#084 The Longevity & Brain Benefits of Vigorous Exercise | Dr. Rhonda Patrick

Norwegian 4x4 vs. 1-min on/off: two proven VO2max training protocols

The 4x4 protocol is one of the best for VO2max. The 1-min on/off protocol offers a less grueling alternative with similar benefits.

"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 BO2 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 VO2 max. So how do you measure VO2 max? 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 VO2 max. So they don't directly measure maximum oxygen uptake, but they predict your VO2 max 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 VO2 max 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, you know, 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, you know, 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, you know, 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, you know, there's some other validated tests, but I think that's probably one of the best 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 VO2 max during exercise using heart rate and your motion data. You know, for best results, you have to make sure all your personal information's in there, like your age and your weight 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 HIT protocol to measure VO2 max improvements you want to see if what you're doing is improving your estimated VO2 max. So I think that the 12-minute run test is a good way to do that. 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 more higher intensity exercise. So they also did the Norwegian four by four VO2 training, VO2 max training protocol I just referred to. And they did that once a week. And I just think it's, like I said, it's simply astonishing that, you know, 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, you know, moderate intensity workouts. And, you know, I do think that, of course, both exercise, you know, training protocols can enhance muscle adaptations and glucose regulation. HIT 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 its understanding. lactate-ate 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 known 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 HIT 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 HIT, 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. HIT 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, you know, again, it's just a longer duration of exercise time to get there. And with the lactate generation that happens with,-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.ondria 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 the more lactate that's able then to be used as energy or to produce 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. If they're putting in 20 hours a week of, you know, the moderate intensity training, then they're doing anywhere, 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 two training also, moderate-intensity training, can increase mitochondrial biogenesis in skeletal muscle. HIT 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 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 palmitol transferase 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 two type of training will get you increases in mitochondrial volume. So 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 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 HIIT just getting you faster and, you know, the moderate intensity zone 2 requiring a larger training volume. But overall, you know, both HIIT 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 Gabala 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, sustain 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 going to 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 glass cow 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 muscle's 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. 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."