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

00:00:00.000 Hey everyone, welcome to the Peter Atiyah drive. I'm your host, Peter Atiyah. The drive

00:00:10.880 is a result of my hunger for optimizing performance, health, longevity, critical thinking, along

00:00:15.940 with a few other obsessions along the way. I've spent the last several years working

00:00:19.660 with some of the most successful top performing individuals in the world. And this podcast

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00:00:28.360 more fulfilling life. If you enjoy this podcast, you can find more information on today's episode

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00:00:41.440 Hey everybody, welcome to this week's episode of the drive. I'd like to take a couple of minutes

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00:04:11.920 My guest this week is Inigo Sanmilan. Inigo is a assistant professor at the University of Colorado

00:04:17.500 School of Medicine, where his areas of research focus on exercise, metabolism, nutrition, sports

00:04:22.740 performance, overtraining, diabetes, cancer, and critical care. And I realize at least one of you at

00:04:27.920 this moment is thinking, how in God's name can one person study all of those things? And the answer is,

00:04:34.100 if you come out of the lens of the mitochondria, it turns out you can have a breadth of focus that

00:04:40.300 covers all those things. And of course, that's exactly what Inigo does is he studies mitochondrial

00:04:45.000 performance and mitochondrial efficiency. And it's based on that, that the moment he and I met a year

00:04:51.220 ago, it was a sort of love at first sight. And we've been geeking out together ever since. Inigo has had a

00:04:58.100 profound impact on my training, the way I talk to my patients about exercise, and the way I've thought

00:05:05.140 about longevity through the lens of mitochondrial performance. He is an internationally renowned

00:05:11.420 applied physiologist. He's worked for at least 20 years with many professional teams, elite athletes

00:05:17.260 across all sports. He himself is a remarkable athlete, which we barely get into. He's so modest and

00:05:22.640 unassuming. He currently works with a number of professional cycling teams at the highest level,

00:05:28.000 including at the level of the Tour de France. He's pioneered a number of things that we get into

00:05:33.780 here, everything from using high-frequency ultrasound to assess glycogen levels, to more importantly,

00:05:40.720 ways in which we can use biopsies at the invasive level and blood tests at the less invasive level

00:05:46.980 to draw on the insights of mitochondrial performance. It would take me an hour to simply explain the

00:05:55.400 treasure trove of stuff we explore in this episode. So I'm not even going to try to say what we get into

00:06:02.400 other than if you're interested in mitochondria, if you're interested in fitness, if you're interested

00:06:08.220 in exercise, if you're interested in metabolic health, all of the above, I think you just need to

00:06:13.700 listen to this one and take my word for it without seeing the running commentary. The show notes, of

00:06:18.180 course, will be especially important for this one because some of this stuff just is better explained

00:06:23.640 through pictures than words. And of course, there will be a nice effective table of contents there.

00:06:28.260 So without further delay, please enjoy my conversation with Inigo.

00:06:35.740 Inigo, thank you so much for making time to sit down today in your new office here.

00:06:40.800 Thank you very much, Peter. It's my pleasure and honor that you're here with us at the University of Colorado

00:06:45.420 at the School of Medicine.

00:06:46.920 I emailed my team. I emailed Nick and Bob and a couple of the guys today when I was on the way over here.

00:06:51.880 I was on the plane and I was reviewing my notes and I thought,

00:06:54.760 I am so excited to sit down with you today and Rick tomorrow because we've had so many

00:07:00.320 kind of off-the-cuff sidebar conversations about mitochondria, mitochondrial function,

00:07:06.900 health, efficiency, etc. And it's sort of like we never have enough time.

00:07:10.420 It's like 15 minutes here and 12 minutes there and an email here and an email there.

00:07:14.500 But it was in preparing for this, the team helped me really kind of put a lot of my thoughts together.

00:07:19.040 But I think before we kind of get into the really hardcore stuff around mitochondria,

00:07:23.100 which is something that I think anybody who's interested in health at any level,

00:07:27.400 whether it's really at the deep cellular level or just at the level of I want to live as long as I can,

00:07:32.540 as healthy as I can, everybody sort of has a sense that all roads point to the mitochondria.

00:07:37.080 But your path to getting there to me is particularly interesting because it starts with looking at

00:07:43.700 athletes. And you yourself, even though you downplay it a lot, you were quite the athlete

00:07:47.380 growing up. So you grew up in Spain and what sports did you play?

00:07:51.000 Yeah, I grew up in Spain and I played for Real Madrid for the academy for six years.

00:07:55.480 And I was always very passionate about sport. Then I, when I turned 16, I discovered cycling and,

00:08:00.700 and that's the way I changed sports. So my dad still thinks that that was the dumbest decision

00:08:05.100 of my life.

00:08:06.260 But is that true statistically with a child growing up in Spain, who's already in the feeder program

00:08:11.600 for Real Madrid, would they have a better chance of having a career as a professional football

00:08:16.240 player than a professional cyclist?

00:08:18.180 That's hard to say, but when you're already at that age in Real Madrid, you can be getting to the

00:08:24.020 top team is very difficult, obviously, but definitely be a feeder to other smaller teams.

00:08:29.100 That's a higher possibility, but you never know, but you have to follow your passion, I guess. And

00:08:33.780 I followed it and I changed to cycling and I got to race professionally for two years at a low level.

00:08:40.380 So I always say that I admit it. I'm a truncated and frustrated professional athlete because I never

00:08:45.480 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

00:08:50.720 nine years old, I've been in the high level of competition up until today on the other side of

00:08:56.600 the table, working with athletes. And that's what I became very familiar with everything related to

00:09:02.380 the elite sport and that, everything that involves.

00:09:05.880 I don't think most people who have not themselves been on a bicycle and trying to do something at a

00:09:12.000 reasonably high level can appreciate that even being a professional quote unquote low

00:09:17.180 level. I assume what you're saying by that is you were not necessarily on a team that was even

00:09:21.860 going to go to the big grand tours and such, but I still think most people don't understand the level,

00:09:27.080 how much higher that is above a general fitness athlete type of thing. So when you were at that

00:09:33.560 level, what was your specialty? Were you a time trialist? Were you, uh, you look too tall to be a

00:09:38.220 climber, but who knows what you weighed back then? Yeah, I was very skinny though. You're taller than

00:09:42.320 me. I'm like five 11. Okay. So you're an inch taller, but I used to be 143, 145 pounds. So I was very

00:09:49.300 skinny. So I used to be a good climber. I was good overall, but I'm better as a climber. But yeah, I,

00:09:56.060 I, is that I appreciate it now when I see people who are category ones or twos or threes as a cyclist

00:10:03.160 or so that their fitness level is very good, that definitely my fitness level was better. But at the

00:10:09.900 same time, there is like a whole world between my fitness level and what the two of the France guys

00:10:15.360 have. It is unbelievable. When I was sort of going through category five, four, three, two, by some

00:10:20.820 metrics, I could maybe time trial at the level of a category two, three, but of course my climbing and

00:10:26.480 sprinting and everything else would have been like a category four. And you realize that the guy who's

00:10:30.800 category one, the guys I used to train with who are collegiate athletes who are exceptional at

00:10:35.500 category one, they're still not even pro. There's still a step between them and a domestic pro and

00:10:41.180 then the domestic pro to get from that level to a European pro and then the European pro to get to

00:10:46.940 a major team and then to be on a major team and the difference between the GC contender and everybody

00:10:52.460 else. We're talking about log orders of ability. It's not subtle. No. And I have all the data from

00:10:59.060 all these years collecting the data and I know very well the physiological parameters typical of a

00:11:05.920 top junior athlete or category three, category two, one, domestic pro, average, pro tour, cyclist,

00:11:13.580 and best of the best. And the difference is amazing. They're very significant. You can really

00:11:18.040 categorize people accordingly. We're going to come back and start to talk about professional cycling

00:11:22.300 and things. And there's so many things I want to talk about because I think for also the person who's

00:11:26.060 not immediately wed to the sport might too easily want to dismiss the accolades of these athletes

00:11:32.340 and the physiologic prowess as simply, well, you know, those guys all use drugs. And while that's

00:11:37.620 probably true at some level with respect to some drugs and certainly a certain class of athletes,

00:11:43.740 it in no way diminishes what their physiology looks like completely off drugs. So we'll come back

00:11:49.580 to all that, but going to you. So after two years at a professional level, what made you decide I'm

00:11:55.920 not going to continue doing this? I'm going to pursue my education and the other things that

00:11:59.800 you've gone on to do. I realized that it's very difficult and you need to be in the right place

00:12:04.080 at the right time at the right moment and that different planets need to be aligned. It is not

00:12:09.480 just the best always get up there to call it destiny, call it whatever, but a lot of things have to

00:12:14.540 happen to become a pro and they were not on my side. But at the same time, I needed to make a

00:12:19.860 decision, either trying to get an education that can not assure me, but at least give me some future

00:12:26.860 professionally speaking outside the sport or try to go for the sport where the planets were not aligned.

00:12:33.020 I didn't know if I could even make it and it would take that sacrifice. So that's what I decided,

00:12:38.700 I think this is not good for me. And then as I was studying also, I had a good possibility of doing

00:12:45.740 a very good internship at a top, if not the top sports medicine clinic in Spain. In fact, the famous

00:12:52.100 PRP therapy was born in that clinic. And that's where I said, I had a good possibility to start

00:12:58.120 internship and then became a part-time job. And at that time I said, okay, I'm just going to stay here

00:13:03.860 and continue. And how long have you been here at the University of Colorado? 11 years.

00:13:08.940 Okay. Now you and I met through an interesting circumstance. It's a funny story. I don't know

00:13:13.480 if you remember the very first time, but I had just flown into Abu Dhabi and I think I came straight

00:13:18.420 from the airport to the training facility. And it was like 11 o'clock at night or something. And you

00:13:23.520 put me right on the bike and we did a VO2 max test. And which anybody who's done a VO2 max test on

00:13:28.340 a bike knows there's nothing very pleasant about it. You've got this mask that is incredibly

00:13:32.140 restrictive. I hadn't done one since I stopped cycling. So that was probably six, five years or six years.

00:13:38.260 And then I think you weren't happy with the air mixer because we were getting weird numbers. And

00:13:42.380 it was at some point, I think when I hit about 50 milliliters per milligram per kilogram, we sort

00:13:47.500 of said that's enough. And that was a good thing because I don't think I had much more. It's amazing

00:13:51.600 how much you lose when you stop training that zone. Yeah. I never thought there could be a day when my

00:13:57.440 VO2 max could be below 50. Like I thought it'll be 50 when I'm a hundred, right? Yeah. That's not true.

00:14:02.600 It really falls away. Yeah. It falls apart. Yeah. So I would be surprised if I could hit 55 today,

00:14:07.720 actually. But we connected immediately because it was a great point in my life where I was almost,

00:14:13.540 I was sort of looking for direction as a former, I don't even want to use the word athlete to

00:14:18.840 describe myself, but as a person who formerly took training very seriously to now someone who was

00:14:24.140 trying to think about reshaping my training around longevity. It was a perfect collision of ideas

00:14:30.440 because I was sort of in search of what to really focus on. And what we immediately clicked over was

00:14:36.460 your protocol for zone two training, which you were instituting heavily with the UAE team and other

00:14:42.640 folks that you were training there. And the rest is history. I mean, it's really completely shaped the

00:14:47.620 way I think about using this type of training as a way to improve mitochondrial function and as a way to

00:14:54.860 test it. I almost think at this point for the listener, we should pause for a moment and explain

00:14:59.460 these energy systems because so much of what I want to ask you about and so much of what your

00:15:04.260 research focuses on assumes a level of understanding I don't want to take for granted. So maybe explain

00:15:11.220 for people what aerobic metabolism means. Okay. So there are different energy systems and those energy

00:15:18.240 systems, they're also used by different muscle fibers in the muscle. There are different conditions

00:15:23.540 like the aerobic condition and anaerobic condition. We tend to believe that the immense majority of

00:15:29.020 activity that we do is aerobic. We tend to believe that any hard effort is anaerobic and therefore the

00:15:35.240 concept of anaerobic threshold. But actually, even what we call the anaerobic threshold is an aerobic

00:15:40.900 activity. So the majority of the efforts that we do are in an anaerobic environment, except for when you

00:15:47.820 do a sprint or when you do maybe like a one minute maximum. Outside that, the majority of the activities

00:15:55.820 that we do are in the aerobic state. Then what changes is the fuels that you use to produce energy.

00:16:05.340 So at the end of the day, what we want to do is to contract the muscles and not only to contract them

00:16:11.620 as fast and as forceful as possible, but what we want also is to do this as efficiently as possible.

00:16:18.620 So for example, for a marathon race or for a 1500 meter race, you need to calculate when you pull

00:16:26.380 the trigger and go for it. And then when you have to deploy all the maximum efficiency that you have.

00:16:33.140 So you need to be very efficient metabolically speaking. So the fuels are very important for that.

00:16:39.020 So the main fuels that we use for exercise are the fatty acids and glucose. And those are oxidized

00:16:46.720 or burned in the different skeletal muscle fibers that we have. So we have the slow twitch muscle

00:16:53.160 fibers and the fast twitch muscle fibers. The fast twitch muscle fibers are divided in two. The type

00:17:00.100 1A and type 2B, if you will. Some people call them type 2X as well, but there are two kinds of muscle

00:17:07.260 fibers. And I just want to interject for a moment because I know a lot of people listening to this

00:17:11.640 have heard the term fast twitch and slow twitch. And the assumption is that they twitch at different

00:17:16.540 speeds, but really it's that they twitch with a different force. And the speed is referring to

00:17:21.240 how quickly they fatigue, not the speed with which they fire. So when you're talking about a type 1

00:17:26.920 or a slow twitch muscle fiber, it's just a less forceful fiber. Whereas a type 2 fiber, and as you

00:17:33.060 said, they're divided into A's and B's with each firing of, with each time that the muscle fiber fires,

00:17:38.980 there are more motor end plates and therefore it's generating more force. But the trade-off is it's

00:17:43.220 going to be more quick to fatigue. And why is that? Why does it fatigue faster? Because it comes down

00:17:47.980 to what you're talking about. Yeah, it's because metabolically they're more stressed. The way we

00:17:52.460 recruit muscle fibers obeys a sequential pattern that is very similar to the stick gears of a manual

00:17:59.060 car. So you first start and you go in first gear. And as the RPMs go up, then you get to a point,

00:18:06.280 you get to the red zone. So that car cannot keep up with that first gear. You need to shift to second

00:18:11.680 gear and you speed up and the RPMs go higher. And then eventually you need to shift to third gear.

00:18:16.820 This is very similar to what happens at the skeletal muscle. The type 1 muscle fibers, slow twitch,

00:18:23.660 they can produce ATP, which is the energy coin, the classic that we always hear about, which is what

00:18:29.780 elicits that muscle contraction. So at low exercise intensities, we don't need to contract the muscles

00:18:36.400 nearly as forceful nor as fast as when we do high intensity. Meaning we don't need to go back and keep

00:18:43.320 firing and keep firing and keep firing. Exactly. And for that, we don't need to generate ATP as fast

00:18:49.600 as we do at higher intensities. And it's about ATP generation, that's exercise intensity. So at low

00:18:56.960 exercise intensities, those slow twitch muscle fibers or type 1 muscle fibers, they are very well

00:19:04.080 designed to use an energy that is good enough to provide ATP. And yet you can do this for a very

00:19:11.140 long time. And that's the diesel gasoline. And that is the fatty acids. However, as exercise intensity

00:19:17.780 increases, the necessity to produce ATP at a higher rate increases as well. And it gets to a point where

00:19:25.960 fatty acids alone are not enough to produce ATP. And therefore you need another energy system.

00:19:33.200 And that energy system is the glucose, which is a faster energy system, which going back to the

00:19:38.580 analogy of the car is like if we had, imagine a car with two tanks, one is gasoline and the other one

00:19:45.940 or regular gasoline and the other one is diesel gasoline. So if you were to go from here to Denver

00:19:51.860 to Kansas, where everything is flat, and you don't need to accelerate or go fast, you would try to be

00:19:56.920 more efficient and would try to use then the diesel gasoline, it's more economical, you get more

00:20:01.860 miles per gallon. But if you want to go to the mountains, and you need to accelerate fast, that

00:20:07.700 diesel might not do the trick, you need extra acceleration. So that's where you utilize the

00:20:13.340 glucose. And that's a very, I mean, the regular gasoline, which is like the glucose for the muscles. And

00:20:18.100 that's kind of how the bioenergetics or the muscles kind of principles start.

00:20:22.420 I like the way you've explained it. And I did a much worse job, I think, probably seven years ago,

00:20:27.000 I wrote a blog post on this. The insight I was trying to get across, I don't know if I did,

00:20:31.560 was that we should not think of aerobic and anaerobic as with or without oxygen,

00:20:36.220 which is sort of the way people are taught in high school biology. Aerobic means in the presence of

00:20:40.980 oxygen. Anaerobic means not in the presence of oxygen. No, it's always in the presence of oxygen.

00:20:44.920 It comes down to the speed with which the muscle is demanding ATP. Aerobic means you're generating ATP

00:20:51.840 at a rate that is slow enough that all of the metabolic demands can be met through mitochondrial

00:20:58.740 oxidation of hopefully mostly fatty acids, but even glucose. Anaerobic just means exactly as you said,

00:21:06.660 the demand for ATP has now exceeded the capacity of the mitochondria. Do you agree with that?

00:21:12.580 Yeah. And even the cytosol. So the cytosol, which is part of the cell, that's where you can oxidize

00:21:18.440 glucose there into pyruvate. And that pyruvate doesn't enter the mitochondria, but you produce

00:21:25.440 lactate, but you produce energy and ATP there. And that can perfectly be still aerobic capacity.

00:21:31.500 And my colleague, George Brooks from Berkeley, he's been studying lactate since the 80s. And he's the one

00:21:37.320 who proved that you can produce lactate under fully aerobic conditions, not necessarily in the

00:21:41.960 mitochondria, but in the cytosol. However, when the ATP demands even exceed the cytosolic production

00:21:49.160 of ATP, that's where you need to use the ATP that is already stored in the muscles. You just don't have

00:21:54.840 time to synthesize it. You need just to use it. And that's why the body stores very, very minimal

00:22:00.820 amounts of ATP. And that's what you develop in the sprint, or you use in the sprint. But you need

00:22:05.880 to resynthesize it very fast. That's the pure anaerobic. You don't need any energy systems.

00:22:11.080 And that goes also that of the confusion that is out there too.

00:22:14.540 And are you saying this is distinct from the creatine phosphate system?

00:22:17.560 Yeah, you can use the creatine phosphate as well. So you can have ATP and you can use the

00:22:21.980 creatine phosphate systems. Those two, they don't need oxygen necessarily. Anything else can be under

00:22:28.260 fully aerobic conditions, like even cytosolic production of ATP in the cytosol without

00:22:34.100 mitochondrial oxidation necessarily, can happen under fully aerobic conditions. And in fact,

00:22:39.920 that's what we also call aerobic glycolysis. And in other areas of biomedical research or medicine,

00:22:46.100 it's called the Warburg effect, which is now a lot of people are into cancer, talk about it.

00:22:50.940 The Warburg effect is that, is the production of lactate or the utilization of glucose

00:22:56.900 glucose in the cytosol, not in the mitochondria, but in the cytosol outside the mitochondria for

00:23:01.560 production of energy. Well, I want to come back to the Warburg effect, but you brought up

00:23:04.640 Brooks and there's a paper that the two of you wrote together somewhat recently. I think it was

00:23:10.700 maybe 2018, if not this year, but it's actually, I'm in the process of writing a book, as you may

00:23:15.440 recall. And in the exercise chapter, I actually really explore that paper that you guys wrote,

00:23:20.440 which looked at the zone two efficiency of world-class cyclists, recreational athletes,

00:23:26.340 and people with diabetes. That's an unbelievable paper. And that's an unbelievable example of,

00:23:33.680 I think the clinical applicability of what we're talking about. So to put it in context,

00:23:38.180 when we got talking back in Abu Dhabi last year about this, I remember you saying, and I'm paraphrasing,

00:23:44.000 so you should clarify if I'm not saying it correctly, that your interest in athletes is in

00:23:50.960 large part due to your interest in diabetes. Because if you want to understand how to fix

00:23:57.860 an example of arguably the most effective mitochondria, why not at least study what the

00:24:03.920 perfect mitochondria look like? Is that a fair statement? Exactly. Yes. And that's kind of what I'm

00:24:08.680 trying to bring to the table in the elite athletes have the perfect metabolism. And mitochondria is at

00:24:15.100 the epicenter of metabolism and health. As you said earlier, there are no other population in the

00:24:20.400 planet with the mitochondria of elite endurance athletes. I was about to say, yeah, you said elite

00:24:24.340 athletes. I would go even sharper. It really, in my mind, comes down to cyclists and runners. Yes. And

00:24:29.740 triathletes. Even more than swimmers because of just the duration of it. It's these people who can go out

00:24:35.760 and function at their anaerobic threshold for hours. And that's only really found in two sports.

00:24:43.440 Oh, yes. And that's what we see that even with an elite athlete. And I work with many elite

00:24:48.260 athletes. Yeah. You compare them and there's huge differences. I guess I should add one. I think

00:24:52.640 cross-country skiers are probably at that level as well. Yeah. So this population is the population

00:24:57.440 in the planet with the healthiest mitochondria. So that's what I call perfection. And that's what I try to

00:25:02.940 bring to the table that in order to study other diseases where mitochondrial dysfunction is at the

00:25:08.860 epicenter as well, we need to understand what perfection is in order to understand imperfection.

00:25:14.360 And what we see in people with type 2 diabetes, for example, they are on the opposite metabolic pole

00:25:19.860 of what a world-class cyclist or runner is. So by knowing the mechanisms of why that metabolism in

00:25:27.340 these world-class athletes works, we can get to understand the imperfection or the imperfect

00:25:33.140 metabolic pathways and potentially develop diagnostic tools and even therapeutics for them as well as

00:25:40.420 prevention programs. Yeah. And really cancer and type 2 diabetes or insulin resistance as part of a

00:25:46.180 spectrum do represent two very common findings in the population. So if you look at what percentage of

00:25:52.980 the United States population either has cancer or is insulin resistant or has metabolic syndrome and

00:25:57.840 or type 2 diabetes or fatty liver disease, all of these things, which are part of a continuum,

00:26:01.620 you're talking about half the country basically that has some form of dysfunction in the mitochondria.

00:26:06.680 In the case of cancer, we can debate how much of that is a genetic insult versus other things. But

00:26:11.240 because I want to talk so much about that, I want to go back and understand perfection a bit more.

00:26:16.060 So there are lots of different ways people codify energy systems. When I was cycling,

00:26:20.100 we used seven zones because that was Andy Coggins FTP based energy system. You write about six zones and

00:26:28.080 others have talked about five, but I want to talk about your six zones because one, I think they're

00:26:33.340 a little easier to explain than the FTP based ones, which if you don't know, if a functional threshold

00:26:38.200 power number doesn't mean something to someone, then seven energy systems based on it is harder to

00:26:43.460 understand. How would you walk us through zones one through six? What do they mean? Because when we start

00:26:48.660 to talk about zone two, I want people to understand the difference between the normal person and the

00:26:54.540 super person and the sick person. So what is zone one? What does that mean?

00:26:58.140 So that's from 25 years working with athletes and also my experience from being a former athlete

00:27:03.500 and being obsessed with training and, and all these things, that's kind of, it led me to develop this.

00:27:09.720 I'm not saying that they're the right things. And maybe in 10 years, I changed my mind or someone

00:27:14.600 else comes with different things are better, but that's what I have right now, at least. So I do this

00:27:19.880 along with the muscle fiber recruitment pattern and the energy systems. So the type one muscle fibers,

00:27:26.740 we know also that because they're the ones who oxidize fat, burn the fat very well, they have the

00:27:34.000 highest mitochondrial density and content because fat can only be burned in the mitochondria. Type

00:27:39.580 two muscle fibers, especially the first type of muscle fibers, type two, the type two A's, they have

00:27:45.780 lower mitochondrial function because- Lower mitochondrial function or density?

00:27:49.440 Density. I'm sorry, because they don't necessarily need to oxidize glucose in the mitochondria. They can do

00:27:54.400 it in the cytosol of the cell and therefore produce lactate, but they can produce ATP fast. So those muscle

00:28:01.840 fibers, they don't contain as much mitochondria. And then the second type of muscle, slow fast to each

00:28:07.680 muscle fiber, the type two B or two X, that is the one that is the pure anaerobic, if you will.

00:28:13.840 And that is the one that barely has mitochondria, has very minimal mitochondria. So starting with that,

00:28:19.560 that's where I started breaking down the zones. So the zone one would represent the minimum

00:28:25.420 stimulation that the muscle fibers receive. It's just prior contraction. That's what would you do

00:28:31.400 on a recovery day or recovery mode. You have very low exercise intensity and you burn a little bit

00:28:37.120 of fat mainly. And that's what we see also. We look at also fat and carbohydrate utilization.

00:28:44.420 Scientifically, we call it fat and carbohydrate oxidation rates, how many grams per minute of

00:28:49.160 carbohydrate and fat you burn. So we know that at these intensities, you burn mostly fat, although you

00:28:55.140 also burn a little bit of carbohydrates, which we can go through that.

00:28:58.680 Yeah. I want to come back to it because there's such an interesting clinical observation that I've

00:29:03.260 seen over the past five or six years. And your paper, your recent paper with Brooks just hammered

00:29:09.820 it home in a much more rigorous way. So yeah, we are going to come back to our cue at rest as a

00:29:16.220 harbinger of these other things that follow under distress.

00:29:19.400 Yeah. So that's the zone one.

00:29:21.340 So just to put that in energy terms for people, you and I walking up the stairs,

00:29:25.700 we were coming from the lobby, we're in zone one.

00:29:28.200 Yeah.

00:29:28.700 Walking down the street.

00:29:29.620 Walking down the street or if you are very fit and you go for a jog, very easy recovery day,

00:29:36.340 that's your zone one.

00:29:37.380 And then for the elite, give us an example. So if you took

00:29:40.160 Meb or someone who's going to run a sub 210 marathon, you have a sense of how fast they could

00:29:45.860 run and still be in zone one. Someone who's used to running 445 to 450 miles, could their zone one be

00:29:52.460 as fast as like a seven minute mile?

00:29:54.560 Yeah. Yeah, absolutely. You can see world-class athletes that, poof, their zone one, it's my

00:30:00.260 sprinting, for example. It's kind of what we see also in cyclists. The recovery day is 200 watts

00:30:06.400 average. And for most mere mortals, 200 watts, they can do that for 15 minutes.

00:30:11.660 Yeah. I just wrote a post about this recently using as an example. For people who ride a bike,

00:30:16.960 200 watts is about how fast it would take you to go 30 kilometers an hour without wind or without

00:30:25.400 elevation. And that's certainly not all out, but that's pretty fast. And if you can imagine being

00:30:32.460 able to ride at that level indefinitely without any metabolic consequence, that's what an elite

00:30:39.080 athlete is doing. And that says nothing, by the way, about their weight. They're doing that at a

00:30:43.700 body weight that is a fraction of most people. Yeah. That's what they call the coffee, right?

00:30:48.980 Yeah. They go for a coffee or ice cream, right? And it's chit chat. And they're like, it's unbelievable.

00:30:54.380 So zone one, does lactate get produced? It should not get produced. Well, we start from the base that

00:31:01.540 there's always lactate produced in the body. So if you were to poke my finger right now or poke your

00:31:07.040 finger right now, we measure lactate in millimolar. What would you expect to measure in me or you?

00:31:12.360 You would be about one millimol. Okay. 0.7 to one millimol. That's kind of like a standard

00:31:18.280 resting levels in a health individual. And in a normal person, so not an elite athlete,

00:31:23.640 but sort of a recreational athlete, what's the highest lactate you'll typically measure in that

00:31:28.840 person if you put them in a treadmill test or a... It depends on the protocol that you do.

00:31:33.540 If it's a very violent protocol or it's a longer protocol, violent protocols, they produce more

00:31:38.500 lactate. You might see 10, 12 millimoles. Whether that protocol, let's say a six minutes maximal effort

00:31:46.660 on a rowing machine, right? And the concept, for example, I've seen world-class rowers to maximal

00:31:53.460 effort with 20 millimoles of lactate. It's very rare. You see very easily 15, 16, 17. That's because

00:32:00.980 we can talk about that later. Their glycolytic capacity, it's off the charts. Whereas people who

00:32:07.460 they're not elite athletes, it's for them that's in protocol, it's more difficult to go over 12

00:32:12.720 millimoles, 10 millimoles because their glycolytic capacity is not so good as the one that the elite

00:32:19.540 athletes have. And sometimes elite athletes have the opposite issue, which is they don't make much

00:32:24.640 lactate at all. They're so efficient. I've actually discussed this with Lance Armstrong after I

00:32:29.740 erroneously had been on a podcast and made the case that he had a very high lactate tolerance.

00:32:34.980 He was talking about it one day informally and he said, no, it's actually the opposite. I would

00:32:39.180 barely produce any lactate. He was usually producing less lactate than others. And again, this was when

00:32:44.040 everybody's on the same drug or everybody's off the same drug. I mean, just genetically, there are

00:32:47.720 some people who probably have more MCT, which we'll come back and talk to and they become more efficient

00:32:52.360 at it. But okay. So that gives us a sense that lactate will go from maybe one to 10. If you're a normal

00:32:58.100 person, maybe one to 20, I actually measured. 20 is difficult. I measured a lactate of 24 in a friend

00:33:04.240 of mine once. Wow. The highest I've ever measured in myself was 19.7. Wow. And that was only a four

00:33:09.820 minute protocol. Wow. Pretty impressive. But also I almost wonder like maybe it's, I wasn't even in

00:33:14.980 particularly great shape at the time, but I wonder if that same exertion under better fitness would

00:33:21.240 have produced less lactate potentially, right? It depends on the protocol, right? If the protocol stops

00:33:25.960 there and what you intend is to produce, mobilize the glycolytic system to the maximum, yeah, you

00:33:31.960 will produce a lot of lactate. If you want to continue and do a longer protocol, eventually

00:33:36.780 you just cannot mobilize as much lactate. I mean, as much glycolytic system, because you

00:33:41.820 have a little bit more of fatigue. I think the difference between the really good people,

00:33:45.260 I mean, when I hit, if I hit, and I've been above 18 and maybe a dozen times, I'm done for half

00:33:50.780 an hour. Like I can barely get up off the floor to go and take a shower. Whereas this friend of mine

00:33:57.980 who was at 24, I saw him go from 24 to 14 in a span of about seven minutes and then jump in the pool and

00:34:07.400 swim another race. And he's world-class. So that's sort of the difference. I think the world-class 0.77

00:34:11.740 athlete can also clear the lactate much quicker than I can. For sure. And that's what happens in the

00:34:16.420 mitochondria and any other part of the body. Because one thing with lactate, we believe that

00:34:21.720 it's a waste product. However, lactate is the most important, if not the most important fuel for the

00:34:28.480 body. That's a profound statement. Yes. Yes. And I completely agree with you that lactate is not a

00:34:33.540 waste product, but say more about that point. So one of the things, the brain prefers to use lactate.

00:34:39.980 So I have heard this. Talk to me about the data on this front. So my colleague, George Brooks,

00:34:44.580 was lactate, man. So yeah, he started doing research with TBI, traumatic brain injury patients

00:34:51.640 at UCLA. It's typical to give them glucose. And then when there's like a brain injury,

00:34:57.700 what the brain in the first place has evolved to use glucose as the main fuel. So when the brain is

00:35:03.860 injured, they use more glucose. However, when it's injured, different metabolic pathways might be

00:35:08.880 dysregulated. So what my colleague George Brooks suggested was to give them lactate. And he showed

00:35:15.260 and he published they do better. Better than beta-hydroxybutyrate, which also seems to be

00:35:20.200 really beneficial in TBI patients for maybe a different reason than lactate, although it could

00:35:24.380 be all similar, which is if you buy the argument, which I find favorable, that part of the insult of TBI

00:35:33.280 is pyruvate dehydrogenase becomes resistant to insulin. That would explain why glucose becomes

00:35:39.500 ineffective in those patients. And it would explain why beta-hydroxybutyrate can bypass it. And the

00:35:44.740 same could be true of lactate. Yes, absolutely. It's an alternative substrate that doesn't get

00:35:49.300 limited through pyruvate dehydrogenase. Is that what you think is happening? Yes, because it has its own

00:35:54.080 transporter in the mitochondria and doesn't need PTH for that. It can enter the mitochondria directly for

00:36:00.220 energy systems like hydroxybutyrate as well. But the thing is like lactate is a faster fuel.

00:36:05.480 So the thing is like also... Yeah, BHB is not a fast fuel. Exactly. Whereas lactate is as fast,

00:36:11.860 if not faster as glucose, because it doesn't have to be processed, if you will. Now the listener might

00:36:16.820 say, wait a minute, what are you guys talking about? Anyone who's ever done a lactate test knows how

00:36:21.180 much pain you're in when your lactate level goes up. So one of the other, I think, misunderstandings is

00:36:26.980 what's actually causing that pain. Because that's, I think, why so many of us have a negative

00:36:31.620 association with lactate. It's not actually the lactate that's causing the physical discomfort

00:36:36.480 that you feel when you're vomiting on the floor after a maximal lactate test. It's the hydrogen.

00:36:41.320 So explain why that's the case and why we tend to confound the two.

00:36:44.820 I mean, there are many causes for pain or fatigue that in different hypotheses from the central fatigue

00:36:50.200 to the peripheral fatigue. And it's very possible that both are interconnected at some point. We don't

00:36:56.220 know the exact mechanisms. At some point, the central fatigue calls for the brain to be the ruler,

00:37:02.240 where the peripheral fatigue is what happens at the cellular level. So it is possible that there's

00:37:07.120 like a crosstalk among both of them and either the chicken or the egg, right? Either one of them

00:37:12.420 says stop. But what we know is that, yeah, it's not lactate itself, but the hydrogen ions associated

00:37:18.000 to lactate, they build up. One of the things that, and it's been researched, they can decrease

00:37:23.300 both the contracted capacity of the muscle fibers, as well as the force by up to 50% or more.

00:37:30.900 So that's one of the things that what we see is like the muscles, they cannot contract as fast or

00:37:36.900 as forceful as before. And this is an important point for people to understand, because if you

00:37:40.940 haven't taken a physiology course, when, why would most people do so? It's also not obvious why you

00:37:46.920 even need ATP to make your muscles contract. It's actually to unleash or unlock the actin myosin

00:37:54.220 contact. It's the relaxation phase of the muscle that requires energy. Exactly. So now, if you imagine

00:38:00.940 anybody who's done that, sit on the rowing machine for four minutes and go as hard as you can, well,

00:38:05.960 at the end of that, anyone who's done it will acknowledge it feels like you can't actually contract

00:38:10.640 your muscle. You've lost the voluntary ability to make them do what you want to do. And it's really

00:38:16.080 two things going on. It's this hydrogen poison. And then on top of that, you're not generating enough

00:38:21.740 ATP to hit all of those fibers that need to be uncoupled from their actin and myosin. So anyone

00:38:28.920 who's been there knows like it, you think I'm going crazy. Why can I not make myself do this?

00:38:33.420 Yeah. And that's where maybe the central fatigue component, the brain might must be factoring in

00:38:37.980 and say, Hey, dude, you know, you're getting to a point that this is not physiological. So I'm going

00:38:44.280 to protect your muscles. And they're telling me through different signals. One might be the

00:38:49.000 hydrogen ions, which also are produced from the hydrolysis or the breakdown or ATP. They produce

00:38:55.220 also hydrogen. So you have the lactate on one hand and the ATP or the fast rate of ATP hydrolysis

00:39:00.900 also produces hydrogen ions. But yeah, as you said very well, like you're conscious once,

00:39:06.700 but there's something at the neuromuscular level also that impedes that. Could be at the local level

00:39:12.780 specifically, but could also perfectly be that the brain says, Hey, let's stop it. And one of the

00:39:18.840 things that we know when people are fatigued is that there's a decrease in adrenaline secretion

00:39:25.640 to protect yourself because adrenaline or epinephrine, we call it here in the US epinephrine

00:39:31.420 in Europe is called adrenaline is the major or one of the major elements involved in the breakdown of

00:39:37.500 glycogen to glucose. We can talk about that later as part of the overtraining, but the adrenergic

00:39:42.900 activity, it's also decreased as well when someone is in a fatigued state.

00:39:48.060 So by the way, Alex Hutchinson's written a great book on this. Have you, have you read his book

00:39:52.260 Endure?

00:39:52.900 I heard about it, but I haven't read it yet.

00:39:55.160 Again, it's good for someone like me who comes into this without world-class knowledge. And I found

00:39:59.640 it a very interesting survey. In fact, I hope to have him on the podcast at some point to go into

00:40:03.360 some real depth on that. So now we've talked about the two ends of the spectrum, the most extreme

00:40:07.860 end and the first end. Let's now get into zone two. What's happening physiologically as that athlete

00:40:12.640 or that person enters zone two?

00:40:15.240 So the zone two is now then when you start stimulating those slow twitch muscle fibers to

00:40:21.580 the fullest. Let's imagine that you're in that first gear that I mentioned earlier in the manual

00:40:26.880 stick car, and then you're in that red zone. And that's where the car is asking you, Hey, shift

00:40:32.580 to second gear. And that's where like you're forcing physiologically because the body adapts

00:40:37.800 to say, no, you get stronger at this gear. That's kind of that zone two is like when you stimulate

00:40:44.180 those muscle fibers before you start changing to a whole different environment where you start then

00:40:51.040 recruiting fully that type two or fast twitch muscle fibers, and therefore the different energy

00:40:57.300 system, which is the glucose. So the zone two coincides also with what we call the fat max,

00:41:04.980 which is exercise intensity at the one you oxidize the highest amount of fat. And then we can see that

00:41:10.940 clearly in the laboratory as we saw in the graph that we can show.

00:41:14.700 Yeah, we're going to include a lot of great pictures here. So if you're looking at the show notes,

00:41:18.400 there's something called the metabolic map, which is a great slide that we'll walk through this. And

00:41:22.100 I think what's very interesting here, this occurs so often in physiology, it's a bit counterintuitive.

00:41:27.940 As you go from zone one to two to three to four, five, and six, you're generating more and more ATP as

00:41:34.800 you go up that chain. So that part is monotonic. It's increasing without stopping, but there's a local

00:41:41.020 maximum that's occurring in zone two, which is your highest amount of fat oxidation. So as you go

00:41:47.960 from zone two to three to four, you will still produce more energy. You will consume even more

00:41:54.560 oxygen. Your VO two max has not been achieved, which is your maximal uptake of oxygen, but you

00:41:59.980 will now become less efficient and you're moving to a less efficient fuel. You're moving away from

00:42:05.560 this diesel example or the fat. So again, I think for a lot of people, the semantics get confusing

00:42:11.000 here because you just said that zone two is your maximum. I mean, maybe a better way to explain it

00:42:16.800 for me is zone two is the place at which your mitochondria are producing the maximum amount

00:42:23.000 under purely aerobic conditions of ATP. Is that fair? Yeah, I would say that too. And that's where

00:42:27.740 you're still recruiting those type one muscle fibers. That's the exercise intensity where you're

00:42:33.280 recruiting the most and they had the highest stimulus. Without tipping into the twos. That's

00:42:38.680 basically it. And since that type one muscle fibers have the highest mitochondria density,

00:42:43.600 you're really stimulating them a lot. As you said before, you need to tap into the fast twitch

00:42:49.800 muscle fibers. And in the moment you tap into the fast twitch muscle fibers is because the ATP demand

00:42:56.500 that you need cannot be covered by fat and you need to switch to a different fuel. And that's where

00:43:04.060 we see a big drop in fat oxidation. And we see an increase also in glucose oxidation. And that's when we

00:43:12.440 start seeing also an increase in lactate as well, because lactate is always, and I forgot to mention

00:43:19.820 that earlier, lactate is the mandatory by-product, not waste product, by-product of glucose utilization,

00:43:28.000 mandatory. Every time you use glucose, you use lactate. And at higher intensity, you produce more.

00:43:34.140 Let's talk about that because again, I think that's more nuanced than most of us would come to this

00:43:38.660 discussion with. We learned in physiology class that a molecule of glucose in the cytosol

00:43:45.040 is turned into two molecules of pyruvate. Under conditions of sufficient cellular oxygen to meet

00:43:52.700 the ATP demand, the pyruvate enters the mitochondria where it undergoes oxidative phosphorylation to make

00:43:59.140 ATP and no lactate is generated. If that ATP demand exceeds the capacity that you just described in zone two,

00:44:07.920 we now have to start turning some of that pyruvate into lactate to generate additional ATP that's

00:44:15.040 faster to generate. In the first case that I described, is there still by necessity some lactate

00:44:21.120 production? Yes, there's some lactate production and we can see that even at rest, we have always a

00:44:26.760 little bit of lactate in our bloodstream. Which is what you said at the outset. You said if you checked

00:44:30.760 my finger or your finger now, we would probably still have somewhere between 0.7 and 1 millimole of

00:44:35.700 lactate. Why is that? That's where we're trying to understand and we believe, my colleague George

00:44:40.760 Brooks and I, that lactate is a major signaling molecule. That when it's regulated, it can signal

00:44:47.600 and maintain homeostasis of different metabolic pathways. It's kind of like a visa for the body,

00:44:54.320 as my colleague George Brooks calls it. When it's dysregulated, as we're starting to see in cancer,

00:44:59.160 for example, or we can see in type 2 diabetes, it can dysregulate different pathways. Every cell in

00:45:06.000 the body produces lactate and pretty much every cell in the body consumes lactate.

00:45:10.800 Including red blood cells, I'm guessing?

00:45:12.760 Yes. They produce a lot of lactate, red blood cells, because they don't have mitochondria.

00:45:17.020 Yeah, I wonder...

00:45:17.700 It's glycolytic mechanism.

00:45:19.100 Yeah. Do the red blood cells account for most of the lactate production we see at baseline?

00:45:23.360 Not necessarily, because there's not so much hemolysis and there's not so much activity in

00:45:28.900 the red blood cells. But there's always some metabolic lactate produced from glucose utilization,

00:45:34.620 because we always use a little bit of glucose, of course, the brain. But that lactate escapes to

00:45:40.940 the blood, to the circulation. And for us, it's significant that it's always so steady also. And

00:45:46.760 every cell in the body produces lactate and almost every cell in the body utilizes lactate. So it's

00:45:51.540 got to be a why. And we believe, and that's what we're trying to scratch the surface, that it's a

00:45:58.620 very important signaling molecule that goes beyond being a byproduct or metabolite. And that's something

00:46:05.220 that we've already seen in cancer, where we have seen that lactate stimulates the expression of the

00:46:12.860 major oncogenes, transcription factors, and cell cycle genes in breast cancer. So it acts, and we have

00:46:19.940 the paper on the review now, it acts as a signaling molecule.

00:46:23.400 So this is interesting, because again, in physiology class, you sort of learn that all of that waste

00:46:27.800 lactate goes back to the liver, and the Cori cycle converts it into glucose, and it becomes now stored

00:46:34.140 glucose. But what you're saying is it's much broader than that. I mean, obviously, the Cori cycle still

00:46:38.880 exists, but it's not even clear how much of the lactate that we're measuring is undergoing that pathway

00:46:44.940 to be converted back to glucose versus itself being consumed as a fuel, correct?

00:46:49.480 Yes. And thanks to the great work that my colleague Brooks did starting in the 80s, what he saw is that

00:46:54.680 the majority of that lactate is oxidized by the slow twitch muscle fibers, by the mitochondria of the

00:47:02.200 slow twitch muscle fibers.

00:47:03.880 And each mole of lactate gives how many moles of ATP under those conditions?

00:47:08.680 I don't have it on top of my mind right now.

00:47:10.340 Is it a small number or big?

00:47:11.060 Yeah. It'll be a smaller number as well.

00:47:13.520 But it's not like the 16 or whatever you get per acetyl-CoA.

00:47:16.980 No, no, no, no. I don't think so. I don't have it on top of my head. But the thing is a constant

00:47:21.100 flux of lactate from the fast twitch muscle fibers to the slow twitch muscle fibers. That's when you

00:47:27.400 start entering that zone three. You start mobilizing more of the glycolytic system, and that's kind of a

00:47:32.620 transition state where you still mix fuels, fatty acids, and carbohydrates, but you start using more

00:47:39.840 carbohydrates, and therefore you start producing lactate. That's said that lactate is transported

00:47:45.920 from mainly from the fast twitch muscle fibers into the mitochondria of the slow twitch muscle fibers,

00:47:52.440 where it's used for energy. It enters directly the mitochondria for energy purposes. And that is the

00:47:58.620 ability that elite athletes have. They can be recruiting fast twitch muscle fibers. They can be

00:48:05.420 utilizing a lot of glucose and producing a lot of lactate. But since they have a very well-developed

00:48:12.220 mitochondria in the slow twitch muscle fibers, they don't need to export it to the blood, and it doesn't

00:48:18.420 accumulate.

00:48:19.240 Yeah. This to me is the grail. This is the stuff that sets apart the best from the rest. Going back to zone

00:48:25.080 two, tell me where you typically see a lactate level there. You and I have talked about a bunch of

00:48:31.940 these numbers when I try to explain this to my patients, because I have many of my patients on

00:48:35.880 a zone two protocol. For a lot of the time, we just use voice. We use ability to talk. I sort of say,

00:48:41.340 look, if you don't want to go through the protocol of poking your finger, zone two is about the highest

00:48:46.240 level of exertion at which you're still able to carry out a conversation. But let's talk more

00:48:50.920 technically. We're really seeing what? Lactate levels of about 1.7 to 1.9 millimole?

00:48:56.460 Yeah. 1.5 to 2. That's something what we see. And that's kind of what corresponds also to that fat

00:49:02.620 max. So today, my data that I showed you from my ride this morning, I was 1.3 and 1.2 on my two

00:49:09.500 meters. So I always do two separate meters. So I average 1.25 millimole. That was clearly not zone

00:49:15.180 two. That was a zone one. It depends the feeder that you get. Like for example, a world-class

00:49:19.440 athlete at zone two is really high. Yeah. Well, I'm not world-class, but just by lactate levels,

00:49:25.280 that's probably not quite there. Yeah. It might not be quite there because it's slightly above

00:49:29.760 resting levels. So there's no accumulation. And it's this accumulation. There's a homeostasis or

00:49:35.720 a steady state below two. So call it 1.7, 1.8, 1.9, where you're right at the limit of not

00:49:42.920 accumulating at a net level, correct? Yes. Yes. So you're pretty much, that lactic comes,

00:49:48.460 you obviously see it in the blood and it comes from the muscles. So that means that the muscles

00:49:53.320 overall are good. First, they're not very metabolically stressed. So therefore, they're

00:49:59.520 not utilizing a lot of glucose. And even if they're stressed, they're clearing the lactate

00:50:04.200 very well because you see in blood 1.5, 1.7, two millimoles, slightly above resting levels.

00:50:11.360 However, when you start seeing higher lactate levels in the blood, that means that your muscle

00:50:17.400 clearance capacity cannot meet. No, I think what you're saying, if I understand is once you hit

00:50:23.220 two, three, four, five millimolar, you're saying that the muscle's ability to recirculate and utilize

00:50:29.880 the lactate is going down. It has to export it into the circulation. Exactly. And that's where it goes

00:50:34.600 to every cell in the body. It goes to the brain, it goes to the kidney, it goes to the heart. The

00:50:38.700 heart is a great utilizer of lactate. And obviously, as you said earlier, it goes to the

00:50:42.680 Cori cycle to be resynthesized back to glucose or to a certain length or form of glycogen.

00:50:48.420 But yeah, that's where we see that in blood. That means that that athlete cannot clear the

00:50:52.480 lactate efficiently. And therefore, that's why it shows up in the blood. And that's where we can

00:50:56.880 see that, for example, one professional athlete at 300 watts, a world-class athlete might, well,

00:51:04.100 let's say, yeah, 300 watts might have three millimoles of lactate, let's say, or two and a half.

00:51:08.540 And a mer-moral might have 12. That means that the power output is the same. But how do you get

00:51:14.620 there? It's different. In the first place, the elite athlete might not need to use so much glucose.

00:51:20.960 And if they do, they produce lactate, but they clear out so efficiently in the slow twitch muscle

00:51:27.080 fibers that it doesn't have to go to the blood. Whereas the person who doesn't have a very good

00:51:33.460 mitochondrial function cannot oxidize lactate very efficiently locally in the skeletal muscle,

00:51:40.040 and they have to export it to the circulation. And that's a way to see the metabolic stress

00:51:45.980 and indirectly, as we published, a way to look at what is the mitochondrial function.

00:51:51.800 So let's talk about that now. I do want to come back and talk about zones three and up,

00:51:55.440 but because this is the perfect point to go back to the paper you and Brooks recently wrote,

00:51:59.820 what you showed that I just thought was so elegant was, as you said, you can either cap the output or

00:52:06.640 clamp the power required or clamp the lactate production and look at the power required. And

00:52:11.780 you did the latter. You basically said, we're going to find everybody's zone two, meaning we're going to

00:52:16.680 find everybody's tipping point, at which point their mitochondria are no longer high enough in

00:52:23.200 function to meet the requirement. And what you showed was world-class cyclists were able to get

00:52:31.140 to an average of something like 300 Watts before they would finally flip that switch and have to start

00:52:38.640 recruiting the fast twitch muscle fibers, which was measured indirectly by lactate production.

00:52:45.200 Conversely, the weekend warrior reasonably fit people, guys like me could get to 200 Watts

00:52:52.520 before that switch got flipped. But most interesting was the people with type two diabetes.

00:52:58.900 I think we're like 120 Watts. Is that about right?

00:53:02.620 Yeah. We've been knowing for years now that a typical characteristic that we know of people

00:53:07.380 with pre-type two or type two diabetes is that they have a poor metabolic flexibility that is called

00:53:13.620 also a poor capacity to oxidize fuels. One of them is fat. We know that fat can only be oxidized in

00:53:20.580 the mitochondria. Therefore, by measuring the fat oxidation of these patients, we can indirectly

00:53:27.360 see the mitochondrial function, especially when we put them in context or in comparison with those

00:53:34.340 ones who are healthy individuals that could be moderately active individuals who don't have

00:53:40.180 diabetes or pre-diabetes or don't have any medications or elite athletes. So that's what we see

00:53:45.080 that. Their fat capacity is very, very low. And that's kind of what we can see indirectly.

00:53:50.740 But it's not often you see in biology such a difference because if the numbers 300 versus 200

00:53:56.760 versus 100 sound extreme, that's nothing compared to when you normalize by weight. So really the answer

00:54:03.660 is in Watts per kilo, what's the difference? And 300 Watts to a professional cyclist who only weighs 60 to

00:54:11.300 65 kilos is just below five Watts per kilogram. Whereas the person with diabetes almost assuredly

00:54:18.540 weighs more. So they're 120 Watts is probably 1.5 Watts per kilo. There are not a lot of examples of

00:54:26.640 things in physiology where you see that much of a difference. You rarely even see that much of a

00:54:31.540 difference in average glucose level between someone with diabetes and not. So this is this functional

00:54:37.440 definition that you guys have proposed is to me very important, just as a clinician, just as someone

00:54:45.620 who's trying to gather more data about a patient to understand their health. It's sort of like in a

00:54:52.900 magic scenario or in a magic world, you would have these data on every single person. You would want

00:54:58.780 to know what is your zone two threshold. And that becomes a way to assess mitochondrial function. Now,

00:55:04.240 the story I was going to tell earlier, this is as good a time as any to tell it about five years ago

00:55:08.620 in some of the most insulin resistant patients that I was taking care of, I began looking at baseline

00:55:14.060 resting respiratory quotient, which you alluded to earlier. This is the ratio of produced carbon

00:55:21.220 dioxide to consumed oxygen. Say a little bit about that number and how to interpret it. And then I'll

00:55:27.260 finish the story. So that's kind of, we can see through expired gases. We can see the amount of CO2

00:55:33.620 that you produce and the amount of oxygen that you utilize. So under resting conditions, and that's

00:55:41.380 what's called a respiratory coefficient or the respiratory exchange ratio. The respiratory exchange

00:55:46.980 ratio is purely at the respiratory level, at the lung level, or the respiratory quotient, it's at the

00:55:53.640 muscle level. They're quite similar, but not academically. You know, that might not the same,

00:55:58.260 but we can call it RQ or RER2. So under normal conditions, you don't produce much CO2. So the

00:56:05.600 ratio, it's always below one, could be 0.7, something like that, for example. That means that

00:56:11.400 it's CO2 divided by oxygen. So that's where you don't produce a lot of CO2. You use more oxygen and

00:56:20.140 therefore the ratio of 0.7. As exercise intensity increases. And so that ratio of 0.7, we can impute

00:56:27.640 from that, that a person is virtually all dependent on fat oxidation at that moment. Probably, yes. And

00:56:34.160 that's what we can use through what's called a stoichiometric equation. You can deduct the amount of

00:56:39.580 fat that is oxidized. Because to oxidize one mole of fat, you need X amount of oxygen and you produce

00:56:46.560 X amount of CO2. So by measuring both, you can see what kind of fuel you're burning. And that's

00:56:52.240 what we're doing in our paper. So as exercise intensity increases, or if the person is not

00:56:57.600 metabolically flexible, they cannot oxidize fat very efficiently. So normally these people, they tend to

00:57:03.740 depend more on glucose or any other extra source of fuel. And that's where you see already people at

00:57:10.760 rest, they have a higher RQs or RERs, which could be in the 80s. Then as exercise, if you were to do

00:57:18.820 exercise, as exercise intensity increases, you start producing more CO2. And therefore the ratio starts

00:57:24.920 getting closer and closer to one. When you, and that's where we see that you start oxidizing more

00:57:31.140 glucose than fat. When the ratio gets to one, yeah, it's just a hundred percent of the fuel that you use

00:57:38.040 is glucose and you don't see any fat, which is kind of what we also call kind of that end of the zone

00:57:44.780 four. Yeah. So this was the observation. I was noticing a subset of patients, again, very hyper

00:57:51.740 insulinemic, insulin resistant by whatever metric you would use to explain it, that had resting RER or RQ

00:57:59.380 of 0.9 to 1, easily 0.95. So what does it mean when someone who is laying down to do this test under no

00:58:11.220 physiologic distress has an RQ of 0.95? What does that mean? Obviously based on what you said,

00:58:18.620 it means they are almost exclusively relying on glucose and not oxidizing any fatty acid.

00:58:24.420 But what is that telling you at a molecular level about the illness or the function of that

00:58:30.080 person's mitochondria? It's a red flag for mitochondrial dysfunction right there, because

00:58:34.940 that's not normal. Obviously after eating a meal of carbohydrates, yeah, for a while, you're going

00:58:39.580 to have a higher RQ, but at rest in the fasting state when someone is in the nineties.

00:58:45.160 This is a morning fasted resting test.

00:58:47.600 It's a red flag that is already telling you that there's something going probably at the

00:58:51.800 mitochondrial level. And this is what we wanted to do this paper that we wrote. We want to see

00:58:57.760 the same thing that is done usually at the EKG level. So when a cardiologist wants to study the

00:59:04.060 heart, if there's any abnormality, resting EKG has a reliability of about 50%. So you could see some

00:59:11.620 red flags already, but you don't see everything.

00:59:14.460 You have to stress the heart to see something.

00:59:16.440 Exactly. And you stress the heart and similar protocol than what we did here. And that's what

00:59:21.860 you do when you do EKG in stress, right? Situations, the reliability is about 95, 97%. So you see a lot

00:59:29.240 of things. So I decided to take the same approach and say, okay, now at rest, as you very well said,

00:59:35.400 you see people in the nineties with RQ and that's a red flag now. Okay. Let's stress those

00:59:41.440 mitochondria.

00:59:42.340 Right. So in other words, the analogy is sometimes you'll do an EKG on somebody at rest.

00:59:46.400 And you'll see changes in the ST segment that tell you immediately there's a problem,

00:59:50.220 but there are many people who have a normal resting EKG, but only when you put them on the

00:59:54.400 treadmill and make them run, do you see that change in the electrical signal that tells you

00:59:58.120 there's a problem. And so similarly, maybe somebody walks around with a resting RQ of 0.8 and you think,

01:00:03.160 oh, they're perfectly fine. But you see that their zone two level, the level at which they tap out

01:00:09.560 at their fat oxidation maximum or their maximum aerobic output is much lower than predicted.

01:00:15.940 And now you have a functional assay.

01:00:18.380 Exactly. You can categorize people by looking at the fat and also looking at the lactate. If you burn

01:00:25.620 very little fat, that means that you don't have a good mitochondrial function. And that confirms it,

01:00:31.120 that test. If you produce a lot of lactate, that means that you don't have a good mitochondrial

01:00:36.260 function either because lactate is metabolized in the mitochondria. So if it's in the blood,

01:00:41.540 that means that the mitochondria cannot metabolize it. So what we did with the three

01:00:45.480 populations from world-class athletes to moderately active individuals with people with metabolic

01:00:50.560 syndrome, which is a companion of type 2 diabetes, pre-type 2 cardiovascular disease as well,

01:00:56.500 or what we call now cardiometabolic disease because 80% of people with diabetes has cardiovascular

01:01:01.500 disease and vice versa. So these people, what we did then with these three groups is then

01:01:05.980 we paired both the fat curve, burning curve in the test, as well as the lactate. And the

01:01:13.600 correlations were in the 90s. So we see that it's a valid indirect test to see the mitochondrial

01:01:20.060 function. Now, as we speak, and in this office right now, we have all the supplies. We're going

01:01:26.020 to do this now with muscle biopsies, and we're going to try to prove not just this, but what are the

01:01:32.740 metabolic pathways? Wait, do you have the IRB approved already?

01:01:35.280 Yes. We're going to start next week. Can I do it tomorrow?

01:01:38.120 We don't have the laboratory set yet. We're in the recruiting patients phase now.

01:01:42.840 I might have to come back and do this. I would love to get a muscle biopsy.

01:01:46.160 Yeah, we can do that because we're going to be looking in the muscle biopsy, mitochondrial density,

01:01:51.060 respiration. We have two different machines, the Ouroborosin Seahorse.

01:01:54.600 How many subjects are you looking to recruit?

01:01:56.900 Well, so far, we want to have about 50. We're going to be recruiting people who are well-trained.

01:02:03.480 It's difficult to...

01:02:04.180 How will you define well-trained?

01:02:05.560 Well, yes. So well-trained are people who are usually competing. Like, for example,

01:02:09.700 in cycling, it would be like a category three, two, and one.

01:02:12.700 Okay. So pretty serious cyclists.

01:02:14.060 Yeah, pretty serious cyclists. I'm going to try to see if I can fool a professional athlete to get a

01:02:18.920 muscle biopsy, which might be difficult, but I'm trying to. Then we're going to have also

01:02:23.140 moderately active individuals who are healthy. Then we're going to have another group that is

01:02:28.220 master's athletes. Those masters who are 50, 60, 70 years, who don't develop type 2 diabetes,

01:02:35.140 and they're very healthy. They don't take any medication to match for the age of diabetes.

01:02:39.980 And then we're going to be looking at pre-diabetics and type 2 diabetes. And we're going to be looking

01:02:44.760 at mitochondrial function, mitochondrial respiration, genomics, proteomics, metabolomics as well,

01:02:50.720 and try to find the exact mechanisms that go wrong. Something that we see in this paper indirectly,

01:02:56.340 we know that's something wrong, but we don't know the exact. This is PDH enzyme, or it is something

01:03:02.080 that an LDH in the mitochondria that is not working, or it's faulty, or it's both of them. And that's

01:03:07.400 where we're going to try to target the mechanism so that it can give us maybe better diagnosis or open

01:03:13.280 the doors for maybe potential therapeutics to target those mechanisms that we have seen that

01:03:17.940 they're dysregulated. Well, my guess is people listening to this, if they're interested,

01:03:21.860 will be able to very easily come and find where the enrollment is. And I might have to come back.

01:03:26.800 And even if I don't fit into one of the nice, neat buckets, I'll just, I'd love to do the muscle

01:03:30.380 biopsy. Now, of course you talk about the need for a treatment here, but you already know,

01:03:36.380 you've already discovered arguably the single best treatment imaginable for this, which is more zone 2.

01:03:41.660 How do you increase mitochondrial function? You train at the maximum level of mitochondrial output,

01:03:46.500 correct? That's my hypothesis. And that's what I have been seeing for 25 years working with elite

01:03:52.320 athletes, that this is the exercise intensity where I see the biggest improvement in fat burning and the

01:03:58.680 biggest improvement in lactic clearance capacity. Therefore, that means that the mitochondria is

01:04:04.120 where you see the biggest improvement. We see also the biggest improvement in performance.

01:04:09.080 Pause there for a moment. You're coaching professional cyclists in the Tour de France.

01:04:12.500 So, do they need to exercise at that low level of intensity?

01:04:17.140 It's not that low level.

01:04:18.320 Well, for them.

01:04:19.160 For them, it's low, but for us, it would be excruciating.

01:04:22.000 But even for them, because for them, their mitochondrial density infraction is so incredible.

01:04:27.380 And the way they recruit the type 1 muscle fibers, it's so big that you need to push it.

01:04:33.080 So, it's having a much bigger gear range in that gear.

01:04:36.660 Exactly. It's like in the first gear that we say, when you get to the 7,000, 8,000 RPM, you're in the

01:04:41.640 red zone. Okay. You push it there. This guy's first gear is in the 15,000 RPM. So, you still need

01:04:49.280 to push into the 15,000, which could be, they really go very fast. But then you see their lactate

01:04:56.460 and the lactate is not more than 1.8. So, it's telling you that.

01:05:00.980 They're just so efficient.

01:05:02.760 They're incredibly efficient.

01:05:04.360 Reusing that lactate and keeping it confined to the muscle as another fuel for the adjacent fiber.

01:05:09.960 Exactly. And if you see that in the blood, there's such low levels of lactate, that means that they

01:05:15.200 have a very good mitochondrial function and they're stimulating that system there. When you see that

01:05:21.260 any athlete or any person is in the 3, 4, 5 millimoles, then you see that that system has

01:05:26.680 given up already. It has to be exported to the circulation.

01:05:30.300 Is the biopsy that you're going to do in this subsequent study going to allow you to

01:05:33.740 differentiate between two plausible hypotheses to explain this observation? One being that they

01:05:38.940 actually make less lactate. The other being their muscles actually utilize more of it before it gets

01:05:44.960 back into circulation. Both of those could explain the observation because you're only sampling in the

01:05:50.080 blood. So, you're only looking at how much lactate is making it to the blood. You don't know if it's

01:05:54.900 just that they make less or they make the same amount, but use it much more efficiently. Do you

01:05:59.660 have a sense of that? We know that because my colleague, George Brooks, who will be also a

01:06:03.580 co-author in this paper, he already has described that. That well-trained individuals, they can get to

01:06:10.040 produce more lactate and at the same time, they utilize it better. So, their gift, I'm using air quotes,

01:06:15.440 the gift of the gifted athlete is not the production of less lactate. It's the ability to re-utilize it

01:06:22.020 more. Exactly. Yes. And we choose the skeletal muscle. And this is a very important point in my

01:06:26.720 opinion because it's probably the first tissue where diabetes starts, skeletal muscle. About 80%

01:06:34.800 of all the glucose or carbohydrates that we oxidize in the body after a meal, they're oxidizing the

01:06:41.560 skeletal muscle. And within the skeletal muscle is in the mitochondria. So, that's why looking at the

01:06:46.140 mitochondria of the skeletal muscle, it gives us a very good ability to describe this in a more precise

01:06:53.120 way. So, again, if you could, sort of as a thought experiment, if you're looking at the muscle of

01:06:58.900 someone who's going to get diabetes in two years versus the muscle of someone who is not,

01:07:06.380 what do you think they look like in terms of differences? So, there'll be many, but I just want to

01:07:10.900 hear you talk through them, right? In terms of, so not talking functional at this point, I'm just

01:07:14.400 talking purely visible. Will there be differences in glycogen capacity of the muscle? Will there be

01:07:19.100 differences in the actual density of mitochondria? Will you see differences in the types of fibers?

01:07:23.940 I mean, again, just playing that game of you know this person's going to get diabetes, this person's

01:07:27.820 not. What looks different? So, you would see very clearly, for example, that well-trained athlete has at

01:07:33.720 least three to four times the amount of mitochondria and the size of the mitochondria. That's very visible

01:07:39.760 that you would see it right away. And this is Toledo from the University of Pittsburgh. He did a great

01:07:45.900 paper where we can show it in the slides as well, where he can show that very well.

01:07:51.760 So, three to four times the number plus larger.

01:07:54.980 Yeah, and that's the number and the density of the mitochondria. Then we delve in the function

01:08:00.700 of the mitochondria, how well they function.

01:08:03.740 That's the zone two that you've been talking about.

01:08:05.720 Yeah, that's one of the things that we believe. It might stimulate different pathways for mitochondrial

01:08:11.020 biogenesis, as well as different pathways for the improvement of the efficiency of the mitochondria

01:08:17.460 itself.

01:08:18.140 Are there other functional tests used besides the amount of basically ATP to lactate,

01:08:24.060 which is what you're doing in a zone two test?

01:08:25.940 Non-invasively, to my knowledge, there are no other ways to look at mitochondrial function.

01:08:31.540 You would need to look at a muscle biopsy.

01:08:33.540 And when they do a muscle biopsy, what functional assay are they doing in vitro?

01:08:38.180 When you look at muscle biopsy, you can, this is kind of what we're going to be doing. You can

01:08:42.820 expose the tissue of the muscle to glucose, pyruvate, or fatty acids and see what is their

01:08:50.060 metabolism. You label them and you see what goes where.

01:08:54.080 I see. So, you will use metabolomics to get a signature of the preference for different circulating

01:09:00.700 fuels.

01:09:01.060 Exactly. So, we would be seeing like this type 2 diabetics, for example, they barely use fat when

01:09:07.400 they're exposed to fat. We trace that fatty acid, but they have a much higher capacity or

01:09:13.840 willingness to use glucose for energy. And that energy might not be happening in the mitochondria

01:09:19.280 either. It happens in the cytosol. That's one of the things that there's what's called the

01:09:23.860 metabolic reprogramming that happens in these patients. Happens in type 2 diabetics, happens in

01:09:29.820 cancer patients as well and in other diseases. There's like a local metabolic reprogramming,

01:09:35.000 but there's also a whole body metabolic reprogramming where you just cannot synthesize

01:09:40.440 fatty acids. I mean, you cannot utilize fatty acids for energy purposes very efficiently because

01:09:45.280 you don't have the mitochondria and you need to rely more on glucose. And at rest, glucose is

01:09:52.600 mainly oxidizing the mitochondria, as you said earlier. Of course, to pyruvate, pyruvate enters

01:09:56.920 the mitochondria. But when your mitochondria at rest are not functioning very well, you need to rely on

01:10:02.440 the cytosolic production of ATP through pyruvate and then lactate. So, this is what we believe these

01:10:10.180 patients rely on the most, the cytosolic glucose utilization, which is what we see in higher

01:10:17.180 exercise intensities in athletes. And that's what we see higher lactate levels as a biomarker

01:10:21.980 for mitochondrial function. Do you see other differences between the very, very fit and

01:10:27.720 someone, again, who's going to go on to get diabetes just to make the experiment such that

01:10:31.720 you're not looking at someone with diabetes in terms of glycogen storage capacity?

01:10:35.360 Yes. We see that too. We see that. So, I developed with a colleague here, John Hill from the School of

01:10:40.980 Medicine, we developed a methodology to indirectly look for glycogen content in a non-invasive way using

01:10:46.320 ultrasound, high-frequency ultrasound. And we validated with the muscle biopsy as well. And

01:10:51.460 another researcher, David Niemann, also validated the system. And we saw very good correlations

01:10:57.680 with the scale that we use. So, just doing a high-frequency ultrasound of the quadricep,

01:11:02.940 you can get to within what degree of accuracy of a muscle biopsy?

01:11:06.580 With the muscle biopsy, we saw in the 90s, the R, the correlation, pre- and post-exercise,

01:11:11.840 using the scale that we use. There are a couple of authors that have done

01:11:15.540 a replication of the study, but they have used a completely different scale. We know that the

01:11:20.280 skeletal muscle glycogen is stored in different parts of the body. I mean, in different pockets

01:11:25.600 of the muscle and in different muscles. So, what we do is we look at the entire image of the rectus

01:11:32.400 femoris, for example. But in the validation, we did not validate the score of the rectus femoris with

01:11:40.420 a high-frequency ultrasound with the one-square-centimeter biopsy sample. We validated the image,

01:11:47.480 the one-square-centimeter image sample from the muscle biopsy with the muscle biopsy.

01:11:53.720 And that's where you have the same size in image. And therefore, you have the correlation.

01:11:59.040 With a couple of authors, they have correlated the entire muscle with different pockets of

01:12:05.180 glycogen everywhere with only the specific size. I got it. But you did apples to apples.

01:12:10.020 Yes. And you have an R-squared of 0.9?

01:12:12.800 The R is, yeah. It's in the 90s, 93, 94, pre- and post.

01:12:17.120 Wow. Without the need of doing this.

01:12:19.080 And if you had to guess, two individuals could differ how much between a person who's fit and

01:12:26.260 someone who's insulin-resistant?

01:12:26.800 Yeah. So this is exactly to your question. So we see it very well. Others have done it before with

01:12:31.300 muscle biopsies, where they have shown that feeder individuals, they can store more glycogen

01:12:36.560 than other individuals. And that's what we see. So on a scale from zero to a hundred that we have,

01:12:41.980 you see the world-class athletes, they can go to 85, 90, a hundred. Whereas someone like myself,

01:12:48.420 I'm considering now like a weekend warrior, right? I just, you know, try to exercise.

01:12:52.880 Oh, hang on, hang on, hang on. What's your FTP right now? I'll be the determinant of whether

01:12:57.040 you're a weekend warrior.

01:12:58.160 You know, to be honest, I-

01:12:59.440 If you had to guess, what is your FTP?

01:13:01.060 I don't even know.

01:13:02.240 Above 300 or below 300?

01:13:04.100 No, no. I don't know.

01:13:06.480 275.

01:13:07.320 Yeah, I would say something like that.

01:13:09.060 Okay. You're not a weekend warrior.

01:13:10.820 No.

01:13:11.520 275 is still respectable.

01:13:12.880 I exercise four or five times a week. But to be honest, I don't use a power meter. I don't

01:13:18.140 use a heart rate monitor. I just go to enjoy the ride.

01:13:20.740 How long does it take you to climb Mount Evans?

01:13:23.720 Oh, poof. I've only done it once and it took me a long time. Since years ago, when I've been

01:13:30.060 playing with numbers all my life and be my own guinea pig, I got to know myself quite well. So I

01:13:35.040 should not say that, but I'm reading numbers all day. And the last thing that I want to do is like,

01:13:39.620 just read my own numbers. You know, when I go there.

01:13:41.920 I haven't got there yet. I've thought about it a lot, but I still obsessively look at all my

01:13:46.960 numbers. And I still use a power meter when I'm doing all of the zone two training. Like I could

01:13:52.660 at this point probably just put it away and ride based on feel, but I don't know why I still love

01:13:58.360 the numbers, even though it depresses me a little bit because the numbers are so bad.

01:14:03.400 But it's interesting that you've been able to sort of separate yourself from that and say,

01:14:06.960 look, I eat, sleep, and breathe the numbers in the lab and with my athletes. But when I'm riding

01:14:12.400 it by myself, you know what? I'm going to just enjoy myself.

01:14:15.100 Yeah. I mean, the laboratory reading all these numbers all day and working with athletes and

01:14:19.320 patients, I just, I just go right in. And I know that I'm stimulating my mitochondria and here and

01:14:25.520 there, that's right too. I bring my portable analyzer with you here and there. And I just double check

01:14:30.500 and like, okay, this is the zone two.

01:14:32.480 So I sort of interrupted you, but you were about to guess what your glycogen storage capacity would be

01:14:36.720 relative to the, so the world class would be say 85 to a hundred.

01:14:39.840 Yeah. So I might be maybe 60 to 70, whereas people with like maybe type two diabetes might

01:14:45.840 be 30 to 40 or 50. They might have a normal glycogen storage capacity or on the low side,

01:14:52.200 but the well-trained athlete, they really increase it as well.

01:14:55.080 It's an irony because the fitter you are and the more glycogen you store, the less you are

01:14:59.940 dependent on it.

01:15:00.800 Yes.

01:15:01.420 Isn't that interesting?

01:15:02.480 Yeah, exactly. But at the same time, it's that energy that you need to move quickly for energy

01:15:07.780 purposes. This is the very interesting thing. On the other side, looking at the fat oxidation,

01:15:12.840 the fat droplet, if you heard about the intramuscular triglycerides, they are highly

01:15:17.320 related to cardiovascular disease and type two diabetes and insulin resistance. And this is

01:15:22.720 the athlete's paradox. What's the name of the researcher? Sorry, I blanked right now. But what

01:15:27.240 he did is like the same approach of looking at, they had been seeing that people with type two

01:15:32.120 diabetes, they have this fat droplet. It's like a little deposit of fat right outside the mitochondria.

01:15:38.740 And it was a characteristic. So what he did is like, okay, I'm going to look at, and then that

01:15:44.360 was in comparison with people without type two diabetes. They didn't have this fat droplet.

01:15:49.080 So what he did is like, okay, I'm going to see if elite athletes or world-trained athletes,

01:15:53.660 what histologically characteristic they have. And he found a big fat droplet as well,

01:15:58.020 adjacent to the mitochondria. So that's the paradox. It's like, wow, why in the world they

01:16:03.460 have that fat stored by the mitochondria? So what it was found that in the people with type two

01:16:09.000 diabetes, that fat is not active. And in fact, it can produce ceramides and other pre-inflammatory

01:16:16.640 mediators that are not only involved with insulin resistance, but maybe with cardiovascular disease

01:16:22.640 or atherosclerosis, they cannot be oxidized in the mitochondria. So they build up outside. Whereas

01:16:29.580 in the well-trained athletes, it's a reservoir there. The fat that we burn in the mitochondria,

01:16:35.960 it comes mainly from the subcutaneous fat and it has to travel. It's a long trip all the way to the

01:16:43.300 muscle. So why not, from an evolutionary perspective, why not having a reservoir right there by the

01:16:49.600 mitochondria? And effectively about 25 to 35% of all the fat oxidation that elite athletes do during

01:16:56.320 exercise, it comes from fat droplet. It's very active. So do you suspect that in the study you're

01:17:01.880 about to embark on, the biopsies will also show this, that in your fittest and your least fit,

01:17:07.020 you'll see the droplets? Yes, we're going to look at that as well.

01:17:09.740 Why do you think that the average people don't have droplets? Does that mean you and I probably don't

01:17:14.120 have too many fat droplets in our muscle? Probably not.

01:17:16.700 I would understand that if everybody had it sort of like structurally, but then there's a

01:17:23.180 functional difference where there's a gradation from the person with diabetes to the world-class

01:17:28.400 athlete, the gradation is in the utilization and activity of it. But why do you think people in

01:17:33.640 the middle of the road like us have actually lost the capacity for that reservoir?

01:17:38.020 Well, I think because we're not elite athletes.

01:17:40.860 But why do the people with diabetes still retain it, but in a static, non-utilizable fashion?

01:17:45.240 And that's what we're trying to find out why. And in my opinion, is the hypothesis one that

01:17:50.000 went to test is that their mitochondrial function is not good. So therefore, fatty acids cannot be

01:17:55.360 transported into the mitochondria and they're sort of building up outside the mitochondria.

01:17:59.960 We can.

01:18:00.760 I see. But we haven't completely built our capacity to use it at high amounts so we don't have the

01:18:05.460 reservoir.

01:18:06.140 It's like the glycogen thing. We don't store 80 or 90 or 100 because we don't need it.

01:18:11.540 And at the end of the day, the body is very wise and it's based on a lot of evolutionary

01:18:16.400 mechanisms. And this is one of them, glycogen storage capacity, as well as the fat right

01:18:23.260 outside the mitochondria.

01:18:24.300 I've always thought of that paradox through the lens of fat flux, which is when you take

01:18:28.520 a snapshot in time, which is what you're doing when you do a blood test or a biopsy, you're

01:18:33.980 looking at something in a moment. It tells you nothing about the velocity.

01:18:37.860 And what I think your example illustrates is that there's such a high turnover of things

01:18:45.800 in the really, really fit person that even if it's elevated, it's not problematic. Another

01:18:51.100 place you see this, by the way, in the blood is free fatty acid concentration. So when you're

01:18:55.620 doing a blood test to screen for diabetes, if you're doing very advanced testing, you're

01:19:01.000 looking at lots of things, not just something as sort of banal as the hemoglobin A1C, but

01:19:05.840 you'll, you'll look at insulin and you'll look at insulin under sort of provocation and

01:19:10.860 you'll look at free fatty acids under provocation. And amazingly, under the most metabolically

01:19:16.360 flexible and least metabolically flexible conditions, you see the same pattern, which

01:19:20.300 is higher free fatty acids. But again, it comes down to flux.

01:19:24.340 Exactly.

01:19:24.780 I suspect that in the person with diabetes, it's just an accumulation of free fatty acid in

01:19:29.420 the plasma. Whereas in the very metabolically flexible person, if you were putting a tracer on

01:19:34.960 that FFA, you'd see rapid turnover.

01:19:37.600 Exactly. Exactly. And exactly. And this blood analysis, they don't use a tracer. So you just

01:19:43.300 see, whoa, there's a lot of free fatty acids going around there. And like, what are they

01:19:46.660 doing? Were they being metabolized for energy purposes in the metabolically flexible? And

01:19:51.320 you see it very well, kind of they're accumulating the other ones. This is kind of what we probably

01:19:56.700 see at the cellular level.

01:19:57.700 So I want to kind of finish the energy zones. Obviously at zone three, you're getting into,

01:20:02.840 you're exceeding the capacity to maintain a stable level of lactate, which tells you you're now

01:20:09.040 exceeding the mitochondria's capacity to be the sole provider of ATP. You are now becoming obligately

01:20:17.140 dependent on glycolysis in the cytosol. By definition, the percentage of fat oxidation is now going down as

01:20:25.920 the percentage contribution from glycolysis is going up. Is this where the lactate threshold

01:20:31.280 now occurs? Because I'm sure there are people listening to this who are going to say, wait a

01:20:35.160 minute, wait a minute. I always thought lactate threshold was around four millimolar. So how does

01:20:39.120 that concept fit in?

01:20:40.440 So I would put the zone three as a transition zone where your glycolytic system starts kicking in at a

01:20:46.800 very high rate because the ATP demand and your fat oxidation says, okay, I think I'm starting to be

01:20:53.920 done here. Now you take over and that's where you start seeing a decrease in fat. Yet you use fat.

01:21:00.480 So it's not a completely glycolytic state. It's a transition phase. That is when we move into the

01:21:05.540 zone four. In the zone four, that's where we see very, very well that the lactate also, you see an

01:21:11.980 inflection point. That kind of where we could see the lactate threshold where like all of a sudden the

01:21:17.280 lactate accumulation is not steady. It jumps and you see the inflection point. And at the same time,

01:21:22.180 that's where you usually start seeing the R of 1.0, the RQ, and there's zero fat oxidation.

01:21:30.280 So we know very well, it's like if there's a lot of lactate and there's no fat oxidation,

01:21:36.400 that's another metabolic transition point that is indicating that you don't burn fat anymore.

01:21:42.660 It just depends on glucose. Yet you can breathe and it's probably done in the cytosol. So you're

01:21:50.600 aerobic and that's the zone four. We'll be calling the lactate threshold, if you will.

01:21:56.460 And what's the clinical significance of that or even the athletic significance of that? I mean,

01:22:00.380 once an athlete goes above their lactate threshold, how long can they sustain that pace?

01:22:06.780 There are many lactate thresholds. So we might believe that lactate threshold could be

01:22:11.460 maximum effort you can sustain for 15 minutes or 20 minutes or the FTP. The FTP could be a way also

01:22:17.320 of lactate threshold for a fate of 40K. So for the person listening to this, who's not familiar with

01:22:21.380 that, FTP is defined as functional threshold power in cycling. We use it as the maximum power that can

01:22:26.880 be sustained for 60 minutes, or sometimes we do a 20 minute test and discount it by about 10%.

01:22:32.880 But I mean, an FTP test for me has never felt linear. You know what I mean? Like if your FTP is 300

01:22:39.660 watts, the pain at minutes 10, 20, 30, 40, 50, 60 is not linear. Like the last 10 minutes hurt more than

01:22:49.460 the first 50. But now that I think about it, whenever I did FTP tests, I was usually doing them on the road,

01:22:56.280 not on a stationary bike. I never had lactate levels throughout, but my intuition is my lactate was

01:23:02.560 increasing non-linearly. I would always FTP test on a hill because it was easiest to maintain a fixed

01:23:08.540 power output. But what's actually, what do you think is happening to a person's lactate when they're at

01:23:12.940 that threshold? I have seen that. And I presented at American College of Sports Medicine, poof, like

01:23:18.060 about 10 years ago. And I have to publish it. It is one of the things that you have so much

01:23:21.940 things going on that sometimes you don't have the time. You need to get some med students working for

01:23:26.200 you. I know. I'm looking at the poster you're bringing up, but you haven't even published yet

01:23:30.720 10 years ago. Yeah. This is 2009 or something like that. But this is where back in the days,

01:23:36.640 a lot of people talked about power. Everybody would just train by power and what's our what's.

01:23:42.600 I started to see at the pro level, a lot of people using just power output and heart rate like as an

01:23:49.020 old school. I was one of those people actually, you know, five years ago where it was, I really didn't

01:23:53.860 pay attention to heart rate at all, except to notice that there were some days when at the same power

01:24:00.700 my heart rate was much higher and I felt and performed much worse. That was about the extent

01:24:04.900 of my observation. Yeah. I wanted to kind of show that with numbers. And that's what I say, like,

01:24:09.780 okay, power is power and speed is speed. The ability of humans to perform relies on the ability to

01:24:17.860 convert chemical energy into mechanical energy. The mechanical energy, that's your power output.

01:24:24.100 The chemical energy is like all the metabolic adaptations that get you there. So this is what I saw,

01:24:29.780 and we can put it. This is a poster you presented about 10 years ago. And by the way, this is,

01:24:34.640 I hope there's a med student out there at the University of Colorado who's listening to this,

01:24:38.540 who's figured out what their next summer's task is going to be, which has helped turning this into

01:24:43.080 a manuscript. But tell us a little bit about this experiment and what it showed, because it's,

01:24:48.180 as I look at the figure, I see it is answering, it is answering the exact question I just asked,

01:24:53.140 actually. So yes, one of the things is that a lot of people start to talk about what's our what's,

01:24:57.920 right? They ditched the heart rate monitor because what's our what's, therefore,

01:25:02.780 metabolically speaking, it's the same thing. But as I said earlier, the ability of humans to

01:25:07.560 exercise depends on the ability to convert chemical energy or biochemical energy into

01:25:11.720 mechanical energy. The mechanical energy is the end product, what's, but how do you get there?

01:25:16.380 So I wanted to see and put it to the test. So I had both a group of elite cyclists,

01:25:21.460 professionals, and a group of recreational cyclists, but well trained as well. And I did a maximal test

01:25:28.280 where I could get that peak power output at the end of the maximal test. One group deleted cyclists,

01:25:34.960 the next test, I put them at 80% of the peak power output from the first test, and the second group

01:25:41.500 at 75%. And then I just let them stay there for 20 minutes.

01:25:46.700 So if the elite cyclist hit a peak power of 400 watts on the previous test, 80% of that,

01:25:57.640 so now you put him at 320 watts and say, you're going to spend 20 minutes here. And it's like

01:26:03.780 similar calculation for the recreational output, though, at a lower level.

01:26:06.840 Exactly.

01:26:07.420 Okay.

01:26:07.820 So the whole thing was like, if watts are watts, it was like the whole battle back in the days

01:26:12.460 is like, okay, then metabolically speaking, we're not going to see changes.

01:26:15.920 In other words, five minutes into this test, whatever's happening in you physiologically,

01:26:21.180 since you're not changing the output or the demand for ATP, there should be no change in

01:26:26.460 anything else.

01:26:27.740 Exactly.

01:26:28.380 So what happened?

01:26:29.320 So what we saw is that after five minutes, both groups, they had about four millimoles of lactate,

01:26:35.360 okay? In the elite athletes, five minutes later, which is minute 10, they had about seven

01:26:41.900 millimoles of lactate. And five minutes later, which is minute 15, they had nine millimoles

01:26:46.860 of lactate. So right there, we see that watts are not watts at the metabolic level. It was very

01:26:52.900 stressful for them and they could not keep it. And this is kind of to what you alluded that

01:26:57.500 you notice that towards the end of some of this FTP, it feels worse. And this is exactly what I was

01:27:04.160 observing with many professional athletes and elite athletes as well. I mean, cyclists,

01:27:08.920 that they would get overtrained more. And they said, Hey, I, I had to do, let's say my coach told

01:27:15.160 me I had to do five hours or four hours at 200 watts. And I do the job and you can see in training

01:27:20.840 picture. So yeah, you do 200 watts, but what's the price?

01:27:25.000 I used to be obsessed with training peaks. And what was the other program called? There's another

01:27:29.600 program we used to use, but where does the TSS show up the training stress score? Is that also

01:27:35.060 training peaks? Yes. And I remember I used to mostly just keep track of kilojoules. In the end

01:27:41.120 of the day, it was how many kilojoules today? What's my TSS and my training score balance and

01:27:48.180 things like that. But I think what this, and by the way, I'm looking at the graph, the recreational

01:27:52.800 athletes basically had the exact same pattern just at lower levels, meaning they fatigued quicker

01:27:58.880 at a lower level, but the pattern is identical. So heart rate, lactate, and... And percentage of

01:28:05.120 VO2 max. And percentage of VO2 max. As well as VO2 max in liters per minute, they all show statistical

01:28:10.020 significance. So we see that watts are not watts. That's when it's starting to throw because I've

01:28:16.740 been always like a big believer of heart rate. And when I was 15, I saved all the money that I had

01:28:23.020 and I bought the sports tester that back in the days was like $200. No, it was, sorry. It was like

01:28:30.120 back in the days was about $500. So I'm talking about 84, 83, no, 86. Sorry. I was my own sports

01:28:38.560 tester. The year Greg Lamond won his first tour. Exactly. Yeah. And that's what I, since then,

01:28:44.280 I've been looking at heart rate a lot because we forget that heart rate is a physiological parameter.

01:28:49.260 Watts is a mechanical parameter, but heart rate is a physiological parameter and response to the

01:28:55.140 physiological and metabolic stress. So if you look in that graph that the audience can see later,

01:29:00.240 when we look at the graph of the lactate and the heart rate, they go side by side. When heart rate

01:29:06.980 goes up, lactate goes up. Well, I've noticed this and I'll show you more of my data over dinner tonight,

01:29:12.300 but for the past year, I've been recording four times a week, my lactate levels on both

01:29:19.080 devices plus heart rate plus power at the end of, I always like, I'll do a minimum 20 minute steady

01:29:28.020 power in a zone two. So anywhere from basically 20 to 45 minutes where the power is clamped.

01:29:33.780 I'm on a bike on an erg. So there's no deviation of power. And there's a very interesting correlation

01:29:39.580 between. So even if you do the same power for four consecutive workouts, you can have different

01:29:45.860 heart rates and you can have different lactates. Now we're going to come back to this because I

01:29:49.380 want to talk about it later. There's another confounder here, which is metformin, which will

01:29:53.080 back burner even with or without metformin. There's a coupling between heart rate. So for example,

01:29:59.300 if you don't sleep well and your heart rate's higher, you're not recovered, your heart rate's

01:30:03.200 higher, you're under more stress for some other reason. And heart rate is higher. Lactate tends to

01:30:07.700 follow it even at the exact same power output. Yes. Yes. And that's what we've shown. And that's

01:30:12.880 where like then Joe Frill started to talk about the coupling where you should maintain the power

01:30:18.300 output and the heart rate as well. So among a bunch of us, we kept pushing for heart rate because it

01:30:24.720 was getting to a point that it was going to be erased. And now everybody trains with both power output

01:30:30.200 and the heart rate. In fact, now the whole HRV, the heart rate variability, it's a big, big deal.

01:30:36.340 And a lot of people look at and listen to their hearts. And I always tell the athletes, the heart

01:30:40.960 rate is going to tell you a lot. This is one of the things also why I decided to try to develop a way

01:30:46.540 to look at glycogen, because I would see that in maximal physiological states, many athletes who were

01:30:53.220 fatigued or restricting carbohydrates, they had a very low maximum lactate levels, very low maximum heart

01:31:01.800 rate. Let's say that athlete that I have tested multiple times, let's say a lactate of 12 and a heart

01:31:08.520 rate of 190. When that athlete is fatigued or tired or restricting severely carbohydrates, that lactate

01:31:16.900 could be maybe four and the heart rate could be maybe 162.

01:31:21.420 And how much adaptation do they have? Because I know you and I have spoken about this before, and I don't know if

01:31:25.500 we're going to get into it on this podcast, because there's so many of the things I want to talk about. But

01:31:29.440 your view has always been that the fat oxidation data that we sometimes see in heavily, heavily

01:31:36.620 carbohydrate restricted or ketogenic athletes may actually be an artifact. We might not actually be seeing

01:31:41.440 fat oxidation of 1.7 to 2 grams per minute. You're saying in a GC contender, in the best cyclists

01:31:49.640 on the planet, what is their maximum fat oxidation in grams per minute?

01:31:53.520 Well, what we're seeing here is normally in the 0.7, 0.8 grams per minute under normal. And we have

01:32:01.700 done these experiments, although we haven't published them, but we have done a normal athlete, like

01:32:07.860 category 2 or 3, they do under normal diet, not super high in carbohydrates, not super low, normal diet.

01:32:14.460 And their fat oxidation, the fat max, it's, let's say, 0.4. Then they do one week of carbohydrate

01:32:21.520 restriction or two weeks of carbohydrate restriction, and their fat max, yeah, it's 0.8. But at the same

01:32:27.840 time, we see that the power output decreases at least 0.5 watts per kilogram, so about 30 to 40 watts.

01:32:36.600 And also we see that the maximum heart rate decreases and the maximum lactic decreases. That said,

01:32:42.260 this is more in a, if you will, a more acute situation.

01:32:46.080 I'll tell you this from my experience and ago, when I began carbohydrate restriction, which was,

01:32:51.080 I went on a ketogenic diet in May of 2011. The first 12 weeks were hell. I couldn't even imagine

01:33:00.320 approaching my anaerobic fitness. So forget lactate threshold or anything. I couldn't even get to the

01:33:07.900 same aerobic level. I remember, I still remember very clearly, November, 2012, 18 months later,

01:33:16.720 it came back and then some. What that suggested to me, and if I could go back in time and do anything

01:33:23.140 different, I would have had muscle biopsies done all along the way. But it struck me at how long it

01:33:30.480 took for that adaptation to take place. Now, I only stayed in that state for three years. So I'm long

01:33:36.820 out of that state now. The only time I'm really in ketosis is around fasting. But it's always sort

01:33:43.780 of piqued my curiosity what a very, very, very long-term state, ketogenic state can do for

01:33:49.980 everything outside of peak sprinting capacity. Because I just, I don't think there's any dispute

01:33:55.140 that peak sprinting capacity has to be glycolytic and anything that impairs glycolytic function makes

01:34:01.540 no sense. So there's such a debate about all of this stuff. I don't think it makes sense for someone

01:34:06.400 trying to win the Tour de France to be on a ketogenic diet. It's just too glycolytic. Even

01:34:10.400 though 96% of that race can be done below peak power output, the race is won and lost under peak

01:34:19.580 conditions. So it makes no sense. But if you're training to win the Western States 100, you

01:34:26.640 technically don't need to sprint ever. If you have a high enough threshold. So I still have that sort of

01:34:32.220 point of view. But again, I'm very curious as to what those adaptations are and how long they take,

01:34:38.520 because I don't think they're going to take place in a month. You bring up a great, great point. I'm

01:34:43.360 extremely curious about that as well, because I have never seen an athlete at the elite level

01:34:49.240 adapting. And I'm going to tell you why in a second. But at the same time, I believe that it cannot be

01:34:55.460 possible that thousands of people around the world who are getting into the ketogenic diet,

01:35:01.400 it might be working for them. And they're making it up. So I believe there's something there. At

01:35:06.480 first, when these things come up, I say, come on, man, give me a break. But then I say, there's so

01:35:11.480 many people out there. There's got to be something. Well, there's one other data point I'll add for you.

01:35:15.760 When I was on a ketogenic diet and cycling voraciously, my capacity to consume carbohydrates

01:35:24.400 was much higher than what people think of as a ketogenic diet for someone at rest. As a general

01:35:30.380 rule for somebody who's normal, about 50 grams of carbohydrates is the limit. Above that, you begin

01:35:37.200 to suppress the production of beta-hydroxybutyrate. But I used to do lots of experiments. And at my most

01:35:43.780 extreme, days when you'd have a three-day period where you would do 100 miles each day for three

01:35:50.820 consecutive days at very high output. So for me at the time, that might've been average power of 185

01:35:59.420 watts, normalized power of 240 watts for seven hours on three consecutive days. When you're at that much

01:36:07.000 demand, I was able to consume 600 grams of carbohydrates and stay in ketosis.

01:36:16.120 Now, I think that's because I'd spent so long adapting. I don't think you can show up and go

01:36:22.280 into ketosis and then a week later eat 600 grams. I mean, I was pushing as hard as I could to see how

01:36:27.760 much of this can I consume. But so there's the other thing to keep in mind, which is at some point,

01:36:32.760 the body became flexible enough that I could break all the rules. I could have 200 grams of protein,

01:36:39.200 600 grams of carbohydrate, and still maintain beta-hydroxybutyrate levels above two to three

01:36:47.520 millimolar. Because I think the machinery with which the BHB was made was, I'd had two years of,

01:36:53.820 in fact, this would have been probably three years in. This is the summer of 13 maybe. So now I'd really

01:37:00.540 been at it for quite a while. And again, biggest regret is not having that. There are lots of

01:37:04.920 athletes out there that I think would be interesting to study. So that's something worth considering.

01:37:09.280 Sorry to interrupt. The thing where I haven't seen that adaptations in elite athletes is that

01:37:14.120 they cannot afford it. You mentioned that it takes months to get there. You don't have months

01:37:19.540 because you get dropped in the races. Your performance is very poor. Your contract is going to be

01:37:25.540 trashed. They're not going to renew you. And you're going to feel like crap. Every single athlete who has

01:37:31.100 tried to go, whether you call it like a ketogenic diet or a carbohydrate restriction, while training

01:37:38.040 and competing for an event, they fail. That's what I've seen in 25 years. And the reason probably is

01:37:44.660 this, because they didn't have one year to say, hey, you're not going to race in one year. You can train

01:37:50.620 very little. Your mission is to get adapted. That's not the way sports works. But what I see is if you

01:37:57.120 restrict carbohydrates, we do blood analysis a lot. We do this metabolic testing in the laboratory.

01:38:03.200 While these athletes are competing, we see right away there's a catabolic response. The body says,

01:38:08.740 holy crap, what's going on here? I need to survive somehow. So you enter in an evolutionary survival mode.

01:38:16.400 So obviously, yeah, your ketones production might increase. Your fat oxidation might increase as

01:38:21.420 well, but your protein breakdown increases substantially as well. And we see this in the

01:38:26.380 blood analysis. That's why you see muscle breakdown all the time.

01:38:29.920 Although again, it's transient, which again speaks to, because if it wasn't transient, I mean,

01:38:34.620 evolution would absolutely demand we preserve protein under long periods of nutrient deprivation,

01:38:41.780 which of course is what the carbohydrate restriction is mimicking. But it's this time

01:38:46.880 course that I think is very unusual. And you're right. There's no professional athlete that could

01:38:50.920 take that chance. And again, we were talking about this earlier. It's like there are some people whose

01:38:55.680 entire lives can be built around chat rooms and discussion boards where they can debate these

01:39:00.140 things endlessly. Neither you nor I have the time for that. So I've largely stopped paying attention to

01:39:05.340 this debate, truthfully. But it's always struck with me how long it took to adapt and the price I paid

01:39:11.440 during that adaptation period. If you were a professional athlete, you would be out of the

01:39:16.280 job. Yeah. Oh, absolutely. And this is why I think that I have never seen that because sooner or later,

01:39:21.340 the athlete, they hit the wall. They just cannot finish races or they just like a, Hey, what's going

01:39:27.020 on here? And then that's when they have to go back. And we see this quite often. Athletes don't always

01:39:32.280 listen to us. They always go to the blocks and see things, you know, internet, or they find where the

01:39:37.780 neighbor is telling them. And a lot of people try many diets and the tendency now, and it was before

01:39:43.800 also was to restrict carbohydrates. And again, I really think that you can adapt because the human

01:39:49.300 physiology is a wonderful machine, but do you have the time to die while you're a competitive athlete?

01:39:55.620 That's what I have a lot of thoughts that I don't think so. Yeah. And again, I think the discussion is,

01:40:01.040 is interesting and academic, but of course, in the end, I still think carbohydrate restriction is a

01:40:05.840 great tool for anyone who's not trying to win the Tour de France. I think that's where people

01:40:10.340 sometimes get hung up, right? It's if you want to win an Olympic gold medal, there are very few sports

01:40:15.860 in which you could probably do that on a ketogenic diet. And if you want to be the best cyclist or

01:40:20.800 runner or swimmer on the planet, very hard to do that on a ketogenic diet. Good news is, by the way,

01:40:26.120 if you're at that level, your mitochondria are so remarkable that your carbohydrate tolerance

01:40:31.280 is unbelievable where it comes back to. And I think where the biggest opportunity is,

01:40:36.200 is the person who is not metabolically very healthy, who thinks they need to drink a liter

01:40:42.520 of Gatorade an hour. And no, actually that person can absolutely be on a carbohydrate restricted diet

01:40:48.700 and they can exercise. And yes, maybe their performance initially is less than what it would

01:40:54.460 be if they still mainlined all the carbohydrates in the world. But in the long run, they're going to

01:40:58.960 produce a much more metabolically healthy phenotype, even though they won't be in the top 0.1% of

01:41:04.900 athletes who will. No, exactly. I agree. And the thing with the elite athletes too, is that yes,

01:41:09.700 and this is kind of what I keep bringing up all the time. There's no population on earth who has as

01:41:16.200 many carbohydrates and simple sugars as these athletes by a landslide, right? These guys at the

01:41:22.780 Tour de France, for example. Yeah. Tell people like, let's take a long stage of the tour. So a 250

01:41:28.300 kilometer stage that has say four high category climbs and one HC climb. So one climb beyond category.

01:41:39.040 Yeah. So these people, they take... First of all, how long would it take them to complete 250

01:41:44.320 kilometer stage with four high category and one non-category, which means it's just a brutal climb?

01:41:49.960 Yeah. It would be more like a 200 and it would be like a five, five and a half hours.

01:41:54.260 And how long would that take you or I to ride right now?

01:41:56.920 Man, that would take us two hours more easily. Yeah. And how long would it take...

01:42:00.460 Or an hour and a half or... Take me two hours more if I'm lucky. How long would that take a person who

01:42:06.640 doesn't ride their bike much? Two days. Yeah. I mean, 14 hours, something like that,

01:42:12.660 because they will have to do multiple stops. And at the HC, they might not even make the climb.

01:42:17.120 Yeah, yeah, yeah, yeah. Or much slower. Yeah. While they do this climb,

01:42:20.860 so the Tour de France depends on the weight, but usually they go between six and 6.5 watts per

01:42:25.860 kilogram. Let's say a person of 70 kilos, which is... 70 kilos is probably 150...

01:42:33.020 154 pounds. So that would be about, yeah, 420, 450 watts. So we cannot do that. You know,

01:42:41.780 like a normal, well-trained person who exercises regularly can maybe do that in 300 watts.

01:42:48.400 But a person who doesn't train can do that in 150 watts only. So that's, poof, that's a long,

01:42:54.960 long time. And their weight is usually significantly higher.

01:42:57.340 And their weight, exactly. So that day, it's hard to believe they can do that in

01:43:01.400 five to six hours, by the way, but they would consume how much on that day, both on the bike

01:43:07.140 and off the bike? So normally what they do, and I haven't published this, but we keep track of this

01:43:12.720 all the time. We keep track of how the amount of carbohydrates per hour. We keep track of the

01:43:17.540 breakfast, what they eat on the bike, after the bike, recovery right away. We have these protocols.

01:43:22.280 And these protocols are very up to what they need or what we think they need. And also based on what

01:43:28.180 their demands are, because they're the ones who like, they need it. You know? And again, as I said

01:43:32.800 earlier, I've seen athletes even restricting carbohydrates in the races, and they get totally

01:43:37.980 destroyed. So these guys, they consume a total of about 12 grams per kilogram of body weight per

01:43:45.460 day of carbohydrates. So if you're 155 pounds, which could be an average weight, let's say 70 kilos,

01:43:52.340 we're talking about close to 150 grams a day of carbohydrates.

01:43:57.140 More than 150. You said how much? 12?

01:43:59.340 850.

01:43:59.980 850.

01:44:00.500 Yeah, yeah, yeah.

01:44:01.260 About 850.

01:44:01.760 I thought you said 150. Okay, yeah.

01:44:02.880 Which is 850 grams of carbohydrates.

01:44:04.860 That's over three, that's almost 4,000 calories of carbs right there.

01:44:08.640 Yeah, 3,500 calories of carbs. And out of those, at least a good 30% of those to 50 is

01:44:15.960 simple carbohydrates. Let's say 30% of those. So we're talking about these people are having

01:44:21.480 daily about 1,500 grams of sugar. I'm sorry, 1,500 calories of sugar. So almost-

01:44:29.380 Give me an example of what type of sugar they're consuming, like gels and goos.

01:44:32.920 Yeah, the gels, the goos, the drinks, and then obviously at breakfast, at lunch and dinner,

01:44:39.020 they're more complex. But during the race, in the first part, we do more solid versus liquid,

01:44:44.520 but towards the end of the race, we do more liquid. So more pure sugar, simply because it's

01:44:49.540 absorbed faster. And that's why you need more energy. But yeah, these people, again, they do

01:44:54.420 about 1,500 calories a day just in sugar. Imagine pretty much your entire daily caloric intake of a

01:45:01.680 normal person, a bowl of sugar. If you want to do this, if you go to a nutritionist and you say,

01:45:07.020 I want to do this, they will shoot you.

01:45:08.020 Yeah, look, if I did that, I'd have diabetes in a month.

01:45:09.960 Oh, of course, of course, of course. And we know that they don't have it. In fact, this is the

01:45:14.420 healthiest metabolically population in the planet.

01:45:17.460 Now, the irony of it is on twofold. One, in many other ways, they're wildly unhealthy. The rate of

01:45:24.140 catabolism, the bone density loss that these guys experience over the Tour de France is debilitating.

01:45:29.520 I mean, these guys, they lose so much muscle, they lose so much bone density. The other thing we see

01:45:34.600 is for many of these athletes, the transition out of being at that level to being civilian again is

01:45:41.500 devastating. Because especially, I actually read an article on this once. I wonder if I could find

01:45:47.440 it. I believe that the answer was more common in males than females, where the rebound effect

01:45:55.880 to becoming metabolically unhealthy was unbelievable. It's very hard to turn that spigot off of

01:46:01.860 you're basically a nonstop eating machine. And then all of a sudden, you're on the path to having

01:46:07.080 diabetes three years, five years, 10 years after being the fittest person in the world.

01:46:11.860 Yeah. And that happened to me when I quit cycling. Between school, work, I was working and traveling.

01:46:19.300 I was working 70 hours a week at least. I was from doing 500 kilometers a week to do 500 kilometers a

01:46:29.540 year. I would exercise literally six, seven times a year and traveling and eating. And one thing that I

01:46:35.480 have observed is like insulin sensitivity. These athletes have the highest insulin sensitivity of

01:46:41.300 any humans as well. There's no insulin resistance because first, we know very well that exercise

01:46:46.480 increases insulin sensitivity and they need it to utilize carbohydrates. It increases insulin

01:46:52.000 sensitivity as well. And the transporters-

01:46:54.480 There's all that efficiency in the mitochondria comes with another benefit, which we didn't really

01:46:58.960 talk about, which was non-insulin dependent glucose uptake is also going up. So now if you take a

01:47:06.380 normal person, we are able to take up glucose with insulin. That's the insulin sensitivity,

01:47:11.820 but we have a second door that doesn't get utilized much, which is the non-insulin requiring door to put

01:47:19.040 glucose in the muscle. And there's no better way to stimulate that than zone two. I mean, I don't know

01:47:23.280 if I have a study that I can point to, but I can clinically tell you without a shadow of a doubt,

01:47:28.540 and I'll tell you how I know it's looking at people with type one diabetes.

01:47:32.560 Yeah, exactly. I was going to mention that.

01:47:34.160 Yeah. You take people for whom you know exactly how much insulin they require. I'm actually going

01:47:39.040 to be writing about one of these patients in my book. He's type one diabetes, completely dependent

01:47:43.700 on insulin. He's completely maniacal. I love him. Three hour brisk walk every night. So that's his zone

01:47:51.120 two. Three hours of zone two a day, right? You know how much insulin this person with type one

01:47:57.760 diabetes requires a day? Two, five in units. About eight to 10 units a day. He has the highest

01:48:05.020 sex hormone binding globulin I've ever seen in a human being, which is inversely proportionate to

01:48:09.840 insulin level. This guy has no insulin. He doesn't require any. I learned from this a lot. I was working

01:48:15.340 with team Novo Nordisk. Yeah. Tell people about what team Novo Nordisk is. So team Novo Nordisk is a

01:48:19.660 professional team where a hundred percent of the cyclists are type one diabetics. These are professional

01:48:25.380 cyclists with type one diabetes. So the whole purpose of team Novo Nordisk was first to show

01:48:30.420 the world that you're not going to not only not die if you have type one diabetes, but you can become a

01:48:36.620 professional athlete to spread the word. Because a lot of people think it's a devastating diagnosis

01:48:41.340 for many. Oh, you're type one. You're going to die soon. And like, no, you're not going to die soon

01:48:46.860 if you take good care of yourself, but even you can become a professional athlete. So that was the one

01:48:51.720 message to spread the world. And the second is that to study diabetes and type one diabetes and

01:48:58.300 the metabolic effects of exercise. Because nowadays, most endocrinologists working with

01:49:04.020 diabetics, they're telling to exercise. The problem is like they go to exercise and they have 0.99

01:49:08.800 many hypoglycemias or hyperglycemias, and they need to correct it. And all the hormonal system goes

01:49:16.360 all over the map. And they go back to their doctors and they have no answers. So it's the

01:49:21.700 number one barrier that they find from exercise. And they many decide not to exercise because they

01:49:29.520 can control their doses very well. And let's explain why that's happening to people. We've

01:49:33.700 talked a lot about the consumption of glucose, but as you're alluding to, whether it's you, me,

01:49:39.120 or someone with type one diabetes, when I exercise very strenuously, my glucose goes way up. So if I'm

01:49:46.520 doing twice a week, I do high intensity exercise. As you can see on my arm, I wear a continuous glucose

01:49:52.860 meter. It's not uncommon, especially if I do it right after a zone two. This is funny because zone two,

01:49:59.320 my glucose steadily falls. Let's say I get on the bike at a hundred. I do 45 minutes of zone two. I get

01:50:05.200 off at 75. You get to bunk sometimes even. I don't go long enough to bunk for sure. So then

01:50:12.400 let's say I get on the air bike and I do a four minute protocol. It's not uncommon for me to go

01:50:18.800 from 75 to 160 because of the hepatic glucose output. Yeah. Glycogenolysis. Yeah. And that person

01:50:26.740 with type one diabetes, that number could easily be 250 because they don't have the insulin to correct

01:50:32.360 it. Exactly. So then they need to correct it and they freak out. So they use a lot of insulin.

01:50:37.740 They overshoot it. Exactly. They overshoot it. And this is exactly to what you pointed out about the

01:50:42.360 non-insulin dependent system, which is the muscle. And this is what it was an educational process. So

01:50:47.300 then with JDRF, the Juvenile Diabetes Research Foundation that we put together,

01:50:52.720 they put together like a group of experts, if you will, to train clinicians about this.

01:50:58.440 So what did you learn? I mean, how do people compete in professional cycling without being on

01:51:06.200 that glycemic roller coaster? So we learned a lot to work on insulin usage, as opposed to insulin

01:51:13.960 correction. And that's what we're taking now to the clinical space because type one diabetes has been

01:51:20.440 about correcting insulin and insulin and insulin and eating carbohydrates. Oh, you go low. Sorry,

01:51:25.420 man. It's just keep eating candy or things like that. And we know that that cannot be very healthy

01:51:30.100 for you in the long term. But the approach has been always that, to correct by either eating or

01:51:36.740 using insulin. But we're trying to really correct it by really tackling insulin administration.

01:51:43.720 So using just longer acting forms, is that the...

01:51:45.940 Either longer acting or less insulin, and therefore also to do exercise. So when you do exercise,

01:51:51.900 as you say, first, your insulin sensitivity increases. So you don't need so much insulin.

01:51:58.040 And as I said earlier, the first tissue that develops type two diabetes or insulin resistance

01:52:03.540 is the skeletal muscle. So when you eat carbohydrates, the big percentage of that are going to go into

01:52:09.520 your skeletal muscle.

01:52:10.580 Are people with type one diabetes who are exercising even more insulin sensitive at the muscle than

01:52:17.220 non-insulin dependent individuals who are matched?

01:52:20.760 They could probably be. So the long-term exposure. This is what I observed, for example,

01:52:26.360 about glycogen. Unfortunately, it wasn't published because the N was very low. But the reviewers,

01:52:32.560 they didn't understand that you cannot do muscle biopsies to a professional cycling team. And there's

01:52:36.760 only one professional cycling team in the world. So I did a tour of Colorado. I did the team

01:52:41.100 Novo Nordisk and another team and look at the glycogen.

01:52:45.100 What did you see?

01:52:45.960 About 25% higher glycogen content before the race and after the race in type one diabetics.

01:52:52.740 And about three times less carbohydrate needs than the non-diabetics, which we already had seen 1.00

01:52:59.800 because we count carbohydrates. And we know that a normal cyclist, they have 20 grams per hour

01:53:07.260 of carbohydrates. They're going to hit the wall in a race. Type one diabetics, they have 20,

01:53:12.560 25 average, and they never have any issues.

01:53:15.280 You must see higher free fatty acid levels then.

01:53:17.660 Yes.

01:53:18.060 So all things equal, do they just have higher fat oxidation across the entire spectrum?

01:53:22.420 They're not very good necessarily at that. And I'm trying to understand that puzzle. But

01:53:26.780 what I believe is like they have a higher glycogen content because insulin drives glycogen synthesis,

01:53:33.400 is the main hormone behind glycogen synthesis. So if you've been for, and the issue of people with

01:53:40.000 type one diabetes, they go from a non-physiological state, which is not producing insulin to the

01:53:45.300 opposite. They use a lot more insulin than normal people over years. So 20 years, usually insulin,

01:53:52.700 it must maybe elicit some adaptations that might, one of them could be increased glycogen synthesis.

01:53:59.380 I have no idea, but that was kind of what we would like to explore further.

01:54:02.580 So do you think that those athletes who were able to get by with as little as 20 grams of

01:54:08.260 glucose per hour, which seems impossible to imagine given their energy requirement,

01:54:13.860 do you think at some point that would cease to be the case? And in the tour of Colorado,

01:54:18.580 maybe the longest stage is what, four or five hours?

01:54:21.140 Yeah. Yeah.

01:54:21.860 But still, that's hard to explain. It's still a week long race, isn't it?

01:54:24.480 Yeah. Yeah.

01:54:25.360 Did you say that their glycogen levels still were 25% higher at the end of the race?

01:54:29.460 Before and after. Yes.

01:54:30.880 That's counterintuitive.

01:54:31.980 Yeah.

01:54:32.460 Sorry, was it, I know it's 25% higher than the non-diabetic, but what about relative to

01:54:37.440 themselves?

01:54:38.360 Oh, they decreased.

01:54:39.500 How much do they decrease?

01:54:40.740 I don't remember. Because not a whole lot, because I mean, in this stage, you have to do

01:54:45.260 it in the same time. And in the tour of Colorado, in the mountains, one hotel is here, the other

01:54:49.500 one is 20 minutes away. So I had to do it in one stage where all of them were on the same

01:54:53.800 floor, two teams. That was a short stage. It was like two and a half hour stage. So they eat

01:54:58.700 normally, and they decreased like 15%, 20% or something like that. So they didn't deplete

01:55:03.120 completely by normal.

01:55:04.160 You could make the case that that team had some of the highest levels of non-insulin-dependent

01:55:09.200 glucose uptake you've probably ever measured.

01:55:10.980 Probably. Probably. Yeah. So that's what, to your question of that, the non-insulin uptake

01:55:16.320 of glucose by skeletal muscle, that's what is a great approach.

01:55:20.440 We don't have a way to measure this in those of us who don't have type 1 diabetes. We're

01:55:24.200 sort of taking a leap of faith that the more we work on our mitochondrial efficiency, the

01:55:28.940 more we will drive that non-insulin-dependent pathway. But really, it's only the person in

01:55:33.420 type 1 diabetes where that can be quantified.

01:55:35.520 And it's a skeletal muscle contraction. First of all, in insulin, what it does, it initiates

01:55:42.660 the cascade of events that translocate the transporters of insulin called the glute force

01:55:47.400 to the surface of the muscle.

01:55:49.200 Glute force. Yeah.

01:55:49.860 Yeah. Glute force. Yeah. Sorry. To the surface of the muscle. And those transporters are stimulated

01:55:55.840 by insulin. So a skeletal muscle, that's the exact same action. It translocates those glute

01:56:01.800 force to the surface. So therefore, there's that non-insulin dependent.

01:56:06.860 And why does exercise increase that ability?

01:56:11.720 We don't know the exact mechanism.

01:56:14.140 It just seems too good to be true. I want to make sure that the person listening to this

01:56:17.380 understands what you just said. So I'm just going to repeat it because it's so profound

01:56:21.480 and you said it like sort of, you know, you said it sort of like matter of factly because

01:56:25.200 of course for you, it's common knowledge. When insulin hits the insulin receptor on a muscle,

01:56:30.300 it sends a cascade of chemical reactions inside the muscle that ultimately results in a tube

01:56:37.420 called the group for transporter being raised to the surface of the muscle and translocating across

01:56:43.760 the membrane. And now you have by passive diffusion, glucose can enter the muscle.

01:56:48.780 The key is this insulin in the lock is the insulin receptor. And the downstream effect that occurs

01:56:55.900 inside the house opens the door and lets the glucose in. What you said after that is you explained how

01:57:01.920 non-insulin dependent glucose works, which is somehow just the contraction of the muscle.

01:57:08.840 So something that's going on inside the house squeezes and out comes the same beautiful

01:57:15.200 glut4 transporter, which now allows the same passive diffusion of glucose into the cell,

01:57:20.940 but this time it didn't require insulin. This is the best of both worlds.

01:57:24.720 This is what Henry Richer from Denmark and Lori Goodyear from Harvard, they've been dedicating many

01:57:31.880 years to study these pathways. So they found that this muscle contraction stimulates these pathways to

01:57:38.160 translocate those glut4 transporters to the surface. And this is why the pancreas in regular people who

01:57:45.880 don't have type one diabetes decreases insulin secretion about 50% during exercise because the

01:57:52.540 muscle, they do the rest. And this is what causes also that hypoglycemia in athletes. If they don't

01:57:59.300 correct their insulin before exercise, they go hypo. So what we were doing, and now we're doing

01:58:05.960 clinically, we're telling people to reduce the dose.

01:58:10.240 Wait a minute. This is interesting now. This is suggesting that the reduction that I'm seeing

01:58:15.740 in glucose when I do my zone two, which is by far the most profound thing. You don't see this at

01:58:21.980 higher levels of intensity. You see the opposite. You see the opposite. Glucose going up. But zone two

01:58:26.420 is a sweet spot where my glucose level always falls precipitously. I shouldn't say precipitously,

01:58:31.760 steadily and consistently. I never thought of it this way. It must be almost entirely the non-insulin

01:58:40.080 independent glucose uptake because it's a low enough level of intensity that my internal glycogen

01:58:45.840 stores are easily providing what is needed. So this is an additional amount through that. So that's,

01:58:54.240 I feel like this is another metric I want to start keeping track of each day I'm doing zone two. It's

01:58:59.060 not just power. It's not just heart rate. It's not just lactate. It's the delta in glucose from start to

01:59:04.020 finish could be yet another metric we look at.

01:59:06.600 And in fact, one of the things is like, I'm trying to try to take this to the clinic for

01:59:11.240 people with type two diabetes is like, uh, if you eat, go exercise right away. Because when you

01:59:17.140 exercise right away, that muscle contraction is going to translocate these glute four transporters

01:59:22.920 without the need of insulin.

01:59:24.280 And I thought it was the opposite. You know, I thought that exercising will increase the insulin

01:59:29.700 dependent portion. And therefore the best time for someone with diabetes to eat was right

01:59:34.640 after exercise. It could be both.

01:59:37.280 It could be both. Yes. I think that might be in a patient by patient base, but if you have insulin

01:59:42.960 resistance, you're going to need to use more insulin after you eat, which it's a patch. It doesn't solve

01:59:49.500 the problem. But if you exercise, then you might need half of the insulin because the other half is

01:59:55.720 going to be provided of the glucose intake into the cell by the muscle contraction. So learning a lot

02:00:01.660 from type one diabetics, we can apply things to type two, I believe. One of the things that we see the

02:00:06.560 opposite effect that we saw in the races, normal people who are told to exercise, they're not fit 0.99

02:00:12.240 enough and they start jogging, right? And they're in zone four already, very glycolytic. They see the

02:00:19.040 opposite. They see post-exercise hyperglycemia where they're, as you said, in the 260s. So, and they inject

02:00:25.980 themselves insulin and they go down and sometimes in the middle of the night and then they go home

02:00:30.980 if it's towards the evening, they eat and they correct it again and sometimes end up in the ER

02:00:35.600 because they have a severe hypoglycemia. But, so one of the things that I started to apply

02:00:41.580 first to the cyclists and then to patients is the cool down. So after people would have this

02:00:48.660 post-exercise hyperglycemia, the muscle contraction stops. And that's why I believe this is why it is

02:00:56.440 happening. First, you have a very high adrenergic activity, high intensity, a lot of adrenaline and

02:01:01.040 that's what causes the breakdown of glycogen into glucose as well as the glucose export from the

02:01:07.540 liver. But then when you stop, that muscle contraction stops completely. So you don't have

02:01:15.340 that cognitive mechanism. You've taken away one of your sinks. Exactly. So that's when you start doing

02:01:19.080 the cool down. And that's a study, another study. I have the data I have to publish, but we could

02:01:24.020 see clearly that everybody started to go down. There's definitely going to be some University

02:01:28.100 of Colorado medical students or undergraduates who have just lined up potentially a half a dozen

02:01:34.120 interesting things to write with you. We started to see the cool down and the cool down would take

02:01:39.100 care of it. So people to the point that they would not need insulin anymore to correct it, whereas before

02:01:44.060 they might need three, four, five units. And now they don't need it anymore because that

02:01:47.800 cool down took care of it. So through JDRF, we've been traveling throughout the country and other

02:01:53.400 places in Europe and even Australia, training clinicians about this so they can go back to

02:01:58.520 their patients. And the cool down has been a basic thing and the feedback we're getting is awesome.

02:02:04.820 This is incredible. You know, it's such a shame that the disease type 1 diabetes and the disease type

02:02:09.600 two diabetes share the same name in diabetes, because I do think for many people, they just

02:02:14.220 sort of think someone has diabetes, but the nomenclature of one versus two is profound. They

02:02:19.880 are really different diseases. Very different. They're completely different. They almost have

02:02:23.240 nothing in common except for high glucose as a potential consequence. I agree 100%. It's a real

02:02:29.300 shame. There's an artifact of history. And this is what I'm trying to also bring the concept of

02:02:34.100 double diabetes that very few people talk about it because it's mixed. Type 2 diabetics, especially

02:02:40.460 now in the US, Novo Nordisk told me that I think about two thirds of the entire insulin that is

02:02:46.440 sold in America, it's for type 2s, not for type 1s. And this is the animal that is different. The type

02:02:53.040 2 diabetic people is a way different animal than it was 50 years ago. I've always been sort of

02:02:57.740 critical of these companies like Novo Nordisk because I feel like there's just too great a conflict of

02:03:03.060 interest for them, right? I mean, first of all, insulin should be basically free. There's absolutely

02:03:07.700 no, from an IP perspective, there's absolutely no reason insulin should cost anything above some

02:03:13.820 nominal amount. So it's this cash cow for drug companies like Novo Nordisk. Don't worry, I'm not

02:03:18.960 going to put you on the spot and have you speak critically at all. I'm going to do all the critical

02:03:22.100 speaking. Yeah, no, because we get funded. This group is funded by Novo Nordisk. Indirectly, what I'm

02:03:27.700 going to do is come around and sort of pay them this compliment and say, I like realizing that there's

02:03:31.500 something good that's done by an entity that I generally view not favorably. Because again,

02:03:35.920 one, the price gouging on insulin to me is the most unethical part of pharma. But then on top of that,

02:03:41.500 there's this issue of two thirds of your sales come from a patient who shouldn't be using your drug.

02:03:49.720 The drug really is for people with type 1 diabetes. If you have type 2 diabetes, almost without

02:03:56.120 exception, changing the way you eat and exercise will at least get rid of the insulin requirement.

02:04:02.420 You may still require other medications, but you shouldn't require insulin. And that's been

02:04:06.620 repeatedly demonstrated. So all that said, rant over, it's nice to see that this type of research

02:04:12.340 is being done because these patients offer us a beautiful physiologic milieu in which you otherwise

02:04:19.020 couldn't see this. So this kind of brings me to, while we're on the topic of diabetes, something else that

02:04:24.200 I want to talk with you about, which is my recent, and by recent, I mean, over the last six months,

02:04:30.080 frankly, maybe nine months, sort of back and forth exploration of my use of metformin. When we very

02:04:36.380 first time met a year ago, we talked about how I use metformin. I've been using it for years

02:04:40.640 with the basic belief that even though I don't have diabetes or insulin resistance, it offers some

02:04:46.860 measure of protection from cardiometabolic disease, inclusive of cancer. And that's all based on

02:04:52.860 data that unfortunately is confined to people with insulin resistance, hyperinsulinemia, or type 2

02:04:59.680 diabetes. So there was always a leap of faith I was taking that if you took a metabolically healthy

02:05:04.940 individual, they would still have some benefit. And when patients would ask me about it, I would say,

02:05:11.140 my belief is that I'm probably receiving less benefit than someone who's more metabolically

02:05:17.900 unhealthy, but I think I'm receiving benefit and I don't see a downside. And then all of that changed

02:05:23.540 a year ago when we met and I started keeping track of my zone two numbers. And what I immediately

02:05:31.320 realized was a gross mismatch between where I knew physiologically, I was clearly in a zone two,

02:05:39.360 just based on perceived effort and my understanding of my fitness level. But I couldn't get over how high

02:05:46.220 my lactate levels were. And then I remember you and I would speak and you would say, well, what is your

02:05:50.540 lactate level fasting? And I'd say, you know, sometimes it's like 1.6, even before I start. I

02:05:56.020 mean, this was back when I was in the business of using as many strips as possible. So expensive,

02:06:01.180 those stupid things. So I would check two times fasting and then every 10 minutes, check double,

02:06:09.160 double, double, double, double. And there was no denying it. I mean, my lactate levels were through the

02:06:15.080 roof. And I said to you, do you think it could be the metformin? And then around this time,

02:06:19.180 a couple of papers came out that suggested that metformin could be blunting the benefits of

02:06:24.040 exercise. So, I mean, let's go back to then and then we'll talk about where we are today in our

02:06:28.600 thinking. But at the time that I told you all of this, what was your thinking about my use of

02:06:32.380 metformin and these numbers we were seeing? Did it make sense to you? Yeah, they make sense in a way

02:06:38.000 that we know that I've seen patients with metformin pre-type 2 diabetic or type 2 diabetic right before

02:06:44.460 entering insulin states. Where at rest, I have even seen two millimoles also.

02:06:50.220 Are you able to differentiate how much of that was due to the metformin versus their...

02:06:54.200 Because there's such a confounder when you look at that population. Had you seen anybody like me where

02:06:58.800 they're... No. I've seen these high levels of lactate at rest. But again, I could not differentiate

02:07:04.620 that. But all these people coincided, they were on metformin. One of the side effects of metformin is

02:07:10.300 lactic acidosis, right? It's rare, but it can happen. So, we know there's something wrong with

02:07:15.740 the lactate. What we don't know are the mechanisms. It would be great to study the mechanisms where

02:07:21.580 there are for... To improve the cardiometabolic health or maybe we might find that might not be

02:07:29.180 what we thought. We know there are some studies that show that metformin decreases mitochondrial

02:07:34.300 function and could be that magical drug against cancer. Because one of the things that we see in

02:07:40.380 cancer, many forms of cancer that have a mitochondrial dysfunction, yet not enough for that cancer cell to

02:07:46.780 be apoptotic. Oh, I see. So, you're saying that maybe in that patient, metformin pushes them over

02:07:52.540 the edge towards apoptosis. Towards the cliff. That's what I believe, if in case that is true,

02:07:59.340 that metformin can cause mitochondrial dysfunction. But the fact that the metformin increases lactate,

02:08:06.060 it's either because it increases the glucose flux into the cell and saturates PDH. And then PDH,

02:08:14.220 the hydrogenase, has a very, what we call low Michaelis constant. So, it saturates very rapid.

02:08:19.980 And in my opinion, acts as a fuse in the body from an evolutionary perspective. If the body sees there's

02:08:25.980 a lot of high flux of glucose, the body might mean, hey, what's going on here? We need to stop it,

02:08:31.020 because it's not good to become hypoglycemic. And maybe the majority of those glycolytic enzymes

02:08:37.180 in the downstream action of glycolysis, they usually have a high Michaelis constant. But when they get to

02:08:44.300 PDH, it's like a fuse. So, when that fuse goes, then pyruvate is converted to lactate. So, that could be,

02:08:52.540 it either increases the flux of glucose into the cell, and that's why it could work

02:08:57.180 well for diabetes or acts as others have shown. This is very interesting. So, this suggests that,

02:09:02.140 let's just talk for a moment about someone with type 2 diabetes who's not taking metformin.

02:09:06.860 Their lactate levels are higher at baseline. You're now really offering two explanations for it.

02:09:12.940 The first is PDH, because their PDH is seeing higher glucose than the non-diabetic. So, that's

02:09:22.220 the first thing it's doing is, as you say, I like that analogy of the fuse. It's just triggering the

02:09:27.420 fuse and shunting more glucose down the pyruvate to lactate pathway. And then, of course, there's

02:09:34.540 everything we spent the first hour talking about, which is, in addition to that, their mitochondria

02:09:39.260 just tap out very early. They're not working well. So, those two things that are related,

02:09:45.260 but quite distinct, would both push up lactate. So, now the question is, which one of those is

02:09:50.780 more likely being driven by metformin? Is it the inhibition of complex 2 in the mitochondria,

02:09:57.020 and it's simply reducing mitochondrial efficiency? If you picture a curve where the x-axis is mitochondrial

02:10:03.900 function, it's just moving you to the left. Exactly. It could be that,

02:10:08.300 and maybe it could be both. What we know, epidemiologically speaking, is that metformin

02:10:15.180 doesn't cure diabetes. And the immense majority of patients, they end up using insulin down the road.

02:10:21.740 So, we know that metformin is not that magical drug for type 2 diabetics. It just kind of gets

02:10:27.660 them by. It buys them time. But eventually, the majority enter insulin. If they don't change their

02:10:33.980 lifestyle and nutrition exercise, they enter insulin. So, why?

02:10:38.540 I mean, so the first thing I did, so I used to take one gram twice a day, a gram in the morning

02:10:43.100 and a gram before bed. I always do my zone 2 first thing in the morning. So, I was basically doing a

02:10:46.860 zone 2 right after taking a gram and basically 12 hours after having taken another gram. So, you could

02:10:53.180 argue I had very high levels. So, I think the first change I made was I just stopped taking a gram in

02:10:59.100 the morning and increased my nighttime dose to 1500 milligrams. So, I reduced my overall dose by 25%

02:11:05.820 but shifted it to the nighttime thinking, well, I should have a lower concentration in my bloodstream

02:11:11.180 in the morning. I saw no meaningful effect. So, 1500 at night was still producing basically

02:11:17.580 the same effect as a gram twice a day. Now, again, keep in mind when you're doing an N of 1,

02:11:22.380 you can't actually make any statistics out of this. It has to be a big signal for me to notice it.

02:11:27.580 So, then I lowered it to a nighttime dose of one gram. I still didn't really see much of a difference.

02:11:32.940 And then what I did is I stopped taking it the night before doing zone 2. So, that meant I now

02:11:43.580 went from taking 14 grams a week, a gram twice a day, to only one gram three nights a week because

02:11:50.700 there's only three nights a week where I don't follow the workout by a zone 2. So, you've gone from

02:11:56.860 taking 14 grams a week to three grams per week. You could argue, why are you taking any of it at

02:12:01.420 that point? And that's when I saw the reduction. That's when I saw the lactate levels start to come

02:12:07.180 down. Okay. And in fact, that latter part of the experiment's only been going on for about three

02:12:11.820 weeks. So, the next step is to stop metformin altogether and ride this out, which makes me think,

02:12:18.300 we should do a little experiment in me, which is, yeah, we should do muscle biopsies, complete

02:12:25.180 proteomics, complete metabolomics, everything that is doable in vitro in the muscle tissue along with the

02:12:33.100 lactate testing and all the other metrics under three states of physiology. One, under full dose of

02:12:39.740 metformin, two, under a complete washout, say 30 days of no metformin. And then the third one I'd

02:12:47.020 think would be very interesting is under complete water fast, where I also, by the way, whenever I

02:12:52.420 water fast, I have no metformin. And I'd like to see what seven days of water fasting with no

02:12:58.300 metformin looks like versus, again, these other two states. So, I think there's an interesting pilot

02:13:03.340 study here. You should come to our study and be part of it and we can do extra biopsies.

02:13:07.880 Yeah. Yeah. I'm totally game to do this.

02:13:09.720 Yeah. It would be very interesting because it's fascinating that the whole role of metformin

02:13:14.120 and also how it can be used in other diseases as well. And it's fascinating that the little

02:13:19.240 that we know about the mechanisms of action at the molecular level yet. I think you bring great

02:13:25.640 point is to try metformin in different states and try to learn what happens at the mixed level,

02:13:31.880 metabolomics, proteomics level, especially the latter ones. Because yeah, we might see pathways,

02:13:37.560 maybe it's mitochondrial dysfunction that causes that, and we can see that quite well. Or maybe

02:13:43.320 it's at that translocation level that transporters.

02:13:45.960 And it would be really interesting, assuming the IRB gives a quick approval for this little

02:13:50.760 added protocol that includes me, if we could recruit somebody with type two diabetes and have

02:13:56.360 them parallel me with, without the metformin, with, without the fast. Because my new hypothesis

02:14:02.840 around metformin is, I just have a stronger conviction, I think, around my old hypothesis,

02:14:07.320 which is the healthier you are, the less helpful it is. I'm now wondering if it goes one step further,

02:14:13.000 which is the healthier you are, the less, I mean, it might actually cease to be healthy. In other

02:14:16.440 words, let's take the extreme example. What would you predict would happen if you gave

02:14:21.640 a Tour de France team a gram of metformin twice a day during the tour? No other change,

02:14:26.760 you just give them a gram of metformin throughout the tour. Do you think it would have no impact on

02:14:31.080 performance or a negative impact? I mean, based on looking at that,

02:14:34.680 it can affect mitochondrial function. And we see because there's increased lactate,

02:14:39.400 in my opinion, and that's the very first take, and by no means I'm an expert on this,

02:14:42.840 it might be detrimental. That's my first take. If you think you had a hard time getting

02:14:47.080 professional cyclists to volunteer for muscle biopsies, think about how much harder it'll get

02:14:51.000 them to volunteer for the take metformin and go off and do the Vuelta.

02:14:56.280 I know. It would be really, really difficult to get IRB for that in the first place and the

02:15:01.880 permission from the manager. Destroy someone's livelihood.

02:15:04.120 Yeah. There's so much more I want to talk about.

02:15:06.440 And I want to talk real quick that the double diabetes, and I forgot, and I'm sorry to interrupt

02:15:10.280 you, is that that's something that worries me because there are many people with type one who

02:15:15.320 also have type two and they're not diagnosed. And I think we need to raise the awareness because if

02:15:20.680 about 50% of US adult population has type two diabetes, yeah, a big number of people with

02:15:26.840 type one diabetes are going to have also type two. Is that a projection of how many people in the

02:15:31.320 United States will have type two diabetes? Right now, about 50% of US adult population

02:15:35.800 have either pre-diabetes or diabetes. Correct. Yeah. And it's about, is it maybe 10% have

02:15:41.000 type two diabetes and the remaining 40% is pre-diabetes? Yeah. And I was thinking there's not

02:15:46.360 such state as being pre-pregnant or pregnant. You're pregnant or you're not. 0.89

02:15:50.440 So yeah, that pre-type two diabetes wouldn't see clinical symptoms yet, but the disease is there

02:15:55.480 already. Yeah. It's just, I mean, our definition of diabetes is so arbitrary and stupid that it's

02:16:00.680 just a continuum and we somehow decide, oh, your hemoglobin A1c crossed this threshold. Boom. And now

02:16:04.920 you need or not. It's kind of like with the same thing with cholesterol. Oh, you're 200, boom,

02:16:09.000 you need a statin. Or 220, you need a statin. And that, no, that's the other thing with statins,

02:16:13.560 that we know that they affect my kind of function. How do we see this? Because in the published

02:16:17.800 literature, five to 10% of people experience muscle symptoms from statins. But what is the

02:16:24.440 functional impact? The functional impact, I mean, we don't know much about it.

02:16:28.680 So you're talking outside of myalgias and muscle pain. The good news is, I always say this to patients,

02:16:33.960 when you're taking a statin, you're going to get the feedback very quick. One in 10 of you is not going

02:16:39.480 to tolerate this and it won't be very subtle and you'll stop the medication and within a week you'll

02:16:45.480 feel better. And again, what's interesting is the disparate data based on how it's studied. But at the

02:16:52.920 individual level, it's pretty straightforward. Yeah, it is pretty straightforward. And one thing

02:16:57.240 that we know too is that it increases also, and there's research done, it increases the possibilities

02:17:02.440 of becoming diabetic. Yeah. So that's the two things I usually say to a patient. I said,

02:17:06.200 there's, cause everyone says, look, if you're going to do a statin, what are the risks? And I say,

02:17:10.600 the short-term risk is myalgias. And again, I just say directionally it's one in 10 people,

02:17:15.720 maybe it's 15%, maybe it's 5%, but you get the feedback quickly and you move on.

02:17:20.120 So the second risk is a long-term risk, which is about a 4% increase in the risk of diabetes.

02:17:25.640 The good news there is that's not a sudden thing. I think the literature is still pretty clear

02:17:29.960 that the benefit still outweighs that risk in terms of mortality. But again,

02:17:35.160 it comes back to the idea of the most potent drugs we have are food and exercise.

02:17:40.520 Absolutely. And it comes back to me as well, that it's not about how many years we live,

02:17:45.160 our longevity, and it's how are the last years that we live, right? And if statins are going to

02:17:50.120 come back to haunt you in 20 years, because they're going to have extra or increase in diabetes,

02:17:55.720 for example, yeah, it might buy you extra time now. But again, if you have food and exercise as

02:18:01.080 your main medicine, the zone two training for me, it's just become such an important part of

02:18:06.200 my training for myself and for my patients. I question, I get asked a lot that I don't

02:18:09.880 know the answer to. So I'm going to ask you is what's the minimum effective dose? Because obviously

02:18:15.400 I would love it if I could wave a magic wand and have one hour per day to do zone two. And then on top

02:18:21.880 of that layer in all other exercise, that would be amazing. But it's not. I only do three hours a

02:18:28.920 week of zone two, typically in four 45 minute to an hour sessions. Do you think that's enough?

02:18:35.160 Yes. So this is what I've seen and I've learned from the athletes. And I would love to do this now

02:18:40.760 with patients. What's the right dose? But we know, or at least I've seen with athletes that if you do that

02:18:46.200 two days a week, one is the dose and the other thing is the frequency. So if you do that two days

02:18:52.280 a week, you maintain. And we see athletes who in the off season, cyclists, for example, or runners

02:18:58.040 or triathletes or swimmers or rowers, if you do the zone two, five days a week, for example,

02:19:04.680 you really push the needle. Then once the season starts, you need to do more higher intensity

02:19:09.720 exercise and training. And then you have the races and you need to recover. So definitely you cannot do

02:19:15.160 this on two every day. So what we see is like two days a week, it tends to maintain.

02:19:19.720 So that's the frequency. What's the dose?

02:19:21.880 Yeah. And the dose, what I see is like, obviously these elite athletes, they need to keep pushing

02:19:26.840 the needle. One hour is not going to do much for them because they have that stimulus already,

02:19:31.400 or two hours, they might need four or five hours. But a patient with type one diabetes,

02:19:36.280 maybe one hour is enough. And that's what I'm trying to fine tune, you know, what would be.

02:19:41.400 What I know very well is that three days a week, it starts moving the needle for five,

02:19:46.760 for sure. And what I've seen or guessing that that's because we don't have any real data.

02:19:53.160 This is about one hour to one hour and a half. It does the trick for those who have type two diabetes

02:19:59.960 or pre-type two diabetes, for example. So we have last year a patient who was diagnosed with,

02:20:05.960 uh, that's what we're saying is like late pre-type two, what the heck is that, you know?

02:20:11.240 And then, uh, with one year doing an hour into an hour and a half, four days a week,

02:20:16.360 she reversed that completely.

02:20:18.360 Okay. That's a pretty big dose. So, I mean, for me, just, it's always for me,

02:20:21.800 Tuesday, Thursday, Saturday, Sunday is zone two. It might be that those Saturday,

02:20:25.800 Sunday workouts, I need to push them longer. Maybe I need to do 90 minutes on each of those days

02:20:30.120 and stay at 45 minutes on Tuesday, Thursday.

02:20:32.600 It could be, but at the same time, it might be your right dose because you're not in that

02:20:36.920 unhealthy population side. So your dose might be lower.

02:20:40.360 But my thinking now is that this is such an important part of cellular longevity,

02:20:45.960 that this is the difference between being a healthy 90 year old and being in my framework,

02:20:51.720 it's one quarter of the equation. What would you do?

02:20:55.480 I would do, and this is my case when I stopped cycling, when I told you earlier, right, I gained 65

02:21:00.200 pounds because I was working 70 hours a week and exercising six, seven days a year.

02:21:05.320 And still eating like a cyclist?

02:21:07.080 And eating like a cyclist. And I'm from the Basque country and we like to eat food because it's one

02:21:11.480 of the best areas in the world. And, and probably also I had insulin sensitivity developed from I was

02:21:17.080 a cyclist, which I would just pull, poor carbohydrates, you know, and then I would not burn them.

02:21:23.000 So maybe I just transform her into fat. I also have a familiar dyslipidemia. 0.63

02:21:28.200 So I have a high triglycerides and high cholesterol genetically. So I didn't take care of myself.

02:21:34.600 I would not exercise and eat a lot. So I gained 65 pounds in about eight years or so. And then I

02:21:40.600 said, wow, I went and did myself a checkup. And then my blood pressure was 125. I was in my mid thirties,

02:21:49.000 125 over 85. So it was getting there in my triglycerides. Once I saw them 800, which is

02:21:58.120 huge off the chart, right? Back in the days, people didn't do A1C. That's when I started to

02:22:03.080 work on these concepts too. And so I started to apply this to myself. So I started doing four

02:22:08.280 days a week. Even one hour was poof. I was bunking because I was not used to that. It was very depressing.

02:22:13.480 I was about to say that must've just been devastating to go from being a professional

02:22:18.920 cyclist to struggling to do four hours a week of cycling.

02:22:22.760 Yeah. And knowing the same roads that you go to and that you couldn't go up the hill,

02:22:27.960 but I lost 35 pounds within seven months.

02:22:31.160 Did you make much change to your nutrition?

02:22:33.240 Exactly. That was, I mean, I decided to, I was willing to eat a little bit less,

02:22:37.800 but not sacrifice many things. Because again, I mean, for me, nutrition is very important from

02:22:43.240 my culture standpoint. I love chocolate. I love wine. I love pasta and bread. It's ingrained in

02:22:50.120 my culture. I was not going to renounce to these things. So that's why I said, okay,

02:22:54.280 I'm going to try to give it a shot. So you weren't going to go on a ketogenic diet.

02:22:57.080 No.

02:22:57.480 And it's an interesting example of there's give and take. The more you're willing to

02:23:01.640 push this type of training, the more you can keep on the other side versus, you know,

02:23:07.960 I've seen more patients than I can count with type two diabetes, not exercise at all,

02:23:13.160 but go on ketogenic diets. Within six months, they're off insulin. Within a year,

02:23:18.040 they have a normalized hemoglobin A1C. But again, so it's almost like two levers.

02:23:22.840 How hard are you willing to pull on each of the levers?

02:23:25.800 Exactly. No, that's a great, great comment for sure. And I think it's a debate. Many,

02:23:30.840 for some people, giving up chocolate is not a problem. For me, it's death. You know,

02:23:35.800 I just love chocolate. It's not that I eat it every day, a whole bar, but it is, or bread,

02:23:41.240 you know? That's one of the things too, that is the balance. I lost 33 pounds and I stopped there.

02:23:47.960 I could not lose more than that. I needed to then increase my dose. So I went from one hour to an

02:23:53.640 hour and a half, four days a week. I lost another 10 pounds. So I lost a total of around 50 pounds,

02:23:59.880 47 to 50 pounds. That was 11 years ago before coming here. And I kind of keep it like that.

02:24:06.280 Now, this is interesting. As you're probably aware, the exercise and weight loss literature

02:24:11.080 suggest that exercise alone is not sufficient for weight loss. I've always wondered if that

02:24:17.000 was an artifact of the fact that they're studying exercise incorrectly, that the prescription,

02:24:21.960 it's either the dose or the frequency or the intensity were not optimized. You were doing a

02:24:28.200 very specific type of exercise. You were not exercising for the number of calories you burned.

02:24:33.800 You were training your mitochondria to become better at fuel partitioning. That's a very technical

02:24:39.880 description of what you did. I think it's important for people who are listening to this

02:24:43.320 to appreciate that nuance. You weren't out there calorie counting saying, okay, I'm doing six hours a

02:24:48.520 day at this many calories because you can achieve that in many different ways. It was almost the

02:24:53.640 maniacal specificity with which you approached this that you basically said, you didn't think

02:24:58.680 of it as I'm exercising six hours a week. It's I'm doing mitochondrial conditioning or reprogramming six

02:25:04.360 hours a week. Exactly. Yeah, I believe so. And that's what we know now with patients when we study in

02:25:09.400 the laboratory that they always tell you, I always train at this intensity. And you know that intensity,

02:25:14.440 they burn zero grams of fat. They burn a lot of calories, but zero are derived from fat.

02:25:19.720 Yeah, they're actually working too hard. Too hard. And eventually, number one,

02:25:23.160 you don't burn much fat. You burn fat in the post-exercise because you might increase your

02:25:28.360 metabolic rate. But can that override the fat burning from the exercise itself? And second,

02:25:35.720 it's too hard. You haven't exercised in a long time to start with, and you get into these

02:25:41.480 high intensity programs that they might not suit you or they might injure you. And many people give

02:25:48.040 up. We see the rate of people giving up from gyms is about 50% or so within X amount of months.

02:25:54.760 They either give up or their adherence decreases a lot. So when I ask these people who get into this

02:26:01.400 extreme, either exercise or diets, I always ask them, and they're successful. I ask them,

02:26:07.480 can you do this for the rest of your life? And the question is, hell no.

02:26:11.720 Yeah. If you can't do it for the rest of your life, you have to come back to the why am I doing

02:26:15.800 this? Using an extreme example to do hill repeats up Alpe d'Huez. Can you do that for the rest of your

02:26:21.960 life? No. Can you do it if your goal is to win the Tour de France? Yes. You're going to do it for

02:26:26.600 five years. You're going to train that hard for five years. You're probably going to take a chunk of

02:26:30.600 time off your life, by the way. But that's your job. You have to be the best climber in the world.

02:26:35.160 Exactly. And to the point of the nutrition, the nutrition is a must. You need to do something

02:26:40.280 with it or do a lot more exercise. But I think it's the balance that we all, I think, need to

02:26:44.800 understand better. Well, that's for me why fasting has become so important. Now you were laughing at

02:26:49.560 me earlier before we started recording about how crazy it is that I can do these long fasts. But

02:26:54.600 in many ways, it's a way to provide me balance. It's like sprinting. It's basically every month,

02:27:00.780 there's just a frequency with which every quarter I do one type of fast and every month,

02:27:04.460 a different type and every week, a different kind. It allows me to keep a balance and it allows me to

02:27:09.260 say, yes, I could do this for the rest of my life. Whereas the reality of it is I couldn't do a

02:27:12.240 ketogenic diet for the rest of my life. As powerful as it was in me, I couldn't do it the rest of my

02:27:16.860 life. So a couple other questions I want to ask you about. You've alluded to cancer twice now.

02:27:21.580 We've spent a lot of time talking about type 2 diabetes as a disease state in which the mitochondria

02:27:27.740 are not functioning well and they provide this great contrast. But you've touched briefly on

02:27:34.080 cancer. Is there any evidence that a patient with cancer has a higher lactate level on account of the

02:27:41.420 fact that they have mitochondria that aren't working as well, the same way that the prismatine type 2

02:27:46.700 diabetes has? So it is a fact in 1923, almost 100 years ago, Otto Warburg from Germany discovered

02:27:54.220 the transformation of a normal cell into a cancer cell at the metabolic level. And the characteristic

02:27:59.880 of cancer cells was that they use a lot of glucose for energy purposes. Now, they use a lot of glucose.

02:28:05.580 Back in the days, there was no genetics or anything. But what struck Warburg is the amount of lactate

02:28:12.080 that they produced. Was that what struck him more than the fact that they use so much glucose even in

02:28:17.860 the presence of sufficient cellular oxygen and insufficient ATP demand? So it was more the lactate

02:28:23.440 accumulation. It was more the lactate accumulation. And that's why he came to conclusion that cancer

02:28:28.940 was a metabolic disease caused by an injury of the respiration system in the cell, which is the

02:28:34.240 mitochondria. And that's what was the thought for many years because of the lactate. Even before

02:28:40.080 glycolysis was invented, Meyerhoff, who discovered glycolysis, sometimes it's called Enden-Meyerhoff

02:28:46.340 pathway, which is glycolysis. Meyerhoff was a student of Warburg. Before they had even found out

02:28:53.420 about glycolysis, the way they measure glycolysis is by measuring lactate. So they would measure how

02:29:00.180 much lactate the cell produces. And that's where they would say, wow, they're using a lot of glucose.

02:29:05.080 But what he saw in cancer cells, there was an aberrant amount of lactate production.

02:29:09.920 And that was one of the things that struck Warburg the most. And now what we see is that lactate is a

02:29:15.480 typical feature of cancers. Cancers produce a large amount of lactate, which is also responsible of the

02:29:22.920 famous microenvironment that a lot of people are talking about nowadays. The lactate microenvironment,

02:29:29.180 I mean, the microenvironment of cancer cells is more acidic than non-cancer cells. And it's a

02:29:34.960 niche for carcinogenesis. The responsible for that microenvironment is lactate. And what we know is

02:29:41.200 that, yes, it's lactate. It's a fact that multiple studies showing that, or every study showing that

02:29:46.640 every study trying to find lactate in cancer, they're going to find higher lactate levels.

02:29:51.140 So this would suggest three distinct, but not necessarily mutually exclusive explanations for

02:29:58.440 the Warburg effect. The first being what Warburg proposed, which is in cancer, there is an injury

02:30:05.120 to the mitochondria. As a result of that injury, the cancer produces, it takes an inefficient path

02:30:11.460 to go. Then there's the 2009 explanation proposed by Thompson, Cantley, Vander Heiden, in that science

02:30:18.960 paper that was sort of a very important landmark paper that said, no, no, that's probably not it.

02:30:24.260 It's the glycolysis and the lactate production is a by-product of metabolic demand for building

02:30:30.400 blocks. It's the cellular nucleotides that are necessary to build the cells. So the mitochondria

02:30:35.580 work okay. What you're seeing is a deliberate and obligate choice to grow. And the need to grow

02:30:42.720 literally from a mass balance perspective requires taking this pathway versus that pathway. And now

02:30:48.580 you're saying, well, a possible third explanation is the cancer relies on lactate as a signaling

02:30:54.580 molecule. And again, these could all be true on some level. We know that they're not all always

02:31:01.780 true. I mean, at least we know that in the case of the Warburg effect, that's not universally true

02:31:06.340 that the cancer damages the mitochondria. What are the next steps in figuring this out? And perhaps

02:31:11.420 more importantly, much more importantly, how do we use this information therapeutically?

02:31:17.140 Yeah. So one of the things is that we have just finished a study. It's under review now,

02:31:21.340 and we're going to replicate it now with more cancer cells, but we have done a study with the MCF7

02:31:26.540 cancer cells, which are the most common type of breast cancer or one of the most common type of breast 0.95

02:31:32.060 cancer cells. And what we have seen is like we expose the cancer cells to glucose. So we did

02:31:39.500 experiment, one exposing the cancer cells to a media that contains nothing, no glucose, no glutamine,

02:31:46.120 which is also highly expressed in cancer. And this can survive a couple of days in that state.

02:31:51.080 Then in another experiment, we just expose them to glucose. That's it. And in the other two other

02:31:57.020 experiments, we added to that glucose media, we added 10 millimoles of lactate and 20 millimoles

02:32:03.200 of lactate. What we did then is like we extracted the DNA. By the way, are those physiologically

02:32:08.720 accurate doses? Do we believe the microenvironment of cancer is that high? It's about 10. Yes.

02:32:14.580 It's 10 times the normal level. There's been studies showing up to 40, but normally, yeah,

02:32:19.760 10 is a typical. And what pH? The pH is usually between six and seven. I was about to say that has to be

02:32:26.560 below seven. Yes, for sure. In fact, the more aggressive in general, the more aggressive the

02:32:31.500 cancer is, the more glycolytic is, and the more lactate is found, and the more acidic the

02:32:37.620 microenvironment is. So we published an idea to propose lactate being the explanation for the

02:32:44.240 world where effect, because what we looked into the medical research is that the genetics stops in how

02:32:52.660 the first cancer cell happens and maybe proliferation in cell cycle genes. But there's a lot more to that

02:33:00.000 in cancer. You need angiogenesis. You need metastasis. You need immunoscape. And you need also the

02:33:05.640 cell-sufficient metabolism the cancer cells have. It's immortal. So that's where like what we saw is

02:33:11.320 that lactate is necessary for each of these major steps in carcinogenesis. But what we wanted to see

02:33:19.500 is like, could lactate also be a signaling molecule? And that's where like what we observe is like

02:33:24.780 looking at transcriptional activity, looking at the RNA expressions of the key oncogenes,

02:33:31.340 transcription factors, and cell cycle genes and proliferation genes in cancer. Lactate overexpressed

02:33:37.360 them between two and eightfold compared to control. And what was the difference between the 10

02:33:42.300 millimolar and 20 millimolar lactate? Did you see a difference in transcription?

02:33:45.740 In 10 in 20, we didn't see much of a difference, but we saw more than in zero. What struck us,

02:33:52.480 and that's kind of hopefully we can show, is that if you cultivate the cancer cells in glucose alone,

02:34:00.040 I give this presentation on the Anderson, but so we looked at the cancer cells and we looked at the

02:34:05.200 major oncogenic, I mean oncogenes, transcription factors, and cell cycle genes. We had no glucose

02:34:11.000 incubation, no glutamine either, just glucose, and then we had a lactate, 10 millimolars,

02:34:18.240 and 20 millimolars. So we did RNA extraction, and we looked at in the cancer cells, where they're

02:34:26.040 without any media, that is no glucose, no glutamine, we didn't see RNA expression.

02:34:31.240 Did the cells live?

02:34:32.520 Oh, those oncogenes. We killed them. We didn't...

02:34:35.320 In other words, there's a very finite period of time in which you're looking to just see...

02:34:38.940 Yes. We look in six hours and 48 hours. So neither in six 48 hours was RNA expressions.

02:34:45.000 Okay. What about glucose by itself?

02:34:46.660 So when you add glucose by itself, we looked into the media, and it was a very high lactate levels.

02:34:53.700 Looks like on your graph, it's almost 30 millimol.

02:34:56.200 Yes. It was almost 30 millimol in the six hours, and because lactate is also used by the cells for

02:35:01.820 energy purposes, over time, we expect it also to see, but we still see about 25 millimolar.

02:35:06.980 This is the waterborne effect. This is what waterborne observed, incubating in cells and

02:35:11.300 say, wow, they use a lot of glucose, but why in the world is this lactate?

02:35:15.500 It's amazing. It's that high.

02:35:16.840 So what we saw then is like this lactate alone was enough to trigger the expression of all the

02:35:24.380 major oncogenes, transcription factors, and even depress the cell arrest genes.

02:35:30.100 So is there an experiment that could be done where you constantly change the media? You have

02:35:36.100 a flux of media that allows them to have a finite amount of glucose, but you constantly strip away

02:35:41.840 the lactate to see what the true baseline level of expression is absent the lactate as the signal.

02:35:48.680 Yeah. So this is now where we're going to be replicating this experiment with multiple cancer

02:35:53.940 cell lines from liver to pancreas, to lung, to kidney, to a thyroid, more glycolytic,

02:36:00.200 less glycolytic, and then do all these kinds of experiments and include also metabolomics.

02:36:05.220 I mean, this is a complicated media device because you basically have to expose them to a bath of

02:36:10.160 constantly moving media that contains glucose, but no lactate. You see what I'm saying? So you have

02:36:16.520 a negative flux of lactate across the cell because what you really want to do is see how does this

02:36:22.360 work with glucose, but no accumulated lactate? Because that would answer the question, is lactate

02:36:28.960 specifically signaling? Because you could still argue here glucose is playing a role.

02:36:33.200 Yes, but we believe this is through the lactate.

02:36:35.460 Through the lactate, but now how do we figure that out?

02:36:37.440 That's what we did in the second experiment. The glucose media is the same. We just added more

02:36:42.660 lactate, and we see a much amplified response. How much is it amplified with...

02:36:47.900 So it was, for example, this is the no lactate versus the lactate. We can see...

02:36:52.320 That looks like about 2x?

02:36:53.800 Yeah, sometimes even 2x. So that's where we saw that the media is the same,

02:36:58.040 but the more when we added the lactate, it really overexpressed the transcriptional activity.

02:37:02.960 Although if I was going to play devil's advocate, you could say that we know that the lactate could be

02:37:07.440 serving a metabolic fuel. So maybe it's conserving more glucose for more glucose to be signaling

02:37:14.240 transcription.

02:37:15.500 Well, we know that lactate is being used by the mitochondria of cancer cells. Everywhere is

02:37:21.360 mitochondria, there's lactate. What we believe is that it's a signaling molecule to really overexpress

02:37:27.700 the transcriptional activity of oncogenes, transcription factors in cell cycle genes in a

02:37:33.320 non-hierarchical way. Because the traditional view of cancer is that you have the oncogenes,

02:37:39.700 they tap on the transcription factors, and they start an array of different downstream signaling

02:37:46.480 that eventually transforms a normal cell into a cancer cell.

02:37:50.140 This is so interesting because it, again, at the meta level, flies in the face of all of the

02:37:55.920 observational data of how much metformin lowers cancer, unless it comes back to your explanation.

02:38:02.500 Because if you just look at these data, all things equal, and by the way, that would be another

02:38:06.780 interesting experiment, add metformin to the dish as well. In theory, it should amplify lactate

02:38:14.280 by poisoning the mitochondria further and drive even greater upregulation of these signals.

02:38:21.220 Unless, to your point earlier, it becomes so toxic to the mitochondria that the cell undergoes

02:38:26.860 apoptosis.

02:38:27.500 Yeah. That's what's, in my opinion, and this is another thing that we want to do,

02:38:31.600 but it's possibly that, yeah, because you're totally right. It can amplify the lactate as we

02:38:36.400 know, so it can amplify that oncogenic or oncogenetic signaling for carcinogenesis.

02:38:42.920 Or maybe it just doesn't matter because these amounts of lactate are so high that we're not

02:38:49.800 seeing that from metformin. Maybe metformin isn't that inhibitory to the mitochondria, and that

02:38:55.880 becomes a red herring in the equation, and the benefits of metformin exist totally elsewhere.

02:39:00.000 We don't know, but it would be very interesting to see all this, because it can have some

02:39:04.420 application, and there's some research groups studying already why.

02:39:07.960 I feel like I need to quit my job and come and be a postdoc in your lab, because there's

02:39:12.060 just so much. The more we talk about this stuff, and I know it's going to get way worse tonight

02:39:15.680 when we have dinner with Rick, because it's going to be like 50 other ideas that I just want to...

02:39:20.860 With the fructose as well. Yeah, that's a lot of things going on there.

02:39:24.800 Let's talk for a few minutes about drugs and cycling. Many people argue that the era from about

02:39:31.880 91 to 2010, there's a 20-year period of time, the 90s and first decade of the 2000s,

02:39:39.080 where the use of drugs was at its highest. I don't think anybody can be a student of this sport and

02:39:45.240 ever say there's been an era when the top athletes weren't using some drug. I mean, even Eddie Merckx,

02:39:50.840 the greatest cyclist of them all, on many occasions, was found to be using an amphetamine

02:39:56.460 or something like that. How much of an impact do you think the performance enhancing drugs of that

02:40:02.600 era, the 90s and 2000s, where again, it's all out in the open now. Everybody understands how much

02:40:07.260 blood doping and how much EPO was being used. Yet you, a moment ago, gave a number of 6 to 6.5

02:40:15.060 watts per kilo as an FTP. I recall reading at the time athletes hitting 7 watts per kilo. Do you think

02:40:24.540 that is about the distinction of with and without EPO? Do you think that's about the magnitude of

02:40:30.400 the improvement? I could not know that number. Yeah, I mean, definitely, we know the times.

02:40:35.780 And back in the days, we didn't have those power meters or cyclists, they didn't use them. So it's

02:40:39.900 difficult to calculate, but it is possible to calculate with the times. I haven't done the

02:40:44.060 numbers, but what we know now is that the times going Tourmalet, Alduez or so are the same times

02:40:51.200 that people were doing in the 80s or early 90s. It's hard to see any of today's cyclists being in

02:40:57.360 the top 20 best times now, as they did before. So that's something that shows that, yeah, cycling,

02:41:04.140 I think goodness is a very clean sport right now. But the other thing is the fact that every

02:41:09.340 cyclist now who wants to do well, they go to altitude. And that's one thing that before didn't

02:41:16.100 happen. And now it's just great to see people going to altitude because it's a physiological way

02:41:21.520 to increase oxygen carrying capacity. Is the data on altitude still the following? So when I last

02:41:28.280 looked into this, which is maybe a decade ago, the answer seemed to be the performance enhancing way

02:41:34.580 to use altitude is to live high, train low, meaning your baseline exposure should be at a low oxygen

02:41:42.620 environment. Your low intensity training should be at a low altitude environment, but your high

02:41:47.700 intensity training should be at sea level. Is that still believed to be the case?

02:41:52.220 That's an ideal scenario, in my opinion. Yes. And I mean, here in Colorado, because we're Colorado here,

02:41:57.700 by force, we need to know, we must know about altitude because we get a lot of athletes every year

02:42:03.060 and we get to study them. And yeah, one thing that happens at altitude, your glycolytic capacity,

02:42:08.920 it starts deteriorating for high exercise intensity. It's like if you had a cap here at altitude. And

02:42:14.960 this is something that everybody tells you when they're here, like, I cannot keep my 100% here.

02:42:19.960 I cannot open up the same gas as I used to have. And if you don't do that for three and a half weeks

02:42:25.760 or three weeks at your altitude, yeah, your glycolytic capacity is going to deteriorate,

02:42:29.600 which for a marathon runner, they don't, couldn't care less. But for a cyclist, for example, it's

02:42:34.920 important. So that's what like the ideal scenario is to really try to find that balance, but it's

02:42:40.380 not easy to do at high altitude levels. Has anyone ever proposed using little portable oxygen

02:42:46.720 producing devices for peak, peak, peak efforts for those who live at altitude to maintain top end?

02:42:52.240 Exactly. And that's done.

02:42:53.600 It is done.

02:42:54.180 Yeah, it is done. Yeah. And that's something that we're building at the university in one of our

02:42:59.420 campuses in Colorado Springs, a sports medicine and performance center where we're going to have

02:43:03.880 one room that is going to simulate sea level conditions. So it's going to be hyperoxic.

02:43:11.060 So it's going to simulate living at sea level because that is going to allow athletes to do very

02:43:17.380 high intensity efforts without killing themselves, because this is the problem that happens here

02:43:22.100 altitude. These athletes who want to do very high intensity exercise, which would they really need

02:43:27.360 also to, they get overtrained. We see a lot of people live in altitude in very bad form and they

02:43:34.020 are going to train or they live with a high oxygen carrying capacity, but poor glycolytic capacity.

02:43:39.800 So that's where like, yeah, by doing this space, it's going to allow athletes to come and they use

02:43:45.560 these facilities while living at altitude. Because the problem that we have here, you have two days

02:43:50.640 driving to the ocean, so you cannot train low and deep high, but at least train low, high intensity.

02:43:56.360 You can simulate that while still living in high environment.

02:44:00.580 So interesting. Miguel Indoran, have you ever met him?

02:44:03.500 Yes.

02:44:04.080 An unbelievable specimen?

02:44:05.580 Yeah. Yeah. And an incredible person too.

02:44:08.180 I've heard he is, so he's got to be what now? He's got to be 60.

02:44:11.700 Yeah. 50s in the high fifties or so.

02:44:14.020 Yeah. Still incredibly fit. I remember reading a paper about him maybe 20 years after he retired.

02:44:20.180 He retired in 95, 96, right? I mean, still unbelievable numbers. I mean, was he just a

02:44:25.680 physical phenom to begin with?

02:44:27.020 Yeah. He was incredible. When I was doing my internship, I was doing it with a endurance

02:44:31.360 physiologist who was a very, very good physiologist. And I learned a lot. And I remember once I was

02:44:38.560 kind of helping there. And the one thing that struck me also was his numbers were unbelievable.

02:44:43.360 And also the amount of sweat that he had. I have never seen anybody sweating so much in my entire

02:44:50.060 life.

02:44:50.420 He was a big guy, right? He was 80 kilos, six foot one, six foot two.

02:44:54.900 It was incredible. Cause usually when you do physiological tests, you might have a few,

02:44:58.980 one towel or a couple of towels, even with fans, people sweat a little bit and you, and back in

02:45:03.800 the days I was, I was just wiping the floors. That's kind of, you do internships in these cases.

02:45:08.580 Yeah. If we do within the right, you need a mob. 0.88

02:45:10.940 And have you seen athletes since?

02:45:12.640 Never.

02:45:13.080 So do you think that's just true, true and unrelated? Or do you think that also spoke to

02:45:16.800 his physiology? Like he had an unusual cooling system.

02:45:18.980 It was like out of this world. I have never seen anybody like him. And if you observed that

02:45:22.780 the two of the friends, everybody was with their shirts wide open, right? And in Duran was always,

02:45:27.580 all seeped up. Always, always, always. And with a hat on. So he had an amazing capacity to dissipate

02:45:33.480 heat, which is a double edged sword. So obviously he drank a lot, but I'm very sure. And back in the

02:45:39.580 days we didn't have the technology that we have nowadays to measure that. What do we do now?

02:45:43.240 Sodium concentration in sweat. We do sweat tests. We have sweat patches and we can measure the

02:45:48.940 sodium concentration in the sweat patches and then tell someone, whoa, you're a heavy sweater in

02:45:54.960 the first place. And you also sweat a lot of sodium. But when someone, and it's something that's

02:45:59.940 very typical using young people or people who are not very well adapted to sweating,

02:46:04.860 you see like the white marks in their shorts or in their helmets, that's salt, literally sodium.

02:46:11.280 But the more mature physiologically an athlete gets, the more they sweat.

02:46:16.160 That is, I have never realized that that is a metric. Yet another little trick of the trade

02:46:21.580 to look at sort of metabolic flexibility is the ability to retain the sodium as just the water leaf.

02:46:27.720 Yes, exactly.

02:46:28.560 Makes total sense.

02:46:29.400 Yeah. It's an evolution. And you sweat more. Back in the days, I was just doing,

02:46:33.380 just wiping the floors, but.

02:46:34.740 Now you'd bet that there's low sodium in there. You'd pull a William Osler and.

02:46:38.900 Yeah.

02:46:39.360 He figured out that diabetes urine tasted like sugar. You'd figure out that Indoran's sweat 0.98

02:46:43.960 tastes like water.

02:46:45.020 I would have tested it for sure. I guarantee you.

02:46:47.680 And when I say, man, there's no salt here.

02:46:50.000 Indoran's interesting because he's right on that precipice where there is no question

02:46:53.700 that the person who won the tour right after him was using Herculean doses of EPO. So Bjorn

02:47:00.620 Reese won in 96 nickname, Mr. 60, right? I mean, hematocrit somewhere between 60 and 66. So

02:47:07.800 you go from Bjorn Reese to Ulrich to Pantani to Armstrong. That's the era. And then before Indoran

02:47:17.020 is Greg Lamond, who, again, I don't really know anything about what he was or wasn't taking,

02:47:22.500 but Indoran has largely been left out of the discussion on blood doping. And I've read articles

02:47:27.540 that have just talked about how he's generally been left alone. No one has come back to him

02:47:31.640 because it's, so I'm not going to ask you to speculate on that because I know that from a

02:47:34.780 personal standpoint, I don't want to put you on that spot, but do you get the sense that he's

02:47:38.840 just been left out of this discussion because of his place in cycling? And it's almost like people

02:47:43.680 don't want to go back and revisit that. I mean, why do you think that is?

02:47:47.020 I don't know. I have no idea, to be honest. I could never give you an answer. I know that he

02:47:52.760 was a freak of nature because of his size in the same manner that before Indoran was Greg

02:47:58.340 Lamond, who was also a freak of nature as well and left out of all this. I have no idea, but I've

02:48:04.960 seen his physiological parameters and I've seen a lot of athletes who don't see those physiological

02:48:09.660 parameters. And also what I always say about Indoran is his head. And I work with a lot of

02:48:15.880 athletes and in cycling, for example, I have never met any athlete. Well, there's one athlete. I will

02:48:22.120 tell you in a few years.

02:48:24.140 Meaning there's someone you work with now who maybe in a few years you'll tell us.

02:48:27.280 Yeah. I don't want to be-

02:48:27.940 No, you don't want to jinx him.

02:48:28.860 Him too. Yes, exactly. But only one athlete with his head. He was calm. He was relaxed. He was super

02:48:35.520 intelligent. He could read the game ahead of things. He would never get nervous about anything

02:48:40.140 and he would never doubt about anything, which is rare in athletes. I've seen athletes getting to

02:48:45.440 the top of the game and falling apart and start crying. There's the fear to lose, but also the fear

02:48:51.740 to win. Because when you win, your life changes for the good or for the bad. And many athletes,

02:48:57.000 they were always nervous trying to find an answer or trying to find a new diet or a new training or

02:49:01.700 something, you know, and that's where like, we're very fragile. Athletes at the high level,

02:49:06.160 very, very, very fragile. If you're considered like an expert or you're a coach or you're someone

02:49:11.780 with a little bit of a name in cycling, for example, and if you go to a race and you see a cyclist,

02:49:17.600 wow, you look fat. I think you gain weight. That cyclist is done.

02:49:21.820 Yeah, exactly. Done.

02:49:23.680 I mean, cyclists are like models in that regard, right? Every ounce matters.

02:49:27.960 Exactly. And that's how they are. But Indurane started the tour with two and a half kilos

02:49:31.440 over. For example, why? The first week in the tour is flat, no gravity. His head is relaxed and calm

02:49:37.480 and like, okay, I can do this, no problem. And in that week, he loses a kilo, kilo and a half.

02:49:42.720 And then he's entered the second week with the mountains with half a kilo over. Okay,

02:49:47.040 no problem, no big deal. He loses it. And then boom, the last week is in perfect weight.

02:49:51.140 It takes a lot of thinking and confidence, right? And saying, hey, I got it. And that's what I think

02:49:56.600 that his head was also unbelievable. LeMond's head was also incredible. I remember as a kid

02:50:02.640 reading LeMond's book. It really, literally changed my way of looking at cycling. I was 15

02:50:08.320 when he won the Tour de France. And that's where I started to see his complete book of cycling. I

02:50:12.940 don't know if you've ever read it.

02:50:13.740 No.

02:50:14.060 It's the best cycling book I've ever read in my life. And it's about how he trained and how he

02:50:21.280 ate and how the way he approached cycling. And back in the days, I'm talking 86, he was super

02:50:26.680 scientific.

02:50:27.340 Yeah. He was so far ahead of everybody else.

02:50:31.500 Everybody else.

02:50:32.200 Yeah. Yeah. We could go on for hours. But I think on this note, we'll bring it to a close

02:50:36.780 only because we're already late for dinner and I don't want to keep Rick waiting. But I want to

02:50:42.440 thank you so much for this. This has been incredibly informative. There is a million follow-up things to

02:50:47.040 do, including we're going to do this biopsy study. So I'm willing to come back to Colorado to do this

02:50:51.860 again, because I really am curious about this metformin question around zone two. And I think that

02:50:57.660 this is going to be one of those episodes where hopefully people are able to see the show notes

02:51:01.480 because so much of what we've talked about, I think, benefits from this type of being able to

02:51:05.800 visually see what this stuff we've talked about. And lastly, I do think there's going to be no

02:51:10.420 shortage of medical students and undergraduate students who are looking for summer projects

02:51:15.220 to come and help you get a lot of these really interesting posters published. So thank you.

02:51:19.940 Well, thank you so much, Peter.

02:51:21.080 For the impact you've had on me personally with respect to how I think about this problem.

02:51:25.220 And then hopefully by extension, how others have as well.

02:51:27.840 Well, thank you so much. It's truly an honor to have you here and to speak with you and

02:51:31.280 be invited to your podcast. Thank you very much.

02:51:35.600 You can find all of this information and more at peteratiamd.com forward slash podcast.

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The Peter Attia Drive - December 23, 2019

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

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