Welcome to the FoundMyFitness podcast. I'm your host, Rhonda Patrick. Today we're diving deep into the science and practicality of incorporating vigorous intensity exercise into our lives. It's not just about living longer. It's about enriching the quality of life at essentially every stage and also influencing brain function. During vigorous exercise, our muscles essentially become mini biochemical labs synthesizing compounds like lactate and myokines. These aren't just muscle-bound. They get into circulation, they travel to far-off tissues, and they signal to them, and they have a variety of benefits, including the synthesis of elements like brain-derived neurotrophic factor, or BDNF, crucial for brain health and neuronal health. They also potentially initiate anti-cancer mechanisms. Not only are muscles little chemical-producing factories, but they also act like sponges to soak up compounds that can be harmful to the brain, improving mental health and reducing neurodegenerative disease risk. We're going to dive deep into the realm of VO2max optimization. VO2max is not just about a measure of cardiorespiratory fitness. It's directly linked to longevity. Essentially, the higher your VO2max, the longer you're likely to live, and there doesn't seem to be an upper limit to the life-extending benefits of enhanced cardiorespiratory fitness, at least within your genetic potential. We'll get into the details of how to calibrate high-intensity efforts with Zone 2 training, methodologies for improving VO2max, with the spotlight on the Norwegian 4x4 protocol, and even touch on some straightforward tactics like assessing VO2max, so the pragmatic test, which is the 12-minute run test. Equally important, we'll navigate through the processes of mitophagy and mitochondrial biogenesis. These are cornerstones for cellular rejuvenation, essentially reversing the aging process on a cellular level. There's a lot of questions to answer. What is vigorous exercise? What is high-intensity exercise? What about Zone 2 training? So let's start by covering what is not vigorous exercise. Zone 2 training is also sometimes known as aerobic-based training. It primarily targets aerobic energy systems and can be sustained for longer durations. We're talking an hour and more. Some experts define this type of training to be around 70% to 80% of maximum heart rate, possibly lower for people that are unfit. It's also defined by the talk test, so you should be able to talk comfortably, but not sing. So you should be a little breathy when you're talking, but still able to talk comfortably. Zone 2 training involves exercising at a moderate intensity. It's a steady-state type of lactate threshold training. Lactate threshold refers to the point at which the body begins to produce lactate at a faster rate than it can clear it away. So keep in mind there's a lot of individual variation in determining the lactate threshold because people can have different baseline lactate levels, for one, which is typically around 0.9 to 1 millimolar, generally speaking. People also have different rates of lactate production and clearance, and even at the same relative exercise intensity. So for example, trained athletes might have a higher lactate threshold in terms of both exercise intensity and lactate concentration compared to untrained individuals. Genetics also play a role. There are many great podcasts out there covering Zone 2 training, including Peter Atiyah's The Drive with guest Dr. Inigo Sanmiglian. Now let's talk about vigorous exercise. So generally speaking, vigorous exercise represents a level of exertion where exercise goes beyond the lactate threshold, which means lactate begins to accumulate in the muscles more rapidly. There are various intensities within vigorous exercise. So a level intensity referred to as the maximal steady state threshold, sometimes called Zone 3, is above the lactate threshold, and it's challenging to hold a conversation, and it's difficult to maintain this level of exercise for longer than 20 to 30 minutes. This level of intensity is somewhere between 80% to 85% max heart rate. However, vigorous exercise also includes exercising at intensities higher than this. So a higher intensity training where there's significant amount of lactate accumulation and you're close to your what's called anaerobic threshold, this is a level of intensity usually around 85% to 95% max heart rate, and it's difficult to maintain for longer than a few minutes. Sometimes this type of training intensity is called Zone 4 training. Then there's the all-out near maximal intensity, and this is sometimes called Zone 5 training. These are shorter intervals, and it's generally hard to maintain this level of intensity for longer than one minute. So when we're talking about high-intensity interval training, it involves alternating between periods of high-intensity vigorous exercise and periods of lower-intensity rest. Depending on the high-intensity interval training or HIIT for short protocol, these can include intervals ranging from Zone 3 to Zone 5, followed by recovery periods. The idea that high-intensity interval training is only anaerobic is a misconception. While high-intensity interval training exercise does rely more heavily on anaerobic energy systems, it still requires significant aerobic metabolism. So HIIT can improve both aerobic and anaerobic fitness, and it's my opinion that getting your heart rate to at least 80% max heart rate, so that being at least 80%, is a really good place to be if you are targeting brain benefits, and we'll dive a lot into that in a minute. But I want to start by talking about cardiorespiratory fitness, healthspan, and longevity. So VO2max is a measure of maximal oxygen uptake, which reflects an individual's ability to utilize oxygen during exercise. It's considered one of the best indicators of cardiorespiratory fitness, and it's associated with improved healthspan, increased lifespan. Higher cardiorespiratory levels, as measured by VO2max, have been consistently linked to reduced risk of mortality and longer lifespan. So in the podcast, when I use the term VO2max, just keep in mind that it's a measurement of cardiorespiratory fitness. The greatest longevity benefit that comes from improving your VO2max is from people starting from a below-average VO2max and moving anywhere above average. So even going from a below-normal VO2max for your age group and gender to a low normal is associated with a 2.1-year increase in life expectancy. Bumping that up, going from a below-normal to high-normal VO2max is associated with a 2.9-year increase in life expectancy, and going even further to the upper limit of normal is associated with 4.9 years, so almost 5-year increase in life expectancy. On average, each unit increase in VO2max, so that's 1 milliliter per kilogram per minute, is associated with a 45-day increase in life expectancy. In another study involving only men for every 10-unit increase in VO2max, so this would be then 10 mils per kilogram per minute, there was a 17% lower risk of death from cancer and an 11% lower all-cause mortality, so dying from many different non-accidental causes of death. Another study published in JAMA in 2018 found that there was no apparent upper limit to the benefit of cardiorespiratory fitness on mortality within normal ranges of human life expectancy, of course. In fact, the study reported that elite performers, these are people that performed in the top 2.3% on the fitness test, had an 80% reduction in mortality risk compared to the lowest performers, so they performed in the bottom 25% on the fitness test. And if you compare the elite performers to the high performers, so these folks did really well but they were just under the elite, they were between the top 25% and the top 2.3%. The elite performers had a 20% mortality risk decline compared to even those high performers. So going back to what I said earlier about just moving out of that low fitness group will give huge advantages on life expectancy. So people in the low fitness group had a five-fold higher risk of death than the elite performers, but what is also so interesting is that the risk of dying due to low fitness was similar or even bigger than risks associated with having heart disease, smoking, or diabetes. So being fitter is really good for your health at every level of fitness, and there's always room for improvement. So the question is, well, how can we improve our VO2max? Lots of different training protocols, zone 2 training, for example, high-intensity interval training, you know, vigorous intensity exercise, all improve cardiorespiratory fitness and can increase VO2max. Fit has been shown to significantly improve VO2max even with shorter training durations. This is because HIIT recruits both aerobic and anaerobic energy systems and increases the intensity of the workout, resulting in greater cardiovascular stress and then adaptations. But this is important. There are individuals who engage in more moderate intensity, you know, steady-state zone 2 training that do not experience significant improvements in VO2max. In fact, research has shown that approximately 40% of people do not see a measurable increase in their VO2max even after engaging in guideline-based moderate intensity exercise, which is about 2.5 hours of this type of exercise per week for several months. But when these what are called non-responders incorporated more vigorous intensity exercise, such as high-intensity interval training, they do start to see improvements in VO2max. So this suggests that adding higher intensity exercise to an exercise routine can help eliminate that non-response and also can lead to greater benefits in cardiorespiratory fitness. The reason for non-response to moderate intensity exercise, it's not completely understood, but the addition of vigorous intensity exercise is important for overall improvements in VO2max. And engaging in more vigorous exercise seems to provide a stronger stimulus for physiological adaptations that lead to increased cardiorespiratory fitness. So again, I think these findings do really sort of highlight the importance of incorporating vigorous intensity exercise, particularly incorporating maybe a high-intensity interval training into a training routine. And obviously, for individuals who are time-pressed and can't dedicate several hours per week to doing a more zone 2 type of training, including shorter sessions of higher-intensity exercise can still have significant improvements in VO2max and overall health. So you might be wondering, you know, how much time do I dedicate to my more vigorous type of exercise versus a more moderate intensity zone 2 type of training? And I really think that answer depends on a lot of factors, your individual goals, what you enjoy doing most, what you're going to do the most. I mean, all of those things are important because at the end of the day, establishing a habit, having an exercise routine that you're going to consistently do is what is most important. For endurance athletes, I mean, the answer is easy, right? You're already dedicating several hours a week to doing more zone 2 training, and about 20% of that training is dedicated to shorter, higher-intensity workouts, more vigorous-intensity workouts. And this is commonly known as the 80-20 rule. But remember, this is people that are doing extensive amounts of training, anywhere between 10 to 30 hours a week. I think it's a common misconception to apply that 80-20 rule to, like, any committed exerciser and any casual exerciser who are doing well under less than 10 hours a week. As you think about someone who is a committed exerciser, maybe you work out three to five days a week. How much of that time should be spent doing vigorous-intensity exercise? I would say for VO2max and other adaptations we're going to discuss, including the brain, about half of that exercise training time, I think, should be spent in vigorous, doing a vigorous exercise. So, again, you want to be at least 80% of your max heart rate or more. Obviously, there's resistance training to incorporate as well into any training program. There's casual exercisers, so people that work out maybe two to three times a week. They should probably spend more than half of their time doing more vigorous-intensity exercise. I think this ensures you're pushing your limits and, you know, making sure that you're getting adaptations, fitness gains in a shorter period of time. There are a variety of VO2max training protocols. So for people that are looking for that more vigorous exercise, you know, using high-intensity interval training to improve their VO2max, the key here is longer intervals. So incorporating longer intervals such as two, three, four, maybe even five minutes at the highest workload you can sustain for that time, and then performing four intervals with rest and recovery in between each of those. So this protocol may require maybe a 20-minute time commitment, but it can lead to significant improvements in VO2max. There's a few examples of VO2max training. Dr. Martin Gibala, who was a recent podcast guest, gave a variety of examples of this. So there's three- to five-minute repeats at the highest sustainable intensity. We talked about you doing those three- to five-minute intervals that you can maintain, and then you rest and recover and repeat those intervals for a total of 20 minutes. I think a popular variation of this is called the Norwegian 4x4 Interval Training Protocol. So the intervals are four minutes long, and you're aiming for about 85% to 95% of your max heart rate or the maximum level of intensity you can maintain for the entire four minutes. These intervals can be brutal. So the recovery period is three minutes long, and the intensity is significantly lower, like light exercise, more like a Zone 1 training exercise. You want to allow yourself recovery time, the clearance of lactate. You want your heart rate to come down significantly so that you can prepare for the next four-minute interval. So these four-minute intervals are repeated four times, and again, in between each interval is a three-minute recovery. So that's the Norwegian 4x4 Interval Training. There's another type of VO2 max training protocol. It's the one-minute on, one-minute off protocol. This is where you perform one minute of intervals at the highest intensity you can do for one minute, and then it's followed by a one-minute recovery period. And then you repeat this interval pattern 10 or maybe five times for about 25 minutes or so. And this protocol also is effective at improving VO2 max, and it does provide a lot of flexibility in terms of time commitment. It's also not as, you know, grueling in terms of like doing a four-minute interval versus a one-minute interval. One-minute intervals are a little bit, you know, less intense and less painful. Obviously, it's important that, you know, these protocols are sort of templates. They vary a lot based on individual fitness, goals. You know, there's other protocols out there that can improve VO2 max. The key is like a longer interval, longer than like a Tabata, like a 20-second interval. And so, you know, probably about at least one-minute at the highest sustainable intensity that you can do. I think the Norwegian 4x4 protocol is probably one of the best out there, one of the best hit protocols out there for improving VO2max. So how do you measure VO2max? Without equipment found in an exercise physiology lab, it's obviously challenging. There are several sort of tests that have been developed and verified for getting an estimate of your VO2max. So they don't directly measure maximum oxygen uptake, but they predict your VO2max based on the relationship between your exercise intensity and your oxygen consumption. They're sort of useful in determining whether or not you're improving VO2max if you're testing a type of training protocol. So there's a couple of really, like I said, validated tests that have been validated in scientific literature that can sort of be done. Probably one of the best ones is the 12-minute run or sometimes called walk test, depending on your level of fitness. It's often also referred to as the Cooper test. And it involves having the participant run or jog as far as possible in 12 minutes. So you're supposed to pace yourself evenly. You don't want to start too fast, and the test should be conducted on a flat surface, so like a track field is the best. You don't want to have hills and stuff because it's about the maximum amount of distance you can cover in 12 minutes. And if you have hills and stuff, that's going to lessen that. It's going to be more challenging, and the distance won't be quite as far. So you'll need a fitness device, something that can record your distance, an Apple Watch or Fitbit or something. And depending on your fitness level, you can walk or you can run or a combination. So the distance covered within that 12-minute period serves as the primary metric for evaluating VO2max, which is then estimated using a formula. So it's distance in meters minus 504.9 and then divided by 44.73. And you can look this formula up. Just look up the Cooper test to find the formulas online. Again, there's some other validated tests, but I think that's probably one of the better ones out there. You'll need a device like an Apple Watch or some sort of other device that can measure your distance. But there's also some of these devices and wearables do estimate VO2max during exercise using heart rate and your motion data. You know, for best results, you have to make sure all your personal information is in there like your age and your weight and gender and, you know, all that stuff. But that's another, you know, possibility. I would say the 12-minute run or walk test is a more – it's a better way to do it particularly if you're trying to do something like the 4x4 Norwegian HIIT protocol to measure VO2max improvements. You want to see if what you're doing is improving your estimated VO2max. So I think that the 12-minute run test is a good way to do that. And then there's some other online calculators. Dr. Gavala mentioned these. This is really just, you know, it's a very, very rough estimate for VO2max. It's something that people just kind of want to get a sense maybe. It's not something to do to test a particular training protocol or to see if you're getting improvements in your VO2max from your training protocol. Okay. So I want to sort of change gears for a minute and talk about, you know, something that I also think is pivotal. And it's a unique role for vigorous exercise in playing a role in enhancing healthspan. And it has to do with changes in heart structure. So as we age, the heart undergoes specific inevitable changes, right, related to the aging process. So it tends to get smaller, it gets stiffer. And this can impact the heart's efficiency, potentially reducing our exercise capacity, elevating our risk for cardiac issues. But there can be exercise interventions like consistent aerobic exercise with a high proportion of it being vigorous intensity that can actually combat some of these effects. So there was a landmark study published from Ben Levine's group, and it was an intervention study and it showed that two years of vigorous exercise in 50-year-olds was able to reverse the aging of their hearts by as much as 20 years, effectively making their hearts look more like a 30-year-old, which in my opinion is simply astonishing. You're taking a 50-year-old heart and making it look like a 30-year-old heart. Now the exercise protocol used in this particular study, it was a protocol that gradually increased the exercise intensity and also frequency. So again, I mentioned it was a two-year intervention. By the end of the first six months, participants were exercising about five to six hours a week with a large portion of training being in that maximal steady state intensity exercise, which I referred to earlier in the podcast. It's often sometimes called zone three. It is a type of vigorous intensity exercise. They also were incorporating higher intensity exercise. So they also did the Norwegian 4x4 VO2 max training protocol I just referred to, and they did that once a week. And I just think, like I said, it's simply astonishing that you take these 50-year-olds and after two years of a more vigorous intensity exercise training protocol, it essentially reversed the effects of aging in the heart. Okay, so let's shift gears yet again and talk a little bit about metabolic adaptations. And again, this is where I think vigorous exercise really shines, particularly high intensity interval training. It improves glucose control, insulin sensitivity more efficiently and more potently than even continuous moderate intensity workouts. And I do think that, of course, both exercise training protocols can enhance muscle adaptations and glucose regulation. HIIT really seems to do it quicker and, again, more robustly, whereas moderate intensity exercise kind of demands longer sessions for comparable outcomes. So research has found that high intensity interval training can enhance the muscle's ability to take up glucose and improve glucose transport capacity. So during high intensity interval training and during vigorous exercise, there's a demand for rapid energy production. And so the body relies both on aerobic, so oxygen using, and anaerobic, non-oxygen using metabolic pathways to generate this energy. The anaerobic pathway can lead to the production of lactate, especially when the intensity of exercise surpasses the point at which the oxygen intake can keep up with the energy demand. And so this is sometimes often referred to as the lactate threshold, as we talked about. For a long time, lactate was considered primarily as a waste product contributing to muscle fatigue. And, you know, this has, of course, been completely reversed. Recent research has, you know, totally changed this understanding. Lactate generated in muscle tissue is transported not only back into muscle and into mitochondria to be used as an energy source, but it also, when it starts to accumulate at higher levels, travels systemically into circulation and gets transported to other tissues like the heart, the liver, the brain, where it's used for energy. It's also used as a signaling molecule. So this is known as the lactate shuttle and was pioneered by Dr. George Brooks, who has really changed the field, and he also happened to be my second podcast guest ever on this podcast. Anyways, lactate, you know, I mentioned it acts as a signaling molecule in those tissues as well. And you can think of a signaling molecule as a chemical messenger that is sending a message to other cells. One of those messages is the upregulation of glucose transport capacity. So vigorous intensity exercise, high-intensity interval training, when that lactate production accumulates, it stimulates the expression and activity of glucose transporters on the muscle known as GLUT4, and this is on the muscle cell membrane. And so that lactate acts as a signaling molecule to increase the transport of glucose transporters on the muscle cells. And this, then, allows for more efficient uptake of glucose from the bloodstream into the muscle, even at rest. And so consequently, then, insulin sensitivity is also improved and blood glucose levels are better regulated. There's been several studies that have demonstrated that HIIT can improve glucose uptake, enhance insulin sensitivity, and decrease the risk of developing type 2 diabetes. This may be due to the intense metabolic stress created during HIIT, which leads to greater activation of glucose transporters and improved glucose clearance. So as I mentioned, both high-intensity interval training, continuous moderate-intensity exercise can also be effective at improving glucose transport capacity in the muscles. HIIT promotes rapid increases in glucose transporters, allowing for that efficient glucose uptake and utilization, whereas continuous moderate-intensity exercise, although it's less intense, still does also enhance glucose transport capacity. It improves the overall fitness of muscles as well. So again, it's just a longer duration of exercise time to get there. And with the lactate generation that happens with high-intensity exercise, you're getting that immediate signal from lactate to increase the GLUT4 transporters. And so it's a very rapid and robust adaptation that happens. There's other metabolic adaptations. So just kind of talking about mitochondria. Mitochondria are very important, and they play a lot of roles in the body. But one of the most important ones is the production of energy in the form of ATP. This is obviously very important for muscles, but also hugely important for the brain, the heart, the liver, pretty much every organ. Athletes are very interested in mitochondrial health because they want their muscles to efficiently and effectively produce energy when they're training. But mitochondria are also very important in the context of aging. As we age, our mitochondria become less efficient at producing energy, and this poses a problem for physical activity, but also just for normal functioning of our organs. Now that problem of mitochondria not producing enough energy can actually be overcome by increasing the mitochondrial volume, or what's called mitochondrial biogenesis. And exercise, particularly vigorous exercise, is one of the best ways to do that. So one of the most powerful indicators of healthy mitochondria is the ability to generate new, healthy, young mitochondria called mitochondrial biogenesis. Vigorous intensity exercise, like high-intensity interval training I mentioned, it's one of the most powerful stimulators of mitochondrial biogenesis. This has to do with the metabolic stress that is induced from vigorous intensity exercise. The lactate itself, again, lactate is a signaling molecule. When you're producing greater amounts of lactate, that actually activates one of the major pathways that regulates mitochondrial biogenesis. It's called PGC1-alpha. And again, lactate's acting as a signal to produce more of that PGC1-alpha. So when we perform vigorous intensity exercise, such as HIIT, that lactate's generated from the muscles. It's shuttled into the mitochondria because exercise increases the number of mitochondria per cell. Again, mitochondrial biogenesis. And each mitochondrion has a lactate shuttle, which means the more mitochondria, the more the lactate shuttles, and the more lactate that's able then to be used as energy or to produce energy. So a translation for that would be, you know, athletes have more mitochondria and they can use lactate better than non-athletes because they have more shuttles to transport the lactate inside the mitochondria where it is used as energy. And this is important to know if you're wanting to understand the bigger picture of where metabolism and lactate utilization fit into, you know, human performance. But it's also important to realize that athletes put around anywhere between, like I said, 10, 20, 30 hours of training in a week if they're endurance athletes. And usually about 80% of that training is in, you know, the moderate intensity zone to training world, with the remaining 20% being vigorous intensity exercise like HIIT. Which means that for average athletes, you know, endurance athletes, if they're putting in 20 hours a week of, you know, of moderate intensity training, then they're doing anywhere between, you know, they're doing, you know, anywhere between four to six hours a week of vigorous exercise like HIIT. So just the portion of their vigorous exercise alone they are doing is more than what committed exercisers are doing. So the question is, what's the best training protocol for a non-athlete, someone that's perhaps a committed exerciser who is interested in health and longevity? Again, both high-intensity interval training, zone 2 training also, moderate intensity training can increase mitochondrial biogenesis in skeletal muscle. HIIT does it more rapidly. It's a more potent stimulus, again, with lactate being a signaling molecule. On the other hand, zone 2 training, you know, which is, you know, doing a more moderate intensity exercise that's sustained for a longer duration does lead to an increase in mitochondrial content. I think the key here is the total volume of training. So higher intensity exercise is a smaller volume, and it can result in more rapid, larger increases in mitochondrial content, while doing a more moderate intensity zone 2 training also does the same thing, but it just requires larger exercise volume or duration. Your muscle's ability to use fat as a fuel is also closely tied to how many active mitochondria you have. So in other words, increasing mitochondrial content also determines the ability of muscles to be able to oxidize fat. Both high-intensity interval training, so vigorous exercise, and zone 2 training increase the capacity for fat oxidation by increasing mitochondrial content. Now by enhancing the growth of new mitochondria, you're increasing the activity of key enzymes involved in fat metabolism. So one of those is the carnitine palmitoyltransferase enzyme, or the CPT enzyme. Both types of exercise training, moderate and also vigorous intensity exercise, do increase the CPT enzyme capacity as well, and, you know, obviously, that is directly related to the utilization of fat as a fuel source. So I think the bottom line here is that, you know, mitochondrial biogenesis, increasing mitochondrial volume is key for mitochondrial health. It's key for improving fat oxidation, as well, and both high-intensity interval training and a more moderate zone 2 type of training will get you increases in mitochondrial volume. Another way that exercise improves mitochondrial health is through a process known as mitophagy or mitophagy, as some people call it. So mitophagy is a type of autophagy which involves the selective removal of damaged or dysfunctional mitochondria from the cell or within the cell. This process really helps maintain mitochondrial quality control and overall cellular health. So when you put stress on mitochondria through exercise, the body triggers, you know, the elimination of damaged mitochondria and the replacement of those mitochondria with new healthy ones through mitochondrial biogenesis. There's not a lot of direct human research on the effects of different training types of different exercise training on mitophagy, but I know of at least one human study that has found particularly vigorous intensity aerobic exercise enhances markers of mitophagy. It's likely that both vigorous exercise, high-intensity interval training, and more moderate exercise training can stimulate this process with HIT just getting you faster and, you know, the moderate intensity zone 2 requiring a larger training volume. But overall, you know, both HIT zone 2 can promote skeletal muscle adaptations including mitochondrial biogenesis, fat oxidation, mitophagy. This is a repeating theme of this podcast and also on the one that I did with Dr. Martin Gibala on high-intensity interval training. I think the choice between the two really depends, again, on individual goals, preferences, the amount of time available for training, and just what you love to do. HIT offers that time efficiency. It potentially has the ability to have rapid improvements and adaptations in mitochondrial content while moderate intensity zone 2 training can yield similar adaptations with a larger volume of moderate intensity exercise, you know, sustained for a longer duration. But I do think that it's important to probably try to incorporate both types of exercise training for a more well-rounded way to kind of cover all your bases. And for those that are committed exercisers, if you're putting in, let's say, anywhere between two to five hours of training a week, it's my opinion that, you know, you should probably be doing a lot of that training or half of that training should be vigorous intensity exercise, not only because the VO2 max improvements we spoke about earlier, but also because of brain benefits. So let's talk about the brain. Exercise intensity like high-intensity interval training has been shown to have unique benefits for brain health. Obviously, all types of exercise are beneficial for the brain, but high-intensity exercise may have additional neuroprotective and cognitive benefits. And one of the mechanisms that's thought to underlie this is, you know, the unique effects of, you know, vigorous intensity exercise or HIT on the brain because of the lactate production. So during high-intensity exercise, lactate is produced in large amounts, as we've talked about, largely as a byproduct of the metabolic stress. You're kind of pushing that anaerobic threshold. And when you produce lactate, it's getting into circulation and it can cross the blood-brain barrier. There are lactate transporters, MCT transporters on the blood-brain barrier, and it can, you know, cross the blood-brain barrier and get into the brain where it then acts as a signal and it triggers a variety of beneficial adaptations. So let's talk about some of those. First, you know, lactate can be used by neurons as a preferential energy source. So it's actually energetically favorable. It takes less energy for mitochondria to use lactate versus glucose. So in fact, neurons are used to using lactate because astrocytes in the brain, which are a supporting cell for neurons, are mostly glycolytic. That means they're mostly using glucose as energy, they're not using mitochondria, and they're producing lactate as a byproduct. So astrocytes are churning out tons of lactate in the brain, and that lactate is being taken up, you know, by neurons through the MCT transporters and used as energy. So there's actually even been studies showing that the brain is working harder during exercise, much like the muscles are working harder, your heart's working harder. And it's been shown that lactate actually fuels the brain during exercise. So that lactate that's being transferred into circulation is being just soaked up by the brain, and it's fueling the brain activity during exercise. Now another benefit of neurons in the brain using lactate as an energy source instead of glucose is it spares glucose. It's freeing up glucose to be used by another biochemical pathway known as the pentose phosphate pathway. And this pathway uses glucose to make precursors called NADPH that's needed for the production of one of the most powerful antioxidant systems in the brain called glutathione. So the less glucose is being taken up by neurons to be used as energy, the more it can be spared to be used in this pentose phosphate pathway to make glutathione. And this has really important relevance not only for just, you know, normal brain aging, right? I mean, if you're able to use more of the lactate as energy and spare glucose and make more glutathione in the brain, generally speaking, that's gonna be more beneficial for just normal brain aging. But it has special relevance also for traumatic brain injury, TBI, because, you know, that when there's that, you know, bolus of damage that's been done, that traumatic brain injury, then glutathione is needed the most. But you're also needing, you know, glucose for neurons as well. And so...and it's also awful because, you know, astrocytes, which are usually making lactate for the neurons, also become damaged during a TBI. And so there's a lactate shortage for neurons. And there's been a few studies showing that infusion, when there's TBI, patients with TBI that get infused with sodium lactate, this actually improves TBI outcomes. And this is, you know, measured by the Glasgow scores. So, you know, generally speaking, I think that this glucose sparing effect also, you know, there's some evidence, again, obviously, direct evidence with TBI outcomes that's been shown to have, you know, improvements in TBI outcomes. I'm proposing a mechanism here with glucose sparing with respect to lactate. Lactate, again, also stimulates mitochondrial biogenesis. Animal studies have shown this in the brain and neurons as well. We don't have direct human evidence of that. But there's no reason to think that wouldn't be a conserved mechanism. So I think, you know, we covered the importance of brain lactate, energetically speaking. It's energetically favorable, right? Neurons preferentially, they prefer to use it. We talked about the glucose sparing. But let's go back to the signaling molecule aspect. As we talked about earlier in the muscles, we talked about it increasing GLUT4 transporters. It's also a signaling molecule in the brain. You know, it's acting as a messenger. It's a way for the muscles to communicate with the brain directly. And when neurons in the brain are using more lactate, they're releasing a variety of neurotransmitters. They release more norepinephrine, for example, so to help the brain working better, to have more focus and attention. It also signals to the brain to make more brain-derived neurotrophic factor, BDNF. And I mean, this is a very powerful neurotrophic factor. It promotes the survival, the growth, and the function of neurons. It plays a crucial role in neuroplasticity. So this is the ability of the brain to adapt, form new connections. Higher levels of BDNF have been linked to improved cognitive function, enhanced memory, protection against neurodegenerative diseases like Alzheimer's disease. If you want to put this in sensational words to explain it, BDNF is the youth elixir for the brain, and exercising muscles produce lactate to help you bathe your brain in it. So that's a little sort of simplistic and more sensational way of thinking about it, but essentially, that's what's happening when the lactate's increasing BDNF in the brain. Lactate is also a messenger, not only in the brain, but at the blood-brain barrier. You know, this is made up of tiny blood vessels. We covered this in a podcast with Dr. Axel Montaigne. So lactate signals to increase another growth factor at the blood-brain barrier called VEGF. And this is vascular endothelial growth factor. This helps grow new tiny vessels. This is called angiogenesis, the growth of new tiny blood vessels. It helps them grow at the blood-brain barrier. It also helps repair damaged blood vessels. I mean, these are things that are, you know, important for preventing the breakdown of the blood-brain barrier. So essentially, VEGF is increasing the vascular density. And breakdown of the blood-brain barrier is a major cause of brain aging. It's a major cause of neuroinflammation. It contributes to the vicious cycle of neuroinflammation. And there's also emerging evidence that now suggests breakdown of the blood-brain barrier is one of the earliest signs of dementia. So again, another reason why vigorous intensity exercise through that just generation of a lot of lactate, then getting to the brain, getting to the blood-brain barrier has unique benefits on overall brain health. It's important to know, I guess, this is, you know, there are benefits to high-intensity exercise on the brain that are not just exclusive to lactate, right? So there's increased blood flow. There's the improved cardiovascular fitness, the release of neurotransmitters, the release of endorphins. You know, all of these things contribute to the positive effects of physical activity on the brain. But vigorous intensity exercise, I do think, has some unique and very robust effects on brain health because of that lactate. And so I really wanted to kind of dive deep into that so that you guys understand that. You know, your muscles are being pushed to work extra hard, and this is then now causing adaptations in the brain that are pretty substantial. In addition to lactate, exercise intensity also affects the muscles' ability to produce other compounds known as myokines. So these are molecules released from muscle cells that signal to non-muscle tissues that the body is physically active. You know, so again, it's similar to what we've been talking about with lactate. Myokines have anti-inflammatory, they have anti-cancer effects. They also participate in metabolic pathways involved in fat oxidation, glucose uptake. They play a role in, you know, in, again, cancer biology as well. So generally speaking, the greater the intensity of exercise, the greater the myokine release. Again, it's one of those you're putting stress on the muscles, and the muscles are then forced to adapt, and one of the adaptations is releasing myokines. Again, duration also matters. So the harder and the longer the muscles work, the greater the myokine release. Some myokines are a little more sensitive to exercise intensity. So IL-6 is probably one of the most well-known myokines. It was initially thought to be a pro-inflammatory cytokine, so a cytokine that plays a role in instigating inflammation. When it is produced from muscle, it acts as a myokine. So it does play a role in inflammation, but when it's produced from muscle during exercise, it's signaling to other tissues to have an anti-inflammatory response. And so you'll often find an even larger production of anti-inflammatory cytokines, such as IL-10 in response to IL-6 produced during exercise. Irisin is another myokine. It's involved in cancer protection. It's involved in bone health, metabolism, and more. And then there's also another well-known myokine known as oncostatin M, and that myokine sort of plays a little more prominent role in, you know, anti-cancer effects. The key here is I think that exercise intensity and or duration are really what increase myokine levels. So you're going for a 2 or 3-mile run, probably crank it up a little more intense, right? You want to be, you know, at least 85% your max heart rate. So you're not going to be really talking during that run. Are you going on an 8-mile run? Maybe duration is on your side, right? And intensity can go down a notch. Since we were just talking about cancer, keep in mind that any level of physical activity is better than none. So a study investigating physical activity in breast cancer and colorectal cancer found women who were more physically active before being diagnosed with breast cancer had about a 23% reduced risk of dying from any cause and a 23% reduced risk of dying from breast cancer compared to those who were less active. Those who were more active before being diagnosed with colorectal cancer had a 26% reduced risk of dying from any cause and about a 25% reduced risk of dying from colorectal cancer. So being active after diagnosis had even stronger benefits for both cancer types. So these women had a 48% reduced risk of dying from any cause and a 28% reduced risk of dying from breast cancer compared to those that were less active after diagnosis. And the individuals with colorectal cancer had a 42% reduced risk of dying from any cause and a 39% reduced risk of dying from colorectal cancer, again, after being diagnosed with the cancer. So I do want to talk a little bit about, you know, there's a lot of mechanisms by which exercise can, you know, dampen cancer metastasis, can improve cancer outcomes, but there's one specific mechanism that involves tumor cells escaping from the original tumor site and then traveling into circulation to other locations, other organs and, you know, other tissues. They sort of take camp there, they grow and divide, and they form a secondary tumor. Those cancer cells are called circulating tumor cells, and that process I just described is often called cancer metastasis, right? Those circulating tumor cells are in circulation for a period of time, and these circulating tumor cells are very sensitive to the shearing forces of blood flow. So when you exercise and blood flow increases, those circulating tumor cells, they actually die, and this happens in a dose-dependent manner. So the more intense the exercise, the more sensitive they are to cell death. Duration is also a key, right? So, I mean, you're talking about increasing the shear forces. Both intensity and duration are key here, and so it's really just a matter of getting that blood flow up, intensity, duration, and that has been shown to kill circulating tumor cells. And, again, this is associated with more positive outcomes with respect to cancer survival. Not only we talked a lot about, you know, muscles being little chemical-producing factories that are producing chemicals like lactate, they're producing myokines, but they also act like sponges to soak up compounds that can be harmful to the brain. So skeletal muscle has the ability to take up a compound known as kynurenine and convert it into kynurenic acid, which is a non-toxic metabolite, and it does this by increasing an enzyme on the muscle called kynurenine aminotransferase. So this essentially reduces the amount of kynurenine available to then be transformed into other harmful metabolites such as quinolinic acid in the brain. So quinolinic acid is a neurotoxin that plays a role in depression. It plays a role in schizophrenia and neurodegenerative disease. And so this is just one other mechanism by which, you know, exercise also seems to improve mental health. It's also, you know, another way that, again, exercise intensity is important here. That is what is increasing that, you know, that enzyme, that kynurenine aminotransferase on the muscle cells to then transport kynurenine into the muscle so that it's not converted into the quinolinic acid. So just another mechanism that I kind of wanted to point out because, again, intensity plays a role here with those aminotransferase transporters soaking up more of that kynurenine. I want to shift gears and talk about short bursts of high-intensity interval training. So this is sometimes called exercise snacks. Exercise snacks are short bursts of vigorous intensity exercise that are incorporated throughout the day. And it can have numerous benefits on metabolism, overall health. These exercise snacks can be as simple as doing some vigorous jumping jacks or vigorous air squats or high knees or burpees, and they can be done in just a few minutes. There might be some distinct metabolic benefits to exercise snacks, particularly when timed around meals. So performing these, you know, short bursts of exercise before or...so directly before or after a meal is particularly effective in controlling blood sugar levels. You know, this sort of thing can lead to a rapid uptake of glucose into the muscles, again, having to do with increasing those GLUT4 transporters. It helps to lower blood glucose levels more efficiently than staying sedentary post-meals. So timing exercise snacks around meals really can help the body handle sugar influx better, and it helps, you know, utilize glucose more effectively and reduces the demands on the pancreas to produce insulin. So it's particularly beneficial for people with both type 1 and type 2 diabetes. In addition to the direct metabolic benefits, exercise snacks can also combat sedentary behavior. So many individuals, even those who engage in regular exercise, still spend a significant portion of their day sitting at their desk, working, being sedentary. Sedentary behavior has been shown to be a modest, independent risk factor for certain types of cancer, and it can also increase the risk of premature death, even among physically active individuals. So by incorporating exercise snacks, individuals can kind of break up those prolonged periods of sedentary behavior and potentially further, you know, reduce their cancer risk and just have a variety of health benefits. So exercise snacks also can enhance cognitive function. It's directly increasing blood flow to the brain, you know, again, that can also just have an immediate mood enhancement, which affects motivation. There's not a lot of direct evidence on exercise snacks in the brain, but, of course, methodologies can differ anywhere between 1 minute to 10 minutes, but there at least is one study showing that 10 minutes of an exercise snack does improve cognitive function. So what could be a good protocol to implement, let's say, during your sedentary time would be perhaps, you know, setting a timer, and every couple of hours, you get up and you do a couple of minutes of, you know, high-intensity interval training. On a very similar note, there's something called vigorous intermittent lifestyle physical activity, VILPA. It's somewhat similar to exercise snacks, but it takes advantage of everyday sort of situations to get your heart rate up high and to do some high-intensity exercise. So for example, instead of...you have to take...they take the stairs every day to work. Well, instead of walking up the stairs, you sprint. You're getting your heart rate high. So these types of VILPAs have been measured in large numbers of people, so there's a variety of publications and studies that have been done measuring, you know, people's...their VILPAs that they're doing. And, you know, just three to four minutes a day of this vigorous intermittent lifestyle physical activity has been shown to be associated with a 25% to 30% reduction in overall mortality risk. When that VILPA duration's increased to about nine minutes a day, it's associated with a 50% reduction in cardiovascular-related mortality and a 40% reduction in cancer-related mortality. And these benefits extend even to individuals who identify themselves as non-exercisers. In other words, these are people that are not necessarily doing leisure time activity. They're not going to the gym. They're not going on runs. But they're still engaging in these VILPAs. So even those people are getting mortality reductions and, you know, cancer mortality, cardiovascular mortality reductions with VILPAs. So I think that, you know, that's also an important benefit to keep in mind. So I hope you guys enjoyed this episode, a deep dive into the science of why vigorous exercise is important. It's important for improving cardiorespiratory fitness, particularly people that don't respond to more moderate-intensity exercise. It's important for metabolic adaptations. It's very powerful at increasing glucose intake into muscles. It's also a very potent stimulator of mitochondrial biogenesis, allowing for mitochondrial adaptations, improving not only mitochondrial volume, but also fat oxidation capacity as well. It's increasing mitophagy, the clearance of damaged mitochondria from muscle tissue. And it seems to have really unique benefits for the brain. And a lot of this does come down to lactate production. The metabolic stress that's induced from vigorous-intensity exercise produces more lactate. This lactate is getting into circulation, going to other tissues, including the brain. And not only is this allowing the brain to use an energetically favorable energy source, so neurons are using lactate as energy, it's allowing the sparing of glucose to be used to make precursors for a very powerful antioxidant, glutathione, in the brain. It's also acting as a signaling molecule in the brain, increasing brain-derived neurotrophic factor. This is hugely important for staving off neurodegenerative disease and just improving cognitive function. It's increasing VEGF at the blood-brain barrier, staving off the breakdown of the blood-brain barrier. It's also increasing myokines in the muscle that have all sorts of benefits. So I think we've covered a lot about the importance of vigorous exercise. And also, the vigorous exercise can be done in short exercise snacks as well. And I think this is a really great way for schools and workplaces to incorporate some sort of physical activity to break up the sedentary time when people are sitting in their cubicles, at their computer, or sitting at their desks for prolonged periods because just those periods of being sedentary in and of itself is a risk factor for early mortality. So again, exercise snacks are a type of vigorous exercise that can be incorporated into everyday life as well as the vilpas. These are things where you're taking advantage of everyday situations like sprinting up the stairs rather than walking up them as well. So I hope you guys enjoyed this podcast, and I'll talk to you soon.