This content is an interview with Dr. Joan Mannick, a pioneer in longevity medicine, discussing the role of the mTOR pathway in aging and the development of mTOR inhibitors as potential therapeutics for age-related conditions and extending healthspan.
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When you inhibit mTor and the torque 2
complex, you actually get hyper lipidmia,
lipidmia,
hyperglycemia, and some evidence you
lifespan. Welcome to longevity roadmap.
I'm Buck Joffrey and uh today's show uh
is a very interesting one. It is with it
is an interview with uh Dr. Joan Manic.
Uh Dr. Manic is really, you know, she is
a very very
wellrespected name in the longevity
field. Um she really is a pioneer at
working at the intersection of aging
science and clinical medicine. And in
this discussion what we're going to what
we do is we really go through her
journey in longevity medicine uh
including sort of her focus on mTor why
she focused on that and what she thinks
the significance of mTor uh is in the
aging process. Now, you've heard of mTor
several times on this show um and we're
going to continue to hear about it
because you know um the a lot of people
including like I think Matt Cberline was
on recently believe that mTor is one of
the key uh one of the key proteins one
of the key
pathways that needs to be addressed if
we are going to continue down this
pathway of trying to treat uh u aging at
the cellular level. Anyway, she is going
to talk about, you know, some clinical
trials she's done. You're going to see
that it's not just a matter of
longevity, but there's a lot of
potential benefit for some of these mTor
inhibitors. Um, the most commonly one,
as you probably know, is rapomyosin, but
there's other mtor inhibitors that she's
working on uh that enhance immune
response in older adults, and that has
other implications as well. Anyway,
fascinating interview. Make sure to
listen. Uh, and if you like what you're
hearing, uh, make sure to subscribe and
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If you're tired of your belly fat, tired
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yourself for the next 50 years, visit
longevityroadmap.com. Welcome back to
the show everyone. Today, my guest on
longevity, she is a true pioneer at the
intersection of aging science and
clinical medicine. Uh Dr. Dr. Joan
Manik. She's a physician scientist and
biotech entrepreneur whose work has been
instrumental in translating biology of
aging into real world therapeutics with
a career uh that started with an MD from
Harvard and faculty roles uh both at
Harvard and in the University of
Massachusetts. Uh she then co-founded uh
I don't know if I'm pronouncing this
right but Restore Bio uh where she led
clinical trials on uh to C1 and
inhibitors like RTB 101 to enhance
immune function in older adults. And
today she's continuing this work as CEO
of tornado therapeutics where she focus
on creating next generation mTor
inhibitors designed for safety and
long-term use. Welcome Dr. Manic. How
are you? Oh, very well and thanks for
having me, Joffrey. So, I've been
fascinated uh even just listening to
some of your podcasts. Obviously, you're
you're a big contributor in this field.
Um, and part of the part of what I'm
curious about is kind of how you got
into it because you're you're an MD and
you're obviously a physician scientists,
but longevity medicine is something uh a
little different. Uh, and when I was
trying to understand that, I I heard you
talking about uh on another show sort of
an aha moment that you had with a paper
from Cynthia Kenyon. Can you tell us a
little bit about that? Sure. So, you're
right. I was a physician. I was an
infectious disease attending and I ran a
basic science lab. And, you know, as a
typical lab person, I was reading I
think it was nature. I'm just kind of
flipping through it and there was a
article by Cynthia Kenyon where she
talked about the fact if she mutated one
gene in a worm she was able to double
the lifespan and that was like fine it's
a worm but what she said in that paper
was what was the aha moment for me she
said this shows that organisms have the
potential to live much longer than they normally
normally
do and that was such a novel concept to
me because you know I was always as an
infectious disease attending I was
always in the ICU and I was just trying
to get people to survive like the next
week and the next two weeks and get them
out of the ICU and the idea that you
know what I'm doing is to
extend you know stop death from
happening in the next week and she's
talking about much longer
lifespans was so interesting to me
because it threw all our sort of medical
education on its head. We were never
taught, oh, certain interventions are
going to make humans live much longer.
Yeah. So, just that sort of scientific
turning how I thought about things on
its head really intrigued me. And it
wasn't about, oh, I want to make people
immortal or I want to be immortal. It
was more, are we
missing, you know, we're we're doing
these little little little things. Are
we missing the big things that science
might be able to do to help people stay
healthier longer or you live a good life
much more dramatic effects than anything
that we're currently doing in medicine?
Yeah. And I I would just add to that
that like you know sometimes uh even as
a podcaster in this space as a physician
people ask me well is this you know I
mean what are you trying to do? you're
trying to live forever. And the funny
thing is for me, it's as much of an
intellectual thing as it is, you know,
yeah, sure, I would love to live longer
and healthier and, you know, see my
grandkids and great grand. Sure, all
that's true. But it's an absolutely
mindblowing concept that you can uh and
in some regards, if you look at it in
hindsight, it's like, why weren't we
thinking like this before, right? like
we've had species around us who live,
you know, hundreds of years longer than
us. Wh why is that? And why are we sort
of doomed to have sort of this pre
pre-programmed, you know, 70some year
lifespan? And looking at that question,
I think is is absolutely fascinating. So
yeah, that's that's great.
um you know um you and you know some
others um in the space who are like
recently interviewed Matt Camberlin to
have the real special interest in in mTor.
mTor.
um what kind of drew you specifically to
the mtor pathway as a as a focus for
aging related drug development and and
maybe just before you kind of get too
deep in that maybe you could just remind
people what mTor is and thing. Sure. So
mTor is the protein in cells that is the
main responder to nutrients. So when you
eat mTor is activated and it stimulates
cell growth pathways. So you need every
organism needs mTor to grow and divide and
and
reproduce. When you inhibit mTor which
happens during periods of fasting
protective pathways get
upregulated that sort of clean up the
cell and you know quiet things down. So
you should sort of have this circadian
rhythm of mTor being on during periods
of the day you're eating that's helping
cells grow and then off to sort of clean things
things
up. And it turns out that that biology
that happens when mTor is inhibited is
quite good for us as we age. And this is
again we don't know this for sure in
humans but this is in every other
species where this has looked been
looked at. If you inhibit mTor in a
yeast, a worm, a fly, a mouse, and now
in a
monkey, you extend lifespan. And this is
remarkable because there's thousands of
proteins in each of these species. And
that, you know, higher up your species,
the more proteins, thousands and
thousands of proteins. one you inhibit
one either genetically or with a drug
called rapamy which is a very specific
inhibitor of this protein lifespan is
extended it's one out of thousands that
is one of those mindbogling
things why why and because in the
species where this has been examined
yeast to marmicetses this is billions of
years of evolution, it's highly likely
that inhibiting this one protein is
going to have benefits for aging for
humans as well. Just for context on
that, um, is is mtor the only one that
has that kind of cross species um, data,
I mean, you know, when you go back to I
guess the Cynthia Spencer or Cynthia
Kenyon uh, I believe that was on IGF-1,
right? And what is downstream of that
M4, right? It's in the same path. Right.
Same pathway. Yeah. Got it. Because in
humans that would be what? The growth
hormone pathway, right? Or the insulin
growth factor, the IGF pathway. It's all
sort of these nutrient responsive
pathways that signal downstream verse
through this protein called mTor. So
there's nothing there's nothing else
that we really know of that has that
continuity across species. Is that fair?
Not yet that I'm aware of. You know, I
think there's lots of pathways that sort
of intersect with mTor that probably if
you target these others, you'll get this
kind of data set too. It's just there's
been so much work done by many different
labs, which is important because
sometimes when something comes out of
one lab, it can't be reproduced. uh over
and over in labs across the world you
either genetically inhibit this protein
or you use this drug rapamy and they get
the same result and that's very you know
you ask why did I particularly like this
that validation in many labs both
genetically and pharmacologically
pharmacologically
across species that are evolutionarily
diverse made me think this is really
something we should test in a human
right And um you know just getting a
little bit more in the weeds there is a
difference between a couple of the
complexes for mTor's tors 1 to C2 um for
those who are kind of interested in in
sort of the the uh details of that could
you explain the importance of that
distinction um because I think as far as
therapeutics that becomes pretty
important you know you're exactly right
so it's inhibiting so mtor signals in
cells in two multi-roin complexes one is
called torque one and one is called
torque 2.
The rapamy, this drug that has these
lifespan extending effects, mainly
inhibits mTor in that torque one
complex, but with chronic use, it can
start inhibiting mTor also in that
torque 2 complex. And it turns out all
the anti-aging effects of mTor
inhibitors and rapamy and the genetic
inhib inhibition seems to be mediated by
inhibiting mTor and the torque one
complex. When you inhibit mTor and the
torque 2 complex, you actually get hyper lipidmia,
lipidmia,
hyperglycemia, and some evidence you
actually decrease lifespan. So an ideal
mtor inhibitor for extending lifespan is
predicted to be one that selectively
inhibits mTor in that torque one
complex. Got it. And and the torque 2
also is responsible I think uh for some
side effects too. Is that right? Yes,
hyp it causes hyper when you inhibit
mTor and the torque 2 complex it causes
hyper lipidmia and hypoglycemia which
are side effects of high doses of
rapamy. Got it. Got it. When you use low
or intermittent doses of rapomycin you
can get it to not cause that hyper
lipidmia and hyperglycemia. So it's that
that explains why in the longevity
community people like for example me um
are taking sort of a pulsatile approach.
So not telling anybody to take the drug
but I I would take I take for example
somewhere between six and 8 milligrams
one time per week. And again, the
concept there is it's enough to
stimulate m to the the torque one
complex, but to kind of skim away from
the torque 2 problem right now. Is are
some of the medications are and stuff
that you guys are looking at sort of
more um specifically targeting uh torque
one so you don't necessarily have to you
know kind of kind of plan for that um
avoiding it through phrinetics. Yeah.
Yeah.
So tornado when I was at Novartis which
was before even restor mentioned I was
on a team that was developing new mtor
inhibitors for aging related
conditions and one of they had their
best rapalog chemists working on this
because it's rapaloges are complicated
structures difficult to make the patent
space is really crowded because mtor
inhibitors have been made for decades
for organ transplant and cancer
educations. But anyway, this team came
up with this portfolio of new rapamy
like molecules, rapaloges that are many
of them, the majority are torque one
selective. They don't inhibit torque 2
at the highest doses they could test. So
these are exciting because these are
predicted to give us more ability to
dose even higher in humans who have
aging related conditions without getting
the side effects of torque 2 inhibition.
So they are predicted and we have to
prove this in humans. They're going to
be safer than rapison but should still
have the same anti-aging effects.
One of the things that I find somewhat
confusing about mTor physiology is that,
you know, I see we're we're hearing that
mTor inhibition promotes longevity
pretty much across species. But then
when you think about the things that
actually raise mTor activation in
humans, um one of the major things that
will actually uh increase that activity
is um is is building muscle, right? You
know, is is you know and and we know
that lean muscle mass is one of the
leading indicators of longevity. So how
do we how do how should we reconcile
this and it and and you know is it
partially a when we're inhibiting this
is there a tissue uh specific targeting
mechanism or how do we avoid building
muscle if we're inhibiting mTor? Yeah
it's a great question. So it's tr
there's interesting things about
inhibiting mTor and muscle. It doesn't
inhibit ba basil protein synthesis in
muscle but it will inhibit like amino
acid stimulated protein synthesis and
probably exercise induced protein
synthesis. So in young people probably
not a good idea. You probably don't need
to be taking an mTor inhibitor because
your muscle you want your muscles to
build. Yeah. The problem as we get older
that has been shown in animals and now
in humans is that mTor gets hyperactive.
and it stops responding to fasting and
it stays on all the time. So you don't
get those periods where it's on and
you're building proteins for your muscle
and then it's off and it's helping re
repair pathways turn on. So the idea as
we get older is we need to turn that
hyperactive mtor down to young levels
and also kind of get back that part of
the time it's on, part of the time it's
off circadian rhythm almost that younger
organisms have. Instead of having it on
all the time, you know, turn it off some
of the time. Well, but let me ask you
this. Do you think cuz in my mind I'm
thinking well why would it be on all the
time in older adults and part of it
makes me think well we're fighting
sarcopenia as we're older so maybe
that's why it's on maybe it has a
purpose to be on maybe it's responding
to the fact that we're losing muscle
constantly is is am I uh missing some so
it's a good question the problem is it's
on in multiple tissues not just muscle
it seems that something that regulates
mTor's activity is getting dysfunctional
as we get older. So it's in multiple
tissues, not every tissue. They've
looked in mice, but multiple tissues, it
gets hyperactive and particularly it
seems like it doesn't shut down during
fasting when it should.
But I would say you would think I mean
people I used to work with David Glass
who's done a lot of work on muscle and
he was like you can't use a rapalog in a
human because we're going to make them
all have no muscle right and then he did
the experiment in older rats which are
one of the best models of sarcopenia and
to his surprise he found the rats
actually some of the muscles not all of
them but they get bigger when you give
an old rat an mtor inhibitor and then
there's also been really interesting
data. Rats as they get old just kind of
sit and they don't move. But in mice
where they move, they actually have
better motor function. You know, they're
able to run longer on a treadmill, hold
on longer on a rod. So, not just muscle
size. And again, it's not all muscles.
Some get bigger and some don't. But it's
weird. you're giving an mTor inhibitor
and they're getting bigger muscle and
better functioning muscle and the
neuromuscular junction gets better. So I
think that the data would suggest
whatever is going wrong in sarcopedia
turning down mTor surprisingly is
actually helping it rather than hurting
it. Interesting. Yeah. Um obviously
there are other implications to one of
your earlier studies lowd dose uh mtor
inhibitors uh improve the immune
response to influenza vaccination uh in
older adults. Um can you walk us through
them I guess sort of that study and and
what you think the mechanism behind that
might be? Sure.
So when I got to I I left academics and
I got eventually recruited to Novartis
to a group called their new indications
discovery unit and this was a really fun
unit where they said you need to figure
out areas of medicine that fall between
traditional big pharma silos like not
it's not GI it's not neuro it's not
endocrine and come up with new drugs for
these new areas. And so the area I chose
after sort of getting a aha moment from
Cynthia Kenyon was to target aging
biology. And because Noardis had a
rapalog called a verily, I'd use a
verily to test can we make something
better in an older adult by giving them
an a rapog, an MTOR inhibitor.
And when you do drug development, you
want to quickly figure out in a short
not expensive trial, is your drug
working or not? Because you don't drug
development costs, you know, many, many
millions of dollars and you don't want
to waste money on things that just
aren't going to work. So, I had to
figure out what is something about aging
that might be able to get better in a
short period of time in a clinical
trial. And I thought well the immune
system because we know when for instance
you take a vaccine and three weeks later
or four weeks later your immune system
is responding better to that antigen in
the vaccine. Mhm. And there was a paper
published that was you know paper
deserves a lot of credit from
Northwestern showing if you gave old
mice rapamy their response to a flu
vaccination got better. So I said, let's
just try this in a human. Let's see if
we give a human an MTOR inhibitor, will
their response to a flu vaccination get
better? But Novartis actually sold this
drug of aerolymus as a
imunosuppressant. So I was like, I had
to sell the company, I'm going to take
your imunosuppressant drug and use it to
enhance immune function older adults. So
a lot of people did not like this idea.
Yeah. But fortunately Mark Fishman and
Dan Vello, Dan Vello was the CEO and
Mark Fisherman was the head of R&D. They
had decided the aging field had advanced
enough that we ought to be doing
something in this space and they got it.
And so what we decided to do was use
very weird doses of this drug, much
lower doses than the doses that enhance
that suppress immune function, saying if
this is going to work, it can't be a
dose that suppresses immune function. So
we're going to use very low doses or
intermittent doses that we don't think
are going to suppress immune function
and that we think will be safe because
that was key for us. this had to be safe
because we didn't know it was going to
have any good effect but we just didn't
want to hurt any of these older
volunteers. So we used very low daily
doses or these once weekly intermittent
doses and these doses were predicted to
just turn down mTor not turn it off and
turning off mTor is what leads to the imunosuppression.
imunosuppression.
So one I guess one question I have and
you know back looking back at med school
obviously you talk about rapamyasin I
mean usually my first exposure to that
was on the transplant units um
anti-rejection drugs I think a lot of
people have that perception of these
types of uh mTory inhibitors in general
and so at higher dose why what are they
doing to the immune system that we use them
them
uh for for anti-rejection basically to
suppress the immune system in the first
place. Yeah, it's a great question.
There are two things main things that
they do. They stop tea cell
proliferation induced by a cytoine
called 2 and they also induce regulatory
tea cells that induce tolerance to the
graft. But it's really interesting
because it it's also been shown they
suppress the immune response to aloe
antigens which are the antigens in a
foreign tissue that you engraft when you
do a organ transplant but they don't
suppress the response to infection
infectious pathogens. Oh really? You
know that's been shown in monkeys. It's
a very different it's like a selective
imunosuppression to some antigens and
not others.
So it's complicated. I don't think
there's so
many effects of mTor inhibition on
different immune cells and it depends on
the dose and the immune cell. So it's
more complicated than just te- cells.
But that T-reg
upregulation and then aector T- cell
downregulation is part of the efficacy I
guess on the on so then on the counter
of that when you're using really low
doses what is it do you think that was
actually enhancing the effect of the
vaccine was it you know I I think about
you know the aging immune system and I
think about immunosinesscent maybe
scinesscent immune cells
um you know maybe cleaning that up. What
what's your thought on on why the help?
Yeah, another great question. In the
mice, what they showed is hematopoetic
stem cells which had hyperactive mTor.
You know, this is a
common theme in the organ systems where
you see benefits. They had hyperactive
mTor. You use rapamy, you suppress that
hyperactive mTor, they're able to make
more naive tea cells that were able to
and B cells that responded to the flu
vaccine. Was interesting in humans, we
didn't see any increase in naive T- cell
or B cell production. What we saw was
less TE-C cell exhaustion, fewer PD1
positive CD8 and CD4 T- cells. It may
have been too mTor inhibitors induce
something called
autophagy and that's where you break
down proteins that are dysfunctional and
recycle them. But autophagy also may be
involved in antigen presentation by
dendritic cells and macrofasages. We
never knew was some of this due to
better antigen
presentation. So we don't know exactly
what the mechanism was but in two
separate studies we showed that enhanced
response to a flu
vaccine. So you um later had a series of
trials using uh I believe one of these
uh uh torque one inhibitors RTB 101
um and basically was designed I guess to
boost antiviral immunity in older
adults. Um what if maybe you could tell
us again I mean is there anything
special about RTB 101 uh other than it
just being specific to Torque 1.
Yeah. So when we did these two vaccine
trials it it was just sort of a proof of
concept to say can you make something
about about aging organ systems work
better. So the proof of concept we did,
we said, you know what, we can make you
respond better to a vaccine. But in real
life, you're not going to use a drug
like a rapalog to give to everyone
before they get their flu vaccine for
many reasons, including you need to be
incredibly incredibly safe with for a
vaccine because you're preventing
diseases in people who don't have any disease.
disease.
So it was more so it was like okay
something's getting better about the
immune system but we're not going to
develop this for a as a flu vaccine
adgivant. So what what else do we see
happening? And we did
non-hypothesisdriven RNA seek in all the
patients who had gotten these low doses of
of
arapalog and we just looked at every
what gene expression changes and to our
surprise almost all the genes that were
significantly upregulated in these older
adults getting mur inhibitors they
weren't metabolic or autophagy or they
were antiviral genes all the
antiviral genes in older adults
get more expressed and this may be part
of the reason they were responding
better to the flu vaccine. Yeah. always
you always see this upregulation of
antiviral immunity and that's
interesting because older adults have a
deficiency in the ability to respond to
have this antiviral response to viruses
as we get older and that's one of the
reasons CO 19 is so bad in older adults
is this antiviral response goes down. So
we thought maybe what would make sense
is to say okay we're not going to treat
just your immune response to one flu ant
or three flu antigens. What if we can
boost your response to all respiratory
viruses because that's the most common
infection that occurs in older adults.
What if we give you give older
adults low doses of an MTR inhibitor
during winter cold and flu season? will
they have fewer respiratory tract
infections most of which are viral.
So basically this is just a you know
this is a prophylactic agent where
you're saying we know that these antivir
you know the antiviral capacity of these
older people is down. We typically will
we'll vaccinate them but why not just
help them with their own immune system.
Right. Exactly. It's like an
imunotherapy for respiratory. But would
you would you still vaccinate? You would
still vaccinate on top of that obviously
but the problem is you know we now have
a flu vaccine a COVID vaccine now we
have an RSV vaccine but there are
hundreds of respiratory viruses most of
them the the virus that causes most
pneumonas in people over the age of 80
is rhino virus well and this was stated
before co so I don't know where co's
going to fall in rhino virus in young
people is what causes the common cold in
older adults
It causes pneumonia and there are
hundreds of different like you know
there is delta and omacron and you know
a few serereotypes of covid there are
hundreds and hundreds of virus so we
can't make a vaccine because there's too
many different strains
circulating so if you could get a drug
that enhanced this the antiviral
response independent of the virus
for older adults that could protect them
from all sorts of different respiratory
virus. It isn't virus specific and so it
would just help you beyond a flu, a co
and an RSV to protect you from these
viruses. Yeah, absolutely. Um so that
study um it it showed some reduced uh
confirmed respiratory infections but I
guess the phase three didn't meet the
primary endpoint. Yeah. Um tell us a
little bit about that. Like I mean what
do you what did you glean from the
results? Um yeah so this was it was a
tricky you no one's ever developed an
imunotherapy to make the immune system
of older adults work better. So we were
going into uncharted territory and the
FDA said to us hey we're going to learn
with you because we've never did this in
the phase 2 trial for an endpoint. They
said you have to have patients with
symptoms of a respiratory tract
infection and they have to have a
positive nasopringial swab showing they
have a
pathogen. With that endpoint, we showed
that our drug could work that it was
suppantly reducing the incidence of
respiratory tract infections. And in
that trial, we had people at
particularly high risk of respiratory
tract infections. So they either had to
have asthma or diabetes or
COPD or be over the age of 85 or
smokers. And we found that only some of
those groups responded well and some
didn't. So in the phase three we
eliminated the groups that didn't
respond which were smokers and COPD and
allowed anyone over the age of 65 to
enroll. But then the FDA decided during
the phase three we we're going to change
what we want as the end point. This was
right before CO and they said no one in
the real world gets a nasopringial swab
when they get a cold or a flu. So you're
not allowed to have that in your
endpoint. You just have to show you
decrease symptoms because that's what
patients care about. This became a very
very difficult
endpoint because it was really tough to
say just based on symptoms. Does this
person have a respiratory tract
infection? Do they have an allergy? Do
they have a C, you know, a CHF
exacerbation when they're coughing and
short of
breath? And so we didn't hit the end
point. And the investigators told us
people are coming
in hitting your diagnostic criteria for
a respiratory tract infection when they
know they don't have one. So the design
wasn't right. We learned you can't do
this without an aophringial swab. And of
course postco I think the FDA now will
say yes people can get a in the real
world get a nasop fringial swab. It
seems sort of strange to me that I mean
I understand their point but on the
other hand getting objective data right
seems more important I know you know
frustrating. Yeah. But the good news
is what we learned is we still weren't
even if we'd had lab confirmed
respiratory tract infections. It's it wasn't
wasn't
right. If we looked what this and and we
also started to get more basic science
data, what the mtor inhibitors really
seem to be doing is decreasing severity
of infection rather than do you get the
are you going to get
infected? it. You probably have more
asymptomatic infection, but what you're
really doing is once you get infected,
that's when that antiviral response
turns on and you get less severe
infection. So, you know, lessons
learned. You have to sort of build up
your scar tissue in these new areas to
kind of get smarter about what to do
going forward in these new areas. And I
think we have a much better
understanding now than we did and we had
to kind of go through those trials to
figure it out. What are you working on
right now?
So we're bringing these new mTor
inhibitors. I should also say that drug
that we used for these respiratory tract
infection trials wasn't a
rapamy analog. It was or TB 101 that
yeah it was a catalytic site inhibitor.
A completely different kind of molecule.
Okay, that doesn't have the same
validation as these rapal logs for
extending lifespan. So we now Novartis
had developed these new rapogs which are
better drugs than we had at
restrobio and we're going to bring them
forward first in just phase one trials
to make sure they're safe to make sure
they get into the tissues that we expect
them to get into and then to go test
them in a variety of aging related
conditions. Is there any other class of
drugs that you think well gosh I'm
focused on mTor but that other class
there is kind of interesting to me as
well and I think there's real promise
I'm just curious because it just seems
like the space there's a lot of noise in
it and obviously you guys know that from
being the scientist but even you know um
physician enthusiasts of longevity like
myself look at it and and find and and
think how is anybody going to, you know,
people are taking supplements and all
that kind of thing. Is there, you know,
what's true, what's not true. Is there
anything out there other than rapamy
that you think has uh that that comes to
mind that you're excited about?
I love Well, first of all, I I should
say here's my problem with the
supplements and a lot of the things
people are doing. All our trials were
placeboc controlled. Yeah. The placebo
effect was
huge. Huge. Doesn't even mean it isn't
real. But like in that phase three
trial, so many people on placebo say,
"I've never had so few respiratory tract
infections." People said, "I've never
had this level of energy often on
placebo." Their vision was better. Their
hearing was better. The amount of benefit
benefit
that people
got they perceived they had this benefit
from placebo was remarkable and I do
think there is probably a real mind to
body biology going on with
placebo so it's just when you give the
supplement if anything that's having a
biologic effect also has side effects if
this is real how do we know the risk
benefit of that supplement
is positive for the benefit. And how do
you know if you just didn't take sugar
pill or meditate or something, you
wouldn't have the
same benefit? So, until I see placeboc
control data, I just am like, is that
really where you want to, you don't know
the risks, you don't know the real
benefit, you don't know if this is all
in your head.
I have issues with that. But what the real
real
science there's probably a lot of really
good things. I mean this field is so
such a nent field. There's probably so
many good targets. It's just rapamy and
we've got that data set already. But the epigenetic
epigenetic
reprogramming that's farther away. we don't
don't
have, you know, all the understanding of
what kind of drugs could we use, what's
the safety profile, but that biology
doesn't just delay aging, it reverses
aging. And so I think that's incredibly
exciting. It needs to be cracked, but I
think that's a great great area of
science to get translated. What do you
think about I'm just sort of wanted to
get your thoughts on some
bigger vision questions and um you know
do you think that there are some genes
that eventually we will
identify that will have a you know
handful of genes that you that that are
will have a
significant direct effect on longevity
that you could target either through
various crisper technologies or you know
any kind of other genetic targeting. I
I'm curious about that because you know
I was speaking to uh uh Charlie Brener.
I don't know if you know Charlie Brener
and he's a NAD pathway guy and very very
smart u discovered that pathway and u
you know he doesn't really he's the
probably the biggest skeptic on uh
anything longevity there is. And I kind
of posed the same question to him is,
you know, what if we found a handful of
genes that were okay, they're not
they're not ever going to be 100%
responsible for what ages us, but what
if we found something that was 20%
responsible for aging us?
Do you think that there's there is that
kind of because when you look at other
species and they and like the whales for
example that are living 4 500 years and
they have certain you know duplicates
and triplicates and quadruplicates of
various types of genes that we don't
have. I mean is that that kind of
thinking interesting to you or do you
think it's kind of pie in the sky? No, I
think I think we don't know. I think all
of this is possible. You know, I know
for mTor, which again I just know
deeply, you need mTor to grow and
reproduce. It's more like a car. Like
your car needs its engine, but as you
get older, the engine needs tuning. It
gets out of whack. And so you have to
tune that
essential part of the car. And I think a
lot of aging may be it's not well
obviously you could have disease
inducing in I'm sure there's some aging
inducing drugs but I mean genes but I
think sometimes it's not the genes maybe
or maybe it's genes that regulate things
like mtor well like for example let's
take mtor um how is mtor different in
whales that live 400 years I what is it?
Is there or is it or is there things
that are different in in species that
live a lot longer than us?
It's so when I was at
Novartis, we did a whole thing of
looking at the genes of long live birds,
shortlived birds, long lived rodents, short-lived
short-lived
rodents, and try to figure out what is
exactly your question. What are the
genetic differences in the longived as
opposed to the
short-lived species?
And it was really complicated and we
didn't come up with an answer and there
was you
know massive amounts of differences and
genes that we didn't know what they did
but doesn't mean that there isn't
something there and more work doesn't
need to be done. We didn't get to the
answer but you know with better AI and
machine learning someone's probably
going to be able to get there. One last
question. If you had unlimited funding
and regulatory freedom, you could do
anything you want. What study would you
launch tomorrow to move the field
forward? But again, I'm so
mic. There are so many
experiments that could be done either in
humans in different aging related
diseases with mTor inhibitors or even in
preclinical species.
We haven't even for this one class of
drugs, we haven't cracked the surface of
you know the dose, the
duration, the
tissues that you need to target and
don't need to target. There is so much
that I would love to do if I had
unlimited funding. I would love to
there's so many human diseases that I
would love to test mTor inhibitors in
and especially our torque one inhibitors
but you never have all those resources.
Yeah. Where can we learn uh about your
work? How do we follow how do people
follow what you're doing? You can just
we have a website tornado therapeutics.
We're still a little bit in stealth
mode, so there's not much to say yet,
but um you know, we'll try to get some
interesting stuff out there soon, so
that people have something to look at.
Thank you so much for your time. I
really do appreciate it. You bet. Thanks
for listening. A quick reminder that
while I am in fact a surgeon, nothing I
say should be construed as medical
advice. Now, make sure to include your
physician in any medical decisions you
make. And also, if you're enjoying the
show, please make sure to show your
support with a like, share, or subscribe.
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