#517: Dr. Peter Attia on Longevity Drugs, Alzheimer's Disease, and the 3 Most Important Levers to Pull

Brought to you by Athletic Greens http://athleticgreens.com/tim all-in-one nutritional supplement and Eight Sleep’s Pod Pro Cover http://eightsleep.com/Tim sleeping solution for dynamic cooling and heating. Dr. Peter Attia (PeterAttiaMD.com http://peterattiamd.com/) is a former ultra-endurance athlete (e.g., swimming races of 25 miles), a compulsive self-experimenter, and one of the most fascinating human beings I know. He is one of my go-to doctors for anything performance or longevity-related. But here is his official bio to do him justice: Peter is a physician focusing on the applied science of longevity. His practice deals extensively with nutritional interventions, exercise physiology, sleep physiology, emotional and mental health, and pharmacology to increase lifespan (how long you live), while simultaneously improving healthspan (how well you live). Peter trained for five years at the Johns Hopkins Hospital in general surgery, where he was the recipient of several prestigious awards, including Resident of the Year, and the author of a comprehensive review of general surgery. He also spent two years at NIH as a surgical oncology fellow at the National Cancer Institute where his research focused on immune-based therapies for melanoma. He has since been mentored by some of the most experienced and innovative lipidologists, endocrinologists, gynecologists, sleep physiologists, and longevity scientists in the United States and Canada. Peter earned his M. D. from Stanford University and holds a B. Sc. in mechanical engineering and applied mathematics. Peter also hosts The Drive https://peterattiamd.com/Podcast/, a weekly, deep-dive podcast focusing on maximizing longevity and all that goes into that, from physical to cognitive to emotional health. It features topics including fasting, ketosis, Alzheimer’s disease, cancer, mental health, and much more. Subscribe on Apple Podcasts https://podcasts.apple.com/us/podcast/the-peter-attia-drive/id1400828889, Spotify https://open.spotify.com/show/63AWQmsSnFNFHUqnRAOFtD, Overcast https://overcast.fm/itunes1400828889/the-peter-attia-drive, or wherever you listen to podcasts. Please enjoy! This episode is brought to you by Athletic Greens https://www.athleticgreens.com/tim. I get asked all the time, “If you could only use one supplement, what would it be?” My answer is usually Athletic Greens https://www.athleticgreens.com/tim, my all-in-one nutritional insurance. I recommended it in The 4-Hour Body in 2010 and did not get paid to do so. I do my best with nutrient-dense meals, of course, but AG https://www.athleticgreens.com/tim further covers my bases with vitamins, minerals, and whole-food-sourced micronutrients that support gut health and the immune system. Right now, Athletic Greens https://www.athleticgreens.com/tim is offering you their Vitamin D Liquid Formula free with your first subscription purchase—a vital nutrient for a strong immune system and strong bones. Visit AthleticGreens.com/Tim https://www.athleticgreens.com/tim to claim this special offer today and receive the free Vitamin D Liquid Formula (and five free travel packs) with your first subscription purchase! That’s up to a one-year supply of Vitamin D as added value when you try their delicious and comprehensive all-in-one daily greens product. * This episode is also brought to you by Eight Sleep http://eightsleep.com/Tim! Eight Sleep’s Pod Pro Cover http://eightsleep.com/Tim is the easiest and fastest way to sleep at the perfect temperature. It pairs dynamic cooling and heating with biometric tracking to offer the most advanced (and user-friendly) solution on the market. Simply add the Pod Pro Cover http://eightsleep.com/Tim to your current mattress and start sleeping as cool as 55°F or as hot as 110°F. It also splits your bed in half, so your partner can choose a totally different temperature. And now, my dear listeners—that’s you—can get $250 off the Pod Pro Cover http://eightsleep.com/Tim. Simply go to EightSleep.com/Tim http://eightsleep.com/Tim or use code TIM. * If you enjoy the podcast, would you please consider leaving a short review on Apple Podcasts https://podcasts.apple.com/us/podcast/the-tim-ferriss-show/id863897795?mt=2/iTunes? It takes less than 60 seconds, and it really makes a difference in helping to convince hard-to-get guests. I also love reading the reviews! For show notes and past guests, please visit tim.blog/podcast https://tim.blog/podcast/?utm_source=podcast&utm_medium=podcast&utm_campaign=podcast-description. Sign up for Tim’s email newsletter (“5-Bullet Friday”) at tim.blog/friday https://go.tim.blog/5-bullet-friday-1/. 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• 0:00Tim Ferriss?

  This episode is brought to you by Eight Sleep. My God, am I in love with Eight Sleep. Good sleep is the ultimate game changer. More than 30% of Americans struggle with sleep, and I'm a member of that sad group. Temperature is one of the main causes of poor sleep, and heat has always been my nemesis. I've suffered for decades tossing and turning, throwing blankets off, putting them back on, and repeating ad nauseam. But now I am falling asleep in record time, faster than ever. Why? Because I'm using a simple device called the Pod Pro Cover by Eight Sleep. It's the easiest and fastest way to sleep at the perfect temperature. It pairs dynamic cooling and heating with biometric tracking to offer the most advanced, but most user-friendly solution on the market.

• 0:44Tim Ferriss?

  I polled all of you guys on social media about the best tools for sleep, enhancing sleep, and Eight Sleep was by far and away the crowd favorite. I mean, people were just raving fans of this. So I used it, and here we are. Add the Pod Pro Cover to your current mattress and start sleeping as cool as 55 degrees Fahrenheit or as hot as 110 degrees Fahrenheit. It also splits your bed in half so your partner can choose a totally different temperature. My girlfriend runs hot all the time. She doesn't need cooling. She loves the heat, and we can have our own bespoke temperatures on either side, which is exactly what we're doing. Now, for me, and for many people, the result: Eight Sleep users fall asleep up to 32% faster,

• 1:28Tim Ferriss?

  reduce sleep interruptions by up to 40%, and get more restful sleep overall. I can personally attest to this because I track it in all sorts of ways. It's the total solution for enhanced recovery so you can take on the next day feeling refreshed. And now, my dear listeners, that's you guys, you can get $250 off of the Pod Pro Cover. That's a lot. Simply go to eightsleep.com/tim or use code TIM. That's eight all spelled out, E-I-G-H-T, sleep.com/tim, or use coupon code TIM, T-I-M. Eightsleep.com/tim for $200 off your Pod Pro Cover.

• 2:10Tim Ferriss?

  This episode is brought to you by Oura, O-U-R-A. It is the only wearable that I wear on a daily basis. Oura is the company behind the smart ring that delivers personalized sleep and health insights to help you optimize just about everything. And I've tried every device out there that you can imagine. This one really makes the cut. I've been using it religiously for at least six months now, and I was introduced to it by Dr. Peter Attia, who's also vetted just about everything. With advanced sensors, Oura packs state-of-the-art heart rate, heart rate variability, HRV, super important to me, temperature, activity, and sleep monitoring technology into a convenient, non-invasive ring. It's tiny, it weighs less than six grams, and focuses on three key insights: sleep,

• 2:55Tim Ferriss?

  readiness, and activity. So I can use it to help focus my attention on the type, volume, intensity of exercise that I should do in a given day. I use it to determine how certain types of alcohol at different times of the day affect my sleep, which they do, and I can see all of that in graph form trended over time. There are tons of actionable insights that have come from using this ring for me. They have a number of incredible people on their team. Dr. Matthew Walker, a professor of neuroscience and psychology at UC Berkeley, and also author of Why We Sleep, the mega hit, is Oura's chief science advisor, as just one example. The Oura Ring is one of the most accurate wearables available because it measures your vitals directly from your finger.

• 3:40Tim Ferriss?

  So it's not deducing that or making a best guesstimate based on a bunch of other things and trying to triangulate. Compared to a medical-grade electrocardiogram, the Oura Ring is 99.9% accurate for resting heart rate and 98.4% accurate for heart rate variability. And I work with HRV doctors, and they recommend that I use the Oura Ring. So try it yourself. It is super cool and super practical, very actionable. The Oura Ring comes in two styles and three colors: silver, black, and matte black. I use matte black. For $299, you can give or get the gift of health by visiting Ouraring.com. That's O-U-R-A-R-I-N-G.com.

• 4:26Tim Ferriss?

  Again, that's Ouraring.com.

• 4:30Tim Ferriss?

  At this altitude, I can run flat out for a half mile before my hands start shaking.

• 4:37Peter Attia?

  Now we're seeing an appropriate time.

• 4:53Tim Ferriss?

  Hello, boys and girls, ladies and germs. This is Tim Ferriss and welcome to another episode of The Tim Ferriss Show. This is a very special edition. I am in the cave of Peter Attia, Dr. Peter Attia, and we'll get back to his bio in a second. We have the incredible videographer who is trapped inside a closet to monitor levels. Everything has been fitted to perfection and that all makes sense shortly. Dr. Peter Attia, who can be found at peterattia, A-T-T-I-A-M-D, dot com, is a former ultra endurance athlete. So imagine swimming races of 25 or so miles, maybe more. A compulsive self experimenter, emphasis on compulsive, and one of the most fascinating human beings I know. He is one of my go to doctors. I would say the go to doctor for me for anything performance or longevity related.

• 5:38Tim Ferriss?

  But here's the official bio to do him some justice. Peter is a physician focusing on the applied science of longevity. His practice deals extensively with nutritional interventions, exercise physiology, sleep physiology, emotional and mental health, and pharmacology to increase lifespan, that is how long you live, while simultaneously improving health span. In other words, how well you live. Peter trained for five years at the Johns Hopkins Hospital in General Surgery, where he was the recipient of several prestigious awards, including Resident of the Year and the author of a comprehensive review of general surgery. He also spent two years at NIH as a surgical oncology fellow at the National Cancer Institute, where his research focused on immune based therapies for melanoma.

• 6:20Tim Ferriss?

  He has since been mentored by some of the most experienced and innovative lipidologists, endocrinologists, gynecologists, sleep physiologists, and longevity scientists in the United States and Canada. Peter earned his M.D. from Stanford University and holds a Bachelor's of Science in Mechanical Engineering and Applied Mathematics. Last but not least, and this would explain the immaculate video and audio setup that I am enjoying today. Peter also hosts The Drive, a Weekly deep dive podcast, and I do mean deep dive focusing on maximizing longevity and all that goes into that, including physical, cognitive, and emotional health. It features topics including fasting, ketosis, Alzheimer's disease, cancer, mental health, and much more. You can subscribe on Apple Podcasts, Spotify, Overcasts,

• 7:05Tim Ferriss?

  or wherever you listen to podcasts. You can find him all over the interwebs, peterattiamd.com, on Twitter, at peteratiaMD, Instagram, same same, peteratiaMD, Facebook, you got it, peteratiaMD, and then on YouTube, peteratiaMD. Peter, welcome back to the show.

• 7:24Peter Attia?

  Wow, that was quite an intro.

• 7:27Tim Ferriss?

  It was incredibly comprehensive.

• 7:30Peter Attia?

  I could have shown up a little later for this.

• 7:33Tim Ferriss?

  So we've, we've had frequent flyer miles on podcasts, including on this show. And last time we used a format that I quite enjoyed, in part because it required minimal preparation for me. And that was going through categories, excited about, changed mind about, and stupid things or absurd things that you do. And I know that you have a number of things that you are excited about, so we may spend more time in that category. So why don't you kick us off, however you like?

• 8:04Peter Attia?

  So yeah, so the nice thing about this is I get to prepare a little bit and I jotted down a few bullet points on each. So I think one of the things I'm really excited about is a very recent thing in that it's come to market really recently. It's been in the works for about five years and it's something called a liquid biopsy. And the reason this is interesting is that when you think about the sort of major chronic diseases, which is the diseases of atherosclerosis, so heart disease, stroke, cancer, and Alzheimer's disease, we don't have a lot of great tools at detecting cancer early. So cancer screening is a somewhat controversial topic. Most people are probably familiar with things like mammograms, colonoscopies, and PSA testing. There are two or three others that rise to the level of having evidence to suggest that we do them, for example, pap smears.

• 8:49Peter Attia?

  But when it comes to some of the really bad actors of cancer, we don't really have great screening tools. And so what a liquid biopsy. Does is it draws a sample of blood and through that tries to predict whether or not you have cancer cells in your body. And tries to do so, of course, when you have very, very few of them, because the evidence is overwhelming. That all things being equal, a cancer when caught early at an early stage is imminently more curable than a cancer caught at a later stage. And probably the most compelling explanation for that is that the longer a cancer gets to fester in your body. The more chance it has to develop mutations and the more mutations it generates, the more difficult it is to target later on.

• 9:30Peter Attia?

  So there are a number of companies that have been doing this, but to me, the most interesting by far is a company called Grail. Because of the method that they've gone about doing this and the method is using something called a cell free DNA as opposed to tumor DNA.

• 9:45Tim Ferriss?

  And just for those listening, Grail as in holy grail.

• 9:49Peter Attia?

  Exactly. Coming out big. As a little side note, Grail was recently acquired by another company called Illumina. Illumina being the largest company that does DNA sequencing. And a very interesting note is the FTC has sued Illumina for antitrust violations in this acquisition. Which if you understand the science of it, and we don't have to get into it in great detail, is literally the dumbest thing I've ever heard. So that the FTC has done this, in my opinion, is actually a tragedy because it is actually going to cost lives. It's going to cost tens of thousands of lives in delay. If this acquisition does not go through, because Illumina has the power to scale this up like no other company would. Putting that aside for a moment, what is cell free DNA?

• 10:34Peter Attia?

  Because that's really at the heart of this.

• 10:36Tim Ferriss?

  Say that one more time.

• 10:37Peter Attia?

  What is cell free DNA?

• 10:38Tim Ferriss?

  Cell free.

• 10:39Peter Attia?

  DNA.

• 10:40Tim Ferriss?

  C E L L hyphen free.

• 10:41Peter Attia?

  Yeah, as in DNA that's not in a cell. So most of the DNA in your body is contained within cells. But when a cell breaks down, or sometimes even when cells spontaneously, like red blood cells are actually typically monocites, white blood cells. Make DNA and then spontaneously release it from them. You can capture these small amounts of cell free DNA. So if you draw somebody's blood, whether or not they have cancer or not, they're going to have a certain amount of this cell free DNA floating around. You have signatures on DNA called methylations. So a methyl group is just a carbon with three hydrogens on it. It's one of the most basic building blocks of organic chemistry.

• 11:20Peter Attia?

  And as DNA acquires these signatures, so remember DNA is made up of these four nucleotides. When they start binding these little methyl groups. That's the ACTG. Exactly, ACTG. As they start acquiring these methyl groups, that tells a bit of a story. And even though there's not a lot of cell-free DNA, when you look at it, the best analogy, and one of my analysts actually came up with this analogy, is it's sort of like looking at meteor fragments that would land in the desert and being able to understand what type of an asteroid they came from. So even though the asteroid is enormous and it shed big chunks of meteor down to earth, and by the time they actually hit the earth, they're just small rocks, a chemical analysis of that would give you a greater idea where it came from.

• 12:04Peter Attia?

  So this type of test can actually detect up to 50 different types of cancers. There are certain ones that it's not very good at detecting, such as prostate cancer, which is not bad because we have other tools that are so good at detecting prostate cancer. But when you do this blood test, you basically get a readout, which says, no cancer detected, or the following have been detected. And it does this with about a 50% sensitivity and about a 97 to 99% specificity. Now, to explain what that means in context requires a little bit of math, and it's worth going into. So sensitivity is the probability that a cancer is truly there if detected by the test.

• 12:45Peter Attia?

  And specificity is the probability that the cancer is not there if not detected by the test. So sensitivity speaks to true positives and specificity speaks to true negatives. Now, at first, 50% sensitivity doesn't sound that good, but you have to remember, it depends on what we call the pre-test probability is. So pre-test probability says, what is the probability that you have cancer before I test you? And that's a function of many things. It's a function of the prevalence of that cancer. It's a function of your age. It's a function of other behaviors. So for example, two people being otherwise identical, except one being a smoker and one not being a smoker are going to have very different pre-test probabilities. But when you start to think about, for example, you, what's your pre-test probability

• 13:30Peter Attia?

  of having pancreatic cancer? It's quite low, fortunately, even though pancreatic cancer is one of the most lethal cancers out there. So in a low probability environment, a modest sensitivity of 50% and a very high specificity produces incredible, what we call positive and negative predictive value. So what do those things mean? So positive predictive value, as it sounds, means what's the probability that if you get a positive test, you truly have cancer? A negative predictive value is, of course, if you have a negative test, what's the probability it's negative? These numbers end up being well north of 90%. In fact, the negative predictive value is about 99.7%. The positive predictive value is in the ballpark of about 97%.

• 14:14Peter Attia?

  So these are really exciting tests, especially when you pair them with some of the other things that we do in our practice, such as relying on a very special type of MRI technology that uses something called diffusion-weighted imaging, that adds sort of a functional dimension to MRI.

• 14:29Tim Ferriss?

  Quick note there, people can, if they really want to deep dive into that subject matter, you have a guest on your podcast, and I've listened to this episode, it does get quite technical.

• 14:41Peter Attia?

  That's right.

• 14:42Tim Ferriss?

  What is the guest's name for people who want to search?

• 14:43Peter Attia?

  Raj, R-A-J, and how do you spell his last name? A-T-T-R-A-A-W-A-L. Of course, I can't spell in my head, but if you just search Raj MRI, it'll pop up. And yes, that's, that's an episode we usually make our patients listen to before they go and get one of those MRIs, so they understand it.

• 15:04Tim Ferriss?

  Follow up to that, unrelated but related to GRAIL, what is it that happened or what technology was developed that suddenly made this possible where it was not possible before? Or what realization? Why did this suddenly come to fruition or only now become available?

• 15:22Peter Attia?

  I think the major insight, and I will be doing a podcast on this, but I need to wait until this FTC issue is resolved a little bit, because the person that I really want to interview for the podcast, who is one of the people that had the biggest hand in developing this, is actually now the chief scientific officer at Illumina. So for him to be able to speak about it, obviously, it would need to make sense that Illumina actually owns the technology again. I would say, and this might change as I get deeper into understanding their journey. I think it was the realization that tumor DNA was not the place to go. So at the outset of this process, people didn't know what to look for. Would you look for RNA of tumors? Because RNA is the template that's telling you to make the protein.

• 16:04Peter Attia?

  And that didn't really pan out because RNA is so unstable by itself. So then pivoting to DNA, the logical choice was, well, let's look for the tumor DNA. You know, if you have pancreatic cancer and we can find the DNA of a pancreatic cancer cell, that would be a good place to start. But you have to be looking for cell-free DNA by definition when you're doing a liquid biopsy because you're not going to sample the organ. And it turns out that tumor DNA represents about 0.1% of cell-free DNA. So I think the big aha for Grail was realizing, no, let's look at cell-free DNA, which is much more abundant, but instead look at the methylation patterns and then specifically figure out what those methylation patterns were. So that was the real puzzle.

• 16:47Tim Ferriss?

  Yeah, the forensic science.

• 16:49Peter Attia?

  Yep.

• 16:49Tim Ferriss?

  That's very cool. I don't know if, if I interrupted a train of thought that had more to say about Grail. Do you want to say more about Grail or do you want to hop to another?

• 17:01Peter Attia?

  Yeah, no, I mean, I just think that this is, I have been waiting for this, like I said, for five years because I think that I'm just less bullish on the idea that we're going to quote unquote cure cancer, right? If you put cancer in perspective, the overall survival for people with metastatic cancer has improved about 5% in 50 years. And virtually all of that improvement has come with a handful of very specific types of cancers. For example, something called the GI stromal tumor and a certain type of testicular cancer for which there's been like very specific behaviors of these that have rendered them quite sensitive to, to certain chemotherapies. But when it comes to, you know, lung cancer, when it comes to pancreatic cancer,

• 17:46Peter Attia?

  when it comes to colon cancer, breast cancer. Once you don't catch it early, you're sort of in the same situation you were in in about 1970. That's pretty depressing when you consider how much progress has been made in cardiovascular disease since that time. So I think the answer in how do you live longer with respect to cancer is

• 18:04Tim Ferriss?

  Prevention.

• 18:04Peter Attia?

  Is prevention first. Well, it's both, right? It's so what can we do to prevent cancer? And not smoking and being metabolically healthy are hands down the two biggest things that you can do. And then the next step is how aggressively can you screen and stack different levels of screening technologies on top of each other? So that the way we kind of describe it to patients is you want to think of like the Swiss cheese approach, right? You want to be able to stack a whole bunch of things on top of themselves so that you just get only one pencil can fit through.

• 18:34Tim Ferriss?

  Yeah, each method or technology in of itself having gaps.

• 18:38Peter Attia?

  That's right.

• 18:39Tim Ferriss?

  When you lay them on top of each other, hopefully the remaining gaps are sort of allowable, if that makes any sense.

• 18:44Peter Attia?

  Absolutely. And it's exactly that. It's basically how do you use multiple technologies to cover the blind spots of others?

• 18:51Tim Ferriss?

  I'm excited about Grail also because it seems like, especially if scaled through Illumina, the ability to have Grail widely distributed makes it just by definition more available, at least as one tool compared to, say, the MRI that we were referring to earlier, which would appear to be site specific. I don't know.

• 19:12Peter Attia?

  Yeah. MRI is going to be far less scalable and frankly far more of a hassle. I mean, if you've, I don't know if you've ever had, well, you haven't had one yet. We got to get you up there.

• 19:19Tim Ferriss?

  Yeah, I've had, for better and for worse, probably quite a few MRIs, not always in ideal circumstances, but this particular MRI, not yet.

• 19:28Peter Attia?

  Yeah. So it's like, how do you drive the cost down? How do you improve the technology? How do you make the algorithm better and better and better? Because it is, under all of this is a huge engine of machine learning that makes it better over time.

• 19:38Tim Ferriss?

  So you mentioned in terms of prevention metabolically healthy, is there anything you're excited about or would like to underscore that relates to developing metabolic health or improving metabolic health?

• 19:55Peter Attia?

  Always. I'd say exercise is so important, right? It can't be overstated. It's potentially one of the most potent drugs we have. But all exercise is not created equal, I would imagine. Correct. For this purpose. Absolutely. And so I think of exercise as having four pillars. You have to be strong on each of those. So if you're strong in three, but not in one, it's sort of like a table that has three legs and not one. It's still a reasonable table, but it's not as strong as a table with four legs. And a table with two legs is pretty pathetic. And obviously a table with one leg is not a table. So the four pillars are stability, strength, aerobic efficiency, and anaerobic performance.

• 20:38Peter Attia?

  And I think that most people understand loosely what three of those are. Could you say those all one more time? Sure. Stability, that's the one that most people don't understand. We can talk about that in a minute. Strength, aerobic efficiency, and anaerobic performance. So I guess we can unpack all of them, but stability is the ability to safely transfer load from the outside world to the body and vice versa, which sounds sort of like a soft explanation. An analogy that I really like using is that of a race car versus a street car. So what makes race cars so unique is that, and why, by the way, a race car

• 21:20Peter Attia?

  that's got half the power of a street car will still knock its socks off on a track, is because the chassis and the tires of the race car are constructed in such a way that every bit of that power is making it to the road. So the analogy I like to think of is that the tires of a race car are like our feet. And stability really does begin with the feet. And most people, myself included, when I was starting, had horrible proprioception with our feet. You know, we don't really know how to load our feet correctly. And a lot of that comes from the fact that we wear shoes all day. Your hands and your feet are actually very similar. And if you think about what you can do with your hands, how easily you can move them around, spread your fingers, sense pressure in different areas, most people can't do that with their feet.

• 22:04Peter Attia?

  And that comes to bite you. So as you think about how it moves up the sort of chain, a very common problem is, which I think accounts for probably more of the injuries that people experience, is this pattern where the pelvis is tilted forward, the ribs are flared up, the erector spinae muscles in the back are sort of locked short, meaning they're locked in concentric load, and the hamstrings are locked long. So they're locked in eccentric load.

• 22:34Tim Ferriss?

  Yeah, it's how someone who's quite lean from a body fat perspective can still look like they have a pot belly.

• 22:40Peter Attia?

  That's right.

• 22:40Tim Ferriss?

  With that anterior pelvic tilt.

• 22:43Peter Attia?

  Which actually, so you've asked me a question, and I think I can answer this with, there are really two things I'm excited about that pertain to exercise. And I'll go down this path, and then we'll come back to the other one. What's the etiology of that position, which I was the king of that position? It's probably...

• 22:59Tim Ferriss?

  What do you mean by etiology?

• 23:00Peter Attia?

  Like, what drives that? Why would a person show up with that posture of ribs flared up, pelvis tilted forward, back tight, hamstrings tight and long?

• 23:11Tim Ferriss?

  Besides wearing six inch stiletto heels.

• 23:13Peter Attia?

  Yeah, which I never wore. I mean, I wore them sometimes, but I don't often wear them.

• 23:17Tim Ferriss?

  You're in good company, Edgar Hoover and all. Continue.

• 23:21Peter Attia?

  So it probably starts with lousy respiration. And I'm not exactly sure why that's the case, but I think somewhere along the way, we stop breathing correctly into our abdomen. Instead of breathing the way we should breathe, which is the diaphragm should go down, the abdomen should come out, the pelvis should actually fill with pressure. We tend to breathe using, so that's the, those are the primary muscles of respiration as a diaphragm. We start using accessory muscles like the pec and the pec minor, and we kind of lift the chest up. There's a very common pattern of respiration. And I think it's that lifting of the chest that is what's bringing the rib cage up. And when that happens, the body is a little bit out of balance,

• 24:04Peter Attia?

  meaning your center of mass shifts forward. And the body senses that. And in an effort to prevent you from falling forward, it's basically tightening those erector spinae muscles. It's pulling you into balance again. But in doing so, it's creating this downstream problem in the hamstrings, which is they're locking. And if there's another thing I've become really obsessed with, it's hamstring control, which is different from hamstring strength. A lot of people, myself included, can have very strong hamstrings. I used to have incredibly strong hamstrings. If you put me on a machine and made me do something in isolation, but I could never recruit them. A simple exercise to demonstrate this, which Beth Lewis had me do for the first time, maybe two and a half or three years ago,

• 24:48Peter Attia?

  was you're laying on your back with your knees up and your feet down. So you're sort of in a back position, knees up, you know, feet on the surface of the ground. And without letting your back tilt into a huge dome underneath it. So while keeping your lower back flat, can you with one leg pull very, very hard back to your butt and feel your hamstring tense? So that is a very specific manner of recruiting hamstring strength. And believe it or not, I couldn't do that while keeping my back down. I would arch like a cat if I tried to do that. There were many more of these types of exercises, but it was through this type of very deliberate,

• 25:31Peter Attia?

  starting on my back and then learning to do hamstring recruitment while standing and while feeling pressure in my feet, that really allowed me to get back to deadlifting with a feeling of safety that I'd never really experienced. Cause I used to deadlift so heavy when I was young and basically got away with using my back to deadlift. Which is obviously not what you want to do. And then I just started having nagging injuries as I got older. So by the time I was in my mid 40s, I'm deadlifting and it's like, oh, my SI joint would bug me and after I'd finished, my back would just feel tight. Age sort of exposes your deficiencies and eventually everybody's going to sort of pay a price for this. Some people do these things naturally better than others.

• 26:17Peter Attia?

  So I think there are some people who can kind of go their entire life lifting heavy weights without having to pay much attention to this stuff, but you know, I certainly wasn't one of them.

• 26:25Tim Ferriss?

  Does that type of training that you're describing, that progression kind of starting back from the foundation with fundamentals, does that have a particular name?

• 26:34Peter Attia?

  There are a couple of different schools of thought that have been implemented into this training. One of them being dynamic neuromuscular stabilization or DNS, which is heavily focused on this ability to find the breath and generate, you know, this concentric abdominal pressure. So creating a cylinder inside the abdomen as opposed to like an upside down triangle where you have some pressure up here, but none down here. And then another school of thought that's been heavily influential here has been something called Postural Restoration Institute or PRI. That's really the one that has focused on this idea of how do you correct what from the side looks like this, right? You know, sort of pelvis down, ribs up, and how do you fix that position?

• 27:17Peter Attia?

  And again, it's, it's hard because it requires fixing everything from the feet to the neck.

• 27:23Tim Ferriss?

  How much of a contributor, if at all, do you think extended sitting is to that configuration with the kind of flared ribs up and anterior pelvic tilt, if any?

• 27:36Peter Attia?

  I think it probably is, and probably for a couple of reasons. You have to sort of think about it as the positive and the negative, right? So one drawback of sitting is that you're not active. It's simply the removal of active time that is a problem. And I think the other problem with sitting is it is simply harder to generate intra-abdominal pressure and it's easier to just rely on these accessory movements of respiration to lift up. So. I think I've said this once before, like if I could be czar for a day, you know, I'd go back to kids when they're in school and, you know, have them in standing desks or squatting. Those would be your two positions, right? So you either, you're kind of squatting

• 28:18Peter Attia?

  to do work, or you're standing to do work, but you're not sitting in the types of chairs that we sit in.

• 28:23Tim Ferriss?

  I think I have an idea for a complimentary short form podcast for you, which is just called Czar for a Day. Five minute, five minute commandments from Zaratea.

• 28:35Peter Attia?

  Yep. And more, more barefoot time. You know, with my first two kids, I wasn't so aware of this when they were young. And now with my youngest, who's almost four, I study this guy like he's the master. His movement patterns are simply unbelievable, which of course, all four year olds should be. I just never noticed it before. But the manner in which he moves and lifts himself and reaches for things and sits around, it's incredible. It is such a spectacle to behold. If you spend more time watching your children, and that's, you know, DNS is modeled on exactly that, right? DNS basically says, it grew

• 29:16Peter Attia?

  out of something called the Prague School in Czechoslovakia, which was originally looking at ways to take children with cerebral palsy and teach them how to move again by realizing that what CP had robbed them of was a lot of the developmental movement patterns that occur in the first two years of life. And once they started to realize you could actually take these kids and retrain their neurologic system to do things in a more functional way, that you could actually do this as a form of rehab, and then ultimately a form of prehab, which is sort of how I like to think of it now.

• 29:52Tim Ferriss?

  I've seen, I don't know how much of this is public, but incredible results from a trainer, also world record holder, or former world record holder in Olympic weightlifting, Jersey Gregorak, working with a number of clients or patients with cerebral palsy, using very incremental.

• 30:15Tim Ferriss?

  Movement rehabilitation and training. I mean, the before and after differences are staggering. I mean, I speak to probably my ignorance of cerebral palsy, but just never was even within my conceptual schema that that would be possible. It's very exciting to see. So, speaking of exciting.

• 30:35Peter Attia?

  Oh, so the other thing on exercise, to get back to your question about the metabolic stuff, is about three years ago, I was becoming more and more interested in this idea of zone two training, which has a very technical definition, and then we can explain proxies for it. But the definition of zone two is the highest level of output you can produce while keeping lactate below two millimol. So lactate is a byproduct of anaerobic metabolism. So when we're sitting here at rest, our lactate level is probably one, if we're metabolically healthy. There are some people who sit around at rest higher than two. If anybody's done lactate testing knows, as you start exerting yourself more and more, your lactate will

• 31:20Peter Attia?

  rise. And peak levels in highly trained individuals can reach above 20 millimol. And that's accompanied by remarkable discomfort, actually. I've always done lactate training when I was being an athlete, which I haven't been in forever. But I was never focused on this aspect of it. I was always focused on something called lactate threshold and peak lactate. So peak lactate, for me, was kind of a marker of just how much pain I could endure. And lactate threshold was a marker of the highest amount of output I could produce for relatively short races. Short for me would be like half an hour or something like that. So knowing my lactate threshold was important for that stuff. But this zone two stuff is way below that. Zone two is by definition, your all day pace. It's

• 32:04Peter Attia?

  basically at a lactate level of two, you should be able to go all day. That's the level at which you do not net accumulate. So you're producing, but you're not accumulating. And so it's the rate at which clearance equals production, and you stay at that level of two.

• 32:23Tim Ferriss?

  Just a very quick note to say that we really nerded out on zone two training with Peter. We got deep into the rabbit hole. It got very, very dense, also actionable. But I moved that section to the end of the episode. So if you want to check that out later, just continue listening. Now, back to the show.

• 32:43Tim Ferriss?

  You mentioned fat utilization or the ability to use fat as a substrate. Are there things, and specifically what's coming to my mind, such as fasting or intermittent ketosis that help you to use fat in such a way that it transfers to zone two training? Is there any crossover, I suppose?

• 33:06Peter Attia?

  Yeah, well, there's no question that ketosis by its very definition is a nutritional state that forces your body to utilize fat. And depending on how much you're intaking, some of that fat could be endogenous. So again, exogenous is the fat that you put in your body. So what fat you eat is exogenous. The fat stores that we have are endogenous. There's a bit of a, I think, just a misunderstanding around ketosis. I think a lot of people assume it is automatically a weight loss diet or a fat loss diet. But of course, that's not necessarily true. It's only a fat loss diet if you use your endogenous fat stores.

• 33:43Tim Ferriss?

  Also turns out a pound of fat has a lot of calories.

• 33:46Peter Attia?

  Yeah. So, you know, I could gain weight on a ketogenic diet if I ate enough. The advantage of ketogenic diets for most people is that they're quite satiating and you don't want to eat endless amounts in the way that if you went on the all Dorito diet, which I've also pioneered, I've got experience with the all Dorito diet. And turns out you can eat a lot. The all licorice, I used to work at a video store when I was in high school called Movies and Munchies. And, you know, it was owned by my friends.

• 34:19Tim Ferriss?

  Video store plus dispensary.

• 34:21Peter Attia?

  Yeah. And they didn't, they just didn't care how much I ate.

• 34:25Tim Ferriss?

  Yeah.

• 34:25Peter Attia?

  And I would literally eat the pound of Twizzlers. Like, you know, they came in that pound, maybe a pound and a half. It was like the biggest bag of Twizzlers.

• 34:33Tim Ferriss?

  You could take out like a mugger with this bag of Twizzlers.

• 34:35Peter Attia?

  Yeah, yeah, exactly. Like, it's a weapon. And if any reasonable group of four people went to a movie, they'd have a hard time finishing one, but I would easily throw that down. Plus, the really big bags of Doritos, plus a really big bag of popcorn, plus God knows what else. Like, that was routine for the night. Just disgusting. Easily four or 5,000 calories of junk food three nights a week was my staple.

• 35:01Tim Ferriss?

  So if we look at the opposite of that fasting, has you, have you changed your mind or had any insights since we last spoke or come to any different conclusions related to fasting? Because you've done a lot of fasting. I mean, you have a lot of experience doing fasts of many different lengths, including, I don't know what the longest fast is that you've done.

• 35:21Peter Attia?

  Probably 10 days.

• 35:22Tim Ferriss?

  10 days, yeah.

• 35:24Peter Attia?

  Yeah, I think that one thing that I absolutely learned through fasting is the enormous importance of strength training throughout a fast. It's very easy. You're going to lose muscle mass when you fast. You have to accept that. So the question is, how do you minimize that damage? How do you lose as little muscle mass as possible? And strength training daily during a fast has become an important part of that. But when you look at time restricted feeding, people call it intermittent fasting, although I don't, I don't like that term very much. I think time restricted makes more sense when you're just talking about, you know, 16 or 18 hours. I'm really starting to see a lot of people who do that excessively and who aren't necessarily training correctly. They lose weight, but they're losing muscle more than they would want to see.

• 36:09Peter Attia?

  And we just had a patient who, we did a DEXA scan on last week. And it was probably the first one we've done in 18 months on him. And in that 18 month period, his body weight had not changed. Maybe he was a bit lighter, actually. He might've lost four pounds. But his body fat was so high, I almost fell off my chair. And he doesn't look chubby. It speaks to how much muscle he's lost. So he, his body fat went from about 18% to 30%.

• 36:40Tim Ferriss?

  Yikes.

• 36:41Peter Attia?

  Which was, you know, it's just a totally unacceptable amount of fat for someone his age. And his visceral fat went up, which I actually care more about than body fat. We can talk about that later. But his visceral fat also went up. So, you know, this is a guy who has religiously been doing his time restricted feeding every day, but he doesn't really lift weights. He walks and does some yoga and stuff like that, but he's not doing strength training. So I think in a person like that, there's a real downside to too much time restricted feeding. And even for myself, like in the last four or five months, I've been, you know, I did a DEXA back in January and I hadn't done one in years. And From January to the last period that I had done a DEXA, my body weight was almost

• 37:24Peter Attia?

  identical. Maybe I was two pounds lighter this year versus the last time, but my body fat was up. I think I went from 10 to 16% body fat. And again, you could say, well, 16 is not the end of the world, but you know, that was a significant loss of muscle and gain of fat. I did wonder if that was just too much because, because I always exercise in the morning, but then don't eat to exercise and then not provide yourself, especially with when you're strength training, to provide yourself with any amino acids every single day to undergo muscle protein synthesis, I think is a little bit risky. So I've been looking at other strategies around that. So for example, front loading the meals.

• 38:00Tim Ferriss?

  Quick question, and then we'll come back to front loading meals. During that period of time, were you doing, and I this, I may be misremembering, but one three day fast a month or one week long fast every quarter? What was the frequency?

• 38:14Peter Attia?

  All of the above. Yeah, I probably spent maybe two years doing seven days a quarter, maybe a year doing of three days a month. But in between, it's also doing lots of time restricted. And honestly, I think the daily time restricted was a bit more the issue. You know, I think the three day fast a month with a lot of lifting, I didn't sense I lost a lot of muscle during that period of time. But I think every day exercising in the morning, not putting calories in until later in the day, it has to be taken in the context of an individual. So if you're someone who's 100 pounds overweight or you have diabetes, it's a totally worthwhile trade off to lose muscle mass because you're losing more fat mass along the way. So you are going to technically get leaner with that approach.

• 38:59Peter Attia?

  But when you take a relatively healthy and lean individual, one has to be a little bit careful and look for alternative ways to sort of get the benefits of that fast.

• 39:08Tim Ferriss?

  So you were saying something about front loading meals?

• 39:10Peter Attia?

  Yeah, so I just find nowadays, although probably not tonight, I'm gonna eat a

• 39:17Tim Ferriss?

  Almost certainly not tonight.

• 39:18Peter Attia?

  I'm gonna eat a little bit more early in the day and a little less late in the day.

• 39:23Tim Ferriss?

  So there may or may not be some mezcal involved.

• 39:26Peter Attia?

  There will be.

• 39:27Tim Ferriss?

  So we won't take either of our aura ring data as the standard for this evening. I totally got caught up in my own fantasy narrative.

• 39:37Peter Attia?

  About mezcal.

• 39:38Tim Ferriss?

  So front loading meals, could you just walk back and explain?

• 39:41Peter Attia?

  In an ideal world, I think that the best way to do time restricted eating would be to eat a big breakfast. So it would be to wake up, exercise, eat a huge breakfast. By huge, I don't mean gluttonous, but I mean, that's your biggest meal of the day. At say, I don't know, like, let's just put some numbers to it. You wake up at six, you work out from seven to eight thirty. At nine o'clock, you're eating your largest meal. You eat another meal at one o'clock that is modest and you don't eat again. That would be a great way to do sixteen hours of not eating a day. That's problematic for two reasons. The first is it's socially problematic. It's really easy to not have breakfast because very few people eat breakfast with other people.

• 40:25Peter Attia?

  But dinner is our social meal and for obvious reasons, it just poses a difficulty to be the guy who never eats dinner.

• 40:32Tim Ferriss?

  Just as a side note, I've been at multiple dinners now. Quite a few, actually, where you've been fasting and we've all been sitting, drinking wine. And you just like pass the cheesecake at the end and you take a big whiff and then continue moving it along. It's entertaining, but it is pretty antisocial.

• 40:51Peter Attia?

  Yeah.

• 40:51Tim Ferriss?

  To be that guy.

• 40:52Peter Attia?

  To be that guy. Yeah, drinking the soda water.

• 40:57Peter Attia?

  And then the other thing is, I think for many people, it is hard to go to bed hungry. And truthfully, in longer fasts, it gets easier because, you know, if you're fasting for seven days, by the time you hit that fifth day, you're, a lot of your hunger has sort of dissipated. But sixteen hours of not eating can generally pose some hunger. And for some reason, I just think psychologically in the evening, we're a little less busy. So it's even more noticeable. Whereas if you're doing the traditional way that people think about not eating for sixteen hours, it's pretty easy to wrap yourself up and work in the morning, skip breakfast and kind of delay your lunch a little bit. So. I don't know that I have a great answer for that, other than I think people should be

• 41:37Peter Attia?

  a little cautious and not just apply the same hammer to every nail and kind of think about their own physiology a little bit and rely on these technologies like DEXA to make sure, which again is so readily available, relatively inexpensive, and provides both good information about body composition and also this thing of visceral fat.

• 41:57Tim Ferriss?

  We'll come to the visceral fat in just a second. On the DEXA note about, I don't know, a year and a half or two years ago, I recall a conversation with a DEXA technician who said to me, "Over the last 12 months, I've seen many cases of people coming in who are newly avowed intermittent fasters, who have had their body composition flip, basically." I mean, not necessarily flip, but they've had massive jumps in the percentage body fat. And I put that on social as a note, not to say that all people who do time restricted feeding

• 42:39Tim Ferriss?

  experience this, and it was hilarious and also frustrating to see how many religious zealots there are around intermittent fasting, who are just like, "Bite thy tongue."

• 42:53Peter Attia?

  Wait, but you said that, according to this tech, that they got better intermittent fasting?

• 42:58Tim Ferriss?

  No, they got worse.

• 42:59Peter Attia?

  They got worse. So it met with what I'm describing.

• 43:02Tim Ferriss?

  It's exactly compatible with what you're saying. But there was a lot of resistance to the idea that that would even be possible, which I found really interesting, more social commentary than anything else.

• 43:16Peter Attia?

  I think it just speaks to sort of why I don't like talking about nutrition very much, because it does lend itself to politics, not literally, but it's sort of the politics-religion ethos, which is whatever you're eating is obviously the only thing. And I guess I just encourage people to be much more attuned to all of the tools, right? So caloric restriction, dietary restriction, time restriction, right? You've probably heard me go on and on about my framework, the three levers. Always pull one, sometimes pull two, occasionally pull three, never pull none. So time restriction, what we're talking about, restricting when you eat, but otherwise not restricting how much or what.

• 43:57Peter Attia?

  Dietary restriction is restricting some of the content in what you eat. So not eating carbs, not eating wheat, not eating meat.

• 44:05Tim Ferriss?

  Not eating Doritos.

• 44:06Peter Attia?

  Right. Not eating sugar. Those are all forms of dietary restriction. And then caloric restriction is restricting the amount. And so if you are never pulling one of those levers, which means you're eating anything you want, anytime, how much, whatever, that's called the standard American diet.

• 44:23Tim Ferriss?

  SAD.

• 44:24Peter Attia?

  Yeah, the SAD. And we've been running a very good natural experiment on that for 50 years, and the data are in. So it turns out that less than 20% of the population, probably less than 10% of the population, is genetically robust enough to tolerate the SAD. So it's a great piece of data. Like, there are people out there who can eat KFC and Doritos and pizza anytime they want, and they're generally okay. To a first order approximation, I would add that we don't really know the answer to this question because we don't have super granular data at the population level. But notwithstanding that, at least at the surface level, it appears that 10% of the population are largely immune to the SAD.

• 45:09Peter Attia?

  But for the rest of the 90% of us schmucks, which I'm certainly in that camp, the SAD is lethal. And so you've got to come up with a way to escape the gravitational pull of the SAD. And that's why I think having these three levers at your disposal is the key. And yeah, I think that what happens is people get so into the camp of their lever, like it's all time restriction, or it's all dietary restriction. Not too many people are in the all calorie restriction group. There's a whole calorie restriction society, and so there certainly are people that are in that camp. But it's usually the first two camps that have the most zealots.

• 45:45Tim Ferriss?

  Levers. I was waiting for the Canadian to come out. I love those levers.

• 45:50Peter Attia?

  Ah, sorry.

• 45:51Tim Ferriss?

  Sorry, I'm so sorry.

• 45:53Peter Attia?

  So sorry.

• 45:54Tim Ferriss?

  Process, process.

• 45:58Tim Ferriss?

  And I also think, I said, "Bite thy tongue." I don't practice my older English much. I think it's "thine tongue," but I'm sure the internet will correct me.

• 46:09Tim Ferriss?

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• 46:52Tim Ferriss?

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• 47:35Tim Ferriss?

  gut health, and energy by visiting athleticgreens.com/tim. You'll receive up to a year's supply of vitamin D and five free travel packs with your subscription. Again, that's athleticgreens.com/tim.

• 47:51Tim Ferriss?

  Quick tactical question, and then I want to ask you about any research or studies that have been interesting to you, that have come out since we last spoke. Is it effective or have you tested using small amounts of branched-chain amino acids to mitigate the muscle loss during what we would otherwise consider fasting? And does that also, if it has any effect? Lessen the benefits of the fast.

• 48:21Peter Attia?

  It depends on what you're doing the fast for. I think if you're doing the fast for weight loss, then the answer is absolutely knock yourself out with branched chain amino acids during strength training because from a caloric perspective, they represent such a pinch.

• 48:35Tim Ferriss?

  Negligible.

• 48:35Peter Attia?

  Yeah, yeah, yeah. Like even if you were to double up on, you know, my favorite BCAAs, which are BioSteel, you know, you're, what are you going to get in there? Forty calories in two servings, right? So not an issue. If you're doing the intermittent fasting, would call it the hope of achieving some amount of the early signatures of autophagy, then I would say that it probably is counterproductive because the amino acids that you use in exercise are exactly the ones that are the most potent stimulators of mTOR. And the whole purpose of fasting, at least in the short term, is to give mTOR a rest. It's

• 49:16Peter Attia?

  to take away that which it senses, and it is the most potent sensor of leucine, which is the most important branched chain amino acid.

• 49:24Tim Ferriss?

  Yeah. So if I could dumb that down for myself, if you are interested in the longevity benefits of fasting, aside from just getting to healthy body composition, you should not take the branched chain amino acids.

• 49:41Peter Attia?

  I mean, I can't say anything with certainty, but it seems counterproductive. Yeah.

• 49:45Tim Ferriss?

  Yeah, got it. All right. Studies. Any papers or studies that you found interesting?

• 49:52Peter Attia?

  Oh, my God. So many. There's a lot.

• 49:55Tim Ferriss?

  If you had to cherry pick a few.

• 49:58Peter Attia?

  Well, look, I think the recent New England Journal paper that you and I have talked about is very interesting, comparing Lexapro to psilocybin. I wrote about it recently, and my little diatribe basically said, I think the paper was, in some ways, misinterpreted. It was positioned as a negative trial, though I saw it as anything but a negative trial.

• 50:17Tim Ferriss?

  Could we zoom out just for a second and give people an overview of the, well, the objective or the hypothesis of the study?

• 50:24Peter Attia?

  Yeah, the question that was being tested was, is an intermittent dose of pure synthetic psilocybin more effective, I think is the way the question was posed, than the top-tier SSRI for patients with depression?

• 50:39Tim Ferriss?

  Yeah.

• 50:40Peter Attia?

  So Lexapro is a relatively new SSRI, very well tolerated.

• 50:44Tim Ferriss?

  Isentalopram?

• 50:45Peter Attia?

  Yeah. You know, has It does have sexual side effects. That's its most common side effect.

• 50:51Tim Ferriss?

  That's true of other SSRIs.

• 50:52Peter Attia?

  Absolutely. Yeah. SSRIs are known for having sexual side effects. Some of them also come with incredible amounts of somnolence, incredible amounts of weight gain.

• 51:01Tim Ferriss?

  Somnolence, sleepiness.

• 51:02Peter Attia?

  Sleepiness, yeah. Lexapro seems to be relatively free of that for most people, which is why it's kind of more of a go-to drug. Comes in two doses, 10 and 20 milligrams. Generally, most people need 20 if they're going to go to it, but you usually start people at 10, go to 20.

• 51:18Tim Ferriss?

  And this is a daily?

• 51:20Peter Attia?

  It's a daily drug. Yep. The participants are divided into two groups. One group is given Lexapro. Let me think. I believe that they all started out at 10 milligrams for three weeks and then were increased to 20 milligrams for three weeks, or maybe it was four plus four. I can't remember. It was a relatively short study. In the psilocybin group, the participants were given, oh, they, by the way, it's an aside, they were also given one milligram of psilocybin, which is an important point I should make.

• 51:46Tim Ferriss?

  And if that word is unfamiliar to folks, so psilocybin is a molecule found in psilocybe mushrooms, also known as magic mushrooms. These are mushrooms that impart psychedelic effects at a sufficient dose.

• 52:00Peter Attia?

  We'll come to talk about that dose. So the subjects were all recruited knowing that they would get psilocybin no matter what, because that was an important recruiting tool. People wanted to be in a study where they were going to get the psilocybin. That has to be taken into account from the standpoint of patient selection. So every trial has to be thoughtful about what type of people it's selecting, and are they representative of the population you're going to want to extrapolate your results to. So I flagged this to make the point that when you have a patient population that says, I really, really want to get psilocybin, and you say, okay, well, you're not going to get necessarily the full dose. There's only a 50/50 chance you're going to get the full dose, but

• 52:42Peter Attia?

  you're going to get some. So you're either going to get one milligram or 25 milligrams. And we'll put in context what those doses mean in a second.

• 52:48Tim Ferriss?

  And just to bracket one thing, what makes this study and paper worthy of discussion is that it is a head-to-head comparison, with lots of nuance, of course, of psilocybin with, I think, two or three sessions total in the intervention arm versus Lexapro, very common SSRI for major depressive disorder.

• 53:11Peter Attia?

  Yep.

• 53:12Tim Ferriss?

  Please continue.

• 53:13Peter Attia?

  Well, so to your point, the group that was in the true psilocybin group received, I think it's just two doses spaced out three weeks apart of 25 mg of psilocybin, which depending on the variant of mushroom, so when you dry a mushroom out, its yield of psilocybin, pure psilocybin can be as low, I mean, I went and reviewed all the lit on this, can be as low as 1.7%, can be as high by weight, can be as high as even 4% or 5%.

• 53:46Tim Ferriss?

  So incredible variability.

• 53:47Peter Attia?

  Yeah, so the 25 mg was clearly a hallucinogenic dose.

• 53:52Tim Ferriss?

  Yep.

• 53:52Peter Attia?

  So probably in the four to five gram of mushroom dose. So they used a number of, well, there's one other point I should explain about research. Generally, when research is done in a credible fashion, you have to call your shot before you do the study.

• 54:08Tim Ferriss?

  Like pointing the centerfield.

• 54:09Peter Attia?

  That's right. You have to be able to not just say, I'm going to hit a homerun. I'm going to hit a homerun over that wall. And that's called your primary objective. So one of the things that is important to understand when you're evaluating research is, was it pre-registered? So when the study.

• 54:25Tim Ferriss?

  Right. Did they call their shot by naming their primary outcome?

• 54:28Peter Attia?

  That's right. And so in the United States, anything that's funded by NIH, for example, has to be pre-registered on clinicaltrials.gov. So I would encourage anybody to go to clinicaltrials.gov and just start perusing. And what you'll see there is a list of all of these ongoing studies. They'll say, you know, it started here and it's a template. So it always looks the same and it's very easy to navigate these things. You know, here are the investigators, here's the hypothesis, here's the experimental design, here's the inclusion criteria, the exclusion criteria, here the primary, here is the primary outcome, here are the secondary outcomes, and it shows you all of that stuff. So you have to pre-register this, you have to state what you're doing. If you don't do that, it becomes very difficult to publish your work in anything prestigious.

• 55:11Peter Attia?

  This, of course, was published in the hands down most prestigious medical journal in the world, the New England Journal of Medicine. So they pre-registered around one type of survey, one type of depressive survey.

• 55:22Peter Attia?

  Because unlike, say, giving people drug to treat cholesterol, where you have an objective metric, you can say, well, did it lower ApoB or LDL-C or something like that. Here, you're relying on subjective outcomes because in such a short study, you're clearly not going to be able to follow people for, wait, was there less depression in this, or was there less suicide in this group or something, you know, like a hard outcome, you know? Did people have, you know, fewer absent days from work or something like that? And it's been a while since I wrote this. The primary survey that they used, I believe, had nine categories, or maybe it was 12. And the difference between the groups, the Lexapro group and

• 56:02Peter Attia?

  the psilocybin group, was not statistically significant. So both groups achieved an improvement in their depressive scores.

• 56:09Tim Ferriss?

  Yeah, I think it was six and four points, respectively.

• 56:13Peter Attia?

  Correct. I think it was a nine-point scale.

• 56:15Tim Ferriss?

  Something like that. But you, you pointed out something very important. And I guess we should just step back for a second. So the upshot, and then let's come back to these questions, but the upshot summary of the study was what?

• 56:29Peter Attia?

  There was no difference between psilocybin and this drug. It was positioned as a negative study.

• 56:34Tim Ferriss?

  Got it. Meaning, it, I mean, I don't want to say failed, because that's just not really how science works, but that the intervention did not, meaning, well, psilocybin in this case, was not superior to.

• 56:45Peter Attia?

  That's right. Is it? Yeah.

• 56:46Tim Ferriss?

  Yes, tied.

• 56:47Peter Attia?

  That's right.

• 56:48Tim Ferriss?

  All right. So this is a topic that is endlessly interesting to me. What we're getting into, it's just study design and really digging into the nuance and how beneficial it is to know how to read a study. And, I mean, this will seem like a friendly plug, but I highly recommend people read a series of articles that you published, and they are called, what is it, Studying the Studies?

• 57:13Peter Attia?

  Studying Studies.

• 57:14Tim Ferriss?

  Studying Studies, to increase your scientific literacy, because we're going to get into some of the weeds, and I think it'll be, I, I, I hope it'll be interesting to people.

• 57:21Peter Attia?

  And the other thing we're doing, if I can plug something, and I don't know when we'll have this out yet, but we're creating a course where about a year ago, we started recording our weekly journal, our monthly journal clubs. So every month inside our practice, we do journal club, which is just like old school journal club for anybody who's been in a lab. So one person will present a paper. It usually takes an hour to an hour and a half and we get into a complete dissection of the paper. And we do it in a really kind of methodical way and the topics vary greatly. So

• 57:52Tim Ferriss?

  Highly recommend everyone do this. Honestly, witnessing the complete mayhem and confusion over the last year with respect to anything science related, certainly the most obvious of which being anything COVID or vaccine related has has made it so clear to me that this is really, I mean, it's hard for me to think of something that is higher priority.

• 58:15Peter Attia?

  Yeah. And we just decided to do this. I mean, you know, we've been doing journal club inside our practice for years, but it occurred to me a year ago, why aren't we recording this to later package and put out there? Because nobody comes out of the womb knowing how to read science. Like we just have to accept the fact.

• 58:32Tim Ferriss?

  Completely learned.

• 58:33Peter Attia?

  It's it is a totally non innate thing. Evolution had zero desire to teach us this skill. So you have to learn it. And some of us were really lucky to be in labs where people were really good mentors and they they beat into you how to do this. And again, the topics that we explore are, you know, the latest on semaglutide, which we'll talk about today, I think, the role of testosterone replacement therapy in men with type two diabetes, a huge paper that came out recently, this topic. So it doesn't matter what the subject matter is, the process of thinking is actually quite similar.

• 59:06Tim Ferriss?

  The process of thinking, dissecting and skeptically, but not necessarily cynically, looking at the purported outcomes, I think, is is really important. So coming back to this paper, super prestigious journal, study comes out, psilocybin versus Lexapro.

• 59:28Tim Ferriss?

  Negative study or negative outcome, rather. Then we have this questionnaire, let's just call it, that is determining the results. And the differences come back as statistically insignificant. However, as you pointed out, when you wrote about this, that doesn't necessarily mean clinically insignificant.

• 59:50Peter Attia?

  And nor does it mean that it wasn't. So let's go back and explain what statistical significance is as well. Cause now there's three points. You reminded me of something else that I think is worth stating. How is statistical significance determined? And what does it mean? We hear this term all the time. Statistical significance is basically asking a question. What is the probability that the difference that's observed between these groups is by chance? To answer that question, you have to know a priori, how big an effect size you would expect to see between these two groups.

• 1:00:21Tim Ferriss?

  A priori, meaning beforehand, you need to know what magnitude of difference you'd expect to see between the two groups.

• 1:00:27Peter Attia?

  That's right. And that's really important because that determines what's called the power of your study.

• 1:00:32Tim Ferriss?

  Part of the importance of guessing correctly, maybe that's not guessing, but determining or speculating or guessing correctly, the magnitude of difference, like the difference in effect sizes, because that also will determine how many subjects you need to recruit.

• 1:00:47Peter Attia?

  That's right. So there's something called a power table, which I think we include in one of the studying studies articles, which I remember when I got to the lab was one of the first things my PI Prinsel investigator showed me. He said, this is going to be one of the most important tables you'll ever pay attention to when you're doing research. It's a complicated table to look at, but on the horizontal axis, it has effect size of treatment A. On the vertical axis, it has difference between treatment A and treatment B. So this will be like 10%, 15%, 20%, da, da, da, da, da, da. And then here it would be like five, 10, 15, 20.

• 1:01:29Peter Attia?

  So for example, treatment A would yield, if you predict it's going to be a 30% effect size versus a 40% effect size, you go to 30%. And 10. Does that make sense? Yeah. You're the baseline plus the delta. And then within each square, you typically have two options at either 80 or 90% power. Obviously, 90% power means an even higher standard and it requires more sample, like it has a greater sample size. So it's very common in research to underestimate or overestimate your effect size. And if you overestimate the effect size, you can underpower a study.

• 1:02:12Peter Attia?

  And I think there's actually a pretty sizable chance that that happened here. Yeah. Because the power analysis suggested they were looking for a four-point difference on this scale. It came back with two. It came back with a little over two. Little over two. Yeah. So it's not surprising that it came back not statistically significant because they had engineered the number of participants to only be statistically significant if there is a difference of four points or greater. So on the one hand, you would say, well, that's really impressive. That was a very high bar. My question is, was it too high a bar?

• 1:02:52Peter Attia?

  Is four points necessary when you're really trying to do a study against the gold standard? It would be one thing if you were doing a study against a placebo where you do want to set a very, very high bar. But this is akin to almost like a phase three drug trial where you're trying to compare a new drug to an existing blockbuster gold standard drug and simply being non-inferior to it. And maybe even potentially better on some of the secondary metrics as this one was. Could be more than enough to advance clinical utilization and promulgate further studies. Yeah. So that was one of my first concerns with this study was I don't think it was powered correctly

• 1:03:36Peter Attia?

  because I, I do wonder if four was too high an expectation against this treatment. Of course, other issues are, was this study long enough? This was a relatively short study and it Could have gone the other way. It might be that after a year it flipped and Lexapro was hands down the winner and psilocybin's effect waned. We don't know, but again, that's another thing to be concerned with. And then the point that you brought up, which is a subset of what we were just talking about is, look, maybe a two and a half point increase is clinically really relevant. And the other point here is-

• 1:04:07Tim Ferriss?

  And I definitely want you to give, if you remember, and it can be rough, but some of the-

• 1:04:12Peter Attia?

  Some of the-

• 1:04:12Tim Ferriss?

  Examples of the questions.

• 1:04:13Peter Attia?

  That's right. And that's, that's the final point here is not all questions are created equal. So some of the questions on that scale are like, are there times when you don't feel good about yourself versus there are days I can't get out of bed? Those are not the same question to me. Like, those are very different questions. A person who says, yeah, like, honestly, more than 50% of the time, I don't feel good about myself. Clearly, that's a problem and clearly that's something you want to address. But that's, that person is probably a lot more functional than the person who says, I can't get out of bed.

• 1:04:46Tim Ferriss?

  Yeah, or I think that, you know, the, another two examples to compare would be-

• 1:04:52Peter Attia?

  Well, it's one about suicidal thought as well.

• 1:04:54Tim Ferriss?

  Right, right. And, or I sleep 10 or fewer hours per day, or 12 or more hours per day, and that might account for, say, a two-point difference on an individual questionnaire. But then another question, which was something like, I feel badly about myself most of the time versus, or on a daily basis versus, say, less than half the time, or something along those lines. Then, as you mentioned, questions that could include suicidal ideation. So not all points are created equal.

• 1:05:25Peter Attia?

  Right.

• 1:05:26Tim Ferriss?

  You know, another thing that, you know, I wondered because I have, you know, in part helped fund research at Imperial College, where this came out of, and a bunch of other places. And in conversations with a number of different neuroscientists, they said, well, these are people are very experienced with designing studies and being polished. They said, well, you know, there are times that when you, you have to choose between the primary outcome measure you think the establishment, so to speak, is going to most respect, or the primary outcome measure that you think is going to move the most. And this could be a case, and I'm not speaking for Robin or anyone else involved with this study, but this could be an example of picking

• 1:06:08Tim Ferriss?

  what the establishment would have wanted to see, and then having the secondary outcome measures-

• 1:06:15Tim Ferriss?

  Move in some, some very interesting ways that maybe in retrospect could have or should have been the primary outcome measure.

• 1:06:25Peter Attia?

  Correct.

• 1:06:25Tim Ferriss?

  If you had more confidence in those to begin with.

• 1:06:27Peter Attia?

  Do you know what the budget was for this study?

• 1:06:30Tim Ferriss?

  For this study, I don't, but I'm glad you mentioned budget simply because I think this underscores how important, at least in the US, because I'm involved with, with Hopkins and UCSF and a number of other places, how important it is to try to open up state and federal funding for this type of research from NIMH, NIH, et cetera, because right now it's easy for someone to say, well, that was stupid. Why didn't they just have 50 people in each arm? And the answer is it costs a lot of fucking money and it's hard to raise money in some cases. So, I mean, that was just the point I want to make, but I don't know what the budget for this was.

• 1:07:13Peter Attia?

  Yeah, I mean, look, I think net, net, this study must be viewed as a very positive finding.

• 1:07:17Tim Ferriss?

  Yeah, I agree.

• 1:07:18Peter Attia?

  Because the side effect profile was obviously higher in Lexapro. So again, people taking Lexapro are far more likely to complain of if they're males erectile dysfunction, sexual malfunction, reduced libido, things like that. How we wouldn't want to explore this to the nth degree, I don't understand. And of course, there's other things I'd want to explore like microdosing, right? These were macro doses. So these were people taking a full hallucinogenic dose every three weeks, I believe. And that's not necessarily an easy thing to do either. So we, you know, I'd want to understand what that's like versus what would taking a couple of milligrams per day, which would be well below the threshold of perception or three times a week or something. You know, you hear a lot of anecdotal talk

• 1:08:01Peter Attia?

  about those things being beneficial to people. I'd like to see that studied. And in some ways that would be an easier thing to study because that's the other limitation of this study, which must be noted, which is technically it was not a blinded study.

• 1:08:14Tim Ferriss?

  Yeah.

• 1:08:15Peter Attia?

  It was a randomized study, but it wasn't a blinded study. There is no confusion about which group you were in.

• 1:08:20Tim Ferriss?

  This is one of the biggest challenges. I think there are ways to solve for it that I find pretty compelling from a scientific standpoint, but it's very hard to blind when you're using hallucinogenic, a much less sort of mystical experience level dosing of psychedelics. And it raises, as you noted, given the frequency of administration. So you have, say, two sessions with psilocybin at clearly psychedelic doses. These would be, I would say, in most people sufficient to produce some type of what you might call mystical experience.

• 1:09:00Tim Ferriss?

  And there are questionnaires that Johns Hopkins has developed, Roland Griffiths and Matt Johnson and that team, to measure mystical experience, ego dissolution, sense of unity, et cetera. But when you look at the results, and we assume for the time being, even though I think people should look really closely at the appendices and the secondary outcome measures, let's say that they're break even. All right, this is a tie. But on one hand, as you said, you have more side effects. You have daily administration. And then, on the other hand, you have administration every three weeks. And I think that were they to, and they may still plan on doing follow ups in other university studies,

• 1:09:42Tim Ferriss?

  there's quite a bit of durability that's seen with this type of administration of psilocybin, even out to six, 12 months. It raises some really interesting questions. The most obvious of which is, how does this work? Because if the SSRIs are on some level, I don't want to say suppressing symptoms, maybe masking tendencies, I don't know the right way to phrase it, but it is a maintenance drug. It's an ongoing administration versus highly intermittent. By what mechanism are these changes taking place? Is it just flooding the brain with a compound that has a biochemical effect? Or does it relate more to changing the content and narrative and sort of what work can be done in those sessions themselves?

• 1:10:27Tim Ferriss?

  Raises a lot of interesting questions.

• 1:10:29Peter Attia?

  Yeah, and I think with MDMA, I think the answer is probably a bit more clear. Prior to MDMA's resurgence and serious treatment for PTSD, antidepressants were the mainstay of therapy for this. And I think it was exactly what you said. I mean, antidepressants for PTSD were a masking agent that had some efficacy, but not tremendous efficacy. I think the runaway success we're seeing of MDMA for PTSD is clearly less about the chemical changes in the brain as a result of the administration of the molecule, and far more about the state of mind that it puts the individual in for the type of therapy that they need to do to go back

• 1:11:12Peter Attia?

  and rectify and come to grips with the traumatic event. And I think you're right, I think it's less clear here, but it also doesn't have to be one or the other. It's certainly possible it could be both.

• 1:11:23Tim Ferriss?

  And there's been, for those people who are interested in reading more, and I can link to these in the show notes for this episode, there has been some great New York Times coverage of the Phase 3 trials related to MDMA-assisted psychotherapy. Includes stories from subjects. It's a very compelling read. The results are really pretty staggering and raise a lot of exciting questions for me about the future of treating mental illness or psychiatric disorders. And I also want to give just a shout out to Rick Perry in Texas, who has been recently very public about exploring psychedelic compounds as possible treatments for things like PTSD

• 1:12:08Tim Ferriss?

  among veteran populations and other subpopulations. That I think is a very courageous and very justifiable stance to take. So I was very excited to see that, especially in the great republic of Texas in which we sit.

• 1:12:22Peter Attia?

  That's right.

• 1:12:23Tim Ferriss?

  Any other studies that come to mind? Or you mentioned ApoB. I'm wondering if you have any thoughts on ApoB that you'd like to share?

• 1:12:32Peter Attia?

  Yeah, certainly, as it pertains to things where I'm evolving my thinking, I'm And what is APOB? Yeah, it's probably worth explaining that before we do anything else. So, most people have heard of cholesterol, and most people are used to seeing a blood test where you would see your total cholesterol, LDL, HDL. If the lab is half decent, it would actually say LDL dash C, HDL dash C, non HDL dash C, VLDL dash C. What does all that mean? So, that means LDL cholesterol, or the cholesterol contained within LDL. HDL cholesterol is the cholesterol contained within LDL. So, why do all these things even exist? So, every cell in our body makes cholesterol. It's an essential molecule for life. So, if you don't have cholesterol,

• 1:13:15Peter Attia?

  you're not going to live more than a few seconds. In fact, you'll die in utero, if we're going to be blunt. So, every cell makes this thing. It makes up the cell membrane of every cell. It's what allows membranes to have fluidity and have transporters sitting across them. It's also the backbone for many of the hormones we make. Now, the problem is cholesterol is not water soluble. So, when you have something that's not water soluble, that needs to be transported through the body, which this does, because, as I said, not every cell makes enough of it to meet their own needs. So, there are net exporters and net importers of cholesterol. You have to have a system that can move it around.

• 1:13:55Peter Attia?

  But just like if you tried to pour olive oil into a glass of water, you would quickly realize they don't mix. And similarly, you can't just move cholesterol through the bloodstream the way you can move things like glucose, sodium, potassium, things that are water soluble. So, glucose just travels through the bloodstream on its own, as does a ketone body, for example, but triglycerides, you know, have to be bound. Things that are fat soluble have to be bound. So, Mother Nature invented something called a lipoprotein, which is a spherical thing that on the outside is water soluble, and on the inside houses these water insoluble, or what we call hydrophobic things,

• 1:14:36Peter Attia?

  namely cholesterol ester and triglycerides. And these lipoproteins exist in two broad families. And the families are defined by the protein signature that wraps around them. So, the two families are the APOB family and the APOA family. Technically, there's a subclass of the APOBs. There's an APOB 100 and an APOB 48.

• 1:15:01Peter Attia?

  But for the most part, anybody that's talking about Apo B is referring to Apo B 100. The Apo B 48 is only something called a chylomicron. That is a very short-lived lipoprotein that gets fat out of your gut. So let's put that guy aside for the moment unless anyone wants to come back and we'll do the advanced course on the weekend.

• 1:15:22Tim Ferriss?

  Okay, advanced course for the midichlorians, nerds out there. All right.

• 1:15:26Peter Attia?

  So your Apo B family consists of very low-density lipoprotein or VLDL, intermediate-density lipoprotein or IDL, low-density lipoprotein or LDL, and LP little A, who is the worst actor of the bunch, which is an LDL with another special lipoprotein wrapped around him called an Apo A or an Apo lipoprotein little A. Not Apo A, I should be really clear. It's Apo lipoprotein little A. You have to specify little A to not confuse it with the Apo A family. The Apo A family is the lineage of the high-density lipoproteins. Most people know that HDL good, LDL bad, but that's a little overly simplistic.

• 1:16:09Peter Attia?

  What we really mean to say is that HDLs do not cause atherosclerosis, LDLs do. But it turns out LDLs aren't the only thing that cause atherosclerosis. Anything with an Apo B on it causes atherosclerosis.

• 1:16:23Tim Ferriss?

  And just, just to, just for the, for the listeners, atherosclerosis, meaning the buildup of plaque within the cardiovascular system?

• 1:16:33Peter Attia?

  Yeah.

• 1:16:33Tim Ferriss?

  Or stiffening or inflammation?

• 1:16:36Peter Attia?

  It's the inflammatory disease of arteries that ultimately results in plaque formation and in the worst-case scenario, results in rupture of this plaque that leads to an acute thrombosis or an acute occlusion. And if it occurs in the wrong spot, that can be fatal, instantly fatal. Got it. So VLDLs stick around for long enough that if you have too many of them, they are atherogenic. IDLs are not really a problem because they just don't last that long. So the transit from VLDL to IDL and then IDL to LDL is so quick that the IDLs are kind of irrelevant. LDLs, of course, are the majority of your Apo B concentration unless you also have a lot of insulin resistance where you might have high VLDLs or if you have a genetic

• 1:17:21Peter Attia?

  condition that predisposes you to have too many of those. The IDLs, again, we don't really worry about those. The LDLs are the lion's share of your Apo B. And about 1 in 8 to 1 in 12 people also have a very genetically high level of LP little a, and that also represents part of the ApoB concentration. So ApoB is a far superior measurement to LDL-C when trying to predict cardiovascular risk. So it is hands down the best biomarker we have for cardiovascular risk because it is the total concentration of all particles capable of inducing atherosclerosis. Now, atherosclerosis is multifactorial, so lots of things drive it.

• 1:18:02Peter Attia?

  Inflammation plays an important role and metabolic health plays a super important role. But we understand that lower ApoB is better. Where I think the data are becoming more and more clear is how low you can push this thing without unwanted effects and how much more benefits you can get. There's always a concern, I think, and understandably so, that if you lower ApoB, you're lowering cholesterol. Because if you have fewer of the particles that carry cholesterol, you have less cholesterol floating around the blood. But what most people don't understand is that that's sort of like saying, I'm going to reduce the number of cars traveling over this bridge.

• 1:18:46Peter Attia?

  Does that necessarily mean you're reducing the number of cars in the city? Not necessarily. So most of the cholesterol in your body is not in the lipoproteins rummaging around through your veins. Again, most of the cholesterol is still sitting inherently in the cells itself. So if you took a person's total cholesterol and it was 200 mg per deciliter and you lowered it, total cholesterol, by the way, at this point, I assume is straightforward to explain, it's the sum of all the cholesterol and all the lipoproteins. So the VLDL, IDL, LDL, LP little a, and HDL. If you bash all of those particles and take out all the cholesterol, that's what your total cholesterol is. If you took that number from 200 to 100, you would say, God, that's a 50% reduction

• 1:19:31Peter Attia?

  in your cholesterol. No, it's a 50% reduction in your serum cholesterol, which might be like a 5 to 10% reduction in your total body cholesterol. So. That's one thing to keep in mind. The other thing to keep in mind is we are born with very, very low levels of cholesterol. So in a child, the ApoB concentration is probably in the ballpark of 30, 20 to 30 milligrams per deciliter. By the time we're adults, a level of 80 milligrams per deciliter would put you at the 20th percentile, meaning 80% of people would have a higher number than 80. What's the upshot of this? The upshot of this is there's no upside to having more ApoB. The upside is in having that number

• 1:20:15Peter Attia?

  be lower and lower and lower. But until recently, it wasn't clear how low you could drive it. And there was a type of drug that was developed about 17, 18 years ago, but it became clinically available. I shouldn't say that, actually. It probably started development in about '05. So it's called 16 years ago. Hit the market in 2014 or 2015, a class of drug called PCSK9 inhibitors. And they work in a manner that's distinct from all previous drugs that lower cholesterol. They work by inhibiting a protein that degrades LDL receptors on the liver. And by inhibiting this thing that degrades them, you get more of the LDL receptors on the liver. It pulls more of the ApoB-bearing particles out of

• 1:20:59Peter Attia?

  circulation, mostly which are LDL particles, but also some LP little A particles. With these trials, we see people achieving levels of ApoB in the 10 to 30 range with no side effects, no consequences. Furthermore, these drugs were developed when populations of people were identified who naturally had mutations in PCSK9 that rendered their PCSK9 ineffective. So this was basically a drug that was designed to mimic a genetic mutation found in people who, over the course of their lives, have no increased risk of any disease and simply have a decrease in their risk of cardiovascular disease. In fact, their risk of cardiovascular disease is virtually nonexistent.

• 1:21:42Tim Ferriss?

  Let me ask a silly question. How does one find people who have such a mutation to track them?

• 1:21:50Peter Attia?

  Well, it started with the opposite. So there's a condition called familial hypercholesterolemia, or FH for short, which are people who have very high levels of cholesterol and very high levels of LDL cholesterol and by extension, very high levels of APOB. And they're pretty easy to spot. But it's a definition that is based on phenotype, not genotype. So it's genetic condition, but it's one phenotype, but 3,000 or more genotypes, meaning there are thousands of different genetic mutations that lead to that. I think it was in the late 90s, one of those genetic pathways was identified as a

• 1:22:30Peter Attia?

  hyper-functioning PCSK9. So a group in Toronto identified PCSK9 and realized that these people had a hyper-functioning version of this protein, and it was constantly degrading LDL receptors. And so they just couldn't clear the APOB out of their circulation, and that's why they had sky-high LDL and total cholesterol. When that population was identified, the question was asked, which is, is there a counterpart to them? And it turns out to be really easy to identify them because they're the opposite. These are people who don't take any medicine to lower their cholesterol, and they have levels like infants. And I remember actually reading that paper when it came out and being blown away, and actually

• 1:23:13Peter Attia?

  thinking, there's no way they're going to be able to do this with a drug. But it turned out, it was, it was actually pretty druggable. It wasn't that hard to do. And in many ways, it's a much cleaner drug than say, a statin. Like statins, which are, despite all the public mayhem around it, and the religious polarizing debates around statins, statins are really safe drugs. 10% of people have unwanted side effects and shouldn't take them, but they're very well tolerated drugs. And in my mind, that's kind of a miracle when you consider what they do, which is they inhibit cholesterol synthesis. And when you think about how important cholesterol synthesis is, it's kind of amazing to me that that works without killing people. My hypothesis for this, by the way, is that statins occurred in

• 1:23:55Peter Attia?

  nature. So the first statins were really copying something that was found in nature called red yeast rice. And as a general rule, I think things that came from nature tend to be a little safer, you know, psilocybin, rapamycin, metformin, some of my other favorite drugs. But the method by which the PCSK9 works is just elegant because it's really just targeting one protein with an antibody that makes it harder for the LDL receptor to break down.

• 1:24:26Tim Ferriss?

  Are there any benefits to lowered or low ApoB outside of cardiac risk, lowering cardiac risk?

• 1:24:36Peter Attia?

  Yeah, there actually is.

• 1:24:36Tim Ferriss?

  Or I shouldn't say cardio, cardiovascular risk.

• 1:24:38Peter Attia?

  Yeah, yeah, yeah. And that's sort of, I mean, I think we've known for a while that it also poses a benefit with respect to Alzheimer's disease, for sure. And that's one of those things where I think one needs to be a little bit careful about never confusing population data with individual data. And it's why I think population data are fantastic, but every patient has to be completely assessed as an individual. So the population-based data, for as long as we've had statins, we've known that lower ApoB or lower LDLC means less risk of Alzheimer's disease. And if you think about some of the paths by which people get Alzheimer's disease, there's clearly a vascular path. So Alzheimer's disease is not a disease. Just in the same way, cancer is not a disease singular.

• 1:25:21Peter Attia?

  It's many diseases, not just tissue type, but even within tissue type. Within breast cancer, for example, you have different receptor profiles, the same within lung cancer. Or even just the mutation can render two cancers completely different animals. And similarly, Alzheimer's disease is a collection of lots of diseases with a final common pathway, but you can get there metabolically, you can get there through a vascular path, you can get there through an inflammatory path, there might even be an autoimmune path there. The vascular path is a big path, in my opinion, and therefore, anything that improves microvascular health, which statins do, should improve the risk of Alzheimer's disease.

• 1:26:03Peter Attia?

  So there was something called the Mendelian randomization that was published, I think, like literally a week ago, and I'll explain what a Mendelian randomization.

• 1:26:12Tim Ferriss?

  This is Gregor Mendel?

• 1:26:13Peter Attia?

  Yeah, yeah. So I guess I should explain what an MR is first. MR is

• 1:26:18Tim Ferriss?

  Mendelian randomization.

• 1:26:20Peter Attia?

  Correct. Is a very elegant tool that allows us to try to infer cause when an experiment is not done. This is a profound idea because when you just observe things without doing an experiment, which by definition means randomly assigning treatments or assigning treatments to randomly separated groups, which is the only way to eliminate all bias. There are other biases that can creep in, which we could, I mean, which are actually discussed in the studying, studying section. I won't go into like performance bias and other things like that. But for much of the questions we're interested in, you can't do that. You have to rely on natural experiments.

• 1:27:02Peter Attia?

  So what MR allows you to do is identify genes that are responsible for the traits at hand and not responsible for other traits and do basically a model of what does that genetic trait tell you when it's present or not present? So the, the idea is in an MR analysis, you're basically assuming that genes can occur randomly, which of course they can. And you're then looking at what is the outcome from that? So for example, in the case of ApoB, you would look at genes that are determining ApoB level.

• 1:27:43Peter Attia?

  And there are many genes that play an important role in understanding how high or low a person's ApoB is. And these genes are set, right? It's sort of like you get the gene, you get, you know, you're not going to change the gene and it's not subject to your behavior. Whereas so many other things like what you eat is a behavior that can also impact your ApoB. It's how do you strip that effect out? The healthy user bias, all of the things that are problematic when trying to infer this. And the MR demonstrated quite clearly that lower ApoB is synonymous with improved all cause mortality, cardiovascular mortality, and even mortality associated with diabetes and things like that.

• 1:28:27Peter Attia?

  To me, the most interesting finding in there was the all cause mortality. On the one level, you could say, well, it's not surprising, given that cardiovascular mortality is the greatest cause of mortality in the developed world. So if you take a big enough chunk out of that, you should improve all cause mortality. But nevertheless, that study combined with a number of other very large cardiovascular trials, namely Fourier, Odyssey, Improve It. Every trial has to have a cool name. Just demonstrate this effect where lower is better. The lower the LDL goes or the APOB goes, the lower the risk goes.

• 1:29:03Tim Ferriss?

  Let's jump to rapamycin, since you mentioned it. And you can give very quick ID on what rapamycin is, but since we last spoke, more bearish, more bullish, and why?

• 1:29:16Peter Attia?

  I'm a bull. Yeah.

• 1:29:19Tim Ferriss?

  Doxycan and Rapa? Diamond Hands? Alright. So what is rapamycin?

• 1:29:25Peter Attia?

  By the way, I mean, I know, I know what the Diamond Hands thing is, but what is it? Where did it come from?

• 1:29:29Tim Ferriss?

  No idea. Yeah, I have no idea where Diamond Hands comes from.

• 1:29:32Peter Attia?

  Okay, I was like, did I miss that somewhere in my, in my?

• 1:29:36Tim Ferriss?

  In your, in your econ classes?

• 1:29:37Peter Attia?

  Yeah, yeah, yeah.

• 1:29:39Tim Ferriss?

  No, I don't think so. Okay. So what is rapamycin?

• 1:29:43Peter Attia?

  So rapamycin is a drug that is a naturally occurring anti fungal agent made by a bacteria that was discovered on Easter Island back in the 1960s.

• 1:29:55Tim Ferriss?

  Otherwise known as Rapanui.

• 1:29:57Peter Attia?

  Right. Rapanui is the correct name for Easter Island and the bacteria Streptomyces Hydrascopici, which was discovered there by a group of explorers, explorers is maybe the wrong word, but people doing sort of medical prospecting, a group from Montreal, I believe, in call it 1966, they took a bunch of soil and dirt back from Rapanui to the lab in Montreal, where it sort of sat there unattended to for about five years. A chemist, a very astute chemist by the name of Suren Sagal.

• 1:30:27Tim Ferriss?

  Right name.

• 1:30:28Peter Attia?

  Yeah, he started mucking around.

• 1:30:29Tim Ferriss?

  Related to Steven Sagal? No.

• 1:30:33Peter Attia?

  And no ponytail, fortunately. So Suren did some really interesting chemistry, isolated the compound and noticed it had these really remarkable properties, which was it was the most potent anti fungal agent he had ever seen, or the world had ever seen, frankly. At the time, as his son Ajit tells the story, who I've gotten to know a little bit, he felt he had basically come on to the biggest blockbuster cure for athlete's foot the world was ever going to know. And right about that time, the company he worked for closed its Montreal headquarters, actually laid many people off, ordered the destruction of all non viable compounds and shipped him off to New Jersey. In one of the greatest acts of scientific fortuity.

• 1:31:19Peter Attia?

  He did not follow orders and he instead stuck said rapamycin into a little mini freezer that he and his family transported to their new home in New Jersey. They kept it in the freezer for many years until ultimately another drug company purchased the company he worked for and the new management said, hey, anybody working on anything interesting? He said, I'm, I'm working on this thing interesting that I haven't looked at in a few years. And they said, bring it out. Must have been an interesting lawyer conversation based on the not following orders. Continue. Yeah. So out came rapamycin, which he named mysin and you know, mysin is typically the, the suffix, I guess, that we use or what's the, what's the second part of a word called

• 1:32:02Peter Attia?

  suffix? Yeah. For antimicrobial agents. And of course, Rappa is a tribute to the Rappanui. Like azithromycin. Correct. It quickly became clear that this had remarkable anti-proliferative properties. So it could stop things from proliferating. So that was obviously a big Not just fungi. Right. Exactly. And in particular, it was very effective at making a certain type of lymphocyte, which is a white type of white blood cell, not proliferate. And it then basically went down the path. Eventually Pfizer then bought Amorous, which was the company that bought his previous company, whose name I don't even remember at this point. Pfizer ended up pursuing this and it was FDA approved in 1999 for treatment

• 1:32:44Peter Attia?

  of organ transplantation. So patients that have an organ transplanted have to be put on a really heavy regimen of drugs to suppress a part of their immune system called the cellular immune system that will attack a foreign organ. That's, what is that called? Host graft? No. No graft versus host is actually when the organ, usually it's in the case of lymphoma or leukemia, when someone has a bone marrow transplant and the, the graft, what they've been transplanted attacks the host. I see. Yeah. This is, this is really host versus graft, but we don't usually call that. Yeah. But traditional sort of, you know, rejection. Actually, I did a really cool podcast on the topic of organ transplantation history with a guy named Chris Sonnen Day. And it's, I mean, I know this subject well, but having the discussion with Chris.

• 1:33:28Peter Attia?

  Really opened my eyes to just what a beautiful story it is and what the big breakthroughs were with drug development. And how, you know, at one point, it was like, all you could give people was prednisone and you couldn't save anybody. And then you had other drugs like cyclosporine that were introduced. But then you get into this third generation of amazing drugs like rapamycin that took organ preservation to a, to a higher level.

• 1:33:52Tim Ferriss?

  Now, you're not swapping kidneys.

• 1:33:56Peter Attia?

  How do you know?

• 1:33:57Tim Ferriss?

  Well, at least not since the last time you sold one. In Tijuana.

• 1:34:04Tim Ferriss?

  Settle a bet, but why would you take rapamycin? I know I'm skipping ahead a little bit.

• 1:34:08Peter Attia?

  Well, let's, yes, let's skip ahead. So, so 99, this drug comes on the market for organ rejection. And about 12 years later, a study gets published by Rich Miller, Randy Strong and colleagues. As part of what's called the interventions testing program or the ITP, which is an amazing NIH funded program that tests molecules that are believed to have a shot at enhancing longevity. And it does so in a really, really rigorous way, probably the most rigorous way we can test small animals. I've interviewed Rich Miller as well, probably one of my five favorite podcasts in terms of like nerding out on all of the molecules that can potentially impact longevity.

• 1:34:50Peter Attia?

  And rapamycin was in many ways, the poster child for the ITP program. Because first of all, it's hard to get anything to live longer. Second of all, when they were making the formulation for the rapamycin to feed the mice, and these were very special mice. These were not your typical crappy lab mice that have no bearing whatsoever to real animals. These are a very special type of mice that are much more akin to real animals. And that's a very important distinction between what happens in 99% of mouse research, which is almost inapplicable to humans. And it's why so many drugs that get tested in these B6 mice and things like that.

• 1:35:33Peter Attia?

  Show some marker of success and then they become wild failures beyond the mice. But this was different. They had trouble getting the formulation to work. And by the time they finally did, the mice were like 20 months old, which means they're almost at the end of their life. They're like 70 year old, 65 year old mice. And they contemplated just scrapping the experiment, but they were like, eh, screw it. Let's just run it late. So they started feeding the treatment group with rapamycin and the placebo group get to continue eating their regular chow. Okay, so it was oral administration? Yes, it was the rapamycin was mixed into their chow. And low and behold, the rapamycin group, despite initiating treatment so late in life, had a staggering improvement in lifespan.

• 1:36:18Peter Attia?

  There's been so many ITPs that have replicated this. I don't want to misquote it, but something to the effect of like a 17 or 19% improvement in the males or in the females and 11 to 12% in the males. And remember, the ITP uses a very rigorous way of assessing this, which is they're taking a look at total life, not just remaining life. It's an even higher bar to clear how much lifespan elongation happens. They, of course, immediately went and repeated the study administering the dose when they were younger and saw an even greater response. This has been repeated over and over and over again. And to my knowledge, there was not a single animal study that has tested this hypothesis that has not found this result. Oh, that's wild. Which again is very unusual. Yeah.

• 1:37:03Peter Attia?

  So it's just replicated over and over and over. It's replicated nonstop. What is also interesting is when looking at other markers, other interesting things, such as vision and hearing and other markers of health span, we continue to see improvements in these things for animals as well. And as I think we even spoke about before, a guy named Matt Kabreline, who I'm just interviewed for a second time for the podcast, has been studying this in companion dogs and looking at heart function. Because as you know, basically two things kill companion dogs primarily, heart failure and cancer. And so the question is, what would you be able to do to mitigate especially heart failure,

• 1:37:44Peter Attia?

  congestive heart failure in dogs, especially large dogs, which are more susceptible to this? And again, the results, though the research is limited because there's not an enormous interest in funding this research and it's expensive to fund research in dogs that live so long. It's all pointing in the same direction. So. When you contrast metformin and rapamycin, you have the opposite thing, right? In metformin, we have tons of human data that are not randomized, but are suggesting in cohorts that metformin is also protective, but in a subset of people that have diabetes. So it's not as clear how protective metformin will be in people that do not. In the ITP, metformin did not succeed. In other words, metformin did not extend life in the mice when given alone.

• 1:38:29Peter Attia?

  When it was given with rapamycin, it did, but you could argue that was all the rapamycin. I'm more bullish on Rappa, simply because I'm, you know, I've been taking it now for three years, outside of

• 1:38:40Tim Ferriss?

  And you can hear dog whistles.

• 1:38:42Peter Attia?

  Outside of the apathos ulcers, which are the most annoying side effect of them. Those are those little

• 1:38:47Tim Ferriss?

  Mouth ulcer.

• 1:38:48Peter Attia?

  Yeah, little mouth sores you get.

• 1:38:49Tim Ferriss?

  Canker sore.

• 1:38:50Peter Attia?

  Yep. Yeah. I don't get them de novo, but if I, like if one of my kids head butts me, which they do at an alarming frequency, um, and my, if I break a piece of my gum, like it's going to be an apathos ulcer.

• 1:39:03Tim Ferriss?

  What is it called again?

• 1:39:04Peter Attia?

  Apathos ulcer.

• 1:39:05Tim Ferriss?

  Apathos?

• 1:39:05Peter Attia?

  Yeah. A P H T H O S.

• 1:39:10Tim Ferriss?

  Phew.

• 1:39:12Peter Attia?

  Yeah.

• 1:39:12Tim Ferriss?

  Yeah.

• 1:39:13Peter Attia?

  Nasty.

• 1:39:14Tim Ferriss?

  Nasty. It doesn't sound fun. Is that the only documented in healthy normals? I don't know who would fund this research, if anyone would, or I don't know what, I guess I don't even know what the measurements, the metrics would be, but

• 1:39:25Peter Attia?

  Well, that gets to the problem. We don't have a meaningful biomarker of aging.

• 1:39:30Tim Ferriss?

  Yeah.

• 1:39:30Peter Attia?

  I mean, that's full stop, the biggest problem in aging research today, hands down. Nothing else matters.

• 1:39:36Tim Ferriss?

  Yeah.

• 1:39:36Peter Attia?

  When you don't have a really good biomarker for aging, we're sort of sitting around twiddling our thumbs, pontificating, doing studies that look at things that aren't that interesting, or things that are interesting, but are like First order, second order, you know, but we just, we can't see the whole polynomial, right? Like if you think back to like what a Taylor series is in calculus, if you're trying to use a polynomial to estimate sine x, the first order term is x equals y. Like that's interesting for about that much. But you know, when you really want to know x minus x cubed over three factorial plus x to the five over five factorial, like when you want to really start figuring out the shape of this thing, you've got a, you're just going to need better tools.

• 1:40:18Tim Ferriss?

  As we're talking about rapamycin, I think naturally a lot of people listening will think of lifespan. It's a term they're more familiar with, right?

• 1:40:25Peter Attia?

  Yep.

• 1:40:26Tim Ferriss?

  Start to finish. What are you clocking in, in terms of years? And then there's health span. And, you know, I took a note, as I always take notes during these conversations about the vision and the hearing. So I'm 40, I guess my memory is also going, 43. And recently had a, not quite an audiology test. I mean, it wasn't, it was quite basic hearing test done and seemed to have some minor hearing loss in the higher ranges on one side. Could have been some of the ambient noise in the room. I don't know. I'd like to try to replicate it. But could one make a compelling argument that rapamycin could improve restoring that

• 1:41:10Tim Ferriss?

  type of hearing? Or is that too much of a stretch?

• 1:41:13Peter Attia?

  No, it's just too soon to say. I, I think it's certainly plausible, but I think it's, it's too early to say. I mean, we've seen that in animals now. We've seen that in animals, but I don't know if that's going to translate to humans.

• 1:41:23Tim Ferriss?

  Has that been seen in multiple species?

• 1:41:25Peter Attia?

  I've only seen it in mice.

• 1:41:27Tim Ferriss?

  In mice?

• 1:41:27Peter Attia?

  Yeah.

• 1:41:28Tim Ferriss?

  These are kind of the feral mice versus the like Holstein cows of mice?

• 1:41:31Peter Attia?

  To be honest with you, I don't remember what mice were used in that study, but it's quite possible. They were your garden variety genetically not so interesting mice. Yeah.

• 1:41:40Tim Ferriss?

  Got it.

• 1:41:41Peter Attia?

  You've hinted at or outright identified a big challenge, which is How do you study a drug in healthy people? And by the way, a drug that has a little bit of a bad rap. Immune suppressing drugs don't have people very excited.

• 1:41:54Tim Ferriss?

  Yep.

• 1:41:54Peter Attia?

  And until 2014, until Christmas Day 2014, or Christmas Eve Day, I didn't think of this as very interesting. So in 2011, you have the first ITP published. And it's like, wow, that's cool. But I used to give this to kidney transplant patients. I'm not taking that. And then you had Joan Manick was the lead author on a study that came out at the end of 2014 that looked at a rapamycin derivative called everolimus. And it was given to 65 year olds in the following fashion. There were four groups, a group that was given a placebo, a group that was given one milligram every day, a group that was given five milligrams once a week, and a group that was given 20 milligrams once a week.

• 1:42:37Peter Attia?

  And they were given this for a period of eight weeks, I believe. And then they were taken off everything for another period of, I believe, six weeks, and then they were challenged with a flu vaccine and then looked to see who mounted the best immune response. And counter to what you would expect, the people on rapamycin developed a better immune response, which flew entirely in the face of what one would have expected. The group getting five milligrams once a week, they had the best response and the fewest side effects. So the 20, we probably don't want to go down this path because it's just more complicated. There are two complexes of mTOR. There's this, have we talked, we gotta talk about mTOR. How does rapamycin work, right? It works by inhibiting something called mTOR,

• 1:43:21Peter Attia?

  the mechanistic target of rapamycin.

• 1:43:23Tim Ferriss?

  We could also refer people to our conversation with David Sabatini.

• 1:43:27Peter Attia?

  Absolutely. Back on Easter Island.

• 1:43:28Tim Ferriss?

  Back on Easter Island. So, long story short, there was a trip. It may or may not have involved some wine

• 1:43:36Tim Ferriss?

  to Rapanui to Easter Island. And one of our tripmates was David Sabatini, who, cue Peter.

• 1:43:45Peter Attia?

  Was the first person to identify how rapamycin worked in mammals.

• 1:43:51Tim Ferriss?

  Yeah, so we we talk about that quite a bit in that episode. So I think let's refer people to if you just search Tim Ferriss Show Easter Island, I can't imagine there are many results and you will see an amazing crow arm displayed by another one of our tripmates, which happens to just be an artifact from a weird panoramic shot. But we did use that photo just to just to shape his nuts a bit. So let's see.

• 1:44:16Peter Attia?

  Yeah, so let's just wrap it up by saying that the five milligram dose seemed to be the sweet spot. Once a week, it produced all the benefit without the side effects. 20 produced a similar benefit, but had too many side effects.

• 1:44:27Tim Ferriss?

  Do you no longer take Metformin?

• 1:44:30Peter Attia?

  I do not.

• 1:44:30Tim Ferriss?

  Hmm, interesting. What were some of I know you referred to was his last name Matt?

• 1:44:35Peter Attia?

  Caberlin.

• 1:44:36Tim Ferriss?

  Maybe it wasn't Matt. Matt Caberlin, I know, something Miller.

• 1:44:40Peter Attia?

  Oh, Rich Miller.

• 1:44:40Tim Ferriss?

  Rich Miller. What are some of the other candidates that are most interesting to you in terms of pharmacological interventions that might extend lifespan or health span?

• 1:44:52Peter Attia?

  There are several others that were found to have significant lifespan enhancement repeatedly. One is a carbos, which is a favorite of our mutual friend Kevin Rose. So the way the ITPs work is really cool. Anybody can suggest a compound. So it's it's basically like, you know, it's like a crowdsourcing thing where you can decide like, I want to know if this molecule has a benefit. And as long as you can write the proposal, which contains the rationale for why, if they buy it like they're going to study it. So a carbos was suggested because the idea is a carbos prevents the absorption of starch. Yep. So if you eat a pizza, you can have half of it leave your body basically without being absorbed.

• 1:45:35Tim Ferriss?

  Footnote for Kevin. I think the ratio of donuts and beer to acarbos does matter probably at some point.

• 1:45:43Peter Attia?

  Oh, sure. Yeah. Yeah. And you can only take so much a carbos. I mean, it is a little hard on your gut. Yeah, because it's in the gut that it's preventing the absorption. And the thinking was, well, a carbos, if it's eliminating a reasonable fraction of your glucose, is got to be a caloric restriction mimetic, or a CRM, as they call them. So let's see if that works. And it turned out a carbos did work. But interestingly, the animals who lived longer weren't any lighter and didn't have any lower levels of average glucose than their shorter-lived counterparts. So whatever Acarbose was doing to extend life, it wasn't through making you eat less, or making you weigh less, or making you even have a lower hemoglobin A1C. It almost assuredly worked

• 1:46:25Peter Attia?

  by the only other thing it did, which was lower the spikes and peaks of glucose. It blunted those. So it spreads out the speed with which glucose is hitting you, but lowers the spikes.

• 1:46:37Tim Ferriss?

  Are you more bullish on Acarbose than Metformin?

• 1:46:41Peter Attia?

  No, I don't think so. I would still probably put Metformin as a more interesting agent. I mean, Acarbose, first of all, is just not an easy agent to take.

• 1:46:49Tim Ferriss?

  Yeah.

• 1:46:49Peter Attia?

  I mean, unless you like diarrhea.

• 1:46:51Tim Ferriss?

  Well, maybe Giardia is also a caloric restriction to medic.

• 1:46:55Peter Attia?

  So, and honestly-

• 1:46:57Tim Ferriss?

  Just your monthly dose of typhoid fever.

• 1:46:59Peter Attia?

  Yeah, yeah, exactly. Right. I'm always one, I'm just one Giardia about away from goal weight. I'm still more, more optimistic about Metformin, but also Metformin is more of a mystery. In fact, our other mutual friend from Easter Island, Nav Chandell, this is one of the things that he works on extensively.

• 1:47:17Tim Ferriss?

  Mr. Crow Arms?

• 1:47:18Peter Attia?

  Yeah. And I'll be having Nav back on the podcast probably in early 22.

• 1:47:22Tim Ferriss?

  Nav is fantastic.

• 1:47:23Peter Attia?

  When, when there's some killer work that he's doing on the mechanisms of Metformin, and we'll, we'll dive back into that. But there is another drug that I think is super exciting that was recently published in the ITP called Kanagaflozin.

• 1:47:38Tim Ferriss?

  Ooh, Kanagaflozin.

• 1:47:40Peter Attia?

  Kanagaflozin, spelt actually as it sounds with a C. And it is a class of drug known as an SGLT2 inhibitor.

• 1:47:52Tim Ferriss?

  Rolls up the tongue.

• 1:47:53Peter Attia?

  Yeah. The SGLT2I. And it's a more elegant version of Acarbose working in the kidney. So the kidney is kind of a cute organ. Cute in that it's really smart. I think evolution figured out that it would be too difficult to know all the things that are bad for you, but it's really easy to know all the things that are good for you. So the way the kidney works is it gets obviously a staggering amount of your circulation, like 25% of your cardiac output is passing through your kidneys with every time your heart pumps. And the first pass of the kidney is to take everything in your blood and dump it out. So it's sort of like saying, I'm going to clean my drawers by throwing everything

• 1:48:35Peter Attia?

  on the floor and then only putting back in my drawers, the things that I want. And because again, it's easier to know you need glucose, you need potassium, you need magnesium, you need sodium, da, da, da, da, as opposed to this toxin might that might appear 100 years from now or a million years from now. So in the reabsorption process, Kanagaflozin blocks the reuptake of glucose. So you end up peeing out a lot of glucose. So this drug obviously was introduced to treat people with type 2 diabetes and it showed remarkable efficacy in doing that.

• 1:49:10Tim Ferriss?

  So in a, in a healthy subject, you would be presenting the sort of traditional old fashioned symptoms of diabetes.

• 1:49:20Peter Attia?

  Yeah, although not quite to the same extent because it's sort of gradient driven. So in the traditional Oslar sense where, you know, literally diagnoses of diabetes was made by tasting the urine and seeing how sweet it was. Those were patients that were presenting with, you know, wildly uncontrolled diabetes with a glucose of like 800 milligrams per deciliter. You know, they're about to have a coma.

• 1:49:41Tim Ferriss?

  I first learned what diabetes was when I was in Japan as an exchange student and it's tounyobio, which is sugar urine disease. And it's really obvious in the characters. I had no idea what diabetes, you know, I heard it on the oatmeal.

• 1:49:56Peter Attia?

  Which is interesting because I'm guessing nobody in Japan actually has diabetes.

• 1:49:59Tim Ferriss?

  Yeah, I

• 1:50:00Peter Attia?

  Today.

• 1:50:01Tim Ferriss?

  Yeah, today, when you have people eating like rice with mayonnaise.

• 1:50:05Peter Attia?

  Yeah.

• 1:50:05Tim Ferriss?

  Slightly more.

• 1:50:06Peter Attia?

  When you were there, yeah, there's probably just like five people with diabetes.

• 1:50:09Tim Ferriss?

  Yeah, very few.

• 1:50:10Peter Attia?

  So Kanagaflozin basically blunts this reabsorption of glucose, very successful drug for the treatment of diabetes and also in people with diabetes is showing better effects when it comes to heart failure, better effects when it comes to mortality. This is really, in my opinion, a first line drug for any patient with diabetes and it does not cause hypoglycemia. So if a normal person takes it, they're not going to have a dangerous drop in blood sugar. So it is also blunting the spikes, but it also seems to lower the average as well. So Kanaga Flozin extended the lives of mice in the ITP. I don't remember the exact numbers. It wasn't quite as

• 1:50:51Tim Ferriss?

  Diabetic or sort of

• 1:50:53Peter Attia?

  No, no, no. These are perfectly normal mice. It wasn't as big an effect as rapamycin, but it was bigger than most other things. There haven't been that many successes in the ITP. Obviously, most drugs fail, but the successes like rapamycin, 17 alpha estradiol, Kanaga Flozin, Acarbose, those are, you know, some of the big successes. And of course, they get tested over and over again to make sure they weren't one

• 1:51:17Tim Ferriss?

  Was the 17 something or other you just mentioned?

• 1:51:19Peter Attia?

  17 alpha estradiol was a very interesting molecule.

• 1:51:22Tim Ferriss?

  17 alpha estradiol.

• 1:51:24Peter Attia?

  Which is not the estrogen. It's not normal estrogen, which is beta estradiol. And 17 alpha estradiol only improved lifespan of male mice. It had no impact on female mice. The thinking being that it somewhat mimicked the estrogen protection benefits in a male, but not in a female because they already had estrogen.

• 1:51:44Tim Ferriss?

  Yeah, that's super interesting.

• 1:51:45Peter Attia?

  Yeah. That's not a molecule that, to my knowledge, is even in clinical trials. Like, I don't even know if there's an IND for that molecule that it's even, I don't know what pharma is doing with that information.

• 1:51:56Tim Ferriss?

  How did that get submitted for the ITP?

• 1:52:01Peter Attia?

  Yeah, it's funny. I asked Rich about that.

• 1:52:03Tim Ferriss?

  Some just backyard chemist is like, hey guys, I inherited a bunch of oil money. Here, I want you to make this.

• 1:52:08Peter Attia?

  No, it was effectively someone who had been studying this molecule and thought like, I wonder if this would be interesting for the hypothesized mechanism that it would offer some of the protective benefits of estrogen without the feminizing effects, right? So it's, it doesn't have the sexual characteristics of estrogen. So the question is, because if you gave a male a whole bunch of estrogen, you're not going to make them live longer.

• 1:52:29Tim Ferriss?

  Yeah.

• 1:52:29Peter Attia?

  Because whatever benefits come from it are going to be offset by a bunch of negatives.

• 1:52:33Tim Ferriss?

  Just to scratch my own itch in curiosity here. So can someone with enough money just push whatever they want through the ITP to get something tested? Or like, what combination of factors lead someone? To be able to take a candidate or something they think is promising like a seventeen alpha.

• 1:52:53Peter Attia?

  I'm talking about money. I think honestly, it's just about having the time like there's a candidate drug that I'd like to put on and I just haven't had the time to write a proposal. Uh, so maybe in a, in a couple of years, I'll, when I finish the book and a few other projects.

• 1:53:05Tim Ferriss?

  With all your spare time.

• 1:53:06Peter Attia?

  Yeah, there is a candidate that I think would be interesting. So no, it's just having a good scientific case for it. Yeah.

• 1:53:11Tim Ferriss?

  That's fascinating.

• 1:53:14Tim Ferriss?

  Huh. Should we do some stupidity? I think absurd things, anything particularly ridiculous that you're doing these days or enjoying?

• 1:53:24Peter Attia?

  I think with the lockdown, with the whole COVID thing, I've never spent more time at home and it's been amazing. Like it's been.

• 1:53:30Tim Ferriss?

  Your dream come true.

• 1:53:31Peter Attia?

  Oh, it's just like, take the most antisocial person in the world and allow him to never have to go out.

• 1:53:39Peter Attia?

  And that's been, I think, really great for my family on some levels, but also it's mean that they've, it meant they've had to put up with more of my stupid jokes and the, like, just the dumb things that I think about. So one of the things that I have been really harping on and just drives my wife nuts is, you know, when you eat a banana, at the very bottom, there's that little nubbin?

• 1:53:58Tim Ferriss?

  Yes.

• 1:53:59Peter Attia?

  You know, the little part? So I am convinced that the nubbin is like lethal. Like if you eat a nubbin, you're gonna die.

• 1:54:07Peter Attia?

  And so I'm the nubbin police of our house. Cause a lot of times, you know how you can never finish bananas? Like you, you buy them, you buy like ten and you might eat three, but then seven are gonna go bad.

• 1:54:19Tim Ferriss?

  Yeah.

• 1:54:19Peter Attia?

  So we peel the bad ones and put them in the freezer to make smoothies later on. Cause we always add, you know, frozen fruit to make my protein shakes or whatever. And when I do it, I'm really careful to never put the nubbin in. I peel it, but I keep the nubbin in the peel and it goes in the trash. But when my wife does it, she just like leaves the nubbin in. So I'm like, of course I don't care, but I act like I care. And I'm like, babe, are you serious? Got a nubbin in here. Like there's people in the house that could eat this. Like, do you understand the nubbin is literally the third leading cause of death worldwide? Not in the developed world. Here it's like the fifth leading cause of death. But when you average it out across the globe, third leading cause of death, nubitis.

• 1:55:01Tim Ferriss?

  Nubitis.

• 1:55:02Peter Attia?

  So, and it just doesn't get old. And I think the more it bugs her, the funnier it is to me. And the same with my daughter, just endless eye rolls and they don't buy it. They really think they claim that you can eat a nubbin and nothing will happen to you.

• 1:55:15Tim Ferriss?

  Depends on your topo chico to nubbin ratio in the house. I think you're pretty heavily weighted in the former. All right, what else do we have on any of the three categories really? If there's something that jumps out where you're like, this is really, for any reason, pulling my attention.

• 1:55:35Peter Attia?

  Uh, let me look at my list here and see what else. Oh, I know something else. I've changed my mind on.

• 1:55:41Tim Ferriss?

  Yeah.

• 1:55:42Peter Attia?

  I'm way, way, way more bullish on sauna than I have ever been before. I used to be in the camp of sauna feels great. It maybe even helps you sleep a bit better, but that's probably about it. There's no way you're going to really live longer because you're in a sauna. While truthfully, we don't have really great prospective data. Or sorry, I should say we have good prospective data. We don't have good randomized data. I think this is one of those things where the burden of evidence in the non randomized data is so strong. It's becoming hard to ignore. So most of the research on this subject has come out of Finland and.

• 1:56:25Tim Ferriss?

  The sauna lobby.

• 1:56:26Peter Attia?

  Yeah.

• 1:56:29Peter Attia?

  And so there's the obvious issues with this, right? The people who can afford to sauna are by definition going to have more time on their hands, more disposable income, probably more education, like all of the standard things. On top of that, if you're going to choose to sauna because you believe it's healthy, what else are you doing because you believe it is healthy? I mean, right. So if the data showed that sauna versus non sauna was like a 5% improvement in mortality, it would be hard to get that excited about it. But when you look at the largest published series on this. You see a benefit in all-cause mortality, a relative risk reduction of 40% and an absolute

• 1:57:12Peter Attia?

  risk reduction of like 18%. Those are

• 1:57:16Tim Ferriss?

  Those are high numbers.

• 1:57:16Peter Attia?

  Those are ridiculous numbers. And that's when you are comparing someone who like saunas four to seven times a week.

• 1:57:25Tim Ferriss?

  I was gonna ask you.

• 1:57:26Peter Attia?

  Yeah. So what's the dose and frequency?

• 1:57:27Tim Ferriss?

  What's the, yeah, what's the dose and frequency and what do you believe the minimum effective dose to be? Kind of like the zone two training, you described what it is. And then you said that.

• 1:57:35Peter Attia?

  Yeah.

• 1:57:35Tim Ferriss?

  It's small three hours a week. I do four times 45.

• 1:57:37Peter Attia?

  Yeah. Just to get to the punchline. I, I think based on the research, the MED is four sessions, 20 minutes, 80 degrees Celsius.

• 1:57:47Tim Ferriss?

  Four sessions times 20 minutes, 80 degrees Celsius.

• 1:57:53Peter Attia?

  Yep.

• 1:57:53Tim Ferriss?

  Oh, you, you're Fahrenheit. What's the conversion there?

• 1:57:59Peter Attia?

  Uh, it's about 175 Fahrenheit.

• 1:58:03Tim Ferriss?

  175 Fahrenheit. Got it.

• 1:58:07Tim Ferriss?

  Dry, wet.

• 1:58:10Peter Attia?

  There's much more literature on dry. You know, I actually had a call with a patient this morning and this topic of saunas came up and she asked if she could substitute steam rooms and such. And I said, we just don't know because we don't have the data. So, you know, the precautionary principle would say if you have access to a dry sauna, that's where we have reams and reams and reams of data. So it's probably where it goes. But look, if you think about what the mechanism of action is.

• 1:58:34Tim Ferriss?

  Yeah. I was gonna ask you next. Is it heat shock proteins? Is it something else?

• 1:58:37Peter Attia?

  I think it's many things. I think it's heat shock proteins. I think it's nitric oxide. I think it's literally vascular tone, right? Reduction in blood pressure, increase in heart rate and cardiac output. So there's a bit of an exercise benefit. I think BDNF has been measured. I can't recall. That could be another potential benefit. So my guess is it's.

• 1:58:54Tim Ferriss?

  BDNF, brain-derived neurotrophic factor.

• 1:58:56Peter Attia?

  Yeah. I think it's probably half a dozen things that are all moving in the right direction. It's funny, when I have done some sauna-ing, I've done lactate checks in there to see if it gets me to like zone two. It's not a pure exercise mimetic because it doesn't even get me to the level of a zone two work. At least when it comes to a pure ATP uptake or ATP production standpoint. But yeah, I've become really optimistic on this and I think it's very promising. And I think it's again, it's the challenge is, is how scalable is it right? Like it's not as it's not that easy to do.

• 1:59:31Tim Ferriss?

  I would imagine also contraindicated for a lot of folks.

• 1:59:34Peter Attia?

  Yeah, yeah, I suspect if you're really far down the line of your health is is suffering and you're, you know, particularly old or something like that, or your heart's a little more frail. Yeah, this might push you a little bit beyond. So again, it speaks to sort of prevention and and hopefully with COVID kind of winding its way down and enough people getting vaccinated, people can get back to gyms where saunas are and things like that.

• 1:59:54Tim Ferriss?

  Yeah, amazing. Preferred method for zone two training? Seems like you do most of your work on a bike.

• 2:00:01Peter Attia?

  I do, I like the bike. It's just my body is so much more efficient on a bike than anything else.

• 2:00:06Tim Ferriss?

  Do you have preferred stationary bike?

• 2:00:08Peter Attia?

  Or do you? I do, I ride my bike, like my road bike on something called a Wahoo kicker.

• 2:00:14Tim Ferriss?

  Wahoo kicker.

• 2:00:15Peter Attia?

  Which is awesome, like hands down.

• 2:00:18Tim Ferriss?

  If someone doesn't have a road bike.

• 2:00:21Peter Attia?

  Then I, my favorite stationary bike is the Kaiser.

• 2:00:25Tim Ferriss?

  Dec Kaiser, no, I don't think that's actually there.

• 2:00:27Peter Attia?

  The Sosa.

• 2:00:28Tim Ferriss?

  K A I S E R?

• 2:00:30Peter Attia?

  Yeah, K A I S E R, I believe.

• 2:00:33Tim Ferriss?

  All right.

• 2:00:34Peter Attia?

  And I think Kaiser makes such a fantastic spin bike.

• 2:00:38Tim Ferriss?

  You want to do one more change your mind about or one more excited? You can dealer's choice.

• 2:00:44Peter Attia?

  Yeah, I'm, I'm pretty excited about GLP one agonists.

• 2:00:48Tim Ferriss?

  Me too, I don't even know what that means. Tell me, Peter.

• 2:00:51Peter Attia?

  All right, so GLP one agonist glucagon like peptide one. They also go by GLP one RAs. So glucagon like peptide one receptor agonists. Okay, so glucagon is a hormone, it's made by the liver, sort of opposes the action of insulin. It's a hormone that produces satiety and can regulate blood glucose levels.

• 2:01:21Tim Ferriss?

  Regulate, meaning it's catabolic?

• 2:01:22Peter Attia?

  Lowers lowers blood glucose. Yeah, it secretes insulin, actually. It results in secretion of insulin to lower blood glucose. So these are a group of drugs that have been around for quite some time. Also a high choice in people with type two diabetes. A trial came out, I want to say 2014. Showing that one of these drugs was actually also pretty good for weight loss in non-diabetics.

• 2:01:50Peter Attia?

  It didn't get a lot of traction. The effect size was reasonable, but it wasn't great. I looked at it quite a bit because I remember at the time I had a patient whose weight was really recalcitrant. It just wasn't clear what it was going to take to help her lose weight. I certainly am not a fan of stimulants for weight loss. Drugs like phentermine can be somewhat effective, but they can also have their side effects and be somewhat habit forming. And we had sort of noodled this and eventually we ended up trying this drug. It didn't really have that much of an effect and I kind of sort of put it aside for a while.

• 2:02:29Peter Attia?

  Until about six or seven months ago, I was talking to someone who had an early line of sight into a trial. It was going to be published and they said, you know, they'd been using it clinically, a newer version of this drug. It's called semaglutide. The trade name is Ozempic. And they said, yeah, you've got to see what this drug can do. So the drug, the dose that's given for people with diabetes is one milligram once a week. So it's an injectable drug. So it comes in a little pen. You, you know, shoot it in your gut or your leg once a week.

• 2:03:00Tim Ferriss?

  Intramuscular or?

• 2:03:03Peter Attia?

  Tiny, tiny little insulin syringe. And he said, yeah, but when we push people up to two and a half milligrams, the weight loss is comical. This is not just people with diabetes. This is anybody. And then sure enough, there was a study that was published probably a couple of months ago, looking at semaglutide in overweight and obese people without diabetes. And the weight loss was through the moon. I mean, it was, you know, we're talking like 20% weight loss.

• 2:03:31Tim Ferriss?

  Holy shit.

• 2:03:32Peter Attia?

  Completely durable as long as you're on the drug. So then it begs the question, what happens when you come off the drug? We haven't seen fully what that looks like yet. I mean, I think we need to see what those studies look like. I mean, my thinking of this, we've now put a lot of patients on this drug. I mean, a lot is relative, but you know, maybe 12, 15 patients we've put on this drug. Some people can't tolerate it because of the nausea. So

• 2:03:56Tim Ferriss?

  Nausea?

• 2:03:56Peter Attia?

  Yeah. I mean, that's definitely one of the side effects.

• 2:03:58Tim Ferriss?

  How often is it administered?

• 2:03:59Peter Attia?

  Once a week.

• 2:04:00Tim Ferriss?

  Once a week? Is the nausea transient or is it?

• 2:04:03Peter Attia?

  Yeah, it tends to fluctuate. So if you inject it on a Sunday and then, you know, usually by the next Saturday, the symptoms are gone. But then when you hit yourself on that Sunday, Sunday, Monday, Tuesday, you'll be a bit more nauseous. Now, again, that's, so it's transient across the week, but it also seems to be transient over time. So the, the dose in the study was 2.4 milligrams. So, you know, two and a half times higher than you're doing it in people with type 2 diabetes. But you don't start people at that dose. You'll start them at half a milligram for a few weeks, then one milligram, then one and a half, then two, et cetera. But basically, we haven't seen any patient who can tolerate the drug that does not lose weight.

• 2:04:41Tim Ferriss?

  Have, have any cycled off? In which case, I mean, obviously, behavior matters a lot and calories matter a lot, but

• 2:04:48Peter Attia?

  Yep.

• 2:04:48Tim Ferriss?

  Do you see a greater

• 2:04:52Peter Attia?

  No, I don't know.

• 2:04:53Tim Ferriss?

  than you would anticipate otherwise?

• 2:04:54Peter Attia?

  And they don't seem to regain all the weight they lost. Now, my biggest concern, I was so fascinated by this before the study came out. We actually did a whole journal club just on this study and went stupidly nerdy on this drug. The biggest concern I would have is, is a drug that lowers glucose but raises insulin such a good idea? And also, it flies in the face of how you would lose weight in that situation, right? It seems to not be entirely clear why would that result in weight loss unless the increase in insulin, along with the glucagon-like peptide are reducing appetite. But what we've discovered in experimenting with a lot of our patients, by experimenting, I mean, just doing a lot of blood tests before and after, is

• 2:05:40Peter Attia?

  While it probably slightly increases your fasting insulin level, it's also clearly increasing muscle insulin sensitivity because postprandial insulin levels seem to be down. And I would bet, though it was not done in this study.

• 2:05:54Tim Ferriss?

  Postprandial, meaning post-meal?

• 2:05:55Peter Attia?

  After meal. I would bet that if they had looked at 24-hour insulin secretion, which you can do by collecting 24 hours of urine and measuring C-peptide, which is, exists in a one-to-one ratio with insulin, because when insulin comes out, it's a prohormone, and then it gets cleaved into insulin and C-peptide. So you should have one C-peptide for every insulin. So if you measure the urinary amount of C-peptide, you know how much insulin was secreted. I'm really disappointed that study didn't do that, but my guess would be that they saw 24-hour C-peptide go down even as resting insulin went up.

• 2:06:31Tim Ferriss?

  Okay, which would mean, and well, please correct me if I'm oversimplifying this, but that on, if you look at the average, it is not net-net leading you to increased insulin levels?

• 2:06:44Peter Attia?

  That's right.

• 2:06:44Tim Ferriss?

  Yeah. That's so interesting. Now, when you say 20% reductions, are we talking about body fat or body weight or?

• 2:06:53Peter Attia?

  Body weight.

• 2:06:53Tim Ferriss?

  Wow, total body weight.

• 2:06:55Peter Attia?

  Yeah.

• 2:06:55Tim Ferriss?

  Wow.

• 2:06:56Peter Attia?

  So, you know, that's, and that's easy. You'll see more.

• 2:06:59Tim Ferriss?

  Yeah, these are in obese people?

• 2:07:01Peter Attia?

  Yeah, we've even put it, we've even had patients who are not even, wouldn't be classified as obese, just slightly overweight. You know, a 200-pound person that in three months is 180 pounds and effortlessly at 180 pounds, right? Like, they've literally reduced their appetite, and they've improved their insulin sensitivity and glucose.

• 2:07:19Tim Ferriss?

  And that's where other interventions failed. So it's not, I mean, I know we're not blinding this or anything with patients, but you don't think that that, you attribute that predominantly to this, this drug, not to?

• 2:07:33Tim Ferriss?

  Say changes in eating or other habits.

• 2:07:36Peter Attia?

  Well, they have changed their eating, but I think it's in response to the drug.

• 2:07:39Tim Ferriss?

  Ah, right.

• 2:07:40Peter Attia?

  So I think the drug is working centrally, peripherally. I think it's working on the fat cells. I think it's working on their brain. I think it's working on their muscles. I think it's doing a lot of things and it's still early days, but I mean, this is a promising drug, in my opinion. And I think there's some people who think that you shouldn't need a drug to help you. And if you need a drug to lose weight, you're somehow a bad person or something like that. But you know, I just, I just think categorically, that's just such a, a simple minded view of the world, right? Like, we live in a world with technology. And just as you don't rub two sticks together when you want to have a fire, if a Zippo lighter is available to you, if you have tried every dietary strategy imaginable and your metabolism

• 2:08:25Peter Attia?

  is not, you know, moving in the right direction, why shouldn't we explore other ways to kickstart that? And the other thing, by the way, is I think you can take these things for a few months, come off them and see if you have formed new habits in the interim. I also think there'll be, in my mind, a model for cycling, three months on, three months off, three months on, three months off. Again, we want to make sure that that doesn't cause some recalcitrance to the medication or something like that. But I think this is exciting. I think this warrants a lot more follow-up. But what it's saying is that things that improve diabetes also improve health. And nothing does that more than exercise and nutrition. That's the reality of it. But not everybody can do enough exercise and the right nutrition with enough ease

• 2:09:10Peter Attia?

  to get the benefits. So the more tools we have in our toolkit that go outside of that, the better.

• 2:09:15Tim Ferriss?

  Dig it. Peter, always so fun to hang. And I want to underscore to me how exciting and interesting it is for people listening to strive to increase their scientific literacy. And you have your series of articles, which we'll put in the show notes. There's a book that I enjoyed tremendously called Bad Science by Ben Goldacre, I believe is an M.D. And enjoyed that so much that had a few excerpts from that book put into the appendix or the appendices of, for our body. Cause I wanted to provide some basics. Are there any other resources or recommendations for folks who?

• 2:10:00Tim Ferriss?

  Want to improve their ability to separate fact from fiction, hype from reality when it comes to headlines, media, studies, and so on. I mean, not to get to Peter T level, but to get to the point where they just have a better ability to separate signal from noise with this kind of thing.

• 2:10:22Peter Attia?

  You know, there's a good newsletter that I subscribe to out of the University of Indiana. It's called the Metabolomics and Energetics or Metabolism and Energetics. It's like a weekly newsletter that comes out on Fridays. And it's, you know, it's pretty detailed, but one of the sections is always headline versus study.

• 2:10:39Tim Ferriss?

  Oh, that's great.

• 2:10:40Peter Attia?

  And that's always a cute one because every week you get to see, they just pick one example because of course there's a billion examples every week of how the headline says something and it turns out to have nothing in common with the study. Now, that's not exactly the question you've asked, but it is a good illustration of just how, if you read something in the media, you should just assume it's being taken out of context and it's incorrect. And unfortunately, I wish I had better answers on.

• 2:11:06Tim Ferriss?

  Well, it'd be like if you saw a headline that said, eating nubbins increases risk of colorectal cancer by 100%. But if the chance is one in 10 billion people and it goes to two in 10 billion people, it doesn't mean you should pay attention to it.

• 2:11:21Peter Attia?

  That's right.

• 2:11:22Tim Ferriss?

  Not to discredit your nubbin.

• 2:11:23Peter Attia?

  And that's a great example of always knowing absolute risk versus relative risk. It's exactly, it's exactly like the kind of stuff we talk about in studying studies is never pay attention to relative risk without knowing absolute risk as well and things like that. So.

• 2:11:36Tim Ferriss?

  Yeah. Peter, I think it might be time for us to prepare for our prandial adventure. That's probably not the way you use it. To have our meal, to have our.

• 2:11:48Peter Attia?

  Our pre-prandial exploration.

• 2:11:50Tim Ferriss?

  Our pre-prandial exploration of various, various cacti. Is agave considered a cacti? Or I guess, what is miscal actually made from? Is it agave?

• 2:12:01Tim Ferriss?

  I know it's like a campfire in your mouth, but that doesn't tell us much about the botanical origins. I know sitol is different. Have you had sitol as a side note? It's a plant, or I should say it's also, it's a beverage. Maybe it isn't a plant, but it's only found in a few parts of Texas and Mexico. And it's sort of in between. Tequila and mezcal.

• 2:12:23Peter Attia?

  Speaking of Texas, can I tell you the only thing so far about Texas I'm not fond of?

• 2:12:28Tim Ferriss?

  Uh, scorpions in your kitchen?

• 2:12:30Peter Attia?

  I, eh, they, I've only found six.

• 2:12:33Tim Ferriss?

  That was, that was this morning in my household. Took care of it. It was fine.

• 2:12:37Peter Attia?

  It's the cactuses when I'm out in the bush. So when I was out.

• 2:12:41Tim Ferriss?

  What are you doing out in the bush?

• 2:12:42Peter Attia?

  Well, when I was out doing that precision shooting a couple of months ago, they were like.

• 2:12:46Tim Ferriss?

  Training for your counter sniper operation.

• 2:12:48Peter Attia?

  That's right. So we had like mats down on the ground and we're laying on our mats and we're shooting off into the distance. And I, I vaguely remember someone saying, stay on your mat.

• 2:12:58Tim Ferriss?

  Oh God.

• 2:12:59Peter Attia?

  And, um, so at one point I'm like loading my magazine and I kind of rolled off the mat and, you know, loaded it and was shooting. And then like that day we're driving home and I'm like, God, why does my butt hurt so much? And why does my leg hurt so much? And, you know, by the time I got home, I realized I was just full of these little micro needles. And, I mean, this is how you know your wife really loves you because like I had to give her a set of tweezers to literally start yanking these needles out of my butt and my leg. And I actually still have some there. Three months later, I still, I can still feel some of the ones

• 2:13:39Peter Attia?

  that broke beneath it. And, and so I'm going on this hunt in about three weeks and it's my first time hunting Axis deer here in Texas. And one of the things that the guy who's taking me said is you, you gotta make sure your shoes, like the cactuses won't go through your boots.

• 2:13:54Tim Ferriss?

  So you're not going to wear your ninja socks for this one?

• 2:13:56Peter Attia?

  Yeah, no, this will not be a barefoot hunt.

• 2:14:00Peter Attia?

  But aside from the cactuses, man.

• 2:14:02Tim Ferriss?

  Yeah, yeah. All good in the Republic of Texas. I have a shirt. Maybe I'll get you one of these. You might've seen it. It says, has a, has a big flag, Texan flag on it. It says most likely to succeed.

• 2:14:16Tim Ferriss?

  They sell those at the airport in Austin, for those who are interested. Well, Peter, off to dinner we go. Thanks again. Is there anything that you would like to mention before we close? Of course, people can find you. Peter Attia, M.D. will basically take them to everything, I would imagine. That's the website, that's Twitter, it's Instagram, that's Facebook, also YouTube. So you've been very consistent with how people can reach you. The podcast is The Drive, which, as mentioned, is a weekly deep dive podcast focusing on all of the nerdy subjects that I find so fascinating that Peter and his guests know so much about. Anything you'd like to add to that?

• 2:14:58Peter Attia?

  I mean, I would just say that some decaffeinated brands of coffee are just as tasty as the real thing. You know what the reference is? What movie is that from?

• 2:15:05Tim Ferriss?

  I don't get the reference. What is that?

• 2:15:07Peter Attia?

  Is that Real Genius? I think it's Real Genius.

• 2:15:09Tim Ferriss?

  Is that Real Genius? You know, I'll give you a bit of Austin trivia. We're going all over the show here, but there is a food truck here in Austin, which I had been told by a former professional tennis player. I had to try it. It had the best chicken wings. And for me, the chicken wings in general are kind of like the pistachios of the fowl family. They're just so much work and you just don't get much out of it. Turns out Tommy Want Wingy, which is the name of this food truck, has incredible chicken wings. They're delicious. I don't know what anabolic they give these chickens, but they're enormous. You can have a full meal. And Tommy Want Wingy.

• 2:15:48Peter Attia?

  Where's he from?

• 2:15:48Tim Ferriss?

  Tommy Want Wingy. Do you know, he's, he's actually at, I think it's Cosmic Cafe. They may have multiple locations. Do you know what reference Tommy Want Wingy is from?

• 2:15:58Peter Attia?

  Well, it's not the Dongar Need Food. That's 16 Candles.

• 2:16:02Tim Ferriss?

  Tommy Boy, Chris Farley, Tommy Want Wingy, the diner scene.

• 2:16:06Peter Attia?

  It's funny. I've seen that movie 100 times. How have I missed that?

• 2:16:09Tim Ferriss?

  Oh, yeah, yeah. Where he's talking about his sales process and he convinces them to the waitress to fire up the kitchen after they've closed. And he grabs, I think it's like a muffin and he's like, let's say it's my prospect. And he walks through this entire thing. We'll link, we'll link to this video in the show notes so that for, for people who want us to get Chris Farley, plus Zone 2 Training, plus Rapamycin in one place. This is probably the only site on the internet that will have all of those in one set of show notes. And Peter, thanks for taking the time, man.

• 2:16:45Peter Attia?

  Thanks, man.

• 2:16:49Tim Ferriss?

  So does that training fall into the aerobic efficiency category?

• 2:16:53Peter Attia?

  Yes, exactly.

• 2:16:54Tim Ferriss?

  Efficiency, I don't want to take us off of where we are too much in the sense that I don't want to create a breakaway, but could you just briefly explain what efficiency means within the aerobic efficiency and then come back to the zone two training?

• 2:17:11Peter Attia?

  Yeah, it comes down to basically substrate usage. So in aerobic activity, you can use glucose or fat. Those are basically the two fuels that the body with oxygen can turn into ATP. So aerobic, most people will recognize means with oxygen and anaerobic means without oxygen. So when you're not demanding much energy of yourself, and energy, of course, we talk about is ATP. So ATP is the currency for energy. When your body isn't demanding much energy, you can make ATP using glucose or using fatty acids. And it's a similar process, but obviously different because they're different molecules. So glucose gets

• 2:17:56Peter Attia?

  turned into something called pyruvate, and that happens in the cell but outside of the mitochondria. And then the pyruvate gets shuttled into the mitochondria where it undergoes a process known as the electron transport chain, where a whole bunch of chemical reactions occur that basically generate a gradient of electrons in the inner membrane of the mitochondria that's ultimately used to produce carbon dioxide and water and a boatload of ATP. With fatty acids, it's a little different. Fatty acids get broken down into smaller chunks of fatty acids that have two carbons called acetyl CoA, and the acetyl CoAs get

• 2:18:36Peter Attia?

  fed into the mitochondria and undergo the same sort of process. So what's nice about that is you have the ability to use both fuels. But when energy demands start to climb, so when you are asking more of yourself, when you're now running, or when you're walking up a flight of stairs, or doing anything that now the body's saying, hey, I need more and more ATP. That glucose system is the first one to cave. So the glucose system, when you turn the glucose into pyruvate, it basically says, I don't have enough oxygen to run this through the mitochondria to do what I need. I'm going to instead turn pyruvate into lactate, which yields some ATP, but a pittance compared to what it could do.

• 2:19:19Peter Attia?

  So pyruvate into lactate will generate 1/16 the ATP that it would if it went into the Krebs cycle, which is horrible, but it's like any port in a storm. It's like, I don't have a choice. As a side note, everybody tends to think that lactate is what causes the soreness when you're doing that. It's actually not the lactate. Hydrogen. It's the hydrogen ion that accompanies the lactate because lactate is acidic. So you don't actually feel anything from the lactate. And lactate itself is actually a pretty remarkable fuel. The brain, there's emerging evidence that the brain actually likes lactate as a fuel and the liver can turn it back into glucose pretty easily. But nevertheless, it's inefficient. It's a horrible way to turn your hydrocarbon into ATP and it does come with this problem of being self-limited.

• 2:20:03Peter Attia?

  So the efficiency speaks to the longer you can use the mitochondria, the better. And this zone two characteristic is really one of the most remarkable ways to separate and differentiate people with different degrees of metabolic efficiency. So Inigo San Milan and George Brooks did a study that I talked about at length in one of the AMAs. Did you say Caesar Milan? I'm kidding. The dog trainer. What were the names again? Inigo. Okay. San Milan and George Brooks. Inigo's been a guest on my podcast as well. They did a study looking at three cohorts of people, professional cyclists, fit people and people with type 2 diabetes.

• 2:20:45Peter Attia?

  Just real quick, how did they define fit? I don't remember exactly, but it would be like people who exercise a certain number of hours a week who were pretty fit. These were people that were probably exercising 10 hours a week or something to that effect. So not just kind of like weekend. 10 hours a week is not trivial. No, not at all. Right? And what they looked at was what were their lactate curves on a bicycle? And at what point did they reach that 2 millimole level? You know, it's just a staggering difference. So all of them would ultimately achieve high lactates, admittedly very different powers. The fitter you are, the more power you generate before you hit that peak lactate.

• 2:21:24Peter Attia?

  The people with type 2 diabetes were reaching this critical threshold at something in the vicinity of 80 to 100 watts. So 80 to 100 watts on a bike, if you don't know what that feels like, it's hard to explain what that would, I wish I had a good conversion for what that feels like. That's not a lot of effort. I guess for someone who spends

• 2:21:46Tim Ferriss?

  Flat ground, slight incline.

• 2:21:48Peter Attia?

  Yeah, flat ground, no wind, going 13 or 14 miles an hour.

• 2:21:53Tim Ferriss?

  Got it.

• 2:21:53Peter Attia?

  Uh, maybe less, which amounts to about 1.2 watts per kilo because you always want to normalize these things to body weight. So 1.2 watts per kilo, one watt per kilo in that vicinity. The reasonably well-trained person was hitting that number at closer to 150 to 170 watts, putting them pretty comfortably in about the 1.7, 1.8 watt per kilo range. So, you know, significantly higher than people with type 2 diabetes. And the professional cyclists were hitting that mark in the vicinity of 320 to 360 watts. And of course, they're even lighter. So they're hitting that number at a staggering four watts per kilo.

• 2:22:37Tim Ferriss?

  What was the total duration of the assessment?

• 2:22:40Peter Attia?

  It's typically done, unlike a ramp test where you're quickly, quickly changing, you typically do long ramps. So 15 minutes, check lactate, 15 minutes, check lactate, or 10 minutes would be about the minimum.

• 2:22:53Tim Ferriss?

  Do you think those results would have looked different had the muscle groups involved been different? Had it been like a hand bike or something like that? I guess I'm wondering if there's any localized effect, just given the training of the cyclists.

• 2:23:07Peter Attia?

  Yeah, it's possible. And certainly there's a, you know, an efficiency that comes from doing the thing that you're being tested on. Typically, lower body exercises are the way to do this because we have so much muscle mass there. When we have patients do their zone two, we basically recommend three things, a bike, a rowing machine, or a treadmill are probably the best ways to get that. And it doesn't have to be running. I mean, when I do-

• 2:23:32Tim Ferriss?

  That to get, you mean to assess or to also train?

• 2:23:34Peter Attia?

  Both.

• 2:23:35Tim Ferriss?

  Both.

• 2:23:35Peter Attia?

  Yeah, because it does need to be pretty steady state. Hiking up and down steep climbs tends to not be a great form of training for this. That's another type of training. But when you're coming in and out and in and out of zone two, it's not the same as sort of planting yourself there, staying there and forcing your mitochondria to adapt to it.

• 2:23:54Tim Ferriss?

  That was actually going to be my next question. So what is the adaptation that one hopes for? Like, what is actually happening to the body when you do effective zone two training?

• 2:24:05Peter Attia?

  So you're increasing the ability of the mitochondria to utilize the substrate. You're increasing the ability of the muscle to actually take in more oxygen. So it's really funny when you compare a really fit person to a really unfit person. And so think about something like a VO2 max test. Everybody's breathing the same amount of oxygen. So let's imagine for a moment that you are the fittest guy in the world and I am not. We're both sitting in this room. We're both breathing in 21% oxygen. If you then put us on a bike and make us go as hard as possible and measure how much oxygen is coming out, you'll notice that much less oxygen is coming out of you than me.

• 2:24:50Peter Attia?

  So the difference is you're able to use more oxygen than I am. And that is probably not mediated at the level of your lungs. That's probably more mediated at the level of your muscles. Now, there may be some differences in the lung as well. This is not an entirely settled question, but there's undoubtedly a bigger delta at the muscles. So that's a big part of it is simply being able to utilize more oxygen. The other thing is perhaps increasing the density of mitochondria. So simply having more mitochondria in the muscle will allow for more of that substrate to enter the mitochondria versus outside. And then, of course, there are transporters and the transporters determine a little bit

• 2:25:34Peter Attia?

  of how the body can sort of utilize lactate, keep it in the cell versus recycle it and get it out of the cell quicker. From a training standpoint, the good news is all of this stuff is trainable, but it does require deliberate form of training. And One thing I don't think we know yet, but it's looking like the minimum effective dose is probably about three hours a week, ideally delivered at sort of 45 to 60 minute intervals. I've asked Inigo about this specifically, you know, would, would, just as a thought experiment, would doing a whole bunch of 15 minute sets a week be sufficient? His view is it would not be, that it probably needs to be at least 45 minutes per session. So

• 2:26:16Peter Attia?

  you could do, say, four, I do four 45s these days as my zone two protocol. At times I've done more, there's times I'm doing four 60 minute sessions a week.

• 2:26:26Tim Ferriss?

  And those should feel, if I'm remembering correctly from what you said earlier, those should not feel agonizing. These should be kind of sustained all day hike type of, I know hike isn't exactly perfect, but assuming it's, it's a, say, flat ground, constant load, this should be something you could sustain for much longer than, say, 45 minutes.

• 2:26:51Peter Attia?

  That's right. And not all of our patients want to use a lactate test. So I lactate test myself every time I do a zone two test. So I have

• 2:26:59Tim Ferriss?

  So unlike you, Peter.

• 2:26:59Peter Attia?

  Right, right. So for three years, I have every session I've ever done recorded by power, heart rate, lactate, all of that stuff. Because you do see variation, by the way. So a given power doesn't always keep me at the same zone two. So how well I slept the night before, my state of hydration, what I've eaten will all impact this.

• 2:27:20Tim Ferriss?

  How are you tracking whether you are in zone two or not?

• 2:27:24Peter Attia?

  By poking my finger. Yep, I'm using that. Okay. So when people don't want to do that, what do we recommend? Well, we recommend figuring out what your zone two heart rate is because you can track heart rate really easily.

• 2:27:35Tim Ferriss?

  So rectal probe most of the time?

• 2:27:36Peter Attia?

  Exactly. No, that's for temperature. So, so heart rate.

• 2:27:41Tim Ferriss?

  Depends on how long it is, right?

• 2:27:42Peter Attia?

  So, yeah.

• 2:27:45Peter Attia?

  Just sitting right here on the Vena Cable. So with heart rate, you want to give somebody a starting point. So one option is you tell people to do a little bit of lactate testing. Maybe test yourself once a month, figure out what your heart rate is. And then going forward, just rely on heart rate for people who never, ever, ever want to poke themselves or just are insulted by how expensive these stupid things are, which they are really stupidly expensive. Like the lactate meter is 250 bucks, but the strips are $4 apiece. So which is just so aggravating because you know, these things cost about 12 cents to make. We usually use two ways of estimating. One estimate is 180 minus your age, which I think is the low estimate.

• 2:28:28Peter Attia?

  So a 50 year old, you'd start them at about 130.

• 2:28:31Tim Ferriss?

  130 what?

• 2:28:32Peter Attia?

  Beats per minute.

• 2:28:33Tim Ferriss?

  Beats per minute.

• 2:28:34Peter Attia?

  Another way to estimate it is if you know your maximum heart rate. So this is usually for people who exercise quite a bit with a heart rate monitor. And they know what their true maximum heart rate is. So let's say a person's out there and they can say, they say, you know what? I can achieve 178 beats per minute just before I feel like I'm going to keel over. That's your max heart rate. I usually start people at about 78% of max heart rate. Now, again, the next thing we layer on that is the sort of the litmus test of how do you feel? Are you able to almost carry out a conversation when you're doing the activity? And the answer should be yes, but I don't really want to. That's about the sweet spot.

• 2:29:18Tim Ferriss?

  It's a strained conversation, but you could do it.

• 2:29:21Peter Attia?

  Yeah, like yesterday I was doing my zone two and my dad called and I'd missed a bunch of his calls. Normally I don't answer the phone when I'm on the bike because I have a fan that is blowing air on me so much. And it's so noisy, but I answered the phone anyway. So, you know, I talked to my dad for five minutes, which mostly meant I let him talk. And I was kind of like grunting a little bit, yeah, uh huh, yeah, okay. Yeah. Uh huh. Uh huh. But I wouldn't want to do this on my bike for a zone two. Like this would be a bit more than I'd want to do. And if you can't talk at all, which you wouldn't be able to talk, of course, if you're doing like a zone five, then you're obviously going too hard.

• 2:29:57Tim Ferriss?

  The long-term benefit, just to reiterate, the long-term benefit of doing zone two training for say, a minimum effective dose of three hours per week is what? And when can someone expect to start to see adaptations that are beneficial?

• 2:30:14Peter Attia?

  Well, the latter is a good question because it probably depends on from where you start. With someone who's starting out really metabolically broken, which by definition is what type 2 diabetes is. That's the most extreme example we have of completely broken metabolism, right? So a complete inability to partition fuel, almost a complete inability to burn fatty acids, which again gets back to your question about efficiency. An efficient engine should be able to run on two fuels. It should be able to run on glucose and it should be able to run on fat. A broken engine can only run on the short-term fuel, which is glucose. That's a brutal cycle to be in. If you can only run on glucose, you're going to be in a tough situation because we can store such a tiny amount of glucose relative to fat

• 2:30:56Peter Attia?

  and you're going to be at the mercy of fluctuating glucose levels constantly. Whereas if you can rely on fat, you're better off. I've seen people make adaptations to this. I would usually say it takes three to six months to start to see some adaptations. I guess over the past two and a half years, my zone 2 power has gone up by 25%.

• 2:31:24Tim Ferriss?

  Power measured in watts.

• 2:31:26Peter Attia?

  Yeah. And to be honest, it's still below what it was nine years ago or seven years ago when I was training as a cyclist. So even though I didn't think of this type of training as a cyclist, I would do these types of workouts as an important part of my overall training. And I was just infinitely fitter back then. So my zone 2 back then was probably 40 watts higher than it is now, although my zone 2 is probably 40 watts higher now than it was two and a half years ago.

• 2:31:56Tim Ferriss?

  Hey guys, this is Tim again. Just a few more things before you take off. Number one, this is Five Bullet Friday. Do you want to get a short email from me? Would you enjoy getting a short email from me every Friday that provides a little morsel of fun before the weekend? And Five Bullet Friday is a very short email where I share the coolest things I've found or that I've been pondering over the week. That could include favorite new albums that I've discovered. It could include gizmos and gadgets and all sorts of things. sorts of weird shit that I've somehow dug up in the world of the esoteric as I do. It could include favorite articles that I've read and that I've shared with my close friends, for instance, and it's very short.

• 2:32:38Tim Ferriss?

  It's just a little tiny bite of goodness before you head off for the weekend. So if you want to receive that, check it out, just go to fourhourworkweek.com. That's fourhourworkweek.com all spelled out and just drop in your email and you will get the very next one. And if you sign up, I hope you enjoy it. This episode is brought to you by Oura, O-U-R-A. It is the only wearable that I wear on a daily basis. Oura is the company behind the smart ring that delivers personalized sleep and health insights to help you optimize just about everything. And I've tried every device out there that you can imagine. This one really makes the cut. I've been using it religiously for at least six months now, and I was introduced to it by Dr.

• 2:33:23Tim Ferriss?

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• 2:34:06Tim Ferriss?

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• 2:34:51Tim Ferriss?

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• 2:35:34Tim Ferriss?

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• 2:36:58Tim Ferriss?

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