#21 How Cryotherapy Affects the Brain, the Immune System, Metabolism, and Athletic Performance

Good day, ladies and gentlemen of the podcast. Today, we go deep. How deep, you say? 20,000 leagues under the sea deep on the topic of cryotherapy and cold water immersion and ice packs and hibernating animals and winter swimming and everything in between. This podcast has been a long time coming. The topic of cryotherapy is a natural complement to some of the material that I've released previously on sauna use or hyperthermic conditioning, as I've called it. But if I were to be completely honest, a big motivation for this podcast has been the great deal of enthusiasm some of my friends have for cryotherapy. Folks like the great and powerful Joe Rogan, also Kevin Rose, and probably more people than you can shake a stick at.

Admit it, you've been thinking about buying one of those tricked-out liquid nitrogen-fueled spaceships yourself, haven't you? Okay, but before we dive in, here's what you need to know. Number 1, The topic of cryotherapy is tricky. There's lots and lots of nuance, and I end up trying to weave a cohesive narrative from studies that focus on any number of different types of cold modalities. So it's not just whole body cryotherapy that's the topic of this discussion. This podcast is going to take you all over the place, and we're going to talk about some deep biochemical level stuff because we have to. I try to bring it home and do give some concise conclusions at the end. I hope that helps a little bit.

You can skip to the last few minutes if you're feeling impatient, but I don't recommend that. Before we get this show on the road, there's just 2 things to know. Number one, this podcast is actually a bird's-eye view at a whopping nearly 20-page report on the subject of cryotherapy. I cover a little of everything discussed today on this podcast and maybe a little bit more. And I provide all of my references in the PDF report. To get it, you need to go to foundmyfitness.com/cryotherapy. Once again, that's foundmyfitness.com/cryotherapy. Cryotherapy. Finally, it's literally impossible that I could spend so much time, weeks, On such an esoteric topic as cryotherapy, if it wasn't for the mad love sent to me by so many of you.

First, a special thanks go to the people that support Found My Fitness financially. There's over 700 people that support this content for as little as a dollar a month, or less than a cup of coffee, and many that support for quite a bit more than that. You can learn more about that at foundmyfitness.com. Once again, that's foundmyfitness.com/crowdsponsor. Crowdsponsor. Also, a special thanks goes to those of you that just voice your enthusiasm by tweeting, Facebooking, and shouting out at me on Instagram or even YouTube comments. You guys are all great. Now on to the podcast. Most of us primarily think of stress as a bad thing, and it is.

This negative stress, called distress, can be the result of or result in inadequate sleep, emotional stress and rumination, poor gut health, and much more. But stress can also be good. Good stress can be referred to as eustress and can include any number of activities, chiefly among them exercise, but in some contexts, probably also things like intermittent fasting, heat stress from using the sauna, and cold stress from things like cold water immersion or cryotherapy. In general, things that fall into the category of eustress have the quality of being hormetic, which means that in the right dose, they serve as a short-term stressor that can trigger cellular responses in the body that exceed what is actually needed to compensate for otherwise damaging insults.

In other words, at the right dose, even things that can be harmful at higher doses can trigger a net gain in resilience. And this occurs by a variety of different mechanisms. Previously, I have written about, I've talked about the hormetic benefits of heat stress, and in particular, through the use of a sauna. Some examples of potential benefits might include improving athletic endurance, preventing muscle atrophy, improving insulin sensitivity, increasing neurogenesis, that's the growth of new brain cells, improved learning and memory, and improving possibly even longevity. So if you want to learn more about the potential benefits of heat stress, you can check out my videos or my podcast, and I also have some PDF reports.

However, in this podcast, I would like to instead focus on some of the empirical benefits and mechanisms at play that short bursts of cold exposure, both through cold water immersion and whole-body cryotherapy, may have on the brain, the immune system, body composition, your metabolism, Exercise performance, recovery, and more. When people think about cryotherapy or cold water immersion, the first thing they think about is perhaps the effect on metabolism or muscle soreness and recovery, maybe athletic performance, or just like the more immediate effects on the body in general. What I find most interesting, and maybe a bit more clear-cut in some ways, are the effects on the brain. It's also an area that just generally interests me more, so let's talk about that first.

There is anecdotal evidence that cold exposure improves mood and has been suggested that cold showers may even be used to prevent and treat depression. Let's take a quick dive into one of the possible mechanisms by which cold exposure may actually improve mood. One of the most consistent and profound physiological responses to cold exposure is a robust release of norepinephrine into the bloodstream, as well as from the locus coeruleus region of the brain. What makes norepinephrine so interesting is that not only is it a hormone, but also a neurotransmitter, and is involved in vigilance, focus, attention, and mood.

The cold induces this robust increase in norepinephrine in both mice and humans, and it's a response mediated by the sympathetic nervous system, the primary purpose of which is to stimulate the body's flight-or-fight response. Decreased norepinephrine neurotransmission is associated with inattention, decreased focus and cognitive ability, low energy, and poor mood in general. Okay. When norepinephrine is depleted in people by pharmacological intervention, it causes depression. In fact, both ADHD and depression are sometimes treated with norepinephrine reuptake inhibitors, which, of course, may come with its own set of drawbacks. Norepinephrine also acts as a hormone, and when released into the bloodstream, acutely increases vasoconstriction, which is the constriction of blood vessels.

This last part, of course, helps to explain why norepinephrine plays a really important part in our response to cold. By increasing vasoconstriction, we decrease the total surface area by which the blood is able to lose heat to the environment. Let's talk about temperatures. Just how cold do you have to get in order to get that hit of norepinephrine? There does appear to be a temperature threshold for activating the sympathetic nervous system. For example, cold water immersion at 68 degrees Fahrenheit or 20 degrees Celsius for 1 hour does not appear to activate norepinephrine release, whereas 1 hour at 57 degrees Fahrenheit or 14 degrees Celsius increased it by 530%. 30% and also increased dopamine by 250%. Personally, I think dopamine accompanies norepinephrine quite nicely.

Long durations, however, aren't necessarily required for a potent release of norepinephrine. A long-term study in humans directly compared people that immersed themselves in cold water at 40 degrees Fahrenheit or 4.4 degrees Celsius for 20 seconds to those that did whole-body cryotherapy for 2 minutes at -166 degrees Fahrenheit or -110 degrees Celsius. 3 times a week for 12 weeks in a row and found that in both cases, plasma norepinephrine increased 2 to 3-fold, which is around 200 to 300%. And this release of norepinephrine didn't seem to be reduced with habituation to cold. Those levels did, however, drop over the course of an hour after the exposure. On a side note, guess what else increases norepinephrine? Heat, as well as lactate, the latter of which is produced by exercise.

If you want to learn more about the role of lactate in the brain and how it's produced More robustly upon exercise, you can check out the interview I did with Dr. George Brooks, who is a renowned exercise physiologist at the University of California, Berkeley, and he's a pioneer of the lactate shuttle theory. It's a very interesting podcast. So finally, one last note about norepinephrine. It also has other profound effects on pain, metabolism, inflammation. This last point in particular may be relevant to the dialogue surrounding mood, since inflammation has the quality of being able to also inhibit serotonin release. But we will return to that topic of pain, metabolism, and inflammation in a moment. I want to talk about cold shock proteins and a particular one in the brain.

In previous articles and videos and podcasts, I've talked ad nauseam about the benefits of heat shock proteins and how they may even be involved in human longevity. Exposure to the other temperature extreme, cold, also triggers heat shock proteins. But in addition to that, there's a class of proteins that are specific to the cold. Cold shock proteins. Much of what we know about the physiological responses to cold come from research on hibernating animals. Hibernation involves a profound metabolic shift that is driven by the fundamental biological need to conserve energy in the winter. When the body is cooled, many, many genes are shut down. The exception, however, are genes involved in lipid metabolism, fat burning, and a group of proteins known as cold shock proteins.

The expression of these 2 categories of genes are greatly increased upon cold exposure. So one particular cold shock protein known as RNA-binding motif 3, RBM3, especially stands out for the purposes of our discussion. RBM3 is found in the brain, heart, liver, and skeletal muscle and increases in activity greatly, even upon mild cold exposure. Synapses between neurons actually break down during cold exposure. Synapses are how neurons communicate with each other, and it's how memories are formed. This interesting phenomenon was first observed from studies done on hibernating animals. However, when animals that hibernate warm back up, close to 100% of the synapses regenerate. That's a pretty amazing feat. The best part is this effect may not be limited to just hibernating animals.

It's also been shown in laboratory mice. which are not hibernating animals. Mice that were cooled using a special protocol that included a pharmacological way to dramatically lower body temperature in combination with cold air exposure at a temperature of 41 degrees Fahrenheit or 5 degrees Celsius for 45 minutes experienced about 26% loss in synapses in their hippocampus, which is the part of the brain responsible for learning and memory. Once these same mice were allowed to warm back up, they were able to rapidly regenerate around 93% of those synapses Synapses that were lost to the cold. Here's the exciting news: the mechanism by which the lost synapses regenerate was found to be dependent on boosting the activity of the cold shock protein RBM3. Guess what?

This cold shock protein is conserved in humans! We have it too! The reason RBM3 is necessary for this restoration of synapses is because of the role this cold shock protein plays in binding to RNA to increase protein synthesis at the dendrites, which are a part of the neuron that communicates with the synapses. This enables RBM3, the cold shock protein, to regenerate those damaged neurons. A single exposure to this cold shock protocol at 41 degrees Fahrenheit, 5 degrees Celsius, for 45 minutes was enough to increase RBM3 in the brain for 3 days in mice. When this procedure was repeated once a week for 2 weeks in a row, Not only did it robustly increase the expression of RBM3 for those 2 weeks, but also for an additional 6 weeks after that.

So the natural next question is, what if synapses could be brought back from insults other than the cold? Say, for example, traumatic brain injury or neurodegenerative disease. This is where things get really interesting. Mice that were experimentally induced to have neurodegenerative disease from prion infection, when exposed to 2 rounds of the cold exposure procedure early in life, were protected against the loss of synapses, allowing them to have more than twice as many synapses in the brain tissue sampled as the mice that did not get the cold treatment 12 weeks after being infected. The experimental cold stress also prevented cognitive and behavioral deficits that would have normally occurred in these mice, as they progressed into later stages of neurodegeneration.

The cold shock they were exposed to increased the expression of the cold shock protein RBM3 for several weeks, and this delayed the neuronal defects that usually occurred in these mice. It may be pretty obvious that the ability to prevent the loss of synapses is pretty significant and would have huge implications if such a thing could be demonstrated in humans. Losing synapses occurs with normal brain aging, and it's accelerated in neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease, and also after traumatic brain injury. Obviously, there are some novel and very interesting mechanisms at play here, and the ability to protect synapses effectively might have huge implications for these neurodegenerative diseases, as well as brain aging in general.

Let's talk about the human relevance of cold shock proteins. This RBM3 stuff is all very new research, and we really don't know if this effect would occur in the same way in humans. The question is, how much does core body temperature need to be lowered to activate cold shock proteins, including RBM3? It appears that a 2-degree Fahrenheit reduction in core body temperature is enough to induce cold shock proteins, including RBM3, in human astrocytes, which are a type of brain cell. As an aside, adding some melatonin to the mix may also have an effect of enhancing RBM3 activation even more. And supplementing with it has also been shown to have an effect lowering core body temperature.

Okay, but to put that into, you know, perspective, how achievable is it to lower core body temperature by 2 degrees Fahrenheit? This is actually a very achievable dip in body temperature that qualifies as only very mild hypothermia since anything below 96.8 degrees Fahrenheit is considered hypothermic. By way of example, in one study, young men that stayed submerged in cold water of 68°F or 20°C for 1 hour were able to lower their rectal temperature to around 96.9°F, which is around 36.1°C. Or if they stayed in 57.2°F or 14°C water for 1 hour, they were able to lower their body temperature to 96.1°F or 35.6°C. Wow. This just goes to illustrate how attainable this level of cold shock is. Let's talk about the effects of cold exposure on inflammation and immune function.

The purpose of inflammation is to eliminate the initial cause of cell injury, clear out dead cells and tissues damaged from the original insult and the inflammatory process, and to initiate tissue repair. However, when this process runs awry in the absence of actual biological threat, We are in trouble. Inflammation has been identified as the key driver of the aging process and is associated with most age-related diseases. A recent study looked at a variety of different biomarkers in old people, age 85 to 99, centenarians, which are 100 years old, semi-supercentenarians, which are 105+ years old, and supercentenarians, which are— 120.

Superly old because they are 110-plus years old, and found that low inflammation was the only biomarker that predicted survival and cognitive capabilities across all age groups. Earlier, we focused mostly on the effects of norepinephrine in the context of its role as a neurotransmitter. But when studies show it can be increased by as much as 5-fold from extreme cold stress, I think it's worth talking a little bit about some of its other roles. One of the roles norepinephrine may also play is in reducing inflammation. Norepinephrine inhibits the inflammatory pathway by decreasing tumor necrosis factor alpha, TNF-alpha, a very potent molecule that increases inflammation.

An excess of the inflammatory cytokine TNF-alpha has been implicated in almost every human disease Ranging from type 2 diabetes to inflammatory bowel disease to cancer to Alzheimer's disease. Believe me, too much of this stuff is bad. In addition to reducing TNF-alpha, norepinephrine has also been shown to decrease other nasty chemicals such as macrophage inflammatory protein-1-alpha, which is produced by immune cells when they're activated and may play a role in rheumatoid arthritis. Reductions in systemic inflammation are, for the most part, usually unambiguously positive. One such example that stands out and where this might especially be the case is arthritis.

In a randomized controlled trial, patients with arthritis underwent whole-body cryotherapy at around -166°F or -110°C for 2 to 3 minutes, 3 times a week for 1 week, and they had significant reduction in their pain. There may be some, you know, multiple mechanisms at play here, including the cold-induced reduction in inflammatory cytokines mentioned a moment ago. Interestingly, another study found that local cryotherapy, in other words, cooling just the affected tissue, was shown to inhibit harmful collagenase activity on collagen. Collagenase is an enzyme that breaks down collagen and it's also, you know, plays a role in arthritis. The cold— the cryotherapy was also shown to decrease the production of inflammatory E2-series prostaglandins.

Some of the pain-alleviating effects of cold exposure, particularly in the case of whole-body cryotherapy, may in fact be due to increased norepinephrine since inflammation itself causes pain. In fact, spinal injection of compounds that induce a release of norepinephrine have been shown to alleviate pain in both humans and animal studies. Let's talk about brain inflammation and mood. Pro-inflammatory molecules such as TNF-alpha and the E2-series prostaglandins have been shown to cross the blood-brain barrier and activate the brain's immune cells known as microglia. This is bad.

It seems very possible that therapeutic strategies that increase norepinephrine, such as cold water immersion and whole-body cryotherapy, may be a good preventative measure which generally lowers inflammation and thus facilitates this preventative process of attenuating what is otherwise a major contributor to aging in general, but in this case, the brain in particular. I've also discussed in a previous publication of mine the fact that inflammatory molecules probably contribute to depression and anxiety by inhibiting the release of serotonin from neurons. This may be another implication of using cold shock to reduce neural inflammatory processes.

Of course, more direct evidence needs to be shown to link cold shock as a strategy for the potential treatment of mood disorders, but it seems like an interesting and promising area of inquiry. All of this talk of cold exposure, either from cold water immersion or cryotherapy, lowering inflammation, may have you thinking that you might be better off with fewer immune cells since they seem to wreak so much havoc. Actually, having a large number of immune cells is generally a good thing. So, as long as they're not unnecessarily active, you know, it's a good thing. I already mentioned how inflammation has been identified as a key driver of the aging process, but I also want to point out that the immune system plays another important role in the aging process.

Aging is associated with immunosenescence, nonfunctional immune cells, and a general reduction in immune cells. In fact, being very long-lived or making it to the age of a supercentenarian is associated with having a healthier biological stock of immune cells. You want to have a good number of a variety of different types of immune cells, but you also want them to be quiet. Unless there's a good reason to be loud. So how does the cold affect our stock of immune cells? Well, it appears to increase them, at least certain types of immune cells. Long-term cold water immersion 3 times a week for 6 weeks in healthy males was shown to increase lymphocyte numbers.

This is in line with the fact that habitual winter swimmers have a higher number of white blood cells compared to non-habitual winter swimmers. Additionally, another study demonstrated that cold exposure in a climatic chamber of around 41°F or 5°C increased white blood cell numbers, including cytotoxic T lymphocytes, which are a specialized type of immune cell that kill cancer cells. : Males exposed to a cold exposure, so a cold room of— that was around 4°C for 30 minutes. Decrease their core body temperature by around 0.4 to 0.5 degrees Celsius, and increase their natural killer T-cell number and activity. Natural killer T-cells are another type of immune cell that kill viruses and tumor cells.

So all of this may serve to bolster the anecdote shared often among communities of winter swimmers, which is that they experience fewer everyday cold and flu symptoms. In fact, an association has been demonstrated in epidemiological studies between winter swimming and a 40% decreased incidence of respiratory tract infections. So more work needs to be done in order to better understand what the long-term effects of chronic cold exposure are on immune cell numbers and functions to state definitively what this all means though. Let's talk about cold exposure, weight loss, and thermogenesis. Taking ice baths has been popularized in part due to the effects of cold on weight loss.

One of the body's ways of responding to cold is to increase metabolism, not to produce energy in the form of adenosine triphosphate known as ATP, but to produce heat to warm the body and in the process burn fat. This process is referred to as cold thermogenesis. There are two types of thermogenesis that occur as a biological response to cold exposure. The first kind of cold-induced thermogenesis occurs in muscle tissue and involves ramping up metabolism in order to produce heat. This works because metabolism is not 100% efficient and produces heat as a byproduct. This is referred to as shivering thermogenesis because the muscle contractions are what actually increase the energy metabolism.

The second type of cold-induced thermogenesis occurs in adipose tissue or fat and does not involve shivering. It is called non-shivering thermogenesis. This type of thermogenesis is what is really responsible for that quote unquote fat burning effect that cold exposure can have and usually happens after the body has adapted to cold exposure. I can tell you firsthand that the body will adapt. I have done 2 whole body cryotherapy treatments back to back, and I shivered a lot the first time. But not at all the second time. So let's talk about non-shivering thermogenesis and brown adipose tissue. This process is partly regulated by norepinephrine, which we already know is robustly induced by cold exposure by anywhere from 2 to 5-fold, depending on the intensity of cold and length of exposure.

Cold-induced norepinephrine increases the expression of a protein known as uncoupling protein 1, UCP1. Which has the effect of uncoupling the mitochondria, those energy-producing powerhouses of the cell. But what does it mean for mitochondria to be uncoupled? When it is said that mitochondria are coupled, we are referring to the coupling of the generation of a unit of energy, ATP, to the transport of electrons. Which have been derived from the food you eat that create an electrochemical gradient across the mitochondria, which is negatively charged on the inside and positively charged on the outside. Mitochondria are a little bit like batteries in that sense. When cold exposure activates the uncoupling protein 1, UCP1, this uncouples the electrochemical gradient.

Meaning there is no longer a negative or positive terminal to the mitochondria. In response, the mitochondria try and reestablish that electrical chemical gradient quite frantically, in fact, by transporting electrons, which are derived from the stored fat called fat oxidation, and producing heat as a byproduct of this process. One of the ways uncoupling protein 1, UCP1, ramps up metabolism is by producing more mitochondria in adipose tissue, which causes a browning effect by converting or transdifferentiating the more common white adipose tissue into its more metabolically active counterpart, brown adipose tissue. You can think about this in simple terms. The more brown adipose tissue your body has, The more fat your body will burn.

The reason it's called brown adipose tissue is because each fat cell has more mitochondria per cell, and the mitochondria make the fat appear brown in color when looking at it under a microscope. Let's talk about cold exposure increasing non-shivering thermogenesis in humans. It was actually thought for some time that human adults had negligible amounts of brown adipose tissue. Increasingly, however, studies are showing that adult humans do have this special type of adipose tissue that is metabolically active. The fact that we even have brown adipose tissue at all in adulthood actually overturns old dogma that once stated that brown adipose tissue was mostly found only during infancy in humans.

In fact, it's now been shown that brown adipose tissue shows an inverse correlation to percent body fat in an individual. The good news is that repeated intermittent cold exposure has been shown to both increase brown adipose tissue in humans and increase our capacity for non-shivering thermogenesis. Healthy young men and women that were exposed to air temperatures of around 59 to 61 degrees Fahrenheit or 15 to 16 degrees Celsius for 6 hours a day for 10 consecutive days increased their brown adipose tissue by 37%. And after acclimating, also increased non-shivering thermogenesis by between 11% and 18%. It's also very interesting to note that if the brown adipose tissue was sampled during the summer months only, it was shown that it could only be detected in around 25% of the participants.

Compared to around 50% of the participants if brown adipose tissue was sampled during the winter. There you have it. Maybe the old dogma, they were sampling brown adipose tissue in the summer. Okay. So if having more brown adipose tissue, which becomes more active in cold, helps us stave off obesity, then it might be reasonably surmised that being cold... : would boost our metabolism. In fact, it does. One study done in a small sample of young men showed that cold water immersion up to the shoulders in 68°F or 20°C water for 1 hour increased metabolic rate by 93%. And 1 hour at 57°F or 14°C increased metabolic rate by 350%. I'd like to discuss one mechanism by which cold exposure may increase the concentration of brown adipose tissue.

One study found that the sympathetic nervous system may be playing a role, a very intimate role, in the production of brown adipose tissue in rats. Experimentally blocking beta-adrenergic receptors, which norepinephrine act on, prevented the production of brown adipose tissue. This relationship is interesting because it might imply that the greater the release of norepinephrine that we can induce from cold, the more browning of our adipose tissue we might expect to occur. Our diet may also be a way we can therapeutically brown our adipose tissue. One study recently showed that consumption of fish oil actually increased the metabolism of mice. Reduced their fat accumulation between 15% to 25%. And this was shown to be likely occurring through a brown adipose tissue-mediated mechanism.

All right, we are going to change gears again. Yes, again, and talk about cold exposure increasing the activity of antioxidant enzymes. One of the side effects of ramping up fat oxidation to burn stored fat for energy is the production of those damaging pesky reactive oxygen species known as ROS that damage nearly everything inside cells, including DNA. This is actually a normal product of energy metabolism and in a way is a natural part of just being alive. How we respond to this damage and mitigate it is ultimately what's important. Reactive oxygen species, by contributing to things like DNA damage and cellular senescence, are a huge component of the very process of aging. They are also a sign of mitochondrial dysfunction.

Being able to prevent that damage from occurring or being able to repair it after it does occur are both extremely important for staying healthy and, for one thing, cancer-free. Interestingly enough, it appears as though exposure to the cold, by functioning as a hormetic stressor, actually activates very potent genetic antioxidant systems, which are exponentially more powerful than any supplemental antioxidants. For example, young men exposed to cryotherapy for 3 minutes at -202°F or -103°C every day for 20 days doubled the activity of one of the most potent antioxidant enzyme systems in the body called glutathione reductase and increased another potent antioxidant enzyme called superoxide dismutase by 43%. You know all that liposomal glutathione you've been dosing?

Well, it doesn't do anything if the enzymes that use it are not active. Similarly, elite kayakers that engaged in whole-body cryotherapy around -248 to -284°F or -120 to -140°C and 40 degrees Celsius for 3 minutes a day for 10 days increased the activity of superoxide dismutase by 36% and glutathione peroxidase by 68%. That is pretty stout. For those of you that are not familiar with superoxide dismutase, this enzyme is in your mitochondria cleaning up all that damage that is being produced every second of every day. In other words, it's awesome.

It is also important to note that the increase in this antioxidant enzyme activity in this case actually took multiple sessions of the whole-body cryotherapy, meaning the more frequent cryotherapy was done, the more robust of an increase in activating these powerful antioxidant systems. Let's talk about cold shock, muscle mass, performance, and recovery. When it comes to cold exposure in the context of exercise, there are 2 important factors to look at: the type of exercise being done and the timing of the cold stress in relation to the Let's talk about timing. Immediately after exercise activity, there is a spike in the production of pro-inflammatory cytokines, which are molecules that activate immune cells and are involved importantly in tissue repair.

The production of reactive oxygen species and inflammation that occurs immediately after exercise are actually necessary to activate genetic pathways that contribute to creating more mitochondria called mitochondriobiogenesis and also play a role in muscle hypertrophy. In fact, macrophages, a type of immune cell that can be activated in response to exercise-induced inflammation, produce high levels of the anabolic hormone IGF-1 in response to even slight injury of muscle tissue. There has been some experimental evidence that indicates that these specific immune cells are also likely involved in satellite cell migration. Satellite cells are a type of muscle stem cell. that serve as precursors to actual muscle cells.

And satellite cell numbers are actually associated very closely with the amount of actual hypertrophy that results from strength training. Let's get back to the exercise-induced inflammatory process. There is an anti-inflammatory response to this inflammation which begins to peak around 1 hour after exercise. At this point, some of the anabolic hormones such as IGF-1 That are increased with the immune activation seem to also return to pre-exercise levels around 1 hour post-exercise. The anti-inflammatory cytokines help keep our immune system from going overboard. They modulate the activity of the immune cells, preventing them from causing excessive tissue damage. You might see where I'm going with this.

In the cases where cryotherapy, cold water immersion, or perhaps even the use of ice packs are used immediately after training, it may undermine certain beneficial effects that actually come from having a small dose of inflammation. In fact, there have been some studies that seem to hint at this fact. We'll dive back into that in a second, but the main thing to remember for now is that the peak anti-inflammatory response occurs 1 hour after the activity and that some inflammation and immune activation before that point is probably a good thing. The other factor that may influence the outcome of studies looking for the effect of cryotherapy or cold water immersion on athletic performance and recovery is the type of exercise we're trying to optimize for.

Exercise inflicts stress upon the body, and in response, the body activates many genes and pathways that build resilience and, and resistance to that stress. What is important to realize is that the type of exercise actually determines characteristics of the adaptation that occurs. So the stress may be predominantly aerobic, such as endurance training, it may be mechanical, such as resistance training, or it could be a mixture of both, such as plyometrics. Activities that are more characteristically aerobic place a greater demand on cells to be able to utilize oxygen for the purposes of energy production. In other words, aerobic activities have a greater need of supporting mitochondria.

Depending on the nature of the exercise, endurance versus resistance, and the time of the cold exposure, pre-exercise, immediately after exercise, exercise or later, there may be very different and somewhat opposing outcomes. I believe these variables can help explain some of the conflicting evidence regarding the benefits of cold exposure in the context of performance that have been showing up in the scientific literature and also have been discussed in the media. Let's talk about strength training. Whole body cryotherapy at -220 to -319 degrees Fahrenheit or -140 to -195 degrees Celsius done, and this is important, 1 hour after plyometric exercise, which included squat jumps and leg curls, showed improvements in a variety of performance measures up to 72 hours after the cold treatment.

These improvements include power at the start of a squat jump, squat and squat jump workup. In addition, pain measures both at rest and at the next squat jumping session were also improved. The next question is, what happens if cold exposure occurs immediately after resistance training during that peak pro-inflammatory process? One study has shown that it may actually blunt some of the long-term muscle hypertrophy benefits, at least if you're doing cold water immersion. Men that perform leg presses and squat jumps twice per week And then immediately engaged in 10 minutes of cold water immersion, in other words, at the point of peak inflammation, had only 1/3 of the increases in muscle mass in their quadriceps 10 weeks later compared to those that did not do cold water immersion post-training.

In addition, after the 10 weeks of training, cold muscle strength was significantly lower in the cold water immersion group compared to the control group. They showed smaller increases in type 2 muscle fibers, which are required for very short duration high-intensity bursts of power. And all of this coincided with the reduction in biomarkers that are usually associated with hypertrophy, including the activation of satellite cells. Basically, if you were looking to make the argument that cold stress, especially cold water immersion, should be avoided after strength training, this last study mentioned would be your holy grail, not only because of the compelling results that the authors demonstrated, but also because they cited other studies that showed similar results with respect to cold exposure and hypertrophy.

Including some that employed clever investigative methods like having participants do hamstring curls, but only immersing one leg in cold water and then going on to measure the difference in hypertrophy between legs afterwards. However, in every single case, both in this study and all of the similar ones cited, there is one singular unifying theme. The method of cooling, whether we're talking about cold water immersion, icing, or otherwise, was generally applied immediately after training. So that leaves us with a few open-ended questions, but the most important one is this: would we still have seen the blunted or reduced hypertrophy training if cold water immersion was done at literally any point other than immediately after strength training?

I don't know the answer definitively because no study has investigated this yet, but it's an area I hope future studies will illuminate for us, especially in light of the fact that the occasional cold stress seems to have the possibility of conferring benefits in many other respects. The fact that the first hour after exercise in particular stands out as an important anabolic window, at least in terms of the endocrine response, may also be especially meaningful in the context of cold exposure and strength For now, it would seem extremely prudent in the context of strength training to exercise caution in how, and especially when, you time any of the various cold modalities, whether we're talking about cryotherapy, cold water immersion, or even the use of cold packs.

We just talked a lot about strength training in the context of cold water immersion. In the case of endurance-related activities, the consequence of cold water immersion, and in particular, whole-body cryotherapy, are slightly more unclear. Unambiguously positive. This may be characteristic of the type of adaptations that occur that are more specific to endurance activities, or it could be the fact that cold exposure was not done immediately post-exercise in many of the endurance-related studies. In addition to the effect cold can have on inflammatory processes, cold stress is able to boost mitochondrial biogenesis. The reason this mechanism exists is pretty straightforward. Mitochondria are able to create heat, something you need when you're cold, as a byproduct of energy production.

As the powerhouses of the cell, it can be said that mitochondria are pretty darn useful for most of our cells, except red blood cells, which don't have them. However, they're especially important if we want to talk about endurance activity. That's because mitochondria and the density or number of them on a per-cell basis affects our aerobic capacity. Mitochondria are what gives us the ability to use oxygen in order to produce cellular energy. And if we do— and if we have more of them, it can be said we may be more adapted to aerobic activity. Here's how it works. Cold exposure activates a gene called PGC-1 alpha, which makes more mitochondria in the muscle. This is referred to as mitochondrial biogenesis, and PGC-1 alpha is the master regulator of this process. Okay.

If mitochondrial biogenesis is the orchestra, then PGC-1 alpha is the conductor. More mitochondria per muscle cell directly translates to aerobic capacity. And a single 15-minute exposure to cold water, around 50°F or 10°C, following high-intensity running increases PGC-1 alpha in muscle tissue. But even more importantly, cold exposure is actually able to increase mitochondrial biogenesis. Yeah. Men that were immersed in cold water at 50°F or 10°C for 15 minutes, 3 times a week, 4 weeks in a row after running were able to increase mitochondrial biogenesis occurring in their muscle tissue. Exercise that is highly aerobic, such as jogging or running, has the characteristic of being very metabolically demanding and thus requiring more muscle fibers that are oxidative.

Or oxygen-using and fatigue-resistant. These types of muscle fibers mostly consist of type 1 or slow-twitch muscle fibers. In contrast, muscle fibers that are specialized for bursts of short-duration power mostly consist of type 2 or fast-twitch muscle fibers, which are muscle fibers that are more glycolytic. Glycolysis is a process that produces energy Okay. That does not require oxygen and makes that stuff called lactate as a byproduct. There is a category of fast-twitch muscle fibers called type 2a that are fast but also oxidative fibers that are more resistant to fatigue. It turns out that PGC-1 alpha, as a part of or in addition to working its magic to trigger mitochondrial biogenesis, Yes, it is magic. Also happens to induce a switch to oxidative fatigue-resistant muscle fibers.

Remember that cold stress induces PGC-1 alpha and this induces mitochondrial biogenesis. It is interesting to note that getting rid of PGC-1 alpha in muscle tissue of mice has been shown to shift muscle fibers from the slow twitch type 1 and fast twitch type 2a muscle fibers that are more both oxygen-requiring and more resistant to fatigue toward fast-twitch type 2b muscle fibers, which are more glycolytic fibers required for very short-duration, high-intensity bursts of power such as maximal and near-maximal lifts and short sprints. In line with this, genetically engineering mice to express more PGC-1 alpha in muscle tissue than they normally have causes their muscle cells to show characteristics of type 1 muscle fibers, such as greater resistance to fatigue.

In my mind, this suggests that PGC-1 alpha-mediated mitochondrial biogenesis may be slightly more beneficial for endurance athletes than those focused purely on brute strength, if for no reason other than the fact that it seems to shift muscle fibers into a configuration that is more conducive to a higher aerobic capacity and more resistant to fatigue. Of course, I can't say that this is absolutely the case because PGC-1 alpha also increases type 2a muscle fibers, and type 2 muscle fibers in general do have a higher capacity for hypertrophy.

So now that we've covered a little bit on why endurance activities may be a little bit less likely to experience specific deleterious consequences of mistimed cold stress, let's talk about what the actual literature says about whole body cryotherapy and cold water immersion in the context of performance enhancements. Elite runners that engaged in whole body cryotherapy 1 hour, 24 hours, or 48 hours post-hill sprinting had a 20% increase in speed and power up to 2 days later. This 20% performance enhancement post cryotherapy may be attributed to the reduction in inflammation and increase in anti-inflammatory factors. Too high of an in— of levels of pro-inflammatory cytokines post-exercise can result in acute performance deterioration and muscle damage.

This can be problematic for training even several days later, since there may be a greater risk of injury due to residual soreness and changes in muscle function. In fact, it has been shown that elite runners who engaged in whole-body cryotherapy for 3 minutes at -166°F or -110°C performed 1 hour post-exercise and 24 hours post-exercise enhanced muscle recovery by decreasing the inflammatory process, so lower IL-1 beta and lower C-reactive protein levels, and increased the anti-inflammatory process IL-1RA at both 1 and 24 hours post-exercise. Another study including elite tennis players also showed performance enhancements that were associated with a reduction in inflammation.

Elite tennis players that engaged in whole-body cryotherapy around -184°F or -120°C twice a day in the morning and evening while training in the afternoon for 5 days had a 2.5-fold decrease in the potent pro-inflammatory cytokine TNF-alpha and a 23% increase in the cytokine IL-6, which has both pro- and anti-inflammatory properties and plays an important role in muscle repair. These professional tennis players also experienced a 4% increase in quote-unquote stroke effectiveness. Meaning they hit more balls in the target zone compared to the players that did not do cryotherapy. Hey, that counts, right? I mean, maybe it's that norepinephrine helping with focus and attention.

These endurance performance enhancements post-exercise cold exposure may also be sustained over a prolonged time period. Elite cyclists that engaged in 15 minutes of cold water immersion around 159 degrees Fahrenheit or 15.3 degrees Celsius for 30 minutes, um, post-training 4 times a week. This training lasted 39 days and consisted of a mixture of low to moderate intensity road rides and high intensity interval sessions on an exercise bike. The cyclists that engaged in the cold water immersion post-training experienced a 4.4% increase in average sprint power, 3% enhancement in repeat cycling performance, and a 2.7% increased power over the 39-day training period. That sounds awesome. So far, we've covered the effects of various cold exposure modalities on building muscle.

But one last area of discussion that I'd like to cover that loosely fits into this area is the topic of muscle atrophy. Quite a bit earlier when we were still talking about some of the interesting brain effects of cold stress, we talked about the effect cold has on the production of cold shock protein, in particular, One called RBM3. We also talked a bit about some of the studies done in hibernating animals, which of course have to be especially capable at resisting some of the negative effects that can occur during cold. One other interesting aspect of hibernation is the fact that animals that experience this phenomenon, at least in the case of black bears, also experience significantly less muscle atrophy than would be expected for such a long period of fasting and general inactivity.

As you might imagine, this probably is pretty useful for a hibernating animal. There is evidence that black bears actually retain protein balance in their skeletal muscle during hibernation when they're fasting. In other words, they are not generally degrading More proteins than they are making in their muscle tissue, which would cause muscle atrophy. This phenomenon is not limited to bears. It's been shown that hibernating squirrels also experience an increase in RBM3 in their brain, cardiac, and skeletal muscle. Skeletal muscle cells from mice have been— that have been engineered to have increased levels of RBM3 have improved muscle cell survival and even larger muscle cell size. after being exposed to a brief period of cold shock.

RBM3 is clearly playing an important role in the muscle in multiple organisms and may be serving as a generalized mechanism for decreasing atrophy. This would also explain why RBM3 is most highly elevated— is the most highly elevated gene in the muscle tissue of black bears during hibernation. RBM3 is not the only cold-inducible protein that is associated, at least in animal studies, with a reduction in muscle atrophy. PGC-1 alpha, the master regulator of mitochondrial biogenesis we talked about earlier, like RBM3, has also been shown to be increased in humans under conditions of cold stress. It has been shown to protect against sarcopenia, which is age-related muscle loss, and metabolic disease in mice that were genetically engineered to make more of it.

While it's important to note that all of these studies that I've discussed in the context of muscle atrophy are animal studies, it shows promise when you see a similar effect conserved across multiple different species of animal because it hints at the fact that this mechanism may not— may actually extend to us as well and is probably not a point of specialization, at least not for one specific species. Finally, one last note on this subject. Heat shock proteins, otherwise known as HSPs, can also be induced to some extent by cold. And I've discussed them in a previous video, podcast, articles.

When I talk about the science of sauna use, I talk about how heat stress and the concomitant elevation of heat shock proteins has been demonstrated to greatly increase muscle regrowth by 30% In rats during the 2-week reloading phase that followed a week of forced immobilization. We've talked a lot about cold water immersion and whole body cryotherapy and cold packs and hibernation and everything in between in an effort to be comprehensive and see where we can make inferences. However, what we have not done is more directly try to compare whole body cryotherapy and cold water immersion in terms of application. This is actually a really important point. So the million-dollar question is, is whole-body cryotherapy the same as cold water immersion? The answer is probably not.

If we dive into the science, we can see that there are 3 factors that really differentiate whole-body cryotherapy from cold water immersion, and all of them have to do with how effectively each technique lowers core body temperature. But I also want to point out that in addition to these 3 factors, which we will discuss in a minute, is the fact that people can remain in cold water for longer durations than cold air cryochambers, and this may affect how robust the cold shock response is. These 3 factors include thermal conductivity. This is essentially how well heat is extracted from the body, how much of the body is exposed to the cold, so surface area, and finally, the temperature gradient.

In each of the mediums, ice, water, and air, They all have different properties that affect how well heat is extracted from the body. Starting with the first factor, thermal conductivity, how well heat is extracted from the body. Ice has the greatest capability to extract heat from the body, followed by cold water, and finally air. Cryotherapy is slightly less effective at heat transfer since it only uses air. The second factor, surface area, also plays a role in cooling the body. In the case of cold water immersion, the surface area of cold water covering the body really depends on the protocol and can vary from Submerging just the legs, or it can involve submersion all the way up to the shoulders. In any case, your head will usually not be submerged in the water.

This is very different from a cryotherapy chamber where the entire body, including the head, is exposed, although some cryochunks do not expose the head to the cool air. Finally, the third factor is the temperature gradient, which is the actual temperature difference between your body temperature, 98.6 degrees Fahrenheit or 37 degrees Celsius, and the modality being used to suck the heat right out of you. This is really where cryotherapy shines because the air temperatures can be as cool as -289°F or -178°C, probably even colder, but that's cold.

Lastly, another important factor to consider when comparing cold water immersion differences with exposure to cryogenic temperatures in the air is the fact that people can stay submerged in cold water for much longer time periods than cryotherapy air chamber. Yeah. : So, what's the final word? Well, what is clear is that there is a very consistent and very robust release of norepinephrine in the brain and the body both in cold water immersion and whole-body cryotherapy. There have even been studies directly comparing the norepinephrine response to cold water immersion, so the whole body submerged for 20 seconds in 40°F water, with whole-body cryotherapy, 2 minutes at -166°F, and found that they are more or less identical, at least in their response, norepinephrine response.

Now, if you were to stay submerged in that cold water for an hour as opposed to just 20 seconds, we know that norepinephrine would increase 500%, which brings us back to the point that exposing the body to cold for prolonged periods may have a more robust effect. Other than that, I'll leave it as an exercise to the reader and listener to make their own value assessment based on the information at hand. It's probably not worth overthinking too much at this point. We've covered a lot, so I think now is as good a time as any to take a step back and ask, what's the big picture message here? In other words, what does it all mean? I think there are many key take-homes from all of this, and I'll try to summarize just a few.

Number 1, cold shock shows some interesting promise for helping diseases of neurodegeneration through a specialized cold shock protein known as RBM3. Will we be taking people and putting them through super traumatic freezing temperatures in the future to prevent Alzheimer's disease? I don't know. But the fact that this neuroprotective synapsing fixing effect happens in mice is a very good sign and hints at some really profound things we may find out in the future are applicable to humans as well. Number 2, norepinephrine, which can go up a huge amount from a variety of different cold stressors, has some pretty interesting properties and is a very versatile neurotransmitter and hormone.

We need it for vasoconstriction as a part of the body's dynamic response to cold, but it also is an anti-inflammatory and also improves focus and attention. For this reason, it may have special relevance for diseases of inflammation like arthritis, as well as mood and even depression. Number 3, giving yourself short bouts of intense cold stress may be applicable if you have some degree of chronic pain because of the analgesic effect, which may also be partly mediated by, you guessed it, norepinephrine. Number 4, there may be some truth to winter swimming improving immune function in regular practitioners. Number 5, in contrast to old dogma, adult humans have brown fat and exposure to cold increases it. Brown fat generally decreases as we get older, especially if we're obese.

Having more of it, however, is associated with trending towards a lower body fat percentage. And finally, the amount of brown fat is directly affected by our exposure to cold. Cold water immersion can definitely increase brown fat, but so can cold air, which means whole-body cryotherapy is probably also effective for this purpose. Number 6, using cryotherapy and cold water immersion in the context of exercise is sort of complicated. You can definitely undermine your gains in the context of resistance training if you're doing cold water immersion immediately after training. In other contexts, however, there may be improvements in performance as well. We still have some unanswered questions and very interesting points surrounding this.

I'm hopeful that the more deleterious effects will be— will turn out to be mostly constrained to the hour-long window of time immediately after training. But I'm not really sure. We need more studies to say for certain. Number 7, when comparing whole-body cryotherapy and cold water immersion, they're probably pretty similar, at least in many of their hormonal, hormonal responses. One key point of difference is that it is possible to stay in cold water for a longer period of time than it is to stay in a cryotherapy chamber, which could put you in danger of local tissue damage. Such as frostbite. Do what strikes your fancy until better evidence emerges.

As a cautionary note, it is prudent to consult a physician before beginning a new workout program, and this is no less true for activities like cold water immersion, winter swimming, or cryotherapy. This podcast and document is for informational purposes only and not medical advice. Use this information at your own risk. Additionally, if you have coronary risk factors or other heart-related risk factors, it is especially important that you consult a medical physician before attempting anything discussed in this article and podcast, but perhaps especially before doing contrast therapy, going from rapidly very hot temperatures to very cold temperatures. Okay, guys, that's it for this podcast. Thank you for listening.

Make sure to go check out the almost 20-page report on cryotherapy I'm giving away by signing up for my newsletter at foundmyfitness.com/cryotherapy. That's C-R-Y-O-T-H-E-R-A-P-Y. Cryotherapy. If you like this content and think it's totally cool that I'd spend a few weeks Yes, weeks putting it together and doing the research to make it all happen, then why don't you make FoundMyFitness your coffee date this month? Yes, ladies and gentlemen, for the price of a latte, you can keep this awesome content coming. Learn more about that at foundmyfitness.com/crowdsponsor. C-R-O-W-D-S-P-O-N-S-O-R. Crowdsponsor. That's it for now. Keep being awesome, you chilly willies. Peace, love, and grass-fed French toast. This is Dr. Rhonda Patrick, over and out.