Jay Feldman 0:05
Welcome to episode 94 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. 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. This episode is part two of our discussion going over a paper regarding the effects of stress on our mitochondria, and in today's episode in particular, we'll be discussing why uncoupling is harmful in certain contexts, and how the polyunsaturated fats or PUFA cause constant, low grade uncoupling. We'll also be discussing the involvement of uncoupling mitochondrial biogenesis, autophagy, heat shock proteins and Hypoxia inducible factors in the stress response. We'll also go over how stress prevents our mitochondria from effectively producing energy, how chronic stress causes insulin resistance, high blood pressure, weight gain, depression and cardiovascular disease, how sugar and fat cravings result from stress, and why listening to them is actually beneficial, and how adaptations to stress get passed on through generations. If this is the first time you're listening into this podcast, then after listening through today's episode, I'd highly recommend you go back and listen to our episodes one through seven, where we took some time to build a foundation as far as the bioenergetic view of health is concerned. To check out these show notes for today's episode, you can head over to Jay Feldman wellness.com/podcast where you can take a look at these studies and articles and anything else that we referenced throughout today's episode, and if you are dealing with any low energy symptoms or chronic health issues, maybe these are related to some of the issues we've been talking about throughout these the series, or part one in terms of insulin resistance and blood pressure issues, weight gain, depression, cardiovascular disease and other related chronic health issues. Or if you're dealing with any other low energy symptoms, this could be chronic cravings and hunger, low energy or fatigue, chronic pain, weight gain, digestive symptoms, brain fog, poor sleep, hormonal imbalances, or various other low energy symptoms or chronic health issues. 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 one of the things I did want to like, we kind of glossed over it, but I want to make sure it was make sure that we explain what it looks like is the inhibition of the respiratory chain activity. I just wanted to, you know, they talked about complex one at one point. So I want to just show a diagram here of what that would look like, what what that actually means for someone who's not as, uh, familiar with or how we produce energy in the mitochondria. Okay, so just the basics here, as far as mitochondrial respiration goes, this is just showing it with glucose coming in. But of course, you could have fatty acids coming in as well, or ketones at some points and things. But anyway, so we have glucose going through glycolysis and then through the citric acid cycle, also called the Kreb cycle, and that produces NADH and FADH two those are also produced in glycolysis. They're also produced in beta oxidation, if you have a fatty acid coming in or a fat coming in. And so those products then go over to the electron transport chain, which is still inside the mitochondria, but it's not, supposedly along the membrane. And there are four complexes here of what's called electron transport chain. And the this, again, the ideas here being, is that when the electrons are dropped off and transported along this train, it creates what's called a proton gradient, and then that proton gradient is used to produce ATP. And so the important piece here just being that various all sorts of different toxic things, or, I mean, it depends on what you consider toxic, but tons of different things can block the function along any of these processes. But specifically they were talking about glucocorticoids blocking complex one here, which blocks the offloading of electrons from NADH and the conversion to NAD. We've talked about this a lot because it's also something that happens when you have excess fat oxidation, which does the same thing, but through a different mechanism. There's a ton of there's a ton of things that will block complex one, there's different things that will block complex four. There's different things that'll block different steps of the citric acid cycle. But the point. Being that if you're blocking anything around here, you're going to be reducing ATP production, and that is going to drive a stress state where you then need to activate the backup pathways to force this to go on more and more to produce some amount of ATP. And yeah, we've we talked about this in the fatty liver disease series, especially. But I just wanted to give somebody a picture if they aren't exactly sure of what we mean when we talk about blocking some component of of the respiratory chain, you know, that being the electron transport chain, or something else in in terms of mitochondrial respiration.

Mike 5:36
Yep, I don't have, well, I guess we'll get to it when we I was going to mention the fatty acid piece, but you already did that. We'll get to it. We talked about in the stress state, you actually you have the glucocorticoids blocking complex one, and you also have high amounts of fat oxidation, which causes an issue between complex one and complex two. And then both of those will create increased ROS generation, like those are both direct mechanisms of increased ROS with decreased ATP,

Jay Feldman 6:03
Right, right, exactly. So going back to the study, we discussed all this, and now onto the catecholamines, so they stay together with glucocorticoids. Catecholamines are the primary hormonal mediators of the fight or flight response. Adrenaline and noradrenaline affects mitochondrial metabolism, mainly by mobilizing energy substrates from body reserves to augment their ability for oxidation. Catecholamine stimulate lipolysis, which is the release of fat, and glycogenolysis, which is the release of glycogen, especially in skeletal muscle, by interacting with b1, and b2 adrenal receptors. In addition, adrenaline acts through the G's protein coupled beta two adrenergic receptor to stimulate adenyl cyclase activity and CA and P production activating protein kinase a...

Mike 6:50
Those are all second messengers in the cell, just right?

Jay Feldman 6:53
Exactly, yeah. Just talking about the mechanism, yeah, exactly. And this signaling pathway modulates numerous processes by stimulating phosphorylation of the CA, MP response element binding protein creb, and by activating peroxisome proliferator activated receptor gamma, coactivator one alpha, so PGC one alpha, which exerts downstream effects that stimulate mitochondrial biogenesis and oxidative phosphorylation, thus controlling adaptive thermogenesis and adipose tissue and skeletal muscle.

Mike 7:26
And we talked about this before in the box, that's the PGC one Alpha, is what we were talking about before, where, if you have enough during stress, you can meet a demand, but if you have too much, you get mitochondrial biogenesis, but you can also get cardiomyopathy.

Jay Feldman 7:40
Right, and that's just in that one specific instance they were looking it can cause any sort of degeneration. But the point being that all of these things are part of a stress response that has a function. It doesn't mean we want to incur encourage that to happen just because it not happening. Well, is a bad thing, right? If you block our ability to adapt, that is bad. Doesn't mean we want to force our adaptation to stress. And yeah, this. The reason why I was wanting to discuss this is some of these things might recomb again when it comes to hormesis, things like PGC, one alphas, you know, are focused on a lot. And these are all just means through which the catecholamines function. And I know they went through glucocorticoids first, but as we mentioned, the catecholamines get released first, and then the glucocorticoids are are second in terms of the chain of stress, stress activity, yep. And so to talk further, I was going to go into thermogenesis specifically with uncoupling. Do you have anything to mention first?

Mike 8:32
No, I'm right. Waiting for uncoupling.

Jay Feldman 8:35
Yeah. So catecholamines also enhanced thermogenesis in brown adipose tissue during this process, energy derived from oxidation of fuel substrates is dissipated as heat rather than being stored as ATP. And this is uncoupling, a coupling occurs via beta three adrenergic stimulation and downstream regulation of specific uncoupling proteins. And then they say that the regulated uncoupling caused by these proteins attenuates mitochondria reactive oxygen species production and protects against cellular damage. So there's a few things to discuss here, but this is something that, again, uncoupling and brown adipose tissue are highlighted excessively in the hormesis realm, or the pro stress realm, or the ketogenic diet realm, all of these things where they're suggesting that this is a state that you want to induce. And it's not that uncoupling is inherently bad, but what it does do, as I think they mentioned, is that it dissipates, it causes the substrate to be dissipated as heat, rather than being stored as ATP. And it's a way to burn off extra substrate, if there's excess substrate and you already have enough ATP. So that's the beneficial situation. We've talked about this before, but you produce a lot of energy that leads to and I guess I'll show the other diagram real quick.

Mike 9:46
Over feeding increases on coupling as well, which is kind of what you're getting at.

Jay Feldman 9:51
So basically, when you're in this state, if you have excessive amounts of ATP, that's going to stop up this chain as well. And so there. Dollars, that will lead to reactive oxygen species production, and that will lead to uncoupling, which we'll get to in a second. But it's not harmful in the state, because you have a lot of ATP, you have a lot of CO two, which isn't shown in this diagram, but that is very different from inducing uncoupling by blocking something along here, producing a lot of reactive oxygen species and then the cell saying, That's so dangerous, this is going to cause a lot of cellular damage. We need to stop that from happening. And so the way they do that is through uncoupling. And it happens when you're stimulated by adrenaline or various other stress hormones. And it also happened, as you mentioned, Mike, in response to fat oxidation. And so that looks like this. So this is showing an uncoupling protein. This one's showing uncoupling protein one where what it's doing is, instead of having the proton gradient that allows for us to produce ATP, it removes the gradient by allowing the protons to come back through. And so what this means is that we're not producing ATP anymore, and it stops the production of reactive oxygen species. So it's kind of like if you had a car and you threw it in neutral and revved the engine a lot, you're using gas, but you're not going anywhere. And in a state where the engine wasn't working well and it was producing smoke, or, you know, it was all sorts of damaging things going on, that's helpful, right? You you want to, like, you want to stop that from happening, and that's what the uncoupling protein allows for, but in a state where you actually want to go somewhere, where, meaning, you want your body to do something and function, you want to be producing ATP. And so this is beneficial. In the context that you you need to turn off oxidative stress, or in the state that you have high ATP levels, and your you don't need more, and so you can burn off the extra substrate you have there at the moment, and then you can also that will also activate other backup, things like increasing mitochondrial biogenesis, which, again, we have two situations here. One, you're producing more mitochondria because you've got really effective energy production, and you want to produce more drive complexity and better function. Or two, you're trying to adapt to future stress, and you're doing this in a low ATP state. And so that's where that difference comes from. But another thing that will do the same thing that this uncoupling protein will do is polyunsaturated fats. So if this membrane is made up of a lot of polyunsaturated fats, you'll have it'll be legally leaky to these protons, which will make your mitochondria much less coupled and make it so that you can't produce ATP as efficiently. And again, that's not ideal. We want really tightly coupled mitochondria. You want to produce that ATP really, really effectively, and then allow that to create uncoupling. You don't want to have already decoupled mitochondria that can't produce ATP efficiently. And you see this. You'd mentioned this before, Mike, we talked about in terms of aging and polyunsaturated fats in the membrane. Were the species that have more polyunsaturated fats here and are more leaky. They have higher metabolic rates, but they produce less energy, and they age way faster and they way shorter lifespans. Whereas the animals that have much more saturated membranes are much less leaky, they produce energy much better, and they live a lot longer, and they function a lot better, and they have better, you know, higher brain complexity and things like that. Now, within a species, a higher metabolic rate, which is when the this is constant, and there's no more PUFA in here, but you have a higher metabolic rate, that means you're just producing more ATP and that's associated with reduced aging. So that's those kind of separation there. But the point being that when you have the equivalent of uncoupling, it drives aging in the wrong context. And, yeah, I'll link back to those aging episodes. I think I already mentioned I would, so that'll kind of explain that concept of more detail.

Mike 13:35
Yeah. Also, when you have, when you have more PUFA inside the membrane there, and you're running higher amounts of fat oxidation then you and you're creating larger amounts of ros. That Ros is more likely to attack that PUFA. You're more likely to get proxy, peroxidized fatty acids. So you have a you have a dual negative effect, where you have, like, the H plus ions able to move across that wall there, if there's more PUFA, because the PUFAs tails are bent, which creates more space, which makes the membrane more fluid. And then you send these can move across, and then you have decreased ATP production. And then with excess fatty acids, you get more Ros, because we talked about the blocking at with between complex one and complex two. And then, essentially, you just now you have a leakier membrane, less ATP production, and more peroxidized fatty acids and damage to the mitochondrial structure. So overall, it's just negative, like, it's just a hard, hard L for the mitochondria, if you saturate them with polyunsaturated fats.

Jay Feldman 14:37
Yeah, yep, absolutely, yeah.

Mike 14:41
They actually talk about this inside the study, directly in that section underneath. So you said there, it's a you highlighted the regulated uncoupling costs by these proteins. Attenuates mitochondria ROS production and protects against cellular damage. Uncoupling protein two and three regulate. Proton leakage in the heart, which can be cardioproductive in ischemia, preconditioning or pathologic and ischemia reperfusion models, increased activity of uncoupling two decreases insulin secretion from pancreatic beta cells. Conversely, uncoupling protein to knock out mice display increased beta cell mass and retain the capacity to secrete insulin in the face of chronic hyperglycemia or hyperlipidemia. In addition, uncoupling protein to knock out mice produce more superoxide, which chronically activates the NF, NF Kappa Beta nuclear factor Kappa Beta system and increases resistance to infection of no mice without uncoupling protein two are more susceptible than normal mice to chemically induced colon cancer, implying that a general reduction of uncoupling protein two activity might have undesirable side effects. This is important because essentially, what you're seeing is that the uncoupling protein two is a release valve when you have too much Ros, it's protecting the cell from that excess amount of ROS now, when you get rid of uncoupling protein to like they did in these transgenic mice, they basically spliced out the uncoupling to protein from their genes. So they didn't, they couldn't produce the protein. Then they the mice, they produce larger amounts of superoxide, so larger amounts of reactive oxygen species now protected them the infection because the respiratory burst from immune cells are are it's essentially like bombing microbes, but it also increased their susceptibility to cancer, because the cells had large amounts of Ros being generated at the mitochondria and specifically in the colon. The other thing that was interesting here is that the increased activity of uncoupling protein two decreases insulin secretion. Why would it do that? Well, if you have cells that are overloaded with substrate and producing large amount of ros, because they have blocks and they're they're increasing uncoupling protein too, to dissipate the protons and lower Ros. Dissipate the protons as heat and lower the ROS that's being produced, then you don't want to have insulin driving more substrate into the cell, that would be counterproductive, because you're already having a bottleneck. So when you knock out that ability, it's like, Oh yeah, that mice didn't become insulin resistant. It's like, yeah, they didn't become insulin resistant because and so they allowed them to just continually, continually produce ROS in their mitochondria, which are already overloaded in ROS, because they were because of a block that they were having, in general, and then it that led to the formation, or the more likely formation, of cancer, because now you just have mitochondria overload with ROS and no release valve to stop that. So it's a very, like, very interesting little explanation there. As far as, like, the importance of of looking at why and where in the context of the uncoupling proteins, they're not just good in general. They serve a purpose. So when you have excess Ros, and the mitochondria wants to lower that, okay, now we have, we're going to create this release valve so we can lower the ROS production uncoupling protein. But that can happen in two states, as you, as you discussed, Jay, is you can have a large amount of ATP production and a large amount of energy production, and it's like, okay, we don't need as much right now, like, we have an adequate amount. So let's dissipate some of this as heat, which isn't a loss, because he's still producing carbon dioxide. You're still producing heat. Great. Now there's another situation where it's like the chain is all jacked up, and it's like, we're just throwing out Ros, like our engine is just smoking. So let's like, Let's lower the flow through the chain by moving stuff through the uncoupling proteins, and lower the amount of smoke that's produced. So we don't destroy the engine, essentially. So they have two different scenarios, and they're very different, even though the proteins are upregulated in both. And it's important to understand that context. And then you're seeing the effects here with the mice, when you take out that uncoupling protein in different scenarios.

Jay Feldman 18:44
Yeah, yeah, exactly. And kind of goes back to what we were discussing earlier, where you block the adaptive response and you get bad effects. So you know that means that we must want to just increase the adaptive response all the time, and it's like, well, not really, unless it's in a proper context, which, yeah, yeah. Like a defense, the absence of a defensive reaction doesn't, you know, being bad doesn't make the defensive reaction good. And just as a as to share another, another quick diagram showing the effects of uncoupling. So there's a diagram here. It's not great, you know, it's not like a great diagram. It's not comprehensive, but it just shows some of the effects of mitochondrial and coupling in different areas. Talks about causing macro autophagy. Specific autophagy talks about driving lipolysis, meaning the release of free fatty acids, part of the stress response. It talks about in the cell how it reduces reactive oxygen species generation, reduces ATP production, which then leads to increases in amp kinase just all of these things that, again, are discussed as supposed, you know, supposing to be beneficial in terms of their hormetic effects, but in reality, are just markers of stress when they're activated in the wrong context, again, as when it's activated due to. Uh, low energy and high reactive oxygen state species states versus high energy, high reactive oxygen species states, yep. So moving on to some of the cytokines and other uh related factors. They described that the release of pro inflammatory cytokines is a major component of the response to stressors such as ischemia reperfusion, injury, trauma, cachexia induced by infections with bacteria and viruses, various cancers and heart failure. Cytokines such as TNF alpha, interleukin one alpha and interleukin one beta can activate the transcriptional activity of PGC one Alpha via direct phosphorylation by P 38 mitogen activated protein kinase, which is MAP kinase, map K, resulting in stabilization and activation of PGC, one Alpha protein and increased downstream expression of genes linked to mitochondrial uncoupling and energy expenditure. So again, coming full circle here is that the increased activity of these inflammatory cytokines, which are produces produced in response to stress and inflammation, causes the same hormetic downstream effects leading to uncoupling and increased short term energy expenditure, which we'll talk about again in a second. But yeah, this just being another major component, just like the other stress hormones, just on a kind of a different level, a smaller, more local level, that that has the sort of effect. And I like that they talk about this happening in all sorts of different scenarios, again, showing how ubiquitous it is, how generalized the stress responses, whether it's in response to cancer or infections or ischemia reperfusion, reperfusion injury, and these are all states that you see a low ATP, high reactive oxygen species situation going on, and so it's it lends a lot of credence to that whole idea of being the real problem, as opposed to, as opposed to not getting enough stress. And I cited a few of those studies in my home races articles, and we may have talked about them in the recent series as well.

Mike 22:02
Yeah, I just wanted to add two things here. The first one is that it's interesting. So you have the increased mitochondrial uncoupling and energy expenditure. So that energy expenditure is because you still have with the increased mitochondrial coupling, in these situations, you're still at an energetic deficit, so you're just moving your all that, all this flow and the substrate that you're you're pushing through. The mitochondria are moving as heat, but you're still ATP deficient, so you're still trying to push stuff through, not get the ATP, and then move it through, uncoupling, because the mitochondria are under stress. They're under excessive ROS another one that the other thing I wanted to talk about really quick was just what is ischemia reperfusion? Because we've mentioned it a few times. Ischemia reperfusion, essentially, if I cut off blood and blood flow and oxygen supply to a tissue, and then I let allow blood flow to go return after it causes serious damage to the tissue. Question is, why? Well, if I cut off blood supply and oxygen to the tissue, then I can cause large amounts of damage inside the mitochondria through the hypoxia that develops and lack of oxygen as an electron acceptor, and then I forcing a movement towards glycolysis. So you cause all types of disruption, and then you return oxygen and and nutrient and substrate to that cell or those tissues. And now you have this, the mitochondria and the tissue are damaged, and you're trying to move substrate through so, and then that causes increases in ROS and a whole bunch of adaptive response or stress responses that cause damage inside those cells and tissues. So and a lot of times ischemia reperfusion is is rescued. They like do all these types of like antioxidant plant compounds and all this type and things like that. And a lot of what they're doing is they're just helping to mop up and deal with the ROS that's generated in these situations. And also, some of them help to activate these adaptive responses that protect the mitochondria under the stressful situations. So it's it's the doesn't the the ischemia reperfusion is essentially an example of the deranged metabolism stuff that we're talking about, and it's a huge example in the literature that they always look at, because there's a paradox before right, where it's like, if I take out blood flow to a tissue, well, when I restore it, it should be getting better. But what usually see the injury, and that's what you see in heart attacks and myocardial infarctions, is you have an ischemia, the you have a thrombosis or an embolus, blocks off the blood supply to a particular piece of heart tissue. That heart tissue dies because it lacks oxygen, depending on how long it's blocked, but then, even if it doesn't die, because it got blocked, when the blood flow returns, you get an area of damage to that tissue, and you wind up getting fibrosis from that damage if you don't treat it effectively.

Jay Feldman 24:52
Yeah. 100% so moving forward, here they talk about a few other cytokines. Things. They talk about the heat shock proteins, again, being one that's cited a lot, because people talk about using temperature exposure, specifically cold temperature, to induce hormetic effects. All of these things just being part of the same pathway. And then they go on and talk specifically more about reactive oxygen species and NF Kappa Beta. So just going to talk a little bit more about that. Unless you had anything to mention here, they discuss endotoxin a little bit, which I think was the main reason I wanted to mention this.

Mike 25:28
I just wanted to say with the heat shock proteins, this one, this one always kind of gets my nerves a little bit like, oh, we want to induce these proteins, and because they're going to refold all the like, improperly folded proteins. And it's like, why were they improperly folded in the first place? Yeah.

Jay Feldman 25:45
Yeah and why? Yeah? Why aren't they just naturally getting or, like, not naturally, but why aren't they being refolded on their own, just like autophagy? Like, why do you just, why do you think you just have a bunch of damaged cells laying around waiting to undergo autophagy? Like, that's not how that works.

Mike 25:58
Yeah. And then they say, Here, they say, the heat shock proteins constant, a highly conserved and functionally interactive network of intracellular chaperones. The chaperones are just kind of like these, these complexes that go and and attach the proteins and can fix their structure, essentially. And they say that this, this aggregate, refold and re nature, misfolded proteins resulting from various environmental and physical and chemical stresses, and they say heat shock protein 2770 and 90 have an implicated in protection against apoptosis, induced by numerous, numerous signals such as heat shock, nutrient withdrawal, Ros, endoplasmic reticulum stress, protein, proteasome inhibition, UV, radiation and chemotherapy induced DNA damage. Heat Shock proteins promote cell survival by preventing mitochondrial alloy, membrane permeable Permeabilization and subsequent cytochrome c release, caspase activation, apoptosis, apoptosis, apoptoso assembly. So the heat shock proteins, again, are an adaptive response, and it's like when you have misfolded proteins or damage protein structures a question, why are we having them in the first place? But when you have those structures, they signal the cell and mitochondria, hey, we're jacked up. We need to, we need to do, you know, start over. So we're going to implode, and then we're going to, like, the body will make use of the components or reassemble them, or get rid of them, whatever it is, and you make a new cell, whatever it is, but the heat shock proteins stop that from happening, because they go and they fix those proteins. So are they good in a situation where you have a bunch of misfolded or aggregated proteins, etc, sure, sure. That's helpful to be able to fix that. However, the question is, is, why are you having those misfolded, damaged proteins in the first place, and should we be inducing them, the heat shock proteins? Like, am I gonna go do something, for example, like generate large amounts of ROS or cause nutrient withdrawal so that I have damaged proteins and then, oh, wow, I'm activating my heat shocks, and now I'm better I know. I'm gonna avoid those situations in the first place so that I don't have to activate the heat shock proteins because the proteins didn't become aggregated or misfolded from the start. That's the that. And that's a lot of the same arguments. It's the same thinking with all these different pathways, but the heat shocks are another one those ones. I always laugh a little bit because it's like, let's, let's get a team to fix this broken house, because we built it like crap in the first place. Like, why don't you build a house the right way to start? Right?

Jay Feldman 28:28
Or it's like, let's start breaking down this house so that somebody else will come and fix it. Like, get rid of it. Like, you know, it's like, I don't know. Maybe you're like, trying to create an insurance claim or something, you know, so you damage the car yourself so that can get scrapped and you can get a new one. Yeah, yeah. Anyway, so moving on to some specifics here, and again, I'd like talk. I like this next part because they discuss things like ionizing radiation and endotoxin being part of these same pathways, or activating the same pathways. So they say that then NF, Kappa Beta pathway is highly sensitive to changes in the intracellular redox environment, and this can be activated by oxidative stress. So it's just again mentioning that inefficient energy production is going to activate these inflammatory pathways, and that includes things or that can be induced by the following things. So they say activating signals such as the pro inflammatory cytokines, TNF alpha, or interleukin six, irradiation, endotoxin and reactive oxygen species can converge toward IKB kinase, which subsequently phosphorylates sir 19 and Sir 23 on the inhibitory subunit of NF Kappa Beta and cause its ubiquitous ubiquitalization, ubiquitylation and release from the NF kappa B complex. Basically, they're saying that it's getting activated. So just pointing out here that things that cause oxidative stress and inhibit energy production, like ionizing radiation, endotoxin and inflammatory cytokines, which is those are going to be reduced or produced by any stress factor that's causing stress is going to induce. And F Kappa Beta, then F Kappa Beta pathway. And they go on and they mention this again. Also, there's one other pathway here that there's a reason specifically why I like to mention this one. So they say another protective mechanism against reactive oxygen species derived cell death involves local activation of C Gen and terminal kinase, which is JNK in the mitochondria, a pathway particularly significant in tumor cell progression. The reason I like mentioning that one is because there's a study cited by none other than Robert Lustig, one of his main studies I believe, that he uses to put forth his idea that fructose is a metabolic poison, just like alcohol and it causes fatty liver disease and on and on. And it's a study where they gave rats a ton of fructose, and I want to say it was independent of glucose, and it caused this major stress reaction that activated this JNK pathway, which is an inflammatory pathway. So for one, if someone's in favor of hormesis, they should be in favor of of ingesting fructose, because it activates this hormetic pathway that they all are trying to activate through other means anyway, so you might as well get your little doses of fructose throughout the day for your little amount of pharmacies. Again, I don't understand why they just decided that some stressors are not good and some are good, when, from their view, fructose really shouldn't be any different. But then when you look at that study further, they actually, for the second, for, like the treatment, they use something that blocked the metabolites of polyunsaturated fats. One of the I want to say, it blocked the lox enzyme, or some product of the lox enzyme, and it completely inhibited the effect of the fructose and activating these stress pathways. So basically, even if you ingest, if the rat ingested way too much free fructose, it still wouldn't even activate these stress pathways unless there was PUFA and PUFA metabolites available. So anyway, that's why I like highlighting that part.

Mike 31:56
Yeah, with these ones, I want to highlight two things. So on the NF Kappa Beta pathway, the section that you read underneath it, it says the P 50 and P 65 dimer trans. So those are the units of NF Kappa Beta that will they then move thereafter, to the nucleus, or so they move to the nucleus and bind to the Kappa Beta domain of target genes, initiating transcription of several antioxidant genes, since of manganese, super dioxide dismutase and gamma glutamyl cysteine synthetase. And essentially what they're doing there is, when you have this exposure to oxidative stress or excess Ros, NF, Kappa Beta, gets activated, and then it signals the antioxidant enzymes to come and help deal with that oxidative stress. Because a lot of people like, oh, well, this is good. It's like, well, you have these enzymes being upregulated because you're, you're signaling high amounts of ros. So it's like, it's, it's good because it helps to deal with the ROS. But you the goal would be to avoid signaling large amounts of ROS from the beginning. And I think that that's, that's an important distinction, right? It's like, let's cause a damaging situation, and then that will induce these protective factors to come on board. Or, let's, why don't we just avoid causing the damaging situation in the first place?

Like, there's, that was the first one I wanted to and I don't know if you want to add something to that, Jay before I talk to the next point.

Jay Feldman 33:19
Yeah. So just thought of a good analogy. I don't know why we haven't thought of this one before, but it's like, so firemen are really they're great. They're really helpful for putting out fires, and it's really good to have them. But that doesn't mean we want to be creating fires so that the firemen have a job to do, right? We just want to make sure that there are firemen available, but we still want to minimize the amount of fires that we create. Like the fires are not a good thing, just because firemen cleaning them up is a good thing. And so when you do a study where you block like, you take away all the firemen, and you create fires, and is really bad. It doesn't mean that you want to just get the firemen, like, active all the time, always putting out fires. You just want to have the firemen there so that you they can be there if needed. But you don't want to be creating more and more fires. That's that's like the misnomer there's just because the firemen get activated when you create fires, does not mean you want to create fires, but you do want to have firemen.

Mike 34:07
Yep, yeah, exactly. The second one I wanted to talk about really quick is it's the it's on the left side. It's the bottom starting paragraph. This is the generation of ros. And what it says is the generation of ROS from mitochondria is a major signaling pathway in response to varying oxygen levels. Cells exposed to hypoxia activate the transcription hypoxic inducible factor one, which is h, i, f1, and downstream targets that regulate glycolysis, mitochondrial oxygen consumption, erythropoiesis, angiogenesis and cellular survival. This pathway is a major pathway, I think, for cancer. And the reason I say that is when you start to create these situations with larger amounts of hypoxia, this factor eight, hypoxia inducible, factor one comes on board and it it. What happens is the mitochondria start to shift towards glycolysis, because. You don't have oxygen, so you can't run cell respiration, and then the mitochondrial oxygen consumption will would like have to concurrently decrease because you don't have the oxygen. And then you have erythropoiesis, so you have increase in red blood cell production. Why? Because now the cells are saying, Hey, we don't have enough oxygen, so the body's saying, Okay, we're going to make more red blood cells to carry oxygen to the tissues, and then we're going to increase angiogenesis. Same thing, we're going to increase the production of vasculature to that supplies to the tissue, so that we can bring more red blood cells on board to supply more oxygen. And then these things also, they help to promote cellular survival. But when you don't have that oxygen, as we talked about, you create a lot of damage inside the mitochondria from the ROS and then you shift towards that lactate metabolism. And that lactate metabolism, metabolism is what we see with the Warburg effect. So there's these, these stress pathways. It's like, Yes, this is like, if you it's an intelligent system right where it's like, okay, we don't have enough oxygen. So we're gonna, we're gonna build, we're gonna build all these things so that we're lowering our oxygen consumption, but then we're increasing our oxygen supply through red blood cells, vasculature, and then we're also and then we're moving towards glycolysis, so we're not using as much oxygen. The mitochondria aren't using as much oxygen, etc, etc, etc. But that's, that's pathology still, because those all of those adaptive changes, if chronically maintained, can lead these are like, these are all features, minus maybe erythropoiesis that you see in cancer. You see increased angiogenesis, you see increased lactate production, and then you see increased like you change, you see changes in mitochondrial oxygen consumption. So there's a it's I just like pointing that out again, the body isn't mate has adaptive processes, but there's only so much that the body can adapt to. So when you have extend this the same thing, if you have extended activation of this situation, this extended hypoxia. Then eventually these adaptive processes break down, and they wind up causing their own problems. For example, like a cancer, where the cancer drives angiogenesis to itself, the cancer moves towards that lactate metabolism. So just important things, I think, to to keep in mind and seeing this like this switch with things where you initially, you can adapt, but then after a while, boom, you ever you're now, you're in problems. Now, you're in metabolic dysfunction. Now the mitochondrial machinery is destroyed. There's an excess of ros, etc, etc, etc,

Jay Feldman 37:33
Yeah, 100% so moving on, they begin to discuss the specifics of what's going on in the mitochondria and acute and chronic stress. And so in first talking about acute stress, they say tissue oxygen consumption and total energy expenditure are increased during the initial phase of the acute stress response. We mentioned this already, but they had focused up until this point just on what was happening outside of the mitochondria with the release of substrate. But so they're saying inside you have increased energy expenditure. Indeed, energy expenditure is initially enhanced by as much as 200% despite significant hyperglycemia. The observed decrease in the respiratory quotient, an RQ of 0.8 suggests that a significant a significant portion of this energy derives from lipid oxidation occurring primarily in the mitochondria. So I guess, just to pause there, they're saying that this, these stress pathways, will almost, well as much as double our energy production in order to deal with the major energy demand that's on hand. Yet this is happening from fat oxidation due to the means through which we have to activate this energy production, and they observe that by saying a low RQ, which means low carbon dioxide production, and yeah, so we're seeing basically a forced reliance on fat oxidation. And we kind of alluded to this earlier, but this is part of why inducing fat oxidation outside of the state is not a good thing, because it parallels all the things that are happening during stress, including increased reactive oxygen species production, inefficient electron transport chain activity, inefficient ATP production, and not for decreased CO two,

Mike 39:13
Which is they directly stating it here. And then the other thing too to keep in mind is that they said, despite significant hyperglycemia, it's not surprising that in this situation, you have hyperglycemia, if you're moving towards fat oxidation, and then these pathways feed forward on themselves, right? Because you have, in this state where you have higher amounts of blood lipids, you will have a Randall effect, to some extent, where you have the cells moving towards more fat oxidation and less glucose oxidation, which and then you also have, so you have a you have the cells oxidizing less glucose, and then you have the liver increasing glucose output through gluconeogenesis. So you have, like you have, and this is where you see the hyperglycemia. This is like a combination of those factors. And then the RQ is literally directly showing geek. Be CO two output. And the reason you see that we discussed it before is that more CO two is generated during carb oxidation than fat oxidation. We have an episode discussing the mechanisms of this, etc.

Jay Feldman 40:11
Yeah, and so. And just to clarify, as far as the Randall effect goes, it's not just happening because there are free fatty acids available, but because there are, there is this dysfunctional respiration that then drives fat oxidation, which then causes a low NAD to NADH ratio, which then inhibits certain aspects of the Krebs cycle and inhibits certain aspects of glycolysis, which favors fat oxidation. So it's not just about the availability of one substrate or the other, but rather various signals that are involved. So yeah, just wanted to make that clear. So moving on. They then say that although a burst in mitochondrial function is necessary for survival during acute stress, for example, in a bout of exercise, excessive demands on mitochondria during critical illness, such as trauma surgery or sepsis, can be detrimental to the cell glucocorticoid induced hyperglycemia and insulin resistance, possibly owing to the effects of stress hormones, cytokines and nitric oxide on the insulin signaling pathway are common in these conditions, and their severity correlates strongly with increased morbidity and mortality. And so it's kind of another way of just saying that if this continues on and you're in a more degenerated state, I guess it's two things. One, if this thing continues on more and more, you're going to be dealing with reduced capacity to handle this response to stress. But then also, if you're already in a degenerated state where you're undergoing trauma or sepsis or critical illness, then you're not gonna be able to respond as effectively as they said, due to the effects of stress hormones, cytokines and nitric oxide, which are all effective they mentioned on on the insulin, insulin signaling pathway. But in reality, it doesn't have so much to do with insulin as much as it does just their effects on respiration. Or nitric oxide is pretty effective at blocking complex four activity, blocking connatase at the Krebs cycle. So you know, you you have inhibited respiration that is basically further impairing the stress response, and that's correlating as they sided with increased morbidity and mortality.

Mike 42:09
Yep, yeah, so you're just basically digging yourself deeper in the hole. That's and it's the stress hormones, which we already talked about, catecholamine, glucocorticoids, the cytokines, il six, tumor necrosis factor alpha. What was it? ILB, and then, and then, now you have nitric oxide, which they've also discussed above as well. But basically the trifecta of get destroyed.

Jay Feldman 42:34
Yeah, yeah. And they describe it further here, and they say that they converge on how this is happening with low ATP and inhibited electron transport chain, and so they say a 30% reduction in complex one activity. Remember, that's the complex where we had highlighted before with respiration.

Mike 42:51
That was the NAD one. That's the one heavy with NAD.

Jay Feldman 42:54
Yeah. So that's one where NADH is dropping off its electrons and it's favored during carb oxidation and disfavored or inhibited during fat oxidation, and so it says a 30% reduction in complex one activity with decreased ATP concentrations, depletion of antioxidant activity and increased nitric oxide production has been described in skeletal muscle biopsies from patients with sepsis and were related to shock severity and adverse outcomes, in addition striking Ultra structural and functional abnormalities were described in liver mitochondria as surgical intensive care patients. So what they're basically saying here is basically, when you aren't producing energy effectively, and you have high amounts of nitric oxide, and you've depleted your antioxidants, you've continued this on so far that your antioxidants aren't able to keep mopping it up. You're you've run out of firemen because there's so many fires. This is what happens in severe shock and is associated with adverse outcomes and intensive care, you know, surgical intensive care and on.

Mike 43:52
And the next line too, says these abnormalities could be prevented or reversed with insulin therapy and strict glycemic control. What essentially, they're doing with the insulin is they're forcing that carb movement into the cell and oxidation. So they're saying, if we force glucose oxidation with exogenous insulin, we can minimize some of these negative effects that happens when the cells get shifted over towards that fat oxidation, etc, etc, etc, that we just the whole pathway that we just talked about, which is essentially what we've just we've described as well, is like you need to get back to glucose oxidation, and you have to start to minimize the fat oxidation and address the dysfunction that's happening in multiple layers inside the cells here and for the shock and sepsis patients. So the main factor that they have going on is that the endotoxin is blocking their respiration on a systemic level and causing and it does it directly at the mitochondria, but it also does it by up regulating tumor necrosis factor alpha, the catecholamines, glucocorticoids, il six. It literally is a potent activator of all of these stress hormones and stress compound and nitric oxide that. We've talked about. It stimulates the immune cells to produce nitric oxide and respiratory bursts. So it's that the that's why the steps this, then, is such a large picture here, because it you're essentially it causes the feature of all of this dysfunction. So, yeah.

Jay Feldman 45:18
Yeah, yeah, definitely. So that essentially describes what's going on in the acute stress situation. We have the burst of backup energy production through driving fat oxidation at a major cost. And now digging into the chronic stress side, we see what happens when we have to rely on the acutely stressful pathways, or the adaptations to acute stress over time. So they state here that although glucocorticoids are crucial for survival during stress, excessive cortisol secretion or chronic administration of synthetic glucocorticoids at pharmacological doses, endogenous or exogenous, Cushing syndrome, respectively, have long been associated with hypertension, depression, immune suppression, osteoporosis and metabolic syndrome, which they describe as visceral obesity, its own resistance, dyslipidemia, hypercoagulation and arterial hypertension, as well as atherosclerosis and cardiovascular disease. Similarly, at the cellular level, the necessary induction of mitochondrial biogenesis in response to the various stressors through the PGC one Alpha signaling pathway can eventually become maladaptive and detrimental to the cell, as evidenced by the cardiomyopathy observed in a murine model of cardiac PGC. One Alpha overexpression, accumulation of abnormally proliferated mitochondria is a characteristic feature of mitochondrial myopathies, described as ragged red fibers, whereas increased mitochondrial biogenesis has been observed in the hearts of diabetic animal models. So a really great quote here. The first piece of it just describing very clearly that, again, while glucocorticoids are necessary for immediate response to stress, and they described it as survival, which is true, if we didn't have these adaptive pathways, as soon as our demands exceeded our supply, we would die. So it's great that we have these, but they come at a major cost over time, and you see that very clearly in the pharmaceutical situations of administering glucocorticoids over time, as well as in Cushing's Syndrome, which is disease that is characterized by elevated glucocorticoids over time, elevated cortisol and so that, they say very clearly, is associated with centrally, completely destroyed metabolic function and all of the disease processes that come with it. So that's very clear, and I think very much depicts and illustrates what goes on when you continuously activate acute stress over time. And then they describe it on the cellular level, on the molecular level, as far as what's going on and the adaptive pathways. And they talked about, you know, previously, about how activating the PGC, one Alpha signaling pathway leads to mitochondrial biogenesis and on from there, and that that's what goes on in the acutely stressful situations. Then they described that this happens in excessive amounts in disease states. So they mentioned diabetic animal models that have increased mitochondrial biogenesis. And then they described one other situation of cardiomyopathy with PGC one Alpha overexpression, which we talked about. Yeah, we've talked about both of these situations, and not only mitochondrial biogenesis, but also autophagy, something that you see in these situations, essentially in any disease process, any degenerative state, you see excessive activation of these signaling pathways, all of the stress pathways, all the adaptive pathways, the ones that are supposed to trigger the hormetic response, and yet they aren't able to do it because they're In such degenerated states. And so this comes back to that hormesis discussion that we had and articles that I've written, and everything again, just showing that the idea that the way to get out of dysfunction and the way to get out of diseased or degenerative states is to increase the activity of these pathways is ludicrous and entirely illogical, because those pathways are already overactive in these states because of the constant stress. The constant adding up cumulative acute stress without any proper recovery or anything like that over time is what leads to those states in the first place. So the idea that we want to be increasing further acute stressors and creating further chronic stress to improve these situations is the exact opposite of what we want to be doing, and is clearly explained here. And so, yeah, I think this is a really great quote that, again, just gets really opposes the hormetic view entirely.

Mike 49:33
Yeah. And I just one thing I want to add here is the specifically to your point on the necessity of glucocorticoids, if you another besides Cushing syndrome, which is an excess of glucocorticoids, which caused these, this whole host of negative problems, particularly metabolic syndrome, cardiovascular disease, etc, in an absence of glucocorticoids, you get something called adrenal crisis, or Addisonian crisis. If you have Addison's disease, which is adrenal deficiency. Right? And essentially it's categorized by like convulsions, from hypoglycemia, a whole bunch of electrolyte abnormalities, low blood pressure, vomiting, diarrhea, passing out, and it can actually lead to death. And basically, what happens? What it's triggered by somebody with weakened adrenal function, winding they're exposed to a stressor, and their body is unable to cope with that stressor because they can't put out enough glucocorticoid to deal with the stressor. So the glucocorticoids job is to help mobilize resources, as we discussed, during a stressor or when a more prolonged or serious stressor, and when, when you're when your body doesn't have those glucocorticoids in that stress situation, you essentially will can die. But on the flip side, a chronic activation of that stressor consistently mobilizes resources and up regulates these pathways like PGC, one alpha, and that also leads to dysfunction. So it's kind of there's a kind of a balancing act in these situations where you want to have, like an exposure to cortisol and the catecholamines in a short stressful period of time is necessary, but too much chronic exposure to those hormones actually creates dysfunction. One of the dysfunction, one of the dysfunctional pathways to discuss is PGC, one alpha and again, the upregulation and mitochondrial biogenesis that we're seeing here is to help us to oxidize or utilize the substrate that we're producing. It's, it's, it's an, it's a necessary response to increase energy output. But this doesn't necessarily mean that that's an ideal thing to be going on, and that's evidenced by this long term outcome of upregulation of mitochondrial biogenesis and PGT one Alpha causing cardiomyopathy in rats, or basically what they're saying showing is that in diabetic models and diabetic animal models, they actually see increased mitochondrial biogenesis. So it doesn't increase bio mitochondrial biogenesis is not always a good thing. The question is, why are the mitochondria? Why is increased production of mitochondria occurring? Is it is it occurring because you are up regulating your your energy expenditure to meet a stressful situation and you need to produce more mitochondria to oxidize more substrates as being liberated? Or is it occurring because, you know, for for a litany of other reasons? So it's always important to look at why it's occurring there, and then also what the effects are, because it doesn't necessarily always mean it's a good thing.

Jay Feldman 52:28
Yeah, well, and to clarify, like kind of that balance that you're getting at, and when we want to be stimulating this pathway, or these sorts of stress pathways, the pathways and our adaptation is always beneficial in that it allows for survival, but is never beneficial to our long term health in that we want to be activating, actively encouraging these pathways so through stress means so we never want, even in acute situations, we don't want to be doing things that are stressful and force the activation of these things and force the Short Term increase in glucocorticoids or adrenaline or anything else because of the these negative, harmful effects. And so the the kind of flip side is that we can activate these things in the context of elevated energy first, right? So it's not that we are up regulating energy expenditure to meet a demand, but rather we have proper substrate and proper metabolic function and all the things required to drive energy production that will increase our ATP, which will end up increasing reactive oxygen species and activate the same pathways, but through a completely different context. And so again, we never want to be encouraging the activity of these pathways through stress, even if they're acutely beneficial in that they prevent us from dying. But if we're doing it by increasing our energy production, that's a different story in a completely different context, and that's what we described in those hermesis episodes.

Mike 53:53
Yeah. And for As another example, thyroid hormone will increase mitochondrial biogenesis, so that would be a state categorized by high thyroid would be different than a state categorized by high glucocorticoids and well, the catacomb means dependent. But the reason the it's not that you're never gonna have I don't think it's possible to go through life without having spikes in glucocorticoids or adrenaline at one point, so it's necessary to have for survival. Yeah, the goal isn't to push that system for mitochondrial biogenesis. It's just unavoidable that that system is like going to be activated at different points in the life, and the goal is to minimize the effects of that system and to not have it chronically activated over a long period of time and essentially deplete the body of its reserves.

Jay Feldman 54:44
And just because people get hung up on this acute versus chronic idea, doing things intentionally that are acute to activate this pathway is still harmful, still completely at odds with our physiology when it is done in. Mean, with the intention of increasing those stress pathways, as opposed to, as you said, this being a byproduct of other of things that are otherwise beneficial. That's, that's, again, an important kind of view to take, but, but we kind of explained that more detail in the hermesis episodes, and it's, you know, kind of explained some examples and the nuance there, and, yeah. And so you see, like you mentioned, the thyroid difference, right? And so you can see some of the differences molecularly in terms of, how are these things being activated? Are you blocking the electron transport chain? Are you blocking ATP production? And is that what's leading to PGC, one Alpha activity, and, you know, leading to mitochondrial biogenesis, or are you doing it by increasing ATP. So you see differences molecularly, like that, but you see the representation in the hormones. So if you're doing something that's supporting thyroid hormone activity and increasing these pathways, versus something that's increasing adrenaline and cortisol and increasing those pathways, that's a clear sign that the adrenaline and cortisol one is going to be doing this through stress, whereas the thyroid hormone, one tends to be doing it by supporting metabolic function and increasing energy production. So that's you can kind of see it on both levels, and both are helpful when you're trying to evaluate whether something is more on one side or the other. Yeah. All right, so moving on in the chronic stress side of things. They then so they're talking a little bit about things that go on during stress, and our ability to deal with stress, and how glucocorticoids are involved there. And they mentioned that glucocorticoids induce increased appetite and food seeking behavior, and they're talking about this in terms of psychological stress or distress in general. They said that stressed individuals report a preference for sweet and savory foods and binge eating. And they mentioned that these metabolic effects are essential in replenishing energy reserves acutely after stressful activity, such as intense exercise. Then they say, however, craving for high sugar, containing in fat, containing comfort foods during chronic psychological stress can be deleterious. Comfort foods appear to reduce anxiety by reducing activities of the HPA, the hypothalamic pituitary adrenal axis and of the angiogenic corticotropin releasing hormone CRH system of the amygdala. So they describe that basically having carbohydrates and fats, which we consider, especially together, to be comfort foods are really effective at turning off our stress systems. Of course, they are caught in this idea that that is going to lead to fat gain, and that's what they say afterward, that that's why that's actually bad. But we've explained why that's not the case. I'm not going to, you know, we've had, you know, multiple episodes describing that, but, yeah, turning off the stress systems when they get activated. By replenishing fuel and replenishing energy is the absolute best thing that you can do. It minimizes the stress. And they're basically describing that our own reasons for having hunger and taste preferences toward those things is because they're really effective at producing energy, turning off the stress systems and stopping the stress and so, yeah, they're kind of phrasing it as a good thing in the short term and a bad thing in the long term. But I think it's kind of a misguided view, a very common view, but we've, you know, kind of explained why that is a not what causes fat gain.

Mike 58:17
Yeah. And the something interesting to point out, I think that I have a article on my computer here, and it's like, it's titled something along the lines of, like, using like sweet foods or sucrose decreases the stress system in like IBS patients or something like that. There's an article around that, and then there's also articles about using sucrose in babies for pain, because it lowers the stress response. I don't essentially the from my perspective, taking in carbohydrates and fat signals to those other hormones, the catecholamines and glucocorticoids that you don't need, we don't need them as much to liberate the substrate, because we already have it coming in now, right? Whether this causes fat gain or not towards the abdomen. I actually think that it doesn't particularly depending on what foods that you're reaching for, um, what? What you actually see the re the other thing they say in the next line is to say the shift of caloric intake to carbohydrates and lipids, together with a high concentration of glucocorticoids and insulin, move fat depots from a more peripheral to a more central distribution, leading to abdominal obesity and associated increased comorbidity, metabolic syndrome, type two diabetes and cardiovascular disease and mortality. Okay, that's does that happen? Yes, but you don't need to have carbohydrates and lipids together with glucocorticoids to do that. You could just have glucocorticoids, and the glucocorticoids will do that themselves. And we talked about this in the fatty liver series. Essentially, the glucocorticoids caused fatty liver by liberating the fat tissues from the fat fatty acids from the fatty tissues of the body, and then over flooding the liver with those fatty tissues. And then. It winds up creating an abdominal obesity, or visceral adiposity. So the glucocorticoid hormones will do that themselves. I don't think that it's just the shift the increased consumption of carbohydrates and lipids. Now, if you're going to increase your consumption of those things, sure will increase your body fat. Sure it will, especially if you overeat on those things. However, what I think it is more likely here is, if you over consume a lot of the garbage processed foods during these states, which are often concocted to be sweet, Fatty, etc, at the same time, you can cause other metabolic aberrations and then increase your body fatness with those and I think that, I think that people tend to see that right when they come from low carb or keto, and they hop into like a more metabolic or bioenergetic approach. A lot of the food choices that can be discussed in that in that frame are, to some extent, processed foods like so, and it's not that they're necessarily bad, but coming from that state, there's already a predisposition with those elevated hormones. And then if you're having any gut issues or things like that, you're you can exacerbate those problems, which is why the recommendation from our end would most likely be to focus your carbohydrate intake on fruits and fruit juices and things along those lines that are less likely to cause it a microbial disturbance, while simultaneously providing nutrition and vitamins and minerals and turning off the stress response. Because you want to have the carbohydrates and fat, you want to turn off that stress response. That's the stress response is driving the adiposity. So if you don't turn off the stress response with carbohydrates and fats, what do you do? You just continue to have the stress response, and then you continue to still put that central adiposity on and develop all these other issues, maybe with slightly less body fat, if I don't know, maybe not, because, depending on the essentially, what it comes down to is, what's the carbon fat source that you're using here you need the carbs and fats to turn off the stress response and replenish stores, and you Want to do that, but you want to make sure in this state, you are in a in a delicate metabolic situation, because you have these chronic elevation of these hormones. You want to make sure that you're doing it in in a intelligent way, instead of, you know, a kind of free for all type of way, and focusing on less nutrient dense carbohydrate sources and fat sources that may also be problematic for the microbiome, and depending on the fat source, may actually make the mitochondrial situation worse. So it what it I guess, the key points to drive home here, what is actually driving that movement towards the metabolic syndrome, cardiovascular disease, etc. It's the the extended stress response from the glucocorticoids and catecholamines. What turns that off? Carbohydrates and fats. What do people crave when they're under those stress responses, carbohydrates and fats? Why? Because it turns off the stress response. What that means is using carbohydrates and fats is actually helpful during a stressful period, but it's important to use the right types of carbohydrates and fats so that you can minimize the extended effects of the these hormones, because you're in a kind of a delicate situation metabolically, and that's essentially what it comes down to. I disagree with their interpretation here overall, because they kind of blame it on the combination. And it's not necessarily the combination, it's more that hormonal pathology.

Jay Feldman 1:03:23
Right, and all the things underlying that which you were getting at, the things that inhibit energy production in the first place, which are going to cause substrate to be driven towards fat, that's what we focused on during those weight loss series, that weight loss series. And it's funny, because they completely contradict themselves, right? They say carbs and fats are really effective at turning off the stress response and turning, you know, decreasing glucocorticoids at those higher levels, you know, at the like, higher up, at the things that, you know, the hormone levels that increase the glucocorticoids at the first point in the first place. And they say, Well, when you have carbs and fat and high stress hormones, then you're going to increase fat gain, even though they just said that those things decrease fat gain. So there's a missing piece there, that is a really critical one, which is that if you are having adequate amounts of carbs and fats, but you still have high stress hormones, that is a sign that you are not actually using those carbs and fats efficiently in order to produce energy and turn off the stress hormones. And that is a sign of dysfunction, of metabolic dysfunction, and that would need to be addressed, and that's what you were getting at that that can happen in people who are chronic dieters or coming from low carb where they've got the really low thyroid activity, really high stress hormones, generally low reproductive hormones to begin with, plus maybe a gut issue, right? Endotoxin is really effective at blocking that conversion energy, which is why it's so tightly associated with metabolic dysfunction. Polyuntaturated fats, the same thing. So if you are having those things together, yes, it'll cause fat gain, but it's not because of the carbs and fats. It's because those carbs and fats are not being properly used. And so it's it's not at all a combination. It's not even it's not overeating, either over feeding against or overeating would still be a result of not being able to produce energy effectively from those substrates. So the issue comes back to inability to properly produce energy, or efficiently produce energy, not the presence of carbs and fats.

Mike 1:05:09
Yep, and the presence of carbs and fats here would actually be helpful, because they'd be they would lower the stress response and hopefully help you to get to a place where you're able to produce adequate energy.

Jay Feldman 1:05:21
Yeah. So anything else to add to this part? Nope. So this next piece, again, a kind of smaller detail, but something I think is worth mentioning. So they say, if psychological stress can lead to oxidative stress, the opposite seems also to be true. So the opposite there being that oxidative stress can lead to psychological stress, and they say over expression of two antioxidant enzymes, glyoxylase and glutathione reductase, one in the mouse brain, was associated with increases in anxious behavior. Thus oxidative stress can could contribute to the complex control of anxious behavior and related conditions such as panic disorder, obsessive compulsive disorder, post traumatic stress disorder, and social and other phobias. So there's a few reasons why I wanted to highlight this. So I want to discuss this. One is this relationship between our mental health, our psychological health, how we see the world, our mood, and what's going on physiologically. And they're talking about it in terms of oxidative stress. There's other features of our physiology as well that are going to directly affect those things, you know, those things in terms of our mental health. And we described this before. I'll link back to the episode where we talked a little bit in more detail about mental health in terms of our physiology and otherwise. But yeah, I think it's a really important piece to highlight. And then I also like this is very similar to what they said earlier in terms of the diabetic state and the cardiomyopathic state, where there's elevated defense reactions that are seen as beneficial from the hormetic side, where they mentioned that elevated antioxidant enzymes is associated with increased anxious behavior, which they're saying is the result of increased oxidative stress. So they're basically like, that's again, flipping. It's completely in contradiction with the hormetic view. It's saying that active, activating those pathways, and increasing the antioxidants to the point that they've put out the oxidative stress. Right? It's just showing elevated antioxidants, just elevated adaptive pathways, and that was associated with, like, a degenerative state that resulted in anxious behavior. And so it's cool to see that they're doing it physiology, like kind of physiology, physiologically first and then that affecting psychology. But also just funny that they're highlighting the increased adaptive response as a sign of the oxidative stress and as a sign of dysfunction. And I will say what, you know, they mentioned panic disorder, OCD, and, you know, a handful of other anxiety related disorders. And I've certainly seen dramatic effects in terms of mood, in terms of anxiety and other mental health related issues, depression, from getting physiological things in place, and so I wanted to highlight that as well. But yeah, do you have anything to add to this?

Mike 1:08:06
Nope, it's pretty I mean, this one's pretty straightforward, essentially. I think the one important thing to add, actually, is that the mental function, mood, thought processes, etc, are directly dependent upon the physiology. And I guess, I mean this, there's the whole argument of like the brain or the mind being separate from the body. I'm not gonna Well, I guess, I guess I'll cover it here, but I don't think that there's any separation. I think that consciousness is a product of the physical structure and the processes that are involved in that structure. So if you alter those processes, then you can, then you send, you effectively alter the consciousness. There's not some separation where you just have mind, and then you have tissue in the mind and habits of tissue, it's the mind is a product of that tissue. So the when you have situations where the tissue is undergoing oxidative stress, and largely the oxidative Well, the oxidative stress can be drive by a lot of things, but usually it's something in some perturbation and the metabolic function, then you also see subsequent perturbation and mental function. So I mean, it's not surprising here that that the things go both ways that oxidative stress can cause psychological issues and psychological issues, psychological issues can cause oxidative stress. And like that, there's a blurred line between, between what's causing what I think in a lot of circumstances, for sure, yeah, and they talk about it above, they say, prolong physical and psychological stress, because each and each induce oxidative damage. And one recent study psychologist psychological stress in mothers and children affected by chronic illness was associated with increased blood concentrations of oxidative stress markers and genetic modification, namely, telomere shortening. Telomeres are a different story, but they go on to basically say that Mitochondrial DNA is. Um, is much more prone to oxidative stress. So they would also expect that the mitochondrial DNA would have been, would have had issues as well. So just something interesting to note there, and I guess a little like, uh, I mean, philosophical uestion to some extent.

Jay Feldman 1:10:14
Yeah, yeah, yeah. And something we did dig into in that previous episode, mental health kind of talking exactly as you said about there not being such a separation between mind and body, so to speak. But what you were just mentioning there is a nice segue into this next feature, feature here, which is, we're just going to talk about this for a brief moment, but talking about kind of inheritance of the stress response through mitochondrial DNA. And we've talked about this, we've kind of talked around this before. We haven't done a deep dive yet, but we're going to in terms of heredity, evolution, genetics, but basically, kind of here, what they're describing and highlighting and illustrating is that our environment directly affects our health through all these mechanisms that we're describing that center around energy availability and that then does get passed down as a way to further adapt to the environment. And they talk about that happening through mitochondrial DNA. And so they're talking about mitochondrial DNA haplogroups, which are just kind of sets of of mutations that have occurred in response to an environment. And so here they describe haplogroup H. And so haplogroup H, the most common in European populations, has been associated with enhanced respiratory chain activity and more uncoupled mitochondria. These qualities would enable the additional heat generation required to adapt to colder climates during evolution, as well as the enhanced ability to fight infection, hence offering a selective advantage that would explain the predominance of that haplogroup in European populations. Indeed, recent provocation, provocative findings connected mtDNA, mitochondrial DNA haplogroup with sepsis associated mortality, namely, the haplogroup H was a strong independent positive predictor of disease outcome in patients admitted to the intensive care unit for severe infection. These intriguing findings open new frontiers mitochondrial and population genetics. And again, something really important to highlight here is that this was environment first. So it's not like somebody has just randomly gotten some gene and they're stuck with it. Instead, this is all just basically looking at our genes as a way to adapt further to our environment, and it gets passed down, but can continually change, and that's what they're describing here, something that happened in a way to adapt to colder environments and forcing more heat generation, and also happens to be better at fighting infections. And I don't think those things are so coincidental, right? Because you're going to be much more susceptible to infections when you have lower body temperature, when you're in a colder environment, and when you have to make adjustments in order to deal with the cold, meaning driving more energy toward generating heat as opposed to generating or more substrate toward generating heat as opposed to generating energy. There's an energy cost there. And so that choice, you know, if you only have a certain set unit of of substrate available, and you're driving more of it toward heat and less toward energy, there's a cost to the energy. Then it's exactly what we talked about. If you were, you know, in the fitness series, if you were forcing excessive exercise and putting a ton of energy toward that. That's less energy for the rest of your physiology to function well. So just because there is an adaptation in this way doesn't make it good or bad, but it makes it better for adapting to a cold environment, which is part of why we would say that you don't want to be so adapted to a cold environment. And it's better to manipulate your environment so that it's warmer, whether you're doing that by having a heater in your house or moving to a warmer place, or having certain types of foods or, you know, wearing clothes on from there. But, yeah, this is an interesting presentation of what happens when you have to adapt to being better at, you know, fighting infections or dealing with cold. And they don't talk about the detriments here. They're just talking about kind of the presentation in terms of those things. But, yeah, interesting piece. Yeah,

Mike 1:14:06
I don't, I'm the most, the most interesting thing for me there is just that the interaction between environment and and the genetics, you know, because there's this idea, there's this the the genetic theory tends to, or the the theory itself is essentially that you just have a series of random mutations, and then the people who the people who have those mutations, that they happen to just be better for that environment, or whatever it is, randomly, and then those are the ones that that survive. So it's like somewhere, randomly. Some guys mitochondrial or actually have to be a woman, because it's passed on by the mother. But some women just randomly got a mitochondrial DNA mutation, and it happened to increase their ability to deal with the cold, and then it passed down, and then her children just survived better than everybody else's, which is just absurd, like the the actual idea that that's how the. Work is absolutely ridiculous. Just even saying out loud sounds ridiculous, that all those things just happened by chance. What seems more likely is that the the organism was placed in an environment, they were exposed to more cold, and then the organisms basically structure it over time, adapted to better handling the cold, and then it was passed it through. And it's, it's not just the one organism adapts, but it's the organisms adapts over a course of couple generations or so, um, passing on to their kids, different at the survival advantages and whatnot. And this is especially interesting to me that a genetic idea, or perhaps the genetic dogma would be considered here in light of the discussion of genetic of mitochondrial genetics. Up above where they say, let me see if I can find it. The first paragraph says, Moreover, enzymatic deficiency from a specific genetic alteration usually occurs when the percentage of mutated mitochondrial DNA reaches 60 to 90% depending on the mutation. So here they're, they're talking about like a mitochondrial mutation, and in a genetic in the context of genetic dogma, which would assume that you need to have this mutation occur, and then that's random. It just happens whenever, and it gets passed down, and it happens to confer some type of random advantage, and then the subsequent generations just out compete all the other generation. It just is, like, it sounds ridiculous, but then to go on and discuss that, in order for in order for a specific enzymatic deficiency or a change in the mitochondria to to like function to occur, you need to have 60 to 90% mutation of the mitochondrial DNA. So you'd have to have a massive alteration in the DNA randomly. And the when they talk about the alterations mitochondrial DNA here, the way they discuss it is through oxidative stress or damage and actually, actually not being a good thing. So you need to have some type of, like, terrible circumstance to drastically mutate the mitochondrial DNA, and then it's a somehow confer some protective advantage randomly that would then be passed on to future generations that out compete other generations. Like, the whole idea is just insane, but it's more like the or again, the organism goes into the environment, and the organism starts adapting to that environment. And over generations, you start to see changes that seems way more likely and makes much more sense overall in the context. And I think that, you know, I think we continue to see evidence for that, and I find it, I mean, that's why I highlighted that point. Personally, I found it very interesting.

Jay Feldman 1:17:40
Yeah, and there are, there is, you know, other evidence for that too. You know, where they change the environment of different organisms, and see very clear, distinct changes in in mutations and, you know, changes in DNA expression that completely change even the outward appearance of the organism. So those are things again we'll have to dig into when we get into the Evolution Series, something that I'm excited to do at some point, but it's kind of keeps getting pushed farther down. But there is some other great evidence for it, too. Of course, as you were saying, this could be explained by randomness. It doesn't seem like it makes a lot of logical sense, but there is actual good evidence that it is not induced by randomness that we'll have to dig into in the future. Yeah.

Mike 1:18:21
Now the randomness just seems highly improbable.

Jay Feldman 1:18:25
Just Yeah, well, and there's a lot of evidence that it's not even the case at all, like that is not what's responsible for it. But yeah, yeah, even on the surface, doesn't seem to be very logical or probable at all. So wrapping up here, I think the only other thing to mention was just kind of their conclusion here, I think we mentioned this earlier, they still subscribe to the hormetic model up here. They're talking about caloric restriction being a good thing. And, you know, it's really crazy considering the rest of the paper, because you would think that it would make it clear that that's not the way to go. But anyway, they conclude here, and just wanted to highlight what they state is that low power or burned out mitochondria are associated with numerous diseases of public health significance, such as sepsis, the metabolic syndrome and type two diabetes. Thus, it appears reasonable to envision a rapid increase in efforts to exploit the unique properties of mitochondria and the development of selective therapeutic agents aimed at increasing mitochondrial resilience distress and preventing or alleviating the burden of many stress related disorders. And, of course, the kind of funny part here is that, you know, they have to come back to some sort of commercial pharmaceutical type reasoning or or solution, right, where they mentioned, what was it the development of selective therapeutic agents aimed at increasing mitochondrial resilience to stress and alleviating the burden of stress. And it's like we don't need some sort of very particular pharmaceutical agent to do those sorts of things. You can just do it by eating good food, avoiding polyunsaturated fats, fixing your gut health, eating enough food, not calorically, restricting, moving, exercising, but in a. And a good amount, not just to burn excessive amounts of calories, reducing the excessive stress in your environment, and not from there. And of course, there are certain supplements, certain compounds that are certainly helpful along the way. But the broad solution here is not just to be taking some pill that they come up with, which undoubtedly will have to come at a cost if it is making up for these things, because unless it is literally energy in a pill, unless it's literally some sort of absorbable ATP that you can take or infused or something which is just kind of with the way things work, is very far fetched for that to actually work in a way that would help, because it would have to get into the cell, and you don't want a lot of ATP just kind of circulating and things like that. So that's not really reasonable, at least currently. And if you are going to try to stop the adaptation to stress and avoid the energy depletion that happens or or the response to the energy energy depletion and will have to come at a cost, you can't just skip those steps, because they're as they as they described in this paper, that's how we adapt, that's how we survive, that's how we respond to these things, so that we we can continue to function. So we don't want to block anything like that, and the only real way to improve resilience to it is by supporting our ability to produce energy. And so of course, there could be some therapeutics that help with that. Maybe they're going to block certain aspects of polyunsaturated fats, or maybe prevent them from being integrated into the cellular structure. Maybe things to block endotoxin absorption and whatnot. So those things, I mean, if you're thinking about it in those terms, there could be things that help, and obviously, a lot of the supplements that we talked about help in those sorts of ways, or help in other ways to support our ability to produce energy. But if the foundational things aren't in place, those things can only help so much.

Mike 1:21:45
Yeah, yeah, it's environmental manipulation. And like, there's a there's a you can affect the organism directly with all these random, obscure compounds, but you can also just make sure the organism lives well, which is ultimately what the outcome is good food, low stress, or decreased stress in environments with lots of different types of interesting stimulation, relationships for humans, relationships, sunlight, etc, like, I think those things go a long way more so than this random mitochondrial gene therapy. The other thing is, a lot of the stuff is like, a lot of the problems in the chronic disease, stuff that are discussed in these situations, they don't have to develop. The the fact that they are developing is act like, clearly aberration, and that wasn't seen before the newer and a lot of this, a lot of the stuff is related to current environments, excessive amounts of stress, and then also just pollution, and then crap diets, just like absolutely crap diets. So and a lot of that can come from a lot of people's a lot of a lot of these solutions can come from adjusting the diet and adjusting the lifestyle and at the most basic level, and then afterwards, then you can try to do more specific things, if more, if there is more needed there, depending on how far gone the an individual system is, but the foundation, as you said, the foundational components have to be there first, because those are the things that went wrong in the beginning. I'd say nine times out of 10 to cause the dysfunction, the actual genetic mutation. Problems like the genetic diseases are extremely rare. They're extremely, extremely rare. So..

Jay Feldman 1:23:31
Yeah, and when you consider our modern environment, typical things, where things are headed, it's, you know, maybe for maybe the best solution currently is looking down that pharmaceutical route, because it's only getting because it's only getting harder and harder for people to create supportive environments around them, unfortunately. And of course, like I think we all still can, and I think there's always a lot that can be done, but for the average person who is just kind of stuck in in all of it, you know, maybe a pharmacy, some sort of pharmaceutical, that'll block the effects of PUFA, is going to be better than nothing. But I nothing. But obviously, as you're you're saying it's not fixing the root of the problem, and none of these things would be problems in the first place if we created really supportive environments. But yeah, it's unfortunate that that's really not what, not the way that things are oriented right now. In fact, they tend to be oriented the opposite way.

Mike 1:24:20
Yeah, yeah. I think it's a it doesn't. It's not that the, like, these different pharmaceutical options or supplement options are bad. I just don't think that they're foundational for for most situations. That's all so I think a combination is helpful.

Jay Feldman 1:24:36
I'm not, I'm like, kind of not saying it tongue in cheek, but I'm not like, actually saying that that's a good solution. It's more like things are, like, with where things are at. It's, you know, things are, unfortunately, so far from optimal that, you know, I guess we're just kind of left with that. That a much worse solution, if you want to call it that, you know, Band Aid kind of approach. But yeah, I'm, I think that is like, I'm. Just, I'm just, it's supposed to be more of just a point, kind of a critique about where things are at societally, as opposed to actually support for that mode of intervention.

Mike 1:25:10
Yeah, well, I mean, the mode of intervention they discuss, they're kind of, like, they get extreme right, like, mitochondrial DNA transplants and like, like, giving mitochondria, like, a mitochondrial transplant, like, it's the it's the same, let it's the same. Western medicine ideology around how to do things, just like, now it's just getting to, like, like, more minute levels, right? So it's like, it's your heart, is your heart's not working. So we're not going to transplant your heart. We're going to transplant your heart's mitochondria. It's always just, like, we're going to cut something out or and give it, like, replaced with something else. Or we're just going to, like, up regulate the PGC one Alpha pathway, or the tfam pathway, or whatever it is, like, it's always some, it's always this, like, very reductionistic. We're going to hit this one pathway and just solve all the problems, looking for some magic bullet. And it, I mean, it makes for like, endless amounts of research, but I haven't, I'm not seeing, like, we're not seeing these magical things happen from these new fangled drugs or whatever, like the immunotherapies and whatnot that that have been promoted.

Jay Feldman 1:26:20
And as you're kind of getting at to so often, when it's advertised as the thing that's going to work, the side effects are just like when you look at the pathways that are being encouraged more and more the it's not getting any closer to actually being beneficial, it tends to be getting much farther away. You know, the things that interestingly and probably not surprisingly, but the least harmful types of pharmaceuticals tended to be the older ones and the ones that were used way early on and hadn't been continually manipulated and weren't as specific to just one pathway, those ones tended to be generally more beneficial having less side effects. But, yeah, the way things are headed is, in that regard, too, just tends to be worse and worse, especially when you're trying to get, you know, not even one drug for one disease, but one drug for one pathway. That's all you know that's increased in one disease, things like that. It just tends to get worse and worse.

Mike 1:27:16
Now, well, most of the most of the, the most prominent drugs that are used currently are mostly any inflammatory things that are either blocking the Cox and lox enzymes or blocking the RAS cascade, and then the other things are basically just like Pat up regulating pathways for disposals of glucose, because the most the largest problems that we're seeing Are can't cancer, but it's a little different the pathways that they try and hit. There are another story. It's heart disease, diabetes, and those are probably the two biggest ones, and then, like lung pathology, COPD and things like that, and a lot of the drugs that are treating those are blocking their cascade, blocking the locks and COX enzymes, or they're trying to stimulate some type of anti inflammatory function in the lungs. And then, besides that, obviously infections, which is antibiotics, so all a lot of those drugs are still old, or the ideology around how they should work are still old, and now they just have combinations the newer immunotherapies for autoimmune diseases or for cancer and whatnot, which they they're questionable in their effectiveness overall, and then also their side effect profile. I mean, those are very specific drugs that are blocking very minute pathways and have a whole, as you said, a whole litany of terrible side effects, like increasing risk of cancer, tuberculosis, other rare infections, etc, and then a whole host of other very questionable they're based their immunosuppressants so but all a lot of it is coming down to blocking inflammatory pathways. This is literally what the drugs are trying to do.

Jay Feldman 1:28:55
Yeah, yeah. And of course, there are different ways to do that, some much less harmful than others. Yeah, yeah. All right, that's going to do it for this series discussing the effects of stress on our mitochondria and metabolism. If you did enjoy it, 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 these show notes for today's episode, you can head over to Jay Feldman wellness.com/podcast where you can take a look at these studies and articles and anything else that we referenced throughout today's episode. And if you are dealing with any low energy symptoms or chronic health conditions, this might be related to various symptoms and conditions we've discussed today. Might be various symptoms or conditions that you've been trying to improve using stress or hormetic means. This could be things like chronic cravings or hunger, low energy or fatigue, chronic pain, weight gain, digestive symptoms, brain fog, poor sleep, hormonal imbalances. Or various other low energy symptoms or chronic health issues, and if you are dealing with these issues, then I'd highly recommend you 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, I'll see you in the next episode.