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Iñigo San-Millán is an internationally renowned applied physiologist and a previous guest on The Drive. His research and clinical work focuses on exercise-related metabolism, metabolic health, diabetes, cancer metabolism, nutrition, sports performance, and critical care. In this episode, Iñigo describes how his work with Tour de France winner Tadej Pogačar has provided insights into the amazing potential of elite athletes from a performance and metabolic perspective. He speaks specifically about lactate levels, fat oxidation, how carbohydrates in food can affect our lactate and how equal lactate outputs between an athlete and a metabolically unhealthy individual can mean different things. Next, he discusses how Zone 2 training boosts mitochondrial function and impacts longevity. He explains the different metrics for assessing one’s Zone 2 threshold and describes the optimal dose, frequency, duration, and type of exercise for Zone 2. Additionally, he offers his thoughts on how to incorporate high intensity training (Zone 5) to optimize health, as well as the potential of metformin and NAD to boost mitochondrial health. Finally, he discusses insights he’s gathered from studying the mitochondria of long COVID patients in the ICU.

We discuss:
0:00:00 - Intro
0:00:10 - The amazing potential of cyclist Tadej Pogačar
0:06:54 - Metrics for assessing athletic performance in cyclists and how that impacts race strategy
0:17:20 - The impact of performance-enhancing drugs and the potential for transparency into athletes’ data during competition
0:26:06 - Tadej Pogačar’s race strategy and mindset at the Tour de France
0:29:58 - Defining Zone 2, fat oxidation, and how they are measured
0:40:04 - Using fat and carbohydrate utilization to calculate the mitochondrial function and metabolic flexibility
0:44:30 - Lactate levels and fat oxidation as it relates to Zone 2 exercise
0:59:54 - How moderately active individuals should train to improve metabolic function and maximize mitochondrial performance
1:06:27 - Bioenergetics of the cell and what is different in elite athletes
1:19:19 - How the level of carbohydrate in the diet and ketogenic diets affects fuel utilization and power output during exercise
1:27:27 - Glutamine as a source for making glycogen—insights from studying the altered metabolism of ICU patients
1:34:27 - How exercise mobilizes glucose transporters—an important factor in diabetic patients
1:39:00 - Metrics for finding Zone 2 threshold—lactate, heart rate, and more
1:58:27 - Optimal Zone 2 training: dose, frequency, duration, and type of exercise
2:10:22 - How to incorporate high intensity training (Zone 5) to increase VO2 max and optimize fitness
2:23:25 - Compounding benefits of Zone 2 exercise and how we can improve metabolic health into old age
2:27:57 - The effects of metformin, NAD, and supplements on mitochondrial function
2:37:45 - The role of lactate and exercise in cancer
2:44:42 - How assessing metabolic parameters in long COVID patients provides insights into this disease
2:52:57 - The advantages of using cellular surrogates of metabolism instead of VO2 max for prescribing exercise
3:02:30 - Metabolomics reveals how cellular metabolism is altered in sedentary individuals
3:08:49 - Cellular changes in the metabolism of people with diabetes and metabolic syndrome

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About:

The Peter Attia Drive is a weekly, ultra-deep-dive podcast focusing on maximizing health, longevity, critical thinking…and a few other things. With over 40 million episodes downloaded, it features topics including fasting, ketosis, Alzheimer’s disease, cancer, mental health, and much more.

Peter is a physician focusing on the applied science of longevity. His practice deals extensively with nutritional interventions, exercise physiology, sleep physiology, emotional and mental health, and pharmacology to increase lifespan (delay the onset of chronic disease), while simultaneously improving healthspan (quality of life).

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Hey everyone, welcome to the drive podcast.

It is so great to be sitting down with you again.

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.

But that said, I really hope you can get out here to Austin so we can train together and do some cool ex-fiz.

And also I need to get out there to sort of do some of the ex-fiz stuff we've talked about.

But you know, I almost don't know where to begin because there's so much stuff we talked about last time that we want to double click on this time.

There's so much that has changed in the interval from when we spoke, gosh, probably 2 years ago, a little over 2 years ago.

Something we didn't really talk about last time, was your work with, Teddy Pogacar, because of course, I don't think anybody knew who he was 2 years ago or 2 and a half years ago.

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.

He looks like something of a different species almost.

And I say that not in the way that people typically say those things of cyclists 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, the UAE team and your work with, Teddy Pogacar, maybe give folks a little bit of an update as to what you've been doing with in professional cycling over the past couple of years.

Well, first of all, thank you very much for, for having me here.

It's a, it's an honor and, really excited for this.

I had a lot of fun last time and I hope to have fun again.

Yeah, my work with with Kade started in late 2018 when he signed up for the team.

And yeah, I was introduced to him by our CEO, Genetti, and our general manager, Machin.

And they told me, hey, just start working with this guy.

And yeah, so I started to work with him and right away I realized that he had very good potential.

And I think like a couple of months earlier, no, or later, I forgot when we had that podcast, I already told you about him, right?

And yeah, and I told him like, yeah, we have a guy that has good potential.

And to put it in perspective, I mean, has good potential is 1 thing.

To then go and do what he did would make that statement the understatement of the century for folks who maybe don't follow cycling as closely, right?

Yeah, I mean, I try to be cautious, right?

And I don't usually say that out loud of people who have...

When I say someone has good potential, it's very good potential.

I don't usually say that lightly of anybody, right?

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?

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

So when you say that, was it specifically his, 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 how he stood out.

So it's kind of like similar tests that I did to you.

And, and, and this is kind of like, where I, I saw that, 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, professional cyclists in this specific case, that's where I have my, my, cheat sheet, right.

Where I know I can categorize where people are.

And that was like, he was like, Whoa, wait on the other side, you know, way above almost everybody that I had tested 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 he's he's first year pro he's pretty much a junior and And then that's where like I could see he could sustain a high amount of power with very low lactate compared to the rest.

And then throughout the trainings, we use TrainingPeaks, the software.

Looking at TrainingPeaks, that's where I would see his different abilities to sustain a given power output for the whole day or for a specific effort, a glycolytic effort on a climb.

And it would see the power output that he would be putting out.

And so altogether, then I saw his trainability, how easy he would get the concepts, how easy he would be comfortable with the training, how easy he would recover.

I talk to him once, twice a day and over WhatsApp too, the feedback.

And I know very well when 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 because 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 a problem.

That's where you start putting together things.

And also around the same time with my 2 colleagues at the university, Angela D'Alessandro and Travis Nenkov, we started to develop a platform for metabolomics where we can look at hundreds, if not thousands of metabolites in the human body.

And We did it at the Tour of California in 2019, which was like around April.

And that's where we analyzed all his metabolites.

And we did already at the training camp in January

And we already saw, wow, this guy has different metabolites, you know, at the glycolytic level, oxidative level, recovery level.

And we confirmed that at the Tour of California.

And this is where putting all together, you know, I saw like, yeah, this guy is different.

So going back to what you said about lactate, I assume that 1 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, That would be a very, I mean, that might be 1 of the most telling graphs you could generate to predict success in the tour, correct?

You see someone at, you know, for example, a normal tempo climbing in the Tour de

France, tempo, ah, that is the whole peloton going up.

I was about to say, wow, I was going to say 4 and a half.

Okay, so wow, the whole peloton is going up at 5 watts per kilo.

And that's what you see like someone at that intensity might have already 6 millimoles.

So you can tell it's going to be very tasking and others might have 1 resting levels, you know, and this is where like this is it really, really predicts performance.

And you can really predict performance in an incredible way.

In fact, when we go to these training camps, Like I'm going to go next week for the first training camp of the year with the team.

We do this, physiological testing and I do this protocol and I get this data.

So right away, I tell the, the team managers, this, this guy is way about the rest, These 3 guys are really, really good immediately behind it.

And then we have all these guys that they're like really, really bad form.

Then we do different training, racing simulation and the Telebook right away.

And the same thing to move it into the season.

You see, okay, all these 3 guys are going to be at a very good level when we started the season.

This guy who we thought that he was going to be a very good level, he's not there at all.

So, and that when, when the season starts, you see that it reflects, very well, what's going to happen.

That's 1 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, 1 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, that'd be slightly above FTP at 70.

I think he was 70 to 75 kilos, but it was in the ballpark of 6 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 that's sort of where the race is won and lost because the race is won and lost by minutes.

It's for a race that is, how many hours does it take to complete the tour?

Yeah, an average about 5, 4 and a half, 5 hours a day.

And yet the difference between the first, second, third guy will be in some cases, seconds, in some cases, a few minutes for someone to win by 5 minutes is considered a blowout.

And it, 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 to me, that's 1 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 at lactate production.

So it gets even more into kind of the critical physiology of recovery.

Yeah, and in fact, we use this metrics a lot for the competition and we did it this year that through the France.

So knowing the power output that he could sustain for, as you very well said, for specific times and climbs, we knew his capabilities.

And 1 of the things that we knew was that in the Alps, he was at a very, very high level.

So like that famous stage where he broke away in Col du Rhum, 35 kilometers to the finish line, we were seeing not only his data, but we see by knowing our writer's data, you can also guess the other writer's data too, right?

So we knew that he was at a very high level and discussing the tactics, you know, because it's part of the thing that we do.

We observe the data that we have, the data that we think the other ones have, and we structure a strategy for the next day.

And hey, does he have the legs to attack?

Should be holding back or what should we do?

And clearly it was like, well, tomorrow, if he attacks 35 kilometers to the finish line, he's going to get there with 3 minutes because 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.

And discussing this with him and the and the manager.

First test the legs and like if you had in fact good legs, boom, try to go for it.

Now, how much of that are you going to determine after a night of sleep, right?

Where you say, we're going to look at his resting lactate first thing in the morning.

We're going to look at his heart rate overnight.

We're going to 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.

Yeah, I think it's more of the latter, right?

Where we have all that physiological data that and the trends and how it is.

And what we see at this level, these guys, they're so good at knowing their feelings.

Sometimes it's just kind of how they wake up.

If you know his capabilities, so if he wakes up fresh and say, hi, how are you doing today?

You're like, oh yeah, I slept like a baby.

You know, and sometimes, yeah, it's just we try not to focus on many other metrics the day off because we have already things and sometimes, you know, Hari Variability, you know, it might not be very precise and we don't want to get then put some ideas in the head.

And in fact, speaking with him, and I'm not going to mention any brand or anything, but looking at Hari Variability someday he said like, look, today he told me that I was fatigued, that algorithm, And I went out there and beat my record.

And, on the climbs, obviously I'm not fatigued, you know, another, other days it tells you you're in top form and, and, I feel a little more fatigued, you know, so this is what these algorithms, we, we need to be careful sometimes and might work with maybe general population, but with this type of athletes, at this level, I really feel that it's better once you have all the work done and they know, you know, you know their capabilities, like, are you ready to go?

You know, it's like, it's like a top, performing performer at a theater, right?

Now it's up to like, are you ready to go?

You know, do you have a good night's sleep?

And a good performer say, yes, I'm ready to go.

Even for me, and I'm not a top level anything, I have not found the predictors of, you know, readiness to be very accurate or to necessarily reflect how well I'm going to perform.

I've had amazing performances by performances.

Like that's, that's the only metric I'm performing in.

When my prediction was that it would not be good.

And I've also had the prediction saying you're on top of the world and I've not performed well.

So, you know, I wish I could say with more clarity what the frequency of those deviations or discordances are, but I can agree that putting the wrong idea in somebody's head when the predictive, when there's nothing you can do about it.

It's sort of like at best, if it was perfectly accurate, it would be great because you could say, look, today, maybe we shouldn't attack today.

You know, 1 of the things I want to ask you about here, and you've spoken about this publicly, so it might be that you're just going to restate the views that you've shared publicly.

But 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 2 decades of the nineties and 2 thousands.

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 we're able to put out somewhere between about 6.8 and 7.1 Watts per kilo, 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, they've just found new ways to cheat, but it's still basically a dirty sport.

Because 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.

And it's something that, yeah, it frustrates me, right, when people think that they're doing 7 watts per kilogram, you know, or 7.2, you know, And then you have the real data from the day.

For example, the short climbs where they would do maybe 7.2, now they're doing 6.3 maybe.

So it frustrates me because I see this data and I always like, gosh, I wish I could just, boom, release it.

You know, like a white way, keeping all these at the end of the day, people can figure that out.

And some people, when I see on the internet, because you can see the weight of the cyclist.

The grade, when it starts, the time, and the wind, you can be very accurate knowing that.

And I see some people that are quite accurate in the internet, but I see other ones that will lower them up.

You know, otherwise they say, I did the formula in 7.2, like, my gosh, I wish I could show him, hey, this is the real data that we're seeing.

But I guess like 2 points there is like 1, it's private data that the team considers like release it, that's team policy.

But the other 1 too is like, you know, even if you release that data, there are always going to be people that are not going to believe you or they might say, oh, they probably altering the data or 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 don't know if it'll be an endless fight, you know.

I just have that frustration that I wish that I could really show that data and people can see it, you know, but there's always going to be someone who is not going to believe it and going to make a lot of noise out of that.

But yeah, But that's the other thing too, is like other teams and other writers are releasing their data, right?

So by releasing their data, you can see pretty much where Pogacar is, you know?

Like, okay, if it's a minute ahead or 30 milliseconds, or sometimes with the same time, you can see, you know, like, whoa, if whatever the writer has done and has entering Bogazar's group or 30 seconds later and has done 5.9, Bogazar is going to be in that neighborhood, right?

Not going to be 7, you know, with 30 seconds ahead.

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 1 of the things about formula 1 that I think the sport has been able to do because of the 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 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.

They could show even more data, certainly, and someone who drives 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 you see the bumps 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?

I would love it because I, it would be so much fun, right?

And, and as you see, I mean, cycling has so many possibilities, you know, to engage people more and, and, and be fascinated by the physiology and looking at these numbers.

It's already in a way, you know, you see some cameras already installed in the front and the back.

So you can see really cool when that, I mean, images when they're preparing a sprint that is like what feels inside and you can see it's really scary.

Sometimes you can appreciate how difficult it is to be at, you know, like a 40 miles an hour sprinting or 35 miles an hour leading to a sprint or in a descent.

And then you can see the power also output in real time.

It's still in that, I think it's a great step.

You don't see in all the riders, but it's estimation only the riders who wear that Vellon or the Vellon decides to do that.

I think that they're still not doing that with all the top contenders, but I think it's a first step and obviously haven't spoken with them, but maybe it's like, hey, let's see what's the feedback.

And I would expect that this will increase, you know?

And I mean, I would love at some point, you know, and as you know very well, that doing the world of biosensors, right, is going to revolutionize sports, where we're going to be able to see, you know, so many different parameters of athletes.

Imagine you could see lactate and glucose in real time.

Which of course is technologically feasible already, so it's just a

So I think that would love for all sports too, right?

Imagine you can see an NBA basketball game, right?

And see that the lactator of LeBron James compared to the other ones, right?

I mean, I would love to see that as a spectator And I hope that someday we were able to see these parameters.

So last thing on the tour, talk to me about Vanthu this year.

Also, I mean, it looked like his toughest stage.

And what's amazing, I think, is the poise on that stage.

It's hard to tell if he was really struggling on the ascent of Van Tu or he was just deciding strategically, I'm going to conserve a little bit of energy here.

What was your take on that or what can you say about that?

Well, it was a very difficult climb and a very long climb.

So you know, Tadej, his mentality is wired, you know, like a champion.

And he, when someone goes and they were full gas in the last part, when Rene Garo attacked.

And you know, Tadej knew that, okay, this is not going to be the top of Bon Ventoux is not going to be the end of the stage.

have a long descent where I could make it.

And I have some partners with me that can help me out.

So I'm not going to panic at all, but I'm not going to also try to waste a lot of energy because I need to now be I have and he also had a big gap you know the whole different thing would have been if he had 20 seconds but having a big gap and knowing that you have a big descent and how calm he is.

That's 1 thing that it's a very important strategy and this is probably, you know, this is what happened.

I have, 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.

It was the previous stage before what's called Bear Lake.

Yeah, it's the top mountain, right, in the tour of California where it's going to be decided.

So the day before 2 cyclists George Bennett and Yigita attacked in a short but very steep climb and there were only like 12 riders left and Yigita and Bennett attacked.

Then there was like a descent and a long highway all the way to the finish line.

So there was plenty of time to catch him up, but Tale didn't follow them up.

No, another rider would have just followed their wheel and Tale decided, no, I'm not gonna follow them.

We have time and I'm gonna take the chance because I'm confident for tomorrow.

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