Lactate: The Key to Metabolic Health, Mitochondria, and Longevity | Dr I igo San Mill n | EP # 385: Full Transcript

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If you've ever felt that burning sensation in your muscles during a workout and been told that this is from lactic acid, it's time to let that go. It's an outdated idea. We now know that lactate is not a metabolic waste product. It's one of the body's most powerful signaling molecules, revealing how efficiently your metabolism and mitochondria are working. Today, I'm joined again by Dr. Inigo San Milan, a worldleading physiologist and researcher whose work has really transformed our understanding of both lactate and metabolic health. He's an assistant professor at the University of Colorado and has worked with elite endurance athletes including tour France champion today pagotchar. In this episode, we'll unpack what lactate really is, how it contributes to glucose intolerance, and potentially the development of type 2 diabetes, and why improving lactate clearance through zone 2 training can enhance endurance performance and long-term health. Please enjoy. Our last conversation we spoke about the importance of of zone 2 training or moderate intensity cardiovascular training as some people may know it as. And really central to that and to your research is this molecule lactate which as you know and as you speak about is often quite misunderstood. So I wanted to come back to to lactate as as the kind of on-ramp for our discussion today and maybe we can start

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discussion today and maybe we can start at a a really high level here in should the average person a a non-athlete should they care about lactate and if so why yes I think they should care about lactate or try to understand what lactate is and I think that it's been a as you said a big uh you know like it hasn't been understood and uh it's going to be a a major biomarker in the next years and uh going forward. But yeah, it is a major biomarker of mitochondrial function and it's probably right now the best biomarker that we have to see what's your mitochondrial function uh in a non-invasive way without the need of doing a muscle biopsy or or a tissue biopsy and it's everywhere. is ubiquitous to every pretty much every single reaction in the body and this its presence across the body is as ubiquitous as the presence of oxygen or CO2 and so tying that together so it's a biomarker of mitochondrial health essentially a window into your mitochondrial health why should people care about that how how do you connect that to to health and I should have rephrased that a little bit better because it's more than biomarker and thanks to the work that Dr. George Brooks has done for the last 54 years at UC Berkeley we know that is a signaling molecule that it's

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that is a signaling molecule that it's responsible for many different functions and homeostasis in the body it it has as Dr. Brooks uh coined it a lack hormone right it has hormone-l like properties because it's has tremendous amount of signaling properties uh for health and also for disease so not only biomarker but it's also a major player in the homeostasis of human metabolism and health as well as a major player in disease and from our last conversation if I recall correctly it can also be used as a a fuel source for producing energy. Absolutely. I forgot to mention that as well. So many functions, but yeah, it's probably the preferred fuel source for the body. It's mainly because it's the most direct fuel. It's it enters mitochondria directly through its transporter. It doesn't have to be broken down like carbohydrates or fatty acids. It enters directly in the mitochondria for for fuel purposes. So right at the top here, this might challenge the way that that people have thought about lactate previously perhaps how what they had learned during university or or afterwards. And what I'm hearing and what I want to underscore here and just throw back at you to confirm is that we should be thinking of lactate as a signaling molecule as a a fuel source rather than some some form of of waste kind of byproduct or metabolic byproduct that

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byproduct or metabolic byproduct that the body produces during exercise that is harmful or toxic and we need to get rid of. Yeah, absolutely. And we've been always thought that uh it's been a or it's been always thought right it's been a waste product as a result of anorobic metabolism and came back from the beginning of uh 1900s where hotel mayorhof Nobel Prize discovered that he placed a frog into like a flask and uh somehow he's he was studying you know the how glycogen was converted to lactate under anorobic conditions and therefore he's ded deduction was that glycogen was used by the muscle and the waste product was lactate and and then he he got the Nobel prize for that. So it became Dogma and other researchers and two other Nobel prizes. They they also were very into glycolytic metabolism and lactate was always there as a waste product. So that was embedded in textbooks for forever and thought that people thought that also was like crystals they would become you know like crystallized and they would uh cause dumps delayed onset of muscle soreness and all kinds of different things. But uh then yeah in the 1980s mid 80s uh George Brooks from the University of Berkeley um California Berkeley he started to to swim upstream against the thought that lactate was a waste product and he's been debunking every single thought that was written about lactate and now we have a whole kind of

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and now we have a whole kind of understanding of of what lactate does and what lactate is. Speaking of of dogma or perhaps misunderstandings and firstly here actually is lactic acid synonymous with lactate? No. So lactic acid is it never sees the the light of the day if you will, right? So the final product I mean the only product that that you see is lactate. It's been used back and forth lactic acid or lactate but uh the real compound that that we see that the real metabolite is lactate. And so what do you think about this idea that you know after you do sprints that real fatigue and burn that you you might feel in your legs that's that's often been attributed to lactic acid. You know people might say you know that's a kind of lactic acid burn post exercise. Is that a myth? Absolutely. It's a myth. Uh and the the thing is that what really causes that burning sensations that we all have felt is uh muscle acidosis right where the pH in the muscle goes from about 7. 2 7. 4 goes all the way down to it depends 6. 5 6. 8 6. 2 depends on the person. So it becomes quite acidic and but that's not due to lactate is due to ATP hydraysis because when there's a high exercise intensity or in the case of a spring a high necessity to replenish ATP at a very fast rate the ATP hydraysis is uh

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very fast rate the ATP hydraysis is uh very very high and therefore the protons are building up in the muscles and that's what causes acidosis but not lactate. Lactate in fact it's a mild buffer during glycolysis. So lactate is always always the end product of glucose metabolism. So glucose enters the muscle and through its transporters mainly it depends on the tissue but let's say muscle is the glute for and then through that it it enters uh the cytool the cell and it's broken down through different steps called glycolysis. It's broken down to pyuvate and then pyuvate enters mitochondria right for oxidation for you for final destination and is uh converted to acetil coa which enters mitochondria for ATP production then there's always always some lactate production so there's always sometime lact some always some lactate production from pyuvate to lactate so lactate is always present however when there's a very high rate of glucose utilization which is called glycolysis. There is a depletion of NAD + that famous compound that is very popular now. So in the step from glyceraldihide 3 phosphate to3 by phosogglycerate which is one of the steps of glycolysis NAD + is consumed and is converted to NADH plus H. So that NAD +

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NAD + is essential for the continuation of glycolysis and homeostasis of the redox status in the cell. So that is the normal homeostasis of the cell. So it can keep functioning otherwise glycolysis will stop. So whether you're exercising or whether is a proliferating tissue or whether is a tumor tissue glycolysis will stop. Right? So the only way to rescue NAD + is the conversion or the reduction of pyuvate into lactate. That's the only way. So in that step pyuvate or lactate it's the result of taking those NADH plus H. So two protons there they are given to lactate in a way. So or lactate is a result of uptaking those protons from pyuvate to lactate and lactate is formed. So in in a way lactate it's a mild buffer because it takes those protons. So it has nothing to do with hydraysis from ATP at the muscle. But in that process what lactate does is like it regenerates NAD + from pyrovate to NAD to lactate it regenerates NAD + and therefore that's the only way for the continuation of glycolysis. And if we were to come back to lactate as a biomarker of mitochondrial function or dysfunction and we were to think about the difference between a diseased person with poor metabolic health and a healthy

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with poor metabolic health and a healthy person or even an athlete. My understanding of this is that the healthy person and the athlete are better at sort of quote unquote recycling lactate and sort of putting it to good use. And that stops at a given intensity that stops the blood lactate levels going up as much as you may see in someone who has poor metabolic health and less capacity to sort of recycle lactate. Is that kind of high level accur accurate? Yes. So there are two events here. One is that if you have a good mitochondria function, you're going to use glucose at a faster rate and you're going to oxidize it or burn it in mitochondria. So what's called the the full oxidation of glucose into ATP through oxos oxidative phosphorilation in mitochondria is going to give you around 34 to 36 ATPs. Right? That's on one hand. If if you don't have enough mitochondria function, you're not going to be able to tolerate that higher glycolytic flux and you're going to be producing more lactate, right? So that alone is going to give you a biomarker of a poorer mitochondrial function when you stress it, the lactate production. The second point is that well-trained athletes that lactate instead of accumulating what it does it's oxidized in mitochondria. So that pyrovate mainly goes from the fast twitch muscle fibers

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goes from the fast twitch muscle fibers which are the glucose users and lactate producers. It goes to the adjacent slow twitch muscle fibers which are richer in mitochondria and that's where it's oxidized to energy. So as you said very well it doesn't show up in the blood. So when you see in the blood lactate at the same exercise intensity relatively to another person you are going to see that yeah the person who has more lactate is because cannot that person cannot oxidize lact or recycle lactic correctly and builds up in the bloodstream because it has nowhere to go and once it's in the bloodstream it's oxidized by every cell in the body whether it's the brain the kidneys the heart right at the lungs it's very well oxidized everywhere and is is lactate increasing in in the blood. Is that a problem or are we still saying that lactate itself is not a sort of toxic byproduct, but this is just more of a a window into that person's metabolic health, which is the real problem. Exactly. That's where you see lactate traveling in the blood. It reflects on one hand that there's a metabolic stress somewhere, right? When we exercise, we know that there's a metabolic stress there, right? So that's why it's a biomarker. That being said, it's not toxic per se because that lactate is going to be oxidized everywhere. So, it's fuel that you're you're in a way you're recycling it somewhere. So, you're giving it fuel, right? But when you see lactate under non exercise conditions, like for example, ICU

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conditions, like for example, ICU patients, lactate becomes along with cortisol, the top predictor of mortality. When you see someone with lactate, very high lactate levels. I think it's above 5 mill moles or 4. 8 eat minerals. I forgot exactly what it is in the ICU, but uh there are very low chances of survival. And uh historically that has been thought to be like lactate acidosis and it was treated right as a lactate acidosis or or a thought that oh boy that that there's a lot of lactate that patient is in acidosis state right when what is telling you is that that patient is in a very high metabolic stress which is very typical ICU patients and that that the two characteristic of this I of ICU patients are very high rate of glycolysis because they're fighting for survival and is is not during a is not one hour or two hours or three like when you go outside and and exercise or high intensity it's 24 / 7 right and second what you have the people with in the acute phase of ICU is glucose intolerance so they have insulin resistance and mitochondrial dysfunction which is going to push even more uh towards the production of lactate I vividly recall the first person that I started with this methodology she was pre-diabetic she has been diagnosed with pre-diabetic on the verge of becoming type two diabetes and so she came to the laboratory and we gave her an individualized exercise program with her training intensities and after just I think it was like 6 7 months she she

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think it was like 6 7 months she she came back to normal. I recently ran my full labs through function health and I have to say the results were eyeopening. Turns out my apo was higher than ideal probably thanks to a little too much coconut yogurt. I also found out I was slightly low in copper, something that I would have never suspected without testing. On the flip side, my biological age came back 13. 3 years younger than my actual age, a calculation based on the work of aging researcher Dr. Morgan Levine. So, all in all, I've got a few tweaks to make to optimize my lipids and nutrient status, but overall, my blood work says I'm doing pretty well. That's what I love about function. You get access to over 160 biomarkers covering everything from hormones and inflammation to nutrients, toxins, cardiovascular risk, and more. And all your results are housed in one beautiful platform, all tracked over time. Once you get your results, you can make informed changes before small issues become big ones. To get started, head to functionhealth. com / simon. The first 10, 000 people get a $ 100 credit toward their membership. That's functionhealth. comsimon. Okay. So it's kind of this this building up of lactate is in a person with poor metabolic health is

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person with poor metabolic health is coming from increased production of lactate. So glycolysis is kind of happening in overdrive presumably because the the mitochondria is not as healthy and good at oxidizing fats. Is that what's happening on that side of the equation? Yes. And then on the other side they're not as good at clearing. So if we think about the machinery within a cell that's responsible here for the building up of lactate. What I'm hearing is that mitochondria not being as functional and and healthy and also those MCT1 and MCT4 transporters which are really important in the muscle fibers for for kind of pushing out lactate from the fast twitch fibers and then receiving it in the slow twitch fibers. Exactly. So there's a whole and this is what Dr. George Brooks discovered what's called the mitochondrial lactine oxidation complex or MLOCK that not many people talk about but it's very important to understand also lactic behavior and uh as you said very well yeah just you need especially high levels of MCT once to be able to accept lactate because lactate cannot penetrate cells by via diffusion it has to be through active transport and it it's taken by the MCT once and then uh into mitochondria so If you have poor mitochondrial function, normally everything kind of builds up around that mitochondria. At the end of the day, you're going to have lower different elements. We can talk later about mitochondria but also you have lower MLOC or mitochondrial lacularation

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MLOC or mitochondrial lacularation complex which is the MCT1 and LDH and also MPC1 which is the mitochondria which different thing and we're going to come to some of the the interventions later in this conversation I'm sure but but just in short this machinery that we're talking about here whether it's the mitochondria or these transporters for shuttling lactate these are not sort of 100% determined by genes. These are affected by lifestyle and something that we can kind of modulate. Yes, we can modulate for the good and for the bad. So exercise is been known to be the best form or the probably the only form that we know of really inducing not just the expression of mitochondria or or enzymes responsible for for mitochondria biogenesis but it is it's really the form of increasing mitochondrial function and being sedentary for example it's going to you know start a decay process of mitochondrial function we have a study we we publish it as a preprint I just have to finalize that the graphs I haven't had the time to to wrap it up to to send it to a peerreviewed but we just wanted to publish it to say hey we we have done this before others would but it is an interesting study we had sedentary individuals versus moderately active individuals and so we did both exercise maximal intensity test with the uh like a cipet right with the gas exchange through the metabolic cart and also we did muscle biopsies to study the

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did muscle biopsies to study the components of the mlock right and how lactate behaved we also did metab abolomics but we we looked at the protein expression we did a transporter expression as well and the flaxes. So we saw how well mitochondria from sedentary and motorally active individuals 150 minutes or more per week would use fatty acids we use glucose we use amino acids and it's very clear that sedentary individuals have a significant decreased in mitochondrial function already and we can see that also uh without the need of doing muscle biopsy by looking at lactate during incremental test. So this is what we wanted to also correlate what we see in the muscle biopsy versus what we see in the metabolic cart right in the test and we saw very clearly that they have a problem already with glucose metabolism. So I can delve in more if you want to. Yeah please please share you know any and and all of the I guess the most important findings that you think the listeners should be aware of from that that paper. Yeah. So the way we have been understanding and studying glucose and approaching it clinically is by what happens at the peripheral level more like right that we're talking about hyperglycemia hyperinsulinemia insulin resistance right even glute for resistance right but that's the first part of the trip for glucose to be fully oxidized it's it's a longer trip than just getting glucose into the

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trip than just getting glucose into the cell and this is what we wanted to see right so glucose the first step is to be taken by the cell through the transporter that's what we know and but then glucose as I mentioned earlier has to be broken down into the cytool inside the cell I mean into pyuvate that's the second part of the trip the third part of the trip is that pyuvate has to enter mitochondria through a transporter in the same way glucose enters the surface cell the surface of the cell for transporter pyuvate does the same thing at the surface of mitochondria right and that's called the MPC or mitochondrial pyrovic carrier and then a fourth part of the trip that pyrovate has to be converted to acetil coa and then enter the crep cycle right and then finally enter the electron transport chain for ATP production so it's it's a long series of events however we've been only focusing on what happens at the peripheral level so our study wanted to see like an inside out model. What if the problem behind the pathogenesis of type two diabetes or glucose intolerance would not be at the surface of the cell but at the mitochondria level. Right? And this is what we saw. We saw that motorally active individuals they have somewhere between 30 to 50% reduced in the mitochondria pyrovic carrier the transporter of pyroate into mitochondria electron electron transport chain the

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electron electron transport chain the complexes especially complex one and complex 2 that we studied we also saw that the flux the oxidation of pyuvic which is the end product of glucose was significantly decreased uh by about 35 40%. We also saw that the transporters for fatty acids are decreased as well CPT1 and CPT2 and also we saw that the oxidation the of of fatty acids were highly decreased. Right? However, and this is was to to us was the big finding the glute for expression was the same in both groups. So these are healthy sedentary individuals. They have no clinical issues at all. They have normal glucose levels and they have in fact yeah they their glucose transport is normal because the transporters are normal. However, the last part of the trip when that pyuvate enters mitochondria for being utilized and being produced ATP is already disregulated compared to motor active individuals and a biomarker through exercise was lactate right without the need of muscle biopsy. So what you're seeing there is you can have an individual who may have normal blood glucose and insulin levels and is sort of quote unquote insulin sensitive or you know doesn't have type 2 diabetes because the first part of that trip's

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because the first part of that trip's okay but they still are having some form of metabolic dysfunction but it's it's lower down in that journey of getting glucose into the mitochondria to produce energy. Exactly. And this this is why it's already disregulated and it's regulated maybe 10, 15, 20 years before someone develops type two diabetes. And this is why it's a great chance that we have to diagnose it and intervene through lifestyle interventions mainly exercise and proper nutrition or develop some therapeutics to target what happens at the mitochondrial level. But yes, absolutely we can see that there is a dysfunction already in those individuals. So, how would we use that on a on an individual or population level? Because where my mind's going is what I'm hearing is that maybe lactate in the blood is a better way to see someone's risk of developing, you know, pre-diabetes or type 2 diabetes way in advance. But then at an individual level to use lactate, I would presume that you need to have baseline levels and then be monitoring how that's changing over time for a given intensity. Exactly. So for that I I use the same approach as a exercise stress test that cardiologists do at rest. If you're laying down the traditional EKG or ECG, the reliability or accuracy of those tests are is about 50%. Right? So from when when we were kids, right? Uh people would just do laying down EKG or EKG for

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would just do laying down EKG or EKG for whatever the physical people don't do that anymore in general, right? What you want to do is you want to stress the heart and that's what's called a stress test. So you put that person on the treadmill and you are increasing exercise intensity. So the heart starts pumping harder and harder until a point that you're going to see some pathology because the heart starts suffering, right? Because it has to work harder. that that accuracy of that stress test is about 90 to 95%. So I'm I'm using the same approach for mitochondrial function. So in in a non-invasive way, right? So at doing resting levels, blood lactate levels, sure in many people are going to be slightly above let's say normal levels are around 1 mill. Many people with some metabolic syndrome might be around 1 mill or might be slightly above 1 mill. People with type two diabetes, full-blown type two diabetes, chances are that lact is going to be two to three millons already, right? So that alone can be for more diseased population can be a biomarker. But for pre-diabetics or people like in the study that we saw like a healthy sedentary individuals, we might see 1 mill. But if we put those people to the test in the same manner as we did as as cardiologists do with the with their patients that's when we tell mitochondria hey speak up. So we're in this case we're not stressing the heart we're stressing the muscles and therefore the muscles get more stressed

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therefore the muscles get more stressed they need to use more oxygen from the heart. So therefore the heart gets stressed as well but especially that glucose starts kicking in. You need more glucose that you're not oxidizing properly in mitochondria. So you're producing more lactate and since you don't have the the slow twitch muscle fibers to oxidize it then it builds up in the blood. So it's a very good test to indirectly measure mitochondrial function indirectly in a non-invasive way can be done in an ambulatory manner right and it's also a good way to since you are there in the same manner that we do with elite athletes for for many years so I have done at least for 30 years we can establish training zones for that patient or that person so we can already intervene with exercise in an individualized manner and when when you're measuring someone's lactate levels at various intensities. What are you benchmarking that against? Do we have data that says, okay, for this gentleman who's 45 years old, you know, at this intensity on the bike, this is what their lactate levels should look like if they're healthy, or or are you just looking at someone's baseline and then how it changes? How are we actually doing this in real life in the lab at an individual level? Yeah, that's a great question. And uh yeah, honestly I I I'm not aware of many people who do this kind of testing, right? I in fact George Brooks and I we we introduced these tests as a potential way to indirectly look into assess

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assess assess function. I've been doing it for a long time. I have my own database from all kinds of populations from elite populations through the France level all the way to people with chronic diseases like type two diabetes, metabolic syndrome, cancer, longcoid patients, COPDs and this is or normal people of all levels, right? So this is why I have my own database and I can then test it against my database. But uh yeah, that's something that like I just hope that this keeps uh growing, right? and more people start adopting tests like this. And how malleable is that? So if if you have data from athletes and and normal people, is that single point data or is that data over time that allows you to see, okay, if I put this person on a certain program, whether they're coming from a kind of, you know, metabolic disease position or a normal healthy adult or an elite athlete, how much can they actually shift that lactate level during exercise. Yeah, that's a great question and this is honestly what I'm very excited about this because and this is what moved me to to do this research because at the uh clinical level I was seeing people with this I mean pre-diabetic mainly obviously diabetic and people with severe chronic diseases you see the lactate behaves very poorly as well as fat oxidation which by the way they go together they don't oxidize

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way they go together they don't oxidize fat but I was seeing that population who pre-diabetes right? Or or on the verge of of being diagnosed with diabetes, they were characterized by having also very poor mitochondrial function. We know that given by lactate production, right, at a same intensity, relative intensity that that people who are healthy, that gave me the idea of like, hey, how about we look at what happens in the muscle in mitochondria and we can see this, you know, and and correlate it. Uh this is what we did. But the whole thing is that I saw that in the same manner that we increase mitochondria function or or for performance because that's what we aim for right we want our athletes to be better and uh a key thing for performance is to have a better mitochondrial function which is what we test in the laboratory I've been testing for almost 30 years looking at lactate as we've been discussing but also fat oxidation when an athlete burns more fat and clears more lact ate both are mitochondrial substrates. So it gives a very strong indirect measurement of mitochondrial function. So when you give a training program and this is what we talked about zone two, zone four, zone three, whatever. What I saw over the years is like these two parameters lactate and pot oxidation improved the most in people who did zone two, right? But that being said, you need to also do for zone four and and other intensities obviously to compete. But in what I saw in these populations is that in the same

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in these populations is that in the same manner that we do with elite athletes, we could do exercise prescription individual individualized for these patients and they improved dramatically. I vividly recall the first person that I I started with this methodology. She was pre-diabetic. She has been diagnosed with pre-diabetic on the verge of becoming type 2 diabetes. And so she came to the laboratory and and we gave her an individualized exercise program with her training intensities and after just I think it was like six seven months she she came back to normal. So we were able to reverse that metabolic dysfunction that it was mild still right but we were able to reverse it and she was put out of the category of being pre-diabetic all along right and then she continued and and a year later she she kept she was really good. So that's what I'm excited about catching these metabolic dysfunctions or these regulations I would say because there still don't show up any clinical symptoms on time because then we can act on time. That's huge. There's no other there's no medication right now that can be so powerful as exercise at early stages. It would be naive to think that the best athletes in the world, they just doing zone two training and then boom, voila. You know, they go through the mountains deploying those that turbo and that high calic capacity just because they train zone 2. No, that's one part of that equation. I've had a bunch of friends ask me recently, Simon, do you actually rate eight sleep? So, here's the truth. I would not promote eight if it hadn't

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people. So if we double click on that and we we might be retracing over some things we've discussed previously. But what is it that that makes it advantageous to have mitochondria that is really good at utilizing fats and turning these fats into energy. So dur during exercise you want to be more efficient at producing ATP right which is energy right that's what we all want right to produce ATP at a fast pace and uh continuing right so we produce that mainly from fats and glucose right carbohydrate source so that's why everything comes down to mitochondria right so the bigger saying figuratively speaking but the better the mitochondria are functioning the better you're going to be able to burn those fuels and and produce ATP faster. Also, the more especially for longer events, the the better you're going to be burning fat, the more you're going to be burning fat and sparing glycogen, right? Which we only have about half a kilo of glycogen in our muscles. And that we need every single bit of it for the last part of the race or the intensity we do. So, that's why we spare glycogen and you can have more towards the end of the event, right? But mainly it's about just producing ATP much more efficient than someone who doesn't have a good mitochondrial function. That's for performance right and for health. Again like mitochondria mitochondrial function is it's it's key for metabolic health

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is it's it's key for metabolic health and metabolic flexibility. That's where everything happens. We hear a lot about metabolic I mean metabolic flexibility nowadays. The ability to switch back and forth carbohydrates. That's it. That's what happens in mitochondria, right? That's where when we switch back and forth and and we have, you know, the luxury, right, of being able to use our randomly, I mean, not randomly, that the fuel that is the most interesting that the given situation that happens in mitochondria. So that's why it's very important for for health and in terms of improving your ability to you know oxidize fats or in in lay terms kind of take take fats shuttle them into the mitochondria and then produce ATP. The reason that moderate intensity cardiovascular exercise or zone two is sort of theorized as being so good for this is that this is the intensity where you are utilizing the most fat on a sort of gram per minute basis. So you're stressing that system the most. And then as you shift into higher intensities, you're not stressing that as much because you start to to use other systems to produce energy. Is that right? Yes, I would say. So at least this is my my these are my observations of 30 years in the laboratory looking at metabolic data from fighting carbohydration rates as well as lactate production as well as from working directly in in the

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from working directly in in the trenches in the battlefield, right? whether are with athletes as with p or patients, right? And this is what I have been observing. I started with zone one to zone six to give me like a chart of how to categorize different energy system that you wanted to stimulate through training. And I mean it just said zone two. That's what I saw the biggest improvements in fat and carbohydrate oxidation during exercise. And yeah, that doesn't mean that it has to be all so too, right? I mean the majority of for for athletes the majority of the competitions are won in in high intensity. Well all the competitions are won in high intensity. So you need to stimulate those energy systems as well. But for me like that that zone two has is the the one that stimulates the highest fat oxidation as you see and this is an event that you see in the laboratory where you see to a point where when you pass that zone two there's no fat oxidation or there's a first there's a sharp decrease in fat oxidation and a sharp increase in lactate and that's a transition zone that I call zone three and you get to a point that you have a no fat oxidation and a very high rate of lactate production which is glycolysis and and this is where you are not stimulating those slow twitch muscle fibers anymore. Right now you're full-blown fast twitch muscle fibers which are burning exclusively glucose. We know as part of the signaling properties of lactate that lactate decreases or inhibits lipolysis.

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lactate decreases or inhibits lipolysis. the tissue level at the adipus tissue. There's a receptor GPR81 that is inhibited by lipolysis and we also showed and we published that lactate also inhibits or decreases the activity of CPT1 and CPT2 in mitochondria. So not only the tissue level of the adiposite tissue level but al the mitochondria itself it decreases the uh activity of CPT1 CPT2 and this is what we see indirectly in the metabolic cart we see a sharp increase in lactate and a sharp decrease in fat oxidation and the correlations right between fat and lactate in elite athletes moy active individuals and metabolic diseased individuals as we have published the correlations is is in the' 9s inverse correlation, but it's a very strong correlation. So that's why we know that something is happening there and that we can trace it. So is lactate signaling acting as a signaling molecule there to fat tissues essentially saying we we have enough kind of energy substrate available. We don't need fat right now. Yeah. In a way saying hey guys your your job is over here now. It's full. This is getting serious. This is now, you know, like a carbohydrate job. So, don't interfere here. Don't come near here to the muscle cells. Thank you for your service. We appreciate it. Boom. We we'll deploy you guys tomorrow or or

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we'll deploy you guys tomorrow or or later on in the exercise, but now we need to focus on carbohydrates, which is a different kind of personal, right? Uh that is necessary. So, that that's kind of what lactate regulates and this is why it's a very important signaling molecule. So if we come back to the individual who has metabolic disease and let's say they're listening to this now and they're they're understanding the me the mechanisms here and it's obvious to me that the mitochondria is very important here in terms of being able to oxidize fats and be very functional. But then also the other part of this equation if you look at it end to end that that influences lactate levels is your ability to shuttle lactate out of fast twitch and then into slow twitch and get that kind of lactate shuttling recycling happening. And I think the zone two piece for stressing the mitochondria and improving fat oxidation capacity that makes a lot of sense. And I I think as as someone, you know, prescribing exercise to this person, I think and and this is what I want your thoughts on. If we were trying to specifically stress like the MCT4 transporter to that's that's kind of ellexing or pushing lactate out of fast twitch muscle fibers. Would highintensity exercise up into zone 3, four, five be better at that because you're recruiting more fast twitch muscle fibers? For sure. 100%. I agree with you and and this is in fact one of the many

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this is in fact one of the many reasons why highintensity exercise is absolutely crucial because we need to stress those mechanisms right that lactate is there and how do you get it out through MCT force therefore how do you stimulate the you know that the the muscles they synthesize more of those transporters and they work better but through highintensity exercise it's one of the very important benefits that along has a increase in the activity of glycolytic enzymes right like glycolysis the faster it happens the faster it's going to produce ATP right so that machinery that toolbone that I call right you only stimulate that through highintensity training and this is why it's through different you know training zones that's that's how I came up with that a way to to try to stimulate some bionergetics that are specific to that zone and in this case would be like zone four or zone five where you isolate that exercise intensity where it's full-blown carbohydration. Forget about the fat, forget about mitochondria. It's about lactate production and glycolytic improvement, right? So, and that's very important. And with the athletes that I train, I mean, I look at their files, right? and and all their best 5 10 20 15 minutes their top 10 about 30 to 40% are during training not competition right so that's telling you that competition they go 100% that's maximum but you can see that

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100% that's maximum but you can see that also in training and in fact this is what we stimulate those training those energy systems right and it's it's way more than just zone two obviously right it would be naive to think that the best athletes in the world they just do train I mean zone two training and then boom voila, you know, they go through the mountains deploying those that turbo and the high glycolytic capacity just because they train zone two. No, that's one part of the equation, right? But for health purposes, it's important to touch zone three and zone four and glycolytic capacity, but it's not so crucial, right? Because you're not going to be competing or deploying that turbo nearly as much. I think you've mentioned the the 8020 rule or many people have it. It might not be you. So you can confirm that at least for elite athletes where 80% of their training time tends to be in zone 2 and then 20% in higher zones. If we're thinking about the the average person out there, let's say they have, you know, 150 to 200 minutes a week of of exercise, which I understand is probably not optimal, but probably realistic for a lot of folks. How much of that time do you think is optimally spent in zone 2 versus higher intensities? And second part of that question, do you think it's optimal to have certain days where you do zone 2 and then certain days where you do high intensity or are these adaptations and the stresses that we we want on the system, are they going

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we we want on the system, are they going to be better if they're occurring within the same session? Yeah, I I agree. First I I would not put like a hard number to 8020 could be maybe roughly but if I mean I think that we need to distinguish between the time or the distribution of the sessions right so if you look at the time you're going to see that even during the competition right you're at 80% or 70% lower intensities I'm not talking about section let's say about soccer football in Europe right the real football but you over. But if you look at what's considered high intensity speed is usually over 21 kilometers an hour. And with GPS systems, we we track that very well. You you have the GPS systems in the players and you know very well the different meters or distance that they cover throughout the entire game at the high intensities uh breaking down into 21 to 24 B and beyond 24 sprinting. So if you look at the high intensity speed in a football player or soccer player, we're talking about 5% of the entire game of the 90 minutes is 5%. When in our minds we think that it it's all the time sprinting up and down, Those are bursts of actions, right? If you look into a swimmer, it's like a 100 meter swimmer, right? It's under a minute the distance. And if you look at the time they or how they exercise, more than 90% of the

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they exercise, more than 90% of the entire workload is in lower exercise intensities. And I always say that we can be that naive to think that the best coaches and the best athlet I mean the best swimmers, they haven't thought about this before us, right? That oh our our distance is less than a minute, 50 seconds. Okay, that's what we have to do. Let's just train 50 second sprints or one minute sprint swimming pom pan. Of course, they have tried it and it doesn't work, right? And this is why you go to the pool and you see the best swimmers in the world just swimming three hours a day up and down. They do the intensity of course, right? But if you look at also rowers, which is that the Olympic distance is six minutes, right? It's a maximum effort six minutes is it's a gonic and it's most of the time they do the lower intensity. So whether is from a scientific standpoint, whether is from an empiric experience standpoint, it takes you to the same boat. Right? It's funny sometimes you see and I don't want to say I don't want to get in trouble with scientists, but many scientists, they have never worked in the trenches. They have never worked with athletes. And they might say study, oh, we have found out that exercise intensity is the only thing that works. Well, if you think that way, you have never worked with an athlete before. Because if you had worked with an athlete, you had tried that. And if you tried that, you're not going to be successful. And if you look at all the best coaches in the world and the athletes that I'm saying, it's a mixture of everything. But the lower extra

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of everything. But the lower extra intensity, it's something that is very prevalent. that example that you just said there of, you know, the the athlete who is training for some form of sprint, they're doing a lot of steady state, moderate intensity cardiovascular work in their training. And of course, they they understand that that's necessary to compete at the highest level and produce their best results. Gets me thinking about you mentioned before that you think, if I heard correctly, lactate levels are best surrogate marker for mitochondrial health. Another test that exists that I think people have heard of and may maybe more people have heard of is V2 max testing which is often associated with more sprint work or higher intensity work even though that's certainly an over simplification. My question to you here is how tightly does V2 max if if we know or or maybe you can speculate correlate with mitochondrial health and lactate levels. Is it possible to have an athlete who has, you know, a great V2 max, but they have poor or suboptimal mitochondrial function? As I always say, I mean, B2 max is for we're talking here about athletes, right? Competitive athletes. B2 max is like the tomato sauce for a pizza, right? It's an ingredient. You just it's a main ingredient. You need to have a good V2 max because V2 max is the representative

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max because V2 max is the representative of your cardiorespiratory adaptations, right? You need to have a very good cardiac output and be able to pump out a lot of blood and you need to be able to uptake a lot of oxygen and and excrete CO2 on time, right? So, you need to have both cardiorespiratory adaptations and obviously what happens at the capillary levels, you know, and the gas exchange has to be very dialed in, right? However, what makes the difference is what happens at the local level, you know, is that the toppings on the pizza, right? And this is what you see in mitochondria. They are related obviously and they're very obvious in more meamortals, right? And a population with chronic diseases as well. That one of the first things that we can see and this is going back to the example that I was mentioning about stressing someone to see their mitochondrial function. This is the exact same concept to look at your V2 max, right? you need to you know stress someone to to reach their maximum aerobic capacity which is the V2 max right so it's a great parameter for a prediction of longevity of health of wellness state right but when it comes especially with athletes it's not the best prediction of mitochondrial function and this is one of the things that we've seen I've seen and many many of us working with elite athletes have seen forever you can see two athletes at the professional level up with the same view two max and one is on the mediocre or middle term of of a professional athlete which already is obviously world class and the other one might be the the

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class and the other one might be the the top of uh of the world right so this is what I haven't done many to max with elite athletes because I I started doing them and they don't really discriminate and you do a view to max just to see ah your view to max is 82 or 81 or 78 sure that's great but that's not what differentiates you from the other athlete or discriminates and this is where you look at the cellular level and that's where you look at lactate and fat oxidation which are more sensitive of of both performance and also mitochondrial function than V2 max. I always say that if you put someone in a room without oxygen or very low oxygen for an hour, a very low concentration of oxygen, that person is going to come out fatigued in the first place, right? But then if you look at one alpha, right, which is the transcription factor responsible for EPO production in red blood cells, it's going to be off the chart. right? So you see the the precursor of the biogenesis of red blood cells. Right? Now, are you going to see an increase in red blood cells and hemoglobin? No, you're not going to see it, you know. So, this is why we have to be careful with these studies where they see precursors of mitochondrial biogenesis there. Yes, it increases the all the levels, but not necessarily might mean that the function increases. Most people still think of creatine as something only for athletes. But while creatine is certainly good for muscle health, that's only part of this mighty supplement story. Researchers at the

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supplement story. Researchers at the University of Kansas Medical Center are even studying creatine today for treating Alzheimer's with preliminary data suggesting that high doses around 20 gram per day can increase brain creatine levels by about 11% in Alzheimer's patients, which may result in improved cognitive function. While the data here is certainly emerging, it's a very positive early signal in a field of science that has thus far largely failed to find helpful interventions. My personal dose of creatine is 10 g of Momentous's creatine monohydrate per day, but I am open to increasing it to 20 g per day as more evidence becomes available. When I'm consistent with this, I notice faster recovery, better focus, and more sustained energy. And with Momentous's new lemon creatine travel packs, it is easier than ever before to stay consistent, naturally flavored, perfectly portioned, and simple to mix with water wherever you are. And every batch is NSF certified for sport, independently tested for purity, label accuracy, and banned substances. So, if you want a creatine that's clean, third party tested, convenient, and effective, look no further. Head to live momentous. com and use the code living proof for up to 35% off your first order. That's live momentous. com and use the code living proof at checkout for up to 35% off your first order. When we're thinking about zone 2 exercise in particular and mitochondrial function, you've spoken about the

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function, you've spoken about the exercise kind of stressing the system and and you become better at burning fats at a given intensity. How does this tie into terms that people may have come across like mitochondrial biogenesis or mitochondrial density? How what's actually happening within the mitochondria indigo that allows you to be better at utilizing fats? Well, it is not it's not just the density, right, or the number. It's is the function, right? And this is why we're looking into the mechanism. So, it's a mechanistic approach, right? rather than a a quantified approach of how many mitochondria you have or the density right and this is where we look in this study that I mentioned we look at the mechanistics and everywhere you look from the uh electron transport chain the complexes right you look at the MCT1's MCT2s you look at the MPC the makanopy carrier you look into oxidation of pyro oxidation of fatty acids you're looking at testing the function and the structure as well right and this This is the important thing. It's just having all the pieces working correctly. It's like you can have uh two people with the same muscle mass, right? And the same, you know, dimensions, but one person is going to be stronger than the other one. They have the same muscle mass, but the function how those muscles work is different. Right? So, this is I always think about Anatoli. you seen the the videos of uh the guy who's strongly

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videos of uh the guy who's strongly strong crazy strong right but I mean compared to the guys that that he he's not a big guy like relatively so it's not about the size or the density right it's the way his muscles function and work is incredible but it is not about the size right so I use that you know similarity with the mitochondria there's some great videos of him people can look them up you may have seen them where He dresses up as like a a cleaner in the gym and because he's not a big guy, he puts on this like oversized kind of cleaning uniform and he looks like he should have no business being in the gym and he wouldn't and he walks over where, you know, some big dude's doing like really heavy deadlifts and while that guy's having a rest, he kind of goes over and acts like he's cleaning and then all of a sudden he just like lifts up that weight like it weighs like 5 kg. and and people obviously observing and just like losing their Yeah, everyone freaks out. Anyway, worth worth watching. But I think those videos definitely kind of speak to the point that you're making there. Tying this this story back to disease prevention. So, we start doing more zone 2 exercise and and I might get you to comment on on how many minutes or remind us on the minutes per week that you think is a good base. We start doing more of that. We're getting the the mitochondria functioning better. We're we have some higher intensity exercise as well. We're getting better at res at

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as well. We're getting better at res at kind of shuttling lactate, recycling it. How specifically is that tied to diabetes for example? Like how is that protecting us against a condition like diabetes? Yeah. So what what I believe is that as kind of what we did in our study, we're looking at the different functions of mitochondria and the key things here are fat oxidation and glucose utilization and that glucose utilization is tied to the mitochondrial pyro carrier which is the whole thing is part of the envelope the mitochondrial lactate oxidative complex right and from the experience this is what I see that uh someone from diabetes or pre-diabetes as as we have shown in this study the The first thing that goes is not the glute force at the peripheral level or is not the hypoglycemia or hyperinsulinemia. The first thing that goes is what happens at mitochondria, right? And and as we've seen the the MPC, the MCT1, the MCT2, the complex one, complex 2, right? And that's the first thing that goes and we know that exercise is the best way to stimulate mitochondria. And within exercise from what we have learned from many years of experience that zone 2 works it's not the only thing obviously because you need high intensities and you remind me about the V2 max right that high intensity exercise is an excellent way to improve your cardiorespiratory adaptations to exercise. there for your V2 max, right? So, you need that

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V2 max, right? So, you need that intensity as well. But we have seen, you know, from empirical evidence that that zone 2 is the one that works the best in worldass athletes, in recreational athletes, in people with type two diabetes with cancer rehab. And that could be a good way to prescribe exercise for prevention and especially these populations that usually have acquired type two diabetes because that's that's the one thing these mechanisms that we are studying could be an explanation why type two diabetes doesn't happen overnight like cardiovascular disease or even cancer. Those are diseases that takes 20 to 25 years to show up. And during those 20 to 25 years, there are different events happening. They're not clinical yet, but there are cellular events that clearly clearly are taking that person to develop that disease. Right? So when someone is usually a type two diabetic many times or most of the times represents that that person hasn't exercised has been sedentary hasn't eaten correctly which makes the thing worse. If you can't metabolize glucose and you have more carbohydrates it's going to make the whole thing worse obviously but you know in that case you want to create sustainability which is another thing that we need to talk about when we talk about exercise prescription. So we're prescribing one exercise. Okay, we want that exercise to be sustainable. We don't want to do magic things in in six months or a year.

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magic things in in six months or a year. We want that that person can do the exercise for the rest of his or her life, right? So you need to have it's like a diet too. You don't want to prescribe an extreme diet. You know that does magic things as we know that all extreme diets work in the short term but in the long term you know 90% don't work. And what we want at the end of the day is is create that sustainability between diet and exercise. So that's when it comes to exercise prescription zone 2, it creates that sustainability. Anybody can do that, right? And if you throw some high intensity here and there, even better, right? But if you just prescribe only high intensity exercise to those ones who haven't exercised forever, I have barely seen that sustainability happening, right? And what you usually see is like people get discouraged, get injured and eventually they suffer. And I always say if if world workass athletes about 80 to 90% of their time of training they they train in lower intensities. They don't train high intensity in in 80 90% of their time. How can we are going to be thinking that people who haven't exercised in decades are going to do that? I firmly see the point you're making now and the results from your your recent study speaking to protecting against diabetes. If we think about diabetes, type two diabetes, there's this obviously very big kind of glucose intolerance component. And the bit that

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component. And the bit that I'm hearing today, which seems to be what's new information to me at least, is that this is not just a problem of getting glucose into the cell as you said, but it's further down the chain. And in the case as you get further down, how do you get pyuvate into the mitochondria? And if you a big part of improving that is through stressing that system with zone 2 training. That's that's what I'm hearing if I was to kind of simplify it. Yeah, any exercise could do that. Zone two maybe does a more refined job, right? But any kinds of exercise can do it. But again, highintensity exercise, it's probably not going to be as efficient. it will help you but in the long term you know you have to be careful with injuries sustainability. So for the person in a go who does have 200 minutes a week to to exercise to cardiovascular exercise what does that split look like zone 2 versus you know high intensity work and back to to my earlier question we kind of went down a different path for a bit there but is would it be more optimal to have high intensity and low and sort of moderate intensity in the same session or in different sessions? I think it's definitely possible to mix it up and I I mix it up all the time myself, right? I every ride I do like a few bursts of high intensity and it works well and also you feel the stamina right of the high intensity which is important to to do and also you have the benefits that possibly high intensity exercise it

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possibly high intensity exercise it stimulates the cardiorespiratory adaptations to exercise better than lower intensity right so I think it's getting the the both of the best of both worlds but the way I would do I try to shoot for 200 to 300 minutes I think that I mean 300 is ideal minutes per week. I know it's a lot in our society and most people can't do it. I even struggle to to have many weeks uh 250 but I try to do that but you know I try to do like a three to four days a week. I like the biking, you know. Uh and then I do uh about zone two the beginning maybe halfway through I do like a burst but not very high but maybe towards the end I do another burst and that that's what I try to stimulate both mitochondrial function and glycolytic function as well without the necessity of like just doing only zone two or only high intensity right and it depends on the terrain depends on where you live right if you live in a flat area or you go to the gym yeah you can do very just a steady steady. If you live in an area with very mountainous terrain, you know, it's going to be very difficult to to stay steady always, right? So those little bursts that you do are like 5 to 10 minutes in in duration or what is what does a burst look like? So I mean I like to do like on zone four, I don't like to go over zoom four and get to like near V2 max because I don't find it at my age and my level. I don't find it pleasant. Many other people find it really pleasant and that's what they want. I'm just happy to

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that's what they want. I'm just happy to have like that burst where like I have to work hard but without feeling the pain if you will, right? But that's my my own option like other people, right? But many others they prefer that high intensity. But yeah, I I think that burst can be in the form of like a zone 4, zone 5, maybe some sprinting. Those are great because you're going to stimulate that those glycolytic enzymes or those MCT4s transporters and it's going to be great for your muscle health in general, right? You have a more robust. Why just focusing on one system when you have can have a robust systems. But that being said, right, that that high intensity just just need to touch it and just touch it. You're going to improve it, right? Well, you need to spend more time and and we still don't know why, but I this is from my experience. you need to spend more time in the zone 2 area to improve there. Is it possible to stress the mitochondria and have healthy mitochondria and have good lactate clearance just doing resistance training? That's a great question which I forgot to to mention right that obviously resistance training is there's tons of scientific evidence obviously you know it's is I'm not even talking about it because we're focusing more on the metabolic aspect right but resistance is very important at least today's a week right and I think we need more research I don't have all the answers of course what I've seen at least is my empirical experience that I've seen more and more people with you know like poor metab metabolic function

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know like poor metab metabolic function that more that the person you know who just goes to the weight room and doesn't do more metabolic or cardiovascular training they look inside mitochondria when you do biopsy or when you do indirect test of mitochondrial function they look more like the sedentary individual then they would look more than the uh morally healthy mo morally active individual those ones who just do weights right now if you look at muscle bi biopsy they will have mitochondria right every where there's muscle there's going to be mitochondria especially if there's lean muscle right but again we will go back to the function and the function I haven't seen that is you can do much I might be wrong that's what I've seen for many years other researchers might might see otherwise but that's at least my my experience well that would be another another argument for not judging a book by its cover yeah absolutely and I I was surprised at the clinic at the university where I started to see several patients who were very bulky they did all the resistance and they they had metabolic syndrome and I man I couldn't understand why I was seeing more of them again I don't have the the quite answers and the questions but I think that you need in the same manner that if you you know to be healthy it's not enough with just cardiovascular training you need to do some resistance I don't think that doing just resistance training, we need to do also metabolic training.

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to do also metabolic training. Has your research or or any research you're aware of attempted to look at whether there's any sex differences here when we're thinking about mitochondrial function, fat oxidation, lactate clearance, and the interventions that that are kind of best at targeting these. I haven't looked specifically with the large populations of uh you know men and women but from from the experience you know working with many women right and men over over these 30 years overall I see two things women have lower glycolytic capacity right and this is something that is is what we see right they don't have the same power output they don't produce as much lactate as men and they have lower glycolytic capacity when it comes to fat oxidation. I am not sure about that. I I would say that overall they might and this is maybe from what I've seen that they might have a lower fat oxidation slightly lower but it's also depends on the level of the person and also what you compare with. I mean unfortunately women they're not as present as men in competitive sports. So when you see in competitive female with a competitive male you're not going to see it. I mean, we see it in I mean out there, right, in the competition. So, I'm not sure if it's it's a a matter of number of people entering the sport or this is a gender necessarily, right? For sure. I

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gender necessarily, right? For sure. I think that definitely the glycolic capacity is decreased and it's a huge thing for performance, but maybe the oxidative capacity in competitive females might be lower, but that's the thing I I still don't have the answer for that. But in the kind of elite cycling world, are men and women kind of doing different types of of aerobic training or is it pretty much across the board similar philosophy? Yeah, the philosophy is quite similar overall. You know, women now they because of the lower power output that they might be, you know, more interested in in doing more strength training, right? I think that they can be they can get a great benefit from that. But the principles are like bio energetic principles across the sports. I worked with many types of sports and the principles don't change in general at least at the metabolic level. You mentioned diet before and there is this idea out there that a low carb or ketogenic diet can be really beneficial for mitochondrial health. And I think at a high level, part of this theory is that if you kind of deprive the body of glucose and you deplete glycogen stores, you're sort of forcing the system to utilize more fats. So you're stressing the mitochondria in a similar way to what we're saying zone 2 training is. At least that's the the kind of concept. Is there any truth to that? By reducing carbohydrates in the diet, you're you're forcing the

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in the diet, you're you're forcing the body to utilize more fats. So, you are stressing the mitochondria, which then leads to some of these positive healthy adaptations. I don't think that a diet can increase mitochondria function. I haven't seen it. I think there are studies where it increases the maybe the markers of biogenesis, mitochondriogenesis, right? But we have to look into these studies with closely because the fact that you increase the biomarkers of biogenesis or even the biogenesis doesn't mean that you improve the function right I always say that if you put someone in a room without oxygen or very low oxygen for an hour a very low concentration of oxygen that person is going to come out fatigued in the first place right but then if you look at one alpha right which is the transcription factor responsible for EPO production in red blood cells is going to be off the chart. right? So, you see the the precursor of the biogenesis of red blood cells. Right? Now, are you going to see an increase in red blood cells and hemoglobin? No, you're not going to see it. You know, so this is why we have to be careful with these studies where they see precursors of mitochondrial biogenesis there. Yes, it increases the all the levels but not necessarily might mean that the the function increases. So when you say the function increases, what outcomes would you be interested in? And is there studies that have I'm presuming there are studies that have looked at a ketogenic or low carb diet and some of these uh more meaningful

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and some of these uh more meaningful outcomes of performance or performance related outcomes. There are multiple studies and laboratory data that it hasn't been published where you see in the metabolic carbs you see increased fat oxidation clearly right with a fat diet or especially like a carbohydrate restriction or ketogenic diet you see like a significant increase in fat oxidation in the metabolic heart but I honestly think that uh it is an artifact because it doesn't necessarily you're measuring fat oxidation and this is what I see So these metabolic carts when you measure fat and carbohydrate oxidation through gas exchange you're using the stochometric equations right. So when when you burn glucose, you utilize an amount of oxygen and you produce another amount of CO2, right? Which is higher than when you burn fatty acids, right? So when you burn fatty acids, you produce less CO2, right? So this these equations in the metabolic car are calculated with the gas exchange and they give you the re the gas exchange ratio. And the one thing is that it's going to give you a number. From there, you can calculate the fat and carbohydrate oxidation rates, which I've been doing for 25 years now. And it's been a great experience. But what I've seen multiple times is that when when you have lower glycogen content in your muscles because you're restricting carbohydrates, your

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restricting carbohydrates, your glycolytic capacity is going to significantly be reduced. Right? But high exercise intensities you cannot oxidize as much carbohydrates or glycogen break down glycogen. Therefore your VCC2 is going to be decreased right and therefore the gas exchange interpreting your your oxygen doesn't change your V2 you know doesn't change but your VCO2 your C decreases is lower than what it was under normal carbohydrate diet. So the the algorithm interprets that therefore you must be burning fat and this is why you say huge increases in fat oxidation in these people and we know that that fat oxidation is a sign of mitochondria function and let's say and I've seen multiple times let's say like at someone with a normal fat oxidation capacity is 0. 4 grams per minute that's their fat max 0. 4 programs per minute. Under these circumstances, I've seen up to one and that's impossible that you can go and more than double your mitochondrial capacity to burn m I mean fatty acids. I don't believe that because I've seen that it takes so much to you know to go from 0. 4 to 0. 6 that I don't see you can do it overnight but it happens you do it overnight. Likewise, if you go back to a normal diet and you replenish your glycogen stoages, you're going to see a sharp decrease in your fat oxidation, which I don't believe that is because of lack of mitochondrial function. So, I

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lack of mitochondrial function. So, I think it's an artifact. And we can also see it by the rear. These people usually don't get to an of one or so. And the lactate a way to see that this decreased lactate capacity is that the maximum lactate usually can be 9, 10, 11, 12 millm moles. In these people you see lactates of two, three, four, it means that they don't have glycogen. So the fact there's a sharp increase in fat oxidation I believe could be an artifact. Okay. So long story short, a low carb diet is not a substitute for zone 2 for stimulating our mitochondria. They seem to be different stimuli in terms of how they're affecting mitochondrial function. Yes, I I believe so. I sent you an email a couple weeks ago with a review that criticized the popularization of zone 2 training. And if I was to kind of summarize it, it was essentially saying, hey, you know, zone 2 training, it's been overhyped. It's based mostly on elite athlete data. And you said you had a few things to say about that review. So, I thought it's only fair for you to respond because I have seen, you know, influencers and a lot of people of course want to jump on these things because it gets a lot of clicks and and whatnot. What were your thoughts of of that review? Were there any fair points? Was it unreasonable? Well, I think like well that more than a review was like an opinion article, right? where it was caterized by the

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right? where it was caterized by the review and it's it's done by a PhD student who's part of the group that they have published extensively in high intensity training right so it's a group that it's a little bit biased as well as bias as I could be so I'm not you know but I don't think it was a fair article to be honest I think that they don't talk much about the benefits of uh what we have been calling for many years aerobic exercise there's plenty of research over the history of physiology ology showing increases in mitochondrial function by looking at oxidative enzymes looking in performance looking in oxygen consumption and also I think that they mis misunderstand maybe the meaning of that zone to training first of all it's not an easy training it depends on your level but if you look at the best cyclist in the world we're talking about 280 300 watts of intensity which more most mernals for one minute 300 watts right super high intensity it would be a heat training right for most people in fact right which it shows that it's not easy at all and the second thing that mentioning earlier about and I don't want to be controversial about this because I wear the two hats as a scientist and I've been a coach for many years but yeah I think it's important that you know like not to neglect what's happening at the real world. You know,

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happening at the real world. You know, if you look into rowing competition at the highest level, running competition, whatever that intensity is, a triathlon at a soccer practice, you're going to see low intensity exercise intensity training period. obviously heat I mean and I've been seeing throughout the podcast right that it's very important to have high intensity training and that you never win a race in the low intensity training but from that to to really kind of neglect right what happens in the real world you know and and what happens and neglect the people who are working in in the trenches you know and they're in that battlefield with athletes always you know I think it can send a wrong message that can be wrongly understood by many and say oh yeah when we don't on to at all. You know, this is uh only high intensity training I think is is not the right thing. I mean, obviously it's it's an opinion, right, more than like a review. That being said, right, I think that and one this is something that we need to work scientifically into the mechanisms, right, of what zone 2 does. I've seen it, you know, throughout 30 years and many others see it and I have uh I get emails from people from around the world every day thinking about how has improved uh their lifestyle. But I think we need to to really look into the scientific, you know, mechanistics of what what it does versus zone three or zone four or zone five. I would love to have the the budget or I would love to someone else to have the budget and do it.

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and do it. Yeah. When I read that review, I thought this is what happens when we live in kind of either or thinking or we ask the wrong questions. Cuz if you ask the question, what's best or best for what? And and I think you've done a beautiful job of explaining today that there are different stimuli affecting different parts of physiology. And rather than having this kind of living in this eitheror world, we can entertain this idea of well perhaps having both is the best outcome and having some type of multi-modal kind of training like you explained that what you do is the best of both worlds. That's a little bit less controversial though, so I can understand why this kind of debate continues. Last question, Indigo. I do think that some people may look to long populations like blue zones or other parts of the world where there are examples of people who seem to avoid metabolic disease or be at low risk of metabolic disease and and live quite long healthy lives and they're not necessarily doing dedicated cycling or zone 2 training or lifting weights or or sprinting. Is your view that these populations could be even healthier with more prescriptive exercise and a greater exercise stress? It's a great question and I don't think I have the uh the answers right. But I think that these people they

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but I think that these people they never stopped moving, right? If you look at a at at a toddler, their uh ability to produce energy is amazing, right? They can't stop moving. They might have they must have an ability to produce ATP that is is from out of this world, right? And then we grow and we start playing on the streets and doing all kinds of errands and we never stop moving. That's normally not anymore but when we were kids or our parents or our grandparents that was their lifestyle and these people in these blue zones are high longevity areas a typical characteristic they never stopped moving. They never became sedentary in the first place. And in light of of our study that we're we're showing is that yeah sedentary individuals even they're healthy their mitochondrial function has decayed significantly. Now these people's mitochondrial function I would love to poke their muscles and then take a sample for sure. I have no doubt that their mitochondrial function is excellent because they it never stopped decaying which happens also to those ones in many other societies that they've been fed forever. when you've been fit forever and you never stopped moving, any exercise is going to work for you because you're always fit, right? That being said, as you said very well, can you improve it? I think so. You know, I I really think that if you're a super fit athlete and you have never stopped and you're 35 years old, can you improve your PRs, your, you know, your your personal best? For sure.

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know, your your personal best? For sure. if you do like a more specific training using this stimulating these training systems that we have. So I think that can be applied to these populations in the blue zones for high longevity. But I think the key thing is that they never stopped moving. And this is the problem that we have in our society that people became sedentary or lose their fitness because they only exercise 50 100 minutes a week and they stopped decaying. And that muscle plasticity and the mitochondrial plasticity is enormous and you can get back to to a very high level through the exercise. And this is what I think is a wonderful drug. I've seen multiple people over the years that been very inspiring. People always remember this. This person was 83 years old and or 82 I forgot 83. He was the world cycling champion. And uh believe me there there's like a category 80 to 85. He was a world champion and his metabolic parameters were those of a 35 year old person. I couldn't believe what I was seeing. I was like you got because to to your question at the beginning right like I have like a a different tiers right of what different performance levels are from metabolic syndrome or disease to work class. This guy was in the category of like a 35 year old healthy individual, right? I couldn't believe it. And he didn't exercise until he was 50. He was obese. He was smoker. He was eating crap. And

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He was smoker. He was eating crap. And when he was 50, something hit and he started to train very seriously. And I think he was also had the time to dedicate time for training, right? But yeah, in 30 years he was the best in the world and was able to reverse his metabolism back to someone in the 30s. I've seen it multiple times. Not that extreme, but I've seen the typical person in their 50s who are struggling week after week with to keep their level of fitness. They're not super fit, but they do exercise. And in the moment they pre-retire or they retire at an earlier age, within one two years they revert their metabolic age 10 years. That's that's unbelievable and really really truly inspiring that exercise is a great vehicle for longevity. Yeah. Wow. That's a a great example. I think that's a a pretty motivating and optimistic place to land the plane here today. In Indigo, I'm sure there's a few listeners right now who are tying their shoelaces on their joggers or or runners and about to hit the pavement. Is there anything that you you think we missed or that you wanted to add to before we we close this out? Oh, I think like uh not that you did a great job at asking very good questions and put me in the corner a few times. I think I appreciate it. It was uh very fun and I really appreciate this time. Well, once again, thank you so much for for being with us, Inigo. Our last episode, I think to date has north of half half a million listens on YouTube alone. So, that was tremendously popular. I appreciate your dedication to

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popular. I appreciate your dedication to science and taking the time to be with us again today and you're welcome back anytime. Well, thank you so much uh Simon for having me back. I really appreciate that uh what you're doing also like informing so many people around the world and uh yeah, just inspiring them and and keeping a healthy lifestyle. So, I appreciate and it's a it's an honor to be part of this movement, too. Thank you. There you have it, friends. I hope you enjoyed this episode. If you did and want to stay up to date with future episodes, be sure to hit that subscribe button on YouTube and follow on Apple or Spotify. Finally, thank you for showing up and the effort that you're making to take control of your health. I look forward to hanging out with you again in the next episode.