Qualy #46 - Rapamycin's effects on cancer, cardiovascular disease, and neurodegeneration
Episode Stats
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Summary
In this episode, we discuss the life-extending properties of rapamycin and the role of autophagy in neurodegeneration and neuro-dysfunction, and the potential link between these two phenomena.
Transcript
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welcome to the qualies a subscriber exclusive podcast qualies is just a shorthand slang for
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a qualification round which is something you do prior to the race just a little bit quicker
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subscribe so without further delay i hope you enjoy today's quali so this may be a theoretical question
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but when we think about the life extending properties of rapamycin do we believe that it is a result of
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delaying the clinical onset of disease let's use a disease where that tends to be more binary like
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cancer but obviously cancer spends probably 70 to 80 percent of its time undetectable but due to
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just the law of growth it becomes detectable only at the end so do we think that in as much as say
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taking you know these agents would allow you to live longer by not dying from cancer at the same
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period of time does it delay the time it takes for cancer to become clinically detectable
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and or delay the demise of the animal once it has that cancer yeah i think specifically you know in
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the case of cancer rapamycin is there's some situations where it has some decent activity but
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in general it's not a cytotoxic agent right it's not going to kill a cancer cell it's really going to
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once an organism has cancer do you know if it's doing anything to prevent the development of cancer
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we don't know that well and the only there actually has been some epidemiological data
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where people have compared cancer rates in transplant patients identical patients who are
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with and without rapamycin and it's actually quite interesting because as you know immunosuppression
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in general is associated with higher cancer rates right the idea that you have less immune
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surveillance that's not seen with rapamycin so it is seen with fkf6 it's not seen with rapamycin and
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the argument has been that rapamycin itself has cancer cell autonomous independent of the immune
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modulation problem so you're presumably getting less immune surveillance because it's immunosuppressant
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although of course that's not proven but you're mitigating that yeah by now directly and they've
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canceled each other out they cancel and you know the size of the effect from the fk506 cohort exactly
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and other immunosuppressants i think cyclosporine have also been looked at that so my bet would be
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that in the case of cancer you're not gonna you're not gonna cure cancer once you've got it but you
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but i also don't think you're going to modulate the incidence like the mutational frequencies that
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are giving you cancer right so if you think of cancer in a way is easier to think about when it starts
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because you say well it starts when you have a cell that has all the requisite mutations to be
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to evade detection exactly has uncontrolled growth so if that's the point it starts i think we're not
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going to affect that but once that cell exists and now has to start growing and and also escaping the
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immune system i do think that's probably what you're going to affect in other diseases like
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cardiovascular disease where you could imagine things like autophagy could be quite modulatory
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i think you can imagine that you're also being affecting the incidence at the exact point at which
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you'd say okay this is an atherosclerotic plaque or not what do we know about rapamycin and tor in
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the brain especially with respect to neurodegeneration yeah that's uh that's a really interesting one and
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that probably is is a really important question for the future so we know autophagy matters a lot in the
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brain if you delete autophagy and really mitsushima was the person who kind of made autophagy interesting
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to lots of people and it was awarded the nobel prize no no he wasn't oh he wasn't he was for
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he didn't share he didn't know which i think was a bit of an oversight in my view but anyhow he he
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basically studied autophagy in the brain made mutations showed you got neurodegeneration right
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so that was a really important finding connects up to lysosomal storage diseases which you know
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autophagy basically autophagy infuses with a lysosome so now you have that connection
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so i think like in all tissues it's a bit of a double-edged sword you clearly need mtrog one
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activity to maintain healthy synapses certainly during brain growth you do if you make mutations
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rambo in a growing animal you basically don't have a cortex yeah right on the other hand you clearly
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need to be able to modulate mtrog one to have some level of autophagy to keep the system healthy
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now you could debate is that in neurons is that in glia it's probably in both people have made
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mutants in certainly in neurons which suggests it's both but then some of those promoters a little bit
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dirty but the real question the brain is what modulates mtrog one because it's not probably
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nutrients because they're so constant you mean like exactly yeah your brain your body your brain
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prioritizes nutrients in the brain over it basically protects your body so if you take an animal and you
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fast it for two days a mouse it loses a lot of weight 25 of its weight and now you take every single
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tissue and you weigh it every tissue has shrunk except some like the thymus have shrunk ridiculously
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the kidney shrinks which you wouldn't expect the heart shrinks the brain nothing now clearly probably
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if you in a mouse you can't do that extrema fast and so the body protects the brain from a nutrient
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point of view yet mtrog one activity is high there clearly we know that we have to modulate autophagy so
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something must be inhibiting mtrog one by the way this is my peripheral argument for why and i'm in the
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huge minority here i do not think the brain is really the appetitive center i think it's the
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modulator but i for that exact reason think it wouldn't make sense for evolution to put our
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appetite center in our brain it should be in the periphery it should be in the liver i think i think
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the liver should be people argue that things like a hypothalamus are in the periphery right
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because they're not protected there are parts of your brain like the hypothalamus
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yeah the point is i think it has to be your appetite center needs to be regulated to something that senses
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very rapid the outside for sure yeah for sure and and exactly where it is you know and the
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bottom line is probably but i never thought of it through the lens that you just explained it which
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was the implication of that for tor is enormous so so does tor look different in the brain or i mean
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obviously the protein won't but do the cofactors around it look really uh you know we keep talking
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we have never done for example biochemistry out of the brain it's something that would be very
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interesting to go and do now i think now it's something we talk quite a bit as a lab to do we haven't
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quite done it at all but then what actually regulates it it's very clear that neuronal activity does
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but there are there like as you're suggesting maybe neuronal specific factors regulate i think that's
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a completely open area i've tried to get some of my students interested in that my brother's a
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neuroscientist he's argued we should really do some work there we just haven't maybe when we run out
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of sensors in the periphery we'll go to the to the brain because and that's that's where i purified
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mTOR was out of the brain so there's a ton of mTOR in the brain and i did that not because i was like
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whatever i basically measured how much there was and it was clear the brain had the most i hope you
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