The Peter Attia Drive - #85 - Iñigo San Millán, Ph.D.: Mitochondria, exercise, and metabolic health

Episode Date: December 23, 2019

In this episode, Dr. Iñigo San Millán, Assistant Professor at the University of Colorado School of Medicine, explains the crucial role of mitochondrial function in everything from metabolic health to elite exercise performance. Iñigo provides a masterclass into the many different energy system pathways, the various fuel sources (including the misunderstood lactate), the six zones of exercise training, and the parameters he uses to measure metabolic health. Additionally, he highlights the power of zone 2 training in its ability to act as a powerful diagnostic tool, and perhaps more importantly as a treatment for mitochondrial and metabolic dysfunction. We discuss: Iñigo’s background in sports and decision to focus on education [7:15]; Explaining the various energy systems and fuels used during exercise [14:45]; Iñigo qualifies energy systems into six training zones [26:00];  Lactate is an important fuel source [33:00]; Zone 2 training—physiologic characteristics, fuel sources, lactate, and the transition into zone 3 [40:30]; Using blood lactate levels (and zone-2 threshold) to assess mitochondrial function [47:00]; Accessing mitochondrial function by looking at one’s ability to utilize fat as fuel (with an RQ test) [55:00]; Athletes vs. metabolically ill patients—mitochondria, fat oxidation, muscle glycogen capacity, “fat droplets”, and more [1:00:00]; Physiologic characteristics of zone 3, zone 4, and the lactate threshold [1:20:00]; Fueling exercise—dietary implications on glycolytic function [1:30:30]; Relationship between exercise and insulin sensitivity (and what we can learn from studying patients with type 1 diabetes) [1:46:30]; Metformin’s impact on mitochondrial function, lactate production, and how this affects the benefits of exercise [2:04:15]; Raising awareness for risk of “double diabetes” [2:15:00]; How to dose zone 2 training, and balancing exercise with nutrition [2:18:00]; Proposed explanation of the Warburg Effect: Role of lactate in carcinogenesis [2:27:00]; Doping in cycling, and the trend towards altitude training [2:39:15] and; More. Learn more: https://peterattiamd.com/ Show notes page for this episode: https://peterattiamd.com/inigosanmillan Subscribe to receive exclusive subscriber-only content: https://peterattiamd.com/subscribe/ Sign up to receive Peter's email newsletter: https://peterattiamd.com/newsletter/ Connect with Peter on Facebook | Twitter | Instagram.

Hey everyone, welcome to the Peter Attia Drive. I'm your host, Peter Attia. The Drive is a result of my hunger for optimizing performance, health, longevity, critical thinking, along with a few other obsessions along the way. I've spent the last several years working with some of the most successful, top-performing individuals in the world, and this podcast is my attempt to synthesize what I've learned along the way to help you live a higher quality, more fulfilling life. If you enjoy this podcast, you can find more information on today's episode and other topics at peterottiamd.com. Hey everybody, welcome to this week's episode of The Drive. I'd like to take a couple of minutes

to talk about why we don't run ads on this podcast and why instead we've chosen to rely entirely on listener support. If you're listening to this, you probably already know, but the two things I care most about professionally are how to live longer and how to live better. I have a complete fascination and obsession with this topic. I practice it professionally, and I've seen firsthand how access to information is basically all people need to make better decisions and improve the quality of their lives. Curating and sharing this knowledge is not easy, and even before starting the podcast, that became clear to me. The sheer volume of material published in this space is overwhelming. I'm fortunate to have a great team

that helps me continue learning and sharing this information with you. To take one example, our show notes are in a league of their own. In fact, we now have a full-time person that is dedicated to producing those, and the feedback has mirrored this. So all of this raises a natural question. How will we continue to fund the work necessary to support this? As you probably know, the tried and true way to do this is to sell ads. But after a lot of contemplation, that model just doesn't feel right to me for a few reasons. Now, the first and most important of these is trust. I'm not sure how you can trust me if I'm telling you about something when you know I'm being paid by the company that makes it, to tell you about it. Another reason selling ads doesn't feel right to me is because I just know myself. I have a really hard time advocating for something that I'm not absolutely nuts for.

So if I don't feel that way about something, I don't know how I can talk about it enthusiastically. So instead of selling ads, I've chosen to do what a handful of others have proved can work over time, and that is to create a subscriber support model for my audience. This keeps my relationship with you both simple and honest. If you value what I'm doing, you can become a member and support us at whatever level works for you. In exchange, you'll get the benefits above and beyond what's available for free. It's that simple. It's my goal to ensure that no matter what level you choose to support us at, you will

get back more than you give. So, for example, members will receive full access to the exclusive show notes, including other things that we plan to build upon, such as the downloadable transcripts for each episode. These are useful beyond just the podcast, especially given the technical nature of many of our shows. Members also get exclusive access to listen to and participate in the regular Ask Me Anything episodes. That means asking questions directly into the AMA portal and also getting to hear these podcasts when they come out. Lastly, and this is something I'm really excited about, I want my supporters to get the

best deals possible on the products that I love. And as I said, we're not taking ad dollars from anyone, but instead what I'd like to do is work with companies who make the products that I already love and would already talk about for free and have them pass savings on to you. Again, the podcast will remain free to all, but my hope is that many of you will find enough value in one, the podcast itself, and two, the additional content exclusive for members to support us at a level that makes sense for you. I want to thank you for taking a moment to listen to this. If you learn from and find value in the content I produce, please consider supporting us directly by signing up for a monthly subscription. My guest this week is Inigo Sanmilan. Inigo is a assistant professor at the University of Colorado School of Medicine, where his areas of research focus on exercise,

metabolism, nutrition, sports performance, overtraining, diabetes, cancer, and critical care. And I realize at least one of you at this moment is thinking, how in God's name can one person study all of those things? And the answer is, if you come at it through the lens of the mitochondria, it turns out you can have a breadth of focus that covers all those things. And of course, that's exactly what Inigo does is he studies mitochondrial performance and mitochondrial efficiency. And it's based on that, that the moment he and I met a year ago, it was a sort of love at first sight. And we've been geeking out together ever since. Inigo has had a profound impact on my training, the way I talk to my patients about exercise and the way I've thought about longevity through the lens of mitochondrial performance. He is an internationally renowned

applied physiologist. He's worked for at least 20 years with many professional teams, elite athletes across all sports. He himself is a remarkable athlete, which we barely get into. He's so modest and unassuming. He currently works with a number of professional cycling teams at the highest level, including at the level of the Tour de France. He's pioneered a number of things that we get into here, everything from using high frequency ultrasound to assess glycogen levels, to more importantly, ways in which we can use biopsies at the invasive level and blood tests at the less invasive level to draw on the insights of mitochondrial performance. It would take me

an hour to simply explain the treasure trove of stuff we explore in this episode. So I'm not even going to try to say what we get into other than if you're interested in mitochondria, if you're interested in fitness, if you're interested in exercise, if you're interested in metabolic health, all of the above, I think you just need to listen to this one and take my word for it without seeing the running commentary. The show notes, of course, will be especially important for this one because some of this stuff just is better explained through pictures than words. Of course, there will be a nice effective table of contents there. So without further delay,

please enjoy my conversation with Inigo. Inigo, thank you so much for making time to sit down today in your new office here. Thank you very much, Peter. It's my pleasure and honor that you're here with us at the University of Colorado at the School of Medicine. I emailed my team, I emailed Nick and Bob and a couple of the guys today when I was on the way over here. I was on the plane and I was reviewing my notes and I thought, I am so excited to sit down with you today and Rick tomorrow because we've had so many kind of off-the-cuff sidebar conversations about mitochondria, mitochondrial function, health efficiency, et cetera. And it's sort of like, we never have enough time. It's like 15 minutes here and 12 minutes there and an email here and an email there. But it was in preparing

for this, the team helped me really kind of put a lot of my thoughts together. But I think before we kind of get into the really hardcore stuff around mitochondria, which is something that I think anybody who's interested in health at any level, whether it's really at the deep cellular level or just at the level of, I want to live as long as I can, as healthy as I can. Everybody sort of has a sense that all roads point to the mitochondria, but your path to getting there to me is particularly interesting because it starts with looking at athletes and you yourself, even though you downplayed a lot, you were quite the athlete growing up. So you grew up in Spain

and what sports did you play? Yeah, I grew up in Spain and I played for Real Madrid for the academy for six years. And I was always very passionate about sport. Then I, when I turned 16, I discovered cycling and that's the way I changed sports. So my dad still thinks that that was the dumbest decision of my life. Is that was the dumbest decision of my life. Is that true statistically? Would a child growing up in Spain who's already in the feeder program for Real Madrid, would they have a better chance of having a career as a professional football player than a professional cyclist? That's hard to say, but when you're already at that age in Real Madrid, you can be getting to the top team is very difficult, obviously, but definitely be a feeder to other smaller teams.

That's a higher possibility, but you never know. But you have to follow your passion, I guess. And I followed it and I changed to cycling and I got to race professionally for two years at a low level. So I always say that I admit it. I'm a truncated and frustrated professional athlete because I never got to the top, but that said, I learned a lot and it's been a school of life all my life. Since I was nine years old, I've been in the high level of competition up until today on the other side of the table, working with athletes. And that's what I became

very familiar with everything related to the elite sport and that everything that involves. I don't think most people who have not themselves been on a bicycle and trying to do something at a reasonably high level can appreciate that even being a professional quote unquote low level, I guess what you're saying by that is you were not necessarily on a team that was even going to go to the big grand tours and such. But I still think most people don't understand the level, how much higher that is above a general fitness athlete type of thing. So when you were at that level, what was your specialty? Were you a time trialist? Were you, uh, you look too tall to be a climber, but who knows what you weighed back then? Yeah, I was very skinny though. You're taller than me. I'm like 5'11". Okay, so you're an inch taller.

But I used to be 143, 145 pounds. So I was very skinny. So I used to be a good climber. I was good overall, but better as a climber. But yeah, I appreciate it now when I see people who are category ones or twos or threes as a cyclist or so that their fitness level is very good, that definitely my fitness level was better. But at the same time, there is like a whole world between my fitness level and what the two of the friends guys have. It is unbelievable. When I was sort of going through category five, four, three, two,

by some metrics, I could maybe time trial at the level of a category two, three, but of course my climbing and sprinting and everything else would have been like a category four. And you realize that the guy who's category one, the guys I used to train with who are collegiate athletes who are exceptional at category one, they're still not even pro. pro, and then the domestic pro to get from that level to a European pro, and then the European pro to get to a major team, and then to be on a major team and the difference between the GC contender and everybody else. We're talking about log orders of ability. It's not subtle. No, and I have all the data from all these years collecting the data. And I know very well the physiological parameters typical of a top junior athlete or category three, category two, one, domestic pro, average, pro tour,

cyclist, and best of the best. And the difference is amazing. They're very significant. You can really categorize people accordingly. We're going to come back and start to talk about professional cycling and things. And there's so many things I want to talk about because I think for also the person who's not immediately wed to the sport might too easily want to dismiss the accolades of these athletes and the physiologic prowess as simply, well, you know, those guys all use drugs. And while that's probably true at some level with respect to some drugs and certainly a certain class of athletes, it in no way diminishes what their physiology looks like completely off drugs. So we'll come back to all that, but going to you.

So after two years at a professional level, what made you decide I'm not going to continue doing this? I'm going to pursue my education and the other things that you've gone on to do. I realized that it's very difficult and you need to be in the right place at the right time at the right moment and that different planets need to be aligned. It is not just the best always get up there to call it destiny, call it whatever, but a lot of things have to happen to become a pro and they were not on my side. But at the same time, I needed to make a decision either trying to get an education that can not assure me, but at least give me some future professionally speaking outside the sport or try to go for the sport where the planets were not aligned. I didn't know if I could even make it and you would take that sacrifice.

So that's what I decided. I think this is not good for me. And then as I was studying also, I had a good possibility of doing a very good internship at a top, if not the top sports medicine clinic in Spain. In fact, the famous PRP therapy was born in that clinic. And that's where I said, I had a good possibility to start internship and then became a part-time job. And at that time I said, okay, I'm just going to stay here and continue. And how long have you been here at the University of Colorado?

11 years. Okay. Now you and I met through an interesting circumstance. It's a funny story. I don't know if you remember the very first time, but I had just flown into Abu Dhabi and I think I came straight from the airport to the training facility and it was like 11 o'clock at night or something. And you put me right on the bike and we did a VO2 max test and which anybody who's done a VO2 max test on a bike knows there's nothing very pleasant about it. You've got this mask that is incredibly restrictive. I hadn't done one since I stopped cycling. So that was probably six, five years or six years. And then I think you weren't happy with the air mixer because we were getting weird numbers. And it was at some

point, I think when I hit about 50 milliliters per milligram per kilogram, we sort of said that's enough. And it was a good thing because I don't think I had much more. It's amazing how much you lose when you stop training that zone. I never thought there could be a day when my VO2 max could be below 50. Like I thought it'll be 50 when I'm a hundred, right? That's not true. It really falls away. Yeah. It falls apart. Yeah. So I would be surprised if I could hit 55 today actually. But we connected immediately because it was a great point in my life where I was almost, I was sort of looking for direction as a former, I don't even want to use the word athlete to describe myself, but as a person who

formerly took training very seriously to now someone who was trying to think about reshaping my training around longevity, it was a perfect collision of ideas because I was sort of in search of what to really focus on. And what we immediately clicked over was your protocol for zone two training, which you were instituting heavily with the UAE team and other folks that you were training there. And the rest is history. I mean, it's really completely shaped the way I think about using this type of training as a way to improve mitochondrial function and as a way to test it. I almost think at this point for the listener, we should pause for a moment and explain these energy systems because so much of what I

want to ask you about and so much of what your research focuses on assumes a level of understanding I don't want to take for granted. So maybe explain for people what aerobic metabolism means. Okay, so there are different energy systems and those energy systems they're also used by different muscle fibers in the muscle. There are different conditions like the aerobic condition and anaerobic condition. We tend to believe that the immense majority of activity that we do is aerobic. We tend to believe that any hard effort is anaerobic and therefore the concept of anaerobic threshold. But actually even what we call the anaerobic threshold is an aerobic activity. So the majority of the efforts that we do are in an aerobic

environment, except for when you do a sprint or when you do maybe like a one minute maximum. Outside that, the majority of the activities that we do are in the aerobic state. Then what changes is the fuels that you use to produce energy. So at the end of the day, what we want to do is to contract the muscles and not only to contract them as fast and as forceful as possible, but what we want also is to do this as efficiently as possible. So for example, for a marathon race or for a 1500 meter race, you need to calculate when you pull the trigger and go for it. And then when you have to deploy all the maximum efficiency that you have. So you need to be very efficient metabolically speaking. So the fuels are very important for

that. So the main fuels that we use for exercise are the fatty acids and glucose. And those are oxidized or burned in the different skeletal muscle fibers that we have. So we have the slow twitch muscle fibers and the fast twitch muscle fibers. The fast twitch muscle fibers are divided in two. The type 1A and type 2B, if you will. Some people call them type 2X as well, but they're two kinds of muscle fibers. I just want to interject for a moment because I know a lot of people listening

to this have heard the term fast twitch and slow twitch. And the assumption is that they twitch at different speeds, but really it's that they twitch with a different force. And the speed is referring to how quickly they fatigue, not the speed with which they fire. So when you're talking about a type one or a slow twitch muscle fiber, it's just a less forceful fiber. Whereas a type two fiber, and as you said, they're divided into A's and B's. With each firing, with each time the muscle fiber fires, there are more motor end plates, and therefore it's generating more force. But the trade-off is it's going to be more quick to fatigue. And why is that? Why does it fatigue faster? is it's going to be more quick to fatigue. And why is that?

Why does it fatigue faster? Because it comes down to what you're talking about. Yeah, it's because metabolically they're more stressed. The way we recruit muscle fibers or base a sequential pattern that is very similar to the stick gears of a manual car. So you first start and you go in first gear. And as the RPMs go up, then you get to a point, you get to the red zone. So that car cannot keep up with that first gear. You need to shift to second gear and you speed up and the RPMs go higher.

And then eventually you need to shift to third gear. This is very similar to what happens at the skeletal muscle. The type one muscle fibers, slow twitch, they can produce ATP, which is the energy coin, the classic that we always hear about, which is what elicits that muscle contraction. So at low exercise intensities, we don't need to contract the muscles nearly as forceful, nor as fast as when we do high intensity. Meaning we don't need to go back and keep firing and keep firing and keep firing. Exactly. And for that, we don't need to generate ATP as fast

as we do at higher intensities. And it's about ATP generation, that's exercise intensity. So at low exercise intensities, those slow twitch muscle fibers or type one muscle fibers, they are very well designed to use an energy that is good enough to provide ATP, and yet you can do this for a very long time. And that's the diesel gasoline, and that is the fatty acids. However, as exercise intensity increases, the necessity to produce ATP at a higher rate increases as well. And it gets to a point where fatty acids alone

are not enough to produce ATP. And therefore you need another energy system. And that energy system is the glucose, which is a faster energy system, which going back to the analogy of the car is like if we had, imagine a car with two tanks. One is gasoline and the other one, or regular gasoline, and the other one is diesel gasoline.

So if you were to go from here to Denver to Kansas, where everything is flat and you don't need to accelerate or go fast, you would try to be more efficient and would try to use then the diesel gasoline. It's more economical. You get more mileage per gallon. But if you want to go to the mountains and you need to accelerate fast, that diesel might not do the trick. You need extra acceleration.

So that's where you utilize the glucose. And that's a very, I mean, the regular gasoline, which is like the glucose for the muscles. And that's kind of how the bioenergetics or the muscles kind of principles start. I like the way you've explained it. And I did a much worse job, I think, probably seven years ago. I wrote a blog post on this. The insight I was trying to get across, I don't know if I did,

was that we should not think of aerobic and anaerobic as with or without oxygen, which is sort of the way people are taught in high school biology. Aerobic means in the presence of oxygen. Anaerobic means not in the presence of oxygen. No, it's always in the presence of oxygen. It comes down to the speed with which the muscle is demanding ATP. Aerobic means you're generating ATP at a rate that is slow enough that all of the metabolic demands can be met through mitochondrial oxidation of hopefully mostly fatty acids,

but even glucose. of hopefully mostly fatty acids, but even glucose. Anaerobic just means, exactly as you said, the demand for ATP has now exceeded the capacity of the mitochondria. Do you agree with that? Yeah, and even the cytosol. So the cytosol, which is part of the cell, that's where you can oxidize glucose there into pyruvate,

and that pyruvate doesn't enter the mitochondria, but you produce lactate, but you produce energy and ATP there. And that can perfectly be still aerobic capacity. And my colleague, George Brooks from Berkeley, he's been studying lactate since the 80s, and he's the one who proved it, that you can produce lactate under fully aerobic conditions, not necessarily in the mitochondria, but in the cytosol. However, when the ATP demands even exceed the cytosolic production of ATP, that's where you need to use the ATP that is already stored in the muscles. You just don't have time to synthesize it. You need just to use it. And that's why the body stores very, very minimal amounts of ATP. And

that's what you develop in the sprint, or you use in the sprint. But you need to resynthesize it very fast. That's the pure anaerobic. You don't need any energy systems. And that goes also that of the confusion that is out there too. And are you saying this is distinct from the creatine phosphate system? Yeah, you can use a creatine phosphate as well. So you can have ATP and you can use the creatine phosphate systems. Those two, they don't need oxygen necessarily. Anything else can be under fully aerobic conditions, like even cytosolic production of ATP in the cytosol without mitochondrial oxidation necessarily can happen under fully aerobic conditions. And in fact, that's what we also call aerobic glycolysis. And in other areas

of biomedical research or medicine, it's called the Warburg effect, which is now a lot of people into cancer talk about it. The Warburg effect is that, is the production of lactate or the utilization of glucose in the cytosol, not in the mitochondria, but in the cytosol outside the mitochondria for production of energy. Well, I want to come back to the Warburg effect, but you brought up Brooks and there's a paper that the two of you wrote together somewhat recently. I think it was maybe 2018, if not this year, but it's actually, I'm in the process of writing a book, as you may recall. And in the exercise chapter, I actually really

explore that paper that you guys wrote, which looked at the zone two efficiency of world-class cyclists, recreational athletes, and people with diabetes. That's an unbelievable paper. And that's an unbelievable example of, I think, the clinical applicability of what we're talking about. So to put it in context, when we got talking back in Abu Dhabi last year about this, I remember you saying, and I'm paraphrasing, so you should clarify if I'm not saying it correctly, that your interest in athletes is in large part due to your interest in diabetes. Because if you want to understand how to fix an example of arguably the most effective mitochondria, why not at least study what the perfect mitochondria look like? Is that a fair statement? Exactly. Yes. And that's kind of what I'm trying to bring to the table.

The elite athletes have the perfect metabolism and mitochondria is at the epicenter of metabolism and health. As you said earlier, there are no other population in the planet with the mitochondria of elite endurance athletes. I was about to say, yeah, you said elite athletes. I would go even sharper. It really, in my mind, comes down to cyclists and runners. Yes, and triathletes. Even more than swimmers because of just the duration of it. It's these people who can go out and function at their anaerobic threshold for hours. And that's only really found in two sports.

Oh, yes. And that's what we see that even with an elite athlete, and I work with many elite athletes, yeah, you compare them and there's a huge difference. I guess I should add one. I think cross-country skiers are probably at that level as well. Yeah. So this population is the population in the planet with the healthiest mitochondria. So that's what I call perfection. And that's what I try to bring to the table that in order to study other diseases where mitochondrial dysfunction is at the epicenter as well, we need to understand

what perfection is in order to understand imperfection. And what we see in people with type 2 diabetes, for example, they are on the opposite metabolic pole of what a world-class cyclist or runner is. So by knowing the mechanisms of why that metabolism in these world-class athletes works, we can get to understand the imperfection or the imperfect metabolic pathways and potentially develop diagnostic tools and even therapeutics for them, as well as prevention programs. Yeah, and really cancer and type 2 diabetes or insulin resistance as part of a spectrum do represent two very common findings in the population. So if you look at

what percentage of the United States population either has cancer or is insulin resistant or has metabolic syndrome and or type 2 diabetes or fatty liver disease, all of these things which are part of a continuum, you're talking about half the country basically that has some form of dysfunction in the mitochondria. In the case of cancer, we can debate how much of that is a genetic insult versus other things. But because I want to talk so much about that, I want to go back and understand perfection a bit more. So there are lots of different ways people codify energy systems. When I was cycling, we used seven zones because that was Andy Coggan's FTPTP based energy system. You write about six zones and others have talked about five, but I want to talk about your six zones because

one, I think they're a little easier to explain than the FTP based ones, which if you don't know, if a functional threshold power number doesn't mean something to someone, then seven energy systems based on it is harder to understand. How would you walk us through zones one through six? What do they mean? Because when we start to talk about zone two, I want people to understand the difference between the normal person and the super person and the sick person. So what is zone one?

What does that mean? So that's from 25 years working with athletes and also my experience from being a former athlete and being obsessed with training and all these things, that's kind of, it led me to develop this. I'm not saying that they're the right things. And maybe in 10 years I change my mind or someone else comes with different things that are better, but that's what I have right now, at least. So I do this along with the muscle fiber recruitment pattern and the energy systems. So the type 1 muscle fibers, we know also that because they're the ones who oxidize fat, burn the fat very well,

they have the highest mitochondrial density and content because fat can only be burned in the mitochondria. Type 2 muscle fibers, especially the first type of muscle fibers, type 2, the type 2As, they have lower mitochondrial function because... Lower mitochondrial function or density? Density, I'm sorry. Because they don't necessarily need to oxidize glucose in the mitochondria. They can do it in the cytosol of the cell and therefore produce lactate, but they can produce ATP fast. So those muscle fibers, they don't contain as much mitochondria. And then the second type of muscle, slow, fast twitch muscle fiber, the type 2B or 2X, that is the one that is the pure anaerobic, if you will. And that is the one that barely has mitochondria, has very minimal mitochondria.

So starting with that, that's where I start breaking down the zones. So the zone one would represent the minimum stimulation the muscle fibers receive. It's just pre or contraction. That's what would you do on a recovery day or recovery mode. You have very low exercise intensity and you burn a little bit of fat mainly. And that's what we see also. We look at also fat and carbohydrate utilization. Scientifically, we call it fat and carbohydrate oxidation rates, how many grams per minute of carbohydrate and fat you burn. So we know that at these intensities, you burn mostly fat, although you also burn a little bit of carbohydrates, which we can go through that. Yeah, I want to come back to it because there's such an interesting clinical observation that

I've seen over the past five or six years. And your paper, your recent paper with Brooks just hammered it home in a much more rigorous way. So yeah, we are going to come back to our queue at rest as a harbinger of these other things that follow under distress. Yeah. So that's the zone one. So just to put that in energy terms for people, you and I walking up the stairs, we were coming from the lobby, we're in zone one. So just to put that in energy terms for people, you and I walking up the stairs, we were coming from the lobby, we're in zone one. Yeah. Walking down the street.

Walking down the street. Or if you are very fit and you go for a jog, very easy recovery day, that's your zone one. And then for the elite, give us an example. So if you took Meb or someone who's going to run a sub 210 marathon, you have a sense of how fast they could run and still be in zone one. Someone who's used to running 445 to 450 miles, could their zone one be as fast as like a seven-minute mile? Yeah, yeah, absolutely. You can see world-class athletes that their zone one, it's my sprinting, for example.

It's kind of what we see also in cyclists. The recovery day is 200 watts average. And for most mere mortals, 200 watts, they can do that for 15 minutes. Yeah. I just wrote a post about this recently using as an example. For people who ride a bike, 200 watts is about how fast it would take you to go 30 kilometers an hour without wind or without elevation. And that's certainly not all out, but that's pretty fast. And if you can imagine being able to ride at that level indefinitely without any metabolic consequence, that's what an elite athlete is doing. And that says nothing by the way about their weight. They're doing that at a body weight

that is a fraction of most people. Yeah. That's what they call the coffee ride. Yeah. They go for a coffee or ice cream ride and it's chit chat and they're like, it's unbelievable. So zone one, does lactate get produced? It should not get produced. Well, we start from the base that there's always lactate produced in the body.

So if you were to poke my finger right now or poke your finger right now, we measure lactate in millimolar, what would you expect to measure in me or you? You would be about one millimolar, 0.7 to one millimolar. That's kind of like a standard resting levels in a healthy individual. And in a normal person, so not an elite athlete, but sort of a recreational athlete, what's the highest lactate you'll typically measure in that person if you put them in a treadmill test or a... It depends on the protocol that you do. If it's a very violent protocol or it's a longer protocol, violent protocols, they produce more lactate. You might see 10, 12

millimoles, whether that protocol, let's say a six minutes maximal effort on a rowing machine, right? And the concept, for example, I've seen world-class rowers to maximal effort with 20 millimoles of lactate. It's very rare. You see very easily 15, 16, 17. That's because, and we can talk about that later, their glycolytic capacity, it's off the charts. Whereas people who they're not elite athletes, it's for them that's in protocol. It's more difficult to go over 12 millimoles, 10 millimoles, because their glycolytic capacity is not so good as the one that the elite athletes have. And sometimes elite athletes have the opposite issue, which is they don't make much lactate at all. They're so efficient. I've actually discussed this with Lance Armstrong after I erroneously had been on a podcast and made the case that he had a very high lactate tolerance. He were talking about it one day informally and he said, no, it's actually the opposite. I would barely produce any lactate. He was usually producing less lactate than others. lactate. He was usually producing less lactate than others. And again, this was when everybody's on the same drug or everybody's off the same drug. I mean, just genetically, there were some people

who probably have more MCT, which we'll come back and talk to, and they become more efficient at it. But okay, so that gives us a sense that lactate will go from maybe one to 10. If you're a normal person, maybe one to 20. I actually measured- 20 is difficult. I measured a lactate of 24 and a friend of mine once Wow, the highest i've ever measured in myself was 19.7. Wow, and that was only a four minute protocol Wow, pretty impressive, but also I almost wonder like maybe it's I wasn't even in particularly great shape at the time But I wonder if that same exertion under better fitness would have produced less lactate potentially, right? It depends on the protocol, right? If the protocol stops there and what you intend is to mobilize the glycolytic system to the maximum, yeah, you will produce a lot of lactate. If you want to continue and do a longer

protocol, eventually you just cannot mobilize as much glycolytic system because you have a little bit more fatigue. I think the difference between the really good people, I mean, when I hit, if I hit and I've been above 18 and maybe a dozen times, I'm done for half an hour. Like I can barely get up off the floor to go and take a shower. Whereas this friend of mine who was at 24, I saw him go from 24 to 14 in a span of about seven minutes and then jump in the pool and swim another race. And he's world-class. So that's sort of the difference. I think the world-class athlete can also clear the lactate much quicker than I can. For sure. And that's what happens in the mitochondria and any other part of the body. Because one thing with lactate, we believe that it's a waste product. However, lactate is the most important,

if not the most important fuel for the body. That's a profound statement. Yes, yes. I completely agree with you that lactate is not a waste product, but say more about that point. So one of the things, the brain prefers to use lactate.

So I have heard this. Talk to me about the data on this front. So my colleague, George Brooks, who is lactate man. So my colleague, George Brooks, who is a lactate man, so yeah, he started doing research with TBI, traumatic brain injury patients at UCLA. It's typical to give them glucose, and then when there's like a brain injury, the brain in the first place has evolved to use glucose as the main fuel. So when the brain is injured, they use more glucose. However,

when it's injured, different metabolic pathways might be dysregulated. So what my colleague, George Brooks, suggested was to give them lactate. And he showed, and he published, they do better. Better than beta-hydroxybutyrate, which also seems to be really beneficial in TBI patients, for maybe a different reason than lactate, although it could be all similar, which is if you buy the argument, which I find favorable, that part of the insult of TBI is pyruvate dehydrogenase becomes resistant to insulin, that would explain why glucose becomes ineffective in those patients. And it would explain why beta-hydroxybutyrate can bypass it. And the same could be true of lactate, right? Yes, absolutely. It's an alternative substrate that doesn't get limited through pyruvate dehydrogenase. Is that

what you think is happening? Yes, because it has its own transporter in the mitochondria and doesn't need PDH for that. It can enter the mitochondria directly for energy systems like hydroxybutyrate as well. But the thing is like lactate is a faster fuel. So the thing is like lactate is a faster fuel. So the thing is like also... Yeah, BHB is not a fast fuel. Exactly. Whereas lactate is as fast, if not faster, as glucose because it doesn't have to be processed, if you will. Now the listener might say, wait a minute, what are you guys talking about? Anyone who's ever done a lactate test knows how

much pain you're in when your lactate level goes up. So one of the other, I think, misunderstandings is what's actually causing that pain. Because that's, I think, why so many of us have a negative association with lactate. It's not actually the lactate that's causing the physical discomfort that you feel when you're vomiting on the floor after a maximal lactate test. It's the hydrogen. So explain why that's the case and why we tend to confound the two. I mean, there are many causes for pain or fatigue that in different hypotheses from the central fatigue to the peripheral fatigue. And it's very possible that both are interconnected at some point and we don't know the exact mechanisms. At some point, the central fatigue calls for the

brain to be the ruler where the peripheral fatigue is what happens at the cellular level. So it is possible that there's like a crosstalk among both of them, and either the chicken or the egg, right? Either one of them says stop. But what we know is that, yeah, it's not lactate itself, but the hydrogen ions associated to lactate, they build up. One of the things that has been researched, they can decrease both the contractive capacity of the muscle fibers as well as the force by up to 50% or more.

So that's one of the things that what we see is like the muscles, they cannot contract as fast or as forceful as before. And this is an important point for people to understand because if you haven't taken a physiology course, why would most people do so? It's also not obvious why you even need ATP to make your muscles contract. It's actually to unleash or unlock the actin my for four minutes and go as hard as you can. Well, at the end of that, anyone who's done it will acknowledge it feels like you can't actually contract your muscle. You've lost the voluntary ability to make them do what you want to do. And it's really two things going on. It's this hydrogen poison. And then on top of that, you're not generating enough ATP to hit all of those fibers that need to be uncoupled from their actin and myosin. So anyone who's been there knows. You think I'm going crazy. Why can I not make myself do this? Yeah, and that's where maybe the central fatigue component, the brain, might be kicking in and say, hey, dude, you're getting to a point that this is not physiological. So I'm going to protect your muscles.

And they're telling me through different signals, one might be the hydrogen ions, which also are produced from the hydrolysis or the breakdown or ATP. They produce also hydrogen. So you have the lactate on one hand and the ATP or the fast rate of ATP hydrolysis also produces hydrogen ions. But yeah, as you said very well, like you're conscious once, but there's something at the neuromuscular level also that impedes that. Could be at the local level specifically, but could also perfectly be that the brain says, hey, let's stop it. And one of the things that we know when people are fatigued is that there's a

decrease in adrenaline secretion to protect yourself. Because adrenaline or epinephrine, we call it here in the U.S. epinephrine, in Europe it's called adrenaline, is the major or one of the major elements involved in the breakdown of glycogen into glucose. We can talk about that later as part of the overtraining. But the adrenergic activity, it's also decreased as well when someone is in a fatigued state. So by the way, Alex Hutchinson has written a great book on this. Have you read his book, Endure? I heard about it, but I haven't read it yet. Again, it's good for someone like me who comes into this without world-class knowledge. And I found it a very interesting survey. In fact, I hope to have him on the podcast at some point to

go into some real depth on that. So now we've talked about the two ends of the spectrum, the most extreme end and the first end. Let's now get into zone two. What's happening physiologically as that athlete or that person enters zone two? So the zone two is that now then when you start stimulating those slow twitch muscle fibers to the fullest, let's imagine that you're in that first gear that I mentioned earlier in the manual stick car. And then you're in that red zone. And that's where the car is asking you, hey, shift to second gear. And that's where like you're forcing physiologically because the body adapts to say, no, you get stronger at this gear. That's kind of that zone too is like when you stimulate those muscle fibers before

you start changing to a whole different environment where you start then recruiting fully the type two or fast twitch muscle fibers and therefore the different energy system, which is the glucose. So the zone two coincides also with what we call the fat max, which is exercise intensity at the one you oxidize the highest amount of fat. And then we can see that clearly in the laboratory as we saw in the graph that we can show. We're going to include a lot of great pictures here. So if you're looking at the show notes, there's something called the metabolic map, which

is a great slide that we'll walk through this. And I think what's very interesting here, this occurs so often in physiology, it's a bit counterintuitive. As you go from zone one to two to three to four, five, and six, you're generating more and more ATP as you go up that chain. So that part is monotonic. It's increasing without stopping, but there's a local maximum that's occurring in zone two, which is your highest amount of fat oxidation. So as you go from zone two to three to four, you will still produce more energy. You will consume even more oxygen. Your VO2 max has not been achieved, which is your maximal uptake of oxygen, but you will now become less efficient and you're moving to a less efficient fuel. You're moving away from

this diesel example or the fat. So again, I think for a lot of people, the semantics get confusing here because you just said that zone two is your maximum. I mean, maybe a better way to explain it for me is zone two is the place at which your mitochondria are producing the maximum amount under purely aerobic conditions of ATP. Is that fair? Yeah, I would say that too. And that's where you're still recruiting those type 1 muscle fibers. That's the exercize intensity where you're recruiting the most. And they have the highest stimulus. Without tipping into the twos. That's basically it. And since that type 1 muscle fibers have the highest mitochondrial density, you're really stimulating

them a lot. As you said before, you need to tap into the fast-twitch muscle fibers. And in the moment you tap into the fast-twitch muscle fibers is because the ATP demand that you need cannot be covered by fat. And you need to switch to a different fuel. And that's where we see a big drop in fat oxidation and we see an increase also in glucose oxidation. And that's when we start seeing also an increase in lactate as well, because lactate is always, and I forgot to mention that earlier, lactate is the mandatory byproduct, not waste product, byproduct of glucose utilization. Mandatory. Every time you use glucose, you use lactate. And at higher intensity, you produce more. Let's talk about that because again, I think that's more nuanced than most of us would come to

this discussion with. We learned in physiology class that a molecule of glucose in the cytosol is turned into two molecules of pyruvate. Under conditions of sufficient cellular oxygen to meet the ATP demand, the pyruvate enters the mitochondria where it undergoes oxidative phosphorylation to make ATP and no lactate is generated. If that ATP demand exceeds the capacity that you just described in zone two, we now have to start turning some of that pyruvate into lactate to generate additional ATP that's faster to generate. In the first case that I described, is there still by necessity

some lactate production? Yes, there's some lactate production and we can see that even at rest, we have always a little bit of lactate in our bloodstream. Which is what you said at the outside. You said if you checked my finger or your finger now, we would probably still have somewhere between 0.7 and 1 millimole of lactate. Why is that? That's where we're trying to understand and we believe, my colleague George Brooks and I, that lactate is a major signaling molecule, that when it's regulated, it can signal and maintain homeostasis of different metabolic pathways. It's kind of like a visa for the body, as my colleague George Brooks calls it, when it's dysregulated, as we're starting to see in cancer, for example,

or we can see in type 2 diabetes. It can dysregulate different pathways. Every cell in the body produces lactate, and pretty much every cell in the body consumes lactate. Including red blood cells, I'm guessing. Yes, they produce a lot of lactate, red blood cells, because they don't have mitochondria. Yeah, I wonder...

It's glycolytic mechanism. Yeah, do the red blood cells account for most of the lactate production we see at baseline? Not necessarily, because there's not so much hemolysis and there's not so much activity in the red blood cells, but there's always some metabolic lactate produced from glucose utilization, because we always use a little bit of glucose, of course the brain, but that lactate escapes to the blood, to the circulation. And for us it's significant that it's always so steady also. And every cell in the body produces lactate, and almost every cell in the body utilizes lactate.

So it's got to be a why. And we believe, and that's why we're trying to scratch the surface, that it's a very important signaling molecule that goes beyond being a byproduct or a metabolite. And that's something that we've already seen in cancer, where we have seen that lactate stimulates the expression of the major oncogenes, transcription factors, and cell cycle genes in breast cancer. So it acts, and we have the paper under review now, it acts as a signaling molecule. So this is interesting because, again,

in physiology class, you sort of learn that all of that waste lactate goes back to the liver and the Cori cycle converts it into glucose and it becomes now stored glucose. But what you're saying is it's much broader than that. I mean, obviously the Cori cycle still exists, but it's not even clear how much of the lactate that we're measuring is undergoing that pathway to be converted back to glucose versus itself being consumed as a fuel, correct? Yes. And thanks to the great work that my colleague Brooks did starting in the 80s, what he saw is that the majority of that lactate is oxidized by the slow twitch muscle fibers, by the mitochondria of the slow twitch muscle fibers. And each mole of lactate gives how many moles of ATP under those conditions? I don't have it on top of my mind right now.

Is it a small number or big number? Yeah, it'll be a smaller number as well. But it's not like the 16 or whatever you get per acetyl-CoA? No, no, no, no, no. I don't think so. I don't have it on top of my head. But the thing is a constant flux of lactate from the fast twitch muscle fibers to the slow twitch muscle fibers.

That's when you start entering that zone three. You start mobilizing more of the glycolytic system. And that's kind of a transition state where you still mix fuels, fatty acids, and carbohydrates, but you start using more carbohydrates. And therefore, you start producing lactate. That said, that lactate is transported from mainly from the fast twitch muscle fibers into the mitochondria of the slow twitch muscle fibers, where it's used for energy. It enters directly the mitochondria for energy purposes.

And that is the ability that elite athletes have. They can be recruiting fast twitch muscle fibers. They can be utilizing a lot of glucose and producing a lot of lactate. But since they have a very well-developed mitochondria in the slow twitch muscle fibers, they don't need to export it to the blood and it doesn't accumulate. Yeah. This to me is the grail. This is the stuff that sets apart the best from the rest. Going back to zone two, tell me where you typically see a lactate level there. You and I have talked about a bunch of these numbers. When I try to explain this to my patients, because I have many of my patients on a zone two protocol, for a lot of the time we just use voice. We use ability to talk. I sort of say,

look, if you don't want to go through the protocol of poking your finger, zone two is about the highest level of exertion at which you're still able to carry out a conversation. But let's talk more technically. We're really seeing what? Lactate levels of about 1.7 to 1.9 millimoles? Yeah, 1.5 to 2. That's something what we see. And that's kind of what corresponds also to that fat max. So today, my data that I showed you from my ride this morning, I was 1.3 and 1.2 on my two meters. So I always do two separate meters. So I averaged 1.25 millimolar. That was clearly not zone two.

That was a zone one. The feeder that you get, like for example, a world-class athlete at zone two is really high. Yeah. Well, I'm not world-class, but just by lactate levels, that's probably not quite there. Yeah. It might not be quite there because it's slightly above resting levels. So there's no accumulation. And it's this accumulation. There's a homeostasis or a steady state below two. So call it one seven, one eight, one nine, where you're right

at the limit of not accumulating at a net level, correct? Yes, yes. So you're pretty much, that lactic comes, you obviously see it in the blood, and it comes from the muscles. So that means that the muscles overall are good. First, they're not very metabolically stressed, so therefore they're not utilizing a lot of glucose. And even if they're stressed, they're clearing the lactic very well

because you see in blood 1.5, 1.7, 2 millimoles. lysinol or glucose. And even if they're stressed, they're clearing the lactate very well because you see in blood 1.5, 1.7, 2 millimoles, slightly above resting levels. However, when you start seeing higher lactate levels in the blood, that means that your muscle clearance capacity cannot meet. No, I think what you're saying, if I understand, is once you hit two, three, four, five millimolar, you're saying that the muscle's ability to recirculate and utilize the lactate is going down. It has to export it into the circulation. Exactly. And that's where it goes to every cell in the body. It goes to the brain, it goes to the kidney, it goes to the heart. The heart is a great utilizer of lactate. And obviously, as you said earlier, it goes to the core recycle to be resynthesized back to glucose or to a certain form of glycogen. But yeah, that's when we see that in blood,

that means that that athlete cannot clear the lactate efficiently. And therefore, that's why it shows up in the blood. And that's where we can see that, for example, one professional athlete, a 300 watts, a world-class athlete might, well, let's say, yeah, 300 watts might have three millimoles of lactate, let's say, or two and a half, and a marmoral might have 12. That means that the power output is the same, but how do you get there? It's different. In the first place, the elite athlete might not need to use so much glucose. And if they do, they produce lactate, but they clear out so efficiently in the slow twitch muscle fibers that it doesn't have to go to the blood. Whereas the person who doesn't have a very good mitochondrial function cannot oxidize lactate very efficiently locally

in the skeletal muscle, and they have to export it to the circulation. And that's a way to see the metabolic stress and indirectly, as we published, a way to look at what is the mitochondrial function. So let's talk about that now. I do want to come back and talk about zones three and up, but because this is the perfect point to go back to the paper you and Brooks recently wrote, what you showed that I just thought was so elegant

was, as you said, you can either cap the output or clamp the power required or clamp the lactate production and look at the power required. And you did the latter. You basically said, we're going to find everybody's zone two, meaning we're going to find everybody's tipping point at which point their mitochondria are no longer high enough in function to meet the requirement. And what you showed was world-class cyclists were able to get to an average of something like 300 watts before they would finally flip that switch and have to start recruiting the fast twitch muscle fibers, which was measured indirectly by lactate production. Conversely, the weekend warrior,

reasonably fit people, guys like me, could get to 200 watts before that switch got flipped. But most interesting was the people with type 2 diabetes. I think we're like 120 watts. Is that about right? Yeah. We've been knowing for years now that a typical characteristic that we know of people with pre-type 2 or type 2 diabetes is that they have a poor metabolic flexibility that is called also a poor capacity to oxidize fuels. One of them is fat. We know that fat can only be oxidized in the mitochondria. Therefore, by measuring the fat oxidation of these patients, we can indirectly see the mitochondrial function, especially when we put them in context or in comparison with those ones who are healthy individuals, that could be moderately active individuals who don't have

diabetes or prediabetes or don't have any medications or elite athletes. So that's what we see that their fat capacity is very, very low. And that's kind of what we can see indirectly. But it's not often you see in biology such a difference because if the numbers 300 versus 200 versus 100 sound extreme, that's nothing compared to when you normalize by weight. So really the answer is in watts per kilo, what's the difference? And 300 watts to a professional cyclist who only weighs 60 to 65 kilos is just below five watts per kilogram. Whereas the person with diabetes almost assuredly weighs more. So their 120 watts is probably 1.5 watts per kilo. There are not a lot of examples of things in physiology where you see that much of a difference. You rarely even see that much of a difference in

average glucose level between someone with diabetes and not. So this functional definition that you guys have proposed is to me very important just as a clinician, just as someone who's trying to gather more data about a patient to understand their health. It's sort of like in a magic scenario, in a magic world, you would have these data on every single person. You would want to know what is your zone two threshold. And that becomes a way to assess mitochondrial function. Now, the story I was going to tell earlier, this is as good a time as any to tell it. About five years ago, in some of the most insulin resistant patients that I was taking care of, I began looking at baseline resting respiratory quotient, which you alluded to earlier. This is the ratio of produced carbon dioxide

to consumed oxygen. Say a little bit about that number and how to interpret it, and then I'll finish the story. So that's kind of, we can see through expired gases, we can see the amount of CO2 that you produce and the amount of oxygen that you utilize. So under resting conditions, and that's what's called a respiratory coefficient or the respiratory exchange ratio. The respiratory exchange ratio is purely at the respiratory level, at the lung level, with the respiratory coefficient, it's at the muscle level. They're quite similar, but not academically. You know, that might not the same, but we can call it RQ or RER2. So under normal

conditions, you don't produce much CO2. So the ratio, it's always below one, could be 0.7, something like that, for example. That means that it's CO2 divided by oxygen. So that's where you don't produce a lot of CO2, you use more oxygen, and therefore the ratio is 0.7. As exercise intensity increases. And so that ratio of 0.7, we can impute from that that a person is virtually all dependent on fat oxidation at that moment. Probably, yes. And that's what we can use through what's called stoichiometric equation. You can deduct the amount of fat that is oxidized.

Because to oxidize one mole of fat, you need X amount of oxygen and you produce X amount of CO2. So by measuring both, you can see what kind of fuel you're burning. And that's what we're doing in our paper. So as exercise intensity increases, or if the person is not metabolically flexible, they cannot oxidize fat very efficiently. So normally these people, they tend to depend more on glucose or any other extra source of fuel. And that's what you see use already people at rest, they have a higher RQs or RERs, which could be in the 80s. Then as exercise, if you were to do exercise, as exercise intensity increases, you start producing more CO2 and therefore the ratio starts getting closer and closer to one. And that's where we see that you start oxidizing more glucose than fat. When

the ratio gets to one, yeah, it's just 100% of the fuel that you use is glucose and you don't see any fat, which is kind of what we also call kind of that end of the zone four. Yeah. So this was the observation. I was noticing a subset of patients, again, very hyperinsulinemic, insulin resistant by whatever metric you would use to explain it, that had resting RER or RQ of 0.9 to 1, easily 0.95. So what does it mean when someone who is laying down to do this test under no physiologic distress has an RQ of 0.95? What does that mean? Obviously, based on what you said, it means they are almost exclusively relying on glucose and not oxidizing any fatty acid. exclusively relying on glucose and not oxidizing any fatty acid. But what is that telling you at a molecular level about the illness or the function of that person's mitochondria?

It's a red flag for mitochondrial dysfunction right there, because that's not normal. Obviously, after eating a meal of carbohydrates, yeah, for a while you're going to have a higher RQ, but at rest in a fasting state when someone is in the 90s. This is a morning fasted resting test. It's a red flag that is already telling you that there's something going probably at the mitochondrial level. And this is what we wanted to do this paper that we wrote. We want to see the same thing that is done usually at the EKG level.

So when a cardiologist wants to study the heart, if there's any abnormality, resting EKG has a reliability of about 50%. So you could see some red flags already, but you don't see everything. You have to stress the heart. Exactly. And you stress the heart and similar protocol than what we did here. And that's what you do when you do EKG in stress, right, situations. The reliability is about 95, 97%. So you see a lot of things. So I decided to take the same approach and say, okay, now at rest, as you very well said, you see people in the nineties with RQ and that's a red flag. Now, okay, let's stress those mitochondria. Right. So in other words, the analogy is

sometimes you'll do an EKG on somebody at rest and you'll see changes in the ST segment that tell you immediately there's a problem. But there are many people who have a normal resting EKG, but only when you put them on the treadmill're perfectly fine. But you see that their zone two level, the level at which they tap out at their fat oxidation maximum or their maximum aerobic output is much lower than predicted. And now you have a functional assay. Exactly. You can categorize people by looking at the fat and also looking at the lactate. If you burn very little fat, that means that you don't have a good mitochondrial function. And that confirms it, that test. If you produce a lot of lactate, that means that you don't have a good mitochondrial function either because lactate is metabolized in the mitochondria. So if it's in the

blood, that means that the mitochondria cannot metabolize it. So what we did with the three populations from world-class athletes to morally active individual with people with metabolic syndrome, which is a companion of type 2 diabetes, pre-type 2 cardiovascular disease as well, or what we call now cardiometabolic disease, because 80% of people with diabetes has cardiovascular disease and vice versa. So these people, what we did then with these three groups is then we paired both the fat curve, burning curve in the test, as well as the lactate. And the correlations were in the 90s. So we see that it's a valid indirect test to see the mitochondrial function.

Now, as we speak, and in this office right now, we have all the supplies. We're going to do this now with muscle biopsies, and we're going to try to prove not just this, but what are the metabolic pathways? Wait, do you have the IRB approved already? Yes. We're going to start next week. Can I do it tomorrow? We don't have the laboratory set yet. We're in the recruiting patient's phase now. I might have to come back and do this. I would love to get a muscle biopsy. Yeah, we can do that because we're going to be looking at the muscle biopsy, mitochondrial density, respiration. We have two different machines, Ouroboros and Seahorse. How many subjects are you looking to recruit? Well, so far we want to have about 50. We're going to be recruiting people who are well-trained. It's difficult to-

How will you define well-trained. It's difficult to- How will you define well-trained? Well, yes. So well-trained are people who are usually competing. Like for example, in cycling, it would be like a category three, two, and one. Okay. So pretty serious cyclists. Pretty serious cyclists. I'm going to try to see if I can fool a professional athlete to get a muscle biopsy, which might be difficult, but I'm trying to. Then we're going to have also moderately active individuals who are healthy. Then we're going to have another group that is masters athletes. Those masters who are 50, 60, 70 years who don't develop type 2 diabetes and they're very healthy, don't take

any medication to match for the age of diabetes. And then we're going to be looking at pre-diabetics and type 2 diabetics. And we're going to be looking at mitochondrial function, mitochondrial respiration, genomics, proteomics, metabolomics as well, and try to find the exact mechanisms that go wrong. Something that we see in this paper indirectly, we know that something's wrong, but we don't know the exact. This is PDH enzyme, or it is something that an LDH in the mitochondria that's not working or is faulty, or is is something that an LDH in the mitochondria that's not working or is faulty, or it's both of them. And that's where we're going to try to target the mechanism so that

it can give us maybe better diagnosis or open the doors for maybe potential therapeutics to target those mechanisms that we have seen that they're dysregulated. Well, my guess is people listening to this, if they're interested, will be able to very easily come and find where the enrollment is. And I might have to come back. And even if I don't fit into one of the nice neat buckets, I'd love to do the muscle biopsy. Now, of course, you talk about the need for a treatment here, but you already know, you've already discovered arguably the single best treatment imaginable for this, which is more zone two. How do you increase mitochondrial function? You train at the maximum

level of mitochondrial output, correct? That's my hypothesis. And that's what I have been seeing for 25 years working with elite athletes, that this is the exercise intensity where I see the biggest improvement in fat burning and the biggest improvement in lactic clearance capacity. Therefore, that means that the mitochondria is where you see the biggest improvement. We see also the biggest improvement in performance. Pause there for a moment. You're coaching professional cyclists in the Tour de France. So do they need to exercise at that low level of intensity? It's not that low level. Well, for them, it's low, but for us, it would be excruciating. But even for them, because for them, their mitochondrial density infraction is so incredible. And the way they recruit that type one muscle fibers,

it's so big that you need to push it. So it's having a much bigger gear range. Exactly, exactly. It's like in the first gear that we say, when you get to the 70,000 RPM, you're in the red zone. Okay, you push it there. This guy's first gear is in the 15,000, 8,000 RPM, you're in the red zone. Okay, you push it there. This guy's first gear is in the 15,000 RPM. So you still need to push into the 15,000,

which could be, they really go very fast. But then you see their lactate, and the lactate is not more than 1.8. So it's telling you that. They're just so efficient. They're incredibly efficient. Reusing that lactate and keeping it confined to the muscle as another fuel for the adjacent fiber.

Exactly. And if you see that in the blood, there's such a low levels of lactate, that means that they have a very good mitochondrial function and they're stimulating that system there. When you see that any athlete or any person is in the three, four, five millimoles, then you see that that system has given up already. It has to be exported to the circulation. Is the biopsy that you're going to do in this subsequent study going to allow you to differentiate between two plausible hypotheses to explain this observation? One being that they actually make less lactate. The other being their muscles actually utilize more of it before it gets back into circulation. Both of those could explain the observation because you're only

sampling in the blood. So you're only looking at how much lactate is making it to the blood. You don't know if it's just that they make less or they make the same amount, but use it much more efficiently. Do you have a sense of that? We know that because my colleague, George Brooks, who will be also a co-author in this paper, of that? We know that because my colleague, George Brooks, who will be also a co-author in this paper, he already has described that, that well-trained individuals, they can get to produce more lactate and at the same time, they utilize it better. So their gift, I'm using air quotes, the gift of the gifted athlete is not the production of less lactate. It's the ability to reutilize it more. Exactly. Yes. And we choose the skeletal muscle.

And this is a very important point in my opinion, because it's probably the first tissue where diabetes starts, skeletal muscle. About 80% of all the glucose or carbohydrates that we oxidize in the body after a meal, they're oxidizing the skeletal muscle. And within the skeletal muscle is in the mitochondria. So that's why looking at the mitochondria of the skeletal muscle, it gives us a very good ability to describe this in a more precise way. So again, if you could, sort of as a thought experiment, if you're looking at the muscle of someone who's going to get diabetes in two years

versus the muscle of someone who is not, what do you think they look like in terms of differences? So there'll be many, but I just want to hear you talk through them, right? In terms of, so not talking functional at this point, I'm just talking purely visible. Will there be differences in glycogen capacity of the muscle? Will there be differences in the actual density of mitochondria? Will you see differences in the types of fibers? I mean, again, just playing that game of, you know, this person's going to get diabetes, this person's not. What looks different? So you would see very clearly, for example, that a well-trained athlete has at least three to four

times the amount of mitochondria and the size of the mitochondria. That's very visible that you would see it right away. And this is Toledo from the University of Pittsburgh. He did a great paper where we can show it in the slides as well, where he can show that very well. So three to four times the number plus larger. Yeah. And that's the number and the density of the mitochondria. Then we delve in the function of the mitochondria, how well they function. That's the zone two that you've been talking about. Yeah, that's one of the things that we believe it might stimulate different

pathways for mitochondrial biogenesis, as well as different pathways for the improvement of the efficiency of the mitochondria itself. Are there other functional tests used besides the amount of basically ATP to lactate, which is what you're doing in a zone 2 test? Non-invasively, to my knowledge, there are no other ways to look at mitochondrial function. You would need to look at a muscle biopsy. And when they do a muscle biopsy, what functional assay are they doing in vitro?

When you look at muscle biopsy, you can, this is kind of what we're going to be doing, you can expose the tissue of the muscle to glucose, pyruvate, or fatty acids and see what is their metabolism. You label them and you see what goes where. I see. So you will use metabolomics to get a signature of the preference for different circulating fuels. Exactly. So we would be seeing like this type 2 diabetics, for example, circulating fuels. Exactly. So we would be seeing like this type 2 diabetes, for example, they barely use fat when they're exposed to fat. We trace that fatty acid, but they have a much higher capacity or willingness to use glucose for energy. And that energy might not be happening in

the mitochondria either. It happens in the cytosol. That's one of the things that there's what's called the metabolic reprogramming that happens in these patients, happens in type 2 diabetics, happens in cancer patients as well, and in other diseases. There's like a local metabolic reprogramming, but there's also a whole body metabolic reprogramming where you just cannot synthesize fatty acids. I mean, you cannot utilize fatty acids for energy purposes very efficiently because you don't have the mitochondria and you need to rely more on glucose. And at rest, glucose is mainly oxidizing the mitochondria, as you said earlier. It goes to pyruvate, pyruvate enters the mitochondria. But when your mitochondria at rest are not functioning very well, you need to rely

on the cytosolic production of ATP through pyruvate and then lactate. So this is why we believe these patients rely on the most, the cytosolic glucose utilization, which is what we see in higher exercise intensity in athletes. And that's what we see higher lactate levels as a biomarker for mitochondrial function. Do you see other differences between the very, very fit and someone, again, who's going to go on to get diabetes just to make the experiment such that you're not looking at someone with diabetes in terms of glycogen storage capacity? Yes. We see that too. We see that. So I developed with a colleague here, John Hill from

the School of Medicine, we developed a methodology to indirectly look for glycogen content in a non-invasive way using ultrasound, high-frequency ultrasound, and we validated it with the muscle biopsy as well. And another researcher, David Neiman, also validated the system. And we saw very good correlations with the scale that we used. So just doing a high-frequency ultrasound of the quadricep, you can get to within what degree of accuracy of a muscle biopsy? With the muscle biopsy, we saw in the 90s, the R, the correlation pre- and post-exercise, using the scale that we use. There are a couple of authors that have done a replication of the study,

but they have used a completely different scale. We know that the skeletal muscle glycogen is stored in different parts of the body. I mean, in different pockets of the muscle and in different muscles. So what we do is we look at the entire image of the rectus femoris, for example, but in the validation, we did not validate the score of the rectus femoris with the high-frequency ultrasound with the one squareimeter biopsy sample. We validated the image, the one-square-centimeter image sample

from the muscle biopsy with the muscle biopsy. And that's where you have the same size in image. And therefore, you have the correlation. A couple of authors, they have correlated the entire muscle, which different pockets of glycogen everywhere with only the specific size. I got it. But you did apples to apples. Yes. And you have an R squared of 0.9. The R is, yeah, it's in the 90s, 93, 94 pre and post.

Wow. Without the need of doing this. And if you had to guess, two individuals could differ how much between a person who's fit and someone who's in yeah so this is exactly to your question so we see it very well others have done it before with muscle biopsies where they have shown that fear individuals they can store more glycogen than other individuals and that's what we see so on a scale from 0 to 100 that we have you see the world-class athletes they can go to 85, 90, 100. Whereas someone like myself, I'm considered now like a weekend warrior, right? I just, you know,

try to exercise. Oh, hang on, hang on. What's your FTP right now? I'll be the determinant of whether you're a weekend warrior. You know, to be honest. If you had to guess, what is your FTP? I don't even know. Above 300 or below 300? No, no. I don't know 275 yeah i would say something

like that okay it's still you're not a weekend award no 275 is still respectable i exercise four or five times a week but to be honest and i don't use a power meter i i don't use a heart rate monitor i just go to enjoy the ride how long does it take you to climb Mount Evans? I've only done it once and it took me a long time. Since years ago when I've been playing with numbers all my life and be my own guinea pig, I got to know myself quite well. So I should not say that, but I'm reading numbers all day. And the last thing that I want to do is like just read my own numbers, you know, when I go there. I haven't got there yet. I've thought about it a lot, but I still obsessively look at all my numbers and I still use a power meter when I'm doing all of the zone two training. Like I could at this point probably just put it away and ride

based on feel, but I don't know why I still love the numbers, even though it depresses me a little bit because the numbers are so bad. But it's interesting that you've been able to sort of separate yourself from that and say, look, I eat, sleep, and breathe the numbers in the lab and with my athletes. But when I'm writing it by myself, you know what? I just enjoy myself. Yeah. I mean, the laboratory reading all these numbers all day and working with athletes and patients, I just go writing. And I know that I'm stimulating my mitochondria. And here and there, that's right, too. I bring my portable analyzer with you here and there. And I just double check.

I'm like, okay, the zone two. So I sort of interrupted you, but you were about to guess what your glycogen storage capacity would be relative to the, so the world class would be, say, 85 to 100. Yeah. So I might be maybe 60 to 70, whereas people with like maybe type 2 diabetes might be 30 to 40 or 50. They might have a normal glycogen storage capacity or on the low side, but the well-trained athlete, they really increase it as well. It's an irony because the fitter you are and the more glycogen you store, the less you are dependent on it. Yes. Isn't that interesting? Yeah, exactly. But at the same time, it's that energy that you need to move quickly for energy purposes. This is the very interesting thing on

the other side, looking at the fat oxidation, the fat droplet, if you heard about the intramuscular triglycerides, they're highly related to cardiovascular disease and type 2 diabetes and insulin resistance. And this is the athlete's paradox. What's the name of the researcher? Sorry, I blanked right now. But what he did is like the same approach of looking at, they had been seeing that people with type 2 diabetes, they have this fat droplet. It's like a little deposit of fat right outside the mitochondria.

And it was a characteristic. So what he did is like, okay, I'm going to look at, and then that was in comparison with people without type 2 diabetes. They didn't have this fat droplet. So what he did is like, okay, I'm going to see if elite athletes or well-trained athletes, what histologically characteristics they have. And he found a big fat droplet as well, adjacent to the mitochondria. So that's the paradox.

It's like, wow, why in the world they have that fat stored by the mitochondria? So what it was found that in the people with type 2 diabetes, that fat is not active. And in fact, it can produce ceramides and other pre-inflammatory mediators that are not only involved with insulin resistance, but maybe with cardiovascular disease or atherosclerosis. They cannot be oxidized in the mitochondria. So they build up outside. Whereas in the well-trained athletes, it's a reservoir there. The fat that we burn in the mitochondria, it comes mainly from the subcutaneous fat and it has to travel. It's a long trip all the way to the muscle. So why not, from a new evolutionary perspective,

why not having a reservoir right there by the mitochondria? And effectively, about 25% to 35% of all the fat oxidation that elite athletes do during exercise, it comes from fat droplet. It's very active. So do you suspect that in the study you're about to embark on, the biopsies will also show this, that in your fittest and your least fit, you'll see the droplets? Yes, we're going to look at that as well. Why do you think that the average people don't have droplets? Does that mean you and I probably

don't have too many fat droplets in our muscle? Probably not. I would understand that if everybody had it sort of like structurally, but then there's a functional difference where there's a gradation from the person with diabetes to the world-class athlete. The gradation is in the utilization and activity of it. But why do you think people in the middle of the road like us have actually lost the capacity for that reservoir? Well, I think because we're not elite athletes. But why do the people with diabetes still retain it, but in a static, non-utilizable fashion? That's what we're trying to find out why. And in my opinion, is the hypothesis, one of the tests is that their mitochondrial function is not good. So therefore, fatty acids cannot be transported into the mitochondria and they're sort of building up

outside the mitochondria. We can. I see. But we haven't completely built our capacity to use it at high amounts so we don't have the reservoir. It's like the glycogen thing. We don't store 80 or 90 or 100 because we don't need it. And at the end of the day, the body is very wise and it's based on a lot of evolutionary mechanisms. And this is one of them, glycogen storage capacity, as well as the fat right outside

the mitochondria. I've always thought of that paradox through the lens of fat flux, which is when you take a snapshot in time, which is what you're doing when you do a blood test or a biopsy, you're looking at something in a moment. It tells you nothing about the velocity. And what I think your example illustrates is that there's such a high turnover of things in the really, really fit person that even if it's elevated, it's not problematic. Another place you see this, by the way, in the blood is free fatty acid concentration. So when you're doing a blood test to screen for diabetes, if you're doing very advanced testing, you're looking at lots of things, not just

something as sort of banal as the hemoglobin A1C, but you'll look at insulin and you're looking at lots of things, not just something as sort of banal as the hemoglobin A1c, but you'll look at insulin and you'll look at insulin under sort of provocation and you'll look at free fatty acids under provocation. And amazingly, under the most metabolically flexible and least metabolically flexible conditions, you see the same pattern, which is higher free fatty acids. But again, it comes down to flux. I suspect that in the person with diabetes, it's just an accumulation of free fatty acid in the plasma. Whereas in the very metabolically flexible person, if you were putting a tracer on that FFA, you'd see rapid turnover. Exactly. Exactly. And this blood analysis, they don't use a tracer. So you just see,

whoa, there's a lot of free fatty acids going around there and like what are they doing where they're being metabolized for energy purposes in the metabolically flexible and you see it very well kind of they're accumulating the other ones is this is kind of what we probably see at the cellular level so i want to kind of energy zones obviously at zone three you're into, you're exceeding the capacity to maintain a stable level of lactate, which tells you you're now exceeding the mitochondria's capacity to be the sole provider of ATP. You are now becoming obligately dependent on glycolysis in the cytosol. By definition, the percentage of fat oxidation is now going down as the percentage contribution from glycolysis is going up. Is this where the lactate threshold now occurs? Because I'm sure

there are people listening to this who are going to say, wait a minute, wait a minute. I always thought lactate threshold was around four millimolar. So how does that concept fit in? So I would put the zone three as a transition zone where your glycolytic system starts kicking in at a very high rate because the ATP demand and your fat oxidation says, okay, I think I'm starting to be done here. Now you take over. And that's where you start seeing a decrease in fat, yet you use fat. So it's not a completely glycolytic state. It's a transition phase. That is when we move into the zone four. In the zone four, that's where we see very, very well that the lactate,

also you see an inflection point. That kind of where we could see the lactate threshold, where like all of a sudden the lactate accumulation is not steady. It jumps and you see the inflection point. And at the same time, that's where you usually start seeing the R of 1.0, the RQ. And there's zero fat oxidation. So we know very well, it's like if there's a lot of lactate and there's no fat oxidation, that's another metabolic transition point

that is indicating that you don't burn fat anymore. It just depends on glucose. Yet you can breathe and it's probably done in the cytosol. So you're aerobic and that's the zone four. We'll be calling the lactate threshold, if you will.

And what's the clinical significance of that or even the athletics significance of that? I mean, once an athlete goes above their lactate threshold, how long can they sustain that pace? There are many lactate thresholds. So we might believe that lactate threshold could be maximum effort you can sustain for 15 minutes or 20 minutes or the FTP. The FTP could be a way also of lactate threshold for a fate of 40K. So for the person listening to this who's not

familiar with that, FTP is defined as functional threshold power in cycling. We use it as the maximum power that can be sustained for 60 minutes, or sometimes we do a 20 minute test and discount it by about 10%. But I mean, an FTP test for me has never felt linear. You know what I mean? Like if your FTP is 300 Watts, the pain at minutes 10, the pain at minutes 10, 20, 30, 40, 50, 60 is not linear. Like the last 10 minutes hurt more than the first 50. But now that I think about it, whenever I did FTP tests, I was usually doing them on the road, not on a stationary bike. I never had lactate levels throughout, but my intuition is my lactate was increasing non-linearly. I would always FTP test on a hill because it was easiest to maintain a fixed power output. But what do you think is happening to a person's lactate when they're at that threshold? I have seen that and I presented American College

of Sports Medicine, poof, like about 10 years ago. And I have to publish it. It's one of the things that you have so much things going on that sometimes you don't have the time. You need to get some med students working for you. Yeah, I know. I'm looking at the poster you're bringing up, but you haven't even published yet from 10 years ago. Yeah, this is 2009 or something like that. But this is where back in the days, a lot of people talked about power. Everybody would just train by power and what's our what's. I started to see at a pro level, a lot of people using just power output and heart rate like as an old school. I was one of those people actually, you know, five years ago where it was, I really didn't pay attention to heart rate at all,

except to notice that there were some days when at the same power, my heart rate was much higher and I felt and performed much worse. That was about the extent of my observation. Yeah. I wanted to kind of show that with numbers. And that's what I say, okay, power is power and speed is speed. The ability of humans to perform relies on the ability to convert chemical energy into mechanical energy. The mechanical energy, that's your power output. The chemical energy is like all the metabolic adaptations that get you there. So this is what I saw and we can put it as. This is a poster you presented about 10 years ago. And by the way, this is, I hope there's a med student out there at the University of Colorado who's listening to this,

who's figured out what their next summer's task is going to be, which has helped turning this into a manuscript. But tell us a little bit about this experiment and what it showed, because it's, as I look at the figure, I see it is answering, it is answering the exact question I just asked, actually. So yes, one of the things is that a lot of people start to talk about watts are watts, right? They ditched the heart rate monitor because watts are watts, therefore, metabolically speaking, it's the same thing. But as I said earlier, the ability of humans to exercise depends on the ability to convert chemical energy or biochemical energy into mechanical energy. The mechanical energy is the end product, watts, but how do you get there? So I wanted to see and put it to the test. So

I had both a group of elite cyclists, professionals, and a group of recreational cyclists, but well-trained as well. And I did a maximal test where I could get that peak power output at the end of the maximal test. One group, the elite cyclists, the next test, I put them at 80% of the peak power output from the first test and the second group at 75%. And then I just let them stay there for 20 minutes. So if the elite cyclist hit a peak power of 400 Watts on the previous test, 80% of that. So now you put him at 320 Watts and say, you're going to spend 20 minutes here. And it's like similar calculation for the recreational athlete though, at a lower level. Exactly. Okay. So the whole thing was like, if watts are watts, it was like the whole battle back in the days is like, okay, then metabolically

speaking, we're not going to see changes. In other words, five minutes into this test, whatever's happening in you physiologically, since you're not changing the output or the demand for ATP, there should be no change in anything else. Exactly. So what happened? So what we saw is that after five minutes, both groups, they had about four millimoles of lactate. Okay. In the elite athletes, five minutes later, which is minute 10, they had about seven millimoles of lactate. And five minutes later, which is minute 15, they had nine millimoles of lactate and five minutes later which is many 15 they had 9 millimoles of lactate so right there we see that what's are not watts at the metabolic level it was very stressful for them and they could not keep it and this is kind of to what you alluded that you notice that towards the

end of some of this FTP it feels worse and this is exactly what I was observing with many professional athletes and elite athletes as well. I mean, cyclists that they would get over-trained more and they said, Hey, I, I had to do, let's say my coach told me I had to do five hours or four hours at 200 Watts and I do the job and you can see on training picture. So yeah, you do 200 Watts, but what's the price? I used to be obsessed with training peaks and what was the other program called? There's another program we used to use, but where does the TSS show up the training stress score? Is that also training peaks? And I remember I used to mostly just keep track of kilojoules in the end of the

day. It was how many kilojoules today what's my tss and my training score balance and things like that but i think what this and by the way i'm looking at the graph the recreational athletes basically had the exact same pattern just at lower levels meaning they fatigued quicker at a lower level but the pattern is identical so heart rate lactate and and percentage of vo2 max. And percentage of VO2 max. As well as VO2 max in liters per minute. They all show statistical significance. So we see that watts are not watts. That's when it started to throw because I've been always

like a big believer of heart rate. And when I was 15, I saved all the money that I had and I bought the sports tester that back in the days was like $200. No, it was, sorry, it was like back in the days was about $500. So I'm talking about 84, 83, no, 86, sorry. I was my own sports tester. The year Greg LeMond won his first tour. Exactly, yeah. And that's what I, since then, I've been looking at heart rate a

lot because we forget that heart rate is a physiological parameter. Watts is a mechanical parameter, but heart rate is a physiological parameter and responds to the physiological metabolic stress. So if you look in the graph that the audience can see later, when we look at the graph of the lactate and the heart rate, they go side by side. When heart rate goes up, lactate goes up. Well, I've noticed this and I'll show you more of my data over dinner tonight. But for the past year, I've been recording four times a week my lactate levels on both devices plus heart rate plus power at the end of, I always like I'll do a minimum 20 minute steady power

in a zone two. So anywhere from basically 20 to 45 minutes where the power is clamped, I'm on a bike on an erg. So there's no deviation of power. And there's a very interesting correlation between, so even if you do the same power for four consecutive workouts, you can have different heart rates and you can have different lactates. Now we're going to come back to this because I want to talk about it later. There's another confounder here, which is metformin, which will backburn her. Even with or without metformin, there's a coupling between heart rate. So for example, if you don't sleep well and your heart rate's higher, you're not recovered, your heart rate's higher, you're under more stress for some other reason, and heart rate is higher, lactate tends to follow it even at the

exact same power output. Yes, yes. And that's what we've shown. And that's where like then Joe Friel started to talk about the coupling, where you should maintain the power output and the heart rate as well. So among a bunch of us, we kept pushing for heart rate because it was getting to a point that it was going to be erased. And now everybody trains with both power output and the heart rate. In fact, now the whole HRV, the heart rate variability, it's a big, big deal. And a lot of people look at and listen to their hearts. And I always tell the athletes, the heart rate is going to tell you a lot. This is one of the things also why I decided to try to develop a way to look at glycogen, because I would see that in maximal physiological states, many athletes who were fatigued or restricting carbohydrates, they had

a very low maximum lactate levels, very low maximum heart rate. Let's say that athlete that I have tested multiple times, let's say a lactate of 12 and a heart rate of 190. When that athlete is fatigued or tired or restricting severely carbohydrates, that lactate could be maybe four and the heart rate could be maybe 162. And how much adaptation do they have? Because I know you and I have spoken about this before, and I don't know if we're going to get into it on this podcast because there's so many of the things I want to talk about, but your view has always been that the fat oxidation data that we sometimes see in heavily, heavily carbohydrate restricted or ketogenic athletes may actually be an artifact. We might not actually be seeing fat oxidation of 1.7 to 2 grams per minute.

You're saying in a GC contender, in the best cyclists on the planet, what is their maximum fat oxidation in grams per minute? Well, what we're seeing here is normally in the 0.7, 0.8 grams per minute under normal. And we have done these experiments, although we haven't published them, but we have done a normal athlete, like category two or three, they do under normal diet, not super high in carbohydrates, not super low, normal diet. And their fat oxidation, the fat max, it's, let's say, 0.4. Then they do one week of carbohydrate restriction or two weeks of carbohydrate restriction, and their fat max, yeah, it's 0.8. But at the same time, we see that the power output decreases at least

0.5 watts per kilogram, so about 30 to 40 watts. And also we see that the maximum heart rate decreases and the maximum lactate decreases. That said, this is more in a, if you will, a more acute situation. I'll tell you this from my experience, Inigo. When I began carbohydrate restriction, which was, I went on a ketogenic diet in May of 2011. The first 12 weeks were hell. I couldn't even imagine approaching my anaerobic fitness. So forget lactate threshold or anything like that. I couldn't even get to the same aerobic level. I remember, I still remember very clearly November, 2012, 18 months later, it came back and then some. What that suggested to me, and if I could go back in

time and do anything different, I would have had muscle biopsies done all along the way. But it struck me at how long it took for that adaptation to take place. Now, I only stayed in that state for three years. So I'm long out of that state now. The only time I'm really in ketosis is around fasting. But it's always sort of piqued my curiosity what a very, very, very long-term state, ketogenic state can do for everything outside of peak sprinting capacity. Because I just, I don't think there's any dispute that peak sprinting capacity has to be glycolytic and

anything that impairs glycolytic function makes no sense. So there's such a debate about all of this stuff. I don't think it makes sense for someone trying to win the Tour de France to be on a ketogenic diet. It's just too glycolytic. Even though 96% of that race can be done below peak power output, the race is won and lost under peak conditions. So it makes no sense. But if you're training to win the Western States 100, you technically don't need to sprint ever if you have a high enough threshold. So I still have that sort of point of view. But again, I'm very curious as to what those adaptations are and how long they take, because I don't think they're going to take place in a month. You bring up a great, great point. I'm extremely curious about that as well, because I have never seen an athlete at the elite level adapting. And I'm going to tell you why in a second. But at the same time, I believe that it cannot be possible that thousands of people around the world who are getting into the ketogenic diet, it might be working for them,

and they're making it up. So I believe there's something there. At first, when these things come up and I say, come on, man, give me a break. But then I say, there's so many people out there. There's got to be something. Well, there's one other data point I'll add for you. When I was on a ketogenic diet and cycling voraciously, my capacity to consume carbohydrates was much higher than what people think of as a ketogenic diet for someone at rest. As a general rule for somebody who's normal, about 50 grams of carbohydrates is the limit. Above that, you begin to suppress the production of beta-hydroxybutyrate. But I used to do lots of experiments. And at my most extreme, you know, days when you'd have a three day period where you would do a hundred miles each day for three consecutive days at very high output.

So for me at the time that might have been average power of 185 Watts, normalized power of 240 Watts for seven hours on three consecutive days. When you're at that much demand, I was able to consume 600 grams of carbohydrates and stay in ketosis. Yes. Now, I think that's because I'd spent so long adapting. I don't think you can show up and go into ketosis and then a week later eat 600 grams. I mean, I was pushing as hard as I could to see how much of this can I consume. But so there's the other thing to keep in mind, which is at some point the body became flexible enough that I could break all the rules. I could have 200 grams of protein, 600 grams of carbohydrate, and still maintain beta-hydroxybutyrate levels above two to three millimolar. Because I think the machinery with which the BHB was made was, I'd had two years of, in

fact, this would have been probably three years in. This is the summer of 13 maybe. So now I'd really been at it for quite a while. And again, biggest regret is not having that. There are lots of athletes out there that I think would be interesting to study. So that's something worth considering. Sorry to interrupt. The thing, what I haven't seen that adaptations in elite athletes is that they cannot afford it.

You mentioned that it takes months to get there. You don't have months because you get dropped in the races. Your performance is very poor. Your contract is going to be trashed. They're not going to renew you. And you're going to feel like crap. Every single athlete who has tried to go, whether you call it like a ketogenic diet or a carbohydrate restriction, while training and competing for an event, they fail.

That's what I've seen in 25 years. And the reason probably is this, because they didn't have one year to say, hey, you're not going to race in one year. You can train very little. Your mission is to get adapted. That's not the way sports works. But what I see is if you restrict carbohydrates, we do blood analysis a lot. We do this metabolic testing in the laboratory. While these athletes are competing, we see right away there's a catabolic response. The body says, holy crap, what's going on here? I need to survive somehow.

So you enter in an evolutionary survival mode. So obviously, yeah, your ketones production might increase. Your fat oxidation might increase as well. But your protein breakdown increases substantially as well. And we see this in the blood analysis. That's why you see muscle breakdown all the time. Although again, it's transient, which again speaks to, because if it wasn't transient, I mean, evolution would absolutely demand we preserve protein under long periods of nutrient deprivation, which of course is what the carbohydrate restriction is mimicking. But it's this time course that I think is very unusual. And you're right,

there's no professional athlete that could take that chance. And again, we were talking about this earlier. It's like there are some people whose entire lives can be built around chat rooms and discussion boards where they can debate these things endlessly. Neither you nor I have the time for that. So I've largely stopped paying attention to this debate, truthfully. But it's always struck with me how long it took to adapt and the price I paid during that adaptation period. If you were a professional athlete, you would be out of the job. Yeah. Oh, absolutely. And this is why I think that I have never seen that because sooner or later, the athlete, they hit the wall. They just cannot finish races or they just like, hey, what's going on here? And then that's when they have to go back. And we

see this quite often. Athletes don't always listen to us. They always go to the blocks and see things, you know, internet, or they find where the neighbor is telling them. And a lot of people try many diets and the tendency now, and it was before also, was to restrict carbohydrates. And again, I really think that you can adapt because the human physiology is a wonderful machine, but do you have the time to adapt while you're a competitive athlete? That's what I have a lot of thoughts that I don't think so. Yeah. And again, I think the discussion is interesting and academic, but of course, in the end, I still think carbohydrate restriction is a great tool for anyone who's not trying to win the Tour de France. I think that's

where people sometimes get hung up, right? If you want to win an Olympic gold medal, there are very few sports in which you could probably do that on a ketogenic diet. And if you want to be the best cyclist or runner or swimmer on the planet, very hard to do that on a ketogenic diet. The good news is, by the way, if you're at that level, your mitochondria are so remarkable that your carbohydrate tolerance is unbelievable. Where it comes back to, and I think where the biggest opportunity is, is the person who is not metabolically very healthy, who thinks they need to drink a liter of Gatorade an hour. And no, actually that person can absolutely be on a carbohydrate restricted diet and they can exercise. And yes, maybe their

performance initially is less than what it would be if they still mainlined all the carbohydrates in the world. But in the long run, they're going to produce a much more metabolically healthy phenotype, even though they won't be in the top 0.1% of athletes who will. No, exactly. I agree. And the thing with the elite athletes too is that, yes, and this is kind of what I keep bringing up all the time. There's no population on earth who has as many carbohydrates and simple sugars as these athletes by a landslide, right? These guys at the Tour de France, for example. Yeah, tell people, like, let's take a long stage of the tour. So a 250-kilometer stage that has, say, four high-category climbs and one HC climb.

So one climb beyond category. Yeah, so these people, they take... First of all, how long would it take them to complete 250 kilometer stage with four high category and one non-category, which means it's just a brutal. Yeah, it would be more like a 200 and it would be like a five, five and a half hours. And how long would that take you or I to ride right now? Man, that would take us two hours more easily. Yeah. And how long would it take? Or an hour and a half. Take me two hours more if I'm lucky. How long would that take for an hour and a half or take me two hours more if i'm lucky how long would that take a person who doesn't ride their bike much two days yeah i mean 14 hours something like that because they will have to do multiple stops at the hc they might not even make the climb yeah

yeah or much slower yeah while they do this climb so they're through the france depends on the weight but they usually they go between 6 and 6.5 watts per kilogram let's say a person of 70 kilos which is 70 kilos is probably 150 154 pounds so that would be about yeah 420 450 watts so we cannot do that you know like a normal well-trained person who exercises regularly can maybe do that in 300 watts. But a person who doesn't train can do that in 150 watts only. So that's poof. That's a long, long time. And their weight is usually significantly higher when they climb.

So that day, it's hard to believe they can do that in five to six hours, by the way. But they would consume how much on that day, both on the bike and off the bike? So normally what they do, and I haven't published this, but we keep track of this all the time. We keep track of the amount of carbohydrates per hour. We keep track of the breakfast, what they eat on the bike, after the bike, recovery. Right away we have these protocols. And these protocols are very up to what they need, or what we think they need. And also based on what their demands are, because they're the ones who like, they need it, you know. And again, as I said earlier, I've seen athletes even restricting

carbohydrates in the races, and they get totally destroyed. So these guys, they consume a total of about 12 grams per kilogram of body weight per day of carbohydrates. So if you're 155 pounds, which could be an average weight, let's say 70 kilos, we're talking about close to 150 grams a day of carbohydrates. More than 150. You said how much? 12? 850.

850. Yeah, yeah, yeah. So I thought you said 150. Okay, yeah. Which is 850 grams of carbohydrates. That's over three, that's almost 4,000 calories of carbs right there. Yeah, 3,500 calories of carbs. And out of those, at least a good 30% of those to 50 is simple carbohydrates.

Let's say 30% of those. So we're talking about these people are having daily about 1, of sugar um sir 1500 calories of sugar so almost give me an example of what type of sugar they're consuming like gels and yeah the gels the goose the drinks and then obviously at breakfast at lunch and dinner they're more complex but during the race in the first part we do more solid versus liquid. But towards the end of the race, we do more liquid, so more pure sugar, simply because it's absorbed faster. And that's why you need more energy. But yeah, these people, again, they do about 1,500 calories a day just in sugar.

Imagine pretty much your entire daily caloric intake of a normal person, a bowl of sugar. If you want to do this, if you go to a nutritionist and you say, I want to do this, they will shoot you. Yeah, look, if I did that, I'd have diabetes in a month. Oh, of course, of course, of course. And we know that they don't have it. In fact, this is the healthiest metabolically population in the planet. Now, the irony of it is on twofold. One, in many other ways, they're wildly unhealthy. The rate of catabolism, the bone density loss that these guys experience over the Tour de France is debilitating. I mean, these guys, they lose so much muscle.

They lose so much bone density. The other thing we see is for many of these athletes, the transition out of being at that level to being civilian again is devastating. Because especially, I actually read an article on this once. I wonder if I could find it. I believe that the answer was more common in males than females where the rebound effect to becoming metabolically unhealthy was unbelievable. It's very hard to turn that spigot off of you're basically a nonstop eating machine. And then all of a sudden you're on the path to having diabetes three years, five years, 10 years after being the fittest person in the world. Yeah. And that happened to me when I quit cycling between school work, I was working

and traveling. I was working 70 hours a week. At least I was from doing 500 kilometers a week to do 500 kilometers a year. I would exercise literally six, seven times a year and traveling and eating. And one thing that I have observed is like insulin sensitivity. These athletes have the highest insulin sensitivity of any humans as well.

There's no insulin resistance because first we know very well that exercise increases insulin sensitivity of any humans as well. There's no insulin resistance because first, we know very well that exercise increases insulin sensitivity and the need to utilize carbohydrates. It increases insulin sensitivity as well and the transporters. All that efficiency in the mitochondria comes with another benefit, which we didn't really talk about, which was non-insulin dependent glucose uptake is also going up. So now if you take a normal person, we are able to take up glucose with insulin. That's the insulin sensitivity. But we have a second door that doesn't get utilized much, which is the non-insulin requiring door to put glucose

in the muscle. And there's no better way to stimulate that than zone two. I mean, I don't know if I have a study that I can point to, but I can clinically tell you without a shadow of a doubt. And I'll tell you how I know it's looking at people with type one diabetes. Exactly. I was going to mention that. Yeah. You take people for whom you know exactly how much insulin they require. I'm actually going to be writing about one of these patients in my book. He's type one diabetes, completely dependent on insulin. He's completely maniacal. I love him. Three hour brisk walk every night. So that's his zone two, three hours of zone two a day, right? You know how much insulin this person with type one diabetes

requires a day? Two, five units? About eight to 10 units a day. He has the highest sex hormone binding globulin I've ever seen in a human being, which is inversely proportionate to insulin level. This guy has no insulin. He doesn't require any. I learned from this a lot. I was working with Team Novo Nordisk. Yeah. Tell people about what Team Novo Nordisk is. So Team Novo Nordisk is a professional team where 100% of the cyclists are type 1 diabetics. These are professional cyclists with type 1 diabetes. So the whole purpose of Team Novo Donor is was first to show the world that you're not going to not only not die if you have type 1 diabetes, but you can become a professional athlete to spread the word. Because a lot of people think it's a devastating diagnosis for

many. Oh, you're type 1. You're going to die soon. They're like, no, you're not going to die soon if you take good care of yourself, and even you can become a professional athlete. So that was the one message to spread the word. And the second is that to study diabetes and type 1 diabetes and the metabolic effects of exercise, because nowadays most endocrinologists working with diabetics, they're telling to exercise. The problem is like they go to exercise and they have many hypoglycemias or hyperglycemias

and they need to correct it. And all the hormonal system goes all over the map and they go back to their doctors and they have no answers. So it's the number one barrier they defined from exercise. And they, many decide not to exercise because they can control their doses very well. And let's explain why that's happening to people. We've talked a lot about the consumption of glucose, but as you're alluding to, whether it's you, me, or someone with type one diabetes, when I exercise very strenuously, my glucose goes way up. So if I'm doing twice a

week, I do high intensity exercise. As you can see on my arm, I wear a continuous glucose meter. It's not uncommon, especially if I do it right after a zone two. This is funny because zone two, my glucose steadily falls. Let's say I get on the bike at 100. I do 45 minutes of zone two. I get off at 75. You get to bunk sometimes even. I don't go long enough to bunk for sure. So then let's say I get on the air bike and I do a four minute protocol. It's not uncommon for me to go from 75 to 160 because of the hepatic glucose output. Yeah. Glycogenolysis, yeah. And that person with type 1 diabetes, that number could easily be 250 because they don't have the insulin to correct it. Exactly. So then they need to correct it and they freak out. So they use a lot of insulin.

They overshoot it. Exactly, they overshoot it. And this is exactly to what you pointed out about the non-insulin dependent system, which is the muscle. And this is what it was an educational process. So then with JDRF, the Juvenile Diabetes Research Foundation that we put together, they put together like a group of experts, if you will, to train clinicians about this. So what did you learn? I mean, how do people compete in professional cycling without being on that glycemic roller coaster? So we learned a lot to work on insulin usage as opposed to insulin correction. And that's what we're taking now to the clinical space because type 1 diabetes has been about correcting insulin and insulin and insulin and eating carbohydrates. Oh, you go low.

Sorry, man. It's just keep eating candy or things like that. And we know that that cannot be very healthy for you in the long term. But the approach has been always that to correct by either eating or using insulin. But we're trying to really correct it by really tackling insulin administration. So using just longer acting forms, is that the... Either longer acting or less insulin, and therefore also to do exercise. So when you do exercise, as you say, first, your insulin sensitivity increases. So you don't need so much insulin. And as I said earlier, the first tissue that develops type 2 diabetes or insulin resistance is the skeletal muscle.

So when you eat carbohydrates, the big percentage of that are going to go into your skeletal muscle. Are people with type 1 diabetes who are exercising even more insulin sensitive at the muscle than non-insulin dependent individuals who are matched? They could probably be. So the long-term exposure. This is what I observed, for example, about glycogen. Unfortunately, it wasn't published because the N was very low. But the reviewers, they did understand that you cannot do muscle biopsies to a professional cycling team. And there's only one professional cycling team in the world. So I did a tour of Colorado.

I did the Team Novo Nordisk and another team. And they looked at the glycogen. What did you see? About 25% higher glycogen content before the race and after the race in type 1 diabetics. And about three times less carbohydrate needs than the non-diabetics, which we already had seen because we count carbohydrates. And we know that a normal cyclist, they have 20 grams per hour of carbohydrates, they're going to hit the wall in a race. Type 1 diabetics, they have 20, 25 average, and they never have any issues. You must see higher free fatty acid levels then.

Yes. So all things equal, do they just have higher fat oxidation across the entire spectrum? They're not very good necessarily at that. And I'm trying to understand that puzzle. But what I believe is like they have a higher glycogen content because insulin drives glycogen synthesis. It's the main hormone behind glycogen synthesis. So if you've been for... And the issue of people with type 1 diabetes, they go from a non-physiological state,

which is not producing insulin, to the opposite. They use a lot more insulin than normal people over years. So 20 years, usually insulin, it must maybe elicit some adaptations that might, one of them could be increased glycogen synthesis. I have no idea, but that was kind of what we would like to explore further. So do you think that those athletes who were able to get by with as little as 20 grams of glucose per hour, which seems impossible to imagine given their energy requirement, do you think at some point that would cease to be the case? And in the tour of Colorado, maybe the longest stage is what, four or five hours?

Yeah, yeah. But still, that's hard to explain. It's still a week-long race, isn't it? Yeah, yeah. Did you say that their glycogen. It's still a week-long race, isn't it? Yeah, yeah. Did you say that their glycogen levels still were 25% higher at the end of the race? Yes, before and after, yes. That's counterintuitive. Yeah.

Sorry, was it, I know it's 25% higher than the non-diabetic, but what about relative to themselves? Oh, they decreased. How much do they decrease? I don't remember. Because not a whole lot, because, I mean, in this stage,

you have to do it in the same time. And whole lot because I mean, in this stage you have to do it in the same time. And in the tour of Colorado, in the mountains, one hotel is here, the other one is 20 minutes away. So I had to do it in one stage where all of them were on the same floor, two teams. That was a short stage. It was like two and a half hour stage. So they eat normally and they decrease like 15, 20% or something like that. So they didn't deplete completely by no means. You could make the case that that team had some of the highest levels of non-insulin dependent glucose uptake you've probably ever measured. Probably, probably. Yeah. So that's what, to your question of that, the non-insulin

uptake of glucose by skeletal muscle, that's what is a great approach. We don't have a way to measure this in those of us who don't have type 1 diabetes. We're sort of taking a leap of faith that the more we work on our mitochondrial efficiency, the more we will drive that non-insulin dependent pathway. But really, it's only the person in type 1 diabetes where that can be quantified. And it's a skeletal muscle contraction. First of all, in insulin, what it does, it initiates the cascade of events that translocate the transporters of insulin,

called the glute force, to the surface of the muscle. Glute force. Yeah, yeah. Yeah, glucose. Yeah, sorry. To the surface of the muscle. And those transporters are stimulated by insulin. So a skeletal muscle does the exact same action.

It translocates those glute force to the surface. So therefore, there's that non-insulin dependent. And why does exercise increase that ability? We don't know the exact mechanism. It just seems too good to be true. I want to make sure that the person listening to this understands what you just said. So I'm just going to repeat it because it's so profound and you said it like sort of, you know, you said it sort of like matter of factly, because of course for you, it's common knowledge. When insulin hits the insulin receptor on a muscle, it sends a cascade of chemical reactions inside the muscle that ultimately results in a tube called the group four transporter being raised to the surface of the muscle and

translocating across the membrane. And now you have by passive diffusion, glucose can enter the muscle. The key is this insulin in the lock is the insulin receptor and the downstream effect that occurs inside the house opens the door and lets the glucose in. What you said after that is you explained how non-insulin dependent glucose works, which is somehow just the contraction of the muscle. So something that's going on inside the house squeezes and out comes the same beautiful GLUT4 transporter, which now allows the same passive diffusion of glucose into the cell, but this time it didn't require insulin. This is the best of both worlds. This is what Henry Reacher from Denmark and Laurie Goodyear from Harvard, they've been dedicating many years to study these pathways. So they found that this muscle contraction

stimulates these pathways to translocate those GLUT4 transporters to the surface. And this is why the pancreas in regular people who don't have type one diabetes decreases insulin secretion about 50% during exercise because the muscle, they do the rest. And this is what causes also that hypoglycemia in athletes. If they don't correct their insulin before exercise, they go hypo. So what we were doing, and now we're doing clinically, we're telling people to reduce the dose. Wait a minute. This is interesting now. This is suggesting that the reduction that I'm seeing in glucose when I do my zone two, which is by far the most profound thing. You don't see this at higher levels of intensity.

See the opposite. You see the opposite. Your glucose going up, but zone two is a sweet spot where my glucose level always falls precipitously. I shouldn't say precipitously, steadily and consistently. I never thought of it this way. It must be almost entirely the non-insulin dependent glucose uptake because it's a low enough level of intensity that my internal glycogen stores are easily providing what is needed. So this is an additional amount through that. So that's, I feel like this is another metric I want to start keeping track of each day I'm doing zone two. It's not just power. It's not just heart rate. It's not just lactate. It's the Delta in glucose from start to finish could be yet another metric we look at. And in fact, one of the things is like,

I'm trying to try to take this to the clinic for people with type 2 diabetes, is like, if you eat, go exercise right away. Because when you exercise right away, that muscle contraction is going to translocate these glutphor transporters without the need of insulin. And I thought it was the opposite. You know, I thought that exercising will increase the insulin-dependent portion, and therefore the best time for someone with diabetes to eat was right after exercise. It could be both. It could be both, yes.

I think that might be in a patient-by-patient base. But if you have insulin resistance, you're going to need to use more insulin after you eat, which it's a patch. It doesn't solve the problem. But if you exercise, then you might need half of the insulin because the other half is going to be provided of the glucose intake into the cell by the muscle contraction. So learning a lot from type 1 diabetics, we can apply things to type 2, I believe. One of the things that we see the opposite effect that we saw in the races, normal people who are told to exercise, they're not fit enough, and they start jogging, right? And they're in zone 4 already, very glycolytic.

They see the opposite. They see in the post-exercise hyperglycemia, where they're, as you said, in the 260s. post-exercise hyperglycemia were there, as you said, in the 260s. So, and they inject themselves insulin and they go down and sometimes in the middle of the night, and then they go home if it's towards the evening, they eat and they correct it again. And sometimes they end up in the ER because they have a severe hypoglycemia. But so one of the things that I started to apply first to the cyclists and then to patients is the cool down. So after people would have this high post-exercise hyperglycemia, the muscle contraction stops. And that's why I believe this is why it is happening. First, you have a very high adrenergic activity, high

intensity, a lot of adrenaline, and that's what causes the breakdown of glycogen into glucose, as well as the glucose export from the liver. But then when you stop, that muscle contraction stops completely. So you don't have that. You've taken away one of your syncs. Exactly. So that's when you start doing the cool down. And that's a study, another study. I have the data I have to publish, but we could see clearly that everybody started to go down. There's definitely going to be some University of

Colorado medical students or undergraduates who have just lined up potentially a half a dozen interesting things to write with you. We started to see the cool down and the cool down would take care of it. So people to the point that they would not need insulin anymore to correct it, whereas before they might need three, four, five units. And now they don't need it anymore because that cool down took care of it. So through JDRF, we've been traveling throughout the country and other places in Europe and even Australia, training clinicians about this so they can go back to their patients. And the cool down has been a basic thing. And the feedback we're getting is awesome. This is incredible. You know, it's such a shame that the disease basic thing, and the feedback we're getting is awesome. This is incredible.

You know, it's such a shame that the disease type 1 diabetes and the disease type 2 diabetes share the same name in diabetes, because I do think for many people, they just sort of think someone has diabetes. But the nomenclature of 1 versus 2 is profound. They are really different diseases. Very different. They're completely different. They almost have nothing in common except for high glucose as a potential consequence. I agree 100%. It's a real shame.

There's an artifact of history. And this is what I'm trying to also bring the concept of double diabetes that very few people talk about it because it's mixed. Type 2 diabetes, especially now in the US, Novonordis told me that I think about two-thirds of the entire insulin that is sold in America is for type 2s, not for type 1s. And this is the animal that is different. The type 2 diabetic people is a way different animal than it was 50 years ago. I've always been sort of critical of these companies like Novo Nordisk because I feel like there's just too great a conflict of interest for them, right? I mean, first of all, insulin should be basically free. There's absolutely no, from an IP perspective,

there's absolutely no reason insulin should cost anything above some nominal amount. So it's this cash cow for drug companies like Novo Nordisk. Don't worry, I'm not going to put you on the spot and have you speak critically at all. I'm going to do all the critical speaking. Yeah, no, because we get funded. This group is funded by Novo Nordisk. Indirectly, what I'm going to do is come around and sort of pay them this compliment and say, I like realizing that there's something good that's done by an entity that I generally view not favorably. Because again, one, the price gouging

on insulin to me is the most unethical part of pharma. But then on top of that, there's this issue of two thirds of your sales come from a patient who shouldn't be using your drug. The drug really is for people with type 1 diabetes. If you have type 2 diabetes, almost without exception, changing the way you eat and exercise will at least get rid of the insulin requirement. You may still require other medications, but you shouldn't require insulin. And that's been repeatedly demonstrated. So all that said, rant over, it's nice to see that this type of research is being done because

these patients offer us a beautiful physiologic milieu in which you otherwise couldn't see this. So this kind of brings me to, while we're on the topic of diabetes, something else that I want to talk with you about, which is my recent, and by recent, I mean over the last six months, frankly, maybe nine months, sort of back and forth exploration of my use of metformin. When we very first time met a year ago, we talked about how I use metformin. I've been using it for years with the basic belief that even though I don't have diabetes or insulin resistance, it offers some measure of protection from cardiometabolic disease, inclusive of cancer.

And that's all based on data that unfortunately is confined to people with insulin resistance, hyperinsulinemia, or type 2 diabetes. So there was always a leap of faith I was taking that if you took a metabolically healthy individual, they would still have some benefit. And when patients would ask me about it, I would say, my belief is that I'm probably receiving less benefit than someone who's more metabolically unhealthy, but I think I'm receiving benefit and I don't see a downside. And then all of that changed a year ago when we met and I started keeping track of my zone two numbers. And what I immediately realized was a gross mismatch between where I knew physiologically I was clearly in a zone two just based on perceived effort and my understanding of my fitness level, but I couldn't get over how high my lactate levels were. And then I remember you and I would speak and you would say, well, what is your lactate level fasting? And I'd say, you know, sometimes it's like 1.6, even before I

start. I mean, this was back when I was in the business of using as many strips as possible. So expensive, those stupid things. So I would check two times fasting and then every 10 minutes, check, double, double, double, double, double. And there was no denying it. I mean, my lactate levels were through the roof. And I said to you, do you think it could be the metformin? And then around this time, a couple of papers came out that suggested that metformin could be blunting the benefits of exercise. So, I mean, let's go back to then, and then we'll talk about where we are today and our thinking. But at the time that I told you all of this, what was your thinking about my use of metformin and these

numbers we were seeing? Did it make sense to you? Yeah, they make sense in a way that we know that I've seen patients with metformin pre-type 2 diabetic or type 2 diabetic right before entering insulin states, where at rest, I have even seen two millimoles also. Are you able to differentiate how much of that was due to the metformin versus their, because there's such a confounder when you look at that population. Had you seen anybody like me where they're... No, no. I've seen these high levels of lactate at rest, but again, I could not differentiate

that, but all these people coincided they were on metformin. One of the side effects of metformin is lactic acidosis, right? It's rare, but it can happen. So we know there's something wrong with the lactate. What we don't know are the mechanisms. It would be great to study the mechanisms where there are for to improve the cardiometabolic health, or maybe we might find that might not be what we thought. We know there are some studies that show that metformin decreases mitochondrial function and could be that magical drug against cancer. Because one of the things that we see in cancer, many forms of cancer have a mitochondrial dysfunction, yet not enough for

that cancer cell to be apoptotic. Oh, I see. So you're saying that maybe in that patient, metformin pushes them over the edge towards apoptosis. Towards the cliff. That's what I believe if in case that is true, that metformin can cause mitochondrial dysfunction. But the fact that the metformin increases lactate, it's either because it increases the glucose flux into the cell and saturates PDH. And then PDH dehydrogenase has a very, what we call low Michaelis constant. So it saturates very rapid.

And in my opinion, acts as a fuse in the body from an evolutionary perspective. If the body sees there's a lot of high flux of glucose, the body might mean, hey, what's going on here? We need to stop it because it's not good to become hypoglycemic. And maybe the majority of those glycolytic enzymes in the downstream action of glycolysis, they usually have a high Michaelis constant. But when they get to PDH, it's like a fuse.

So when that fuse goes, then pyruvate is converted to lactate. So that could be, it either increases the flux of glucose into the cell, and that's why it could work well for diabetes or access other sub-choles. This is very interesting. So this suggests that, let's just talk for a moment about someone with type two diabetes who's not taking metformin. Their lactate levels are higher at baseline. You're now really offering two explanations for it. The first is PDH because their PDH is seeing higher glucose than the non-diabetic. So that's the first thing it's doing is, as you say, I like that analogy of the fuse. It's just triggering the fuse and shunting more glucose down the pyruvate to lactate pathway. And then of course, there's everything we spent the first hour talking about, which is in addition

to that, their mitochondria just tap out very early. They're not working well. So those two things that are related, but quite distinct would both push up lactate. So now the question is which one of those is more likely being driven by metformin? Is it the inhibition of complex two in the mitochondria? And it's simply reducing mitochondrial efficiency. If you picture a curve where the X axis is mitochondrial function, it's just moving you to the left. Exactly. It could be that and maybe it could be both. What we know epidemiologically speaking is that metformin doesn't cure diabetes. And the immense majority of patients, they end up

using insulin down the road. So we know that metformin is not that magical drug for type 2 diabetics. It just kind of gets them by. It buys them time. But eventually the majority enter insulin. If they don't change their lifestyle, their nutrition, exercise, they enter insulin. So why? I mean, so the first thing I did, so I used to take one gram twice a day, a gram in the morning and a gram before bed. I always do my zone two first thing in the morning. So I was basically doing a zone two right after taking a gram and basically 12 hours after having taken another gram. So you could argue I had very high levels. So I think the first change I made was I just stopped taking a gram in the morning and increased my nighttime dose to 1500 milligrams. So I reduced my overall dose by 25%, but shifted

it to the nighttime thinking, well, I should have a lower concentration in my bloodstream in the morning. I saw no meaningful effect. So 1500 at night was still producing basically the same effect as a gram twice a day. Now, again, keep in mind when you're doing an N of one, you can't actually make any statistics out of this. It has to be a big signal for me to notice it. So then I lowered it to a nighttime dose of one gram. I still didn't really see much of a difference. And then what I did is I stopped taking it the night before doing zone two. So that meant I now went from taking 14 grams a week, a gram twice a day to only one gram three nights a week. Cause there's only three nights a week where I don't follow the workout by a zone two. So you've gone from taking 14 grams a week to three grams per week. You could

argue, why are you taking any of it at that point? And that's when I saw the reduction. That's when I saw the lactate levels start to come down. And in fact, that latter part of the experiment's only been going on for about three weeks. So the next step is to stop metformin altogether and ride this out, which makes me think we should do a little experiment in me, which is, yeah, we should do muscle biopsies, complete proteomics, complete metabolomics, everything that is doable in vitro in the muscle tissue, along with the lactate testing and all the other metrics under three states of physiology. One, under full dose of metformin. Two, under a complete washout, say 30 days of no metformin. And then the third one I'd think would be very interesting is under complete water fast, where I also, by the way, whenever I

water fast, I have no metformin. And I'd like to see what seven days of water fasting with no metformin looks like versus, again, these other two states. So I think there's an interesting pilot study here. You should come to our study and be part of it and we can do extra biopsies. Yeah, yeah. I'm totally game to do this. Yeah, it would be very interesting because it's fascinating the whole role of metformin and also how it can be used in other diseases as well. And it's fascinating the little that we know about the mechanisms of action at the molecular level yet. I think you bring a great point, is to try metformin in different states

and try to learn what happens at the mix level, metabolomics, proteomics level, especially the latter ones. Because yeah, we might see pathways. Maybe it's mitochondrial dysfunction that causes that. And we can see that quite well. Or maybe it's at that translocational level of the transporters. And it would be really interesting, assuming the IRB gives a quick approval for this little added

protocol that includes me, if we could recruit somebody with type 2 diabetes and have them parallel me without the metformin, without the FAST. Because my new hypothesis around metformin is, I just have a stronger conviction, I think, around my old hypothesis, which is the healthier you are, the less helpful it is. I'm now wondering if it goes one step further, which is the healthier you are, the less, I mean, it might actually cease to be healthy. In other words, let's take the extreme example. What would you predict would happen if you gave a Tour de France team a gram of metformin twice a day during the tour? No other change. You just give them a gram of metformin twice a day during the tour?

No other change. You just give them a gram of metformin throughout the tour. Do you think it would have no impact on performance or a negative impact? I mean, based on looking at that, it can affect mitochondrial function. And we see because there's increased lactate, in my opinion, and that's the very first take. And by no means I'm an expert on this. It might be detrimental. That's my first take. If you think you had'm an expert on this. It might be detrimental. That's my first take. If you think you had a hard time getting professional cyclists to volunteer for muscle biopsies,

think about how much harder it'll get them to volunteer for the take metformin and go off and do the Vuelta. I know it would be really, really difficult to get IRB for that in the first place. And the permission from the manager. Destroy someone's livelihood.

Yeah. There's so much more I want to talk about. And I want to talk real quick that the double diabetes, and I forgot and I'm sorry to interrupt you, is that that's something that worries me because there are many people with type 1 who also have type 2 and they're not diagnosed. And I think we need to raise the awareness

because if about 50% of U.S. adult population has type 2 diabetes, yeah, a big number of people with type 1 diabetes are going to have also type 2. Is that a projection of how many people in the United States will have type 2 diabetes? Right now, about 50% of US adult population have either pre-diabetes or diabetes. Correct. Yeah. And it's about, is it maybe 10% have type 2 diabetes and the remaining 40% is pre-diabetes? Yeah.

And I was thinking there's not such state as being pre-pregnant or pregnant. You're pregnant or you're not. So yeah, that pre-type 2 diabetes wouldn't see clinical symptoms yet, but the disease is there already. Yeah. It's just, I mean, our definition of diabetes is so arbitrary and stupid that it's just a continuum and we somehow decide, oh, you're hemoglobin A1C cross this threshold.

And now you need or not. It's kind of like with the same thing somehow decide, oh, you're hemoglobin A1C cross this threshold. Boom, and now you need or not. It's kind of like with the same thing with cholesterol. Oh, you're 200, boom, you need a statin. Or 220, you need a statin. And that know, that's the other thing with statins, that we know that they affect my kind of function. How do we see this? Because in the published literature,

5% to 10% of people experience muscle symptoms from statins. But what is the functional impact? The functional impact, I mean, we don't know much about it. So you're talking outside of myalgias and muscle pain. The good news is, I always say this to patients when you're taking a statin, you're going to get the feedback very quick. One in 10 of you is not going to tolerate this and it won't be very subtle and you'll stop the medication and within a week you'll feel better. And again, what's interesting is the disparate data based on how it's studied, but at the individual level, it's pretty straightforward.

Yeah, it is pretty straightforward. And one thing that we know too is that it increases also, and there's research done, it increases the possibilities of becoming diabetic. Yeah. So that's the two things I usually say to a patient. I said, there's, because everyone says, look, if you're going to do a statin, what are the risks? And I say, the short-term risk is myalgias. And again, I just say directionally, it's one in 10 people. Maybe it's 15%, maybe it's 5%, but you get the feedback quickly and you move on.

So the second risk is a long-term risk, which is about a 4% increase in the risk of diabetes. The good news there is that's not a sudden thing. I think the literature is still pretty clear that the benefit still outweighs that risk in terms of mortality. But again, it comes back to the idea of the most potent drugs we have are food and exercise. And it comes back to me as well that it's not about how many years we live, our longevity, and it's how are the last years that we live, right? And if statins are going to come back to haunt you in 20 years because they're going to have extra or increase in diabetes,

for example, yeah, it might buy you extra time now. But again, if you have food and exercise as your main medicine. The zone two training for me, it's just become such an important part of my training for myself and for my patients. I question, I get asked a lot that I don't know the answer to. So I'm going to ask you is what's the minimum effective dose? Because obviously I would love it if I could wave a magic wand and have one hour per day to do zone two. And then on top of that layer in all other exercise, that would be amazing. But it's not. I only do three hours a week of zone two, typically in four 45 minute to an hour sessions. Do you think that's enough? Yes. So this is what I've seen and I've learned from the

athletes. And I would love to do this now with patients. What's the right dose? But we know, or at least I've seen with athletes that if you do that two days a week, one is the dose and the other thing is the frequency. So if you do that two days a week, you maintain. And we see athletes who in the off season, cyclists, for example, or runners or triathletes or swimmers or rowers, if you do the zone two five days a week, for example, you really push the needle. Then once the season starts, you need to do more higher intensity exercise and training. And then you have the races and you need to recover. So definitely you cannot do zone two every day. So what we see is like two days a week, it tends to maintain.

So that's the frequency. What's the dose? Yeah. And the dose, what I see is like, obviously these elite athletes, they need to keep pushing the needle. One hour is not going to do much for them because they have that stimulus already, two hours, they might need four or five hours. But a patient with type one diabetes, maybe one hour is enough.

And that's what I'm trying to fine tune, you know, what would be. What I know very well is that three days a week, it starts moving the needle, four or five for sure. And what I've seen or guessing that that's because we don't have any real data. This is about one hour to one hour and a half. It does the trick for those who have type two diabetes or pre-type two diabetes, for example. So we have last year, a patient who was diagnosed with, that's what we were saying is like late pre-type 2 diabetes, for example. So we have last year a patient who was diagnosed with,

that's what we were saying, is like late pre-type 2. What the heck is that, you know? And then with one year, doing an hour into an hour and a half, four days a week, she reversed that completely. Okay, that's a pretty big dose. So, I mean, for me, it's always for me Tuesday, Thursday, Saturday, Sunday is zone 2. It might be that those Saturday, Sunday workouts, I need to push them longer. Maybe I need to do 90 minutes on each of those days and stay at 45 minutes on Tuesday, Thursday.

It could be, but at the same time, it might be your right dose because you're not in that unhealthy population side. So your dose might be lower. But my thinking now is that this is such an important part of cellular longevity, that this is the difference between being a healthy 90 year old and being in my framework, it's one quarter of the equation. What would you do? I would do, and this is my case when I stopped cycling, when I told you earlier, right? I gained 65 pounds because I was working 70 hours a week and exercising six, seven days a year.

And still eating like a cyclist? And eating like a cyclist. And I'm from the Basque country and we like to eat food because it's one of the best areas in the world. And probably also I had insulin sensitivity developed from I was a cyclist, which I would just pull poor carbohydrates, you know, and then I would not burn them. So maybe I just transform it into fat. I also have a familiar dyslipidemia. So I have a high triglycerides and high cholesterol genetically. So I didn't take care of myself. I would not exercise and eat a lot. So I gained 65 pounds in about eight years or so. And then I said, wow, I went and did myself a checkup.

And then I said, wow, I went and did myself a checkup. And then my blood pressure was 125. I was in my mid-30s, 125 over 85. So I was getting there. In my triglycerides ones, I saw them 800, which is huge off the chart, right? Back in the days, people didn't do A1C. That's when I started to work on these concepts too. And so I started to apply this these concepts too. And so I started to apply this to myself. So I started doing four days a week. Even one hour was poof,

I was bunking because I was not used to that. It was very depressing going to- I was about to say that must have just been devastating. Oh my gosh. To go from being a professional cyclist to struggling to do four hours a week of cycling. Yeah. And knowing the same roads that you go to and that you couldn't go up the hill. But I lost 35 pounds within seven months. Did you make much change to your nutrition?

Exactly. I mean, I decided to, I was willing to eat a little bit less, but not sacrifice many things. Because again, I mean, for me, nutrition is very important from my culture standpoint. I love chocolate. I love wine. I love pasta and bread. It's ingrained in my culture. I was not going to renounce these things. So the other side versus, you know, I've seen more patients than I can count with type 2 diabetes not exercise at all, but go on ketogenic diets. Within six months, they're off insulin. Within a year, they have a normalized hemoglobin A1C.

But again, so it's almost like two levers. How hard are you willing to pull on each of the levers? Exactly. No, that's a great, great comment for sure. And I think it's the debate. Many, for some people, giving up chocolate is not a problem. For me, it's death. I just love chocolate. It's not that I eat it every day, a whole bar, but it is, or bread. That's one of the things too, that is the balance. I lost 33 pounds and I stopped there. I could not lose more than that. I needed to then increase my dose. So I went from one hour to an hour and a half, four days a week. I lost another 10 pounds. So I lost

a total of around 50 pounds, 47 to 50 pounds. That was 11 years ago before coming here. And I kind of keep it like that. Now, this is interesting. As you're probably aware, the exercise and weight loss literature suggest that exercise alone is not sufficient for weight loss. I've always wondered if that was an artifact of the fact that they're studying exercise incorrectly, that the prescription, it's either the dose or the frequency or the intensity were not optimized. You were doing a very specific type of exercise. You were not exercising for the number of calories you burned. You were training your mitochondria to become better at fuel partitioning. That's a very technical description of what you did. I think it's important for people who are listening

to this to appreciate that nuance. You were not there calorie counting saying, okay, I'm doing six hours a day at this many calories because you can achieve that in many different ways. It was almost the maniacal specificity with which you approached this that you basically said, you didn't think of it as I'm exercising six hours a week. It's I'm doing mitochondrial conditioning or reprogramming six hours a week. Exactly. Yeah, I believerial conditioning or reprogramming six hours a week. Exactly. Yeah, I believe so. And that's what we know now with patients when we start in the laboratory that they always tell you, I always train at this intensity. And you know that intensity, they burn zero grams of fat. They burn a lot of calories, but zero are derived from fat.

Yeah, they're actually working too hard. Too hard. And eventually, number one, you don't burn much fat. You burn fat in the post-exercise because you might increase your metabolic rate. But can that override the fat burning from the exercise itself? And second, it's too hard. You haven't exercised in a long time to start with, and you get into these high-intensity programs that they might not suit you or they might injure you. And many people give up. We see the rate of people giving up from gyms is about 50% or so within X amount of months. They either give up or their adherence decreases a lot. So when I ask

these people who get into this extreme either exercise or diets, I always ask them, and they're successful. I ask them, can you do this for the rest of your life? And the real question is, hell no. Yeah. If you can't do it for the rest of your life, you have to come back to the, why am I doing this? Using an extreme example to do hill repeats up Alpe d'Huez. Can you do that for the rest of your life? No. Can you do it if your goal is to win the Tour de France? Yes. You're going to do it for five years. You're going to train that hard for five years. You're probably going to take a chunk of time off your life, by the way, but that's your job. You have to be the best climber in the world. Exactly. And to the point of the nutrition,

the nutrition is a must. You need to do something with it or do a lot more exercise. But I think it's the balance that we all, I think, need to understand better. Well, that's for me why fasting has become so important. Now, you were laughing at me earlier before we started recording about how crazy it is that I can do these long fasts. But in many ways, it's a way to provide me balance. It's like sprinting. It's basically every month, there's just a frequency with which every quarter I do one type of fast and every month a different type and every week a different kind. It allows me to keep a balance and it allows me to say, yes, I could do this for the rest of my life. Whereas the reality of it is I couldn't do a ketogenic diet for the rest of my life. As powerful as it was in me, couldn't do it the rest of my

life. So a couple other questions I want to ask you about. You've alluded to cancer twice now. We've spent a lot of time talking about type 2 diabetes as a disease state in which the mitochondria are not functioning well, and they provide this great contrast. But you've touched briefly on cancer. Is there any evidence that a patient with cancer has a higher lactate level on account of the fact that they have mitochondria that aren't working as well, the same way that the person with type 2 diabetes has. So it is a fact in 1923, almost 100 years ago, Otto Warburg from Germany discovered the transformation of a normal cell into a cancer cell at the metabolic level.

And the characteristic of cancer cells was that they use a lot of glucose for energy purposes. Now, they use a lot of glucose. Back in the days, there was no genetics or anything. But what struck Warburg is the amount of lactate that they produced. Was that what struck him more than the fact that they use so much glucose even in the presence of sufficient cellular oxygen and insufficient ATP demand? So it was more the lactate accumulation? It was more the lactate accumulation. And that's why he came to conclusion that cancer was a metabolic disease caused by an injury of the respiration system in the cell, which is the mitochondria. And that's what was the thought for many years because of the lactate. Even before glycolysis was invented, Meyerhoff, who discovered glycolysis,

sometimes it's called Enden-Meierhoff pathway, which is glycolysis. invented, Meyerhoff, who discovered glycolysis, sometimes it's called Enden-Meierhoff pathway, which is glycolysis, Meyerhoff was a student of Warburg. Before they had even found out about glycolysis, the way they measure glycolysis is by measuring lactate. So they would measure how much lactate the cell produces, and that's where they would say, wow, they're using a lot of glucose. But what he saw in cancer cells, there was an aberrant amount of lactate the cell produces. And that's when we say, wow, they're using a lot of glucose. But what he saw in cancer cells, there was an aberrant amount of lactate production. And that was one of the things that struck Warburg the most.

And now what we see is that lactate is a typical feature of cancers. Cancers produce a large amount of lactate, which is also responsible of the famous microenvironment that a lot of people are talking about nowadays. The lactate, which is also responsible of the famous microenvironment that a lot of people are talking about nowadays. The lactate microenvironment, I mean, the microenvironment of cancer cells is more acidic than non-cancer cells, and it's a niche for carcinogenesis. The responsible for that microenvironment is lactate. And what we know is that, yes,

it's lactate. It's a fact that multiple studies showing that, or every study showing that, every study trying to find lactate in cancer, they're going to find higher lactate levels. So this would suggest three distinct, but not necessarily mutually exclusive explanations for the Warburg effect. The first being what Warburg proposed, which is in cancer, there is an injury to the mitochondria. As a result of that injury, the cancer produces, it takes an inefficient path to go. Then there's the 2009 explanation proposed by Thompson, Cantley, Vander Heiden in that science paper that was sort of a very important landmark paper that said, no, no, that's probably

not it. a very important landmark paper that said, no, no, that's probably not it. It's the glycolysis and the lactate production is a byproduct of metabolic demand for building blocks. It's the cellular nucleotides that are necessary to build the cells. So the mitochondria work okay. What you're seeing is a deliberate and obligate choice to grow and the need to grow literally from a mass balance perspective requires taking this pathway versus that pathway. And now you're saying, well, a possible third explanation is the cancer relies on lactate as a signaling molecule. And again, these could all be true on some level. We know that they're not all always true. I mean, at least we know that in the case of

the Warburg effect, that's not universally true that the cancer damages the mitochondria. What are the next steps in figuring this out? And perhaps more importantly, much more importantly, how do we use this information therapeutically? Yeah. So one of the things is that we have just finished a study. It's under review now, and we're going to replicate it now with more cancer cells. But we have done a study with the MCF7 cancer cells, which are the most common type of breast cancer, or one of the most common type of breast cancer cells. And what we have seen is like we expose the cancer cells to glucose. So we did an experiment, one exposing the cancer cells to a media that contains nothing, no glucose, no glutamine,

which is also highly expressing cancer. And this can survive a couple of days in that state. Then in another experiment, we just expose them to glucose. That's it. And in the other two other experiments, we added to that glucose media, we added 10 millimoles of lactate and 20 millimoles of lactate. What we did then is like we extracted the DNA. By the way, are those physiologically accurate doses? Do we believe

the micro environment of cancer is that high? It's about 10. Yes. It's 10 times the normal level. There's been studies showing up to 40, but normally, yeah, 10 is a typical. And what pH? The pH is usually between six and seven. I was about to say that has to be below seven. Yes, for sure. In fact, the more aggressive in general, the more aggressive the cancer is, the more glycolytic is, and the more lactate is found, and the more acidic the macroenvironment is. So we published an idea to propose lactate being the explanation for the world war effect because what we looked into the medical research is that the genetics stops in how the first cancer cell happens and maybe proliferation in cell cycle genes but

there's a lot more to that in cancer you need angiogenesis you need metastasis you need immune escape, and you need also the cell-sufficient metabolism that cancer cells have. It's immortal. So that's where like what we saw is that lactate is necessary for each of these major steps in carcinogenesis. But what we wanted to see is like could lactate also be a signaling molecule? And that's where like what we observe is like looking at transcriptional activity, looking at the RNA expressions of the key oncogenes, transcription factors, and cell cycle genes and proliferation genes in cancer. Lactate overexpressed them

between two and eight fold compared to control. And what was the difference between the 10 millimolar and 20 millimolar lactate? Did you see a difference in transcription? In 10 and 20, we didn't see much of a difference, but we saw more than in zero. What struck us, and that's kind of hopefully we can show, is that if you cultivate the cancer cells in glucose alone, I give this presentation on the Anderson, but so we looked at the cancer cells and we looked at the major oncogenic, I mean oncogenes, transcription factors, and cycle genes. We had no glucose incubation, no glutamine either, just glucose. And then we added lactate, 10 millimolars, and 20 millimolars.

So we did RNA extraction, and we looked at in the cancer cells, were there without any media, that is no glucose, no glutamine, we didn't see RNA expression. Did the cells live? Or those oncogenes. We killed them. We didn't. In other words, there's a very finite period of time

in which you're looking to just see. Yes, we look in six hours and 48 hours. So neither in six 48 hours was RNA expression. Okay, what about glucose by itself? So when you add glucose by itself, we looked into the media and it was a very high lactate levels. Looks like on your graph, it's almost 30 millimole. Yes, it was almost 30 millimole in the six hours. And because lactate is also used by the cells for energy purposes over time, we expected also to see, but we still see about 25 millimolar.

This is the waterboard effect. This is what waterboard observed. Incubating in cells and say, wow, they use a lot of glucose, but why in the world is this lactate? It's amazing it's that high. So what we saw then is like this lactate alone was enough to trigger the expression of all the major oncogenes, transcription factors, and even depress the cell arrest genes. So is there an experiment that could be done where you constantly change the media? You have a flux of media that allows them to have a finite amount of glucose,

but you constantly strip away the lactate to see what the true baseline level of expression is, absent the lactate as the signal. Yeah, so this is now where we're going to be replicating this experiment with multiple cancer cell lines, from liver to pancreas to lung to kidney to thyroid. More glycolytic, less glycolytic. And then do all these kinds of experiments and include also metabolomics. I mean, this is a complicated media device because you basically have to expose them to a bath of constantly moving media that contains glucose, but no lactate. You see what I'm saying? So you

have a negative flux of lactate across the cell because what you really want to do is see how does this work with glucose, but no accumulated lactate? Because that would answer the question, is lactate specifically signaling? Because you could still argue here glucose is playing a role. Yes, but we believe this is through the lactate. Through the lactate, but now how do we figure that out? That's what we did in the second experiment. The glucose media is the same. We just added more lactate. And we see a much amplified response. How much is it amplified with? So it was, for example, this is the no lactate versus the lactate.

We can see. That looks like about 2X. Yeah, sometimes even 2X. So that's where we saw that the media is the same. But the more, when we added the lactate, it really overexpressed the transcriptional activity. I was going to play devil's advocate. You could say that we know that the lactate could be serving a metabolic fuel. So maybe it's conserving more glucose for more glucose to be signaling transcription.

Well, we know that lactate is being used by the mitochondria of cancer cells. Everywhere is mitochondria, there's lactate. What we believe is that it's a signaling molecule to really overexpress the transcriptional activity of oncogenes, transcription factors, and cell cycle genes in a non-hierarchical way. Because the traditional view of cancer is that you have the oncogenes, they tap on the transcription factors, and they start an array of different downstream signaling that eventually transforms a normal cell into a cancer cell. This is so interesting because it, again,

at the meta level flies in the face of all of the observational data of how much metformin lowers cancer, unless it comes back to your explanation. Because if you just look at these data all things equal, and by the way, that would be another interesting experiment, add metformin to the dish as well, in theory, it should amplify lactate by poisoning the mitochondria further and drive even greater upregulation of these signals, unless, to your point earlier,

it becomes so toxic to the mitochondria that the cell undergoes apoptosis. Yeah. That's what's in my opinion. And this is another thing that we want to do, but it's possibly that, yeah, because you're totally right. It can amplify the lactate as we know. So I can amplify that, that oncogenic or oncogenetic signaling for carcinogenesis. Or maybe it just doesn't matter because these amounts of lactate are so high that we're not seeing that from metformin. Maybe metformin isn't that inhibitory to the mitochondria and that becomes a red herring in the equation and the benefits of metformin exist totally elsewhere. We don't know, but it will be very interesting to see all

this because it can have some application and there's some research groups studying already why. I feel like I need to quit my job and come and be a postdoc in your lab because there's just so much, the more we talk about this stuff. And I know it's going to get way worse tonight when we have dinner with Rick because it's going to be like 50 other ideas that I just want to. With the fructose as well. Yeah, that's a lot of things going on there. Let's talk for a few of things going on there. use of drugs was at its highest. I don't think anybody can be a student of this sport and ever say there's been an era when the top athletes weren't using some drug. I mean, even Eddie Merckx,

the greatest cyclist of them all on many occasions was found to be using an amphetamine or something like that. How much of an impact do you think the performance enhancing drugs of that era, the nineties and two thousands, where again, it's all out in the open now. Everybody understands how much blood doping and how much EPO was being used. Yet you a moment ago gave a number of six to 6.5 Watts per kilo as an FTP. I recall reading at the time athletes hitting seven Watts per kilo. Do you think that is about the distinction of with and without EPO? Do you think that's about the magnitude of the improvement? I could not know that number. Yeah, I mean, definitely we know the times. And back in the days, we didn't have those

power meters or cyclists, they didn't use them. So it's difficult to calculate, but it is possible to calculate with the times. I haven't done the numbers, but what we know now is that the times going Tourmalet, Aldouez or so are the same times that people were doing in the 80s or early 90s. It's hard to see any of today's cyclists being in the top 20 best times now as they did before. So that's something that shows that, yeah, cycling, I think goodness, it's a very clean sport right now. The other thing is the fact that every cyclist now who wants to do well, they go to altitude. And that's one thing that before didn't happen. And now it's just, it's great to see people going to altitude because it's a physiological way to increase oxygen carrying capacity.

Is the data on altitude still the following? So when I last looked into this, which is maybe a decade ago, the answer seemed to be the performance enhancing way to use altitude is to live high, train low, meaning your baseline exposure should be at a low oxygen environment. Your low intensity training should be at a low altitude environment, but your high intensity training should be at sea level. Is that still believed to be the case? That's an ideal scenario, in my opinion. Yes. And I mean, here in Colorado, because we're Colorado here, by force, we need to know, we must know about altitude because we get a lot of athletes every year and we get to study them. And yeah, one thing

that happens at altitude is your glycolytic capacity, it starts deteriorating. The high exercise intensity. It's like if you had a cap here at altitude. And this is something that everybody tells you when they're here, like, I cannot keep my 100% here. I cannot open up the same gas as I used to have. And if you don't do that for three and a half weeks or three weeks at your altitude, yeah, your glycolytic capacity is going to deteriorate, which for a marathon runner, they couldn't care less. But for a cyclist, for example, it's important. So that's where the ideal scenario is to really try to find that balance,

but it's not easy to do at high altitude levels. Has anyone ever proposed using little portable oxygen producing devices for peak, peak, peak efforts for those who live at altitude to maintain top end? Exactly. And that's done. It is done. Yeah, it is done. Yeah.

And that's something that we're building at the university in one of our campuses in Colorado Springs, a sports medicine and performance center, where we're going to have one room that is going to simulate sea level conditions. So it's going to be hyperoxic. So it's going to simulate living at sea level because that is going to allow athletes to do very high intensity efforts without killing themselves. Because this is the problem that happens here, altitude. These athletes who want to do very high-intensity exercise, which they really need also to, they get overtrained. We see a lot of people living altitude in very bad form,

and they're overtrained, or they live with a high oxygen carrying capacity but poor glycolytic capacity. So that's where, like, yeah, by doing this space, it's going to allow athletes to come and they use these facilities while living at altitude. Because the problem that we have here, you have two days driving to the ocean, so you cannot train low and live high. But at least train low, high intensity, you can simulate that while still living in high environment. So interesting. Miguel Enduran, have you ever met him?

Yes. An unbelievable specimen? Yeah, yeah. And an incredible person too. I've heard he is, so he's got to be what now? He's got to be 60? Yeah, 50s, in the high 50s or so. 50s, yeah. Yeah. Still incredibly fit. I remember reading a paper about him maybe 20 years after he retired. He

retired in 95, 96, right? I mean, still unbelievable numbers. I mean, was he just a physical phenom to begin with? Yeah, he was incredible. When I was doing my internship, I was doing it with an endurance physiologist who was a very, very good physiologist. And I learned a lot. And I remember once I was kind of helping there. And the one thing that struck me also was his numbers were unbelievable. And also the amount of sweat that he had.

I have never seen anybody sweating so much in my entire life. He was a big guy, right? He was 80 kilos, six foot one, six foot two. It was incredible. Because usually when you do physiological tests, you might have a few, one towel or a couple of towels. Even with fans, people sweat a little bit. And back in the days, I was just wiping the floors. That's kind of, you do internships. In these cases, yeah, if we do it in Durant,

you need a mop. And have you seen athletes since? Never. So do you think that's just true, true and unrelated? Or do you think that also spoke to his physiology? Like he had an unusual cooling system. It was like out of this world. I have never seen anybody like him. And if you observed in the Tour de France, everybody was with their shirts wide open, right? And Indurain was always all zipped up, always, always, always, and with a hat on. So he had an amazing capacity to dissipate heat, which is a double-edged sword. So obviously he drank a lot.

But I'm very sure, and back in the days, we didn't have the technology that we have nowadays to measure that. What do we do now? Sodium concentration in sweat. We do sweat tests. We have sweat patches and we can measure the sodium concentration in the sweat patches and then tell someone, whoa, you're a heavy sweater in the first place and you also sweat a lot of sodium. But when someone, and it's something that's very typical, we see young people or people who are not very well adapted to sweating. You see

like the white marks in their shorts or in their helmets, that's salt, literally, sodium. But the more mature physiologically an athlete gets, the more they sweat. That is, I have never realized that that is a metric. Yet another little trick of the trade to look at sort of metabolic flexibility is the ability to retain the sodium as just the water leave. Yes, exactly. Makes total sense. Yeah, it's an evolution. And you sweat more.

Back in the days, I was just doing just wiping the floors. Now you'd bet that there's low sodium in there. You'd pull a William Osler and he figured out that diabetes urine tasted like sugar. You'd figure out that Enduran sweat tastes like water. I would have tested it for sure. I guarantee you. I would have said, man, there's no salt here. Enduran's interesting because he's right on that precipice where there is no question that the person who won the tour right after him was using Herculean doses of EPO. So Bjorn Ries won in 96, nickname Mr. 60, right? I mean, hematocrit somewhere between 60 and 66. So you go from Bjorn Ries to Ulrich to Pantani to Armstrong. That's the era. And then before Indoran is Greg Lamond, who, again, I don't really know anything about what he was or wasn't taking.

about what he was or wasn't taking. But Indiran has largely been left out of the discussion on blood doping. And I've read articles that have just talked about how he's generally been left alone. No one has come back to him because it's, so I'm not going to ask you to speculate on that because I know that from a personal standpoint, I don't want to put you on that spot, but do you get the sense that he's just been left out of this discussion because of his place in cycling? And it's almost like people don't want to go back and revisit that. I mean, why do you think that is? I don't know. I have no idea, to be honest. I could never give you an answer. I know that he was a freak of nature because of his size in the same manner that before Indurain was Greg LeMond, who was also a freak of nature as well and left out

of all this. I have no idea, but I've seen his physiological parameters, and I've seen a lot of athletes. You don't see those physiological parameters. And also, what I always say about Indurain is his head. And I work with a lot of athletes. And in cycling, for example, I have never met any athlete. Well, there's one athlete. I will tell you in a few years.

Meaning there's someone you work with now who maybe in a few years you'll tell us. Yeah, I don't want to be- No, you don't want to jinx him. Him too. Yes, exactly. But only one athlete with his head. He was calm. He was relaxed.

He was super intelligent. He could read the game ahead of things. He would never get nervous about anything. And he would never doubt about anything, which is rare in athletes. I've seen athletes getting to the top of the game and falling apart and start crying. There's the fear to lose, but also the fear to win. Because when you win, your life changes for the good or for the bad. And many athletes, they were always nervous trying to find an answer or trying to find

a new diet or a new training or something, you know, and that's where like, we're very fragile. a new diet or a new training or something, you know, and that's where like, we're very fragile. Athletes at the high level, very, very, very fragile. If you're considered like an expert or you're a coach or you're someone with a little bit of a name in cycling, for example, and if you go to a race and you see a cyclist, wow, you look fat. I think you gain weight. That cyclist is done. Yeah, exactly. Done. I mean, cyclists are like models in that regard, right? Every ounce matters. Exactly. And that's how they are.

But Indurain started the tour with two and a half kilos over, for example. Why? The first weekend the tour is flat, no gravity. His head is relaxed and calm. They're like, okay, I can do this. No problem. And in that week he loses a kilo, kilo and a half. And then he entered the second week with the mountains with half a kilo over.

Okay, no problem, no big deal. He loses it and then boom, the last week is in perfect weight. It takes a lot of thinking and confidence, right? And saying, hey, I got it. And that's why I think that his head was also unbelievable. LeMond's head was also incredible. I remember as a kid reading LeMond's book. It really literally changed my way

of looking at cycling. I was 15 when he won the Tour de France. And that's where I started to see his complete book of cycling. I don't know if you've ever read it. It's the best cycling book I've ever read in my life. And it's about how he trained and how he ate and how the way he approached cycling. And back in the days, I'm talking 86, he was super scientific. Yeah. He was so far ahead of everybody else. Everybody else. Yeah.

Yeah. We could go on for hours, but I think on this note, we'll bring it to a close only because we're already late for dinner and I don't want to keep Rick waiting, but I want to thank you so much for this. This has been incredibly informative. There is a million follow-up things to do, including we're going to do this biopsy study. So I'm willing to come back to Colorado to do this again, because I really am curious about this metformin question around zone two. And I think that this is going to be one of those episodes where hopefully people are able to see the show notes because

so much of what we've talked about, I think benefits from this type of being able to see the show notes because so much of what we've talked about, I think, benefits from this type of being able to visually see what this stuff we've talked about. And lastly, I do think there's going to be no shortage of medical students and undergraduate students who are looking for summer projects to come and help you get a lot of these really interesting posters published. So thank you. Well, thank you so much, Peter. For the impact you've had on me personally with respect to how I think about this problem, and then hopefully by extension how others have as well. Well, thank you so much. It's truly an honor to have you here and to speak with you and be invited to your podcast.

Thank you very much. You can find all of this information and more at peterottiamd.com forward slash podcast. There you'll find the show notes, readings, and links related to this episode. You can also find my blog at peterottiamd.com. podcast. There you'll find the show notes, readings, and links related to this episode. You can also find my blog at peterottmd.com. Maybe the simplest thing to do is to sign up for my subjectively non-lame once a week email where I'll update you on what I've been up to, the most interesting papers I've read, and all things related to longevity, science, performance, sleep, etc. On social, you can find me on Twitter, Instagram, and Facebook, all with the ID PeterAttiaMD, but usually Twitter is the best way to reach me to share your questions and comments. Now for the obligatory disclaimer, this podcast is for general

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