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August 14, 2018
The Peter Attia Drive – David Sabatini, M.D., Ph.D.: Rapamycin and the Discovery of mTOR — The Nexus of Aging and Longevity?
Key Takeaways Rapamycin (a drug) acts on a protein called mTOR (it inhibits its function) Insulin, glucose, and amino acids activate mTOR mTOR is responsible for many things, but perhaps most important is its regulation of autophagy By suppressing mTOR through things like fasting, we increase autophagy Human data suggests that an intermittent dosing of rapamycin is most beneficial Intro This interview was recorded in August of 2017 as Peter was doing research for his new book, mentioned a few times now There’s no release date as of yet David has done lots of work in his career with the mechanistic target of rapamycin (mTOR) and rapamycin (also know as sirolimus) The compound rapamycin is the only known pharmacological agent to extend lifespan all the way from yeast to mammals—across a billion years of evolution Check out another relevant podcast – Peter and David on The Tim Ferriss Show David a currently a professor of biology at MIT Rapamycin and mTOR mTOR is a protein through which the drug, called rapamycin, acts David discovered mTOR as an MD-PhD student at John Hopkins He has continued to study mTOR after graduating and into his career at MIT After finishing his MD-PhD, David worked in Solomon (Sol) Synder’s neuroscience lab at MIT Sol was currently working with/studying a drug called FK506 (aka Tacrolimus), which is an immune suppressant It’s used mainly after organ transplants to lower the risk of organ rejection by the body FK506 targets calcineurin in the brain – it inhibits it They were studying the modulation of calcineurin in the brain using FK506 Calcineurin essentially activates the immune system, and FK506 blocks it’s activity Rapamycin was being used as a control drug in their studies (it looks like FK506, but doesn’t do exactly the same thing – although similar) Rapamycin is also an immuosuppressant (like FK506) – but it achieves this effect in a different manner than FK506 Rapamycin – It inhibits activation of T cells and B cells (which are vital to the body’s immune response) by reducing their sensitivity to interleukin-2 (IL-2) through mTOR inhibition FK506 – It achieves its immunosuppressive effect by inhibiting the production of interleukin-2, a molecule that promotes the development and proliferation of T cells, Rapamycin At the time, rapamycin very much interested David, so he decided to study it There were a slew of papers at the time that showed it had anti-fungal, immunosuppressant, and anti-cancer effects Note from Podcast Notes – all you need to know is that rapamycin inhibits mTOR The origins of mTOR RAFT1 (Rapamycin and FKBP Target 1) This was the original name for mTOR when David discovered it Around the same time, at Harvard, Stuart Schreiber discovered the same protein, calling it FRAP1 (FKBP Rapamycin Associate Protein) Both Stuart and David realized that rapamycin acts with a co-receptor (a protein called FKBP aka FK506 binding protein) – so it binds to it Side note – during this time, David recalls frequently working until 1am in the lab, and being back in at 7-8am. He often just slept there. David’s paper on the discovery of RAFT1 (now known as mTOR) was published in Cell in 1994 mTOR was discovered first in rat brains via a method called silver staining Rapamycin was approved by the FDA in 1999 Okay..A quick recap It’s now known there are two mTOR complexes mTOR Complex 1 (mTORC1) centered around RPTOR RPTOR = Regulatory Associated Protein of mTOR By “centered around” – it just means “joined together with” mTOR Complex 2 (mTORC2) centered around RICTOR Note from Podcast Notes – they just kind of jumped into the mTOR complexes, so here is where it gets quite difficult to follow, we try our best 🙂 So what does mTOR do? Many things… Regulates autophagy (cell death), regulates cell size and growth, and many metabolic pathways Peter – “mTOR sits at the center of the universe for some of the things we care a lot about, potentially longevity” This is realized now, but upon its discovery, David had no idea mTOR was this important Why is it that, rapamycin, or the inhibition of mTOR (specifically, mTORC1) can extend life? We don’t know the answer yet One of the MANY things mTORC1 regulates, is autophagy Autophagy is the self eating process where a cell breaks down its own damaged components, and remakes them – this is essentially the cell rejuvenating itself Key – Note from Podcast Notes – it sounds like by inhibiting mTOR, we increase cell autophagy mTOR (Complex 1 and 2) acts a general contractor for the cell – it does LOTS of things It has a finger in every major process in the cell What’s the simplest way to manipulate a cell so lots of things are changed – modulate mTOR “To impact the state of the cell, to rejuvinate it, to slow the aging process, you probably have to do 100 things, and the only way to do all those things with one button, is to go after mTOR” It’s difficult though, because mTORC1 regulates many things So you don’t want to shut it off completely – it’s probably required for the growth of any normal cell (to make it’s organelles, to make its protein, to divide …mTORC1 is essential) Rapamycin is not a complete mTORC1 inhibitior – it only partly inhibits it mTORC1 has dozens of substrates, and rapamycin only inhibits some of them and not others Note – this isn’t really explained…what’s a substrate??!! Autophagy is only relatively weakly modulated by rapamycin “The key substrates in the autophagy pathway are not as effected because they get into the kinase domain of mTORC1, still” If you inhibit mTORC1 long enough, it is thought to inhibit mTORC2 Glucose, Insulin, and mTORC1 Insulin and glucose seem to activate mTORC1 This is why, when we fast, we suppress mTOR. and autophagy levels are increased Remember when we eat glucose, our insulin levels rise to shuttle the glucose into our cells Think about a muscle cell – it needs to decide if it’s in an anabolic state (a state of building – that’s why they call them anabolic steroids) or a catabolic state (a state of breaking down) The cell wants two pieces of information to decide this: That the environment it lives in a fed state – reflected by the presence of insulin That you it has the nutrients it needs – the presence of glucose serves this function, or amino acids… With amino acids… …Like leucine and arginine, they are brought into the cell through receptors in the cytosol, that then downstream result in the activation of mTORC1 Both of these amino acids have to be present to activate mTORc1 mTORC1 wants to drive anabolism (growth) – it’s goal is to detect when something is missing for that – it turns off when something is missing The default. – when everything is there it’s on The removal of anything turns it off (so when we fast) It needs to detect both leucine and aregenine to be on, at least in most tissues – but its tissue dependent It’s a good question – why did evolution choose these two amino acids to activate mTOR? This is why fasting supresses mTOR (lack of nutrients and amino acids, so mTOR is inhibited), but if you fast and have something like coffee, mTOR might not be suppressed – we just don’t know Note from Podcast Notes – this isn’t really discussed, this last bullet point is a thought of our own. Methionine is an amino acid Lots of literature exists which shows that methione restriction has beneficial effects on homeostasis – lifespan extension effects have also been observed There are some papers for flies, that suggest that some of the methionine restriction effects go through the TOR pathway (it inhibits mTOR) When you fast an animal, methionine levels drop the most out of all amino acids The liver can make arginine Leucine is released during a fast when muscle breaks down More on Rapamycin Human data suggests that an intermittent dosing of rapamycin is beneficial “If you want to chemically induce autophagy without fasting, an intermittent dose of rapamycin make sense” “Cycling anabolism/catabolism might be the single most important thing to do” – Peter This comes back to… Intermittent dosing of rapamycin Every other day feeding strategies When we think about the life-extending properties of rapamycin, do we believe that it is a result of delaying the clinical onset of disease and/or delaying the demise of the animal once it has the disease? As an FYI cancer spends 70-80% of the time undetectable – it becomes detectable only at the end We don’t know if rapamycin is doing anything to prevent the development of cancer It general rapamycin is not a cytoactive agent – it won’t kill a cancer cell David’s bet would be that you’re not going to cure cancer if you’ve already got it, but you might slow its growth Rapamycin and TOR in the brain Autophagy is really important in the brain You need mTORC1 activity to maintain healthy neuron synapses, but you need to be able to modulate (so inhibit) mTORC1 to have some level of autophagy to keep the system healthy But we don’t know what modulates mTORC1 in the brain It’s not nutrients like in muscle tissue, because of how much your brain prioritizes nutrients over other tissues in the body The body protects the brain from a nutrient point of view David’s Dream Experiment
Being able to understand, in different tissues, in a temporal fashion, in response to a variety of different diets, what those tissues are doing So basically, a description of what all these different tissues are doing across time in response to different diets