Jay Feldman 0:04
Welcome to episode 76 of the energy balance podcast, where we teach you how to live without constant hunger and cravings, fatigue, brain fog, poor sleep and other low energy symptoms by maximizing your cellular energy. I'm Jay Feldman. I'm a health coach and independent health researcher, and joining me again today is my good friend Mike Fave. Mike and I have been studying health and nutrition together for a long time now, and Mike also draws on his experiences from working within the healthcare industry. Today's episode is part two of our hormesis series, where we'll be discussing why caloric restriction is not responsible for lifespan extension, and also why the caloric restriction research does not actually support the concept of hormesis. Now, if you're not familiar with hormesis, we began discussing this in part one of this series, so I'd recommend taking a listen to that episode. But in general, hormesis is a concept that's claimed to be the reason why many things are supposed to be healthy, things like calorie restriction, exercise, various plant compounds like resveratrol or sulfurophane, as well as things like cold dermogenesis, fasting, low carb diets, ketogenic diets and on from there. And another factor here is certain adaptive responses, things like autophagy and mitochondrial biogenesis and uncoupling, which are also looked at through this hormetic lens. So we'll be diving into all of those. But today, in specific we'll be talking about how the largest body of evidence cited in favor of hormesis actually does not support it at all. We'll be talking about why caloric restriction is not responsible for slowing aging and extending lifespan, and what is actually responsible. And then we'll also be discussing the many factors that confound the calorie restriction research, including differences between the organisms that are being researched, poor research design, amino acid restriction, polyunsaturated fats in the diet, as well as endotoxin and various other confounding factors. To check out this show notes for today's episode, you can head over to Jay Feldman wellness.com/podcast where you can take a look at the studies and articles and anything else that we referenced throughout today's episode. And if you are struggling with any low energy symptoms, maybe you've been following a hormesis or hermetic type approach, where you've been doing various things with the effort of creating those beneficial adaptive responses. Maybe you haven't been doing that, but either way, maybe you're experiencing various low energy symptoms, things like chronic cravings and hunger, low energy or fatigue, brain fog, digestive symptoms, hormonal imbalances, poor sleep or insomnia or various other low energy issues, or potentially various chronic health conditions, whether those are diabetes, heart disease, autoimmune conditions or anything else along those lines. If you are dealing with any of those symptoms or conditions, 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 a 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.

In terms of some of the physiology here, in terms of The biochemistry here, of what like, we've kind of presented it as, uh, as some absurdity, because a lot of it does carry that absurdity. But there is also a lot that can be argued, for people who are saying no, like when you cause a little bit of stress, you activate all these defensive reactions, you increase your antioxidant status, you increase glutathione, you create autophagy, you create mitochondrial biogenesis. Don't you want more mitochondria there? There are all there are all these reasons that people cite for these things, and so it's so I want to talk about those and why that still does not mean that we want to be doing things with like that are in favor of hormesis or or trying to create a hormetic response. So when people are discussing hormesis and the like, what that damage and stress looks like, I think we alluded to this a little bit when talking about those when going through those studies, those figures describing that they cause oxidative stress and energy depletion, and so that's basically what's going on on a physiological level when we're using when somebody is trying to create that stress or damage they're doing so in one of those two ways, either directly creating damage and reactive oxygen species production and oxidative stress, or. Am I indirectly doing so, where you're interfering with normal energy production or normal cellular function and creating a depletion in energy. And so a very a couple of common examples here, again, we talked about calorie restriction, which is a very clear one, right, where if you're taking in less fuel, you're going to be producing less energy. You're causing a an energy depletion. And a more extreme example would be like a long term fast or starvation, where, again, unequivocally causing energy, energy depletion, and this is cited as how it's causing hormesis, but some other ones would be factors that are oxidants, that cause oxidative stress directly. And so you have various plant compounds that'll do this, and then that will cause a reactive antioxidant response. So you have all of these pathways that get involved with those responses, that that because they're involved in these and again, this is where some of that reductionism comes in, because they're involved in these adaptive responses. They're ubiquitously cited as beneficial, and their effects are ubiquitously cited as beneficial. And again, these are the mitochondrial biogenesis, autophagy, uncoupling, those sorts of things. So the process here the kind of stepwise orders. First you have the production of reactive oxygen species and creation of oxidative stress and the depletion of energy and or the depletion of energy, generally, they go hand in hand due to the nature of energy production. And these stimulate a couple things. The oxidative stress stimulates a reactive antioxidant pathway, and that this often involves some inflammation signals like NF, kappa, beta. It also includes NRF two, which is one of those signals that will lead to the production of glutathione and other antioxidants. And then you have the activation of AMPK, which is the sensor that goes off when energy is low. It also goes off when there's substantial oxidative stress. So either of those things will activate amp kinase. And then, as I mentioned, these will activate all of these backup pathways. It'll activate things that increase antioxidants. It will increase the NAD to NADH ratio, which is another one that people love and we talk about, too, as a beneficial thing. Having a high NAD to NADH ratio because it stimulates energy production and allows you to continue utilizing glucose effectively. But other people reckon it's something that's associated with all sorts of health features, and a low NAD to NADH ratio is associated with all sorts of degenerative conditions. So it's recognized as one of those endpoints that you want. But the way that the NAD to NADH ratios increased in these situations is typically through what are called NAD salvage pathways. And this involves the activation of an enzyme which is NA MPT, which is activated by any form of stress you can come up with, which will then increase. It basically just recycles, leads to the recycling of the of NAD and increases the NAD availability so the next piece there is that when you start to activate these NAD salvage pathways, you then activate the sirtuins, which everybody loves is, you know, and those are known as the the anti aging genes that you want to be turning on. And there are some others here that involve, like, activation of heat shock proteins and various other things, and all of these work together to signal for increases in autophagy, increases mitochondrial biogenesis and uncoupling. And so this is why they're cited as beneficial, because they activate these defenses. And part of the kind of the way that this has been reverse engineered to be determined as beneficial is by doing things like calorie restriction, which is known throughout the research field as the most reliable way to increase lifespan. I think it was. I think they mentioned that in that Mediterranean diet article, is defense for why the Mediterranean diet works is because it works the same way as calorie restriction, and calorie restriction is widely known as the best way to extend lifespan, and which is, again, part of why everyone's kind of jumping on this bandwagon. They all want to be like calorie restriction, and a lot of them are so. So you have this research on something like calorie restriction, which is why they regard it as the most consistent way to extend lifespan and slow aging, and monkeys and rats and and yeast and nematode and flies.

Mike 9:25
What about sapiens?

Jay Feldman 9:27
That's, I mean, that's up for debate, but people have all sorts of of ideas there. It's also up for debate, as you said, with rodents and primates too, like you talked about the issue with that, those primate studies, and there's a ton of issues with calorie restriction studies that we'll get to, but I'm just trying to explain why, like some of the evidence in favor, quote, unquote, of hormesis, some of those hundreds of studies in favor of it, are all these calorie restriction studies, where, when they do calorie restriction, they see extension and lifespan in various organisms, and they see activation of all these pathways. You see high AMPK, meaning low energy. So you see high reactive. Oxygen species, meaning high oxidative stress, you see the activation of all these antioxidant defense systems. See the activation of all these NAD salvage pathways to increase their tuans. You see increases in autophagy using increases in mitochondrial biogenesis. You see increases in uncoupling. And so you put this all together, and it's from that view, it's like, oh, well, if those things are all being seen in the most anti aging health promoting intervention, then all those things must be good and be partially responsible for those effects, and sometimes they are directly responsible for those effects, when you're looking at things like C elegans, for example. But we'll get to that. So I'd say that's one piece why people are all in favor of hormesis. Another one too, is that they'll find a couple of things. There's so one other kind of section of research in favor of hormesis is that they find that in aging and degeneration, you see reductions in autophagy, and you see reductions in uncoupling sometimes, and reductions in mitochondrial biogenesis. So then that's kind of reverse engineered to say, Oh, well, if there's less of those things in aging, then doing more of them must be better. That's another line of thinking that you see. And then the last one again, is that they find that when they knock out parts of the adaptive pathway, when they say we're going to take out the NRF two pathway, or we're going to take out your amp kinase activity. We're going to take out your ability to activate sirtuins. Bad things happen. Aging happens, degeneration happens. They the organism can't properly respond to stress. So again, that's another piece of logic that they say, Oh, well, you definitely want to be doing all these things. You want to be activating those things, because if you take them out, the organism is dysfunctional. So I would say that those are kind of the three main areas that you see in favor of hormesis is again relying on on bodies of evidence that are regarded as as like long standing truths, like calorie restriction and the pathways there. The second one being the defects in adaptation, pathways that go on in degeneration, and then the last one being studies where you're seeing the manipulation of those particular molecular pathways, and you're blocking them, and you're seeing worse responses, worse outcomes. And so people see those things and they say, Oh, well, then we definitely want to be doing these things to cause stress, because that's obviously how we got that long lifespan, and how we oppose aging, and how we don't have diabetes and heart disease and all of that. So we need to be activating these pathways. Those are the keys to health. And I don't know if you want to add anything before we talk about before we kind of like take those arguments apart and explain why none of those are really good reasons to be purposely or intentionally activating these pathways, and instead, if we actually pick apart the research properly, are reasons not to do those things?

Mike 12:49
Well, I was gonna jump into picking them apart.

Jay Feldman 12:51
I know you were, but that's waiting for it, I know. So let's talk through the problems with this view of hormesis and this idea that, you know, activating these, these stress pathways with, quote, small amounts of stress or damage is beneficial. And there's a lot of different angles to consider here. I want to definitely talk through a lot of the research, you know, outline, you know, talk through the problems with those three things that we just mentioned, as well as some others, some other factors. Of course, we've already talked a little bit or we, you know, especially to start off, we talked about how arguing in favor of this view also means that you're arguing, at least for the most part, in favor of a lot of other things that you know, a lot of people might not be on board with. As far as the idea that various chemicals in our environment are hormetic. Chemicals in our food are hormetic, things like mercury and arsenic and on from there, things like various chemotherapeutic agents, ionizing radiation, cigarette smoke, alcohol, endotoxin, that these are because all of these things are activating the same pathways, and, according to a lot of the research, having the same hormetic responses. So that's it. Is something again, I want to highlight here, when we're talking about various issues when it comes to hormesis, is that when you're arguing for these physiological processes as being beneficial, you're also arguing in favor of the exposure of us to these other things, unless you have some reason why you would need to exclude those things. But in doing so, you have to exclude that these pathways are universally beneficial, regardless of other problems caused and on from there, which is generally what's you know, what those in favor of hormesis are arguing for, not, I should say are not arguing for they're arguing that these things are universally beneficial, activating these defensive responses. So that's, that's a, you know, again, a first piece that I think is important to emphasize. Do you want to add anything there?

Mike 14:48
No, I don't have anything to add to that point there.

Jay Feldman 14:50
=Okay, so the main point that I want to like, the main kind of thesis, I guess, against this view of hormesis. This from my end, would be that damage and stress do cause a physiological, adaptive defensive response that helps an organism protect against future damage. Damage protect against future stress. But the main argument that I would make here is that this is not beneficial in terms of the long term health and capacity of an organism, whether that's longevity or opposing aging or opposing degenerative conditions, or all the opposite things supporting optimal brain function and just optimal health in various ways, I would argue that these things do not lead to that, and instead, actually do the opposite. They actually lead to aging. They lead to degenerative processes and do not extend lifespan in a meaningful way, and on from there. So that's kind of the thesis that we'll be defending here and explaining the problems with the hermetic view.

Mike 15:53
Well, I think it's also that the benefits that they're seeing in these different scenarios aren't necessarily due to the damaging effect there, and there may be other factors explaining them. So you had the three different hypothes, or pieces of hormesis, which was the calorie restriction reductions in adaptive responses in states of aging and degeneration and then if you're blocking the adaptive responses, you wind up causing issues. It's like there's explanations for for all of those pieces that don't have to be viewed through the the hormetic lens. They if you look at them in in a variety of different ways, you can find in in what you would find in the research as well is that the general explanation is kind of, as far as from a hormesis perspective, is very simple. It doesn't really look at the nuances in those in the pictures. And so then it can lead to kind of skewed interpretations, where, as an example in caloric restriction, it's like, oh, just decreasing how much you're eating make is, is what leads to longer lifespan. And as we'll find in a second, you're going to read some quotes for us where it's like, it's not necessarily decreasing how much you're eating, but, and as we already discussed, it could be what type of food you're eating, but then it can also be what, what are you comparing that decreased food intake to? Then that's that's a really huge piece. So that's an that's just, those are just quick examples of the nuance aspect of this. And I think, and as we talked about before, like the the frame or the context or the lens of hormesis, doesn't allow you to interpret things in these other, these other pathways, or come to make sense of these things in a different lens. So it's important to look at, okay, we're seeing in this study that caloric restriction is having beneficial effects. Then the next it's not. Then, okay, do caloric restriction? The next question is, how is it working, and why? And so that's, that's what we're trying to get at. Because we're not denying that in some of these studies, you do see a benefit. There's no question about that. We're not saying the studies are wrong. We're saying, what is the interpretation of these studies that make sense in general? And we're basically it's an argument against the idea for Mises being the piece that makes sense.

Jay Feldman 18:14
Yeah, yeah, that. That's such a huge point. So so we're not necessarily saying that various interventions, whether it's caloric restriction or fasting or exercise, don't have some sort of benefit. But the question is, how are they doing it? Are they doing it because the stress or damage caused by those things is causing an adapt, an adaptive defensive response that accounts for those benefits, or are there various other reasons that can fully account for those benefits that have that are maybe even happening, and we'll argue that are happening despite the stress, not because of the stress. So, yeah, that's, that's a really good point to highlight there before we kind of dig in. Yeah. So with that in mind, yeah, let's start talking through some of those. You know, those three main areas of research that are point that are pointed to in favor of hormesis and the first one being calorie restriction, as you know, as we talked about earlier, being the universally acknowledged and agreed upon intervention for reducing aging, extending lifespan. You know, we know that. And again, from the hormesis argument, this is happening because of stress, and it's able to cause life extension. And all sorts of organisms, of course, extending to humans, based on these mechanisms. And there's a lot of problems with that research, and we'll start so some of it is kind of separated based on what organisms are being looked at, and then part of it is also separated based on, even in certain organisms, what is actually accounting for the benefit? As you said, is it the stress, or are there other confounding factors that are responsible for benefits that do not go through the or do not fall under the hormesis? Yeah, fall under the hormesis umbrella. So let's start with those lower organisms. A lot of the calorie restriction research comes from these lower organisms. And lower organisms are used in research a lot when you're. Trying to understand basic mechanisms and then apply them to, you know, higher quote, unquote, organisms like mammals and, you know, trying to extend these pathways into different circumstances. But the problem is that a lot of times that's not valid for various reasons, and that definitely comes into play here with the calorie restriction research in terms of longevity.

Mike 20:21
There's everything's taken out of context with all with the comparative studies, and that's so it's like you seeing an effect in one type of animal, but what's the context of that animal? And the same thing goes with the vet, some vegetarian arguments, and we've talked about that before, but yeah, it's you have to always put it in context. It always needs a frame for which to make sense of it. If you can't just be making sense of the point in space and nowhere.

Jay Feldman 20:44
Yeah. No. I mean, that's a great example, right? A lot of the people in favor of hormesis are not in favor of vegetarianism, and they would be very quick to acknowledge or agree that just because a vegetarian diet is better for a cow or for an elephant and they're big and strong does not mean that that same thing will happen in a human who goes on a grass based diet, you know. Yeah, so, and you see that same comparison here, which is a great point. So to dig into that a little bit, again, a lot of the caloric restriction research has started and is based around what's called C elegans, which is a very small, microscopic nematode worm and a very kind of, as I said, basically like a lower organism. And what happens is, when you introduce any stress, including calorie restriction, to this organism, you see that there's a lifespan extension. But what's often not talked about is the way that this life extension comes about. So I'm gonna read some quotes that describe this, and yeah, and I'll set the study in the in the notes. There's several quotes here. It's kind of long, but I think it's easy to understand, and worth going through all the pieces, because it really paints a very clear picture. So the first of these being that the dour phase and C elegans represents another global metabolic shift that is relevant to lifespan determination. Under optimal conditions, a developing worm passes quickly from a second stage larva to a third stage larva when conditions are less than optimal, perhaps because of a lack of food or overcrowding, rather than proceeding to the third stage, the worm enters an alternative stage known as dour in this somewhat suspended state, the worm can exist for up to three to six months. This represents a significant increase in lifespan, since under normal conditions, the worm survives for less than a month. So in this first quote, we're kind of seeing the main point that we're going to get to, which is that the main confounding variable here in using C elegans research is that they enter what's called the dower phase, which is a hibernation state that not only prevents their development, but also is basically a suspended hibernation state, which, as we'll get to in a moment, is not really a viable living state, and significantly extends lifespan. As I said, the worm can exist for three to six months, when normally the worm survives for less than a month. So you're extending lifespan by three to six times three to 600 to six times three to 600% and but this is not at all comparable to other organisms that don't hibernate, and also, it's not comparable to an actual extension in living lifespan. It's just a like hibernation state for an extended period of time.

Mike 23:18
It's like a sleeping pod in one of those sci fi movies where you're traveling through space and you have, like, a decade to travel, and you go to sleep in these pods, and you wake up, like, the same age, right?

Jay Feldman 23:29
Right, Yeah. It's like, there you go. Your lifespan's extended because you were unconscious for 10 years, you know? Yeah, yeah. So moving on. They say once in the dour stage, the larvae undergo a number of morphological and metabolic changes. Among these changes is the development of a hard and impermeable cuticle. The dower larvae no longer actually feeds, but rather depends on internal primarily fat stores, to maintain their energetic needs. Of particular interest is that there is also a significant shift away from the use of the Tricarboxylic Acid Cycle, also known as the TCA cycle, or Krebs cycle, and the use of electron transport and heavier reliance on alternative energetic pathways, the entry into dower also results in a nearly four fold decrease in oxygen consumption when compared to the third stage larva. So the point that they're highlighting here is that in this hibernation state, the metabolic knob, the the volume knob, is turned all the way down, basically, which is expected in hibernation, in any hibernating animal. But there's a couple important points here, and we're later on going to compare this to humans, which I do think this is actually pretty comparable, where you see basically when, like, you basically see fasting and a reliance on on the fat stores. So you're seeing increases in fat oxidation and reduces, reductions in glucose oxidation, and also a reduction in Krebs Cycle activity. They'll also be talking about electron transport chain activity. So you're seeing a huge decrease in metabolism, which is a part of this shift into a hibernation state. And. In DC, elegance and and is a direct response to stress, basically a conservation of energy. Now all this is, is a mechanism to conserve energy when, and they'll talk about this in more detail, when this organism is under stressful conditions, without a lot of food, a lot of crowding. And, you know, as we'll kind of get to it a bit, the exact same argument can be made for what happens in humans when you expose them to stress like that.

Mike 25:23
Yep, and other mammals too. You see any type of hibernation state you move to bad oxidation or a heavy reliance on bad oxidation or lower oxygen consumption. And it's it's just interesting because that same pathway is seen across multiple different animals and when moving to the hibernation state. So just interesting to point out.

Jay Feldman 25:46
Yeah and it's a two way street, right where, if you increase the fat oxidation, for example, and force fasting, where you're running on your fat stores, it shifts you into that hibernation state in the same you know, it's it functions on both Pathways because you're mimicking that state. We've talked about that before, how just reducing carb intake, just restricting carbohydrates, mimics a fasting state. And then we've also talked extensively about how in that starvation, I should say a starvation state, but in that fasting, starvation state, you turn down that metabolic dial and you see that hormonally, yeah, yeah. Thyroid activity, you know, steroid hormone production, like the reproductive hormones, and on from there, so So moving on. They then say, Indeed a recent intriguing hypothesis is that a number of long lived C elegans mutants can be best understood by tracing the various energy generating pathways, and worms in particular, these authors suggest that diversion away from the TCA cycle and the classic electron transport chain and toward alternative energy pathways, is a common element of both the dower as well as many long lived phenotypes. Nonetheless, in Worms, these alternative energetic pathways, by reducing flux through the electron transport chain, were postulated to result in reduced reactive oxygen species generation. So they're just kind of detailing what's going on metabolically when you're turning down that clock. They're just saying that in all these long lived states, you're seeing less flux through mitochondrial respiration, through the traditional pathways of the TCA cycle and the electron transport chain. And they mentioned that this is done to reduce reactive oxygen species generation. We'll get to that later on, about how we have so many so many so many of these adaptive processes are done in this way, as a defensive reaction to reduce the oxidative stress, but that comes at the cost of less energy, because you're not running through these cycles. And I mean that directly applies to uncoupling and other things that we'll discuss.

Mike 27:35
I'm just laughing because it reminds me of when, like we were talking about the STD one stuff, and I know there's been a lot of questions about that, but like creating ROS inside the cell so that the cell becomes insulin resistant like that is an adapt and it's supposedly only at the fat, but that's an adaptive mechanism to supposedly stop the cell from taking in more substrate to oxidize.

Jay Feldman 27:58
Right, right? Yeah, exactly. So it's like kind of the juxtaposition, right? Instead of increasing metabolism, that's decreasing metabolism, yep. All right, so the last quote from this study, just to cap off this part, they say it's important to note that the increased reliance on these alternative pathways can often result in energetically crippled, albeit long lived animals mitochondrial based metabolism and the TCA cycle presumably evolved in large part because the ability to produce the most ATP molecules per unit of nutrient consumed. Sorry, it's because of the ability to produce the most ATP molecules per unit of nutrient consumed, reducing an organism's reliance on such pathways may allow a worm to survive for an extended period of time in the controlled laboratory environment, but would probably place this animal at a significant disadvantage in the real world, where only the fastest and reproductively fittest survive. So again, what they're kind of pointing at, just to close that loop, is that you're shifting in this animal that we're citing for caloric restriction, increasing longevity, is entering into a hibernation state with a low metabolism, low energy production as a defensive reaction to stress, and this would result in a significant disadvantage in the real world, as opposed to a laboratory setting, where this worm probably wouldn't survive. So even if you were wanted to make the argument that hibernation was was a good thing somehow, or whatever, I mean, in the real world, they're saying that this animal wouldn't even survive then. But survive then, but that's kind of beside the point, because either way, the hibernation is not the equivalent of an actual extension of livable lifespan. It's just an extension of non livable lifespan.

Mike 29:34
Yeah, and then the lifespan that the worm does have when it comes out of the dower state it, they mentioned that it's energetically crippled, so like it, it's weakens the worm overall, even though it lives for a longer period of time. The one thing that's interesting here is you can tell the frame of the article is from a kind of Neo Darwinistic sense, because it's talking about only the fastest and the reproductively fittest survive. And then there's kind of a conflation. In there where they're saying the the ideal places to get the most ATP molecules per unit of nutrient. And the re the conflation based on the the, I guess the flow of the quotes, for me is kind of it's the sense of like, if you're gonna, if you oxidize more carbohydrate, you'll generate more Ros, but then you won't live as long. But that's not necessarily reality. From what we've talked about before, what we've gone over before, even talking in the fatty liver series, that the better you're able to oxidize the carbohydrate at the cell, the more and the more you can flux the electrons through the electron transport chain appropriately and generate ATP, the less ROS you're going to be generating, whereas you start to rely more heavily on fat oxidation. And this is something directly discussed in the SCD, one paradigm that the more have more fat oxidation you have, the more ROS you're starting to generate. And if you have any breakdowns in the flow inside the electron transport chain and at the Krebs cycle, then what winds up happening is you start getting more generation of ros. So I the state that you want to be in would be to be able to oxidize carbohydrates effectively, and with such you're generating less ROS overall. And then also you're not like again, you don't have to rely on a backup adaptive pathway to be able to manage the ROS and that's going to be, I think, a key point in what we're talking about here, because the backup pathways are there, like the sirtuins or amtk and whatnot, to help manage some of the issues of not having that flow working appropriately. But then the question becomes, let's have the flow work appropriately. And you're seeing that here with the worm, it winds up going into backup pathways that cripple its energy production and then also all of its functions, which is another piece to keep in mind there the worm while it's in the dower state, it doesn't eat and it doesn't reproduce and it doesn't develop any further, it stays in a suspended animation. And I think we can draw parallels to that to some extent, or at least loosely, to people who are running these types of paradigms where libido gets decreased, mood regulation gets decreased, mental function gets decreased. You start to see mood disorders and and like brain fog and all types of uncomfortable symptoms for people so it's you can see some elements play out, but again, it's so important with the nuance. And the nuance here, in in this argument, is the idea of the dower state for the worm. Because if you were to just read a study and you say, Oh, look, the worms that calorically restricted lived x months, whereas worms who aren't only live like less than a month or a month. So then it's like, Oh, that's great. So caloric restriction works, but when you get into the nuance and the detail, it's like, oh, the dower state basically, okay, so the worm just doesn't do anything for the majority of those months until the food becomes available again. So, yeah, it's like a bear hibernating for the winter. It's like, you want to live your whole life sleeping in a cave.

Jay Feldman 32:59
Right? Yeah, yeah. 100% 100% and, and you mentioned a lot of the carb versus fat oxidation in terms of reactive oxygen species and SCD one. So I'll link back to those studies on the Ross theory of obesity and ICD one theory of obesity, where we talked on those things in more detail, because we will be talking today about this ATP versus reactive oxygen species ratio and in terms of energy production, and that will be, that will be a key point, but it's we aren't going to dig into the weeds as much as we did in those in those episodes. Yeah. So one last quote, just talking about C elegans, kind of on a on another vein, not talking as much about crowding and and food restriction, but in TED, instead talking about various mitochondrial poisons that inhibit mitochondrial respiration, and some of these are things that are looked at to be beneficial in various circumstances. And so the quote here they state, it's well known but still surprising, that low doses of paraquat rodinone or pearsidin, a extends C elegans lifespan via increased reactive oxygen species levels. Similarly, Metformin blocks complex one of the electron transport chain and extends lifespan through a reactive oxygen species mediated mechanism. However, this seems to be something specific to C elegans, since feeding metabolic poisons has not been reported to extend lifespan and other model organisms, and metformin does not increase longevity in fruit five fruit flies either. We'll talk more about fruit flies in a second, but I wanted to bring that up for two reasons. One, it just highlighted the difference between what happens when you try to extend research in these animals to other species, where, in this case, you can use what they describe as metabolic poisons, and I think is a pretty accurate description, even though these things like Metformin are considered to be some of the healthiest under this guise of hormesis. But, yeah, you can use these things and extend lifespan and C elegans, but you don't see that in other organisms. And we've talked extensively about this with metformin, about how it. It's the electron transport chain function at complex one, increases reactive oxygen species production. And is in speaking of other things that are hermetic, Metformin is one of those things that's, you know, one of those interventions that's considered to be hormetic, and it is supposed to increase lifespan and increase glucose tolerance or insulin sensitivity and health span as well, you know, reduce aging. And a lot of people in favor of hormesis take Metformin even though they don't have diabetes. A lot of the biohackers will do this under the guise of hormesis. Yeah, and, and I like how they describe it here as a metabolic poison, and explain that that they haven't even been able to see Metformin extend lifespan and even fruit flies, let alone humans. And we'll talk, you know, it's for the same reason as everything else that we're going to be discussing, but I just like that they highlight that there.

Mike 35:48
Well, yeah, and we've, we've talked about Metformin before, and I think the Metformin is going to come full circle when we start talking about some of the plant compounds and the microbiome and whatnot, because met Metformin has other effects besides its metabolic effects that may be beneficial, especially because Metformin isn't absorbed extremely well, and that's something that I guess I'll drop that hint there, that we'll talk about in a little while. But essentially, Metformin shifts, and even within diabetics, it shifts the cell even further into that stress state, and basically is inhibiting its ability to oxidize completely through the electron transport chain. And so what winds if you're not going to do that, then you then you start to see those changes in the NAD NADH ratio, which causes the backup pathways that everybody thinks are the certs, AMPK, whatever it is to start to elevate. And it's like, Oh, that's good, because now the NAD to NADH ratio is going to be adjusted back to having higher NAD so. And then you also with metformin. The other thing you see is you do see a movement in diabetics to produce more lactate with metformin, because the electron transport chain has been closed down and so met. And people using Metformin can get situations where they get lactic acidosis, which is actually extremely dangerous. So you're seeing, essentially, it is a metabolic poison. Now it does, yeah, I'll just leave it there, because I go, we'll go too much until there's, I'll get, I'll jump ahead too much.

Jay Feldman 37:17
Yeah, yeah. And we did a, we did talk about, we did talk about that more detail in a previous episode. I'll link to that, and then, yeah, we will come full circle later, as you said, and put that in some other in some context, in terms of the gut, things that you hinted at and whatnot. But I also so you mentioned the sirtuins. And again, this is something else I wanted to highlight here. Is that not only do you have the fact that caloric restriction in C elegans extends lifespan, and so that's taken to mean that calorie restriction extends lifespan in humans, which is, as we describe, a huge problem, but then you also have the identification of all these molecular pathways as far as the mechanisms through which the calorie restriction extends lifespan, and those are also extended to human extended to humans. So you mentioned sirtuins. So in C elegans, for example, the sirtuin pathways are mediating between calorie restriction and extending lifespan, among other pathways. So then that's another thing that's extended, where they say, Okay, well, then activating the sirtuins must expend extend lifespan in humans. And then you have the next extension, which is that anything that increases the sirtuin activity will extend lifespan. So you've got these two assumptions built on an underlying very, very flawed extension from this sort of research. And we'll see that in a second. Again, they do this with the yeast studies and everything else. But that's where you start to get into the problem with focusing on these pathways, the things that we talked about already, heat shock proteins, hypoxia inducing factors, amp kinase, NRF, to all these pathways that are decided to be these extremely beneficial adaptive pathways.

Mike 38:57
And do you see the most current thing with these pathways? And I think is a good example, as well as the idea of when I mentioned is the NAD to NADH ratio. And so you have people who are trying to modulate the NAD to NADH ratio through things like sirtuins and am PK. And those are back again. That's a backup system when you have some degree of pathology going on, or maybe not pathology, but things aren't working 100% correctly, and so then the other idea too is, oh, I'm going to get infusions of nicotinamide riboside or nicotinamide mononucleotide, which will directly increase NAD. But when you look at the system as a whole, the NAD to NADH ratio is a proxy marker for how well things are fluxing through the electron transport chain. So you don't want to like my question would be, is it really that the NADH NAD to NADH ratio is what you are shooting for in and of itself? Because it was, if it was the NAD to NADH ratio in and of itself, that was something that we were focusing. Analysis that was like the thing that we wanted to adjust, or is the NAD to NADH ratio a proxy of the electron transport chain flow. So my my assumption and my perspective is more that it's the proxy marker for flow through the electron transport chain and trying to adjust it through these other pathways by raising these adaptive mechanisms or just giving more NAD doesn't necessarily solve the problem. If things aren't flowing through the electron transport chain. And so that's that's where you that's just where the nuance becomes careful. Becomes very important. You have to be very careful, because the mechanism by which you're adjusting things may it's if the marker is a proxy marker, it may not be the outcomes that you want. And you see that, you see that in other areas, as as an example, looking at cholesterol in the blood is, is the total amount of cholesterol in the blood? The actual indie Is that what you actually want to worry about, or is the total amount of cholesterol in the blood a proxy for other things going on. And then you want to figure out what the other things are going that are going on, and fix them, and then recognize, and then recognize the cholesterol is just a marker, an indicator. It's telling you, hey, something's going on, the NAD to NADH ratio. Hey, something's going on. Um. And so it's like, let's fix the underlying problem so that things are functioning appropriately, instead of inducing these hormetic pathways to get this proxy marker to be where we want to be. And that's the problem, I think, with having like focusing too heavily on proxy markers. And I mean, that's the it's essentially the hormetic and bio hacking systems is an allopathic approach of let's look at these proxy markers and then try to adjust these proxy markers. And then if my proxy markers are within a certain level, therefore I must be healthy. So it's a bunch of conflations, rather than actually getting to the root piece of what does this marker actually mean being a proxy marker, and how can I adjust the underlying levels of that, that marker in the correct direction. Instead of just, hey, I'm just gonna, I need more NAD, so I'm gonna get infusions, $1,500 infusions of and nicotinamide riboside or whatever there, I know they're expensive every week, so that my NAD NADH ratio is good, and I'm and I'm healthy. It's the same thing too. Like with glutathione infusions, it's like, I need to get more glutathione because it's in an antioxidant, whereas, like, if you want with and it's not that those things aren't helpful, but it's like you can increase glutathione by adjusting diet and and other factors in your lifestyle that are using the glutathione and then having a lack of production of glutathione. So it's like affecting those things from the top and the bottom, instead of just hitting glutathione, I think is a much more solid strategy. And then maybe in the meantime, if you had to, and I'm not recommending using, but if you had to use it, something like that, that's just the idea is getting to that nuance piece, why is, why is this happening?

Jay Feldman 42:58
Yes, totally. And that's also where you have the danger of when you're looking at these proxy markers, then you have this idea that, again, fasting anything that's where medical you know, fasting anything that triggers fat oxidation, reduces carb oxidation, causes stress on and on, that these things will increase the NAD to NADH ratio eventually. But first they do it by depleting the NAD 10 NADH ratio, depleting NAD and depleting ATP and activating these stress pathways. I think we talked about this already, how you activate amp kinase, and then na MPT, which is the NAD salvage pathway, that ends up increasing NAD and increasing sirtuins. And so you look at those end products as that was the goal. So we're okay without considering the as you said, that these are just proxy markers, and just because something increases those end products does not make it beneficial. And the way, the mechanism that through which that you do that matters, and as we're arguing, and we'll continue to explain why doing this through stress pathways is probably the worst way to do it. And it's not beneficial as a whole.

Mike 44:00
Well, And it's especially like that too, because when you see these these pathways do like fasting and caloric restriction, elevate stress hormones as well, and then lower thyroid hormone function, lower androgens, lower progester, lower steroids in general. So you're seeing like, wow. Okay, so we have these proxy markers elevating at the cell, and then we have, in some animal studies, these beneficial effects. But then it's also known that moving in these certain in these certain directions, also causes problems. And so it's like you're going to, if you go into caloric restriction, you are going to elevate the adaptive stress hormones, including the glucocorticoids, and you are going to have lower thyroid function. So then the next arguments from there that that the hormetic approach and the bioacking approach has to extend is okay, so maybe high thyroid function is bad. And then that's where you see that they're looking through this lens, and it's like, oh, so the hay flick limit and the rate of living theory, oh, they all start to make sense, because if you burn too fast, then you know, oh, then you're gonna get too much ROS and but. And then when you start seeing, okay, so if I'm going to do fasting, I'm going to up regulate adrenaline growth hormone, and I'm going to upregulate fatty acid oxidation. And then when you look at the mechanism, you see, oh, fatty acid oxidation actually creates more ROS than than carbohydrate oxidation. So it's like then. So now you have huge inconsistencies. You have massive inconsistencies in all of the approaches together, and you can't rectify them, and that's where things start to break down. Not to mention that, besides the theoretical, the theoretical machinations that we can go through here when you, when you get down to it, if you run keto for a long period of time, you run intermittent fasting for a long period of time, you there's a lot of people who start to get issues, they start to get a whole host of different problems. And there's literally forums dedicated to people talking about, hey, I did carnivore, keto, low carb, whatever it is, for an extended period of time, and I felt like crap after, you know, initially I felt great, and then afterwards I started to have problems. And so it's like, and that was us, because we were on board with this stuff beforehand, and we were, like, involved in those mechanisms, thinking about things like, oh, you know, carbs. Or, you know, carbs cause this, and we need to oxidize fat and metabolic flexibility, which, in the context of having a low carb diet means absolutely nothing. But that's fine. Um, so we started, like looking in all these pathways and plant compounds and sulfur fain and whatever else. And then you start to not feel well, and you start to, you know, you start to have all these symptoms. And so then instead of like, you know, doubling down and with your real life experience, you say, okay, maybe I have to adjust. And then when you adjust, and then you start, you start feeling, oh, I put in carbs. And it's like, oh, now I'm not getting stressed out in all these different situations. And oh my, my hormonal profile looks a lot better. Even prominent advocates are showing this, these types of things, right coming out like, I think Paul saladinos profile, his hormonal profile improved when he came off of his key ketotic diet. So and he, like, he moved off the ketotic diet because his hormonal profile wasn't looking good. And I've seen that with clients as well, and I know you have too. So it's just, yeah, it's just you have the real world results aren't matching what you're seeing in these studies, and that's because the nuance of the studies isn't being fully described. And so you start getting, there's a whole lot of conflation and proxy markers being used to look at things, and then it becomes befuddled. And then it's like, if somebody can talk through these obscure mechanisms with ridiculous names, then it's like, Oh, this guy must know what he's talking about. And and people get, I think there's this air of like, getting obsessed with the with with the language and the terminology and the all the pathways and stuff, but I've the whole context is thrown out the window.

Jay Feldman 47:43
Yeah, you see that a lot. I'm gonna link, I'll link back to those rate of living theory episodes we've talked about that in the past, about why that is not a valid theory, and other theories of aging that make much more sense. The rate of living theory has largely been, you could say, debunked, disproven, whatever, and so of subsequent theories. But yeah, we explain all that in previous episodes. I'll link to those. It's hard when we're talking through this not to extend this out to all those other areas, because it's so clear, right? Every every single quote that we're gonna be describing here is translated exactly to all those different contexts. So let's, let's let's dig back into the research and see what we can get through before we we zoom back out so on to the next lower organism we talked through, C elegans, the nematode, and one of the next ones to discuss is yeast. And yeast is another organism that's used in a similar way. But there are reasons, again, for for why we should not be extending that calorie restriction research that shows longevity, or that shows increased longevity in yeast to other organisms like humans, and what confounding factors there are. So this quote states, similarly, in yeast, a simple reduction of available glucose in the media results in life extension. This paradigm has been used as a model of calorie restriction. Caloric restriction and experimental evidence suggests that life extension under these conditions requires the NAD dependent D acetylace Sir two or cert the sirtuin two. It has also been shown that caloric restriction activates sir two activity, although the precise details remain controversial, more relevant to our discussion is that, is that this particular yeast appears to shift their utilization from glucose, from fermentation under normal conditions, to predominantly mitochondria based aerobic respiration. When glucose is limiting, this metabolic shift results in an increase in overall oxygen consumption and and yeast, therefore caloric restriction leads to longer life, but presumably higher metabolic rate. So we're seeing, again, some opposite effects here from what you're seeing in other organisms, and this has to do with the the fact that yeast tend toward fermentation as their kind of basic state when they have glucose. Available. But there again, the restriction of these things shifts them into a stress state, which for them, ends up being more aerobic based and repeat has compared this, interestingly, to cancer, basically, where, when you stress yeast out, and this is known it, it will basically extend filaments out and rapidly divide and go through prolonged cell division where it will grow and in this case, basically extend lifespan, but very similar to C elegans as doing so through stress induced mechanisms. And is not at all relatable to other organisms in this way, it's not, it's not representative of what happens in other organisms.

Mike 50:46
Yeah so essentially, when the yeast have an excessive amount of glucose availability, they will shift towards lactic acid fermentation, or, I guess it's alcoholic fermentation for yeast, yeah. And then, and so essentially, they're burning through the carbohydrate and getting less amount of energy per unit. However, when they have decreased access to glucose, they shift towards the aerobic respiration, which provides them with more, more ATP per unit of glucose that they have, or, yeah, more ATV per unit of glucose that they have and act, and it also increases the metabolic rate. Or they're essentially generating more ATP under less with a with less glucose availability, which kind of makes sense? Um, to some extent, if you if you think about it, for the for yeast, they'll flux the when they have an excess availability of glucose in the substrate, they just start running through it, yeah. But the question of how applicable that is to humans is an entirely different story.

Jay Feldman 51:49
Right, right, exactly. And that's the point here. Is that these are fermentative organisms in their in their base when they're exposed to glucose. Yeah. Moving on to the the next one, which would be fruit flies, specifically Drosophila, is the one that's that's used in modern research, which is another one where they're looking at a lot of calorie restriction. Oh, one thing I want to highlight, too, with the yeast situation, was, again, just highlighting the activity of the sirtuins as a mediator of the lifespan extension. Again, this is what we were talking about. Where you you see these, you know that just the assumptions and extrapolations from this research looking at these pathways and then trying to apply that to other situations that it doesn't necessarily apply to. And so they were kind of discussing that there, in terms of the sirtuins being being mediators. But anyway, moving on to Drosophila and then some other fruit flies as well that are all kind of studied in the same way. There's several quotes here I'm going to read again explaining why this is not as simple as just calorie restriction extends lifespan, and that we should be extending this out to other organisms. So they state here, in initial studies, nutrient restriction in Drosophila used to be imposed by the dilution of the food mixture, which tended to increase lifespan in comparison to those fed the more concentrated medium. However, the validity of the dilution based regimen was challenged by Benz's group, who showed that the increase in lifespan ascribed to food dilution was abolished if the flies fed the relatively concentrated medium were offered ad libitum access to water, which suggested that longevity extension by food dilution and insects was due to a hydration rather than a caloric restriction effect. So this is, again, like a very simple one, and we'll kind of talk about a parallel situation in rodents, where the initial research in Drosophila showing caloric restriction improving lifespan was really just that the ones that were quote, unquote calorie restricted were just more hydrated, and the dehydrated ones didn't live as long, so it wasn't actually anything to do with their calorie restriction. Do you have anything to mention there? Should I go on to the next quote?

Mike 53:50
No, go ahead, that one's pretty that's pretty obvious.

Jay Feldman 53:55
So the next one, and this is talking about kind of few other research showing extension lifespan and Drosophila when they've kind of controlled for things like hydration. So they state, furthermore, a low yeast to carbohydrate ratio, rather than the amount of food intake, was identified to be the critical, critical factor in the modulation of longevity in Drosophila and other species of fruit flies. Accordingly, in more recent studies, variations in yeast to sucrose ratios are employed to affect dietary restriction. Quote, In fruit flies, ingestion of proteins above and then they go on to state, ingestion of proteins above a certain threshold level, especially by males, has a detrimental or toxic effect on longevity and fitness, suggesting that flies have poor tolerance for over consumption of proteins. Just add some context real quick before we go on, they're feeding the flies, yeast and various forms of carbohydrates, talking about sucrose, and the yeast is the protein source here. So what they're talking about is that it's the ingestion of the proteins and the reduced carbohydrates that is the problem, and that causes lower lifespan in these organisms. And so that's kind of a mediator for the. Dietary or caloric restriction. So then they go on to say, interestingly, it has been reported recently that the longevity of ad libitum fed mice also is prolonged by a diet that is low in protein and high in carbohydrate content. And then they go on to say that the author's main contention was that longevity extension of ad libitum fed animals is achieved by alteration and the ratios of the macronutrients rather than the amount of calories. So that's talking about the rodents. We'll get back to that in a second. But just to highlight here again, with the fruit flies, that what they were saying here was that an adjustment of the macronutrients, basically where less protein and high carbohydrate supported extended lifespan, and it was not the calorie restriction that was responsible. Again, just talking through these confounding factors here, where some people, especially initially, are extrapolating from this research, saying, Oh, it was just calorie restriction. If we calorie restrict any other organism like ourselves, we'll live longer, when in reality, here was because of a reduced protein intake and higher carb intake.

Mike 55:57
Yeah. So essentially, and this is a problem. This is, again, example of problems looking at things through the lens of hormesis, where it's like, there has to be a hormetic effect that's causing this. It can't be explained by any other simple factor, which is, like, with the flies, it's like, oh, it's hydration. And then with with the with the flies here, again, it's like, or even with the mice, it's like, oh, maybe it's the because maybe it's the macronutrient of the foods. Maybe they're eating too much protein, because when they did the caloric restriction for the animals, they just dropped fat and carbs really low. So then and, and this is the any type of nutrition, any type of anyone reading nutrition research, the first critique of any nutrition study besides the, well, I guess the second critique. So the first critique of any nutrition study is that it was a questionnaire, which is usually garbage, but obviously that doesn't happen fruit fruit flies and rats. But the second main critique is like, oh, but they changed so many factors in the diets, because it's kind of hard to control all the variables. And as as we'll continue going and you'll see across all the different species, rats, yeast, monkeys, I think we talked about the monkeys previously, but when you look across all these different studies, what you wind up seeing is that it's adjustment of other factors, so whether they're having too much protein in the diet, and we've talked about having too much methionine, or not enough methionine to glycine, causing problems, or whether they're just eating like a pure Crap diet, where we talked about, in the monkeys, they gave them corn oil and sucrose and one and one. And in one caloric restriction study, and the ones that ate less corn oil and sucrose lived longer, whereas in another caloric restriction study, they gave them a whole foods diet. And like there was no benefit with the caloric restriction and now here again, now we're seeing with with rats and mice and all this type of stuff, that if you, if you give the mice, what was it? It was too much protein, and their diet, they didn't do as well, whereas, if they had more carbohydrate, and then the same deal with the with the fruit flies, and then with the worms, it was like the caloric restriction led to actually negative effects, considering the dower state. But then also the flies, if you dehydrate them, they don't live as long. So, like, all of these are kind of like, to some extent, no type of things, like, if you, if you dehydrate, if somebody lives their whole life dehydrated, they're probably not going to live very long. And then there's also the protein stuff is maybe a little separate, but it's, it's, there's other studies that have and it's known, even within the the hormesis field, that too much methionine, or certain amino acids, can actually lead to lead to decreased lifespans. Now it doesn't mean to go severely decreased methionine, because there was negative side effects of not having enough of those proteins despite living a longer lifespan. So again, yeah, that's just, there's other mechanisms besides hormesis here at play. And it's like we need to parse all that out before we just everybody starts eating 1000 calories a day.

Jay Feldman 58:52
Yeah, yeah, absolutely. And then just you mentioning that made me think of how another piece that you see here is you have all these assumptions that calorie restriction was what created these benefits, and then, as you said, the assumption is that's because of the stress and on from there. But then you have these situations of epidemiological research in humans where they're looking at people in various cultures and always pointing to this idea that they're calorie restricted, and that's why they're healthier, whether it's Mediterranean diet, so to speak, or the Okinawans, or whatever it is, they always point to this idea of calorie restriction because of this assumption built on all this research and ignorance of ignorance of these confounding variables that really make it clear that it's not about the calorie restriction.

Mike 59:37
Yeah, and in all, like the blue zone studies, and all these, in all these, so, like, I think there's the Okinawans, there's the there's a play a spot, I think, in Costa Rica, there's the Sardinians, and then there's the the abcians, the people the Caucasus Mountains of, I think, Georgia and Russia. And they all eat, like, pretty. Like different diets, but there's discrepancies about the discussion of the various elements of their diets in each area, whereas, like with the Okinawans, like you have to take into context, okay, World War Two. So, like, their diet completely changed after World War Two, and then the Abkhazian diet is a high carb diet, because I actually there was a research done on the occasion, somebody like, wrote a book on it. So I actually have the book, and I think they're, if I remember correctly, and don't quote me, but I'm pretty sure they're eating, like, 400 grams of carbohydrates a day, or something from like grapes and fruits. And they were, like, pretty low fat. So it's like a kind of flies in the face of because the hormetic crowd tends to go with like, a lower carbohydrate approach, right, right? So you have this weird mix of low carbohydrates. But like, then there's because I don't know how to, like, describe as like an amalgamation of things that, and the reason it's an amalgamation is because there is no context. And then the, then there's other spheres, like the plant based sphere, which also, which tends to rely on the Blue Zones, stuff, which the context is literally, oh, that is plant based, where, so, like, it's just, like, a very simply, some simple, basic context that just and the carnivores. It's like, oh, it's animal based. It's like no kind of, like grand underarching theory to try and bring all the pieces together, just kind of a mix of random things here and there, or a really simple idea that just extremely basic, just out of nowhere, like, oh, it's all animal foods period. Oh, it's all plant foods period. So, and that's, I'm bringing that up because that's a big comparison to the bioenergetic perspective, which actually has, like an in depth grand arching, I guess, hypothesis that can unify these different elements and make sense of them.

Jay Feldman 1:01:55
Yeah, yeah, absolutely, absolutely. I'm going to circle back to some of the research in terms of some of the higher organisms now. So you were touching on a little bit of it with rodents and the amino acids. We'll talk about that, and then also some of the primate studies as well. So within the rodent studies, there's a lot of different factors to consider, and we have talked about these in those episodes, talking about aging. And the reason for that is because a lot of these are not considered when you're looking at, you know, with all the rate of living theory ideas, and in this case, the hormesis ideas as well. So yeah, there's several confounding variables. The last study we were talking about in when regarding the fruit flies, the Drosophila explained one of the factors here with the macronutrients, just talking about how just having a lower protein and higher carbohydrate diet is enough to extend lifespan. And you see that you had mentioned this in terms of amino acids as well, where you don't even necessarily need that. But if you just restrict methionine and then also cysteine and tryptophan can be considered there as well, if you restrict those types of amino acids, that will extend lifespan on its own. So again, you see this situation where caloric restriction is not even necessary. You just can restrict these amino acids, and you see the same extension in lifespan. And then you don't even have to restrict those amino acids either. You can just add glycine to balance out that that glycine and methionine ratio and that mimics the same methionine quote, quote, methionine restriction, which extends lifespan. So this is just another situation where you you know a huge confounding variable here when you're looking at calorie restriction is that it naturally restricts amino acids like methionine, but if you just restrict those amino acids, you don't actually need to do any calorie restriction, and you have the same extension and lifespan. We've talked about that before. In a little more detail. Is there anything you want to add there before we talk about some of the other confounding factors?

Mike 1:03:50
No, there's, there is.. No. go ahead.

Jay Feldman 1:03:54
Okay, okay, so one, so that's one that's talked about a lot those amino acids, but one that, I mean, there's a couple that are not talked about as much, but one in particular is this whole ad libitum idea, or not idea, but confounding variable. And so what ad libitum means, ad libitum feeding, is that this is animals that have are free to eat as much food as they want. And so there's a quote from the study discussing how this variable affects the calorie restriction research, and they state that a further misgiving is that the control animals in these studies fed ad libitum become overweight and prone to early onset of diseases and death, and thus may not be the ideal control animals for studies concerned with comparisons of longevity, reexamination of body weight and longevity data from a study involving over 60,000 mice and rats conducted by a National Institute on Aging sponsored project suggests that calorie restriction related increases in lifespan of specific genotypes is directly related to the gain in body weight under the ad lib. Feeding regimen, in other words, like a way to summarize that is that the calorie restriction didn't increase longevity, but instead, the ad libitum feeding shortens longevity. And so when you're comparing what they describe as overweight and animals that are prone to early onset of diseases and death with calorie restriction, of course, calorie restriction will look better. Any intervention is going to look better because you're comparing it to shortened lifespan, essentially. So yeah, a huge confounding factor that, again, is another one that completely negates a lot of the calorie restriction research, at least in terms of calorie restriction, calorie restriction, and especially Hermes, is offering the benefits, but instead just pointing to mice and rats was the problem, yeah, under ad libitum, feeding of terrible food, you know, vegetable oils and refined, you know, corn starches and sugar and on from there being a problem, which I think no one's arguing with.

Mike 1:05:56
So essentially, it was ad libitum was the issue. The animals were getting fat and obese and developing metabolic syndrome for their fed ad libitum crap diets, and then, so it's like, obviously the other group was going to look better, right? And they will, they do this in other types of studies too, like pharmaceutical companies are known for doing this in their research. Will? They'll compare, they'll compare their new drug to, like a, like, a sub therapeutic dose of another drug, and then turn around and say, Look, our new drug is better. And do you have to So, like, it's the same kind of deal here, where, when you're you're looking at you have one group where it's like, of course, it's going to perform better. And so I we talked about that. This bridges into the primate studies that I talked about, I think I did. I talk about them in the previous episode.

Jay Feldman 1:06:43
You did, but why don't you just highlight them again real quick, just in terms of the specifics of calorie restriction?

Mike 1:06:47
So I'm gonna read a so I'm gonna read a quote here really quick, and then we can explain it after. So the potential importance of dietary composition to the retardation of aging with caloric restriction is reinforced by the recent idea that differences in diet composition could have contributed to the different outcomes. And the two studies investigating the influence of caloric restriction on lifespan and rhesus macaques, which are types of monkeys, in particular, the study at the Wisconsin National Primate Research Center demonstrated a longevity increase in the caloric restriction group, while no differences were observed between the diet groups and the National Institutes of Aging study. Interestingly, if we compare the diets used in the Wisconsin National Primate Research Center and the National Institutes of Aging rhesus macaque studies, it is unveiled that all of the National Institutes of Aging monkeys received a whole food diet rich in phytochemicals, whereas the Wisconsin National Primate Research Center monkeys received semi purified diets with sucrose and corn oil. Although experiment experimental validation is needed, the possibility exists at the beneficial effects on lifespan of the combination of phytochemical rich Pesco vegetarian diet diets and mild caloric restriction in the National Institutes of Aging monkeys are already maximized. So what they so the conclusion that the researchers were drawing from this still is through the hormetic lens, but essentially what they were showing was that in the Wisconsin group, the Wisconsin research group, the monkeys were fed corn oil and sucrose, and so when they were calorically restricted. The group that didn't eat as much corn oil and sucrose did better. Clearly, makes sense, right? And I mean, if take an regular American and feed him less corn oil and sucrose, you know, put him on a carnivore diet, and he's guaranteed to get better where, you know, he may get some diarrhea and his sleep may not be as good, but he's not going to die of corn oil and sucrose, right?

Jay Feldman 1:08:41
Same thing with the vegetarian diet, whatever it is, the point you're getting is any dietary invention is intervention is going to show benefits compared to standard diet, standard American.

Mike 1:08:50
Yep. So in the other group, all the monkeys, the other study from the National Institute of Aging, all the monkeys were on a Pesco vegetarian diet. So monkeys are technically mostly vegetarian, and then they had some fish for their protein, and so there was no difference between the group that was calorically restricted or not. They tried to explain it as, oh, maybe the plant compounds in the monkey's diets, like had a hormetic effect, and that's why the caloric restriction didn't show a benefit. But as we're seeing with the rat studies here, what makes more sense is that perhaps the other, the other monkeys in the caloric restricted group in from Wisconsin that were fed corn oil and sucrose, the reason they actually saw the benefit there is because they just weren't eating crap. So that's that's and this is what I'm talking about again, with the lens. It's like, we have to explain it through hormesis. It can't be through something simpler. It has to be through this mechanism of, oh, the plant compounds in the National Institutes of Aging monkeys diets that was Pesco vegetarian. Oh, that's what made that's what that's why you didn't see the difference. It's not just because the other group of monkeys at the Wisconsin research. Rich area were just fed crap diets, and the ones that ate less crap live longer. So it's like, that's that's where you see this lens, and that it happens in the research as well. So you have to be careful when you're going through it. But I think that's a great example, again, of like, the actual diet composition being extremely important. And I do want to add something tangential here, but this flies in the face of the If It Fits Your Macros, crowd BS, where it's like, you just need to have your macros and you can eat what like, and eat whatever you want, and you'll be fine. And that does just, I we're kind of talked about, like carnivore, this and that, but it's like, all of these factors from all these different diets, I think need to be incorporated and understood. Because there are, there are some p like understanding macronutrient ratios and amounts and types is important, and it's helpful. So that's that's valuable from there, and then understanding the value of different plant foods, on the microbiome and on health in general, that's valuable understanding the value of animal foods and and what they offer to your body. That's valuable understanding the like the hormetic pathways and like, for example, that excess methionine can cause issues with lifespan, and that you can balance that with glycine, that is valuable. So it's not that you need to take yourself and park yourself in a camp on bioenergetic, on paleo, on this, on that. It's, let's take all of the elements from these different areas, because every one of these dietary approaches Dietary Approaches has has value. It's not that they're all complete crap. It's just that there's some crap in with some of the truth. So you take the different pieces and then you create your own system and put everything together. From there with paleo, you look okay, there's issues with grains and beans and nuts and seeds. A lot of people don't digest them well, and there's reasons why. Okay, let's take that information, but that doesn't mean that you need to then go to carnivore, because all plant foods are bad. It's like, okay, there some plant foods have a super beneficial effect. So there's, I just want, I know that's tangential to where we're at, but I did want to, I did want to touch on that. Do you want to bridge into PUFA now too? Because I do have the study up with the rats in the PUFA group with caloric restriction.

Jay Feldman 1:12:05
Go for it.

Mike 1:12:06
Okay, so the so the study I have here...

Jay Feldman 1:12:11
Just to explain context so, so circling back to rodents, another factor that is not considered, you know, is a confounding factor with the caloric restriction research is the presence of the polyunsaturated fats in the diet. Yep.

Mike 1:12:26
So the study I'm going to read is essentially the quote that I'm going to read or talk about is that they did caloric restriction in mice that are either fed soybean oil, lard or fish oil, and essentially the mice that received the fish oil actually performed the worst. And it was related, I think it was related to increased peroxidative stress at the cell, which we've talked about before with polyunsaturated fats. And the researchers were kind of like, they didn't expect this to occur. They thought that the fish oil was going to be beneficial. So it was a interesting study. So let me, let me get to the result here. Okay, so it's basically it was its lifespan was increased in calorically restricted mice consuming so lard had the greatest lifespan. Soybean oil had the next greatest lifespan, and then the fish oil containing diets had the least lifespan. There are no differences in prevalence of Neoplasms or other major measures of end of life pathology between the three caloric restricted diet groups, thus differences in lifespan between caloric restricted lard mice and other calorically restricted groups were likely due to delay in onset or disease, rather than preventing the occurrence of specific disease conditions. Longevity improvement in the caloric restricted lard group is consistent with the membrane theory of aging and questions the efficacy of feeding diets high in PUFA to calorically restricted animals. Further, these results research, these results, suggest that lipid composition of the diet should be considered when designing diets to maximize the lifespan extension with caloric restriction. So again, what we're seeing here is that the that changing the diet in the caloric restriction studies, in and of itself, is important despite the caloric restriction so you're seeing that it's so it's it's not as simple as, oh, just eat less calories. And again, we talked about this, because calories doesn't really mean anything. Your body doesn't heat water up one degree Celsius, one milliliter of water by one degree Celsius, one at a time, it your body is is oxidizing, it through the electron transport chain. So again, calories is a proxy value. It's not a legitimate value, but our body doesn't there's the 200 years ago, or however long ago, there was no calories. There's no concept of calories right now, it's literally just a proxy for food volume and or energy. I guess food energy loosely, because, like alcohol, it has a caloric value, yet it provides minimal energy. And then that, that's where it's the same. Yeah. So there's other factors involved. And essentially, even within caloric restriction, you're seeing other factors. But here you're showing that the polyunsaturated fatty acids actually perform the worst. And in fact, the Omega three, the highly unsaturated, poly unsaturated fatty acids, perform the worst. So there's something, there's other pieces in here where they talk about this directly. And essentially they they say, they say, here we observe the skeletal muscle mitochondria from the calorically restricted phase. Restricted fish group had increased lipid peroxidation compared with both the control and the lard groups, despite consuming a diet containing twice the amount of antioxidant, T butyl hydroxychlone as the other groups, these results are in agreement with other studies showing that fatty acid unsaturation index is positively associated with the level of mitochondrial oxidative damage. So what they were saying there is that the unsaturated fatty acids increase the lipid peroxidation despite having more antioxidants present, and then that led to mitochondrial damage. Which led to mitochondrial damage means decrease energy production. So the other thing they talk about here with this, and I want to get to one piece at the end, so I can highlight that lens piece again, but the calorically so it says, when we studied the effects of dietary fat and calorically restricted mice, it was found that calorically restricted fish oil group had lower complex one activity than the calorically restricted soy group, and lower complex two activity than both the clerically restricted soy and calorically restricted large groups, a decreasing in complex one activity in the clerically restricted large group was the only difference between the lard and the soy groups. And I think the deep freeze complex one with the lard group compared to the soy is because the lard group specifically had more saturated fatty acids, which has an effect on the NADH and FADH two ratio, which we talked about before, with the I think ubiquinone shuttle between complex one and complex two, whereas the fish oil literally just lowered both complexes. And what they talk about too with the fish oil is, this is a little separate, but essentially the fish oil group had more proton leak as well, which we which will decrease ATP production. So just in the proton leak is once the mitochondria. The electron transport chain takes the carriers NADH and FADH two, it uses the electrons from those carriers to pump protons into the inner membrane, and then those it creates a gradient, or a buildup of protons in those inner membrane kind of like filling a balloon with water, and then at the what happens is you put a little water wheel at the end of the balloon that's at pace. The water flows through and drives a energy production. But with the with the fish oil group that made the balloon, it actually made the balloon leaky, or the mitochondria leaky, so the water was able to get out, and you get less ATP production. So overall, even despite the anti inflammatory effect of the Omega threes, here, you're seeing increased lipid peroxidation, decreased energy production, and actually worse outcomes in the Omega three group. And then the authors, at the end of the paper tried to discuss this in the context of, well, maybe the calorically restricted group already had like, an enough hormetic effect. So the Omega threes peroxidative effect was like, was worse because they were like, made things worse because they were already having the hormetic effect. And again, it's just trying to explain things through the context of hormesis, instead of just looking and saying, perhaps the Omega threes weren't really a good idea here. And again, even the large so the Omega six soybean oil group and the lard, which both have omega six, performed better and they were less unsaturated than fish oil.

Jay Feldman 1:18:38
Yeah. And just to add in something real quick to what you mentioned at the end, with the problem of looking all that still through that stuck lens of hormes, kind of like what we talked about and the first part here about the Mediterranean diet, how you're just like forcing everything through this lens, even when it really makes no sense. But this is it brings up a huge conceptual and logical problem that we'll get to in a bit after we're digging done digging through some of this research in terms of how much stress is the right amount of stress for causing hormesis, and if you're doing calorie restriction, but you're also eating fish oil, but you're also stressed because of your job and you're not getting enough sleep. And we'll, we'll, kind of, I'll put this in better context in a bit when we actually talk about it, but it makes it virtually impossible to apply in a real context, which is, which is kind of what they're saying here. It's like, oh, the this theory of of hormesis is sound and built, in fact, so this study can't conflict with it. Instead, it must. We must have just had a little bit too much stress. So that went a little bit past that hormetic zone, and that was the problem. It's like a bulletproof excuse, right? You know, it's it, it's a, it's, it's a way to dismiss anything that could go, that could show a negative effect. Is always too little stressors, too much stress, obviously, even though those things are virtually impossible to measure in any realistic context. But yeah, we'll kind of circle back to that.

Mike 1:19:57
Yeah. Oh, and I think that's why, that's why we, I. Pre we preface this entire podcast with the idea of allostatic load and Hans Selye, Hans Ellie's general adapt, general adaptation syndrome. Because the idea is that, like, I guess the easiest way to see it is that you have, like, a load of stress, and there's different types of stress. And then there's also, we talked about the specific effects, but the the general idea is to not create an excessive amount of stress over the system's capacity to large extent, and while also taking into consideration the the the specific effects.

Jay Feldman 1:20:37
Yeah, that, I just want to clarify. That doesn't mean that there is a right zone of stress that is hormetic. It just means that more strict, like more stress, the worse, essentially.

Mike 1:20:47
Yeah, and exactly, you know, depending on what that what the specific effects and that stress are. So everything comes down to, like, a risk versus reward type of situation, right? Sure. And this is where, and that's why context is extremely important. So like, if you slept two hours last night, and I'm going to just put in a real life example, if you slept two hours last night and you didn't eat the day before, going and doing a heavy workout is not going to be a good thing. Whereas, if you slept well and you ate well, and then you went to go do a workout, then while the workout is going to apply stress on your system, the specific effects of that workout. And I'm talking about a weight workout, I'm not talking about that. I'm going to run 35 miles a week, stuff. But the specific like I'm the weight workout, the anabolic effect, the hormonal effect that you get from that workout, is beneficial, but it wouldn't be beneficial if you were in if your allostatic load was already high. And if this is understood by people, this is entirely understood by by tons of people in the workout sphere. And also even these researchers understand it, which is just like it's implied in the research that we need to find, we need to find how to optimize how we're going to do things. And so like the idea of manipulating the environment, and for example, with the worms. It's like in the laboratory setting, where we control the worms environment, so when they're in the dower state, they don't die. It's like, yes, that is a that is a great thought process for that's applicable with extension to us, where it's like, let's manipulate the very the environment that we're in and the the resources that we have in that environment, so we can optimize our function. Let's not which is counter to the hormetic idea of let's apply all these little stresses so we have some added like adaptive process. It's okay. Let's make sure that we have access to adequate food. Let's make sure the food quality is super high. Nutrient dense, macronutrient dense. Make sure. Let's make sure we get access to sun. Let's make sure we have communities and good relationships and stuff like that. And let's build all of that to build all that out together and improve things. And it's essentially increasing, it's like goes. It kind of goes hand in hand with the increasing energy and structure hypothesis, because as we increase energy flow, we can increase complexity and structure, and things continue, can continually get better, which is a bit it is anti entropic, which is the where the hormetic, I think the hormetic approach comes from, and it's like an entirely antithetical and I think it's extremely important to recognize that, because when you start going down the hormetic approach, it does. I think it's a slippery slope of, let's just, like, stress ourselves in all these little ways that we get this, like this, this specific effect, or this, this beneficial or adaptive effect. Instead of, let's just try and improve our environments altogether. It's like it you're focusing. It takes you away from the main important focus.

Jay Feldman 1:23:35
Yeah, and yeah. We'll break that down in detail, in a little bit, in terms of how we can balance those stressor versus specific effects, and the difference between looking at it as if the stressor effects are beneficial as opposed to them being harmful and we want to outweigh them, and how that applies to situations like the one you mentioned where someone's already under stress. Because, yeah, we'll dig into that in a little bit. I wanted to add a little bit more context also to what you had mentioned in terms of this PUFA study in the calorie restriction. You were talking a little bit about the membrane saturation and unsaturation, and how the fish oil increased the permeability, because the Omega threes were integrated into the membrane structure, making it more unsaturated. We talked about this phenomenon and the importance of it in those aging episodes, because it's, it explains a lot of the other quote, unquote theory, well, a lot of the earlier, older theories of aging and how they're incomplete, and lends Creedence to the bioenergetic view. But just to, just to at least incorporate it into the calorie restriction idea. Basically, what they've found is that one of the another mediator, another confounding variable, that allows for calorie restriction to extend lifespan is that it inherently reduces the membrane saturation. So just to share a quote here, they they say that the Life Extending effect of calorie restriction. Is primarily due to its influence on membrane fatty acid composition, resulting in peroxidation resistant membranes, and consequently less oxidative damage to cellular components. So again, what they're saying here is that, through various mechanisms, calorie restriction makes the membranes more saturated, which protects them against oxidative stress, and also other factors like permeability. And this is accounting. This is accounting, this accounts for the lifespan extension. So in support of what you just mentioned, that study looking at PUFA, which was calorie restriction plus different levels of polyunsaturated fats, even if we took the calorie restriction out of the equation, based on the idea that reducing membrane unsaturation extends lifespan, you can just feed a rat instead of a huge the PUFA based diet with corn oil, if you fed them a more saturated best based diet, saturated fat based diet, that would extend lifespan. As an extrapolation from this idea, well, they saw that, yeah, that's exactly what they saw. But they but they were looking only they Kelly restricted all groups, right?

Mike 1:25:59
Yeah, but you're so what you're saying is, I know your extension was that you didn't have to calorically restrict, right? But since all the groups were calorically restricted, you're kind of seeing the same thing anyway, because they're all in that same state.

Jay Feldman 1:26:11
Yes, yeah. And I'm just saying that you would see that even if they weren't in a calorie restricted state. And it's another confounding variable that just like the amino acid restriction and the ad libitum versus calorie restriction and the macro ratio. Macro ratios just restricting the PUFA alone, which is, I haven't seen research looking at this, for whatever reason, they don't seem to like to consider that on its own, without calorie restriction, that alone should create the same benefits, so to speak, as calorie restriction without the calorie restriction.

Mike 1:26:42
Well, the what my point is, is that, and I agree 100% so I'm not there's no discrepancy there. But my point was that is that, since they did calorically restrict them, and you technically calorically caloric restriction, would increase saturation of of membranes, the fact that, when they calorically restrict them, and they fed them fish oil based and the fish oil group did like still did worse. Shows the negative impact of having highly unsaturated fatty acids on the membrane. The other thing to point out here is that the comparison groups here were lard and soybean oil, and the soybean oil still did better than the fish oil group, right? And the lard group did, I mean, did better than both, but understandably, because the lard is lower in Omega six and much higher in saturated and monounsaturated, although not that much. Um, then not that like, it has a really high proof of content compared to, like, a beef tallow or butter, macadamia oil or cocoa butter, or coconut oil, or anything like that. So it's, it's just like, it actually proves the point even further, to some extent, because you have a situation where the membranes would technically be more saturated, and when you're adding even then, like, at that point, adding in fish oil was worse.

Jay Feldman 1:27:54
Yeah, yeah.

Mike 1:27:55
So the idea here, the ex, the extrapolation here, from all of this so far is, don't be dehydrated. Don't eat a whole bunch of unsaturated fatty acids and make the memories unsaturated eat. Don't eat a lab based diet. You know, eat a, like, a whole foods diet, etc. It's like, that's and this is what we're essentially always getting at. It's like, it's these simple extrapolations. It's not that you need to starve yourself for the rest of your life and use willpower to do it, and get nicotinamide riboside infusions and expose yourself to like, cryogenic baths and like, go swim in cold water, or do Wim Hof breathing and breathe off all your CO two so you get stress responses. Like all of those things are useless to focus on, if you're focusing on, okay, I'm eating right. I'm getting sleep every night. I'm getting sunlight. I have good relationships. Like, those are the focus for lifespan, not these weird niche you know, blood flow, occlusion therapy while I'm intermittent fasting under red light, and like, running on a treadmill, like, you don't need to do all of that. It's like a tangential thought process, and just even comparing them right now is absolutely absurd. Because how, like, I guess it's not even a good argument, because there you could argue against it, but it's like, I don't know any centenarians that were doing blood flow restriction therapy and cold thermogenesis with the idea I'm going to live to 100 it's not a solid argument, so I won't go there, but yeah, it's just, it's kind of the whole like, that's the thing itself. Just seems absurd. Like, I think if you were to tell a five year old the difference be like, I just want to have my chicken my my chicken nuggets would catch up.

Jay Feldman 1:29:37
Yes. Yeah.

Mike 1:29:43
I go. My point being is that it's just like insane, and it's like, the listening to the contrast is insane in general. And even, like, even a child could tell you that.

Jay Feldman 1:29:52
Yes, yeah, logically, when you go from start to finish like that, it really doesn't, it doesn't hold up, and you don't get that. When you're just told, Hey, fast and that increases lifespan we see in all these studies, or caloric restriction, just eat less and you're gonna extend your life. You know so and that's again, big picture wise, what we're really showing here is that stress induced by caloric restriction is not responsible for lifespan extension. Instead, there's all these other variables. There's one other that, one other that we haven't talked about yet, which is the gut and endotoxin. And this is a another huge, huge variable, and there's a great study looking at this in calorie restricted mice or rats. I don't remember which it was, but it looks like it was mice, and I'm going to read a couple of quotes here, but basically what they did was they did calorie restriction, and they looked restriction, and they looked at what happened in the gut, and they found that there was all these changes to the gut, and those seem to be responsible for various, you know, another confounding variable responsible for all these benefits. So what they did was they transplanted the same microbiome for the calorie restricted plants to not mice, to not non restricted mice, and found that it had the same benefits. So they say that the calorie restricted microbiota transplantation was sufficient to improve the glucose tolerance after oral glucose gavage and to increase the sensitivity to insulin. Then the next piece is that they were looking at the influence of endotoxin, or lipopolysaccharide, which is one of the main toxins from the gut that inhibits energy production causes a ton of stress and on and on. And we've talked about this in extensively in previous episodes. And what they found was that if they just added endotoxin back in to the calorie restricted mice, it reversed the reverse the situation. And so what they just to share their quote here they say that reconstituting LPS using osmotic mini pumps at a dose of 300 micrograms per kilogram per day was sufficient to completely revert the calorie restriction mediated increase in the glucose tolerance without affecting the insulin levels during the test and diminish the improved sensitivity to insulin and cold Tolerance. LPS replenishment in the calorie restricted mice completely prevented the calorie restriction induced Browning, and the calorie restriction induced increase in m2 macrophage polarization and eosinophil infiltration. So what again, just to put that into more clear terminology, basically adding endotoxin back in to the improved microbiome with less endotoxin was sufficient to reverse the benefits from calorie restriction. Again, these even though they're eating less, if you just add endotoxin back, because what they're saying is that part of the benefit of eating less was you had less endotoxin. You just add that endotoxin back, it causes all these issues. And another thing I want to mention here, which is, in some ways, the non specificity of stress and the adaptation to stress, where they talk about how adding LPS back in reduced cold tolerance, and we're going to talk about this again, conceptually in a bigger picture, in a moment, just in terms of this idea that just because you increase your tolerance to stress does not mean that you've improved The health of the organism. But I find it particularly and we'll circle back to this idea just particularly interesting, that you stress out an organism, and all of a sudden it's able to tolerate all sorts of stress better, whether it's related or unrelated to the actual stressor in the first place. In this case, you're seeing the stressor of calorie restriction, food restriction, energy restriction, and then you're seeing it in you're basically saying cold improvements and cold tolerance because of that stress. But, yeah, we'll, we'll circle back to that later.

Mike 1:33:31
Well, I mean, I have a study for that as well, for the caloric restriction endotoxin in the gut, and I want to preface it here. So there's this particular bacteria I've talked about before is called akermensia mucinophila. And akermensia mucinophila increases the mucus production in the gut and strengthens the gut barrier, and that decreases LPS influx into the body. And so I'm just going to read, I'm going to read a little quote here. Okay, so it says the positive, the exact mechanism by which a mucin affiliate exerts a beneficial pact on health have not been fully elucidated. The positive modulation of mucus thickness and gut barrier integrity by a mucinophila. Mucinophila could be the key for its its aforementioned probiotic activities. Amy cinephile supplementation was able to restore mucus sickness and obese and type two diamet diabetic mice, where gut mucus was disrupted by the high fat diet treatment. The treatment also resulted in significant reduction of serum lipopolysaturide, which is endotoxin metabolic endotoxemia, and improved metabolic profile. LPS is a major component of the outer membrane of gram negative bacteria, and its presence in the circulation often indicates gut permeability, thus a disruption of intestinal mucus. Intestinal mucus is synthesized. So it's basically just saying that, but what they say down here was that acromancy acrementium, using a Fela mucinla, was able to do. Decrease endotoxin by 50% in mice. So with that extension here I have, oh, here it says, so the LPS reducing ability by up to 50% reduction in serum of a mucinified supplementation was also confirmed in Dio mice model. So it was a type of mice which could be due to its ability to restore the thickness of mucin layer and gut barrier function that that were once damaged by the that were damaged by the high fat diet. So when we come over here, I have an Islamic fasting study, which essentially shows according so what they did in this study was they looked at the the abundance of akermansia mucinophila and bacteriorates Fragilis in people who are doing Ramadan fasting. And what they say here is, according to our president's study, acromancy and mucinophila becomes more abundant after Ramadan fasting. Amucci is a mucin degrading bacteria which resides in the mucus and it's relatively abundant. Is relative abundance is correlated, inversely correlated with body weight. Everard et al just demonstrated that dramatically decreased levels of a mucinophila and both died and do synthetically obese mice one so essentially, all they're saying is that in the Ramadan fasted subjects, they had an increase in acromancy mucinophila, and in other studies with mice, and that increase in acromancy mucinophila is associated with decreased body weight gain and body fat gain, and also better lipid profiles. And then, essentially, what they're showing in the mice studies that a decreases circulating LPS by increasing the gut barrier. So fasting, and a lot of people, they when they do intermittent fasting, or any type of fasting, what they realize is that their gut feels a lot better. So what we're seeing that, you know, they don't have gut issues, they don't have bloating. I think George St Pierre, the famous fighter, had developed ulcerative colitis at one point, and he credited intermittent fasting with helping him out a ton. And it could be by increasing acromancy and mesenophilia and decreasing endotoxin production and issues inside his gut overall. And you're essentially seeing that in humans and Ramadan fasting, we have increased acromancy mesenophilia. And then we know through other studies that acromancy mucinophilia decreases endotoxin by strengthening the gut so that could be another explanation for the benefits of fasting, besides the fact that we've calorically restricted someone.

Jay Feldman 1:37:18
Yeah, and just add on. I know George same here was recently doing a carnivore diet with Paul saladinos advice or oversight. So just bringing that full circle. Yeah, but, but, yeah. So the point that we're getting at here is that another confounding factor is endotoxin and gut health. And again, the idea here the application being that you don't need to calorie restrict to see those improvements. There are lots of ways that you can improve your gut health and reduce endotoxin production and exposure without calorie restriction. And again, the other piece here too being that the calorie restriction is not working by increasing stress. That is not the hormesis. The stress induced factors are not responsible, but in this case, they're talking about less endotoxin being responsible. Being responsible, which is the opposite of increasing stress. It's reducing stress to it and damage to a very significant extent, considering how damaging and stressful it is to be exposed to high amounts of endotoxin.

Mike 1:38:16
So that would be a specific effect there,

Jay Feldman 1:38:18
Exactly, exactly, Yep, yeah.

Mike 1:38:21
And that's where the specific effect outweighs the stressful effect in certain situations, if you were having high amounts of endotoxin or anything like that, which would actually be normal inside the standard American diet, right, right?

And the point being that, and we'll get to this later, there are lots of things that you can do that don't come with the stress, that calorie restriction and fasting do that still have that same benefit of less endotoxin?

Yeah. And I do want to add one thing here, just the sneak peek that's tangential again, is that Metformin is great at increasing acluencia, mucinophila in the gut through antibiotic effect.

Jay Feldman 1:38:56
Yeah, yeah. All right, we're going to end that episode there and pick back up in part three, if you did enjoy today's episode, please leave a like or comment. If you're watching on YouTube and if you're listening elsewhere, please leave a review or five star rating on iTunes. All of those things really do a lot to help support the podcast and are very much appreciated. To check out the show notes for today's episode, you can head over to Jay Feldman wellness.com/podcast where you can take a look at the studies and articles and anything else that we referenced throughout today's episode. And if you are dealing with any low energy symptoms, maybe these are a result of trying something like calorie restriction or other modalities that are meant to improve your health for an extended period of time, or maybe not, but either way, if you are dealing with any lower energy symptoms, things like chronic cravings and hunger, joint pain, fatigue, weight gain, digestive symptoms, hormonal imbalances, brain fog, insomnia, or anything else along those lines, or if you're dealing with any chronic health issues again, things like autoimmune conditions, diabetes, heart disease or any. Thing on from there, then head over to Jay Feldman wellness.com/energy, where you can sign up for a free energy balance mini course, where I'll explain how these different symptoms and conditions are really caused by lack of energy, and I'll also walk you through the main things that you can do from a diet and lifestyle perspective to maximize your cellular energy and resolve these symptoms and conditions. So to sign up for that free energy balance mini course, head over to Jay Feldman, wellness.com/energy, and with that, I'll see you in the next episode.