May 10, 2026 • 37 mins
We follow rapamycin from a soil sample on Easter Island to the center of longevity science, then break down how mTOR decides between growth and repair. We also confront the “friendly fire” problem that shows up with chronic dosing and explain why current trials focus on precision pulsing and measurable biomarkers.
• the 1975 discovery story and why rapamycin was shelved then revived for organ transplantation
• how TOR genes led to mTOR and why phosphorylation changes protein shape and function
• mTOR as a nutrient and energy sensor integrating leucine, arginine, ATP, oxygen, and insulin
• why nonstop mTORC1 activity links to senescence, SASP inflammation, and age-related decline
• how rapamycin inhibits mTORC1 to unlock autophagy and act as a calorie restriction mimetic
• what mTORC2 does for cell survival and why losing it can wreck glucose control
• animal evidence across species including late-life mouse benefits and sex differences
• why companion dog trials matter and what improved heart function suggests
• the Fang study logic behind insulin resistance with chronic exposure and later adaptation
• how human trials use intermittent dosing plus epigenetic clocks, cytokines, metabolic labs, and functional tests
Keep questioning the world around you. Keep an eye on those clinical trials, and don’t forget to let yourselves take out the trash.
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
Available transcripts are automatically generated. Complete accuracy is not guaranteed.
SPEAKER_01 (00:00):
In 1975, scientists isolated a single vial of dirt
from literally one of the mostremote places on planet Earth,
Easter Island, Rappa Nui.
SPEAKER_00 (00:08):
Right, right.
SPEAKER_01 (00:09):
And they were out there looking for um an
antifungal compound, likesomething to just treat simple
infections.
Athlete's foot, whatever.
SPEAKER_00 (00:17):
Exactly.
SPEAKER_01 (00:18):
But instead, what they found buried in that soil
was a master biological switch.
A switch hidden inside abacterium that can quite
literally command a living cellto stop aging, which is just
insane to me.
SPEAKER_00 (00:30):
Aaron Powell I mean, it sounds completely like
science fiction when you frameit like that.
SPEAKER_01 (00:33):
Aaron Powell It totally does.
SPEAKER_00 (00:34):
Aaron Powell But the biochemistry backing this up is
incredibly concrete.
I mean, we are looking at amolecule that interacts with the
fundamental infrastructure ofhow eukaryotic life basically
decides whether to grow orwhether to hunker down and
repair itself.
SPEAKER_01 (00:47):
Aaron Powell Yeah.
And I have been pouring overthis giant stack of research you
send over for this deep dive.
We're talking data from the NIH,uh, the Dog Aging Project, UT
Health San Antonio, and it isjust staggering.
SPEAKER_00 (01:00):
Aaron Powell It really is a paradigm shift.
SPEAKER_01 (01:01):
So our mission today is to completely demystify MTOR
signaling, figure out how thisdrug rapamycin actually works,
and look at the clinical trialsthat are trying to hack the
biology of aging.
And you know, for everyonelistening with us right now,
whether you're just trying tofigure out how to get a few more
healthy years with your goldenretriever, or you're tracking
your own metabolic health,understanding this specific
(01:24):
biological switch is honestlythe ultimate shortcut to
understanding the entire futureof longevity medicine.
SPEAKER_00 (01:30):
Absolutely.
And to really grasp themagnitude of what we're doing in
clinical trials today, I thinkwe have to look at the sheer
serendipity of that 1975expedition.
SPEAKER_01 (01:39):
The dirt expedition.
SPEAKER_00 (01:40):
The dirt expedition, yes.
So Canadian researchers fromAyers Pharmaceuticals were
systematically screening soilsamples from all around the
world.
SPEAKER_01 (01:47):
Just scooping up dirt everywhere.
SPEAKER_00 (01:49):
Pretty much.
They were looking for novelantibiotics produced by
bacteria.
And in this particular samplefrom Rapanui, they isolated a
bacterium called Streptomyceshygroscopicus.
Streptomyces hygroscopicus, andthat bacterium produced a very
specific metabolite.
SPEAKER_01 (02:04):
Which is the magic compound we're talking about
today.
SPEAKER_00 (02:06):
Exactly.
A macrolide compound.
And because of its origin onRapanui, they named it
Rapamycin.
SPEAKER_01 (02:13):
Okay, that makes sense.
SPEAKER_00 (02:14):
And initially, yes, it did kill fungi.
But as they started testing iton mammalian cells, the data
started coming back with thesebizarre anomalies.
SPEAKER_01 (02:25):
Wait, what kind of anomalies?
Like it was killing themammalian cells too.
SPEAKER_00 (02:28):
Not killing them, exactly.
It was halting theirproliferation.
It wasn't just targeting fungalpathogens, it was stopping human
cells from dividing.
It possessed massive, massiveimmunosuppressive properties.
SPEAKER_01 (02:40):
Oh, whoa.
Which completely derailed itsuse as an antifungal, right?
I mean, you don't want to shutdown a patient's entire immune
system just to cure athlete'sfoot.
SPEAKER_00 (02:49):
You absolutely do not.
That would be catastrophic.
SPEAKER_01 (02:51):
Right.
Friendly fire.
SPEAKER_00 (02:52):
Exactly.
So the compound was actuallyjust shelved for a while.
It wasn't until the 1980s and90s that the medical community
realized its true utility wasactually in organ
transplantation.
SPEAKER_01 (03:03):
Oh, because of the immune system thing?
SPEAKER_00 (03:05):
Yes.
If you give a patient a newkidney, their immune system will
naturally recognize that kidneyas foreign tissue and attack it.
SPEAKER_01 (03:13):
Because the body is like, hey, this doesn't belong
here.
SPEAKER_00 (03:15):
Precisely.
Rapamycin was phenomenal atsuppressing that specific immune
response, mainly by stopping Tcells from dividing.
So the FDA eventually approvedit as a transplant
immunosuppressant.
SPEAKER_01 (03:28):
But the wild part to me about all of this is that
they were prescribing thisincredibly powerful drug for
years before anyone actuallyknew how it worked on a
molecular level.
SPEAKER_00 (03:37):
That happens more often than you'd think in
medicine, honestly.
SPEAKER_01 (03:40):
Really?
It was just a black box.
They were just like, hey, itstops cells from dividing.
Let's use it.
It wasn't until what 1991 thatthe curtain finally got pulled
back.
SPEAKER_00 (03:47):
Yeah, 1991, Michael Hall and his team in Switzerland
were studying yeast.
Just simple single-celledbaker's yeast.
SPEAKER_01 (03:54):
Just baking bread.
SPEAKER_00 (03:55):
Right.
They exposed the yeast torapamycin and isolated the
specific genes that the drug wastargeting.
And they called them TOR1 andTOR2 target of rapamycin.
And shortly after that,researchers discovered the
mammalian equivalent, henceMPOR, the mammalian target of
rapamycin.
SPEAKER_01 (04:13):
Or the mechanistic target of rapamycin, depending
on which of these papers you'rereading.
I saw both terms thrown around alot.
SPEAKER_00 (04:19):
Right.
I personally prefer mechanisticas it accurately reflects its
role across different species.
But yes, mammalian is commontoo.
SPEAKER_01 (04:27):
Okay, so this is where I think we really have to
establish what MTOR actually isbiochemically, because it is the
absolute linchpin of this entiredeep dive.
SPEAKER_00 (04:38):
It is the core of everything we're discussing.
SPEAKER_01 (04:40):
The paper called it a serinenthrine protein kinase.
unknown (04:44):
Yes.
SPEAKER_01 (04:44):
Okay, let me stop you there.
Because serenanthrinine proteinkinase is the exact kind of
phrase that makes people's eyesjust completely glaze over.
SPEAKER_00 (04:52):
Fair enough.
It is a mouthful.
SPEAKER_01 (04:53):
I want to make sure we actually explain the physics
of this to the listener.
So a kinase is an enzyme thatadds a phosphate group to
another molecule, right?
Phosphorylation.
SPEAKER_00 (05:02):
That is the textbook definition, yes.
SPEAKER_01 (05:04):
But practically, and correct me if I'm visualizing
this wrong, adding a phosphategroup isn't just like tagging
the protein with a sticky note.
That phosphate group is highlynegatively charged.
SPEAKER_00 (05:16):
Extremely negatively charged, yes.
SPEAKER_01 (05:17):
So when a kinase like MTOR slaps a phosphate onto
a target protein, that massivenegative charge repels other
parts of the protein, right?
Like magnets pushing away fromeach other.
SPEAKER_00 (05:28):
That's exactly what happens.
SPEAKER_01 (05:29):
Forcing the whole 3D structure of the protein to
physically contort and changeits shape.
It's like putting a bulkypadlock on a machine part so it
either locks into place orphysically just can't fit into
the machinery anymore.
SPEAKER_00 (05:42):
That is a phenomenal way to visualize it.
I love that.
You are physically altering thetopography of the protein so it
either activates or deactivates.
SPEAKER_01 (05:49):
It's mechanical.
SPEAKER_00 (05:50):
Highly mechanical.
And MTOR uses this locking andunlocking mechanism to act as
the ultimate sensory integratorfor the cell.
SPEAKER_01 (05:58):
The sensor, like a thermostat.
SPEAKER_00 (06:00):
More complex than a thermostat.
It sits there monitoring theentire environment.
It detects amino acids,specifically leucine and
arginine from the proteins weeat.
It monitors cellular energylevels via ATP.
Okay.
It detects oxygen levels.
It monitors growth factors likeinsulin.
It takes in all this data tomake a decision.
SPEAKER_01 (06:21):
You know, I was trying to come up with an
analogy for this because I keepseeing it described as a general
contractor in the literature,but that feels a little small to
me.
I feel like MTOR is more like anational economy.
SPEAKER_00 (06:34):
A national economy.
Okay, I am intrigued.
Walk me through the economics ofa cell.
SPEAKER_01 (06:38):
Okay, so imagine MTR is the Federal Reserve and the
government rolled into one.
SPEAKER_00 (06:42):
A powerful entity.
SPEAKER_01 (06:43):
Right.
When times are good, whenthere's plenty of cash, which is
cellular energy, and plenty ofraw materials, which are the
amino acids, the MTOR shifts thecell into a peacetime boom
economy.
SPEAKER_00 (06:55):
Oh, I see where you're going with this.
SPEAKER_01 (06:56):
It says build, multiply, synthesize.
It drives the creation of newproteins, new lipids, and tells
the cells to proliferate.
It's the ultimate growth state.
Everything is booming.
SPEAKER_00 (07:08):
I will absolutely adopt that metaphor because it
perfectly captures the dualityof the system.
SPEAKER_01 (07:12):
Yeah.
SPEAKER_00 (07:13):
Definitely.
A peacetime boom economy iswonderful for a developing
nation, or in biology, adeveloping human child.
SPEAKER_01 (07:22):
Because they need to grow.
SPEAKER_00 (07:23):
Exactly.
You want explosive growth.
You want to build muscle, bone,and neural tissue.
But, and this is the crucialpart, what happens to an economy
that literally never stopsbuilding?
SPEAKER_01 (07:33):
Never stops.
SPEAKER_00 (07:34):
Right.
If it just keeps producinggoods, adding infrastructure,
and endlessly consumingresources without ever managing
its waste or experiencing amarket correction.
SPEAKER_01 (07:44):
Oh man, you get hyperinflation, you get a
massive buildup of useless junk,empty ghost cities, and
eventually the whole system justcollapses under its own weight.
SPEAKER_00 (07:53):
Which is precisely what happens in biology when
MTOR becomes hyperactive andthat peacetime growth state
refuses to shut off.
SPEAKER_01 (08:01):
Whoa.
So growth isn't always good.
SPEAKER_00 (08:03):
Unending growth in an adult organism isn't youth,
it's cancer or senescence.
We see this in severepathologies.
SPEAKER_01 (08:09):
Like what?
SPEAKER_00 (08:10):
Well, there's a rare progressive lung disease called
lamb lymphangioleomyomatosis.
SPEAKER_01 (08:16):
That's a long word.
Lamb.
SPEAKER_00 (08:18):
Lamb is easier, yes.
In lamb, smooth muscle-likecells just endlessly proliferate
in the lungs until they formthese destructive cysts.
It's unchecked growth.
SPEAKER_01 (08:28):
That sounds awful.
SPEAKER_00 (08:29):
We also see it in tuberous sclerosis complex,
which is a genetic disorderwhere benign tumors grow in the
brain, kidneys, and heart.
SPEAKER_01 (08:36):
And cancer, obviously, like unregulated
growth is the literal definitionof cancer.
SPEAKER_00 (08:40):
Aaron Powell Exactly.
Both lamb and tuberosclerosisare actually driven by mutations
in genes that are supposed toinhibit MTR.
SPEAKER_01 (08:48):
So the breaks are cut.
SPEAKER_00 (08:49):
The genetic breaks fail, and MTR runs wild.
The peacetime economy overheats.
And even in healthy adults,chronic unending MTOR activation
drives something calledsenescence.
SPEAKER_01 (09:01):
Oh, senescence! That is fascinating.
I was reading about that.
It's when a cell basicallyreaches the end of its useful
life, it stops dividing, but itrefuses to die.
It just sits there like azombie.
SPEAKER_00 (09:12):
A very toxic zombie.
Right.
Senescence cells aren't justinactive, they secrete a
cocktail of inflammatorycytokines, chemokines, and
protestases.
We call it the SASP, thesenescence associated secretory
phenotype.
This chronic, low-gradeinflammation actually degrades
the surrounding healthy tissue.
It's a primary driver of theaging process itself.
SPEAKER_01 (09:32):
So the goal isn't just to grow forever.
We actually need the economy tooccasionally experience a
recession.
We need to stop building.
Yes.
Which brings us to the structureof MTR itself.
Because as I was reading the UTHealth papers, I realized MTR
isn't just one monolithicentity.
It operates in two entirelydifferent complexes, two
different crews running theeconomy.
SPEAKER_00 (09:51):
MTORC1 and MTORC2.
SPEAKER_01 (09:54):
Right.
SPEAKER_00 (09:54):
And understanding the division of labor between
these two complexes is the onlyway to understand both the
promise and the danger ofrapamycin.
SPEAKER_01 (10:02):
Okay, let's break down the first crew, MTORC1.
SPEAKER_00 (10:05):
So MTORC1 is defined by the presence of a specific
scaffolding protein calledRaptor.
SPEAKER_01 (10:10):
Raptor.
Like the dinosaur.
SPEAKER_00 (10:12):
Sure, like the dinosaur.
This is the complex that acts asthe peacetime economy you
described.
SPEAKER_01 (10:16):
Got it.
SPEAKER_00 (10:17):
It is acutely sensitive to nutrients.
Yep.
And crucial to our deep divetoday, it is acutely sensitive
to rapamycin.
SPEAKER_01 (10:23):
And when we say sensitive, we mean rapamycin
physically jams the gears ofthis specific complex.
SPEAKER_00 (10:29):
It creates a wedge.
Rapamycin enters the cell andbinds to a small protein called
FKBP12.
SPEAKER_01 (10:34):
Okay, rapamycin grabs this little FKBT12
protein.
SPEAKER_00 (10:37):
Yes.
And this new rapamycin FKBP12complex then physically docks
onto MTORC1 right next to thekinase domain, effectively
blinding it.
It physically blocks thesubstrates from accessing the
active site.
The padlock.
Exactly.
It locks it down.
SPEAKER_01 (10:52):
So the peacetime economy is artificially shut
down by this drug.
SPEAKER_00 (10:55):
Shut down instantly.
And the downstream effects ofthis are profound.
When MTORC1 is active, itnormally promotes translation,
the making of new proteins byphosphorylating targets like
N6K1 and 4EBP1.
SPEAKER_01 (11:07):
Okay, wait.
The 4E BP1 interaction isbrilliant.
Let me see if I have this right.
SPEAKER_00 (11:11):
Go ahead.
SPEAKER_01 (11:12):
From what I understand, 4EBT1 is normally a
suppressor.
Like it wraps around the proteinmaking machinery and stops it.
But when MTORC1 phosphorylatesit, when it adds that bulky
negative phosphate group wetalked about, it forces 4EBP1 to
change shape and release itsgrip, which allows the cell to
suddenly manufacture newproteins.
SPEAKER_00 (11:32):
That is the exact mechanical reality, yes.
SPEAKER_01 (11:35):
It's so cool.
SPEAKER_00 (11:36):
It really is.
But more important for ourdiscussion on aging is what
MTORC1 does to catabolicprocesses.
SPEAKER_01 (11:42):
Catabolic meaning breaking things down, right?
SPEAKER_00 (11:45):
Yes, breaking down molecules.
When MTRC1 is running the boomeconomy, it puts a hard physical
break on a process calledautophagy.
SPEAKER_01 (11:52):
Autophagy, literally self-eating, if you look at the
green.
SPEAKER_00 (11:55):
Yes.
And returning to your economicmetaphor, if MTORC1 is peacetime
consumerism, autophagy is thewartime rationing economy.
SPEAKER_01 (12:03):
Ooh, I like that.
SPEAKER_00 (12:04):
When resources are incredibly scarce, a nation
stops building new shoppingmalls and starts melting down
old cars and scrap metal tobuild tanks.
SPEAKER_01 (12:11):
It recycles from within.
SPEAKER_00 (12:13):
Exactly.
It uses its own garbage as fuel.
SPEAKER_01 (12:15):
I love that.
So instead of just leaving allthe misfolded proteins and
damaged cellular machinery lyingaround, the cell builds these
little molecular garbage bags,what I call autophagosomes.
SPEAKER_00 (12:25):
Autophagosomes, yes.
SPEAKER_01 (12:26):
And it sweeps it all up, melts it down, and uses the
raw amino acids to survive.
SPEAKER_00 (12:31):
And the mechanical way MTRRC1 stops this is by
phosphorylating two initiationproteins called ULK1 and ATG13.
SPEAKER_01 (12:38):
More padlocks.
SPEAKER_00 (12:39):
More padlocks.
By placing those phosphatepadlocks on the initiation
proteins, MTORC1 physicallyprevents the autophagus and
garbage bags from ever forming.
The wartime recycling factoriesare basically padlocks shut.
SPEAKER_01 (12:52):
Which is fine when you're young and healthy and
flooded with nutrients.
But as we age, if we never flipthat switch, the cellular scrap
metal just piles up.
SPEAKER_00 (13:00):
It accumulates relentlessly.
SPEAKER_01 (13:02):
Just trash everywhere in the cell.
SPEAKER_00 (13:03):
Literally.
We see a buildup of misfoldedproteins and highly
dysfunctional exhaustedmitochondria.
This accumulation underpinsage-related cellular failure
across the board.
SPEAKER_01 (13:13):
Like neurodegenerative diseases.
SPEAKER_00 (13:15):
Precisely.
Alzheimer's is characterized byamyloid beta plaques and
tautangles.
Parkinson's involvesalpha-cinuclein aggregation.
SPEAKER_01 (13:23):
Oh wow.
SPEAKER_00 (13:23):
These are all toxic proteins that a robust
autophagic system shouldtheoretically clear out.
SPEAKER_01 (13:28):
Okay, so here is the absolute genius of rapamycin,
then.
If you give a cell rapamycin, itbinds to that FKBP12 protein,
wedges into MTORC1, and shuts itdown.
Yes.
And because MTORC1 is shut down,the bulky phosphate padlocks are
removed from ULK1 and ATG13.
SPEAKER_00 (13:48):
To break her off.
SPEAKER_01 (13:49):
The itophagosomes form.
The cell suddenly switches intothe wartime rationing economy
and starts melting down thetoxic amyloid plaques and broken
mitochondria, even though thebody isn't actually starving.
SPEAKER_00 (14:01):
It is the ultimate biochemical trick.
SPEAKER_01 (14:03):
Dude, that is wild.
SPEAKER_00 (14:04):
It is a calorie restriction mimetic.
SPEAKER_01 (14:06):
Mimetic.
So it mimics calorierestriction.
SPEAKER_00 (14:09):
Yes.
You get the profound cellularrepair benefits of starvation
without the physiological traumaof actual famine.
SPEAKER_01 (14:15):
Okay.
That is just incredible.
But so that's the peacetimecrew, MTORC1.
You mentioned a second complex,MTORC2.
SPEAKER_00 (14:22):
Yes, the other side of the coin.
SPEAKER_01 (14:23):
Now from what I read, this is where the whole
anti-aging narrative hits amassive wall of complication.
SPEAKER_00 (14:28):
A very steep wall.
MTORC2 is the structuralmaintenance crew.
It contains a different coreprotein called Richter rather
than Raptor.
SPEAKER_01 (14:34):
Raptor and Richter.
Okay.
SPEAKER_00 (14:36):
Yes.
And its primary job is notnutrient sensing, it regulates
the actin cytoskeleton, which isthe physical scaffolding that
gives a cell its shape, and itpromotes cellular survival by
activating a downstream kinasecalled act.
SPEAKER_01 (14:49):
So it's keeping the physical house from falling
down.
SPEAKER_00 (14:52):
Exactly.
SPEAKER_01 (14:53):
And rapamycin doesn't wedge into MTORC2.
SPEAKER_00 (14:57):
It does not.
The Richter protein physicallyblocks the rapamycin FKBP12
complex from binding.
Oh.
So acutely, rapamycin only shutsdown the boom economy of MTORC1
while leaving the vital survivalscaffolding of MTRC2 completely
operational.
SPEAKER_01 (15:13):
That sounds like a perfect drug.
You turn on the recycling, clearout the Alzheimer's proteins,
and keep the cellularscaffolding strong.
SPEAKER_00 (15:19):
In theory, yes.
SPEAKER_01 (15:20):
Which totally explains why the animal trials I
looked at were so overwhelminglypositive.
I mean, they didn't just testthis in a petri dish, they put
it in basically every modelorganism we have.
SPEAKER_00 (15:30):
The evolutionary conservation of the MTR pathway
is staggering.
SPEAKER_01 (15:33):
It's the same switch in everything.
SPEAKER_00 (15:35):
Practically, Rapamyxin extends the lifespan
of yeast, it extends thelifespan of C.
elegans, the microscopicnematode worms, it works in
Drosophila, the fruit flies, andthen, of course, the mammalian
trials.
SPEAKER_01 (15:48):
The 2009 Harrison study from the interventions
testing program, I spent a lotof time on this paper because it
seems like the moment thelongevity community just went
into absolute overdrive.
SPEAKER_00 (15:58):
It was a huge paradigm shift.
Before 2009, the idea of apharmacological intervention
reliably extending mammalianlifespan was highly speculative.
SPEAKER_01 (16:07):
Just a pipe dream.
SPEAKER_00 (16:08):
Exactly.
SPEAKER_01 (16:08):
And the methodology of that study is what makes it
so bulletproof, right?
Because they didn't just usethose highly inbred lab mice
where one weird genetic corkcould skew all the data.
SPEAKER_00 (16:18):
No, they used genetically heterogeneous mice.
SPEAKER_01 (16:20):
Which mimic the messy genetic diversity of a
human population.
SPEAKER_00 (16:24):
Precisely.
SPEAKER_01 (16:24):
And more importantly, they didn't start
feeding them rapamycin when theywere pups.
SPEAKER_00 (16:28):
This is the critical detail.
They started the interventionwhen the mice were 20 months
old.
SPEAKER_01 (16:32):
And in marine physiology mouse years, 20
months is roughly equivalent toa 60-year-old human.
That is the part that genuinelystopped me in my tracks.
You take a mouse that is alreadyentering its senior years, you
start giving it rapamycin, andit still significantly extends
both the median and maximallifespan.
SPEAKER_00 (16:52):
It's quite profound.
SPEAKER_01 (16:53):
It's not just preventative if you start at
birth, it's practicallyrestorative late in life.
SPEAKER_00 (16:59):
It delayed age-related decline across
multiple organ systems, itpreserved liver function,
maintained tendon elasticity,mitigated cardiac hypertrophy.
SPEAKER_01 (17:08):
That's insane.
SPEAKER_00 (17:09):
However, you noted some nuances in the ITP data
when you were reviewing thematerials earlier.
SPEAKER_01 (17:14):
Oh, yeah.
The sex differences really stoodout to me.
When you look at the lifespancurves, rapamycin works in both
sexes, but the lifespanextension is noticeably more
pronounced in female mice thanin male mice.
SPEAKER_00 (17:25):
Yes, that's accurate.
SPEAKER_01 (17:26):
And then you compare that to another drug the ITP
tested, uh 17 alpha estradiol,which extended lifespan only in
male mice and did absolutelynothing for females.
Right.
So are we looking at a hormonalinterference with MTOR, or do
male and female livers justmetabolize the drug differently?
SPEAKER_00 (17:44):
That is a highly sophisticated question,
honestly.
And the answer is likelypharmacokinetic.
SPEAKER_01 (17:48):
Pharmacokinetic, so how the drug moves through the
body.
SPEAKER_00 (17:51):
Right.
Female mice seem to maintainhigher blood levels of rapamycin
than males given the exact samedose in their shell.
They simply clear the drug fromtheir systems more slowly.
SPEAKER_01 (18:02):
Oh, so they just have more of it in their
bloodstream.
SPEAKER_00 (18:05):
Essentially, yes.
But the broader point iscritical.
Aging pathways are oftensexually dimorphic.
SPEAKER_01 (18:12):
Dimorphic, meaning two different forms.
SPEAKER_00 (18:14):
Yes.
What works for a male biologymay not perfectly map onto a
female biology, which makestranslation to human trials
incredibly complex.
SPEAKER_01 (18:23):
Which perfectly brings me to the intermediate
step between mice and humans,the dogs.
SPEAKER_00 (18:28):
Ah, yes, dogs.
SPEAKER_01 (18:30):
I am obsessed with the dog aging project.
SPEAKER_00 (18:32):
It's a remarkable initiative, primarily driven by
the University of Washington andTexas AM.
SPEAKER_01 (18:36):
Dr.
Kate Creevy and her team, theyjust got a$7 million NIH grant
for the Tri-Aid trial.
SPEAKER_00 (18:42):
The test of rapamycin in aging dogs.
SPEAKER_01 (18:44):
Yes.
And what's brilliant about thisis that they aren't locking a
bunch of beagles in a sterilelab.
They are enrolling 580 companiondogs, pet dogs, living in normal
homes, sleeping on couches,eating dropped food off the
kitchen floor.
SPEAKER_00 (19:00):
The environmental variable is crucial here.
Lab mice live in apathogen-free,
temperature-controlled,perfectly regulated bubble.
SPEAKER_01 (19:09):
Yeah.
Real life is messy.
SPEAKER_00 (19:10):
Exactly.
Companion dogs share ourenvironment.
They drink our water.
They're exposed to the sameambient pollutants.
They share our circadiandisruptions.
SPEAKER_01 (19:20):
They stay up late with us.
SPEAKER_00 (19:21):
They do.
And biologically, they age inways that perfectly mirror human
decline.
They develop osteoarthritis,they suffer from cardiac
stiffening, they even experiencecanine cognitive dysfunction.
SPEAKER_01 (19:32):
Which is functionally very similar to
human dementia.
SPEAKER_00 (19:34):
Yes, it is.
SPEAKER_01 (19:35):
And because a large breed dog naturally only lives
10 to 12 years, you can actuallyrun a clinical trial and see the
results in a reasonable timeframe.
You don't have to wait 80 years.
I was reading the pilot studydata they published before
Triad, where they gave lowintermittent doses of rapamycin
to a small cohort of middle-ageddogs.
The cardiac data was incredible.
(19:56):
It improved fractionalshortening.
SPEAKER_00 (19:58):
Right.
Let's define fractionalshortening so the listeners
understand what that implies.
SPEAKER_01 (20:02):
Okay.
From my understanding,fractional shortening is the
percentage of blood the leftventricle of the heart pumps out
with every single contraction.
Yes.
As mammals get older dogs andhumans, the heart muscle gets
thicker, stiffer, and lesselastic.
It turns into an old rubberband.
SPEAKER_00 (20:17):
Aaron Powell A very apt description.
SPEAKER_01 (20:19):
It can't fully relax between beats to fill with
blood, which is diastolicdysfunction, but rapamycin
seemed to physically reversethat stiffening in the dogs.
SPEAKER_00 (20:28):
It restored the elasticity of the myocardium.
The heart could pump moreefficiently.
SPEAKER_01 (20:32):
That's basically giving them puppy hearts back.
SPEAKER_00 (20:34):
In a sense, yes.
And we are seeing similarlypromising safety profiles in
non-human primate studies.
SPEAKER_01 (20:41):
Oh, the monkeys.
SPEAKER_00 (20:42):
Yes.
There is an ongoing trial with66 middle-aged marmoset monkeys
receiving rapamycin in theirdiet.
So far, the toxicity ispractically non-existent at the
doses used, with only minorshifts in metabolic markers.
SPEAKER_01 (20:56):
Okay, so let's just pause for a second and look at
the scoreboard here.
SPEAKER_00 (20:59):
Let's hear it.
SPEAKER_01 (21:00):
We have yeast, worms, and flies living longer.
We have 60-year-old equivalentmice becoming incredibly
resilient.
We have pet dogs getting moreelastic hearts.
We have monkeys tolerating itperfectly.
The wartime recycling economy ofautophagy works.
It does.
So I am going to ask theobvious, slightly chaotic
question (21:20):
why is this not in the water supply?
Why aren't we all taking a dailypill of rapamycin with our
morning coffee?
SPEAKER_00 (21:27):
Because of the Fang study.
SPEAKER_01 (21:28):
Ah, yes.
The Fang study.
This is where the story getsincredibly dark.
SPEAKER_00 (21:31):
Aaron Powell I wouldn't call it dark.
I would call it a profoundlesson in the arrogance of
pharmacology.
SPEAKER_01 (21:36):
Okay, fair.
SPEAKER_00 (21:36):
Remember when we said that rapamycin is acutely
specific to MTORC1?
Yeah.
And that it leaves thestructural survival crew MTORC2
completely alone?
SPEAKER_01 (21:45):
Right, because the Richter protein physically
blocks it from binding.
SPEAKER_00 (21:49):
That remains true for the intact MTORC2 complex.
SPEAKER_01 (21:53):
Intact.
Key word.
SPEAKER_00 (21:54):
But if you dose an animal chronically, if you flood
their system with rabamycinevery Every single day at high
doses.
You initiate what you so aptlydescribed earlier as friendly
fire.
SPEAKER_01 (22:05):
Walk me through the physics of the friendly fire
because this is the catch.
SPEAKER_00 (22:09):
This is the massive catch.
The cell is constantly degradingold proteins and synthesizing
new ones, including new MTRmolecules.
Right.
When rapamycin enters the cell,it binds to that FKBP12 protein
and that combined unit seeks outfree MTR molecules to shut down
MTORC1.
SPEAKER_01 (22:25):
Okay.
SPEAKER_00 (22:25):
If you constantly flood the cell with rapamycin,
it acts like a sponge,sequestering every single newly
synthesized free MTOR moleculefloating in the cytoplasm.
SPEAKER_01 (22:34):
Oh wow.
So it's like stealing all thelumber before the second crew
can even build the house.
When the cell realizes it needsto build a new MTORC2
scaffolding complex, it reachesinto the toolbox for the core
MTRR protein, and the toolbox iscompletely empty.
SPEAKER_00 (22:49):
Precisely.
Rapamycin stole all the parts.
You have starved the supplychain.
Over a period of chronicexposure, the existing MTORC2
complexes degrade naturally, andthe cell physically cannot
assemble replacements.
SPEAKER_01 (23:03):
So you have now inadvertently shut down both
MTORC1 and MTORC2.
Exactly.
And shutting down MTORC2 is ametabolic disaster.
I was reading the Fang andcolleagues paper, and the data
is honestly terrifying if you'relooking at this as a longevity
biohacker.
SPEAKER_00 (23:19):
It is sobering data.
SPEAKER_01 (23:21):
They gave male mice continuous rapamycin, and within
two weeks, the mice developedsevere glucose intolerance and
insulin resistance.
They basically induce type 2diabetes in a fortnight.
SPEAKER_00 (23:30):
And hyperlipidemia, spiking cholesterol, and
triglyceride levels.
It is the exact opposite of ahealthy metabolic profile.
SPEAKER_01 (23:36):
How does shutting down the scaffolding crew cause
diabetes?
I'm trying to wrap my headaround that.
SPEAKER_00 (23:41):
It comes down to a highly complex, almost
counterintuitive feedback loopinvolving a protein called
IRS-1.
SPEAKER_01 (23:47):
IRS-1, insulin receptor substrate one.
SPEAKER_00 (23:50):
Yes.
Let's trace the wiring here.
Under normal, healthyconditions, when MTORC1 is
active and building thepeacetime economy, it needs a
way to tell the rest of thecell, hey, we have enough
resources, stop absorbing more.
SPEAKER_01 (24:02):
Makes sense.
SPEAKER_00 (24:03):
It does this by phosphorating and actively
degrading IRS-1.
SPEAKER_01 (24:07):
So it's a negative feedback loop, a shutoff valve.
SPEAKER_00 (24:10):
Exactly.
Now when you introduce rapamycinand crush MTORC1, you remove
that negative feedback.
IRS-1 is no longer degraded.
SPEAKER_01 (24:18):
It builds up.
SPEAKER_00 (24:19):
It builds up massively.
And this accumulation of IRS-1hyperactivates an upstream
signaling pathway called PI3K.
SPEAKER_01 (24:26):
Wait, wait, I think I followed this.
So PI3K is screaming at thepancreas that the cell needs
more insulin, causing insulinlevels to spike massively to
handle the glucose, whicheventually burns out the
receptors and causes insulinresistance.
SPEAKER_00 (24:39):
That is the exact mechanical cascade.
You pull the lever to stop thecellular trash buildup via
autophagy, and the insulinfactory suddenly goes completely
haywire.
SPEAKER_01 (24:47):
Friendly fire.
SPEAKER_00 (24:48):
And the importance of MTORC2 for male longevity
specifically cannot beoverstated.
If you look at genetic knockoutstudies, where scientists
engineer male mice to be borncompletely lacking the Richter
protein, meaning they have zeroMTORC2 function, those mice
actually live shorter lives.
SPEAKER_01 (25:07):
Shorter.
So hitting MTORC2 is undeniablytoxic.
SPEAKER_00 (25:10):
Undeniably.
SPEAKER_01 (25:11):
But then the Fang study gets even weirder, right?
Because they didn't stop thetrial at two weeks when the mice
got diabetes.
They kept forcing the mice totake rapamycin.
SPEAKER_00 (25:20):
Yes, they maintained the chronic dosing protocol.
And around the six-week mark,the physiology began to
transition.
Okay.
By 20 weeks of continuousrapamycin exposure, the insulin
levels dropped back down, andthe mice actually showed
improved insulin sensitivitycompared to the control group.
SPEAKER_01 (25:36):
Well, it caused diabetes and then it effectively
cured the diabetes it caused.
That makes absolutely zerosense.
SPEAKER_00 (25:41):
I know, it sounds contradictory.
But it makes perfect sense ifyou view the body as an
infinitely adaptable homeostaticmachine.
Right.
The initial shock of MTORC2starvation caused a metabolic
crisis.
But over 20 weeks, the bodydownregulated other receptors,
shifted its metabolic pathways,and adapted to the new
(26:02):
biochemical reality.
SPEAKER_01 (26:04):
It just figured out a workaround.
SPEAKER_00 (26:06):
Eventually settling into a hyperefficient
insulin-sensitive state, yes.
SPEAKER_01 (26:09):
Okay, but as a human being, I don't want to spend 20
weeks in a diabetic state hopingmy body figures out a
workaround.
SPEAKER_00 (26:15):
No sensible physician would ever recommend
that.
Which is why the holy grail ofthis entire field is developing
a protocol or a new moleculethat perfectly isolates MTORC1
without ever bleeding over intoMTORC2.
SPEAKER_01 (26:29):
Right.
I saw a paper by Cameron andcolleagues talking about trying
to design drugs around the Crimdomain of SIN1.
SPEAKER_00 (26:35):
Yes, SIN1.
SPEAKER_01 (26:36):
What exactly is SYN1?
SPEAKER_00 (26:37):
SIN1 is another structural component of the
MTORC2 complex.
The Crim domain, which standsfor conserve region in the
middle, is the specific physicallatch that MTRC2 uses to grab
onto and activate its targets,like the ACE survival kinos.
SPEAKER_01 (26:50):
So if we can target the Crim domain, we can control
MTORC2 directly.
But the paper pointed out thatmost of the pharmaceutical
funding for this is coming fromcancer research, not longevity
research.
SPEAKER_00 (27:01):
That is the bottleneck.
SPEAKER_01 (27:03):
And in cancer, they want the exact opposite outcome.
A tumor relies heavily on MTORC2to survive and vascularize.
So oncologists are trying todesign small molecules that
block the crim domain to killthe scaffolding crew.
SPEAKER_00 (27:17):
That's the tragic irony of the funding structure
right now.
Billions of dollars are beingpoured into dual MTOR inhibitors
for oncology.
SPEAKER_01 (27:25):
Drugs designed to ruthlessly crush both MTORC1 and
MTRC2.
SPEAKER_00 (27:30):
Exactly.
But for geroscience, the studyof aging, we desperately need a
drug that guarantees MTORC2remains 100% operational.
We need a pure unadulteratedMTORC1 inhibitor.
SPEAKER_01 (27:42):
And since we don't have that perfect magical
molecule yet, we have to rely ondosing strapper geese.
Which brings us to the humanclinical trials happening right
now.
SPEAKER_00 (27:50):
Finally, we are moving out of the era of
speculative internet forumbiohacking and into rigorous
NIA-funded clinical validation.
SPEAKER_01 (27:57):
Yes.
Dr.
Ellen Craig and Dr.
Dean Kellogg at UT Health SanAntonio are at the forefront of
this.
SPEAKER_00 (28:02):
They are.
SPEAKER_01 (28:02):
They are running a trial with 84 healthy older
adults, ages 65 to 90, and theentire premise of the trial is
precision dosing.
SPEAKER_00 (28:11):
Precision intermittent dosing.
The logic is elegant, honestly.
If chronic exposure starves thecell of free MTOR and destroys
MTORC2, the solution is simplyto not expose the cell
chronically.
SPEAKER_01 (28:25):
You pulse it.
SPEAKER_00 (28:26):
You pulse it.
They are testing regimens likeone milligram per day for a very
short duration of eight weeks,or a single five milligram dose
given just once a week.
SPEAKER_01 (28:35):
Okay, so walk me through what happens in the body
when you pulse it like that.
So you flood the system on aMonday.
SPEAKER_00 (28:40):
Right, Monday morning.
The rapamycin hits MTOR-C1 hard,the boom economy shuts down, the
bulky phosphate padlocks comeoff ULK1 and ATG13.
SPEAKER_01 (28:49):
Autophagy kicks into high gear.
SPEAKER_00 (28:50):
Yes.
And the cellular garbage trucksroll out to clear up the
misfolded proteins.
But then, because you don't takeanother pill on Tuesday or
Wednesday, the drug clears outof the bloodstream.
SPEAKER_01 (29:00):
It clears out before it has the chance to sequester
enough free MTOR to disrupt theassembly of the MTOR-C2
scaffolding.
SPEAKER_00 (29:06):
That's exactly it.
The patient gets the profoundautophagic repair benefits of
MTORC1 inhibition, completelydodging the hypolipidemia and
insulin resistance of MTOR-C2inhibition.
SPEAKER_01 (29:19):
That is incredible.
And there's precedent for thisworking in humans, right?
I read about a trial using atopical 8% rapamycin cream on
the skin.
SPEAKER_00 (29:28):
A phenomenal localized study.
SPEAKER_01 (29:29):
Because by applying it topically, they avoided
systemic metabolic issuesentirely.
SPEAKER_00 (29:34):
Yes.
And the skin biopsy showed adefinitive reduction in markers
of cellular senescence.
The SASP was suppressed.
The skin was, at a biologicallevel, acting younger.
Just from a cream.
Furthermore, previousshort-term, low-dose systemic
trials in older cohortsdemonstrated zero clinically
relevant adverse cognitive orimmune side effects.
(30:00):
Well, this is where dose makesthe poison.
At massive daily doses for atransplant patient, yes, it
paralyzes T cell proliferation.
But at a low intermittent dose,a derivative of rapamycin,
called a Rapolog, actuallyimproved the immune response of
elderly patients to a seasonalinfluenza vaccine.
SPEAKER_01 (30:20):
Shut up.
It made their immune systemsharper.
SPEAKER_00 (30:22):
It rejuvenated hematopoietic stem cell
function.
SPEAKER_01 (30:25):
I am mind-blown.
SPEAKER_00 (30:26):
By clearing out the senescent garbage in the immune
compartments via autochogy, theremaining immune cells were more
robust, functional, andresponsive to the vaccine
antigen.
SPEAKER_01 (30:36):
Okay, that completely blows my mind.
But I do have a really pragmaticquestion about these human
trials.
SPEAKER_00 (30:40):
Sure.
SPEAKER_01 (30:41):
When Dr.
Craig and Dr.
Kellogg are running this studyat UT Health, how do they
actually know if it's working?
You can't run a human lifespantrial.
SPEAKER_00 (30:49):
No, you can't.
SPEAKER_01 (30:49):
It would take 80 years and cost$3 billion to see
who lives longer.
Are they just like seeing if an80-year-old can walk up a flight
of stairs faster?
SPEAKER_00 (30:58):
Functional metrics like grip strength and gate
speed are tracked.
Yes, they're important.
But to truly measure theefficacy of a longevity
intervention in a realistic timeframe, the field relies on
biomarkers of aging.
SPEAKER_01 (31:10):
Biomarkers.
SPEAKER_00 (31:11):
We are measuring the molecular footprints of decay.
SPEAKER_01 (31:14):
Like the epigenetic clocks?
I keep hearing about those.
SPEAKER_00 (31:17):
Epigenetic clocks are currently the gold standard.
We analyze DNA methylationpatterns.
Over time, certain regions ofyour DNA accumulate methyl
groups, which actually changeshow your genes are expressed.
Okay.
By analyzing these patterns, wecan determine the biological age
of your cells, which might bevery different from your
chronological age.
SPEAKER_01 (31:36):
So you could be chronologically 75, but if the
rapamycin pulsing is working,your DNA methylation clock might
read 68.
SPEAKER_00 (31:43):
That is the goal.
We also heavily monitor themetabolic markers we discussed
earlier, ensuring insulinsensitivity remains stable or
improves.
SPEAKER_01 (31:52):
To make sure we aren't hitting MTORC2.
SPEAKER_00 (31:54):
Exactly.
We run comprehensive cytokinepanels in the blood to look for
reductions in IL6 and TNF alpha,which proves we are successfully
suppressing that toxic SSP fromthe senescent cells.
Got it.
And borrowing directly from thedog aging project, we measure
cardiac fractional shorteningvia echocardiogram to track the
physical elasticity of themyocardium in humans.
SPEAKER_01 (32:16):
We are literally trying to prove that the
biological odometer of a humanbeing is rolling backward even
while the calendar keeps movingforward.
SPEAKER_00 (32:24):
We are decoupling chronological time from
biological decay.
SPEAKER_01 (32:27):
This entire journey is just it's a testament to how
wild science actually is.
I mean, let's just trace theexact through line here.
SPEAKER_00 (32:35):
Let's do it.
SPEAKER_01 (32:36):
It starts in 1975 with a handful of dirt from
Easter Island.
Rapin Nui.
A team looking for athlete'sfoot medicine accidentally
discovers rapamycin.
That molecule leads scientiststo identify MTOR, this ancient
conserved master switch thatacts as the economic engine for
every eukaryotic cell on Earth.
SPEAKER_00 (32:55):
A switch that integrates the availability of
amino acids, ATP, oxygen, andinsulin to dictate whether a
cell builds or whether itrepairs.
SPEAKER_01 (33:02):
Right.
And we figured out that whilethe boom economy of MTORC1 is
great for building muscle, ifyou let it run forever, it shuts
down the garbage trucks.
It stops autophagy.
SPEAKER_00 (33:10):
The amyloid plaques build up, the mitochondria burn
out, and we age.
SPEAKER_01 (33:15):
But by pulsing rapamycin, we can wedge the
gears of MTORC1, take off thosephosphate padlocks, and trigger
that wartime rationing economywhere the cell melts down its
own toxic waste to survive.
SPEAKER_00 (33:27):
And we observe this working spectacularly across
species (33:29):
yeast, nematodes, flies.
SPEAKER_01 (33:32):
The genetically diverse mice in the 2009
Harrison study starting at 60human years old, the companion
dogs in the triad trialregaining heart elasticity, the
marmoset monkeys all pointing tomassive lifespan and health span
extension.
SPEAKER_00 (33:45):
But then the reality check.
SPEAKER_01 (33:47):
The reality check.
The friendly fire.
SPEAKER_00 (33:49):
Chronic exposure, sequesters-free MTOR, preventing
the assembly of the MTRR-C2structural complex.
SPEAKER_01 (33:56):
Which rips away the negative feedback loop on IRS-1,
spikes the PI3K pathway, anddrops the mice straight into
insulin resistance and diabetes,a catastrophic metabolic cost.
SPEAKER_00 (34:06):
And so the absolute cutting edge of human science
right now, the UT health trials,is the delicate art of precision
dosing.
SPEAKER_01 (34:11):
Get in, shut down the boom economy, trigger
autophagy, and get the drug outof the system before the
scaffolding crew starves.
SPEAKER_00 (34:17):
It is a remarkable summary of a staggeringly
complex biological cascade.
And to bring this out of thelaboratory and back to the
listener, I think it's vital torealize that understanding MTOR
is not just an academic exercisewhile we wait for a
prescription.
SPEAKER_01 (34:33):
No, definitely not.
SPEAKER_00 (34:34):
This biochemistry dictates your daily life.
It explains the mechanics ofyour diet.
SPEAKER_01 (34:40):
Because amino acids trigger MTOR.
SPEAKER_00 (34:42):
Specifically, leucine, found in high
concentrations in animalprotein, is a potent activator
of MTOR C1.
SPEAKER_01 (34:50):
Ah.
This explains why hyper-highprotein diets are excellent for
building muscle in the shortterm, like for bodybuilders, but
might be detrimental tolong-term longevity if they
never sell MTOR to rest.
SPEAKER_00 (35:02):
Exactly.
It also provides the exactmechanical explanation for why
intermittent fasting isbiologically effective.
SPEAKER_01 (35:08):
Because fasting naturally depletes the amino
acids and the cellular energy.
It physically removes the cashfrom the economy, which
naturally shuts down MTORC1,which naturally removes the
break on ULK1, and naturallyturns on autophagy.
SPEAKER_00 (35:22):
You got it perfectly.
SPEAKER_01 (35:23):
Fasting is basically doing exactly what rapamycin
does.
You just have to actually endurethe hunger to get there.
SPEAKER_00 (35:29):
Diet, metabolism, and the rate at which you age
are all speaking the exact samechemical language.
SPEAKER_01 (35:35):
It fundamentally changes how you look at a meal
or a workout or even just amissed night of sleep.
It's all just inputs into thismaster switch.
Okay, well, before we wrap thisup, you have a habit of dropping
these massive perspectiveshifting thoughts at the end of
our discussions.
SPEAKER_00 (35:50):
I try my best.
SPEAKER_01 (35:51):
Where does this all ultimately lead?
SPEAKER_00 (35:54):
Well, if you extrapolate the trajectory of
this research, whether it'sprecision rapamycin dosing or a
future molecule targeting thecrumb domain that perfectly
isolates MTORC1, it raises adeeply profound philosophical
question.
SPEAKER_01 (36:07):
Aaron Powell Okay, I'm ready.
SPEAKER_00 (36:08):
Right now, this intervention works by tricking
the cell into a state of famine.
It activates ancientevolutionary repair mechanisms
that were specifically designedto keep us alive during
starvation.
SPEAKER_01 (36:19):
Right.
We are hacking a survivalresponse.
SPEAKER_00 (36:21):
Aaron Powell But if juroscience perfects this, if we
create a daily protocol thatcontinually initiates ultimate
cellular repair without a humanbeing ever having to experience
true starvation, disease, or theaccumulation of metabolic waste,
how does that change thefundamental human experience?
Oh wow.
If the autophagic recycling isperfectly optimized and the
(36:44):
senescent SASP never sets in todegrade our tissues, do we have
to completely rewrite ourdefinition of a normal lifespan?
SPEAKER_01 (36:52):
That is heavy.
SPEAKER_00 (36:54):
Have we just assumed aging is an inevitable law of
physics when in reality it issimply a biochemical disease
that we finally learned how tocure?
SPEAKER_01 (37:02):
We just needed the instruction manual.
And it was buried in the birthon an island in the middle of
the Pacific.
That is absolutely incredible.
Thank you for walking throughthis massive stack of research
with me today.
SPEAKER_00 (37:11):
It was my pleasure.
SPEAKER_01 (37:12):
And to everyone listening, keep questioning the
world around you.
Keep an eye on those clinicaltrials, and don't forget to let
yourselves take out the trash.
We will see you next time.
In 1975, scientists isolated a single vial of dirt
from literally one of the mostremote places on planet Earth,
Easter Island, Rappa Nui.
SPEAKER_00 (00:08):
Right, right.
SPEAKER_01 (00:09):
And they were out there looking for um an
antifungal compound, likesomething to just treat simple
infections.
Athlete's foot, whatever.
SPEAKER_00 (00:17):
Exactly.
SPEAKER_01 (00:18):
But instead, what they found buried in that soil
was a master biological switch.
A switch hidden inside abacterium that can quite
literally command a living cellto stop aging, which is just
insane to me.
SPEAKER_00 (00:30):
Aaron Powell I mean, it sounds completely like
science fiction when you frameit like that.
SPEAKER_01 (00:33):
Aaron Powell It totally does.
SPEAKER_00 (00:34):
Aaron Powell But the biochemistry backing this up is
incredibly concrete.
I mean, we are looking at amolecule that interacts with the
fundamental infrastructure ofhow eukaryotic life basically
decides whether to grow orwhether to hunker down and
repair itself.
SPEAKER_01 (00:47):
Aaron Powell Yeah.
And I have been pouring overthis giant stack of research you
send over for this deep dive.
We're talking data from the NIH,uh, the Dog Aging Project, UT
Health San Antonio, and it isjust staggering.
SPEAKER_00 (01:00):
Aaron Powell It really is a paradigm shift.
SPEAKER_01 (01:01):
So our mission today is to completely demystify MTOR
signaling, figure out how thisdrug rapamycin actually works,
and look at the clinical trialsthat are trying to hack the
biology of aging.
And you know, for everyonelistening with us right now,
whether you're just trying tofigure out how to get a few more
healthy years with your goldenretriever, or you're tracking
your own metabolic health,understanding this specific
(01:24):
biological switch is honestlythe ultimate shortcut to
understanding the entire futureof longevity medicine.
SPEAKER_00 (01:30):
Absolutely.
And to really grasp themagnitude of what we're doing in
clinical trials today, I thinkwe have to look at the sheer
serendipity of that 1975expedition.
SPEAKER_01 (01:39):
The dirt expedition.
SPEAKER_00 (01:40):
The dirt expedition, yes.
So Canadian researchers fromAyers Pharmaceuticals were
systematically screening soilsamples from all around the
world.
SPEAKER_01 (01:47):
Just scooping up dirt everywhere.
SPEAKER_00 (01:49):
Pretty much.
They were looking for novelantibiotics produced by
bacteria.
And in this particular samplefrom Rapanui, they isolated a
bacterium called Streptomyceshygroscopicus.
Streptomyces hygroscopicus, andthat bacterium produced a very
specific metabolite.
SPEAKER_01 (02:04):
Which is the magic compound we're talking about
today.
SPEAKER_00 (02:06):
Exactly.
A macrolide compound.
And because of its origin onRapanui, they named it
Rapamycin.
SPEAKER_01 (02:13):
Okay, that makes sense.
SPEAKER_00 (02:14):
And initially, yes, it did kill fungi.
But as they started testing iton mammalian cells, the data
started coming back with thesebizarre anomalies.
SPEAKER_01 (02:25):
Wait, what kind of anomalies?
Like it was killing themammalian cells too.
SPEAKER_00 (02:28):
Not killing them, exactly.
It was halting theirproliferation.
It wasn't just targeting fungalpathogens, it was stopping human
cells from dividing.
It possessed massive, massiveimmunosuppressive properties.
SPEAKER_01 (02:40):
Oh, whoa.
Which completely derailed itsuse as an antifungal, right?
I mean, you don't want to shutdown a patient's entire immune
system just to cure athlete'sfoot.
SPEAKER_00 (02:49):
You absolutely do not.
That would be catastrophic.
SPEAKER_01 (02:51):
Right.
Friendly fire.
SPEAKER_00 (02:52):
Exactly.
So the compound was actuallyjust shelved for a while.
It wasn't until the 1980s and90s that the medical community
realized its true utility wasactually in organ
transplantation.
SPEAKER_01 (03:03):
Oh, because of the immune system thing?
SPEAKER_00 (03:05):
Yes.
If you give a patient a newkidney, their immune system will
naturally recognize that kidneyas foreign tissue and attack it.
SPEAKER_01 (03:13):
Because the body is like, hey, this doesn't belong
here.
SPEAKER_00 (03:15):
Precisely.
Rapamycin was phenomenal atsuppressing that specific immune
response, mainly by stopping Tcells from dividing.
So the FDA eventually approvedit as a transplant
immunosuppressant.
SPEAKER_01 (03:28):
But the wild part to me about all of this is that
they were prescribing thisincredibly powerful drug for
years before anyone actuallyknew how it worked on a
molecular level.
SPEAKER_00 (03:37):
That happens more often than you'd think in
medicine, honestly.
SPEAKER_01 (03:40):
Really?
It was just a black box.
They were just like, hey, itstops cells from dividing.
Let's use it.
It wasn't until what 1991 thatthe curtain finally got pulled
back.
SPEAKER_00 (03:47):
Yeah, 1991, Michael Hall and his team in Switzerland
were studying yeast.
Just simple single-celledbaker's yeast.
SPEAKER_01 (03:54):
Just baking bread.
SPEAKER_00 (03:55):
Right.
They exposed the yeast torapamycin and isolated the
specific genes that the drug wastargeting.
And they called them TOR1 andTOR2 target of rapamycin.
And shortly after that,researchers discovered the
mammalian equivalent, henceMPOR, the mammalian target of
rapamycin.
SPEAKER_01 (04:13):
Or the mechanistic target of rapamycin, depending
on which of these papers you'rereading.
I saw both terms thrown around alot.
SPEAKER_00 (04:19):
Right.
I personally prefer mechanisticas it accurately reflects its
role across different species.
But yes, mammalian is commontoo.
SPEAKER_01 (04:27):
Okay, so this is where I think we really have to
establish what MTOR actually isbiochemically, because it is the
absolute linchpin of this entiredeep dive.
SPEAKER_00 (04:38):
It is the core of everything we're discussing.
SPEAKER_01 (04:40):
The paper called it a serinenthrine protein kinase.
unknown (04:44):
Yes.
SPEAKER_01 (04:44):
Okay, let me stop you there.
Because serenanthrinine proteinkinase is the exact kind of
phrase that makes people's eyesjust completely glaze over.
SPEAKER_00 (04:52):
Fair enough.
It is a mouthful.
SPEAKER_01 (04:53):
I want to make sure we actually explain the physics
of this to the listener.
So a kinase is an enzyme thatadds a phosphate group to
another molecule, right?
Phosphorylation.
SPEAKER_00 (05:02):
That is the textbook definition, yes.
SPEAKER_01 (05:04):
But practically, and correct me if I'm visualizing
this wrong, adding a phosphategroup isn't just like tagging
the protein with a sticky note.
That phosphate group is highlynegatively charged.
SPEAKER_00 (05:16):
Extremely negatively charged, yes.
SPEAKER_01 (05:17):
So when a kinase like MTOR slaps a phosphate onto
a target protein, that massivenegative charge repels other
parts of the protein, right?
Like magnets pushing away fromeach other.
SPEAKER_00 (05:28):
That's exactly what happens.
SPEAKER_01 (05:29):
Forcing the whole 3D structure of the protein to
physically contort and changeits shape.
It's like putting a bulkypadlock on a machine part so it
either locks into place orphysically just can't fit into
the machinery anymore.
SPEAKER_00 (05:42):
That is a phenomenal way to visualize it.
I love that.
You are physically altering thetopography of the protein so it
either activates or deactivates.
SPEAKER_01 (05:49):
It's mechanical.
SPEAKER_00 (05:50):
Highly mechanical.
And MTOR uses this locking andunlocking mechanism to act as
the ultimate sensory integratorfor the cell.
SPEAKER_01 (05:58):
The sensor, like a thermostat.
SPEAKER_00 (06:00):
More complex than a thermostat.
It sits there monitoring theentire environment.
It detects amino acids,specifically leucine and
arginine from the proteins weeat.
It monitors cellular energylevels via ATP.
Okay.
It detects oxygen levels.
It monitors growth factors likeinsulin.
It takes in all this data tomake a decision.
SPEAKER_01 (06:21):
You know, I was trying to come up with an
analogy for this because I keepseeing it described as a general
contractor in the literature,but that feels a little small to
me.
I feel like MTOR is more like anational economy.
SPEAKER_00 (06:34):
A national economy.
Okay, I am intrigued.
Walk me through the economics ofa cell.
SPEAKER_01 (06:38):
Okay, so imagine MTR is the Federal Reserve and the
government rolled into one.
SPEAKER_00 (06:42):
A powerful entity.
SPEAKER_01 (06:43):
Right.
When times are good, whenthere's plenty of cash, which is
cellular energy, and plenty ofraw materials, which are the
amino acids, the MTOR shifts thecell into a peacetime boom
economy.
SPEAKER_00 (06:55):
Oh, I see where you're going with this.
SPEAKER_01 (06:56):
It says build, multiply, synthesize.
It drives the creation of newproteins, new lipids, and tells
the cells to proliferate.
It's the ultimate growth state.
Everything is booming.
SPEAKER_00 (07:08):
I will absolutely adopt that metaphor because it
perfectly captures the dualityof the system.
SPEAKER_01 (07:12):
Yeah.
SPEAKER_00 (07:13):
Definitely.
A peacetime boom economy iswonderful for a developing
nation, or in biology, adeveloping human child.
SPEAKER_01 (07:22):
Because they need to grow.
SPEAKER_00 (07:23):
Exactly.
You want explosive growth.
You want to build muscle, bone,and neural tissue.
But, and this is the crucialpart, what happens to an economy
that literally never stopsbuilding?
SPEAKER_01 (07:33):
Never stops.
SPEAKER_00 (07:34):
Right.
If it just keeps producinggoods, adding infrastructure,
and endlessly consumingresources without ever managing
its waste or experiencing amarket correction.
SPEAKER_01 (07:44):
Oh man, you get hyperinflation, you get a
massive buildup of useless junk,empty ghost cities, and
eventually the whole system justcollapses under its own weight.
SPEAKER_00 (07:53):
Which is precisely what happens in biology when
MTOR becomes hyperactive andthat peacetime growth state
refuses to shut off.
SPEAKER_01 (08:01):
Whoa.
So growth isn't always good.
SPEAKER_00 (08:03):
Unending growth in an adult organism isn't youth,
it's cancer or senescence.
We see this in severepathologies.
SPEAKER_01 (08:09):
Like what?
SPEAKER_00 (08:10):
Well, there's a rare progressive lung disease called
lamb lymphangioleomyomatosis.
SPEAKER_01 (08:16):
That's a long word.
Lamb.
SPEAKER_00 (08:18):
Lamb is easier, yes.
In lamb, smooth muscle-likecells just endlessly proliferate
in the lungs until they formthese destructive cysts.
It's unchecked growth.
SPEAKER_01 (08:28):
That sounds awful.
SPEAKER_00 (08:29):
We also see it in tuberous sclerosis complex,
which is a genetic disorderwhere benign tumors grow in the
brain, kidneys, and heart.
SPEAKER_01 (08:36):
And cancer, obviously, like unregulated
growth is the literal definitionof cancer.
SPEAKER_00 (08:40):
Aaron Powell Exactly.
Both lamb and tuberosclerosisare actually driven by mutations
in genes that are supposed toinhibit MTR.
SPEAKER_01 (08:48):
So the breaks are cut.
SPEAKER_00 (08:49):
The genetic breaks fail, and MTR runs wild.
The peacetime economy overheats.
And even in healthy adults,chronic unending MTOR activation
drives something calledsenescence.
SPEAKER_01 (09:01):
Oh, senescence! That is fascinating.
I was reading about that.
It's when a cell basicallyreaches the end of its useful
life, it stops dividing, but itrefuses to die.
It just sits there like azombie.
SPEAKER_00 (09:12):
A very toxic zombie.
Right.
Senescence cells aren't justinactive, they secrete a
cocktail of inflammatorycytokines, chemokines, and
protestases.
We call it the SASP, thesenescence associated secretory
phenotype.
This chronic, low-gradeinflammation actually degrades
the surrounding healthy tissue.
It's a primary driver of theaging process itself.
SPEAKER_01 (09:32):
So the goal isn't just to grow forever.
We actually need the economy tooccasionally experience a
recession.
We need to stop building.
Yes.
Which brings us to the structureof MTR itself.
Because as I was reading the UTHealth papers, I realized MTR
isn't just one monolithicentity.
It operates in two entirelydifferent complexes, two
different crews running theeconomy.
SPEAKER_00 (09:51):
MTORC1 and MTORC2.
SPEAKER_01 (09:54):
Right.
SPEAKER_00 (09:54):
And understanding the division of labor between
these two complexes is the onlyway to understand both the
promise and the danger ofrapamycin.
SPEAKER_01 (10:02):
Okay, let's break down the first crew, MTORC1.
SPEAKER_00 (10:05):
So MTORC1 is defined by the presence of a specific
scaffolding protein calledRaptor.
SPEAKER_01 (10:10):
Raptor.
Like the dinosaur.
SPEAKER_00 (10:12):
Sure, like the dinosaur.
This is the complex that acts asthe peacetime economy you
described.
SPEAKER_01 (10:16):
Got it.
SPEAKER_00 (10:17):
It is acutely sensitive to nutrients.
Yep.
And crucial to our deep divetoday, it is acutely sensitive
to rapamycin.
SPEAKER_01 (10:23):
And when we say sensitive, we mean rapamycin
physically jams the gears ofthis specific complex.
SPEAKER_00 (10:29):
It creates a wedge.
Rapamycin enters the cell andbinds to a small protein called
FKBP12.
SPEAKER_01 (10:34):
Okay, rapamycin grabs this little FKBT12
protein.
SPEAKER_00 (10:37):
Yes.
And this new rapamycin FKBP12complex then physically docks
onto MTORC1 right next to thekinase domain, effectively
blinding it.
It physically blocks thesubstrates from accessing the
active site.
The padlock.
Exactly.
It locks it down.
SPEAKER_01 (10:52):
So the peacetime economy is artificially shut
down by this drug.
SPEAKER_00 (10:55):
Shut down instantly.
And the downstream effects ofthis are profound.
When MTORC1 is active, itnormally promotes translation,
the making of new proteins byphosphorylating targets like
N6K1 and 4EBP1.
SPEAKER_01 (11:07):
Okay, wait.
The 4E BP1 interaction isbrilliant.
Let me see if I have this right.
SPEAKER_00 (11:11):
Go ahead.
SPEAKER_01 (11:12):
From what I understand, 4EBT1 is normally a
suppressor.
Like it wraps around the proteinmaking machinery and stops it.
But when MTORC1 phosphorylatesit, when it adds that bulky
negative phosphate group wetalked about, it forces 4EBP1 to
change shape and release itsgrip, which allows the cell to
suddenly manufacture newproteins.
SPEAKER_00 (11:32):
That is the exact mechanical reality, yes.
SPEAKER_01 (11:35):
It's so cool.
SPEAKER_00 (11:36):
It really is.
But more important for ourdiscussion on aging is what
MTORC1 does to catabolicprocesses.
SPEAKER_01 (11:42):
Catabolic meaning breaking things down, right?
SPEAKER_00 (11:45):
Yes, breaking down molecules.
When MTRC1 is running the boomeconomy, it puts a hard physical
break on a process calledautophagy.
SPEAKER_01 (11:52):
Autophagy, literally self-eating, if you look at the
green.
SPEAKER_00 (11:55):
Yes.
And returning to your economicmetaphor, if MTORC1 is peacetime
consumerism, autophagy is thewartime rationing economy.
SPEAKER_01 (12:03):
Ooh, I like that.
SPEAKER_00 (12:04):
When resources are incredibly scarce, a nation
stops building new shoppingmalls and starts melting down
old cars and scrap metal tobuild tanks.
SPEAKER_01 (12:11):
It recycles from within.
SPEAKER_00 (12:13):
Exactly.
It uses its own garbage as fuel.
SPEAKER_01 (12:15):
I love that.
So instead of just leaving allthe misfolded proteins and
damaged cellular machinery lyingaround, the cell builds these
little molecular garbage bags,what I call autophagosomes.
SPEAKER_00 (12:25):
Autophagosomes, yes.
SPEAKER_01 (12:26):
And it sweeps it all up, melts it down, and uses the
raw amino acids to survive.
SPEAKER_00 (12:31):
And the mechanical way MTRRC1 stops this is by
phosphorylating two initiationproteins called ULK1 and ATG13.
SPEAKER_01 (12:38):
More padlocks.
SPEAKER_00 (12:39):
More padlocks.
By placing those phosphatepadlocks on the initiation
proteins, MTORC1 physicallyprevents the autophagus and
garbage bags from ever forming.
The wartime recycling factoriesare basically padlocks shut.
SPEAKER_01 (12:52):
Which is fine when you're young and healthy and
flooded with nutrients.
But as we age, if we never flipthat switch, the cellular scrap
metal just piles up.
SPEAKER_00 (13:00):
It accumulates relentlessly.
SPEAKER_01 (13:02):
Just trash everywhere in the cell.
SPEAKER_00 (13:03):
Literally.
We see a buildup of misfoldedproteins and highly
dysfunctional exhaustedmitochondria.
This accumulation underpinsage-related cellular failure
across the board.
SPEAKER_01 (13:13):
Like neurodegenerative diseases.
SPEAKER_00 (13:15):
Precisely.
Alzheimer's is characterized byamyloid beta plaques and
tautangles.
Parkinson's involvesalpha-cinuclein aggregation.
SPEAKER_01 (13:23):
Oh wow.
SPEAKER_00 (13:23):
These are all toxic proteins that a robust
autophagic system shouldtheoretically clear out.
SPEAKER_01 (13:28):
Okay, so here is the absolute genius of rapamycin,
then.
If you give a cell rapamycin, itbinds to that FKBP12 protein,
wedges into MTORC1, and shuts itdown.
Yes.
And because MTORC1 is shut down,the bulky phosphate padlocks are
removed from ULK1 and ATG13.
SPEAKER_00 (13:48):
To break her off.
SPEAKER_01 (13:49):
The itophagosomes form.
The cell suddenly switches intothe wartime rationing economy
and starts melting down thetoxic amyloid plaques and broken
mitochondria, even though thebody isn't actually starving.
SPEAKER_00 (14:01):
It is the ultimate biochemical trick.
SPEAKER_01 (14:03):
Dude, that is wild.
SPEAKER_00 (14:04):
It is a calorie restriction mimetic.
SPEAKER_01 (14:06):
Mimetic.
So it mimics calorierestriction.
SPEAKER_00 (14:09):
Yes.
You get the profound cellularrepair benefits of starvation
without the physiological traumaof actual famine.
SPEAKER_01 (14:15):
Okay.
That is just incredible.
But so that's the peacetimecrew, MTORC1.
You mentioned a second complex,MTORC2.
SPEAKER_00 (14:22):
Yes, the other side of the coin.
SPEAKER_01 (14:23):
Now from what I read, this is where the whole
anti-aging narrative hits amassive wall of complication.
SPEAKER_00 (14:28):
A very steep wall.
MTORC2 is the structuralmaintenance crew.
It contains a different coreprotein called Richter rather
than Raptor.
SPEAKER_01 (14:34):
Raptor and Richter.
Okay.
SPEAKER_00 (14:36):
Yes.
And its primary job is notnutrient sensing, it regulates
the actin cytoskeleton, which isthe physical scaffolding that
gives a cell its shape, and itpromotes cellular survival by
activating a downstream kinasecalled act.
SPEAKER_01 (14:49):
So it's keeping the physical house from falling
down.
SPEAKER_00 (14:52):
Exactly.
SPEAKER_01 (14:53):
And rapamycin doesn't wedge into MTORC2.
SPEAKER_00 (14:57):
It does not.
The Richter protein physicallyblocks the rapamycin FKBP12
complex from binding.
Oh.
So acutely, rapamycin only shutsdown the boom economy of MTORC1
while leaving the vital survivalscaffolding of MTRC2 completely
operational.
SPEAKER_01 (15:13):
That sounds like a perfect drug.
You turn on the recycling, clearout the Alzheimer's proteins,
and keep the cellularscaffolding strong.
SPEAKER_00 (15:19):
In theory, yes.
SPEAKER_01 (15:20):
Which totally explains why the animal trials I
looked at were so overwhelminglypositive.
I mean, they didn't just testthis in a petri dish, they put
it in basically every modelorganism we have.
SPEAKER_00 (15:30):
The evolutionary conservation of the MTR pathway
is staggering.
SPEAKER_01 (15:33):
It's the same switch in everything.
SPEAKER_00 (15:35):
Practically, Rapamyxin extends the lifespan
of yeast, it extends thelifespan of C.
elegans, the microscopicnematode worms, it works in
Drosophila, the fruit flies, andthen, of course, the mammalian
trials.
SPEAKER_01 (15:48):
The 2009 Harrison study from the interventions
testing program, I spent a lotof time on this paper because it
seems like the moment thelongevity community just went
into absolute overdrive.
SPEAKER_00 (15:58):
It was a huge paradigm shift.
Before 2009, the idea of apharmacological intervention
reliably extending mammalianlifespan was highly speculative.
SPEAKER_01 (16:07):
Just a pipe dream.
SPEAKER_00 (16:08):
Exactly.
SPEAKER_01 (16:08):
And the methodology of that study is what makes it
so bulletproof, right?
Because they didn't just usethose highly inbred lab mice
where one weird genetic corkcould skew all the data.
SPEAKER_00 (16:18):
No, they used genetically heterogeneous mice.
SPEAKER_01 (16:20):
Which mimic the messy genetic diversity of a
human population.
SPEAKER_00 (16:24):
Precisely.
SPEAKER_01 (16:24):
And more importantly, they didn't start
feeding them rapamycin when theywere pups.
SPEAKER_00 (16:28):
This is the critical detail.
They started the interventionwhen the mice were 20 months
old.
SPEAKER_01 (16:32):
And in marine physiology mouse years, 20
months is roughly equivalent toa 60-year-old human.
That is the part that genuinelystopped me in my tracks.
You take a mouse that is alreadyentering its senior years, you
start giving it rapamycin, andit still significantly extends
both the median and maximallifespan.
SPEAKER_00 (16:52):
It's quite profound.
SPEAKER_01 (16:53):
It's not just preventative if you start at
birth, it's practicallyrestorative late in life.
SPEAKER_00 (16:59):
It delayed age-related decline across
multiple organ systems, itpreserved liver function,
maintained tendon elasticity,mitigated cardiac hypertrophy.
SPEAKER_01 (17:08):
That's insane.
SPEAKER_00 (17:09):
However, you noted some nuances in the ITP data
when you were reviewing thematerials earlier.
SPEAKER_01 (17:14):
Oh, yeah.
The sex differences really stoodout to me.
When you look at the lifespancurves, rapamycin works in both
sexes, but the lifespanextension is noticeably more
pronounced in female mice thanin male mice.
SPEAKER_00 (17:25):
Yes, that's accurate.
SPEAKER_01 (17:26):
And then you compare that to another drug the ITP
tested, uh 17 alpha estradiol,which extended lifespan only in
male mice and did absolutelynothing for females.
Right.
So are we looking at a hormonalinterference with MTOR, or do
male and female livers justmetabolize the drug differently?
SPEAKER_00 (17:44):
That is a highly sophisticated question,
honestly.
And the answer is likelypharmacokinetic.
SPEAKER_01 (17:48):
Pharmacokinetic, so how the drug moves through the
body.
SPEAKER_00 (17:51):
Right.
Female mice seem to maintainhigher blood levels of rapamycin
than males given the exact samedose in their shell.
They simply clear the drug fromtheir systems more slowly.
SPEAKER_01 (18:02):
Oh, so they just have more of it in their
bloodstream.
SPEAKER_00 (18:05):
Essentially, yes.
But the broader point iscritical.
Aging pathways are oftensexually dimorphic.
SPEAKER_01 (18:12):
Dimorphic, meaning two different forms.
SPEAKER_00 (18:14):
Yes.
What works for a male biologymay not perfectly map onto a
female biology, which makestranslation to human trials
incredibly complex.
SPEAKER_01 (18:23):
Which perfectly brings me to the intermediate
step between mice and humans,the dogs.
SPEAKER_00 (18:28):
Ah, yes, dogs.
SPEAKER_01 (18:30):
I am obsessed with the dog aging project.
SPEAKER_00 (18:32):
It's a remarkable initiative, primarily driven by
the University of Washington andTexas AM.
SPEAKER_01 (18:36):
Dr.
Kate Creevy and her team, theyjust got a$7 million NIH grant
for the Tri-Aid trial.
SPEAKER_00 (18:42):
The test of rapamycin in aging dogs.
SPEAKER_01 (18:44):
Yes.
And what's brilliant about thisis that they aren't locking a
bunch of beagles in a sterilelab.
They are enrolling 580 companiondogs, pet dogs, living in normal
homes, sleeping on couches,eating dropped food off the
kitchen floor.
SPEAKER_00 (19:00):
The environmental variable is crucial here.
Lab mice live in apathogen-free,
temperature-controlled,perfectly regulated bubble.
SPEAKER_01 (19:09):
Yeah.
Real life is messy.
SPEAKER_00 (19:10):
Exactly.
Companion dogs share ourenvironment.
They drink our water.
They're exposed to the sameambient pollutants.
They share our circadiandisruptions.
SPEAKER_01 (19:20):
They stay up late with us.
SPEAKER_00 (19:21):
They do.
And biologically, they age inways that perfectly mirror human
decline.
They develop osteoarthritis,they suffer from cardiac
stiffening, they even experiencecanine cognitive dysfunction.
SPEAKER_01 (19:32):
Which is functionally very similar to
human dementia.
SPEAKER_00 (19:34):
Yes, it is.
SPEAKER_01 (19:35):
And because a large breed dog naturally only lives
10 to 12 years, you can actuallyrun a clinical trial and see the
results in a reasonable timeframe.
You don't have to wait 80 years.
I was reading the pilot studydata they published before
Triad, where they gave lowintermittent doses of rapamycin
to a small cohort of middle-ageddogs.
The cardiac data was incredible.
(19:56):
It improved fractionalshortening.
SPEAKER_00 (19:58):
Right.
Let's define fractionalshortening so the listeners
understand what that implies.
SPEAKER_01 (20:02):
Okay.
From my understanding,fractional shortening is the
percentage of blood the leftventricle of the heart pumps out
with every single contraction.
Yes.
As mammals get older dogs andhumans, the heart muscle gets
thicker, stiffer, and lesselastic.
It turns into an old rubberband.
SPEAKER_00 (20:17):
Aaron Powell A very apt description.
SPEAKER_01 (20:19):
It can't fully relax between beats to fill with
blood, which is diastolicdysfunction, but rapamycin
seemed to physically reversethat stiffening in the dogs.
SPEAKER_00 (20:28):
It restored the elasticity of the myocardium.
The heart could pump moreefficiently.
SPEAKER_01 (20:32):
That's basically giving them puppy hearts back.
SPEAKER_00 (20:34):
In a sense, yes.
And we are seeing similarlypromising safety profiles in
non-human primate studies.
SPEAKER_01 (20:41):
Oh, the monkeys.
SPEAKER_00 (20:42):
Yes.
There is an ongoing trial with66 middle-aged marmoset monkeys
receiving rapamycin in theirdiet.
So far, the toxicity ispractically non-existent at the
doses used, with only minorshifts in metabolic markers.
SPEAKER_01 (20:56):
Okay, so let's just pause for a second and look at
the scoreboard here.
SPEAKER_00 (20:59):
Let's hear it.
SPEAKER_01 (21:00):
We have yeast, worms, and flies living longer.
We have 60-year-old equivalentmice becoming incredibly
resilient.
We have pet dogs getting moreelastic hearts.
We have monkeys tolerating itperfectly.
The wartime recycling economy ofautophagy works.
It does.
So I am going to ask theobvious, slightly chaotic
question (21:20):
why is this not in the water supply?
Why aren't we all taking a dailypill of rapamycin with our
morning coffee?
SPEAKER_00 (21:27):
Because of the Fang study.
SPEAKER_01 (21:28):
Ah, yes.
The Fang study.
This is where the story getsincredibly dark.
SPEAKER_00 (21:31):
Aaron Powell I wouldn't call it dark.
I would call it a profoundlesson in the arrogance of
pharmacology.
SPEAKER_01 (21:36):
Okay, fair.
SPEAKER_00 (21:36):
Remember when we said that rapamycin is acutely
specific to MTORC1?
Yeah.
And that it leaves thestructural survival crew MTORC2
completely alone?
SPEAKER_01 (21:45):
Right, because the Richter protein physically
blocks it from binding.
SPEAKER_00 (21:49):
That remains true for the intact MTORC2 complex.
SPEAKER_01 (21:53):
Intact.
Key word.
SPEAKER_00 (21:54):
But if you dose an animal chronically, if you flood
their system with rabamycinevery Every single day at high
doses.
You initiate what you so aptlydescribed earlier as friendly
fire.
SPEAKER_01 (22:05):
Walk me through the physics of the friendly fire
because this is the catch.
SPEAKER_00 (22:09):
This is the massive catch.
The cell is constantly degradingold proteins and synthesizing
new ones, including new MTRmolecules.
Right.
When rapamycin enters the cell,it binds to that FKBP12 protein
and that combined unit seeks outfree MTR molecules to shut down
MTORC1.
SPEAKER_01 (22:25):
Okay.
SPEAKER_00 (22:25):
If you constantly flood the cell with rapamycin,
it acts like a sponge,sequestering every single newly
synthesized free MTOR moleculefloating in the cytoplasm.
SPEAKER_01 (22:34):
Oh wow.
So it's like stealing all thelumber before the second crew
can even build the house.
When the cell realizes it needsto build a new MTORC2
scaffolding complex, it reachesinto the toolbox for the core
MTRR protein, and the toolbox iscompletely empty.
SPEAKER_00 (22:49):
Precisely.
Rapamycin stole all the parts.
You have starved the supplychain.
Over a period of chronicexposure, the existing MTORC2
complexes degrade naturally, andthe cell physically cannot
assemble replacements.
SPEAKER_01 (23:03):
So you have now inadvertently shut down both
MTORC1 and MTORC2.
Exactly.
And shutting down MTORC2 is ametabolic disaster.
I was reading the Fang andcolleagues paper, and the data
is honestly terrifying if you'relooking at this as a longevity
biohacker.
SPEAKER_00 (23:19):
It is sobering data.
SPEAKER_01 (23:21):
They gave male mice continuous rapamycin, and within
two weeks, the mice developedsevere glucose intolerance and
insulin resistance.
They basically induce type 2diabetes in a fortnight.
SPEAKER_00 (23:30):
And hyperlipidemia, spiking cholesterol, and
triglyceride levels.
It is the exact opposite of ahealthy metabolic profile.
SPEAKER_01 (23:36):
How does shutting down the scaffolding crew cause
diabetes?
I'm trying to wrap my headaround that.
SPEAKER_00 (23:41):
It comes down to a highly complex, almost
counterintuitive feedback loopinvolving a protein called
IRS-1.
SPEAKER_01 (23:47):
IRS-1, insulin receptor substrate one.
SPEAKER_00 (23:50):
Yes.
Let's trace the wiring here.
Under normal, healthyconditions, when MTORC1 is
active and building thepeacetime economy, it needs a
way to tell the rest of thecell, hey, we have enough
resources, stop absorbing more.
SPEAKER_01 (24:02):
Makes sense.
SPEAKER_00 (24:03):
It does this by phosphorating and actively
degrading IRS-1.
SPEAKER_01 (24:07):
So it's a negative feedback loop, a shutoff valve.
SPEAKER_00 (24:10):
Exactly.
Now when you introduce rapamycinand crush MTORC1, you remove
that negative feedback.
IRS-1 is no longer degraded.
SPEAKER_01 (24:18):
It builds up.
SPEAKER_00 (24:19):
It builds up massively.
And this accumulation of IRS-1hyperactivates an upstream
signaling pathway called PI3K.
SPEAKER_01 (24:26):
Wait, wait, I think I followed this.
So PI3K is screaming at thepancreas that the cell needs
more insulin, causing insulinlevels to spike massively to
handle the glucose, whicheventually burns out the
receptors and causes insulinresistance.
SPEAKER_00 (24:39):
That is the exact mechanical cascade.
You pull the lever to stop thecellular trash buildup via
autophagy, and the insulinfactory suddenly goes completely
haywire.
SPEAKER_01 (24:47):
Friendly fire.
SPEAKER_00 (24:48):
And the importance of MTORC2 for male longevity
specifically cannot beoverstated.
If you look at genetic knockoutstudies, where scientists
engineer male mice to be borncompletely lacking the Richter
protein, meaning they have zeroMTORC2 function, those mice
actually live shorter lives.
SPEAKER_01 (25:07):
Shorter.
So hitting MTORC2 is undeniablytoxic.
SPEAKER_00 (25:10):
Undeniably.
SPEAKER_01 (25:11):
But then the Fang study gets even weirder, right?
Because they didn't stop thetrial at two weeks when the mice
got diabetes.
They kept forcing the mice totake rapamycin.
SPEAKER_00 (25:20):
Yes, they maintained the chronic dosing protocol.
And around the six-week mark,the physiology began to
transition.
Okay.
By 20 weeks of continuousrapamycin exposure, the insulin
levels dropped back down, andthe mice actually showed
improved insulin sensitivitycompared to the control group.
SPEAKER_01 (25:36):
Well, it caused diabetes and then it effectively
cured the diabetes it caused.
That makes absolutely zerosense.
SPEAKER_00 (25:41):
I know, it sounds contradictory.
But it makes perfect sense ifyou view the body as an
infinitely adaptable homeostaticmachine.
Right.
The initial shock of MTORC2starvation caused a metabolic
crisis.
But over 20 weeks, the bodydownregulated other receptors,
shifted its metabolic pathways,and adapted to the new
(26:02):
biochemical reality.
SPEAKER_01 (26:04):
It just figured out a workaround.
SPEAKER_00 (26:06):
Eventually settling into a hyperefficient
insulin-sensitive state, yes.
SPEAKER_01 (26:09):
Okay, but as a human being, I don't want to spend 20
weeks in a diabetic state hopingmy body figures out a
workaround.
SPEAKER_00 (26:15):
No sensible physician would ever recommend
that.
Which is why the holy grail ofthis entire field is developing
a protocol or a new moleculethat perfectly isolates MTORC1
without ever bleeding over intoMTORC2.
SPEAKER_01 (26:29):
Right.
I saw a paper by Cameron andcolleagues talking about trying
to design drugs around the Crimdomain of SIN1.
SPEAKER_00 (26:35):
Yes, SIN1.
SPEAKER_01 (26:36):
What exactly is SYN1?
SPEAKER_00 (26:37):
SIN1 is another structural component of the
MTORC2 complex.
The Crim domain, which standsfor conserve region in the
middle, is the specific physicallatch that MTRC2 uses to grab
onto and activate its targets,like the ACE survival kinos.
SPEAKER_01 (26:50):
So if we can target the Crim domain, we can control
MTORC2 directly.
But the paper pointed out thatmost of the pharmaceutical
funding for this is coming fromcancer research, not longevity
research.
SPEAKER_00 (27:01):
That is the bottleneck.
SPEAKER_01 (27:03):
And in cancer, they want the exact opposite outcome.
A tumor relies heavily on MTORC2to survive and vascularize.
So oncologists are trying todesign small molecules that
block the crim domain to killthe scaffolding crew.
SPEAKER_00 (27:17):
That's the tragic irony of the funding structure
right now.
Billions of dollars are beingpoured into dual MTOR inhibitors
for oncology.
SPEAKER_01 (27:25):
Drugs designed to ruthlessly crush both MTORC1 and
MTRC2.
SPEAKER_00 (27:30):
Exactly.
But for geroscience, the studyof aging, we desperately need a
drug that guarantees MTORC2remains 100% operational.
We need a pure unadulteratedMTORC1 inhibitor.
SPEAKER_01 (27:42):
And since we don't have that perfect magical
molecule yet, we have to rely ondosing strapper geese.
Which brings us to the humanclinical trials happening right
now.
SPEAKER_00 (27:50):
Finally, we are moving out of the era of
speculative internet forumbiohacking and into rigorous
NIA-funded clinical validation.
SPEAKER_01 (27:57):
Yes.
Dr.
Ellen Craig and Dr.
Dean Kellogg at UT Health SanAntonio are at the forefront of
this.
SPEAKER_00 (28:02):
They are.
SPEAKER_01 (28:02):
They are running a trial with 84 healthy older
adults, ages 65 to 90, and theentire premise of the trial is
precision dosing.
SPEAKER_00 (28:11):
Precision intermittent dosing.
The logic is elegant, honestly.
If chronic exposure starves thecell of free MTOR and destroys
MTORC2, the solution is simplyto not expose the cell
chronically.
SPEAKER_01 (28:25):
You pulse it.
SPEAKER_00 (28:26):
You pulse it.
They are testing regimens likeone milligram per day for a very
short duration of eight weeks,or a single five milligram dose
given just once a week.
SPEAKER_01 (28:35):
Okay, so walk me through what happens in the body
when you pulse it like that.
So you flood the system on aMonday.
SPEAKER_00 (28:40):
Right, Monday morning.
The rapamycin hits MTOR-C1 hard,the boom economy shuts down, the
bulky phosphate padlocks comeoff ULK1 and ATG13.
SPEAKER_01 (28:49):
Autophagy kicks into high gear.
SPEAKER_00 (28:50):
Yes.
And the cellular garbage trucksroll out to clear up the
misfolded proteins.
But then, because you don't takeanother pill on Tuesday or
Wednesday, the drug clears outof the bloodstream.
SPEAKER_01 (29:00):
It clears out before it has the chance to sequester
enough free MTOR to disrupt theassembly of the MTOR-C2
scaffolding.
SPEAKER_00 (29:06):
That's exactly it.
The patient gets the profoundautophagic repair benefits of
MTORC1 inhibition, completelydodging the hypolipidemia and
insulin resistance of MTOR-C2inhibition.
SPEAKER_01 (29:19):
That is incredible.
And there's precedent for thisworking in humans, right?
I read about a trial using atopical 8% rapamycin cream on
the skin.
SPEAKER_00 (29:28):
A phenomenal localized study.
SPEAKER_01 (29:29):
Because by applying it topically, they avoided
systemic metabolic issuesentirely.
SPEAKER_00 (29:34):
Yes.
And the skin biopsy showed adefinitive reduction in markers
of cellular senescence.
The SASP was suppressed.
The skin was, at a biologicallevel, acting younger.
Just from a cream.
Furthermore, previousshort-term, low-dose systemic
trials in older cohortsdemonstrated zero clinically
relevant adverse cognitive orimmune side effects.
(30:00):
Well, this is where dose makesthe poison.
At massive daily doses for atransplant patient, yes, it
paralyzes T cell proliferation.
But at a low intermittent dose,a derivative of rapamycin,
called a Rapolog, actuallyimproved the immune response of
elderly patients to a seasonalinfluenza vaccine.
SPEAKER_01 (30:20):
Shut up.
It made their immune systemsharper.
SPEAKER_00 (30:22):
It rejuvenated hematopoietic stem cell
function.
SPEAKER_01 (30:25):
I am mind-blown.
SPEAKER_00 (30:26):
By clearing out the senescent garbage in the immune
compartments via autochogy, theremaining immune cells were more
robust, functional, andresponsive to the vaccine
antigen.
SPEAKER_01 (30:36):
Okay, that completely blows my mind.
But I do have a really pragmaticquestion about these human
trials.
SPEAKER_00 (30:40):
Sure.
SPEAKER_01 (30:41):
When Dr.
Craig and Dr.
Kellogg are running this studyat UT Health, how do they
actually know if it's working?
You can't run a human lifespantrial.
SPEAKER_00 (30:49):
No, you can't.
SPEAKER_01 (30:49):
It would take 80 years and cost$3 billion to see
who lives longer.
Are they just like seeing if an80-year-old can walk up a flight
of stairs faster?
SPEAKER_00 (30:58):
Functional metrics like grip strength and gate
speed are tracked.
Yes, they're important.
But to truly measure theefficacy of a longevity
intervention in a realistic timeframe, the field relies on
biomarkers of aging.
SPEAKER_01 (31:10):
Biomarkers.
SPEAKER_00 (31:11):
We are measuring the molecular footprints of decay.
SPEAKER_01 (31:14):
Like the epigenetic clocks?
I keep hearing about those.
SPEAKER_00 (31:17):
Epigenetic clocks are currently the gold standard.
We analyze DNA methylationpatterns.
Over time, certain regions ofyour DNA accumulate methyl
groups, which actually changeshow your genes are expressed.
Okay.
By analyzing these patterns, wecan determine the biological age
of your cells, which might bevery different from your
chronological age.
SPEAKER_01 (31:36):
So you could be chronologically 75, but if the
rapamycin pulsing is working,your DNA methylation clock might
read 68.
SPEAKER_00 (31:43):
That is the goal.
We also heavily monitor themetabolic markers we discussed
earlier, ensuring insulinsensitivity remains stable or
improves.
SPEAKER_01 (31:52):
To make sure we aren't hitting MTORC2.
SPEAKER_00 (31:54):
Exactly.
We run comprehensive cytokinepanels in the blood to look for
reductions in IL6 and TNF alpha,which proves we are successfully
suppressing that toxic SSP fromthe senescent cells.
Got it.
And borrowing directly from thedog aging project, we measure
cardiac fractional shorteningvia echocardiogram to track the
physical elasticity of themyocardium in humans.
SPEAKER_01 (32:16):
We are literally trying to prove that the
biological odometer of a humanbeing is rolling backward even
while the calendar keeps movingforward.
SPEAKER_00 (32:24):
We are decoupling chronological time from
biological decay.
SPEAKER_01 (32:27):
This entire journey is just it's a testament to how
wild science actually is.
I mean, let's just trace theexact through line here.
SPEAKER_00 (32:35):
Let's do it.
SPEAKER_01 (32:36):
It starts in 1975 with a handful of dirt from
Easter Island.
Rapin Nui.
A team looking for athlete'sfoot medicine accidentally
discovers rapamycin.
That molecule leads scientiststo identify MTOR, this ancient
conserved master switch thatacts as the economic engine for
every eukaryotic cell on Earth.
SPEAKER_00 (32:55):
A switch that integrates the availability of
amino acids, ATP, oxygen, andinsulin to dictate whether a
cell builds or whether itrepairs.
SPEAKER_01 (33:02):
Right.
And we figured out that whilethe boom economy of MTORC1 is
great for building muscle, ifyou let it run forever, it shuts
down the garbage trucks.
It stops autophagy.
SPEAKER_00 (33:10):
The amyloid plaques build up, the mitochondria burn
out, and we age.
SPEAKER_01 (33:15):
But by pulsing rapamycin, we can wedge the
gears of MTORC1, take off thosephosphate padlocks, and trigger
that wartime rationing economywhere the cell melts down its
own toxic waste to survive.
SPEAKER_00 (33:27):
And we observe this working spectacularly across
species (33:29):
yeast, nematodes, flies.
SPEAKER_01 (33:32):
The genetically diverse mice in the 2009
Harrison study starting at 60human years old, the companion
dogs in the triad trialregaining heart elasticity, the
marmoset monkeys all pointing tomassive lifespan and health span
extension.
SPEAKER_00 (33:45):
But then the reality check.
SPEAKER_01 (33:47):
The reality check.
The friendly fire.
SPEAKER_00 (33:49):
Chronic exposure, sequesters-free MTOR, preventing
the assembly of the MTRR-C2structural complex.
SPEAKER_01 (33:56):
Which rips away the negative feedback loop on IRS-1,
spikes the PI3K pathway, anddrops the mice straight into
insulin resistance and diabetes,a catastrophic metabolic cost.
SPEAKER_00 (34:06):
And so the absolute cutting edge of human science
right now, the UT health trials,is the delicate art of precision
dosing.
SPEAKER_01 (34:11):
Get in, shut down the boom economy, trigger
autophagy, and get the drug outof the system before the
scaffolding crew starves.
SPEAKER_00 (34:17):
It is a remarkable summary of a staggeringly
complex biological cascade.
And to bring this out of thelaboratory and back to the
listener, I think it's vital torealize that understanding MTOR
is not just an academic exercisewhile we wait for a
prescription.
SPEAKER_01 (34:33):
No, definitely not.
SPEAKER_00 (34:34):
This biochemistry dictates your daily life.
It explains the mechanics ofyour diet.
SPEAKER_01 (34:40):
Because amino acids trigger MTOR.
SPEAKER_00 (34:42):
Specifically, leucine, found in high
concentrations in animalprotein, is a potent activator
of MTOR C1.
SPEAKER_01 (34:50):
Ah.
This explains why hyper-highprotein diets are excellent for
building muscle in the shortterm, like for bodybuilders, but
might be detrimental tolong-term longevity if they
never sell MTOR to rest.
SPEAKER_00 (35:02):
Exactly.
It also provides the exactmechanical explanation for why
intermittent fasting isbiologically effective.
SPEAKER_01 (35:08):
Because fasting naturally depletes the amino
acids and the cellular energy.
It physically removes the cashfrom the economy, which
naturally shuts down MTORC1,which naturally removes the
break on ULK1, and naturallyturns on autophagy.
SPEAKER_00 (35:22):
You got it perfectly.
SPEAKER_01 (35:23):
Fasting is basically doing exactly what rapamycin
does.
You just have to actually endurethe hunger to get there.
SPEAKER_00 (35:29):
Diet, metabolism, and the rate at which you age
are all speaking the exact samechemical language.
SPEAKER_01 (35:35):
It fundamentally changes how you look at a meal
or a workout or even just amissed night of sleep.
It's all just inputs into thismaster switch.
Okay, well, before we wrap thisup, you have a habit of dropping
these massive perspectiveshifting thoughts at the end of
our discussions.
SPEAKER_00 (35:50):
I try my best.
SPEAKER_01 (35:51):
Where does this all ultimately lead?
SPEAKER_00 (35:54):
Well, if you extrapolate the trajectory of
this research, whether it'sprecision rapamycin dosing or a
future molecule targeting thecrumb domain that perfectly
isolates MTORC1, it raises adeeply profound philosophical
question.
SPEAKER_01 (36:07):
Aaron Powell Okay, I'm ready.
SPEAKER_00 (36:08):
Right now, this intervention works by tricking
the cell into a state of famine.
It activates ancientevolutionary repair mechanisms
that were specifically designedto keep us alive during
starvation.
SPEAKER_01 (36:19):
Right.
We are hacking a survivalresponse.
SPEAKER_00 (36:21):
Aaron Powell But if juroscience perfects this, if we
create a daily protocol thatcontinually initiates ultimate
cellular repair without a humanbeing ever having to experience
true starvation, disease, or theaccumulation of metabolic waste,
how does that change thefundamental human experience?
Oh wow.
If the autophagic recycling isperfectly optimized and the
(36:44):
senescent SASP never sets in todegrade our tissues, do we have
to completely rewrite ourdefinition of a normal lifespan?
SPEAKER_01 (36:52):
That is heavy.
SPEAKER_00 (36:54):
Have we just assumed aging is an inevitable law of
physics when in reality it issimply a biochemical disease
that we finally learned how tocure?
SPEAKER_01 (37:02):
We just needed the instruction manual.
And it was buried in the birthon an island in the middle of
the Pacific.
That is absolutely incredible.
Thank you for walking throughthis massive stack of research
with me today.
SPEAKER_00 (37:11):
It was my pleasure.
SPEAKER_01 (37:12):
And to everyone listening, keep questioning the
world around you.
Keep an eye on those clinicaltrials, and don't forget to let
yourselves take out the trash.
We will see you next time.
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