201 - Deep dive back into Zone 2 Training | Iñigo San-Millán, Ph.D. & Peter Attia, M.D.

1. 0:00 – 0:10

   Intro

   1. PAPeter Attia0:00

      [upbeat music] Hey, everyone. Welcome to "The Drive" podcast. I'm your host, Peter Attia. [upbeat music] Iñigo,

2. 0:10 – 6:54

   The amazing potential of cyclist Tadej Pogačar

   1. PAPeter Attia0:10

      it is so great to be sitting down with you again. Uh, last time, of course, we did this in person, but these days I've become too lazy to travel around and do podcasts in person.

   2. ISIñigo San-Millán0:18

      [laughs]

   3. PAPeter Attia0:19

      So do it by video. But that said, I really hope you can get out here to Austin so we can train together and do some cool X phys. And, and also I need to get out there, uh, to, to sort of do some of the X phys stuff we've, we've talked about. But y- y- you know, I, I almost don't know where to begin because there's so much stuff we talked about last time that we wanna double click on this time. There's so much that has changed in the interval from when we spoke, uh, gosh, probably two years ago, a little over two years ago.

   4. ISIñigo San-Millán0:46

      Mm-hmm.

   5. PAPeter Attia0:47

      I thought one place we could pick it up, uh, something we didn't really talk about last time, uh, was your work with, uh, Tadej Pogačar, because of course I don't think anybody knew who he was two years ago, uh, or two and a half years ago. And of course now he is, um... I don't know. I mean, I think it's safe to say he has the potential to potentially go down as the greatest Tour de France cyclist of all time, given how young he is. Not to put that expectation out there, but to win the Tour at such a young age, to not just win the yellow jersey, but the white jersey, the polka dot jersey repeatedly, um, uh, he, he looks like something of a, of a different, uh, species almost. Uh, and I say that not in the way that people typically say those things of cyclists in a, in a way that's suspicious of anything. So I don't know, maybe for, for the listeners who are not familiar with the Tour de France, not familiar with, with your work with, uh, the UAE team and your work with, uh, Tadej Pogačar, maybe give folks a little bit of an update as to what you've been doing [smacks lips] with, in professional cycling over the past couple of years.

   6. ISIñigo San-Millán1:50

      Yeah. Well, uh, first of all, thank you very much for, for having me here. Uh, it's, uh, it's an honor and, uh, really excited for this, and I appreciate the opportunity. Um, I had a lot of fun last time and, uh, yeah, hope to have fun again. Um, yeah, my work with, with Tadej started, um, in, uh, late 2018 when he signed up for the team and, uh, yeah, I was introduced to him by our CEO, Gianetti, and our general manager, uh, Matxin. Um, and they told me, "Hey, just start working with this guy."

   7. PAPeter Attia2:25

      And he was what at the time? 19 maybe?

   8. ISIñigo San-Millán2:27

      Um, uh, yeah, yeah, 19. He was 19, uh, uh, at the time. Uh, just had turned 19, in fact. And yeah, so I started to, to work with him and right, right away I realized that, uh, he had very good potential. And I think like a, you know, a couple months earlier, no, or later, I forgot, when we had that podcast, I already told you about him, right? Uh, and, uh, and yeah, and I told that like, yeah, we have a guy that has good potential. Uh, and yeah, that was, that was Tadej.

   9. PAPeter Attia3:02

      And, and to put it in perspective, I mean, has good potential is one thing. To then go and do what he did-

   10. ISIñigo San-Millán3:09

       Yeah

   11. PAPeter Attia3:09

       ... is, would make that statement the understatement of the century, um-

   12. ISIñigo San-Millán3:13

       [laughs]

   13. PAPeter Attia3:13

       ... for folks who, who maybe don't, don't follow cycling as, as closely, right?

   14. ISIñigo San-Millán3:18

       Yeah. Yeah. I mean, I try to be cautious, right? I, I don't usually say that a lot of people, uh, who has, who have actually good potential.

   15. PAPeter Attia3:25

       Yeah, we talked, we talked about it over dinner that night. Yeah.

   16. ISIñigo San-Millán3:27

       Yeah. Yeah. When I say someone has good potential, it's very, it's good potential. I don't usually say that lightly of anybody, right?

   17. PAPeter Attia3:36

       What did you see in him in 2018, 2019 that led you to believe that even amongst that class, because professional cyclists, you know, from a physiologic standpoint, are all very special individuals. What did you see in him that made you think he has potential in your understated way?

   18. ISIñigo San-Millán3:57

       Well, first the, the physiological testing that, uh, we, we started doing right off the bat, I saw like that he had, uh, amazing, uh, capabilities, you know, at the, uh, you know, the oxidative, uh, um, capabilities, like ability to clear lactate and, uh, uh, and, and to put out great amount of power output for long periods of time.

   19. PAPeter Attia4:21

       So when you say that, was it specifically his, um, FTP that impressed you, or was it his, as you said, lactate clearance? Was it shorter bursts of power that were higher than FTP, but the speed with which he could do or the successive repeats that he could do? I mean, tell me some of the testing you were putting cyclists through and, and how he stood out.

   20. ISIñigo San-Millán4:46

       So it wa- it's kinda like similar test that I did to you, right? And, uh, and, and this is kinda like, uh, where I, I saw that, um, uh, at a given power output, his lactate levels, blood lactate levels were extremely low. And since I've been doing this specific protocol for 20 years with professional athletes, uh, professional cyclists in this specific case, that's where I have my, um, my, um, uh, um, cheat sheet, right? Where I know I can categorize where people are. And that was like, he was like, whoa, way on the other side, you know, way above almost everybody that I had tested or, or around the same category. And for that age, that's what I saw, like, whoa, first of all, he is at a different category and, and he's, he's first year pro. He's, uh, pretty much a junior. Um, and, uh, and then that's where like I could see he could sustain, um, high amount of power, uh, with very low lactate compared to the rest. And then throughout the trainings, uh, looking, we use TrainingPeaks, the software, uh, looking at TrainingPeaks, that's where I would see, uh, his different abilities to sustain, um, a given power output for, for the whole day or for a specific effort, a glycolytic effort on a climb, and, and we'd see the power output that he would be putting out. And, and, and so altogether then I saw his trainability. how easy he would, um, get the concepts, um, how easy he would, uh, um, comfortable, uh, with, with the training, how would he, easy he would recover. I, I, I, you know, I, I like the feedback. I talk to him once, twice a day and, uh, you know, over WhatsApp too, you know, uh, the feedback and, and, and, and you, I know very well when, when a, a hard week is or what a hard week is. And when you see this kid telling you, "Yeah, I'm pretty good. I'm recovering very well," when other ones are telling you, "Woof, I had to take it a little bit easier today 'cause I couldn't do this effort," and we're talking about high-level pros, and you see this kid telling you like, "Yeah, there's no problem," that's where you start putting together things.

3. 6:54 – 17:20

   Metrics for assessing athletic performance in cyclists and how that impacts race strategy

   1. ISIñigo San-Millán6:54

      Um, and also around the same time, uh, with my two colleagues at the university, uh, uh, um, Angelo D'Alessandro and Travis Net- Netkov, we developed, uh, we started developing a platform for metabolomics where we can look at, um, you know, hundreds if not thousands of, of metabolites, um, in the human body. Uh, and we did it at the Tour of California in 2019, which was like around April. Um, that's where, uh... And he won it. And, and that's where when we analyzed all his metabolites, and we did already at the training camp in January 9, 2019, uh, and we already saw, wow, this guy has different metabolites, you know, at, at the, uh, glycolytic level, oxidative level, um, um, uh, recovery level. And we confirmed that at the Tour of California. Uh, and this is where putting it all together, you know, I saw like, yeah, this guy is different.

   2. PAPeter Attia7:48

      So going back to what you said about lactate, I assume that one of the data points that is most telling of a cyclist is if you plot on the X-axis watts per kilo, and on the Y-axis lactate production, uh, that would be a very-- I mean, that might be one of the most telling graphs you could generate-

   3. ISIñigo San-Millán8:08

      Yeah

   4. PAPeter Attia8:09

      ... to predict success-

   5. ISIñigo San-Millán8:10

      Yeah

   6. PAPeter Attia8:10

      ... in the, in the Tour, correct?

   7. ISIñigo San-Millán8:13

      Absolutely. Absolutely. You see someone at, you know, for example, a, a normal tempo climbing in the Tour de France, uh, tempo, uh, that is the whole peloton going up, it is about five watts per kilo.

   8. PAPeter Attia8:24

      There's gotta be four-

   9. ISIñigo San-Millán8:26

      Yeah.

   10. PAPeter Attia8:26

       Is it five? I was about to say, wow.

   11. ISIñigo San-Millán8:27

       Yeah.

   12. PAPeter Attia8:27

       I was gonna say four and a half. Okay. So wow.

   13. ISIñigo San-Millán8:28

       Yeah.

   14. PAPeter Attia8:29

       The whole peloton is going up at five watts per kilo.

   15. ISIñigo San-Millán8:32

       Yeah, something like that. And, and that's where you see like someone at, at that intensity might have already six millimoles.

   16. PAPeter Attia8:39

       Yes.

   17. ISIñigo San-Millán8:39

       So you can tell he's gonna be very tasking and, and, and, and others might have one, resting levels, you know? And this is where like, this is it really, really predicts performance. Um, and, and you can really predict performance in, in, in, in, in a, in an incredible way. In, in fact, when we go to these training camps, like I'm going to go next week for the first training camp of, of, of the year with the team. We do this, uh, um, uh, physiological testing, and I do this protocol, and, and I get this data. So right away I tell the, uh, the team managers, "This, this guy is way above the rest. These three guys are really, really good immediately, immediately behind it. These two guys are the, or the, the, the third level. And then we have all these guys that they're like really, really bad form." And it, and it pretty much works, you know? Then we do different training, um, uh, racing simulation and, uh, and they tell it, boom, right away, this is, this is how it is. So this is why it's very predictive. And the same thing too, moving into the season. You see, okay, all these three guys are gonna be at a very good level when we start the season. This guy w- who we thought that he was gonna be a very good level, he's not there at all. So, uh, and, and that when, when the season starts, you see that it reflects, um, uh, very well what's going to happen.

   18. PAPeter Attia10:01

       Yeah. That's one of the things about cycling that I really love. I mean, I don't know if you saw, but I interviewed Lance Armstrong back in, oh gosh, probably back in June, or maybe it came out in September. But, you know, one of the things that we talked about was both on and off EPO or blood transfusions, you sort of knew where you stood before the race based on your FTP in watts per kilo. So, you know, when he was-- He talked about when he was off EPO, he could hold 450 watts for 30 minutes. So that would be slightly below FT-- or that would be slightly above FTP at 70, I think he was 70 to 75 kilos. But it was in the ballpark of six watts per kilo. And then of course on EPO it was 7.1 watts per kilo, a huge difference. But you knew that number going in, and you sort of knew like only the GC contenders could do that. I think that's the thing that a lot of people don't understand about cycling, which is there's relatively few moments in the Tour when you need to sustain that level, but they always occur at the most important strategic times, right? And, and that's sort of where the race is won and lost, 'cause the race is won and lost by minutes. It's, it's, for a race that is-- How many hours does it take to complete the Tour? 100 hours or something?

   19. ISIñigo San-Millán11:20

       That's a good question. Um, um, yeah, an average of about five hou- four and a half, five hours a day.

   20. PAPeter Attia11:26

       Yeah.

   21. ISIñigo San-Millán11:26

       Yeah. So something like that. Yeah.

   22. PAPeter Attia11:27

       It's about, it's, it's about 100-hour race.

   23. ISIñigo San-Millán11:30

       Yeah.

   24. PAPeter Attia11:30

       And yet the difference between the first, second, third guy will be, in some cases, seconds.

   25. ISIñigo San-Millán11:35

       Yeah.

   26. PAPeter Attia11:35

       In some cases, a few minutes. For someone to win by five minutes is considered a blowout. And it, and, and so what it really tells you is that there are a handful of minutes in that race, there are a handful of climbs and time trials that set apart the winners from everybody else. And that's, to me, that's one of the beautiful things about cycling physiology, is you have these metrics, and now I think it's not just FTP, it's watts per kilo with, at lactate production. So it gets even more into kind of the, the critical physiology of recovery.

   27. ISIñigo San-Millán12:09

       Yeah. And in fact, we use these metrics a lot, um, uh, for the competition, and we, we did it this year at the Tour de France So knowing, uh, the power output that he could sustain for, as, as you very well said, for specific times, um, um, and, and climbs, we knew his capabilities. And one of the things that, uh, we, we, we knew was that, uh, in the Alps, he was at a very, very high level. So, uh, you know, like that famous stage where he broke away in Col du Romme, uh, 35 kilometers to the finish line, we are seeing not only his data, but we see by knowing our riders' data, you can also guess the other riders' data too, right? Um, uh, it's not rocket science.

   28. PAPeter Attia12:56

       Right.

   29. ISIñigo San-Millán12:57

       So we knew that he was at a very high level, um, in discussing the tactics, you know, 'cause it's part of the thing that we do. We, we observe the data that we have, uh, the data that we think the other ones have, and we, we, we structure a, a str- strategy for the next day, and, "Hey, does he have the legs to attack? Uh, should we be holding back or what should we do?" And clearly it was like, well, tomorrow if, if he attacks 35 kilometers to the finish line, he's gonna get there with three minutes 'cause the other guys, they're not at that level, you know? So why wait to the end of the tour when we can try to solve the situation? So w- we knew his capabilities very well, and discussing this with him and the, and then the manager, um, yeah, that was the, the, the, the, the strategy. First test the legs, and like, uh, if he had in fact good legs, boom, try, go, go for it, and that's exactly what he did.

   30. PAPeter Attia13:49

       Now, how much of that are you gonna determine after a night of sleep, right? Where you say, "We're gonna look at his resting lactate first thing in the morning. We're gonna look at his heart rate overnight. We're gonna look at his heart rate variability overnight." So in addition to the subjective, for example, how he felt during the previous day's attacks, coupled with some of that objective data, does that partially formulate the strategy also, or is it mostly based on historical data from training where you say, "I know that when he's at this many watts per kilo for this many minutes, he has the capacity to recover"?
4. 17:20 – 26:06

   The impact of performance-enhancing drugs and the potential for transparency into athletes’ data during competition

   1. PAPeter Attia17:20

      day."

   2. ISIñigo San-Millán17:21

      Mm-hmm.

   3. PAPeter Attia17:22

      You know, one of the things I wanna ask you about here, uh, and you've spoken about this publicly, so it might be that you're just gonna restate the views that you've shared publicly. Um, but [clears throat] I've always felt that now that we have such great transparency from the sort of that high octane era of sort of the maximum probably cheating in cycling, which, you know, in my view is kind of that two decades of the '90s and 2000s, and we, we pretty much know now what kind of numbers cyclists were putting out when they were being assisted by EPO and blood transfusions, and we sort of know that the best of the best were able to put out somewhere between about 6.8 and 7.1 watts per kilo, uh, at FTP. We also know today that cyclists are not doing that, right? Those numbers are nowhere to be found in the Peloton. Now that's, that's information you and I share confidentially, right? That's not public knowledge, but I know it, you know it, and anyone coaching people at that level know that nobody's putting out 7.1 watts per kilo. You don't need to be at 7.1 watts per kilo to win The Tour today. You could probably win The Tour today at 6.1 watts per kilo. Do you think that making that data public would put to rest a lot of the criticisms that say the sport is still, you know, it- they've just found new ways to cheat, but it's still basically a dirty sport? Because I, I think when you look at the data objectively, it would be very hard to say that today based on what we know from the era when drug use was rampant.

   4. ISIñigo San-Millán19:05

      No, I think you make a very good point. Uh, and, and it's something that, uh, yeah, it, it fru- it, it, it frustrates me, right? When, when people think that they're doing seven watts per kilogram, you know, or 7.2, you know. Um, and then you have the real data from the day. Um, and this is way lower. You know, you see like, you know, for example, like the, the short climbs where they would do maybe 7.2, now they're doing 6.3 maybe. And the longer climbs, uh, they're doing 5.5, 5.8. Um, so it, it fru- it fru- frustrates me 'cause I see this data and like, and I always like, "Gosh, I wish I could just, boom, release it." Um, and I, I, I, that... I have, I have absolutely no problem. Uh, I know Tadej has no problem with that. It is more that, uh... And, and we debated it with the team. Let's do it, you know? Like, uh, why, why keeping all this? At the end of the day, people can figure th- that out. Uh, uh, and some people, what I, what I see on internet, 'cause you can see the po- uh, you know, like the weight of the cyclist, uh, the, um, uh-

   5. PAPeter Attia20:11

      The grade of the climb

   6. ISIñigo San-Millán20:12

      ... the grade-

   7. PAPeter Attia20:13

      The gra- yeah, yeah

   8. ISIñigo San-Millán20:13

      ... when it starts, the time, um, and the wind, you know. You can be very accurate at knowing that. And, and, and I, and I see some people are quite accurate, internet, but I see other ones are all over the map. You know, otherwise they say, "I, I did the formula and it's 7.2." Like, my gosh, I wish I could show him, "Hey, this is the real data that we're seeing." But I, I, I guess like two m- two points there is like, one, u- um, it's, um, um, private data that the team considers, like not release it. That's, that's team policy. But the other one too is like, you know, even if you release that data, there are always gonna be people that are not going to believe you, or they might say, "Oh, they, they probably altering the data."

   9. PAPeter Attia20:56

      Mm-hmm. Yeah. Well-

   10. ISIñigo San-Millán20:57

       Or, or they're, they're tricking it somehow, you know, or putting more weight to the data so it looks like there's less power output. And I, I do- and I don't know if it's, it'll be an endless fight, you know? Um, uh, but I don't know. It's, I, I don't have the answer. Uh, I just, I just have that frustration that I wish that I could really show the data and, and people can, can see it, you know? But, but, uh, but I'm, there's always gonna be someone who not gonna believe it and gonna make a lot of noise out of that. Um, but, um, yeah. [laughs] But the other, that's the other thing too, is like other teams and other riders are, are releasing their data, right? So by releasing their data, you can see pretty much where, where Pogačar is. You know, like, okay, if he's a minute ahead or 30 minute seconds, or sometimes with the same time, you can see, you know, like, whoa, if whatever the rider has done and has entering Pogačar's group or, or 30 seconds later and has done 5.9, uh, Pogačar is gonna be in that neighborhood, right? Not gonna be seven, you know, with 30 seconds ahead.

   11. PAPeter Attia22:01

       You know, in the spirit of releasing data, the other thing it would potentially do, especially if you could see it in real time, I don't know if you watch Formula 1, but one of the things about Formula 1 that I think the sport has been able to do because of the ad- advances in technology is make more of the data available to the viewer. So if you're watching Lewis Hamilton driving a lap, you know, you see what he sees now. You can see, and it's not-

   12. ISIñigo San-Millán22:29

       Yeah

   13. PAPeter Attia22:29

       ... like the end of the world data, but you see his speed, you see what gear he's in, you see the difference between throttle and brake pressure. Uh, they could show even more data certainly, and someone who drives-

   14. ISIñigo San-Millán22:39

       Sure

   15. PAPeter Attia22:39

       ... would appreciate it if you really saw brake bias and if you saw brake pressure and lockup and things like that. And you can hear the drivers speaking with their race engineers. So, you know, it basically allows you to come more and more into what they're doing. This year they introduced a new camera angle, which is what the driver sees, and I think it's fantastic because historically you see above them and it looks so smooth, but that's not at all what it feels like to be in a race car. So now they just literally put like a camera at their shoulder, and now you see how restrictive the halo is.

   16. ISIñigo San-Millán23:12

       Yeah.

   17. PAPeter Attia23:12

       You see the bumps-

   18. ISIñigo San-Millán23:13

       The bumps, right

   19. PAPeter Attia23:13

       ... and it looks a lot faster. You know, I've had this discussion with a number of people, which is if you could show the same sort of information in cycling, if every time the camera went over to a cyclist, you saw their heart rate, their watts per kilo, their speed, you know, all of these other things, and you could hear some of the communications back and forth with their teams, yes, that changes the sport. Strategically now you have to be careful what you say on the radio. But it also allows you to see kind of the human element of this sport a little bit more. Do you think that will ever happen, where you'll be able to flip on the Tour de France and you'll be able to actually see real-time physiology?

   20. ISIñigo San-Millán23:55

       I would love to see that, that day. I would love it, uh, because I, I, it, it would be so much fun, right, for the, for the viewer and, and as you see, I mean, cycling has so many possibilities, you know, for, for, to engage people more and, and, and, and be fascinated by the physiology in looking at these numbers. Um, uh, you know, there, there's this, um, the, the, it's already in a way, you know, you see some cameras already installed in the front and the back So it's called with Velon, right?

   21. PAPeter Attia24:24

       Mm-hmm.

   22. ISIñigo San-Millán24:24

       So you can see really cool when that, I mean, images when they're preparing a sprint that is like what, what feels inside. And you can see it's really scary. Sometimes you can appreciate how difficult it is to, to be at, you know, like a 40 miles an hour, uh, uh, sprinting or, or 35 miles an hour leading to a sprint or, or in a descent at 60 miles an hour.

   23. PAPeter Attia24:45

       Or a 70 mile an hour descent.

   24. ISIñigo San-Millán24:47

       Or 70 mile an hour descent.

   25. PAPeter Attia24:47

       Right.

   26. ISIñigo San-Millán24:48

       Exactly. And then you can see the power also, uh, output in real time. Uh, um, it, it's still in that... I, I think it's a great step. Um, uh, you don't see all the riders, uh, uh, but it's estimation only the riders who wear that Velon or that Velon decides to do that. And I think that they're still not doing that with all the top contenders. But I think it's a first step and, and, and obviously haven't spoken with them, but maybe it's like, "Hey, let's, let's see, let's see what's, what's the feedback." And I think that people are loving it. And I, and I would expect that this will increase, you know. And, and I mean, I would love at some point, you know, and as you know very well, the, the, in the world of biosensors, right, it's going to revolutionize sports where we're gonna be able to see, you know, so many different parameters of athletes in real time.

   27. PAPeter Attia25:38

       Yeah. Imagine you could see lactate and glucose in real time.

   28. ISIñigo San-Millán25:41

       Yeah. Absolutely.

   29. PAPeter Attia25:42

       Which of course is technologically feasible already. So it's just a question of-

   30. ISIñigo San-Millán25:45

       Exactly. Yeah
5. 26:06 – 29:58

   Tadej Pogačar’s race strategy and mindset at the Tour de France

   1. PAPeter Attia26:07

      So last thing on the, on the Tour. Um, talk to me about Ventoux this year. What, what, that was a, that was a tough stage. Um, also, uh, I mean, kind of showed, it, it looked like his toughest stage. Was that, is that a fair assessment?

   2. ISIñigo San-Millán26:22

      Yes, probably. Yeah.

   3. PAPeter Attia26:24

      And, and what's amazing I think is the poise on that stage. Um, it, uh, it's hard to tell if he was really struggling on the ascent of Ventoux or he was just deciding strategically, "I'm going to conserve a little bit of energy here." What, what was your take on that or what can you say about that?

   4. ISIñigo San-Millán26:39

      Well, it was, it was a very, uh, difficult climb, um, and, and a very long climb. So, um, you know, Tadej, his mentality is wired, you know, like a champion. And, and, and he, when someone goes, and they were full gas in the last part when, uh, Vingegaard attacked and, and, you know, Tadej knew that, okay, it, this is, this is not gonna be the, the top of Mont Ventoux is not gonna be the, uh, the end of the stage.

   5. PAPeter Attia27:05

      Right. "I have a long descent where I could make it up."

   6. ISIñigo San-Millán27:07

      It's a very, very long descent.

   7. PAPeter Attia27:09

      Yeah.

   8. ISIñigo San-Millán27:09

      And, and I have some partners with me, you know, that they can help me out. Uh, so I'm not gonna panic at all, but I'm not going to also try to, uh, uh, waste a lot of energy, um, 'cause I need to now be, I have-- And he also had a big, uh, gap, you know. Uh, the, a whole different thing would've been if he had 20 seconds. But having a big gap and knowing that you have a big descent and how calm he is, uh, that's one thing that, um, is a very important strategy. And, and this is pro- You know, this, this is what happened. Um, I, I have, uh, you know, this reminds me in a way what happened the first year that he was pro when he was 19 at the Tour of California. Um, uh, it was the, the previous stage before, um, um, [lip smacks] what's it called? Bear Lake. No, what is the mountain? Bear Lake. I think it's Bear Lake. Yeah. It's the, it's the top mountain, right, in, in the Tour of California, uh, where it's gonna be de- decided. So the day before, uh, two cyclists, George Bennett and Higuita attacked in a, in a short but very steep climb. Um, and there were only like 12 riders left, and Higuita and Bennett attacked. Uh, then there was like a descent and a long highway all the way to the finish line. So there was plenty of time to, to ca- to catch them up. But, um, Tadej didn't follow them up. You know, another rider would've just followed their wheel. And Tadej decided, "Nope, I'm not gonna follow them. We have time, and I'm gonna take the chance, uh, uh, 'cause I'm confident for tomorrow." And, and, and, and when I asked him, like, uh, as, as soon as he crossed the finish line, I'm asking, "Are you okay? Uh, why, why did you, why you didn't, um, um, follow the, their attack?" And he said, "Well, I, I just wanted, uh, I wanted to know who is going to be good tomorrow. So I know those two guys are gonna be good tomorrow, but I wanted to take my time and see the other 10 guys, how they're breathing, what's their body language, and, uh, take my time to observe, uh, to, to start preparing my strategy for tomorrow." And in fact, that's what he did. Um, so they were then caught up, you know, like two, three kilometers to the finish line. So all those 12, 13 guys, whatever they were, they got together. And the next day, in fact, he knew these, those two guys attacked. He just followed them, and he just eliminated one by one. But, uh, uh, that, that's what, that's how this guy thinks, you know. Uh, his strategy, like no panic. Plenty of time today. I have a good gap, uh, in the GC. Why am I gonna go full gas, uh, when I know that he's going to go full gas and, and he might lose energy for tomorrow, uh, f- because he might pay for this at this time of the, of the Tour de France, and we have plenty of time to, to, to catch him up. Um, so that's kind of the strategy that he had, too.

6. 29:58 – 40:04

   Defining Zone 2, fat oxidation, and how they are measured

   1. PAPeter Attia29:58

      How much time does someone like Tadej spend in Zone 2, which we're gonna talk a lot about, right? So, um, and let's do it more as percentage of training time, 'cause I think absolute numbers will be very large given [chuckles] that that's his job. But when you think about the percentage of time he spends in that energy zone How does it change over the course of the year? So presumably during the winter months, a greater amount of his time would be spent there as he's base building, uh, right before a race when he's kind of sharpening, maybe less. But what would be the range of time?

   2. ISIñigo San-Millán30:37

      Yeah. No, that's a-

   3. PAPeter Attia30:37

      Or percent rather. Yeah. Yeah

   4. ISIñigo San-Millán30:38

      ... great question. So yeah, when-- And you're right, when, when we talk about percentages, it's more... I, I, I like to, to put it this way, more like a percentage of days dedicated, you know, to cultivate that energy system.

   5. PAPeter Attia30:50

      Mm.

   6. ISIñigo San-Millán30:50

      Right? Um, obviously, if you put in, in just every single minute together, right? [exhales] The ma- you know, like, uh, the majority is gonna be that, right? But I would say more in days. Um, uh, so, and then the, you know, so yeah, in, in the winter months might be about 80%-

   7. PAPeter Attia31:09

      Wow

   8. ISIñigo San-Millán31:09

      ... of the, of the, of the, uh, 70% to 80% of the days. As the season gets closer, he starts increasing more the intensity days and sessions, and then just, you have, you start the season. So, uh, when you start the season racing, and you have... It depends, right? You, you might have one, one stage race of, uh, five, seven days, and then you have a five-day block or one week to recover, and then you have the next stage race. So in that week, we do a lot of recovery. We might do some sessions here and there. Um, and then, uh, after a, a few blocks of, um, um, races, that's where you have another long time to train, period to train, uh, going to altitude towards the Tour de France or, or towards the next, uh, goal, and that's where you may revisit, you know, uh, those, those, these different energy systems and, uh, and train specifically. But, uh, but yeah, we, we, we alternate and, and, and I think each, each, each energy system has a time in the year and, uh, in the calendar where it's built, um, in order to try to achieve what we want.

   9. PAPeter Attia32:19

      So let's remind people now w-with this, you know, uh, I've put out a few posts on social over, gosh, the past year and even in the past little while, and anytime I'm talking about zone two, it's really one of the topics that generates the most curiosity, the most, the most inquiry from people. I think people really intuitively kind of resonate with this. And then, of course, a million questions follow because there's, there's so much minutia and detail around it, and, and a lot of that we're gonna cover today. But let's start from a place of maybe someone hasn't heard the first podcast where we go through some of the semantics of this. Define zone two.

   10. ISIñigo San-Millán32:57

       Okay. [chuckles] Okay. So, um, zone two or Z2, right? Um, I, I started using it, like, about 25 years ago, um, and I just have a very simple, um, name, zone two. [chuckles] Um, it is, from my s- um, point of view, it is the exercise intensity at the one you are stressing the mitochondria and oxidative capacity to the most. Uh, this is where you're recruiting mainly type one muscle fibers. This is where you are mobilizing the highest amount of fat, um, both from lipolysis, from adipose tissue, as well from fat oxidation inside the mitochondria, the mitochondria. And this is also where, um, uh, you stimulate all those, uh, energy, that ener- that bioenergetics, which is, um, oxidative phosphorylation. This is where you burn, uh, both the, uh, um, fat ox- the fat inside the mitochondria as well as the glucose inside the mitochondria. There's not a very high glycolytic flux that, um, it's going to be transformed into pyruvate and reduced to lactate, but that flux still is, uh, oxidized inside mitochondria. And, uh, uh, this is, looking at from bioenergetic standpoint, this is what I would consider the zone two. And what I have seen is that, throughout the years, is that this is the exercise intensity that, um, um, achieves or, uh, stimulates that mitochondrial function and fat oxidation and lactic clearance capacity the most 'cause, um, that's the other thing too. This is where, um, there are other things involved in lactate. So lactate is a great fuel to the cells. It's, in fact, it's probably the preferred fuel for the cells, for most cells in the body. This is a work that my colleague and mentor and friend, uh, George Brooks discovered, right? Um, could have, you should have him someday in the podcast 'cause he's fascinating. I mean, he, he, I mean, I, I would not be surprised if someday soon we hear that, um, um, he, uh, he, he will, he, he wins the Nobel Prize. He's amazing guy. I... And, and every time I talk to him, I'm still learn a lot of things, and then I've been translating a lot of, of his research. But, um, but yeah, that, that's how I see that, uh, you know, you, you have, um, within the mitochondrial function, you see how lactate is oxidizing the mitochondria back to energy, right? So, um, and that happens at that, uh, i-in those muscle fiber types. Those muscle fiber types in, in the mitochondria, those fiber, fiber types also develop, um, these transporters which are MCT1s, which are the ones is the, that transport lactate inside the cell and inside the mitochondria. So when you stimulate that training zone, you stimulate all these energy systems and the components that come with them.

   11. PAPeter Attia35:56

       So let's talk about the different ways that one can go about estimating this. Based on the definition you've just given, it seems to me that the purest way to estimate this would be via indirect calorimetry because that will actually tell us the fat oxidation. Is that, is that a fair assessment?

   12. ISIñigo San-Millán36:16

       Yes, it's a very good assessment. And, uh, and, and, and that usually, exactly, that, that, that usually correlates with the, uh, uh, the fat max. That's how we, we call it too, right? The, uh, with, with fat oxidation. And wh-when you see there's You start oxidizing fat and might increase in many cases, and gets to a point that is, uh, it max out, which is the fat max, and then it, it starts going down sharply, right? As exercise intensity increases.

   13. PAPeter Attia36:44

       So, so let's tell people how that's measured, 'cause I think it's, um... We do this with all of our patients, um, and I find it to be not that easy to explain because there's some physiology involved and there's some math involved. But l- let me try to see if I can explain this to folks. So, uh, you know, you, you hook me up to an indirect calorimeter.

   14. ISIñigo San-Millán37:07

       Mm-hmm.

   15. PAPeter Attia37:07

       So you're gonna put a, a little plug on my nose. You're gonna put a, um, a, a mask over my nose and mouth. That mask has the ability to measure the amount of oxygen that I consume-

   16. ISIñigo San-Millán37:20

       Mm-hmm

   17. PAPeter Attia37:20

       ... because it has a sensor for O2, so it knows that the O2 that's coming in is at 21%. The air is coming in at 21% O2, and whatever I exhale is the difference between that. So you can now tell how much O2 was consumed, and you can have a similar sensor for carbon dioxide, so you know how much carbon dioxide is produced. So it's very easy to measure consumed oxygen and produced carbon dioxide, provided you can completely isolate around the nose and the mouth.

   18. ISIñigo San-Millán37:49

       Yeah.

   19. PAPeter Attia37:49

       As you hook a person up to some form of ergometer, usually a bike, but could be a treadmill, a rowing machine, or something like that, you can increase the demand on the muscle. So you increase the wattage or the speed or the something.

   20. ISIñigo San-Millán38:04

       Mm-hmm.

   21. PAPeter Attia38:06

       You then get out these numbers, VO2 and VCO2, which are what we just talked about. So consumption of oxygen, production of carbon dioxide. These numbers fit into a relatively straightforward linear equation called the Weir equation, and it tells you three things. It tells you total energy consumption in, uh, kilocalories per minute.

   22. ISIñigo San-Millán38:30

       Mm-hmm.

   23. PAPeter Attia38:31

       And then the ratio of VO2 and VCO2 tell you how much of that energy is coming from fat oxidation and how much of it is glycolytic.

   24. ISIñigo San-Millán38:42

       Yeah.

   25. PAPeter Attia38:42

       So at any moment in time, you can look at a VCO2 and a VO2, which are usually measured in liters per minute, and you can convert that into a total grams of fat oxidation and a total grams of glucose oxidation per minute.

   26. ISIñigo San-Millán39:02

       Yeah.

   27. PAPeter Attia39:02

       And so you could then plot on the X-axis work or power, and on the Y-axis you could plot fat oxidation.

   28. ISIñigo San-Millán39:13

       Mm-hmm.

   29. PAPeter Attia39:14

       So, n- again, describe for people what the shape of that curve looks like and what differentiates Pogačar from the average human being.

   30. ISIñigo San-Millán39:24

       Yeah. So a- again, I mean, y- you explained it very well. Uh, and, and, yeah, those are based on, uh, stoichiometric equations based on the, uh, how, uh, the combustion of carbohydrates and, and, and, and, and fatty acids are, are done in the body. Um, this, um, um, already in the 1920s, uh, Francis Benedict was the, the-- one of the first ones who, probably, probably the first one who started to, to look into this at, at, at this level. Um, and o- obviously we have evolved, uh, into, um, do it in a more automatic way, right? With these indirect calorimetries machines or called metabolic carts, right?

7. 40:04 – 44:30

   Using fat and carbohydrate utilization to calculate the mitochondrial function and metabolic flexibility

   1. ISIñigo San-Millán40:04

      So yes, uh, um, as exercise intensity increases, you start, um, y- you, you oxidize... I mean, you need more oxygen, right? So your VO2 increases, and then you produce or give up, uh, more CO2. Um, so this is kinda what it shows. Uh, when you're in a more, um, lipolytic state, uh, more, more fatty oxidation state, uh, you, you, you still consume oxygen, but you do not produce as much CO2, right? Uh, when you are more into a more glycolytic state, which is higher exercise intensities, uh, when you're, um, recruiting the Type 2 muscle fibers and therefore using more glucose for energy purposes, uh, you're going to consume more oxygen and you're gonna produce more CO2, right? So plug in all these numbers into the stoichiometric equations. It's going to give you that profile, right, in the X, uh, and the Y-axis, and it's gonna see what is the, um, the fat oxidation throughout a ramp state, uh, a ramp test. And this is where you're gonna see that, um, elite athletes like Pogačar, they have an amazing fat oxidation capacity compared to other competitive athletes or recreationals or, or people with even, uh, um, um, uh, type 2 diabetes or metabolic syndrome or in a recent study we, we have published with, uh, COVID patients. So, so it reflects in a way, uh, uh, ultimately what happens in your mitochondria and how the mitochondria oxidizes those fuels at different exercise intensity. So for example, let's say at, at, at an intensity of, uh, uh, 200 and let's say 200 watts, like an elite, elite athlete, uh, doesn't need to incur in that glycolytic capacity as much as someone who is not very well trained. So the elite athlete, they can still recruit the, uh, slow twitch muscle fibers and rely a lot on fat, you know, to produce ATP because they have an amazing mitochondrial function, and they don't re-- and they're very efficient metabolically speaking. Uh, therefore, they're gonna be oxidizing a lot of fat. However, someone whose mitochondria are not working as well, uh, whether you are like a recreational athlete or, or sedentary individual or someone with type 2 diabetes, uh, which is one of the hallmarks of the disease, that mitochondrial impairment or dysfunction at 200 watts. Uh, uh, you fully rely on, on glucose pretty much because, you know, you cannot sustain that effort, uh, with, with, with fat alone. And, and this is what you're going to be seeing, this gas exchange, the CO2 and the VO2, and you can just plot it into the equation, and it's going to give you all that, um, um, uh, what I call metabolic map, where, where you see the, the fat oxidation, the, the carbohydrate oxidation, and then I plug in also the lactate, and that's where everything comes together quite well. And you can then first, in an indirect way, calculate the mitochondrial function and metabolic flexibility, how flexible they are at using fats or carbohydrates, and also you can determine training zones. And this is, this is what I, I, I've been using this methodology for, for about 16, 16 years, 17, something like that.

   2. PAPeter Attia43:42

      I didn't think to ask you this earlier, but if you have it handy, do you wanna pull up a graph of what fat oxidation looks like versus power so that people can see the difference between a highly trained individual, a, you know, a reasonably trained individual, an untrained individual, and at the other end of the spectrum, somebody with type 2 diabetes?

   3. ISIñigo San-Millán44:05

      Sure. So, uh, let me share screen then, right? And hopefully this works. Okay. So this is from a, uh, a publication, right, uh, that my colleague George Brooks and I published in 2017. So this i- this is, uh, uh, the formula, and, and we, we have realized that this is flipped, so we need to [chuckles] send a n- um, we're working now with the editor to change it because the formula is flipped here

8. 44:30 – 59:54

   Lactate levels and fat oxidation as it relates to Zone 2 exercise

   1. ISIñigo San-Millán44:30

      in the method, in the method section. [chuckles]

   2. PAPeter Attia44:32

      Which is so funny, by the way. I like seeing that. I, I, you know, I, I'm embarrassed to say when we do this for our patients, we do it in two steps, which yields the same result, but we in- we first calculate energy expenditure-

   3. ISIñigo San-Millán44:44

      Mm-hmm

   4. PAPeter Attia44:45

      ... using the Weir coefficients of 3.-

   5. ISIñigo San-Millán44:47

      Mm-hmm

   6. PAPeter Attia44:47

      ... point nine four times VO2 minus, uh, or one plus one point, I think it's one two times VCO2. And then we convert that to fat ox and carbohydrate oxidation using the ratio of, uh, VCO2 to VO2, and I never even thought to do what you've done here, which is so much more logical, which is combine them into a single equation for each.

   7. ISIñigo San-Millán45:12

      Well, we use what, what Fryan, uh, observed already n- in 1983, uh, and this is... it's Fryan's equation. Um, and, and it's been validated with, uh, tracers, with, uh, stable isotope tracers, and, uh, yeah, and, and, and, and that's what it shows. Uh, there's a very high correlation. Now, furthermore, in, um, in a study that we, we were gonna be publishing soon, we have validated this, um, um, fat oxidation and carbohydrate oxidation directly with mitochondrial respiration. So in muscle biopsies, we inject, um, uh, directly, uh, fatty acids, uh, pyruvate, representative of carbohydrates, right, and, and, uh, glutamine, representative of, uh, amino acids, and then we can see that there's a very high correlation between this, this indirect methodology, uh, to look at mitochondrial function and the direct methodology, which is through muscle biopsy and, and injecting the substrate-

   8. PAPeter Attia46:09

      Yeah

   9. ISIñigo San-Millán46:09

      ... and see how it's oxidized, right? So beautiful-

   10. PAPeter Attia46:11

       So these two graphs are really powerful. So let- let's, let's talk-

   11. ISIñigo San-Millán46:15

       Yeah

   12. PAPeter Attia46:15

       ... about what the first graph is showing us. The first graph-

   13. ISIñigo San-Millán46:18

       Yeah

   14. PAPeter Attia46:18

       ... is... so both of these graphs, it's important to note, have the same X-axis.

   15. ISIñigo San-Millán46:23

       Mm-hmm.

   16. PAPeter Attia46:23

       In other words, the independent variable here is the-

   17. ISIñigo San-Millán46:27

       Yeah

   18. PAPeter Attia46:27

       ... workload in watts. That's the metric that matters in cycling, which is, I think, the easiest way to do this test.

   19. ISIñigo San-Millán46:34

       Mm-hmm.

   20. PAPeter Attia46:34

       And so you're increasing wattage. This is a progressive increase in workload.

   21. ISIñigo San-Millán46:39

       Yes.

   22. PAPeter Attia46:40

       And, and what you're plotting on the Y-axis, your dependent variable here-

   23. ISIñigo San-Millán46:44

       Mm-hmm

   24. PAPeter Attia46:44

       ... in the first graph, figure one, is blood lactate.

   25. ISIñigo San-Millán46:48

       Mm-hmm.

   26. PAPeter Attia46:48

       So, um, what stands out to me is a couple of things. So you have, uh, the triangles represent metabolic syndrome, the squares represent kind of a modestly trained athlete, and then the little diamonds represent a professional athlete.

   27. ISIñigo San-Millán47:04

       Mm-hmm.

   28. PAPeter Attia47:05

       The first thing that stands out to me, and we're gonna talk about this later, so I'll put a little pin in this, is that the people with metabolic syndrome have a resting lactate that's almost two millimole.

   29. ISIñigo San-Millán47:15

       Mm-hmm. Mm.

   30. PAPeter Attia47:16

       Yeah?
9. 59:54 – 1:06:27

   How moderately active individuals should train to improve metabolic function and maximize mitochondrial performance

   1. ISIñigo San-Millán59:54

      there. I don't know if it makes sense.

   2. PAPeter Attia59:55

      So, so, no, it, it completely makes sense, and this is definitely the level of nuance that I, I don't think we captured in the first podcast. And I, and I wanna now ask, uh, a more telling question specifically for the middle person here, so the, the one that's called the moderately active individual, where again we have a disparity, right? So based on these data, the moderately fit individual hits a lactate of two millimole at 175 watts, [lips smack] but hits a max fat oxidation at, gosh, 125 watts. So it's a 50 watt difference. So now the question for you is, when that person comes to you and says, "Iñigo, I want to improve my metabolic function, I want to improve my mitochondrial performance, I want to improve my fuel partitioning, my flexibility," all the things we talk about Are you going to train them as a Zone 2 of 125 watts or as a Zone 2 of 175 watts as represented by these deltas?

   3. ISIñigo San-Millán1:01:00

      That's a very good question, and normally I would try to do something in the middle. Normally, and again, th- this, this, um, yeah, it, it, it might not coincide perfectly, but normally they, they, they, they do, they do quite well. And, and, and another parameter that if, if, if you allow me, I can show you in this paper, this is what when decided we see individually, right, the lactates.

   4. PAPeter Attia1:01:25

      Yes.

   5. ISIñigo San-Millán1:01:25

      And then we see the fat oxidation. But there where I decided to, to cross them over, right? And this is, this is what we saw in this graph over here. Uh, we're gonna... Yeah. So this is... Can you see it okay?

   6. PAPeter Attia1:01:38

      Yes.

   7. ISIñigo San-Millán1:01:39

      So this is where you see the, the, the lactate versus, I mean, sorry, the lactate versus the fat oxidation.

   8. PAPeter Attia1:01:46

      Mm-hmm.

   9. ISIñigo San-Millán1:01:46

      Right? In the, uh, elite athlete, and the R is, uh, 0.97. Um, uh, this is through Bonferroni equation, so this is an average, right, of all of them. Um, and this is where you see the same, uh, pattern, uh, the same graph for the moderately active, and this is also what you see in the, um, people, person with metabolic syndrome. The correlations are very, very strong. They're almost perfect, right? So this is what normally fat oxidation and, and, and, and, and, and lactate, they go together, right?

   10. PAPeter Attia1:02:21

       So for people who are gonna be listening to this, Iñigo, and not able to see what we're seeing, can you describe the differences between these graphs? These are obviously showing the same data that we discussed earlier, but now we're using two Y-axes. So let's even just talk about it as looking at the elite athletes.

   11. ISIñigo San-Millán1:02:41

       Mm-hmm.

   12. PAPeter Attia1:02:41

       So you're basically plotting the decline in fat oxidation, or in their case, the initial increase in fat oxidation followed by a decline in flat, fat oxidation, and on the same graph you're showing the increase in lactate production, again, both plotted to the same X-axis of power. Does the, does the cross point here indicate any significance? So they're crossing at about 325 watts. Is there anything about that that means anything? I mean, to me, I think it's an artifact of the graph because it's really just a function of how you scale it, correct?

   13. ISIñigo San-Millán1:03:16

       Yes. Yeah, exactly. I mean, it shows to me that, yeah, the crossover point for blood lactate and fat oxidation, it's, uh, very high obviously in the elite athletes, very far to the right. Um, it's-

   14. PAPeter Attia1:03:29

       Right. So and then of course in the moderately fit people it's, looks like it's closer to 100 and maybe 80 watts.

   15. ISIñigo San-Millán1:03:36

       Exactly.

   16. PAPeter Attia1:03:36

       And in, and in the unfit individual it's about 125 watts.

   17. ISIñigo San-Millán1:03:40

       Exactly.

   18. PAPeter Attia1:03:40

       A person with metabolic syndrome.

   19. ISIñigo San-Millán1:03:42

       Yeah. And again, I mean, if we, if, if you started, and I'm sure you have seen this, but if you started with the metabolic syndrome, for example, at, at 25 watts, you might see... Or, or in, even in the recreational athlete even earlier, you might see a similar pattern as you would see in the elite athlete, but a much lower watts obviously. It is that, um, we, we just did the same protocol for everybody, uh, just to show the concept, right? Um, that, um, you know, both fat oxidation and, and lactate go together. And also when we look into, and I'm sorry, I should have gone this to this directly. When we look into fat oxidation and carbohydrate oxidation, we see the same concept, right? So we see as exercise intensity increases, you need to oxidize more carb- carbohydrates. Um, and then as exercise intensity increases, you might get to the fat max, and then when the moment you switch to the glycolytic fibers, uh, you cannot use much fat for en- uh, energy purposes. So you see a, a, a sharp decline, and eventually fat oxidation disappears. Um, and it's all through glycolytic, and the same pattern we see in the rest of populations with also very high, um, uh, statistical significances and correlations. Um, so that, that's where like all these elements, fat oxidation, carbohydrates, and lactate, they're very well connected. Um, if we look in the other graph, this is the correlation between lactate and carbohydrates, right? We see that overall the correlations are quite good because yeah, lactate is the byproduct of, of, of, of, um, um, glucose utilization, right? You may see that in the elite athletes though, the gap is wider here, and this is for the same reason that we've seen earlier. They use a lot of glucose.

   20. PAPeter Attia1:05:32

       They're using so much of... They're using so much fat there as well is really the point, right?

   21. ISIñigo San-Millán1:05:36

       Yeah.

   22. PAPeter Attia1:05:37

       So the bigger the gap between the blood lactate curve and the carbohydrate oxidation curve, the more efficient the individual is.

   23. ISIñigo San-Millán1:05:44

       Yes.

   24. PAPeter Attia1:05:44

       The more they're able to oxidize fatty acid than they have to require glucose.

   25. ISIñigo San-Millán1:05:50

       And clear lactate.

   26. PAPeter Attia1:05:52

       Yes.

   27. ISIñigo San-Millán1:05:52

       'Cause, uh, again, the mandatory byproduct of, of glucose oxidation is, uh, uh, lactate. So here the lactate doesn't show up in the blood. It stays in the muscle.

   28. PAPeter Attia1:06:03

       Yeah, that's interesting. It's, it's, it's, it's hard to disentangle those two because you, you mention a good point that I omitted. This in part reflects the lactate shuttle.

   29. ISIñigo San-Millán1:06:14

       Yes.

   30. PAPeter Attia1:06:14

       This in part reflects the ability for them to reuse lactate as a fuel as opposed to just letting it get out there with hydrogen and start to poi- poison sarcomeres.

10. 1:06:27 – 1:19:19

    Bioenergetics of the cell and what is different in elite athletes

    1. PAPeter Attia1:06:27

       So let, let me see the, the other slide that you, you wanted to show that explains I think how the, um, MCT transporters work.

    2. ISIñigo San-Millán1:06:35

       Yeah. So this is a little bit more of the, the, the, the bioenergetics of the cells, of the main two, uh, um, um, substrates, which are fatty acids and lactate, I mean, and pyruvate, and also lactate, right? So normally glucose goes through glycolysis and it ends up... And this is, this is the cytosol. This is the outside of the mitochondria, the inside of the cell. Uh, and glucose once it's, when it, it enters the glu- the, the cell, it's, uh, oxidized to pyruvate. That pyruvate needs to enter the mitochondria Through what's called a mitochondrial pyruvate carrier, and it's oxidized to acetyl-CoA, which enters the Krebs cycle. Right? This is a complete oxidation of, uh, glucose through oxidative phosphorylation in the Krebs cycle and electron transport chain. Then, uh, fatty acids have the same mechanisms to, uh, I mean, g- g- I mean, they also get converted to acetyl-CoA, but through different mechanisms. Fatty acids are transporter, uh, through CPT1 and then CPT2, go through beta oxidation, acetyl-CoA, and enter the cell, right? But every time that you use glucose, um, um, you produce pyruvate, and every single time that pyruvate is gonna be reduced to lactate, always. Right? And, uh, and this is the key concept. So, uh, when you have a, a constant glycolytic flux, right, uh, you're going to, in, in one of the steps of glycolysis, you're going to utilize NAD, right? Um, and it's going to be, uh, transformed to NADH plus, um, hydrogen. So if you use this mechanism a lot, you're going to replenish NAD. I mean, you're gonna deplete NAD. The only way that rescues NAD is the reduction of pyruvate to lactate, which replenishes NAD going back for glycolysis, and this is absolutely necessary for the continuation of glycolysis. But anyways, and this was an aside note, but this lactate enters the cell, right, through a specific... I mean, the mitochondria through a specific transporter, MCT1, and has a specific enzyme, LDH, that, uh, um, um, oxidizes lactate back to pyruvate and going back to the, um, Krebs cycle. So again, this is an extra fuel, but for that, you need to have these, uh, transporters very well developed. Right?

    3. PAPeter Attia1:09:01

       Yeah, yeah. Let me, let me try to explain this to people who aren't able to see the graph, because this is such an important point, right? So you're showing a picture of, uh, the mitochondria, and you're-- we're looking at the outer mitochondrial membrane.

    4. ISIñigo San-Millán1:09:14

       Mm-hmm.

    5. PAPeter Attia1:09:14

       We're talking about three transporters, three things that let substrates from the outside to the inside, where they will undergo the most efficient form of ATP production. So the first is we have the fatty acids. They enter directly, and they undergo, uh, uh, an oxidation where they get truncated into little two carbon chains, and they enter the Krebs cycle. We, we get that one, and we know why that one's very good. Uh, what I think is very interesting here is when you contrast the two different fates of glucose byproducts. So the traditional way that we think about this, glucose being reduced to pyruvate, pyruvate directly entering the cell through its own carrier, and then being converted to acetyl-CoA, which follows the same fate as the fatty acid. [lip smack] Now, when energy demand increases, and we just looked at graph after graph that demonstrate that no matter how fit you are, at some point you have to produce more lactate.

    6. ISIñigo San-Millán1:10:18

       Mm-hmm.

    7. PAPeter Attia1:10:18

       So you now don't have sufficient cellular oxygen to go down that first route, so you start making lactate. But if you have enough MCT1 transporters on the outer mitochondrial membrane, you can now bring that lactate in the cell and actually do the reverse of what just happened. Turn that lactate back into pyruvate. Pyruvate becomes acetyl-CoA, and everybody wins the game again. The game being won, of course, because now you're making 32 units of ATP instead of just the two units you would make converting pyruvate to lactate. So it begs a very important question.

    8. ISIñigo San-Millán1:10:55

       Mm-hmm.

    9. PAPeter Attia1:10:55

       Which is, earlier when you spoke about what makes Pogačar so remarkable physiologically, one of those things is he must have a boatload of MCT1 transporters on his mi- outer mitochondrial membrane.

    10. ISIñigo San-Millán1:11:12

        Mm-hmm.

    11. PAPeter Attia1:11:12

        And that must explain, in part, why his lactate levels are so much lower than everybody else's at a comparable work level. How much of that is genetic, and how much of that is a result of his training?

    12. ISIñigo San-Millán1:11:26

        Exactly. So you're right. Uh, he has a, a much higher level to oxidize lactate, right? So there's a genetic component, no doubt about it. But, uh, there's also an epigenetic component, right? Um, and as we know nowadays, right, the genes are not your fate necessarily, right? Um, um, from the genes to, to be, um, um, able to, to, to be transcribed and, and, you know, and, and form a protein with biological action, uh, the, the, the, the probability is, is, is less than 20%. That's kinda what the science is showing, uh, roughly, right? Th- this is the whole from, um, uh, genetics to, um, uh, transcriptomics, pro- proteomics, and metabolomics, right? It's about 20% chances that one gene is gonna be ultimately expressed. Obviously, we're still on, trying to understand all this. So these elite athletes, probably they have a much higher possibilities, right? But there's a long journey, and this is where, uh, uh, epigenetics occur, right? It's like what you eat, how you rest, how you train, and I think that the training is, uh, an also an important component of this. Uh, uh, um, this is, for example, why we train, train very, very specifically this energy system, and we try to dial in as much as we can specifically to try to stimulate this bioenergetics system and in- in- increase the, the MCT1s, the transporters for lactate, as well as all the components in the, uh, Krebs cycle, right, which is the mitochondrial respiration. And also to, to increase also the mitochondrial pyruvate carrier, 'cause, uh, as, uh, we might discuss later, this is already dysregulated in people or downregulated in people who are sedentary. Right? But, um, but the, the, the thing is, like, if you see this next slide. Can you see it okay?

    13. PAPeter Attia1:13:20

        Yes.

    14. ISIñigo San-Millán1:13:21

        So this is, this is what, you know, uh, makes the difference in these athletes, right? So this is a fast twitch muscle fiber, and they use glucose. So this is when you're like a, a high exercise intensities, climbing or running at a high intensity, uh, or swimming or whatever the activity you do, you need glucose because, uh, glucose is, is, is, it, as you said very well, it yields less ATP, uh, but it does it much faster, right, than, uh, than, than, than the diesel gasoline, which is the, uh, the, the, the, the fat. So but when you use glucose, uh, uh, you're always gonna produce pyruvate. So that pyruvate, that, you know, the higher the intensity, the more glucose you need, the more pyruvate you will need, and the more lactate that you will produce. So that lactate has, as I said earlier, two routes. One route is like, it's exported through the MCT4s, which is the transporter of lactate outside the fast twitch muscle fibers. Uh, something that also is trainable, right? The, the capacity to export lactate through high intensity exercise. And then it travels to the adjacent-

    15. PAPeter Attia1:14:29

        Hmm

    16. ISIñigo San-Millán1:14:29

        ... uh, slow twitch muscle fibers. Uh, and, uh, if we blow up these, uh, uh, mitochondria in the slow twitch muscle fibers, this is what will happen. Uh, the entrance of that lactate, it goes through another transporter, so MCT1 is the same family, but instead of 4 it's, uh, it's called MCT1. And as I s- mentioned earlier, that lactate is converted to pyruvate and acetyl-CoA and goes into the Krebs cycle. So in these well-trained athletes like Pogačar, for example, uh, um, they have an amazing ability to oxidize the lactate inside mitochondria, right? At some point, every single human, uh, gets to a point that they cannot sustain the effort anymore, right? But what makes the, the, the difference is obviously is like these guys can do 400 watts for a long time versus a mere mortal who can not even do two strokes at 400 watts, right? So what happens is, like when you have a lot of... When you don't have a, the right MCT1 and mitochondrial function, uh, this lactate is going to ac- uh, increase and accumulate, right? And it's not lactate per se, but the hydrogen ions associated to lactate, uh, elicit an, um, um, acidosis of the microenvironment of the muscle, which is something that we know and we have learned also from cancer, the famous, uh, uh, cancer microenvironment, which is very acidic. And that's going to interfere with different functions in the muscle with both the, um, the, uh, uh, the, the, the contractual f- the contractive force and the velocity of the muscle fibers. Uh, I'm not saying that this is the cause of fatigue by no means because there are, there are multiple theories, and we're still trying to understand the central fatigue as well, and everything probably is interrelated or it must be interrelated. But the bottom line is, like when this lactate cannot be oxidized, it is exported to the blood. And this is why you see that people with metabolic syndrome, for example, or, or type 2 diabetes, who are characterized by having a very poor mitochondrial function, they cannot do an exercise, oxidize this lactate. In the moment they start using glucose, which is very fast also because they don't have the fast twitch mu- the slow twitch muscle fibers mitochondria to use fat. They need to rely on glucose. That's that metabolic reprogramming or partitioning they have. They produce lactate, but they cannot oxidize the lactate. That's why this lactate chooses mandatorily the route of being exported to the blood. And in the blood then it goes in, uh, to any tissue in the body. So this is what I meant earlier about what is two millimoles versus one millimole.

    17. PAPeter Attia1:17:01

        Yeah.

    18. ISIñigo San-Millán1:17:02

        Whereas Pogačar, for example, uh, he, uh, oxidizes a lot of this lactate. So by the time that Pogačar saturates this transporter and this mitochondrial capacity to oxidize lactate, it's a tremendous amount of, uh, uh, power output and a tremendous amount of glucose that he puts out. So this is why the, the one millimole or 1.5 millimole in, in, in, in, in a world-class athlete doesn't necessarily represent the same metabolic status of a 1 milli- 1.5 or two millimoles, uh, in the blood of a normal person. Does it make sense?

    19. PAPeter Attia1:17:36

        It makes complete sense. This is, this is a fantastic tutorial in, in muscle physiology. Um, and again, this very important distinction between, uh, lactate production at the, at the local level and lactate that we measure at the global level, right?

    20. ISIñigo San-Millán1:17:55

        Mm-hmm.

    21. PAPeter Attia1:17:56

        That's the challenge we have. When we are measuring lactate, we cannot impute lactate clearance and lactate production.

    22. ISIñigo San-Millán1:18:03

        Exactly.

    23. PAPeter Attia1:18:03

        We can only impute the sum of those.

    24. ISIñigo San-Millán1:18:06

        Exactly. And we think, I mean, or it's originally thought, right, that these athletes, they don't use as much glucose, right? Well, in, in fact, the research shows, and Brooks and his team showed it, that, uh, and others too, that the well-trained athletes, in fact, they use more glucose because they have to. You cannot do 400 watts without massive amount of carbohydrate oxidation. And this is what we also see in the indirect calorimetry that, you know, you see people, recreationals or people with metabolic syndrome, they have like four, uh, grams per minute at max carbohydrate oxidation, whereas elite athletes, they can get to six and a half-

    25. PAPeter Attia1:18:44

        Yeah

    26. ISIñigo San-Millán1:18:44

        ... right, grams per minute. It's massive amount of glucose. Uh, and they produce a lot more lactate. But the key is like they, it doesn't show up in the blood. It's the rate of appearance in the blood because it's oxidized in the muscle, so it doesn't show up in the blood. It's the, it's the balance of, of, of lactate production and lactate oxidation-

    27. PAPeter Attia1:19:07

        Right

    28. ISIñigo San-Millán1:19:07

        ... uh, uh, without getting to, uh, the blood. And, and this is what, it correlates a lot also with, with the fat oxidation as well, uh, and the graphs that I was showing earlier.

11. 1:19:19 – 1:27:27

    How the level of carbohydrate in the diet and ketogenic diets affects fuel utilization and power output during exercise

    1. PAPeter Attia1:19:19

       So one of the things I want to ask you about here that is a bit of a confounder when we do this type of analysis is the carbohydrate content within the diet. So I'll share with you-

    2. ISIñigo San-Millán1:19:30

       Yeah

    3. PAPeter Attia1:19:30

       ... my data, but I've now seen this with multiple people, including, uh, one individual who's remarkably fit. So, uh, uh, God, it's how many years now? Ten years ago, I was on a ketogenic diet for three years, and part of that three-year window overlapped with... The, the very end of that three-year period was when I kind of got back into cycling. So, um, [clears throat] at my fittest as a adult cyclist, I was back eating a lot of carbohydrates. But there was about a six to 12-month period when I was still in ketosis and I was kind of getting back into cycling shape. And I do have one VO2 max test from that window of time, probably six months after getting back to cycling, uh, and still on ketosis. I've gone back and looked at the data, and they're very interesting. So what, what I would observe is maximum fat oxidation was 1.3 grams per minute, and that occurred almost immediately, and it sustained until I hit my... Well, let me think. I-- it was sustained until about... So at the time, my FTP was about 4.1 watts per kilo. This would've been sustained until about 3.5 watts per kilo. [lips smack] So at 3.5 watts per kilo, I was still oxidizing about 1.2 grams per minute, and then that sort of fell off, and glucose become, becam- became then the dominant fuel source. At the fit, at the fit, at the completion of the test when I was done, you know, when I failed, I was obviously not oxidizing any fat, um, and glucose oxidation was just under six grams per minute. Um, yeah, about six grams per minute to about 24 kcal per minute. [lips smack] So, um, I've also seen this with another athlete who's been in ketosis for seven years, uh, is a very fit cyclist. Actually, he just sent me his data. Um, and it's, it's comparable, right? So he's... In fact, he's much fitter than I was. So his FTP, his 20-minute FTP test is about 412 watts for 20 minutes. Um, and surprisingly, he has decent glycolytic power. So that's the other thing, is I never really had good power at the low end because I only cared about time trialing, so it didn't n-nothing, it didn't matter how much I could hold, how many watts I could hold for two minutes or three minutes. I only cared about one hour. But, you know, this guy could still hold, you know, 1,200 watts for 15 seconds. Even for three minutes, he's north of 500 watts, 600 watts. Um, and again, fat oxidation is w- is, you know, one, 1.5 grams per minute. So [clears throat] it becomes a bit confusing because y- it would be very difficult to define Zone 2 by maximum fat oxidation. So ketosis is an extreme example.

    4. ISIñigo San-Millán1:22:45

       Mm-hmm.

    5. PAPeter Attia1:22:46

       But given how much RQ, respiratory quotient, the ratio of VCO2 to VO2, depends on baseline carbohydrate intake, how do we make the adjustment so that we understand and we're not being misled? Because if you just looked at my data-

    6. ISIñigo San-Millán1:23:03

       Mm-hmm

    7. PAPeter Attia1:23:03

       ... you would dramatically overestimate my mitochondrial efficiency.

    8. ISIñigo San-Millán1:23:08

       Yeah. Mm-hmm.

    9. PAPeter Attia1:23:09

       Wha- is, is, is that a situation where you say, "Well, actually, the lactate might be the more..." And unfortunately, I don't have lactate data from that test, so I can't tell you what my lactate levels were doing. But, um, a- again, it might not be a problem in the Peloton because you're not gonna be in ketosis if you're trying to win the Tour de France. But-

    10. ISIñigo San-Millán1:23:28

        Mm

    11. PAPeter Attia1:23:28

        ... uh, we do see a great degree of carbohydrate and fat variation in the diet amongst people that we're trying to test. So how, how do you make that correction?

    12. ISIñigo San-Millán1:23:38

        Yeah. So I, I, uh, in my humble opinion, uh, what we see in these cases, 'cause I see them all the time too, is that there's an artifact in the, uh, uh, metabolic cart. Um, the metabolic cart measures, uh, gas exchange. And, and then through the equations, it, it, it kind of says, "Okay, this gotta be," or, "This person is, must be burning fat or burning carbohydrates," right? Um.

    13. PAPeter Attia1:24:04

        Uh, but it was calibrated. The, the equations are calibrated on high-carb diets, presumably.

    14. ISIñigo San-Millán1:24:10

        Yeah. And so the thing is like a- as you exercise, no matter what fuel you're using, you, you, you keep increasing oxygen consumption, right? But if you don't have much carbohydrates, you're not gonna produce much CO2. So that's going to, uh, tweak, you know, uh, um, um, mis- or mis- mislead that, uh, um, stoichiometric equation because the, uh, the, the algorithm is going to in, in, think that, "Oh, whoa, he's using a lot of oxygen and not producing enough CO2, so he's gotta be burning a lot of fat." That's when you see fats in north of one gram per, per minute, right? So th- those are fat oxidations that it, I think they're an artifact. And I see this because three days later, you know, when you change the diet of that person, uh, three days later, uh, that person's fat oxidation might be 0.35, right? So there's no way that the mitochondria adjusts, you know. First, like it reflects a very high fat oxidation capacity in someone who we know very well, who is not an elite athlete, whose mitochondrial function is not incredibly high to be able to oxidize so much, uh, fa- fat, right? And in three days. Um, uh, reduces like by three or four times, right? So I, I, I, I attribute this to an artifact of the gas exchange, and this is where, uh, um, uh, looking at lactate, uh, it should give you those parameter. You, you know, you... Normally what I see in these, in these individuals is that you see maximum lactates of two, three millimoles, right? Because simply they don't have carbohydrates. Um, also the thing where you see that, yeah, my maximum grams per minute of, uh, of carbohydrates was in the six, but you're in ketosis, right? So how can you have enough glycogen or glycolytic capacity to elicit such a high carbohydrate production?

    15. PAPeter Attia1:26:08

        Well, I mean, I think even when you're in ketosis, you know, you're, you still... Remember, my blood glucose is still, you know-

    16. ISIñigo San-Millán1:26:15

        Yeah

    17. PAPeter Attia1:26:15

        ... four to five millimole, right?

    18. ISIñigo San-Millán1:26:17

        Yeah.

    19. PAPeter Attia1:26:17

        I mean, it's, it's, it's, uh... So, so, uh, I would really like to see this studied because, again, even if you're only eating 50 grams of glucose a day, think of how much glycogen you're making from all the glycerol, from all the fat that's-

    20. ISIñigo San-Millán1:26:33

        Yeah

    21. PAPeter Attia1:26:33

        ... being converted to ketones. So, I, I mean, I think Jeff Volek and Steve Phinney have looked at this, and when they put people into very, very strict ketosis but do muscle biopsies-

    22. ISIñigo San-Millán1:26:44

        Mm-hmm

    23. PAPeter Attia1:26:44

        ... they're still seeing 60% of the glycogen content in the muscle that was there under high-carb conditions.

    24. ISIñigo San-Millán1:26:52

        Yeah.

    25. PAPeter Attia1:26:53

        So I, I, I mean, I think my capacity to oxidize five and a half to six grams of glucose per minute was still there. Um-

    26. ISIñigo San-Millán1:27:00

        Mm-hmm

    27. PAPeter Attia1:27:00

        ... it just wasn't, you know, it just took a long time to get there, I think, is the difference.

    28. ISIñigo San-Millán1:27:05

        Yeah.

    29. PAPeter Attia1:27:05

        Um, so I guess the question is, if the VCO2 estimation is off because of the stoichiometric coefficients, do you think the VO2 estimation is off also?

    30. ISIñigo San-Millán1:27:17

        I don't know. I don't think so because, you know, as you said very well, you know, like, uh, the, you know, like ketones are used for energy purposes,

12. 1:27:27 – 1:34:27

    Glutamine as a source for making glycogen—insights from studying the altered metabolism of ICU patients

    1. ISIñigo San-Millán1:27:27

       and then we have a, a third element which is absolutely key in bioenergetics, which is glutamine. Right? Uh, glutaminolysis is highly expressed and utilized. We have learned that from ICU patients. ICU patients is a great model to study metabolism or stress metabolism. ICU patients, um, they utilized for wound healing about, uh, three times more glucose at rest, um, than what we have, right? Um, and it's part of the, the healing process. Glucose is, is instrumental for cell proliferation, wound healing, and part of that is lactate, too, as a byproduct in a single molecule. But, um, but we see that, um, um, um... And this is a study that we published, uh, looking indirectly a methodology to look at glycogen. Uh, and we did it with a, with a... It's a, it's a pilot study we did with, uh, ICU patients. They don't have glycogen, and it makes all the sense in the world because if you enter a ICU, first of all, normally you have a-

    2. PAPeter Attia1:28:26

       Sorry. When you say they don't have glycogen, you mean liver glycogen, muscle glycogen-

    3. ISIñigo San-Millán1:28:32

       Muscle glycogen

    4. PAPeter Attia1:28:32

       ... are depleted by how much? And, and-

    5. ISIñigo San-Millán1:28:34

       Yeah, so-

    6. PAPeter Attia1:28:34

       ... and depleted to what level?

    7. ISIñigo San-Millán1:28:36

       Yeah. So let's say that, let's say that you have 500 grams, you know, of, of, of glycogen, um, uh, if you have a full high carbohydrate diet.

    8. PAPeter Attia1:28:45

       Yes.

    9. ISIñigo San-Millán1:28:45

       So that might not be the case of someone entering the ICU, first, because they might not be elite athletes, or they might have maybe 300 grams. Uh, or they might not have that adaptation to hold more glycogen. So let's say they have 300 grams or so. Uh, and then, uh, by the time they get into that condition, the body uses about three times the glucose at rest. Now, an athlete, uh, use that same glucose, but at higher intensities, but only for a reduced amount of time, two hours, three hours, four hours, whereas the ICU patient is 24/7, right? So eventually the body is going to run out of glycogen in the muscle, or it's gonna be under huge stress. So the, the body has evolutionary mechanisms, 'cause it's a wonderful machine, and it needs to continue. So it increases, um, another route, which is, um, glutaminolysis. So glutamine is an excellent source of fuel. It enters directly the mitochondria. Uh, we have seen in a, in, in, in the publication that we're gonna, uh, show, uh, now that, um, when we publish it, is that when we, when we, uh, inject mitochondria with, uh, with glutamate, uh, it's incredibly well oxidized.

    10. PAPeter Attia1:30:02

        And what's the source of, of glutamate in these ICU patients? Are they breaking down muscle?

    11. ISIñigo San-Millán1:30:08

        Exactly. So th- this is, this is where, uh, cachexia comes into place. We know that pretty much every single ICU patient becomes, uh, um, cachectic or suffers from muscle, muscle waste, and this is the syndrome, right? Post-ICU muscle waste syndrome. Um, and, and this is where, like, where, wh- why do they get cachectic or catabolic, right? And, and, and, and why they overexpress tremendously levels of glutamine because they need it for either, uh, enter the, uh, the Krebs cycle for energy or for gluconeogenesis.

    12. PAPeter Attia1:30:41

        Mm-hmm.

    13. ISIñigo San-Millán1:30:41

        So this is one of the things that, uh, we learn a lot from ICU. These ICU patients, they have, uh, hyperglycemia, right?

    14. PAPeter Attia1:30:49

        Yep.

    15. ISIñigo San-Millán1:30:49

        Uh, yet they're not giving them usually because they have hyper- hyperglycemia. It's true, too, that in the acute ICU phase, they also, uh, have insulin resistance, right? But obviously this hyperglycemia, and ICU doctors historically have seen this, it's like, "Whoa, this patient has hyperglycemia, poof, off the chart." So obviously we're not gonna give them IVs of, uh, Faria, of, of glucose. We're gonna give more protein and gluco- I mean, and fat. And in fact, glutamine has shown that increased survival rate in these patients, right? Uh, but where is this gly- hy- hyperglycemia is coming from when you do not have glycogen? It comes probably from proteolysis, right? Where you break down pro- protein from your muscles to, uh, to release glutamine

    16. PAPeter Attia1:31:37

        But, I mean, I think we could, we would only know that if we understood hepatic glucose stores, because regardless of how much glycogen is in the muscle, it's never going to make its way into circulation because the muscle can't fully dephosphorylate it. So do we have a sense of what the hepatic glycogen content is? 'Cause I, I can't imagine the body would ever let anything compromise that, given that if the liver can't produce glucose continuously, the brain dies.

    17. ISIñigo San-Millán1:32:06

        Mm-hmm.

    18. PAPeter Attia1:32:06

        So it, it might be that this is true, true, and unrelated, right? It could be that the, the, the muscles are depleting glycogen because of high utilization, [lips smack] but the liver, through gluconeogenesis-

    19. ISIñigo San-Millán1:32:18

        Exactly

    20. PAPeter Attia1:32:19

        ... has plenty of glucose. That's what's making it into the circulation because of hypercortisolemia, because of other-

    21. ISIñigo San-Millán1:32:27

        Exactly

    22. PAPeter Attia1:32:27

        ... acute phase reactants.

    23. ISIñigo San-Millán1:32:28

        Yeah.

    24. PAPeter Attia1:32:29

        And so we have hyperglycemia, but it's all being mediated by the liver, which has no trouble maintaining glycogen levels.

    25. ISIñigo San-Millán1:32:35

        Yeah. Exactly.

    26. PAPeter Attia1:32:35

        And again, from an evolutionary perspective, you much rather err on the side of hyperglycemia than hypoglycemia-

    27. ISIñigo San-Millán1:32:43

        Yes. Yes

    28. PAPeter Attia1:32:43

        ... under a period of stress.

    29. ISIñigo San-Millán1:32:44

        Absolutely, and it's, and it's necessarily. And, and that's, I think, what's the source of that gluconeogenesis, right? So it's probably, uh, glutaminolysis, right? Coming from-

    30. PAPeter Attia1:32:54

        Yeah
13. 1:34:27 – 1:39:00

    How exercise mobilizes glucose transporters—an important factor in diabetic patients

    1. ISIñigo San-Millán1:34:27

       patients. And, and that's the other thing too. Once, once you exercise, and this is a very important concept for people with type 2 diabetes, with type 1 diabetes, um, uh, and hyperinsulinemia, is that you have insulin resistance, right? Um, and, and, um, and you have difficulty to translocate, therefore to translocate the GLUT4 transporters to the surface of the muscle, the sarcolemma. And we know that probably the first tissue or organ where diabetes, uh, debuts, starts, is the skeletal muscle.

    2. PAPeter Attia1:35:00

       Absolutely.

    3. ISIñigo San-Millán1:35:00

       Because about 80% of the carbohydrates that we have, they're oxidized in skele- in skeletal muscle. And, and because we're at rest, are, uh, should be oxidized within the mitochondria of the skeletal muscle, that pyruvate, right? This is what we're doing research and seeing it clearly. But, um, but, uh, when you have, uh, insulin resistance, you cannot translocate those transporters. Now, we have a second, um, um, um, a way to translocate those transporters that not many people know about, and that's muscle contraction.

    4. PAPeter Attia1:35:32

       Right. This is the, this is the insulin independent-

    5. ISIñigo San-Millán1:35:35

       Exactly

    6. PAPeter Attia1:35:36

       ... glucose uptake, which, which also seems to be heavily dependent on fitness, right?

    7. ISIñigo San-Millán1:35:40

       Absolutely.

    8. PAPeter Attia1:35:41

       The fittest athletes here-

    9. ISIñigo San-Millán1:35:43

       Mm-hmm

    10. PAPeter Attia1:35:43

        ... require virtually no insulin to translocate glucose into the muscle through the insulin independent pathway.

    11. ISIñigo San-Millán1:35:51

        Yeah.

    12. PAPeter Attia1:35:51

        And a- and actually, this, I think we may have even discussed this, I don't know, over dinner one night. But you look at the type 1, uh, diabetics-

    13. ISIñigo San-Millán1:35:58

        Yeah. Mm-hmm

    14. PAPeter Attia1:35:58

        ... who are highly, highly active, require very little insulin.

    15. ISIñigo San-Millán1:36:02

        Exactly. And, and this is because they have a, a, uh... And this is, this explains, um, uh, the hypoglycemia in these patients shortly after they start exercising, right? They might have some- something to eat, and they inject themselves with insulin, and, and there's nothing you can do once you have insulin on board, right? So that insulin is gonna translocate those transporters, and it's going to start bringing insulin inside. But in the moment-

    16. PAPeter Attia1:36:28

        Glucose

    17. ISIñigo San-Millán1:36:28

        I mean, sorry, glucose. Thanks. In the moment you start exercising, you do the same function through contraction of exerci- of, of the muscles. So you have two mechanisms acting at the same time, pooling more glucose inside the cells, leading to hypoglycemia. So this is what we, we learned a lot with type 1, uh, persons with, people with type 1 diabetes and exercise. But this concept... And, and then we can prevent them. So for example, do not inject yourself before exercising, right? Uh, because exercise alone is going to take care of that glucose, right?

    18. PAPeter Attia1:37:01

        That's right.

    19. ISIñigo San-Millán1:37:01

        Uh, but we can take these concepts also with people with type 2 diabetes, uh, that, that they have, uh, insulin resistance or pre-type 2 diabetes. It's like, why not exercising right after you eat, right? Because that, that, that carbohydrate you have, um, you know, like you don't have the... You have insulin resistance already, but when you exercise, you're not gonna need that insulin, and yet you can translocate those transporters, and you bring glucose levels down. And I'm sure that you, you, you see this all the time where your, uh, glucose sensors with your text come, right?

    20. PAPeter Attia1:37:35

        Yes. And, and, and there's... I've gone periods of time when I've done incredibly frequent lactate testing. So, you know-

    21. ISIñigo San-Millán1:37:42

        Mm-hmm

    22. PAPeter Attia1:37:42

        ... lactate testing every 30 minutes for a day or something insane like that, which is incredibly expensive and incredibly painful on your fingers.

    23. ISIñigo San-Millán1:37:48

        [laughs]

    24. PAPeter Attia1:37:49

        But you learn how much, for example, a meal impacts lactate.

    25. ISIñigo San-Millán1:37:55

        Yeah.

    26. PAPeter Attia1:37:55

        So, um, when I wake up in the morning, my re- my resting lactate level varies between... And this is, I've been tracking this over a period of [lip smacks] uh, probably 40 days. So 40 days-

    27. ISIñigo San-Millán1:38:10

        Mm-hmm

    28. PAPeter Attia1:38:11

        ... of tracking. What r- what range do you think my morning resting lactate level has been over a 40-day period? How much variability do you-

    29. ISIñigo San-Millán1:38:19

        In the m-

    30. PAPeter Attia1:38:20

        In the morning.
14. 1:39:00 – 1:58:27

    Metrics for finding Zone 2 threshold—lactate, heart rate, and more

    1. PAPeter Attia1:39:00

       So the high-carb meal raises lactate.

    2. ISIñigo San-Millán1:39:03

       Absolutely.

    3. PAPeter Attia1:39:04

       It, so it becomes a bit of an artifact in a way.

    4. ISIñigo San-Millán1:39:07

       Yeah.

    5. PAPeter Attia1:39:07

       Which now gets me to some of the, the... We, we've talked about this at the level of the most precision possible, the way in which I would measure it in a patient, you would measure it in a world-class athlete, where we have the ability to do indirect calorimetry and lactate testing. But now I wanna talk about it in the way that we train-

    6. ISIñigo San-Millán1:39:28

       Mm-hmm

    7. PAPeter Attia1:39:28

       ... people, normal people.

    8. ISIñigo San-Millán1:39:30

       Mm-hmm.

    9. PAPeter Attia1:39:31

       So we've talked about this, um, call it, you know, difference, right? Between the lactate level, uh, that you measure in the blood, which is now heavily influenced by production and clearance, and then we've talked about the gold standard, which would probably be fat oxidation, but even that can be confounded. But let's take off the table the people who are consuming a high-fat, low-carbohydrate diet because-

    10. ISIñigo San-Millán1:39:56

        Mm-hmm

    11. PAPeter Attia1:39:56

        ... that confuses things a bit. If I have a patient, and I'm looking at their biometrics, and we do a Zone 2 test based on looking at their fat oxidation during an escalated test of part of a VO2 max test, and it comes back that their maximum fat oxidation, which is, you know, 0.3 grams per minute-

    12. ISIñigo San-Millán1:40:18

        Mm-hmm

    13. PAPeter Attia1:40:19

        ... occurs at a wattage [lip smacks] of 1.5 watts per kilo. That's a pretty average person. And I say, "I want that number higher."

    14. ISIñigo San-Millán1:40:31

        Mm-hmm.

    15. PAPeter Attia1:40:31

        Both the absolute number of fat oxidation, but where it occurs on the graph.

    16. ISIñigo San-Millán1:40:35

        Mm-hmm.

    17. PAPeter Attia1:40:35

        Now I want you in a year to be 2.5 watts per kilo. Let's talk about two things. One, how they should train, and that means duration, intensity, frequency, et cetera. And secondly, what we should use as the readout to know we're in the right training zone, given that they won't be able to train daily or weekly or whatever frequency with indirect calorimetry. And by the way, let's assume that some people will want to use the point-of-care lactate meters-

    18. ISIñigo San-Millán1:41:08

        Mm-hmm

    19. PAPeter Attia1:41:08

        ... and some people will not.

    20. ISIñigo San-Millán1:41:09

        Mm-hmm.

    21. PAPeter Attia1:41:10

        So let's start with what's our surrogate for training zone, and starting with what we knew. So we learned-

    22. ISIñigo San-Millán1:41:17

        Mm-hmm

    23. PAPeter Attia1:41:17

        ... that, uh, t- 1.5 watts per kilo was maximum fat oxidation, but we want to increase that to 2.5. So what metric do you use to train them?

    24. ISIñigo San-Millán1:41:28

        So yeah, so normally what I do is like starting with the metabolic test, I translate that information into whether it's watts, uh, or, or speed or heart rate. Uh, all of them normally they correlate quite well. Um-

    25. PAPeter Attia1:41:43

        Okay

    26. ISIñigo San-Millán1:41:43

        ... and you can individualize it. There are people, they don't have a power meter. Okay, you can do heart rate, for example.

    27. PAPeter Attia1:41:48

        Right.

    28. ISIñigo San-Millán1:41:48

        Um, or, or people that just obviously they run or they walk, uh, you can do speed or, or, or heart rate as well, right? They're very good surrogate. So that's, that's a first metric, the surrogate, right? Then it's about, at least from my experience, uh, the three main principles that I've learned over the years on how to apply this. Uh, so first is, uh, frequency. How many, uh-

    29. PAPeter Attia1:42:13

        Be- before we go-

    30. ISIñigo San-Millán1:42:14

        Yeah
15. 1:58:27 – 2:10:22

    Optimal Zone 2 training: dose, frequency, duration, and type of exercise

    1. PAPeter Attia1:58:27

       So-

    2. ISIñigo San-Millán1:58:28

       Yeah

    3. PAPeter Attia1:58:28

       ... so let's, let's now... So we've got a very good handle on the metrics we're going to be using. So now let's talk about two scenarios. The first is the person who is new to this type of training. So they've listened to this podcast, or they're one of my patients, and I've made the case convincingly to them that you really need to do this type of training. I want to come back, by the way, to a justification for that. So let's explain why high intensity training is not sufficient. But we'll, we'll park that for a moment. But they really don't have much of a background in this type of training, right? They [lip smack] you know, maybe they do some high intensity training. They do some weights. They play some tennis. Uh, but they really don't do the sort of steady state sustained cardio that we're talking about. Um, [lip smack] how would you structure a training program in dose, duration, frequency, uh, for that individual? And tell me a little bit about the choices that you would take, uh, make if they're agnostic to running, walking, cycling, rowing, swimming. Uh, uh, you know, again, I have my biases there, but I want to kind of hear what you have to say about it.

    4. ISIñigo San-Millán1:59:37

       Yeah, no, I think, yeah, that's a great, um, question. And, and I also, you know, before that, I want to apologize to many of your audience, um, um, uh, because I, I, I get a lot of emails, you know, asking me about these questions, and, and it's hard to, uh-

    5. PAPeter Attia1:59:52

       Well, that's why we're doing the podcast-

    6. ISIñigo San-Millán1:59:54

       Yeah. Exactly

    7. PAPeter Attia1:59:54

       ... so that you don't have to apologize. It's easier to do it this way.

    8. ISIñigo San-Millán1:59:56

       I appreciate it-

    9. PAPeter Attia1:59:56

       Yeah

    10. ISIñigo San-Millán1:59:56

        ... uh, this way. But see, I get emails, um, and, uh, and, and, and before I used to see people here at the university, but now the university, you know, we're no- don't have these services. So I'm trying to convince them that these services are important to offer to, to population. But anyways, I want to apologize because I cannot answer to everybody. But yeah, so, uh, my, my, my, I have the three, three main rules or parameters that I have learned over the years. So one is the duration, right? Um, we have in, in mind sometimes that this is, like, endurance training, long day. Like, like, I only have s-six hours a week or seven hours a week at most, right, to do this type of training or less. So I, there's no way I can do that.

    11. PAPeter Attia2:00:37

        It, it's usually less because they might have six hours a week for total exercise.

    12. ISIñigo San-Millán2:00:41

        E-exactly.

    13. PAPeter Attia2:00:42

        And we're gonna take half of that for strength training.

    14. ISIñigo San-Millán2:00:44

        Exactly. 'Cause, which is very important, as you know.

    15. PAPeter Attia2:00:47

        Right.

    16. ISIñigo San-Millán2:00:48

        Uh, it, um, uh, and it, and it's, it's my... It's where I fail 'cause I, [laughs] I should do more of that. And I try to, to get a little bit more of time to do that. But I, oh, it's not easy, but I aspire really to, to, to dial that in. But, uh, but yeah, you're right. They might have less than six hours, and they might think like, "Well, v- I'm, I'm not an endurance athlete, so you need to do four hours to do, to accomplish this. So therefore, I'm just gonna move to do just high intensity and just get out of the way." Well, that, that's not completely true, right? Uh, you can accomplish very important mitochondrial adaptations and very important, um, um, metabolic adaptations by exercising one hour, right? So this is one, is the, uh, uh, um, uh, the duration. Let's start by the duration, right? So, uh, um, if you try to do that one hour to one hour and a half range, uh, you're on target. Um, you don't need to do five hours, six hours.

    17. PAPeter Attia2:01:42

        And is that in one setting?

    18. ISIñigo San-Millán2:01:44

        I'm sorry?

    19. PAPeter Attia2:01:45

        Is that total or one setting?

    20. ISIñigo San-Millán2:01:47

        What do you mean?

    21. PAPeter Attia2:01:49

        Uh, meaning-

    22. ISIñigo San-Millán2:01:49

        Oh, sorry

    23. PAPeter Attia2:01:49

        ... is it one to one and a half hours per week, or-

    24. ISIñigo San-Millán2:01:52

        Oh

    25. PAPeter Attia2:01:52

        ... does that need to be in one continuous-

    26. ISIñigo San-Millán2:01:55

        Yeah. So-

    27. PAPeter Attia2:01:56

        ... uh, exercise bout?

    28. ISIñigo San-Millán2:01:57

        Yeah, I'm sorry. Let, let, let me, let me may- maybe go back to that, the frequency, right, the, the dose. So the frequency that I see is that, uh, this type of training, uh, ideally needs to be done between three to four days a week, ideally. Uh, um, what I've seen... And, and how can I know this? Uh, I know this because I've seen in the laboratory everything Right? The person who trains one day at these, um, zones or two days or three days or four days or high intensity, low intensity, and I see the adaptations. How do I see the adaptations? Again, looking at mitochondria, I mean, at fat oxidation, lactate clearance capacity, both surrogates of mitochondrial function, right? So I've been identifying the, the, the dose of that training. So if you train once a week there, uh, chances are that, uh, you're gonna deteriorate over time, and especially as we age. Uh, something that I see, for example, in high intensity exercisers and bodybuilders, that they have a very poor mitochondrial function compared to people who do more, uh, uh, um, a little bit of everything, right? So one day a week is not gonna work. Two days a week, it, it might maintain what you have. But if you are new to an exercise program, might not be enough. Three days a week, now we're starting to, to, to, to see for sure. Four days a week, now we're talking. Ideally, five days a week or six, but not, not everybody has obviously six days a week to train. But I think that we all can... I mean, you are a very busy guy. I'm a very busy guy. Uh, and we try to squeeze four or five days a week, maybe six in the summer. But four to five days is achievable for most individuals and, and, and, and put aside an hour to an hour and a half, right? So I would say that four days a week is ideal, right? That's the r- that, that, that's the first principle. The second principle is the duration, going back to what I was saying, right? With, with, with one hour, maybe Pogačar needs four hours, five hours, uh, uh, to keep increasing those huge mitochondria for a long time. But an, a mere mortal, uh, and especially someone who might be pre-diabetic or might be out of fitness or, or hasn't exercised in a long time or, or, or someone who coming from a disease or, or, or a mother who just had a baby and has been out of, uh, of say for a while. You know, one hour, um, if you walk or if you run, uh, might do, might be very, very good for you. Uh, one hour walk, you know, you, or run, you, you might have to bring it up. That's, that's part of the plan too, right? You cannot start off the bat with one hour. You might start by 20 minutes, 30 minutes, 40 minutes, increasing it, maybe about an hour. And if you bike, for example, about an hour, 20 minutes, hour and a half, that's what I see that if you do that for four days a week, things are starting to move.

    29. PAPeter Attia2:04:47

        Even, even if you bike on a trainer where you can be much more efficient and-

    30. ISIñigo San-Millán2:04:52

        Mm
16. 2:10:22 – 2:23:25

    How to incorporate high intensity training (Zone 5) to increase VO2 max and optimize fitness

    1. PAPeter Attia2:10:22

       Yeah, so I wanna, wanna talk about that. So how do we bring in the an- other energy systems? Of, of the, of the four pillars of exercise in my-

    2. ISIñigo San-Millán2:10:29

       Yeah

    3. PAPeter Attia2:10:29

       ... world, uh, stability, strength, low-end aerobic, which I describe really as, like, talk about it as kind of mitochondrial efficiency.

    4. ISIñigo San-Millán2:10:38

       Mm-hmm, mm-hmm.

    5. PAPeter Attia2:10:38

       And then high-end aerobic, which is peak aerobic capacity-

    6. ISIñigo San-Millán2:10:42

       Mm-hmm

    7. PAPeter Attia2:10:42

       ... slash anaerobic performance. So anaerobic power, peak aerobic, low-end aerobic mitochondrial efficiency, strength, stability. Of those four, I, for some reason, struggle to make the time-

    8. ISIñigo San-Millán2:10:57

       Yeah

    9. PAPeter Attia2:10:57

       ... for the peak aerobic, in part because I n- o- one, it's the least enjoyable, truth, if we're gonna be brutally honest. If you're doing it right, it hurts the most.

    10. ISIñigo San-Millán2:11:08

        Yeah.

    11. PAPeter Attia2:11:09

        It's also no longer as relevant because I don't compete at anything, right?

    12. ISIñigo San-Millán2:11:13

        Exactly.

    13. PAPeter Attia2:11:13

        Like, it was... I actually really enjoyed that type of training when I competed because you have to spend time in that energy system, and you see the rewards-

    14. ISIñigo San-Millán2:11:21

        Mm-hmm

    15. PAPeter Attia2:11:21

        ... of, you know, repeating 60 minute, you know, re- re- you know, 60 minutes of repeating two-minute intervals or something like that.

    16. ISIñigo San-Millán2:11:28

        Yeah.

    17. PAPeter Attia2:11:29

        So if we're, if we're really talking about this from the lens of health, maximizing health, the data are unambiguous that VO2 max is highly correlated with longevity in a, in, in, unlike f- there are not many variables that are more strongly correlated.

    18. ISIñigo San-Millán2:11:47

        Mm-hmm.

    19. PAPeter Attia2:11:48

        So but the levels don't have to be that high, right? We're not, I mean-

    20. ISIñigo San-Millán2:11:51

        Yeah

    21. PAPeter Attia2:11:51

        ... Pogačar's VO2 max is probably 85, you know, or it's probably in the 80s at least in terms of, uh, milliliters per, uh, minute per kilogram. But someone my age, to be considered absolutely elite, which means the top 2.5% to 2.7% of the population, which carries with it a fivefold reduction in risk to the bottom 25% of the population.

    22. ISIñigo San-Millán2:12:16

        Mm-hmm.

    23. PAPeter Attia2:12:17

        Uh, my VO2 max requirement is about 52, 53 milliliters per minute per kilogram. So the question is, can I use that as the gauge for how much high intensity training I need to do, basically just enough to make sure I maintain that VO2 max? Or do you think about it in a different way?

    24. ISIñigo San-Millán2:12:38

        Well, I think about it more, a- again, the, the bioenergetics, energy, energy systems, right? I think that, uh, uh, ultimately, and we know that, um, longevity is also high related with mitochondrial function and metabolic health. I think that more and more, and, and, and this is why you see in so many fields in, in, in medicine nowadays, right? That everybody's, is stumbling upon mitochondria, right? Um, um, and, and so there's an aging process where we lose mitochondrial function, uh, and there's like a, a sedentary, um, a component, right? Where we lose mitochondrial function. Um, I wish that we could have a medication, a pill that you could take it and increase the mitochondrial function 'cause it would increase, uh, metabolic health and longevity. But the only medication that we know is exercise, and the medic- and within exercise that the right, the dose that we see that improves the most and, and also is sustainable in the long term, which is another important concept, you know? Uh, very high intensity training is not sustainable. Very extreme diets are not su- sustainable. If you combine both, it's even worse, and this is what a lot of people are doing together. But you need to have some sustainability. But this is what it, we've seen this, this is important to improve that mitochondrial function. But going back to the, that high intensity I think is necessary because we also lose glycolytic capacity as we age, and it's important to stimulate it. As you very well said, for all of us who are not competing, I couldn't care less about, um, um, being super high intensity, uh, bec- I'm not competing. Uh, but that said, I want to have also my adrenaline rush, you know? So, uh, like many people, I, I would-

    25. PAPeter Attia2:14:19

        But how much does it feed into it? So for example, if, and I've often thought about this now as I just wanna make sure my Zone 2 is above three watts per kilo, would I be better off taking that extra training? If I have one additional training session per week, should I make it an additional Zone 2 workout? So then d- I do four now. Should I be doing a fifth one or should I be taking that fifth one and doing a VO2 max protocol? And that's, that's what we'll typically prescribe to our patients is a four by four protocol of, you know, highest intensity sustained for four minutes, followed by four minutes of recovery, and, and then repeat that four, five, six times.

    26. ISIñigo San-Millán2:14:59

        Mm-hmm.

    27. PAPeter Attia2:14:59

        Uh, you know, when you put that, when you put a warm up and cool down on either end of that, you know, that's a little over an hour. Um, so you could... Would you spend that hour doing that in an effort to make your Zone 2 even better?

    28. ISIñigo San-Millán2:15:12

        Yeah.

    29. PAPeter Attia2:15:13

        Or would you just do an extra hour of Zone 2?

    30. ISIñigo San-Millán2:15:16

        No, that's a really good question. So what, what I, what I, I, I agree. I agree that, uh, you can, if you have a fifth day, you can convert it into any type of high intensity, uh, session structured. Or what I can tell people also, "Hey, if you're a cyclist or a runner and you wanna go with your friends like a club ride."
17. 2:23:25 – 2:27:57

    Compounding benefits of Zone 2 exercise and how we can improve metabolic health into old age

    1. ISIñigo San-Millán2:23:25

       So I see the typical person who just retired or, or as we, like as I discussed earlier, aspire to pro- pre-retire at the age of 60 or a little bit before. In the moment they, uh... And, and these are like people like us. We are struggling to, to, to squeeze in time, you know, and do five hours here or six hours a week here, or 10 at max. Um, but then they have the whole time in the world, and they can sleep in. They don't have o- they're not overworked. Uh, you know, and they can exercise. It's unbelievable and super inspiring how much they improve in their 60s. I've seen people-

    2. PAPeter Attia2:24:04

       Hmm

    3. ISIñigo San-Millán2:24:04

       ... in their 70s with the metabolic parameters of, of, of people active, moderately active, uh, in their 30s.

    4. PAPeter Attia2:24:14

       Wow.

    5. ISIñigo San-Millán2:24:14

       I saw, uh, the, the world champion in the cycling who's 81 in the category of 80 to 85, believe me there's a category of [chuckles] that, uh, whose p- metabolic parameters were those of someone in their 30s, healthy, active. So this is incredibly inspiring that I think that we're rewriting what's been taught to us in the books.

    6. PAPeter Attia2:24:36

       Now, in fairness, was, was that person of an elite athlete? Were they a professional athlete in their 20s and 30s?

    7. ISIñigo San-Millán2:24:43

       Never, and this is what s- struck me. He was-

    8. PAPeter Attia2:24:46

       Oh, wow

    9. ISIñigo San-Millán2:24:46

       ... uh, a smoker, hypertensive.

    10. PAPeter Attia2:24:49

        Hmm.

    11. ISIñigo San-Millán2:24:49

        And he started, uh, cycling because he needed to change his lifestyle in his 40s. 'Cause that's the same question, like, "Whoa, you must have been doing this all your life." Like, "No, I started riding my bike when I was in my 40s. I was a smoker. I was heavy. I was hypertensive." Like, what? So it's incredible that [chuckles] 40 years later he's in a better health than when he was. [chuckles]

    12. PAPeter Attia2:25:11

        But, but I'll tell you, what I, what I take away from that as well is the benefits and the more, the importance of compounding. You see-

    13. ISIñigo San-Millán2:25:19

        Mm-hmm

    14. PAPeter Attia2:25:19

        ... you alluded to it earlier, and I think the listener could be forgiven if they missed this point. You can make relatively quick changes in your glycolytic efficiency. You t- you can take an untrained person with a VO2 max of 20 mils per mig, um, per minute, um, or migs, uh, uh, mil per gig per minute, and you could take them from 20 to 30 in a period of months-

    15. ISIñigo San-Millán2:25:47

        Yeah

    16. PAPeter Attia2:25:47

        ... with the right amount of training. A 50% improvement in a few months.

    17. ISIñigo San-Millán2:25:52

        Exactly.

    18. PAPeter Attia2:25:53

        It's very difficult to see a 50% improvement in mitochondrial function in a few months.

    19. ISIñigo San-Millán2:25:59

        Exactly.

    20. PAPeter Attia2:26:00

        And, and, and you, you've already made this point, but I just wanna restate it 'cause it's important to set expectations, and it speaks to why this level of training should be thought of in the same way that you think of accumulating wealth.

    21. ISIñigo San-Millán2:26:12

        Mm-hmm.

    22. PAPeter Attia2:26:13

        Which is you gotta-

    23. ISIñigo San-Millán2:26:14

        Yeah

    24. PAPeter Attia2:26:14

        ... you... It's, it's day in and day out, day in and day out, j- small compounded gains over years, and years, and years [swallows] is why a 40-year-old overweight smoker can become a world champion at 80. It's because he probably never once again got out of shape in that 40 years.

    25. ISIñigo San-Millán2:26:36

        Abso- absolutely. Absolutely. And this is in- incredibly inspiring. You know, uh, when I see these people in their 60s just retired, and they come to do their first test, and one year later they come back I mean, it gives me the goosebumps because it is like, oh my gosh, like how can you improve so much? And, and they're, they're like-- And they say like, "Look, I'm, I'm 64 and I, I, I feel strong as, as when I was in my 30s," you know? And like, oh. And so this is where we're, we're, we're gonna be, you know, like... And of course no medications, you know, um, really good state of mind, uh, which is absolutely key for longevity, right? Um, normal diet. They can in-- They're not a strict with one of these or not that. They, they, they eat in moderation, but they can have a little bit of everything, right? Uh, uh, which is also, in my modest opinion, is part of the enjoyment of life, um, um, eating what you like in moderation as well. Um, so it's incredibly inspiring to see all these examples and, and, and, and in a way where we're rewriting what we've been, been taught for years, that once you turn 40, everything is going down. You can really, really change. And again, you know, your, you know, your, your, your own, your own body, and you can really, you know, take ownership of that and improve it

18. 2:27:57 – 2:37:45

    The effects of metformin, NAD, and supplements on mitochondrial function

    1. ISIñigo San-Millán2:27:57

       at any age.

    2. PAPeter Attia2:27:57

       So what-- You mentioned drugs. I wanna talk about one drug in particular and maybe some supplements. Um, you and I have spoken so much about this and, you know, myself and another person are committed to funding a study that we're gonna be doing once the, um, uh, once we get through kind of the backlog of, of COVID, uh, issues at the university. Um, but, uh, uh, the, the question really arises around the use of metformin-

    3. ISIñigo San-Millán2:28:26

       Mm-hmm

    4. PAPeter Attia2:28:26

       ... and whether or not there's sort of a true impairment of mitochondrial function, or whether the elevated lactate levels we see in patients taking metformin is an artifact of the drug itself, but says nothing of the mitochondrial function. Do you have any more insight into this question that, that, that we struggle with greatly because-

    5. ISIñigo San-Millán2:28:48

       Yeah

    6. PAPeter Attia2:28:48

       ... we have some patients who take metformin who achieve, uh, who, who, who receive much benefit from taking metformin, but it makes it confusing to interpret their Zone 2 data. And it makes me ask the question, sh- you know, it's a more import-- Uh, in those patients, it's maybe less relevant, but now it becomes relevant when we think about using metformin as a geroprotective agent, an agent to enhance longevity.

    7. ISIñigo San-Millán2:29:13

       Yeah. I-- That's a thing that, um, w-we need a lot, a lot of, uh, um, um, research on that, I think, to understand this better. Now we-- It's, it's strange that it definitely it seems to work in many patients, right? Obviously, for those ones in the pre-diabetic, first stage diabetes, uh, is the, it's a very good, uh, medication that's been used for, for a long time with good results. But how about the long term, the long-term results, right? Um, we know that, uh, metformin in-inhibits Complex 1, which is key for mitochondrial function in the electron, electron transport chain. Um, so we don't know the long-term effects of metformin, right? Um, uh, in longevity. This is where I think that we need more, more, more information as well. Uh, we see, uh, or I see like someone showing up with, uh, um, lactate of 3.5 millimoles at rest, and the first thing I ask is like, "Are you on metformin?" And many times they yes, and I'm sure you see the same thing, right? Like, wow. So, um, so it's, it's definitely an artifact. And why do you see at rest 3.5 millimoles or 3 millimoles of lactate?

    8. PAPeter Attia2:30:21

       A-and by the way, is their fat oxidation commensurately suppressed? Because when you, when you metabolically, uh, test them on the cart, do you see in that individual a very, very low fat oxidation? If s- if not, it might suggest that, that, that lactate level of 2 or 3 millimole is, is an artifact but doesn't-

    9. ISIñigo San-Millán2:30:42

       Yes

    10. PAPeter Attia2:30:42

        ... really speak to what's happening in the mitochondria, right?

    11. ISIñigo San-Millán2:30:44

        And that's a great question. Um, I haven't seen people taking metformin as a, a, um, um, um, um, um, um, um, medication, you know, for longevity, for example, or for health. What I see people on metformin are already clinical patients.

    12. PAPeter Attia2:30:59

        Yeah. So, so in other words, it's confound... So of course they're low because-

    13. ISIñigo San-Millán2:31:02

        Yeah.

    14. PAPeter Attia2:31:03

        Yeah.

    15. ISIñigo San-Millán2:31:03

        So they're taking metformin in the first place because of their clinical condition, which is driven by a mitochondrial impairment or dysfunction. So it's, it's difficult to discern, but I mean, I'm sure you, you, you, you have more experience of people taking metformin who are, um-

    16. PAPeter Attia2:31:16

        We do. But, but... Yeah.

    17. ISIñigo San-Millán2:31:18

        Yeah.

    18. PAPeter Attia2:31:18

        But that's why this study that we're-

    19. ISIñigo San-Millán2:31:20

        Yeah

    20. PAPeter Attia2:31:20

        ... eventually gonna get around to doing is gonna be so important 'cause it will answer this question directly.

    21. ISIñigo San-Millán2:31:25

        Yeah. And, and we can do the muscle biopsies and as you say, it's like, i-i-is it... Does it really mess up with the whole mitochondrial function or can even like, uh, the mitochondrial function overall override that inhibition of Complex 1 and, and override other pathways? I, I, I don't think we know the answer to that.

    22. PAPeter Attia2:31:45

        Do you have an insight into any other, uh, supplements? There's, uh, no, no shortage of, of supplements that are out there, uh, that, that are touted as sort of, you know, longevity-boosting agents and mitochondrial health agents. So, so the most talked about of all of these, I think, is the precursors to NAD. So the most common of these would be NR, uh, or NMN.

    23. ISIñigo San-Millán2:32:10

        Yeah.

    24. PAPeter Attia2:32:10

        Both of which are, uh, pretty clear that they are precursors to NAD. There's certainly some debate about how clinically relevant it is. Do you have a point of view on whether or not taking a supplement that boosts, uh, NAD, at least in the plasma? I don't-- I still don't know how well it's boosting NAD in the cell. But-

    25. ISIñigo San-Millán2:32:32

        Yeah

    26. PAPeter Attia2:32:33

        ... um, nevertheless, do you, do you have a sense of if that is beneficial to the mitochondria, um, both theoretically, but more importantly experimentally?

    27. ISIñigo San-Millán2:32:41

        Yeah. Well, that's, yeah, that's a great point, and this is like I, I don't think we have the answer, but I think we need to be cautious about how we, we interpret this data. Um, um, you know- It's definitely been shown multiple times that, um, NAD levels and at the cellular level are, and even mitochondrial level are decreased with aging, right? Therefore, the whole thing, whoa, if it's low, let's take it, right? But it's not only NAD. Um, I mean, if you look at so many metabolites, you know, in, at the cellular level, in mitochondrial level, they're downregulated with aging, right? The question is why are they, they, are they downregulated? Uh, is, is because mitochondria per se to start out with is downregulated, so it doesn't need so much NAD because cannot take it, right? Or other supplements or other metabolites, right? So this is, this is at least how I think of, um, um, NAD, it's as, as we mentioned earlier, it's very important in glycolysis. It's, uh, in redox sta- status, right, to maintain redox, and it's very important in the, uh, in, in, in, in, uh, glycerol 3-phosphate to, to 3-biphosphoglycerate phosphate, where NAD is utilized, uh, to convert, um, uh, glycerol 3-phosphate to 2,3-phosphoglycerate, uh, but it's depleted, and this is why the only thing that rescues that is lactate, right, as we mentioned. Now, taking NAD, is that gonna increase longevity? I don't think so. That's my opinion, because longevity is not just one supplement or two or three or four or five. It's a compendium on, on an incredible amount of things that happen at the cellular level, and I don't think that one supplement... I remember those days where resveratrol was the thing, right, for longevity, and everybody was... Not everybody. A lot of people were buying resveratrol, and there are studies with mice showing that increased 50% longevity in mice, so therefore let's do it in humans. Well, as you probably know, a lot of people started taking resveratrol when they were 50, and they're dead now. You know? Uh, it didn't increase, it doesn't increase longevity in humans, right?

    28. PAPeter Attia2:34:46

        Yeah. I mean, and, and I think, you know, I think the data in the, in the mice, we can debate the merits of that.

    29. ISIñigo San-Millán2:34:51

        Yeah.

    30. PAPeter Attia2:34:51

        I, I wanna ask you about a theoretical risk, though.
19. 2:37:45 – 2:44:42

    The role of lactate and exercise in cancer

    1. ISIñigo San-Millán2:37:45

       a lot of hype over NAD, and, and, and we saw this. So we would love to, to, to do it at a much higher level, because my question, which might be a, a disruptive question, is like, as, you know, what if you have a, a small tumor that you're unaware of, like, uh, in the pancreas or in the colon or in the lung? Could NAD over time, day after day after day, could favor that glycolytic flux to that tumor and, and, and increase the growth?

    2. PAPeter Attia2:38:15

       In the literature, I'm, I've never looked, because it just kind of occurred to me when you had that slide up earlier, right, earlier when you showed the mitochondrial slide.

    3. ISIñigo San-Millán2:38:23

       Yeah.

    4. PAPeter Attia2:38:23

       Um, it occurred to me that there you have that lactate escape from the tumor.

    5. ISIñigo San-Millán2:38:26

       Mm-hmm.

    6. PAPeter Attia2:38:26

       Hey, this would feed it. But has anybody in the literature examined this question? It seems like a very common... It, it seems like a, a, a reasonable question to ask.

    7. ISIñigo San-Millán2:38:36

       Yeah. I, there are a couple studies, um, I think one's a review. Uh, it, it's more at the conceptual level, right? And this is what got me thinking like, yeah, this is, this is something that for us working in cancer metabolism, we look into this, right? Uh, um, looking at, you know, like obviously, you know, one of the things that we have shown is that lactate is an oncometabolite. Lactate, it, uh, uh, we have shown, uh, we have a first paper, and we have, like, a, like, a good six, seven papers more to come. Uh, we've been working hard for three years looking into this. But we saw that lactate regulates the, um, um, ge- the genetic expression of the m-most important genes in breast cancer. We're, we're seeing the same thing now with lung cancer. Uh, uh, and lactate, as we keep talking about this, is the, is the mandatory byproduct of glycolysis. And, and as Warburg saw in 1923, uh, the characteristic of cancer cells or most cancer cells is the high glycolytic flux. But what struck Warburg was not the glucose itself, was the lactate production. Um, so anyways, we, we are showing that it's an onco-metabolite. So if you f- if you have a high glycolytic rate in a cell, you're gonna produce a lot of lactate, right? Uh, if you cannot clear that lactate, it's going to drive cell growth and proliferation, as we're seeing. And in fact, we're now, um, uh, blocking lactate production, both through genetic engineering as well as DCA, for example, and we're seeing that, uh, cancer, uh, growth and proliferation completely stops within hours. So, uh, again-

    8. PAPeter Attia2:40:16

       Now, that poses an interesting dilemma, right?

    9. ISIñigo San-Millán2:40:18

       Yeah.

    10. PAPeter Attia2:40:18

        Which is exercise would increase your capacity for clearing lactate in the long term, but in the short term raises lactate. So it begs the question, in a cancer patient specifically, what's the net impact of exercise?

    11. ISIñigo San-Millán2:40:35

        Yeah. So, uh, this is what we're working on, the, the, the hypothesis, you know, with my colleague, George Brooks. Um, so he's shown that acute response to lactate, uh, it increases, uh, overexpression, um, uh, about 600 and something genes. I forgot right now, right? All these genes are involved in cellular homeostasis and in the benefits of exercise, right? So we know very, very well through his work that lactate is a signaling molecule. Now, the question is, like, we, we know this at an acute exposure, which is exercise. You do exercise, boom, boom, boom, you're out. But cancer, uh, uh, uh, doesn't do that. Cancer accumulates lactate, and it keeps accumulating, and this i- this is the main responsible for the, uh, um, um, tumor microenvironment, which is acidic. And the more acidic the tumor microenvironment, the more metastatic the cancer is and the more aggressive. Like, the more glycolytic a tumor is, and this is very well documented, the more glycolytic the tumor is, the more aggressive it is. And the more lactogenic, that is more lactate, uh, the tumor produces, the more aggressive it is. Now, why is that lactate accumulating, right? That's what we need to try to find out. But we know that that, that acu- that, that, that is not acute anymore. It's chronic exposure to lactate. Um, so can exercise counteract that, right? Um, uh, when we see that exercise might be beneficial for many patients, but again, going back to the right intensity. Uh, we know the, um, the particles which are exosomes, right? They're microvesicles in the body. They're main responsible for metastasis. We have seen that, uh, and this is another publication we're gonna have in, in, in breast cancer cells, in lung cancer cells. Uh, we are looking at the protein content and the microRNAs of those exosomes released by these cancer cells, and it's incredible the information that they have there. Uh, if you were to genetically engineer, uh, um, a molecule that can be, um, um, uh, you know, injected into a tissue and transform into cancer, you would replicate an exosome. It has, uh, all the components needed. On the, on the other side, muscles also release exosomes, and this is, could be one of the why the benefits of exercise as an organ, you know, in the crosstalk between skeletal muscle and messy, many organs. Uh, we know that if you have, um, um, a very good, um, muscle health, right, your health overall, your metabolic health is gonna be good. Could you be releasing great exosomes? They're very, uh, pro-oxidative, uh, which counteract the glycolytic phenotype of cancer, and could those exosomes travel directly to the cancer cells and, uh, and counteract that, and penetrate into, inside the cancer cells, and transform the glycolytic phenotype of the cancer cells into more oxidative phenotype and keep cancer at bay? We don't know yet, but we're, we're suspecting that, uh, we're scratching the surface of something that potentially could be a very interesting thing to understand better the effects of exercise as well as neurotherapeutics.

    12. PAPeter Attia2:43:55

        Yeah, I just, I, I mean, the more, the deeper I go in the rabbit hole into all things that relate to longevity, the more convinced I am that if you're gonna rank order things, if you were forced to rank order things, you c- there's nothing that ranks above exercise as the single most potent tool or agent we have to impact longevity. And yet, paradoxically, in the acute setting, exercise seems to do everything incorrectly, right? In the very short, acute setting, if you look at it in that narrow context, exercise does not appear to be geroprotective. But of course, when you look at the chronic impacts of exercise and what's taking place after the bouts of exercise, uh, the data seem undeniable.

20. 2:44:42 – 2:52:57

    How assessing metabolic parameters in long COVID patients provides insights into this disease

    1. PAPeter Attia2:44:43

       Uh, I wanna kind of pivot from exercise a bit into a subset of that, which is something you published this year in long COVID patients.

    2. ISIñigo San-Millán2:44:51

       Mm-hmm.

    3. PAPeter Attia2:44:52

       So, um, y- you know, we'll, we'll link to the study so people can see it, but you demonstrated that in people with long COVID Uh, even previously healthy people, they basically from a mitochondrial standpoint end up looking like people with type 2 diabetes when they're done in terms of fat oxidation, lactate production.

    4. ISIñigo San-Millán2:45:15

       Yeah.

    5. PAPeter Attia2:45:16

       So first question for you is, what fraction of patients recovering from COVID do you believe are susceptible to that phenotype?

    6. ISIñigo San-Millán2:45:25

       That's, that's a great question, and they're trying to understand that. So, um, everything is started by, um, you know, National Jewish Hospital is, is, is probably, if not always with Mayo Clinic, competing for the top one pulmonology hospital in the country. So, um, you have these people with long COVID who are, are struggling, you know. Um, they, they go up the stairs and they can't breathe. So the first thing they do is they go to different doctors, and they end up going to this top hospital. So they do, uh, um, um, you know, pulmonary function test, and it's completely normal. They, then they, okay, the next suspicion is because COVID also affects, um, um, um, the, the cardiac muscles, right? So let's just do a-- let's look at the cardiac function. It's completely normal. And, uh, uh, they're very good at this hospital where they do, um, uh, metabolic testing. They do, uh, CPET testing. That's how you call it medically, right? Uh, the physiological testing, and they even do lactate. We've been-- I've been interacting with them a few times. So they do lactate, uh, as well. So they contacted me and, and said, "Iñigo, look, we've seen these patients. We have 50. 25 of them, they had previously, you know, underlying conditions," right? The other 25, uh, they were normal people, and in fact, uh, most of them, they were moderately active. Some of them, they were doing marathons, triathlons, you know, and, uh, the average is 50, so they're not, you know, very old either. So but their pulmonary function is completely normal and cardiac function is completely normal, so we suspected there's some metabolic issue here. So they send me all the information, the raw information, and I apply the methodology that, uh, that we've been discussing, ri-right? Looking at fat oxidation and lactate, um, uh, production as a surrogate for metabolic function and-- or, or metabolic flexibility and mitochondrial function. And I was shocked because they were significantly worse than people with type 2 diabetes and metabolic syndrome, which could explain why these people cannot go up the stairs and where before they were doing marathons. Now, w-what are the mechanisms? Uh, we know that, um, uh, viruses, multiple viruses are, are known to hijack mitochondria for their own benefit to-- for reproduction. Uh, could COVID do the same thing? So I'm sus- we are suspecting it, and we're trying to understand that, uh, at a more at a cellular level. Now, unfortunately, the majority of these long COVID, 'cause as you know, there are people with long COVID syndromes that within weeks, months, they improve, they go back to normal. But there are a handful of people, um, that I am assuming they're gonna be growing, right? That after one year they haven't improved a bit. This is the concern. Like, can we do e- can we use exercise as a therapeutic way to stimulate mitochondrial function if in fact there's a mitochondrial dysfunction which is severe? Because if that's the, the situation, it's gonna expose these patients to multiple diseases, right? Um, so this is, uh, an area of concern.

Episode duration: 3:15:40