Jay Feldman 0:04
Welcome to episode 77 of the energy balance podcast, where we teach you how to live without constant hunger and cravings, fatigue, brain fog, poor sleep and other low energy symptoms by maximizing your cellular energy. I'm Jay Feldman. I'm a health coach and independent health researcher, and joining me again today is my good friend Mike Fave. Mike and I have been studying health and nutrition together for a long time now, and Mike also draws on his experiences from working within the healthcare industry. Today's episode is part three of our series discussing hormesis, which, if you're not familiar with it is the concept that is claimed to be the reason why many of the things that are suggested in the alternative health and biohacking space are healthy, things like caloric restriction, exercise, various plant compounds called thermogenesis, fasting, low carb diets, saunas, resveratrol and various other interventions. And in today's episode in particular, we'll be discussing why you don't want to be forcing autophagy, mitochondrial biogenesis and uncoupling, which again, is one of the narratives that you hear by people in favor of hormesis. And in today's episode, we'll be talking about why the stress caused by caloric restriction, exercise, cold, dermogenesis, fasting, ketogenic diets, Wim, Hof breathing and supplements like resveratrol is not supportive of our health. We'll also be talking about why autophagy, mitochondrial biogenesis and uncoupling are not always beneficial, but might be in certain contexts. We'll also be talking about whether being tolerant distress is a sign of health, why it's virtually impossible to apply hormesis in a practical sense, and the difference between reactive oxygen species that are produced in a high energy state versus those that are produced in a low energy state. And I should have mentioned this in part one of this series, but if you are new to this podcast, I'd highly recommend you go back and listen through episodes one through seven of the podcast, where we took some time to build a foundation as far as the bioenergetic view of health is concerned. To check out the show notes for today's episode, you can head over to Jay Feldman wellness.com/podcast where you can take a look at the studies and articles and anything else that we reference throughout today's episode. And if you are dealing with any low energy symptoms, maybe these are symptoms you've been trying to improve through a hormetic lens. And this could be things like low energy or fatigue, chronic cravings or hunger, joint pain, brain fog, other digestive symptoms, poor sleep or insomnia, or various hormonal imbalances, or various other chronic health conditions, things like autoimmune conditions or heart disease or diabetes or anything on. From there, then head over to Jay Feldman wellness.com/energy where you can sign up for a free energy balance mini course, where I'll explain how these different symptoms and conditions are really caused by lack of energy, and I'll also walk you through the main things that you can do from a diet and lifestyle perspective to maximize your cellular energy and resolve these symptoms and conditions. So to sign up for that free energy balance mini course, head over to Jay Feldman wellness.com/energy, and with that, let's get started.

So I think we've spent a good amount of time discussing the calorie restriction problems and all those confounding variables, and we see parallels, and again, all sorts of other research. But I want to talk about some of the other conceptual situations here and problems with this, thinking of, you know, thinking of things in terms of hormesis, as we've kind of been pointing out. So a couple of the other things we had always already pointed to as far as support for hormesis. One is that you see, over time in aging and degenerative conditions, you see reductions in adaptive responses. So you see, to be more specific, you'll see reductions or defects in autophagy. And you see this in obesity, type two diabetes, Parkinson's, Alzheimer's, rheumatoid arthritis, cardiovascular disease, cancer, liver disease, any sort of degenerative condition, you're going to see impairment in autophagy. If you also see, maybe, in a lot of cases, you'll see lower levels of uncoupling, and I'm assuming things like lower levels of mitochondrial biogenesis, things like that. And so what you're pointing at here is a is a problem with the adaptive response, and I've and so this is again, by people in favor of hormesis. They'll point to this and say, if you have less autophagy, and let's say diabetes or heart disease, then more autophagy must be better. It must be the opposite of that state. And so we should just do things to increase autophagy. And there's just a lot logical fallacy, a logical problem here, with that, that extrapolation, that assumption, which is that basically, just because you have defects and ended up in an adaptive response, does not mean that. Increasing the stimulation of that adapted for response is beneficial, or does the opposite? In fact? Well, we'll get to in a second. But so so it doesn't mean that that that is inherently beneficial. It just means that in a degenerated state, you are not able to adapt as well. And that also kind of conflates with the other view from the hormesis side, which is that when you block these pathways, if you block the ability to have autophagy in response to various stressors, or if you block the ability to uncouple in response to various stressors or anything else, then you don't respond to this stressor as well and potentially cause degeneration. And again, same thing here. No, there's no like we don't disagree that you need to be able to adapt properly to stimuli, but that doesn't mean that the stressors are beneficial. It just means that a reduction in proper adaptation is harmful, and some rather direct support for this is so you see in all these degenerative states that you have reductions in the adaptive responses, but you also see increased reactive oxygen species in these states, and reactive oxygen species are the trigger for that adaptive response. So you still have the trigger, but the response is not happening, which is a suggestion that we don't need to be activating the trigger more. We don't need to be forcing oxidative stress and adding more stressors to increase these pathways. We instead need to fix the ability to adapt to these pathways and whatever is causing that problem in adaptation and that defect in adaptation. So there's just, again, a complete logical fallacy there, that in Sup, you know, in this hormetic idea, we want to be increasing the exposure to hormetic things, to increase these adaptive responses to reverse aging and degenerative conditions, even though you already have excessive amounts of oxidative stress in these conditions, and they're not and they're not responding well in these conditions. And another problem with this view is, and we kind of talked about this, there are beneficial specific effects to exercise and fasting and whatever else, and you see benefits of those interventions in these states. You see benefits from exercise in these states. You see benefits from, you know, from fasting in these states, calorie restriction in these states, all those things. And you if you were arguing favor of hormesis, you would have to argue that the reason you're seeing these benefits is because of the stress and oxidative stress, specifically and lack of energy that they're causing, but these states are already characterized by low energy and excess oxidative stress, so that state you're only driving further, and instead, there's so instead, in that case, it doesn't make any sense to claim that the risk that the reason why you're having these benefits is for The increases or due to the increases in oxidative stress and energy depletion, but rather, they're due to specific effects, which is our whole argument. And I know I was throwing a lot of words and terminology in there, so if there's any I don't know if it came across clearly, or if there's anything you want to kind of sum up there to help me out, Mike?

Mike 7:58
I was just going to put a lens to it, which is essentially it's like with these chronic diseases. What I kind of see is, I look at it through Hans Selye general adaptation syndrome, so an issue, you have alarm, and then you have resistance, and then you have fatigue. So a lot of the chronic diseases, in my perspective, are kind of or at least a way to look at it is that their people are in the fatigue stage. Their body is not able to mount that adaptive response effectively anymore, because it was already adapt, like trying, already mounting that response over an extended period of time, right? And when you look and when you look at like, like, the the view there, or the the model there, of with which to look at these things is you have like, a litany of stressors simultaneously. So you have poor sleep, you have smoking, you have poor diet, you have job stress, you and then you have, you know, immobility, whatever it is or injury. And so you have all these things going to the bucket. And the body is desperately trying to maintain some degree of homeostasis right, to manage itself, to maintain its general function, and so it relies on all these adaptive pathways. And then eventually you exhaust the adaptive pathways. Once you exhaust the adaptive pathways, then you just get like, then that's you, and you'll see that. But at the exhaustion period is then you just see, like, these Frank chronic diseases, where the adaptive pathways are kind of blown out, and things just start, things start to degrade. So like a lot of the markers or indicators that we're looking at, like cholesterol or triglycerides or any or these different whatever they are, whatever lab value you're looking at, cortisol, prolactin, um, those are all indicators of these adaptive responses you're because the and the other lens that I like to look at things through with this is that you have like, the body is intimately connected to the environment all the time. There's no separation, but there's everything is responding to everything else. And so you have this like constant like give and take give and take give and take give and take give and take. And the body is essentially like the cells of the body have come together to maintain an overall environment, and so you it's they need the resource. You need resource to do that. And over time, if you don't provide resource, and you increase expenditure of that resource because of whatever you have going on, not to mention you have factors going into the system that are impairing the ability to use the resource, then you just get, like, Frank breakdown. And that's what you're seeing with heart disease, that's what you're seeing with cancer, that's what you're seeing with all the chronic diseases, and they all run through the same pathways. All the research is saying, Oh, it's inflammation, it's it's oxidation, it's inflammation, it's oxidation, whatever it is. That's why you need antioxidants and anti inflammatories. It's all the common stuff. It's everyone. And then where you see these science magazine articles where it's like, oh, inflammation is the new killer, like, whatever it is. So I think that, yeah, I think, I think it's important to look through the lens of alarm, resistance, fatigue, and then, like a constant interplay where you have to give resource to the system and remove the negative factors on the system. And this is again, opposite of a hormetic response, which is you need to apply a stress to get an adaptive response. What we're saying is you need to minimize the stress and provide a resource to deal with the stress that you already have going on, instead of just keep applying stresses, keeping applying stresses on a system that's already broken and unable to adapt to the stress. Is a horrific idea. It doesn't make any sense, and this becomes important. This doesn't mean that exercise is something like that is bad, and it doesn't mean it. It means that there's a context for exercise. If you have somebody who's a frank diabetic with heart disease, it's understood that you're not going to have them squat 400 pounds today.

Jay Feldman 11:46
Yeah, well beyond that too. It also like the key point there, and just to interject, is that the exercise is not beneficial because of the stress, right? If exercise is beneficial in type two diabetes, which is already a state of very, very high stress on that cellular level then and then adding it wouldn't make sense for adding more stress to somehow, all of a sudden, be beneficial. Instead. Exercise is beneficial for other reasons.

Mike 12:10
Yeah, yeah, well, for including, like, you like enhancing utilization of glucose and having a beneficial horror um hormonal effect, and then having beneficial effects on the gut, depending on the type of exercise that you're doing, and increasing blood flow and lymphatic flow and and all that type of stuff. So there's a whole host of benefits there, which are the specific effects, which are separate from like the stress itself, yes, yeah, yeah.

Jay Feldman 12:37
And we'll, we'll talk about that later, in specifics, in specific with exercise, but that's why something that's even very, very minimally stressful, like walking or doing daily activity around the house, is so beneficial, even though it's barely causing any stress, so to speak, it has a very low stress or effect, but it's still very beneficial.

Mike 12:54
Yeah, I think the the approach that both of us come from with this, and like the perspective, and I guess I'll say for me, but I think we had enough conversations on it. But it's, it's, it's finding it's, it's things are going to come with some degree of stress, and it's, and you want to have that specific the specific effects have the benefits like exercise and whatnot. It expends energy. But this, the goal is to find a level of exercise where you're not over taxing your system and you're still receiving the benefit from the specific effect. And that's the same thing with almost everything that now this isn't a case. You have to be careful with what you look at here, because it's like, oh, the specific effect of cold thermogenesis is like...

Jay Feldman 13:38
we'll get to it. We'll get to we'll talk because we'll talk about how to navigate that that field and of evaluating potential stressors through that lens. Before we do, I want to, I want to talk through a couple other conceptual problems with the hormetic view. We've talked through several, obviously research based, talking about, also the we've talked a lot about the conflation of these specific effects and stressful effects, or stressor effects. And another piece, too, in and we've talked about this in extrapolation from these studies, is the assumption that anything that activates those stress pathways is beneficial. Anything that increases the sirtuins is beneficial. You know, again, just kind of poor extrapolations from those the kind of research, there's also, again, the idea that how much and resistance to stress is beneficial, and so this is again, a conceptual problem, so to speak, or question so to speak as far as whether it's a good thing for us to be able to tolerate a lot of cold without it affecting us, or for us to be able to run many, many miles without it affecting us, or for us to be able to go very long time without food without it affecting us. Are those good things? And there's, I guess I'm just going to share my my thoughts there, because I don't think that there's. Is beyond the research that we've already gone through. I don't think there's too much to explain in those terms, but I guess what I would say is that a very healthy organism that's functioning on a very high energy plane, like producing a lot of energy and in a very high metabolic state, should a have and we'll talk about this in more detail, but a will have a lot more resistance to stressors, but when it feels stress and starts to shift out of its very highly metabolic state and shifting toward basically the dower state, right the fat oxidation and and the turning the dial down of all those of all of our functions that should be noticeable, because if it's not noticeable, like if it's not noticeable, that's probably a sign that those functions are already turned down. You're not noticing a decrease in libido because your libido is already in the tank. You're not noticing a decrease in energy because you're already fatigued. You're not noticing problems with your sleep because you're already not sleeping well. And so to be able to handle exorbitant amounts of stress and not notice a change in those things, I don't think is a sign of health. I think it's a sign of already being in a constant stress state. And I think you see that shift when you're coming from all these interventions that add in a lot of stress, whether it's low carb or fasting or carnivore diets and excessive exercise and on from there, that when you start to add more carbohydrates in and do things to reduce stress, you notice a lot more if you go X amount of time without eating, or if you wake up and decide not to have breakfast, or if you push it too hard in the gym, you start to feel those that difference that bump up in stress hormones because you're coming from a state that's low in the stress hormones. And so again, this is just, I guess, more than anything, I'm just providing an alternative conceptual framework here that I know you agree with as well, to this idea that we want to be really tolerant to a lot of stress, and again, providing a framework that suggests otherwise.

Mike 16:55
I mean it, and I guess it's different, people don't really see to some extent, I think the extent of what like the body can handle, like the body can handle absurd amounts of stress now you don't want to be there. And the reason I the reason I say this, because I see it when I work in the hospital, and like, I think I told people that I did move back to work in the hospital. So I have been working for the past week or so, I just started and just the level, like you have people with I'll give an example. I have a patient who has, like, had multiple heart attacks in the past, was sent, placed, is obese. Blood Pressure runs almost to the two hundreds, even with medication at times, and they're in their 70s, almost 80s, and the doctor is going to, you know, cut, take, cut a leg out of their vein, or a vein out of their leg, cut a vein out of their leg, and then they're gonna crack open the chest and place it on the heart, and the body at that age, will heal from that now, is the healing going to be perfect? No, but just like you're already in this massive dysfunction, you have obesity, you have metabolic syndrome, you have, like, severe over activation of the renin angiotensin aldosterone system, probably ridiculous amounts of estrogen, probably a large amount of glucocorticoids, and you can the body will still somehow find a way to recover, maybe not to the best extent that it could be from having a major surgery like that. It's just like, it's it's insane, and the the body just adapts to that level of stress. It every it you get to a plateau, and it just that becomes a new normal. And even working as a nurse, the when working as a nurse and not working as a nurse like you just get used to, you know, if you're working 14 hours a day and you don't get to eat and you don't get to go the bathroom, whatever it is like, that just becomes normal, and you don't feel it, and people don't feel it, and things creep up over time, and you just start getting these, like nagging things, and it just builds up, builds up, builds up, builds up, builds up. But it takes years for a lot of people, takes their body years, and it's just a slow degradation, but every step down becomes a new normal, and so you don't feel any of the stuff that you have going on. Yeah, yeah. And I think that's, that's the that's like, it being able to handle that stuff is, like, Could your body handle more than you think it could? Yes, but the question is, do you want to push it there? And my answer is going to be No, and it's just from, from pushing it there, knowing, like, it's not a good place to be. It does wear on you. There are costs to that, but you may not pay them right now.

Jay Feldman 19:38
And you might not ever pay them, but maybe your children will, or your grandchildren, you know, like, like you may have been, not you personally, Mike, but somebody may have been blessed genetically, you know, and won the genetic lottery where they can eat McDonald's and do whatever, and they've got the six pack abs and the perfect hairline and and, you know, perfect metabolic function and everything else. But them, just, you know, taking on that stress over time. If it doesn't affect them, it'll affect the their offspring and on from there. And you see that in in various studies, like, you know, the pottingers Cat study that we've referenced in the past, where you feed just one generation poor food, and it affects was it five to seven generations further down. So, yeah, there's, and I do think the concepts that Hansell, you put out with the adaptation Energy Tank being drained is a good one. Again, I think we mentioned this, or I mentioned this, but the only problem there's the idea that, yeah, that the adaptation energy is finite, as opposed to us being able to replenish it, which is a huge, huge difference. Or, yeah, differing point that I think is worth emphasizing, but it's a good conceptualization of the cost of that stress and how it leads to that degeneration over time. Another example that we have talked about in the past is is operating on low amounts of sleep for a long time, even, like six hours a night, which is pretty average, I would assume, for most people, and not realizing how much of a of a toll it takes, yeah, on your mental capacity, your focus, your energy, your personality. And so many people who I know in the in those states are, you know, they're totally fine operating on six hours a night like they've they've always been that way. Yeah, but you, you feel the difference for sure when you're doing that versus when you're sleeping more, right? Like you are very aware of that difference. Oh, yeah, but I do. It's easy to get stuck in the cycle and forget how different it was and just feel like this is how you are and this and of course, we can extrapolate this to all sorts of contexts about how we just evaluate people's behavior around us as if it's not affected by the various chemicals, problems with the food they're taking in, lack of sleep, all those things. But those things have massive effects on our behavior, personalities, obviously health and on from there. And so this is just kind of a, yeah, a way to conceptualize those things is through that. I mean, just as these things are all costs of stress placed on on the body, and the the depletion of our of our energy, and the resorting to hibernation type states and degenerative states when we can't when we can no longer adapt effectively, essentially.

Mike 22:20
Yeah, and as far as the finite piece goes, like, there are studies showing, go ahead.

Jay Feldman 22:24
Sorry, real quick. I wanted to add in that degenerative states are actually still a part of the adaptation. I shouldn't I didn't mean, like, I kind of delineated there. Like, if you can't adapt well enough, then you hit degeneration. But the degeneration tends to be part of the adaptation. Basically, it's just a further conservation of energy and a further resort to the backup pathways that we just call pathology, and we call that disease. But in reality, it's a completely normal response. It's just the next step of adaptation.

Mike 22:52
It's on the same spectrum, exactly.

Jay Feldman 22:53
yeah, just further down. The further down.

Mike 22:55
Yep, yeah, there's um. What is going to say is, as far as like that, the the the inability or the the finite amount of reserve energy that you have, like, there's studies showing that just in one generation of rats being fed a good diet, they can reverse some of the epigenetic change, epigenetic changes that you see with with like a like one a generation of poor feeding. And I think the reason that we don't really see the benefit, or the reason why, I guess Hans Selye, and this is me, can entirely speculating, I'm not putting what I don't want to put words in his mouth, or, like, you know, say something that maybe he didn't say, or not. But I think the reason why he the idea was that it was finite, was because, like, it's, it takes a monumental amount of energy to bring things to start regressing those pathological situations, and it takes, like, it's like, a whole lifestyle change, and it's a whole it's a whole framework, a whole mindset change that needs to take place. And a lot of times, I think, in modern society, number one, people aren't willing to do it. And then number two, people like it's very difficult to do. And then the other thing I want to talk about, and just briefly mention, is that I think that and I something I see in the hospital, and this isn't any science, this isn't like a research study or whatnot, but this is my general observation. I think the older populations like, because I work with a lot of elderly people, I work, I work with a lot of old people. I think the older populations have more of that reserve energy in them. And like, I talk to them all the time, because I asked them about their childhoods. Like yesterday, I had two patients who were 87 years old. They had a lot of chronic disease, don't get me wrong, but when you ask them, like the guy was telling me when he grew up, first of all, obviously, he was breastfed. There was no formula that his parents could afford to get. But when he grew up, like he's like, every Saturday and Sunday, we woke up, we went fishing, we cleaned all the fish that we caught, and we like, that's what we were going to eat for the for the next. Next few days, and then we went out dancing and then, and then, as, like, during the week, like, we had to work the farm, and we had, like, our eggs in the farm, and our milk from the farm, and we grew our own vegetables. And it's like growing, like, there's a series of critical periods during the during your life, when you're an infant, making sure the mother's healthy when you're in the womb then, or I guess that's when you're in your fetus, but then when you're an infant, when you're born, making sure you're being you're breastfed, and then as you grow up as a kid, eating high, high quality, nutrient dense foods that aren't causing issues. And that's all the way up until you stop growing through puberty and all that stuff. So that's probably like in brain development up to 25 so if you can maintain a solid, healthy lifespan in that period of time and or a solid healthy lifestyle, and have that strong family network, have that community, have you know that you don't have to do hard physical labor every day, but like, be moving around and have access to high quality food, make sure your breastfed, your mom was healthy when you're born and whatnot, then I think that gives you like a large reserve of of of stored energy, or potential energy, or however you want to call it,.

Jay Feldman 26:10
Basically in structure, right in structural complexity. It's like that exactly used to build complexity that can be taken from later.

Mike 26:16
Exactly. So then down the you have a longer span down the road where you can treat yourself like crap. And I think the older generations got that, and I think that what I'm seeing now is the newer generations are sicker, sicker, sicker, sicker, sicker. You know, I have younger, younger, younger, younger. Exactly. I have like 40 year olds with strokes, and I have 90 year olds with strokes, and the 90 year old with a stroke gets out of the hospital and doesn't need as much rehab as the 40 year old, which is insane. It's absolutely insane. So it's just like, and I think it comes down to that having that solid build up in nutrition, it's like. And the other thing that people don't realize, too, is that you can, if you ask back, and you you ask people, um, you know about grandma, grandpa, whatever it is, or you have the older people in the hospital. They their generations live to old age. They had, there's like, Oh, my grandma 100 my grandma was 98 and she didn't have any of this stuff, and she didn't have any disease and and so and my grandmother, she lived to 98 and her diet was, you know, sugar, chicken, pork, fat, bacon, um, to whatever she like green like collard greens and bacon fat, like things like that, which is antithetical to the current diets. But they grew up eating all that type of stuff, living on these like, technically a bioenergetic diet, and being breastfed, not having all these insults to their systems, so they're able to progress longer. I think that that's something that I think that's a very real phenomenon as all and from my perspective, even though it hasn't been, I don't think it's been studied so much.

Jay Feldman 27:48
I agree it's something that I think is evident, definitely evident.

Mike 27:53
Well, your grandfather is, your grandfather is pretty strong, too/

Jay Feldman 27:56
And he's 90

Mike 27:59
yeah. And he's in, like, just, I think it's just a different way that people were raised, because these, like, later generate, like, there's, I know, like, I have friends who are like, 30 years old, like, pre diabetic and just like, that's unheard of. That was cancer in children back in the day, unheard of autoimmunity disease, they're, they're popping up new ones all the time, like it's there's definitely something going on, just like compared to, I think, previous generations. And I don't think it's just diagnosis.

Jay Feldman 28:30
Yes, that's often cited as we're just better at diagnosing these things. But when you ask people who rounded at that, you know, people did not have these issues when they were in their classrooms. I mean, I know, like in in my childhood classrooms, I had people with type one diabetes, and I remember, like, wondering why they got their juice, you know, they got to have juice whenever they needed, you know. So, yeah, that's things that were just not heard of. And, yeah, I agree. You can't just chalk it all up to better diagnosis another like, it's a good transition to this next idea that I think is a huge, huge problem in the concept of hormesis, which is the fact that stress is cumulative. And you this is, this means that is cumulative across the board of all spectrums of anything that causes a stressor effect, whether it's chemical toxins in your food, pollutants in the air, you know, on from there, cold, excessive heat, lack of carbohydrates, lack of food, lack of nutrients, excessive exercise, all those things, but also over time, right where the stress that you experienced yesterday or last year or 20 years ago or that your parents experienced also has an effect on you, and this makes like, you know, we've, I think we've outlined a lot of reasons why this idea of hormesis does not there's a lot of problems with it, and why I think it really is not compatible with human physiology, and doesn't make sense. But even if you were. To argue in favor, if you were arguing in favor of it, or if you felt like it was legitimate, it's almost impossible to apply in a real sense. You know, people will say you just need to do a ketogenic diet, or you just need to exercise, you just need to take resveratrol or Metformin, because these things are all hormetic. But the idea with hormesis is that there is a very specific dose. It used to be an extremely specific dose that was supposed to be five times the amount of the no observed effect level, but they kind of did away with that when you started adding all these other factors. And it doesn't make sense, but there was the idea is that there's a specific range where the stress is beneficial, because it allows you to have these adaptive responses. And if it's too much stress, it's too much stress, it's harmful. If it's too little, it's harmful. But when you take like that earlier paper on the Mediterranean diet, where they're talking about how every single food in the Mediterranean diet has hormetic effects, is slightly stressful because the polyphenols and and whatever else, and fish oil, I don't know if they were really studying that, but we would cite that is something that's

Mike 30:59
This was the monkeys, right?

Jay Feldman 31:02
No, no. This was, this was a study talking about the Mediterranean diet being beneficial because of hormesis.

Mike 31:07
Oh, from the first episode?

Jay Feldman 31:09
Yes, yes, yeah. And so, if you can, if you're considering those things, and you're also considering that you walked around today and that you had to get out of bed, and that you, you, you know the but your body temperature was a little off, and that had to re regulate, and you fasted in the morning. Fasted in the morning, and then you did an exercise session in the afternoon, and you got in a fight with your significant other, and you were busy with work. So work was stressful. When you consider all these things. First off, how is it ever possible to measure the absolute amount of stress there to make sure that it's in an optimal range, like you could argue, oh, it's just based on how you feel and the effect, which I guess you would have to because would have to because it's virtually impossible to calculate, or, I don't know, yeah, like, put these into any sort of numerical fashion, fashion that would make any sense, or to, yeah, to be able to determine the absolute amount here. But then on top of that, it's like, at what point would it be too much stress, like it seems like, when you regard that everything in your environment, if, even if you want to say, okay, that earlier paper where they said water is hormetic that's ridiculous and and whatever else, but even if you want to just stick to the agreed upon hormetics, how could you ever determine what that ideal amount is that would give you the proper results, especially when you're adding all them together, like it at what point? So does that? Because, like, if you really try to apply it, it's like, okay, if you do a ketogenic diet, but you don't exercise, and you don't take resveratrol, and you don't do all these other things, that's hormetic. But if you do all those other things too, is that also in that same hormetic range, and you worked eight hours a day, or you were two hours a day, like, at what point does this? Is this ever actually applicable in a realistic sense?

Mike 32:52
Yeah and is there synergy, or is it additive, right? It's like, if you have a synergy of cold thermogenesis, intermittent fasting and exercise and saunas, yeah, that's another one, yeah. And so many times and saunas, how many times? Like, how many multiple times? Is that stressful, versus if you were to just, you know, eat a normal diet and do like, a and go in the sauna, right? And that's right. So it's like, the other thing too is like, it's like, the quantification of that stuff.

Jay Feldman 33:17
Thank you. That's the word I was looking for, quantification.

Mike 33:21
Yes, like, all the different effects of all the different things together, we we can't, like the quantity the way to quantify it, or you won't really quantify it. You qualify it. And I think the qualification of that is how you feel. And so, like, for example, with with what we were doing when we were in college together, it was like we were, you know, we were lifting heavy weights almost every single day, and then we were in class. We were intermit fasting, we weren't eating a lot of carbs. We were when we weren't sleeping a lot, and then, like, it came, like, things came to a head where it's like, okay, I wasn't hormetic anymore. It was just like, Okay. Now we're now, we're just stressed. Like, we're like, our adaptations ceased to be what it should be. And, and that's the problem with the perspective, is that it's like, that doesn't make sense at all, that it's like, oh, we, we crossed the line on hormesis. It was like, no, like, we, we just had, it wasn't hormesis. We just had too much stress, right? And like, the whole perspective of hormesis, like, is it obfuscates what's actually going on. As far as what we're looking at as the idea that there's a general amount of stress, there's a certain amount that you're able to tolerate. It accumulates over time, and the goal is to basically minimize, minimize that for what your body is capable of managing. It's not about keep adding it on so you have some adaptive effect. It's not, it's not a more pain, more gain, or no pain, no gain, whatever the idea is. Like, the concept of hormesis leads to this, like the extension I think that a lot of people take is like, Oh, more. It's in it. Oh, I think this is not even just for hermesis, but in any dietary approach, more must be better. So. I like, even working with people like, Oh, I'm low carb, but now I'm no carb, and it's like, well, it's not working for me. It's like, well, you can't go negative carbs. So what's the next step that you're going to do? It's like, you have to, there's a certain point where you have to be like, Okay, this, this, this lens, or this, this paradigm or frame just doesn't work. Like, it's not a whole picture. And I think hormesis winds up getting into, into that area, and especially because like, study it. And I guess the parallel to this too, like the quantification piece, or the synergy versus additive um, is where you see something like, like, even with nutrient research, um, you you won't be able to see, like a nutrient research, like they only look at vitamin D, but what's the what happens when you do vitamin D, calcium, magnesium, and vitamin K and A all together? Like, the effect is obviously much different. So it's the same. The same thing applies to, like, the hormetic situation,

Jay Feldman 35:55
Yeah, absolutely. And again. Just the last point to to add on to this, which we talked about earlier, is when you consider all of the immensely stressful, toxic, damaging things in our environment and that everyone is being exposed to all the time, especially to people on the standard American diet and a standard American life and on from there, and especially the ones who are also experiencing various degenerative states because of it, then how could you say that adding stress is Going to put them into the right hormetic zone to create benefits. And if you want to take the idea that fasting or calorie restriction or exercise is beneficial in these cases, which has been shown to be the case because of the specific effects, not the stress, but that's the then that's the point. It couldn't be because of the stress, because you're only adding stress on to an already extremely stressed organism. So there's no way to to describe that other than that, it's way past the stressful zone. But there's other specific effects that are actually helping to reduce stress and that are having other benefits that, again, are not because of hormesis.

Mike 36:55
Yeah, and this isn't semantics, right? And we'll get into that in the next it's not a semantic thing. This is like, the frame is important. We'll get into that in the next couple episodes.

Jay Feldman 37:03
Yep, exactly. So with all these things in mind, there's obviously a lot of conceptual issues and and issues in the research and everything when it comes to hormesis. And what I'd like to do now is basically propose an alternative that I think we've talked about this before, but, but we'll call it anti hormesis, basically because the I think we're we'll basically make the argument that the opposite of everything that we've discussed, the opposite of hormesis, is actually the route that we want to be be taking, more or less. And to begin here, I want to kind of create some juxtaposition here and illustrate some of the differences that can happen when you are functioning through an anti hormetic means or or approach, as opposed to a hormetic approach, especially in terms of the various adaptive pathways we've been talking about in terms of uncoupling and autophagy and mitochondrial biogenesis and things like that, which, as we said, are not inherently problematic. But that doesn't mean we want to be doing anything that will stimulate them or increase their their activity, or increase the Yeah, their the functioning of these pathways. And what we'll get into here in a second is that we can actually be inducing these paths. Inducing these pathways through almost the exact opposite means that most people are suggesting when it comes to hormesis, things like ketogenic diets and semi starvation that's called fasting, or excessive exercise, or cold thermogenesis or resveratrol, whatever it is. And in order to do that, we have to talk through some of the physiology here that you know, we've already been talking about, but specifically in terms of the the activity of these pathways. And so we've already discussed that the the there are a couple of signals that act to stimulate all these pathways, and that comes down to oxidative stress, through the production of reactive oxygen species, as well as direct oxidative damage and also depletion of energy, and those are all ways that you can increase the activity of these pathways. But there are different contexts that you can do this that result in in different responses, and there's some important distinctions to make there. So the main way that I want to draw this distinction is between the production of reactive oxygen species in a low energy state that can also coincide with energy depletion, and then the production of reactive oxygen species in a high energy state, and how both of these will activate the same adaptive pathways, for the most part, not the exact same, but some of the Same in terms of things like uncoupling or mitochondrial biogenesis. But in the case of of the low energy situation, the low energy context, it comes with a lot of damage and destruction and stress that causes long term issues, whereas when it's done in the high energy state, you have the opposite. You have the building of further complexity and structure and development, if you will.

Mike 40:00
Yeah, and it's, well, I just want to say that it's not it. We're not talking about all the pathways. It's not it's not talking about AMPK and certs and all that type of stuff. You're specifically referring to here, the ROS generation signaling from at the mitochondria, electron transport chain, etc. And the differences there between the between the hormetic states or versus the high ATP states, which would be, that's what we're, I guess, defining here as the higher energy states. You know, I just wanted to clarify that that's all.

Jay Feldman 40:32
Yeah, and some of the pathways will be activated in both situations. It's not really going through all the like worth going through all the details there, but yeah, so some of them will, and it's an important consideration. So when we're looking at the low energy oxidative stress situation, this is what happens when either there are things that are directly oxidatively damaging, things like ionizing radiation or lipid peroxides, that are actually damaging the structure of the of the cells, but we also have all of the various factors that can block our ability to efficiently produce energy, specifically along the electron transport chain, but sometimes along the various aspects of the Krebs cycle as well. Is where these things have their effects. And this is again, directly things that are directly caused by some of so many of the hormenic interventions we've discussed. So this would include things like endotoxin, elevated levels of nitric oxide, lipid peroxides, various metabolites with the polyunsaturated fats, some of the more traditional hormetics Like methylmercury and arsenic, and also some of those newer ones, like resveratrol. And then also a lot of the environmentally induced sort of hormetic interventions, things that will create hypoxia, or that will create excess lactate, or that will create a high FADH, two to NADH ratio. And this is things like ketogenic diets, Wim, Hof, breathing, fasting, excessive exercise, cold thermogenesis. So again, like inducing the whole heat shock protein pathways, all of those things, those all converge into, into an inhibition of of mitochondrial respiration, or of efficient mitochondrial respiration. And so what happens in these states? And we've kind of discussed this already, but basically, you think you described it as when, at least in terms of the pine saturated fats in the past, where it's like if you were, if you had a hydroelectric dam that you're using to produce energy, but then you had a bunch of holes in that dam, you start to lose the power for you know, you lose the amount of flow that's going through that hydroelectric dam, and losing the ability to produce energy. And that tends to be what's happening a lot of these, in some of these situations, but in other ones, you just have a you have various ways that the electron transport chain gets blocked. For example, with the FADH two to NADH ratio, you reduce NADH offloading at complex one to two competition for ubiquinone. So that's going to slow down. It's going to lead to a lower NAD 10 ADH ratio, yeah, and a backup. And so it slows down everything. It slows down the electron transport chain. It slows down the Krebs cycle. You have similar things with nitric oxide that has inhibition along the electron transport chain and also throughout the Krebs cycle, where, for example, it inhibits econotase, which is one of those enzymes that moves things through the Krebs cycle. And then you also have inhibition throughout the few of the complexes of the electron transport chain. So all of these things are basically directly leading to increased reactive oxygen species production and inefficient energy production, leading to a lack of ATP, and you then have a furthering of this state. Because what happens is when you generate a lot of reactive oxygen species. In addition to all the adaptive pathways to protect against this, all of the activation of the antioxidant systems and everything, you also have the increase, increased activity of the uncoupling proteins which drive uncoupling, which basically prevents further ATP production. Well, I guess it's just a I guess it's just a I should say it prevents further rate of oxygen species production at the cost of ATP production, because you're basically burning through the substrate without actually connecting the Krebs cycle and the electron transport chambers. Yeah, yeah, yeah.

Mike 44:17
It's basically like the when you have the electron carriers, which are NAD NADH and FADH two, moving through their they're basically they're holding on to electrons that are used at the electron transport chain. When any of those steps get blocked, those elect with, you know, whether it's nitric oxide, whether it's too much FADH two, whether it's any other type of mitochondrial poison, what essentially winds up happening is the R, the electrons basically have to go somewhere, and they have to do something. So you wind up getting this, you wind up getting this ROS generation at the sites like before, where they're where it's being blocked. And so the cell basically res. Registers that ROS generation, and then that ROS serves as a signal like, hey, we have a problem going on here. And it's, it's in combination with the ATV being being produced. And this be, this is where the really important, I guess, fulcrum com differentiates between, like, hormetic response with increased ROS versus an increased ROS from excess energy generation is if there is ROS like, like, an increase in ROS with, well, an adequate or a large amount of ATP being produced, that's a different state than if there's Ros being produced with ATP depletion. And so the ATP depletion is that hormetic approach where there's different blockages, whether the Krebs cycle, or in the Krebs cycle, you may not get the necessarily the ROS, because you're not generating electron carriers. But at the electron transport chain, if you're having the blockages there and then you're generating the ROS, what you can essentially see is, and you're not producing the ATPs, the cell starts up, regulating all these pathways to try and salvage what's going on at the cell, and then also manage that ROS and the step, the kind of like backup step that gets put into place is the cells, just like, All right, we're not going to take these at these electron carriers and put them to the electron transport chain. If it's not working, we're going to use the uncoupling protein to kind of get rid of the electron to protect ourselves from the ROS, and then that same kind of thing happens, but it's different when you have higher amounts of ATP, where it's like, we have a lot of energy being produced, and we can take some of this excess energy that or deal the essentially excess energy, and we can convert that into heat. So you have, now you have a state where you have heat generation and ATP production and the ROS is managed, versus a state where you have just heat generation, lots of ROS and like, not so much ATP. And that's those are both very different states, because, as we know, like, and you can put this in the context, every single thing that that exists, that functions, requires energy. So, like, there's a difference between, you know, having a car with engine problems and it has, you know, I guess it's going to be not a perfect analogy, but essentially, the cell won't have the energy to deal with the stress is what it will come down to, because it's ATP depleted, and then it has to go to all these different backup pathways. And there are backup pathways in place. However, there's only so long that you can run with those backup pathways.

Jay Feldman 47:33
Yeah, and we've talked about this with the car analogy. It's like shifting the car into neutral and revving the engine, where that energy, the potential energy in the in the gasoline from the fuel is being forced to just toward heat production. It's not actually translating into usable energy, which, for a car, allows it to move. And obviously, when you're neutral, you're decoupling those two things, the actual movement of the car from the burning of the fuel. And so when you had mentioned the excess excess fuel becomes or the excess energy becomes heat. It's really the excess fuel, right? It's not like we're converting ATP to heat. So just to Yeah, a little clarification. The substrate, yeah, exactly the excess substrate, carbs or fats, or whatever they are. And yeah. So that was a good description of what's going on and again, to clarify, I just to clarify a couple things I mentioned earlier. So for example, a low FADH two to NADH ratio. The means to which that blocks the electron transport chain is because of the competition at complex one and two for ubiquinone. We talked about this in a previous episode, so I'll link to it. But that basically causing what a lot of people cite is a good thing is reverse electron transport, where you basically from complex two to one, you start to have this reverse transport of electrons, where things are going backward, and then are getting offloaded into reactive oxygen species, and then you end up with the buildup of NADH which slows the rest of the of the Krebs cycle and everything down. So these are just different means through which you're driving reactive oxygen species generation. Again, same thing happens with something like nitric oxide, which is produced in any sort of stress state where you have the inhibition of complex four, and then also you can end up with inhibition of complex one as well from nitric oxide metabolites. And yeah. So when we are driving this high reactive oxygen species and low ATP state. As you said, this is not conducive to health, considering that energy is the currency of health, more or less, it allows everything to function, or allows all of our cells to function, our organs to function, and on from there. And this is not a state that's conducive to these to these things. And we've talked about how again, you app. What happens in these states initially is you activate these adaptive pathways, and that allows for the restoration of ATP production, but it comes at a cost of borrowing from basically future resources and driving stress and turning down the thyroid dials and the reproductive hormone dials in an effort to protect against against that future. Stress. And what happens is, is when this is happening over time and you lose you're no longer able to activate that backup pathway as as efficiently to bring the ATP production back. Is you tend to see all the degeneration that we've discussed earlier, the degeneration, the chronic health conditions, all of that. And you see this state happening in various degenerative conditions, both like chronic health issues and also cancer. It's very clear as well that this state of low ATP and high reactive oxygen species drives these conditions, drives these situations. So just going to share a couple of quotes here describing that. So this first one, they are just they're discussing the this situation and neuropathological conditions, various neurodegenerative conditions. They talk about things that involve aging and hypoxia and ischemia, necrosis. And so they state, taken together, Our results suggest that ATP and reactive oxygen species productions are decoupled under neuropathic conditions, which may compromise axonal function and integrity. So they're there again, discussing how in these states, you have basically a situation where the reactive oxygen species production is going on and you're not getting ATP generation with it, and that basically producing these states. And see this in, as I mentioned, in cancer as well, and the states that drive cancer, there's a couple of great quotes describing this. Did you want to add anything about the neurodegenerative one?

Mike 51:36
Well, I was just going to say that almost every single chronic disease is characterized by an energy depletion to some so eat to some extent. And even if it's cardiovascular disease, it like, for example, any type of damage to the heart, like if you're going to have a heart attack or anything like that, it is characterized by a lack of blood flow, and therefore a lack of oxygen and nutrients being transported to the cells of the cardiac myocytes and muscle cells, with also a lack of ability to remove waste product. And then you wind up, you see the metabolic shift towards an excess, like a movement towards lactic What's it? Lactic acid fermentation, or glyco like excess glycolytic activity. And then you get the build of a lactate and that literally what what they're testing for in the hospital for, besides, obviously, like enzymes being released into the bloodstream, like troponin or creatine kinase. So it's like all the markers that they're looking at for, all these for the even like heart disease or heart attacks, are markers of deranged energy metabolism, and then also, like enzymes being released into the bloodstream from cellular damage. So like every single step of the of all these chronic diseases is characterized by these bear and that's just one example, but by this some type of issue with energy metabolism and a lack of the cell having energy even sepsis, when you're seeing people have sepsis, literally endotoxin, and the and the immune response to it, destroying energy production. And then you basically just get massive fluid and electrolyte and basically metabolic derangements. And it's characterized again, by increased lactate, which I know you're going to get to here in a second, with some of the cancer metabolism. So I just wanted to put that front and center, like it all comes through, that it's always some, to some extent, about energy metabolism and the different ways that it is taxed or deranged.

Jay Feldman 53:32
Yeah, yeah. And we've basically, well, I mean, so you mentioned sepsis. Sepsis is, like, a very clear example of it, for sure, but we've also explained how this is involved in virtually every pathological state throughout this whole podcast, right? That's what we've talked about in terms of heart disease, in terms of autoimmune conditions, in terms of men and women's Hormonal Health. I'm sure you know, I know we've done it. We've talked about blood pressure and cholesterol, which, of course, are involved in the heart disease situation. We've talked about diabetes, all of these things are, are all states characterized by by a lack of energy, same with obesity and weight gain and all of that. So yeah, and so you see this in canter as well. And perhaps surprisingly, you also see increases in things like uncoupling, which everyone is trying to encourage with this exact, you know, through these exact mechanisms of ATP depletion and reactive oxygen species generation. So in this in this study, or this paper, they state recent evidence suggests that mitochondrial uncoupling, the abrogation of ATP synthesis in response to mitochondrial membrane potential, promotes the Warburg effect in leukemia cells and may contribute to chemo resistance. So they're there. They kind of took a little side note to describe what uncoupling was, which was basically the stopping of ATP production. But they're talking about evidence suggesting that this is going on in leukemia and is allowing them to prevent, to be, protected, against, against chemotherapy drugs. And then in the next couple quotes, they state, since fatty acid oxidation has been linked to chemo resistance and mitochondria on coupling, it is tempting to speculate that Warburg observations may indeed be the result of the preferential oxidation of fatty acids by cancer cell mitochondria. So I like this because they're describing how fatty acid oxidation again, whether it's ketogenic diet, low carb diet, serration, fasting or any sort of stress which encourages fatty acid oxidation, drives mitochondrial uncoupling and is involved in this cancer metabolism. And then the last quote that they state is that glycolysis remains the critical pathway by which cancer cells meet their energy demands, not because of permanent, transmissible alterations to the oxidative capacity of cells, but rather because of the inability of uncoupled mitochondria to generate ATP. So I think that they paint a really nice picture here, where basically you have an extremely stressed out cell that is not properly able to respond and adapt, essentially, and because it is in the state of low ATP and high reactive oxygen species, it resorts to uncoupling because it can't produce more reactive oxygen species or oxidative stress without it being so damaging that the cell would die. And so it's basically in this permanently coupled state. Yeah, it's stuck in this uncoupled state, but then it needs to produce energy. It still needs to produce ATP, and so it's has to resort just to glycolysis as its ATP production pathway, which, of course, is extremely inefficient. There's a ton of problems that come with that you end up with a lot of lactate and and we talked about this again in previous episodes, so I'll link to those. But yeah, so you're seeing this like, basically, what you're seeing is the state that you're trying to induce by hormesis, is the degenerative state, and there's a huge cost to that. And of course, there in the short term, the body will adapt to try to move out of that state. But yeah, we've, we've already discussed all the conceptual problems with that being a good thing.

Mike 56:58
Well, yeah, so it says there the hormetic state that's being at least, that's currently being discussed, or are being looked at as usually some type of ATP depletion with increased ROS generation to to invoke these different pathways. And what you're showing with this cancer state is that you literally have ATP depletion because the there's too much ROS generation at the electron transport chain, so the cell is forced to it's essentially exhausted as backup pathways. And now it can't couple the Krebs cycle and the electron transport chain. So it just has upregulated uncoupling. And then to meet its energy it would, and I think with the uncoupling is probably just that's where it's burning through the fatty acids and then with the with whatever, the other glucose supply, just running glycolysis and then producing lactate, and then so the cell is able to, like, maintain itself in the state. But as you see with cancer, like all the metabolic process and arrangement that you're seeing there, essentially just degrades the rest of the organism, because it's not there's it's not cohesive anymore,

Jay Feldman 58:00
Yeah, well, and the other piece there, which is that everyone talks about how sugar, or, sorry, how sugar, how cancer runs on sugar, right? Sugar is the main fuel. But I like that they're pointing out here that fatty acid oxidation is actually what is driving the state that's forcing the excess of glycolysis and...

Mike 58:17
Well, cancer runs on everything.

Jay Feldman 58:19
Exactly, yeah, and runs. It can run on amino acids for fuel, fats, ketones, glucose. So all those people who are saying that you just want to restrict glucose and you'll you'll kill, the cancers are missing big pieces there.

Mike 58:31
I think the picture there, though, is that, like, the whole perspective is, like, the same thing as the allopathic perspective of everything, like, we're gonna cut, we're gonna burn, we're gonna kill, we're gonna chemotherapy. We're gonna whatever it is, like, poison, whatever the problem is, instead of, right? Like, if you change the perspective where it's like, okay, there's a metabolic issue, the question isn't like, how do we just destroy all of these cells? The question is like, how do we fix whatever the metabolic arrangement is in that area? And then I also, and I know this is tangential, but, but it would that from that perspective as well, the cancer situation becomes less of like, oh, there's just this one tumor in this one stop, one, this one spot in the body, but like, there's a metabolic there's, like, some type of metabolic problem all, like, systemically. So then even from that perspective, it just doesn't make sense to just, okay, we're just gonna go blast your whole body with chemotherapy, which literally causes extreme amounts of ROS and causes causes energy metabolism, issues and inflammation to kill these, like individual tumors or cancer cells, and then, like, I mean, one of the number one side effects of using chemotherapy and radiation, I think, is cancer. So it's like, you destroy the current cancer now, and which is, which may be a product of the body's current state, and then you wind up, like, also destroying other areas of the body simultaneously. So like, when you change. To the metabolic approach. And you look at things from, okay, what? What's the derangement going on in the cell? The question then becomes less, how do we kill all these cells? The question becomes more of, how do we like correct whatever the metabolic derangement is systemically and then also locally?

Jay Feldman 1:00:18
Yeah. And again, another, I'm going to move on to move on to the next study here, getting at that systemic nature here, and getting, you know, again, connecting these states to the production of a cancer situation. So they state the ability of uncoupling proteins to uncouple ATP synthesis from respiration, and the fact that uncoupling protein two is overexpressed in several chemo resistant cancer cell lines and primary human colon cancers have led to speculate, I'm assuming it means, led us to spell, to speculate about the existence of a link between uncoupling proteins and the Warburg effect. Glycolytic ATP production may concile the advantages of uncoupling protein to overexpression with the need of energy to sustain rapid cell growth. So again, kind of stating what we just discussed here, that glycolytic ATP production happens as a result of uncoupling and that this is something that's seen in colon cancer and chemo resistant cancer cell lines. Then they state last but not least, it is important to take into account that uncoupling proteins are largely associated with fatty acid oxidation. Several cancer cells resistant to chemotherapeutics and radiation often exhibit higher rates of fatty acid oxidation, and it has been observed that inhibition of fatty acid oxidation potentiates apoptotic death induced by chemotherapeutic agents. So what they're saying there is that fatty acid fatty acid oxidation, burning fat, is what's driving uncoupling in these states, and that the cancer cells that are doing the best at being cancerous, that are resistant to chemotherapy and radiation, are burning fat at a higher rate, and then inhibiting their ability to burn fat allows them to die through apoptosis, which is a kind of more organized cell death, as opposed to something like necrosis. And this can be induced by chemotherapy chemotherapeutic agents. So basically, you're saying that this, they're saying it directly the fat oxidation, but also the low ATP, high reactive oxygen species state, with the uncoupling, is essentially responsible for the cancerous nature of the of these cells. Yeah, and that the more cancerous it is the more it's in the state, which, again, is a sign of how degenerated the system is and not being able to properly adapt to it. But kind of talking about adaptation energy before, and the idea here that all of this adaptation is coming at a cost is, and we talked about this in terms of all these problems with hormesis, driving the state and putting, you know, forcing the state is getting closer and closer to a perpetual state in this situation where you are no longer able to properly adapt to it. And not to mention that the adaptations to it are not beneficial in the first place, inherently.

Mike 1:02:59
Well, and it makes sense too, as far as, like the the increased ROS generation with the excess fatty acid oxidation, and that's the that's exactly what you were talking about before, with the competition between complex one and complex two, with ubiquinone and the FADH two to NADH ratio, where excess fatty acid oxidation is going to raise that FADH two ratio and cause ROS generate RS production, I think, at complex one, because of the lack of ubiquinone available to basically shuttle electrons from complex one. And so this is all driven by so the fatty acid oxidation, it kind of becomes like a perpetuating cycle, right, where you have more fatty acid oxidation, which creates more ROS generation, and then this, then the cell basically has to up regulate uncoupling to kind of manage that problem, to lower that Ros. But it's not generating ATP, so it's forced to move into glycolysis. And we actually we that, and that goes hand in hand with the apoptosis piece, because we've seen in the fatty liver series that we went over where, when in fatty liver disease, the cells, essentially, when they were, when they were energy depleted, to a large extent, were unable to go undergo apoptosis or autophagy, and were unable to undergo mitophagy, so that with A lack of energy, they weren't able to clean up the damaged pieces, essentially, in that pathological state. And when you look in the fatty liver state, because the fatty liver is the first step, depending on what's going on in the cell that in the liver, the individual that could lead all the way to hepatocellular carcinoma. And what you start to see with fatty liver is an overload of fatty acids at the liver and then an upregulation of fatty acid oxidation at the liver that essentially, as the cells become excessively exposed to ROS generation, and especially if there's large amounts of polyunsaturated fatty acids allowing the cells to become damaged, then the cell. End up, gets becoming sclerotic or or fibrost, and so you get hepatic cirrhosis. And then the cirrhosis, which is scarring, it's just basically the liver becomes the large scar the cells that are left over, because the energy metabolism at this point is so deranged, it can essentially lead to the cancerous state where so what you're seeing is that the cancer is kind of like an end state of extreme metabolic derangement characterized by excess fatty acid oxidation through the mechanisms that we keep talking about with upregulated uncoupling and then also requiring to they're essentially they're using glycolysis, because they can't properly respire. So it's like, we need to get energy somehow. So, like, even, even though our we can't, like, burn our car, like, burn fuel so that our car can run, we still need our car to run. So we're just gonna, I don't know we're gonna do. We're gonna, like, I don't know what you would do, just, like, kind of burn your fuel somehow, like, light it on fire. And just like, keep lighting all of your fuel on fire, you're producing all this smoke inside the car, but you're still able to drive just a little bit. I don't know, it's not a perfect my analogies are kind of off today, but haha

Jay Feldman 1:06:15
Yeah, but you, you brought up a great point, bringing back to the fatty liver situation, where everything we described in the fatty liver disease series could be described as hormesis, right, the generation of further reactive oxygen species and all of those adaptive pathways. And we, we, you clearly see that too is, you know, in all these, all those states.

Mike 1:06:36
And we talked about it with AMPK and the sirtuins and NRF two and uncoupling protein upregulation. Those were all features of fatty liver. And you had hinted at one point in the series, like, hey. Like, this is also, this is what everybody's targeting for, hermesis. Like, it was, like, an offhanded comment that we were, like, kind of laughed about together.

Jay Feldman 1:06:57
So yeah, and I didn't remember that exactly, but that's a really, you know, as far as, like, for someone who's trying to understand the physiology here and what's going on in energy production and what's causing these states, I would look back at that series, because we took a lot of time to actually go through all those pathways and processes and explain, like, with diagrams of what's going on in uncoupling. How is, how is something like fasting or PUFA or whatever, driving a low energy, high rate of oxygen species state. So I would definitely, and we talked about that FADH two NADH ratio, and explain that in detail, all of those things. So I would go back and listen to that episode. But what you were basically describing is that when you drive these hermetic pathways further and further, you first end up with degeneration, with some adaptation, which was basically the fatty liver situation, and then you end up with things like scarring and which is like the kind of later steps there and cirrhosis, right? Which is, is a precursor to cancer, which, as you said, is like the end point there. Of what you could say is, is excess hormesis. You just continue down the hormetic pathways long enough, and you end up with with that cancer state, as as the cells are no longer in a position energetically to be able to adapt to these things, because it's continually depleted over and over again on the small scale, which then comes at the large scale, as well, as we've talked about numerous times, how these things drive inflammation locally, which drives systemic stress to deal with that inflammation, activate those backup energy production pathways while turning down the long term thermostats. Things that we see when we look at thyroid hormone we see when we look at reproductive hormones over time, when in response to all these states.

Mike 1:08:34
Yeah, and the other thing too I wanted to mention is it removes cancer from being necessarily genetic or any of these pathologies, from necessarily being genetic, and puts it squarely on metabolism. Now this doesn't mean that genetics, some genetic predisposition, isn't prevalent in the sense that the that, whatever that specific area is, is going to be the weakest link in the chain. That's fine, but you still have a weak you still have the whole chain, and it's like you just don't have to apply pressure to that chain. And the pressure that you apply to the chain is the most important point in my perspective. And I think we would agree, because that's where that pressure is, the stress in the system, and that's why understanding the stress pathways overall and the allostatic load that we talked about in specific effects becomes extremely important, because you don't want to put, there's no point in put. The idea here is, let's not put the pressure on that chain. Let's not try to find out what your genetic predisposition is through trial and error of bad lifestyle, whatever it is, it's like if you you don't even have to go there. And then, I guess the extension of this, I know I'm I keep going a little tangential, but there's, like with the new elements of epigenetics, it's if the current generations are able to remove the pressure from the chain would what does that eliminate that genetic predisposition over time?

Jay Feldman 1:09:59
You're right, it's a great point, and it is all tangential, but, but it's a, it's a great thought process you can keep if you wanted to add something else there.

Mike 1:10:08
No, I was, well, I was just gonna say, because, like, the genetic predisposition for things had to start somewhere, right? So, and it like, so it's hard to say that it was just an inborn because at some point in time, like it had like, then that's the idea, I mean. And it kind of goes back to, like a religious thing of, like, some, some type of Original Sin type of thing. But the idea there is essentially that there was always error in the in from the start. But that also doesn't make sense like that. But I didn't want to go too far on that, because that's now becomes more philosophical.

Jay Feldman 1:10:43
And it's more of a discussion on evolution, which, which is a discussion we'll definitely have at some point, and breaking down things like genetics and epigenetics. And because it is, yeah, it's an important line of thinking. And of course, when we're looking at these things on the on the minuscule level, we want to bring it out to those larger things, you know, those larger, uh, lenses, because it's so there's so much value there. But go ahead. Go ahead. Well, what I was going to say is one important piece that I do want to touch on in terms of zooming out to that larger lens, is, not only are we wanting not to add stress to that chain or or put pressure on that that chain and finding the weakest link. But we can do the opposite, right? We can, we can heal and regenerate those links, and heal, you know, and repair. And those are all the things that require the exact opposite state, the excess energy state, which has its own adaptations that some of which are, as we were saying, they're very similar to the low energy state. It's a it's a kind of, it's a nice contrast of context where you still see the same things like potentially mitochondrial biogenesis. You know, there's got to be some way to produce mitochondria that's not just by driving stress, as much as you can within the right zone, of course, which is an unquantifiable zone. All right, we're going to end that episode there and pick back up in part four, the final part of this series, discussing hormesis. If you did enjoy today's episode, please leave a like or comment. If you're watching on YouTube and if you're listening elsewhere, please leave a review or five star rating on iTunes. All of those things really do a lot to help support the podcast and are very much appreciated to check out the show notes for today's episode, head over to Jay Feldman wellness.com/podcast where you can take a look at the studies and articles and anything else that we referenced throughout today's episode. And if you are dealing with any low energy symptoms, maybe these are symptoms you've been trying to correct or resolve using a hormetic approach. This could be symptoms like chronic cravings and hunger, fatigue, joint pain, weight gain, bloating or other digestive symptoms, poor sleep or insomnia, hormonal imbalances, brain fog, or various chronic health conditions or various other chronic health issues. Then head over to Jay Feldman wellness, comm slash energy, where you can sign up for a free energy balance mini course, where I'll explain how these different symptoms and conditions are really caused by lack of energy, and I'll also walk you through the main things that you can do from a diet and lifestyle perspective to maximize your cellular energy and resolve these symptoms and conditions. So to sign up for that free energy balance mini course, head over to Jay Feldman wellness.com/energy, and with that, I'll see you in the next episode.