FoundMyFitness - #023 Dominic D'Agostino, Ph.D. on Modified Atkins Diet, Ketosis, Supplemental Ketones and More

Episode Date: March 23, 2016

Dr. Dominic D'Agostino This podcast is with Dr. Dominic D'Agostino, an assistant professor at the University of South Florida in Tampa and all-around expert on ketosis. In this podcast we discuss: (00:00) Introduction (03:46) Ketosis has abundant therapeutic potential  (10:20) What to eat to maintain nutritional ketosis (19:58) Does a high-fat diet harm the gut? (29:14) Adaptations to a ketogenic diet expand mitochondrial capacity (38:45) How the brain uses ketones (46:36) Ketones improve Alzheimer's symptoms (unless you have an APOE4 allele) (57:17) Are ketone supplements a "magic pill?" (01:07:32) Why cancer cells may need sugar (01:23:51) Metformin is more than a diabetes drug (01:30:33) The body creates sugars while in ketosis (01:36:21) Restricting glutamine to slow cancer growth (01:43:24) Ketone supplements taste awful, but likely improve health If you're interested in learning more, you can read the full show notes here. Join over 300,000 people and get the latest distilled information straight to your inbox weekly: https://www.foundmyfitness.com/newsletter Become a FoundMyFitness premium member to get access to exclusive episodes, emails, live Q+A's with Rhonda and more: https://www.foundmyfitness.com/crowdsponsor

Hello, my friends. Today's podcast is with Dr. Dominic Dagostino, an assistant professor at the University of South Florida in Tampa and an all-around expert on ketosis. I have to warn you guys right now, this is a fantastic podcast. In this podcast, Dom and I discuss Dom's efforts at teasing out the differences between induced nutritional ketosis through a low carbohydrate high-fat diet and ketosis from the dietary introduction of exogenous ketones like beta-hydroxybutrate, especially in the context of therapeutic and performance enhancing effects. His work on formulating ketone esters, the difference is intolerability between medium chain triglyceride powders versus liquids, as well as the amount of supplemental medium chain triglyceride a person would need to consume in order to achieve

mild ketosis without carbohydrate restriction. The differences between different types of ketogenic diets, the modified Atkins diet, which has been demonstrated to have similar efficacy to the classical ketogenic diet and the treatment of drug-resistant epilepsy and how this may be a slightly more practical option for achieving therapeutic nutritional ketosis. The importance of making the correct carbohydrate choices, even and maybe especially in the context of a ketogenic diet, with a diverse variety of raw vegetables being the most favorable. What keto adaptation is and what it means at a physiological level to be keto adapted and how this is distinguished from short periods of ketosis we experience in our day-to-day lives. Some of DOMs,

ideas around cycling various dietary strategies as a way of promoting metabolic flexibility, how ketones, when used as a source of energy, may result in a net reduction in the number of damaging reactive byproducts known as reactive oxygen species than what may be produced by other forms of energy metabolism, while also producing more ATP from proportionately the same amount of oxygen. And so much more, oh my lord, there's so much more. Okay, before we get to the podcast, just a couple of quick things. Get on my weekly newsletter at foundmyfitness.com. It's quick, it's simple, and it's awesome. You can unsubscribe if you don't like it, but if you do like it, you can forward it to your friends and for no cost at all,

put them on the path to increasing their health span, well-being, cognitive and physical performance through deeper understandings of biology. This podcast will also be available shortly on YouTube. YouTube is sometimes useful, especially for very technical conversations like this, where it can be helpful to clarify, for example, that in one instance when Dom or myself says MCT, we may mean a special type of fat known as medium chain triglyceride, whereas in another instance, we mean monocarboxylate transporter, which is something completely different. If you haven't already, go check out my YouTube channel by going to foundmyfitness.com forward slash YouTube or just Google Found My Fitness YouTube. That works too. And finally, this podcast is brought to you by the makers

of deoxyhydro blah blah blah and all. Whoa, wait a minute, that didn't sound right, did it? That's because it isn't true. This podcast is actually brought to you by people like you for as little as a couple of bucks per month. You too can be a part of the awesome that has found my fitness. I like to think of crowd sponsoring your favorite podcaster, and me, as sort of like being a part of a collective of people that actually have real magical powers that allows them to be able to send fist bumps over the internet. So if you're interested in having magical powers, go to foundmyfitness.com forward slash crowd sponsor. That's found myfitness.com forward slash C-R-O-W-D-S-P-O-N-S-O-R crowd sponsor.

I'll be sitting here, coffee mug in hand waiting to intercept your fist bump while simultaneously also putting together another podcast or newsletter or video or something hopefully valuable to you all. And now on to the podcast where we do the tucky-tucky. Hello everyone. I'm sitting here with Dr. Dominic Degasino in Tampa, Florida. Dominic is an assistant professor at the University of South Florida, where his primary research focus is on metabolic therapies, particularly nutritional ketosis, ketone supplementation,

and how they affect a wide variety of pathological conditions, ranging from neurological disorders like ALS to epilepsy, to muscle wasting and cancer. So very, very interesting stuff that Dominic's doing here in Florida. he showed me some of his really cool equipment, which is super exciting and very interesting some things I hadn't seen before. So welcome, Dominic. Thanks for having me. Yeah, thanks for inviting us to your lab. Have you here in my lab, yeah.

Super cool. So tell us a little bit about some of your more recent interests and research where you're sort of been, what have you been looking at. Okay. So more recently, I'd say within the last. three to five years and took a while to develop them, but, you know, as you know, we're working on ketone supplementation. And the idea is to kind of mimic the therapeutic effects and performance enhancing effects of the ketogenic diet. So, you know, nutritional ketosis achieved through a dietary means with a low-carbohydrate, high-fat diet, has therapeutic effects for a broad range of

neurological disorders, in particular of seizures. And you can make the argument that pretty much every neurological disorder is some way linked to a metabolic dysregulation. And we're interested in understanding how nutritional ketosis may help to preserve and sort of stabilize brain energy metabolism to metabolically manage these seizure disorders. So in the process of understanding and studying the ketogenic diet, we are developing a broad range of ketone supplements, which can include ketone esters and ketone mineral salts, which where we combine a ketone body, beta-hydroxybutyrate, to an essential electrolyte and create a wide variety of salts. And we're working. A lot of the work now is focused on formulating these to make them tolerable,

to make them palatable, and to understand their things. therapeutic potency for different types of disorders. Yeah, so you mentioned that at the root or at the heart of a lot of these neurological disorders is a metabolic dysfunction and how, first of all, when we talk about nutritional ketosis, to me, it's such a broad way of describing it. You know, like, what is nutritional ketosis? And how do you achieve it? So nutritional ketosis could be, it's defined, it kind of has the same definition in my mind.

It's achieving and sustaining a level of blood ketones. And I think when people say they've done the ketogenic diet, they did that, you know, it didn't work for them or it did work for them. I would ask the question, well, did you measure blood ketones? Did you confirm, in fact, that you were able to achieve a state of ketosis defined as an elevation of. blood ketones, above 0.5 millimolar at the very least. Ideally, you want to stay between 1 and 3 millimolar of ketones. And when you've achieved that state, I'm talking about blood ketones, yeah, which is kind of the gold standard. And this can be measured. There's a number of different devices out there that measure blood ketones. And when that, the state of nutritional ketosis

is achieved, you're also not only, you know, not only that biomarker is kind of there and we have technologies to measure it, but it would also be important to measure your blood glucose and maybe insulin levels too. So when we, the suppression of the hormone insulin drives hepatic ketogenesis. It drives, you know, drives the body's ability to make ketones. And that has therapeutic implications for type 2 diabetes obviously. So my definition of nutritional ketosis would be an elevation of blood ketones and the kind of the difficulty in prescribing that or telling someone to do it is that the way to implement that is kind of similar with everyone, but everyone responds differently depending on where you're coming from. So if you have an obese subject that's type 2

diabetic is going to be different than an athlete or different. And women, there's some differences between women and men, I think. So, you know, defining nutritional ketosis is relatively easy within elevation of blood ketones, but implementing it and being able to, for the individual to commit to it and have that kind of ability to control their diet, which is very the linked to lifestyle has been sort of a difficult thing to do. And that's where ketone supplementation kind of comes in and can allow someone to rapidly achieve nutritional ketosis and sustain it and perhaps get many of the therapeutic benefits that we're just finding out now. We know that ketones are more than just the metabolite. They're more than just an energy metabolite that the

brain can use, but they are metabolites, especially beta hydroxybutyrate, are very powerful signaling molecules. And we're just beginning to understand sort of the therapeutic effects of these metabolites as signaling molecules. And that's a big thrust of our lab right now. Oh, you're interested in looking at the signals like, interesting. Yeah, I'm familiar with some of Eric Burdine's work at Glasstown and how these science book. Pioneer. Yeah, it's very, I'm very interested in beta-hydroxybeterate as, you know, not only as a source of energy from mitochondria, so being able to be converted into a thermodynamically favorable. source of energy, but also, you know, the fact that it's able to change cell signaling

in brain and, you know, it's able to turn on genes that are involved in dealing with stress better. Some of these genes are involved in longevity, box O3 for one. Absolutely. So it's all very interesting. But something that I, like in my mind that I'm not exactly certain about is that nutritional ketosis. So, you know, eating a high-fat diet. And of course, there's, okay, what types of fat are you eating? Are you eating more polyunsaturated or eating more saturated? How much protein are

you eating? What types of carbohydrates? Are you getting fiber? I mean, there's so many different diets very complicated. But there is no doubt that there are interesting therapeutic effects from nutritional ketosis. I am interested in the, you know, the actual end product, which is, you ketone bodies and these signaling molecules like beta hydroxybuterate, being able to get those maybe even without having to eat a high-fat diet, you can get them from fasting, from intense exercise, right? Also, you can achieve. Post-exercise.

Yeah, post-exercise. Absolutely. So I guess kind of the question I had for you with nutritional ketosis, but besides how do you define it was, what do people eat to obtain that? Like, how do you get, you know, blood ketone levels between one and three millimolar? Like, what do you have to eat? What do you not have to eat? Mm-hmm.

Okay. That's a good question, and it varies depending on who you talk to and what's optimal. I think a good way to approach it would be to describe what has been used classically and how the diet has evolved over the last two to three decades, I think, with some of the work with Eric Kosoff at Johns Hopkins has kind of advanced the idea of using a modified Atkins diet or modified keogynic diet. And I can kind of talk a little bit about strategies that I use, I think, and others that I know use to achieve that state and sustain it for optimal performance and health, I think.

So in taking a step back, the classical ketogenic diet would be like a 4-1 or 3-1 diet, and that's kind of the ratios of the macronutrients, four being fat, and one being a combination of carbohydrates and protein together. So pretty protein restricted diet. And the ketogenic diet is not a high protein diet. It's actually moderate to low protein diet. And most people don't understand that. They think, especially in the fitness community, if they go on a ketogenic diet,

if they say they've been on a ketogenic diet, what they will describe to me would be a very low carbohydrate, high protein, moderate fat diet. But the ketogenic diet, you know, as it is used classically for drug-resistant epilepsy, the original, was like 90% fat, like 85 to 90% fat and maybe about 10% protein typically and 8 to 10% protein and very minimal amount of carbohydrates. And it was heavily based upon the use of dairy fat. So dairy was the primary kind of vehicle, yeah, to get calories in. to you. And we know that, you know, the use of dairy, especially in some people, dairy protein

in particular, but even sometimes dairy fat too, can have negative consequences for some people. So there's a wide variety of kind of ketogenic diets out there. And the ketogenic diet has been defined by this ratio of macronutrients. But what we're learning now is that it's more than just macronutrients to optimize the diet, especially for individuals. The sources of the macronutrients, the fatty acid profile, the type of protein, it allows for some amount of carbohydrates and the types and quality of the carbohydrates as it relates to gut health and gut microbiome, I think, is really important. I think it's really important to optimize the diversity of carbohydrate sources in the

form of raw vegetables. And I think that can optimize the diversity. of the gut microbiome, too. I think those two are linked. The diversity of the foods in your diet and the diversity of your gut microbiome. I've seen that just through feedback. It's not really studied, but it's something everyone knows and knows should be studied. So the classical ketogenic diet is very strict to follow. There's a few studies showing that it can influence a lipid profile in a negative way, meaning a high elevation of LDL. And, And in kids, I think that followed the diet, they had a high level of triglyceride.

There was one study that's often referenced in regard to the ketogenic diet being atherogenic. You know, the triglycerides were really high in some of the kids. It's probably a very complex gene-nutrient interaction as well. Absolutely. There's some, I'm not sure if you're familiar with any of this work. It's something I'm getting into recently is this nutrigenomic field. And particularly, there's peak.

PPR, gamma, and PPR alpha, which is important for ketosis, their polymorphisms that are associated with not being able to respond well. So it's very likely that some of these people that don't respond well or may have that polymorphism. Yeah, undoubtedly, because there's some people that really have a negative effect. But I would say it's kind of few and far between maybe as high as 20% in some circles. But generally speaking, if you have a dietitian that's pretty savvy, and has worked with enough people. I really emphasize experience because there's no substitute for experience. You could know as much, you know, you can know all the biochemistry behind nutritional ketosis,

all the pathways or whatever. But working with a dietitian, I always stress that in people that want to try the ketogenic diet to start off with a good dietitian, they can tailor and tweak the diet for your specific needs. And I find that for me personally, a diet that's low in dairy is. is really essential because I just don't do good with the area. And nuts have been a staple on, for some people, for the ketogenic diet. And I have like a mild nut allergy. So that's another food that kind of had to eliminate.

But despite that, I've been following what I call a modified ketogenic diet. And I think it's pretty similar to the modified Atkins diet that Eric Kosoff has been using at Johns Hopkins. He's at Johns Hopkins, mainly a neurologist, but has a team of dietitians working with him and has done incredible job advancing sort of the use of the ketogenic diet. You know, he follows in the steps of John Freeman, who was really a pioneer in getting the neurology world to recognize the ketogenic diet as a viable metabolic therapy for drug-resistant and epilepsy and did a lot of work with the Charlie Foundation and work with them to help promote awareness of the diet, education of the diet.

So some work that Eric Kosoff has been doing over the years in publishing on is showing that the modified Atkins diet has much of the therapeutic potency of the strict classical 4 to 1 ketogenic diet. So instead of 90% fat, the modified Atkins diet is roughly a very much. 65 to maybe 70% fat, which is kind of what I follow now in about 20 to 30% protein, with the balance being still very low in carbohydrates, like no more than 5% or 10% carbohydrates. But it's more liberal in the use of protein. And it's also advocates the use of medium chain fatty acids can be incorporated into

the diet. So by following a diet that's more liberal with the protein and less not restrictive or less in less of a need of such a high fat content, I've been able to maintain a moderate state of ketosis as do many of the therapies or many of the patients that are benefiting from this therapy for a wide range of disorders. So I think that makes the diet more accessible to people. I think the biggest hurdle now is just compliance. So people know the benefits of the diet.

Some of them are a little concerned with the side effects of the diet as far as lipid profiles being altered. What about gut? The gut, yeah. Have you been looking, how long have you been doing this modified kinesogenic diet? It's sort of evolved from. 2008 to 9, I started experimenting with it because that's when I got interested in using... And you've continued on ever since then? Yeah, I've never really gotten out of ketosis.

Yeah. That's quite a one time. If I did, I may have reverted back to like a low-carb paleo, which is, you know, maybe up to 40 or 50% fat or protein on some days. So I've been a little more liberal on the protein at times. But yeah, I've been following for a long time, and I do blood work. The reason I ask is because it's the one, like I mentioned, I'm very interested in nutritional ketosis, which is why I'm excited to talk to because you know so much more about it. And I'm trying to like get to the bottom.

There's this conflict in my head with eating a lot of fat and its effects on the gut because, you know, I know a lot of gut researchers. A lot of my friends are looking at gut health. And one of the main things that you do to induce endotoxin, which is released from infectious. I remember it's one of the main things you do to induce gut mobility is you give a high-fat diet. You feed, you know, mice. You feed this is all done in animals, of course, which is there's lots of problems with that. And what's the typical fat source for that?

Is it lard or is it a variety of different fat sources? I mean, there's lard, there's corn oil. I mean, so there's, you know, there's a variety of different fat sources, but, you know, fat itself, in order to be digested, you have to make these bile acids like deoxycholic acid, which, you know, which causes endotoxin release. It also acts as a surfactant. I mean, it's like a detergent, you know, so I am, I'm not convinced that it's not, you know, not healthy, but I'm not, I'm sort of trying to get to this. There's a disconnect in the literature because there's so much. much information out there showing the benefits of a ketogenic diet, nutritional ketosis. Let me ask this question real quick. So when endotoxin is released, you know, from these

bile acids, so there would be a predictable, a characteristic cytokine profile that would reflect that, right? Yes. So there's a cytokine profile and there's also you measure endotoxy in the blood, which is a very tricky thing. do because there's a lot of false positives. Yes. And I know someone who's trying to develop an essay to make it actually, because he's very OCD about it. And it's not out there for clinical use yet because of that reason.

And even doing it in animal studies, there's a lot of researchers that don't really do it right, measuring endotoxin. Is there any benefit to endotoxin? So when I go exercise, right, and you measure my blood and we look at reactive oxygen species or inflammatory mediators, you could look at the blood and say, don't do that. This is not a good thing to do. Whereas, you know, if you have periodic spikes, maybe an endotoxin, is it, is it stimulating a hormetic effect where it's enhancing my resilience or resistance to two toxins? Do we know that? So endotoxin, I would say, based on everything that I've known and researched and for my interactions

with people that have been, you know, doing this research, it's not like reactive oxygen species. It's a potent signaling molecule that has this formatic effect. It increases mitochondrial biogenesis. It increases all these genes involved in dealing with stress. There's lots of benefits. Endotoxin released from the gut, one, it causes more VLDL production because VLDS sucks it up. So that's part of the reason why inflammation is also correlated with an increase in LDL number.

It also binds to APOB. it binds to the part, it binds to where the LDL receptors bind, so that LDL can't be recycled as well, so it kind of prevents. There's not, there's a lot of bad things about endotoxin being released. Now, I don't know maybe there is some sort of slight benefit from endotoxin being released. You know, I don't want to get too into the endotoxy world. I'm just, I'm just saying that there is in my, I'm trying to like understand my mind how. So you might be a little bit biased because. Because the high fat diet work is endotoxin.

I'm a little bit, I need to get educated. I mean, I understand endotoxin from kind of like a basic science point of view. Yeah, yeah, from sepsis bad. But I do know, you know, when your body's challenged, even things like radiation. I mean, there's some things, you know, I don't know of any case where an auto-antibody is a good thing, right? But I know most of the things that are bad out there do have some benefits. It's the level.

Absolutely. It's the level. Dose is very important. And the phenotype's ability to adapt to that chemical, that stimulus is really important. Like old people don't adapt to, you know, older phenotypes don't adapt to, you know, in oxidative stress stimulus, like as robust. So I would be interested. And there's ways to simulate endotoxin, right?

experimental models and that's something that we can do challenge perhaps running experiment where we have animals on different diets where we can challenge them and look at it inflammatory cytokines we're doing a lot of that work now and good health in general gut mobility I would love to see yeah we're doing that too yeah research could go in that direction because there's so many unanswered questions and there's a lot of bad data out there like so from the high fat diet and the effects on the gut because when you look at control diets and the high-fat diets, there's, well, the control diets have, like, 50% more fiber.

And it's like, well, that's not really the same thing if you're just changing, you know, fat. So there's, you have to sift through, like, all sorts of crap. And it's like, I'm still, there's lots of data you just have to throw out, but still at the end of the day, I just, I'm uncertain. And I'm, and I'm weary about me eating a high-fat diet. Not to mention the fact that I have certain gene polymorphisms that may not be as compatible. But because of that, because of gut health, that's a good health. my major limiting factor for me is gut health. And I would like to see more research on ketogenic diets and gut health.

That's something that I think is important. How to optimize it. Yeah. Or just what the effects are. Like maybe there, you know, for one, you're starving out probably a lot of the pathogenic sugar eating bacteria. So there's probably some good things going on. And then there's, well, what effect is medium trained triglycerides has?

Is it the same as long chain fats? Maybe not, right? So maybe, so there's different types of fat, you know, there's studies that have been coming out on very recently showing the effects of polyunsaturated fat on gut, you know, biome and how it has a positive effect. So maybe if you eat, you know, certain types of fat, more of these types of fat versus, yeah, there's lots of things out there to be explored. Undoubtedly shifts it.

Yeah. It shifts it. I mean, your gut microbiome, you know, has an appetite for whatever you're feeding it. And that probably influences profoundly your own appetite. So I think if you have sugar eating gut microbes, you're probably going to be craving sugar if you go, you know, a few hours without having sugar. Yes. And I think I would be very interested in not only like shifting someone from a high-carb diet

to two or three different types of ketogenic diets, I think would be important with specific fatty acid compositions and fiber compositions. And I think it's a diversity of the fiber that's incorporated. Diversity, yes. It is very important. There have been, you know, there's lots of different types. types of bacteria and they're eating different precursors to generate a lot of these other signaling molecules, which in FIS and things like that, that are regulating your immune system.

They're regulating, you know, literally, hematopoices, T-Regs, natural killer cells, you know, lots of, and this is a whole blooming field of research. That's also another reason I've been a little hesitant to experiment with this because I'm so, fiber is so important to me. Fiber from vegetables, you know, I'm not adverse to fiber from fruits, so fiber from fruits, legumes, beans, like I like to get a lot of fiber in my diet. And so I don't know if that, is that compatible with it? I get more fiber on a ketogenic diet, you know. We're talking about a well-formulated ketogenic diet as Jeff Volick likes to, and because that is really important,

because you talk to people that eat ketogenic diets and it's all over the board. But I think a well-formulated QJank diet would have an abundance of, of, of, you know, fiber sources from everything from, you know, green vegetables, of course, but would include a salad. And I think it's really important from a gut microbiome perspective to get in raw vegetables, I think, from what I've known and a half dozen individuals that I talked to that are kind of, you know, experts in this field. They would, they think that that has a pretty profound effect. And I've always done that. And I would say my gut health has not, it may have, maybe due to what I eliminated in my diet.

I grew up in an Italian family eating a lot of pasta bread. So they were the staple foods. And I gravitated toward a paleo diet, mid-90s, early 2000s, and then the ketogenic diet. And I have never had better gut health than when on a ketogenic diet. But my diet is, like I said, more of a modified Atkins and has a pretty liberal amount of vegetables in it. And I think the benefit to including the vegetables, they're just carriers for the fat. And they also slow protein digestion, which helps minimize the insulin spike that you can get from protein and helps keep me in ketosis.

But, I mean, getting back to your question about the ketogenic diet or high fat diet influencing endotoxin or factors, I would think that would show up like in the literature that if some, and maybe it does. But usually a high fat diet is in the context of a high carbohydrate diet too. So that's what we don't know. When we talk about, you know, LDL particles being elevated, like even skyrocketed, LDL little P. That is only understood in the context of a high-fat diet, which also includes sugar, like a Western diet. Absolutely. So we don't yet understand lipidomics and the shifts in lipid profile of the ketogenic diet.

LDLP specifically, we don't understand it in the context of keto-adaptation. Okay, what's that? Keto adaptation, I would, it's kind of a term that Jeff Bola can see Finney coined, but I think it's very descriptive in my mind as a physiological process when your body has adapted to using fatty acids and ketones for fuel, where you've biochemically, physiologically shifted your metabolism from burning glucose as the primary fuel to burning glucose to burning glucose and also equal or maybe more in some cases ketone bodies, primarily from your central nervous system.

So when that happens that, you know, acutely you get an elevation of blood ketones. And over time, what you do is get an upregulation of the transport mechanisms. So your ability to sort of make ketones, utilize ketones, and metabolize ketones in the cell is dramatically increased, as is the oxidative capacity of your cells. Actually start making more heat. After, yeah, it's sort of driven by being in a state of ketosis, enhances fat oxidation over time. So when we say keto adaptation, we should probably say keto and fat adaptation.

So there's studies out there that show our metabolic physiology changes pretty profoundly from eating this. We basically, we burn what we eat, right? So the high carbohydrate diet, we are pretty much burning that as fuel. And our bodies can adapt remarkably well to burning a macronutrient profile that's reflective of the ketogenic diet. And when we do that, a lot of really remarkable beneficial metabolic processes happen, including mitochondrial biogenesis, reduction of Ross, reduction of inflammation, a reduction of specific inflammatory cytokines that may be associated with age-related chronic diseases are reduced. So reduction of Ross, because I would, you know, I guess some of Richard Beach's

have put some ideas out there about the... Ketone's direct effect. Yeah, about, because it's so funny, because in my mind, I always think about, like, well, if you're inducing your mitochondria to work more, you're going to make more react-to-oxygen species, right? And that's sort of what I think would be a driver of killing abnormal cells, cancer cells that are primed to die. They're expressing way more pro-ipopotic proteins. You know, they've countered it with anti-apoptotics. All they need is a little push, a little reactive oxygen species push to death. And that's increased initially.

It is. Okay. So, yeah, it actually activates like Nerf 2 and stuff. So when someone gets on a ketogenic diet, there's, it's a stress. Yeah, so you are making more, because if you're causing your mitochondria to only work, right, that's the only way you can make energy, then you think that you have to be making reactive oxygen species. At least if you're looking in the context of a cancer cell, which would be like glycalaic and not using their mitochondria at all, right? Yeah, yeah. Then definitely there would be a much more increase in Ross. So the ketones, so you're saying that it can suppress Ross, is that through some of what Richard Veach has put out there in the semi-uiconone,

it's like oxidized Q makes it less available. Because that's the most. If Q is oxidized, yeah. So Q is ubiquinone. Yeah, ubiquinone. If ubiquinone is oxidized, which is achieved with our beta-hydroxybutrate metabolism, if that's oxidized, then you have less availability for that electron to react with molecular oxygen in the metabolic pathway.

So you would produce less superoxide anion, which is your precursor to more reactive oxygen species. And that's been shown elegantly in a number of models, including the cardiac model, which he did the Langrenhorn model, the perfuse heart preparation, showing that you get a greater hydraulic efficiency of the heart in the presence of ketones. You know, with a given amount of oxygen, you can generate proportionally more ATP energy currency. Is there another way that ketones also suppress well? Or is that through the... Well, acutely... ...active metaceptive act of activating mitochondria, then increasing NRF2 and things like that.

Yeah, that would be a secondary effect. I would say from an acute point of view, as simply as a metabolic fuel, the mitochondrial efficiency is greater. So you will have a greater mitochondrial membrane potential, a greater driving force for ATP synthase to make ATP. So it energizes the mitochondria in a way that would be expected from... a metabolic fuel that's sort of superior from a bioenergetic point of view. So you have a greater capacity to generate ATP for a given amount of oxygen that's available. So with that occurring,

the metabolic efficiency of the cell would be sort of preserved. You're using less oxygen to make the same amount of ATP, less reactive oxygen species. And of course, if you're shifting away from glycolysis and shifting more towards oxidative phosphorylation. So in the context of a cancer cell? In the context of, yeah, any kind of cell, like your tissue really, skeletal muscle or cancer cell. Yeah, you are forcing the body in a way and it's a stress initially to upregulate mitochondrial machinery, really.

And more mitochondria. Metacondrial will start, you know, budding off and creating mitochondrial biogenesis. So the number of mitochondrial biogenesis. Yeah, the number of mitochondrial. Then the proteins that are associated with the electron transport chain, those proteins are upregulated. So you make more of these proteins. Yeah, it acts very similar to lactate.

I don't know if you're familiar with any of like the brain work in George Brooks. Lactate. Very interested in Lactate as a graduate student. Yeah. It goes to the same transporter, right? Yeah, MCT. I studied lactate as sort of an undergrad and graduate student like I am studying ketones now as an alternative fuel.

looking at it in the brain? Yeah, during hypoxia. So I studied the neural control of autonomic regulation, so brain hypoxia and what our brains do under hypoxia. And lactate is a big player in preserving, you know, brain function, viability, health. And I, you know, study lactate as an alternative energy source under hypoxia. And now I think of ketones as like the alternative energy source, you know, when your brain is under normal physiology. And I think that, you know, there's some uses for lactate, too, as a fuel. I think when we exercise, you know, we're creating lactate and we feel good. It's not really talked about.

It's something that I want to study and maybe talk about a little bit more, is that lactate, you're also sending, not only are you sending ketones to your brain, but you're sending lactate to your brain. And I think that's maybe not talked about that much, but there's potential out there for lactate supplements. Yeah, George Brooks and you see Berkeley, he's, I don't know if you're familiar with any of his work. A little bit.

He pioneered the whole lactate shuttle theory, but he's been looking at the effects of, you know, lactate generated during exercise, for example, when you're forcing your muscles to work harder and you're making a lactate, it gets over, it crosses over the blood-brain barrier, you know, gets into neurons. So neurons themselves actually use lactate generated from astrocytes. So they're using neuron, I mean, neurons are actually using lactate. It's also thermodynamically energetically favorable source of energy, much like ketones. And so neurons like doing that because, one, it's easier and two, because glucose can then be freed up to be, you know, shunted in the pentose phosphate pathway, which can be used to generate NADPH, which is, you know, important for glutathione recycling, right, which makes sense. Well, I think there's a lot of parallels between, you know, ketone bodies and ketone supplements and how they're not only being used as a preferential source of energy in the brain. Do you know anything about this, about like how it frees up glucose then to be used for other metabolic pathways? Yeah, yeah.

Yeah, it's thought that some of the work by Stephen Cunane, I think, is shedding light on this, too. If you... Where is he at? He's in Canada. I forget the institute that he's at. Joe LaMonna has done some similar work, and he's Case Western. And looked at the kind of the interaction. of what does the brain prefer?

What's the preferred fuel source for the brain? I get this question a lot. I think it depends on, you know, I don't know if it's right to say that the brain always prefers ketones. The brain, yeah, the brain, yeah, and neurons and asteroids. But, yeah, I guess, I mean, maybe we're definitely biased towards understanding neurons relative to astrosites. I think most people are asking the question. Astrocytes are fascinating.

I think we need to study that more. But I think in the context of like aging in a context of traumatic brain injury or pathology, I think the brain will really prefer to use ketones because or in the context of some kind of stress, you know, hypoglycemia or something like that, I think the brain will also prefer to use ketones. So why do you think that is? Well, I think, yeah, there's a whole host of reasons that are things that can cause. impaired brain energy, brain glucose metabolism. And that could be internalization of the

glut-3 transporter, which occurs, it's kind of linked to Alzheimer's pathology. Glut-3, yeah. And there's a couple key enzymes that are either deficient or not active like they should be, pyruvate dehydrogenase complex, is deficient in... So wait, are these in... Are the Glute 3 changes in... Astrocytes or in neurons? Primarily in neurons. Neurons. Yeah.

So the glucose transporter are in neurons. It's not. But so if neurons are using lactate primarily, they're, the astrocytes are actually what's... Shuttling the lactate. The astrocytes are using glucose, and that's why they're bringing the glucose. And they're producing the lactate. The neurons are using the lactate because it's, you know, getting chinted and converted into

parruvate. And the contribution of that is not completely known, but it's pretty simple. But it's a pretty significant contribution during hypoxia, I would think. There's been studies out there showing that not even, not just during hypoxia, but actually just under normal physiology. It's a key player. It is. Yeah, the neurons are getting lactate continually from astrocytes, which are generating it.

But that the astrocytes become apparent during, for whatever reason, it's not known. Alzheimer's disease, traumatic brain injury. So they can't make that lactate. And neurons have to start using the glucose. which then is. But I mean, that's just one... Yeah, I've heard about that. I haven't looked into that. Yeah, so there's some key enzymes in that people look at, not only just the lactate levels. I think that I have no idea what they're looking at.

But for the pyruvate dehydrogenase complex, you're saying that's also a barient in some of these disease states, because then you wouldn't be able to use the lactate because you can convert it into pyruvate. So anyways, it's all kind of, I totally interrupted you though, but you were talking about, what were you talking about, the aberrant enzymes like Lute 3 and pyruididia adrogynase and how these are aberrant in different neurological disorders. Yeah. I think, well, maybe the question that we're trying to get at is the contribution of ketones as a brain energy source. Right. you know, and especially in sort of in academia in circles where I teach, it's not even still not really known as not, it's not really accepted or understood that much.

But I think the capacity, the metabolic flexibility of the brain to be able to use ketones, we can exploit that, you know, and that's, we do that with nutritional ketosis. And it's altering brain energy metabolism and the neuropharmacology of the brain in ways we don't completely understand now, meaning the neurotransmitters in the brain. So I could draw off GABA. So you have more GABA. The GABA to glutamate ratio is shifted in favor of higher GABA. So there's a higher GABA to glutamate ratio when one is on the ketogenic diet.

And all, in people that are not, you know, having normal people as well? Yeah. It's thought that. And there's different reasons for that. There's glutamic acid, decarboxylase, an enzyme. Is that how it affects, is that how it helps with epilepsy? That's part of it. I think there's about 20 or more things going on.

If you look at all the signaling pathways, it's actually what happens, yeah, with metabolism. But I think a key player in that is an elevation of GABA to glutamate. And we need glutamate to make GABA, right? But the enzyme is elevated and the pathways are shift in favor of more glutamate to GABA, which has a stabilizing effect on your cell membrane and neuronal activity in general. How readily did ketones cross the blood-brain barrier? Is it? It's thought, you know, up to five-millimeter, maybe six-seven millimolar.

They can readily cross the blood-brain barrier. You have to get that high before they start crossing? No, like, you start impeding. Yeah, once you get like, like, like, you know, levels up that high. It hasn't really been studied in depth. We did brain metabolomics to show that when we looked at the ketone levels in brain tissue and ketone levels in the blood, and there's a high correlation there. Interestingly, we had a diet too that was high in medium chain fatty acids. Although I heard medium chain fatty acids could readily cross the blood

brain barrier, you know, long chain fatty acids typically don't short chain fatty acids. sort of do. But we found very high levels of medium chain fatty acids, you know, indicative of them. And these were normal, healthy animals. So when you take medium chain fatty acids, they are readily, you know, from the looks of our metabolomic data, just readily crossing the blood brain barrier and capable of being used as fuel. It's fascinating. Which is very, yeah, it was really interesting. I kind of, I heard about that, but when you see the data, you know, at the really high levels. brain, then how are they, so then what happens? So they're used? Yeah, they, they, they're medium chain

fatty acids can be oxidized just like fatty acids for fuel. Yeah. Oh, interesting. Oxyative. But ketones are also very high in the brain and to really capture and understand it, you have to sort of capture the brain tissue really quick and freeze it and then do an analysis because the brain's, you know, using it as fuel after you take it. Your brain's kind of still alive. Sort of the stuff that I was showing you in the lab where we can take the brain out and cut it like a piece of bread and then record from it. So that brain is still active.

So it kind of uses the metabolites. So to get a very clear snapshot of the difference in tissue versus blood is a little tricky, as is getting ATP levels in the brain. It's a little tricky. We're working on that to be able to do. do that. Another question, which I think will involve radio tracers, is actually to do like a ketone pet scan where we can look specifically at the regional distribution of ketones and figuring out what areas of the brain may be preferentially shuttling them and using them as fuel.

And how that may change under different pathologies, how that may change under oxygen deprivation, glucose deprivation, high oxygen as they study, oxygen toxicity. Please look at genetic states like APOE4. Yes. Because that's one thing. Yeah, I'm very interested in some of this work you're talking about in ketone supplements, helping with neurological disorders like Alzheimer's. It's been shown that that is dependent on APOE status.

And it just is disappointing to me because I really want to understand why. I just do you have any idea? You're referring to the Henderson paper where they looked at axona. Yeah, AC 1202. So the finding was in that study, which is relatively small, that at least not with a diet, but using a ketone supplement that was formulated with 20 grams of medium chain triglycerides. So they gave it to their patients, I think one, just once a day. And they did show fairly convincingly that the elevation of beta-hydroxybutyrate correlated with an improvement in cognitive function.

But that correlation was not observed in the APOE4 positive group, which was a little bit. It's kind of surprising. I would like to see that study done using the ketogenic diet or maybe the ketogenic diet formulated with ketone supplementation. And so the question is it didn't have a negative effect, but the question is, you know, why didn't it have a positive effect? Was there not another study where they actually did the ketone supplement, beta-hydroxybeterate? I thought there was, but I could be mistaken just from my lack of understanding. Yeah. Because that C8 is ketogenic.

Yeah. Well, they use caprylic triglyceride, C8, which kind of makes a lot of ketones, vocally speaking. Unless the APOE is changing the way. making ketones, right? Good, fatty acid. But they measured, you said they measured beta-hydroxybutyrate and everyone. Yeah. The levels were the same.

Because it's like, I want to understand why there was no positive benefit in April before carriers, because that's the one thing that, it seems so promising, right? That these ketone, potentially ketone supplements or a ketogenic diet could help modulate, you know Alzheimer's disease. Yeah, we, and I think you could do it in different ways. My student presented yesterday, I mean, she presented this week, but she graduated with her PhD yesterday, and her work showed that there's a remarkable increase in blood flow. And previous work has shown that ketone bodies can increase brain blood flow by 30 to 40 percent. So that's another, when you have vascular dementia, when you have a decrease, you know, that being, staying in a state of

Or just brainaging in general. Yeah. Can have a profound effect. Did she understand any of the mechanisms or do you know how you talk about it? Yeah, we're looking at that. Well, we did eschemic wounds, which, I mean, I guess you could kind of relate to an age brain, right? We've clogged arteries. We did a Doppler blood flow measurement and showed that it spiked up considerably when we can elevate ketones.

One of the things, it was not dependent upon. VEGF. So we looked at all the different factors. So VEGF was not increased in the wound. And we looked at a couple other things that we thought would be increased. The one thing that stood out in the data was adenicin. So adenicin levels are significantly elevated. Now, adenisin sort of thought to make us sleepy, you know, when we drink coffee. It's like a denizen receptor antagonist. There's high levels of ATP sort of being used. And we think that they may be causing an elevation of adenicin. But we really have to delve into the metabolomics to understand why that's happening.

Regardless, adenicin is a very powerful vasodilator. And it's in higher concentration significantly in the blood. And that may be increasing the perfusion of tissues, peripheral tissues. That's true. Did it have any effect on the blood brain barrier at all? We haven't looked at that. We haven't looked at that.

My colleague has been kind of looking at that a little bit. We know with fasting and the ketogenic diet that you can increase permeability to the blood brain barrier. You mean ketosis through fasting or both combining the two? Sort of, yeah, fasting-induced ketosis or even the ketogenic diet can help increase the permeability of the blood brain barrier to a wide variety of things. So if you are sort of the implications from his perspective that if you're getting, you're getting a chemotherapy drug. If you're getting some kind of drug that needs to cross the blood

brain barrier that's impaired in some way, you might be able to get that across faster in a state of, you know, fasting ketosis or the ketogenic diet. So maybe if you're fasting, maybe, you know, there's just less stuff in your blood. There's competition of things getting through and your blood's sort of clear and you introduce the drug and you get more rapid transport because there's co-transporters and other things. Or things, or things, that may, that might be in their diet, that may be impeding transport. There's multiple independent lines of evidence to suggest that being in a state of ketosis can help better transport things across.

But when we talk about permeableizing the blood-brain barrier, that's like a bad thing, right? Making it more permeable. But in general, though, you get a knockdown of neuroinflammation from the diet and from therapy of ketosis, which is something. thing. The epilepsy world is very interested in. So there's this pet scan technique that allows us to look at neuroinflammation in the brain. And we know that at this a conference that I recently came from, that may be an excellent predictor of when someone's going to have a seizure.

It'll be really cool to you. Is possibly see if some of those effects were mediated through this pentose phosphate shot because glutathione in the brain is one of the major ways of producing inflammation, right? Yeah. So let's say you do this in an animal model and then you inhibit some of the pentose phosphate enzymes that are using glucose now instead to make an ADPAH and see, oh, is that mitigated? Do you now not have that same effect? It'd be interesting to see if that's part of the mechanism.

It undoubtedly is, yeah. Probably, right? It's part of that and sort of plays into all that. So I have another question for you. Thanks for letting me jump all over the place because I'm super interested in this. and don't. Yeah, we need to follow up on the studies. So one of the studies is sort of we want to do, just following back up on that question, is where ketones are being metabolized and what their contribution is to normal brain energy metabolism and disease states and hypoxia states and

traumatic brain injury. It's a lot to do. And there's overlap too. That's the direction of, yeah, where we're going with our research is understanding that. Just to jump back again before I asked this other question to George Brooks thing, is that He's doing some interesting work, working with some positions at UCLA, I believe, with traumatic brain injuries. So these are people that come in with like head gun, jogging. And they're looking at infusing lactate because he's, you know, the lactate guy. But ketone bodies would work the same way. I think it would work better from what we know.

Yeah. I think a cotail of the two would be. And I've been debating whether or not to really study lactate, sort of the same way I'm studying ketones, and maybe make lactate esters or lactate, and just to see what kind of results we see, you know, starting with our oxygen toxicity model and then working from there, which is an excellent model. Obviously, with the lactate, you have to have intact blood-grained barrier. No oxygen's getting there. You will get then lactic acid build up, right?

Yeah. Because then the mitochondria aren't going to be able to use the lactate, which is converted into perruvate as energy, so it builds up. But he has been doing some work and looking at this glucose sparing in the brain. And, you know, so, of course, kitchen bodies would work very similarly. In theory. Do you know how he gives? Does he use, like, a lactate?

There's alpha-l-poli-lactate, I think. That's like in a sports supplement and some other things. He actually designed. Oh, really? Yeah, he's got a patent. I was using that back in. 1991 and two. Cynomax, yeah. That's his. When I race mountain bikes, that was like my go-to supplement, alpha-el polylactate. You should, you should get into that George. He's great.

Yeah, so he, let's see, what was I just going to say? I lost my train of thought. The delivery or the... Oh, yeah. So the delivery, he's doing, in this specific study, they're doing it intravenously, so... Okay. But I was mentioning, yeah, the blood-brain barrier has to be intact, otherwise they can go the opposite way where it's actually bad for you. Oh, yeah. Yeah. But it would be really interesting to see, you know, so the question is, one, we'll lactate or, you know, beta-hydroxybeterate or whatever, you know, ketone get into the

MCT shuttle better. So there's questions of, you know, which one gets in there and can they be used together and just all sorts of interesting things. But, okay, so that was, I'm sort of interested in this in my, for my own, The neuroprotective capacity seems really compelling. I mean, from what we know about lactate, I'm approaching it going back to my old PhD studies or whatever during hypoxia, but it would relate to so many traumatic brain injury is hypoxia. So you're mitigating the damage.

And also traumatic brain injury is inducing damaged. And so glutathione is one of the major ways of mitigating that. And there's been a study showing that early on it's important. If you get that early on, it prevents the whole. cascade. Yeah. So I think that ketones and lactate both seem to have huge potential for glucose sparing. But that, you know... I think chilling, chilling the body and infusing ketones, lactate with a couple major few cofactors that can, are part of the bioenergetic use of these things would be a home run. Yeah, get some students on it. Yeah, that's,

these are grants that I'm kind of working on in writing. But I'm not sure the, funding agencies are ready to fully. They want like the magic pill thing, but... So, okay, to bring you back to the magic pill, I'm kind of interested. So let's say someone like me that my diet is mostly, I eat a lot of plants, a lot of greens, broad spectrum, carrots, I eat a lot of vegetables. So I get a ton of fiber. I eat a lot of fish, and I do eat like beans, so I'm not averse to legumes or even to oats.

fiber. Let's say I wanted to, I'm like super interested in beta-hydroxybutyrate because I've been following a lot of the research from Eric's lab and I want to get some of those benefits. I want to increase my FOXO3. I want to reduce my lipid proxidation. I want some of that signaling effect. Plus I want beta-hydroxybutyrate to be around to get into the brain. Can I potentially take a beta-hydroxybutyrate whatever delivery source, you know, powder, kill whatever it is and potentially achieve some of those same benefits that you get from nutritional ketosis or ketosis from fasting. Yeah.

Let's say, but I don't eat a lot of, I don't eat refined carbs. So I'm not getting a huge insulin spike for the most part. So, do you know? So, yeah, you want to have your cake and eat it. But I don't eat cake. No, I just eat fiber. You want to have your carbs in? Yeah, that's really what we're working on right now.

And understanding in a head-to-head comparison to see if we can derive the same kind of benefits from ketone supplementation as we can with a ketogenic diet. We know the first kind of convincing study of this that we did was with CNS oxygen toxicity in our rat model. And in that case, the rats were eating a high carbohydrate standard rodent chow model. And we administered via an oral route a ketone supplement in the form of a ketone ester. That's probably one of the more powerful forms of exogenous ketones that we've developed. And that had the ability to prevent CNS oxygen toxicity from happening. for almost over 500% delay in that time to CNS oxygen toxicity. And that could not be achieved with fasting.

It could not be achieved with anti-seizure drugs. So when it comes to enhancing and preserving brain energy metabolism in the face of a tremendous oxidative stress that breaks down brain energy metabolism, we're able to enhance that and preserve that. So we've also studied in our animal model of cancer. metastatic cancer, simply giving ketones to the animals on a high-carbohydrate diet, it was almost you know, unexpected the level of enhanced survival that we had with ketone supplementation. This is a model of metastatic cancer, and the primary tumor was it was derived from a glial

Blastoma, a GBM. And that tumor cell line is so aggressive that when it's injected or implanted into the flank of the animal, there's rapid systemic metastasis to all the organs and the brain. And it's a model that was developed by Professor Tom Seafrid at Boston College. Didn't he publish a paper on? It made the cover of the International Journal of Cancer. When I wanted to do the study initially, I wanted to do a brain tumor model, like with our diet and our stuff. And he sort of wouldn't let me use the model. He's like, well, use this model of metastatic cancer because it's the most aggressive thing

out there. And no one will – he's like, if you create a cure, something that can cure this animal of metastatic cancer, you basically stumbled upon something that has the potential to cure cancer. So that kind of intrigued me. So I knew working with this model would be kind of difficult because of it's just. tumor burden, but the animals died so quick from the tumor burden. But it allowed us to screen a variety of things and just using this model, understanding that in aggressive metastatic cancer,

the cells are highly glycolytic, and they're highly in favor of using glucose and glutamine probably as an energy source. We have not, or looking at ways to target glutamine, but have not really kind of implemented that yet in a combination therapy. But regardless, the animals are eating a high carbohydrate diet with ketone supplementation, and it reduced tumor growth and proliferation. We think that the ketones may be altering glucose metabolism. Well, we think so. There's more sort of apoptosis in the tumors that were there.

But just overall, there's just less tumor growth and less tumor burden and enhance, most importantly, a 50 to 60 percent increase in survival time when animals definitely. are supplemented with this. And it wasn't, although the animals tend to eat a little bit less if they're in ketosis naturally, which makes a ketone supplement kind of an attractive thing for people that are dieting. Because when you're sending energy to the brain in the form of ketones, it has sort of a satiating effect on your body. And it kind of shuts off that hypoglycemic trigger that makes you want to binge or create

food. So is it changing ghrelin and leptin signaling? We think so. Yeah, we think so. That's the next thing to look at. It does impact the satiety centers of the brain. It's not like you don't want to eat, but you have control over your appetite. I know what? I just thought of loric acid, which is C12, suppresses ghrelin in the gut, which is the hunger hormone. Yeah, yeah, yeah. That's kind of interesting, right? Is that specific for loric acid? I knew certain fats, really lark acid? Yeah, yeah. That's interesting. I'll look that up. Sorry, I didn't interrupt, but anyways. No, no, that's interesting. Let's continue because this is really cool.

So you fed them a normal carbohydrate diet, gave them this ketone ester. The same ketone ester, which is... The tumor burden was decreased, survival time. Yeah, survival time increased. Yep, yep. And so that was, you know, another demonstration, and the data looked very similar to the ketogenic diet. So we did this study.

They were eating less, you said, right? They were eating slightly less, so we went back. We were thinking, well, maybe we were. we're just getting a calorie restriction effect. Because if you have a mouse model or any kind of cancer model and you overfeed it, you know, the tumors are going to go faster. And if you underfeed it, you know, you're going to restrict some of the tumor growth. So they were eating a little bit less, but maybe only 10% drop in body weight.

So we went back and we did a calorie restriction control experiment. And although there was a decrease in tumor, it was nothing like the ketone supplement. So ketones, you know, we know undoubtedly they have anti-cancer. effects, and it could be maybe through their expression of their gene expression, you know, as a histone deacetylase inhibitor. We think that they inhibit glycolysis. We think that they influence a number of, you know, pathways associated with cancer growth. Did you measure mitochondrial respiration? Of the tumor and the tissue? Just, yeah, or any tissue, like so, let's say they,

We looked at Ross production. Yeah, it can knock down reactive oxygen. In the tumor or in production? In normal tissue, yeah. Now, it's kind of interesting, too, that in the tumor tissue in previous experiments, I showed that it could knock it down significantly. But I think in the paper that we published, it was a slight decrease. Yeah, in Ross production.

That's interesting. We don't know. We do, our experiments are sort of like a top-down approach. We find out what works. And then we're mechanistically going after it and we're doing omics work, you know, metabolomics in particular and Western blots and assays. And so now we're going after the mechanism. And if we understand a mechanism, we can kind of work backwards and tweak the molecule

or adjust the diet in ways that may enhance a therapeutic. It would be really interesting to do some of, I don't know if you can radio label these ketone ice stores and see, like, are they being used as a carbon source for ATP? Are they being used for something else, right? Tracer studies, that's what we want to do. Yeah, we're going to partner with a company that has sort of the market on doing these tracer fate association. So they, you know, several, I think even doing a 13-gater.

carbon glucose tracer fate association study where we give this and we give ketones. We look at the fate of glucose in the presence and absence of ketones and see how that may be influencing. There you go. Is it going into a plantis loss? Yes. This is all stuff I really want to know. I'm like super excited. I'm going to do it. Yeah. And I wanted to do this from the beginning, but I think we want to find out what works first. And then now that we've identified sort of things at work with the diet and ketone supplementation, hyperbaric oxygen, I was telling you. We also study, we do a lot of metformin work. We have, I have one excellent PhD student and Nate Ward, he's looking at the effects of metformin and on survival, tumor growth, and doing a lot of

the cell-based assays. And he's also looking at dichloroacetate, DCA. So it activates pyruvate dehydrogenase. So he's looking at each one individual and also in combination as a cancer therapy. Okay. I'll give you some of my ideas. Okay. So I, just because I want to be tested. But with DCA, so I did a lot of work in my graduate research, I had a lot of cancer metabolism.

You know, I was in contact with Craig Thompson, Ralph D. Bartini's. You know, we can't like all those people I were talking about earlier. And I did a lot of glucose withdrawal studies, glutamine withdrawal studies, blah, blah, blah, like all that stuff. So I've got a lot of interest in it stemming back from years and years ago. And I also was very active in apoptosis, working with some of the top guys in the field, got green. So the way I think about all of this and the intersection between them is that, like, you know,

cancer cells are, here's why I think cancer cells are glycolytic. So, I mean, the Warburg effect, I know that you've talked about this. and published on it. Is it a cause or a consequence? Yeah, damage respiration. Right. So I don't think, and I think even Otto Warburg himself published immediately after his original science paper, because he originally theorized damaged mitochondria with a cause of it.

But then it's not. It's not that the mitochondrial are damaged enough that they're not respiring. We don't really, even to this day, I don't think we have really shown that or disproven that, like thoroughly. I mean, it's, I don't think it's a cause, but the reason I think that cancer cells become glycolytic, I don't know what causes it or how I think the reason they do is because they don't want to use their mitochondria. And the reason they don't want to use their mitochondria is because mitochondria produce Ross. And that will drive, that's, this is the whole basis of how you kill a cancer cell,

chemotherapy, chemotherapeutic drugs. The way they work is because they induce a little bit of rase. active oxygen species, toxicity through a variety of mechanisms. Some more than others, but yeah. Right, through a variety of mechanisms. Augment oxidative stress, yeah. Which then pushes the cancer cell of death because normal cells don't have boatloads of, you know, proopopause.

If you look at, you know, any cancer cell, they have like boat loads of it. I mean, just tons and tons of proopatotics, but they've countered it and they're ready to die. You just need those little, little push. Yeah. And any, and DCA activates mitochondria. And I think that's part of how. Hyperbaric oxygen, too.

Hyperbaric oxygen. We were talking about this, too. I think that's also. Naturally stimulated, yeah. Yeah. But so I'd like to see someone sort of test that because I think that possibly DCA wouldn't be as potent at killing cancer cells if you gave it knack or something that's going to sequester the reactive oxygen species.

So could you block it? Yeah. That's another interesting. Right. That would be a good control to do. And studies have shown, you know, that, you know, giving mice, you know, supplemental vitamin E, something that's going to, you know, potently sequester reactive option species,

actually allows tumors to go faster. And this has been, you know, in recent years. Yeah, and acetyl cysteine, too. Mack as well, yeah. With metastatic melanoma, I think, came out. And then also there was one in lung cancer. Yes. I think it was the same group publishing it.

Yeah. But, so I think that part of the reason, because cancer cells are so smart, that I think that they, that not having their mitochondria active is very beneficial to them, because... Or less mitochondria, too.

Less, yeah, less mitochondria. Just a deficiency and there's, yes, reports of there's debate, you know, are the mitochondria defective or are there just a decreasing number of mitochondria? I think it's both. I think that mitochondria are structurally and functionally impaired, and I think there's a deficiency of them. You mean in cancer cells? I think in cancer cells, but I think in just normal cells, if you, you know, if you're

drinking alcohol and bombarding the liver with oxidative stress that you're damaging mitochondrial, you're damaging the mitochondria. And over time, you are going to induce the Warburg effect by causing progressive damage mitochondrial oxidative phosphorylation, you know, the cell's ability to maintain energy status through mitochondrial oxidative phosphory will be, its capacity will be impaired. So it will activate oncogenes and oncogenes that drive and glycolate. You'll have some cells will die. The ones that survive are the ones that go on and activate the complement of genes

that cause a transformation of a normal cell to a cancer cell. And that's how I sort of say that this progressive damage, you could do it with radiation, you could do it with chemotherapy agents, you could do it with inflammation. Chronic inflammation is damaging respiration. And it's that damage respiration that can kill off cells and the ones that survive that are hardy enough to activate the genetic program that allow them to survive, are kicking on the oncogenes that will then go on and produce a warburg phenotype. So that's sort of the metabolic theory of cancer in a nutshell. And it differs from what the thought leaders in the field are saying that it's, more of a default state to ensure the preservation of the cancer that exists, but not the cause.

But there's still this elusive enabling factor that we still don't know. And I think the metabolic theory nicely explains, you know, is a pretty elegant explanation as to how a normal cell, you know, converts to a cancer cell. And there's genes involved, definitely, but I mean, at the very most, the most we can link hereditary effect to cancer is maybe about 10%. You know, 7% I think was the number that was, it's being thrown around now, but about 10% of cancers are from a hereditary. But the epigenetics, I think, is something that will, yeah, and that's something that's evolving. very fast. I mean, I think that DNA damage, that's pretty, pretty well shown, damaging DNA, both mitochondrial and nuclear DNA damage, you know, that can lead to aberrant, you know,

cell, like, cell. And I think the mitochondria are more important because the mitochondria have less of a robust DNA repair mechanism. And also the DNA of the mitochondria have more coding regions. So if you bombard cells with radiation, you know, classically, radiation biologists are taught that that radiation is directly damaging nuclear DNA, and then that kicks on causes the genomic instability that causes cancers. But I think what is being more appreciated now is that the mitochondria are selectively vulnerable because their DNA repair mechanisms are far less robust. they have much greater coding regions within their DNA, and they're the ones kind of calling the

shots. They're making the energy. And if the energy status of the cell goes down, that's going to trigger the nucleus. That's going to trigger an energetic crisis in the nucleus, and the nucleus is going to kick on oncogenes to transform the cell from a normal to a cancer cell. So the stability of the nuclear genome is tightly regulated to the energetic state of the cell. Yeah, so I have a little bit of a different way of thinking about most things. I'm also doing a lot of research on this experimentally, and so I measure damage DNA

and I measure mitochondrial function after I induced radiation. In primary cells? In humans and blood cells, yeah. But so mitochondria, you mentioned that nuclear day have more repair mechanisms, and that's true, but mitochondria have very elegant and beautiful way of repairing damage through fusion, right? Mitochondyl fusion and vision. This is a process. I mean, this is how we are able to repair damage mitochondria because they're

constantly fusing with healthy mitochondria, changing, I mean, exchanging their DNA content, proteins, things like that, and phizzing back apart. So, of course, when those mechanisms become impaired, then that's, you start to have more accumulation of damage one because they can't repair. Fission proteins, the production of the proteins that caused that are also tightly linked oxidative stress. Yeah, so, I mean, there's lots of different ways to repair damage mitochondria is something that I also did a lot of work on in graduate school. But I don't think it's clear. I don't think that the metabolic theory of cancer.

Far from clear. You know, when you drop the ATP status in the cell, what happens is the cell dies and apoptosis gets triggered. That's the primary. Before oncogenes are activated, the cell, you know, dies. Unless it's, you know, if it's more gradual, then you have, you know, the activation. Most cells die. So you have, you know, 999 cells die. and then you have one that kind of activates the complement of genes that can allows it to survive, gives it survival advantage.

That's what you get with chemo too or radiation when you blast cells with a tumor with radiation. You get those few that can survive. And if you do that over and over to the tumor with course of chemos, you're kind of making a super cancer because you're increasingly, you know, selecting for the most. aggressive, glycolytic, you know, hearty stem cell-like tumor cell by hitting it with more chemo, just causing more DNA damage and more transformation and mutagenicity. So, do you see it like that? I'm not, I don't know. I'm not against standard of care, but I'm just, I'm in favor of.

In graduate school, I wanted nothing more to believe that mitochondrial dysfunction was the cause of cancer. but I just couldn't prove it to myself. You know, I kept trying and trying would have been so much easier from my graduate. My graduate career would have been shorter for one, but I just couldn't find

enough evidence to convince myself of it. And that doesn't mean that it doesn't, it's not true. It just means that I just, so far, don't. It may be. I don't think that's the origin of cancer. I think that metabolic dysfunction plays a very important role,

and causing cancer, primarily through inflammation, through, you know, all the effects of, like, you know, the insulin signaling and, you know, the inflammation and the reactive options species, just all these things that are damaging the cell. But I don't necessarily see it as the way that you sort of describe it as them. Yeah, them changing or activating oncogenes. I just, I don't think that's really been shown. I don't think anyone's studying that because, or studying it in the way that would make it clear. And I think it may vary between cancers like leukemia and lymphoma and relative to glialblastoma.

I mean, we know these are just, they have a different metabolic and a different gene signature. Glioblastoma has, you know, hundreds, if not thousands of genetic mutations. So, hence the name Gleoblastoma Multi for me, all these different cell types and everything. Whereas other types of, like, for leukemia, for example, Gleevac works marvelously well because it's targeting, you know, something that's very specific. So I think you're, I think it's, it'll be impossible to get a clear answer to this. And I don't think it's, I think maybe I'm a centrist. So I'm somewhere in between the, uh, the, uh, genetic versus metabolic, but leaning more towards a metabolic origin for many solid tumors.

But there's some cancers that just kind of throw me a curveball, like different types of lymphoma and leukemia, testicular cancer. And they're all responsive to chemo, many of them are. So what about, like, you know, for me, when I think of mitochondrial dysfunction to me, that leads more to neurological dysfunction, neurological disorders, less for cancer, less of cancer, you know, like when you're mitochondrial mutations, genetic mitochondrial mutations and mitochondrial genes, there's much more, you know, it has much more of an effect on causing certain types of neurological disorders rather than like cancer, right? There's one, like one, I think the

a sex and dehydrogenaseaseasease here, one of the components. I know this because I was trying to figure this out in graduate school. It was like a huge question. And they're really bad diseases. Yeah, these mitochondrial. So that's what I usually think of, when I think of my mitochondrial dysfunction, I always think of it as being more of it playing a causal or initiating role in neurological disorders and neurological dysfunction and not so much as it plays a role. I think that mitochondrial dysfunction and abnormal metabolism plays a role in cancer, but I don't think it's that initiator the way you were describing it. I think that's been shown.

But. I'm going to prove you wrong. Right. No. Well, our lab is, you know, we're not, we're just trying to find, you know, the answer. And I think that, you know, as we move forward and develop the tools, I think the answer will start to get a little bit more clear, at least using the models that we're using. But I think regardless, even of the origin,

The origin is important because if we, the way we treat and prevent cancer is going to be different if we know the origin, you know, for sure. You know, if it is a mitochondrial versus genetic origin or whatever origin. And, I mean, there's a case for viral origins of cancer too, but these viruses are sort of the ones that damage mitochondria, too. I've been sort of interested in the viral origins of cancer. It will influence, you know, how we prevent cancer. So in addition to developing therapies, we want to study animal models and maybe inducers of carcinogenesis and then adapt them or do treat them prior to or put them on a therapy prior to letting them live out their lives if they're prone to spontaneously forming tumors or, letting them live a few months prior to the introduction of a carcinogenic agent and then seeing after X amount of time whether the tumors form. So can we prevent, you know, this has a profound,

you know, implications for people who've been, went through chemotherapy or had cancer in the past and should they be on some kind of preventative there? Should they do a therapeutic fast? I get this question a lot, you know, for four or five days to a week, you know, every two or three times a year, should they do that? Would it help them purge their body of precancerous cells and put that metabolic stress? And these are important questions that no one's really trying to answer, at least from a point of a prevention sort of idea. So I think that's sort of on my horizon as the next big thing. Can we develop and implement, you know, have these protocols available for someone to do?

could be intermittent fasting. I personally like ketogenic intermittent fasting, where you're taking in ketogenic fats and ketone supplements throughout the day and through 20 hours of the day, and you have a four-hour window where you eat a well-balanced ketogenic meal that's rich in vegetables and high-end fats protein. And I think that could be something that could be implemented and something that I personally am interested in writing up a protocol for that. the work the study is done with metformin and showing that people who type 2 diabetics that are taking metformin have a 62% less chance of getting pancreatic cancer that's we need to study that

you know should that be part of a comprehensive preventative therapy that people should do I mean I question should I have my parents on this like should they or yeah I'm metformin or you know my mom actually had you know cancer years ago I mean I mean, should she be on something like this? Should everybody be after, you know, the age of 50 if most of their family members have died of cancer? Have there been any long-term studies on the effects of metform? Because I'm very interested in it, but I'm always hesitant with any drug or anything that's curbing biological systems. Yeah.

Well, there's, you know, hundreds of thousands, if not millions of people on metform. And so I would say, yeah, there's a long-term data out there, whether, and a lot of, retrospective studies have been done. It's relatively safe drug. Lactic acidosis could be a problem in higher doses for some people, maybe with renal insufficiency or impaired liver function. And then another thing that creeps up could be vitamin B12 deficiency. So if you are, our ability to absorb vitamin B12 as we age is decreased, so maybe a sublingual form or even B12 injection, in people that are older? That's a question.

That's a question I don't know an answer to, but I can speculate that it may influence the transporter, and it also tends to make stools loose for some people. Things go through you a little bit faster. It impairs not a good word. It changes the gut microbiome favorably. So nature, there's a paper that came out, about two weeks ago, showing that there was a favorable shift in the gut microbiome with metformin,

and that may explain it's type 2 diabetic, you know, it's glucose lowering effects. That sort of hit me as like, wow, I had not really given that a whole lot of thought, but it's something I think we should be looking into. So I was like, yeah, we need to collect all the, you know, start collecting the feces from these animals that we're doing metformin on to figure out what's going on with the gut microbiome. but I think it's influencing the absorption of B12 in some way that I don't really know. Does metformin, is it doing anything in addition to mimicking a lot of the same signaling pathways that coloric restriction does?

Like, is there something additional that, you know? Yeah, AMP kinase for sure. Right. So without a doubt, I mean, it's it's mimicking many of the pathways associated with calorie restriction and with fasting. To what degree it's mimicking that relative to, you know, a length or duration of fasting. I don't know. We're trying, we're doing some work right now looking at Amph Kinesis and MTOR and downshund. and upstream and upstream signaling insulin and these things and trying to get a picture of this,

at least in a rodent model. And then I would like to ultimately replicate some of this stuff in humans. But what I think it's, I think metformin would be best used maybe in pulsing it a few times a year. A lot of these things, metabolic interventions tend to work best when you cycle them, I think. And I really have not been doing that, but I think it's a theory that I've been working on in my scrapbook. Because your body is similar with keto adaptation, that your body can kind of reset to that level. Initially, fasting of the ketogenic diet is sort of a stress, and it can induce a hormetic effect and gene transcription.

And then we sort of get used to that. You know, our gluconeogenesis is upregulated to that level. but I think it's good to maybe pick, you know, probably not a high-carb diet, but maybe a paleo diet, you know, a low-carb, ketogenic diet, maybe something in between and do some intermittent fasting on occasional days. So I think this promotes metabolic flexibility. It allows our body to adapt to different situations without being kind of overwhelmed by the stressor of it.

So I think to some extent it is chormesis. And interestingly, metformin causes mitochondrial stress. And actually, mitochondrial damage, some researchers coined the term, you know, that it's stimulating reactive oxygen species production and causing mitochondrial dysfunction. Metformin is. And this is kind of well known in the field. So the general feeling is that, well, if I take metformin and I go exercise, why is it not killing my exercise capacity or my V-O-2 max or making me lethargic or tired.

It's not doing that. Actually, I think it's enhancing. Does it affect biogenesis? It does. So, yeah, so the thought that, you know, it's kind of stimulating. There's a hormetic effect. It's damaging the mitochondria. Some people believe this.

And you get a secondary, yeah, effect through that way. Like, it's kind of like an exercise drug. But I approached it from the perspective that metformin could lower blood glucose, at least if it was high and it activated antkines, and it may decrease circulating insulin. So I approached it as a cancer drug from that perspective. But the more conferences we go to, there's a plethora of data coming out of metformin, and a lot of people are studying it from the perspective of impaired. complex one or complex two activity in the mitochondria. So they're looking at it from that

perspective. I know. It's very interesting. Especially giving its effects on longevity and cancer. Yeah, yeah. And I think our most recent data did show an increase in Ross production in our cell line. That's also how it's killing for cancer cells. Yeah, could be. You mentioned when you were talking about gluconogenesis, you triggered something in my mind. I wanted to ask you, I forgot. So when you're in nutritional ketosis or fasting-induced ketosis, you need to make glucose. You know, you still need glucose. Your red blood cells have no mitochondria, and your red blood cells are important, right? So you're making glucose through this process that you mentioned called gluconeogenesis.

And... Glucose does not bottom out. It's not like one or the other. Yeah. Yeah. You're, you're You're pulling fuel source from that. So I wanted to ask you about, like, how has anyone looked at, you know, where this glue, so, you know, if you are on a, you know, pretty strict, you know, ketogenic diet or whatever it is you're doing to get into ketosis, what, so is the, does the liver use, like, glycerol, lactate, like, both as a primary source to make glucose? and is that glucose predominantly going to red blood cells or does it go, you know, has that been

looked at to see like where, you know. So red blood cells, like, are they getting enough of their glucose? Are they, you know. I think so. I mean, you'd probably have to severely calorie strict in those cases. You could become anemic or impair your immune system is also too highly dependent to some extent on glucose and glutamine. So yeah, you have lactate, you add the glystrol back bone, the fat.

of fats. Yes, yes. So glycerol backbone and fatty acids or of triglycerides for sure. Lactate, yes, and amino acids. Gluconeogenic amino acids in your diet also are a source of glucose. Gluconeogenic amino acids in your skeletal muscle. Your muscle is constantly breaking down, remodeling, especially in athletes. So they're all sources. The contribution of each of these gluconeogenic sources in each individual probably varies tremendously. But I would say that, so glucose is always going to be there, and the body ensures through very powerful homeostatic mechanisms that your glucose is going to stay, rarely go below three, maybe 2.5 millimolar, myel drop tube to four, and stay within a pretty tight range.

But what does change considerably from a glucose regulation standpoint is that insulin. Insulin bottoms out to the point where I've seen enough blood work to show that in many cases, insulin and IGF1 is below the reference range. So insulin signaling goes down. So if insulin's down, you know, all those insulin pathways that you see on your flow charts are all going to be suppressed. and IGF1, obviously, it's going to be lower. And I think that's a really important, important to consideration to factor in as it relates to cancer therapeutics, cancer biology, cancer prevention even, but also from the perspective of muscle metabolism. And I think by keeping insulin signaling sort of low, you upregulate factors that make you more responsive to insulin.

So I think, you know, and ketones can kind of compensate for a deficiency in insulin. And that was a lot of the, you know, reviews by Richard Beach talked about that. And the ketones themselves are anti-catabolic or protein sparing. So if you're in a state of ketosis, you're protecting gluconeogenic amino acids and skeletal muscle from being degraded. So you are, you know, as a metabolic fuel, but you're also, there's evidence that you're inhibiting proteolytic enzymes and pathways that would otherwise be chewing up your muscle tissue over time.

That's super cool. So it's anti-catabolic. Yeah. So ketones are anti-catabolic. So then you're probably not using the gluconogenic amino acids as much. From skeletal muscle, yeah, not as much. So the idea is that you want to keep pumping in the fat, too. If you're on a ketogenic diet, if it's not sufficient with ample amounts of fat, you're

probably much more catabolic. So you want to ensure that you're, you know, using the fatty acids, go to the mitochondria. They're using the mitochondria happy, as do the ketones. And then the glycerol is kind of shuttled. And it's a very nice, kind of an elegant pathway to ensure that we have that flux of glucose for vital functions like the red blood cells and making, there's a number of neurotransmitters and hormones that require, you know, a baseline level of insulin. or glucose to be used. Man, we've talked about bringing you a lot of things. Yeah.

It's just so many things to discuss, but I'm really, like, thankful that you can probably talk for like four or five days, nonstop before we like collapse. You see how I get. I get, like, really excited. And I'm like, okay, wait, I got to ask you this question. I have this idea. Yeah. And then you're just like full of information.

So it's kind of neat. A fun field to be in, right? I mean, I'm always, I feel like I'm so lucky to be in. in an area of, you know, being in an occupation where discovery, we have the potential to discover something new that can impact the population and get paid for. So because you totally, I'm sorry to change the subject, but you, you're talking about glutam analysis and I have done a lot of research on this and there are questions that I would love to be answered, but have you been. So since you're looking at this and you have resources,

I'll just throw it out there. You know, so obviously when you said, you know, in the This is, this is well-known literature, that glucose and glutamine are both, you know, cancer cells love them. It's like crack for cancer cells, both glucose and glutamine. And I've been a lot of studies on various types of cancer cells, and these are in vitro. So this is not in an animal model. Yeah. Where I withdraw glucose, and the cancer cells will proliferate slower, some of them will die.

But if there's glutamine there, you know, they'll be far away. What's your level of glutamine? two milomolar. So then I would start withdrawing the glutamine. Yeah. And glutamine withdraw, this is all in vitro, though. Glutamine withdrawal would kill him within like 24 hours. Yes.

So glutamine. Pretty lethal. Yeah. Very lethal. And has been shown by at least some of the studies that were initially done by Ralph de Bartini's when he was with William Thompson. And later when he established his own lab, where he radio-labeled and showed that actually it was being used predominantly for a macro molecular synthesis and not for you know which is

of course that makes sense because a lot of tumor cells aren't using their red kind of making fatty acids actually making fatty acids protein so like for new synthesis um so the question for you um the question that i have and this is so that's one end of the spectrum okay glutamine seems bad when you're looking from an in vitro's perspective and and i've did these studies but many people have published on this you're familiar with the literature. But then there's the other perspective where glutamine is really, really, like your gut cells.

It's very, very healing and therapeutic for gut. And when you take glutamine orally, the gut takes it. It's not getting into your bloodstream. It's not being, you know, so... The gut and the liver take its share and very little of it actually gets into the bloodstream. Right. So that's what I'm

getting at. The question is, if you have a mouse model of, you know, a solid tumor that's not gut-oriented, so it's not colon cancer. Let's say it's, you know, you've got a pancreatic cancer. Brain tumor. Brain tumor. Then you give the mouse glutamine, is that really, you know, so is it really going to affect

the tumor or is it just going to help the gut? I mean, of course, it could indirectly affect it. But the question for me, in my mind is, well, yeah, if you had a tumor in the gut, man, that's like crack for the tumor. or do not take glutamine. You know, but on the other hand, if you've got gut issues, you know. Can be helpful. Right?

Do you see what I'm getting at? Yeah. This is something that I've thought about. I'd stay at night. Yeah, thinking about stuff like this. I'm not alone. Yeah, yeah, yeah. Because it's like, well, in vitro, it's very different because the way our bodies are working

in the way glutamine, you know, when we take glutamine, it's affecting our gut, you know, it's very important. Yeah. It helps. I've taken, I mean, I've helped me. Yeah, it's helped me with gut. But then this whole, you know, this whole like conflict in my head room, you know, I'm like, cancer cells love it.

Yeah. But the question is if I'm taking to orally and I have some, you know, cancer cells in my, you know, I don't know, my liver or something, then I guess you said liver is one thing that does, it does use it. But so the question is, is that harming me or is it helping me? Should you take it or not? Yeah, I get the question a lot. For GI cancers and liver cancer, I would say do not supplement glutamine.

Yeah. And I would say under most conditions, I would say in those states actually try to look up, you know, the glutamine content of food and you might want to avoid it or minimize glutamine, high glutamine containing foods. Otherwise, I wouldn't really pay too much attention. Some patients really stress out about it, you know. But I think if you just keep your protein low to moderate or keep your protein at a level to enjoy. sure proper, you know, regeneration and just kind of replenishment of your normal cells and prevent protein deficiency. And being in a state of ketosis will help with that to some extent. But glutamine is pretty low on the... The classical ketosis, right? Yeah. Yeah. Yeah. And I think that will lower your blood glutamine levels. Just being on a ketogenic diet will do that. And then you could further lower it by selecting protein

food sources that are lower on the end of, you know, are glutamine or not, or avoiding protein types of supplements, avoiding glutamine supplementation altogether. And you may be able to further suppress glutamine by taking a supplement that's like high branch chain amino acids, high essential amino acids. So taking a supplement that is formulated in a way that kind of gives you essential amino acids excluding, you know, glutamine, of course. Glutamine's not essential amino acid. It's conditionally essential. But then you, I don't think you'll run the risk of being deficient in glutamine in

any way. But I would avoid, I would pay attention to it if you have a GI cancer or liver cancer. Liver I didn't know, but yeah, GI always definitely. So if you have, say, for example, like a brain tumor and you're taking a drug that can impair, you know, systemically you're taking something that impairs your GI function, then it may be helpful to take a little bit of glutamine because I don't, I really don't think, the gut's going to be very greedy when it comes to glutamine. So I think just, you know, maybe even 5, 10 grams of glutamine to help repair your gut.

We know that if your gut permeability is impaired, that can wreak havoc in your body as far as systemic inflammation. So try to try to, there's other ways to repair your gut too, but I think glutamine may be a factor, you know, in helping to ensure proper good. Yeah, there's definitely other ways. I mean, I think that, like I was saying, fiber, good diet, things like that. Yeah, exactly. But glutamine has been used in oncology. So, yeah, glutamine for helping people with chemo, combating the issues with chemo.

Yeah. I mean, glutamine has almost been like a staple, you know. So they give it to chemo patients out of... help them recover part of the immune system, too. Because your gut regulates the immune system as well. Your gut is, like, what, like 70% of your immune system, right? Yeah. It's huge.

So we want to keep your gut as healthy as possible. And there are many drugs out there that really impair gut mobility. And diets, yeah, diets, yep. Cool. All right, Dom. Endless amount of things. I know, right? Just keep going.

Yeah, I've had like 100. things pop into my head about like, should I bring that? Yeah, should I not? No, I don't know. Bring it up. I'm always interested in new things. We do have ketone esters here, and not too many people are brave enough to try them, but we have a lot of studies going on using a wide range.

They're all different types of ketone supplementation, and I know that was kind of one of your main interests that you wanted to hit on. Yes. And I would say stay tuned because we have so much going on. right now with like all these studies looking at ketone supplementation and the answer that I want to really focus on is what kind of benefits are we deriving? There's been so much work on the diet, you know, what kind of benefits can we mimic which is purely a ketone supplementation and and can we further augment

the therapeutic efficacy of the ketogenic diet with supplementation? So a diet and then we supplement, you know, 10, maybe 20% of the calories with some form of ketone supplementation. Hopefully we work to formulate it in a way that it makes it pleasurable to taste and not taste like gasoline. If we can do that. Does it really like gasoline? Yes. Yeah, like jet fuel, really. Yeah, it's pretty bad. But the ketone esters do, but we're working on the ketone salts that you might know of, you know, ketokanea, ketone, there's a couple ketone products out there. Or drawbacks to one or the other? The salts are like, you know, as far as ketogenic potential are pretty similar to MCTs.

They're another level up from MCTs, I would say, right now. But they're being formulated. We're formulating them and testing them in ways to make them closer in potency to the ketone esters. And I think... Are these available, like, to consumer? Not for human use yet, but we're working on doing all the safety studies and then all the palatibility work and formulating them in a way that probably within the next six months to a year that they will be out.

Oh, so we're tracking them for therapeutic purposes, so for clinical trials, for specific diseases, and then it kind of worked backwards to the consumer broad market eventually. And for oxygen toxicity, obviously. That was the original application for auction. I'm also really interested in it just for movement disorders. My mother has orthostatic tremor. And she's not the kind of person that is very compliant. I mean, she may try something for like a couple of days, maybe a week.

That's typical. Very typical. And it drives me crazy because I feel like I have so much knowledge that I could help her. And it's just very hard to get her to get any movement. but I would, I'm very interested in the potential use of petone esters or whatever delivery method, you know, is that's, that's the best in potentially helping reduce her tremor. Because, you know, when she stands still, her leg shake, you know, and it's very, it's inhibiting to her life. I mean, you know, having to, when she's walking, she's fine. Yeah.

But if she stands, she stands in line. From sitting to standing and just... No, even walking to standing. Just just standing. So standing still. It's called orthostatic tremor. Yeah. And it's not...

I mean, it's common and not... Yeah, I've heard that. But it's not like... It's not as common as essential tremor. Yeah. But she also has essential tremor as well. Yeah. Kind of interesting.

But, yeah, so I'm extremely interested in the potential benefits of nutritional ketosis. Yes. but like I said, she's not very compliant, so I'm sort of like, okay, possibly, you know, giving her some sort of ketone ester and seeing how that would affect. Because then again, if she... I might want to start with MCTs. MCTs. I mean, something, what I showed you today, the MCT powder by Quest Nutrition.

Yeah. It's really pretty close, you know. It's very potent from a ketogenic perspective. And if you were to take, you know, four to six to up to eight scoops a day, which would be tolerable. and of course of the day, she would be in a mild state of ketosis and would be getting the benefits. Really? Do you think that would be easier than like the MTC oils? From perspective of GI tolerance, yeah. Many people, you know, I would say, you know, up to 40 or 50% of people are going to have some tolerability issues with liquid MCTs. At least a big dose that gets you up into sustainable ketosis. You can incorporate MTCs. You can incorporate

MCT's in your food, even salad dressings cook with it, mix it in with different things. But the MCT powder I found was you can get levels about twice as higher than you can with the oil, just simply because your GI tolerance is much better in a powder form. So it's formulated in a way that kind of allows a sustained, slower release of the MCT instead of a liquid which tends to – some people just can't tolerate the liquid at all. I can tolerate fairly high amounts, relatively speaking, but I could tolerate much higher amounts with an MCT powder. You can put it like, and you can mix it with water, coffee, tea, whatever.

I put it in coffee. Yeah, you think it. Yeah. Yeah. Yeah. Yeah. Yeah. So, uh, so they really nail that.

Coffee makes her term much worse. That's just she doesn't drink coffee. No stimulants. Yeah. What about decaf coffee or something like that? Um, I think she, it's a good vehicle for MCTs. I mean, you could put like butter and MCT, you know. I know you don't like sweeteners, but I just put a little pinch of stevia in there.

Stevea is okay. And it makes it a really enjoyable drink for me. Yeah. Yeah, that's great, that it's available because I'm kind of, that would be something to probably try seeing if that has any effect on your tumors. As you know, diet's key, though. Yeah, because if you're like eating a bunch of refined crap and processed foods and just terrible diet, it's not much that ketones are going to do, right?

Yeah. And what I find in people that are resistant is that if you can introduce foods that replace other foods, you know, which is good. And I think Quest Nutrition, too, is making a line of, they're not out yet, but I've tried everything from a ketogenic Oreo to a ketogenic brownie to ketogenic chocolate bars. So these are foods that when you eat them. you are in ketosis and they taste as good or good as their high sugar counterparts that are on the market. So I see that as almost like the next frontier, like designing, developing ketogenic food products from whole food ingredients that are, you know, from natural sources and not synthetic sweeteners or artificial flavors and things like that, that will allow you to, will ensure greater compliance of nutritional ketosis.

mainly at first maybe targeting, you know, disease populations, but undoubtedly, you know, people from all walks of life will be wanting to use these foods, especially if they taste good. And I can tell you from kind of a beta tester point of view that it is possible to create a line of food products from crackers to chips to, you name it, really. It's possible to, it's pretty easy to make something taste good when you're working with fat. Because fat has fat and salt kind of make things are really good on our palate, you know, and they're very satiating. So we'll eat it a little bit, and it's just enough to sustain us and give us the energy that we need without overeating.

Yeah. I'm excited about, you know, the ketone supplements, obviously, but I'm excited about a line of ketogenic diet food products that can ensure compliance. and people who really need it. Because I see that's where there are people who know the diet would help them from a therapeutic standpoint, but they just lose interest after trying to follow through with the diet. Yeah, and it would help eliminate a lot of suffering, especially for some of these people with these, like you said, drug-resistant seizures.

Yeah, for sure. Well, super cool, Dom. Thanks for speaking with me and for doing all this really cool research. I'm going to keep following your research. Thanks for visiting. If people want to learn more about your research, what you do, things you talk about. about anything related to your research work. Can they hear more about you?

I would say I'm working on a more interactive, a broader site, but for right now, Ketonutrition.org, I think, would be the site to go to where I compile a bunch of links on there with dietitians, ketogenic savvy, registered dietitians that I recommend, books, talks from IHMC, which I'm excited to listen to your IHMC talk this week. is that on there. So I would say that ketonutrition.org. Ketoniturgetion.org. And what about social media?

Yeah. Facebook. You can find me on Facebook, on Twitter, LinkedIn, Pinterest. Maybe I go there sometimes. But Facebook, Twitter, and LinkedIn are sites where I will post information about our research or related research in the area of nutritional ketosis and metabolism. Awesome.

Thanks a lot, Tom. Thank you. Thanks for having me. Thanks for listening, folks. This was a fantastic podcast, and Dom is full of interesting information, especially when it comes to the topic of all things, ketosis. Now remember, ladies, gentlemen, licensed acupuncturists and chiropractors, if you would like to send magical fist bumps over the internet,

then you can do so by pledging just a few dollars to Found My Fitness by going to Found My Fitness.com forward slash crowd sponsor. That's FoundMyFitness.com forward slash C-R-O-W-D-S-P-O-N-S-O-R, crowd sponsor. Also, go give Dom a shout out and let him know how awesome you think thought this podcast was. You can find him at Twitter.com forward slash Dominic Dagestey 2. That's D-O-M-I-N-I-C-A-G-O-S-T-I-I-N-R-T-I-I-O-N-E-O-G. Or go check out his website and grab some of his other social media hotspots at ketonut-N-R-I-O-N-R-N-O-N-O-N-U-T-R-N-O-N.

Thank you for listening. thank you, Dom, for coming on the podcast. Tudaloo for now.