Peter Attia MD#85 – Iñigo San Millán, Ph.D.: Mitochondria, exercise, and metabolic health
EVERY SPOKEN WORD
150 min read · 30,047 words- 0:00 – 0:04
Intro
- PAPeter Attia
[upbeat music]
- 0:04 – 7:51
Why the Podcast Has No Ads and Today's Guest
- PAPeter Attia
Hey, everyone. Welcome to The Peter Attia Drive. I'm your host, Peter Attia. [upbeat music] The Drive is a result of my hunger for optimizing performance, health, longevity, critical thinking, along with a few other obsessions along the way. I've spent the last several years working with some of the most successful top-performing individuals in the world, and this podcast is my attempt to synthesize what I've learned along the way to help you live a higher quality, more fulfilling life. If you enjoy this podcast, you can find more information on today's episode and other topics at peterattiamd.com. [upbeat music] Hey, everybody. Welcome to this week's episode of The Drive. I'd like to take a couple of minutes to talk about why we don't run ads on this podcast and why instead we've chosen to rely entirely on listener support. If you're listening to this, you probably already know, but the two things I care most about professionally are how to live longer and how to live better. I have a complete fascination and obsession with this topic. I practice it professionally, and I've seen firsthand how access to information is basically all people need to make better decisions and improve the quality of their lives. Curating and sharing this knowledge is not easy, and even before starting the podcast, that became clear to me. The sheer volume of material published in this space is overwhelming. I'm fortunate to have a great team that helps me continue learning and sharing this information with you. To take one example, our show notes are in a league of their own. In fact, we now have a full-time person that is dedicated to producing those, and the feedback has mirrored this. So all of this raises a natural question. How will we continue to fund the work necessary to support this? As you probably know, the tried and true way to do this is to sell ads. But after a lot of contemplation, that model just doesn't feel right to me for a few reasons. Now, the first and most important of these is trust. I'm not sure how you can trust me if I'm telling you about something when you know I'm being paid by the company that makes it to tell you about it. Another reason selling ads doesn't feel right to me is because I, I, I just know myself. I have a really hard time advocating for something that I'm not absolutely nuts for. So if I don't feel that way about something, I don't know how I can talk about it enthusiastically. So instead of selling ads, I've chosen to do what a handful of others have proved can work over time, and that is to create a subscriber support model for my audience. This keeps my relationship with you both simple and honest. If you value what I'm doing, you can become a member and support us at whatever level works for you. In exchange, you'll get the benefits above and beyond what's available for free. It's that simple. It's my goal to ensure that no matter what level you choose to support us at, you will get back more than you give. So for example, members will receive full access to the exclusive show notes, including other things that we plan to build upon, such as the downloadable transcripts for each episode. These are useful beyond just the podcast, especially given the technical nature of many of our shows. Members also get exclusive access to listen to and participate in the regular Ask Me Anything episodes. That means asking questions directly into the AMA portal and also getting to hear these podcasts when they come out. Lastly, and this is something I'm really excited about, I want my supporters to get the best deals possible on the products that I love. And as I said, we're not taking ad dollars from anyone. But instead, what I'd like to do is work with companies who make the products that I already love and would already talk about for free and have them pass savings on to you. Again, the podcast will remain free to all, but my hope is that many of you will find enough value in, one, the podcast itself and, two, the additional content exclusive for members to support us at a level that makes sense for you. I want to thank you for taking a moment to listen to this. If you learn from and find value in the content I produce, please consider supporting us directly by signing up for a monthly subscription. My guest this week is Iñigo San Millán. Iñigo is a assistant professor at the University of Colorado School of Medicine, where his areas of research focus on exercise metabolism, nutrition, sports performance, overtraining, diabetes, cancer, and critical care. And I realize at least one of you at this moment is thinking, "How in God's name can one person study all of those things?" And the answer is, if you come at it through the lens of the mitochondria, it turns out you can have a breadth of focus that covers all those things. And of course, that's exactly what Iñigo does, is he studies mitochondrial performance and mitochondrial efficiency. And it's based on that, that the moment he and I met a year ago, it was a sort of love at first sight, and we've been geeking out together ever since. Iñigo has had a profound impact on my training, the way I talk to my patients about exercise, and the way I've thought about longevity through the lens of mitochondrial performance. He is an internationally renowned appi- applied physiologist. Uh, he's worked for at least 20 years with many professional teams, elite athletes across all sports. He himself is a remarkable athlete, which we barely get into. He's so modest and unassuming. He currently works with a number of professional cycling teams at the highest level, including at the level of the Tour de France. He's pioneered a number of things that we get into here, everything from using high-frequency ultrasound to assess glycogen levels to, more importantly, ways in which we can use biopsies at the invasive level and blood tests at the less invasive level to draw on the insights of mitochondrial performance. It would take me an hour to simply explain The treasure trove of stuff we explore in this episode, so I'm not even gonna try to say what we get into other than if you're interested in mitochondria, if you're interested in fitness, if you're interested in exercise, if you're interested in metabolic health, all of the above, I think you just need to listen to this one and take my word for it without seeing the running commentary. The show notes, of course, will be especially important for this one because some of this stuff just is better explained through pictures than words, and of course, there will be a nice, effective table of contents there. So without further delay, please enjoy my conversation with Iñigo. [upbeat music] Iñigo, thank you so much for making time to sit down today in your new office here.
- IMDr. Iñigo San Millán
Thank you very much, Peter. It's my pleasure and honor that you're here with us at the University of Colorado at the School of Medicine. [chuckles]
- PAPeter Attia
I emailed my team. I mailed Nick and Bob and a couple of the guys today when I was on the way over here. I was on the plane, and I was reviewing my notes, and I thought, "I am so excited to sit down with you today and Rick tomorrow," because we've had so many kind of off-the-cuff sidebar conversations about mitochondria, mitochondrial function, health, efficiency, et cetera, and it's sort of like we never have enough time. It's like 15 minutes here and 12 minutes there and an email here and an email there, but it was in preparing for this, the team helped me really kind of put a lot of my thoughts together. But I think before we kind of get into the really hardcore stuff around mitochondria, which is something that I think anybody who's interested in health at any level, whether it's really at the deep cellular level or just at the level of I wanna live as long as I can, as healthy as I can, everybody sort of has a sense that all roads point to the mitochondria. But your path to getting there to me is particularly interesting because it starts with looking at athletes. And you yourself, even though you downplay it a lot, you were quite the athlete growing up. So you grew up in Spain, and what sports did you play?
- 7:51 – 13:09
From Real Madrid Academy to Pro Cycling and Science
- IMDr. Iñigo San Millán
Yeah, I grew up in Spain, and I played for Real Madrid at the academy for six years, and I was always very passionate about sport. Then I-- when I turned 16, I discovered cycling and, and that's the way I changed sports. So my dad still thinks that was the dumbest decision [chuckles] of my life. But-
- PAPeter Attia
Is that true statistically? Would a child growing up in Spain who's already in the feeder program for Real Madrid, would they have a better chance of having a career as a professional football player than a professional cyclist?
- IMDr. Iñigo San Millán
That's hard to say, but when you're already at that age in Real Madrid, you can be-- getting to the top team is very difficult obviously, but definitely be a feeder to other smaller teams. That's a higher possibility, but you never know. But you have to follow your passion, I guess, and I followed it, and I changed to cycling, and I got to race professionally for two years at a low level. So I always say that I admit it, I'm a truncated and a frustrated professional athlete 'cause I never got to the top. But that said, I learned a lot, and it's been a school of life all my life. Since I was nine years old, I've been in the high level of competition up until today on the other side of the table working with athletes, and that's what I became very familiar with everything related to the elite sport and that everything it involves.
- PAPeter Attia
I don't think most people who have not themself been on a bicycle and trying to do something at a reasonably high level can appreciate that even being a professional, quote-unquote, low level-- I assume what you're saying by that is you were not necessarily on a team that was even gonna go to the big Grand Tours and such, but I still think most people don't understand the level, how much higher that is above a general fitness athlete type of thing. So when you were at that level, what was your specialty? Were you a time trialist? Were you-- uh, you look too tall to be a climber, but who knows what you weighed back then.
- IMDr. Iñigo San Millán
Yeah, I was very skinny though.
- PAPeter Attia
You're taller than me. You're how-
- IMDr. Iñigo San Millán
I'm like 5'11".
- PAPeter Attia
Okay, so you're an inch taller.
- IMDr. Iñigo San Millán
But I used to be 143, 145 pounds.
- PAPeter Attia
Oh, wow. Okay.
- IMDr. Iñigo San Millán
So I was very skinny. So I used to be a good climber. I was good overall, but I'm better as a climber. But yeah, I, I-- is that I appreciate it now when I see people who are category ones or twos or threes as a cyclist or so that their fitness level is very good, that definitely my fitness level was better. But at the same time, there is like a whole world between my fitness level and what the Tour de France guys have.
- PAPeter Attia
It is unbelievable. When I was sort of going through category five, four, three, two, by some metrics, I could maybe time trial at the level of a category two, three, but of course, my climbing and sprinting and everything else would have been like a category four, and you realize that the guy who's category one, the guys I used to train with who are collegiate athletes who are exceptional at category one, they're still not even pro. There's still a step between them and a domestic pro, and then the domestic pro to get from that level to a European pro, and then the European pro to get to a major team, and then to be on a major team and the difference between the GC contender and everybody else. We're talking about log orders of ability. It's not subtle.
- IMDr. Iñigo San Millán
No, and I have all the data from all these years collecting the data, and I know very well the p- physiological parameters typical of a top junior athlete or category three, category two, one, domestic pro, average pro tour cyclist, and best of the best, and the difference is amazing. They're very significant. You can really categorize people accordingly.
- PAPeter Attia
We're gonna come back and start to talk about professional cycling and things, and there's so many things I want to talk about because I think for also the person who's not immediately wed to the sport might too easily want to dismiss the accolades of these athletes and the physiologic prowess as simply, well, you know, those guys all use drugs. And while that's probably true at some level with respect to some drugs and certainly a certain class of athletes, it in no way diminishes what their physiology looks like completely off drugs. So we'll come back to all that. But going to you, so after two years at a professional level, what made you decide, "I'm not gonna continue doing this. I'm going to pursue my education," and the other things that you've gone on to do?
- IMDr. Iñigo San Millán
I realized that it's very difficult, and you need to be at the right place at the right time at the right moment, and that different planets need to be aligned. It is not just the best always get up there to-- call it destiny, call it whatever, but a lot of things have to happen to become a pro, and I-- they were not on my side. But at the same time, I needed to make a decision either Trying to get an education that can not assure me, but at least give me some future professionally speaking outside the sport or try to go for the sport where I-- the planets were not aligned. I didn't know if I could even make it, and, uh, it would take that sacrifice. So that's what I, I decided, "Eh, I think this is not good for me." And then I, as I was studying also, I had a good possibility of doing a very good internship at a top, if not the top sports medicine clinic in Spain. In fact, the famous PRP therapy was born in that clinic.
- PAPeter Attia
Oh, wow.
- IMDr. Iñigo San Millán
And that's where I said, "Hmm," I had a good possibility to start internship and then became a part-time job. And at that time I said, "Okay, I'm just gonna stay here and continue." [chuckles]
- PAPeter Attia
And how long have you been here at the University of Colorado?
- IMDr. Iñigo San Millán
Eleven years.
- 13:09 – 23:02
Meeting in Abu Dhabi and the Energy Systems Explained
- PAPeter Attia
Okay. Now you and I met through an interesting circumstance. It's a funny story. I don't know if you remember the very first time, but I had just flown into Abu Dhabi, and I think I came straight from the airport to the training facility, and it was like 11 o'clock at night or something, and you put me right on the bike and we did a VO2 max test. And which anybody who's done a VO2 max test on a bike knows there's nothing very pleasant about it. You've got this mask that is incredibly restrictive. I hadn't done one since I stopped cycling, so that was probably six, five years or six years. And then I think you weren't happy with the air mixer 'cause we were getting weird numbers, and it was-- at some point, I think, when I hit about 50 milliliters per milligram per kilogram, we sort of said, "That's enough." And it was a good thing 'cause I don't think I had much more. [both chuckling] It's amazing how much you lose when you stop training-
- IMDr. Iñigo San Millán
Yeah
- PAPeter Attia
... that zone.
- IMDr. Iñigo San Millán
Yeah.
- PAPeter Attia
I never thought there could be a day when my VO2 max could be below 50.
- IMDr. Iñigo San Millán
Yeah.
- PAPeter Attia
Like, I thought it'll be 50 when I'm 100, right?
- IMDr. Iñigo San Millán
Yeah.
- PAPeter Attia
That's not true.
- IMDr. Iñigo San Millán
Yeah.
- PAPeter Attia
It really falls away.
- IMDr. Iñigo San Millán
Yeah, it falls apart. Yeah.
- PAPeter Attia
So I would be surprised if I could hit 55 today, actually. But we connected immediately because it was a great point in my life where I was almost-- I was sort of looking for direction as a former-- I don't even wanna use the word athlete to describe myself, but as a person who formerly took training very seriously to now someone who is trying to think about reshaping my training around longevity. It was a perfect collision of ideas because I was sort of in search of what to really focus on, and what we immediately clicked over was your protocol for zone 2 training, which you were instituting heavily with the UAE team and other folks that you were training there, and the rest is history. I mean, it's really completely shaped the way I think about using this type of training as a way to improve mitochondrial function and as a way to test it. I almost think at this point for the listener, we should pause for a moment and explain these energy systems because so much of what I wanna ask you about and so much of what your research focuses on assumes a level of understanding I don't wanna take for granted. So maybe explain for people what aerobic metabolism means.
- IMDr. Iñigo San Millán
Okay. So there are different energy systems, and those energy systems, they're also used by different muscle fibers in the muscle. There are different conditions like the aerobic condition and anaerobic condition. We tend to believe that the immense majority of activity that we do is aerobic. We tend to believe that any hard effort is anaerobic and therefore the concept of anaerobic threshold. But actually, even what we call the anaerobic threshold is an aerobic activity. So the majority of the efforts that we do are in, in an aerobic environment, except for when you do a sprint or when you do, uh, maybe like a one-minute maximal. Outside that, the majority of the activities that we do are in the aerobic state. Then what changes is the fuels that you use to produce energy. So at the end of the day, what we want to do is to contract the muscles and not only to contract them as fast and as forceful as possible, but what we want also is to do this as efficiently as possible. So for example, for a marathon race or for a 1,500-meter race, you need to calculate when you pull the trigger and go for it, and then when you have to deploy all the maximum efficiency that you have. So you need to be very efficient metabolically speaking. So the fuels are very important for that. So the main fuels that we use for exercise are the fatty acids and glucose, and those are oxidized or burned in the different skeletal muscle fibers that we have. So we have the slow twitch muscle fibers and the fast twitch muscle fibers. The fast twitch muscle fibers are divided in two, the type one A and type two B, if you will. Some people call them type two X as well, but there are two kinds of muscle fibers.
- PAPeter Attia
Now, I just wanna interject for a moment because I know a lot of people listening to this have heard the term fast twitch and slow twitch, and the assumption is that they twitch at different speeds, but really, it's that they twitch with a different force, and the speed is referring to how quickly they fatigue, not the speed with which they fire. So when you're talking about a type 1 or a slow twitch muscle fiber, it's just a less forceful fiber, whereas a type 2 fiber, and as you said, they're divided into As and Bs, with each firing of-- with each time the muscle fiber fires, there are more motor end plates, and therefore it's generating more force. But the trade-off is it's going to be more quick to fatigue.
- IMDr. Iñigo San Millán
Mm-hmm.
- PAPeter Attia
And why is that? Why does it fatigue faster? 'Cause it comes down to what you're talking about.
- IMDr. Iñigo San Millán
Yeah. It's because the metabolically they're more stressed. The way we recruit muscle fibers or base a sequential pattern that is very similar to the stick gears of a manual car. So you first start and you go in first gear, and as the RPMs go up, then you get to a point you get to the red zone, so that car cannot keep up with that first gear. You need to shift to second gear, and you speed up and the RPMs go higher, and then eventually you need to shift to third gear. This is very similar- To what happens at the skeletal muscle. The type 1 muscle fibers, slow twitch, they can produce ATP, which is the energy coin, the classic that we always hear about, which is what elicits that muscle contraction. So at low exercise intensities, we don't need to contract the muscles nearly as forceful nor as fast as when we do high intensity.
- PAPeter Attia
Meaning we don't need to go back and keep firing and keep firing-
- IMDr. Iñigo San Millán
Exactly
- PAPeter Attia
... and keep firing. Yeah.
- IMDr. Iñigo San Millán
Exactly. And for that, we don't need to generate ATP as fast as we do at higher intensities. And it's about ATP generation that's exercise intensity. So at low exercise intensities, those slow-twitch muscle fibers or, uh, type 1 muscle fibers, they are very well designed to use an energy that is good enough to provide ATP, and yet you can do this for a very long time, and that's the diesel gasoline, and that is the fatty acids. However, as exercise intensity increases, the necessity to produce ATP at a higher rate increases as well, and it gets to a point where fatty acids alone are not enough to, uh, produce ATP. And therefore, you need another energy system, and that energy system is the glucose, which is a faster energy system. Which going back to the analogy of the car is like if we had-- imagine a car with two tanks. One is gasoline and the other one-- or regular gasoline, and the other one is diesel gasoline. So if you were to go from here to Denver to Kansas, where everything is flat, and you don't need to accelerate or go fast, you would try to be more efficient and would try to use then the diesel gasoline. It's more economical. You get more mileage per gallon. But if you want to go to the mountains and you need to accelerate fast, that diesel might not do the trick. You need extra acceleration, so that's where you utilize the glucose, and that's a very-- I mean, the regular gasoline, which is like the glucose for the muscles. And that's kinda how the bioenergetics or the muscles kinda principles start.
- PAPeter Attia
I like the way you've explained it, and I did a much worse job, I think, uh, probably seven years ago. I wrote a blog post on this. The insight I was trying to get across, I don't know if I did, was that we should not think of aerobic and anaerobic as with or without oxygen, which is sort of the way people are taught in high school biology. Aerobic means in the presence of oxygen. Anaerobic means not in the presence of oxygen. No. It's always in the presence of oxygen. It comes down to the speed with which the muscle is demanding ATP. Aerobic means you're generating ATP at a rate that is slow enough that all of the metabolic demands can be met through mitochondrial oxidation of, hopefully, mostly fatty acids, but even glucose. Anaerobic just means, exactly as you said, the demand for ATP has now exceeded the capacity of the mitochondria. Do you agree with that?
- IMDr. Iñigo San Millán
Yeah, and even the cytosol.
- PAPeter Attia
[clears throat]
- IMDr. Iñigo San Millán
So the cytosol, which is a part of the cell, that's where you can oxidize glucose there into pyruvate, and that pyruvate doesn't enter the mitochondria, but you produce lactate, but you produce energy and ATP there. And that can perfectly be still aerobic capacity. And my colleague George Brooks from Berkeley, he's been studying lactate since the '80s, and he's the one who proved that, that you can produce lactate under fully aerobic conditions, not necessarily in the mitochondria, but in the cytosol. However, when the ATP demands even exceed the cytosolic production of ATP, that's where you need to use the ATP that is already stored in the muscle. You just don't have time to synthesize it. You need just to use it, and that's why the body stores very, very minimal amounts of ATP, and that's what you develop in a sprint or you use in a sprint. But you need to resynthesize it very fast. That's the pure anaerobic. You don't need any energy systems. And that goes also that of the confusion that is out there too.
- PAPeter Attia
And are you saying this is distinct from the creatine phosphate system?
- IMDr. Iñigo San Millán
Yeah, you can use a creatine phosphate as well. So you can have ATP, and you can use a creatine phosphate system. Those two, they don't need oxygen necessarily. Anything else can be under fully aerobic conditions, like even cytosolic production of ATP in, in the cytosol without mitochondrial oxidation necessarily can happen under fully aerobic conditions. And in fact, that's what we also call aerobic glycolysis. And in other areas of biomedical research or medicine, it's called the Warburg effect, which is now a lot of people into cancer talk about it. The Warburg effect is that, is the production of lactate or the utilization of glucose in the cytosol, not in the mitochondria, but in the cytosol outside the mitochondria for production of energy.
- 23:02 – 26:11
Elite Athletes as the Model of Perfect Mitochondria
- PAPeter Attia
Well, I want to come back to the Warburg effect, but you brought up Brooks, and there's a paper that the two of you wrote together somewhat recently. I think it was maybe 2018, if not this year. But it's actually-- I'm in the process of writing a book, as you may recall. And in the exercise chapter, I actually really explore that paper that you guys wrote, which looked at the zone two efficiency of world-class cyclists, recreational athletes, and people with diabetes. That's an unbelievable paper, and that's an unbelievable example of, I think, the clinical applicability of what we're talking about. So to put it in context, when we got talking back in Abu Dhabi last year about this, I remember you saying, and I'm paraphrasing, so you should clarify if I'm not saying it correctly, that your interest in athletes is in large part due to your interest in diabetes because if you want to understand how to fix an example of arguably the most defective mitochondria, why not at least study what the perfect mitochondria look like? Is that a fair statement?
- IMDr. Iñigo San Millán
Exactly. Yes, and that's kinda what I'm trying to bring to the table, in the elite athletes have the perfect metabolism, and mitochondria is at the epicenter of metabolism and health, as you said earlier. There are no other population in the planet with the mitochondria of elite endurance athletes.
- PAPeter Attia
I was about to say, yeah, you said elite athletes. I would go even sharper.
- IMDr. Iñigo San Millán
Right.
- PAPeter Attia
It really, in my mind, comes down to cyclists and runners.
- IMDr. Iñigo San Millán
Yes, and triathletes. Yeah.
- PAPeter Attia
Even more than swimmers because of just the duration of it. It's these people who can go out and function at their anaerobic threshold for hours.
- IMDr. Iñigo San Millán
Yeah.
- PAPeter Attia
And that's only really found in two sports.
- IMDr. Iñigo San Millán
Oh, yes. And that's what we, we see that even within elite athlete, and I work with many elite athletes, yeah, you compare them, and there are huge differences.
- PAPeter Attia
I guess I should add one. I think cross-country skiers are probably at that level as well.
- IMDr. Iñigo San Millán
Yeah, those ones too. Yeah, so this population is the population in the planet with the healthiest mitochondria, so that's what I call perfection. And that's what I try to bring to the table, that in order to study other diseases where mitochondrial dysfunction is at the epicenter as well, we need to understand what perfection is in order to understand imperfection. And what we see in people with type 2 diabetes, for example, they are on the opposite metabolic pole of what a world-class cyclist or runner is. So by knowing the mechanisms of why that metabolism in these world-class athletes works, we can get to understand the imperfection or the imperfect metabolic pathways and potentially develop diagnostic tools and even therapeutics for them as well as prevention programs.
- PAPeter Attia
Yeah. And really, cancer and type 2 diabetes or insulin resistance as part of a spectrum do represent two very common findings in the population. So if you look at what percentage of the United States population either has cancer or is insulin resistant or has metabolic syndrome and/or type 2 diabetes or fatty liver disease, all of these things which are part of a continuum, you're talking about half the country basically that has some form of dysfunction in the mitochondria. In the case of cancer, we can debate how much of that is a genetic insult versus other things.
- 26:11 – 40:09
The Six Training Zones, Zone 1, and Lactate Myths
- PAPeter Attia
But because I want to talk so much about that, I want to go back and understand perfection a bit more. So there are lots of different ways people codify energy systems. When I was cycling, we used seven zones because that was Andy Coggan's FTP-based energy system. You write about six zones, and others have talked about five, but I want to talk about your six zones because, one, I think they're a little easier to explain than the FTP-based ones, which if you don't know-- if a functional threshold power number doesn't mean something to someone, then seven energy systems based on it [chuckles] is harder to understand. How would you walk us through zones one through six? What do they mean? Because when we start to talk about zone 2, I want people to understand the difference between the normal person and the super person and the sick person. So what is zone one? What does that mean?
- IMDr. Iñigo San Millán
So that's from 25 years working with athletes and also my experience from being a former athlete and being obsessed with training and, and all these things. That's kind of... it led me to develop this. I'm not saying that they're, they're right things, and maybe in 10 years I change my mind or someone else comes with different things that are better. But, uh, that's what I have right now at least. So I do this along with the muscle fiber recruitment pattern and the energy systems. So the type 1 muscle fibers, we know also that because they're the ones who oxidize fat, burn the fat very well, they have the highest mitochondrial density and content because fat can only be burned in the mitochondria. Type 2 muscle fibers, uh, especially the first type of muscle fibers, type 2, the type 2As, they have lower mitochondrial function because-
- PAPeter Attia
Lower mitochondrial function or density?
- IMDr. Iñigo San Millán
Sorry, uh, density. I'm sorry. Because they don't necessarily need to oxidize glucose in the mitochondria. They can do it in the cyto- in the cytosol of the cell, and therefore produce lactate, but they can produce ATP fast. So those muscle fibers, they don't contain as much mitochondria. And then the second type of muscle, slow/fast twitch muscle fiber, the type 2B or 2X, that is the one that is the pure anaerobic, if you will. And that is the one that barely has mitochondria, has very minimal mitochondria. So starting with that, that's where I start breaking down the zones. So the zone one would represent the minimum stimulation the muscle fibers receive. It's just pure contraction. That's what would you do on a recovery day or recovery mode. You have very low exercise intensity, and you burn a little bit of fat mainly. Uh, and that's what we see also. We look at also fat and carbohydrate utilization. Scientifically, we call it fat and carbohydrate oxidation rates, how many grams per minute of carbohydrate and fat you burn. So we know that at these intensities you burn mostly fat, although you also burn a little bit of carbohydrates, which we can go through that.
- PAPeter Attia
Yeah, I want to come back to it because there's such an interesting clinical observation that I've seen over the past five or six years, and your paper, your recent paper with Brooks just hammered it home in a much more rigorous way. So yeah, we are gonna come back to RQ at rest as a harbinger of these other things that follow under distress.
- IMDr. Iñigo San Millán
Yeah. So that's the zone one.
- PAPeter Attia
So just to put that in energy terms for people, you and I walking up the stairs, we were coming from the lobby, we're in zone one.
- IMDr. Iñigo San Millán
Yeah.
- PAPeter Attia
Walking down the street.
- IMDr. Iñigo San Millán
Walking down the street or if you are very fit and you go for a jog, very easy recovery day, that's your zone one.
- PAPeter Attia
And then for the elite, give us an example. So if you took Meb or someone who's gonna run a sub-two ten marathon, you have a sense of how fast they could run and still be in zone one. Someone who's used to running four forty-five to four fifty miles, could their zone one be as fast as like a seven-minute mile?
- IMDr. Iñigo San Millán
Yeah. Yeah, absolutely. You can see-
- PAPeter Attia
Wow
- IMDr. Iñigo San Millán
... world-class athletes that w- their zone one, it's my sprinting, for example. It's kind of what we see also in cyclists. Their recovery day is two hundred watts average, and for most m- mortals, two hundred watts, they can do that for fifteen minutes, you know.
- PAPeter Attia
Yeah. I just wrote a post about this recently using as an example, I-- for people who ride a bike, two hundred watts is about how fast it would take you to go thirty kilometers an hour Without wind or without elevation. And that's certainly not all out, but that's pretty fast, and if you can imagine being able to ride at that level indefinitely without any metabolic consequence, that's what an elite athlete is doing, and that says nothing, by the way, about their weight. [laughs] They're doing that at a body weight that is a fraction of most people's.
- IMDr. Iñigo San Millán
Yeah. That's their, what they call the coffee ride.
- PAPeter Attia
Yeah.
- IMDr. Iñigo San Millán
They go for a coffee or ice cream ride, and it's chitchat, and they're like, "It's un- unbelievable." [laughs]
- PAPeter Attia
So zone 1, does lactate get produced?
- IMDr. Iñigo San Millán
It should not get produced. Well, we start from the base that there's always lactate produced in the body.
- PAPeter Attia
So if you were to poke my finger right now or poke your finger right now, we measure lactate in millimolar. What would you expect to measure in me or you?
- IMDr. Iñigo San Millán
You would be about one millimole.
- PAPeter Attia
Okay.
- IMDr. Iñigo San Millán
0.7 to one millimole. That's kinda like a standard resting levels in a healthy individual.
- PAPeter Attia
And in a normal person, so not an elite athlete, but sort of a recreational athlete, what's the highest lactate you'll typically measure in that person if you put them in a treadmill test or a-
- IMDr. Iñigo San Millán
It depends on the protocol that you do. If it's a very violent protocol or it's a longer protocol, violent protocols, they produce more lactate. You might see 10, 12 millimoles. Whether that protocol, let's say, uh, a six minutes maximal effort on a rowing machine, right, on the Concept, for example. I've seen world-class rowers to maximal effort with 20 millimoles of lactate. It's very rare. You see very easily 15, 16, 17. That's because, and we can talk about that later, their glycolytic capacity, it's off the charts, whereas people who, they're not elite athletes, it's, for them, in that same protocol, it's more difficult to go over 12 millimoles, 10 millimoles because their glycolytic capacity is not so good as the one that the elite athletes have.
- PAPeter Attia
And sometimes elite athletes have the opposite issue, which is they don't make much lactate at all. They're so efficient. I've actually discussed this with Lance Armstrong after I erroneously had been on a podcast and made the case that he had a very high lactate tolerance. We were talking about it one day informally, and he said, "No, it's actually the opposite. I would barely produce any lactate." He was usually producing less lactate than others. And again, this was when everybody's on the same drug or everybody's off the same drug. I mean, just genetically, there are some people who probably have more MCT, which we'll come back and talk to, and they become more efficient at it. But okay, so that gives us a sense that lactate will go from maybe 1 to 10 if you're a normal person, maybe 1 to 20. I actually measured-
- IMDr. Iñigo San Millán
20 is difficult
- PAPeter Attia
... I measured a lactate of 24 in a friend-
- IMDr. Iñigo San Millán
Whoa
- 40:09 – 51:51
Zone 2, Fat Max, and Lactate Clearance
- PAPeter Attia
Let's now get into zone 2. What's happening physiologically as that athlete or that person enters zone 2?
- IMDr. Iñigo San Millán
So the zone 2 is the, now then when you start stimulating those slow-twitch muscle fibers to the fullest. Let's imagine that you're in that first gear that I mentioned earlier in the manual stick car, and then you're in that red zone, and that's where the car is asking you, "Hey, shift to second gear." And that's where, like, you're forcing physiologically because the body adapts to say, "No, you get stronger at this gear." That's kinda that zone 2 is like when you stimulate those muscle fibers before you start changing to a whole different environment where you start then recruiting fully the type 2 or s- or fast-twitch muscle fibers, and therefore the different energy system, which is the glucose. So the zone 2 coincides also with what we call the fat max, which is exercise intensity at the one you oxidize the highest amount of fat, and then we can see that clearly in the laboratory as we saw in the graph that we can show later.
- PAPeter Attia
Yeah, we're gonna include a lot of great pictures here. So if you're looking at the show notes, there's something called the metabolic map, which is a great slide that we'll walk through this. And I think what's very interesting here, this occurs so often in physiology, and it's a bit counterintuitive. As you go from zone 1 to 2 to 3 to 4, 5, and 6, you're generating more and more ATP as you go up that chain. So that part is monotonic. It's increasing without stopping. But there's a local maximum that's occurring in zone 2, which is your highest amount of fat oxidation. So as you go from zone 2 to 3 to 4, you will still produce more energy. You will consume even more oxygen. Your VO2 max has not been achieved, which is your maximal uptake of oxygen. But you will now become less efficient, and you're moving to a less efficient fuel. You're moving away from this diesel example or the fat. So again, I think for a lot of people, the semantics get confusing here because you just said that zone 2 is your maximum... I mean, maybe a better way to explain it for me is zone 2 is the place at which your mitochondria are producing the maximum amount under purely aerobic conditions of ATP. Is that fair?
- IMDr. Iñigo San Millán
Yeah, I would say that, too, and that's where you still recruiting those type 1 muscle fibers. That's the e- exercise intensity where you recruiting the most, and they have the highest stimulus.
- PAPeter Attia
Without tipping into the 2s.
- IMDr. Iñigo San Millán
Exactly.
- PAPeter Attia
That's basically it.
- IMDr. Iñigo San Millán
And since that type 1 muscle fibers have the highest mitochondrial density, you're really stimulating them a lot, as you said, before you need to tap into the fast-twitch muscle fibers. And in the moment you tap into the fast-twitch muscle fibers is because the ATP demand that you need cannot be covered by fat, and you need to switch to a different fuel, and that's where you, we see a big drop in fat oxidation, and we see an increase also in glucose oxidation, and that's when we start seeing also an increase in lactate as well because- Lactate is always, and we f- I forgot to mention that e- earlier, lactate is the mandatory byproduct, not waste product, byproduct of glucose utilization. Mandatory. Every time you use glucose, you use lactate. And at higher intensity, you produce more.
- PAPeter Attia
Let's talk about that because, again, I think that's more nuanced than most of us would come to this discussion with. We learned in physiology class that a molecule of glucose in the cytosol is turned into two molecules of pyruvate. Under conditions of sufficient cellular oxygen to meet the ATP demand, the pyruvate enters the mitochondria, where it undergoes oxidative phosphorylation to make ATP, and no lactate is generated. If that ATP demand exceeds the capacity that you just described in zone 2, we now have to start turning some of that pyruvate into lactate to generate additional ATP that's faster to generate. In the first case that I described, is there still, by necessity, some lactate production?
- IMDr. Iñigo San Millán
Yes, there's some lactate production, and, and we can see that even at rest, we have always a little bit of lactate in our bloodstream.
- PAPeter Attia
Which is what you said at the outset. You said if you checked my finger or your finger now, we would probably still have somewhere between .7 and 1 millimole of lactate. Why is that?
- IMDr. Iñigo San Millán
That's where we're trying to understand, and we believe, my colleague George Brooks and I, that lactate is a major signaling molecule, that it, when it's regulated, it can signal and maintain homeostasis of different metabolic pathways. It's kind of like a visa for the body, as my colleague George Brooks calls it. When it's dysregulated, as we're starting to see in cancer, for example, or we can see in type 2 diabetes, it can dysregulate different pathways. Every cell in the body produces lactate, and pretty much every cell in the body consumes lactate.
- PAPeter Attia
Including red blood cells, I'm guessing.
- IMDr. Iñigo San Millán
Yes. They produce a lot of lactate, red blood cells, because they don't have mitochondria.
- PAPeter Attia
Yeah, I wonder if-
- IMDr. Iñigo San Millán
It's glycolytic mechanism.
- PAPeter Attia
Yeah, do the red blood cells account for most of the lactate production we see at baseline?
- IMDr. Iñigo San Millán
Not necessarily, because there's not so much hemolysis, and there's not so much lactivity in the red blood cells. But there's always some metabolic lactate produced from glucose utilization because we always use a little bit of glucose. Of course, the brain. But, uh, that lactate escapes to the blood, to the circulation. And for us, it's significant that it's always so steady also. And every cell in the body produces lactate, and almost every cell in the body utilizes lactate. So there's gotta be a why. And we believe, and that's where we're trying to scratch the surface, that it's a very important signaling molecule that goes beyond being a byproduct or a metabolite. And that's something that we've already seen in cancer, where we have seen that lactate stimulates the, uh, expression of the major oncogenes, transcription factors, and cell cycle genes in breast cancer. So it's acts, and we have the paper under review now, it acts as a signaling molecule.
- PAPeter Attia
So this is interesting because, again, in physiology class, you sort of learn that all of that waste lactate goes back to the liver, and the Cori cycle converts it into glucose, and it becomes now stored glucose. But what you're saying is it's much broader than that. I mean, obviously, the Cori cycle still exists, but it's not even clear how much of the lactate that we're measuring is undergoing that pathway to be converted back to glucose versus itself being consumed as a fuel, correct?
- IMDr. Iñigo San Millán
Yes. And thanks to the great work that my colleague Brooks did starting in the '80s, what he saw is that the majority of that lactate is oxidized by the slow-twitch muscle fibers, by the mitochondria of the slow-twitch muscle fibers.
- PAPeter Attia
And each mole of lactate gives how many moles of ATP under those conditions?
- IMDr. Iñigo San Millán
I don't have it on top of my mind right now.
- PAPeter Attia
Is it a small number or a big number?
- IMDr. Iñigo San Millán
Yeah, it'll be a smaller number as well.
- PAPeter Attia
But it's not like the 16 or whatever you get-
- IMDr. Iñigo San Millán
No. No, no, no
- PAPeter Attia
... per acetyl-CoA.
- IMDr. Iñigo San Millán
No. No. I don't think so. I don't have it on top of my head. But the thing is a constant flux of lactate from the fast-twitch muscle fibers to the slow-twitch muscle fibers. That's when you start entering that zone 3. You start mobilizing more of the glycolytic system, and that's kind of a transition state where you still mix fuels, fatty acids, and carbohydrates. But you start using more carbohydrates, and therefore you start producing lactate. That said, that lactate is transported from, mainly from the fast-twitch muscle fibers into the mitochondria of the slow-twitch muscle fibers, where it's used for energy. It enters directly the mitochondria for energy purposes, and that is the ability that elite athletes have. They can be recruiting fast-twitch muscle fibers. They can be utilizing a lot of glucose and producing a lot of lactate. But since they have a very well-developed mitochondria in the slow-twitch muscle fibers, they don't need to export it to the blood, and it doesn't accumulate.
- PAPeter Attia
Yeah, this to me is the grail. This is the stuff that sets apart the best from the rest. Going back to zone 2, tell me where you typically see a lactate level there. You and I have talked about a bunch of these numbers. When I try to explain this to my patients, 'cause I have many of my patients on a zone-2 protocol, for a lot of the time, we just use voice. We use ability to talk. I sort of say, "Look, if you don't wanna go through the protocol of poking your finger, zone 2 is about the highest level of exertion at which you're still able to carry out a conversation." But let's talk more technically. We're really seeing, what, lactate levels of about 1.7 to 1.9 millimole?
- IMDr. Iñigo San Millán
Yeah, 1.5 to 2. That's something what we see, and that's kinda what corresponds also to that Fatmax.
- 51:51 – 1:06:54
Zone 2 Power as a Test of Mitochondrial Function
- PAPeter Attia
So let's talk about that now. I do wanna come back and talk about zones three and up, but because this is the perfect point to go back to the paper you and Brooks recently wrote, what you showed that I just thought was so elegant was, as you said, you can either cap the output or clamp the power required or clamp the lactate production and look at the power required, and you did the latter. You basically said, "We're gonna find everybody's zone two," meaning we're gonna find everybody's tipping point, at which point their mitochondria are no longer high enough in function to meet the requirement. And what you showed was world-class cyclists were able to get to an average of something like three hundred watts before they would finally flip that switch and have to start recruiting the fast-twitch muscle fibers, which was measured indirectly by lactate production. Conversely, the weekend warrior, reasonably fit people, guys like me, could get to two hundred watts before that switch got flipped. But most interesting was the people with type two diabetes I think were like a hundred and twenty watts. Is that about right?
- IMDr. Iñigo San Millán
Yeah. We've been knowing for years now that a typical characteristic that we know of people with pre type two or type two diabetes is that they have a poor metabolic flexibility that is called also, a poor capacity to oxidize fuels. One of them is fat. We know that fat can only be oxidized in the mitochondria. Therefore, by measuring the fat oxidation of these patients, we can indirectly see the mitochondrial function, especially when we put them in context or in comparison with those ones who are healthy individuals. That could be moderately active individuals who don't have diabetes or pre-diabetes or don't have any medications or elite athletes. So that's where we see that their fat capacity is very, very low, and that's kinda what we can see indirectly.
- PAPeter Attia
But it's not often you see in biology such a difference, because if the numbers three hundred versus two hundred versus one hundred sound extreme, that's nothing compared to when you normalize by weight. So really, the answer is in watts per kilo, what's the difference?
- IMDr. Iñigo San Millán
Yeah.
- PAPeter Attia
And three hundred watts to a professional cyclist who only weighs sixty to sixty-five kilos is just below five watts per kilogram, whereas the person with diabetes almost assuredly weighs more, so their one hundred and twenty watts is probably one point five watts per kilo. There are not a lot of examples of things in physiology where you see that much of a difference. You rarely even see that much of a difference in average glucose level between someone with diabetes and not.
- IMDr. Iñigo San Millán
Yeah.
- PAPeter Attia
So this is-- this functional definition that you guys have proposed is, to me, very important just as a clinician, just as someone who's trying to gather more data about a patient to understand their health. It's sort of like in a magic scenario or in a magic world, you would have these data on every single person. You would wanna know what is your zone-two threshold, and that becomes a way to assess mitochondrial function. Now, the story I was gonna tell earlier, this is as good a time as any to tell it. About five years ago, in some of the most insulin-resistant patients that I was taking care of, I began looking at baseline resting respiratory quotient, which, uh, you alluded to earlier. This is the ratio of produced carbon dioxide to consumed oxygen. Say a little bit about that number and how to interpret it, and then I'll finish the story.
- IMDr. Iñigo San Millán
So that's kinda we can see through expired gases. We can see the amount of CO2 that you produce and the amount of oxygen that you utilize. So under, uh, resting conditions, and that's what's called a respiratory coefficient or the respiratory exchange ratio. The respiratory exchange ratio is purely at the respiratory level, at the lung level, where the respiratory equation, coefficient, it's at the muscle level. They're quite similar, but not academically. You know, that might not the same, but we can call it RQ or RER too. So under normal conditions, you don't produce much CO2. So the ratio, it's always below one. Could be 0.7, something like that, for example. That means that it's CO2 divided by oxygen. So that's where you don't produce a lot of CO2. You use more oxygen, and therefore the ratio is 0.7. As exercise intensity increases-
- PAPeter Attia
And so that ratio of 0.7, we can impute from that that a person is virtually all dependent on fat oxidation at that moment.
- IMDr. Iñigo San Millán
Probably, yes. And that's what we can use through what's called stoichiometric equation. You can deduct the amount of fat that is oxidized, because to oxidize one mole of fat, you need X amount of oxygen, and you produce X amount of CO2. So by measuring both, you can see what, what kind of fuel you're burning, and that's what we're doing in our paper. So as exercise intensity increases or if the person is not metabolically flexible, they cannot oxidize fat very efficiently. So normally, these people, they tend to defend-- to depend more on glucose or any other extra source of fuel, and that's why you see use already people at rest, they have a higher RQs or RERs, what could be in the 80s. Then as exercise... If you were to do exercise, as exercise intensity increases, you start producing more CO2, and therefore the ratio starts getting closer and closer to one. When you... And that's where we see that you start oxidizing more glucose than fat. When the ratio gets to one, yeah, it's just 100% of the fuel that you use is glucose, and you don't see any fat, which is kinda what we also call kinda that end of the zone four.
- PAPeter Attia
Yeah. So this was the observation. I was noticing a subset of patients, again, very hyperinsulinemic, insulin resistant by whatever metric you would use to explain it, that had resting RER or RQ of 0.9 to one.
- IMDr. Iñigo San Millán
Mm-hmm.
- PAPeter Attia
Easily 0.95.
- IMDr. Iñigo San Millán
Mm-hmm.
- PAPeter Attia
So what does it mean when someone who is laying down to do this test under no physiologic distress has an RQ of 0.95? What does that mean? Obviously, based on what you said, it means they are almost exclusively relying on glucose and not oxidizing any fatty acid. But what is that telling you at a molecular level about the illness or the function of that person's mitochondria?
- IMDr. Iñigo San Millán
It's a red flag for mitochondrial dysfunction right there because that's not normal. Obviously, after eating a meal of carbohydrates, yeah, for a while you're gonna have a higher RQ. But at rest in a fasting state, when someone is in the nineties-
- PAPeter Attia
Yeah. This is-
- IMDr. Iñigo San Millán
Exactly.
- PAPeter Attia
This is a morning-
- IMDr. Iñigo San Millán
Yep
- PAPeter Attia
... fasted resting test.
- IMDr. Iñigo San Millán
It's a red flag that is already telling you that there's something going probably at the, uh, mitochondrial level, and this is what we wanted to do this paper that we wrote. We want to see the same thing that is done usually at the EKG level. So when a cardiologist wants to study the heart, if there's any abnormality, resting EKG has a reliability of about 50%. So you could see some red flags already, but, uh, you don't see everything.
- PAPeter Attia
You have to stress the heart to see something.
- IMDr. Iñigo San Millán
Exactly, and you stress the heart in similar protocol than what we did here, and that's what you do when you do EKG in stress, right, situations. The reliability is about 95, 97%. So you see a lot of things. So I decided to take the same approach and say, "Okay, now at rest," as you very well said, you see people in the nineties with RQ, and that's a red flag. Now, okay, let's stress those mitochondria.
- PAPeter Attia
Right. So in other words, the analogy is sometimes you'll do an EKG on somebody at rest, and you'll see changes in the ST segment that tell you immediately there's a problem. But there are many people who have a normal resting EKG, but only when you put them on a treadmill and make them run do you see that change in the electrical signal that tells you there's a problem. And so similarly, maybe somebody walks around with a resting RQ of 0.8 and you think, "Oh, they're perfectly fine," but you see that their zone 2 level, the level at which they tap out at their fat oxidation maximum or their maximum aerobic output, is much lower than predicted, and now you have a functional assay.
- IMDr. Iñigo San Millán
Exactly. You can categorize people by looking at the fat and also looking at the lactate. If you burn very little fat, that means that you don't have a good mitochondrial function, and that confirms it, that test. If you produce a lot of lactate, that means that you don't have a good l- mitochondrial function either because lactate is metabolized in the mitochondria. So if it's in the blood, that means that the mitochondria cannot metabolize it. So what we did with the three populations from world-class athletes to moderately active individual with people with metabolic syndrome, which is a companion of type 2 diabetes, uh, pre-type 2 cardiovascular disease as well, or what we call now cardiometabolic disease, because 80% of people with diabetes has cardiovascular disease and vice versa. So these people, what we did then with these three groups is then we paired both the fat curve, burning curve in the test, as well as the lactate, and the, uh, correlations were in the nineties. So we see that it's a valid indirect test to see the mitochondrial function. Now, as we speak, and in this office right now, we have all the, uh, supplies. We're gonna do this now with muscle biopsies, and we're gonna try to prove not just this, but what are the metabolic pathways.
- PAPeter Attia
Wait, do you have the IRB approved already?
- IMDr. Iñigo San Millán
Yes. We're gonna start next week. We already have-
- PAPeter Attia
Can I do it tomorrow?
- IMDr. Iñigo San Millán
We don't have the laboratory set yet. We're in the recruiting patients phase now.
- 1:06:54 – 1:19:58
Muscle Differences: Mitochondria, Glycogen, and the Athlete's Paradox
- PAPeter Attia
So again, if you could, sort of as a thought experiment, if you're looking at the muscle of someone who's going to get diabetes in two years versus the muscle of someone who is not, what do you think they look like in terms of differences? So there'll be many, but I just want to hear you talk through them, right, in terms of... So not talking functional at this point. I'm just talking purely visible. Will there be differences in glycogen capacity of the muscle? Will there be differences in the actual density of mitochondria? Will you see differences in the types of fibers? I mean, again, just playing that game of you know this person's gonna get diabetes, this person's not.
- IMDr. Iñigo San Millán
Yeah.
- PAPeter Attia
What looks different?
- IMDr. Iñigo San Millán
So you would see very clearly, for example, that well-trained athlete has at least three to four times the amount of mitochondria and the size of the mitochondria. That's very visible that you would see it right away. And this is Toledo from the University of Pittsburgh. He did a great paper where we can show it in the slides as well, where he can show that very well.
- PAPeter Attia
So three to four times the number plus larger.
- IMDr. Iñigo San Millán
Yeah, and that's the number and the density of the mitochondria. Then we delve in the function of the mitochondria, how well they function.
- PAPeter Attia
That's the zone 2 that you've been talking about.
- IMDr. Iñigo San Millán
Yeah, that's one of the things that we believe it might stimulate different pathways for mitochondrial biogenesis as well as different pathways for the improvement of the efficiency of the mitochondria itself
- PAPeter Attia
Are there other functional tests used besides the amount of basically ATP to lactate, which is what you're doing in a zone 2 test?
- IMDr. Iñigo San Millán
Noninvasively, to my knowledge, there are no other ways to look at mitochondrial function. You would need to look at a muscle biopsy.
- PAPeter Attia
And when they do a muscle biopsy, what functional assay are they doing in vitro?
- IMDr. Iñigo San Millán
When you look at muscle biopsy, you can... This is kind of what we're gonna be doing. You can expose the tissue of the muscle to, uh, glucose, pyruvate, or fatty acids and see what is the metabolism. You label them, and you see what goes where.
- PAPeter Attia
I see. So you will use metabolomics-
- IMDr. Iñigo San Millán
Yes
- PAPeter Attia
... to get a signature of the preference for different circulating fuels.
- IMDr. Iñigo San Millán
Exactly. So we would be seeing, like these type 2 diabetics, for example, they barely use fat when they're exposed to fat. We trace that fatty acid. But they have a much higher capacity or willingness to use glucose for energy, and that energies might not be happening in the mitochondria either. It happens in the cytosol. That's one of the things that there's what's called a metabolic reprogramming that happens in these patients, happens in, uh, type 2 diabetics, happens in cancer patients as well, and in other diseases. There's like a local metabolic reprogramming, but there's also a whole body metabolic reprogramming, where you just cannot synthesize fatty ac- I mean, you cannot utilize fatty acids for energy purposes very efficiently because you don't have the mitochondria, and you need to rely more on glucose. And at rest, glucose is, uh, mainly oxidized in the mitochondria, as you said earlier. It goes to pyruvate. Pyruvate enters the mitochondria. But when your mitochondria at rest are not functioning very well, you need to rely on the cytosolic production of ATP through pyruvate and then lactate. So this is what we believe these patients rely on the most, the, this cytosolic and glucose utilization, which is what we see in higher exercise intensities in athletes, and that's where we see higher lactate levels as a biomarker for mitochondrial function.
- PAPeter Attia
Do you see other differences between the very, very fit and someone, again, who's gonna go on to get diabetes, just to make the experiment such that you're not looking at someone with diabetes, in terms of glycogen storage capacity?
- IMDr. Iñigo San Millán
Yes. We see that too. We see that. So I developed with a colleague here, John Hill from the School of Medicine, we developed a methodology to indire- indirectly look for glycogen content in a noninvasive way using ultrasound, high-frequency ultrasound, and we validated with the muscle biopsy as well. And another researcher, uh, David Nieman, also validated the system. Uh, and we saw very good correlations with the scale that we use.
- PAPeter Attia
So y- just doing a high-frequency ultrasound of the quadricep, you can get to within what degree of accuracy of a muscle biopsy?
- IMDr. Iñigo San Millán
With the muscle biopsy, we saw in the 90s the R, the correlation pre- and post-exercise using the scale that we use. There are a couple of authors that have done a replication of the study, but they have used a completely different scale. We know that the skeletal muscle glycogen is stored in different parts of the body, I mean, in different pockets of the muscle and in different muscles. So what we do is we look at the entire image of the rectus femoris, for example. But in the validation, we did not validate the score of the rectus femoris with the high-frequency ultrasound with the one square centimeter biopsy sample. We validated the image, the one square centimeter image sample from the muscle biopsy with the muscle biopsy, and that's where you have the same size and image. And therefore, you have the correlation. With our couple authors, they have correlated the entire muscle with different pockets of glycogen everywhere with only the specific size.
- PAPeter Attia
I got it. But you did apples to apples.
- IMDr. Iñigo San Millán
Yes.
- PAPeter Attia
And you have an R squared of .9?
- IMDr. Iñigo San Millán
The R is, yeah, it's in the 90s, uh, 93, 94 pre and post-
- PAPeter Attia
Wow
- IMDr. Iñigo San Millán
... without the need of doing this, so.
- PAPeter Attia
And if you had to guess, two individuals could differ how much between a person who's fit and someone who's insulin resistant?
- IMDr. Iñigo San Millán
Yeah. So this is exactly to your question. So we see it very well. Others have done it before with muscle biopsies, where they have shown that fitter individuals, they can store more glycogen than other individuals, and that's what we see. So on a scale from zero to 100 that we have, you see the world-class athletes, they can go to 85, 90, 100, whereas someone like myself, I'm considered now like a weekend warrior, right? I just, you know, try to exercise.
- PAPeter Attia
No, hang on, hang on, hang on.
- IMDr. Iñigo San Millán
[laughs]
- 1:19:58 – 1:32:46
Zone 4, Lactate Threshold, and Why Watts Are Not Watts
- PAPeter Attia
So I want to kind of finish the energy zones. Obviously, at zone 3, you're getting into you're exceeding the capacity to maintain a stable level of lactate, which tells you you're now exceeding the mitochondria's capacity to be the sole provider of ATP. You are now becoming obligately dependent on glycolysis in the cytosol. By definition, the percentage of fat oxidation is now going down as the percentage contribution from glycolysis is going up. Is this where the lactate threshold now occurs? Because I'm sure there are people listening to this who are gonna say, "Wait a minute, wait a minute. I always thought lactate threshold was around four millimolar. So how does that concept fit in?"
- IMDr. Iñigo San Millán
So I would put the zone 3 as a transition zone where your glycolytic system starts kicking in at a very high rate because the ATP demand and your, uh, fat oxidation says, "Okay, I think I'm starting to be done here. Now you take over." And that's where you start seeing a decrease in fat. Yet, you use fat, so it's not a completely glycolytic state. It's a transition phase. That is when we move into the zone 4. In the zone 4, that's where we see very, very well that the lactate also you see an inflection point. That kind of where we could see the lactate threshold, where, like, all of a sudden the lactate accumulation is not steady. Zoom, it jumps, and you see an inflection point. And at the same time, that's where you usually start seeing the R of 1.0, the RQ, and there's zero fat oxidation. So we know very well it's like if there's a lot of lactate and there's no fat oxidation, that's another metabolic transition point that is indicating that w- you don't burn fat anymore. It's just dependent glucose, yet you can breathe, and it's probably done in the cytosol, so you're aerobic, and that's the zone 4. We'll be calling that lactate threshold, if you will.
- PAPeter Attia
And what's the clinical significance of that or the even the athletic significance of that? I mean, once an athlete goes above their lactate threshold, how long can they sustain that pace?
- IMDr. Iñigo San Millán
There are many lactate thresholds. So we might believe that lactate threshold could be maximal effort you can sustain for 50 minutes or 20 minutes or the FTP. The FTP could be a way also of lactate threshold for a f- 40K.
- PAPeter Attia
So for the person listening to this who's not familiar with that, FTP is defined as functional threshold power. In cycling, we use it as the, the maximum power that can be sustained for 60 minutes, or sometimes we do a 20-minute test and discount it by about 10%. But, I mean, an FTP test for me has never felt linear. [chuckles] You know what I mean? Like, if your FTP is 300 watts, the pain at minutes 10, 20, 30, 40, 50, 60 is not linear.
- IMDr. Iñigo San Millán
No.
- PAPeter Attia
Like, the last 10 minutes hurt more than the first 50. But now that I think about it, whenever I did FTP tests, I was usually doing them on the road, not on a stationary bike. I never had lactate levels throughout, but my intuition is my lactate was increasing non-linearly. I would always FTP test on a hill because it was easiest to maintain a fixed power output. But what's actually ha- what do you think is happening to a person's lactate when they're at that threshold?
- IMDr. Iñigo San Millán
I have seen that, and I presented at American College of Sports Medicine, poof, like about 10 years ago, and I have to publish it. It's one of the things that you have so much things going on that sometimes you don't have the time.
- PAPeter Attia
You need to get some med students working for you.
- IMDr. Iñigo San Millán
Yeah, I know. [laughs]
- PAPeter Attia
I'm looking at the poster you're bringing up that you haven't even published yet-
- IMDr. Iñigo San Millán
No
- PAPeter Attia
... from 10 years ago.
- IMDr. Iñigo San Millán
Yeah. This is 2009 or something like that. But this is where back in the days a lot of people talked about power. Everybody would just train by power, and watts are watts. I started to see at the pro level a lot of people using just power output and heart rate, like as in old school.
- PAPeter Attia
I was one of those people actually, you know, five years ago where it was I really didn't pay attention to heart rate at all except to notice that there were some days when at the same power my heart rate was much higher and I felt and performed much worse. That was about the extent of my observation.
- IMDr. Iñigo San Millán
Yeah. I wanted to kind of show that with numbers, and that's what I say, like, "Okay, power is power, and speed is speed." The ability of humans to perform relies on the ability to convert chemical energy into mechanical energy. The mechanical energy, that's your power output. The chemical energy is like all the metabolic adaptations that get you there. So this is what I saw, and we can put it as-
- PAPeter Attia
This is a poster you presented about 10 years ago, and by the way, this is-- I hope there's a med student out there at the University of Colorado who's listening to this who's, uh, figured out what their next summer's task is gonna be, which is help turning this into a manuscript. But tell us a little bit about this experiment and what it showed because it's-- as I look at the figure, I see it is answering, it is answering the exact question I just asked, actually.
- IMDr. Iñigo San Millán
So yes, one of the things is that a lot of people start to talk about watts are watts, right? They ditched the heart rate monitor because watts are watts. Therefore, metabolically speaking, it's the same thing. But as I said earlier, the ability of humans to exercise depends on the ability to convert chemical energy or biochemical energy into mechanical energy. The mechanical energy is the end product, watts, but how do you get there? So I wanted to see and, and put it to the test, so I had both a group of elite cyclists, professionals, and a group of recreational cyclists, but well-trained as well, and I did a maximal test where I could get the peak power output at the end of the maximal test. One group, the elite cyclists, the next test I put them at 80% at the, uh, peak power output from the first test, and the second group was 75%. And then I just let them stay there for 20 minutes.
- PAPeter Attia
So if the elite cyclist hit a peak power of 400 watts on the previous test, 80% of that, so now you put him at 320 watts and say you're gonna spend 20 minutes here, and it's like similar calculation for the recreational athlete, though at a lower level.
- IMDr. Iñigo San Millán
Exactly.
- PAPeter Attia
Okay.
- IMDr. Iñigo San Millán
So the whole thing was like if watts are watts, it was like the whole bottle back in the days. It's like, okay, then metabolically speaking, we're not gonna see changes.
- PAPeter Attia
In other words, five minutes into this test, whatever's happening in you physiologically, since you're not changing the output or the demand for ATP, there should be no change in anything else.
- IMDr. Iñigo San Millán
Exactly.
- PAPeter Attia
So what happened?
- IMDr. Iñigo San Millán
So what we saw is that after five minutes, both groups, they had about four millimoles of lactate, okay? In the elite athletes five minutes later, which is minute 10, they had about seven millimoles of lactate. And five minutes later, which is minute 15, they had nine millimoles of lactate. So right there we see that watts are not watts at the metabolic level. It was very stressful for them, and they could not keep it. And this is kind of to what you alluded, that you notice that towards the end of some of this FTP, it feels worse. And this is exactly what I was observing with many professional athletes and elite athletes as well, I mean, cyclists, that they would get over-trained more. And they said, "Hey, I, I had to do... Let's say my coach told me I had to do five hours or four hours at 200 watts, and I do the job," and you can see on TrainingPeaks. So yeah, you do 200 watts, but what's the price?
- PAPeter Attia
I used to be obsessed with TrainingPeaks and what was the other program called? There's another program we used to use, but where does the TSS show up, the training st- stress score? Is that also TrainingPeaks?
- IMDr. Iñigo San Millán
Yes.
- PAPeter Attia
And I remember I used to mostly just keep track of kilojoules. In the end of the day, it was how many kilojoules today, what's my TSS, and my training score balance, and things like that. But I think what this-- and by the way, I'm looking at the graph. The recreational athletes basically had the exact same pattern just at lower levels.
- IMDr. Iñigo San Millán
Yeah.
- 1:32:46 – 1:46:54
Ketogenic Diets, Adaptation Time, and Elite Carbohydrate Intake
- PAPeter Attia
I'll tell you this from my experience, Iñigo. When I began carbohydrate restriction, which was, uh, I went on a ketogenic diet in May of 2011, the first 12 weeks were hell I couldn't even imagine approaching my anaerobic fitness. So forget lactate threshold or anything like that.
- IMDr. Iñigo San Millán
Yeah [laughs] .
- PAPeter Attia
I couldn't even get to the same aerobic level. I remember, I still remember very clearly, November 2012, 18 months later, it came back and then some. What that suggested to me, and if I could go back in time and do anything different, I would have had muscle biopsies done all along the way. But it struck me at how long it took for that adaptation to take place. Now, I only stayed in that state for three years, so I'm long out of that state now. There's-- The only time I'm really in ketosis is around fasting. But it's always sort of piqued my curiosity what a very, very, very long-term state, ketogenic state can do for everything outside of peak sprinting capacity, because I just, I don't think there's any dispute that peak sprinting capacity has to be glycolytic, and anything that impairs glycolytic function makes no sense. So there's such a debate about all of this stuff. I don't think it makes sense for someone trying to win the Tour de France to be on a ketogenic diet. It's just too glycolytic. Even though 96% of that race can be done below peak power output, the race is won and lost under peak conditions.
- IMDr. Iñigo San Millán
Exactly.
- PAPeter Attia
So it makes no sense. But if you're training to win the Western States 100, you technically don't need to sprint ever if you have a high enough threshold. So I still have that sort of point of view, but again, I'm very curious as to what those adaptations-
- IMDr. Iñigo San Millán
Yeah
- PAPeter Attia
... are and how long they take, 'cause I don't think they're gonna take place in a month.
- IMDr. Iñigo San Millán
You bring up a great, great point. I'm extremely curious about that as well, because I have never seen an athlete at the elite level adapting, and I'm gonna tell you why in a second. But at the same time, I believe that it cannot be possible that thousands of people around the world who are getting into the ketogenic diet, it might be working for them and they're making it up. So I believe there's something there. At first, when these things come up and I say, "Come on, man, give me a break." But then I say, "There's so many people out there. There's gotta be something."
- PAPeter Attia
Well, there's one other data point I'll add for you. When I was on a ketogenic diet and cycling voraciously, my capacity to consume carbohydrates was much higher than what people think of as a ketogenic diet for someone at rest. As a general rule, for somebody who's normal, about 50 grams of carbohydrates is the limit. Above that, you begin to suppress the production of beta-hydroxybutyrate. But I used to do lots of experiments, and at my most extreme, you know, days when you'd have a three-day period where you would do 100 miles each day for three consecutive days at very high output. So for me at the time, that might have been average power of 185 watts, normalized power of 240 watts for seven hours on three consecutive days. When you're at that much demand, I was able to consume 600 grams of carbohydrates and stay in ketosis.
- IMDr. Iñigo San Millán
Nice. [laughs] Nice. Wow.
- PAPeter Attia
Now, I think that's because I'd spent so long adapting.
- IMDr. Iñigo San Millán
Yeah.
- PAPeter Attia
I don't think you can show up and go into ketosis and then a week later eat 600 grams. I mean, I was pushing as hard as I could to see how much of this can I consume.
- IMDr. Iñigo San Millán
Wow.
- PAPeter Attia
But, so there's the other thing to keep in mind, which is at some point the body became flexible enough that I could break all the rules. I could have 200 grams of protein-
- IMDr. Iñigo San Millán
Yeah
- PAPeter Attia
... 600 grams of carbohydrate, and still maintain beta-hydroxybutyrate levels above two to three millimolar.
- IMDr. Iñigo San Millán
Yeah.
- PAPeter Attia
Because I think the machinery with which the BHB was made was-- I'd had two years of... In fact, this would have been probably three years in. This is the summer of '13 maybe. So now I'd, I'd really been at it for quite a while. And again, biggest regret is not having that. There are lots of athletes out there that I think would be interesting to study.
- IMDr. Iñigo San Millán
Yes.
- PAPeter Attia
So that's something worth considering.
- IMDr. Iñigo San Millán
Sorry to interrupt. The thing why I haven't seen that adaptations in elite athletes is that they cannot afford it. You mentioned that it takes months to get there. You don't have months because you get dropped in the races. Your performance is very poor. Your contract is gonna be trashed. They're not gonna renew you, and you're gonna feel like crap. Every single athlete who has tried to go, whether you call it like a ketogenic diet or a carbohydrate restriction, while training and competing for an event, they fail. That's what I've seen in 25 years. And the reason probably is this, because they didn't have one year to say, "Hey, you're not gonna race in one year. You're gonna train very little. Your mission is to get adapted." That, that's not the way sports works. But what I see is if you restrict carbohydrates, you know, w- we do blood analysis a lot. We do this metabolic testing in the laboratory. While these athletes are competing, we see right away there's a catabolic response. The body says, "Holy crap, what's going on here? I need to survive somehow." So you enter in a, in an evolutionary survival mode. So obviously, yeah, your ketones production might increase, your fat oxidation might increase as well, but your protein breakdown increases substantially as well. And we see this in the blood analysis. That's why you see muscle breakdown all the time.
- PAPeter Attia
Although again, it's transient, which again speaks to... 'Cause if it wasn't transient, I mean, evolution would absolutely demand we preserve protein- under long periods of nutrient deprivation, which of course is what the carbohydrate restriction is mimicking. But it's this time course that I think is very unusual. And you're right, there's no professional athlete that could take that chance. And again, I [chuckles] we were talking about this earlier, it's like there are some people whose entire lives can be built around chat rooms and discussion boards where they can debate these things endlessly. Neither you nor I have the time for that, so I've largely stopped paying attention to this debate, truthfully. But it's always struck with me how long it took-
- IMDr. Iñigo San Millán
Yeah
- PAPeter Attia
... to adapt, and the price I paid during that adaptation period.
- IMDr. Iñigo San Millán
Yeah. If you were a professional athlete, you would be out of the job.
- PAPeter Attia
Yeah. Oh, absolutely.
- IMDr. Iñigo San Millán
And this is why I think that I have never seen that, because sooner or later, the athlete, they hit the wall. They just cannot finish races, or they just like, uh, "Hey, what's going on here?" And then that's when they have to go back. And we see this quite often. Athletes don't always listen to us. They always go to the blogs and see things, you know, Internet, or they find what the neighbor is telling them, and a lot of people try many diets. And the tendency now, and it was before also, was to restrict carbohydrates. And again, I really think that you can adapt because the human physiology is a wonderful machine. But do you have the time to adapt while you're a competitive athlete? That's what I have a lot of thoughts that I don't think so.
- PAPeter Attia
Yeah. And again, I think the discussion is, is interesting and academic, but of course in the end I still think carbohydrate restriction is a great tool for anyone who's not trying to win the Tour de France. I think that's where people sometimes get hung up, right? It's if you want to win an Olympic gold medal, there are very few sports in which you could probably do that on a ketogenic diet. And if you want to be the best cyclist or runner or swimmer on the planet, very hard to do that on a ketogenic diet. The good news is, by the way, if you're at that level, your mitochondria are so remarkable that your carbohydrate tolerance is unbelievable.
- IMDr. Iñigo San Millán
Exactly.
- 1:46:54 – 2:04:19
Type 1 Diabetes, Non-Insulin Glucose Uptake, and the Cool-Down
- PAPeter Attia
also, there's, uh, all that efficiency in the mitochondria comes with another benefit, which we didn't really talk about, which was non-insulin dependent-
- IMDr. Iñigo San Millán
Exactly
- PAPeter Attia
... glucose uptake is also going up. So now if you take a normal person, we are able to take up glucose with insulin, that's the insulin sensitivity, but we have a second door that doesn't get utilized much, which is the non-insulin requiring door to put glucose in the muscle, and there's no better way to stimulate that than zone 2. I mean, I don't know if I have a study that I can point to, but I can clinically tell you-
- IMDr. Iñigo San Millán
Yeah
- PAPeter Attia
... without a shadow of a doubt, and I'll tell you how I know, it's looking at people with type 1 diabetes.
- IMDr. Iñigo San Millán
Yeah, exactly. I was gonna mention that.
- PAPeter Attia
Yeah. You take people for whom you know exactly how much insulin they require. I'm actually gonna be writing about one of these patients in my book. He's type 1 diabetic, completely dependent on, on insulin. He's completely maniacal. I love him. Three-hour brisk walk every night.
- IMDr. Iñigo San Millán
Mm-hmm.
- PAPeter Attia
So that's his zone 2. Three hours of zone 2 a day.
- IMDr. Iñigo San Millán
That's brutal.
- PAPeter Attia
Right? You know how much insulin this person with type 1 diabetes requires a day?
- IMDr. Iñigo San Millán
Two, five in units.
- PAPeter Attia
About eight to 10 units a day. He has the highest sex hormone binding globulin I've ever seen in a human being, which is inversely proportionate to insulin level. This guy has no insulin.
- IMDr. Iñigo San Millán
Yeah.
- PAPeter Attia
He doesn't require any.
- IMDr. Iñigo San Millán
I learned from this a lot. I was working with Team Novo Nordisk.
- PAPeter Attia
Yeah. Tell people about what Team Novo Nordisk is.
- IMDr. Iñigo San Millán
So Team Novo Nordisk is a professional team where 100% of the cyclists are type 1 diabetics.
- PAPeter Attia
These are professional cyclists-
- IMDr. Iñigo San Millán
Yeah
- PAPeter Attia
... with type 1 diabetes.
- IMDr. Iñigo San Millán
So the whole purpose of Team Novo Nordisk was first to show the world that you're not going to not only not die if you have type 1 diabetes, but you can become a professional athlete. To spread the word, 'cause a lot of people think it's a devastating diagnosis for many. "Oh, you're type 1. You're gonna die soon." I'm like, "No, you're not gonna die soon if you take good care of yourself, but, and even you can become a professional athlete." So that was the one message to spread the word, and the second is that to study diabetes and, uh, type 1 diabetes and the metabolic effects of exercise because nowadays most endocrinologists working with diabetics, they're telling to exercise. The problem is, like, they go to exercise, and they have many hypoglycemias or hyperglycemias, and they need to correct it, and all the hormonal system goes all over the map, and they go back to their doctors, and they have no answers. So it's the number one barrier that they find from exercise, and they many decide not to exercise because they can control their doses very well at home.
- PAPeter Attia
And let's explain why that's happening to people. We've talked a lot about the consumption of glucose, but as you're alluding to, whether it's you, me, or someone with type 1 diabetes, when I exercise very strenuously, my glucose goes way up. So if I'm doing... Twice a week, I do high intensity exercise.
- IMDr. Iñigo San Millán
Mm-hmm.
- PAPeter Attia
As you can see on my arm, I wear a continuous glucose meter. It's not uncommon, especially if I do it right after a zone 2, this is funny, 'cause zone 2 my glucose steadily falls.
- IMDr. Iñigo San Millán
Exactly.
- PAPeter Attia
Let's say I get on the bike at 100.
- IMDr. Iñigo San Millán
Mm-hmm.
- PAPeter Attia
I do 45 minutes of zone 2. I get off at 75.
- IMDr. Iñigo San Millán
You get to bonk sometimes even [laughs] and sometimes-
- 2:04:19 – 2:18:02
Metformin, Lactate, and a Proposed N-of-1 Experiment
- PAPeter Attia
this. So this kind of brings me to, while we're on the topic of diabetes, something else that I want to talk with you about, which is my recent, and by recent I mean over the last six months, frankly, maybe nine months, sort of back and forth exploration of my use of metformin. When we very first time met a year ago, we talked about how I use metformin. I've been using it for years with the basic belief that even though I don't have diabetes or insulin resistance, it offers some measure of protection from cardiometabolic disease, inclusive of cancer. And that's all based on data that unfortunately is confined to people with insulin resistance, hyperinsulinemia, or type 2 diabetes. So there was always a leap of faith I was taking that if you took a metabolically healthy individual, they would still have some benefit. And when patients would ask me about it, I would say, "My belief is that I'm probably receiving less benefit than someone who's more metabolically unhealthy, but I think I'm receiving benefit, and I don't see a downside." And then all of that changed a year ago when we met, and I started keeping track of my zone 2 numbers. And what I immediately realized was a gross mismatch between where I knew physiologically I was clearly in a zone 2 just based on perceived effort and my understanding of my fitness level, but I couldn't get over how high my lactate levels were. And then I remember you and I would speak, and you would say, "Well, what is your lactate level fasting?" And I'd say, "You know, sometimes it's like one point six." Even before I start... I mean, this was back when I was in the business of using as many strips as possible. [both chuckling] So expensive, those stupid things. So I would check two times fasting and then every 10 minutes check.
- IMDr. Iñigo San Millán
Wow.
- PAPeter Attia
Double, double, double, double, double.
- IMDr. Iñigo San Millán
Man.
- PAPeter Attia
And there was no denying it. I mean, my lactate levels were through the roof. And I said to you, "Do you think it could be the metformin?" And then around this time, a couple of papers came out that suggested that metformin could be blunting the benefits of exercise. So, I mean, let's go back to then, and then we'll talk about where we are today in our thinking. But at the time that I told you all of this, what was your thinking about my use of metformin and these numbers we were seeing? Did it make sense to you?
- IMDr. Iñigo San Millán
Yeah. They make sense in a way that we know that I've seen patients with metformin, pre type 2 diabetic or type 2 diabetic right before entering insulin states, where at rest I have even seen two millimoles also.
- PAPeter Attia
Are you able to differentiate how much of that was due to the metformin versus their... 'Cause there's such a confounder when you look at that population. Had you seen anybody like me where they're-
- IMDr. Iñigo San Millán
No. No. I've seen these high levels of lactate at rest, but again, I could not differentiate that. But all these people coincided, they were on metformin. One of the side effects of metformin is lactic acidosis. Right? This is rare, but it can happen. So we know there's something wrong with the lactate. What we don't know are the mechanisms. It would be great to study the mechanisms, whether are for to improve the cardiometabolic health, or maybe we might find that might not be what we thought. We know there are some studies that show that metformin decreases mitochondrial function and could be that magical drug against cancer. Because one of the things that we see in cancer, many forms of cancer have a mitochondrial dysfunction, yet not enough for that cancer cell to be apoptotic.
- PAPeter Attia
Oh, I see. So you're saying that maybe in that patient, metformin pushes them over the edge towards apoptosis.
- IMDr. Iñigo San Millán
Towards the cliff. That's what I believe if in case that is true, that metformin can cause mitochondrial dysfunction. But the fact that the metformin increases lactate, it's either because it increases the glucose flux into the cell and saturates PDH, and then PDH, the dehydrogenase, has a very, what we call low Michaelis constant, so it saturates very rapid. And in my opinion, acts as a fuse in the body from an evolutionary perspective. If the body sees there's a lot of high flux of glucose, the body might mean, "Hey, what's going on here? We need to stop it because it's not good to become hypoglycemic." And maybe the majority of those glycolytic enzymes in the downstream action of glycolysis, they usually have a high Michaelis constant. But when they get to PDH, it's like a fuse. So when that fuse goes, then pyruvate is converted to lactate. So that could be it's either increases the flux of glucose into the cell, and that's why it could work well for diabetes or acts as others have shown.
- PAPeter Attia
This is very interesting. So this suggests that... Let's just talk for a moment about someone with type 2 diabetes who's not taking metformin. Their lactate levels are higher at baseline. You're now really offering two explanations for it. The first is PDH, 'cause their PDH is seeing higher glucose than the non-diabetic. So that's the first thing it's doing is, as you say, I like that analogy of the fuse. It's just triggering the fuse and shunting more glucose down the pyruvate to lactate pathway. And then, of course, there's everything we spent the first hour talking about, which is in addition to that, their mitochondria just tap out very early. They're not working well. So those two things that are related but quite distinct would both push up lactate. So now the question is which one of those is more likely being driven by metformin? Is it the inhibition of complex two in the mitochondria and it's simply reducing mitochondrial efficiency? If you picture a curve where the X-axis is mitochondrial function, it's just moving you to the left.
- IMDr. Iñigo San Millán
Exactly. It could be that and maybe they-
- PAPeter Attia
Could be both
- IMDr. Iñigo San Millán
... it could be both. What we know epidemiologically speaking is that metformin doesn't cure diabetes, and the immense majority of patients, they end up using insulin down the road. So we know that metformin is not that magical drug for type 2 diabetics. It just kinda gets them by, it, it buys them time. But eventually the majority enter insulin. If they don't change their lifestyle, their nutrition, exercise, they enter insulin. So why?
- PAPeter Attia
I mean, so the first thing I did... So I used to take one gram twice a day, a gram in the morning and a gram before bed. I always do my zone two first thing in the morning, so I was basically doing a zone two right after taking a gram and basically 12 hours after having taken another gram. So you could argue I had very high levels. So I think the first change I made was I just stopped taking a gram in the morning and increased my nighttime dose to 1,500 milligrams. So I reduced my overall dose by 25%, but shifted it to the nighttime thinking, "Well, I should have a lower concentration in my bloodstream in the morning." I saw no meaningful effect.
- IMDr. Iñigo San Millán
Right.
- PAPeter Attia
So 1,500 at night was still producing basically the same effect as a gram twice a day. Now again, keep in mind when you're doing an N of one, you can't actually make any statistics out of this. It has to be a big signal for me to notice it. So then I lowered it to a nighttime dose of one gram. I still didn't really see much of a difference. And then what I did is I stopped taking it the night before doing zone two. So that meant I now went from taking 14 grams a week, a gram twice a day, to only one gram three nights a week, 'cause there's only three nights a week where I don't follow the workout biozone two. So you've gone from taking 14 grams a week to three grams per week. You could argue, why are you taking any of it at that point? And that's when I saw the reduction. That's when I saw the lactate levels start to come down.
- IMDr. Iñigo San Millán
Okay. Very interesting.
- PAPeter Attia
And in fact, that latter part of the experiment's only been going on for about three weeks. So the next step is to stop metformin altogether and ride this out, which makes me think we should do a little experiment in me.
- IMDr. Iñigo San Millán
Yeah.
- PAPeter Attia
Which is, yeah, we should do muscle biopsies, complete proteomics, complete metabolomics, everything that is doable in vitro in the muscle tissue, along with the lactate testing and all the other metrics under three states of physiology. One, under full dose of metformin, two, under a complete washout, say 30 days of no metformin, and then the third one I think would be very interesting is under complete water fast, where I also, by the way, whenever I water fast, I have no metformin, and I'd like to see what seven days of water fasting with no metformin looks like versus, again, these other two states. So I think there's an interesting pilot study here.
- IMDr. Iñigo San Millán
You should come to our, our study and be part of it and we can do extra biopsies.
- PAPeter Attia
Yeah, yeah. I'm totally game to do this.
- IMDr. Iñigo San Millán
Yeah. It would be very interesting 'cause it's fascinating the, the whole role of metformin and also how it can be used in other diseases as well and, and it's fascinating the, the little that we know about the mechanisms of action at the molecular level yet. I think you bring great point is to try metformin in different states and try to learn what happens at that mix level and metabolomics, proteomics level, especially the latter ones because yeah, might, we might see pathways, maybe some mitochondrial dysfunction that causes that, and we can see that quite well. Or, uh, maybe it's at the translocation level of the transporters.
- PAPeter Attia
And it would be really interesting, assuming the IRB gives a quick approval for this little added protocol that includes me, if we could recruit somebody with type 2 diabetes and have them parallel me-
- IMDr. Iñigo San Millán
Yeah
- PAPeter Attia
... with, without the metformin, with, without the fast. Because my new hypothesis around metformin is I just have a stronger conviction, I think, around my old hypothesis, which is the healthier you are, the less helpful it is. I'm now wondering if it goes one step further, which is the healthier you are, the less... I mean, it might actually cease to be healthy. In other words, let's take the extreme example. What would you predict would happen if you gave a Tour de France team a gram of metformin twice a day during the tour? No other change. You just give them a gram of metformin throughout the tour. Do you think it would have no impact on performance or a negative impact?
- IMDr. Iñigo San Millán
I mean, based on looking at that, it can affect mitochondrial function, and we see because there's increased lactate, in my opinion, and that's the very first take, and by no means I'm an expert on this, it might be detrimental. That's my first take.
- PAPeter Attia
If you think you had a hard time getting professional cyclists to volunteer for muscle biopsies, think about how much harder it'll get them to volunteer for the take metformin and go off and do the Vuelta.
- IMDr. Iñigo San Millán
[laughs] I know. It would be really, really difficult to get IRB for that in the first place and, and the permission from the manager.
- 2:18:02 – 2:27:19
Zone 2 Dosing, Iñigo's Own Weight Loss, and Sustainability
- PAPeter Attia
The zone 2 training for me, it's just become such an important part of my training for myself and for my patients. A question I get asked a lot that I don't know the answer to, so I'm gonna ask you, is what's the minimum effective dose? 'Cause obviously I would love it... If I could wave a magic wand and have one hour per day to do zone 2, and then on top of that layer in all other exercise, that would be amazing, but it's not. I only do three hours a week of zone 2, typically in four 45-minute to an hour sessions. Do you think that's enough?
- IMDr. Iñigo San Millán
Yes. So this is what I've seen and I've learned from the athletes, and I would love to do this now with patients. What's the right dose? But we know, or at least I've seen with athletes, that if you do that two days a week, one is the dose and the other thing is the frequency. So if you do that two days a week, you maintain. And we see athletes who in the off-season, cyclists for example, or runners or triathletes or swimmers or rowers, if you do the zone 2 five days a week, for example, you really push the needle. Then once the season starts, you need to do more higher intensity exercise and training, and then you have the races and you need to recover. So definitely you cannot do zone 2 every day. So what we see is like two days a week, it tends to maintain.
- PAPeter Attia
So that, that's the frequency. What's the dose that they need?
- IMDr. Iñigo San Millán
Yeah. And the dose, what I see is like, obviously these elite athletes, they need to keep pushing the needle. One hour is not gonna do much for them-
- PAPeter Attia
Yeah
- IMDr. Iñigo San Millán
... 'cause they have that stimulus already, or two hours. They might need four or five hours. But a patient with type 1 diabetes, maybe one hour is enough, and that's what I'm trying to fine-tune, you know, what would be. What I know very well is that three days a week it starts moving the needle, four or five for sure, and what I've seen or guessing at as, as, 'cause we don't have any real data, this is about one hour to one hour and a half. It does the trick for those who have type 2 diabetes or pre-type 2 diabetes, for example. So we have last year a patient who was diagnosed with, uh, that's what we were saying is like late pre-type 2. What the heck is that, you know? And then, uh, with one year doing an hour and to an hour and a half four days a week, she re-reversed that completely.
- PAPeter Attia
Okay. That's a pretty big dose. So I mean, for me, just it's always for me Tuesday, Thursday, Saturday, Sunday is zone 2. It might be that those Saturday, Sunday workouts, I need to push them longer. Maybe I need to do 90 minutes on each of those days and stay at 45 minutes on Tuesday, Thursday.
- IMDr. Iñigo San Millán
It could be, but at the same time it might be your right dose because you're not in that unhealthy population side.
- PAPeter Attia
Okay.
- IMDr. Iñigo San Millán
So your dose might be lower.
- PAPeter Attia
But my thinking now is that this is such an important part of cellular longevity that this is the difference between being a healthy 90-year-old and being... In my framework, it's one quarter of the equation. What would you do?
- IMDr. Iñigo San Millán
I would do, and this is my case, when I stopped cycling, what I told you earlier, right, I gained 65 pounds because I was working 70 hours a week and exercising six, seven days a year.
- PAPeter Attia
And still eating like a cyclist?
- IMDr. Iñigo San Millán
And eating like a cyclist. And I'm from the Basque Country, and we like to eat food 'cause it's one of the best areas in the world [chuckles] . And, and probably also I had insulin sensitivity developed from I was a cyclist, which I would just, boom, poor carbohydrates, you know? And then I would not ... burn them, so maybe I just transform more into fat. I also have a familiar dyslipidemia, so I have, uh, high triglycerides and high cholesterol genetically. So I didn't take care of myself. I would not exercise and eat a lot, so I gained 65 pounds in about eight years or so. And then I, I said, "Wow." I went and did myself a checkup, and then my blood pressure was 125. I was in my mid-30s, 125 over 85, so oof, was getting there. And my triglycerides once I saw them 800, which is huge, off the chart, right? Back in the days, people didn't do A1c. That's when I started to work on these concepts, too, and so I started to apply this to myself. So I started doing four days a week. Even one hour was, poof, I was bunking 'cause I was not used to that. It was very depressing going to the-
- PAPeter Attia
I was about to say, that must have just been devastating-
- IMDr. Iñigo San Millán
Oh my gosh [laughs]
- PAPeter Attia
... to go from being a professional cyclist to struggling to do four hours a week of cycling.
- IMDr. Iñigo San Millán
Yeah, and knowing the same roads that you go to and that you couldn't go up the hill. But I lost 35 pounds within seven months.
- PAPeter Attia
Did you make much change to your nutrition?
- IMDr. Iñigo San Millán
Exactly. That was... I mean, I decided to... I was willing to eat a little bit less, but not sacrifice many things because again, I mean, for me, nutrition is very important from my culture standpoint. I love chocolate. I love wine. I love pasta and bread. It's ingrained in, in my culture. I was not going to renounce to, to these things. So that's when I said, "Okay, I'm gonna try to give it a shot."
- PAPeter Attia
So you weren't gonna go on a ketogenic diet?
- IMDr. Iñigo San Millán
No.
- PAPeter Attia
And, and, and it's an interesting example of there's give and take.
- IMDr. Iñigo San Millán
Yeah.
- PAPeter Attia
The more you're willing to push this type of training-
- IMDr. Iñigo San Millán
Right
- PAPeter Attia
... the more you can keep on the other side versus, you know, I've seen more patients than I can count with Type 2 diabetes not exercise at all, but go on ketogenic diets. Within six months, they're off insulin. Within a year, they have a normalized hemoglobin A1c. But again, so it's almost like two levers. How hard are you willing to pull on each of the levers?
- IMDr. Iñigo San Millán
Exactly. No, that's a great, great comment for sure, and I think it's a debate. Many... For some people, giving up chocolate is not a problem. For me, it's death, you know? [laughs] I just love chocolate. It's not that I eat it every day a whole bar, but it is... or bread, you know? That's one of the things, too, that is the, the balance. I lost 33 pounds, and I stopped there. I could not lose more than that. I needed to then up increase my dose, so I went from one hour to an hour and a half four days a week. I lost another 10 pounds, so I lost a total of around 50 pounds, 47 to 50 pounds. That was 11 years ago before coming here, and I kinda keep it like that.
- PAPeter Attia
Now, this is interesting. As you're probably aware, the exercise and weight loss literature suggests that exercise alone is not sufficient for weight loss. I've always wondered if that was an artifact of the fact that they're studying exercise incorrectly, that the-
- IMDr. Iñigo San Millán
Yeah
- 2:27:19 – 2:39:25
Cancer, Lactate, and the Warburg Effect
- PAPeter Attia
You've alluded to cancer twice now. We've spent a lot of time talking about Type 2 diabetes as a disease state in which the mitochondria are not functioning well And they provide this great contrast, but you've touched briefly on cancer. Is there any evidence that a patient with cancer has a higher lactate level on account of the fact that they have mitochondria that aren't working as well, the same way that the person with type 2 diabetes has?
- IMDr. Iñigo San Millán
So it is a fact, in 1923, almost 100 years ago, Otto Warburg from Germany discovered the transformation of a normal cell into a cancer cell at the metabolic level, and the characteristic of cancer cells was that they use a lot of glucose for energy purposes. Now, they use a lot of glucose. Back in the days, there was no genetics or anything. But what struck Warburg is the amount of lactate that they produced.
- PAPeter Attia
Was that what struck him more than the fact that they used so much glucose, even in the presence of sufficient cellular oxygen and insufficient ATP demand? So it was more the lactate accumulation?
- IMDr. Iñigo San Millán
It was more the lactate accumulation, and that's why he came to conclusion that cancer was a metabolic disease caused by an injury of the, uh, respiration system in the cell, which is the mitochondria, and that's what was the thought for many years because of the lactate. Even before glycolysis was invented, Meyerhof, who discovered glycolysis, sometimes it's called Embden-Meyerhof pathway, which is glycolysis. Meyerhof was a student of Warburg. Before they had even, uh, found out about glycolysis, the way they measure glycolysis is by, uh, measuring lactate. So they would measure how much lactate the cell produces, and that's the way they would say, "Wow, they're using a lot of glucose." But what he saw in cancer cells, there was an aberrant amount of lactate production, and that was one of the things that struck Warburg the most. And now what we see is that lactate is a typical feature of cancers. Cancers produce largest amounts of lactate, which is also responsible of the famous microenvironment that a lot of people are talking about nowadays. The lactate microenvironment, I mean, the, the microenvironment of cancer cells is more acidic than non-cancer cells, and it's a niche for carcinogenesis. The responsible for that microenvironment is lactate. And what we know is that, yes, it's lactate. It's a fact in multiple studies showing that, uh, or every study showing that every study trying to find lactate in cancer, they're gonna find higher lactate levels.
- PAPeter Attia
So this would suggest three distinct but not necessarily mutually exclusive explanations for the Warburg effect, the first being what Warburg proposed, which is in cancer, there is an injury to the mitochondria. As a result of that injury, the cancer produces... It takes an inefficient path to go. Then there's the 2009 explanation proposed by Thompson, Cantley, Vander Heiden in that science paper that was sort of a very important landmark paper that said, "No, no, that's probably not it. It's the glycolysis and the lactate production is a byproduct of metabolic demand for building blocks." It's the cellular nucleotides that are necessary to build the cells, so the mitochondria work okay. What you're seeing is a deliberate and obligate choice to grow, and the need to grow, literally from a mass balance perspective, requires taking this pathway versus that pathway. And now you're saying, well, a possible third explanation is the cancer relies on lactate as a signaling molecule. And again, these could all be true on some level. We know that they're not all always true. I mean, at least we know that in the case of the Warburg effect, that's not universally true that the cancer damages the mitochondria.
- IMDr. Iñigo San Millán
Yeah.
- PAPeter Attia
What are the next steps in figuring this out? And perhaps more importantly, much more importantly, how do we use this information therapeutically?
- IMDr. Iñigo San Millán
Yeah. So one of the things is that we have just finished a study. It's under review now, and we're gonna replicate it now with more cancer cells. But we have done a study with the MCF-7 cancer cells, which are the most common type of breast cancer or one of the most common type of breast cancer cells. And, uh, what we have seen is, like, we expose the cancer cells to glucose. So we did experiment, one exposing the cancer cells to a media that contains nothing, no glucose, no glutamine, which is also highly expressed in cancer, and this can survive a couple of days in that state. Then another experiment, we just expose them to glucose. That's it. And in the other two other experiments, we added to that glucose media, we added 10 millimoles of lactate and 20 millimoles of lactate. What we did then is, like, we extracted the DNA.
- PAPeter Attia
By the way, are those physiologically accurate doses? Do we believe the microenvironment of cancer is that high?
- IMDr. Iñigo San Millán
It's about 10, yes.
- PAPeter Attia
It's 10 times the normal level.
- IMDr. Iñigo San Millán
There's been studies showing up to 40. But normally, yeah, 10 is a typical-
- PAPeter Attia
And what pH?
- IMDr. Iñigo San Millán
The pH is usually between six and seven.
- PAPeter Attia
I was about to say, that has to be below seven.
- IMDr. Iñigo San Millán
Yes, for sure. In fact, the more aggressive, in general, the more aggressive the cancer is, the more glycolytic it is, and the more lactate is found, and the more acidic the microenvironment is. So we published an idea to propose lactate being the explanation for the Warburg effect because what we looked into the medical research is that the genetic stops in how the first cancer cell happens and maybe in proliferation in cell cycle genes, but there's a lot more to that in cancer. You need angiogenesis. You need metastasis. You need immune escape, and you need also the cell sufficient metabolism the cancer cell have. It's immortal. So that's where, like, what we saw is that lactate is necessary for each of these major steps in carcinogenesis. But what we wanted to see is, like, could lactate also be a signaling molecule? And that's where, like, uh, what we observe is, like, looking at transcriptional activity, looking at the RNA expressions of the key oncogenes Transcription factors and cell cycle genes and proliferation genes in cancer, lactate overexpress them between two to-- and eightfold compared to control
- PAPeter Attia
And we saw... And what was the difference between the 10 millimolar and 20 millimolar lactate? Did you see a difference in transcription?
- IMDr. Iñigo San Millán
In 10 and 20, we didn't see much of a difference, but, uh, we saw more than in zero. What struck us, and that's kinda hopefully we can show, is that if you cultivate the cancer cells in glucose alone... I give this presentation on the Anderson, but, uh, so we looked at the cancer cells, and we looked at the major oncogenic, I mean, oncogenes transcription factor and cell cycle genes. We had no glucose incubation, no, uh, uh, glutamine either, just glucose. And then we added lactate 10 millimolars and 20 millimolar. So we did RNA extraction, and we looked at, in the cancer cells, were there without any media, that is no glucose, no glutamine, we didn't see RNA expression-
- PAPeter Attia
Did the cells live?
- IMDr. Iñigo San Millán
... of those oncogenes. We killed them. We didn't-
- PAPeter Attia
In other words, there's a very finite period of time in which you're looking to just see-
- IMDr. Iñigo San Millán
Yes. We look in six hours, in 48 hours. So neither in six, 48 hours was RNA expressions.
- PAPeter Attia
Okay. What about glucose by itself?
- IMDr. Iñigo San Millán
So when you add glucose by itself, we looked into the media, and it was a very high lactate levels.
- PAPeter Attia
Looks like on your graph, it's almost 30 millimole.
- IMDr. Iñigo San Millán
Yes. It was almost 30 millimole in the six hours, and because lactate is also used by the cells for energy purposes over time, we expect it also to see, but we still see about 25 millimolar. This is the Warburg effect. This is what Warburg observed incubating in cells and said, "Wow, they use a lot of glucose, but why in the world is this lactate?"
- PAPeter Attia
It's amazing it's that high. [chuckles]
- IMDr. Iñigo San Millán
So what we saw then is, like, this lactate alone-
- PAPeter Attia
Was enough to trigger-
- IMDr. Iñigo San Millán
... was enough to trigger the expression of all the major oncogenes transcription factors and even depress the cell arrest genes.
- 2:39:25 – 2:40:31
Cycling's Drug Era, Altitude Training, and Miguel Indurain
- PAPeter Attia
Let's talk for a few minutes about drugs in cycling. Many people argue that the era from about '91 to 2010. For-- There's a 20-year period of time, the '90s and first decade of the 2000s, where the use of drugs was at its highest. I don't think anybody can be a student of this sport and ever say there's been an era when the top athletes weren't using some drug. I mean, even Eddy Merckx, the greatest cyclist of them all, on many occasions was found to be using an amphetamine or something like that. How much of an impact do you think the performance-enhancing drugs of that era, the '90s and 2000s, where, again, it's all out in the open now. Everybody understands how much blood doping and how much EPO was being used. Yet you, a moment ago, gave a number of six to 6.5 watts per kilo as an FTP. I recall reading at the time athletes hitting seven watts per kilo. Do you think that is about the distinction of with and without EPO? Do you think that's about the magnitude of the improvement?
Episode duration: 2:53:02
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