← The Neuro Experience
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- [00:00]
A
I think that we need to take that step. Under microscope, it looked like that cancer was from skeletal muscle, but it is. Skeletal muscle doesn't really exist.
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B
Even just 30 minutes of exercise per day can down regulate 13 types of cancer.
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A
Athletes have the best skeletal muscle of all humans.
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B
I want to talk about glucose and lactate and how that relates to your understanding of cancer research.
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A
Cancer cells produce great amounts of lactate. We need to really understand better Dr.
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B
Inigo San Milan, a world renowned expert in metabolism, exercise physiology and cancer biology. He is also a pioneer in advocating for Zone 2 exercise, showing how this specific intensity of training can enhance mitochondrial function, support longevity, and even play a role in cancer prevention. Let's just map it out for everybody. Zone one is literally sedentary, correct?
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A
Yes, exactly. So it depends on.
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C
Inigo.
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B
Welcome to the podcast. I'm so excited to have you here.
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A
Thank you very much, Lisa. I appreciate your invitation and very excited to be here.
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B
All right, I'm going to get right into one of the most exciting and boldest statements that I've heard you say, and that is you've said elite athletes might hold the key to curing cancer. And you've mentioned quite notably that cancer rates don't exist with more with people who have more skeletal muscle. So I'd love for you to draw the connection between skeletal muscle cells and cancer.
- [01:36]
A
Well, I mean, elite athletes might not hold the the cure for cancer, but my whole many clues and answers about how a perfect metabolism works originated by skeletal muscle. Historically, it's been thought that rhabdomyosarcoma, which is muscle cancer, was one more cancer or rare cancer affecting children as a genetic disease or in rare situations as a metastatic cancer. But it's been known recently it's been found that skeletal muscle as it is rhabdomyosarcoma, doesn't really exist. Being raised from skeletal muscles because under the microscope it used to be thought and it looked like it was skeletal muscle cancer. But the latest research shows that those cells that gave rise to cancer were from within the vessels that are within the muscle cells. They're immature cells. They maturated within those vessels. Under microscope, it looked like that cancer was from skeletal muscle. But as it is, skeletal muscle doesn't really exist. This is why skeletal muscle is the best organ to find some clues about cancer is the largest organ in the body, yet an organ that doesn't see cancer. Athletes have the best skeletal muscle overall, humans. So I think that the connection between athletes as well as muscle metabolism can give us a very good Answers about the origin of cancer as well as potential therapeutic interventions.
- [03:25]
B
That's really interesting and mind blowing to me. Does that have any, I want to get into the actual connection there. Does that have anything to do with the amount of IL6 that is getting secreted from the muscle cell during a muscle contraction? And I've read research from Ben to Peterson actually who stated that even just 30 minutes of exercise per day can downregulate 13 types of cancer. And when I was looking into it a bit more and researching it, I know it has a lot to do with the myokine activity. And there was one statement that I found that said something about natural killer cells and the amount of IL6 that's getting secreted, which interacts with the natural killer cells, which can downregulate tumor growth. So is that the, Is that the pathophysiology right there?
- [04:23]
A
That could be one. I think I'm more keen about at least my humble opinion about the exosomes or myokines from skeletal muscle. It is very well known and it's a growing area of research in cancer. Exosomes, which are, as we know, cells derived from cancer, they contain the genetic material from the cancer cell. They originated exosomes that used to be thought like they were the poop of cells. Now with better technologies, we know very well that those exosomes are full of genetic material as well as proteins. You have mRNA's, micror and hundreds of proteins that represent that organ, where they come from. They are released in cancer and many may not survive, but some they might target a candidate organ and get into that organ. These proteins that these exosomes have are amazing. We have a study that we haven't published yet, but we found in both in breast and lung cancers about 700 to 800 proteins. In those exosomes related to all the process that you would need for a genetically engineered cell to infect a tissue. You have first anchor proteins that will anchor to the recipient organ. Then you have proteins that alter and change the extracellular matrix so that that exosome can get in. And they have proteins that are going to be lysing the exosome and releasing all the genetic content and especially mRNA's and micrornas and changing the phenotype of that cancer cell. But anyways, this is a big area now in metastases originated by exosomes from cancer cells. In the same way skeletal muscle has been very well known that releases a huge amount of exosomes as well, which are called exokines or myokines if you change the phenotype of that muscle or the metabolism of that muscle, the exosomes that you're going to be releasing from very healthy muscles. The question is, could they either keep at bay multiple organs in the body, including those ones who might be target organs for cancer, or could they counteract the exosomes steroid from cancer cells? I think that this could be an area of significant research and potentially therapeutic interventions in the future as we understand this exosome world better. We're still scratching the surface, but it's, it's a fascinating area.
- [07:29]
B
It really is. I, so I, I work in neurosurgery. Most of the cases I, I'm going into are neuro oncological. So my research now has, it's very much targeted towards Alzheimer's disease, which it has been for most of my career. But it is taking a shift into the, into the brain tumor space because that's just where I am, that's where the operations are occurring. And so right now my entire research, I'm doing a case study. We, we just, we just extracted a frontal lobe tumor and I'm doing a case report on that. And the amount of research I found on metastases, literally stage three cancer survivors who have been gone into remission due to high intensity aerobic exercise. So that's, that's extremely promising too. So it's not just in the prevention space, but it's also, these exosomes can also have an effect on stage three cancer outcomes.
- [08:36]
A
That's, that's fascinating. I would love to know more about that research because it's really fascinating. And as you know, exosomes from skeletal muscle can cross our blood brain barrier.
- [08:46]
B
Right.
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A
And there's a whole new area there to, to understand relating not just to cancer but other diseases like type, like type 2 diabetes in the connection with Alzheimer's as well. Right. As, as you know, skeletal muscle can elicit and especially in lactate derived from skeletal muscle can have good benefits and can increase neurogenesis in the brain. So how in the world can the lactate from skeletal muscle can get to elicit neurogenesis? That's all these areas are really fascinating.
- [09:19]
B
Yeah. So lactate, let's, let's talk about that because I know it's a big part of your research and lactate is often misunderstood. We went through this phenomenon, I don't know how you felt about this phenomenon of people saying that it's the lactic acid burning your quads. That's what it is. And we now know that that's a myth, it's been debunked. But I read a book actually. It was inspired by you. It was the book on Otto Warburg and yeah, it was. Remind me of the title. It was his autobiography.
- [09:51]
A
Could be Rendezvous by Sam Apple.
- [09:53]
B
That's. It was Sam Apple's rendezvous. Yes. And it, it blew my mind. So I want to talk about Otto Warburg's findings on glucose and lactate and how that relates to your. Your understanding of cancer research.
- [10:10]
A
So yeah, so Otto Warburg was an amazing scientist and he, he's one of the most remarkable biochemists or specialists in cellular metabolism biochemistry in history. In fact, from his laboratory he, we know that he got, he obtained the Nobel Prize. But he was the mentor of two other Nobel Prizes winners. One of them was Meyerhoff, Otto Meyerhoff who discovered glycolysis with MDIM and it was used to call the MD Meyerhoff pathway and now it's called glycolysis. And Meyerhoff started working in glycolysis with Warburg in his laboratory. And he was his main ward, his mentor. And then the other person was Hans Kripps, the guy who came up with Krebs Cycle. He was also Warburg's mentee. Amazing things happening the laboratory in Berlin in the 1920s. Anyways, in 1923, Warburg, he wanted to study the bioenergetics or metabolism of cancer cells. He injected or infused cancer cells with glucose, with fat, fatty acids as well as with protein and he wanted to know their metabolism. What he saw is that cancer cells, they had a higher preference to use glucose and they use more glucose than non cancer cells. What really struck Warburg is that cancer cells produce also great amounts of lactate. In fact, back in the days that didn't have like we have nowadays, like ways to analyze lactate with these very nice machines that we have or even the small handle analyzers. And we didn't measure in blood, I mean we measuring blood. But Warburg used to measure lactate in terms of total weight of the tissue or the organs. So the total weight of the of lactate was somewhere around 12 to 15% as average. So it's a significant amount of lactate. And he was so incredibly smart and advanced back in the days over 100 years ago, 102 in fact that he deducted or he posited that because pyruvate has to be oxidized in mitochondria, right. And otherwise you will see a higher lactate concentration because pyruvate is reduced to lactate. He Already deduced back in the days that the cells, cancer cells must have a problem with the respiratory system, which is mitochondria, so they could have a mitochondrial dysfunction because of lactate. Lactate was the clue, the clue for war work to really posit that lactate, I mean the cancer was an injury to a respiratory system.
- [13:19]
B
That's, that's, I think that, that. So then that I guess was the birth of metabolism and the mitochondria and how the mitochondria is a key player in all cause mortality. Really if you look at a lot of the research in whether it's cancer, cardiovascular disease, Alzheimer's disease, you can really pretty much look back to metabolic disorders or dysfunctions of the mitochondria.
- [13:46]
A
Yes, that's right. And, but I think that we have to be a little more careful with that because ultimately any organ that is affected by any disease, including viral diseases, right. They're going to suffer dysregulated by energetics, dysregulated cellular metabolism. Right. So we're going to see mitochondrial dysfunction in the end of any stage. So we have to be careful maybe not to think that all diseases or many diseases are metabolic diseases because in fact pretty much every disease in the end stage is going to have that metabolic disorder at the cellular level. And this is one of the things that is typical of diseases. But in fact for sure there are other many diseases that are more and more prevalent because we know a lot more about bioenergetics and how type 2 diabetes, Alzheimer's disease and even cancer are characterized by significant dysregulation of cellular bioenergetics. Way ahead than when it's not end stage. Like other diseases, it's happened at the beginning of the stages.
- [14:57]
B
So talk to me about the research you're doing with the nanoparticles to actually block lactate in cancer cells. What does that prove?
- [15:07]
A
Well, we did just a pilot study trying to. We didn't block that. We did this blocking with, you know.
- [15:15]
C
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- [16:06]
A
That is Zocdoc.com neuro in genetic engineering blocking LDH but with nanoparticles, which is had some money to create a pilot nanoparticle and to try to prove. I mean have a proof of concept. So we created a particle that could target cancer cells based on how we created that nanoparticle to detect some features of cancer. I can say much because we still don't have the funds to complete the research study. But what we saw that we threw those nanoparticles into lung cancer cells. A549, that's the cell that we use which is non small cell lung cancer. It's just all the nanoparticles and then we. We use fluorescence to trace the nanoparticles and all the nanoparticles they left the spent media and all they got in and surrounded the cancer cells. That was a proof of concept that these nanoparticles they just didn't float around the media. There was in vitro of course, and they just surrounded the cancer cell and it got in the cancer cell. And I mean they're multiple groups around the world now working with nanoparticles trying to modify them. Because if you have a nanoparticle that can penetrate a cancer cell or surrounded but spatially penetrated, then you can load that nanoparticle with many types of medications that can destroy that cancer cell and targeting specifically that tissue instead of targeting other areas in the body. It seems like nanoparticles have a significant role potentially in therapeutics in cancer in the near future. But we need more funds. That was a point.
- [18:11]
B
Yeah. Of course that's like the. Yeah. Unfortunately here in the United States I think NIH funding is actually getting cut. So it's quite scary. But nonetheless we.
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A
These are types of things. Sorry. That NIH would not fund though. That's a problem.
- [18:28]
B
Oh yeah. Interesting. Probably because it's not a pharmaceutical drug.
- [18:34]
A
Well, I think new ideas are usually hard to. Don't have much of a room with an NIH scope. Right. You know, the high risk, high reward. You know we all talk about. I mean it's very. We know that high risk, high rewarding in research should be quite important. But for nih it's only 0.5% of the total budget per year. So it's hard for new ideas to be funded by nih unfortunately. And you need donors are now more important than NIH for many studies. Also, industry relationships are important. But anyway, that's a whole different thing. Sorry, didn't want to.
- [19:20]
B
No, I want to. Now I really want to talk about interventions. So we've discussed, now we've discussed the importance of skeletal muscle. I would love to talk about Zone 2 training and your hypothesis on training in ZO2 and really, really deconstruct what that is. Still, to this date, no matter how much information you have put out there on podcasts, either as a guest or just as yourself, people still don't have a clear understanding of Zone two. So I'd love to deconstruct that. And what are some of the findings that have led you to believe that training in this zone could be, I guess, quote, unquote, cancer preventing?
- [20:06]
A
So, yeah, so thanks for the question. So when I, I mean, I started Zone 2, at least my Zone 2, about almost 30 years ago, and the way I started it was because I wanted to define a little bit more what happened at the bioenergetic level. I was transitioning from being an athlete, a competitive athlete, to start working with athletes. And I wanted to really understand better, you know, how could I work better with athletes? Because as an athlete, all I thought, all I heard was, you have to do aerobic training. Low intensity, but long. Right. And I was like, what the hell is that? You know, like, everything is aerobic exercise all the way until your VO2 max. So from 0 to VO2 max, everything is aerobic. So there's a huge array of exercise intensities. Right. So I didn't quite understand which one. And then 60% of the maximum heart rate, 70% of your VO2 max, how do you measure that and how you give the one size fits all, you know, that was kind of more like what was prevalent also. Yeah, I just didn't quite. I was not happy with how I used to train, you know, and with this concept. So I started to get into more like what happens when we stimulate one exercise? I mean, one energy system. Right. Is different or it should be different. If we stimulate more the oxidative system than the glycolytic system, you should have different changes at the metabolic level. At the cellular level, it should be different. Also when we do sprinting or high intensity or torque, it should elicit different responses. This is why you would see different athletes training different concepts all the time. So anyways, that's why I decided to. Okay, can we just name it some way? So that's why I decided I built this. What I call metabolic map with different training zone from zone one to zone six. And I started to work with athletes based on those zones. So what I saw is like zone two, when I was working with athletes.
- [22:32]
B
Wait, so let's just, let's just break that down. Zone one is. And there's a lot of exercise physiologists that don't use the six zone model. There's a lot of exercise physiologists that just use the five zone model. So I don't know what your take is on that, but let's just map it out for everybody. Zone one is literally sedentary.
- [22:51]
C
Right now.
- [22:52]
B
You and I are in zone one, correct?
- [22:54]
A
Yes, exactly. So, yeah, and you're right. So it depends on the training zones. It depends on the person. Right. I just, to me, it was like six zones that I, I just decided to, to, to. To start with. But yeah, zone one would be when you're very easy intensity, right? You, you always burn carbohydrates. And this is, this is something that there's a misconception thinking that at low intensities, all you burn is fat. That's not true. At low intensities, you burn also carbohydrates. You don't burn much carbohydrates, but you burn carbohydrates all the time. That being said, at zone one, you burn fat also because what you stimulate are. I mean, the muscle fibers are recruited are the type 1 muscle fibers, which are characterized by oxidizing fat and also having a higher mitochondrial content because fat can only be oxidized in mitochondria. Therefore, when you measure in the laboratory fat oxidation, which I started a long time ago measuring it, I could see that you could very. See very well how fat tends to increase during exercise. And it gets to a point, you get like a, to like a. The maximum fat oxidation, and then it starts going down. But we're going to be there in a second. But so if you see that fat has been oxidized, it's a signature or it's a clue that you're recurring type one muscle fibers. Right? But at low exercise intensities, you're not burning much fat, you're not burning many carbohydrates, and you're not producing much lactate. So it's a low exercise intensity. Then you increase exercise intensity and therefore the necessity to produce ATP is faster, but you still can produce ATP from fat sources. So you start oxidizing more fat and you also produce more, a little bit more of lactate. But still are within, almost within resting levels. But the main thing is like this is where you could be burning the most fat. You're stressing those type 1 muscle fibers to their highest point before fat is not fast enough to produce ATP. So you have to change to glucose and therefore stimulating or recruiting type 2 muscle fibers. This is where you like have the highest fat oxidation. And this is zone 2. This coincides also with the first inflection point of lactate. So you go from resting levels almost of lactate during recovery or easy exercise to a slightly elevated over resting levels in lactate. So that's a metabolic event that I saw back in the days. And so what I did is like I, I translated this, translated this into heart rate. Power output was starting to become popular little by little in athletes or speed in runners, right. So, and that was like the zone 2. Then you find another. As exercise intensity increases, then you, you need to produce ATP faster than we did before and fat is not fast enough to produce ATP on time. And therefore you need to switch to a different fuel. And that fuel is glucose. So when you start using glucose, you start recruiting the fast twitch muscle fibers first. You recruit the type 2As, and therefore you see clearly that you start also oxidizing more carbohydrates with the metabolic heart in the laboratory. And at the same time you see lactate keeps increasing and there's a sharp decrease in fat oxidation. And that's what I call zone three, which could be a transition zone until you hit another metabolic event, which is when you don't burn fat anymore. And that's when you start full stimulating glycolysis because fat is not fast enough at that intensity gets to a point that zone four, that fast fat is not fast enough and then it's not needed anymore. And then glucose is highly oxidized. And that's also when glycolysis starts accumulating to lactate because the glycolytic flux into mitochondria is not sustained by mitochondria. So you need to that pyruvate, which is the end product as we know of glucose is reduced to lactate and therefore lactate starts accumulating and goes to the blood. And this is what we see, a change in lactate, another inflection point of lactate, which coincides both when fat disappears and that inflection point of lactate. That's why I call zone four and, and then zone five. It's another transition point that is pretty much when you get to the VO2 max. And that's where you, you know, obviously you still don't burn fat, you don't been far anymore. And then, you know, glucose oxidation keeps going up, going up and lactate still much higher. And it gets to a point where you reach your VO2 max and then zone six, that's when you're beyond your VO2 max. That's your first anaerobic zone, although all the rest of them are aerobic. But your first anaerobic zone is zone six is the exercise intensity that you use when you sprint or you do super high intensity exercise of under 30 seconds or so. So in a nutshell, that's how I, in my mind at least that's how you map the zone, the zones and start to work with athletes. It depends on which bioenergetics an athlete needed to use. Right? It's not the same. A marathon runner. Marathon runners, they never sprint, so they don't need to spend so much time sprinting. But a 1500 meter runner, they need to sprint also. Or swimmers, swimmers don't need to spend so much time high intensity, although that's their world. But we know that for swimmers clearing lactate is very important because not lactate per se, but the hydrogen ions associated to lactate are the ones that build up and they can cause that acidosis and a decrease in both muscle contraction force and velocity. So if you can clear lactate better than your rival, slightly better, you can get farther probably. And this is one of the reasons why swimmers, for example, like, they do long like zone two swimming, for the most part they don't, you know, that let's say 100 meter swimmer is under, under a minute, but they tend to, to train most of the time, you know, like at lower intensities. Anyways, you can see this in many different.
- [30:26]
B
I was, I was a triathlete back in my day. I raced for Australia. So I ended up competing. Well, I, I qualified for Beijing and London. And so my, yeah, so my, that's my, my, my background in athleticism, let me tell you, I'm definitely not there anymore. I hung the, hung the shoes up back in 2013, so it's been quite a while. But I, I still have the mentality of an athlete in my head. And I have to tell you, I trained probably 40 hours a week and it was three training sessions a day. A lot of it was spent in zone two. There was really, we would do something called a brick session on a Sunday, but which involved, you know, riding, running, riding, running just to get our body accumulated and acclimatized. To you know, getting on and off the bike and they, they used to hurt me so hard. Our hill sessions used to hurt me. But I have to say my swim sessions were very, were hardly ever in threshold. I think on Wednesdays. My, my coach sometimes whether he was in a good mood or not, I don't know what it was but he would just slam us with 101 hundreds. I remember and he used to say this one thing to me. He used to say bad swimmers can't swim slow. And I never understood that. And he said if you want to excel in the water, you want to be able to swim really, really slow. And that's where we would develop our aerobic fitness. This is where we would probably be in zone two. And that's where I got the technique and my foundations of swimming down packed. But yeah, that was, that was, that's, that was my first understanding of.
- [32:11]
C
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- [33:15]
B
Off threshold training and the feeling of lactate. Yeah, nice.
- [33:21]
A
No, that's quite impressive. Yeah, yeah.
- [33:25]
B
So I would love to now understand zone two in terms of all of the benefits that you have found, whether it's in metabolism, whether it's in cancer. Because in my opinion, and this is something that I give patients in terms of protocols, it is, I think that everyone should be training in zone 2 or zone 5. If you are a, if you are just training for longevity. Right. Everything is specific. If you're an athlete, evidently you have to be specific to your sport. But I think for longevity purposes I want to live to 100. I want to live a good life. I want to try my best to fight off all cause mortality in any way possible. And these End these diseases such as cancer, cardiovascular, cardiovascular disease and Alzheimer's. I want to be spending predominantly most of my time in zone two, whether that's three hours a week if you have, and then spending a minimal amount of time in that VO2 max training phase, maybe 20 or 30 minutes a week, and then reserve the rest for resistance training. So how do you feel about that?
- [34:38]
A
Oh, I agree with you 100% and this is what I recommend and what I try to do with myself too. But you're right, I think that what I saw back in the days, but 30 years ago when I started working with athletes is that those ones who would come with their coaches might not pay attention to the zones and might be training at different intensities. Right. Or those athletes, you could see the ones who might not pay much, much attention either, or they really paid attention. Right. So those ones who didn't train or train at different intensities, I didn't see when they came back for a follow up in the, in the immense majority of cases, they did improve the lactate clearance capacity and fat oxidation. So fat can only be oxidized in mitochondria and lactate can only be oxidized in mitochondria as well. So both are mitochondrial substrates. So by measuring fat oxidation and lactate clearance capacity, you can have a good indirect way and we have a publication on that, of what is your mitochondrial function during exercise. So those ones who didn't train there, they didn't tend to improve that much. So that's why I realized, wait, this intensity has something that is very good or can, can really elicit a different metabolic adaptations specifically to mitochondria. And I started obviously using with a lot of athletes of so many sports and very successful with the leading world athletes that worked really well. And now people have been using it for, for a while and I just, yeah, just it seems to be an intensity worse. That being said, it's critical also to, to improve, to train at different intensities. I always say you don't win a race in zone two. You win a race, whatever is the event in the high intensity. Whereas your view 2 max or over review 2 max or close to your view 2 max. Right. So you definitely need to train there in order to improve. And when I work with my athletes, yeah, it's just, yeah, it's really hard training also, you know, they, they don't like it much because it's, it's really high intensity, really suffering. It's not ozone 2 as people think. Right. But, but I Agree. Also for longevity purposes. If, if we can improve mitochondrial function in, in, in elite athletes through Zone two. And we know that mitochondrial function is key for health and longevity. Yes, I think that that should be a philosophy. And this is what I also do with, with people with. For longevity purposes or health span purposes. Right. But as you said also like high intensity is very important because as we age we are glycolytic system declines. Right. And we get slower, we don't get as fast and we want to get maintenance, you know, that, that maintain that intensity that, in that those bioenergetics of high intensity. So the only way to do that is by sensing simulating that. So I would agree that definitely, yeah, 20, 30 minutes a week are important to, to touch it, to stimulate it and even retraining tech to touch it a little bit.
- [37:49]
B
But you've actually mentioned that at minimum you should be doing 45 minutes per session for Zone 2 to really be able to get that mitochondrial biogenesis. I think you, I mean can you grow new mitochondria from Zone two training?
- [38:06]
A
Well, I think you can grow, but especially is the function, right? The function is, is more efficient. All the different transporters or different enzymes involving oxidative phosphorylation in lactic cleanse capacity, those seem to probably increase. And I would love to get funds and do more research into this, right. Specifically to get to the bottom of the question. What are the elements, they're the most expressed during Zone two that contribute to those improvements in bioenergetics and exercise performance and maybe in health. Right. So that we can even understand this better. But yeah, that extra intense seems to work. But intensity, high intensity is also very important because we need to improve also or maintain our glycolytic capacity. And with 45 minutes to an hour, I think it's a minimum per session ideally. But I'm finding more and more is that, and I'm quite, I mean I'm very stubborn and I think that I'm getting quite obsessed about. This is like the 150 minutes a week that we used to hear or people still prescribe. They're not enough to maintain your health span and your fitness. I really think that we need to aim for 250 to 300 minutes a week. A combination of everything. Right. But 150 minutes a week, it's not going to cut it, I think.
- [39:44]
B
Yeah, that's. That actually is in line with my, my distaste in the current physical activity guidelines, which is telling the public, which is a set of guidelines written by The CDC that informs the public on the minimum requirement of exercise and they have actually stated that it should be 150 minutes of moderate to vigorous physical activity per week. Two statements that I hate with that, the word physical activity because if you're Talking to a 70 year old, my mother, for example, she's not quite 70, but she's, she's near that age. And she says to me, but Louisa, I did the gardening today. And that frustrates me because she just hears that physical activity is anything above sedentary, which is actually true. So I, I would love to lobby against that statement and say that it should, should be a minimum of 300 minutes of moderate exercise per week. Physical activity is just a commission on top of your, what you need to be doing on top of your workload.
- [40:50]
A
I agree. And well, the, the WHO has changed those guidelines, those recommendations. Now they are between 150 to 300 minutes. But I don't think they're being pushing it hard enough because you know what, what people think out there and, and most of the messages out there by especially clinical Communities are like 150 minutes a week. But as you say, you know, it's just like gardening is not like a physical activity per se, but as you know, also in the blue zones, right, you see a lot of people are gardening and doing a lot of activities outside. But these same people, they also walk a lot and they go up the hills in these villages in Italy, for example, right. Or they go to take care of their gardens on top of the hills. Right. So they do a lot of physical, the real physical activity on top of gardening, which is very good for agility, for range of motion, even for strength. But the physical activities should be watched or seen, seen differently.
- [41:58]
B
And what is it specifically about Zone 2 that relates to cancer prevention? Is it the fact that you are helping the mitochondria function better? And therefore if the mitochondria is functioning better, it's not dysfunctional, it's able to fight off diseases mainly because it increases our innate immune system. I would.
- [42:24]
A
Yeah. So probably think, yeah, we don't know for sure. Right. We need to, that's why we need more funds to understand this. In area of exercise oncology, what I've seen from my empiric evidence and experience is that can, I mean, cancer patients who exercise and they, you put him in a stone too. And you work with them there with you monitor them quite well, they're going to improve fat oxidation and also lactate clearance capacity. Therefore they're going to improve Mitochondrial function, that's for sure, that is going to happen in their muscles. Now, going back to what we were speaking about earlier about the exosomes, then the exosomes or exokines in your skeletal muscle are better than what they were before. Now, could that be the release of those exosomes? Exosomes, could they counteract the exosomes from cancer? I have no idea. But something happens in the skeletal muscle of cancer patients for sure, without a doubt. And might be also the other molecules that we don't know very well. Right. But for sure, mitochondrial function improves. And we know that cancer, as Warburg discovered, they had a shift, right, from the glycolysis into mitochondria to lactate production, which is the Warburg effect. Zone two does in a way the opposite to the Warburg effect. Again, could those exosomes release from skeletal muscle, contract the exosomes from cancer, or go directly to cancer organs and decrease carcinogenesis? That's something that we need to understand better, I hope.
- [44:18]
B
How many of this, how many of these of the. How much of this research is in humans?
- [44:25]
A
Oh, I, to my knowledge there's no research in humans on this. Unfortunately, there's. I haven't like to the level of get to know, you know, what happens at the by energetic level. Looking into muscle biopsies, looking into exosomes, looking into interactions. The crosstalk between skeletal muscle and cancer is still, I'm not even, I don't even think it's at its infancy. It hasn't been born with.
- [44:53]
B
So how do you feel so confident withdrawing the correlation between exercise and, and cancer? Because this is a question I get, you know, I'm on social media and obviously this podcast is fairly large. So we get a lot of people debating the idea of, oh, but we aren't mice, we aren't rats.
- [45:13]
A
Yeah, well, we know from epidemiological studies, you know, we know that exercise decreases, right. Both the recurrence and the mortality of cancer patients. Right. It can decrease 21 to 35% the recurrence in cancer patients as well as the mortality, somewhere between 30 up to 45%. So we know that it's difficult to know what are the effects of exercise in terms of prevention, because epidemiologically it's hard because if a disease doesn't happen, you don't know exactly why it doesn't happen all the time. But we know that cancer patients who have been diagnosed with cancer go through cancer. Exercise seems to be a benefit significantly for some of them, up to 45 50% decrease in mortality and recurrence. Right. What we don't know, we have no clue whatsoever what are the molecular systems, you know, or the, the mechanisms. We have no idea what's going on. And, and I think that that's what we need more resources to find out for things that I was saying is that like do we improve mitochondrial function or is it because we just release IL6 and other mediators? Is it because the exosomes is everything? That's where we need to really understand better in humans. Because with these we can really improve the guidelines for exercise oncology. We know it's exploding, it's a big deal now around the world, exercise oncology, but at this point, very few centers around the world they do actually individualized exercise prescription to cancer patients in the way that we do it now. And this is why sometimes on colleges they have mixed feelings about exercise. They all, they all recognize it's good, the majority, but sometimes they're like, I'm not sure if it works or yes, you know, make it make the patients worse.
- [47:14]
B
Like for example, like, okay, so your.
- [47:17]
C
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- [48:37]
A
Is not prescribed the exercise that he or she needs, and let's say that's a much higher intensity, it's going to incur in a glycolytic way, right? It's going to bring glycolysis More so, in one way, he or she is not stimulating mitochondrial biogenesis as much or that oxidative metabolism because he or she is training in a glycolytic pathway, number one. And then what happens when you utilize a lot of glucose, which is the future of cancer, right? You're going to deplete your glycogen storages. And in fact, that happens when so many cancer patients, especially stage 4 highly aggressive cancer patients, we see muscle waste, we see cachexia. And this is my hypothesis. But my hypothesis is from what we have learned in other diseases like ICU patients and even athletes who restrict carbohydrate immensely into a high intensity, they lose muscle mass when you have low glycogen content or your glycogen content disappears, you start tapping on your muscle for gluconeogenesis, right? So you can, you have branching amino acids that can turn into glucose in the liver through gluconeogenesis. And also you have a glutamine, which is very highly overexpressed pathway, both in cancer and also ICU patients. And because it goes straight into mitochondria for energy purposes. So the whole thing is like, if you are a cancer patient who already has some cachexia, it's probably that your glycogen levels are quite low. If you exercise at a high level, you might accelerate, right. The utilization of glucose, therefore the cachexia and, and the muscle weakness. So anyways, that, that's as opposed to someone who is maybe training in a more oxidative phosphorylation pathway through like zone two, for example. So I think that it's important to prescribe exercise correctly in order to really say that exercise is good or, or bad. That's my humble opinion.
- [50:48]
B
Yeah, that's, I love that. And I mean, if we had another 10 hours, we'd probably be able to go into protein requirements for muscle protein synthesis. So it doesn't break down muscle, maybe starts to break down fat. But then we're, we're moving into a different direction. So, okay, let's, let's, let's move into the, the later part of this because we're going to end this soon. If lactate metabolism, then after everything you're saying, lactate metabolism and arguably hypertrophy, more muscle size is one of the keys to cancer prevention. What would the ultimate protocol be for the average person in terms of, we've got, let's, let's break it down into high intensity aerobic training, which is your VO2 max, your zone 2, and then your resistance training.
- [51:44]
A
So I would Say, excuse me, that it's similar protocols of what we use with the. For longevity or health span. I think that having a patient, a cancer patient, training more on the zone two, it's going to improve fat and car and fat oxidation, lactic cleanse capacity, therefore probably mitochondrial function. It's not going to be very tasking. This is something that we need to have into account, right, because of chemotherapy, radiotherapy, different medications, that they're going to make the person much weaker. And so adding sustainability to an exercise program is very important. And zone two is. It adds that sustainability for these patients. So I think that that is to be a base for cancer patients.
- [52:31]
B
Now just on that. Sorry, I just want. I'm sorry to cut you off because I know I get asked this a lot. Not, not everyone is walking around with a lactate meter. So if people want a general idea of if they're in zone two, and I know this is such a hard statement to provide, but would you say it's maybe if even if they've got a heart rate monitor, maybe 65% of their maximum heart rate.
- [52:55]
A
Yeah, I would. It depends because, you know, especially with people with medications and treatments, heart rate fluctuates. I'm not sure that would be like a good parameter to look at heart rate. I mean, a percentage of a heart rate. But I think for those people who don't have access to a laboratory or a lactate meter or those clinicians who don't have a laboratory lactate meter, I think that the talking test, the talk test is quite similar. I mean, it's quite accurate. Sorry. So if you exercise at an intensity where you can talk like we're doing now, you're definitely not in zone two. Right. If you talk a little bit, if you need to put more effort to talk, but yet maintain a normal conversation, that's probably a zone 1. When you can maintain a normal conversation but have some difficulty, not to the level that you can't keep talking, but it's difficult. That's probably your zone too. When you go to an intensity where it's very hard to keep a, A talk, you know, then it's probably you're past your zone too. So, and this is what I've seen in, in the laboratory, you know, taking a lactate sample and looking at fat oxidation and talking, just talking to the athlete, right? And, and listening to the athlete, how they articulate, how they speak, it really coincides. You know, those are that intensity. So it's quite similar to that capability of maintaining conversation. And your lactate levels, they correlate quite well.
- [54:34]
B
Yeah. Okay. I'm gonna, that's what I'm going to be telling people.
- [54:38]
A
Yeah. And, but, but the one thing that I, I think, you know, within. We know that exercise oncology is, it's exploding is everywhere now. But I think that we need to take that next step from, from just prescribing exercise and to really individually prescribe it in the same manner that we do with elite athletes. Okay, right. Something more accurate that it's, it's very feasible to do. We just have to put more time and some investment, but it's super feasible to do.
- [55:09]
B
I think so too. Okay, so we've got that zone two and then we move over to high intensity training. For me, what I, what I personally do is I just maintain my four minutes on, four minutes off protocol by four times once a week right now. And this is more of a maintenance stage of my VO2 max. If I want to increase it, maybe I can do maybe two of those sessions a week.
- [55:35]
A
Yeah, I think in that respect, I mean, definitely there are many variations. Right. Of high intensity glycolytic training and depends on which bion objectives you want to stimulate according to your sport. When it comes to health span longevity, I, I think it, as long as you touch that energy system, you're going to be fine. That's what I think. You know, you need to do like a few times a week, somewhere between 20, 30, 40 minutes a week. And if you do that in, in whatever different versions of, you know, like as you say, four by four or you can do like, you know, like a lower intensity, but maybe 10 minutes of high, of a total high intensity. I think as long as you touch that energy system, you're going to stimulate that glycolytic system and I think it's going to be good for you that, you know, with elite athletes we have very specific prescribed exercise intensity in power output or in heart rates and different durations as well. Depends on the event. For healthspan and general population, I would say that it's quite general. As long as you stimulate that whatever you think you feel more comfortable with that 4 minutes, 5 minutes, 10 minutes, 15. That's my suggestion.
- [56:58]
B
And then resistance training.
- [57:00]
A
Yeah. And resistance, as we know, is key to preserve muscle mass. And that's something that we all should do regardless of the age. Well, as long as we're adults, of course. But I think, yeah, I think the research shows that two days a week should be fine. Right. For most people. And I think that, yeah, it's just like as you said at the beginning, most of the work maybe in zone 2, then 20 to 40 minutes or 20, 30 minutes in high intensity and to leave some time, you know, during the week for resistance training that I think two days a week should be important. I think that one one day a week is not going to cut it in long term. I think two days a week are pretty good and three times a week my take time from other activities in our busy agendas. And I don't think that for general purposes, healthspan in this case or longevity from 2 to 3 is going to be a big jump. In my humble opinion. I think two should be enough.
- [58:05]
B
Yeah, well this is definitely going to be a part one indigo. I think part two will have to keep diving in. I think I can do a 10 part series with just you. So thank you so much for your time. In our next one, hopefully we'll go over what exactly you're doing in your lab and how you train some of the best cyclists in the world. But for today I just want to say thank you so much for being part of the Neuro Experience podcast.
- [58:32]
A
Well, thank you very much, Luis. I really appreciate the invitation and yeah, hopefully listeners like it. Thank you very much. Appreciate it.