 All right, it's great to be here. So, how many of you know in great detail what hormesis is? How many of you kind of know or don't have a clue? All right, good. So you're not wasting your time here then. Well, this picture, somebody running up a trail and getting some good exercise, but that's kind of a vague concept of hormesis and I think we're gonna get into a little bit of detail about what hormesis exactly is. And so the subtitle of my talk is the biology of beneficial adaptation to stress. People think stress is always bad, but stress can be good. I write a blog called Getting Stronger. The byline is train yourself to thrive on stress. I think that's kind of a catchy byline and you'll hopefully understand what that means when you get through this talk. I've given three previous talks at AHS. One of them was on nutritional supplements. I don't think they're always a good idea. Another talk in Berkeley was on how to reverse myopia and then in Boulder, I talked about the benefits of living at high altitude and the implications for that. But this year, I'm gonna talk more fundamentally about hormesis. So we have a lot of epidemics of metabolic disorder, cancer, depression, obesity. There's some thoughts within this organization about what causes those. A lot of the ideas that you're hearing here come out of the concept that stress is at the root of all of the problems or one of the key drivers. But I think I would like to turn that on its head and propose that maybe we suffer from a lack of beneficial stress. The key is understanding what beneficial stress is. So first, hormesis. It's not homeopathy. People get that confused all the time. It's actually a real scientific concept. It's a concept in toxicology which was first controversial and is now becoming better accepted. There is a researcher, Edward Calabresi and Suresh Ratan who've done countless studies. There's over 9,000 case reports of hormetic effects. And I'll get into that a little bit. But first, what is hormesis? It's the beneficial response of an organism to a low dose stressor that would otherwise be detrimental or even lethal at a high dose. It works by activating some endogenous responses, some defense and repair mechanisms in your body. And the result is that you're better off than where you started. You get a super compensation. You end up stronger than before you experienced the stress. Now here's what a hormesis toxicology plot looks like. You'll see a dashed line running through the center here. That's the baseline of whatever organism is tested. Could be a human, it could be a plant or a microbe. It's been done on all kinds of organisms. You expose it to a stress which is down here at the bottom, a dose. And initially you actually get a stimulation effect, a beneficial response. If you go too high, however, into the red zone, you get a detrimental effect. And most toxicology is looking at much higher doses. But in this low dose regime, you can actually get a stimulation effect. The issue is what's that cutoff between benefit and adverse effects? So here's some typical curves from toxicology. You're showing two plots here. One is the effect of alcohol on the hormones in a rat looking at testosterone, luteinizing hormone. And you can see that initially at very low levels of alcohol, there's a stimulating effect. The rat gets more testosterone. But at high levels, it's suppressing. Here's another plot showing the effect of an herbicide, 2,4-D, on oysters, on oyster growth. And actually this herbicide, toxic chemical, at a very low dose gives a stimulation effect. Why is that? Because there's probably a defense response in the oyster. But at high levels, it's detrimental. So again, over 9,000 toxicology studies looked at and about one-fifth of them showed hormesis. So this is pretty interesting. Of course, that dose is different for, the cutoff dose is different for every particular agent. So sometimes it's in the PPM level. Sometimes it's much higher. So there's a huge variation in the hormetic dose. Why is there hormesis? Why is there hormesis in every microbe, in every plant, in every organism? And that's for a simple reason. Without it, the species would have died out because the environment is stressful. If you didn't have the ability to adapt to stress, you're gone. Here's an example of some coral from the area of American Samoa. And recently they found that the coral growing in the warmer waters are now more resistant to bleaching. That's an adaptation. We all ourselves can experience adaptations to environmental stress. So it's ubiquitous in nature. So what's the connection then with ancestral health? A lot of the talks here are focusing on novel foods, novel chemicals, but maybe we look at the other way about what's missing. What's missing from our modern environment that our ancestors had. Here's a quote from Alastair Nunn. I think it's a great quote. And he was sort of surveying the mechanisms of hormesis, but relating it back to ancestral health. I'll just read it. Ancient man was a hunter-gatherer, often traveling long distances to find food, avoid threats, and seek shelter. In contrast, many modern Western societies have transformed their surroundings in order to minimize or even eliminate environmental threats and stresses that our ancestors were exposed to, including food and water shortages, predation, infections, extreme of temperature, and the need to carry out regular physical activity. So we're suffering from a lack of hormesis. That's a big difference in our modern society. Okay, so that's a little bit about what hormesis is. Beneficial response to low-dose stressors that give you a compensating benefit. But what are the mechanisms? How does it actually work? So the rest of this talk is not gonna be so much practical steps that you can take, but I think if you understand the theory behind it and understand the underlying basis, you can apply it. My blog has got post after post of how this applies in many different cases, but I wanna give you the basic principles. And for that, I've looked at all the studies on hormesis, and I think they fit into four different levels from the very low structural hormesis, your bones and your tissues and your muscles and even your eyes, we'll get into that. The next level is defense. That's your immune system and also your xenobiotic defense. That's a system of phase one and phase two detox enzymes that protect you against chemical toxins, but also against the phytonutrients in broccoli. The metabolic hormesis, the next level, which is how hormesis can upregulate your whole utilization of energy. And I think the ketogenic dieting is a form of hormesis. And finally, very important, but not to be overlooked, psychological hormesis. And we'll talk about what that means and the neurological basis for it. Okay, so let's start with structural hormesis. So there's four types of hormesis that I'd like to talk about here. Resistance exercise, weight-bearing exercise, playing the guitar, barefoot running and distance focusing. All right, and each of these has a hormetic effect. So let's get into them. So let's start with resistance exercise and muscle growth. This is the most familiar example of hormesis. We're all familiar with it. When you go to the gym, you lift weights, and straining your muscles causes a microtrauma and an inflammatory response. And specifically, it's mediated by growth factors like IGF-1, growth hormone, and myogenic regulatory factors called MRFs. And then what happens is these stimulate the satellite cells, their stem cells in your muscles, to differentiate and grow into microfibals that grow in fuse-rether fibers, and you get a resulting supercompensation that results in a net increase in muscle size. If you have too much of this, right, that's the red part of the hormetic curve, you can get delayed onset muscle soreness, pulled muscles, so you wanna be in that hormetic zone. Supercompensation, very important concept to understand here, because when you start training, and this applies to any kind of hormesis, not just lifting weights, you get a net decrease in function, right? That's shown in the red part of this curve here. And it takes you maybe a couple of days to recover, but if you do it right, you actually end up stronger than you started out. And if you can do this in repeated cycles, you're moving up that curve. Another example is strengthening your bones. When you lift weight, weight-bearing exercise, this is very important, and people is to get older too. You're actually putting a load onto the bone, and the fluid around the osteocytes compresses them, and this generates the release of proteins called focal adhesion kinase that stimulates new bone growth. And then you get the secretion of collagen that mineralizes and stronger bone, right? If you do it too much, bone fracture, right? We're always talking about the right level of stress here. Calus formation, very familiar to all of us who write, do ballet, barefoot running, do rock climbing like I do. And this is what happens when you expose the skin to friction or pressure. You actually cause the production of an enzyme called transglutaminase that cross-links the skin and makes it tougher. So it's an example also of specific hormesis. There's a general concept called the sed principle, specific adaptation to imposed demand. And what that means is the stress gives you the benefit where it's applied. If I lift weights with my upper body, it doesn't benefit my lower body. If I play the guitar with my left hand, I don't get the calisthenes on my right hand. Can we apply this to the eyes? I gave a talk in Berkeley on myopia. I'm not going to go through all of the evidence for this or the technique. You can watch that video, but I want to just talk about the mechanism here because it turns out that the way you focus actually changes the structure of your eye long-term. Short-term, you can see that when you're looking up close, the crystalline lens expands and you get a different, and you're able to focus on near objects and when you're looking at in the distance, it flattens out. But what happens in myopia is that normally your vision is focused on the back of the retina, but if you do a lot of near work, computers and reading, you're starting to focus in front of the retina, all right? Now what happens then, and I'll explain the biochemistry of this, now you need a corrective lens because you need to shorten the eye, but that distance correction causes further elongation and what we call axial myopia and then you go through a cycle where you have to get stronger and stronger and stronger lenses and it's not really correcting the problem, it's actually making it worse. And why is this? There's a great series of papers called the incremental retinal defocus theory, IRDT, by a couple researchers like Hung and Siafretta and they've shown that repeated defocus cycles cause the release of neuromodulators like glutamate, acetylcholine, GABA, dopamine, serotonin and this actually weakens the eye because it changes proteoglycan synthesis in the sclera, that's the white of your eye, which is most of your eye and what happens then is the eye becomes longer and it elongates and repeated cycles of this lead to permanent myopia and hyperopia is of course the reverse, you're focusing not too close, but too far and this has been shown experimentally in different animals, in chicks, in monkeys but also in humans and what you can see here is a study showing the change in axial length in microns based on the time of exposure to a positive or a negative defocus and you can see in only a short number of minutes to an hour you're already seeing small changes and there have been further follow-up studies showing that for longer cycle periods the change in axial length increases even more so. So how do you apply hormesis here? You reverse the process. You use print pushing or what we call reader lenses plus lenses when working up close to stimulate defocus in the opposite direction or you spend a lot more time when you're outside with progressively weaker lenses and you can look at my video to see more detail on this from the Berkeley talk. Okay, the next level of hormesis up from structural is defense hormesis and this is the strengthening of your immune system and your xenobiotic defenses and I'll give, I've got a few examples here. Probiotic microbes actually stimulate the training of our immune system, our Tregs, our regulatory T cells. Food allergens at low levels can be used in immunotherapy to improve and lessen the response to allergy. Xenobiotic chemicals, not just phytochemicals but even toxins interact with our NRF2 system to upregulate our endogenous phase two enzymes and even certain aromatic chemicals like poly aromatic hydrocarbons, some of the compounds found in charred meat can upregulate our cytochrome P450 system to stimulate that and make us more prone to be able to defend ourselves against some of these toxins. So I'll just talk about a few of these in the interest of time. One of them has to do with probiotics and now I'm thinking of them as hormetic agents. All right, there's a great book here which I would really encourage you to read. It's called An Epidemic of Absence, A New Way of Understanding Allergies and Autoimmune Diseases by Moises Foleskof Manoff and he goes through case after case of specific different allergenic issues and autoimmune diseases and shows how while most of us think that the problem has to do with the introduction of novel foods or chemicals, in fact immunologists are starting to see the importance of the microbiome and the disappearance of the ancient microbiome which helped us regulate our response to foreign bodies and specifically these regulatory T cells are educated by the microbes so that they moderate the B and T cells response basically calming the overreaction of for example, IGE response to pollen, dust, mites and certain food stuffs. Of course as with any hormesis exposure to the wrong microbes at the wrong time creating infection or delayed exposure can actually lead to autoimmune disease and allergy as well. So here's a couple examples and he lays these out in the book and I can't go into all of them but I would encourage you to read it. Asthma, really interesting study in here comparing the Corellians who lived in the part of Finland that after the Second World War went with the Soviet Union versus the Finns, the modern Finns. And the Corellians did not modernize their water supply. They still lived on farms. The Finns did and what happened? Huge difference in the incidence of asthma and autoimmune disease and this was traced to the presence or absence of microbes such as helicobacter pylori and T. gondi in the water supply. Allergies have been associated with urbanization and one of the interesting findings of the book is that people who grew up on farms where they were exposed to cowsheds or animal feces in Sweden and Uganda had much lower incidence of asthma and allergies but they had high prevalence of lactobacillus, parasites and worms, helmets, right? And the disappearance of these from our microbiome is associated with the rise of asthma and autoimmunity. A number of other examples here. The other thing I would point out here is the importance of timing, all right? So sometimes it's important when you're exposed to the microbe. Classic example, MS. We're all exposed to the Epstein-Barr virus, most of us are, but in a cleaner and cleaner environment there's less of that, right? So what they found is that people who were not exposed to Epstein-Barr until their teens or their 20s were more prone to get MS similar to the prevalence of mononucleosis. Those who were exposed at a much earlier stage tend to be protected. Autism, similar story but this goes back to childhood or maybe even in utero, all right? Now let's talk about the other type of defense which is the xenobiotic metabolism. This is your defense against foreign chemicals like, well, phytochemicals but also other toxins. What's really interesting is that the NRF2 which is the transcription factor is stimulated by these chemicals, basically aromatic chemicals like phyto-nutrients and found in peppers or in carrots or in broccoli or by exercise. And when it's stimulated you get the production of a number of autoimmune, antioxidant enzymes such as glutathione transferase, glutathione peroxidase, superoxide dismutase and these are your endogenous antioxidants. Paradoxically if you take a lot of antioxidants orally, exogenously, you suppress the NRF2 system. So you may get a stoichiometric short-term benefit but you're turning off your body's ability to make catalytic antioxidants which are far more powerful. Now let's get into the third level of hormesis, metabolic hormesis. Some of you might recognize this character, Vim Hof. He's a big believer in cold exposure as am I and I'll talk about four stimuli that turn on your metabolic-hormetic systems. Cardio and high-intensity weight training, fasting, carbohydrate restriction which turn on autophagy and keto adaptation, cold exposure which turns on thermogenesis and hypoxia. What's interesting and I gave a little preview of this when I talked about altitude when it was in Boulder is that all of these fit into a single stress response system. This stress sensor which is called PGC1-alpha which is peroxisome, proliferator-activated GC1-alpha. It binds with your P-PAR receptor and it's sensitive to cold, to altitude, to exercise and to calorie restriction and these transcription factors are throughout the body. They're in your liver, they're in your muscle tissue, your fat, they're in your brain but there's a couple important pathways that come out of the PGC1-alpha transcription factor. One is it's the master regulator of mitochondrial biosynthesis. The more it's stimulated, the more mitochondria you'll grow, right? That's your energy system. It turns on, in your muscle, something called FNDC5-iracin which is a hormonal system that converts white fat to brown fat. Makes you more metabolically active. It stimulates your BDNF, your brain-derived neurotrophic factor which is very important for neurogenesis and ultimately for mood. So it has important effect on appetite suppression, your desire to exercise your insulin sensitivity and on a process called autophagy which we'll talk about a little bit. So what is the primary thing that it does is it inhibits what's called mTOR. mTOR is a pathway that is very good to have when you're young because it stimulates protein synthesis and growth but when you get past middle age it can lead to processes like cardiovascular disease, cancer, neurodegeneration because it becomes overactive. So you don't want that mTOR process to be going into old age and mTOR basically is inhibited by the PGC1-alpha cascade through a protein called red one. It also turns on this process called autophagy which I think you've heard a few people talk about but it's basically a cellular house cleaning process. You have all these damaged proteins and lipids inside your cell when you fast or when you have the PGC1-alpha cascade when you expose yourself to cold or exercise this process turns on and you clean out a lot of these damaged proteins which if they accumulate can lead to all kinds of metabolic problems. So how does autophagy promote longevity? Well, again, it clears out the aggregated proteins it reduces inflammation, senescence, oncogenesis but it also upregulates your innate immune response and removes intracellular pathogens. Now a little aside, why do we age? There's three different theories of why we age. There's the genetic programming theory which says it's just in our genes. It's inevitable. We have a finite lifespan. There's the damage accumulation theory which says it's free radicals, right? Too much oxidation going on. So you should take antioxidants. And then Mikhail Black-Osclinny and Volter Longo and Ron Rosdale have proposed this hyperfunction theory which says it's mTOR. The mTOR process goes too long. It causes inflammation, too much cell division ultimately leads to all of the metabolic disorders. And this is where hormesis would be beneficial because it shuts down that process. So the question is what about this middle theory, the damage accumulation theory? A really good example, a counter example of the damage accumulation theory is the naked mole rat. Now ordinary lab rats can live a few years, right? But there's this weird-looking rat that's all wrinkly that lives underground called the naked mole rat, which can live, not just three years, but can live up to 30 years. Interestingly, when it's been analyzed, it's absolutely wracked with oxidative stress. It's, you know, all of its proteins are cross-linked and there's plaques and it looks like a mess, right? Wrinkly, but it has a huge antioxidant defense. Those sources of oxidation have turned on its endogenous antioxidants and it's protected and it has very low mTOR. So which theory is right? The accumulated damage theory or the mTOR theory. BDNF is also up-regulated by this whole pathway and that's, again, this hormone that is not just in your brain, but in your muscles that carries out really useful processes like neurogenesis and it tends to be, low BDNF tends to be associated with obesity in the muscles. It's also associated with improved insulin sensitivity. So you wanna have BDNF. Also, it surprisingly makes us want to exercise, right? So having this cascade in place improves the urge to exercise. So it's really everything kind of going in the right direction. One way I like to think about this is two different cycles. There's the virtuous cycle of Hormesis where if you have Hormesis, you grow more of these mitochondria, you have more energy, you have an urge to exercise and you're willing to go out and take cold showers and restrict your calorie. You have more energy to do that. On the other hand, there's the vicious cycle of inflammation. If you have eaten an inflammatory diet and you're sitting around comfortably and you're eating too much food, then your mitochondria are not growing, you have less energy, so you wanna eat more and that's a reinforcing cycle. And I won't go into too much detail here, but since a lot of you are interested in ketoadaptation, I think this is another example of metabolic Hormesis, right? So we have a lot of flexibility. We can eat a high carb diet, a low carb diet, but when you go into a fasted state, you start producing ketones and you get a lot of the benefits of nutritional ketosis that people here have talked about. What's not often recognized is that true ketoadaptation takes a long time. It can take two to three weeks and that's because you have to adjust your glycogen stores and your liver and your muscle and your kidney. It takes time to grow more mitochondria, it takes time to upregulate your antioxidant enzymes and there's adjustments in your membrane lipids, et cetera. And if you wanna read more about this, I think Stephen Finney and Jeff Follett have written a good book on ketoadaptation and the biochemistry that underlies it. So now let's go to the highest level of Hormesis, psychological Hormesis. Again, this is not just some weird spiritual thing, there's actually hard science and psychology and neurology behind it. So I'll give two illustrations of psychological Hormesis, which I define as the increased resilience in the face of discomfort by voluntarily exposing yourself to stress. All right, so there's two guys, Richard Solomon and JD Corbett who in 1974 did some research which led to what they called the opponent process theory of emotion. And they wanted to explain two things. Why is it that people become addicted? But also why is it that stressful experiences can lead to a feeling of well-being? And as examples, they looked at several pleasures here on the left side of addictions that were pleasurable in the short term but led to very difficult subsequent withdrawal symptoms, alcohol, cocaine, gambling, eating highly palatable sweet foods, smartphones, all right? And then on the other side, challenges that had the reverse effect. They were terrifying or actually very unpleasant in the short term, but they gave rise to sustained feelings of good feeling. The first case study they went after was skydiving, but they looked at firefighters, marathon runners, and I would add in my own which is cold showers which fits into the same category. So I wanna read you a quote which I think really describes this to a T. This is the interviews with military parachutists. During the first free fall, before the parachute opens, the military parachutists may experience terror. They may yell, their pupils dilated, their eyes bulging, their bodies curled forward and stiff, their heart racing and breathing irregular. After they land safely, they may walk around with a stunned and stony-faced expression for a few minutes and they usually smile and chatter and gesticulate, being very socially active and then they appear to be elated. After many parachute jumps, the signs of effective habituation are clear. The fearful reaction is usually undetectable and instead the parachutists look tense, eager or excited and during the free fall, they experience a thrill. The activity is high with leaping and shouting and euphoria. The period, often described as exhilaration, decreases slowly but lasts often two to three hours. So starting out, terrified and then you get a brief period of pleasure afterward but with time, that terror goes away, you're habituated but you get a long and sustained period of pleasure and they represented this with a very nice set of diagrams and I want to explain this. On the left you'll see what I described in the initial period of that for the parachutists. The state A here is an intense state. It can be pleasant or unpleasant. So it could be the addiction if you reverse it but let's take the pleasure one first. A state of fear with the, sorry, let's take the skydiving first. An intense state of fear with a delayed positive response, right? But with time, that state A, that fear is diminished but the positive response is deeper and longer. With the addiction, the opposite is true. You have an intense pleasure taking the drugs or the alcohol or gambling or whatever but with time, when you don't drink anymore you get a down, you're coming down. The more you do it, however, the addict requires more and more substance. Otherwise they're gonna have a very weak positive feeling and their down and their withdrawal is gonna be harder and harder. So these are the exact mirror images of each other which is kind of interesting. Now is this just psychology? Right? No, it actually has a neurological basis on the receptor level. Let's look at dopamine receptors in the brain. In this study by Nora Volko, you look at PET scans, positive emission, tomography scans of the brains of people who are smokers, alcoholics, obese or cocaine addicts. The normal are on the bottom here, all right? And red means highly stimulated. This is where you have very active dopamine receptors. You can see they've all got a lot of red in their striatum. But the smoker, the alcoholic, the obese and the cocaine addict, it's far diminished. They're just not activating their dopamine receptors. So that stimulus of the pleasure has actually caused the body to hormetically, homeostatically down-regulate the receptors. Similarly, here's a case where cocaine addicts, this is over a six-month period and 12-month period. You can see they're just not getting the same response over time in their basal danglia. And similarly, here's the opposite. Can you use hormesis to actually reverse the process? This is the other side of the opponent process theory. Well, here's a study of caloric restriction, fasting in laboratory rats after four months. And they had obese and lean mice. And you can see here that when they had unrestricted food access, which is in the top, they had very low dopamine receptor activation. But here's the rats after they practiced fasting for four months, intermittent fasting, and they have a lot of dopamine activation. They're happier, all right? And there's similar studies here in humans looking at activation of dopamine receptors in meth addicts, showing that the meth addicts, when they were abstinent and combined that with exercise, had significant up-regulation in their D2 receptors where the ones that did not exercise, no change, all right? Antidepressants, similar story. The idea with antidepressants is SSRIs increase the concentration of serotonin in the synapse. So you get a sense of well-being. However, there's been found to be a tolerating, a tolerance effect, where at least in certain individuals, the five HT2A receptors, the serotonin receptors are down-regulated, making them less responsive. So again, the thing you have to consider in exposing yourself either to pleasure or pain is there's an immediate effect and then there's a secondary effect and that's what sometimes is not taken into account. So here's how I would summarize psychological hormesis in terms of what I would call the receptor control theory. Whatever the receptors we're talking about, serotonin, dopamine, or in the case of even other metabolic effects, insulin, leptin, whatever the receptors are, the more you stimulate them, the more down-regulated and the reverse is true. Individuals have set points. We tend to have the same body fat through life unless we change something. We tend to have the same level of pleasure through life unless we change something. So what I've shown here then in this diagram is here's an individual who is a little bit heavier and maybe unhappy, does not have a lot of receptors. Has a very low receptor density. Here's your average person in the middle and here's the person who's practiced hormesis. They've grown all their D2 receptors. They've grown a lot of serotonin receptors. They're able to be happy on less food with less exogenous stimulant because they're generating, the receptors are much more sensitive to dopamine, right? So they can function with less input. And so essentially, just like you have a body fat set point, I think you have a pleasure set point and you can affect that. And that's not a day-to-day thing. This is a long-term thing. It takes time to change that. So psychological hormesis in short, I think is engaging in physical challenges where you can increase your pleasure budget, your pleasure set point and make yourself more resilient when you do face those stresses, all right? So I'll try to bring it to a close here. At all four levels we've talked about, the structural, the defense, the metabolic and the psychological, there's a couple principles that apply. First of all, plasticity. We're all much more adaptable than we realize. We can change significantly. Second, specificity. All of these stresses that I've talked about are very specific to a particular muscle, to your callus, to a particular metabolic pathway, to a particular psychological response to a chemical or activity, all right? So think about it not as a general type of a stimulus, but a very specific one. Third one, very important, supercompensation. We showed that the diagram for muscle growth, but this applies to every single one of these. When you have a hormetic stress, you're gonna lose some capability in the short term, but if you do it right, you'll get a supercompensation and then each cycle builds your capacity. Secondary adaptation, these are not primary adaptations, not immediate responses, but the secondary adaptation takes weeks sometimes. And finally, intermittency, very important. We talked about stress. What we're talking about here are acute stresses that are applied occasionally, not chronic stresses which wear us down. So let me just illustrate a few of these last two points. Primary and secondary adaptation, resistance exercise, focusing, fasting, cold exposure. We get benefits in hours to minutes and then they disappear. But the secondary response is what you're aiming at. Muscle hypertrophy, changing the length of your eye, ketoadaptation, true adaptation to cold or stress. This takes typically weeks to months, repeated cycles. And this is where most people give up and they don't realize that they try one or two cold showers and it's uncomfortable and it's never for them. They try fasting for a day. They can't adjust so they give up. The adaptations take time. Stress oscillation, very important. You can't just be stressing yourself all the time. You have the active phase, the workout, activating your sympathetic nervous system, fasting, you lose a little weight. But really, you also have to give yourself some rest to allow that stress, that adaptation to consolidate. You have to allow recovery of your muscles. You have to allow rest and sleep. You have to allow when you're fasting some time also to eat and you can't be challenging yourself psychologically all the time. All right, so to wrap it up, cornemesis is everywhere in nature. There are studies on microbes, plants and animals. It operates at multiple levels from the basic tissue repair to psychological resilience. In moderation, hormetic challenge leads to supercompensation. You end up better than where you started. You can increase your performance. Think of it like an investor. You have to make an investment which is taking something out of you in the hopes of getting a better long-term return. Beyond the advent of novel foods, I think the real mismatch here is that we've lost hormesis. We've lost the microbes. We've lost the exercise. We've lost the dietary challenges. And if we add those back, I think we'll no longer have such a mismatch. So get out there, do a little hormesis, try intermittent fasting, try cold showers, and maybe even rock climbing or skydiving. Thank you. Excellent talk as always. And this is a great topic. And it just occurred to me at the end here that when you're describing homeostasis, which is a typical process of defending a set point of subtype that's all throughout our physiology. And there's this also concept of allostasis where under conditions of a chronic damaging condition, your body learns to defend a new homeostasis because it can't achieve the optimal one. What hormesis seems to suggest is a third type of this process of maybe you'd call it hypostasis where the hormesis is actually causing you to change the homeostatic set point in a beneficial way. So it's more stable rather than less stable, like the opposite of allostasis. What do you think about that? No, I agree. In fact, I do think there's positive allostasis and negative allostasis. So I would say that hormesis is positive allostasis, right? It's the idea of changing your set point, your body fat set point, your pleasure set point through the supercompensation effect. But yeah, I would agree. I think it's a kind of allostasis. Hi, Todd, thanks for your talk. Big fan of your work. Have you thought about the novelty of the hormetic stressors? So most of the things that you talked about, it would seem that humans would probably have a lot of practice dealing with that type of stressor. But I wonder about things like electromagnetic fields that we've recently introduced into our environment that may be acting like a hormetic stressor, right? Maybe they're interfering with mitochondrial function, but humans have never seen that type of stressor before. Would you expect there to be a difference with things that we introduce that we don't have practice with? It's a good question, but a lot of these things we think are novel are we're actually able to deal with. So for example, radiation hormesis, I didn't go into it, it's a controversial area. There's always been radiation in the environment and studies of people who live near natural radiation, sometimes they've shown a benefit. Chemicals, it's a bit of a mixed bag there, but a lot of the novel chemicals are related to chemicals in nature, which are also stressors. But you're probably right that they're stressors that we have never experienced and then we would not be able to defend ourselves. And I also wonder that, especially with electromagnetic field, it's like the pulsiticity is gone, right? Like you're talking about intermittent and now you're bathing it at a level you never see before. You need the intermittency, I think, yeah. Thank you. Yep. Would you place eating polyphenols into hormesis? Yes, the polyphenols, these are the phytonutrients. These are in plants. And this is what our NRF2 system, our phase one, phase two antioxidant systems, are designed to detoxify. And when we eat the polyphenols, we increase our endogenous antioxidants. Yeah. All right, thank you, everybody.