rapamycin and easter island
the connection between these two is an
international tale
with plot twists that reads like fiction
you
you can't make this stuff up
this week we're talking about rapamycin
a drug that was formerly used as an
immunosuppressant
and as an anti-cancer drug but that's
now being used
to extend lifespans and health spans
we'll start out by going over its
history which is pretty darn interesting
then we'll move on to a discussion about
some studies that i've recently read
that might be changing my mind with
regard to taking rapamycin and finally
we'll be taking a look at my biggest
concern with rapamycin which is
the role that it plays with sarcopenia
the story of rapamycin and the discovery
of the mtor pathway
is both interesting and convoluted it
began
in 1964 with a scientific expedition
to easter island inhabitants of easter
island tended to walk around barefoot a
lot yet
they didn't get tetanus which was pretty
common in other similar environments
especially ones with a lot of horses
now this aroused the curiosity of this
researcher
named georges nogradi and he figured
that the answer
was probably in the soil so he joined an
expedition of 40 canadian scientists
going to easter island to study the
islanders before the chilean government
disrupted their isolation
by building a new airstrip he divided
the island
into 67 parcels and he collected soil
samples from each
now he was only able to detect the
spores in a single sample so
he packed away his samples and donated
them to a research lab in montreal
owned by a year's pharmaceutical after
researchers
isolated microorganisms from the soil
coax them to grow
and were able to screen the brew of
chemicals that they produced
they found that one of the bacteria
produced a compound
that could kill fungi they called it
rapamycin after
rapanui the name given to easter island
by the polynesian islanders that lived
there
and they considered it an anti-fungal
but they discovered
that they could also keep cells from
multiplying so
they sent samples to the u.s national
cancer institute for screening
and the nci found that it had an
incredible activity
against solid tumors so it turned out
that rapamycin was also a
potent anti-cancer drug but then in 1982
ayerst decided to close its montreal
research lab
and all work on rapamycin came to a halt
but
before the lab was closed a
microbiologist
named seren seagal decided to do a
large-scale fermentation of the
bacterium
pack it up and take it home where he
stored it in his freezer
next to the ice cream in a package
labeled do not eat
and there it stayed for the next five
years
the segal family moved to princeton and
in 1987
ayers merged with wyeth another
pharmaceutical firm
segal was able to convince upper
management to reopen
investigations into rapamycin and that's
when it was discovered
that rapamycin could suppress the immune
system
and prevent the rejection of
transplanted organs so
rapamycin added immunosuppressant
to its growing list of therapeutic
effects
eventually other scientists were trying
to identify and understand
the biological function and biochemical
mechanism of its target
the protein that responded to rapamycin
it took years for scientists to
understand that this target
acts as a central hub of the nutrient
signaling pathway
this target was named mtor for
mechanistic target of rapamycin
and that's how mtor and the mtor pathway
was discovered
in the mid 2000s researchers were
investigating the effects
of manipulating genes in the mtor
pathway
and they discovered that dialing back
mtor's activity
extended the lifespans of yeast nematode
worms
and fruit flies now they knew that
rapamycin could inhibit
the mtor pathway so they were curious to
see what happened
if they fed rapamycin to mice
they wanted to perform the experiment on
eight-month-old mice waiting until they
were mature
before starting the experiment but it
took them a while before they could
figure out
how to formulate the drug so that it
could be put into the mouse food
by the time they figured it out the mice
were 20 months old but
they decided to go ahead and see what
would happen
if they fed these older mice rapamycin
the results were groundbreaking and this
study made the history books
male mice lived an extra six months
about nine percent longer than the
control mice
and female mice did even better living
14 percent longer
other researchers performed similar
experiments on dogs and marmosets
small primates that have similar risks
for chronic diseases
as humans rapamycin extended lifespans
in every animal that they tested it on
and so
rapamycin added longevity drug to its
now impressive list
of beneficial effects
i've always been somewhat skeptical
about rapamycin
and i've always felt that there are
better ways of suppressing the mtor
pathway which is
one of the primary strategies to slow
the aging process
now i've talked about that in an earlier
video which you can access right here
but recently i've been digging around in
the research regarding rapamycin
and i found some information that just
might make me
rethink my position now the entour
pathway
is super complex and it responds to
nutrients found in our diet
and the foods that we eat and it
responds primarily
to amino acids the mtor pathway is
anabolic and its activation is required
for cellular growth rapamycin
inhibits the mtor pathway and this is
important because
once the mtor pathway is inhibited it
allows for activation of the ampk
pathway which is responsible for
cellular repair
and for autophagy which is the recycling
of cellular components
the ampk pathway and the mtor pathway
are
antagonistic when one is switched on the
other
is switched off so balancing the mtor
pathway and the ampk pathway is critical
in extending health spans now i've
talked about this before and if you
watch those videos
then you'll know that while i'm a fan of
occasionally inhibiting the mtor pathway
i've never been a fan of using rapamycin
to do it
i've always felt that there are better
ways to accomplish that
for one thing rapamycin is a universal
mtor inhibitor meaning that it shuts
down the mtor pathway
across all tissue types now i've always
felt that there are
other better ways to control the mtor
pathway
it also has a long half-life the period
of time that takes your body
to clear out half of the drug and that's
between 62
and 82 hours but i recently read several
articles and studies
that might be changing my stance on
rapamycin
there was this paper in which the author
cites several reasons
why he thinks that rapamycin should
absolutely be taken
as an anti-aging drug while he didn't
win me over completely
he did make some good points he claims
that rapamycin has gotten a bad rap and
that there have been a number of bad
side effects
that have been attributed to rapamycin
that are simply not true
one was a risk of cancer and he talks
about rapamycin's proven
anti-cancer properties and how it's been
demonstrated to prevent cancer
not cause it he talks about its
metabolic effect and how safe it is
he talks about how rapamycin extends the
lifespan
even if started late in life unlike some
other longevity
interventions like calorie restriction
which has proven somewhat ineffective
if started once you're already old then
there's this paper which takes a look at
a variety of drugs
that might have the ability to slow the
aging process
now this paper refers us to all the
studies that have been conducted
on longevity that have used rapamycin to
extend lifespans
it talks about just how many there have
been about
how they've been conducted on a large
variety of different species
like yeast worms fruit flies mice
dogs and marmosets and how rapamycin has
extended
life spans in every single study it
talks about the dog study in which
researchers saw
improved left ventricle systolic and
diastolic function
just like they saw in the mouse studies
and that there's a new dog study
underway
to test cognitive and heart functions
immunity and incidents of cancer
it talks about the marmoset study which
was the first study done on primates
now the study looks at a lot of drugs
and it compares them in their ability to
positively impact any of the nine
hallmarks of aging
and rapamycin comes out on top having a
positive impact
on six of the nine hallmarks it's the
only one that impacts so many
and it does quite a bit better than most
of the other drugs
now there's a new study that i don't
believe is launched yet called the pearl
study
it stands for participatory evaluation
of aging
with rapamycin for longevity study now
this is sort of a grassroots
volunteer study that's a bit different
it's crowd funded and crowdsourced
they'll be taking 200 participants who
are between the ages of 50 and 85 years
of age
and they'll follow them over the course
of a year taking measurements at the
beginning
at six months and at 12 months they'll
be dividing them
into four groups plus a control group
and they'll be giving them different
dosing regimens
this is the first study to see if
rapamycin extends lifespans on humans
as well as it does on mice
immunosuppression is an age-related
problem for the elderly
they have a decline in naive lymphocytes
they have a reduced response to vaccines
and they're prone
to increased infections all signs of a
declining immune system
now this same paper talked about how
elderly mice
showed a similar lower response to
vaccines and how mice treated with
rapamycin
showed an increased level of naive
lymphocytes
and a boosted response to vaccines it
also referred to a study in humans
that showed an improved immune response
after six weeks of treatment
and this study on the use of rapid logs
drugs that are
similar to rapamycin to treat covid
seems to back up the claim that these
drugs
can actually improve immunity now in a
previous video
i talked about how important the mtor
pathway is
to the immune system and how rapamycin
suppresses immunity
that's because i bought into the belief
that rapamycin is an immunosuppressant
which is how it was
originally labeled by the fda but it's
not an immunosuppressant it's actually
an immunomodulator these are compounds
that can help
support immune function by modifying
generally in a beneficial way
the immune system's response to a threat
and
it's this mislabeling of rapamycin as an
immunosuppressant that is primarily
responsible
for rapamycin's bad rap
so one of the big reasons that i was
down on rapamycin
was because i'm concerned about
sarcopenia so i exercise a lot to
prevent that
because the mtor pathway is so important
to building
muscle taking rapamycin to shut down the
mtor pathway
seemed counterproductive but this paper
seems to contradict that thinking it
states that mtorq1 activity
has long been known to be induced in
aging muscle
the mtor pathway has two complexes mtor
complex 1 or m torque 1
and m torque 2. chronic activation of m
torque 1
stimulates progressive muscle damage and
loss
in one study they found that when m
twerk one was activated in certain mice
it produced enlarged muscle fibers at
around two months of age
but as these mice grew older they found
that this beneficial effect
morphed into muscle fiber damage at
around six to nine months of age
eventually resulting in a 50 loss of
muscle mass
by the age of 18 months and this was
accompanied
by a reduced survival rate what they
then found
was that by inhibiting the mtor pathway
with rapamycin
they were able to prevent this
age-related loss of muscle
inhibiting mtorq1 protected the aging
muscle from atrophy
it reduced the apoptosis that was
associated with reduced muscle fiber in
aging skeletal muscles
and in another study they found that
inhibiting mtorc1 with rapamycin
preserved
both fiber size and muscle weight i
think that the key here
is chronic activation of mtorq1 let's
take a look at akt
dependent activation of mtorc1 as near
as i can tell
akt dependent activation means
activation that is a result
of some form of stress the akt signaling
pathway
promotes survival and growth in response
to extracellular signals so
i think that akt dependent activation
means that mtorc1 gets activated as a
result of this type of signaling
and i think that a weight training
session might be an example of this
akt dependent activation of mtorc1 is
beneficial
and it prevents muscular atrophy however
akt
independent activation of mtorq1 in
other words
activation of mtorq1 that does not
depend on the akt
signaling pathway is detrimental to
muscle tissue and it triggers protein
degradation
and muscular atrophy now i believe that
this is the form of activation
that can become chronic later in life
and that's so bad
i also believe that this is a form of
activation that is prevented
by shutting down mtorc1 with rapamycin
now i could be wrong about all of this
and if any of you guys have any
information on this
let me know in the comments
so what does all this mean how does it
affect my stance on taking rapamycin
to inhibit the mtor pathway i think that
i'm becoming convinced
that taking rapamycin might not be a bad
idea but
i would still need to figure out dosing
and scheduling
there's a number of studies that
indicate that taking rapamycin
later in life is still a good thing and
that there are plenty of benefits
that can still be obtained they also
show that its benefits remain
even if you're taking it transitionally
meaning if you cycle
it the pearl study is testing several
different dosing regimens
they're testing two and a half
milligrams taken three times a week
five milligrams taken once a week five
milligrams taken twice a week
and 10 milligrams taken once a week now
i'll be really interested
in finding out how this study wraps up
and what they conclude from it
particularly about dosing and then
there's the cost
rapid myosin ain't cheat depending on
which dose you might choose to go with
it would cost somewhere between 100 and
200 a month
and that's from good rx and that's if
you can get it
rapamycin is a prescription drug and
using it as a longevity intervention
would be an off-label use so i think
that most doctors would probably
be unwilling to prescribe it so even
though
it's probably not my best interest i
think for now i'm probably
going to continue to not take it if any
of you guys
are taking rapamycin let us know in the
comments tell us your experience and
tell us
where you obtained it i think we'd all
like to know
hope you guys enjoyed this video check
out this playlist
for more information on the mtor pathway
and balancing it with the ampk
pathway that's it for me i'm outta here
catch you next week