Kind: captions
Language: en
and he said i thought i was gonna fail
but do you see what i'm saying
and i said yeah i see it
what are you seeing i said the future
david sinclair welcome back to the show
hey thanks tom dude i'm really excited i
actually want to give the audience a
message i'll look into your eyes but i'm
talking to them uh this i think is going
to be one of the most important podcasts
that i ever do and long time listeners
of my show will understand
for a long time i was really focused on
living forever and that was the dominant
thing i thought about as i mapped out my
life and then about a year or two ago it
started to feel more important to
recognize my mortality and part of it
was i i had really lost faith that it
was going to happen in my lifetime
and
i definitely want it to happen in
researching you for this episode i am
regaining belief that it we really may
hit health escape velocity in my life
and so in the first half of the show i
want to talk about um why we age exactly
and you've gotten extraordinarily good
at mapping that out with real conviction
and then in the second half we'll talk
about what we can do on an individual
level to really slow that down or
possibly even reverse it so i want
people to stick with me because i'm
actually going to start with a story and
a quote
and
i want to make sure that people
know the map of where we're going
so first the story on christmas eve um
i was
throwing a little party for my family
and it was a poker party we had a dealer
come he was 40 years old
and the energy's high imagine balloons
everywhere it was actually a birthday
party happens to be somebody's born in
my family on new christmas eve
and i go into the kitchen to get a drink
and my wife runs in and says we think
the dealer's having a heart attack
she's like you need to get in there
right now and so
i rush in to the room where this is all
set up and he's just sitting there
holding his head like this
and i said i don't think he's having a
heart attack i think he's having a
stroke
and
you know long story short he ends up not
surviving
and so
he was in a
coma for i guess five days and and they
end up taking him off life support life
support and he passes away and i was
like this guy is 40.
and so
the question really becomes how do we
get good at understanding where we're at
biologically what is our real age not
our as you say not the number of times
that the earth has gone around the sun
but how old are we really from uh
the things that we can measure and are
they giving us real information so
that's the story now the quote this is
you in your own podcast this is a quote
pulled from your first episode
in my lab now we can control aging very
precisely at will we can speed it up as
fast as we want in an animal and even
reverse it so aging is now controllable
we have the technology to control how
fast we age we can measure that slow it
down and even reverse it it's going to
fundamentally change the course of human
history
i have the [ __ ] chills man
so
that's a big statement it's a bold
statement and what i want to do now is
walk through what do we know
how do we measure it and then we'll
later get to what we do about it but i'm
a big believer if you understand the
mechanisms you can make change
what are the mechanisms why for real why
do we age
yeah
yeah so when i wrote my book lifespan um
it was a theory
about why we age and when i boiled it
down
to its essence
i realized and i theorized that aging
was a loss of information
so in our body we have two types of
information when we're born or even when
we're conceived there's the one that we
all know about we can get our dna red
that's the genome
but there's this other layer
called the epigenome
and why is that important because if you
just have dna and there's six feet of it
in every cell
it's just a chemical it's not going to
give you life what gives you life
is the the system that reads the dna the
right way but we've got this chemical
that's
like a hard disk driver or flash memory
that has these letters
atcg that's it period they're just four
four chemicals that get strung in
different order
and the cell
can write those down can build those
chains and that's how we copy the dna i
don't i run the risk of taking us off
track here but i'm very curious how
where does it get the letters
the the enzyme or the protein enzyme
proteins
synonyms yeah okay so where does the
protein go gra is there a bucket of
letters like i had as a kid that it like
reaches into and grabs one of the
letters out there are
yeah they're floating around and then
literally atcgs
they are
we're filled with the building blocks of
dna and proteins one are the dna bases
atcg they float around
and because they're just floating around
they're
buzzing around and so an enzyme
sees
probably 10 000 molecules in a second
it's really quick and it picks the ones
at once so okay i want an a and it's
it's basing it's looking at the dna and
it says you need a c right now and it
reaches out grabs a c you need a g now
it grabs the g that's literally what's
happening yes that is insane i cannot
believe i've never asked that question
that you're freaking me out all right
keep going and how does it know whether
it's a g or a c to put down
because it's copying the dna you've got
one strand that has the actg
and that protein will
look for what matches the g and a g
always matches a c
and an a always matches a t
so there are pairs of dna that make the
rungs in that ladder of that spiral that
double helix
but you
generally you actually need a template
that's why we have double strands one of
them is a template the other one you
then match to that
in the other direction so it's not like
my fly here which is a zipper that goes
up
it's a zipper that does
that as it's being built interesting uh
but we we get that from our parents
right without any dna there's nothing to
copy
getting back to the memory there's
something i think you'd like to hear
uh because you're very much into uh
digital and nft world
it turns out that
the best way to store memory now is
biologically
in a little test tube we can store all
of human information
and we we're built what we but humanity
is building the machines
to write down
those letters
and store all the world's information in
order and then the readers to get that
information back out so why is that
important because
computers don't last for a thousand
years
and you can't fit
all the world's
data in a test tube but technology is
pretty much there to be able to do that
whoa
okay so that's insane
going back to the reader the reader is
that little um
protein enzyme that's grabbing the
the matching pairs
and building it up and so all day long
it's just like here's a half and i need
to match that half is that the idea yeah
well there are two things you can do
with dna you can copy the dna so that
the cell has extra chromosomes that then
divide and you have new cells
that's copying the genetic material but
then you can also use the gene
so it's a string of a few thousand of
those letters
to make more protein
and so instead of make copying it making
dna this is where rna comes in so we've
heard about rna based vaccines mrna
is one type
the cell makes the mrna it's called
messenger rna because it's a messenger
and now that message which might be a
thousand of these letters floats away
from the chromosome
and another machine grabs that and now
has its own template to grab not dna
bases not the atcg but amino acids 20 of
them so it's programmed to look for
these
um sentences basically so rather than an
individual letter i'm here for a whole
sentence or a maybe even a chapter it
tells me to do
something and is that something to
create a new protein is that what all of
these do mostly okay mostly you can you
can make
rnas and you can make
protein but and dna but mostly
we're pretty much made of protein those
proteins are either structural from
muscle or they carry out chemical
reactions making new dna making proteins
making lipids making energy without
making energy both of us would be dead
in less than 30 seconds we need to
always be making it
it's quite uh we're always 30 seconds
away from death as great as you
mentioned
life is tenuous when you get down to
that level
and so what what happens with aging is
that the ability of the cell to know
which genes to read
goes awry
those proteins that would normally turn
on a gene that makes a brain cell know
to be a brain cell get lost those
proteins instead of reading the brain
cell gene
will go off and get distracted and start
reading a liver gene or a skin cell gene
okay so now here's where i think we have
to get away from metaphor distracted and
now get into and i know your theory
quite well because i've gone through it
so many times
but there's a part of it that i don't
understand well and that's the sirtuins
so
since we haven't said that word yet
today
talk to me or explain
what is the
when the the reading of the information
begins to go wrong
what happens that causes that to go
wrong because it's not like the
the protein gets bored and starts
watching baseball right so it's not
distracted in that way but there
actually is something going on that we
can actually see and understand
what is that thing
well so the sortuans we have seven of
these genes that make seven different
proteins in our cells each one
uh they're very ancient so the sirtuin
actually controls which genes are on and
off
okay so the spooling of the dna yeah so
so that six feet of dna is not just
flailing around in liquid that would not
be life what the cell does from
conception and before that tell people
why that wouldn't be life you threw that
off but that's actually really
fascinating so if the dna is just a
fully naked strand that could be read in
its entirety you don't have life that
isn't self-evidently
clear
why wouldn't that be life
well you need to organize it very well
because we're multicellular a bacterium
doesn't need to worry about it because
it's just one cell it knows what it
needs to do
and its offspring are very similar
our bodies are made of a trillion cells
and each one
literally is different
right even if you measure an adjacent
cell it's behaving slightly differently
but if you take a brain cell a nerve
cell compared to a liver cell it's
totally different but remember they have
that same six feet of dna
so what we need to do is multi-solar
organisms to survive is to get rid of
not rid of but but hide and compact and
silence
parts of our dna that are not useful for
that cell type so the reader isn't told
your job is to read and recreate liver
cells it's told read whatever is exposed
and there's some other mechanism this is
your job is to hide everything that
isn't a liver cell and that's a certuin
the sertune is the one that hides
everything yeah and sir stands for
silent information regulator
and that was the clue to this whole
information theory of aging it was right
there in the name
and what we find is that those spools so
if you zoom let's zoom up on the genome
now you'll see that most of it is
compacted because most of the genome is
is not used
we use a few percent of it the genome is
another word for your strand of dna
correct yes so most of it is bundled up
in these little packages and when we say
it's bundled up is it put in something
or is it just squished together in a way
that's impossible to read
it's really
precisely packaged there are four
proteins called histones okay and they
make a circular little ball
and they love dna so what happens is the
dna wraps around those histones so you
get
two wraps around one histone and it's
wrapped around by a certain
in part in part but there are there are
enzymes that do this as well more
machines that grab dna and wrap it
around twice grab another histone stick
it in it next to it and wrap it around
more
so it's like spooling you're wrapping
string around a ball and then you get
these balls on a string it's called
and that for the technically minded is
called chromatin and if you take those
balls on a string and then wrap those up
into bigger bundles
eventually you get what we call a
chromosome which you can see with your
eye or at least with a pretty weak
microscope
this is incredible
we start bundling it we have the
sirtuins
their job is to silence the vast
majority of the information on the dna
and then we have this other enzyme that
comes in and it its job is to read what
is exposed so the information theory is
you've got the whole
all the possible things hey you're an
eye cell you're an eyebrow you're a
heart cell you're a brain cell you're an
amygdala brain cell so it's like all of
these incredibly specific instructions
and they're all linked together and so
what we have to do is come up with some
very intricate clean way of
making sure that the right information
is read at the right time and the
solution that nature has given us is
this wrapping of the bundling of dna i
think is the word that most people use
to make it impossible to read everything
but certain sections but what parts of
the bundle are exposed are epigenetics
at work which are based on environmental
cues that we give our body well kind of
epigenetics refers to all those machines
that bundle up the dna
and read the dna that's the epigenetic
system
it's like
in a computer the code would would be
one thing and then all the machinery to
read that code which is the computer
um is the epigen epigenome so which is
kind of complex you can't say oh that's
an epigenome protein there there are
hundreds but certains are major players
and they from birth say that this gene
needs to stay off because
it's a liver gene that's working
shouldn't work in the brain so don't
expose it don't expose it so we've got
bundles bundles bundles a big loop
bundles bundles bundles and some of
these loops are really important for
when we're developing
as an embryo
one of these big loops it's called hox
and there are 13 hox genes hox
and they get red in a certain order the
first ones get red and tell the the
little embryo this is your tail uh which
eventually goes away in humans but we
have a tail and then others your
midsection then this is your your upper
body then your neck and your head that's
what this hox does
and and eventually once you're born it
gets bundled away okay we don't need
those anymore we've built the body it's
got a head and a tail
hox is there but when we were looking at
older cells
um in mice and in humans guess what
that bundle of hox developmental genes
started to
open up again because the sirtuins got
moved away and did some other things
during aging and now we've got
genes that tell us head to tail coming
on in our body when they shouldn't and
that's part of the problem with aging
which is genes getting turned on when
they should be kept off for decades
and then cells start to get confused
does the revealing of the wrong things
that unbundling
[Music]
does it happen because the sirtuins are
not
rebundling them or are they actively
going in and unbundling things that they
shouldn't
well what we think is happening is that
they physically
move away to other parts of the dna
molecule where they shouldn't normally
be that's the distraction
they get called away to do other things
they are very good at handling
emergencies these are emergency survival
proteins
that they have two roles one is to make
sure that everything's good every day
super optimal health stay young
but they also
through i think evolution
and very early in evolution their role
was to
put out the fire
uh and so they go away they actually
leave where they should
so that they're bundling and for a few
minutes until the emergency is fixed
they actually float away go repair
something so it might be a broken
chromosome somewhere else
over on another chromosome they go there
they fix it and then somehow they find
their way back to make sure that bundle
is
you know maintained
but if you keep doing that
and we every cell gets at least one
broken chromosome every day
and that's that's trillions in in our
body every day these swatuns get i call
it distracted but basically they're
doing this other role putting out the
fire
and then coming back
if you do that for decades eventually
some of them they're lost they don't
find their way back and these loops that
shouldn't of dna that should never be
turned on start to come on
i may have been wrong then maybe
distracted isn't a metaphor it's they
literally have so much work to do which
would make sense and so now to actually
use a metaphor you talk about for people
that know what a cd is
uh that you would get these scratches in
your cds and it would cause the songs to
not play right
it was really obnoxious actually
and that idea of aging
you're going to get these scratches
you're going to get the the fires that
have to be put out the sirtuin is going
to get busy dealing with breaks and
whatever and so it's got to go handle
that put out that fire deal with that
break
um and
as we age there's an accumulation of
damage that we do and so these things
are constantly busy
and
therein lies
the information theory of aging that the
sirtuins are too busy to maintain the
integrity of the bundling of the dna in
a given region which will be different
everywhere
but it's no longer holding to the
integrity of just be a brain cell just
be a liver cell just be a pancreas cell
and
the readers are only instructed to read
what's exposed and so now if your brain
cell also
has a little bit sticking up for skin
cell or tail or whatever
now all of a sudden you have a
dysfunctional cell in your brain
that's aging as i see it that cells lose
their identity we call it x
differentiation which is an old theory
but this is what we've given a name to
it and so cells when you're
developing from an egg fertilized egg to
a baby to an adult that's called
differentiation okay cells get their
identity the bundles and loops get
established that's youth that's health
x differentiation is what happens after
that
but then the question is
with the scratches on the cd
can you get rid of them can you polish
them can you get those bundles that have
been exposed to go back
to where they came from and reset the
age of a cell
and get the brain to wake up and
remember
oh crap oh yeah i forgot i am actually a
brain cell or an eye cell
so this was the big question that i had
after figuring that other stuff out we
just talked about
was is there a backup copy of a youthful
epigenome what does that mean does the
cell know that that loop that's come out
that it needs to go back in
for that to be the first time
well we inherited that from
our parents that pattern does it
memorize that like okay if i'm a sirtuin
am i only floating around a given area
so i know hey this is how it's supposed
to look so we get some signal that it's
like okay we're done growing head tail
bundle those back
and now this is what it should look like
forever and
how would it know that
well what it what the cell does in part
is it puts chemical tags
on regions that need to be bundled up
known as methylation that's dna
methylation right
and you can also put methyls these
little chemicals hydrogens
uh on a carbon you can also put them on
those bundling proteins called histones
which we talked about beads on a string
can be modified but the most important
one for long-term maintenance
of the epigenome is this dna methylation
once you put a dna methyl
carbon hydrogen hydrogen on a dna
molecule which goes on the letter c not
all four but mostly it's on the c a
little bit on an a
then that tags that gene for a certain
behavior
mostly it means shut that gene down and
leave it alone
but over time
possibly due to sort of moving away
perhaps other things
that dna methylation
pattern across the genome the millions
of these little tags
starts to go away they're dissolved or
broken down somehow
well there are enzymes called dna
d-methyl lasers that take them off
and they they start to do that job when
they shouldn't why would we do that job
ever what's the use case for that there
must be one
uh yeah well cells that come from stem
cells need to grow into different cell
types
we have stem cells that grow skin stem
cells that grow at all times yeah we
need those if we get damaged we need to
rebuild if you if i cut part of your
liver out it'll regrow into a new liver
because you've got stem cells our gut is
always replacing itself
because it's it's hitting all sorts of
things down there
so they're little stem cells but for
those stem cells to rebuild five or ten
different other cell types
you need to be able to
alter that pattern of dna methylation
even when you're an adult
but that system goes wrong in a way that
doesn't make us healthier it does the
opposite
it makes cells more stupid cells forget
what type of cell they should be and
that's x differentiation
but now the question is can you
redifferentiate can you get them to go
back to the way they're simple as stem
cells if stem cells are the ones that
carry
that like
pluripotency of like we could become
anything because it sounds like i mean
to your point about the liver cell
there are already some that are doing
this that know who the liver is gone
i know what i need to do though to
rebuild it yeah and so
is that just that that mechanism is
limited to the liver and the intestines
and therefore it's not doing that job
elsewhere or
well we could we could have reversed
aging just by making all cells
a stem cell we have the technology to do
that that was the 2016 nobel prize
yamanaka professor yamanaka discovered
that there are four genes that if you
put into adult cells will erase
all their identity all those loops and
bundles would just get erased those
methyls will get erased and then you
have a primordial pluripotent stem cell
and any high school student can do that
these days just put four genes
internally
okay but you don't want to do that
because you would become the world's
biggest tumor
that doesn't sound fun yeah that's not
age reversal that's instant death um and
if you do that in a mouse i i we haven't
done much of this but there are labs
that do this
uh the mice die within a couple of days
they just get riddled with tumors
well
over time if you do it a little bit they
get tumors but if you turn it up a lot
then the cells just forget what to do
and the mouse dies
even without tumors the cells just need
to know how to work
so you don't want to do the yamanaka
treatment in a living thing other than a
cell in the dish
but we did stand on the shoulders of
professor yamanako because we thought
what if we could find a combination of
those genes that doesn't take you all
the way back to zero to be a stem cell
but it could take you back to an earlier
state
that would never go back to being a stem
cell because we don't want to get
cancer while we're getting younger and
so it'd be like polishing the scratches
on your cd
but make sure you don't do it too much
because you'll erase everything you've
got to maintain some surface
and it was a few years of work and i had
a student in the lab a brilliant hard
working guy yuan chen
lu
and yuan cheng was pretty frustrated he
kept putting genes into these old cells
in the dish
and they would turn cancerous or they
would die
that was one or two uh uh outcomes of
this uh this binary so they would either
replicate uncontrollably
without remembering when to shut off or
they just have a yes i'm out of here
this is too crazy
uh but we hit upon a magical combination
and he was literally about to quit his
phd he said i can't do this anymore whoa
i got to change topics i'm i'm i'm out
of here because it's never going to work
david you're insane you can't partially
reverse aging it's not going to work
and
he had every reason to believe that i
mean how crazy is it the the cell would
remember okay this gene here needs to go
back to that state and this gene over
here needs to do that
how could there be a memory in the cell
of youth and we didn't nobody knew until
we did the experiment
and the experiment that i said he should
do before he quits
was to don't use all four of these
yamanaka genes
and and in fact one of them causes
cancer we know that
so it didn't take too much of a genius
to say look just leave out that gene
it's called c-mic
and see if the other three would work
and no one knew if three was sufficient
most people thought it wasn't
and he put those three genes in and
they're called o
for oct4 sox2 s and klf4 osk
and if you're wondering what do these
genes actually do they make proteins
that turn genes on and off during
development right starting to see the
theme here and they work with sirtuins
and those dna methyls all right so he
put in those three genes into old human
cells in the dish
and they they looked fine they kept
growing they didn't turn into a tumor
they didn't grow uncontrollably and they
didn't die and then when he measured the
patterns of which genes were on and off
they resembled a young cell again
and that was a eureka moment in the lab
i would say we could reverse aging in
the skin in a dish
but the real experiment that changed
everything was
he then made a virus a domesticated
virus we call it an aav
and he could now deliver those genes
into a living organism which in our case
is typically an old mouse
and he did a very clever thing he said i
want to work on the eye his father had a
biotech company that that is trying to
solve
blindness cube blindness
and i said the eye you're kidding me i
know nothing about the eye
blindness has never been cured
uh
you know
how's it gonna be possible to deliver
this into an eye
let's just do the liver i understand the
liver it's it's easy we'll just get it
in he said no trust me i've got the good
feeling about the eye right all right
fine and i've learned over the years if
somebody really wants to do something
let them go do it and usually they're
right
there's this thing in science where you
have this gut feeling but you're not
really sure where it's coming from
so there's a spirituality yeah
and i've learned to tap into that as do
students it's one of the things i teach
them
so he took an old mouse actually the
first experiment was he actually
caused the mouse to become blind
uh and then he put the virus into the
eye just
straight in turned on his three
yamanaka genes oscar
uh
and then he looked four weeks later
at what happened in that eye
and he found out that the optic nerve
that was damaged
started and for the most part grew back
and that never happens optic nerves
don't grow back if you go blind from
damaging your eye you're not going to
see again
same with your spinal cord same with
your brain damage the central nervous
system with nerves in your body does not
grow back
it's a factor biology and here was one
change showing
he was able to do that so why is that
relevant to aging because when you're
very young
if you damage your optic nerve
or even your spine or your brain it can
grow back but we lose that ability as we
get older and here was
taking the eye back so young
that it could regenerate and function
but then he did something very clever
he then put it into a mouse that we gave
glaucoma to so pressure in the eye
damages vision
and then he also did it to old mice that
had just aged and were blind as well
and he started to cure blindness with
his treatment
and we could now measure the age of
those nerve cells and they were
literally younger and those those
bundles and those loops we can measure
those and the dna methylation the
chemicals we can measure those
and he was sending them back
75-80 percent of their age but not to
zero
or not 100
so he sent me that i i don't know if i
still got it on my phone but it's
recorded in my book
because uh
he sent me this text that said
david i've got to show you these photos
and he sent me an image of the nerve
which is a long
strand it's orange we stained it orange
so you can see it
and the damaged one just looked like
there were a few dead cells but the one
that was reprogrammed
was bright orange all the cells almost
all had survived the damage and then
they started to grow back towards the
brain from the eye of the brain and you
could see it's like a jellyfish tail and
he sent me pictures of that
and he said i thought i was going to
fail
but do you see what i'm seeing
and i said yeah i see it
what are you seeing i said the future
wow
and that lit is literally what we saw
so now we know you can reprogram
other tissues it doesn't have to be the
optic nerve it can be the retina it can
be
the cone cells of the eye
and so we're
reversing aging of the eye that's not
hard at all
but we can reverse the age of the liver
the skin
other labs are doing the spleen
thymus
through this method so it's it seems to
be
a somewhat if not
universal method of resetting the age of
the body
safely
safely is the key
and because i started a biotech company
called life biosciences that wants to
cure blindness and other age-related
diseases using this method
for the last two and a half years we've
been doing safety studies
in mice and now we're in non-human
primates and those animals are fine we
can blast these three genes
in the animal and they're fine they
don't get tumors
their eyes are healthy you don't get uh
malformation of the eye so it's great we
lucked out humanity lucked out that we
can actually do this and that there's a
backup copy of youth in each of our
cells that can be
tapped into
that's crazy do we know what is going on
that allows it to realize what it's
supposed to look like what the bundling
of that cell is supposed to look like
because that is what's going on right it
suddenly remembers up these are sticking
out they shouldn't right and how do we
go from it has so many fires to put out
that it's just roaming all over the
place and it can't get back how do we
sort of give it that breather
to come back and go not only do i
remember how to bundle this but i've got
the time to dedicate
to bundling it correctly again
well the bundling it takes a few days um
and
a week you're getting pretty close a
month you've now got vision back
um and then actually by the way if you
stop the treatment we now i didn't know
this when we talked last but when you
stop the treatment it's long lasting
that mouse will still have young eyes
six months later
and i always not i still do i want to
test how many times can you reset
because if it's if it's once it's
interesting if it's 100 times it's super
interesting no joke
and we we couldn't do that experiment
because the mice were dying from old age
with super young eyes so we got to reset
once but now we're resetting
entire mice
and by the way you mentioned earlier the
quote from my podcast we can actually
control aging in the other direction we
now know how to distract and move the
sortuans away we cut chromosomes and let
them move away
and those gene packages open up the same
as aging so we can make a mouse
poor things that we can make them age
rapidly so if you were to come to my lab
i could show you a mouse that's a twin
and it's brother let's say brother and
sister the brother will be 50 older than
its sister but they were born on the
same day
and now we're reversing the age of those
mice
our main mouse is called lisa by
coincidence and we're taking lisa and
we're going to rejuvenate her uh so that
she hopefully gets back to being so
better up and now you want to see if you
can take her back jesus man like this is
i mean you said that this is going to be
remembered as the moment that human
history changed i mean but that's crazy
if this ends up working out like this is
really banana if you were diagnosed with
a serious heart condition tomorrow
would you inject yourself with this
stuff like if this was like terminal
you've got they're like you got two or
three months bera
yeah
well uh
so i am a self-experimenter
if i think if you gave me a week to live
i'd be on a plane back to boston today
to try this i mean there is nothing to
lose it's all about risk reward right
yeah yeah and i we know what the risk of
not doing anything is i'll probably be
dead in a week but that's true for aging
too we know what's going to happen if we
do nothing that's why i take some risk
in taking supplements and doing
different diets because i know that the
end is not pretty right we all are in
denial
most of us that that's going to happen
to us it's just slow motion
if it's not a week it's a decade or a
few decades from now that were gonna
suffer i watched my mother die in front
of me she suffocated to death
and and you know nobody should go
through that as a human being
um
experiencing suffocation and i don't
think children should watch that either
but the the point there is that we're in
denial i mean i don't want to be a
debbie downer here but
we don't think about what it's like at
the end it is not fun it's not typically
like oh you just go to sleep
that's those are lucky ones so i'm i'm
in a race against time to figure out how
to safely reset the age of the body i
would try it even even though i think a
lot of people and harvard medical school
will be upset that i've said that
but realistically and i'm always honest
i would seriously consider it
if i was given
even months to live i'd be on a flight
to
your lab and of course i would do it
after hours with somebody else so don't
worry but like i'd have to try this i
mean that's
really crazy well that please don't
email me i'm not able to do this it
would be illegal i know right i'm
kidding yeah but i'm not kidding at all
well on the other hand
there are supplements and there are
medicines on the market that show a lot
of promise against yeah and i think
that's where we need to go so
what are the things that we can do today
to slow aging
uh so that we don't end up needing this
or so that we can live long enough that
this goes through all the safety and all
that and it becomes an actual actual
just like uh standard of care procedure
well before we get into what we can do
today just because it's a continuum of
this resetting
what my lab and many others now are
doing is racing to find easier ways to
reset the age of the body
gene therapy
it's here but it's not going to be you
know mainstream soon it's always going
to be expensive
hundreds of thousands of dollars of
treatment what happens when you can take
a pill that will reset your age by a
year
happy birthday dad
take this pill incredible and if you
reset your age by a year every year
that's pretty interesting velocity uh
and yeah and there are experiments now
where people have reversed their dna
methylation age which we can now measure
uh by a couple of years
and that only takes a year so now people
going back at least their bloodstream is
going back younger than that year took
them forward wow
so we are on the verge of something
super interesting in humanity it opens
up all sorts of questions about what's
the world going to look like for maybe
us certainly for our kids
but getting back to what we can do every
day
the main concept that i think we all
need to remember
um is that our bodies respond well to
perceived adversity
those of us who
you know like to struggle in life i know
you're that kind of guy it's don't give
up
just keep going our bodies respond well
to that as long as you're not doing long
lasting harm
an adversity mimetic
which can be
don't eat so much don't eat so often
exercise be cold be hot
there are some other tweaks to that
high pressure oxygen therapy is another
theme
these put the body in a state of
adversity mimicry
and what that does to the body is it
says oh my goodness i could be dead next
week i could run out of food i could be
you know chased down by that tribe over
the hill or a saber-toothed tiger i've
got to hunker down and become more
robust and don't put so much energy into
these other things you know maybe wound
healing would be one thing you could
take away from for a little bit
and put into long-term survival
um
those are the the roles of the sirtuins
remember the sirtuins do two things they
slow down aging on the dna but they also
go and repair things and if you don't
have enough so two an activity or enough
sort of proteins in your body so in
other words you don't make enough of
these little machines or the ones that
you have are pretty inactive and lazy
that don't have enough of the fuel that
they need to work
then you're going to age more rapidly
and when the crap hits the fan and you
get a broken chromosome then you're not
going to have as much ability to repair
that you might get cancer
and so what my role or my goal in in my
lab and in my
experiments with my body is to
make those processes that respond to
adversity super active every day so that
it's slowing down the aging process
until we have the technology to reset
the body and reverse it
so i have a gas hypothesis on why that
would work
um because you've talked about like as
we get into mtor and
some of your diet recommendations so
basically there there are things like
getting into mtor which is growth if you
want to add muscle you're gonna have to
get into mtor you're gonna have to give
your body the signal to grow which times
are good there isn't these you know
adverse things
and great if you're young great if
you're trying to put on muscle but it
may have these long-term consequences
versus putting your body into this
actually things are hard
now is not the time let's dial back
let's make sure that we stay strong and
my gut instinct is that from an
evolutionary standpoint that would be a
mechanism designed to make sure that you
live long enough for times to return to
good so that you can procreate
and that you're sort of going into like
a
semi-hibernation to like la outlast
whatever
environmental problem there is
so that you can
uh still be around when the environment
changes does that ring true for why this
mechanism works
it does except hibernation gives the
impression that you don't have as much
energy right and that's not true that
wasn't going to be the right word yeah
not true
people who do what i do have way more
energy than someone who sits around and
doesn't exercise and and eats too much
and our bodies rev up and make more
energy so that we can repair the body we
need that energy to fix the dna and get
rid of the old proteins and survive
so think of it as hunkering down but
but also having more energy to be able
to survive anything that comes at you
and so the converse to adversity
mimetics which is what i try to do
are the abundance mimetics so you
mentioned mtor mtor will sense if you're
eating a steak lots of amino acids great
build new muscle that's going to work
but an ad
abundance memetic is not going to make
you live longer we know that you can
manipulate this mtor
uh enzyme complex we call it let's call
it a gene the mtor gene you can
manipulate that
in a mouse and give it less or more of
the mtor
activity and when you do that
their lifespan changes and the more you
have of it let's say you've now made it
like the mouse is full of abundance
it'll live short
and vice versa it'll live longer if you
turn down the activity of that gene
and you can do that i mean we can't
genetically engineer ourselves easily
these days
and i say easily you can but not easily
but what you can do is by eating things
that are right you can make mtor believe
that there's adversity and turn on the
repair systems all right so what does
this adversity memetic look like from a
lifestyle perspective so you rattled off
a few things really fast but i imagine
um
diet and exercise are probably going to
be two of our most important things and
then knowing some of your views on
supplements i think we should get into
that as well
right well i do talk a lot about
the tweaks on exercise and diet but been
in a very scientific and detailed way
sometimes i i feel a bit silly saying oh
diet and exercise like why is this guy
who studies
the process of aging and the molecular
basis of it talking about these
diet and exercise we've known that for
decades but what we haven't known is how
they work we just discovered that just
by looking at thousands of people who
live longer who don't and okay eat that
diet
fast that time
do that kind of exercise we know those
people live longer but we didn't know
why so now we do so we can tweak it we
can maximize the benefit of those
lifestyle changes
but it's worth pointing this out because
i think it's empowering
so point one is we can measure our
biological age we can look at the dna
methylation we can look at our
bloodstream i do that
and some people don't do that because
they're scared of learning their
biological age what if it's too high
what am i gonna do but information
knowledge is power
an important point number two is that
eighty percent of your longevity and
your health in old age is controllable
and only twenty percent is dictated by
your genes the re the genome the rest is
the epigenome that responds to how we
live
so that's why i'm all gung-ho for for
changing your lifestyle because it's
gonna it could give you two more decades
of life and i'm not kidding
if you just do the five things that
doctors recommend typically don't smoke
don't over drink get enough sleep get a
bit of exercise and don't be overweight
if you do that versus someone who
doesn't you live on average 14 years
longer and that's just the stuff we know
of
but there gets to be some really
interesting stuff that is just now at
least making my level of awareness
and
i think that some of this speaks to this
idea of the um
adversity memetic so
when you pointed out that a type 2
diabetic so diet-induced
lifestyle-induced diabetes
is
going to live longer
than somebody without diabetes
if they're taking metformin
that's insane to me here's my hypothesis
and you'll tell us whether this makes
any sense so
insulin seems like the problem child
here and so by elevating my glucose
levels i have to pump all this insulin
into the system the insulin is
potentially damaging things somehow some
way i don't understand the mechanism but
its over abundant presence causes damage
to the cells in some way shape or form
by
taking metformin it's keeping my blood
glucose levels down which means that
it's going to keep my
insulin levels down and therefore i
wouldn't be doing the damage to the
system so even though i may be in taking
the things that turn into glucose
because of the use of metformin i'm
actually keeping my insulin response
down so therefore i never get that thing
that ends up damaging the system and
therefore even though i started as a
type 2 diabetic and that's why i'm on
the metformin
because of its impact on insulin i never
get the damage isn't occurring at the
level that it would even for somebody
who is not a diabetic
does that sound about right kind of
kind of let's go back to what is
metformin metformin is a derivative of a
plant molecule
that
inhibits the cell's ability slightly to
make energy and in response so it's
acting on the mitochondria
yes so mitochondria in high school we
were taught they're the power packs of
the cell they do a lot more they make
amino acids they make fat they do all
that stuff but we need them for energy
without mitochondria we're dead again in
30 seconds um and the way and so i'm
drawing this because they're like little
bacteria in our cells they float around
and they make energy for us in fact
like four billion years ago actually
only one billion years ago uh
mitochondria were free-floating bacteria
that were subsumed by us it's crazy so
we have little pets in our body and they
have their own dna
which does get mutated over time
the reason
metformin seems to work one of them is
that it inhibits the ability of
mitochondria to make the energy so
mitochondria are like a hydroelectric
dam
there's water but in this case it's
hydrogen atoms not water that gets
pumped into a reservoir which is between
two membranes on the outside of the of
the the bubble of the bacterium
thing
so now hydrogen atoms are really acidic
that's what acid is lots of hydrogen
protons and when you get a lot of
something it likes to equilibrate
remember that you go from a lot too
little it flows
but there's a membrane in between from
the high level to the low level in so
internal is low high is outside
and the cell puts this little
uh generator in between
that outside space in the inner space
uh the outer membrane space and then a
membrane says what we call it
and this little little power generator
sits there and those protons shoot
through a pore
in that protein
and at the bottom is a is a generator it
spins literally if the protein is
spinning
at thousands of times per second oh and
as it's spinning it's doing a chemical
reaction to make what's called atp
adenosine triphosphate doesn't matter
its name that atp is chemical energy
that we use
to to live to make things to grow
uh and so what metformin does is that it
reduces the
the ability of cells to
uh make that
those proton gradients it's called and
so you don't build up as much power and
you don't make as much atp
initially you have to do with glucose
why do you give that to a diabetic
well what happens is
that there's a process called
mitochormesis
hormesis is adversity what doesn't kill
you makes you stronger and mido is the
mitochondria are experiencing adversity
or perceived adversities the
mitochondria are freaking out i can't
make enough energy i don't have enough
enough atp
okay and what gets activated is a
protein called
ampk
is a regulator of energy in our bodies
that senses when we don't make enough
energy
and what metformin does is it comes in
and it activates that ampk
step and now the cells are freaking out
that
they're not making enough energy and in
response
they'll make more
and so you have a little drop in energy
temporarily when you take a pill
but then the cell rebounds and starts
making a lot more
energy and you actually mitochondria
will multiply you get more of these
little bacteria
in your cells so taking metformin causes
a
replication of your mitochondria yeah
okay ampk starts
but i still don't know how this ties
into glucose
well when you when you activate ampk you
don't just make more mitochondria but
cells start to put out a new protein
that we haven't talked about new to this
chat are called glute4 and that's stands
for glucose transporter number four and
it goes to the outside of the cell
right on the very what we call plasma
membrane and it sits there and now its
job is to suck the glucose out from the
liquid around so it's no longer waiting
for insulin to come around to push the
glucose into the cell it's like yo
i need glucose
to help with this energy
creation
it does and it so it makes more of this
protein but it also becomes
what we call insulin sensitive so the
little bit of insulin that you have
around if you're a type 2 diabetic
works better okay you get more insulin
receptor which is the protein that
senses insulin so all in all what
happens to that cell just to summarize
because it's a bit complicated
is that by tricking the cell into
thinking it doesn't have enough energy
it panics adversity hormesis and it'll
go now and
put the protein on the surface to grab
the glucose and be more sensitive to the
hormone insulin that tells the cell to
suck it in
why is that good because then your
glucose levels in your bloodstream will
come down
and you're no longer type 2 diabetic
there are two reasons i believe why
being type 2 diabetic accelerates aging
why you don't want to have high levels
of glucose and why i try to keep my mind
you think insulin is is irrelevant in
this chain
i do it's a signaling molecule okay um i
mean over time your pancreas will suffer
because it has to make more and more of
it but that's not what's aging your
brain and your muscle and all these
other things what's going on is two
things
one is that that glucose
will attach to proteins all the time it
just sticks to it and in fact the
diagnosis of type 2 diabetes is to look
at an abundant protein in your body in
your blood that you can access at your
doctor's office and figure out what
percentage of that protein
is stuck to glucose
and that's hemoglobin
in your red blood cells and if you've
got
five percent or less hemoglobin attached
uh to the glucose you're healthy and
then you get 6.5 you're pre-diabetic and
higher than that you're heading towards
type 2 diabetes and that's just all
about glucose attaching to proteins
and glucose attaching to proteins messes
things up
and they can really not work well but
that's really not the root cause of
aging as i've told you
what's also going on is that the high
levels of glucose
are making your cells
complacent tons of energy got lots of
this stuff going around the hormones
your brain thinks that it's good you're
swimming in treacle um and so your
adversity
and repair systems the sirtuins they
don't work as hard and so your clock is
ticking faster that's why type 2
diabetics have others they don't work as
hard or they're lumbering under the
weight of glucose that stuck to them
interestingly both so tunes will get
attached to sugar
but they also they don't
turn on like they get attached to sugar
or sugar gets attached to them sugar
gets attached to that okay yeah
but what's also a real problem is that
that adversity system is complacent
and so by keeping your glucose levels
down even at a young age well i'm not
young but even at a young age
your your body will be in this adversity
state versus abundance
and
that can explain why type 2 diabetics
are older when you measure it and also
are susceptible to heart disease
dementia and even certain types of
cancer and why metformin the drug that
keeps your glucose levels down and
activates this mito hermesis defense
doesn't just protect you against type 2
diabetes
it by looking at tens of thousands of
patients who that have taken metformin
they also have lower levels of heart
disease dementia frailty and cancer
is bananas it is bananas do you take
metformin i do
so i'm going to walk through what i
think is your ideal protocol minus t