 Yeah, so my talks, I'm gonna challenge the, I guess low carb diet, how about that? Okay, so my talk is gonna be broken up into three main parts. So if you were to start from just a regular diet and transition towards a low carb diet, so how you get there, how you get to the fat burning state, and then what happens once you're there? So the effects of having a bunch of free fatty acids in the blood and some other things. And then effects specific to certain types of fatty acids, in particular, polyunsaturated fatty acids, which is most of what I personally study. So what I'm not gonna do is to show some data and say, oh, see, it's better to have a high carbohydrate diet. Cause I could come up here and show the exact opposite. I'm sure you've all been online and you have these dueling papers thing. And so look at this data, look at that data. What I wanna do is have a broad look at what's bolded, which is fatty acids and their nature in nature, into the organism, what they're used for, and whether it makes sense that a mammal, a mammalian metabolism would want to focus on burning fats rather than sugar. Okay, so in order to burn fat at any appreciable rate, you have to go through a period of hypoglycemia. So you lower your carbohydrate intake. Your liver will defend your glycemia for a while. And so, of course, insulin will go down, glucagon will go up, other hormones, growth hormone. And many more than these four, but this is just an example, epinephrine cortisol. They all do slightly different things, but they're all related towards the objective of defending glycemia, starting to liberate other energy substrates. And interestingly, if you were to just stop eating entirely, this is the exact same hormonal profile that you would see in the blood. Increased glucagon for a while, growth hormone, epinephrine cortisol, et cetera, et cetera. So basically, to the body, initially, and long-term, at least in my contention, is that low blood sugar looks like starvation. There's not a separate way for the body to go, oh, there's low blood sugar. It just goes, oh, low energy problem. So on the left there are adipocytes, and on the right is lean tissue. And when people say that they eat to have access to their fat or to feast on their fat, you can't do that without at least some access to your lean, so you're always gonna be breaking down some lean tissue if you're getting at a lot of your fatty tissue to be a fat burner. And that's when we get into gluconeogenesis. So the big picture question about this is, why does the body insist so strongly, and at such a cost, metabolically, to make sugar from protein? And it can do this from exogenous, which are dietary amino acids, dietary proteins, or endogenous, which is your lean tissue. And depending on, now if you're eating a very high protein, low carbohydrate, moderate fat diet, you won't even get close to like ketosis or anything like that because you'll just be doing so much gluconeogenesis with those dietary amino acids. But there's sort of a seesaw effect when you lower the dietary amino acids than the cortisol, and it's cortisol that mainly does this. So epinephrine and cortisol both initiate gluconeogenesis, but mostly cortisol's the big player. It'll start to go towards your tissues and it's kind of a delicate balance. Like you can't go low enough protein because a certain amount of blood sugar will be defended no matter what. And this is just an example of how this works. Allanine is an amino acid that's a good example because it's really easy to make into glucose. Some amino acids can't get made into glucose directly. They can get thrown into the citric acid cycle. And the thing is, you basically end up with the same thing, you end up with glucose. It costs a little bit of calories, which might be a reason why people lose weight on a high protein diet because they're basically just cutting out, say, 20% of their calories in this conversion process. But the thing that you get is you get liberated ammonia, which if anybody's in the previous talk, you don't want that. It might not necessarily cause kidney disease, but it's certainly not good if you don't need that. There's no reason to have more ammonia in your system at all. Some of it gets excreted as ammonia in the urine, some of it gets made into urea, but that's a saturable pathway. And I'm sure people are familiar with the rabbit starvation. So if you're eating a very low carb diet and you're just eating protein, like the Inuit, when they just have rabbits, you can die from that. So that's the ammonia excretion. So gluconeogenesis turns on, and then you get your lipolysis, and this is where you get the big dividends from all those fat deposits you've been building up. Over the years, the main actor here is hormone-sensitive lipase, and it basically just goes to the fat cells. It's turned on by epinephrine, which was on that big four of hormones. So it's dependent on that. And of course, that's a stress hormone. So this is something that happens in stress. You don't even have to necessarily be in a low carbohydrate state for this to happen. You could just get really scared or hurt or something. You start to liberate these free fatty acids. And even, let's say you could cut out gluconeogenesis totally, which you can't. But let's say you could. You'd still be getting some gluconeogenic substrate from this because every triglyceride that is broken down deesterified releases a glycerol, which is half of a glucose. Energy speaking, one half of a glucose for three fatty acids is not much. So that's not a big concern, but just goes back to the theme that glucose seems pretty central. And it's very difficult to completely cut it out of your energy metabolism. OK, so we've gone through gluconeogenesis and lipolysis. And now you're in a state where you are not using a lot of dietary carbohydrate. You're making a little bit out of amino acids and some other things like glycerol. And you're liberating a lot of fat. And that's when these start to compete, the substrates compete, which is the Randall cycle in the cell. And this is actually why you can't. So you have to make a choice. Most things in the body, this is about as close as an on-off switch as you get. Some people say, oh, this turns on that gene. But really what they mean is it increases at 15% or something. But oxidizing mainly glucose versus mainly fat is pretty close to an on-off switch when you really saturate your body with one or the other. And basically the product of fatty acid oxidation, acetyl-CoA, and then some malonyl-CoA, inhibits at every step glucose oxidation. But specifically, more than anything else, the pyruvate dehydrogenase complex. So glucose is still brought into the cell and it is still put through glycolysis and what you just end up with. And this is another reason why I think this isn't a particularly good thing is you end up with some pyruvate that doesn't go towards acetyl-CoA and ends up going towards lactic acid, which usually just gets sent to the liver and spit out as glucose again. Which is where most of the blood sugar from diabetes comes from really is the liver making glucose when it doesn't have to out of lactic acid. But you're still oxidizing mostly fat. And one thing that happens when you're doing that is you evolve less CO2 than burning carbohydrate. And the way to measure that that clinicians use is the respiratory quotient. This is usually just a diagnostic tool. So if some researchers or clinicians wanted to say, what does this drug do to the substrate that this person or this lab animal burns, they just put them in an indirect calorimeter and measure the oxygen inhaled, the CO2 exhaled, and get a ratio. But I think there's a lot of health consequences to this. Like here we are in Boulder. And I think there's a talk tomorrow about altitude. And I think that CO2, I don't think it's a coincidence that places like Boulder have really, really much better health outcomes than the average. And even some of those mythical places, like the Hunza Valley, has anybody heard of that? They try and sell raisins from there, the Hunza raisin. I think that's high altitude too. So a lot of these mythical, long-lived, healthy places. And there's a lot of simple reasons, and then maybe some more complex, longer-term reasons. So acutely, of course, you absolutely need CO2. That's why I titled this The Product of Cellular Respiration. Some people will teach you it's a byproduct of cellular respiration. Maybe even a toxic byproduct of cellular respiration. Of course, it's true that if you just breathe pure CO2, you'll die. But what's also true is that you cannot get oxygen into the cells at multiple levels without proper CO2. So at the micro level, there's something called the Bohr effect, which is that hemoglobin holds on to oxygen, the four oxygens it holds. According to how much pressure of CO2 there is coming out of those cells into the blood. So the more CO2 there is, it kicks off the first oxygen and either replaces it with a hydrogen that goes through bicarbonate or with a CO2 itself, which makes the next oxygen easier to fall off and until all of the oxygen goes into the cell and then the hemoglobin takes some CO2 and some hydrogen, takes it back to the lungs. And the reverse process happens where the high oxygen pressure fills it back up again. And that's one of the reasons why hyperventilation or hypocapnea for many reasons, but this is the most common one you might see, is so dangerous. If you didn't know how important CO2 was, you might think, oh, hyperventilation. Now there's a bunch of oxygen, but it doesn't get into the cells at all, which is seen here. When you're not hyperventilating, this is oxygen uptake into the cells in the brain, which is really important. You've got a lot of activity, yet when there's an extremely high pressure, higher than normal, of oxygen in the blood and lower or about as close to zero as you can get just through voluntary hyperventilation, you'll get almost no oxygen into those cells, which is why hyperventilation really needs to be addressed immediately or the person could, you know, anything from pass out to have a seizure, die, and there's an even more distal reason for this, which is capillary dilation. So even past the whole getting oxygen off of hemoglobin, not a lot of oxygen, not a lot of blood is delivered to areas that don't have dilated capillaries, and without CO2, capillaries tend to, they do not stay open very well. So those are things that are generally considered acute problems, like if you're hyperventilating, oh, you have to stop hyperventilating right now. And perhaps the RQ, I mean, you know, having an RQ of 0.7, you're burning fat versus one, is not the same thing as hyperventilating at all. But I do think that things add up and there's other things that are going on, one of which is removing cellular calcium. So the brain that is not getting enough CO2, it's not getting enough oxygen, but it's also not able to stop the inappropriate firing of neurons. So whenever a cell fires, its intracellular calcium transitory goes up and the faster it can get rid of it and relax again, it's just a better situation all around. And most cellular calcium leaves with CO2 and also cellular water. So you don't really want a lot of calcium floating around for a long time. And also protein carboxylation. So it's not just for vitamin K, if you were here for Chris Masterjohn's talk. So that's a carboxylation that activates certain proteins. But there's a quasi carboxylation that happens if there's a lot of CO2 in cells and in the blood where it associates with, for example, HBA1C. So that's a protein that if it's all messed up with glycation, that's one of the diagnoses for diabetes. And there's vulnerable groups within that protein, amide bonds. And those are what get glycated or they can get oxidized as well from lipid peroxides and all kinds of things. And having CO2 floating around, it's sort of kind of a weak ionic bond associates with those very vulnerable to attack bonds and protects them. So it keeps proteins from getting all messed up. All right, something else that happens when you are not oxidizing a lot of carbohydrate and using mainly fat is thyroid hormone tends to take a hit. And there's a good reason for that. I remember, I was here in 2013 and there was a panel about low carb and there was an athlete that was doing long-term endurance athletics on a zero carb diet. And I asked him, oh, how's your testosterone? He said, testosterone's fine. Oh, how's the, how's your thyroid? He's like, thyroid's taking a little hit. And the reason why is not the fiber gland itself. So the thyroid gland itself produces a very little minority of active thyroid hormone. It mainly produces the precursor. And the real thyroid gland, really, or that makes active thyroid hormone is the liver. At least 60% of active T3 is converted from T4 in the liver. And if you look at one of the main things that blocks that, there's our friend cortisol, which is chronically up-regulated from a very low carbohydrate diet. When I say low carb, just consider that zero carb, ketogenic, something that's heading you in that direction. I'm talking about all the same thing. And outside of this process, so it's inhibited here, and outside of thyroid, outside of cortisol, just having enough carbohydrate, this is old research that was not followed up on, which is when you know it's good research, by the way. In the 70s, they just took rats and if the rats did not have carbohydrate, mostly as glycogen in the liver, even if they didn't have high cortisol, they did much less conversion to active thyroid hormone. Which makes complete sense, because the body sees glucose as pretty much a proxy for energy. So why would you make a hormone that up-regulates your metabolism and burns more energy when your organ and your gland and your body as a whole is perceiving low energy? All right, so that's what's happening from fats in general. And now I'm gonna transition into polyunsaturated fats, which basically do the same things that I consider negative, except way, way, way worse. Okay, this is data that I generated myself. This first graph at the top is a glucose tolerance test and I have mice and they're on four diets. The black bar is a low-fat control diet, just a regular mouse chow, what you would see, just not any type of experiment. And then these three diets are high-fat diets. Fat makes up 45% of the calories, which is a lot for a mouse. And the pink one is referred to as 1%, and then the green one's 15%, and the purple is 22.5%. And that refers to the amount of linoleic acid. And how I made these diets was basically, so this one's mostly coconut oil, saturated fat from coconut oil. This one's in the middle, and this one's vegetable oil. I think we used safflower and sunflower, but it's basically the same as soybean oil. Those are all really, really similar. So this one's almost completely vegetable oil like you'd buy at the store. And this one's mostly coconut oil. And this one's in between. So giving a glucose tolerance test, which is a dose of glucose that we injected from insaline solution into the mice, based on their body weight, all of the high fat groups had slower glucose disposal than the low fat group. So that was a bummer because I wanted that to be different. But when we did an insulin tolerance test, there was a difference. So this, instead of giving them a graded glucose dose, the insulin was per body weight, gave them the injection. And it was actually the very saturated and the middling diet behaved in glucose disposal like the low fat diet, whereas the super duper vegetable oil diet mice had reduced glucose disposal from an insulin dose, which is an important lesson that just because you have the same glycemia does not mean you have the same insulin resistance. It might just be that your pancreas is secreting more insulin to, and you can't do that forever. So that's why a lot of people do the clamp so that you can really accurately see the hyperinsulinemic euglycemic clamp to really see how much insulin it takes to achieve a certain glycemia. And why this happens, there's probably several reasons. I mentioned the Randall cycle before, and fatty acids don't appear to participate in that cycle at the same level. And this is one way that it was measured, acylcarnitine production, which is produced from the enzyme that shuttles fatty acids into the mitochondria, carnitine, palmitoyl transferase. Now it ends up that saturated fats, you can get them into the mitochondria without that, just not very much. But if it's a saturated fat, in particular a short chain saturated fat, it doesn't have much trouble and these liver cells in particular, they didn't produce as much acylcarnitine when the mice were on those diets, versus olive oil, which as we know is mostly monounsaturated, and then these are the polyunsaturated ones. It's not a direct line, but you can clearly see that the highly saturated fat diet was much closer to the low fat diet than it was to any of the other high fat diets. So that's something that happens with just having fatty acids in the blood and polyunsaturated fatty acids in the blood in general. But they don't just hang out there intact, they also break down. This is something that most people are familiar with, just different breakdown products. This is the end game thing here, malandialdehyde. But every time one of these conjugated double bonds gets attacked by, usually something catalyzed by a metal and a peroxide, it can either add an oxygen to that bond or break the chain entirely. And these are pretty bad customers and they end up doing things like glycation, which Glucose gets a bad name from that because it's called glycation, maybe it should be called puffaation. Because you look at these proteins or they have stuff stuck on them, it looks kind of like glucose, okay, it's glycation. But glucose isn't responsible for most of the glycation. And of course it's not responsible for any of the lipid peroxides that attach to things or chain react. And then also lipoproteins get attacked by these products as well. So if you have a lipoprotein floating around and it has a lot of puffa and then you have a lot of free fatty acids at the same time that are a lot of puffa, then you have things that can bounce off of each other and break each other down. So those are non-enzymatic metabolites, things that just happen, it's not an intentional thing, it's an accident that's happening in the blood chemistry, sometimes in the cells, but mostly in the blood. But there's also these icosanoids, this is the whole family here. Got your prostaglandins, leukotrines, et cetera, et cetera. And you can substitute arachidonic acid with other polyunsaturated fats like the omega-3s. And they will be acted on by these enzymatic systems and they'll make slightly different molecules that are either, say, less inflammatory, not always anti-inflammatory. That's usually, sometimes there's a little bit of a weird semantic game where if one thing's less inflammatory than the other and then it's called anti-inflammatory. But if it's causing inflammation, then that doesn't seem appropriate. But anyway, so these are things that are happening pretty much constitutively expressed enzymes. So it's basically the amount of puffa you have fluid and around is the amount of these products that you'll have. And some of them are considered necessary for cell differentiation and development, activation of certain metabolic pathways, but you can't get zero anyway. It's sort of like saying oxygen is necessary. Or fat is necessary. I mean, it's really, really hard to get these things low enough so that you wouldn't have enough prostaglandins to activate certain cell processes. So those are things that are generally understood by everybody right too much of the inflammatory eicosanoids are bad and of course lipid radicals and all that. But some of the most interesting research that I've found about puffas is super old and not followed up on, so points there. And this is so native virgin puffa have, they're being studied for having like hormone-ish qualities and they do, they seem to. This is a really old, so forgive this figure. It's from 1913. Looks like it's made on a typewriter. At the turn of the 20th century, tuberculosis was a very active area of interest. There wasn't vaccines yet. And it was called consumption. People would just kind of waste away and they'd be coughing up blood. Pretty much the only treatment was to feed them a lot and make them rest all the time. Just doesn't, not very convincing. So these two doctors, Joblin and Peterson, they found out that the tuberculosis bacterium, it secretes what they called soaps of unsaturated fatty acids, which is the same thing as saying salts, which is the same thing as saying the ionic form of the fatty acid with a counter ion. So these bacteria are secreting these soaps and it inhibits tryptic digestion. And they hypothesize, well this is how it survives, especially in the lungs, you get this necrotic tissue, which might be broken down pretty illitically, but if it can stop that process from happening then it has a little house from which to spread out. So they discover this and then they started synthesizing their own versions of those molecules and they found that if they did it with saturated fats, so the way to interpret this graph is this is the percent of digestion of a protein. So they throw in some protein, throw in some trypsin, sometimes other proteolytic enzymes and this is how much of it gets digested and if you start with a saturated soap, this y-axis at the top here is the concentration. So at a high concentration of the soap versus a low concentration. So all they could really get with a super high concentration of a saturated soap was a little bit less than a 30 something, it still worked at 70%, pretty good. And pretty rapidly as they decrease the concentration you got full digestion, which you would normally get just throwing the enzyme into the substrate in a tube and shaking it. Whereas with an unsaturated soap just like the tuberculosis was producing, you would get complete inhibition at a very high concentration and then in this stepwise fashion they showed that you have to reduce the concentration quite a bit to get a complete digestion of the protein. And so this got me thinking, what is one of the main, oh wow really? Okay, thank you, all right, I will hurry up. So one of the main things that PUFA is actually given out as a health food for is lowering LDL, right? PUFA lowers LDL, it's a huge selling point. Of course, everybody here knows LDL is a killer, right? Heart disease. So we really wanna lower that, but how does it lower it? So if you have cholesterol in your cell it stops SREVP which is this protein that up regulates enzymes that both produce cholesterol and also pull it in from the circulation. So if you have enough cholesterol it stops the translocation of that protein into the nucleus by blocking the proteolytic cleavage. That's pretty well understood. And that's just basic negative feedback, right? You have the cholesterol, you don't need more cholesterol. Now for some reason when researchers are trying to study how PUFA does this they're on this hunt for receptors which if you know anything about modern biochemical research or biomedical research is that's where the money is. You wanna find a receptor, that's how you're gonna get grants and stuff like that. You wanna find a mechanism, a receptor mechanism, a specific receptor mechanism even if it has 10 ligands, it's specific. And so there's the P-PARS, there's a few so-called membrane receptors I think GPR 40 and 120 that's supposedly buying these PUFA and either turn up or turn down transcription of these SREBP regulated proteins and lower circulating LDL by some way. But if you just take the look that PUFA, oh that inhibits proteolytic cleavage maybe in this other situation other than in tuberculosis well it could be just doing it that way sort of in a basically toxic fashion preventing the cell from making cholesterol even if it doesn't have any. And so I got very obsessed with this idea and I started looking for any kind of enzymatic activity that was studied with PUFA and I found glucuronosil transferase which is this enzyme that pharmaceutical companies look at. It just, it tags certain classes of drugs to be excreted in the kidneys. And it's been known for a long time that just putting naked, just pure bovine serum albumin in a preparation increases the rate by lowering the KM. So the KM is the amount of substrate that you get half of the maximum velocity of the reaction for all of you biochemists out there. So the lower the KM the faster the reaction. So these researchers of a particular group they were like oh we're gonna look into why this happened. So they did it with bovine serum albumin and fatty acid free albumin also increased the rate but human serum albumin didn't and they eventually whittled away at the different factors and found human serum albumin on like bovine serum albumin and of course fatty acid free albumin had a lot of PUFA and they specifically used the phrase inhibitory fatty acids which has not grossed over into any other field talking about PUFA so it's been sequestered in the drug metabolism field but apparently they consider these general inhibitors of enzymes in general and these are just their figures. So this is the bovine serum albumin. This one looks the same as the fatty acid free so the higher the concentration of it the faster the rate this is the human. So it starts off here and then the rate goes up at first with a low concentration and then it crashes down the rate of reaction. And before I finish up you might think that I'm only talking about omega six but I'm not so I'm a little bearish on the omega three story. A lot of the early research showing that it's so great has not been able to be replicated very well. So as early as the early 2000s they repeated some of those seminal studies and got some pretty negative results and a little bit more recently taking a meta analysis of a lot of different randomized trials mostly cardiovascular and some other ones. Only two out of 18 had a benefit in the primary endpoint so most of the time it's cardiovascular but neurocognitive et cetera. All right so in conclusion why you don't want to be a fat burner maybe I don't know if you believe me is there's a few inescapable facts of it which is that you're also going to be a muscle burner to some extent so there's some data that shows you can protect breaking down a significant lean tissue if you eat enough fat if you go into ketosis or if you need enough protein or whatever but you're always breaking down some more than if you were eating a high carbohydrate diet. And of course when you break down that muscle you're oxidizing glucose so you're doing the same thing. The hormonal profile and the physiological profile in general is sort of like a combo between starvation metabolism the hormones that are upregulated. Of course you're not starving because you're bringing in food protein and fat mostly in your diet so in that sense it's kind of like the diabetic metabolism except without the hyperglycemia because diabetics are burning they're making lactic acid out of glucose instead of making CO2 they're burning a lot of fatty acids and doing a lot of gluconeogenesis even when they have hyperglycemia so it's kind of a mashup of starvation and diabetes the super you know the zero carb metabolism and then the big picture idea is if you think of what fatty acids are what they're used for in nature so seeds seed plant seeds use them to inhibit sprouting enzymes until conditions are favorable. Fish in really really cold waters use them so that they don't get really hard like butter in the fridge. And mammals with a high metabolic rate big brains they do use them but they don't use them preferentially for metabolism and it's just really hard to get away from the fact that they produce glucose you produce glucose when you have excess or you produce fatty acids when you have excess glucose so signaling you have excess energy. You produce glucose not when you have excess fatty acids but when you have insufficient glucose and you make it out of muscle. So basically that's my point is to question the idea that fat is an appropriate substrate for big brain warm-blooded high metabolic rate animals. And thank you for your attention this is my website. Question. I'm definitely not a biochemist so I'm not sure I followed everything but my sense from your presentation is you know what I heard is negatives of pulling fatty acids out of the cells and negatives of metabolizing polyunsaturated fatty acids. I didn't hear very much about diets that are based foundationally on saturated fatty acids. I wonder if you could talk a little bit about that maybe. Yeah I wanted to sort of have the transition go okay this is the problem with burning fat in general and then go to so I don't think I made that quite as explicit but the low CO2 happens whether it's saturated or unsaturated. The hormonal profile if you're eating a low carbohydrate diet that looks the same actually I don't know if that's really been compared but it looks pretty much the same but yeah I mean you're not gonna have all that reactive crap happening in your blood. And one other thing I think at a previous AHS there was a neat presentation from somebody named Jay Stanton on metabolic flexibility I don't know if you're familiar with it at all but he essentially said that it's really a good idea to the way I interpret is kinda exercise your different ATP production systems and so it's not so good to be always in ketosis it's not so good to be always burning glucose it's better to oscillate some. Do you have any thoughts on that from a biochemical perspective? Well no biochemistry if you walk into a biochemist lab and ask them they won't have a perspective on that because they really don't care about ideas like this but yeah I think that there's value in the idea of thinking that something like hormesis exists maybe in all situations maybe in some situations I'm painting a really broad brush about the biochemistry actually mostly cellular physiology of what's going on. Okay so possibly. So you're essentially throwing out a cautionary note but you're stopping short of you know certitude here. Yeah well I guess I'm just trying to ask different questions like a really big like almost like so there's a really big question in paleo which is what are we designed to consume and it's always focused on genetics and I've been very turned off with genetic science recently and people that study that it doesn't there just doesn't seem to be a lot of originality there so I'm looking more from like a cell point of view like what is the eukaryotic cell? What does it do? How is it different than a prokaryotic cell? Questions like that. So from a physiology standpoint isn't serum CO2 really dependent upon breathing not on what you're eating? I mean I know my experience and I'm a person that's been keto adapted for seven years and my experience was and I ski a lot and so I go up and being keto adapted I breathe much less at 12,000 or 13,000 feet and I ski all day all fasted and it's no big deal and also looking at Dr. Biteko the Russian scientist who had breathing, he was looking at the Bohr effect and looking at asthma and stuff like that that it's really how much you breathe in the sensing of CO2 in your blood which is how those relate versus what you're eating. Definitely at an acute level that's for sure I mean you can increase your blood CO2 instantly by just reducing your breathing rate and yeah, Butenko is great and I think that his methods are valid and good. I don't know about cellular CO2 as much though if you can really get at that and I think CO2 being in the cell is just as important as being in the cell and leaving the cell. But that process, the process of CO2 being created in the cell from oxygen and from whatever substrate you have and exiting the cell and taking stuff out with it I think is essentially what you carry out excels what differentiates them from prokaryotic cells. So I see that as essentially important. Any other questions? Your comment about the carbohydrates resulting in less muscle loss is definitely not my experience. I was able to only stop muscle wasting with a saturated fat, ketogenic diet. So I'm curious how that could be. What kind of diet were you eating before? We're standard, very healthy, probably 80% vegetable about equal protein and fat. Before that now I'm probably 80% fat and I actually stabilized, I stopped 30 pounds of muscle loss with it in your comment it was just kind of contradictory. Well if you pump up saturated fat I mean if you had a lot of polyunsaturated fat floating around that might have been a good thing. But also if you are oxidizing glucose properly and eating enough calories you're essentially eating a high saturated fat diet because you're producing saturated fat from those carbohydrates. But I mean your experience is your experience and of course I can't deny it. So what are some of those substances that exit with CO2 from the cell? I would say the most important are water, liquid water that's not bound to protein and calcium. And is there a reason why those function, why those exiting is important? Yes, you want as little free water in the cell as possible. That's actually how MRI machines look for cancer by the amount of free water and prokaryotic cells, dividing cells, six cells all have more free water than healthy cells. So basically my opinion is that you want no free water in the cell at all and you want it just kicked out immediately. And with calcium it's just excitotoxic to have persistent intracellular calcium. I think that's, is that all we have time for? Okay, one more, quick one please. I'm wondering if you've looked into research in the longevity area where they have suggested that lower T3 and slightly higher cortisol actually correlate better with longevity? I haven't really looked into that specifically. I've definitely looked into more general, like I've definitely seen studies, oh this low carb population has more longevity than this higher carb population. But for example, I think grains would probably be bad for longevity, specifically. So I don't know, but if you have any of that information I'd love to see it. In fact I'd love to see any contradictory information. Thank you. On my website, my email's on there. Yeah, always open to new ideas. Thank you very much. Thank you.