Dr. Peter Attia on Longevity Drugs, Alzheimer's Disease, and The 3 Most Important Levers to Pull | Transcription

Note: This transcription is split and grouped by topics and subtopics. You can navigate through the Table of Contents on the left. It's interactive. All paragraphs are timed to the original video. Click on the time (e.g., 01:53) to jump to the specific portion of the video.

Introduction

Intro (00:00)

Hello boys and girls, ladies and germs. This is Tim Ferris and welcome to another episode of The Tim Ferris Show. This is a very special edition. I am in the cave of Peter, Tia, Dr. Peter, Tia, 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 Atia, who can be found at PeterAtia.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. But here's the official bio. To do 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. 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 MD from Stanford University and holds a Bachelor of Science in Mechanical Engineering and Applied Mathematics. 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 Overcast, or wherever you listen to podcasts, you can find him all over the interwebs, peteratiumd.com on Twitter @peteratiumd. Instagram, same same, peteratiumd, Facebook, you got it, peteratiumd, and then on YouTube, peteratiumd. Peter, welcome back to the show. Wow, that was quite an intro. It was an incredibly comprehensive intro. I could have shown up a little later for this. So we've had frequent flyer miles on podcasts, including on this show.

Health And Nutritional Testing Topics

Excited About (02:56)

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? Well, 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. 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. 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 cell-free DNA as opposed to tumor DNA.

Cell-free DNA Testing (05:08)

And just for those listening, Grail is in, holy grail. 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 what is cell-free DNA? Because that's really at the heart of this. So that one more time? What is cell-free DNA? Cell-free. Like C-E-L-L-HIPM-free. 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 or actually typically monocytes, 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. A methyl group is just a carbon with three hydrogens on it. It's one of the most basic building blocks of organic chemistry. 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. So the 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. 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. 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 of having pancreatic cancer? It's quite low.

The Sensitivity & Specificity Of The Cologuard (09:14)

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%. 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. A 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. That's right. That's my best name for people who want to search. 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 "Rodge MRI," it'll pop up. And yes, that's an episode we usually make our patients listen to before they go and get one of those MRIs so they understand it. So 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? 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. And 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. 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. 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. Yeah, the forensic science.

Metabolic health (12:45)

That's very cool. I don't know 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? Yeah, no. 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. So for example, something called the GI Stromal Tumor and a certain type of testicular cancer for which there's been very specific behaviors that have rendered them quite sensitive to certain chemotherapies. But when it comes to lung cancer, when it comes to pancreatic cancer, 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. And 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 prevention.

Prevention - The MGB/U还] # """^{-\colorbox{highèg verd undnier}}PartII Version1 Powerhouse WH Chanhi" (14:03)

Prevention for a second. Well, it's both, right? 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, you know, 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. Yeah. Each method or technology in of itself having gaps, that's when you lay them on top of each other, hopefully the remaining gaps are sort of allowable if that makes any sense. Absolutely. And it's exactly that. It's basically how do you use multiple technologies to cover the blind spots of others? I'm excited about Grille also because it seems like, especially if scaled through alumina, the ability to have Grille 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. 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. You got to get you up there. 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. Yeah. 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 under all of this is a huge engine of machine learning that makes it better over time. 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? Always. I'd say, you know, 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 and 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. And I think that most people understand loosely what three of those are. Could you say those all one more time? Sure. Stability. Mm hmm. That's the one that most people don't understand. We can talk about that in a minute. Strength. Mm hmm. 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, I don't know, kind of 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 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. And that comes to bite you. So as you think about how it moves up the sort of chain, a very common problem is the 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 spina 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. Yeah. It's how someone who's quite lean from a body fat perspective can still look like they have a pot belly. That's right. With that anterior pelvic tilt. Which actually, so you've asked me a question and I think that 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. So what's the what's the etiology of that position, which I was the king of that position? It's probably what do you mean by etiology? Like what drives that? Why would a person show up with that posture of ribs flared up, pelvis tilted forward, tight hamstrings tight and long, besides wearing six inch the Lito heels? Which I never wore. I mean, I wear them sometimes, but I don't often wear them. You're in good company. You're in good company. You're in good school. You're in good school. 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 learning or we stop breathing correctly into our abdomen. So we 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 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. This is 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, meaning your center of mass shifts forward. And the body senses that 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 just 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. So 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, is laying on your back with your knees up and your feet down. The back position knees up, feet on the surface of the ground. And without letting your back tilt into a huge, make 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 with that while keeping my back down. My back, I would arch like a cat if I tried to do that.

Characterizing the Six State Adapt, part 1439, Medium Scale SVM SVM 044R Powerhouse VSM Powerhouse SVM] (22:05)

There were many more of these types of exercises, but it was through this type of very deliberate, 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 because 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. So it's sort of, what 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. 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.

Progressive neuromuscular stability - Peter (23:04)

But I certainly wasn't one of them. Does that type of training that you're describing, that progression kind of starting back from the foundation of fundamentals, does that have a particular name? 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 breadth and generate 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. And that's really the one that has focused on this idea of how do you correct what from the side looks like this, sort of pelvis down, ribs up, and how do you fix that position. And again, it's hard because it requires fixing everything from the feet to the neck. How much of a contributor, if at all, do you think extended sitting is to that configuration with the flared ribs up and anterior pelvic tilt, if any? 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. So 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, I'd go back to kids when they're in school and have them in standing desks or squatting. Those would be your two positions, right? So you either you're kind of squatting to do work or you're standing to do work, but you're not sitting in the types of chairs that we sit in. I think I have an idea for a complimentary short form podcast for you, which is just called czar for a day. Five minute commandments from czar to you. Yep. And more barefoot time. That's another thing, right? 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, like I study this guy like he's like 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, it is such a spectacle to behold. So you know, if you, 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 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. So 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 and the regarach working with a number of clients or patients with cerebral palsy using very incremental movement, rehabilitation and training. I mean, the before and after differences are staggering. And it's, it's, I mean, I speak to probably my ignorance of cerebral palsy, but just never was even within my like conceptual schema that that would be possible. It's very exciting to see. So speaking of exciting. Oh, so the other thing on exercise to get back to your question about the metabolic stuff is, you know, 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 millimole. So lactate is a byproduct of anaerobic metabolism. So when we're sitting here at rest, our lactate levels probably one, if we're metabolically healthy, there are some people who sit around at rest higher than two. But if anybody's done lactate testing knows, you know, as you start exerting yourself more and more, your lactate will rise. And you know, peak levels in highly trained individuals can reach above 20 millimole. And that's accompanied by remarkable discomfort, actually. So I've always done lactate training when I was, you know, being an athlete, which I haven't been in forever. But I was never focused on this aspect of it. As 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, like, you know, meaning 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, right? Zone two is by definition your all day pace. It's basically at a lactate level or two, you should be able to go all day. Because 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. So does that training fall into the aerobic efficiency category? Yes, exactly. Just a very quick note to say that we really nerd it out on zone two training with Peter. We got deep into the rabbit hole. We 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.

Fat utilization (29:54)

Now back to the show. So 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 I'm. 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 in taking, 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. Also, turns out a pound of fat has a lot of calories. Yeah. So, you know, I could gain weight on a ketogenic diet if I ate enough, right? Now 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 liquor, I used to work at a video store when I was in high school called Movies and Munchies. And it was owned by my friends to videos to our plus dispensary. And they just didn't care how much I ate. 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. You could take out like a mugger with this bag of Twizzlers. Yeah, 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 for 5,000 calories of junk food three nights a week was my day full. So we look at the opposite of that fasting has you have you changed your mind or had any insights since we last spoke come to any different conclusions related to fasting. Yeah, I mean, I think because you've done, I mean, for the record, you've done a lot of fasting. I mean, you have a lot of experience doing fasts of many different lengths, including without a note, the longest fast is that you've done. Probably 10 days. Yeah. Yeah, I think that, you know, one thing that I absolutely learned through fasting is that 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, which is or 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, I, I'm, 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.

Intermittent fasting (33:37)

And, you know, 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. Might have lost four pounds, but his body fat was so high, I almost fell off my chair and he doesn't look chubby, right? But he's, it's, it speaks how much muscle he's lost. So he, his body fat went from about 18% to 30%. Yikes. 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. You know, he, he walks and, you know, does some yoga and stuff like that, but he's not doing strength training. So I think in a person like that, there, 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 dexaback in January and I hadn't done one in years. And from the, from January to the last period that I had done a dex, my body weight was almost 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. And I, I did wonder if that was just too much because, because I always exercise in the morning, but then don't eat. So you, you know, to exercise and then not provide yourself with, especially with when you're strength training to provide yourself with any amino acids every single day to, you know, undergo muscle protein synthesis, I think it's a little bit risky. So I, so I've been looking at other strategies around that, right? So for example, front loading the meals. Quick question. When, 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, one three day fast a month or one week long, fast every quarter. What was the frequency? All of the above. Yeah. Probably spent maybe two years doing seven days a quarter, maybe a year doing of three days a month. And then, 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. Because I think you can, you relatively, you can, 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, it has to be taken in the context of an individual. So if you're someone who's a hundred 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. Yeah. Right. So you are going to technically get leaner with that approach. 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. So you were saying something about front loading meals? Yeah. So I just find nowadays, although probably not tonight, I'm going to eat almost certainly not tonight. I'm going to eat a little bit more early in the day and a little less late in the day. So I'm going to... There may or may not be some discount involved. Yes, there will be. We won't take either of our ora-ring data as the standard for this evening. So I totally got caught up in my own fantasy- Fantasy about mass-galates. So front loading meals, can you just walk back and explain?

16hr FA (37:38)

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. A huge, I don't mean gluttonous, but I mean, that's your biggest meal of the day. At say, I don't know, 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 16 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, but dinner is our social meal. And for obvious reasons, it just poses a difficulty to be the guy who never eats dinner. The other thing- Just as a side note, I've been at multiple dinners now. I have quite a few actually, where you've been fasting and we've all been sitting, drinking wine, and you're just like past 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 to be that guy. To be that guy. Drinking the soda water. And then the other thing is, I think for many people it is hard to go to bed hungry. And truthfully and longer fasts, it gets easier because if you're fasting for seven days, by the time you hit that fifth day, a lot of your hunger has dissipated, but 16 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 16 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 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. Well, let's 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 experience this, and it was hilarious and also frustrating to see how many religious zealots there are around intermittent fasting who were just like, "Bite thy tongue." Wait, wait, wait, but you said that according to this tech that they got better intermittent fasting or worse? No, they got worse. They got worse. They were. So they got worse. They were. So they met with what I'm describing. It's exactly compatible with what you're saying. Yeah. Yeah. But there was a lot of resistance to the idea that that would even be possible, right, which I found really interesting, more social commentary than anything else. And 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.

The politics of nutrition (41:31)

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. Dietary restriction is restricting some of like some of the content in what you eat. So not eating carbs, not eating wheat, not eating meat, not eating like Doritos, 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 as much as you want, whenever you want of, you know, whatever, anything you want, anytime, how much, whatever, that's called the standard American diet. Sad. 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 that's a great piece of data. Like there are people out there who can, you know, eat KFC and Doritos and pizza anytime they want. 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 not withstanding that, at least at the surface level, it appears that 10% of the population are largely, you know, immune to the sad. 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, you know, 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 there are. So there certainly are people that are in that camp. But it's usually the first two camps that have the most salads. Leavers. I was waiting for the Canadian to come out. I love those levers. I'm sorry. I'm sorry. I'm so sorry. I'm so sorry. Process. Process. And I also think I said bite thy tongue. I don't practice my older English much. I think it's thine tongue, but sure the internet will correct me. 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 branch chanamino acids to mitigate the muscle loss during what we would otherwise consider fasting? And does that affect? Does that also, if it has any effect, lessen the benefits of the fast? 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 branch chanamino acids during strength training. Because from a caloric perspective, they represent such a miserable. Yeah, yeah, yeah. Like even if you were to double up on my favorite BCAA's, which are bio steel, you know, you're going to get in there 40 calories in two servings, right? So not an issue. If you're doing the intermittent fasting, we'd 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 to take away that which it senses, and it is the most potent sensor of leucine, which is the most important branch chain amino acid. Yeah.

Branch Chain Amino Acid (BCAA) Supplementation During Fasting (46:14)

So if I could dumb that down for myself, if you are interested in the longevity benefits of fasting, aside from just getting too healthy body composition, you should not take the branch chain amino acids. It seems to me, I mean, I can't say anything with certainty, but it seems counterproductive. Yeah. Got it. All right, studies. Any papers or studies that you found interesting?

Psychedelic Drug Comparative Study

Lexapro vs Psilocybin Comparative Study Results (46:43)

Oh my God. Since so many, there's a lot. If you had to cherry pick a few. 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. It just turned back around. Could we zoom out just for a second and give people an overview of the objective or the hypothesis of the study? 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? Yeah. So Lexapro is a relatively new SSRI, very well tolerated. Is it telepran? Yeah. It does have sexual side effects. That's its most common side effect. That's true of other SSRI. Absolutely. SSRI are known for having sexual side effects. Some of them also come with incredible amounts of somnolence, incredible amounts of weight gain. Some of them sleepiness. Yeah. Lexapro seems to be relatively free of that for most people, which is why it's 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 usually start people at 10 and go to 20. This is a daily... It's a daily stretch drug. Yep. So 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 4 plus 4. I can't remember. It was a relatively short study. In the psilocybin group, the participants were... Oh, they were... By the way, it's an aside. They were also given 1 milligram of psilocybin, which is an important point I should make. And if that word is unfamiliar to folks, psilocybin is a molecule found in psilosophy mushrooms also known as magic mushrooms. These are mushrooms that impart psychedelic effects at a sufficient dose. 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 flag 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 you're going to get some." One milligram or 25 milligrams, and we'll put it in context what those doses mean in a second. And just to bracket one thing, so what makes this study in 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.

Psilocybin Doses, Purported Amount in Mushrooms, and Hallucinogenic Doses (49:49)

Yep. Please continue. Yep. 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 milligrams of psilocybin, which depending on the variant of mushrooms, so when you dry a mushroom out, it's 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%, so the-- Incredible variability. Yeah, so the 25 milligrams was clearly a hallucinogenic dose. So probably in the 4 to 5 gram of mushroom dose. So they used a number of-- well, there's one other point I should explain about research. Generally, when research has done an incredible fashion, you have to call your shot before you do the study. Pointing to center field. That's right. You have to be able to-- not just say I'm going to hit a home run, I'm going to hit a home run 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-- Right, did they call this shot? Did they call the primary outcome? 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, 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 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. This of course was published in the hands down most prestigious medical journal in the world in the New England Journal of Medicine. So they pre-registered around one type of survey, one type of depressive survey. Because unlike, say, giving people drug to treat cholesterol, where you have an objective metric, you can say, well, did it lower APOB or LDLC 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 fewer absent days from work or something like that? So the, 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 the psilocybin group, was not statistically significant. So both groups achieved an improvement in their depressive scores. Yeah. I think it was six and four points, respectively. Correct. I think it was a nine point scale. Something like that. Yes.

What Cant the Study Tell Us? (53:30)

I think that's 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? There was no difference between this drug and it basic between psilocybin and this drug. It was positioned as a negative study. Got it. Meaning it, I mean, I don't want to say failed because it's just not really how science works. But the intervention did not, meaning psilocybin in this case, was not superior to... That's right. Yes, Talvram. Ty. That's right. All right. So this is a topic that is endlessly interesting to me. What we're getting into, which is study design and really digging into the nuance and how beneficial it is to know how to read a study. But I highly recommend people read a series of articles that you published and they are called, what is it, studying the studies or studying studies, studying studies to increase your scientific literacy because we're going to get into some of the weeds and I think it will be... I hope it'll be interesting to people. 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 monthly journal club. 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 I 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 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. Yeah, and we just decided to do this. I mean, 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? We just have to accept the fact.

How to Think Critically (56:00)

It's completely learned. It's 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 beat into you how to do this. And again, the topics that we explore are the latest on semagluetide, which we'll talk about today, I think. The role of testosterone replacement therapy in men with type 2 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 so. Yeah, the process of thinking dissecting and skeptically, but not necessarily cynically looking at purported outcomes, I think, is really important. So coming back to this paper, super prestigious journal, study comes out, psilocybin versus lexopro negative study or negative outcome rather.

The 3 Important Points (56:51)

Then we have this questionnaire, let's just call it, that is determining the results.

The Questionnaire Import (57:07)

And the results come back, the differences come back as statistically insignificant. However, as you pointed out, when you wrote about this, that doesn't necessarily mean clinically insignificant. Depending. That means that it wasn't, so let's go back and explain what statistical significance is as well, because 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. A priori, meaning beforehand, you need to know what magnitude of difference you expect to see between the two groups. That's right. And that's really important because that determines what's called the power of your study. And that is how you need to, sorry to keep jumping in here, but the part of the importance of 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. 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, principal 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, because the table has on, it's a complicated table to look at, but on the like 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%, and then here it would be like 5%, 10%, 15%, 20. 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. 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 under power a study. And I think there's actually a pretty sizable chance that that happened here. 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. A little over two. Yeah. That was true. 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. And 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? Is four points necessary when you're really trying to do a study against the gold standard? Right? 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. So that was one of my first concerns with this study was I don't think it was powered directly because I do wonder if four was too high in 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.

Health Study Analysis And Outcomes

Clinical Relevance (01:01:42)

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.

A strength of this study (01:01:52)

And then the point that you brought up is 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- And I definitely want you to give if you remember and it can be rough. Yeah. Some of the examples of the questions. That's right. And that's the final point here is not all questions are created equal. Right? 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. Those are very different questions. A person who says, "Yeah, 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 person is probably a lot more functional than the person who says, "I can't get out of bed." Yeah. Or I think that another two examples to compare would be- Well, one about suicidal thought as well. Right. 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 than as you mentioned questions that could include suicidal ideation. So not all points are created equal. Right. You know, another thing that I wondered because I have 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 who are very experienced with designing studies and being published." They said, "Well, you know, there are times when 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 what the establishment would have wanted to see and then having the secondary outcome measures move in some very interesting ways that maybe in retrospect could have or should have been the primary outcome measure. Correct. If you had more confidence in those to begin with. So it's just you know what the budget was for this study?

Secondary outcome measures (01:04:40)

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 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 easier 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. I mean, look, I think net net, this study must be viewed as a very positive finding. Because the side effect profile was obviously higher in LexaPro, so again, people taking LexaPro are far more likely to complain of if their males erectile dysfunction, sexual malfunction, reduce libido, things like that. You know, how we wouldn't want to explore this to the end of the degree, I don't understand. And of course, there's other things I'd want to explore, like microdosing, right? These were macrodoses. So these were people taking, you know, a full hallucinogenic dose every three weeks, I believe. And that's not necessarily an easy thing to do either. So 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 hear a lot of anecdotal talk 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. It was a randomized study, but it wasn't a blinded study. There was no confusion about which group you were in. 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 excite the topic. And it raises, as you noted, given the frequency of administration, so you have to 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. 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 two and they may still plan on doing follow ups in other university studies, there's quite a bit of durability that's seen with this type of administration of psilocybin, even out to six, 12 pounds. It raises some really interesting questions, right? 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, right? 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, instead of what work can be done in those sessions themselves? Raises a lot of interesting questions. Yeah, and I think with MDMA, I think the answer is probably a bit more clear.

MDMA Assisted Therapy (01:08:59)

I think when you, prior to MDMA's resurgence and serious treatment for PTSD, antidepressants were the mainstay of therapy for this. I think it was exactly what you said. 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 and rectify and come to grips with the traumatic event. 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. There's been, for those people who aren't 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 three 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, just about the future of treating mental illness for psychiatric disorders. 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 among veteran populations and other subpopulations. That I think is a very courageous and very justifiable stance to take. I was very excited to see that, especially in the great Republic of Texas in which we sit. 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? Yeah, certainly as it pertains to things where I'm evolving my thinking. And what is APOB? Yeah, it's probably worth explaining that before we do anything else. Most people have heard of cholesterol.

How does a lipoprotein look like? (01:11:26)

And most people are used to seeing a blood test where you would see your total cholesterol, LDL, HDL. And 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 that mean? So that means LDL cholesterol or the cholesterol contained with an LDL, HDL cholesterol is the cholesterol contained with an 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, 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. So it 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. But just like if you tried to pour olive oil into a glass of water, you would quickly realize they don't mix. 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 to the bloodstream on its own as does a ketone body, for example. But triglycerides 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, namely cholesterol ester and triglycerides. And these lipoproteins exist in two broad families.

ApoB family (01:13:31)

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 ApoB's. There's an ApoB 100 and an ApoB 48. But for the most part, anybody that's talking about ApoB is referring to ApoB 100. The ApoB 48 is only something called a chylomicron. It 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. Okay, advanced course for the midichlorins and nerds out there. So your ApoB 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 ApoA or an Apolipa protein, little A. Not ApoA, I should be really clear. It's Apolipa protein, little A. You have to specify little A to not confuse it with the ApoA family. The ApoA family is the lineage of the high-density lipoproteins.

Cholesterol Levels And Inhibitor Research

What is ApoB, and how does it translate to total cholesterol? (01:14:52)

Okay. Most people know that HDL good LDL bad, but that's a little overly simplistic. 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 ApoB on it causes atherosclerosis. And just for the listeners. Atherosclerosis, meaning the buildup of plaque within the cardiovascular system. Yeah, it's the imdefining or inflammation. 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. 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 HDL occurs to LDL is so quick that the IDLs are kind of irrelevant. LDLs of course are the majority of your ApoB concentration. Unless you also have a lot of insulin resistance where you might have a lot of VLDLs or if you have a genetic 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 ApoB. And about one in eight to one 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 LDLc 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 multi factorial so lots of things drive it. 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. So 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. 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.

How are cholesterol and serum cholesterol related? (01:18:02)

So if you took a person's total cholesterol and it was 200 milligrams per deciliter and you lowered it, and by 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, LLA, 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 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 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?

PCSK9 Inhibitors (01:19:08)

The upshot of this is there's no upside to having more APOB. The upside is in having that number 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, well, developed about 17, 18 years ago, but it became clinically available. I shouldn't say that actually. It's probably started development in about 05. So it was 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 circulation, mostly which are LDL particles, but also some LP-LA 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, the risk of cardiovascular disease is virtually nonexistent. Yeah, that's a silly question. How does one find people who have such a mutation to track them? 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 hyperfunctioning PCSK9. So a group in Toronto identified PCSK9 and realized that these people had a hyperfunctioning 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 then it was realized, and I remember actually reading that paper when it came out and being blown away and actually thinking there's no way they're going to be able to do this with a drug. But it turned out 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 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. Silasaben, Rapa Myson, 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.

Low Apolipoprotein B Benefits Beyond Cardiovascular Risk Reduction (01:23:37)

Are there any benefits to lowered or low APOB outside of lowering cardiac risk? Yeah, there actually isn't a cardio, cardiovascular risk. 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 at the population-based data, for as long as we've had statins, we've known that lower APOB or lower LDL-C 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. 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. So 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. 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- - This is a bigger Mendel. - Yeah, yeah. So I guess I should explain what an MR is first. MR is- - Mendelian randomization. - 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, right? 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 are actually discussed in the studying study 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. 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 idea is in an MR analysis, you're basically assuming that genes can occur random. 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.

Bioavailability (01:27:14)

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're not going to change the gene. And it's not subject to your behavior, right? Whereas so many other things like what you eat is a behavior that can also impact your APOB. So 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. To me, the most interesting finding in there was the all cause mortality. I, you know, 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 trial, or not that trial, 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. Let's jump to rap my son, since you mentioned it and we can give very quick idea on what rabble my son is. But since we last spoke more bearish, more bullish and why. I am, I'm a bull. Yeah. Dogecoin and Rappa. Diamond hands. All right. So what is Rappa? By the way, I mean, I know, I know what the Diamond hands thing is, but what is it? Where did it come from? Like no idea. Yeah. No idea where a Diamond hands comes from. Okay. I was like, did I miss that somewhere in my, in my reading? In your, in your econ classes? Yeah, yeah. No. I don't think so. Okay. So what is Rappa my son? Rappa my son 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. Otherwise known as Rapa Nui.

Rapacanin (01:29:41)

Right. Rapa Nui is the correct name for Easter Island and the bacteria streptomyces hydroscopicus, which was discovered there by a group of explorers. This 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 Rapa Nui 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 Seren Segal. Right name. Yeah. He started dis-steveting around the Segal? No. And no ponytail, fortunately. So Seren 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 onto the biggest blockbuster cure for athletes' 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, he did not follow orders. And he instead stuck said Rapa Myson 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 working on this thing interesting that I haven't looked at in a few years." And they said, "Bring it out." It must have been an interesting lawyer conversation based on the non-falling orders. You're continuing. So out came Rapa Myson, which he named. Myson is typically the suffix that we use. What's the second part of a word called? Succia for antimicrobial agents. And of course, Rapa is a tribute to the Rapa Nui. Like a Zithro Myson. Correct. So it quickly became clear that this had remarkable anti-proliferative properties. So it could stop things from proliferating. So that was obviously a big part of just fungi. Right, exactly. And in particular, it was very effective at making a certain type of lymphocyte, which is a 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 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 graft, what they've been transplanted, attacks the host. I see. Yeah, I see. This is really host versus graft. But we don't usually call it that. But traditional rejection. Actually, I did a really cool podcast on the topic of organ transplantation history where they got named Chris Sonnenday. And it's, I mean, I know this subject well, but having the discussion with Chris really opened my eyes to just what a beautiful story it is and what the big breakthroughs were with drug development and how, 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 Cyclosporin that were introduced. But then you get into this third generation of amazing drugs like Rapa Mycin that took organ, you know, preservation to a higher level. Now you're not swapping kidneys.

Rapamycin Effects And Other Drug Candidates

Ethanolamine vs. Citrate (01:33:51)

How do you know? Well, at least not since the last time you sold one in Tijuana. Settle a bet. But why would you take Rapa Mycin? I know I'm skipping ahead a little bit. Well, let's, yeah. So let's skip ahead. 29, 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. It's probably one of my five favorite podcasts in terms of like nerding out on all of the molecules that can potentially impact longevity. And Rapa Mycin was in many ways the poster child for the ITP program because first of all, it's hard to get anything to live longer. And of all, when they were making the formulation for the Rapa Mycin to feed the mice, and these were very special mice.

Results of giving rapamycin to mice (01:35:06)

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 show some marker of success and 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, ah, screw it. Let's just run it late. So they started feeding the treatment group with Rapa Mycin and the placebo group get to continue eating their regular chow. Because it was oral administration. Yes, it was the Rapa Mycin was mixed into their chow. And lo and behold, the Rapa Mycin group, despite initiating treatment so late in life, had a staggering improvement in lifespan. 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 use the very rigorous way of assessing this, which is they're taking a look at the remaining life or sorry, they're taking a look at total life, not just remaining life. So it's a it's an even higher bar to clear what 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 is not a single animal study that has tested this hypothesis that has not found this result of that's wild, which again is very unusual. Yeah, so it's just replicated over and over and over. It's replicated non stop. 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 Kebreline, 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, 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. When it was given with rapamycin it did, but you could argue that was all the rapamycin. I'm more bullish on rapa simply because I've been taking it now for three years outside of... You can hear dog whistles. Outside of the apthus ulcers, which are the most annoying side effect of them, those are the little mouth, ulcer, little mouth sores you get. A little canker sore. Which I don't get them de novo, but if one of my kids headbutts me, which they do at an alarming frequency, and if I break a piece of my gum, it's going to be an apthus ulcer. Although... What is it called again? Apthus ulcer? Apthus. Yeah. A-P-H-T-H-O-S. Yeah. Nasty. It doesn't sound fun. So that's the only... is that the only documented... In healthy normals, I don't know who has... it would fund this research if anyone would. I don't know what... I guess I don't even know what the measurements, the metrics would be. Well, that gets to the problem. We don't have a meaningful biomarker of aging. I mean, that's full stop, the biggest problem in aging research today. Hands down. Nothing else matters. 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... 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 when you really want to know x minus x cubed over three factorial plus x to the five of five factorial, like when you want to really start figuring out the shape of this thing, you've got to... you're just going to need better tools. So as we're talking about Rap Mysen, I think naturally a lot of people listening will think of lifespan.

Is rapamycin going to improve hearing? (Part 1) (01:40:46)

It's a term they're more familiar with. Start to finish. What are you clocking in in terms of years? And then there's health span. And I took a note, as I always take notes during these conversations, about the vision and the hearing. I'm 43 and recently had a... not quite an audiology test. I mean, it wasn't... it was quite basic hearing test. 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 Rap Mysen could improve restoring that type of hearing? Or is that too much of a stretch? It's just too soon to say.

Drug Testing in healthy people (01:41:37)

I think it's certainly plausible, but I think 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. Has that been seen in multiple species? I've only seen it in mice. In mice. Yeah. And those are the feral mice versus the Holstein cows of mice. 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. 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, right? Immune suppressing drugs don't have people very excited. 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 Everolomus. 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. 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 they were challenged with a flu vaccine and then looked to see who mounted the best immune response and, you know, counter to what you would expect. The people in 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 was in the best. They had the best response in 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, we got to talk about mTOR. How does rapamycin work?

How does Rapamycin work (01:43:51)

It works by inhibiting something called mTOR, the mechanistic target of rapamycin. We could also refer people to our conversation with David Sabatine. Absolutely. Back on Easter Island. Back on Easter Island. So long story short, there was a trip. It may or may not have involved some wine. Two Rapinoe to Easter Island, and one of our tripmates was David Sabatine, who, QVeter, was the first person to identify how rapamycin worked in mammals. Yeah. So we talked about that quite a bit in that episode. So I think if you just search Tim Ferris 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 shape his nuts a bit. So let's see. Yeah. So let's just wrap that up by saying that the 5 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. Do you no longer take metformin? I do not. Interesting. What were some of I know you referred to? Was his last name Miller? Oh, Rich Miller. 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? 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. A carbos was introduced by... So the way the ITPs work is really cool. Anybody can suggest a compound.

What are other interesting candidates (01:45:44)

So it's basically like a crowd sourcing 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, they're going to study it. So a carbos was suggested because the idea is a carbos prevents the absorption of starch. So if you eat a pizza, you can have half of it leave your body basically without being absorbed. Still, footnote for Kevin. I think the ratio of donuts and beer to a carbos does matter, probably at some point.

Unique Health And Wellness Method Challenges

Acarbose is a carb-restricted mimetic. (01:46:20)

Oh, sure. Yeah, yeah, yeah. And you can only take so much a carbos. I mean, it is a little hard on your gut 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 going 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 hadn't... 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 a carbos 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 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. Are you more bullish on a carbos than metformin? No, I don't think so. I would still probably put metformin as a more interesting agent. I mean, a carbos, first of all, is just not an easy agent to take, unless you like diarrhea. And maybe GRT is also a caloric restriction mimetic. So it honestly... It's your monthly dose of typhoid fever. Yeah, yeah, exactly, right. I'm always one. I'm just one GRT about away from goal weight. I'm still more optimistic about metformin, but also metformin is more of a mystery. In fact, our other mutual friend from Easter Island, Nav Chandel, this is one of the things that he works on. Mr. Crow Arms. Yeah. And I'll be having Nav back on the podcast probably in early 22. Nav is fantastic. When there's some killer work that he's doing on the mechanisms of metformin, and 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 Canaga Flowsin. Ooh.

Limitations of Canaga Flowsin. (01:48:16)

Canaga Flowsin. Canaga Flowsin. Spelt actually as it sounds with a C. Mm-hmm. And it is a class of drug known as an SGLT2 inhibitor. It rolls up the tongue. Yeah. The SGLT2I. And it works in the kidney. It's a more elegant version of a carbose working in the kidney. So the kidney is kind of a cute organ, cute in that it's really smart, right? 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 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, as opposed to this toxin that might appear 100 years from an hour, a million years from now. So in the reabsorption process, Canaga Flowsin 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. So in a healthy subject, you would be presenting the sort of traditional, old-fashioned symptoms of diabetes. Yeah, although not quite to the same extent because it's sort of gradient driven. So in the traditional O slur sense, where literally diagnoses of diabetes was made by tasting the urine and seeing how sweet it was, those were patients that were presenting with wildly uncontrolled diabetes with a glucose of like 800 milligrams per deciliter. They're about to have a coma. I first learned what diabetes was when I was in Japan as an exchange student and it's toenobial, which is sugar urine disease. And it's really obvious in the characters. Like no idea what diabetes, you know, I heard it on the oatmeal. Interesting because I am guessing nobody in Japan actually has diabetes. Today, when people eating like rice with mayonnaise, slightly more. When you were there, yeah, there's probably just like five people with diabetes. Yeah, very few. So Canaga Flowsin mimics or 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.

anti-aging methods used in mice (01:51:30)

So it is also blunting the spikes, but it also seems to lower the average as well. So Canaga Flowsin extended the lives of mice in the ITP. And I don't remember the exact numbers. It wasn't quite as diabetic or so. No, no, no, no, no, no, these are perfectly normal mice. It wasn't as big an effect as Rapa Mysen, but it was bigger than most other things. There haven't been that many successes in the ITP. Obviously, most drugs fail. The successes like Rapa Mysen, 17 alpha estradiol, Canaga Flowsin, Acarbos, those are some of the big successes. And of course, they get tested over and over again to make sure they weren't one who's the 17 something or other. 17 alpha estradiol was a very interesting molecule. 17 alpha estradiol, 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. Yeah, that's super interesting. Yeah. And 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 farm is doing with that information. How did that get submitted for the ITP? Yeah, I asked Rich about that. I'm just backyard chemist. He was like, yeah, it was it was inherited a bunch of oil money here. I want you to make this. 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 without the without the without the feminizing effects, right? So it's it doesn't have the sexual characteristics of estrogen. So the question is, you know, because if you gave a male a whole bunch of estrogen, you're not going to make them live longer. Yeah. Because whatever benefits come from it are going to be offset by a bunch of negatives. So just to scratch my own itch in curiosity here is 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 17 alpha. I was trying 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. So maybe in a in a couple years, I'll when I finish the book and a few other. For experience. Yeah, I there is a there is a candidate that I think would be interesting. And so so no, it's just having a good scientific case for it. Yeah, that's fascinating. Should we do some stupidity?

Is eating banana with its nubbin really dangerous? (01:54:19)

I think a third things anything particularly ridiculous that you're doing these days or enjoying. I mean, there's so many. 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 a dream come true. It's just like take the most antisocial person in the world and allow him to never have to go out. And that's been I think really great for my family on some levels, but also it's mean that they've they've meant they've had to put up with more of my stupid jokes and the like just the dumb things that I think about. And 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. Yes. You know, the little part. So I am convinced that the nubbin is like lethal. Like if you eat a nubbin, you're going to die. And so all I do, I'm the nubbin police of our house because a lot of times, you know how you can never finish bananas. Like you buy them, you buy like 10 and you might eat three, but then seven are going to go bad. Yeah. So we peel the bad ones and put them in the freezer to make smoothies later on because we always add, you know, frozen fruit to like make my protein shakes or whatever. And when I do it, I'm really careful to never put the nubbin in like 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, right? Are you serious? Like kind of nubbin in here. Like there's people in the house. They could eat this. Like do you understand like the nubbin is like 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, no bite us. No bite us. So, and it just doesn't get old. I think the more it bugs her, the funnier it is to me. And the same with my daughter, like just endless eye rolls and the nubbins.

On saunas: Jdr II (01:56:19)

They don't buy it. They really think they claim that you can eat a nubbin and nothing will happen to you. Depends on your topochiko to nubbin ratio in the house. I think you're pretty heavily weighted in the former. All right. What else? I think it's a category is really if there's something else I've changed my mind on. 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. That's probably about it. Like there's no way you're going to really live longer because you're in a sauna. And 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 the sauna lab. Yeah.

How frequent and high temperature (01:57:25)

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, you know, 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 risk reduction of like 18%. Those are high numbers. Those are ridiculous numbers. And that's when you are comparing someone who own a sauna's four to seven times a week. I was going to ask you. What's the dose and frequency? 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, bath, small, just a week. I do four times 45. Yeah. Just to get to the punchline, I think based on the research, the MED is four sessions, 20 minutes, 80 degrees Celsius, four sessions, times 20 minutes, 80 degrees Celsius. Oh, you have Fahrenheit. What's the conversion there? That is about 175 Fahrenheit. 175 Fahrenheit. Got it. Dry, wet. 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 the, 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, I was going to ask you next, is it heat shock proteins? Is it something else? I think it's many things. I think it's heat shock proteins. I think that's nitric oxide. I think it's like literally vascular tone, right? Reduction in blood pressure. It's an, you know, increase in heart rate and cardiac output. So there's a bit of an exercise benefit. I don't know if BDNF, I think BDNF has been measured. I can't recall that could be another potential benefit. So my guess is it's an enough brain drive, neuro terrific factor. 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 saunaing, I've done lactate checks in there to see if it gets me to like zone two. It's not, so it's not a pure exercise, mimetic because it doesn't even get me to the level of a zone two workout, at least when it comes to a pure, you know, ATP uptake or ATP production standpoint.

Weight Loss And Nutritional Evaluation

How to incorporate (02:00:13)

But yeah, I've become like really optimistic on this. And I think it's, I think it's very promising. And I think it's, again, it's the challenges is how scalable is it, right? Like it's not as, it's not that easy to do. I would imagine also contraindicated for a lot of folks. Yeah. Yeah. I suspect, you know, if you're, 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 would, 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. Yeah. Amazing. Preferred method for zone two training seems like you do most of your work on a bike. I do. I like the bike. It's just my body is so much more efficient on a bike than anything else. Give preferred stationary bike or do you? Yeah, I do. I ride my bike, like my road bike on something called a wahoo kicker. Wahoo kicker. Which is awesome. Like hands down. If someone doesn't have a road bike, then I, my favorite stationary bike is the Kaiser. K-A-I-S-E-R? Yeah, K-A-I-S-E-R, I believe. And I think Kaiser makes such a fantastic spin bike. Amazing. You want to do one more change your mind about or one more excited? You can dealer's choice? Yeah, I'm pretty excited about GOP one agonists. Tell me to. I don't even know what that means. Tell me Peter. All right, so G-L-P-1 agonist, glucagon-like peptide one. They also go by G-L-P-1-R-A's. So glucagon-like peptide one receptor agonist. 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. So regulate, meaning it's catabolic. Lower's blood glucose. It secretes insulin, actually, results in secretion of insulin to lower blood glucose. So these are a group of drugs that have been around for quite some time. So kind of a high choice in people with type 2 diabetes. The 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. It didn't get a lot of traction.

Stimulant weight loss history (02:02:59)

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 get her to help her lose weight. I certainly am not a fan of stimulants for weight loss. Drugs like Fenthermine can be somewhat effective, but they can also have their side effects and be somewhat habit forming. We had sort of noodled this, and eventually we ended up trying this drug. It didn't really have that much of an effect. I kind of sort of put it aside for a while. Until about six or seven months ago, I was talking to someone who had an early line of sight into a trial that was going to be published, and they said they'd been using it clinically. A newer version of this drug. It's called semagluetide.

Drug therapy breakthrough for obesity (02:03:56)

The trade name is ozempic. They said, "You've got to see what this drug can do." The dose that's given for people with diabetes is 1 milligram once a week. It's an injectable drug. It comes in a little pen. You shoot it in your gut or your leg once a week. One milligram muscular or a tini little insulin syringe. But when we push people up to 2.5 milligrams, the weight loss is comical. This is not just people with diabetes. This is anybody. Then sure enough, there was a study that was published probably a couple of months ago looking at semagluetide in overweight and obese people without diabetes. The weight loss was through the moon. We're talking 20% weight loss. Completely durable as long as you're on the drug. Then it begs the question, what happens when you come off the drug? We haven't seen fully what that looks like yet. I think we need to see what those studies look like. My thinking of this, we've now put a lot of patience on this drug. I think a lot is relative. Maybe 12, 15 patients we've put on this drug. Some people can't tolerate it because of the nausea. That's definitely one of the side effects. Is it administered? Once a week. Once a week, is the nausea transient or is it? Yeah, it tends to fluctuate how far you are. If you inject it on a Sunday, 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. Again, so it's transient across the week, but it also seems to be transient over time. The dose in the study was 2.4 milligrams, so 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 and one milligram, then one and a half, then two, etc.

What causes weight loss with an anti-diabetic drug? (02:05:57)

But basically, we haven't seen any patient who can tolerate the drug that does not lose weight. Have any cycled off, in which case, obviously, behavior matters a lot. Calories matter a lot, but do you see a greater balance than you would anticipate otherwise? And they don't seem to regain all the weight they lost. Now my biggest concern, and 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 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. It seems to not be entirely clear why would that result in weight loss unless they increase in insulin along with the glucagon like peptide are reducing appetite.

The One Drugs Listening To (02:06:53)

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 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, postprandial meaning postmeal, 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 CPEPtide, which exists in a one-to-one ratio with insulin because when insulin comes out, it's a pro-hormone and then it gets cleaved into insulin and CPEPtide. So you should have one CPEPtide for every insulin. So if you measure the urinary amount of CPEPtide, 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 CPEPtide go down even as resting insulin went up. 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. That's right. Yeah. That's so interesting. Yeah, this drug is currently... Have you seen 20%? Now, when you say 20% reductions, are we talking about body fat or body weight or... Body weight. Wow. Yeah. Yeah. Wow. So, you know, that's... And that's easy. You'll see more. Yeah. 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.

How To Figure Out Which Foods Are Worth Eating & Which Are Not (02:08:37)

Wow. Like they've literally reduced their appetite and they've improved their insulin sensitivity and glucose-disciplined. 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 drug not to say changes in eating or other habits. Well, they have changed their eating, but I think it's in response to the drug. Uh... Yeah, right. 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, um... You know, I look, I think... I think there's... There's some people who think that you shouldn't need a drug to help you. And like, 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 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, um... You know, if you have tried every dietary strategy imaginable and your metabolism is not, you know, moving in the right direction, why shouldn't we explore other ways to kick start 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. Um, I also think they'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. 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 in nutrition.

Efficiency And Heart Rate Measurement

Increase your ability to separate signal from noise. (02:10:38)

That's the reality of it. But not everybody can do enough exercise in the right nutrition with enough ease to get the benefits. So the more tools we have in our toolkit that go outside of that, the better. 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 Goldaker, who believes in MD, and enjoyed that so much that had a few excerpts from that book put into the appendix or the appendices for our body because I wanted to provide some basics. So there are any other resources or recommendations for folks who want to improve their ability to separate fact from fiction, hype from reality when it comes to headlines, media, studies, and so on. Not to get to Peter at Tia level, but to get to the point where they just have a better ability to separate signal from noise with this kind of thing. You know, there's a good newsletter that I subscribe to out of the University of Indiana. It's called the, I think it's called 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. Oh, that's right. 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 basically just because you, if you read something in the media, it's, you should just assume it's in, it's, it's being taken out of context and it's incorrect. And unfortunately I wish I had better answers on. 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. That's right. And that's a great, discret it, your nubbin. And that's a great example of always knowing absolute risk versus relative risk. That's exactly, that's exactly 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. 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, to have our, our preprandial exploration, our preprandial exploration of various, various cacti is agave considered a cacti? Well, I guess what is miscal actually made from? Is it agave? I know it's like a keel of fire in your mouth, but that doesn't tell us much about the botanical origins. I know sotol is different. Have you had sotol as a side note? It's a plant or I should say it's a bit, 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 miscal. Speaking of Texas, can I tell you the only thing so far about Texas I'm not fond of? Scorpions in your kitchen. I've only found six. That was this morning in my household. Took care of it, it was fine. It's the cactuses when I'm out in the bush. So when I was out, what are you doing out in the bush? Well, when I was out doing that precision shooting a couple months ago, they were like training for your counter sniper operation. That's right. So we had like mats down on the ground and we're laying on our mats and we're, you know, shooting off into distance. I vaguely remember someone saying, stay on your mat. Oh, God. Oh, God. And so at one point I'm like loading my magazine and I kind of rolled off the mat and 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 you know, it went through my pants. 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 that broke beneath it. And so I'm going on this hunt in about three weeks and it's me, my first time hunting access deer here in Texas. And one of the things that the guy who's taking me said is you got to make sure your shoes won't get poked like the cactus is one of your boots. So you're not going to wear your ninja socks for this one? Yeah, no, this will not be a barefoot hunt. But aside from the cactus is, man. Yeah, yeah. All good in the Republic of Texas. I have a shirt. Maybe I'll get you one of these. You might have seen it. It says has a big flag, Texan flag on it. It says most likely to secede. Yeah. They saw those at the airport and Austin for those who are interested. Peter off to dinner. We go. Thanks again.

Peter Attia (02:16:10)

Is there anything that you would like to mention before we close? Of course, people can find you. Peter at Tia MD will basically take them to everything. I would imagine that's the website. That's Twitter. It's Instagram, 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. The Peter and his guests know so much about anything you'd like to add to that? I would just say that some decaffeinated brands of coffee are just as tasty as the real thing. You know what their reference is? What movie is that from? I don't get the reference. What is that? Is that real genius? I think it's real genius. Is that real genius? I think so. 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. I had the best chicken wings. For me, the chicken wings in general are kind of like the pistachios of the foul family. There's just so much work and you just don't get much out of it. Turns out, Tommy Watt Wingy, which is the name of this food truck, has incredible chicken wings. They're delicious. I don't know what antibiotics they give these chickens, but they're enormous. You can have a full meal. Tommy Watt Wingy. Where's he? Tommy Watt Wingy. Do you know he's actually at, I think it's Cosmic Cafe. They may have multiple locations. Do you know what reference Tommy Watt Wingy is from? Well, it's not the donger need food. That's 16 candles. Tommy Boy, Chris Farley, Tommy Watt Wingy, the diner scene. It's funny. I've seen that movie a hundred times. How have I missed that? Oh, yeah. Yeah. We're talking about his sales process and he convinces them to the waitress to fire up the kitchen after they've closed. He grabs, I think it's like a muffin and he's like, "Let's say it's my prospect." He walks through this entire thing. We'll link to this video in the show notes. So that for people who want us to get Chris Farley plus Zone 2 training plus Rapa Mysen in one place, this is probably the only site on the internet. We'll have all of those in one set of show notes. And Peter, thanks for taking the time, man. Thanks, man.

Efficiency In Particular (02:18:42)

Could you just briefly explain what efficiency means within the aerobic efficiency and then come back to the Zone 2 training? 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, an 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 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 in 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-CoA's get 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 is 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. So pyruvate into lactate will generate one-sixteenth 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."

Zone 2 Primer - Think about the data (02:21:20)

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 lactated 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, 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. So the efficiency speaks to the longer you can use the mitochondria, the better. This Zone 2 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. Do you say Caesar Milan? I'm kidding. Oh, the dog trainer. Yeah. Well, were the names again? Inigo. Okay. San Milan and George Brooks. Inigo has 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. 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 war. 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 two millimole level? And it's just a staggering difference. So all of them would ultimately achieve high lactates, admittedly very different powers, right? The fitter you are, the more power you generate before you hit that peak lactate. But 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 mean, I guess for someone who spends any time on ground sliding, yeah, flat ground, no wind going 13 or 14 miles an hour, 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, 1 watt per kilo in that vicinity. The reasonably well-trained average, you know, not average, 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 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 4 watts per kilo. What was the total duration of the assessment? It's typically done, you know, unlike a ramp test where you're quickly, quickly changing, you typically do long ramps. So, you know, 15 minutes, check lactate, 15 minutes, check lactate, or 10 minutes would be about the minimum. Do you think those results would have looked different had the muscle groups involved had 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. Yeah, it's possible. And certainly there's 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. You know, 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- Not to get you into assess or to also train. Both. Both. Yeah. Because it does need to be pretty steady state. So, you know, 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. 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? 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, you know, 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. 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 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. Three hours per week. Yeah, ideally delivered at sort of 45 to 60 minute intervals. I've asked InnaGo about this specifically, you know, 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 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. 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 the hike isn't exactly perfect, but assuming it's a say flat ground constant load, this should be something you could sustain for much longer than say 45 minutes. 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 so unlike you Peter. 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 too. So how well I slept the night before my state of hydration, what I've eaten will all impact this. So you're tracking whether you are in zone two or not by poking my finger. I'm using that. Okay. So when people don't want to do that, what do we recommend? What we recommend figuring out which zone to heart rate is because you can track heart rate really easily. So rectal probe most of the time. Exactly. No, that's for temperature. So heart rate depends on how long it is. Right. So hot. Yeah. Just sitting right here on the vena cave. So with heart rate, you want to give somebody a starting point.

Functional Threshold (02:30:12)

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 meters, 250 bucks, but the strips are $4 a piece. So which is just so aggravating because you know these things cost about 12 cents to make.

Two Ways to Measure Heart Rate (02:30:30)

We usually use two ways of estimating. One estimate is 180 minus your age, which I think is the low estimate. Right. So a 50 year old would start them at about 130, 131 beats per minute. 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.

Heart Rate Performance Testing

Heart Rate is 78% of Max Heart Rate (02:31:09)

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

Heart Rate Test (02:31:45)

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 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. Yeah. Okay. Yeah. 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. 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?

Duration Of Health Benefits

How Long Until Benefits? (02:32:41)

Well the latter is a good question because it probably depends on from where you start. Right. So, you know, with someone who's starting out really metabolically broken, which by definition is what type two 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. And that's a brutal cycle to be in, right? 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 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. You know, 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 two power has gone up by 25 percent. Power measured by watts. 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 two back then was, I mean, probably 40 watts higher than it is now, although my zone two is probably 40 watts higher now than it was two and a half years ago. Mm. a little bit of a bit of a little bit of a bit of a bit of a bit of a bit of a bit.