I tested once in the laboratory on an 80 or 81-year-old gentleman. I thought, "Boy, you've been doing sports all your life, right? So, man, you chose the right lifestyle, right?" And he told me, "Actually, no. Actually, until I was, uh, in the early 50s, I was obese, I was hypertensive, I used to smoke. I had a very poor lifestyle. I didn't exercise a lot." And one day, I started to ride and bike and think about life and things like that. And ever since then, this was an individual in the early 50s, uh, sedentary, very poor, healthy lifestyle. And then, you know, 30 years later, at 81 years old, his metabolic health was that of someone in their 30s who's healthy. That's unbelievable. Hard to believe. And this is how that that person, obviously an 81-year-old, that's an example of what exercise can do for your longevity, right? That person was not on any medication.

Hey friends, in today's conversation, I sit down with Inigo San Milan, PhD, from the University of Colorado to talk about exercise, specifically moderate-intensity cardiovascular training, otherwise known as Zone 2 training, and how this type of exercise affects metabolic health. This episode is extremely detailed, which is exactly what I had hoped for. Dr. San Milan is one of a few across the globe who is truly an expert in this field of science. We're very lucky to have had this time with him, so I wanted to ensure we went deep on a topic that is absolutely critical to optimizing our health span and longevity. If you do want to skip through some of the more nerdy scientific basis for Zone 2 training and jump straight to the practical stuff, fast forward to about 90 minutes into this conversation, where we begin talking about how an individual can set up Zone 2 training. I will also be doing a follow-up episode with Drew Harris, exercise physiologist and regular guest on the Proof, to further summarize the practical takeaways from today's episode on Zone 2 training. So no stress if things don't land the first time; it's a lot to take in over one conversation. I hope you enjoy it. This is me and Inigo San Milan, PhD.

Something that I think we'll talk about at various points today is metabolic health. What is, what is your definition of metabolic health, and why should the listener care about this?

Yeah, that's a good question. And I think this is, this is something that we're, um, understand more and more, right? As, as, you know, and, and many people know, right? The traditional, um, definition of metabolic health is the compendium of, um, multiple parameters like your lipid profile, your blood pressure levels, uh, your glucose levels, right? And your body mass index, or at least your, uh, waist ratio. So, um, circumference. Sorry. So, but, but as, as we know more about the adaptations or what happens at the cellular level, right? We are getting to, to an inflection point in the, in the field of, of medicine where, um, metabolism has gone from being the, the poor brother to being the, the Crown Prince, right? Right. I mean, you look at the curriculum of medical schools, um, uh, even still today, they barely have any courses, right? Or notions of metabolism at the cellular level. While at the research level, the advances have been immense that we can already use to help people, as well as to understand diseases at a level that we have never been, right? So, so this is why metabolic health implies more mitochondrial function in place, also more fitness in place, longevity, right? So people nowadays are not happy just to have good cholesterol levels, right? Or, or good blood pressure, right? Or good A1C or, or glucose levels, right? People want to be fitter, want to live longer, not necessarily in the amount of years because we all want more, but to live better, right? And, uh, and want to be healthier. So all these, I would put it in the new basket, if you will, of metabolic health.

A lot of your work seems to focus on how efficiently we can take the, I guess, potential energy in food, be it carbohydrates or fat, and turn that from chemical energy into a mechanical energy, contract the muscle, and move the skeleton. Do you also consider sort of fuel partitioning? You know, I'm interested in some of Professor Roy Taylor's work. I'm not sure if you're familiar with him and his work looking at type 2 diabetes and this concept of personal fat threshold being sort of integral to metabolic health, in that, once we kind of spill over or store fat beyond our subcutaneous fat capability, it starts to get in between and within organs, and that seems to also be a sort of key component of metabolic health.

Yeah, absolutely. There's no doubt about it. That's a big component. Um, abdominal fat is, is highly associated, uh, with cardiometabolic disease. And also, uh, there's more and more research. One of the leading researchers is, uh, I call it here at the University of Colorado, Dr. Brian Bergman, with his research in the intramuscular fat, which is highly, and, and others, right? They have, they've been doing research, extensive research on this, linking that intramuscular fat with the, uh, insulin resistance and type 2 diabetes as well. So, yeah, definitely fat, the connection between fat and, and metabolic diseases is there for sure. And we are doing already in our laboratory, and, uh, yeah, which we can talk in more detail later, if you want.

Sure. How much of your understanding of, of how exercise specifically influences metabolic health has come from your work with elite athletes? And why, why are elite athletes sort of this, a good model for studying metabolic health?

Yeah, that's a good question. Thank you. So, I always say, it's difficult, or, or, or, or not very, you know, it's difficult to understand imperfection. You wouldn't know perfection in the first place, right? So, um, and elite athletes are that the perfect machines. They're perfection. And, uh, they're the Ferraris or the Lamborghinis, right? So from the lessons that we have learned from working with the perfect machines, we can understand or have a, uh, a reference of what perfection is, so that we can understand imperfections. So this is why I've been trying to bring forth for, for a couple of decades into the clinical space, right? To push, to try to understand, I mean, to try to bring the lessons that we have learned working with elite athletes so that we can understand different diseases better, as well as the application of different interventions, like exercise, especially, and, and also even nutrition.

How much of the sort of cardiometabolic disease burden that we see today do you feel is, is explained by sedentary lifestyles and a lack of, of specific cardiovascular training versus other things like nutrition, which you just mentioned?

So, I, I'm gonna wear my, my, uh, cell physiology background, right? And try to see this from, from a decrease in mitochondrial function or a decay in the mitochondrial function. So, the mitochondria, you know, is, as we know, the powerhouses of the cells. And this is how we have been learning about that for, for decades, right? However, not until, until recently, relatively speaking, we've been very interested in mitochondrial function. And now, what we see is like, pretty much no matter which medical field you get into and you talk to leading researchers, uh, in, in, in multiple medical fields, everybody's stumbling upon mitochondria, right? In mitochondrial function. Now, when it comes to cardiometabolic disease, um, there are two main events that happen, um, when it comes to nutrition. One is the metabolization of, uh, carbohydrates and the, uh, and fats. So, um, um, during postprandial conditions, after a meal, um, about 80% of all carbohydrates are burned or metabolized in, in skeletal muscle, right? Uh, and it's time to really call skeletal muscle an organ. It's probably the largest organ in the body, and it's very important to, to see these. Because within skeletal muscle, uh, at rest, carbohydrates, which are turned into glucose in the blood, no matter what type of carbohydrate you have, whether it's good or bad carbohydrates, they're all going to become glucose in the blood. Like fructose, most of the fructose that you ingest is converted by the liver into glucose, right? So all that has to be metabolized. And under resting conditions, about 80% are done in, in skeletal muscle. And within skeletal muscle, this happens in mitochondria. So if you have a dysfunctional mitochondria or, or a mitochondria that is impaired, you're going to have a metabolic challenge because you're going to have to burn that glucose. And if you don't do it correctly, eventually you're going to have a problem because that glucose is going to be building up in the blood, causing hyperglycemia, high blood glucose levels. And the pancreas reacts to that because it's dangerous to have high glucose levels. And the pancreas reacts by releasing insulin. And insulin triggers the, uh, the transportation of glucose inside the cell. But it's not just about the transfer of glucose inside the cell, which is what we've been hearing for decades, right? The world of type 2 diabetes has been involved more at the peripheral level, if you will, at the level of hyperglycemia, insulinemia, or hyperinsulinemia, insulin resistance, even GLUT4, which are the transporters of glucose that are stimulated by insulin, right? But we need to start talking about pyruvate and about the fate of glucose inside the cell, because this is absolutely key. Because one thing is to transport glucose inside the cell, and the other thing is to metabolize glucose to ATP and energy in mitochondria, or inside the cell, right? So this is the key aspect.

So there's two sort of critical things here we're talking about with regards to glucose and metabolic health. One is the ability to get glucose from circulation into the muscle cell. And you sort of alluded to the fact that that's been the story for a long time. And earlier, you spoke about intramuscular fat, and so to my understanding, part of that story has been that as fat starts to accumulate in muscle tissue, it can make it harder to get glucose into the cell. Yeah. But what you're adding and saying is that the story of metabolic health and glucose metabolism, and the difference between someone with poor metabolic health and an elite athlete, goes beyond that. And we need to begin thinking about, once that glucose is within the cell, how it is being metabolized, which I believe from, from your work, and it's something that we're going to discuss, comes down to the function and health of the mitochondria.

Exactly. And, and, and then the problem is, like, if you don't metabolize that glucose in mitochondria, inside the cell, within mitochondria, then, uh, you have a metabolic challenge. And eventually, yeah, you're going to increase, uh, or you're going to elicit a condition of, uh, hyperglycemia, hyperinsulinemia, eventually insulin resistance. But the same thing, and the same thing happens also, or the same metabolic, uh, problem happens with fats, because, uh, fats can only be oxidized in mitochondria as well, right? So when fats cannot be oxidized in mitochondria, they build up. You cannot utilize them as energy. So you store them. You store them in adipose tissue, but you also store them adjacent to mitochondria in, um, in the muscle, right? And that eventually increases their reservoir or the deposits of, of fat inside muscle, right? Which is again, as I said, at the beginning, right? It's highly related to insulin resistance, right? And, and that could be a connection between cardiovascular disease and type 2 diabetes. We know that about 80%, not 8%, I don't want to say a percentage yet because we still have to learn more, but a big, a big number of people who take to diabetes, they also have cardiovascular disease, and vice versa. And this is what's been now termed more like a cardiometabolic disease, right? Because it's the combination of both diseases, right? So, so this is what, uh, probably a big nexus for this is, uh, it happens in, in mitochondria.

Let's define the term "metabolize." I know that term gets used a lot, and it's certainly, uh, sort of widely used within the literature talking about mitochondrial health and energy metabolism. But we may, we may take it a little bit for granted. And perhaps someone's, you know, wondering, what does that actually mean to metabolize something?

Yeah, so it is, it is to, uh, convert to energy, right? So, um, the food that we have, we, we, uh, we have, right? We need to metabolize them to energy. So, and, and we live in, and for, and that happens in mitochondria. So if you cannot metabolize it correctly to energy, uh, you are going to pose a metabolic challenge to that cell, and because it's not going to be able to convert it to energy efficiently. So it, either it's going to be building up, right? Uh, and, and as in the case of fat, it's not good that it builds up around muscle. It's indicative. If it is in the case of glucose, because it's, it's an immediate challenge, metabolic challenge, because you cannot have high blood glucose levels because it can be dangerous, right? Um, um, and another thing that happens too, is that when glucose cannot be metabolized correctly inside mitochondria, my pyruvate, pyruvate turns into lactate. And lactate is a key metabolite for, it's a signaling molecule. It's one of the most important signaling molecules. And this is that the work, the 52 years of work that my colleague and mentor, George Brooks, from Berkeley, has been doing. Pretty much everything we know about lactate is because of him. And now the implications of, of lactate in health. So we know that lactate is a great, um, signaling molecule that is probably very important for cellular homeostasis. But when it builds up and is, is too much lactate inside the cell, it, uh, becomes detrimental to the function of the cell. And, and we have seen that in different research that we and others have done. Um, but that's, that's the problem of not being able to metabolize nutrients efficiently. And this is happening already in, as a big part of Alzheimer's. Alzheimer's has been historically only focusing on, um, the, uh, the amyloid plaque, uh, and, um, which is there, of course, and is highly related to the progression of the disease. But the whole thing is that every single drug against the amyloid plaque has failed. Now, that has led to many researchers to try to look into different angles to understand Alzheimer's. And one of them has been insulin resistance and mitochondrial dysfunction in, in Alzheimer's, which is a, it's a hallmark. Before it was, it was daring to even mention that, right? The connection between Alzheimer's and diabetes, or called type 3 diabetes. But it's a, it's now highly widely recognized as a hallmark of diabetes, insulin resistance, and, um, mitochondrial dysfunction. So there's a big problem for Alzheimer's patients to metabolize glucose as well.

I want to put a pin in lactate and come back to it once we've kind of walked through the different energy systems that the body is using and how this may change at sort of different exercise intensities. I know there's a whole sort of lactate, lactic acid story, and I've heard you before sort of clarify a few things. So I think it's important that we do come back to that. Another term I want to define here, Inigo, at the outset, that is thrown out a lot, is metabolic flexibility. What does metabolic flexibility actually mean?

Yeah, so, uh, the, yeah, the term metabolic flexibility, um, it's not a new term. We are starting to use it more, right? But, it's a term that it was coined over, uh, of 25 years ago by, uh, Kelly and, uh, Mandarino, as well as Goodpastor. Um, and, and, and even before that, in the late 1700s, um, um, it was thanks to the work of, uh, Lavoisier, who, uh, started to look into aerobic, um, metabolism. And, um, so he started everything related to, uh, cellular respiration. But the, the, the, the term metabolic flexibility, um, in a very, uh, simple way, is the ability of humans to, to, uh, burn fat and carbohydrates and to, to switch back and forth. So when there is a carbohydrate availability, um, like elite athletes, for example, or, or fit individuals, they can use them very rapidly for energy purposes, and they metabolize it very rapidly. Um, when there is not much carbohydrate availability, then you switch very well and very efficiently to utilize, uh, fatty acids for energy purposes, or when you're fed, fatty acids, you can metabolize it very well, right? And all that happens in mitochondria, where most of that happens in mitochondria. And at rest, everything happens in mitochondria. During exercise, it can happen in the, in the cytosol, so while it's inside the cell, but not in mitochondria, right? Because you can use it through the, uh, aerobic glycolysis. But, uh, during, uh, rest, under resting conditions, yeah, everything happens in mitochondria. So that's again, it's at the epicenter of metabolic flexibility. So people who are, you know, metabolically inflexible, there are people who cannot metabolize fatty acids or glucose properly, right? And therefore, yeah, as we mentioned earlier, it, it's going to pose a metabolic challenge because you can increase blood glucose levels on one hand, has also increased the fat deposits in the muscles, as well as then in the adipose tissue.

Inigo, is it, is it those things that are driving the increased risk of conditions like fatty liver disease and type 2 diabetes and cardiovascular disease, or is it the building up of lactate and other changes that are occurring, or is it sort of a, a coalescence, so to speak, of all of these factors?

Yeah, I think, I think there's a lot of, you know, multifactorial, right? In, in these processes of diseases. But, uh, many of these elements are, are, are working together. Um, I, I really think, and it's my opinion, that everything starts by a mitochondrial decay or a metabolic dysfunction. And where, as we mentioned, it's, you cannot metabolize nutrients efficiently, which can lead to, uh, disease. Because, yeah, again, hyperglycemia and increased fatty acid storage. But the, the, the, the, the core question for that is like, where the, what causes that mitochondrial dysfunction, right? So, what, what happens in mitochondrial dysfunction? The main element that we know, besides, uh, infections, or besides mutations that can happen, right? Um, at the, at the level of acquired, uh, decay of mitochondrial function, is like physical activity. Is the main mechanism. In the same manner that we know that the only thing that we know that exists to improve mitochondrial function is exercise. The same thing happens when there's a lack of physical activity. Yeah, mitochondrial function is going to decay. So when you have, as we have, an immense majority or immense amount of population who are not physically active, to have a lot of mitochondrial dysfunction or decay happen in this population, combined with an excessive amount of food that we have. So that's an, an explosive mixture, right? That eventually, it is going to lead to disease, right? So if you have poor mitochondrial function and you, you add more glucose or carbohydrates that you're, you're adding, yeah, you're just adding gasoline to the fire. And likewise, and this, this, you're going to see rapidly because it's an immediate metabolic challenge. You need to deal with that right away, right? Because you're going to have high glucose, blood glucose levels. But with the fat, it's not an immediate challenge. It is stored, but it keeps being stored. Stored. Down the road, it's going to lead to disease. But I think everything happens by, by a mitochondrial decay due to a lack of physical activity, right?

So for the average person in Western developed countries, the current lifestyle is kind of stoking this metabolic fire in in two directions. One is that that lack of stimulus to keep the mitochondria healthy, and as you say, leading to mitochondrial decay. And I know that your work has looked very specifically at how can we exercise with intent? How can we provide the best stimulus, which we're going to get to, which is the practical side of this conversation? But then the fire is also being stoked through the consumption of a diet that is leading to excessive calorie consumption and, and frankly, I guess, energy toxicity to an extent, too many calories beyond the person's requirements.

You've mentioned, you've mentioned the word "aerobic" a few times, and we've been speaking about mitochondria. And when I hear the word aerobic, I think about oxygen. I think about energy being produced in the presence of oxygen, and this occurring in the mitochondria. Can you explain how this works? I think that most people appreciate the importance of oxygen in sustaining life, but but maybe do not fully appreciate how oxygen is involved in the production of energy.

So, I mean, oxygen is, it's, it's necessary, right? At the, in, in doing them, what we call oxidative phosphorylation, right? Which is the production of ATP. Oxygen needs to be present, right? Um, um, but that's, that's at the very end spectrum of the, of that, of the chain, right? Of events of metabolizing a nutrient, right? So, that's what, you know, like most of the energy, um, metabolize nutrients, metabolites are under aerobic conditions. However, we, we've been having, you know, that this idea that when you exercise, uh, at high intensity, it's anaerobic, right? How many times we hear that, "Oh, I was doing anaerobic interval training. I was I was anaerobic really hard today, training for 20 minutes." When that's not anaerobic, right? And this is what I think it's time to, to, to kind of change a little bit the perception of these more from an energetic standpoint than from an oxygen standpoint. Because everything, pretty much up until VO2 max, until you reach your maximum oxygen consumption, which is almost your maximum effort, is aerobic, right? Beyond that point, uh, yeah, it's, it's, it's, uh, ATP cannot be synthesized, right? With the help of oxygen, and it needs to be, the ATP that is stored in the muscles, it needs to be utilized for energy purposes, and that does not require an aerobic metabolism. So that's why it's called anaerobic, right? Exercise. But everything up until then, it's aerobic. What it changes is the types of fuels that you use. So within the big range of aerobic metabolism, you can use a lot of fatty acids and then not much carbohydrates, or you can use a lot of carbohydrates and not much, or not many fatty acids, right? So that's the key point. You know, what is the fuel that you're using, right? Within the whole, um, um, aerobic room? Because that's going to determine, um, what is going to be the metabolic outcome, as well as, uh, for energetic stimulus and cellular level, what are you going to stimulate? What metabolic pathway? What type of bioenergetics are you going to stimulate with one exercise intensity or another? Right? You're still stimulating aerobic metabolism, but you might elicit different changes at the cellular level with different exercise intensities.

Okay, so let's, let's step through this as intensity is increasing, so the listener can appreciate what changes are happening with regards to the substrates that are being used to produce energy, where that energy is being produced. And Inigo, it may make sense here to start introducing zones. I think people have heard, you know, Zone 1, Zone 2, Zone 3, Zone 4, Zone 5. So if you think it's a good idea, perhaps as we're talking about the changes that are occurring with regards to how energy is being produced and where it's being produced, we can kind of pair that with the zone/intensity.

Yeah, I mean, again, the way I see zones is from, you know, like a cellular metabolism glasses, right? Um, uh, what, so I see, for example, this is also based on the muscle fiber recruitment pattern, which is going to also, um, uh, elicit different fuel utilizations and fuel partitioning, right? So when we start exercising very easily, like a very easy walk, for example, or a very easy bike ride for those ones who are fit on the bike, the body prefers to use fat for energy purposes. Now, that doesn't mean that we don't use glucose, right? Because we also use glucose. There is a misconception that at low intensities, we do not use glucose. We do use glucose. And this is, I've been for almost two decades, measuring in the laboratory, fat and carbohydrate oxidation rates at a wide range of exercise intensities. All the exercise intensities seen in grams per minute, how much, how many carbohydrates and fatty acids you burn or oxidize at different intensities, right? Which has helped me tremendously to understand the bioenergetics and metabolic map, as I call it, of whatever the series of events of different intensities. So again, at a different, at a slow intensity, we deploy a lot of the fat, um, and then we use a little bit of glucose, right? It's very low intensity, and we, we deploy, we recruit the slow-twitch muscle fibers. That's what I call, uh, Zone 1, right? And again, when it comes to zones, the multiple zones, people have different, um, terminologies and and interpretations. So I'm just giving you mine, right? So, so then as exercise intensity increases, then the muscle contraction gets faster, right? And stronger. So it, it needs a higher metabolic demand to produce ATP. So that's what you start burning even more fat, right? But you also start burning more glucose, also, but not as much, uh, fluctuation in glucose, uh, utilization as it is in fat, right? So, and this, this glucose at this stage is being being used to produce energy within the mitochondria. All of this is still occurring in the mitochondria, normally? Yes, because it's, uh, the glycolytic flux, as we call it, allows the velocity of the glucose to be used through pyruvate in mitochondria. Yes, although some is reduced or transformed to lactate in the cytosol of the cell, and therefore, there's a little bit of lactate production, which also coincides with this intensity, little bit, which is about baseline levels or a little bit above baseline levels, right? But, but this is where, um, at this intensity that I call Zone 2, this is where you, um, uh, reach a point where you oxidize the highest amount of fat, right? And, and this is a key point because fat is oxidized exclusively in mitochondria, right? So when you reach a point where you achieve the maximum fat oxidation, it's that, yeah, you're putting those mitochondria to work at that bioenergetic system, which is the fatty acid oxidation and oxidative phosphorylation, to to the max. So this is what I use this Zone 2 to prescribe exercise. This is what I see that this is where you oxidize the most amount of fat. So we can see in many people when we do this test in the laboratory, we can see that this, we can translate this into a heart rate, for example, or into pace or into power. So that is the exercise intensity that releases the highest fat oxidation.

Then we, we start, we continue increasing the exercise intensity, and the metabolic demand, it becomes even larger, right? So you need to produce ATP faster. And this is where there's an inflection point where fat cannot continue producing ATP at the same rate as before. So this is where glucose is, um, called in at a higher rate because ATP from glucose is produced significantly faster than from fat, right? So that's when glucose starts to be recruited. And then you see in, in the laboratory at this intensity, you see that fat starts to drop significantly. There's a significant drop in fat oxidation, and there's a significant increase in glucose oxidation or utilization. And, and at the same time, you see also an inflection point also for lactate, because lactate and glucose go together, as I was saying earlier, it's about glucose flux. The higher the glucose flux into the cell, the higher the lactate accumulation, right? So, so this is what's starting to happen in this Zone 3, that I call, which is a transition zone, before we enter a whole different, um, bioenergetic terrain, which is glycolysis, right? Or, or, yeah, with the glycolytic system. So this is when exercise intensity is now so hard that fat can no longer provide ATP, or, or, you know, like, or be associated for ATP production, right? And this is when you need to, uh, start deploying, um, um, I mean, carbohydrates and glucose. And this is what we see that at this intensity, fat oxidation completely disappears. It's gone. At the same time, you see a big increase in glucose oxidation and a sharp increase in lactate, because the glucose flux. And this is also what lactate also has the, uh, endocrine, paracrine, and autocrine functions. So the endocrine function of lactate is that when it accumulates in the cell and cannot be metabolized in mitochondria, it goes to the blood. And it goes to the blood, it inhibits lipolysis, which is the breakdown of fatty acids from adipose tissue. So when it inhibits lipolysis, you're not going to be able, in the first place, to bring the fatty acids to to the muscles to be burned. Right? And then secondly, and we have published this recently, two years ago, that we saw and we demonstrated that lactate as an autocrine, um, function, it also inhibits the fatty acid transporter. So in, in the muscles, fatty acids, they have a door, which are the CPT-1 and CPT-2, in my, in mitochondria, outside and inside mitochondria, they transport fatty acids, right? So lactate inhibits both doors. So when you have a high glycolytic flux and you use a lot of glucose, the fat disappears for several reasons: first, because of necessity to produce ATP, right? At a faster rate. And second, because of the actions of lactate on both adipose tissue and also on, on the transporters for fat. So it's a way to, to feed-forward mechanism, right? To, to kind of get fat out of the way and say, "Hey, fat, you're done. Your job is done. Now we go into glucose." And this is what I call the Zone 4, right? Or people call also lactate threshold, although there are many interpretations of lactate threshold, also of our FTP, functional threshold power, etcetera. Right? And then, but all this is aerobic. All this is 100% aerobic metabolism, right? Although this is what I was mentioning earlier, the misconception is like we're already in the anaerobic state, and that's why people call it anaerobic threshold. We're still aerobic, right? Then we move on into the next, uh, phase, which is, it's, it's an intensity that this is where you reach your VO2 max. This is an intensity where, uh, uh, you max your aerobic capacity, right? Your lactate is off the chart, your, your glucose utilization and the glucose flux in, in the cells are off the chart. There's no fat oxidation either, but you're, you're at the intensity where you, um, uh, have the highest aerobic capacity. And, and this is the VO2 max, and I call that the Zone 5, right? And then lastly, we call, I call the Zone 6, which is pure anaerobic. This is when we're talking about sprinting or about efforts that last two or three minutes, right? Where, uh, that oxygen that you were referring to earlier is not enough, or even glucose is not enough to maintain, I mean, to synthesize ATP, and then the muscles, they need the ATP that's stored in the muscles already without the need of oxygen.

I have a lot of questions. That was beautifully explained. Let me, let me try and summarize some of that, and you can let me know if I've got anything wrong. But at at lower intensities, the body is is using the oxidative phosphorylation system, this aerobic energy production system, whereby energy is being produced within the mitochondria. And at very low intensities, that's primarily, but not exclusively, being being done by using fat as the substrate. There is some glucose. And that's fat is predominating as the substrate of choice at sort of Zone 1 and 2. And then as you start to go up above Zone 2, you start to see an increase in the amount of aerobic glycolysis, so using glucose to produce ATP within the mitochondria. And the oxidation of fat starts to go down as you go up from Zone 3 to Zone 4. But all of this is still aerobic. And then once you go into Zone 5, you start to get this anaerobic glycolysis, so we're now able to produce ATP from glucose without the presence of oxygen. And then above that, is that where the phosphocreatine system would kick in? The the sort of third energy system?

Yeah, the ATP-PCr, yes. Exactly. Is what's stored in the muscle already and it doesn't require oxygen for that. Yeah. And that's the pure anaerobic system that we have, right? Everything else is aerobic. There are some like, uh, sparks of anaerobic metabolism, right? But, but yeah, this is like the predominant is always aerobic.

So I have a few questions. The first is, for a given amount of oxygen, is it, is it accurate that we can produce more ATP from glucose than from fat?

Well, I mean, more rapidly. The, the, the, the important aspect, and this is why there's a transition, right? It depends on the muscle fiber recruitment pattern. The way I would approach it is like, how fast can you produce ATP? That's going to dictate, uh, the fuel that you use, right? So ATP, so from, I mean, derived from fat is significantly much higher amount, uh, from of ATP derived from fat than it is from glucose. However, it's significantly slower. So that's why when you're in the lower intensities, recruiting the slow-twitch muscle fibers, you, uh, yeah, you don't, you don't need to oxidize or use so much glucose as at high intensities, where then fat cannot be oxidized because it's not fast enough, and you need to switch to a different fuel, which is the glucose, right? Which gives you significantly less amount of ATP total, right? Per mole oxidized, but it gives you a much higher amount of ATP, which is why the muscles need that fast contraction, and that's why you have the fast-twitch muscle fibers.

So why does the body prefer to use fat at lower intensities? Is that, is that a survival adaptation? Just that there's more potential energy in the form of fat available in the body, and it makes sense to conserve energy from carbohydrates for when you need to shift into a sort of higher intensity to escape predation, for example?

Yeah, absolutely. And, and this is, this is the, the one thing, you know, the way we store food, right? So carbohydrates are like gold, right? That, that the body can only store about, uh, 500 grams, you know, of carbohydrates. Whereas, so we're talking about that's a, uh, 2,000 calories, you know? Whereas the, the, the skinniest individual, can store more than 10,000 calories from fat, right? Because fat is everywhere, right? So, uh, it's kind of, in a way, fat is in a, it's kind of an unlimited source of fuel, right? Whereas, uh, carbohydrates or glycogen, right? That's how we store like carbohydrates, as you know. So glycogen is a very, very small storage compared to fat. So that's why it's gold. And this is why, uh, yeah, which is that, as, as our evolution, you know, we're, uh, aerobic creatures, we're slow, in general, creatures, right? We walk a lot, or we run at a low pace, right? And we can even beat horses in long endurance, you know, because we're more efficient metabolically speaking. The horse has a lot of, um, um, fast-twitch muscle fibers. We have a lot of slow-twitch muscle fibers. And those mechanisms, as they allow us, like, um, I cannot cite the research now, but, uh, but there's been a few studies on, on how, and, and competitions are very long competitions, like, like a 100 miles or so, where of a horse versus a human, and a human can get to beat the horse, right? Obviously, bigger for both. But anyways, that you still want to get out of a context. But yeah, we are born, our evolution, we're born to, uh, to, uh, to burn fat, as glucose, but to be able to store a lot of fat. But our evolution has told us that a key energy, not just for high-intensity exercise when we have to run away from a from a bear or from a lion, right? Or when we have to get engaged into very high stressful situations, but also for the brain, right? We need your glucose. And so that's why it's, uh, the storage is very small, and that's gold for the body. So the body is going to try to defend as much as possible the glucose or the glycogen storages by then trying to be more efficient at burning fat.

Yeah, there's a really nice review paper. I'm sure you've come across this. It was in Nature Metabolism by Mark Hargreaves. And I'll put figure two up on the screen for those that are watching on YouTube. But it speaks to the potential energy that's available in the form of fat in adipose tissue and glycogen in the liver and muscle. And it sort of makes it very clear that there is this order of magnitude more potential energy in the form of fat stored in adipose tissue, as you've just kind of walked us through.

The next question I have is, you, you stress the importance of the point of maximum fat oxidation quite a lot. And my understanding of where you're coming from there is that during, um, specific exercise, namely Zone 2, at this point of maximum fat oxidation, we're providing a very specific, direct stimulus to the mitochondria, which then causes it to upgrade or adapt or grow stronger, which we can get into a little bit as to exactly what happens. But my question is, why that is the best intensity to stimulate the mitochondria? Because you just made it clear as well that when we go into Zone 3 and Zone 4, this is still aerobic. So even though the the contribution of fat to the production of ATP may be declining, glucose is ramping up, and that glucose is being used to produce ATP within the mitochondria. So why is it that we're we're chasing a stimulus to directly target the production of ATP from fat within the mitochondria, as opposed to just the total amount of ATP that's produced within the mitochondria, regardless of whether it's coming from fat or glucose? I'm not sure if I articulated that well.

Yeah, that's a great question. And, uh, yeah, it's, it's a complicated, and we're, we're still trying to really, um, uh, answer it, I guess, you know, in a more articulated way, right? And, and, uh, in a more scientific way, if you will, right? So what, what I have seen from 30 years of, uh, of work with, uh, with athletes, with patients, and research, is that that's the intensity. When I started using it, and by no means I'm saying I invented it, it's Zone 2, because that, you know, who knows who started? I just say that my Zone 2, the way I see it, I started using it 30 years ago, and this is what I, what I first I saw looking at lactate clearance capacity, that that intensity, it was the one that improved the most lactate clearance capacity in performance. So, um, um, lactate is a, it's a mitochondrial substrate, because lactate can only be oxidized in mitochondria, or or be converted back to pyruvate to be actually that's in mitochondria. So lactate is a great product. Lactate, it's a great proxy or surrogate for mitochondrial function. Then about 18 years ago, I started to add fat and carbohydrate oxidation rates in the laboratory, and to measure, as to measure, as I mentioned earlier, fat oxidation. And I could see also that that intensity was the one that improved fat oxidation the most, right? So that's what I developed this, this indirect methodology to look at, or or to assess mitochondrial function in a non-invasive way, without doing muscle biopsies. So by looking at lactate and looking at fat oxidation, both are mitochondrial surrogates or mitochondrial substrates, right? So we can indirectly measure that. So, and, and my colleague George Brooks and I, we published in 2017 a study looking at the correlations between fat oxidation and lactate blood lactate levels, denoting lactate clearance capacity, and the correlations, whether you were like an elite athlete, an active, a moderately active individual, or a person with a metabolic disease, metabolic syndrome, the correlation was was incredibly high. So that's why we know that they both can be very good surrogates for mitochondrial function. Now, that being said, again, this is why at first it was trial and error, right? I was saying, okay, which intensity of the ones I defined in my dictionary, which intensities to improve mitochondrial function the most? I see two ones, one, two, three, four, five, right? So with thousands of tests that I've done, all right, this is what I saw constantly, constantly, that this was the intensity that improved, uh, mitochondrial function the most, and also I saw that this was the intensity that improved performance the most. So this is what I saw this with with my athletes. It was very successful to see this with results. And now this is where I, from the beginning, I was saying, from lessons learned from athletes, can we use these, um, to, to prescribe exercise to populations with chronic diseases to stimulate mitochondrial function? So again, this is a way, and, and I'm sorry if I didn't do the best way, but this is my way to explain why Zone 2 is important to stimulate mitochondrial function. Not saying that the other ones are not going to do that, right? But what I've seen that this is the most efficient, and I've seen over 30 years, for for almost 30 years.

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Okay, so you're looking at lactate not so much as a problematic compound, which it has been kind of labeled over the years, but more so as a window into the mitochondria to tell you how well the mitochondria in that person is functioning. So when you looked at people with metabolic syndrome, what you saw compared to sort of average people and elite athletes was that for a given sort of intensity, they were producing much more lactate, and so that was telling you that their mitochondria was not as healthy and not functioning as well as the others who, at that same intensity, were producing much less lactate.

Yes, exactly. It's a, it's a great surrogate to see what the mitochondrial functioning. And it's going to become more and more, uh, part of the regular blood analysis that people do. Like when people look at blood glucose levels, like, what are your risks in blood glucose levels, right? So soon we're going to see, what are your resting lactate levels? Because what we see in populations with that metabolic syndrome, um, or obesity, or type 2 diabetes, we see that at rest, they have about two to three times the level that healthy people have. So if we have at rest, if you look at athletes, the resting levels of lactate, there are 0.6, 0.8. More active individuals, healthy individuals, this is kind of our standard, how would we like to be, we're around one millimole. But we see that people with type 2 diabetes, metabolic syndrome, obesity, cardiometabolic disease, they have at rest, many of them, two to three millimoles. So that's about two to three times the levels that healthy individuals have. So imagine that your blood glucose levels are two times or three times as high as what the normal should be in healthy individuals, right? So I think that this is, it's getting to be, it's going to be more and more a parameter for health. Resting lactate levels. And, yeah, but that, but that lactate, yeah, it's, um, it's, uh, it's a great fuel. So that's the other thing too. So lactate, we've seen as a toxic product, is probably the best fuel in the body because, uh, it's, it's, it's, it's, it's, it's, it's, it's, it's, it's metabolized faster than glucose, significantly faster than glucose. So if you give, uh, most cells in the body the possibility to use glucose or, or, or lactate, they're going to prefer to use lactate. The brain is a great lactate user. The heart is a great lactate user. The kidneys, the muscles, obviously. But it happens in mitochondria. So you need to have a good mitochondrial function. And, and the problem is not when it comes to exercise, it's not the lactate, but it is the hydro.

Hydrogen ions are associated with lactate, which elicits an acidic microenvironment in the muscle. This is the other thing that we see in cancer: the famous now, uh, tumor microenvironment. This is the microenvironment around cancer cells, which is very acidic, and that's a niche for cancer growth, for carcinogenesis, for metastasis, right? That is a big deal area, a big area of research now. And that tumor microenvironment, and that acidic microenvironment, is caused by lactate from the tumor cells, which is dysregulated in skeletal muscle. Is this related during exercise, and, uh, um, or accumulating in people who don't clear it correctly into energy? And those hydrogen ions accumulate, and they might—it's part of the fatigue, not everything by any means. There are multiple aspects of fatigue: central fatigue, peripheral fatigue, local fatigue, that we still are trying to understand and explain. But this is a part of that where the excess of hydrogen ions from lactate can impair both the speed and the force of muscle contraction.

Okay, so lactate itself is not necessarily a problem if we can clear it and we can shuttle it back in and use it as an energy substrate. But if our mitochondria are dysfunctional, it can build up. And along with that lactate coming for the ride are these hydrogen ions, which change the pH within the cell, that then can affect, perhaps contribute to fatigue and, and power. Yes, yes.

And when it comes to disease, uh, it's lactate. Um, it's highly related to disease, you know, when it's not—when it accumulates chronically. Because during exercise, lactate, even in people, in a person who is not fit, lactate is going to accumulate fast. But when the exercise ceases, lactate levels don't accumulate; they return back to baseline. But in diseases like cancer, or when there's a significant mitochondrial dysfunctioning, people with type 2 diabetes, that lactate accumulates chronically, right? And especially in cancer, the more aggressive the cancer is, the more lactate is produced. And, uh, through our research, we're showing that lactate acts as an oncometabolite, that is, it regulates the expression of, uh, sorry, it *irregulates* the genetic expression of, uh, the, the extra version of the main, or the most important genes involved in cancer. We're doing this with breast cancer. We have published one paper; we have another one under review now. And then we have two more papers coming out with two types of lung cancers. Um, and then we also see that, um, lactate also regulates the transcription of the main proteins that are dysregulated in cancer.

And now, what we're trying to intervene. And in the study that we have now under review, we are, um, with genetic engineering, we're knocking out, knocking down, the enzyme that produces lactate, which is LDHA. And then in breast cancer cells, we see that when we knock out that enzyme, no lactate is produced, and no gene, no there's no protein expression of those dysregulated proteins coming from these regulated genes in cancer, right? So it's a key regulator of cancer. That already also harbored a century ago, proposed because now we talk a lot, we hear a lot about sugar, the connection of sugar and cancer, right? And that comes from the renaissance of the Warburg effect. So although Warburg's discovery in 1923, that cancer cells, they utilize a lot of glucose, and that was the first metabolic transformation of a normal cell into a cancer cell characterized by that. But what really struck Warburg was the excessive amount of lactate produced by cancer cells. Now, that was back in the days. Unfortunately, he didn't have the technology that we have nowadays to understand that better, and the genes were not discovered, right? And so, but, uh, yeah, um, he already, he was so smart and so ahead of us that a century ago, he already posited that cancer could be a metabolic disease, which is not quite entirely correct. But there's no doubt that the metabolic factor in cancer is crucial. But the way how he described an injury of cellular respiration or mitochondrial function was lactate, because he already said, "Okay, wait a minute. If lactate cannot be oxidized or burned in mitochondria of cancer cells, it's because mitochondria are not working properly. So maybe there's an injury of cellular respiration." So this is the main thing that he proposed a hundred years ago.

Yeah, that's fascinating and some cutting-edge sort of insights, I guess, into where the world of cancer research and treatment might be headed from a metabolic health point of view. My head is sort of thinking at the moment about two different ways of keeping lactate down. And I'm sort of wondering if you've been able to elucidate this from your research: looking at elite athletes or looking at Zone 2 training interventions. Is it that elite athletes have a greater capacity to clear lactate, or are they just producing less lactate because they're better at oxidizing fats?

That's a great question also. And it's been demonstrated by different researchers, and among them, George Brooks, that the fitter an athlete is, or a person is, in fact, they produce more lactate, mainly because, in the same manner that their mitochondrial function is more robust and more efficient, their glycolytic system, which I also call, you know, in colloquial terms, the turbo, the turbo, it also works better, right? And in fact, we look at lactate as a sign of high glycolytic function, which is key for performance, right? So those athletes with very high lactate levels at very high intensity levels, they're really good at the turbo, right? So they produce a lot of lactate because they use a lot of glucose for energy. Some athletes can oxidize six, seven grams per minute. Those intensities were very good athletes, or the top ones, can oxidize seven or eight, right? But the side effect of that is they're going to be producing a lot of lactate, right? But the virtue they have, because they have a very robust mitochondrial function, is that they clear that lactate from the fast-twitch muscle fibers, which is where lactate is produced. They clear it in the adjacent slow-twitch muscle fibers and in mitochondria of slow-twitch muscle fibers. And for that, you need transporters also. So you need two doors, two transporters: MCT4s and MCT1. So MCT4s are the doors that take lactate out of the fast-twitch muscle fibers, and you need to stimulate that intensity training, not just to improve the turbo, the glycolytic capacity, but to improve the capacity of that door to shuttle lactate out, right? And then the slow-twitch muscle fibers, when you stimulate those, you, as I mentioned, not only improve or stimulate mitochondrial function because that's where they're the most present, because fast-twitch muscle fibers cannot burn fat much, so the mitochondrial content is much less. But also the MCT1s are present in those slow-twitch muscle fibers. So you stimulate those as well. So that's how, kind of in a nutshell, the lactate shuttle, that was discovered by George Brooks in the '80s, already works.

Let me throw that back to you and see if I've heard all of that correctly. So lactate clearance can be improved or is a product of our ability to get lactate out of these fast-twitch muscle fibers, which are going to be activated and utilized at higher intensities. I'm thinking sprinting or resistance training, for example. And so that stimulus is going to help increase the number of the MCT4 transporter you mentioned, that helps get lactate out of those muscle fibers or muscle cells, we could call them. And then the lower intensity work, so Zone 2, which is mostly stimulating the slow-twitch, slow-to-fatigue muscle fibers, muscle cells, is acting in a way to increase the MCT1 transporter in those cells. So you get this sort of nice push-pull, I guess, lactate clearance system where if you're doing the right training modalities or intense training at the right intensities, have the right stimulus in place, you can get the lactate out of the fast-twitch muscle fibers, get it back into the slow-twitch muscle fibers, which keeps lactate levels down and also acts as an energy substrate. Exactly. Absolutely.

And this is why I, yeah, the way you see training or exercise prescription is that right? It's like a, from a bioenergetic standpoint, and as I always say, which energy system you want to stimulate today, right? So that's where it's partitioning of cellular bioenergetics through exercise. And we're talking about two completely different systems: the glycolytic system and the oxidative phosphorylation system, the lactate shuttle system out of the cells, and the lactate receiving cells, the type 1 muscle fibers. And everything is different intensities of exercise are going to elicit different adaptations and different responses. Therefore, different adaptations. But we all are talking, and all this happens within an aerobic world, right? So still, everything that we're talking about here is aerobic, right? So you can produce plenty of lactate under aerobic conditions. So again, it's just like that, that's how it's important when you prescribe exercise, whether it's for an athlete or for a fitness enthusiast, or for longevity purposes, or for patients, to really identify training zones. Because whatever you exercise, the intensity that you exercise is going to stimulate one pathway significantly more than the other, right? So yeah, you want to really target and want to know what you want to do. Do you want to improve your glycolytic capacity, your turbo, because you're very good at, let's say, you're very diesel, you're very good at, very efficient in metabolizing fats and lactate in mitochondria, but you're not good at high intensity, you know? So you need to stimulate that by identifying your weakness. But for health purposes, that's more maybe for performance. Although we lose, like, a little capacity as we age, and we want to kind of maintain some of that, or a big part of that. But for health purposes, the main problem that happens as we age for longevity purposes, it's a matter of mitochondrial decay. As we don't exercise as much as when we were kids, some mitochondrial decay. And again, what I've seen in my experience for almost 30 years is that that Zone 2 is the one that improves mitochondrial function the most. And that's because it's targeting mostly the slow-twitch muscle fibers, where most mitochondria are found. Yeah, that's how I see it. And again, like the way I see is through fat oxidation in the laboratory, as lactate clearance capacity, that's the area for me, or at least from my experience, is without a doubt. And many others, you know, they've been telling me this, this is where we see that this is the way you improve the most, right? We might be wrong, and maybe in 20 years, 30 years, we might be talking about different methodologies of training or different understanding. Sure, of course, right? Things of all. But that's my experience that has been working very successfully with elite athletes, with some of the best athletes in the world, as well as at a clinical level. I've had very good experiences with people with chronic diseases when it comes to exercise prescription.

I want to get into all of the practical elements of Zone 2, and we can perhaps kind of further define it. But just quickly to close off on this conversation about lactate clearance on the MCT4 side of things and the stimulus to activate the fast-twitch muscle fibers and increase MCT4, so you're better at clearing lactate from those muscle cells. Are we talking about Zone 4/Zone 5 training here?

Exactly. Yeah, this is where you have to stimulate that turbo, that glycolytic capacity, right? So that's where you improve not only just the glycolytic pathway, the whole glycolysis, right, which is faster and more efficient, therefore the turbo, right? But it also improves those MCT1s. Because lactate is the mandatory obligatory byproduct of glucose utilization. The more glucose you use, the more lactate you produce. So that's where, like, when you stimulate that energy system, you're going to use a lot of glucose and you're going to produce a lot of lactate. And that lactate has to be shuttled out of that fast cell. And the way that is through the MCT4s, and it's shuttled into the adjacent cell. And as long as the, and this is why it's very important, I always say that for performance, right, for those athletes, you know, you win the races or the competitions in the high intensity levels, obviously, right? But because you produce so much lactate, you really need, you depend on that mitochondria of these slow-twitch muscle fibers, because that's where you're going to be shuttling the lactate into for lactate clearance capacity, as well as for fuel, right? And so the toolbox keeps working better and better and better, right? And this is what we see that as an athlete increases performance, let's say at 350 watts, which for normal people, it's almost impossible even to turn the pedals, 350 watts, an athlete today might have a lactate of 8 millimoles. And maybe one year, specifically working to improve lactate clearance capacity, that lactate from 8 millimoles is going to go to 4 millimoles, maybe at 350 watts. Or that athlete can sustain that intensity that before was only sustainable for three minutes or so, now that athlete can sustain the intensity for 40 minutes, for example. Right? So that's absolutely key to performance. And at the same time, for the everyday person, should they do a protocol that lowers their lactate in that way for a given intensity? That again is a window into mitochondrial function, which speaks to their metabolic health and risk of cardiometabolic disease. So there's a benefit up for grabs here for the athlete that's looking to race better, but also for the everyday person who's just looking to live better for longer. I think this is really, really helpful. Inigo, in terms of my undergraduate, I remember one of my lecturers just bolding and underlining this statement: "Structure reflects function." And speaking to the importance of specific stimuli to create a very specific adaptation. I think you've stepped us through really, really nicely the different stimulus that is kind of Zone 2 training, which is mostly targeting slow-twitch muscle fibers, Zone 5 or Zone 4-5, the fast-twitch muscle fibers. But the way that these can kind of work together to improve metabolic health and performance. A lot of people speak about an 80/20 split: 80% of time in Zone 2, 20% of time at Zone 4-5 high-intensity work. And that's commonly something said within the endurance community. Is that a kind of rule or protocol that you also recommend, both for an athlete and also for the everyday person just looking to improve their metabolic function?

Yeah, I mean, that's part of the polarized training that, it's been trending, right, for a while. And I embrace it. I particularly embrace it because this is actually what we do with athletes. If you look at, and this is counterintuitive, right? And, but if you look at the percentage of workload of an athlete throughout an entire year, it doesn't matter if that athlete is a marathon runner, or a triathlete, or a cyclist who's more pure endurance, or that athlete's a swimmer, or a rower, which is really high intensity. The immense majority of the entire workload of that athlete throughout the year is in the lower intensities, more in the Zone 2, in the Zone 1, right? And a very small percentage is in the very high intensities, right? And this is something that we can see this very well nowadays. We have all these platforms where we capture the information, right, where we see this in these individual athletes. Team sports are a little bit different because it's high intensity all the time, mixed with lower intensity. But in the individual sports, we see this all the time. And, um, and, yeah, so that works. That works. And it also is necessary because if the conception that many people still have, that elite athletes, they train hard and intervals and intervals and hard all the time, that's not sustainable. That's not sustainable. And in fact, we really are careful with athletes when we prescribe intervals because, yeah, it can put you in a very dangerous spot for overtraining and decrease performance. So we really need to mitigate. It's not sustainable. And if you keep pushing for that, you're going to end up overtrained. So that's where, like, by default, and this is again, this is just been evolution of the sport, right? I always say, we cannot be so naive to think that the best athletes and coaches in the world, over decades, they haven't thought about these concepts, right? Of course, they have, intuitively. I would say a swimmer, let's say a 100-meter swimmer is usually under a minute, right? So it's super high intensity. So intuitively, what would a swimmer need? Just do one-minute intervals all day, right? But when you see swimmers, elite swimmers, and in Australia, you guys have some of the best in the world, right? Great school of swimmers, they're swimming hours and hours and hours and hours, right, at lower intensities. What lower intensities for them? For us, it has to be unsustainable, right? Because that's the other thing we haven't talked about, the, the, what's low intensity for an athlete and what's low intensity for a normal person, right? But for them, relatively speaking, it's a lower intensity, right? And this is what, that's why they can sustain hours and hours and hours. But, yeah, but it's counterintuitive. I understand. I know. But that's the way it's been, evolution of sports.

Okay, so if we come back to this idea of building your aerobic base, how much of this would you say is influenced by mitochondrial function versus the amount of oxygen that we have available, our VO2 max?

That's another great question. So, and this is something that we have learned a lot in the last two or three decades. So we used to measure performance or predict performance based on VO2 max, right? And it still is, it's a very good parameter because, um, it's, it represents the cardiorespiratory adaptations to exercise. But definitely, and that's for sure, and this anybody who does a lot of testing, physiological and metabolic testing, can tell you that VO2 max is not, it doesn't discriminate. So it gets to a point that is so well expressed that it doesn't make the difference. And this is what we see all the time. You see two athletes with the same VO2 max, right? So therefore, um, yeah, they're supposedly as good. And then one athlete is much better than the other, right? And then you go at the cellular level, right? And then you see that, yes, that athlete at 350 watts has 8 millimoles of lactate, and the other one has three or four, despite of the same VO2 max. So this is why VO2 max, it's a great surrogate for health, of course, and for fitness, no question, right? But, you know, looking, and this is from looking from a cardiorespiratory standpoint, and this has been the norm, right, for forever, VO2 max. But by looking now in the last two decades, especially at the more cellular level, we're seeing that that's what makes the difference. And within the cellular level, and you know, everything happens, or the queen of the cells, or the queen, because they come from the mother, we should say, our mitochondria.

And when we're thinking about stimulating the mitochondria through Zone 2 training, are we mostly thinking about improving the function of those mitochondria, or are we also thinking about improving the number of mitochondria that are found within muscle fibers?

That's a good question too. And it's usually both, right? So we improve both the number and the function of mitochondria. Definitely, I believe, and this is what we still need to do more and more research because there are different studies showing things, you know, but I think that, in my humble opinion, it's more the function. But they usually go together, right? You see mitochondrial content in type 2 diabetics or obese individuals is significantly lower than in more active individuals. And when you put those athletes to, there is this great researcher that was from Pittsburgh, Toledo, he started doing these studies where with mitochondrial function, that was 20 years ago, but not many people listened to him. But he was looking at people with obesity and looking at the mitochondrial content in the muscle. And after, I believe it was like four, five, six months of aerobic training, back in the days, they still talk about aerobic training, what we still do, they improved their, they triple the number of mitochondria. So in the same way that you reduce the number by being sedentary, you can increase the number of mitochondria in the size, triple the number and the size of mitochondria. And the function also will significantly improve. So all things come together.

Yeah, so that's worth sort of underlining that we're not born with a set number of mitochondria that's fixed for life. We can do something about this. And if I heard correctly, if we've lived one, two, three decades living a very sedentary lifestyle and lost a bunch of mitochondria, if we then commence exercise, particularly specific exercise, and do the right dose and frequency, which we'll get into, we can actually build new mitochondria and bring some of these back.

Yeah, absolutely. And, you know, and this comes within the plasticity of skeletal muscle. I mean, we're still focusing on skeletal muscle, right? Although it happens also in the heart and in the brain too. But the plasticity of skeletal muscle is extraordinary. So, yeah, yeah, it can deteriorate over time, for sure. And it will if you don't do exercise. And something that we see on the outside of people who don't exercise. But also, it can improve significantly over time, as we see also, you know, from the outside of people, you know. But imagine what happens in the inside, right, at the cellular level. There's an incredible amount of improvements that happen at the cellular level. So, yeah. And it comes because, yeah, the body, at the end of the day, is very wise. And we, humans, we haven't evolved to become sedentary. We are, our genes are still, you know, made to be active, right? And being sedentary has been a byproduct of progress, as opposed to be the norm. But unfortunately, we've been growing, you know, with this notion, and then being sedentary or healthy sedentary has been the norm. And then doing physical, and being physically active is being a control, or it's an intervention. With that, the real intervention for us humans, as part of the evolution, has been to become sedentary, which is leading to disease. You know, so this is what I got, a lot of research data in medical research for decades, they've been using sedentary as a control, the healthy sedentary individuals, when we know that the immense majority of those healthy sedentary, they they are going to encounter populations with diseases. And we already have a very interesting study that we are putting the manuscript together with really cool findings of sedentary people who are healthy and they don't have any clinical conditions, and they already have significant metabolic dysregulations compared to people who are active, moderately active, not elite athletes. So we're already seeing that, uh, 15, 20 years probably before they have some disease, we already see signatures, markers of metabolic dysfunction and mitochondrial decay.

And one of those, I'm assuming, being lactate as an early predictor of disease?

Lactate is never a predictor. We're looking doing this by looking at different markers in the muscle, doing muscle biopsies, and metabolomics. We look at a lot of metabolites that are happening in mitochondria and look in itself at mitochondrial function, where we do is like we get a muscle biopsy and we inject it, we homogenize the mitochondria of those subjects, and we directly inject in mitochondria different substrates. We inject fatty acids, we inject carbohydrates, amino acids, and we see how mitochondria metabolize those. Right? So we see significant differences already in sedentary individuals. And then also some transporters that I cannot say yet until it's polished. But there's a key transporter that is significantly downregulated that can be 10 years, 15 years ahead of type 2 diabetes. That is already a signature and could be a hallmark of this population who are sedentary.

That's exciting. Sounds very promising. I look forward to reading about that. What you were talking about earlier about the sedentary lifestyles we're living in, the deterioration that occurs with that, reminds me of a quote from Frank Booth. I'm sure you know him or have come across his work. He said that the current human genome requires and expects us to be physically active for normal functioning. And I think a prior guest, Paul Taylor, shared that with me on my show, and it's kind of stuck in my mind.

We have already great examples of our very primitive civilizations that still exist in our world. And there are especially two populations: the Hadza hunter-gatherers in Tanzania, and also the Sani hunter-gatherer population in Bolivia. So the very primitive populations, they don't have any contact or they haven't had any contact forever with civilization. They haven't even evolved. They have the same tools and the same dresses as they had, you know, like a thousand years ago, two thousand years ago, right? And then there are a few researchers, especially Punter and Kaplan, who just went into these tribes and started to study the incidence of diseases as well as obesity, body fat percentage, their habits, how much time they were exercising a day, as well as what was their nutrition. So those were the real primitive civilizations, right? So the rate of obesity among these populations was about 2%. We're talking about now, or overweight or obesity in our civilized world, is somewhere between 50 and 70%. Type 2 diabetes in this population was 1%. We're talking that in the U.S. alone, 52% of adults are pre-diabetic or diabetic already. And I always say that being pre-diabetic, you know, you already have the disease. There's no term such as being pre-pregnant or pregnant. You're pregnant or you're not, right? So the same thing with pre-diabetes. They also have the lowest cardiovascular disease and atherosclerosis plaque percentage observed in any humans in the world. So the life expectancy is, in fact, similar to the US. The problem that they have is that, like, the majority of fatalities that they have, about 70% of fatalities are due to infections. They don't have medications, they don't have antibiotics, right? And then they have a lot of fatalities due to trauma, accidents, right? But only about 10% of their deaths are due to non-communicable diseases, whereas in our population, there's about 70% due to non-communicable diseases. So, and then the habits of these people, they're walking between 110 and 135, 140 minutes a day. You know, the American Heart Association, American Medical Association, American, I mean, all these associations, they're saying about 150 minutes a week, right? That's pretty much what they do a day, right? And then we look at their diet, and they're pretty much plant-based diet. They're a hunter-gatherer population. They hunt whenever they can. Probably like the people in the Paleolithic. We have the idea, the people in the Paleolithic, all were sick, I mean, 180 meters or six foot tall and super strong, you know, and they were good, hold up a bear with one hand and a lion with the other and eat them alive, right? That's probably not true. They were probably very slim, very fragile people who were to survive and didn't have the strength to overtake a lion or a bear. But yeah, they were hunter-gatherers. They would hunt whenever they could. But in the meantime, they had a plant-based diet. And the diet in these people is somewhere between 65 and 70% in carbohydrates, which is about 34, 33, 30 to 35% higher than the US in carbohydrates. And they have about 15-25% protein and only about 10-14% fat. So this is the paradox of these populations who have almost non-existent levels of obesity, of type 2 diabetes, of cardiovascular disease, and yet they have very high concentrations of carbohydrates in their diets.

It sort of puts to rest this idea that carbohydrates or glucose are inherently bad for metabolic health. That must be something that you, as someone who is so close with the research in this area and conducting your own studies, you must shake your head when you come across those sort of claims.

And I always go back to the same thing. And it's just like, yeah, if you don't have good functioning mitochondria, and if you have carbohydrates, that's bad. That's that's as I said earlier, that's adding gas to the fire. That's going to make your condition worse because you need to metabolize it. And therefore, yes, for someone with poor mitochondrial function, maybe a more protein-based diet and carbohydrate reducing it is needed. Right? But if you are a healthy individual, you exercise, you're good, you know, like these populations that I described, right? They do in one day what is recommended for our civilization for one week. Which, by the way, very few individuals get to meet the 150 minutes required per week, right? So these people, I would love at some point to travel to these areas and do a muscle biopsy of these populations and see their mitochondrial function. Because I'm very sure it's going to resemble a lot to those that we see in very individuals who exercise a lot, and they have the same eating habits, eating a high carbohydrate diet, low fat, and moderate protein.

I'm glad that you brought up that point about pre-diabetes. And I think that's another one worth kind of underlining: metabolic health or metabolic disease and dysfunction, I should say, is it more of a spectrum? Would you agree? So it's not as though you go from being metabolically healthy to the next moment being diagnosed with type 2 diabetes. So if someone's listening today and is thinking, "Well, I live a pretty sedentary lifestyle, but I don't have type 2 diabetes." What you're saying is, despite the fact that you haven't been diagnosed with a metabolic condition, if we were to take out the microscope, take a biopsy of your muscle tissue, we would be able to identify that there is decay, deterioration occurring, mitochondrial dysfunction, and you are on the path to metabolic disease, despite not currently having it.

Yes, without a doubt. And, and, yeah, and exactly. And this is why, yeah, it's sedentary individuals, even, you know, they're healthy now, they're the majority are going to encounter cardiometabolic disease in the forms of type 2 diabetes, cardiovascular disease, both. They're going to have a higher chance of developing cancers. There's more and more data around cancer at this point. There's a lot of epidemiological data, more than scientific cellular data, of what being sedentary does to you, or obese, right? So being obese or being sedentary, it can increase about 50% chances of many cancers, right? So that's absolutely astronomical, right? But we're still trying to find out that more. But yes, we know that also Alzheimer's, people who are sedentary, they have higher risk for Alzheimer's and dementia disease, you know. And this is also, you know, you told me yesterday an article, right, about cardiorespiratory fitness, and cardiorespiratory fitness is highly associated to a higher risk for mortality more than any other disease.

Yeah, in that paper that I sent you, there were a bunch of really interesting findings. Some that stood out to me were the fact that the higher the subject's cardiorespiratory fitness in that paper, and that paper was looking at, I believe, over 700,000 U.S. veterans, the lower their risk of death during that follow-up period. But one of the really interesting things that kind of stuck out to me was the authors' sort of calculated what someone could achieve if they went from low fitness, so essentially the most sedentary people, just to moderate fitness. What would that do to their risk of death? And they found that that would halve someone's risk of premature death, just again, just going from low fitness to just moderate. And that that could probably be achieved with 150 minutes of moderate-intensity cardiovascular training a week, or Zone 2 training.

Absolutely. And this, and I've seen, I'll tell you, like an example that I, it's incredibly inspiring, and it was even hard, it was very hard to believe, but it's true. So the, um, I tested once in the laboratory an 80, 81-year-old gentleman who was world champion cycling, world champion of the 80 to 85-year-old bracket, which believe me, it exists, which is great to see, right? Anyways, I was fascinated because his metabolism, his metabolic efficiency during the test that I do was that of someone in their 30s or 40s, healthy and active, right? I, it was unbelievable. I keep that test like a treasure because it's an absolute treasure to see those adaptations. Right? So anyways, I right away I thought, well, you've been doing sports all your life, right? So man, you chose the right lifestyle, right? And he said, actually, no. Actually, until I was in the early 50s, I was obese, I was hypertensive, I used to smoke, I had a very poor lifestyle, I didn't exercise at all. And one day I started to ride my bike and think about life and things like that. And ever since then, so to your point, what you said, this was an individual in the early 50s, sedentary, very poor healthy lifestyle, and then 30 years later, at 81 years old, his metabolic health was out of that of someone in their 30s. Whose health? That's unbelievable, hard to believe. And this is how that person, obviously, 81-year-old, that's an example of what exercise can do for your longevity. That person was not on any medication at 81 years old. And it was a fit, slim individual. It was hard to believe. But hey, this is how the magic of exercise, right? If we were able to put exercise in a pill and take it every day, it would be the most sold medication in history.

But that's another point. That's a very hopeful, promising message story for people to hear. And I guess speaks to the incredible capacity for the human body to adapt should you provide the right stimulus at any point in time, and that it's never too late to get started.

And sorry to your point, it's in our genes, right? And what we say, it's embedded in our genes. So we have the genes. Humans are genes. Maybe in 10,000 years, our genes will evolve to be sedentary. I don't think we'll be around in 10,000 years because we're so dumb in the first place. But if we were around, maybe our genes, they adapt to become sedentary. But at this point, we're too young as a race, as a species, for our genes to adapt to become sedentary. So they're ready to get the ball rolling with exercise anytime.

I have mixed feelings about that because I love moving my body. Hey friends, if you'd like to stay connected and reinforce the valuable insights from this show, so let's connect on Instagram. You can find me at Simon Hill. That's at Simon Hill. I look forward to seeing you there. All right, let's dive back into the episode. I think it would be a good point now for us to sort of double-click on Zone 2 and explain to people how they can set this up in their own life, how they can know that they're in Zone 2, and how much Zone 2 training they should be sort of targeting or working towards on a weekly basis in order to provide enough stimulus to get these adaptations happening that we've been talking about and then reap the benefits from improved metabolic health. Just quickly before we get there, you mentioned Herman Ponce. Just as a reminder to listeners, Herman Ponce was on the show a little while back, so you can go back and listen to that episode and hear all about the Hearts. For sure. Yeah, so that was great that you mentioned him and his book, "Burn," is a really good read for anyone that wants to kind of deep dive his work with the Harts. So Zone 2, Inigo, let's let's define it. I know we probably have earlier in the conversation, but simple definition, what does Zone 2 actually mean?

So again, there are probably different definitions. Some of them are closer, others are a little bit more separate. I just have my own definition that I've been using for 30 years. And for me, that's the exercise intensity where someone can improve mitochondrial function the most. Not the only one, not the only zone, because other zones are going to always be beneficial. Any zone will be beneficial. But from what I've seen, looking at fat oxidation in the laboratory, lactate clearance capacity as mitochondrial surrogates, and as mitochondrial sisters, and therefore surrogates for function, that's what I see. And, yeah, that's how I cannot define in a nutshell Zone 2.

I think many of the listeners will be thinking, "How do I know that I'm in Zone 2?" And there are a lot of different calculations online, there are running tests, there are lab tests, etc. How do you encourage people to think about this?

That's a great point. So I think that as we're starting to look at exercise prescription for the mass market and for many people, as opposed to just elite athletes, we're going to see more and more exercise physiology or metabolic laboratories around the world. And in fact, it's happening. Until recently, there were very few laboratories around the world who did this test to specifically find out your training intensities based on heart rate or power output. And they were only for the elite athletes. And then now, more and more are popping up around the world. And people are not so scared to go to a laboratory because I remember when I started doing this in the U.S. for health purposes with patients 15 years ago, people were scared because they said, "Oh, I'm not an elite athlete," or they would see a cycling jersey or a runner's jersey and they would say, "I'm not one of those." No, but this is not about that. This is about you. And so anyways, those laboratories and those tests, they're becoming more sophisticated. And people running those tests, they're all more and more professionals. Before, there were not that many professionals working in this area. And people would go to their local university and, with all the respects to graduating undergrad students, you know, they were seen and tested by them. Right? Now you see a lot of professionals who were undergrad or graduate students and became into this field. So that's on one hand. But there are people out there that they cannot find the place. There's not a laboratory in their town, or maybe it's too expensive and they cannot afford it. So for those, and from my experience, I think that the breathing and talk test is a great way. And I'll explain it. So like, when you and I talk like this now, when you can maintain a conversation like this, you're in your Zone 1, you're recovering, you're not stimulating much. Zone 2, it would be like a hard conversation to maintain. If you imagine yourself exercising with someone else, you could maintain a conversation, but it would be costly. You will be talking with some difficulty, but you could maintain it. Not for a long time, not for one hour, because it would be too fastidious, but you could maintain it. That would be kind of what we see the results in the laboratory, and it kind of corresponds to that. Right? And then Zone 3 would be an exercise intensity where it's very difficult to maintain a conversation, very difficult, just exchange a few phrases or a few words. Right? Then so for no conversation, that's it, you know, maybe one word you can say, you know. And then Zone 4 and 5. There's no possibility, right? But I think that, and I honestly, and I know it might sound old school, but we have now watches and all these algorithms, you know, that gives us zones, you know, that the immense majority are far away from giving you the right intensities because those algorithms are not individualized yet. It'll happen at some point, right? But at this point, I really think that the talk test is much more accurate than the immense algorithms that you find out there in all these brands telling you the training zones. So it's easy to do. And again, from my experience, and the data, the hardcore data from the laboratory, it's not that it matches perfectly, but it corresponds quite well.

And I think, you know, it's just worth us remembering that there are so many people living in sedentary lifestyles. So trying to remove barriers to just get people moving is a great thing. And what you've just described there is really accessible to people. Are you a little bit puffy? Perhaps you have a little bit of sweat happening, but you can carry that conversation. If you were on the phone to someone, they would know you're exercising, but they could still have a bit of a conversation with you without it being too interruptive. And the good thing with that too is that as you get fitter, you can be displacing that intensity. So now maybe someone is sedentary and obese, overweight, and maybe just just walking around the block might be tiring, but that might be the Zone 2 for example. But maybe in one year, that person can do like a brisk walk and be at that same intensity. Right? So that's what you can guide yourself through this simple test, which at the same time, this Zone 2 intensity is something that is sustainable for life, you know? And again, I also say that any intensity will help. And you need, as we discussed, higher intensity to maintain your fitness and your glycolytic capacity. And obviously, we haven't talked about resistance exercise, which is very important. And you know more than I do. But the thing is like, yeah, it is when it comes to both exercise and diets, you know, I always ask people who do these extremes.

Extremes exercise routines and extreme diets, and they have great results. The men's majority are just temporary because they miss major go back to where they were. And when you ask them, "Can you do this for the rest of your life?" the answer is no. So if you cannot do a diet or an exercise for the rest of your life, it's not going to work. So you need to have some sustainability, both in your nutrition and both in your exercising.

When it comes to exercise, zone two is something that anybody can do for the rest of their lives. You mentioned some of those algorithms, and I think the most crude sort of calculations that are out there are using max heart rate, 220 minus age, and then kind of just multiplying that out by the various intensities of the different zones. And perhaps a step better, there's calculations like the Karvonen formula, which I'm sure you're familiar with, that uses heart rate reserve. If someone is going to go out and use a calculation out there, the Karvonen sort of formula or a formula that's using heart rate reserve is better than one that just uses max heart rate, probably. But still, the thing is, and this is what I've also learned working with athletes and also regular people, is that the heart rate response to exercise is so individual. You can have someone with the same age and, uh, one's maximum heart rate might be 180 and the one one might be 200, right? Or 160 and 200, right? Um, so, and and regarding the cardio reserve, that could vary significantly also among individuals. So I think it's probably more accurate, right? But, uh, um, but I don't think we're there yet, uh, looking into into these algorithms when it comes to heart rate, uh, because it varies a lot. And I think that, again, it's one of the things, it doesn't represent necessarily what happens at a cellular level. I think that, um, uh, the the future is going to come in the, uh, um, biosensors where we're going to be, uh, we're working with one company with one biosensor already that we think is going to be a big deal at some point. But the biosensors that they're, you know, kind of people have now, some glucose, that if you're type 1 diabetic, it's a game changer. If you're not, it's cool to see how your glucose goes up and down. Eventually, it's physiology and metabolism 101. And eventually, yeah, you just, uh, you can get some education. But eventually, you will not be using it much because you're not type 1. But the more sophisticated biosensors are coming with more metabolites to come directly from your cells. And that's where you're going to be guiding, um, exercise in a much specific way.

What do you think about the devices I sent you a few on email that you breathe into that sort of supposedly tell you what type of fuel you're using to produce ATP? Um, yes, so those are a very good, um, uh, that's a, that's a very good question, uh, out there. And, uh, without a doubt, it's, it's, it's a, um, it's a start of, of, of a movement of trying to understand better, uh, your how your metabolism works, right? Um, but, uh, one of the things is that they, you know, they need to be very well calibrated. And this is, this is my, my problem that I have, right? And this is my, my experience from, um, uh, for 30 years working with all these metabolic carts. So we're using the laboratory metabolic carts, who are like $30,000 worth, very expensive, very delicate, and those are the state of the art. And they really need to be very calibrated. So they have CO2 sensors and, and oxygen sensors as well. So, um, and believe me, they get decalibrated all the time. They're very sensitive. So, and if they're not correctly calibrated or they get decalibrated, they're going to give you false readings, which happens all the time. And in fact, there's a brand, I don't want to name any brands, but there's a brand that I've been using to do my research and to get this calculated all these years, which to me is the best how there is, the most accurate, and you can see the accuracy very well. Um, but the problem is, is that it's not as fancy or has these graphs, uh, or hasn't evolved in 30 years as other brands, right? Other brands, they have these nice and fancy graphs, but maybe they're not as accurate as, did you sell their brand, right? But anyways, but we're still talking about equipment that is $30, $30,000 worth, right? But these devices are like $200, $300, $400, uh, sure. So some of them, they have CO2 sensors, right, and O2 sensors. But how do you know, first, that they're, how do you calibrate them, right? And, uh, therefore, how do you know that the readings are right? And second, how do you know when they stop functioning? Because we know from these very expensive carts that you need to replace the sensors often, sometimes every year, sometimes every two years, three years, right? And that's the thing, you know, like I see that the concentration to calibrate them, you need to really put our oxygen and CO2. And the way they do this when you do the calibration from ambient air, right? The metabolic cart gets oxygen, and it has to read 20.94, which is the oxygen concentration. And then CO2 is usually the one that is the most problematic. It has to read 0.03 percent, right? So when you calibrate those manually or automatically, uh, multiple times, you see that the CO2 concentration is 0.05 or 0.06 or 0.01 in the cart. The metabolic cart allows you to proceed with the test, right? So without a doubt, you're going to have false readings. And again, we're talking about a $30,000 very sophisticated piece of equipment. Now, how do I know in these small devices that the reading that I have is the actual one, right? So that's, and, and again, I'm not criticizing necessarily, right, those devices because I think that, uh, they can give you like a trend in where you are, you know, and, and if you're burning more fat or less. But I think that, um, yes, uh, I, I, I don't know, if I don't know the calibration, the precise calibration, I, I don't, I don't trust and much, you know. And then you go to some of the websites of, not all, but some of these devices, and when you go to a website, you see "Hack your metabolism," "Own your metabolism," you know, or "The most advanced metabolic machinery." It's, it's a red flag, right? Because there's not such a thing, right?

Now, you see greens, right? That, um, they go to their website, and you can, all the more sophisticated piece of metabolic measurement, you can have it. Like, come on, it's just, it's a ring for B6. That reminds me of the way kind of zone two or training at max fat oxidation is often conflated with this magical fat burning zone and fat loss or body fat loss. Is that, is that something that you could clarify for the listeners? Yes, and, and the thing too, is like, when we talk about this, this is an excellent question too, and I like to address because when we talk about fat max and fat oxidation, we're talking about very, very, very small amounts of fat that someone oxidizes, you know? So we're talking about, like, for example, if you're an okay fit individual, your fat max is going to be 0.4 grams per minute, around that, you know, amount. If you're a world-class athlete, we're talking about 0.8. Uh, if you're a moderately, moderately healthy individual, your fat max is going to be about 0.3 grams per minute. So I just do the math, right? If you are exercising, uh, 60 minutes at your fat max, and let's say you're 0.35, you're actually losing 21 grams of fat. That's it, right? In one hour, right? So there's no magic, like, "Oh wow, yeah, I just, I just burned so much fat today." No, it's not such a thing like that, you know? You burn a little bit, but a little bit every day, right? If you, if you then also match this with proper nutrition, right? And, and stay, uh, at some caloric deficit, then yeah, those 21 grams of fat, right, times, uh, uh, if you do this five days a week, right, times, uh, four weeks per month, yeah, yeah, that's half a kilo, right? So let's have a kilos, it's not bad. You put that in 12 months, in that six kilos that you lose, right? And that's again, that's exercising one hour. If you exercise an hour and a half, we're talking about, uh, uh, nine kilos, which is could be incredibly beneficial for your health, right? So this is what I think that there's no magic bullet that, "Oh wow, your, your fat max." People sometimes think, "Oh, I'm losing so much fat, therefore I can have a burger, a cheesy greasy burger because I exercise." You know? And that's the other thing too, of many of these machines or even watches or so, like, "You burn 700 calories today." Yeah, but they're not telling you the partitioning, right? You could have burned 100 of those 700 calories derived from carbohydrates and zero from fat because your exercise mode or dosage was not the right one, right? Or you might have a 50/50 or 70/30. So that's going to obviously impact, right, how much progress you make when it comes to lose weight. And this is one of the reasons why a lot of people who exercise regularly, they cannot lose weight. And because they say, "Man, I'm burning 700 calories or 1,000 calories every time I exercise, and I can't lose weight." Well, first, you're probably overeating for how much you burn. And second, you're not burning much fat, if at all, when you exercise. So this is why it's, it's a tricky concept. And it's about patience.

Patience, also, doesn't it just come back to energy balance at the end of the day? So in your workout, if you burn or expend 400 calories from mostly fat versus someone else who works out for a shorter duration but also expends 400 calories mostly from glucose, isn't the net effect on their body weight going to be the same despite the difference in substrates being used to produce energy? I don't think necessarily. That's my opinion. Um, that there's like a, there's energy balance is very important, for sure. But it's also an, um, energy efficiency and the type of substrate. So if you want to lose fat, you want to burn more fat than glucose because that comes from adipose tissue, right? The thing is that, um, we're used to also seeing a lot of people doing high-intensity exercise and who are already very fit to start with, right? So they have a good, probably because they, they haven't achieved metabolic decay since they were kids. They've been fit and doing exercise and moving a lot, right? Um, but, and, and they, you see these people doing this high-intensity exercises and they're very fit, uh, and they don't have much fat, um, and, yeah, that's, uh, and that's maybe the, the calorie balance is more important for them. But maybe for people who are overweight or obese, um, uh, the energy balance should be more towards, uh, burning more fat and restricting also calories from your diet to achieve that balance, or calorie balance, as well as to improve mitochondrial efficiency through specific targeting of, uh, training intensities. I guess I'd always just looked at the, the kind of how the, the dietary intervention trials looking at low-carb diets that are high in fat versus high-carb diets, low in fat, and at least at the 12-month mark, and some of this could be adherence, there doesn't seem to be a big difference in in body fat. And the way that I've reconciled that is that the people in the high-fat diet, although they're burning more fat or oxidizing more fat, it's dietary fat, not necessarily stored body fat. But that's that's interesting for, for us, for me to kind of think about further.

Coming back to to zone two, so you've got the talk test, being a little bit puffy, a little bit sweaty. We spoke about those different formulas that are out there, and it sounds like that if someone is using any of those algorithms or formulas, they're they're still going to want to come back to the talk test and pair the two together. Um, I, I recently did a VO2 max test in a lab, and through that VO2 max test, they calculated my zones. I know that's different to lactate testing per se. I noted that there was, there's an upper and a lower bound. So for me, zone two came out at 129 to 142 beats per minute. Let's just pretend that that is my accurate zone two. And you might say that we need to do lactate testing to get very accurate. But my question to you is, when I am going out and doing zone two training sessions, does it matter where I'm sitting in that range? Do I need to get right up to 142 beats per minute at the upper sort of bound in order to get the stimulus that we need to drive these adaptations? Yeah, that's a great question too. And it's good that you have like relatively like a small range. I've seen people getting a range of 30 beats per minute, you know, for zone two. And I guarantee you that there's not such a big range. You know, we usually the range is somewhere between 5 and 10 beats per minute, right? Um, um, at least with my calculations and, and how they work with for me. Um, but yeah, absolutely. Um, I think that you want to go more towards in the middle, right? Uh, to be more conservative towards the high end, um, of zone two. That's when you're going to push those, uh, bioenergetics the most, right? And, and drive into fat max before you start engaging more, uh, the fast-twitch muscle fibers and, and switching more towards increasing glucose as energy fuel. Um, but, uh, but yeah, but you need to be very sure that the zone two is that zone two. If you go in the high end, otherwise I would stay more in the middle.

So if we are dipping in and out of zone two, does that make that training session somewhat redundant or diminish the sort of returns that you're going to get? So if you're doing say 60 minutes on a stationary bike, but 45 minutes of that was zone two sporadically throughout that session, you were dipping down back to zone one and then at some points you were going into zone three. And this is something that I think people who go out and do rucking or hiking face because they're going up and down hills. Is that a problem? If we're doing zone two training, do we really need to get into zone two and then stay in that zone? That's a great question too. And I think that, um, and this is my humble opinion, I think that it comes to the, uh, the timing that you spend at your zone two. Um, and, and, and like, as you said, some people who are doing sporadic leads or ones or threes on two, um, if they're only doing these for 45 minutes, um, maybe that the actual portion of zone two might be 30 minutes. And, and what I have seen is that, um, and is one of the three pillars that I see is one, to identify the training zones, the intensity that's right. Second is the frequency, how many days you do this. And the third one is the duration, right, of each, of which a session, right? So I see great results with people when they reach around one hour, right? So like if you do one hour purely a zone two, you're going to get good benefits. But if you go and go a little bit above and below, or even to zone four here and there, yeah, you might want to have a longer session, which is an hour and a half, for example, whereas those 30 minutes is like when you oscillate. But the pure zone two is in that one hour, right? So, uh, that's where you have the stimulation within one section. That's kind of how I see it. And it also depends on your form and your peak. Let's say that you do like a high-intensity interval in the middle of the session, and you only do one hour. So if you do a high-intensity interval, you can have a lot of lactate, and it's going to be there for, it's going to be there for about 15 minutes. And as we saw, lactate is going to inhibit glycolysis, it's going to inhibit my, um, transportation. So you might lose about 10-15 minutes of the session, which, again, if you do an hour and a half, it's no big deal. Like I do that, you know, when I go on the bike, I do usually an hour and a half, an hour 45 minutes. So I don't have much time, but that's enough for me. But yeah, here and there, I do glycolytic intervals because I love to do them, and they're good. And, um, and now with applications like Strava, you want to see where you fit in with the rest. And they're dangerous, but anyways, I see that, um, I mean, and I love this, you know, this side of trying to compete with your, with yourself, right? But yeah, I do this for maybe seven, ten minutes, like a zone four interval, and then I'm in a relatively good form within, in 10 minutes, I'm going to go back to normal level. So yeah, I sacrifice, you know, 15 minutes out of my an hour and 40 minutes. So I'm good. I'm still doing hour and 20 minutes or so that's on two, right? So, but yeah, I think it's about duration at zone two, um, that you can afford. And ideally, ideally with in a session that is consecutive minutes in zone two. Yeah, that, that, yes, that's that's the thing. Yeah, like if people do a lot of intervals into an intervals into intervals, no, I mean, you're, you're, it's not going to be your zone two, you're going to be recovering from the interval, right? And you're going to be still going through a lot of glucose, right? Um, so I think that again, like I like to to to have it more towards the end of the session, or if you have like a good hour and a half, hour or 40 minutes, you can have one interval in the middle of the session, or two hours. And, uh, yeah, if you can afford any viewer moderately fit, yeah, in 10 minutes on the downhill or so, you can come down to like, uh, zone two, right? But if you're not very fit, and, uh, you want to do several intervals, you're going to be up there, it's going to be taking time to come back to zone two towards the end, which is what I do. So I tend to do 60 minutes of zone two on a stationary bike, and then at the end of that session, not every session, but at least a couple times a week, I'll do a HIIT and get into zone four or five out the back of it. And, and I sort of treat the zone two as a warm-up, yeah, in, in that. So in that session.

Dose-wise, across a week, we've mentioned 150 minutes a few times in this conversation. Is 150 minutes of zone two per week, is that the minimum dose that would be required to build healthy mitochondria? I don't know. I, I personally question those numbers. Right? I mean, I think that we as humans, in our health, we've gotten so low, right? That, um, the recommendations of 150 minutes, you know, are, in my, that's my opinion, you know, they're probably not enough. I would do more. Um, and I think that more research is coming out, right? That if you do more minutes, you know, your your health is going to be better, and your longevity, it's going to be better. Beyond X amount of minutes, which I forgot how many now, you're not going to see much benefit. But I think that, uh, 150 is kind of borderline, uh, especially for people who want to, uh, delay many diseases and for longevity. 150 minutes, like, uh, at the end of the day, uh, yeah, it's just, if you do, I mean, yeah, it's, I don't think it's enough. I think that some, some of them were more in the 300 to 400 minutes a week, it's ideal, which is twice. Yeah, I think I've seen some research suggesting that there's continued benefits up to 10 hours a week, and maybe it's diminishing returns after that. Maybe there's just not enough subjects doing more than 10 hours to get a good amount of data.

You mentioned 60 minutes in a session being perhaps ideal. I know a number of people will be thinking, okay, let's say I do 300 minutes per week. Can I, can I split that up into 10 30-minute sessions, or does each session really need to be at least 60 minutes in duration? Yeah, yeah, I think that it comes to to your schedule, right? If you can do that, boom, and get out of the way, in my opinion, doing it continuously, it's better than to, uh, to break it apart. But sometimes people, yeah, and, and I, I have clients and patients all the time, right? They ask me, "Hey, I just don't have, I can do 30 minutes walking to work or or brisk walking or before work, and then 30 minutes afterwards or something like that, right?" If that's the case, it is what it is, right? But I just want to go back to what you were saying real quick about that the benefits, uh, because it just came up to my mind. I see people, um, who are in the late 50s, early 60s, who've been for years, uh, doing 150 minutes, 200, struggling with time, right? But maintaining being fit, right? Because they're moderately active, right? But being fit, but always struggling with work, family, etc. And then they, they retire early, earlier, if they're like those who are lucky, right? Or pre-retired, or they work, you know, like 20 hours a week or part-time or something like that. And then they start exercising and training in a more serious way, doing 10 hours a week, for example, or eight hours a week, right? We're talking about 500 minutes, 600 minutes. And in one year, within one year, their metabolic fitness increases dramatically. Their mitochondrial function, their fat burning capacity, lactogenesis capacity. And then you see data in people in their 60s that it resembles the metabolic data of people in their 30s. So this is kind of not as extreme as like the example of the 81-year-old person that I told you. But I see this all the time, and it's incredibly inspiring to see that you can get a metabolic fitness of someone in their 30s when you're 65. Right? It's attainable for those ones who can afford the time. But also, I think it speaks a lot, uh, in the, in the about that probably we need more minutes than 150 to to be better, you know, for longevity, for metabolic health, than 150 minutes. We can do better. That's maybe the right way to put it.

Yeah, I want to speak to you about the best modalities that that someone can use for their zone two training. And you, you've mentioned walking a few times here, and you spoke about the hearts are doing 150 minutes of walking per day. I'm sure there are people thinking, well, I, I go for a walk every day. I walk down to the shops. So when it comes to walking, what sort of counts as zone two training, and perhaps what doesn't count? So, yeah, that's a good point. So I think that for, for most people, if the, if the exercise is working, it's going to be a brisk walk, right? Like a slow walk might not be enough to recover or improve that decay, you know? It might, it might be good to maintain. And this is what we see in in blue zones and areas in Europe, for example, in the Mediterranean countries, right? Where people live longer and healthier than for example, here in the US. And they're always walking to work, working to shop, right? Or even within here in the US, in in cities like New York, right? In New York, uh, people don't have big pickup trucks to go and buy food for two weeks, right? People have to live in small apartments, small refrigerators. 85% of people in Manhattan, for example, they don't even own a car. So that means they have to walk all the time to the store, and it keeps them walking, you know? And if, if, uh, before that, you've been, uh, you've been exercising for years, that yeah, that walking alone might maintain, uh, or or slow down the decay significantly, right? But if you already have a decay and you want to improve it, there's no walking might not do much for you. You might want to do a brisk walk, right? And then eventually improve, improve, and you might end up maybe slow jogging, and maybe a faster jogging or something like that, you know? Or, um, yeah, or if you're on the bike, you might start very easy on the bike. And, but again, this talk test I was mentioning, I think they can guide a lot of people. Ideally, ideally, you want to go to a laboratory and get your specific training zones and wear a heart rate monitor or something like that. Or now, these watches can give it to you, but ideally is that. But if not, the talk test can help you.

And you mentioned the blue zones there, that gets me thinking about the enjoyment that comes with the way that you're moving your body. You spoke before also about consistency, right? So we could overcomplicate this to the point where someone ends up choosing a form of exercise that they hate because it gives them the best sort of time in zone two. But there's rucking, there's cycling, there could be stationary, it could be outdoors, there's jogging, that could be on a treadmill in a gym or it could be outdoors, there's swimming laps, there's all these different modalities. And I guess enjoyment has to be a big part of this so that you keep showing up day in day out. Exactly. And this was part of the sustainability that we're talking about, right? And it depends on your fitness level that you have to start up with. If you have a very high fitness level, as the people we were talking about who do more high intensity, right, and all kinds of exercise, but that might be good. But if you're someone who's been sedentary for 20 years, uh, maybe just walking around the block, it's going to be quite tasking, right? So then you don't want to take on jogging or swimming. If you don't have a good swimming technique, swimming, it can be really, really hard exercise for you, right? Or, or cycling, yeah, if you live in a mountain zone and and you haven't cycled in a long time and you're overweight or obese, probably not not your sport, right? But you might be doing a stationary bike. So I think that it is important to, when you engage in an exercise program, to know, as you said, very well, what do you enjoy, what do you think is sustainable, and also for that, you need to be, what fits me the most? Is it running? Is it, is it, for my niece also, I have knee problems. For someone might say, I have knee problems, so I cannot run, or, you know, but I prefer swimming because I used to be a swimmer for example, a long time ago in school, so I have good technique. I don't know. So I think it's important to fit the type of exercise and individualize it.

Yeah, there's some really important takeaways here for people. One, you sort of emphasize the importance of trying to get up to 300 to 400 minutes a week ideally of zone two, which is a bit above the kind of 150-minute recommendations, or that's the lower end of the recommendations anyway. And then this idea of the exercise you're doing being relative to your baseline fitness. So the commonality among everyone that's doing zone two training is that the perceived exertion is going to be the same, and you're going to be in that same position of being able to have a conversation but being a bit puffy. It's just that the fitter person will be doing more work, so they might be out jogging at a much faster pace or swimming laps much faster. And someone else might be at that same level of perceived exertion, the same puffiness, and the same ability to have a conversation, just taking a little stroll down to their shops. And over time, that talk test is still going to be what you're going to use to guide your zone two, but you're going to be able to do more and more as you get more aerobically fit and the mitochondria are being upgraded, so to speak. Yeah, I agree. I agree. And this is, this is what we see with many, with many people who start exercising. This is exactly what they tell you, you know, like, "Wow, I can go faster at the same perceived effort, right? And I can talk." Like, you know, "I can still talk before I, at this, I used to go with my partner, whatever, and I couldn't talk past this walking speed. Now I can talk, no problem, right?" So that, those are the things that are important to keep in mind.

I regularly do resistance training for sort of 60 to 90 minutes, and I wear a Whoop, sort of wearable fitness tracker. And within that, it breaks down the time that you're in different zones during your workout. And something that I've observed is that during that 60 to 90 minute resistance training session, about 45 minutes of of that are are in zone two, or it tells me they're in zone two. Would that count towards my weekly zone two target? I don't think so. I think that what it picks up is like when you're recovering from lifting, right? Uh, it picks up, let's say your zones. Now, you entered with the test that you did, 129 to 140, right? So it picks up when you get there in between sets or intervals, boom, yeah, you might be in that zone, right? So that's why, yeah, you might see the majority of the time actually you're in zone two, but, but it's a recovery phase, right? It's not a metabolic phase where you specifically stimulating that mitochondria function, right? Because, yeah, as you know, like when you, when you do resistance exercise, it's, it's more the ATP-phosphocreatine system that you engage, uh, which is quite tasking, and then you need to replenish that ATP, and you do that usually by increasing glycolysis, um, and, and then, uh, one of the things that, uh, that happens, he's like, yeah, it's just, but obviously the heart rate decreases, and it might be perceived by the, the watch or the heart rate monitor that you're in zone two, simply by the fact that you're, um, um, decreasing. But I think that, in my humble opinion, that that, um, that resistance days, obviously, are really important to do, um, uh, but I think there is something that you need to isolate, right? So it's okay, this is my days for resistance training, or I'm just going to isolate this session completely from the rest, or I'm going to do zone two as, as a warm-up, for example, and at the end, I'm going to do resistance training, or I'm going to do resistance training in the morning and zone two in the afternoon, whatever. But yeah, I think they need to be isolated.

In a perfect world, where would we position zone two training? I know there's some discussion around, are you able to stress the mitochondria more if you're doing your zone two training in a fasted state, or perhaps you're following a high-fat, low-carb diet? Are these strategies that would allow you to increase fat oxidation and sort of further stress, um, the mitochondria to get those adaptations that we're trying to achieve or unlock? Possibly, possibly. I am, I'm definitely open to that. But I think we need to be careful because when you tell people to fast and exercise, it can be a double-edged sword, where people can overdo it and become catabolic. So they really have to manage their intensity and their frequency very well. But, uh, yeah, it could, it could simulate my kind of fat oxidation. Although, yeah, we have to be careful with that. I, I think that, uh, the truly way to improve fat oxidation is to improve mitochondrial function first, rather than doing it in a fasting state or restricting carbohydrates. There are a lot of, you know, anecdotal data and even some scientific articles showing how fasting increases fat oxidation in the laboratory, right? Well, that's an artifact, in my, my humble opinion, from 30 years doing this testing. Because one of the things that happens, if you are fasted and or you have, you've been restricting carbohydrates, you don't have much glycogen. So when you do this metabolic testing and people do now substrate utilization to see how much carbohydrates and fat you do or you are, or even your RER, then you see, yeah, this person is burning more fat under this stage. But yeah, it's not, in fact, in many cases, because, you know, you don't have as many as much glycogen, so you cannot burn or utilize as many as many carbohydrates. And then this, uh, metabolic cards function through what's called stoichiometric equations, right? So in order to burn, uh, one gram of fat, you need X amount of VO2, and you produce X amount of CO2. And the same thing for fat. Therefore, these equations can be, can be equivocal. Because if you don't have enough glycogen, you're not going to engage glycolysis so much. Therefore, your CO2 production is going to be less. Also, you're going to be producing less lactate, and that's going to fool the machine interpreting that, "Oh boy, he's not, he's narrow, she's not burning so much, uh, uh, carbohydrate, therefore must be burning a lot of fat, right?" So, uh, it could be equivocal. And then we have seen that, uh, yeah, you know, "Oh, you've improved your fat oxidation tremendously with this diet and blah, blah," and then, uh, two days later, just in two days, that person goes to a normal carbohydrate diet, and fat oxidation decreases by half, right? And, and that doesn't mean that the mitochondria in two days, all of a sudden, "Whoa, I am not burning fat now." Is this that it's probably an artifact from the, uh, from the test itself.

So if I wake up in the morning and make a big bowl of oats, rich in carbohydrates, and have some banana in there and some other fruit, and then I go and do, so I have a lot of carbohydrates on board, and I go and do my zone two training session an hour after that, is that in any way going to impair that zone two session? It depends on how feeling, how metabolically flexible you are, I would say, right? If you're normally flexible, you should not impair much. I'd still with a low 30 to 40 minutes, right, for those carbohydrates to be metabolized and then via or via a stored as glycogen, right? And then you can burn more fat. But, but still, you know, the intensity is going to override that, that high hyperglycemia. So, uh, one of the things that you do when you start exercising, um, is, uh, increase cortisol levels as well, and catecholamines, and those are important for lipolysis, so you're going to bring down more fat. And that is going to override, uh, in many instances, that the possible slight hyperglycemia that you might have, which, by the way, it's also be managed by insulin, right? And, but there's, there's a threshold that we still don't know very well, like, it's called the cortisol threshold, because cortisol is necessary for lipolysis, right? For breaking down the fat to use it. But past X and, like, uh, exercise intensity, cortisol is absolutely needed to, uh, break down glycogen for energy, right? And in cortisol, then at least it's vasoconstriction to the adipose tissue and catecholamines, and therefore shut down lipolysis. So it's a paradox that it opens up lipolysis, but it also shuts it down, right? So, but I think that in early exercise intensities, I mean, low exercise intensities, you can override the effects of having a banana, for example.

Are there any nutritional or supplementation recommendations that are evidence-based that can help improve someone's zone two pace or the adaptations that they derive from zone two training? I, I'm, I'm not aware of, you know, of, uh, science-based that I, that at least I believe, you know. I think that the best way to improve is exercise. Um, but, uh, yeah, that's, that's, that's what I think.

Yeah, have you heard of a compound called Urolithin A? I've seen some, some marketing in just the recent months, but maybe over the last year or so. And I quickly researched it ahead of today's conversation. I really didn't know much about it. But it seems to be a compound that we, or our bacteria in our gut, naturally produce from certain polyphenols found in berries and pomegranates, etc. And I looked up online some of the, the sort of more popular brands and I won't mention brands here that are promoting this product. And, you know, some of the claims of that this postbiotic will energize cells, increase muscle strength, that it's a molecule that will activate mitophagy, which we haven't spoken about, but to my knowledge, is kind of the clearance of dysfunctional mitochondria. Do you have a view on Urolithin A? Is it something that you've, you've sort of looked at at all? Well, not, not a whole lot, but I, but I think like, yeah, I just, I, I, I, yeah, I don't have much knowledge about it to tell you, but, uh, but I, I'll be, uh, still, uh, I will doubt about the big benefits of these supplements, right? I, I really, yeah, I, I don't buy the whole idea that one supplement is going to really make a difference in, um, mitochondrial function or, or it's going to alter, you know, the epigenetics, you know? Like, I, I really, I really, I really doubt it, you know? Um, uh, you know, like, there's like one recent one that is now the big deal, although, yeah, I think it's, it's now on the slope down, that is, um, um, um, NMN, right? Or anymore, like, uh, yeah, nicotinamide mononucleotide, right? Which is a, um, like a precursor of, uh, NAD, right? Because as we age, NAD levels in the cells, they tend to decrease, um, and therefore the supplement, uh, is going to, it's a precursor for NAD and it's going to increase, and therefore the cellular function, etc., etc., right? I don't know. I've seen people saying, "My gosh, since this, I am the strongest person in the world. I've been all the records. I feel amazingly strong." And one month or two months later, they don't tell you that anymore, or six months later, right? So I think there's a lot of placebo involved in many of these things. And in fact, we haven't published it because it's a small sample, but, um, for cancer, we have seen that, uh, NAD, for example, um, can accelerate glycolysis, because NAD, it's, it's a big part of the glycolytic pathway that is utilized by cancer cells, right? So we did this experiment with mice where we implanted aggressive tumors. It was like a, um, triple-negative breast cancer tumor. And, uh, one group of mice, we didn't, we gave them placebo, right? And the other one, we gave them the, uh, NMN. And, uh, yeah, within, within 21 days, the, the growth of the tumor was 15% higher in the, uh, in the, uh, in the group with the supplement, right? So I'll be cautious about this, because can that fuel tumor growth? If you have a small tumor, can you fuel with that? We don't know. I think we need our evidence more.

Is like people taking also these longevity drugs to improve from mitochondrial function to liver, 20 years longer, or get rid of diabetes, which is rapamycin, right? So for rapamycin, it's a, it's a key, uh, it's part of a key pathway, um, for cell growth and proliferation, right? And, uh, there are a lot of, uh, negative and, and positive feedbacks in those pathways. And I always like to say, don't, don't mess up with Mother Nature and biology if you're healthy, right? Because why did you take in this, uh, supplement? And this is going to dysregulate another one that is going to take to a complete dysregulation of that pathway and lead to a disease down the road, like could be the case of NAD supplementation, right? Dysregulates even more, probably could do that. I'm not saying this because, yeah, we need a lot of research on both sides, right? So, uh, yeah, I'm, I can, I can, uh, yeah, I, I think that we have to be careful with with some of these supplements, which more and more are sophisticated and can get to, can really do biological actions more than just having like the typical vitamin C or, you know, or vitamin, uh, uh, A or even D, right? I think that now some supplements can be very targeted, you know, specific.

Yeah, I'm glad that you flagged that. It's a reminder to kind of remain cautious when new supplements enter the market and there's not a lot of long-term data on them. Is it frustrating for you that the longevity science community, I mean, clearly mitochondrial dysfunction has been identified as one of the hallmarks of aging, but a lot of the focus on addressing that has been through the use of various compounds. And I certainly haven't seen many scientists from this field talking about the enormous benefits that are up for grabs with very specific exercise, namely zone two. Do you wish that was more front and center or prime time? Yeah, I, I definitely think that, uh, exercise is, is definitely a way much more powerful than any of these supplements or compounds, right? Um, and, uh, and it's very healthy. The effects of, uh, exercise, they're like more and more research showing at the molecular, cellular level, and the exokines, uh, which are little vesicles produced by skeletal muscles that they go to many organs and they can, they can keep disease at bay. This is something that no other supplement can do. And as I was mentioning, some supplements, there are so specific, they're so targeted on pathways, they're very important for cellular cycle and cellular growth, that we might not want to touch if we're healthy, you know? Because that might dysregulate the whole pathway or other pathways, you know? And, and there's a lot of money involved with this. There's weak science. There's science done with mice, who tend to live two years only, and they say, "Oh, they live three months more." There are four, could be 10 years more for a human. It's a different ballpark. And I remember one of the supplements that came out, resveratrol, right? That, uh, it came up 30 years ago or something like that, life, right? Because it was shown that mice who were taking resveratrol every day, they would live longer. And therefore, this is going to be the best import or most important longevity. That's when kind of the first longevity supplements start to come out, right? Now, the people who were 50 years old 30 years ago taking resveratrol, they haven't lived 20, 30, 40 years more, I guarantee you, right? And it faded away, you know? And like the same way that most supplements will fade away. But exercise will continue. But again, that's what I was saying, if we could encapsulate the benefits of exercising, a pill, yeah, that would be the most, uh, sole drug ever in history. Everybody would jump on it.

Okay, to summarize things here for the listeners before we let them go, I think two of the most important things that we've spoken about when it comes to metabolic health is firstly, being good at converting chemical energy from our food into mechanical energy, which requires healthy mitochondria. And the best stimulus for building healthy mitochondria being this zone two training that we've spoken about, and trying to get to sort of three to four hundred minutes of that per week. And then another important part of metabolic health being the storage of energy, particularly fat, in the right place, which means storing fat subcutaneously rather than sort of between or within organs, which comes back to partly someone's personal fat threshold, but really will be achieved by finding a way of eating that leaves you feeling satisfied for without needing excessive.

calories beyond your energy requirements so that you don't get into that state of energy toxicity. Um, and that the Zone 2 training, um, doesn't mean or shouldn't get in the way of other important forms of training. So you still want some Zone 5, 4, 5 high-intensity work. We spoke about how the two of those kind of work together to help you better clear lactate and of course, resistance training as well.

Was there anything that we didn't discuss today or perhaps that we, we spoke about briefly that you kind of wanted to add to?

No, I think, yeah, you summarized things very well. I did, you did a great job at, uh, summarizing and everything that we've been discussing too and, and breaking down every single aspect of our podcast. Um, and, uh, and I appreciate it. Um, I just think that maybe just the thing that would add is, is like, uh, there's a lot of hype around Zone 2 that maybe people are getting like, because in our society, how societies, people taking things to the extremes and, uh, that now for some people everything is on too, when it's not right. Uh, and, and believe me, I've been doing Zone 2 for, for 30 years with my athletes and, and patients as well. But, uh, they're more than that. And as you said very well, you know, there are other intensities that are necessary to do. And, uh, um, all the forms of exercise like resistance training, right? That Zone 2 is another panacea of, of health and everything. You know, it's a very important part, I think, and I, I believe it strongly. Um, but yeah, it's just like we, we have to still be on track that there are other things, you know, that you can do. Um, it's like in nutrition, we cannot say that when nutrition is the best and that's it. Now, I think that, you know, could be better than others, right? But I think that, um, yeah, we need to do things in moderation.

Also, we didn't discuss this, but it kind of comes to mind now. Zone 3 and Zone 4 are often considered or said to be no man's land or or junk volume. Is that an oversimplification and do Zone 3 and Zone 4 have a place within someone's cardiovascular training sort of regime?

I don't think so. I think that, uh, they both are going to be good zones, right? And again, it depends on how much time you have. You know, for example, with my athletes, that the world-class cyclists, for example, that they train, you know, a 20, 2 to 27 hours a week, right? So they have a lot of sessions of Zone 2, but they also have a lot of time they spend, not as much as Zone 2, obviously, but they spend sessions specifically at Zone 4 and even so, 3, right? Uh, which are necessary also for, for performance to improve those, especially so far as we discussed those glycolytic pathways and the MCT4s. For people who don't have more than, uh, five hours, six hours a week, um, you know, I, I would recommend more to focus on the Zone 2 and, uh, and, and on the Zone 4. Um, you know, either at the end of a Zone 2 session or maybe dedicating, if you exercise four days a week, uh, you can do another two days on your own or one day and all out, right? But, but I, I would maybe isolate those two points, those two zones, Zone 2 and Zone 4. I think they're quite important. Uh, one for the glycolytic capacity, which is the turbo, and the other one for more the mitochondrial function.

There you go. This has been incredibly informative. Thank you so much. Thank you for all of your work, your research, your contribution to, to science. I think we'll have to get you back on to, to continue the conversation. I'm sure the community is going to come, come back to me with a number of, of questions. So perhaps next time I'm in Colorado, um, I might actually be there later this year. I have some friends that live at in Boulder, so perhaps we could, uh, continue the conversation.

Yeah, absolutely. Yeah, let's meet whenever you're here. Let me know. I'll be happy to, uh, to meet for lunch or coffee. Absolutely. And let me know. And yeah, it's, uh, thank you. Thank you for inviting me to your show. Uh, your podcast. I'm, uh, yeah, it's been a pleasure. And thank you also for your, uh, contributions. Uh, because it is very important that people like you are, uh, really, uh, sending the message, you know, and that which is huge and really, really important. Then from, you know, something that, uh, scientists and clinicians are not great at doing that, right? Uh, but, uh, people like you, you're with your science background, of course, uh, your understanding and your research, it's, it's, it's important that that your contributions, uh, are, are well, well noted for sure.

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.

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Zone 2 Training: The Science Behind Peak Metabolic Health | Dr Inigo San Millan | The Proof Podcast

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