_01 (08:54):
Literally, people genuinely believe they could
drink their way to geneticlongevity.
SPEAKER_00 (08:59):
It is a brilliant marketing pitch because it tells
people exactly what they want tohear.
Drink wine, eat chocolate, liveforever.
SPEAKER_01 (09:06):
Yeah.
SPEAKER_00 (09:07):
Unfortunately, the clinical reality is
significantly more sobering.
SPEAKER_01 (09:12):
Come on, ruin the red wine dream for me.
Why doesn't it work?
SPEAKER_00 (09:15):
Well, the premise isn't entirely fabricated.
It is based on isolatedbiochemistry.
Many of these plant-derivedbioactive molecules, which fall
under the general category ofpolyphenols, they do show an
ability to interact with andinfluence sertuan activity.
SPEAKER_01 (09:30):
Okay, so it's not a total lie.
SPEAKER_00 (09:32):
No, but almost all of that foundational evidence
comes from preclinical studies.
SPEAKER_01 (09:36):
Meaning in vitro, like isolated cells floating in
a petri dish.
SPEAKER_00 (09:40):
Exactly.
Or, at best, geneticallyidentical mice living in highly
sterile cages.
The problem happens when you tryto translate a chemical reaction
in a glass dish to the digestivesystem of a living human being
eating a salad.
You run straight into the brickwalls of dose, matrix, and
bioavailability.
SPEAKER_01 (10:00):
Okay, explain bioavailability in this context,
because I assume when I eat ablueberry, my body is absorbing
the nutrients, right?
SPEAKER_00 (10:06):
Aaron Powell It absorbs some, yes.
But polyphenols like resveratrolare heavily subjected to what we
call first pass metabolism.
What's that?
When you swallow it, it goesstraight to your liver.
And your liver's primary job isto look at foreign chemical
compounds, break them down, andexcrete them.
SPEAKER_01 (10:21):
Oh.
SPEAKER_00 (10:22):
So the bioavailability, the actual
amount of intact resveratrolthat makes it past the liver and
into your bloodstream to reachyour cells is fractions of a
percent.
SPEAKER_01 (10:30):
Oh wow.
So the liver basically justviews it as biological waste and
filters it out.
SPEAKER_00 (10:35):
Mostly, yes.
The amount of resveratrol youwould need to consume to
actually alter your Sirtuanpathways in a meaningful way, is
staggeringly high.
You couldn't physically drinkenough red wine to reach that
therapeutic dose without dyingof acute alcohol poisoning
first.
SPEAKER_01 (10:51):
Which would, ironically, be very bad for your
longevity.
SPEAKER_00 (10:54):
It would, very bad.
And we also have the matrixeffect.
SPEAKER_01 (10:58):
The matrix effect, like living in a simulation.
SPEAKER_00 (11:01):
Not quite.
In a petri dish, you areapplying pure isolated curcumin
directly to a cell.
In human life, you are eatingturmeric mixed with fats,
fibers, and stomach acid.
All of those things physicallyalter how the chemical is
absorbed.
SPEAKER_01 (11:16):
That makes sense.
SPEAKER_00 (11:17):
So while these are undeniably healthy foods with
general antioxidant properties,the idea that adding capers and
green tea to your diet is goingto biologically hyperactivate
your sertuan genes is just notsupported by clinical reality.
SPEAKER_01 (11:29):
Okay, so salads and wine aren't the magic fix.
Which brings us back to the coremechanical problem.
The NAD plus decline itself.
If NAD plus is so universallyimportant, if it literally keeps
the mitochondrial lights on andthe security system running, why
do we run out of it?
Like, does the human body justget tired of manufacturing it,
or is something activelydestroying it?
SPEAKER_00 (11:50):
That has been the central investigative question
in aging research for decades.
We know empirically that NADplus levels drop severely with
age.
The data we are looking at fromhuman tissue samples shows a
roughly 50% drop by middle age.
SPEAKER_01 (12:04):
50%?
That's massive.
SPEAKER_00 (12:06):
It's a huge loss.
And for a very long time, thescientific community blamed that
decline on enzymes like PRP1 andSRT1.
SPEAKER_01 (12:13):
Wait, PRP1, that's the enzyme that repairs DNA
damage, right?
SPEAKER_00 (12:16):
Yes.
PRP1 is a major consumer of NADplus cell auto.
So the prevailing theory wasbeautifully simple.
As we get older, we are exposedto more UV radiation, more
toxins, and we accumulate morecellular damage.
Right.
Therefore, PRP1 has to workovertime to fix all that broken
DNA.
And because it consumes NAD plusto do its job, it just
aggressively burns through ourentire molecular fuel supply.
SPEAKER_01 (12:38):
Honestly, that sounds completely logical.
You get older, you sustain moredamage, the repair crew uses up
all the supplies.
So uh why are you sayingprevailing theory in the past
tense?
SPEAKER_00 (12:49):
Because it turned out to be wrong.
SPEAKER_01 (12:51):
Really?
SPEAKER_00 (12:51):
Yes.
When researchers finallydeveloped the tools to
accurately measure the actualprotein levels of PARIP1 and
SERAT1 in aging mammaliantissues, looking at the liver,
white adipose tissue, thespleen, skeletal muscle, they
found the exact opposite of whateveryone expected.
SPEAKER_01 (13:07):
Hang on, you're telling me the entire longevity
field pointed at PRP1 and said,that's the guy draining the
tank, but they didn't actuallycheck the real levels in aging
bodies.
How does an entire scientificcommunity get that backward?
SPEAKER_00 (13:20):
It's a great question, and it comes down to
methodology.
Early studies often measuredenzyme activity during states of
acute stress.
SPEAKER_01 (13:26):
Okay.
SPEAKER_00 (13:27):
If you blast a cell with radiation, PRP1 activity
skyrockets.
Scientists extrapolated fromthose acute damage states to
assume that chronic aging workedthe same way.
SPEAKER_01 (13:36):
Ah, I see.
SPEAKER_00 (13:37):
But when they measured resting baseline
protein levels across a naturallifespan, they found that PRP1
and RCPA1 levels actuallydecrease during chronological
aging.
SPEAKER_01 (13:48):
Wait, so the things we thought were eating all the
NAD plus are actuallydisappearing from the cell too?
SPEAKER_00 (13:52):
Exactly.
They are fading away rightalongside the NAD plus fiddle
number.
And while it shocked researchersat first, it actually aligns
perfectly with a much olderevolutionary concept called the
disposable soma theory.
SPEAKER_01 (14:05):
Okay, what is the disposable soma theory?
SPEAKER_00 (14:08):
It's a theory proposed in the late 1970s.
It suggests that organisms havea strictly limited energy
budget.
Evolutionarily speaking, aspecies only needs an individual
to survive long enough to reachsexual maturity, reproduce, and
maybe rear the next generation.
SPEAKER_01 (14:23):
Right.
Get your genes into the nextpool.
SPEAKER_00 (14:25):
Yes.
So it is biologicallyadvantageous to invest your
limited cellular energy intoimmediate growth and
reproduction, rather thaninvesting massive amounts of
energy into permanentlymaintaining and repairing the
physical body, the somaindefinitely.
SPEAKER_01 (14:38):
So the body basically says, look, you
reproduced, you passed on yourgenes, my job here is done.
I'm not wasting any more energykeeping your DNA pristine.
SPEAKER_00 (14:46):
Essentially, yes.
Evolution has no incentive tokeep you vibrant at 80 years
old.
SPEAKER_01 (14:51):
Man, that is just brutally coldly efficient and
kind of depressing, honestly.
But if parap1 is fading away andthe repair crew is packing up
and going home, it means theyaren't the ones draining the NAD
plus Soka.
Correct.
Which means there's a missingculprit.
SPEAKER_00 (15:06):
Precisely.
Scientists realized they werehunting the wrong suspect.
If Parap1 isn't draining thereservoir, what is?
And that brings us to the actualundeniable villain of our
cellular biology story.
SPEAKER_01 (15:18):
Okay, let's hear it.
SPEAKER_00 (15:19):
An enzyme called CD38.
SPEAKER_01 (15:20):
CD38, it sounds like a tax form or some bureaucratic
filing curve.
What does it do?
SPEAKER_00 (15:25):
It is what we call an Nidase, meaning its primary
biological function is tolocate, bind to, and literally
chew up NAD plus molecules.
SPEAKER_01 (15:33):
Oh wow.
SPEAKER_00 (15:34):
And unlike PRP1, which fades as we age, the
expression in the activity ofCD38 increase aggressively over
time.
The studies show that in alltissues tested, CD38 levels
increased by two to three timesduring chronological aging.
SPEAKER_01 (15:50):
So wait, the body actively ramps up the production
of the very thing, destroyingits own energy supply.
SPEAKER_00 (15:55):
Yes.
If you look at tissue stains ofan aging liver, both the total
number of CD38 positive cellsand the intensity of the CD38
expression within those cellsshoot up dramatically.
SPEAKER_01 (16:05):
That is wild.
It's like a metabolic game ofPac-Man.
But as you get older, the gameglitches, and suddenly there are
three times as many Pac-Men onthe board, and they're just
aggressively hunting down andeating all your energy pellets.
SPEAKER_00 (16:16):
That is a phenomenal visualization, truly.
And the data supports itperfectly.
When researchers plotted therising curve of C D38 activity
against the falling curve of NADplus levels in aging tissues,
the inverse correlation wasnearly flawless.
As the Pac-Man multiplies, theNAD plus drops.
SPEAKER_01 (16:32):
But hold on, correlation isn't causation,
right?
How did they prove this wasn'tjust two things happening at the
same time?
Like maybe we just get gray hairand more CD38, but one doesn't
cause the other.
How did they prove CD38 isactually the one pulling the
trigger?
SPEAKER_00 (16:48):
They proved it through genetic manipulation.
It's detailed in a reallyfascinating study published in
the journal Cell Metabolism.
They use water called CD38knockout mice.
SPEAKER_01 (16:58):
Knockout mice! Meaning they went into their DNA
and literally deleted the genethat creates CD38.
SPEAKER_00 (17:04):
Exactly.
They engineered a lineage ofmice to completely lack the CD38
enzyme.
So we have our wild type mice.
SPEAKER_01 (17:11):
Which is the normal mice, right?
SPEAKER_00 (17:12):
Right.
The normal unmutated mice you'dfind in nature.
And we have our CD38 knockouts.
The researchers just let themage normally and watch what
happened to their cellularbatteries.
SPEAKER_01 (17:21):
Did the knockouts turn into super mice?
SPEAKER_00 (17:23):
Biochemically, you could definitely call them that.
The results were striking.
The knockout mice maintainedyouthful, high capacity NAD plus
levels, even when they werechronologically old.
SPEAKER_01 (17:35):
No way.
SPEAKER_00 (17:36):
Their NAD plus reservoir simply didn't crash
because the Pac-Man wasn't thereto eat it.
SPEAKER_01 (17:40):
Whoa.
So just by deleting that oneenzyme, the battery stays green.
SPEAKER_00 (17:45):
Yes.
And because their NAD plusstayed high, their downstream
cellular machinery remainedtotally intact.
The researchers specificallymeasured the activity of the
mitochondrial complexes, complexone, three, and four.
SPEAKER_01 (17:58):
Which are the physical stations on that ATP
assembly line we talked aboutearlier?
SPEAKER_00 (18:02):
Correct.
In normal old mice, thosecomplexes degrade.
In the knockout mice, theirfunction was perfectly
preserved.
They demonstrated higher oxygenconsumption, and their SRT3
activity, that mitochondrialsecurity guard, stayed highly
functional.
SPEAKER_01 (18:17):
Okay, that is incredibly compelling.
But did they test it in reverse?
Like if you take a young,healthy cell and force it to
make too much CD38, does itinstantly age?
SPEAKER_00 (18:25):
They did exactly that.
They took normal, healthy humancells, kidney cells in this
specific experiment, and theygenetically forced them to
overexpress CD38 to just floodthe intracellular environment
with the NIDAS.
SPEAKER_01 (18:36):
Let me guess.
Complete metabolic collapse.
SPEAKER_00 (18:39):
Total dysfunction.
By artificially ramping up CD38,they induced severe NAD plus
loss, which, as we now know,immediately suffocated the
mitochondria.
The respiration rate plummeted,and the fill showed a massive
increase in lactate release.
SPEAKER_01 (18:53):
Why lactate like lactic acid from working out?
SPEAKER_00 (18:56):
Exactly the same thing.
When mitochondria fail and canno longer process oxygen for
energy, the well panics.
It falls back on a primitive,highly inefficient backup system
called fermentation to survive.
A byproduct of cellularfermentation is lactate.
So a spike in lactate is amassive flashing warning light
that the mitochondria aresuffocating.
(19:18):
The CD38 literally choked outthe cell's energy supply by
degrading all the NAD plus andNADH.
SPEAKER_01 (19:24):
Okay, so CD38 is definitively the saboteur.
We've solved the mystery of whythe battery is blinking red.
So I mean, logically, if we knowCD38 is the thing eating our NAD
plus Dell, the obvious next stepis figuring out how to outpace
the destruction.
SPEAKER_00 (19:38):
That's where most people's minds go, yes.
SPEAKER_01 (19:40):
Can we just swallow more NAD plus steps?
Because I've seen bottles ofstraight NAD plus online.
Can we just take a pill andflood the system faster than the
Pac-Man can eat it?
SPEAKER_00 (19:48):
You would think it would be that simple, but
unfortunately, it is physicallyimpossible.
You cannot just take NAD pluspills to raise intracellular
levels.
SPEAKER_01 (19:57):
Why not?
If it's the exact molecule thebody needs.
SPEAKER_00 (20:00):
Because of the physical structure of the
molecule itself.
NAD Plus is a very large, bulkymolecule, and crucially, it
carries a heavy electricalcharge.
SPEAKER_01 (20:10):
Okay, and why does that matter?
SPEAKER_00 (20:11):
The membrane that surrounds every cell in your
body is specifically designed torepel large, charged molecules
to protect the interior.
If you put pure NAD plus intoyour bloodstream, it just
bounces right off the cellularwalls.
It cannot enter the cell whereit's actually needed.
SPEAKER_01 (20:28):
Oh, so it's like trying to shove a completely
assembled Ferrari through thefront door of your house instead
of just bringing in the partsand building the car in the
living room.
SPEAKER_00 (20:36):
Exactly.
The cell membrane is a lockeddoor for the fully assembled
car.
And those individual car partsare what biologists call
precursors.
If you want to raise the NADplus levels inside the
mitochondria, you have to feedthe cell the smaller, uncharged
raw materials that it can easilyabsorb, pull inside, and then
assemble into NAD plus MELLER.
SPEAKER_01 (20:57):
Okay, and this brings us to the massive
billion-dollar supplementindustry, the precursors.
You hear two acronymsconstantly, NMN and NR.
SPEAKER_00 (21:06):
Yes.
Nicotinamide mononucleotide,which is NMN, and nicotinamide
riboside, which is NR.
Both of these molecules exist toutilize what we call the NAD
plus salvage pathway.
SPEAKER_01 (21:17):
The salvage pathway, like a molecular recycling
center.
SPEAKER_00 (21:20):
That's exactly what it is.
Biology is highly efficient.
Normally, when enzymes likecertumans use a molecule of NAD
plus to repair some DNA, theydon't destroy it completely.
They break off a piece, leavingbehind a byproduct called NAM or
nicotinamide.
The salvage pathway takes thatleftover NAM and painstakingly
recycles it back into fresh NADplus mellar.
SPEAKER_01 (21:39):
So why do we need supplements if we have a
built-in recycling center?
SPEAKER_00 (21:42):
Aaron Ross Powell Because the recycling center has
a bottleneck.
The conversion relies on a veryspecific enzyme called NAPT.
That is the rate limiting stepin the salvage pathway.
SPEAKER_01 (21:51):
Rate limiting meaning uh like rush hour
traffic all trying to merge intoa single lane.
It can only go so fast no matterhow many cars are waiting.
SPEAKER_00 (21:59):
Correct.
Now a very common questionpeople ask is why spend a
hundred dollars on fancy NMNsupplements when I can go to the
pharmacy and buy a giant bottleof basic vitamin B3 niacin for
five dollars.
Niacin is an NAD plus precursortoo.
SPEAKER_01 (22:15):
Right.
I've seen longevity guys talkabout basic niacin.
Does that work?
SPEAKER_00 (22:19):
It does raise NAD plus NA, but it comes with
severe biological penalties.
Taking high doses of nicotinicacid basic niacin triggers a
massive release ofprostaglandins in the body.
SPEAKER_01 (22:30):
And what does that do?
SPEAKER_00 (22:31):
This causes intense dilation of the blood vessels,
resulting in severe full bodyskin flushing.
It feels like a horrible sunburnfrom the inside out, and it's
incredibly uncomfortable.
SPEAKER_01 (22:41):
Okay.
Nobody wants a permanentinternal sunburn.
What if we just take pure NAM,the recycled byproduct you
mentioned?
SPEAKER_00 (22:47):
If you try to flood the system with too much NAM, it
runs straight into that NAMPTtraffic jam we mentioned.
It can't process it fast enough.
SPEAKER_01 (22:54):
So it just backs up.
SPEAKER_00 (22:55):
Worse than that, if massive amounts of NAM pool up
inside the cell waiting to berecycled, it actually causes
feedback inhibition.
The excess NAM literally bindsto the sertuans and turns them
off, which is the exact oppositeof the longevity effect you're
trying to achieve.
SPEAKER_01 (23:13):
Oh wow.
So cheaping out on basic Bvitamins could actually
accelerate aging by shuttingdown the security guards.
That is terrifying.
Okay, so basic vitamins are out.
What makes NR and NMN somathematically special?
SPEAKER_00 (23:25):
They are molecularly designed to bypass those exact
bottlenecks.
They essentially jump the line.
NR is highly praised in theliterature because it's a very
small molecule, meaning iteasily slips right through the
cell membrane without needing aspecial door.
SPEAKER_01 (23:38):
Okay, what about NMN?
SPEAKER_00 (23:39):
NMN is slightly larger, but recent
groundbreaking researchdiscovered that our bodies have
evolved specific transporters, aprotein called SLC12A8, found
heavily in the gut, that act asdedicated turnstiles, actively
pulling NMN directly into thecells.
SPEAKER_01 (23:53):
So they slip past the cell walls, bypass the
traffic jam, and immediatelyassemble into NAD plus C.
We did it.
We figured out the puzzle.
Just take NMN, build the batteryfluid, and outpace the C D38
Pac-Man.
SPEAKER_00 (24:06):
If only human biology were that cooperative.
Yeah.
This is where the literaturedrops a massive frustrating
bombshell.
You remember our saboteur?
SPEAKER_01 (24:14):
CD38, the Pac-Man.
SPEAKER_00 (24:16):
Well, what researchers found is that CD38
doesn't just destroy fullyassembled NAD plus and B, it is
also the primary enzyme in themammalian body that degrades NMN
in vivo.
SPEAKER_01 (24:27):
Wait, what?
Are you serious?
SPEAKER_00 (24:28):
Completely serious.
In vivo just means inside theliving organism rather than in a
test tube.
CD38 acts as what we call anectoenzyme.
SPEAKER_01 (24:36):
Meaning what?
SPEAKER_00 (24:37):
It means that while the enzyme is anchored in the
cell membrane, a large portionof its catalytic destructive
machinery actually faces outwardinto the extracellular space.
SPEAKER_01 (24:45):
Into the bloodstream.
SPEAKER_00 (24:46):
In your bloodstream.
Oh no.
Yes.
When you swallow an expensiveNMN supplement and it enters
your bloodstream, it doesn'tjust neatly float to the cells
that need it.
The outward-facing CD38 enzymesrecognize the NMN in the blood
and actively chew it up beforeit can even cross the membrane
to do its job.
SPEAKER_01 (25:05):
That is genuinely devastating.
So you're spending all thismoney on these cutting-edge
supplements, and your body isliterally using its own aging
enzymes to intercept and eat themedicine before it even reaches
the cellular living room.
SPEAKER_00 (25:17):
In a very large part, yes.
They tested this dynamicdirectly.
They took wild type mice andgave them an intravenous
injection of NR.
Then they measured the blood.
The levels of NR droppedviolently, a 25% decrease in
just the first 75 minutes.
SPEAKER_01 (25:31):
Because the CD38 was immediately ripping it apart in
the blood.
SPEAKER_00 (25:34):
Exactly.
But then they took the C D38knockout mice, the ones without
the Pac-Man enzyme, and gavethem the exact same injection.
In those mice, the circulatinglevels of NR and MN and fully
formed NAD plus stayedsignificantly more stable.
Wow.
Even two and a half hours later,the knockout mice had vastly
higher levels of the precursorcirculating their plasma.
SPEAKER_01 (25:55):
So the Pac-Man isn't just eating the power pellets
inside the cell, it has itsmouth hanging outside the cell,
eating the delivery trucksbringing the new power pellets?
SPEAKER_00 (26:03):
That is a perfect way to conceptualize an
ectoenzyme.
SPEAKER_01 (26:06):
Wait, hold on.
I'm looking at a logical gaphere.
If CD38 is sitting in thebloodstream chewing up all the
NMN, how do all these humanclinical trials claim that
taking NMN raises blood NAD pluslevels?
If the delivery trucks aregetting destroyed, how is the
cargo getting delivered?
SPEAKER_00 (26:24):
That is a very askewed question.
It comes down to two factors: saturation and tissue (26:26):
undefined
distribution.
When you take a massive clinicaldose, say a thousand milligrams
of NMN, you're throwing so manydelivery trucks at the system
that you temporarily saturatethe CD38 enzymes.
SPEAKER_01 (26:40):
Oh, they just can't eat it fast enough.
SPEAKER_00 (26:41):
Exactly.
They are eating as fast as theycan, but a certain percentage of
the NMN simply slips past thebottleneck and makes it into the
cells.
Furthermore, certain tissues,particularly the liver, are
incredibly efficient atabsorbing these precursors the
second they enter circulation,converting them into NAD plus D
and then releasing them backinto the blood in different
forms.
SPEAKER_01 (27:01):
Okay, so it's a brute force attack.
You just overwhelm the Pac-Manwith sheer volume.
SPEAKER_00 (27:05):
Precisely.
But it brings us to the mostcrucial part of this entire deep
dive.
We've talked extensively aboutmice.
Mice living in sterileenvironments get longer
lifespans, better muscles, andpreserve mitochondria from these
precursors.
SPEAKER_01 (27:18):
Right.
SPEAKER_00 (27:18):
But what actually happens when complex human
beings take them?
Because I know regular peopleright now taking a thousand
milligrams of NMN every singlemorning.
I need to know if the expensivepowder sitting in their medicine
cabinets is actually reversingtheir biological age, or if they
just have really, reallyexpensive NMN-rich urine.
SPEAKER_01 (27:37):
This is where we make the critical transition
from the preclinical hype to theharsh clinical reality, right?
Let's look at the human clinicaltrials, specifically focusing on
the comprehensive reviewscompiled in 2025 and 2026.
SPEAKER_00 (27:49):
The reality check.
SPEAKER_01 (27:50):
Bring it on.
I need the truth.
Start with the good news, ifthere is any.
SPEAKER_00 (27:54):
There is definitively good news.
The trials unequivocally provethat oral precursors,
specifically NR, at doses ofaround 1000 milligrams a day,
and NMN at similar doses, aresafe for human consumption.
SPEAKER_01 (28:07):
Okay, so it won't hurt you acutely.
SPEAKER_00 (28:09):
Right.
They do not cause acutetoxicity.
And as we just discussed, theydo successfully and reliably
raise NAD plus levels in humanwhole blood.
SPEAKER_01 (28:18):
So the brute force method works, the blood battery
gets charged.
SPEAKER_00 (28:22):
Yes, and we see significant NAD plus increases
specifically in PBMCs.
SPEAKER_01 (28:26):
Which are what?
SPEAKER_00 (28:27):
Peripheral blood mononuclear cells.
They are a critical component ofyour immune system, things like
T cells and B cells circulatingin your blood.
Elevating NAD plus in thosecells could theoretically help
maintain immune function as weage.
SPEAKER_01 (28:40):
That's definitely a plus.
SPEAKER_00 (28:41):
But beyond just blood markers, there are some
very promising specific clinicalapplications emerging.
For example, a landmark 2026study focused on patients with
Parkinson's disease.
SPEAKER_01 (28:51):
Oh, neurodegeneration.
That's a huge target foranti-aging.
SPEAKER_00 (28:55):
Massive.
In this trial, they gaveParkinson's patients a high
daily dose of NR using magneticresonance spectroscopy, which is
a specialized MRI technique thatuses powerful magnets to
actually measure the chemicalbonds of specific metabolites
inside living tissue.
They proved that the oral NRactually increased cerebral NED
plus levels.
SPEAKER_01 (29:14):
Whoa.
Wait, it crossed the blood-brainbarrier.
That is notoriously difficult todo.
Most drugs just bounce right offthe brain's defense system.
SPEAKER_00 (29:22):
It is a phenomenal finding.
Showing that an oral supplementcan alter the neurochemical
environment of the human brainopens up massive therapeutic
potential for diseases likeParkinson's and Alzheimer's.
SPEAKER_01 (29:34):
That is legitimately incredible.
SPEAKER_00 (29:36):
Additionally, in broader populations, we see some
trials showing mild butstatistically significant
improvements in muscle endurancein older adults.
We also see some slightcardiometabolic improvements,
like reduced arterial stiffnessand more favorable lipid
profiles in certaindemographics.
SPEAKER_01 (29:54):
Okay, so it's not totally fake.
It is doing something tangiblein the human body.
But uh you use the words mildand slight.
You're an analytical person.
I sense a massive butt hoveringover this data.
SPEAKER_00 (30:04):
A very large butt.
While the blood levels of NADplus reliably go up across the
board, the human trialsconsistently reveal something
deeply baffling to theresearchers.
When they take physical biopsiesof the patient's skeletal
muscle, the NAD plus steadystate levels remain completely
unchanged.
SPEAKER_01 (30:21):
Wait, what?
Unchanged?
But you just said they recordedmild improvements in muscle
endurance.
How on earth is the enduranceimproving if the battery inside
the muscle tissue isn't actuallycharging?
SPEAKER_00 (30:32):
That is the grand mystery currently confounding
the field.
It's not that the supplementisn't reaching the muscle
tissue.
We know for a fact it is gettingthere.
SPEAKER_01 (30:41):
How do we know that if the levels don't go up?
SPEAKER_00 (30:44):
Because when researchers analyze those muscle
biopsies, they see massivespikes in the metabolites of NAD
plus breakdown.
When NAD plus is used anddiscarded by the cell, it
creates clearance products,specifically things like MenAM,
which stands for methylatednicotinamide.
The muscle biopsies areabsolutely flooded with MenAM.
SPEAKER_01 (31:03):
Let me make sure I'm wrapping my head around this.
So the engine is running, theexhaust pipe is blowing out
massive clouds of smoke, meaningall those breakdown metabolites.
But when you check the gas tank,the actual NAD plus level looks
exactly the same.
SPEAKER_00 (31:14):
That is a brilliant analogy.
Yes.
It suggests there is a massivemetabolic flux occurring.
The muscle tissue is rapidlypulling in the precursors,
aggressively building NAD plusray, and then instantly burning
it up to power the cell, but itnever allows the baseline,
steady state reservoir toactually rise.
Wow.
And this highlights afundamental, inescapable
(31:35):
difference between laboratorymice and human beings.
Humans are not simply giantmice.
SPEAKER_01 (31:40):
I mean, I would hope not, but biochemically, what's
the difference here?
SPEAKER_00 (31:43):
It comes down to the basal metabolic rate.
A mouse lives incredibly fastand dies very young.
Their baseline cellularmetabolism is roaring
constantly.
So when you flood a mouse withNAD plus precursors, their rapid
metabolism immediatelyincorporates it, yielding these
massive, highly visiblephysiological rejuvenations.
SPEAKER_01 (32:01):
Oh, I see.
SPEAKER_00 (32:01):
In humans, our evolutionary strategy is a slow
burn.
Our metabolic rate issignificantly lower.
This slower biology dictates avery different, much more
conservative response to how NADplus deficits are generated and
how they were repaired.
The human body is highlyresistant to rapid cellular
reprogramming.
SPEAKER_01 (32:18):
Okay, that actually makes total sense.
A mouse is like a Formula Onesports car constantly redlining,
so if you inject premium fuelinto the system, the engine
screams to life immediately.
Humans are more like a massivediesel freight train just idling
along.
You pour in premium fuel and thetrain just keeps idling exactly
the same way.
SPEAKER_00 (32:36):
Well said.
But the slower metabolism isn'teven the most complex hurdle.
There's another uniquely humancomplication that researchers
recently uncovered, and itcompletely rewrites how we view
these oral supplements.
We have to talk about themicrobiome.
SPEAKER_01 (32:51):
The gut bacteria.
What do the microbes in mystomach have to do with my
cellular DNA repair?
SPEAKER_00 (32:56):
Everything, it turns out.
During these human trials,researchers noticed a very
strange anomaly in the bloodwork.
When human participants swalloworal NR capsules, their blood
work suddenly shows a massive,unexpected spike in a specific
molecule called NAD.
SPEAKER_01 (33:12):
NAAD, what is that?
SPEAKER_00 (33:14):
NAD is a chemical intermediate, is a part of the
priesthandler pathway.
And if you recall from ourearlier biochemistry discussion,
the priest handler pathway isthe specific metabolic route the
body uses to process nicotinicacid, which is basic, cheap,
flush-inducing niacin.
SPEAKER_01 (33:31):
But wait, you explicitly said earlier that NR
uses the salvage pathway tobypass the bottleneck.
It doesn't use the price handlerpathway.
Why would a niacin marker bespiking in the blood if they are
taking NR?
SPEAKER_00 (33:43):
Exactly.
It made absolutely zerobiochemical sense until
researchers zoomed out and lookat what was happening in the
human digestive tract before thesupplement even reached the
bloodstream.
When you swallow a capsule ofNR, it drops into your gut.
And your gut microbiome, thetrillions of bacteria living in
your intestines, intercepts ahuge portion of it.
SPEAKER_01 (34:01):
Wait, the bacteria eat the supplement.
SPEAKER_00 (34:03):
Yes.
Specific strains of gutmicrobiota express an enzyme
called nicotinidase.
When the highly advanced,expensive NR molecule floats by,
the bacteria snatch it up anduse that enzyme to physically
cleave the riboside group rightoff the molecule.
They strip it down.
And what's left over after theystrip it?
Nicotinic acid, basic niacin.
SPEAKER_01 (34:25):
You've got to be kidding me.
SPEAKER_00 (34:26):
I am not.
The bacteria covert it toniacin.
Then your intestinal wallabsorbs that bacteria created
niacin, which forces your liverto process it through the price
handler pathway, generating allthat NAAD we see in the blood
tests.
SPEAKER_01 (34:39):
So let me get this straight.
You go online, you pay absolutetop dollar for chemically
advanced, highly stabilizednicotinamide ribocytes
specifically designed to bypassthe cellular bottlenecks.
And your own gut bacteria justmug the supplement in your
stomach, strip it down, and turnit back into the cheap$5
pharmacy niacin before your bodyeven gets a chance to use it.
SPEAKER_00 (34:56):
In a significant number of cases, yes, it
completely reshapes ourunderstanding of how oral
precursors actually work in aliving human.
It's a prime example of whyhuman biology is so much more
stubbornly complex than isolatedcell cultures in a lab.
SPEAKER_01 (35:11):
Okay, this is genuinely blowing my mind.
So if we review the facts, theclinical results in humans are
mostly mild.
The muscle battery levels don'treally rise at all.
The CD38 Pac-Man is eating thesupplement in the blood, and our
gut bacteria are interceptingthe payload in the stomach.
SPEAKER_00 (35:27):
Aaron Powell Yes.
That is an accurate summary.
SPEAKER_01 (35:29):
Aaron Powell Why is the hype so deafening?
Why is everyone from techbillionaires to fitness
influencers pushing NMN and NRas a miracle fountain youth
cure?
Why is there a billion-dollarindustry built on this right
now?
SPEAKER_00 (35:40):
Aaron Powell We have to have a very frank
conversation about the hypeproblem in modern science.
The anti-aging industry hashistorically always been
susceptible to hyperbolicclaims, but NAD plus boosters
are currently the absoluteepicenter of the storm.
The commercialization of NR andNMN has been vastly artificially
amplified by a combination ofcelebrity endorsements and
(36:00):
highly prominent vocalresearchers.
SPEAKER_01 (36:02):
Yeah, I mean, you can't talk about NMN without
talking about those hugecelebrity scientists from places
like Harvard, right?
They're on every major talkshow, writing books, constantly
talking about this stuff.
SPEAKER_00 (36:14):
Aaron Powell Yes, their advocacy, along with
others, has brought massivemainstream visibility to
molecules like NMN.
And while the foundationalbiology they study is real, we
absolutely must look at thestructural conflicts of interest
driving the narrative.
Many of the human clinicaltrials validating these
supplements are heavily industryfunded.
Shocking.
(36:34):
For example, companies likeChromodex are massive funders of
NR research, and they aresimultaneously one of the
largest patent holders andcommercial sellers of NR
supplements in the world.
SPEAKER_01 (36:44):
That feels like a massive red flag.
We investigated our own productand found it to be amazing.
SPEAKER_00 (36:49):
To be fair to the scientific process, industry
funding does not automaticallyinvalidate a study's raw data.
The blood levels really do goup.
But the conflict of interestdictates how that data is
framed.
They are highly motivated tohighlight surrogate markers,
shouting, look, blood NAD plusincrease by 40%, rather than
(37:09):
acknowledging the lack of hardclinical endpoints.
SPEAKER_01 (37:13):
Explain the difference between a surrogate
marker and a clinical endpoint.
SPEAKER_00 (37:17):
A surrogate marker is a biological number on a
piece of paper.
Blood pressure, cholesterollevels, or in this case NAD plus
concentration in the blood.
A clinical endpoint is an actualphysical health outcome.
Did the patient live longer?
Did they avoid a heart attack?
Did their biological agingactually slow down?
Right.
The industry markets thesurrogate marker as if it is a
(37:37):
guaranteed clinical endpoint.
SPEAKER_01 (37:38):
Right.
We changed a number on yourblood test, is biologically very
different from we just made yourorgans genetically 10 years
younger.
SPEAKER_00 (37:45):
Exactly.
And the direct consumermarketing machine completely
blurs that line for the averagebuyer.
But honestly, the marketing spinisn't even the most concerning
part of the industry right now.
It's the catastrophic lack ofquality control and the hidden
theoretical risks that nobodywants to talk about.
SPEAKER_01 (38:02):
Aaron Powell Quality control.
Like are people just straight upnot getting what they pay for?
SPEAKER_00 (38:06):
Far from it.
SPEAKER_01 (38:06):
Okay.
SPEAKER_00 (38:07):
Because NMN and NR are legally classified and sold
as dietary supplements, they arenot regulated by the FDA like
pharmaceutical drugs.
Independent laboratory analysesof the commercial market have
found massive widespread purityissues.
Some of the most popularcommercial NMN supplements on
Amazon contain 30 to 70 percentless active ingredient than what
is legally claimed on the label.
SPEAKER_01 (38:28):
So it's basically expensive flour.
SPEAKER_00 (38:30):
Or worse.
Some independent tests foundbatches heavily contaminated
with basic unrefinednicotinamide, the NAM we
discussed earlier.
SPEAKER_01 (38:38):
Oh no.
SPEAKER_00 (38:39):
And as we established, if you take massive
unregulated doses of raw NAM, itactually causes feedback
inhibition, shutting down yourSertuan longevity genes.
You are essentially payingpremium prices for highly
unpredictable, unregulatedchemistry that could be actively
working against you.
SPEAKER_01 (38:57):
That is infuriating.
You think you're buying a highlyengineered Ferrari part for your
cellular engine, and you'reactually getting a counterfeit
dirty lawnmower spark plug.
SPEAKER_00 (39:05):
And this brings us to a much darker, much more
serious biological reality.
A theoretical risk that thelongevity influencers almost
universally ignore.
SPEAKER_01 (39:14):
Okay, I'm braced.
What is it?
SPEAKER_00 (39:15):
We have spent the last half hour talking about how
NAD plus is the fundamentalnon-negotiable fuel for cellular
energy and rapid DNA repair,correct?
SPEAKER_01 (39:24):
Yeah, it's the battery fluid.
It fuels everything.
SPEAKER_00 (39:26):
Well, think about human pathology for a second.
What specific type of cell hasthe highest, most aggressive
energy demand in the entirehuman body?
What type of cell is constantly,furiously multiplying, ignoring
all biological stop signs, andis utterly desperate for raw
metabolic fuel and constant DNArepair mechanisms to survive its
own rapid mutation?
SPEAKER_01 (39:46):
Oh man, oh no, cancer cells.
SPEAKER_00 (39:49):
Exactly, cancer.
Preclinical models have recentlyilluminated a very concerning
dark side to artificial NAD plusaugmentation.
In highly specific mouse modelsof lymphoma and certain types of
breast cancer, researchers foundthat providing the mice with NAD
plus precursors actually rapidlyaccelerated tumor progression.
SPEAKER_01 (40:09):
Because cancer relies on glycolysis and the
salvage pathway, right?
So if you flood the body withNMN, you aren't just fueling the
healthy cells.
You're giving the cancer cellsthe exact premium fuel and
repair kits they need tomultiply out of control.
SPEAKER_00 (40:22):
That is the exact mechanism.
Cancer cells experience massiveamounts of oxidative stress and
DNA damage because they divideso recklessly.
They desperately rely on PREPenzymes to constantly patch
their broken DNA so they don'tsimply die.
And as we know, PRP strictlyrequires NAD plus to function.
Man.
By taking massive doses ofprecursors, you are
theoretically ensuring thecancer's repair mechanisms never
(40:44):
run out of fuel.
SPEAKER_01 (40:45):
That is a staggering reality check.
SPEAKER_00 (40:48):
Now, it is absolutely crucial that I state
this clearly.
We do not have clinical evidencethat taking NR or NMN causes new
cancers to form in healthy humanbeings.
It does not seem to be acarcinogen in that way.
SPEAKER_01 (41:00):
Okay.
That's somewhat of a relief.
SPEAKER_00 (41:02):
But human biology is messy.
If a person has an undiagnosed,dormant microtumor, which many
aging adults do, or if they havea personal history of cancer and
remission, flooding theirsystemic circulation with highly
bioavailable NAD plus precursorscould theoretically act as a
metabolic accelerant for thosedormant cells.
(41:22):
It is a profound biologicalgamble that the bright,
optimistic, direct-to-consumermarketing completely ignores.
SPEAKER_01 (41:29):
Wow, okay.
That is that's a lot to process.
That completely changes how Iview those little white bottles.
If I'm taking all this in, letme try to synthesize the big
takeaways from this entire deepdive.
SPEAKER_00 (41:39):
Please do.
It's a complex web.
SPEAKER_01 (41:40):
Okay.
On a fundamental level, NAD plusis undeniably our vital cellular
fuel.
It is the literal electricityfor the mitochondria.
It's the required fuel thatallows the Sertuan security
guards to repair our DNA, andlosing it is a core reason why
we biologically age.
That part is true.
SPEAKER_00 (41:55):
Completely true.
The foundational biology issolid.
SPEAKER_01 (41:58):
But as we age, a rogue outward-facing enzyme
called CD38 acts like abiological Pac-Man.
It aggressively multiplies andjust starts eating our NAD plus
supply, causing the whole systemto choke.
And while laboratory scientistshave figured out that you can
use precursor parts like NR andNMN to bypass the cell walls and
theoretically rebuild thebattery, the human translation
(42:20):
is an absolute mess.
SPEAKER_00 (42:22):
A messy, unpredictable translation.
SPEAKER_01 (42:24):
Yes.
The CD38 Pac-Man intercepts thesupplements in the blood.
Our gut bacteria hijack thecapsules in our stomachs and
downgrade them to cheap niacin.
The actual anti-aging results inhuman muscle tissue are
incredibly modest compared tothe marketing hype.
You're probably buyingcounterfeit or underdose
supplements anyway, and worst ofall, if you happen to have a
hidden microtumor, you mightjust be handing it the exact
(42:45):
premium peel it needs to killyou.
SPEAKER_00 (42:47):
You have captured the nuance perfectly.
The biochemistry of NAD isundeniably fascinating.
And as we saw with theParkinson's brain data, it holds
profound, legitimate therapeuticpromise for specific
degenerative diseases whenadministered correctly.
But biology is incrediblystubbornly complex.
(43:08):
Preserving human health span anddelaying mortality is never ever
going to be as simple asswallowing a single isolated
compound from a plastic bottleyou bought on the internet.
SPEAKER_01 (43:18):
Yeah.
It's a sobering reminder for youlistening right now.
Whenever someone promises you abiological shortcut or tries to
sell you immortality for 80bucks a month, rid the fine
print.
SPEAKER_00 (43:27):
Exactly.
You cannot outsmart millions ofyears of evolutionary biology
with a single chemical loophole.
And honestly, looking at thetotality of this research, it
leaves us with a lingering,somewhat provocative question
about the entire futuredirection of the longevity
field.
What's right now, the entireindustry is spending billions of
dollars trying to out supplementthe aging process.
(43:48):
We are desperately trying toflood our bodies with massive,
unnatural doses of NAD plusprecursors, just hoping that
enough molecules slip past thegut bacteria, survive the liver,
and eventually.
The cellular defenses to make atiny difference in the tissue.
SPEAKER_01 (44:03):
Right.
We're just blindly throwingthousands of power pellets into
the maze, hoping we outpace thePac-Man by sheer volume.
SPEAKER_00 (44:09):
Aaron Powell Precisely.
But if C D thirty eight is theprimary undeniable driver of
this age-related decline, ifit's the Pac-Man that not only
drains our natural endogenousNAD plus reservoir, but also
actively chews up the expensiveNMN supplements we swallow
before they even reach the cell,shouldn't the future of
anti-aging medicine pivotcompletely?
Instead of trying to endlesslyfuel the system, shouldn't we be
(44:33):
focused on finding a safe,precise way to simply switch off
the Pac-Man?
SPEAKER_01 (44:36):
Oh wow, yeah.
Don't buy more gas, just unplugthe C D thirty eight.
SPEAKER_00 (44:39):
Yeah.
Exactly.
Instead of constantly trying torefill a biological bucket that
has a massive growing hole init, perhaps the next great leap
in human longevity won't be anew highly marketed precursor
supplement at all.
Perhaps the true breakthroughwill be a targeted molecular C D
thirty eight inhibitor,something that just patches the
hole, turns off the enzyme, andallows our bodies to naturally
(45:01):
restore their own youthfulenergy levels without
interference.
Just something to criticallythink about the next time your
feed serves you an ad for amiracle longevity pill.
I want you to imagine something for a second.
Imagine if your cells.
Uh every single one of thetrillions of microsopic cells
keeping you alive right now hada tiny battery indicator
floating right above them.
SPEAKER_00 (00:13):
Like exactly what you see in the top right corner
of your phone screen.
SPEAKER_01 (00:16):
Yes, exactly like that.
And you know, when you're a kid,that battery is just pegged at
100%.
It is bright solid green.
Right.
You can run around a playgroundall day, scrape your knee,
bounce back the next morning,and your internal machinery just
hums along.
But as you get older, thatlittle battery icon starts
draining.
It drops to 80%, then 50%.
(00:37):
And eventually, somewhere inmiddle age, it starts blinking
that terrifying, anxious,flashing red.
SPEAKER_00 (00:44):
Which is honestly a very visceral way to visualize
chronological aging versusbiological aging.
Trevor Burrus, Jr.
SPEAKER_01 (00:50):
It's the worst feeling when your phone does it,
and it's worse when your bodydoes it.
You know, your energy dips, yourmuscles just don't recover after
a workout, your focus blurs.
The fundamental machinery ofyour body just sort of it grinds
down.
SPEAKER_00 (01:02):
Aaron Powell And that blinking red battery isn't
just a metaphor, it is the exactbiological mechanism we are
unpacking for today's deep dive.
Because that cellular battery ispowered by a very real, very
heavily researched moleculecalled NAD plus Nair.
SPEAKER_01 (01:19):
Right.
NAD plus C, which stands fornicotinamide adenine
dinucleotide.
SPEAKER_00 (01:25):
Right.
You nailed the pronunciation.
SPEAKER_01 (01:26):
Thank you.
I practiced.
But seriously, I mean, I can'teven open my phone lately
without seeing a techbillionaire or some fitness
influencer trying to sell me apill that supposedly boosts this
stuff.
The obsession is justeverywhere.
SPEAKER_00 (01:38):
It really is.
It sits at the absolute centerof the modern anti-aging
industry, but uh moreimportantly, it sits at the
center of the human agingprocess itself.
SPEAKER_01 (01:47):
Yeah.
SPEAKER_00 (01:48):
So today we are going to cut straight through
the marketing campaigns.
We have a massive stack ofscientific literature in front
of us.
SPEAKER_01 (01:53):
Well, it is a mountain of papers.
SPEAKER_00 (01:55):
Literally.
We've got clinical reviews from2025 and 2026, deep cellular
biology studies, metabolicprofiles.
And our mission today is to lookat exactly what happens inside
human cells when that batterydrains.
SPEAKER_01 (02:07):
Because the hype right now is completely
unhinged.
You have entire supplementempires built overnight, people
claiming they've found theliteral cure for aging, and you
know, consumers spendingbillions on NAD plus precursors
like NMN and NR.
SPEAKER_00 (02:20):
Aaron Powell Which is why we need to separate the
genuine, fascinating cellularbiology from the frankly
dangerous commercial hype.
The transition from we reversedaging in a laboratory mouse to
this pill works in complex humanbeings is incredibly fraught.
SPEAKER_01 (02:37):
So fraught.
Let's unpack the actual biologyfirst, because before we can
understand why we're losing ourvitality, we really need to
understand what powers it in thefirst place.
SPEAKER_00 (02:45):
Exactly.
SPEAKER_01 (02:46):
So uh NAD plus gas, the battery fluid, what exactly
is this molecule doing inside ofus?
SPEAKER_00 (02:52):
Aaron Ross Powell Well, at its core, NAD plus is
an essential coenzyme for energyproduction.
You can kind of think of it as abiological shuttle bus.
Aaron Powell A shuttle bus?
For what?
For electrons.
It is absolutely critical forthe fundamental metabolic
processes.
And I'm talking about thefoundational mechanics of
keeping a mammal alive.
Things like glycolysis, thetricarboxylic acid cycle,
(03:13):
oxidative phosphorylation.
SPEAKER_01 (03:14):
Okay, wait, hold on.
Let's not lose anyone in thebiochemistry right out of the
gate.
Let's break those down.
Glycolysis is just, I mean,that's just breaking down sugar,
right?
SPEAKER_00 (03:23):
Basically, yes.
Glycolysis literally meanssplitting sugar.
When you eat a carbohydrate, itenters the cell and an enzymatic
process splits that glucosemolecule to extract energy.
Right.
But to do that, the cell needsto move electrons around.
This involves what we call redoxreactions.
SPEAKER_01 (03:41):
Redox, meaning reduction and oxidation.
SPEAKER_00 (03:44):
Precisely.
Oxidation is when a moleculeloses an electron, and reduction
is when a molecule gains anelectron.
NAD plus is the molecule thatswoops in, grabs those
high-energy electrons from thesugar you ate.
Which reduces the NAD plus itinto a form called NADH, and
then it acts as that shuttlebus, physically carrying those
electrons to the mitochondria.
SPEAKER_01 (04:04):
Aaron Powell, so it's literally like a
microscopic dump truck justmoving energy from my breakfast
into my cellular engines.
SPEAKER_00 (04:10):
Aaron Powell That is exactly what it is.
And once it drops off thoseelectrons at the mitochondria,
it powers that third process Imentioned, oxidative
phosphorylation.
SPEAKER_01 (04:18):
That's a mouthful.
SPEAKER_00 (04:19):
It is, but it's just the actual assembly line inside
your mitochondria where ATP isgenerated.
SPEAKER_01 (04:23):
Aaron Powell And ATP is the energy currency.
SPEAKER_00 (04:25):
Right.
The chemical energy currencyyour body uses to contract
muscles, fire neurons, keep yourheart beating.
SPEAKER_01 (04:30):
So to put it in completely different terms, uh I
want you to imagine your body isthis massive, high-tech, smart
home.
SPEAKER_00 (04:38):
Okay, like this.
SPEAKER_01 (04:39):
Without NAD plus show, it's like the electrical
grid just goes offline.
Right.
Without that physical carriermoving the electrons, the
lights, which are yourmitochondria, they just flicker
and die.
The security system, which wouldbe your DNA repair mechanisms,
it completely shuts down.
The whole house just goes dark.
SPEAKER_00 (04:56):
Aaron Powell That is a highly accurate analogy.
Because in healthy cells, theentire respiration-driving ADP
synthesis relies entirely on theratio between the empty dump
trucks.
And NAD plus NADH.
When your NAD plus levelsdecline, the transport system
halts.
That leads directly tomitochondrial dysfunction.
SPEAKER_01 (05:16):
Which is bad.
SPEAKER_00 (05:16):
It's universally recognized as one of the primary
hallmarks of aging.
Your cells literally suffocatebecause they just can't process
energy.
SPEAKER_01 (05:25):
Dude, that's wild.
And it doesn't stop with justthe mitochondria shutting down
because when we talk about NADplus area, we also have to talk
about the sirtuins.
SPEAKER_00 (05:33):
Ah, yes, the sirtuins.
SPEAKER_01 (05:35):
Which, going back to the smart home thing, those
would be the security guardsrunning the house, right?
SPEAKER_00 (05:40):
The sirtuins are fascinating.
In humans, we have seven ofthem, Sert T1 through CirceRT7.
In the longevity community,you'll hear them constantly
referred to as the longevityproteins.
SPEAKER_01 (05:50):
Right.
SPEAKER_00 (05:51):
Biochemically, they are NAD plus independent
diabetylysis.
SPEAKER_01 (05:56):
Okay, stop right there.
Diacylase explain what thatactually means in plain English,
because that gets thrown arounda lot in these longevity blogs,
and it sounds superintimidating.
SPEAKER_00 (06:05):
Let's break the word down.
A deacetylase is an enzyme thatremoves a specific chemical tag
called an acetyl group fromother proteins.
Think of an acetyl group as aphysical clamp on a piece of
machinery.
When the clamp is on, themachine behaves one way, or
maybe it's turned offcompletely.
SPEAKER_01 (06:21):
So the sirtuin comes along, rips the clamp off, and
suddenly the machine changesbehavior, like flipping a
molecular switch.
SPEAKER_00 (06:28):
Yes, that is the exact mechanism.
And through this deacetylaseactivity, sirtuans manage
immense cellularresponsibilities.
They regulate cellular stressresponses, they initiate DNA
repair when you're exposed toradiation or toxins.
SPEAKER_01 (06:44):
Wow.
SPEAKER_00 (06:45):
And they control mitochondrial biogenesis.
SPEAKER_01 (06:47):
Which means building new mitochondria.
SPEAKER_00 (06:49):
Exactly.
It's the cell's ability to buildbrand new mitochondria when the
old ones wear out.
SPEAKER_01 (06:54):
That's incredible.
So they're just constantlypatrolling the cell, flipping
switches, telling the body, hey,clean up this misfolded protein,
fix that broken strand of DNA,build more engines.
SPEAKER_00 (07:03):
They are the master regulators.
For example, look at Sort3.
Sort 3 is localized specificallyinside the mitochondria.
Its job is to regulate keymetabolic enzymes like IDH2 and
LCAD.
SPEAKER_01 (07:14):
And what do those do?
SPEAKER_00 (07:15):
Well, IDH2 is an enzyme that protects the cell
against severe oxidative stress.
It neutralizes the toxicbyproducts of energy production.
SPEAKER_01 (07:24):
Sort of like cleaning up the exhaust fumes.
SPEAKER_00 (07:26):
Exactly.
And LCAD stands for long-chainacylcoa dehydrogenase.
It's the enzyme that allows yourbody to break down stored fat
for energy instead of justrelying on sugar.
SPEAKER_01 (07:35):
Oh wow.
So Certi3 is basically the bossthat turns on the fat-burning
furnace and the antioxidantdefense shield.
SPEAKER_00 (07:41):
Yes.
But here is the critical,non-negotiable catch in all of
this biology.
Sertuans are strictly dependenton NAD plus Shay.
SPEAKER_01 (07:51):
Right.
The NAD plus a dependent part ofthe name.
If there's no electricity in thesmart home, the security guards
can't do their jobs.
They don't have the fuel.
SPEAKER_00 (07:59):
They are physically incapable of functioning without
it.
When sirtuans remove that acetylplant we talked about, they
actually consume a molecule ofNAD plus in the process.
SPEAKER_01 (08:09):
Oh, they use it up?
SPEAKER_00 (08:10):
Yes.
If NAD plus levels drop below acertain threshold, the sirtuins
just go dormant.
The DNA damage accumulates, themitochondria don't get rebuilt,
and you age.
SPEAKER_01 (08:20):
Okay.
That makes perfect terrifyingsense.
But wait, since we're talkingabout fueling sirtuins, uh, I
have to ask about this.
Because maybe four or five yearsago, the internet completely
lost its mind over cert foods.
SPEAKER_00 (08:30):
The certfood diet, I knew we would end up here.
SPEAKER_01 (08:33):
Dude, people were obsessed.
I mean, the entire pitch wasthat certain foods contain
natural compounds that basicallyforce these sirtuan pathways to
activate.
SPEAKER_00 (08:40):
Yes, I remember.
SPEAKER_01 (08:41):
We're talking drinking green tea for the
catechins, eating bowls ofberries for anthocyanins, red
onions, turmeric for curcumin,and the big one, drinking red
wine and eating dark chocolatefor the resveratrol.
SPEAKER_00 (08:53):
The dream diet.
SPEAKER_01 (08:54):
Literally, people genuinely believe they could
drink their way to geneticlongevity.
SPEAKER_00 (08:59):
It is a brilliant marketing pitch because it tells
people exactly what they want tohear.
Drink wine, eat chocolate, liveforever.
SPEAKER_01 (09:06):
Yeah.
SPEAKER_00 (09:07):
Unfortunately, the clinical reality is
significantly more sobering.
SPEAKER_01 (09:12):
Come on, ruin the red wine dream for me.
Why doesn't it work?
SPEAKER_00 (09:15):
Well, the premise isn't entirely fabricated.
It is based on isolatedbiochemistry.
Many of these plant-derivedbioactive molecules, which fall
under the general category ofpolyphenols, they do show an
ability to interact with andinfluence sertuan activity.
SPEAKER_01 (09:30):
Okay, so it's not a total lie.
SPEAKER_00 (09:32):
No, but almost all of that foundational evidence
comes from preclinical studies.
SPEAKER_01 (09:36):
Meaning in vitro, like isolated cells floating in
a petri dish.
SPEAKER_00 (09:40):
Exactly.
Or, at best, geneticallyidentical mice living in highly
sterile cages.
The problem happens when you tryto translate a chemical reaction
in a glass dish to the digestivesystem of a living human being
eating a salad.
You run straight into the brickwalls of dose, matrix, and
bioavailability.
SPEAKER_01 (10:00):
Okay, explain bioavailability in this context,
because I assume when I eat ablueberry, my body is absorbing
the nutrients, right?
SPEAKER_00 (10:06):
Aaron Powell It absorbs some, yes.
But polyphenols like resveratrolare heavily subjected to what we
call first pass metabolism.
What's that?
When you swallow it, it goesstraight to your liver.
And your liver's primary job isto look at foreign chemical
compounds, break them down, andexcrete them.
SPEAKER_01 (10:21):
Oh.
SPEAKER_00 (10:22):
So the bioavailability, the actual
amount of intact resveratrolthat makes it past the liver and
into your bloodstream to reachyour cells is fractions of a
percent.
SPEAKER_01 (10:30):
Oh wow.
So the liver basically justviews it as biological waste and
filters it out.
SPEAKER_00 (10:35):
Mostly, yes.
The amount of resveratrol youwould need to consume to
actually alter your Sirtuanpathways in a meaningful way, is
staggeringly high.
You couldn't physically drinkenough red wine to reach that
therapeutic dose without dyingof acute alcohol poisoning
first.
SPEAKER_01 (10:51):
Which would, ironically, be very bad for your
longevity.
SPEAKER_00 (10:54):
It would, very bad.
And we also have the matrixeffect.
SPEAKER_01 (10:58):
The matrix effect, like living in a simulation.
SPEAKER_00 (11:01):
Not quite.
In a petri dish, you areapplying pure isolated curcumin
directly to a cell.
In human life, you are eatingturmeric mixed with fats,
fibers, and stomach acid.
All of those things physicallyalter how the chemical is
absorbed.
SPEAKER_01 (11:16):
That makes sense.
SPEAKER_00 (11:17):
So while these are undeniably healthy foods with
general antioxidant properties,the idea that adding capers and
green tea to your diet is goingto biologically hyperactivate
your sertuan genes is just notsupported by clinical reality.
SPEAKER_01 (11:29):
Okay, so salads and wine aren't the magic fix.
Which brings us back to the coremechanical problem.
The NAD plus decline itself.
If NAD plus is so universallyimportant, if it literally keeps
the mitochondrial lights on andthe security system running, why
do we run out of it?
Like, does the human body justget tired of manufacturing it,
or is something activelydestroying it?
SPEAKER_00 (11:50):
That has been the central investigative question
in aging research for decades.
We know empirically that NADplus levels drop severely with
age.
The data we are looking at fromhuman tissue samples shows a
roughly 50% drop by middle age.
SPEAKER_01 (12:04):
50%?
That's massive.
SPEAKER_00 (12:06):
It's a huge loss.
And for a very long time, thescientific community blamed that
decline on enzymes like PRP1 andSRT1.
SPEAKER_01 (12:13):
Wait, PRP1, that's the enzyme that repairs DNA
damage, right?
SPEAKER_00 (12:16):
Yes.
PRP1 is a major consumer of NADplus cell auto.
So the prevailing theory wasbeautifully simple.
As we get older, we are exposedto more UV radiation, more
toxins, and we accumulate morecellular damage.
Right.
Therefore, PRP1 has to workovertime to fix all that broken
DNA.
And because it consumes NAD plusto do its job, it just
aggressively burns through ourentire molecular fuel supply.
SPEAKER_01 (12:38):
Honestly, that sounds completely logical.
You get older, you sustain moredamage, the repair crew uses up
all the supplies.
So uh why are you sayingprevailing theory in the past
tense?
SPEAKER_00 (12:49):
Because it turned out to be wrong.
SPEAKER_01 (12:51):
Really?
SPEAKER_00 (12:51):
Yes.
When researchers finallydeveloped the tools to
accurately measure the actualprotein levels of PARIP1 and
SERAT1 in aging mammaliantissues, looking at the liver,
white adipose tissue, thespleen, skeletal muscle, they
found the exact opposite of whateveryone expected.
SPEAKER_01 (13:07):
Hang on, you're telling me the entire longevity
field pointed at PRP1 and said,that's the guy draining the
tank, but they didn't actuallycheck the real levels in aging
bodies.
How does an entire scientificcommunity get that backward?
SPEAKER_00 (13:20):
It's a great question, and it comes down to
methodology.
Early studies often measuredenzyme activity during states of
acute stress.
SPEAKER_01 (13:26):
Okay.
SPEAKER_00 (13:27):
If you blast a cell with radiation, PRP1 activity
skyrockets.
Scientists extrapolated fromthose acute damage states to
assume that chronic aging workedthe same way.
SPEAKER_01 (13:36):
Ah, I see.
SPEAKER_00 (13:37):
But when they measured resting baseline
protein levels across a naturallifespan, they found that PRP1
and RCPA1 levels actuallydecrease during chronological
aging.
SPEAKER_01 (13:48):
Wait, so the things we thought were eating all the
NAD plus are actuallydisappearing from the cell too?
SPEAKER_00 (13:52):
Exactly.
They are fading away rightalongside the NAD plus fiddle
number.
And while it shocked researchersat first, it actually aligns
perfectly with a much olderevolutionary concept called the
disposable soma theory.
SPEAKER_01 (14:05):
Okay, what is the disposable soma theory?
SPEAKER_00 (14:08):
It's a theory proposed in the late 1970s.
It suggests that organisms havea strictly limited energy
budget.
Evolutionarily speaking, aspecies only needs an individual
to survive long enough to reachsexual maturity, reproduce, and
maybe rear the next generation.
SPEAKER_01 (14:23):
Right.
Get your genes into the nextpool.
SPEAKER_00 (14:25):
Yes.
So it is biologicallyadvantageous to invest your
limited cellular energy intoimmediate growth and
reproduction, rather thaninvesting massive amounts of
energy into permanentlymaintaining and repairing the
physical body, the somaindefinitely.
SPEAKER_01 (14:38):
So the body basically says, look, you
reproduced, you passed on yourgenes, my job here is done.
I'm not wasting any more energykeeping your DNA pristine.
SPEAKER_00 (14:46):
Essentially, yes.
Evolution has no incentive tokeep you vibrant at 80 years
old.
SPEAKER_01 (14:51):
Man, that is just brutally coldly efficient and
kind of depressing, honestly.
But if parap1 is fading away andthe repair crew is packing up
and going home, it means theyaren't the ones draining the NAD
plus Soka.
Correct.
Which means there's a missingculprit.
SPEAKER_00 (15:06):
Precisely.
Scientists realized they werehunting the wrong suspect.
If Parap1 isn't draining thereservoir, what is?
And that brings us to the actualundeniable villain of our
cellular biology story.
SPEAKER_01 (15:18):
Okay, let's hear it.
SPEAKER_00 (15:19):
An enzyme called CD38.
SPEAKER_01 (15:20):
CD38, it sounds like a tax form or some bureaucratic
filing curve.
What does it do?
SPEAKER_00 (15:25):
It is what we call an Nidase, meaning its primary
biological function is tolocate, bind to, and literally
chew up NAD plus molecules.
SPEAKER_01 (15:33):
Oh wow.
SPEAKER_00 (15:34):
And unlike PRP1, which fades as we age, the
expression in the activity ofCD38 increase aggressively over
time.
The studies show that in alltissues tested, CD38 levels
increased by two to three timesduring chronological aging.
SPEAKER_01 (15:50):
So wait, the body actively ramps up the production
of the very thing, destroyingits own energy supply.
SPEAKER_00 (15:55):
Yes.
If you look at tissue stains ofan aging liver, both the total
number of CD38 positive cellsand the intensity of the CD38
expression within those cellsshoot up dramatically.
SPEAKER_01 (16:05):
That is wild.
It's like a metabolic game ofPac-Man.
But as you get older, the gameglitches, and suddenly there are
three times as many Pac-Men onthe board, and they're just
aggressively hunting down andeating all your energy pellets.
SPEAKER_00 (16:16):
That is a phenomenal visualization, truly.
And the data supports itperfectly.
When researchers plotted therising curve of C D38 activity
against the falling curve of NADplus levels in aging tissues,
the inverse correlation wasnearly flawless.
As the Pac-Man multiplies, theNAD plus drops.
SPEAKER_01 (16:32):
But hold on, correlation isn't causation,
right?
How did they prove this wasn'tjust two things happening at the
same time?
Like maybe we just get gray hairand more CD38, but one doesn't
cause the other.
How did they prove CD38 isactually the one pulling the
trigger?
SPEAKER_00 (16:48):
They proved it through genetic manipulation.
It's detailed in a reallyfascinating study published in
the journal Cell Metabolism.
They use water called CD38knockout mice.
SPEAKER_01 (16:58):
Knockout mice! Meaning they went into their DNA
and literally deleted the genethat creates CD38.
SPEAKER_00 (17:04):
Exactly.
They engineered a lineage ofmice to completely lack the CD38
enzyme.
So we have our wild type mice.
SPEAKER_01 (17:11):
Which is the normal mice, right?
SPEAKER_00 (17:12):
Right.
The normal unmutated mice you'dfind in nature.
And we have our CD38 knockouts.
The researchers just let themage normally and watch what
happened to their cellularbatteries.
SPEAKER_01 (17:21):
Did the knockouts turn into super mice?
SPEAKER_00 (17:23):
Biochemically, you could definitely call them that.
The results were striking.
The knockout mice maintainedyouthful, high capacity NAD plus
levels, even when they werechronologically old.
SPEAKER_01 (17:35):
No way.
SPEAKER_00 (17:36):
Their NAD plus reservoir simply didn't crash
because the Pac-Man wasn't thereto eat it.
SPEAKER_01 (17:40):
Whoa.
So just by deleting that oneenzyme, the battery stays green.
SPEAKER_00 (17:45):
Yes.
And because their NAD plusstayed high, their downstream
cellular machinery remainedtotally intact.
The researchers specificallymeasured the activity of the
mitochondrial complexes, complexone, three, and four.
SPEAKER_01 (17:58):
Which are the physical stations on that ATP
assembly line we talked aboutearlier?
SPEAKER_00 (18:02):
Correct.
In normal old mice, thosecomplexes degrade.
In the knockout mice, theirfunction was perfectly
preserved.
They demonstrated higher oxygenconsumption, and their SRT3
activity, that mitochondrialsecurity guard, stayed highly
functional.
SPEAKER_01 (18:17):
Okay, that is incredibly compelling.
But did they test it in reverse?
Like if you take a young,healthy cell and force it to
make too much CD38, does itinstantly age?
SPEAKER_00 (18:25):
They did exactly that.
They took normal, healthy humancells, kidney cells in this
specific experiment, and theygenetically forced them to
overexpress CD38 to just floodthe intracellular environment
with the NIDAS.
SPEAKER_01 (18:36):
Let me guess.
Complete metabolic collapse.
SPEAKER_00 (18:39):
Total dysfunction.
By artificially ramping up CD38,they induced severe NAD plus
loss, which, as we now know,immediately suffocated the
mitochondria.
The respiration rate plummeted,and the fill showed a massive
increase in lactate release.
SPEAKER_01 (18:53):
Why lactate like lactic acid from working out?
SPEAKER_00 (18:56):
Exactly the same thing.
When mitochondria fail and canno longer process oxygen for
energy, the well panics.
It falls back on a primitive,highly inefficient backup system
called fermentation to survive.
A byproduct of cellularfermentation is lactate.
So a spike in lactate is amassive flashing warning light
that the mitochondria aresuffocating.
(19:18):
The CD38 literally choked outthe cell's energy supply by
degrading all the NAD plus andNADH.
SPEAKER_01 (19:24):
Okay, so CD38 is definitively the saboteur.
We've solved the mystery of whythe battery is blinking red.
So I mean, logically, if we knowCD38 is the thing eating our NAD
plus Dell, the obvious next stepis figuring out how to outpace
the destruction.
SPEAKER_00 (19:38):
That's where most people's minds go, yes.
SPEAKER_01 (19:40):
Can we just swallow more NAD plus steps?
Because I've seen bottles ofstraight NAD plus online.
Can we just take a pill andflood the system faster than the
Pac-Man can eat it?
SPEAKER_00 (19:48):
You would think it would be that simple, but
unfortunately, it is physicallyimpossible.
You cannot just take NAD pluspills to raise intracellular
levels.
SPEAKER_01 (19:57):
Why not?
If it's the exact molecule thebody needs.
SPEAKER_00 (20:00):
Because of the physical structure of the
molecule itself.
NAD Plus is a very large, bulkymolecule, and crucially, it
carries a heavy electricalcharge.
SPEAKER_01 (20:10):
Okay, and why does that matter?
SPEAKER_00 (20:11):
The membrane that surrounds every cell in your
body is specifically designed torepel large, charged molecules
to protect the interior.
If you put pure NAD plus intoyour bloodstream, it just
bounces right off the cellularwalls.
It cannot enter the cell whereit's actually needed.
SPEAKER_01 (20:28):
Oh, so it's like trying to shove a completely
assembled Ferrari through thefront door of your house instead
of just bringing in the partsand building the car in the
living room.
SPEAKER_00 (20:36):
Exactly.
The cell membrane is a lockeddoor for the fully assembled
car.
And those individual car partsare what biologists call
precursors.
If you want to raise the NADplus levels inside the
mitochondria, you have to feedthe cell the smaller, uncharged
raw materials that it can easilyabsorb, pull inside, and then
assemble into NAD plus MELLER.
SPEAKER_01 (20:57):
Okay, and this brings us to the massive
billion-dollar supplementindustry, the precursors.
You hear two acronymsconstantly, NMN and NR.
SPEAKER_00 (21:06):
Yes.
Nicotinamide mononucleotide,which is NMN, and nicotinamide
riboside, which is NR.
Both of these molecules exist toutilize what we call the NAD
plus salvage pathway.
SPEAKER_01 (21:17):
The salvage pathway, like a molecular recycling
center.
SPEAKER_00 (21:20):
That's exactly what it is.
Biology is highly efficient.
Normally, when enzymes likecertumans use a molecule of NAD
plus to repair some DNA, theydon't destroy it completely.
They break off a piece, leavingbehind a byproduct called NAM or
nicotinamide.
The salvage pathway takes thatleftover NAM and painstakingly
recycles it back into fresh NADplus mellar.
SPEAKER_01 (21:39):
So why do we need supplements if we have a
built-in recycling center?
SPEAKER_00 (21:42):
Aaron Ross Powell Because the recycling center has
a bottleneck.
The conversion relies on a veryspecific enzyme called NAPT.
That is the rate limiting stepin the salvage pathway.
SPEAKER_01 (21:51):
Rate limiting meaning uh like rush hour
traffic all trying to merge intoa single lane.
It can only go so fast no matterhow many cars are waiting.
SPEAKER_00 (21:59):
Correct.
Now a very common questionpeople ask is why spend a
hundred dollars on fancy NMNsupplements when I can go to the
pharmacy and buy a giant bottleof basic vitamin B3 niacin for
five dollars.
Niacin is an NAD plus precursortoo.
SPEAKER_01 (22:15):
Right.
I've seen longevity guys talkabout basic niacin.
Does that work?
SPEAKER_00 (22:19):
It does raise NAD plus NA, but it comes with
severe biological penalties.
Taking high doses of nicotinicacid basic niacin triggers a
massive release ofprostaglandins in the body.
SPEAKER_01 (22:30):
And what does that do?
SPEAKER_00 (22:31):
This causes intense dilation of the blood vessels,
resulting in severe full bodyskin flushing.
It feels like a horrible sunburnfrom the inside out, and it's
incredibly uncomfortable.
SPEAKER_01 (22:41):
Okay.
Nobody wants a permanentinternal sunburn.
What if we just take pure NAM,the recycled byproduct you
mentioned?
SPEAKER_00 (22:47):
If you try to flood the system with too much NAM, it
runs straight into that NAMPTtraffic jam we mentioned.
It can't process it fast enough.
SPEAKER_01 (22:54):
So it just backs up.
SPEAKER_00 (22:55):
Worse than that, if massive amounts of NAM pool up
inside the cell waiting to berecycled, it actually causes
feedback inhibition.
The excess NAM literally bindsto the sertuans and turns them
off, which is the exact oppositeof the longevity effect you're
trying to achieve.
SPEAKER_01 (23:13):
Oh wow.
So cheaping out on basic Bvitamins could actually
accelerate aging by shuttingdown the security guards.
That is terrifying.
Okay, so basic vitamins are out.
What makes NR and NMN somathematically special?
SPEAKER_00 (23:25):
They are molecularly designed to bypass those exact
bottlenecks.
They essentially jump the line.
NR is highly praised in theliterature because it's a very
small molecule, meaning iteasily slips right through the
cell membrane without needing aspecial door.
SPEAKER_01 (23:38):
Okay, what about NMN?
SPEAKER_00 (23:39):
NMN is slightly larger, but recent
groundbreaking researchdiscovered that our bodies have
evolved specific transporters, aprotein called SLC12A8, found
heavily in the gut, that act asdedicated turnstiles, actively
pulling NMN directly into thecells.
SPEAKER_01 (23:53):
So they slip past the cell walls, bypass the
traffic jam, and immediatelyassemble into NAD plus C.
We did it.
We figured out the puzzle.
Just take NMN, build the batteryfluid, and outpace the C D38
Pac-Man.
SPEAKER_00 (24:06):
If only human biology were that cooperative.
Yeah.
This is where the literaturedrops a massive frustrating
bombshell.
You remember our saboteur?
SPEAKER_01 (24:14):
CD38, the Pac-Man.
SPEAKER_00 (24:16):
Well, what researchers found is that CD38
doesn't just destroy fullyassembled NAD plus and B, it is
also the primary enzyme in themammalian body that degrades NMN
in vivo.
SPEAKER_01 (24:27):
Wait, what?
Are you serious?
SPEAKER_00 (24:28):
Completely serious.
In vivo just means inside theliving organism rather than in a
test tube.
CD38 acts as what we call anectoenzyme.
SPEAKER_01 (24:36):
Meaning what?
SPEAKER_00 (24:37):
It means that while the enzyme is anchored in the
cell membrane, a large portionof its catalytic destructive
machinery actually faces outwardinto the extracellular space.
SPEAKER_01 (24:45):
Into the bloodstream.
SPEAKER_00 (24:46):
In your bloodstream.
Oh no.
Yes.
When you swallow an expensiveNMN supplement and it enters
your bloodstream, it doesn'tjust neatly float to the cells
that need it.
The outward-facing CD38 enzymesrecognize the NMN in the blood
and actively chew it up beforeit can even cross the membrane
to do its job.
SPEAKER_01 (25:05):
That is genuinely devastating.
So you're spending all thismoney on these cutting-edge
supplements, and your body isliterally using its own aging
enzymes to intercept and eat themedicine before it even reaches
the cellular living room.
SPEAKER_00 (25:17):
In a very large part, yes.
They tested this dynamicdirectly.
They took wild type mice andgave them an intravenous
injection of NR.
Then they measured the blood.
The levels of NR droppedviolently, a 25% decrease in
just the first 75 minutes.
SPEAKER_01 (25:31):
Because the CD38 was immediately ripping it apart in
the blood.
SPEAKER_00 (25:34):
Exactly.
But then they took the C D38knockout mice, the ones without
the Pac-Man enzyme, and gavethem the exact same injection.
In those mice, the circulatinglevels of NR and MN and fully
formed NAD plus stayedsignificantly more stable.
Wow.
Even two and a half hours later,the knockout mice had vastly
higher levels of the precursorcirculating their plasma.
SPEAKER_01 (25:55):
So the Pac-Man isn't just eating the power pellets
inside the cell, it has itsmouth hanging outside the cell,
eating the delivery trucksbringing the new power pellets?
SPEAKER_00 (26:03):
That is a perfect way to conceptualize an
ectoenzyme.
SPEAKER_01 (26:06):
Wait, hold on.
I'm looking at a logical gaphere.
If CD38 is sitting in thebloodstream chewing up all the
NMN, how do all these humanclinical trials claim that
taking NMN raises blood NAD pluslevels?
If the delivery trucks aregetting destroyed, how is the
cargo getting delivered?
SPEAKER_00 (26:24):
That is a very askewed question.
It comes down to two factors: saturation and tissue (26:26):
undefined
distribution.
When you take a massive clinicaldose, say a thousand milligrams
of NMN, you're throwing so manydelivery trucks at the system
that you temporarily saturatethe CD38 enzymes.
SPEAKER_01 (26:40):
Oh, they just can't eat it fast enough.
SPEAKER_00 (26:41):
Exactly.
They are eating as fast as theycan, but a certain percentage of
the NMN simply slips past thebottleneck and makes it into the
cells.
Furthermore, certain tissues,particularly the liver, are
incredibly efficient atabsorbing these precursors the
second they enter circulation,converting them into NAD plus D
and then releasing them backinto the blood in different
forms.
SPEAKER_01 (27:01):
Okay, so it's a brute force attack.
You just overwhelm the Pac-Manwith sheer volume.
SPEAKER_00 (27:05):
Precisely.
But it brings us to the mostcrucial part of this entire deep
dive.
We've talked extensively aboutmice.
Mice living in sterileenvironments get longer
lifespans, better muscles, andpreserve mitochondria from these
precursors.
SPEAKER_01 (27:18):
Right.
SPEAKER_00 (27:18):
But what actually happens when complex human
beings take them?
Because I know regular peopleright now taking a thousand
milligrams of NMN every singlemorning.
I need to know if the expensivepowder sitting in their medicine
cabinets is actually reversingtheir biological age, or if they
just have really, reallyexpensive NMN-rich urine.
SPEAKER_01 (27:37):
This is where we make the critical transition
from the preclinical hype to theharsh clinical reality, right?
Let's look at the human clinicaltrials, specifically focusing on
the comprehensive reviewscompiled in 2025 and 2026.
SPEAKER_00 (27:49):
The reality check.
SPEAKER_01 (27:50):
Bring it on.
I need the truth.
Start with the good news, ifthere is any.
SPEAKER_00 (27:54):
There is definitively good news.
The trials unequivocally provethat oral precursors,
specifically NR, at doses ofaround 1000 milligrams a day,
and NMN at similar doses, aresafe for human consumption.
SPEAKER_01 (28:07):
Okay, so it won't hurt you acutely.
SPEAKER_00 (28:09):
Right.
They do not cause acutetoxicity.
And as we just discussed, theydo successfully and reliably
raise NAD plus levels in humanwhole blood.
SPEAKER_01 (28:18):
So the brute force method works, the blood battery
gets charged.
SPEAKER_00 (28:22):
Yes, and we see significant NAD plus increases
specifically in PBMCs.
SPEAKER_01 (28:26):
Which are what?
SPEAKER_00 (28:27):
Peripheral blood mononuclear cells.
They are a critical component ofyour immune system, things like
T cells and B cells circulatingin your blood.
Elevating NAD plus in thosecells could theoretically help
maintain immune function as weage.
SPEAKER_01 (28:40):
That's definitely a plus.
SPEAKER_00 (28:41):
But beyond just blood markers, there are some
very promising specific clinicalapplications emerging.
For example, a landmark 2026study focused on patients with
Parkinson's disease.
SPEAKER_01 (28:51):
Oh, neurodegeneration.
That's a huge target foranti-aging.
SPEAKER_00 (28:55):
Massive.
In this trial, they gaveParkinson's patients a high
daily dose of NR using magneticresonance spectroscopy, which is
a specialized MRI technique thatuses powerful magnets to
actually measure the chemicalbonds of specific metabolites
inside living tissue.
They proved that the oral NRactually increased cerebral NED
plus levels.
SPEAKER_01 (29:14):
Whoa.
Wait, it crossed the blood-brainbarrier.
That is notoriously difficult todo.
Most drugs just bounce right offthe brain's defense system.
SPEAKER_00 (29:22):
It is a phenomenal finding.
Showing that an oral supplementcan alter the neurochemical
environment of the human brainopens up massive therapeutic
potential for diseases likeParkinson's and Alzheimer's.
SPEAKER_01 (29:34):
That is legitimately incredible.
SPEAKER_00 (29:36):
Additionally, in broader populations, we see some
trials showing mild butstatistically significant
improvements in muscle endurancein older adults.
We also see some slightcardiometabolic improvements,
like reduced arterial stiffnessand more favorable lipid
profiles in certaindemographics.
SPEAKER_01 (29:54):
Okay, so it's not totally fake.
It is doing something tangiblein the human body.
But uh you use the words mildand slight.
You're an analytical person.
I sense a massive butt hoveringover this data.
SPEAKER_00 (30:04):
A very large butt.
While the blood levels of NADplus reliably go up across the
board, the human trialsconsistently reveal something
deeply baffling to theresearchers.
When they take physical biopsiesof the patient's skeletal
muscle, the NAD plus steadystate levels remain completely
unchanged.
SPEAKER_01 (30:21):
Wait, what?
Unchanged?
But you just said they recordedmild improvements in muscle
endurance.
How on earth is the enduranceimproving if the battery inside
the muscle tissue isn't actuallycharging?
SPEAKER_00 (30:32):
That is the grand mystery currently confounding
the field.
It's not that the supplementisn't reaching the muscle
tissue.
We know for a fact it is gettingthere.
SPEAKER_01 (30:41):
How do we know that if the levels don't go up?
SPEAKER_00 (30:44):
Because when researchers analyze those muscle
biopsies, they see massivespikes in the metabolites of NAD
plus breakdown.
When NAD plus is used anddiscarded by the cell, it
creates clearance products,specifically things like MenAM,
which stands for methylatednicotinamide.
The muscle biopsies areabsolutely flooded with MenAM.
SPEAKER_01 (31:03):
Let me make sure I'm wrapping my head around this.
So the engine is running, theexhaust pipe is blowing out
massive clouds of smoke, meaningall those breakdown metabolites.
But when you check the gas tank,the actual NAD plus level looks
exactly the same.
SPEAKER_00 (31:14):
That is a brilliant analogy.
Yes.
It suggests there is a massivemetabolic flux occurring.
The muscle tissue is rapidlypulling in the precursors,
aggressively building NAD plusray, and then instantly burning
it up to power the cell, but itnever allows the baseline,
steady state reservoir toactually rise.
Wow.
And this highlights afundamental, inescapable
(31:35):
difference between laboratorymice and human beings.
Humans are not simply giantmice.
SPEAKER_01 (31:40):
I mean, I would hope not, but biochemically, what's
the difference here?
SPEAKER_00 (31:43):
It comes down to the basal metabolic rate.
A mouse lives incredibly fastand dies very young.
Their baseline cellularmetabolism is roaring
constantly.
So when you flood a mouse withNAD plus precursors, their rapid
metabolism immediatelyincorporates it, yielding these
massive, highly visiblephysiological rejuvenations.
SPEAKER_01 (32:01):
Oh, I see.
SPEAKER_00 (32:01):
In humans, our evolutionary strategy is a slow
burn.
Our metabolic rate issignificantly lower.
This slower biology dictates avery different, much more
conservative response to how NADplus deficits are generated and
how they were repaired.
The human body is highlyresistant to rapid cellular
reprogramming.
SPEAKER_01 (32:18):
Okay, that actually makes total sense.
A mouse is like a Formula Onesports car constantly redlining,
so if you inject premium fuelinto the system, the engine
screams to life immediately.
Humans are more like a massivediesel freight train just idling
along.
You pour in premium fuel and thetrain just keeps idling exactly
the same way.
SPEAKER_00 (32:36):
Well said.
But the slower metabolism isn'teven the most complex hurdle.
There's another uniquely humancomplication that researchers
recently uncovered, and itcompletely rewrites how we view
these oral supplements.
We have to talk about themicrobiome.
SPEAKER_01 (32:51):
The gut bacteria.
What do the microbes in mystomach have to do with my
cellular DNA repair?
SPEAKER_00 (32:56):
Everything, it turns out.
During these human trials,researchers noticed a very
strange anomaly in the bloodwork.
When human participants swalloworal NR capsules, their blood
work suddenly shows a massive,unexpected spike in a specific
molecule called NAD.
SPEAKER_01 (33:12):
NAAD, what is that?
SPEAKER_00 (33:14):
NAD is a chemical intermediate, is a part of the
priesthandler pathway.
And if you recall from ourearlier biochemistry discussion,
the priest handler pathway isthe specific metabolic route the
body uses to process nicotinicacid, which is basic, cheap,
flush-inducing niacin.
SPEAKER_01 (33:31):
But wait, you explicitly said earlier that NR
uses the salvage pathway tobypass the bottleneck.
It doesn't use the price handlerpathway.
Why would a niacin marker bespiking in the blood if they are
taking NR?
SPEAKER_00 (33:43):
Exactly.
It made absolutely zerobiochemical sense until
researchers zoomed out and lookat what was happening in the
human digestive tract before thesupplement even reached the
bloodstream.
When you swallow a capsule ofNR, it drops into your gut.
And your gut microbiome, thetrillions of bacteria living in
your intestines, intercepts ahuge portion of it.
SPEAKER_01 (34:01):
Wait, the bacteria eat the supplement.
SPEAKER_00 (34:03):
Yes.
Specific strains of gutmicrobiota express an enzyme
called nicotinidase.
When the highly advanced,expensive NR molecule floats by,
the bacteria snatch it up anduse that enzyme to physically
cleave the riboside group rightoff the molecule.
They strip it down.
And what's left over after theystrip it?
Nicotinic acid, basic niacin.
SPEAKER_01 (34:25):
You've got to be kidding me.
SPEAKER_00 (34:26):
I am not.
The bacteria covert it toniacin.
Then your intestinal wallabsorbs that bacteria created
niacin, which forces your liverto process it through the price
handler pathway, generating allthat NAAD we see in the blood
tests.
SPEAKER_01 (34:39):
So let me get this straight.
You go online, you pay absolutetop dollar for chemically
advanced, highly stabilizednicotinamide ribocytes
specifically designed to bypassthe cellular bottlenecks.
And your own gut bacteria justmug the supplement in your
stomach, strip it down, and turnit back into the cheap$5
pharmacy niacin before your bodyeven gets a chance to use it.
SPEAKER_00 (34:56):
In a significant number of cases, yes, it
completely reshapes ourunderstanding of how oral
precursors actually work in aliving human.
It's a prime example of whyhuman biology is so much more
stubbornly complex than isolatedcell cultures in a lab.
SPEAKER_01 (35:11):
Okay, this is genuinely blowing my mind.
So if we review the facts, theclinical results in humans are
mostly mild.
The muscle battery levels don'treally rise at all.
The CD38 Pac-Man is eating thesupplement in the blood, and our
gut bacteria are interceptingthe payload in the stomach.
SPEAKER_00 (35:27):
Aaron Powell Yes.
That is an accurate summary.
SPEAKER_01 (35:29):
Aaron Powell Why is the hype so deafening?
Why is everyone from techbillionaires to fitness
influencers pushing NMN and NRas a miracle fountain youth
cure?
Why is there a billion-dollarindustry built on this right
now?
SPEAKER_00 (35:40):
Aaron Powell We have to have a very frank
conversation about the hypeproblem in modern science.
The anti-aging industry hashistorically always been
susceptible to hyperbolicclaims, but NAD plus boosters
are currently the absoluteepicenter of the storm.
The commercialization of NR andNMN has been vastly artificially
amplified by a combination ofcelebrity endorsements and
(36:00):
highly prominent vocalresearchers.
SPEAKER_01 (36:02):
Yeah, I mean, you can't talk about NMN without
talking about those hugecelebrity scientists from places
like Harvard, right?
They're on every major talkshow, writing books, constantly
talking about this stuff.
SPEAKER_00 (36:14):
Aaron Powell Yes, their advocacy, along with
others, has brought massivemainstream visibility to
molecules like NMN.
And while the foundationalbiology they study is real, we
absolutely must look at thestructural conflicts of interest
driving the narrative.
Many of the human clinicaltrials validating these
supplements are heavily industryfunded.
Shocking.
(36:34):
For example, companies likeChromodex are massive funders of
NR research, and they aresimultaneously one of the
largest patent holders andcommercial sellers of NR
supplements in the world.
SPEAKER_01 (36:44):
That feels like a massive red flag.
We investigated our own productand found it to be amazing.
SPEAKER_00 (36:49):
To be fair to the scientific process, industry
funding does not automaticallyinvalidate a study's raw data.
The blood levels really do goup.
But the conflict of interestdictates how that data is
framed.
They are highly motivated tohighlight surrogate markers,
shouting, look, blood NAD plusincrease by 40%, rather than
(37:09):
acknowledging the lack of hardclinical endpoints.
SPEAKER_01 (37:13):
Explain the difference between a surrogate
marker and a clinical endpoint.
SPEAKER_00 (37:17):
A surrogate marker is a biological number on a
piece of paper.
Blood pressure, cholesterollevels, or in this case NAD plus
concentration in the blood.
A clinical endpoint is an actualphysical health outcome.
Did the patient live longer?
Did they avoid a heart attack?
Did their biological agingactually slow down?
Right.
The industry markets thesurrogate marker as if it is a
(37:37):
guaranteed clinical endpoint.
SPEAKER_01 (37:38):
Right.
We changed a number on yourblood test, is biologically very
different from we just made yourorgans genetically 10 years
younger.
SPEAKER_00 (37:45):
Exactly.
And the direct consumermarketing machine completely
blurs that line for the averagebuyer.
But honestly, the marketing spinisn't even the most concerning
part of the industry right now.
It's the catastrophic lack ofquality control and the hidden
theoretical risks that nobodywants to talk about.
SPEAKER_01 (38:02):
Aaron Powell Quality control.
Like are people just straight upnot getting what they pay for?
SPEAKER_00 (38:06):
Far from it.
SPEAKER_01 (38:06):
Okay.
SPEAKER_00 (38:07):
Because NMN and NR are legally classified and sold
as dietary supplements, they arenot regulated by the FDA like
pharmaceutical drugs.
Independent laboratory analysesof the commercial market have
found massive widespread purityissues.
Some of the most popularcommercial NMN supplements on
Amazon contain 30 to 70 percentless active ingredient than what
is legally claimed on the label.
SPEAKER_01 (38:28):
So it's basically expensive flour.
SPEAKER_00 (38:30):
Or worse.
Some independent tests foundbatches heavily contaminated
with basic unrefinednicotinamide, the NAM we
discussed earlier.
SPEAKER_01 (38:38):
Oh no.
SPEAKER_00 (38:39):
And as we established, if you take massive
unregulated doses of raw NAM, itactually causes feedback
inhibition, shutting down yourSertuan longevity genes.
You are essentially payingpremium prices for highly
unpredictable, unregulatedchemistry that could be actively
working against you.
SPEAKER_01 (38:57):
That is infuriating.
You think you're buying a highlyengineered Ferrari part for your
cellular engine, and you'reactually getting a counterfeit
dirty lawnmower spark plug.
SPEAKER_00 (39:05):
And this brings us to a much darker, much more
serious biological reality.
A theoretical risk that thelongevity influencers almost
universally ignore.
SPEAKER_01 (39:14):
Okay, I'm braced.
What is it?
SPEAKER_00 (39:15):
We have spent the last half hour talking about how
NAD plus is the fundamentalnon-negotiable fuel for cellular
energy and rapid DNA repair,correct?
SPEAKER_01 (39:24):
Yeah, it's the battery fluid.
It fuels everything.
SPEAKER_00 (39:26):
Well, think about human pathology for a second.
What specific type of cell hasthe highest, most aggressive
energy demand in the entirehuman body?
What type of cell is constantly,furiously multiplying, ignoring
all biological stop signs, andis utterly desperate for raw
metabolic fuel and constant DNArepair mechanisms to survive its
own rapid mutation?
SPEAKER_01 (39:46):
Oh man, oh no, cancer cells.
SPEAKER_00 (39:49):
Exactly, cancer.
Preclinical models have recentlyilluminated a very concerning
dark side to artificial NAD plusaugmentation.
In highly specific mouse modelsof lymphoma and certain types of
breast cancer, researchers foundthat providing the mice with NAD
plus precursors actually rapidlyaccelerated tumor progression.
SPEAKER_01 (40:09):
Because cancer relies on glycolysis and the
salvage pathway, right?
So if you flood the body withNMN, you aren't just fueling the
healthy cells.
You're giving the cancer cellsthe exact premium fuel and
repair kits they need tomultiply out of control.
SPEAKER_00 (40:22):
That is the exact mechanism.
Cancer cells experience massiveamounts of oxidative stress and
DNA damage because they divideso recklessly.
They desperately rely on PREPenzymes to constantly patch
their broken DNA so they don'tsimply die.
And as we know, PRP strictlyrequires NAD plus to function.
Man.
By taking massive doses ofprecursors, you are
theoretically ensuring thecancer's repair mechanisms never
(40:44):
run out of fuel.
SPEAKER_01 (40:45):
That is a staggering reality check.
SPEAKER_00 (40:48):
Now, it is absolutely crucial that I state
this clearly.
We do not have clinical evidencethat taking NR or NMN causes new
cancers to form in healthy humanbeings.
It does not seem to be acarcinogen in that way.
SPEAKER_01 (41:00):
Okay.
That's somewhat of a relief.
SPEAKER_00 (41:02):
But human biology is messy.
If a person has an undiagnosed,dormant microtumor, which many
aging adults do, or if they havea personal history of cancer and
remission, flooding theirsystemic circulation with highly
bioavailable NAD plus precursorscould theoretically act as a
metabolic accelerant for thosedormant cells.
(41:22):
It is a profound biologicalgamble that the bright,
optimistic, direct-to-consumermarketing completely ignores.
SPEAKER_01 (41:29):
Wow, okay.
That is that's a lot to process.
That completely changes how Iview those little white bottles.
If I'm taking all this in, letme try to synthesize the big
takeaways from this entire deepdive.
SPEAKER_00 (41:39):
Please do.
It's a complex web.
SPEAKER_01 (41:40):
Okay.
On a fundamental level, NAD plusis undeniably our vital cellular
fuel.
It is the literal electricityfor the mitochondria.
It's the required fuel thatallows the Sertuan security
guards to repair our DNA, andlosing it is a core reason why
we biologically age.
That part is true.
SPEAKER_00 (41:55):
Completely true.
The foundational biology issolid.
SPEAKER_01 (41:58):
But as we age, a rogue outward-facing enzyme
called CD38 acts like abiological Pac-Man.
It aggressively multiplies andjust starts eating our NAD plus
supply, causing the whole systemto choke.
And while laboratory scientistshave figured out that you can
use precursor parts like NR andNMN to bypass the cell walls and
theoretically rebuild thebattery, the human translation
(42:20):
is an absolute mess.
SPEAKER_00 (42:22):
A messy, unpredictable translation.
SPEAKER_01 (42:24):
Yes.
The CD38 Pac-Man intercepts thesupplements in the blood.
Our gut bacteria hijack thecapsules in our stomachs and
downgrade them to cheap niacin.
The actual anti-aging results inhuman muscle tissue are
incredibly modest compared tothe marketing hype.
You're probably buyingcounterfeit or underdose
supplements anyway, and worst ofall, if you happen to have a
hidden microtumor, you mightjust be handing it the exact
(42:45):
premium peel it needs to killyou.
SPEAKER_00 (42:47):
You have captured the nuance perfectly.
The biochemistry of NAD isundeniably fascinating.
And as we saw with theParkinson's brain data, it holds
profound, legitimate therapeuticpromise for specific
degenerative diseases whenadministered correctly.
But biology is incrediblystubbornly complex.
(43:08):
Preserving human health span anddelaying mortality is never ever
going to be as simple asswallowing a single isolated
compound from a plastic bottleyou bought on the internet.
SPEAKER_01 (43:18):
Yeah.
It's a sobering reminder for youlistening right now.
Whenever someone promises you abiological shortcut or tries to
sell you immortality for 80bucks a month, rid the fine
print.
SPEAKER_00 (43:27):
Exactly.
You cannot outsmart millions ofyears of evolutionary biology
with a single chemical loophole.
And honestly, looking at thetotality of this research, it
leaves us with a lingering,somewhat provocative question
about the entire futuredirection of the longevity
field.
What's right now, the entireindustry is spending billions of
dollars trying to out supplementthe aging process.
(43:48):
We are desperately trying toflood our bodies with massive,
unnatural doses of NAD plusprecursors, just hoping that
enough molecules slip past thegut bacteria, survive the liver,
and eventually.
The cellular defenses to make atiny difference in the tissue.
SPEAKER_01 (44:03):
Right.
We're just blindly throwingthousands of power pellets into
the maze, hoping we outpace thePac-Man by sheer volume.
SPEAKER_00 (44:09):
Aaron Powell Precisely.
But if C D thirty eight is theprimary undeniable driver of
this age-related decline, ifit's the Pac-Man that not only
drains our natural endogenousNAD plus reservoir, but also
actively chews up the expensiveNMN supplements we swallow
before they even reach the cell,shouldn't the future of
anti-aging medicine pivotcompletely?
Instead of trying to endlesslyfuel the system, shouldn't we be
(44:33):
focused on finding a safe,precise way to simply switch off
the Pac-Man?
SPEAKER_01 (44:36):
Oh wow, yeah.
Don't buy more gas, just unplugthe C D thirty eight.
SPEAKER_00 (44:39):
Yeah.
Exactly.
Instead of constantly trying torefill a biological bucket that
has a massive growing hole init, perhaps the next great leap
in human longevity won't be anew highly marketed precursor
supplement at all.
Perhaps the true breakthroughwill be a targeted molecular C D
thirty eight inhibitor,something that just patches the
hole, turns off the enzyme, andallows our bodies to naturally
(45:01):
restore their own youthfulenergy levels without
interference.
Just something to criticallythink about the next time your
feed serves you an ad for amiracle longevity pill.
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