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Peter and I explore the fascinating applications of Rapamycin for longevity. We also discuss fasting, inflammation, aging, mindfulness, and supplements. Full show notes here.

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00:00:00every two cameras here before we get started heading over to Instagram at Kevin Rose follow me up there and you'll see all the chaos set him up to always supposed to crazy little stories there and and photos also check out my meditation app Oak meditation. Calm completely free this could be some additional courses here in the next few months that you want to check out is always been to train you up and then get you to practice meditation on your own without the need of instruction we're not going to be one of those apps for you, there's a thousand different courses our goal is to train you and then let you sit and practice and have a great unguided timer for you to check it out we got some good reviews Oak meditation calm today I have Peter attia on the show and if Peter has been my dock here for the last gosh I want to say like maybe three, four years and we were introduced by Tim Ferriss cuz he's been on the Tim Ferriss show a bunch of times and Peter is a very unique doctor in that he's not
00:01:00primary care physician so you don't go to see Peter if you have a cold or the flu there's other doctors for that he specializes in longevity specifically making sure that you know you don't die from cancer dementia heart disease heart disease for me being the big one cuz all the men on my father's side are now dead from heart disease which is scary and sad I'm and it's something that we addressed Peter and I dressed and have now of course correct and fix that through fasting and a combination of other things he also works on inflammation and he's just insanely dialed into the latest and greatest that's going on in the world of science and that is because not only does he pour through and read through the scientific literature on his own and figure out the things you can fly to his practice but he also has a team of researchers that go through and look at all of the hundreds of thousands of newly published papers per year. Then find out which ones are legitimate
00:02:00and the distill those down and he then applies those to his patients and then also I'm talks about them on his podcast Peter attia drive so definitely check out his podcast he is just move to a listener-supported model which I think is great I'm so he's not having advertisers on there or anything like that you could access when you when you actually pay for his podcast to all detailed notes show notes which are just really in-depth so they are like books for like Fifty page books for each by Cassie can go in there and actually read through and get all the links to anything and everything that he talks about their it's just really cool and you also get to ask him stuff on his Clinic accept you don't have to pay the crazy amounts of money that he can charge cuz he works with professional athletes and all kinds of crazy people out there and that's what you do when you have a really sore after awesome product that he'd
00:03:00that's what his private clinic but this kind of get you there and get you access to him and I like seeing that he's doing this to really help out more people so supportive podcast check it out the Peter t a drive today going to talk about a fascinating drug called rapamycin and there was a 2014 paper that came out that show the rep of mice and could extend the median lifespan 23% in male mice and 26% and female mice they're calling it rap myosin a lack of a caloric restriction or calorie restriction in it he'll so you get all of the benefits of Clark restriction but just by taking uphill now this has not been used for longevity meaning you can't go to your doctor and say hey sign me up for rapamycin it is used as an immunosuppressant I'm so if you get a organ transplant or something like that that's what it's being used for I'm probably you wouldn't use those types of doses for the kind of longevity side of things
00:04:00Peter is fascinated with this this compound and with good reason and we really dig into it now here's the thing if you've ever heard about Peter talk about rapamycin and I currently have cuz he has podcast with you know Tim Ferriss talking about it yes podcast on his own show talking about it and I've always had with this is that Peter as you'll see on my podcast he's like 5 levels above everyone else in the room so half the time you talked about the shit I'm just like what are you talking about little bits here and there and you know I I have a scientist why so I can be like what is supposed to mean when he says this so I can always ask questions but I said Peter like listen like this podcast we're going to break it down like I'm five you know like that there's that famous subreddit it's like to explain to me like I'm 5 I just really take your time and tell me really what's going on with this compound and so we go very slow and very deep into the the inner workings of rapamycin
00:05:00think you'll find this conversation pretty awesome because it's it's it's kind of for us people that are not scientists and you'll get an understanding of how and when you might be able to have access to something like this to increase longevity and we talked about a bunch of different of the rapid fire questions around longevity and different things like curcumin and a bunch of stuff that I just want to get his take on really fun podcast. The awesome guy and good personal friend so I hope you enjoy it and absolutely if you're in front of a phone and just pull up notepad and we're going to your favorite podcast app after you get done listening to us and check out the PRT a drive awesome show all right enjoy Peter thank you for being on the show so much for having me excited to finally have you because you are crazy longevity doctor for pretty much all of my friends lot of people attack a lot of really famous athletes and celebrities but you're not a celebrity doctor
00:06:00that's considered bad guy l a kind of crazy you know I'll fix your face whatever maybe but you're actually a longevity doctor with a lot of researchers at work for you I want to talk about the research the Yu-Gi-Oh tell me about the researchers what they do day today you know what kind of fairies a little bit bye bye season and right now almost every thread of our research isn't helping me write this book that is crushing my soul I think everybody which I'm happy to explain cuz that's been a humbling experience but I think it's anybody's listening to this in writing a book they'll appreciate the lessons of of doing such a thing go right now yeah every bit of analytical horsepower is basically on Gathering data and assimilating effectively writing a run internal meta-analyses on all of the topics that are germane to to the the topics
00:07:00try to put into the book along with maybe you know strip 10% of our band with remaining for the other really important part of a research which is just really answering any clinical question that shows up so you know those things can be really mundane but I feel like we are patient a month ago who had an estradiol level of 300 so estradiol is one of the three estrogen hormones in a man should never have an estradiol level of 300 normal level is like 15 to 30 in a woman when she's ovulating might be that high so when I first saw it I was like a little Panic like what could be going on so called the lab had them you know redo the test they redid the test and was still 300
00:07:39yes and then we did a whole bunch of other tests to follow up to make sure we weren't missing something like you know some rare cancer and all that came back negative and and then one of the analysts I said look this has to be a laboratory error we have to find out how it is cuz we checked it with multiple labs and everybody kept getting the same stupid High number and it turned out that all the labs are using a very similar Eliza technique analyzes just a type of acid that you use witch-hazel you know an enzyme that you link and wash and repeating recycle but it turned out that there's a Gold Standard whey liquid chromatography and mass spec for pain but once we ran it with that we got a normal levels and so Ralph who's the analyst who was basically doing all this work was like you know became an expert on all of the different contaminants the chimp interfere with the Eliza based a Saison hormones so now we're looking at me like oh my God like how many times have we been fooled by this and I'm so anyway those are kind of like what
00:08:39cool projects that are very sexy but we're always served like responding to those things that were confused by all this is the point I was trying to get this is the difference between you know looking up a doctor in on ZocDoc in going there and dealing with someone that has data that is 5 10 15 years out of date and actually having your own analyst you know in house that are currently do they report back to you on the latest findings I mean there's so many new published studies that are coming out every single day this is something about a hundred thousand studies make their way onto PubMed in the English language each month but by most estimates you no fewer than 1% of those are actually relevant meaning you know something sexy to 70% of those will never be cited again meaning they're not even remotely useful and then of course you know this episode of those don't apply to your area of interest mean I can't obviously keep up with most literature and really focusing on literature
00:09:39has to do with cardiovascular disease cancer neurodegenerative disease insulin resistance naturally Nash and all those clusters of things along with all of the literature directly related to longevity especially based on fasting and all of the fasting mimicking molecules inside rapamycin metformin to Lester simplify the problem and say there's like a thousand papers a month that are coming out that are directly or indirectly relevant to what we do I certainly can't even have analysts just reporting in to me so that we have a head analyst Bob Kaplan who I've talked about always have my podcast a bond and then analysts that your kind of reporting with a bob sew if it were up to me like I would sit in a room with analysts every minute of every day and that's all we would do but I think just from the standpoint of trying to get work done mostly I just try to talk to Bob every single day and then Bob directs the projects out to each of the analyst so that you know again some of our projects are very proactive like we're asking a question
00:10:38and some of them are very reactive like the best virgin exam so proactive question would be patient asked once like what's really the best way to prevent blood clots on airplanes and prior to that I thought I was just recommended patients take a baby aspirin before they get on their plane especially if they have a high LP little a to the procoagulant or if they you know have some other evidence of endothelial dysfunction like elevated lppoa to or something like that but you know when the patient asked me point-blank I was like well truthfully I haven't actually looked this up so that like that that's just one of like a hundred examples of yeah she did all the research on that and found out that the day on baby aspirin sucks baby aspirin really doesn't seem to matter that much airplanes in blighted Trials obviously Heparin would be the gold standard but that's so impractical low-molecular-weight Heparin which is slightly less impractical but for most people it still Overkill
00:11:38start to find out these supplements that you can actually buy on Amazon like there's actually this product called a flight tabs Flite tabs that contains grass meaning do you like FDA generally regarded as safe frame molecules that are really good at finding the blood in the manner that it gets basically sticky for lack of a better word in airplanes airplanes have a couple of negative things going for you right the hypoxia so the reduction oxygen concentration increases the quail ability of blood the dehydration does cuz we almost always get dehydrated there in the position we're in so those are the things that are driving the risk and then if you add on top of that owe you a smoker or you're on birth control pill or some some other thing is driving and I know a huge risk know but yeah when you're playing a game of inches like all that stuff matters yeah I was talking to a pilot when I was in a flight and we were having an issue with the plan we had to return to the airport and you sitting next to me and I was just like a man is like a little
00:12:38cuz I don't like that he's like I have nothing to worry about is like he's like I fly every single days like this issue I run into people dying on my planes like that's the number one thing that I have to deal with people have major events on planes you know some type of cardiac event or a stroke or you know so that's really funny school I I had this girlfriend who was a flight attendant and I was a lot of fun just like this is pre 9-11 so like it was just really easy to travel anywhere to like our dates were always a trip like you know you leave SFO and go to Vegas for a couple of hours cuz he had those body systems but she said the same thing effectively which was the things she is most stressed about our flight is like if something goes wrong is there a doctor is there a nurse is there a paramedic on this plane that you know we can get to quickly if someone's having chest pain or someone's having an allergic reaction right and I never thought of that before and she's like yeah we are not on this plane to serve you peanuts
00:13:38right we do that but we are on this plane to keep people safe that's crazy I want to jump into some of the crazy stuff you do because I feel like I listen to podcasts obviously a lot of people do with Peter to drive if you haven't heard it it's phenomenal but there's some stuff where it just way over my head he does the average person I'm like, man I just didn't get that last 5 minutes I want to go there's a very famous like subreddit called explain it to me like I'm five the people absolutely love for you really take the time to go in and myosin was something where I get like half of what you're saying like can you talk to people about rapamycin what's going on in that world and how it actually works I mean this is a topic of a knife a few things I enjoy talking about more do you mean for example like the story of how it was discovered and they figured out it worked or just specifically take for granted that it's a molecule that probably an ant is longevity and now how does it work on the longevity side
00:14:38so now that we have access to taking this yeah I will say this the short answer is
00:14:45even when I discuss this with the world's experts on this topic which I've had the privilege of doing in fact I have an entire chapter of my book is devoted to caloric restriction of rapamycin and sew in hours and hours of interviews with these with these folks it's clear to me that we don't exactly know what the relative contribution of the different things that rapamycin does to its longevity so maybe I'll start from the beginning by saying
00:15:13if you look at the administration of rapamycin across about a billion years worth of evolutionary animal models tone everything from yeast to worm-like C elegans which is a model worm freeflys mammals meissen dogs and things like that this this compound seems to universally increase wife never seems to disproportionately do it in females over males but the question then is why so what do we know that rapamycin does so
00:15:47the number of people but I think David sabatini probably deserves most of the credit in mammals though Michael Hall had done this first and used elucidated the relationship between the molecule and the protein that it was targeting so when when you take a molecule you know whether it be vitamin D or biscuits rapamycin they're generally binding to Something in the body and when they bind to Something in the body that usually kick off a response what were they going for what I should say they're buying into something so there's probably lots of things that you could take in the you know if you if you ate a piece of sand or silica presumably wouldn't do anything that would go out there but I think it's biologically relevant is going to exert its exert its effect by binding to either receptor or some epitope or no triggering some enzymatic response
00:16:47the body for this Divine to sew rapamycin binds to a complex it's not really just one thing but it's a complex that was eventually named cuz initially had a different name that was eventually named mtor which way back stood for mammalian Target of rapamycin but today stands for mechanistic Target of rapamycin so where is mtor in the body in the stomach is it actually does there's got to be some cells that probably Express M12 lot last but
00:17:28tight I can't think of an exception right now so I would say every cell to some extent Express is on 4th July take a pill of rapamycin I swallow it down and break some of my stomach and hits the cells and it binds to these cells my stomach has to get inside the cell first okay so the receptors are not actually on the surface of the cell so for example some things that you take work by binding to receptors outside the cell but most things have to make their way into the cell and an even easier example of explaining this is looking at something I think most people can understand more quickly which is the relationship between insulin and glucose so glucose obviously has two common ways it gets in your body the first as you ingest it you eat something that gets broken down into glucose but at least as much glucose gets recirculated through your liver so your liver is constantly spitting out little amounts of glucose right I think that's the single most
00:18:28appreciated function of the liver that's a separate story this is why you can be fasting and still have glucose in your blood actually this is why you and I are able to sit here and have had this discussion for 12 minutes and not be dead so I did the calculations somewhat recently at my weight which is about 80 kilos or 81 kilos and my blood volume in my blood glucose I have about seven minutes worth of life in my circulation before I would die if my liver couldn't make a constant drip of glucose but you're right so certainly when your fasting but but truthfully for any human once they're cut off the umbilical cord function of liver is essential for life with respect to that okay so now the question is what good is glucose if it's floating around in your bloodstream the answer is not the bloodstream is simply how we transport the glucose from you know one place to another it has to get inside the cell and every cell in the body can you lies glucose so it's either one of us important fuels
00:19:28imaginable. Let's take a muscle cell for example cuz that's they think the easiest way for people to think about muscle has two ways to get glucose into it one of them does not depend on insulin and one of them does let's just focus on the ladder cuz That's Amore well understood this hormone called insulin that's made in a totally unique part of the body called the pancreas in a particular cell within the pancreas or cluster of cells it binds to a receptor on the surface of a cell this is one of those times where it's buying into the surface outside the cell that triggers off a chemical reaction inside the cell that shoots a transporter up from the inside of the cell across the membrane and its sits there fixed across the membrane is it touching the insulin or is it outside
00:20:28when you can draw the picture so you have this insulin receptor that basically you know gets triggered by insulin that triggers a chemical Cascade inside the cell that leads to the release of this thing called the glute for transporter which is like a think of it as a tube and the tube gets shot up from inside the cell or it's called the cytoplasm through the membrane of this cell and now glucose can freely flow in kallang its gradient because the glucose concentration is higher in the bloodstream than in the cell
00:21:03no with many drugs you you are actually able to get the drug into the cell quite easily that they're small enough that they get in quite easily and their targets are usually somewhere inside the cell now if you take you know I totally extreme example if you look at a class of drug called antisense oligonucleotides or Asos these are drugs that quite easily make their way into the cell and they have a very specific job of getting not received this album to the nucleus where they disrupt the process of the cell. Trentino transmitting information from DNA to RNA so they block that so that the cell can't make RNA of the DNA that can't make this thing so I talked on the podcast a lot about LP little a and how you know somewhere between 1 and 10 and 1 in 5 people are too high a level of this which ones are at risk for premature heart disease and this class of drugs are attempting to block the creation of the ape a little a
00:22:03eliminate this particle all together by doing that so that's an example of a drug that gets all the way into the cell then into the nucleus and then it's job is to actually block this process of turning DNA and RNA to make a rapamycin what rapamycin does is it binds to the protein that is a bigger butt is a piece of his bigger complex called mtor and it deactivates so sometimes when you buy into something you make it go more active some of the insulin receptor when insulin binds to the insulin receptor it's activating something to put in the case of rapamycin inhibiting
00:22:40Navistar gets a bit more complicated cuz they were really two ways that mtor gets organized one question now so this is lettuce a you take a dose of this how much I mean you said that every cell right descent or like how much of this is actually getting affected then of your body is just a small subset I must be right I can't go all throughout your body actually is systemic I think the bigger question is
00:23:07Rh are all the cell's equally susceptible to it for example is the mtor in your liver being equally turn down is the end tour in your muscle or the mtor when your fat self we don't have the answer to that I don't have the answer to that I mean I think there is probably some data and animals that would give us some indication of that but I can't promise I can touch the top of my head that I know the differential expression or activation in or lack thereof but at the same time me to rapamycin was approved in 1999 by the FDA for a totally different indication which is for immune suppression so organ transplant things like that that's right yeah so you know heart transplant liver transplant kidney transplant patients immune system suppressed only using the most egregious type of corticosteroids you know drugs that are a totally blunt tool for blocking immune to the immune system and of course rapamycin
00:24:07is a multi-generational later drug that has is it's much more elegant at suppressing the particular part of the immune system that is is responsible for turning off him for that it doesn't listen to me when I most interesting questions is because you know when I first became obsessed with rapamycin end for which I realize I haven't fully answer the question yet on what it's doing the Paradox that I couldn't wrap my mind around was how is this drug which you know 20 years ago you know where maybe whatever 17 years ago when I started my residency we would give this drug to all these transplant patients I was very familiar with rapamycin and it only considered it through the lens of immune suppression
00:24:47but then in 2009 all of this new literature started exploding so 10 years later that was saying oh no this is this is like extending life and not subtly like it's it's not a subtle extension of Life how can something that blocks the immune system extend life right now I think we got our first insight into that in 2014 when Joan manic who was there to Novartis and is now at a company called restore bio published a paper looking at an analog of rapamycin called everolimus and they showed that certain dosing patterns of either very low doses daily like 1 mg or weekly dose is at higher doses 5 mg into ml
00:25:33did the exact opposite at least in a model which was they gave us to humans for something like eight weeks then wash them out then vaccinated them and if your immune system is weaker you should have a lower response to the vaccine but they actually saw the opposite these patients who are all 65 years old and older actually had an enhanced immunity is it because you hit the immune system it beat it down and then it comes back stronger very good question and so I don't I don't know the answer that guy could be one mechanism wear cycling it is what's creating an immune response it could also be that at that you're hitting a certain subset of the immune cell at this lower infrequent Oso through the cells called t cells which are you know what the most important cells in this type of immunity where the body is policing what is self vs non-self is this the killer T cell that we've heard about it over the years like well then the girl
00:26:33the CD4 T-cell there there are a whole bunch of different ones but there's a subset of those guys so so the CD 3 is how we Define the T-cell but there's one that also carry something called cd25 and that's a regulatory T-cell and so turning on the immune system happens when you turn off the regulatory to another hypothesis which are actually hoping to raise money through like Star podcast to fund some of this type of research cuz I don't think anybody has looked at the selective effect on the regulatory T-cell of rapamycin so the hypothesis the question I want to ask is Dos rapamycin in certain ways are you selectively targeting the regulatory T-cell which will actually ramp up immunity and maybe the dose of N2 are the doses that we were giving patients back on the transplant Ward just
00:27:25indiscriminately whacked T cells so as you as you see by the nature of the question you're asking like you know there's more things we don't know then we do know but the point is that that man of paper in December of actually work coming up to almost four years since it came out December 2014 that paper was like the moment I became obsessed with rapamycin you know prior to that I was super interested and then I became obsessed because that said to me that the one thing I'm most afraid of seems to not be the case under certain conditions on the other thing that people would tend to be afraid I would like she goes back to your question by the way and torque and organize itself in two ways it can organize itself around a protein called Raptor and if it does that it's called M4 complex one and it can also organize itself around a protein called Richter and if it does that is called into a complex to
00:28:18it seems that most of the longevity benefits happened when you inhibit mtor complex one but not enter complex to see organize itself around what do you mean by that exactly like these protein is more than one protein and they're sort of like you know confirmation Ali like bound to each other so they're done covalently bound to each other mean they don't have like super strong you know concrete bonds holding them but they sort of wrap around each other I say and when what tends to happen is like you know a molecule like an amino acid for example will hit one piece of it and then that will trigger the movement, the conformational change in another piece and then that will kick off a signal that goes you know down and down the pathway it's his inhibition of M4 complexed that also seems to produce some of the other unintended consequences of rapamycin which by the way there's some debate about so most people would say we'll get a drawback of rapamycin is it creates insulin resistance you know these patients that were
00:29:18rapamycin seem to have a higher incidence of diabetes and Berlin who I would consider probably one of the only two to three people that I think knows more than anybody in the world you're mine has always called out of the question that you made a good point which is if everything we think we know about rapamycin is based on a transplant patients were we don't know that much right because those patients have a lot of other issues going on and they're never just unwrapped of mice and they're on rapamycin and glucocorticoids and MMF you know we also have to sort of say maybe we're starting from scratch here like maybe we really don't understand in Inhumans how to dose this be in DOS or frequency to produce that resulted in theory what you would want to do is inhibit them for complex one without inhibiting mtor complex to so what is the result when that happens again Road ends and now I never seen any results in humans like
00:30:18restore by a witch is this company that I bet I know nothing about this company I'm not involved in it anyway so I just know what sort of publicly available and they are a public company so I've seen their presentations and you know all the stuff that they presented during their IPO I was followed that with interest they are using something called everolimus because I said it's basically rapamycin and I can't quite tell but I think they're also combining it with another class of drug called iPic kinase and they're replicating the works at Novartis did so John manecke who led their work at Novartis is now at restore bio and they're going after different indications to if you're going down the path of drug development you have to have an indication and Longevity cuz he's so it's hard to develop a drug to treat something that is not a disease and secondly that's a really high bar to clear takes a long time to show that the drug can make you live longer so instead of focusing on things like pneumonia
00:31:18in an ideal world is the everolimus study for Novartis can be reproduced you should be able to reduce the rates of pneumonia in elderly people do to the Boost in immune function correct and so it would almost be like a foreman in that way then it would have a primary prescription for one particular thing and they actually have the outcome be longevity are currently available by prescription so you glad you could technically use either of these off-label what I did was not approved for longevity find it very soon led by nir barzilai and his colleagues is also going to look at some of these other more longevity based metrics and I believe someone will can look this up in and get much more accurate data but I think we're store biohaze
00:32:11come up with a number of indications are looking at that are much shorter and easier to measure and clinical trials and obviously longevity is the ultimate goal to produce a version of this that you know will be sought in Mass markets on label for that purpose you know perhaps but to your question so what is what is rapamycin do so when you turned down mtor what are you doing it seems that you are mimicking what happens to a body when it is a nutrient sparse environment so when nutrients are well and taxol it more complicated as which nutrients I would say the simplest way to explain it is mtor is probably the best thing we have at sensing amino acids amino acids are the building blocks of proteins now there are two amino acids in particular that are really important when it comes to nutrient levels the first is the amino acid that seems to be most sensitive to activating
00:33:11mtor and that's in amino acid called leucine which is one of the branched chain amino acids most people who listen to those who have you know who are into fitness probably know that you can buy branched-chain amino acids it a health food store whatever and there were three of them leucine isoleucine and valine and as their name suggests are branched chain so they have a side chain that's branch on them and that's why they have that name and social I think the fitness or bodybuilding Community was wise to sort of realize there was something about branched chain amino acids that were really valuable and if you want to grow your muscles you had to have a lot of these things in you and mostly a sham so most acids are bird feathers concentration of these things there's only a handful of companies that there's only two companies I'm aware of that make a legitimate branched chain amino acids are ones we asked me this now with it with a shoe company
00:34:11and they are the original company that they created that true you know Pharma grade branched chain amino acid and the other is a company in Canada called biosteel other companies so someone's listen to some Same Old you know how how do I buy the stuff lots of companies I believe are also now selling branched chain amino acids that contain amino acids provided by a motel by basically if a patient comes to me and says hey I want to be a branched chain amino acids I'm putting them on biosil cuz I think it's the best product out there and if they keep for some reason can't stand the taste cuz truthfully I don't like the taste that much myself at a little too sweet I say well let's just look for something else that at least has imagine about a stamp on it so that we know it's coming in with the right stuff side quest on that though like we used CDs this just for my workout days like 10 5 1 or whatever these different ratios are BCAAs are what do you recommend I lift weights
00:35:11who was the first author on this paper and I think it was in September of 2015 and September 2016 they actually found the leucine sensor on mtor I mean obviously the most exciting work on a tour and wrapping my Santa's coming out of David sabatini's lab which is like a Powerhouse for the stuff may take a 20 brightest postdocs in the country who care about this problem that's where they're going to go to MIT and that's where they're going to study it so not surprisingly that's where they actually demonstrated this so the short answer is do any of the other amino acids even matter is it should you just be taking Lucy and I don't think we know the answer a couple of issues one is Maybe by providing some of the other brands chain amino acids you minimize the Scavenging of loosing from a clinical perspectives if you take out. If you know what you know someone who's being trying to just get bigger muscles would care about the other problem is these amino acid don't stick around that long to the things you shouldn't have to nurse this amino acid mixture
00:36:11how to work out if you want to be hitting that loosing sensor all the time and presumably other people are going to eventually try to come up with analogs of leucine that are much longer-lasting that could you fight off conditions like sarcopenia which is your muscle wasting as you get older so loosing is so clearly essential to turn on mat for a 2-3-2 turn on mtor but the interesting thing is when you fast you're loosing levels don't go down to the body is so good at keeping loosing levels at a regulated level but even when you fast it will create loosing out of other amino acids but so you don't you don't need to do a supplement losing if your fasting that's correct you don't need to supplement lose if you're fasting but if you do need to supplement if you want to grab me by the need is a strong word if you want to Stack the odds in your favor of gaining muscle you should be adding loosing to Lucy insertive always maintains a certain level but if you want to put on muscle you actually
00:37:11to go above and beyond that contrast that with another amino acid called MiFi any which I think he probably talked about Auctioneer podcast when you talked about fasting science very different animal finding is probably one of the amino acids that we are most sensitive to when we fast another word when we fast the first thing we'll see if one of the first signatures you'll see is a reduction in the fining so there's also something pretty special about Miss America and I'm poor and basically when end tour activities turn down the body is more likely to undergo this process of Papa ji Mai tawhiti we also think there's anything wrong with it is real quick for people that don't know if you look at it from the derivation of its words autophagy so Auto is self AG is eating so this is a process by which cells eat themselves and if you listen to that you're thinking of why is that a good thing under the right conditions it's a very good thing it's a very good thing
00:38:11if you can selectively take the cells that are for devil cancerous dysfunctional have defective DNA in them something like that and get them out of the circulation you can recycle other parts that they have their valuable that we have cancer cells in our body all the time right are we do from time to time before it's really scary makes you I mean I did my post talking to me knowledge e and end with an immunologic answer lab and I think I was just wrong for that because of the it just have humbled I was by how much are immune system is doing like yeah how often it is winning you know it's it's sort of like you could compare to Homeland Security right people. People don't really care much for Homeland Security right that you don't realize like almost every minute of every day it's winning right we we learn about it when it's when it doesn't write like you know
00:39:11there's not a lot of side and you know good at your job in certain jobs in the immune system's one of those things where it's like a it's a it's a thankless job that is remarkable in system is virtually all of the time recognizing cancer as non-self and terminating it and unfortunately the times that it doesn't is when we did go on to develop cancer so they can click the wrong the reason to fast is okay I get to go in and then clear out some of these potentially sells it would have the potential of turning cancerous is that is that right but what it has any agent I think it's other pieces of a tooth so
00:39:52view with a biopsy your leg took a piece of muscle out of your music a little chunky or vastus lateralis out of the side of your leg today and let's take a picture of time machine I could take you back 10 years ago and I could do it then and I could put you in a time machine and send you forward 10 years and do it again do you think I could under you know with with the right laboratory equipment figure out if they were randomly sampled which one was 10 years ago which ones now and which ones I think it would be one of the first things that would actually tell me will you would notice I have read of mice in my blood inflammation the biggest difference I would see between you 10 years ago today at 10 years from now is you will see an ever-increasing amount of inflammation in your muscle muscle well you would see sort of the cytokines that the show up in the other inflammatory cells that are there so you'd see more macrophages or you know whatever the immune cell disease or is he know my sites that have
00:40:52monocytes have differentiated you'd see more of the chemical signals and inflammatory cells use to speak to each other and so you probably heard this term before which is inflammation because information on Aging are so tightly wound together and a very interesting paper came out in the last 6 months that shed some light on this so
00:41:16if it take a little bit of a detour to understand why this is relevant so I want to give the punchline first one of the other benefits of low nutrient States temporarily and or rapamycin which in a pill basically delivers that is very high set a table veggie is like the self-heating selfie while there's a comprable process called my cough Ajit basically recycles mitochondria takes mitochondria that installs damaged and puts them in the lysosome which of these little digestible balls of enzymes that like you know get them out of the way basically recirculating so if I go into yourself into your nucleus you have your DNA you have about twenty thousand genes in your DNA and you got those from your parents both of them and amazingly they have their own jeans as well and I spoke about this in detail, the canoe adoption doubt on my podcast one of the episode summer recently
00:42:10and the mitochondria Richard because I have I think it's 37 jeans and what they're all maternal she got them off of your mom but which is interesting in itself but the thing that's really interesting is why the hell did they get to keep all their DNA like why didn't why do they keep those thirty-seven jeans and not just throw them all into the nucleus where you have far more protective mechanisms of them
00:42:31but one of the things we know is that mitochondrial DNA is bacterial in origin does a very important point right so you were human DNA is human the DNA in a nucleus looks like it came from a human but the DNA is 37 little paltry jeans in your mitochondria look like they came from bacteria crazy crazy is what happens if any of that DNA gets out of your mitochondria into the cytoplasm I feel like we're starting the movie here like or something's going to like yeah kill us in your body system looks like Curious bad and I'm if I quit the immune system is really trying to do is recognize what's not self evolutionarily it's way easier to know what self is and then kill everything else forces learn to kill everything that's not self if that makes sense yeah hypothesis for a while but one of the reasons that we see
00:43:27increase inflammation with aging is that as we age we get more mitochondrial breakdown and has more mitochondria breaking down maybe that's a listening and response and a really elegant paper demonstrated this by giving so I can't remember what the model was it used but no Cersei took animals and exercise them and you can exercise to the point where it's to hard restart your breakdown mitochondria's of the mitochondria like anything else in the body will start to break down if they get too hot but the mitochondria probably a bit more susceptible to heat because they're generating so much ATP it says everybody else's the cortical Powerhouse of the cell so there's this molecule called sting sting and it blocks the body's ability to sense mitochondrial DNA
00:44:16so if you took two groups of animals and you exercise the crap out of them so that they burned up their mitochondria and started to shoot at mitochondrial DNA through their little damage mitochondria and you gave one of them sting and the other one a placebo and the one that got sting had no inflammation which is what ended up happening you would have much more confidence in the hypothesis that some of this aging inflammation response we seized due to mitochondrial dysfunction ultimately break down and a well-intended immune response to the damage mitochondria because of course he thinks it's bacterial crazy so if you can mitigate that process by taking of mitochondria out of circulation out of circulation putting those guys in the lysosomes that would be a great stuff you could take so you by putting them in wrapping them in this would be called liposome lysosome then they're not out of the game
00:45:16Nazis bacteria so they don't trigger there at the information basically I know you got a lot of fasting so many of my patients done with my fasting at this point I mean generally one of the things that people experience is just a reduction in inflammation when they fast even even the timer for shrimp and Junior 4 a.m. to fasting we see reductions and inflammation so again is that because even something as trivial As Time restricted feeding is kicking off enough my top a g and a half a g I'm not sure but certainly at the level of you no longer water fat water only fast sand or the use of rapamycin it seems to be happening so why not just take a little bit of this and every once in awhile just a little floater in Friday night's just dropped
00:46:16admit there's no downside
00:46:28Tim it's funny cuz he keeps a running list of like his favorite attia isms and he basically asked the same question and I was like upside down side and I said we'll look I think that the following three things have to be true if you're taking the correct dose of rapamycin one glycemic response should be unchanged or improved we shouldn't get worse for taking too much of it right it should get worse but you're dating the right decision secondly immunity especially innate immunity is T-cell driving me and you should get better not worse and 3 etapa G should increase there's no way to measure that not yet so so temperature the information should be flat downright reactive protein
00:47:28recite a kind what you can do nowadays you can do that commercial everything I want I also saw you out there tell me I look at every one of them TGIF and then presses factor means look at everything and basically what I said is I'm not worried about taking too much I'm worried about not taking enough and Temple that was the funniest thing ever but it's the truth right like the other thing we didn't talk about is the most obvious side effect of rapamycin is a plus ulcers in the mouth sores behind yeah yeah by the way every time they seemed to be not much worse when you took 5 mg once a week vs 1 M everyday but a 20 mg once a week vs 5 mg once a week you got no benefit you got no immune benefit but you have more side effects
00:48:28suggested to me that there's no benefit in taking 20 mg once a week you're better off at probably 5 Mac heaberlin who I've had on a podcast as well has done to me by far the most interesting work in models closest to us with his companion docks and there if you extrapolate from the doses that they're giving the dogs it seems that you know I don't know for someone your size are my size it's it's sort of in the four to six maybe eight mg dose range the frequencies a bit of a tough question in Matt's experiments their dosing it I believe every other day or every third day
00:49:07we could you clearly need to do this in a pulsatile fashion I guess I shouldn't say well because you don't want to trigger the inhibition of them to work to and what happens is if you constitutively give meeting if you everyday give rapamycin you don't allow tour to be recirculated and therefore it within a couple of days of doing that maybe even within two days of consecutive dosing you start to inhibit the creation of mtor too complex to have a pretty good handle that that's not what if that's not a good thing I'm not going to get the dosing too close together gets back to the ER is Anna Faris likes which is I don't want to do too little of it either so I don't know if you want me to guess what the right doses I would say it's five 2
00:50:007 mg of 426 mg probably every four to seven days is probably in the right dose but shy of having I think an insight into the you know call it the signature of etapa G light APA G maybe even other things that are more interesting eye inflammation we talked about certainly but maybe things like you know a progenitor cell function senescent cell function you know that it would I in interviewing mat for my book and he also thinks it was reasonable evidence to suggest that another benefit of rapamycin is inhibiting senescent cells can you explain what those are ya senescent cells are these cells in our body that basically are Bad actors let's say you have a muscle cell and its you know it's a perfectly functional muscle cell at senescent muscle cell would come along and deactivate that or make that sell less effective so the senescent cells seem to be reprogrammed cells did theirs dicks
00:51:00you know I haven't actually there's one person I want to speak to about this hoochie Rhonda's interviewed her name is Judith Campisi she's the buck Institute and she certainly I would say one of the three people that knows more about anybody else and it's been so long since I've actually heard Rhonda's interview with her I don't know if they get into the telia logic reasons for this cuz sometimes you ask yourself like white technically there is no reason we need a puppy or LDL particles so it's still a bit of a head-scratcher and similarly like why we need senescent cells so maybe someone like Judith a Rhonda wood would know that I don't know the answer why we have them so yeah they generally just fit into the dick category
00:51:47where how far away are we from from am I taking this and in Inhumans like when when do we when do we get you know actually license to go out and have her doctor prescribed this Suite 10 years out legally efficient can write a prescription for this anybody can take it now so I think the question is what we want to see to know that we're not taking too much or we're taking enough I again II
00:52:14you know I'm probably a I have a higher risk tolerance in most people right so I mean you know I take rapamycin but I have never written a prescription for it for another patient how do you know if you're impacting your immune system I mean you're in New York right now I'm like walking around see people cough I'm thinking like totally confident that the dosing that I'm using is congruent with all of the data that I've assimilated over the past four years and speaking with the smartest people in the world in one finger have more brain power than I have in my entire body so I feel like
00:52:56I feel some degree of confidence that said I also had been through waiting on the sidelines for a couple of years to take it hoping that I could you know fun some of the research they would develop these assays to figure things out and then I kind of had this Epiphany which was like wait I can just tap house till I start taking it cuz I'm young 95% is my first time publicly declaring us I didn't want to bring it up dodging the question that's awesome wow. Heading over two months now for the first two months I had a mouth sore I never went without one so I would have it and as soon as one got better a new one would form and I remember thinking
00:53:45well it's kind of sucks cuz I'm only taking you know at 5 mg what is a dose that in the studies you know a relatively few people had these things but I was like I can deal with this like okay fine so they just stopped wow and I haven't had one since so I don't know if there's an adaptation. I don't know what to make of that but I've never had an abscess also since residency so you know like I'd gone what 12 years without ever having one of these and then boom I had like two straight months of them how's your glucose levels everything good thing I noticed a difference and so my suspicion is that if you're such thing as a physician in New York who actually quite liberally prescribed rapamycin and I talked with him a lot because he's also one of the other guys that I think is you know Siri interesting in that he's got probably the most clinical experience with it and so
00:54:40when I spoke with him for the first time which is a little over a year ago maybe was two years ago now I was really pleased that all of my calculations based on all of the animal data almost exactly the prediction that he was using clinically so I when I said to him you know I believe it needs to be this toast to this dose given to soften to this off and how do you do it and he said we do with this tune is this to this the overlap is like 90% I think based on what I've learned from him the worse your glucose levels are starting out the more of an improvement you can get crazy at so I think you know patience it like he has patients that are like losing weight on it and you know having all of these sort of benefits from it amounts insulin glucose levels are improve hemoglobin A1c is improving all these sorts of things but again his patient populations different from me and also different from my patient population died which is the most my patients are actually quite insulin sensitive and if they're not we're going to get them here quickly
00:55:40is starting out with much more metabolically ill patients it seems so but I put it on that very interesting about your blood levels anything change
00:55:50I'm assuming your informational markers were all fine. I haven't done I want to wait another
00:55:58oh God couple of months before I do and I felt like I needed like you know six months is under my belt to really and I think I'm only three months and now so if I want to wait another three months and do another big battery testing but what I really want to do is you know get an IRB in you know what you know and why you were on site or one of these places and actually start you know doing small and of 1 experiments to to start looking at this sort of signature of a kapha g light APA g&n maybe come up with you know better angles because
00:56:32that you would want to do in concert is at least I think as a positive control is do all of that sampling during one of these long fasts that I like to do cuz I don't think that's going to produce the exact same phenotype meaning of talking to produce the same look and feel as taking rapamycin but there must be things that are overlapping there it's it's quite an interesting data science problem because I don't think the answer is going to jump out and I don't think you're presentable one I've talked about when I fast my uric acid goes through the roof and then there were two pretty plausible explanations for that but only one of those would have to do with the top 50 someone explanation is the more you break down ribonucleotides and we break down RNA you you could certainly expect to see uric acid go up
00:57:19that would be congruent with more Itachi another explanation is that uric acid and beta hydroxybutyrate or acetoacetate I think compete for the same transporter in the two maybe when your fasting because your ketones are so high your eyes out competing uric acid maybe that's grabbing my ass and so
00:57:45I guess I'm sure somebody listen to this thinks I'm an idiot and that's understandable because everybody has their own tolerance for risk but I'm very comfortable with what I understand about metformin and rapamycin and I think that me and my risk appetite and everyone has a different level I think the risk of not taking it is higher than the risk of taking it but
00:58:07you know one of the great mottos that I've learned from one of my patients who runs a hedge fund what you think it's like serve a great mantra for investors is strong convictions loosely held and I think the same as absolute ruin medicine so just answer reserve the right to change my mind any minute any day you know I mean think about the four years you and I have known each other how many times have I change my direction on a supplement or a drug or point of view so this is how I feel today I have a very strong conviction but it is loosely held that has different data merge I may decide to stay or I need more information or what not measuring cardiac function in dogs is that right there on rapamycin and have you done any of that now that we've been a really interesting thing and it's funny you bring that up I don't think I would have shown enough of the benefit so in Matt's dogs what they were doing so as soon as you know being a pet lover especially the larger companion dog
00:59:07they're basically going to die from a handful of things that are quite predictable as we talked about memory we talked about putting toaster my dog on your die in accidents or be euthanized or they're going to die from heart failure every different heart diseases they get dilated cardiomyopathy so their heart muscles stretch out and the more heart muscle stretches the more it loses the contractile elements that that allow it to have strength when it contracts oh the things get stretched at some point you go too far and that to the heart becomes dilated and it becomes referred to as a dilated cardiomyopathy so one of the questions that Matt Diamond think Matt was directly trying to figure out the effect on this I think it was in his first study which was just a toxicity study so very shorts that you like 12 weeks and the goal was to figure out like let's make sure we can give my son his dog
01:00:07diaper rash with a confirmed what was interesting was they also improve the ejection fractions of the dogs that had already shown signs of cardiomyopathy and again I talked with Matt about why he thinks that might be the case you know I talked with you my idea how much and my talk with you within the cardiac myocytes maybe is allowing regeneration of some of these cardiac cells that now disproportionately are out competing and outweighing the sort of defective ones and maybe that's what's allowing this but if you think has been profound mean that we talked about a 10% Improvement ejection fraction that was seen in these dogs and that's yo to put that in perspective so today I had a patient who needed a cardiac MRI for a sun related reason I was pretty sure he was healthy but I wanted to look at something very very specific and the ejection fraction came back again 62% that's a perfectly normal ejection fraction fraction it means what percentage of the blood gets sent out of the heart through
01:01:07aorta every time the heart beats at rest 60% is a perfectly reasonable ejection fraction when you're under great stress meaning when your under great aerobics dress if you want a treadmill are doing a stress test we would see that number go up so that the hard at the hardest squeezing harder pumping harder and of greater percentage of the blood is getting out then that that's not do today in Crescent Beach for a minute it's due to the VA in and out two separate things yet measured in liters per minute to how many liters per minute of blood is exiting the heart and you're basically you break out into two variables beats per minute and ejection fraction and so both of those ago up under under stress and it's interesting both of them go up so much they didn't have a super super well-trained athlete the increase in
01:02:07cardiac output from like completely being at rest to max out can be 20 x through both a combination of increase ejection fraction and increase heart rate certainly 10 to 12 x and even reasonably well trained athlete so if you're walking around with an ejection fraction of 20% at rest vs. my patient today who is call at 60% at rest the person who has an ejection fraction 20% rest doesn't have a normal life so you and I when we came up here till we walk up the stairs we walked up three or four flights of stairs to get to my apartment right now they're not doing so you want her to think about what would your life look like when your ejection fraction goes below 20% it's not the wife that you are I live in Frank least not to like most people want to LIT most people say like I don't want longevity without yeah I mean that's actually what was going to be my final question about rapamycin was on the cognitive side let's say Okay Peter you nailed that man your delivery 1:30
01:03:07at what you know like are you getting any benefit on the in the brain side as well I think it's a bit too soon to say we actually did an internal document on this and I would say that right now there's probably still a paucity of data it's actually I've had patients you know say to be like hey I want to put a little bit of money into some Alzheimer's research what's an interesting topic and my view is don't find anything traditional you know like to put another million dollars into an amyloid beta or Tau antibody is not a great use of funding because like it's one more million into a pot of billions that is as far as I can tell doing nothing right if someone had $1000000 burning a hole in their pocket I'd want to know what happens if you give rapamycin two people in the earliest stages of cognitive decline and the reason I think you have to do that as you can if you just take a bunch of normal people it would take too long to follow them to see if there is a difference I think what you need to do is identify high-risk people so people people with one or two copies of an 8 Bowie for Jean and
01:04:07strong family history who are just showing the first objective signs of cognitive impairment so this is exactly the type of people that Richard Isaacson at Cornell studies and you know I want to know what what is a what is an RCT look like a rap of versus Euro rapper + best of Lifestyle versus placebo plus plus best of Lifestyle for that and I think you would get an answer to that in in a year so to me that's a very interesting question and there's definitely preliminary data that suggests that it in certain models that the rapamycin is also improving or I should say delaying the onset of cognitive impairment have you noticed anything like the nootropic wise in your own nothing I have not I mean set up amounts of something about her liver have a month's yeah yeah really nothing at the end of this year
01:05:07I don't get a cold every year but the get I think that's it's hard to make much of an inference I also live in a Petri dish so yeah I mean I think I want to get some muscle biopsies done I want to get some fat biopsy. I want to get some super hardcore biochemistry done in and really start looking at the stuff I guess I'm just a huge when I'm like almost an old guy I wanted to go through just like a quick rapid fire cuz we spent a lot of time on rapamycin but I want to get your take on a few things I don't do rapid fire anything I don't have a bone in my body I heard any podcasts all the timer for 60 seconds that was so miserable as I could how how far we in how many minutes I don't like an hour to meet your time yeah let's let's get through a few days so are combos for preventing diabetes
01:06:07it basically prevents you from absorbing glucose so it comes out if your you know your your your stool he has a quick version of that is I can take one of these I go eat four slices of pizza and I don't see my glucose Spike that's right so it is that preventing diabetes then I don't know that it has been studied formally is a diabetes prevention agent but it is a very efficacious way to lower glucose and it's certainly one if I would consider 15 drugs that I consider super interesting yeah it's like for me when I'm on that line of like pre-diabetics of him to wake up in the morning on my Tammy why is my blood sugar at you know 105 or 110 or whenever you know what they get a little worried is cortisol you have the same problem I do which is too much cortisol at night means too much glucose in the morning you said recently it's kind of why I'm struggling to see the evidence for and I just got an email from one of those head Physicians of the professional team the other day
01:07:07I heard you talking about this you know we've got all these players going to go get these things and you know they're there really aren't effective Transporters that bring NAD into the cell so giving intravenous NAD while everybody I know who's had it done says the same thing it feels horrible to say they get nauseous you clearly feel it I don't think that means it's doing what you think it's doing which is you have to believe into the cell into the mitochondria Alters the ratio of NAD to nadh of complex 1 and activates a certain like that's a huge stretch my mind there is no evidence for any step along that chain reaction is increased blood plasma levels of its of it right not ever actually getting into a Sal interesting is giving n a d precursors either intravenously or through routes that can go around the liver so nicotinamide riboside and our or NM and which are precursors to NAD
01:08:07I think we know is the cell has to make its NAD so you want to give it to sting at uses to make in it because it could bring that into thinking that actually taking I would potentially work well I mean one study that has looked at this most rigorously found that it didn't do anything because it couldn't get past the liver in any significant amounts so the NR got taken up by the liver and made into NAD they're out your liver stopped but that's not really what we're really going to hit the muscles that explains my awesome list so so but I think if you could you could introduce to intravenously give an r or n a man I think would be very interesting and that to me is the question that you could deliver it to get past the liver how else would you do you put on the tongue for example I can't use it if you could if you could create it in the dissolvable lozenge that we go straight into your circulation directly like a Nitro
01:09:07someone or something like that Kirk human human is one of those things that I've been four years ago is not on my radar I was not particularly impressed I thought it was all a bunch of nonsense but I think there's really some pretty good day. Hunter humans anti-inflammatory benefits and in particular so much more compelling data on a particular formulation of a Caldera cumin which at least in Racine actually improvements in cognition in high-risk individuals with it so that might be due to better absorption that are bioavailability and might be due to a slightly different formulation but certainly the makers of Thera cumin to figure this out because the Arbitrage on pricing between curcumin and cumin is staggering it's insane you take it like three times a week what are you doing what's the protocol for that I'm actually taking curcumin just once a day and I'd honestly like this is one of those things that I've just been so busy thinking about other problems I haven't thought about this much lately as should I be switching to etheric human I guess I'll
01:10:07instrumental very high risk I mean my echo is 33 and have a family history of ADA Cheapskate though I just kind of pissed when I go to Amazon and I see you like I can by the pure encapsulations curcumin which is a really good marinade a bottle for you
01:10:31is man Yugi okay yes how do you manage stress what do you deal with a lot of hedge-fund guys Tech guys like how do you get people that are under a ton of daily stress how do you distress them I don't think I think if you were to go through all of the
01:10:59what I think are the five interventions that we have control over that can influence longevity one of them is nutritional biochemistry so everything about how you eat when you eat you know. Her research and Clarke fanfiction passing the second one is everything good with exercise physiology third one is everything to do with sleep physiology 4th one is everything to do with managing hypercortisolism Mia which is just a more technical way of saying Straz and in the fifth one is all of the Exotic Miss molecules you can take drugs hormone supplements if I do a siren assessment of where does Peter attia stack up on those five pillars I am by far failing the most on the Amanda hypercortisolism I just don't think I am exceptional at that or even as good at that as I am at the others I think it's really hard but like you never even talked about this earlier today I think meditation is van with the best tool and I have found mindfulness meditation to be
01:11:52especially valuable because it's less relevant to me when I'm doing the practice and more relevant to me when I'm in the situation that is distressful so the way I do you think about this is not can I reduce my stress like I've chosen a profession you've chosen a profession that the people listening it's a chosen profession is going to create stress is going to compose stress so instead what I'm interested in is how much can I tolerate distress that's that's the question is how do I create a big enough Reservoir to enhance distress tolerance and that's really they pick up the question so obviously all these other things matter like when your nutrition sucks like your resilience goes down when you haven't slept when you know all these other things are not working in your favor those things suck but you know how to help with Sam Harris who is for me then probably the best teacher on this table yeah he's got a great course in his app
01:12:52and also I just think like I think there are lots of great teachers out there there's so many great meditation teachers and I've been taught by several but it all comes down to like to explain something in in in a way that you can listen to it and I just think that the first time I really learn this stuff from Sam and spoke with him at length about it it really resonated and it's when I realized that it's it's not about the state of meditation it's the trait of the discipline of the practice of control and I think about and so the other thing I think about a lot and I'm people probably heard me talk about this is you know David Foster Wallace gives his beautiful commencement address in 2005 at Kenyon College called This is water and you can find this on YouTube it's a 24-minute commencement speech I've downloaded it is a you know use the YouTube to MP3 converter so I have it sitting on my phone and I listen to it at least once a month and sometimes more often when we're done with this or listen to this before you leave sweet
01:13:52it is it is imperative and you it and you have to listen to it like three or four times before you start to get it and now I Know It Off by heart and I'm starting to get it you know it's real I mean I'm starting to fully internalized what he is talking about and so I guess it's a long-winded way of saying I think it is a journey and I think everybody struggles with a different thing for some of my patients exercise is just so important to them that all of our battle is around like how do we create at least a minimum effective dose of exercise to get the benefit and for other people you know for me this is the biggest challenge for some people food is the biggest arms they can't imagine that I have patients that convinced me that they can't go 12 hours without eating even though I try to explain to them that evolutionarily that's impossible like our species wouldn't be here if we could only go 12 so I'm blue toots funny bring this up here's another example of tight conviction loosely held I had a friend go through a real
01:14:52really serious operation earlier this year it was your there's no two ways about it and this is about as big an operation is a human can go through like this is this is you know top three things that you can do that would scare the crap out of you like rain or it's I didn't require a circulatory arrest like it's such a big heart operation they act like you know your brain basically has to be stopped from getting blood for certain. Time and obviously like any human in the situation he was like looking for like what age can I get going into this and he showed me a whole bunch of ideas that he had him
01:15:29you know I had some of the made sense but a lot of them did and then one of the Mystic at me with this idea methylene blue and I was like yeah I heard it cuz you and I had talked about it before but I was like I don't I don't buy it and I said lucky ultimately you have to ask your surgeons cuz this is your so far outside of baseball on this one that they're the worst thing you could do is take something and not have the anesthesiologist insurgents know what you're taking Ray and the medical team basically kibosh the whole thing so you end up going to the procedure had none of the stuff done by the way did amazingly well in one of the best outcomes of ever seen for the type of operation he had so high fives all round and fast forward I interview a guy by the name of Francisco Gonzalez limonada podcast is not come out yet at least as of this recording so I don't know when this is going to come out but try two weeks from now so I'll actually be similar maybe the the the one with the Francisco will probably come out till January but we spent half the podcast talking about methylene blue because in preparing for the podcast by MZ went read all of his papers along with his collaborator Jack
01:16:29UT Austin and I was like blown away by this data and I was like it is another example of like Peter like you dumb fuck like you think you know should have you don't know it like you were dismissive of this methylene blue idea and yet if you look at these data it's pretty damn impressive so for the person does not methylene blue is this is a this is a industrial die or has been around fish tanks like it was created for clothing and stuff like that in the original blue jeans things were made using these methylene blue in the mid-to-late 1800s it has one generally accepted medical used today which is the treatment of methemoglobinemia or methemoglobinemia meaning when someone generates too much of this thing called met hemoglobin which is what happens when you have too much carbon monoxide binding to the electron transport chain you can give methylene blue and it basically overrides the system and allows the mitochondria make ATP so they have an emergency rooms in emergency room
01:17:29Africa's well to Larry and Larry yeah people got into the fancy drugs to treat malaria methylene blue turned out to be a really effective drug and actually in many ways a better drug I think not I mean I still think that the work that people are doing with malaria drugs in Africa is amazing but there's a slippery slope to those drugs a lot of those drugs have really nasty neurological side effects are the dreams are just insane yeah and I actually have a friend from undergrad who ended up being on one of these drugs and I he's never quite been the same since Tim and I were going to China one time and we were where we are going was a pretty bad area and my doc gave me some and I I didn't take it I just roll the dice cuz I've heard such bad things about these blurring it's it's it's I got really scared with this one friend of mine when I saw that he just never quite got better so the question then becomes how can this this methylene blue be used outside of malaria or methemoglobinemia in particular with respect to cognitive enhancement in the answer is
01:18:29if you buy the thesis which I do that one of the major drivers of Alzheimer's disease is an energy deficit of a neuron then where does where do you backlog energy deficit it's almost assuredly in the mitochondria so I think there are multiple ways to get energy deficit in the brain one of them is through inefficient you know transport of What's called the silk Highway through pyruvate dehydrogenase silver pyruvate through pyruvate dehydrogenase to see look away so you can become insulin-resistant you can also have microvascular disease and that's really what Francisco and and Jack Focus their research on and I'm there their models have actually shown that you know methylene blue can overcome a great deal of that and what's really interesting is methylene blue per se is not permitted IP prospective an interesting compound companies create derivatives of it there then patentable and there was a famous clinical trial that we discuss in some detail of his podcast
01:19:29that looked at methylene blue light compound along with some antitower drug and so that the the study was methylene blue light compound anti-drug versus anti-drug trustingly the primary outcome of this study was changes in the MRI the secondary outcome was improved cognition the study failed out of primary outcome on a secondary outcome it did show an improvement in cognition and so is created a little bit of a divide in the world so there are some people who said look rigorously if it fails the primary outcome it fails right and that's actually the right answer it mean if a study failed primary outcome you don't know if it was powered correctly incorrectly or what the substance you no sense of analysis looks like
01:20:16but I think that it's worth asking the question what is the primary outcome should be cognitive impairment and not the changes in the MRI and to what if you do that study without a drug like a drug which in my opinion and I'm not an expert in Alzheimer disease obviously but I'm not convinced that these antitower Auntie Emily drugs are beneficial I think they might actually be countered counterproductive so I'm really hopeful that somebody meaning of drug company comes along again and starts to test this question of methylene blue like drugs in early cognitive impairment especially for those patients who fit into the subset that I bit is more of this energy disrupted state so those patients that are either probably getting there through insulin resistance and or microvascular disease but it creates a huge diagnostic dilemma today or a huge treatment the one which is
01:21:10should we be even considering using methylene blue in patients with early cognitive impairment again it's a question for a medical legal standpoint you certainly can I mean it's an FDA-approved compound now you can use anything off label if you want but again it begs this question right like you know where do we what is the risk tolerance so that's that's one that you know I don't really know the answer to but I mean on the end of one forums in all the forms out there with all these stuff experimenters a lot of people reporting very positive improvements in memory when taking methylene blue but it seems a lot of the sources of dried up and gone away so the artist want I want to make sure that I leave people with something very important here you absolutely positively cannot take this compound unless it is 100% pure so you can't just go on Sigma chemicals and buy methylene blue in other words that use out there for the purpose of industrial you know died dies and colors and he's like that you can't be taking any
01:22:10stop so you need Pharma grade math leeandlie if you're ever going to take it and that's that's a fear I have is it people listening this or who have seen the forums are thinking great I'll just get you know some of its 95% pure yeah absolutely don't cut up old jeans and make TV or yeah people do we reach it outside to ask questions on protocol of choice these days I'm still doing this once a quarter one week fast and it's sandwich on either end by ketosis so your bladder only guy yeah the hardcore that is it Saturday I got to tell you like I've done a lot of the you know 5-day hypochlorite fast including the the formal fmd is a modified fmds I don't find water only to be any harder and I find the benefits so much greater so it's like let's say it's 10% harder which I don't feel it is I feel like it's literally easier but if it were 10% harder but it's giving me twice the benefits just a no-brainer that you think that a minimum of three
01:23:10cases where the benefit start to thicken I just noticed something biochemically in my body changes at about the 72-hour Mark that doesn't happen at 24 or 48 hours is there anything we can add on let me throw up once you tell me what you think of this is broscience but water only I'm doing weight lifting as well maybe a little cardio and then also some hot sauna at night so I'm trying to really break down everything my body get into that really true fasted State won't be a time for you to kick in there be a fence all speculation but like do you think there's anything there that we can do to speed this up and reduce it from 3 down to something cuz 52 does work they've shown some studies like what what do you think about that again I think all of these things work because they're always being compared to the lowest of the low which is the standard American Diet Sprite so so this is this is to me like what always makes me laugh right here like the do you know the plan
01:24:10based diet and the keto people in the carnivore people and they're all arguing back and forth and it's like dude as long as you compare anything to a standard American diet like you can't get worse when you combine carbohydrates sugars specifically fats in the ratios that they show up by default in our diet like anything is a dramatic Improvement so for me the more interesting question isn't is you know this time restricted feeding valuable vs.. But yeah it's about you all right that's pretty clear from from Sachin stata what's way more interesting to me is what is the truly optimal regimen by which we should be faster and 7 days once a quarter three days once a month one day once a week and every day was a lot of people do tuition so far is it needs to be at least 3 days so if it if you pause it for a moment that what you're saying is not true which by the way I don't think I think what you're saying could be true that you could get you could read
01:25:10stop and speed up the process by doing some of those other things but let's just assume for a moment did three days is like a hurdle in which you have to clear which name I think has something to do with enough like glycogen depletion think you know you just edit it also probably depends on the metabolic state of the person so everything is based on my numbers but I'm going into these things pretty healthy I know there was other patients and Jason Fung really soon who's in a big a phenomenal you know physician who's got a great amount of experience with fasting and patients he has a much thicker patient population and I do actually see what Jason's opinion is on the minimum. But I suspect in Jason's patients three days is not enough to get the fat out of the liver get the glycogen in the liver and in the muscle down to 50% of Baseline to start to actually kick off all of these sub cellular processes but it all comes down to like we need these tasks like I'm sitting here speculating and it's driving me bananas because
01:26:10I just get pissed I don't have the answer this question why I get pissed that every year that goes on I'm still trying to fly an airplane using instruments without being able to see the Horizon but I don't know how the instruments work you've been kind of your personal patch on the side been trying to figure out how to measure a tapa G how much closer are you to figure out that problem I mean I think at this point to things are standing in the way and one of them is easy to solve things are changing the way it's just $2 but that's pretty easy to solve because I think frankly I've had I've been approached by so many of my patients alone who have just said like look like will match what you put in so like you know me and five patients will putting some money we can do this think it's really that hard on the financial side to side is the the way in which it should be done and I've talked so much about this with the people who are the world expert in the space some of them I haven't even out of the podcast you have been there so long list of people who really are dialed into this new Eileen White someone who I have not yet interviewed at Rutgers but you know
01:27:10I mean since I seen the spacer are legendary on and you know you you had out another five or six people and you can do this the question is who's going to organize and who's going to do it until you know when you talk to a lot of these folks they all say the same thing which is interesting but it would be really hard to get a postdoc to work on that it's not sexy enough cuz this is the this is the interesting thing right when you go into the best jobs in the country they are attracting the best postdocs in the country these people want to win Nobel prizes like they aren't putzing around for I don't care about a publication like they have to move the needle is people are trying to do groundbreaking work and frankly my little egg Harbour g-project is not you know who's going to win a Nobel Prize tracking that problem so a bit of the problem is just the war for talent to do this that said I really think that you know one if I can you know a little more time in my schedule maybe try to be a little less clinically busy which is a goal I have four 2019
01:28:10and your Cobble together when I think you're the reason a lot of resources to do this or a project You Are My Hope Is that a year Miami get out of here for now. Maybe three years from now we can say at least hey three days once a month produces the equivalent of fact as you know this or that but not this or that you know I just I want to have some marker of that and also your you alluded to it but I think it's really important to lift weights while fasting because it really holds off the muscle mass loss cuz they're there their weight training is stimulating and tour complex in the muscle which is kind of a place you don't want to turn it off and you took it down but you you want to dial it down more and other organs yeah last question your favorite excuse but have you tried any mushrooms and sense of like lion's mane archaga or or any of these Rishi or anything that has had a positive impact on you and then kind of brought
01:29:10speaking is there any favorite nootropic where you actually said this one thing has actually done something meaningful to their my cognition or my energy anything stand out there a weird person in this regard because nothing seems to do much for me outside of modafinil and even my desk. And it's like by the way even 201 go to bed caffeine does nothing to me that a positive or negative can I travel a lot and I come in and out of time zones a lot and it's not uncommon for me to do 12-hour time zone swaps so my jet lag protocol heavily relies on my don't take National normally I don't steal much from it regardless but I just know that when I'm
01:30:06literally 12 hours offset from my home time zone I can function perfectly with modafinil when I shouldn't be functioning at all so I never have any difficulty with chat line then you don't have a problem falling asleep after that no I mean some my protocol is like you is a little last week I was in the Middle East so I left LAX at 4 p.m. so that meant it was 4 a.m. where I was going so I immediately put myself in that time zone now knowing that in the morning I woke up at 4 a.m. did a super hard workout you want to sleep is basically about balancing adenosine cortisol and melatonin wake up really early for which is maybe an hour earlier than I would normally wake up hard hard workout times to build up some adenosine
01:30:55and then in the airport I know that I want to be able to sleep the second I get on the airplane to the second the plane like even while we're standing there I'm already telling a flight attendant I'm not doing anything other than going into a coma wake me up in 6 hours with so so my, cocktail is like these Kirk parsley sleep cocktail but I take a double dose I take 600 phosphatidylserine and then depending on the time of day if I need it also take 10 or 20 mg of adult autism so Enzo and but I never use like ambien or Lunesta during those things I don't find those things actually pretty productive sleep so that's like saying I'll pay you just went out use when out late you're going to bed at 4 a.m. you wake up at 10 a.m. then I take just 200 and modafinil so it's like a placebo toes forming your Landing in the Middle East at that point at 9 p.m.
01:31:49uzo aduba to work and then you go to bed and I have very little difficulty going to bed and I further difficulty waking up so it's like you just forced yourself on to that time zone and then I do the exact same trick and reverse switch usually because you usually leave their very late at night it just means you just stay up and then it usually means you're going to either have to stay up on the plane for for 5 hours or you go to bed to put it on you find me to East Coast or West Coast again all of these things that you've described I have patients who have told me anecdotally that they have had incredible experiences with lion's mane and things like that every one of the things I have tried I have felt zero but I also think that is that seems to be true of a lot of substances I mean even when I've taken suicide than or other agents like that I seem to require several doses they say I seem to require 426 * what everybody else needs yeah I mean
01:32:49Forex yeah it's not sex at one point crazy Peter thank you so much for being on the show
01:32:57thanks for having a man we didn't talk watch it so that much that's a good thing is we think of my watch right now get the holding keys to watch Love and Miss Thing beautiful have them myself awesome that was so much fun we have to have Peter back on every six months or so obviously so much is changing and in science like every month there's just a whole slew of newspapers so to get him to come back on and talk about stuff that he's excited about definitely got to do that so that is it for this podcast for the full show notes head on over to Kevin Rose. Com you'll also find a link there to the iTunes Store we give us a 5-star review I really appreciate it will help us get recommended to more people and in turn will have better guest on the show that's it for this episode be well

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