The Ketogenic Protocol for Longevity & Cellular Health with Dr. Dominic D'Agostino #255

You know, my great passion in life has always been muscle building and movement. And in order for us to move effectively, people don't always think of all the potential influences on how well we move, how well we think, and ultimately how well we perform.

Today's guest is pushing the envelope of human performance, not only from a physical perspective. But from a mental perspective. He resides in Tampa, Florida, a neighbor of mine and an incredibly brilliant human. He's doing work with NASA on how to really push the performance of the human system.

Period. We dive today into mitochondrial health, the two most important interventions for high performance who want to optimize health on a daily basis. We talk a little bit about metformin and its impact on mitochondrial health. We talk about ketones and you may recognize this man's name as being the most famous name in the world of ketogenic dieting. Dr. Dominic D'Agostino joins me today to discuss.

Uh, I know that kind of sounds like they're two dichotomous things, but we do dive into some really interesting thoughts and and things that Dom is studying now, ultimately that do tie very closely into what does high performance look like and how do we push that and ultimately how that actually implicates in obviously ketogenesis and cancer.

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As we continue to get better and bigger and things are just moving in the right direction. So thank you guys all very much. I appreciate it. Enjoy the show with Dominic Agostino. See ya.

to not only understand mitochondrial dysfunction as a consequence of like these extreme environments, but to develop C biological countermeasures to mitigate mitochondrial dysfunction in these extreme environments. And I've been working mostly with the Office of Navy Research and NAFSI to understand this. And we have environmental chambers. I forget, Ben, if you've been into our lab before. I've ever okay. Yeah. So

We have a variety of different environmental chambers where we can simulate these extreme environments. And we a part of what I did with my postdoctoral fellowship was developing atomic force microscopy, laser scanning, confocal microscopy, where we can like look at the mitochondrial function under these extreme environments and look at reactive oxygen species production. We do electrophysiology in these uh fluorescence imaging.

So from our perspective, it's very basic science research, but over the years, you know, after we first connected, I was probably mostly all basic science, but then now we do clinical research, you know, some of that's being done at Duke. And then Florida Medical Clinic. And then I became a subject myself in uh extreme environment. I was part of NASA's extreme environment mission operations, which is you lived underwater.

And then my wife was on uh mission twenty-three, which was an all-female crew. Three of those aquanauts are on the International Space Station right now. That's Shell Lingren. He was my commander, uh Samantha Christopheretti, who's an Italian. astronaut and uh Jessica Watkins who's a female and I believe she was

selected even for the Artemis mission. So she might be a future moonwalker. So there was uh yeah, so we we actually trained with, you know, astronauts and stuff and did a variety of different testing on them. We used like the aura ring. The polar V800 to look at uh heart rate variability. So a lot of what we were doing in the lab looking at

Mitochondria looking at cells and different rodent models, we've moved that into human research experiments in an extreme environment. And one would be the space analog mission Nemo. NASA's extreme environment mission operations. So I'm involved in sort of moving that science into human application. And really with a focus now is understanding like how do these environments disrupt our performance?

our cognitive performance, our physical performance, and probably most important, our overall health and longevity in these extreme environments. And then developing countermeasures, which could be exercise, it could be dietary, it could be nutraceutical, or it could be uh pharmacological. There's pharmacological agents that mitigate muscle loss, you know, bone loss and cognitive function. So kind of looking at all these different things.

You know, obviously higher performers, but uh you know, tell me if I'm wrong, the mitochondria is obviously play such a massive role in everything we do. If we can upregulate their ability to withstand huge amounts of stress, it almost feels like it it's like making them them a more powerful version of the species.

For example, you know, is an enzyme you know made in the mitochondria. So the mitochondria are not only generate ATP that the cells use, but They are very powerful signaling molecules and they communicate back and forth with the nucleus of the cell. You know, we always say the mitochondria call the shots.

So even in the context of things like cancer, when the mitochondria become damaged, ATP levels fall. And then through a retrograde response, that basically cell tells the nucleus that there's an energetic crisis. And that began to cascade to nor to transform a normal cell into a cancer cell, which upregulates things like glycolysis.

and sugar metabolism, and that's, you know, eventually the the transform cell has a w what we call a Warburg phenotype, which is damaged mitochondrial respiration and compensatory fermentation. So the cells ferment. And they're they're using fermenting fuels like glucose and glutamine for their survival. A similar thing is happening happening in a very protracted way in the context of a space environment.

Or even an undersea environment where there's a higher concentration of oxygen and even a higher concentration of CO two. The partial pressure of CO two in International Space Station is similar to a submarine where it's like

two to eight thousand parts per million of CO two and this is causing redox stress. So this is something that we study in the lab, how it affects you know, neural control, how it affects brain function, physical function, the gut microbiome, our gut permeability, the high CO2 tends to damage the tight what are called the tight junctions in the gut.

And that makes the gut leaky. We had the same tight junctions on the blood brain barrier. So it also makes the brain kind of leaky and contributes to inflammation. You know, when I was in these extreme environments, I measured HS C RP.

Which is kinda like a global, you know, and and other measures, but I measure HR HSCRP probably a hundred times through in the lab and different kits and it's always super low, like 0.1, 0.2, unless I have some kind of infection, and these extreme environments shoot it up.

almost to like where I have an infection. So we know that over time, you know, we have to figure out how it's doing it, why it's doing it, and developing countermeasures against it. But the countermeasures that are being developed, much like many military projects, those technologies can be applied to the everyday person, right? So for for not only performance enhancement, but just general health.

Whereas a cancer cell metabolism essentially de differentiates from deriving the majority of its energy from mitochondrial oxidative phosphorylation. you know, the electron transport chain. There's a gradual progression of decreased mitochondrial function and mitochondrial number. to relying more on glycolytic glutaminolysis metabolism, where you're deriving energy from glucose.

So cancer cells in many ways have especially more aggressive tumors that are metastasizing and growing very fast. They have super high rates of glucose metabolism, 100 to 200 times higher. And as a consequence of that, we can image cancer tumors with a fluorodeoxyglucose PET scan or FTG PET scan. So the tumor lights up very intensely. And what you're imaging there is a hyper absorption and metabolism of glucose relative to driven by glycolysis relative to mitochondrial function.

Which and mitochondria use fatty acids and ketones for fuel. So that's sort of falls into this idea that is true to some extent is that if you're in a state of low glucose consumption, low glucose, low blood glucose, low insulin, low IGF one. uh which would be facilitated with a ketogenic diet.

and high fatty acid oxidation, high ketones, that would basically marginalize the growth and development of the tumor. So going off a bit of a tangent, but the Warburg effect, a simple, if I had to have a one sentence description of the Warburg phenotype, it would be damaged mitochondrial respiration leads to compensatory fermentation. So we know that the DNA have of our cells have very robust repair mechanisms.

If we're exposed to environmental toxins, if we're exposed to like in space radiation, if we're exposed to viruses, tend to damage the mitochondria to a greater extent than the nuclear DNA. So progressive damage to oxidative damage, inflammation, viruses, cancer, radiation, all these things tend to damage the mitochondria and the mitochondrial DNA more than the nuclear DNA.

And essentially what happens, you have progressive mitochondrial dysfunction and the DNA repair mechanisms of the mitochondria are not as robust as the nucleus. And then the nucleus, the brain of the cell.

is really sensing that there's inflammation and an energetic crisis and that kicks on a survival mechanism. And some of those survival genes are called oncogenes. And oncogenes, when they are expressed, starts the transformation of a normal healthy cell that would have healthy, robust mitochondria, that mitochondrial damage starts to transform a normal healthy cell into a precancerous cell.

And then progressive damage to the mitochondria and activation of certain oncogenes can push the cell to the point of no return. And in some cases that cell dies, uh, but in some cases, if that cell goes on to live on. the oncogenes endow the cell with what we call the hallmarks of cancer, which is unbridled proliferation, inflammation, metas metastasis. you know, aberrant cellular metabolism. So that cell transforms to what is called a Warburg phenotype.

So uh and some people think that the Warburg effect, the benefit of that for the cancer cell is directing uh carbons to biosynthesis and but it also allows the tumor to basically live in a hypoxic environment. where if you're deriving energy from glycolysis, then you're not as dependent upon oxygen and oxid you know, oxidative phosphorylation.

So I became very interested in why this happens and after it happens, after the fact, you have a Warburg phenotype. How can we change the metabolism of our physiology and the cell environment to limit the growth? and target the Warburg phenotype to kill that that particular cell type. And that has become a big thrust of an unexpected direction of our research in 2009 or 10. I started studying that.

Space radiation is called galactic cosmic radiation. It's a bit different. It's like uh you got solar particle events and uh basically charged ions kind of going through your body, which can Make NICs in your DNA, mitochondrial and nuclear DNA, and double-stranded NICs create mutations and then uh, but it's really impacting the mitochondria.

So getting back to your question, you know, if you have cancer, and this would apply mostly to not so much to leukemia and different forms of uh lymphoma, but solid tumors. We're mostly interested in like brain cancer is what we have kind of started focusing on.

There are different strategies that you could use, you know, I think of the ketogenic diet, caloric restriction and ketogenic diet and diets that restrict fermentable fuels. will decrease, will take the foot off the gas pedal, so to speak, of cancer growth. So it'll slow it down. It will not cure cancer. I don't care whatever anybody says, some some people

look at different animal studies and and say and think that different dietary patterns, whether it be the budwig diet or the vegan diet or this diet, it would be the cure for cancer. And that's not the case. But these nutritional therapies and that's what they are, medical therapies.

can can be used in as a standalone therapy, you know, if cancer has been very advanced or if standard care is not working, but we're very interested in using a modified ketogenic diet that I call like a protein sparing modified ketogenic diet that's supplemented.

So it's a ketogenic diet that has higher amounts of protein to mitigate cancer cachexia. It's modified with the types of fatty acids that comprise a ketogenic diet is much higher percentage wise in fat. So We want to use, you know, omega three fatty acids, less omega-6s. We want to use medium chain triglycerides because they're more ketogenic. And we also want to incorporate different types of prebiotic fiber into the ketogenic diet to preserve and sustain.

the gut microbiome because that's really important for barrier function in the gut. It also makes uh short chain fatty acids like butyrate, which can be

for different fermentable fuels. So we usually use a common like some soluble and insoluble fiber mix. But when you're formulating like a diet for someone, you want to have a diversity, mostly like things that are very like greens. So very dark greens, dark leafy greens.

Yeah, broccoli of course is good, uh asparagus, things like that, things that are just mostly water and fiber. But then a lot of a big part of what we do is actually developing ketone supplements that do two things really. They elevate ketones in the blood and ketones have, you know, they provide energy to healthy cells, but not so much cancer cells. They have epigenetic effects. They have s anti-inflammatory signaling effects.

They preserve and can protect the brain from radiation if someone's undergoing like radiation therapy for a brain tumor. And they have anti-catabolic effects. So uh we've published on this showing that. And that may be like from an evolutionary perspective, when you're fasting, you

start mobilizing fatty acids for fuel, the fats do not cross the blood brain barrier. So the liver converts the fats to ketones. And then the ketones can preserve your CNS function and many people become more lucid, like in a fasted state. And then The ketone bodies actually prevent the breakdown of skeletal muscle, they actually have anti-catabolic effects. So if we're fasting, if we w we did not make ketones, first of all, we would not have brain energy. Our brain energy would would tank.

Right. But the beta-hydroxybutyrate and acetoacetate prevent alanine from breaking down. A major gluconeogenic amino acid in skeletal muscle is alanine. So we'll start breaking down skeletal muscle. To liberate glucaneogenic amino acids to preserve our normal, there's very powerful homeostatic mechanisms that maintain blood glucose. And part of that process is breaking down skeletal muscle to get access to it. But if ketones are elevated, then that has a tremendous.

Anti-catabolic effect by virtue of preventing uh the breakdown of skeletal muscle, by preventing uh gluconeogenesis and also to some extent glycogenolysis. So supplementing ketones to that diet that I described, a protein sparing, modified, supplemented ketogenic diet with ketones would be a way to keep glucose low and elevate, yeah, glucose low and elevate ketones to where they're at at about in millimolar concentrations at about three or three point five.

So glucose is usually, you know, five, six, seven, eight in some people in America, millimolar. We're talking millimolar concentrations, which is like a, you know, 100 milligrams per deciliter in US units, depending upon the units. But essentially what you're doing is getting the level of glucose down, bringing the level of ketones up to where the millimolar concentration in the blood is about equal. And we call that a glucose ketone index of one. And the standard American diet has favors

glucose to where it's like 25 to one. A clinical ketogenic diet is like maybe four to one, but a really restricted, a really a modified ketogenic diet that I'm talking about that's really engineered. for optimal therapeutic efficacy produces a glucose ketone index of about one. You can't get rid of glucose altogether. It's not like your body's switching to fats and ketones. Your glucose will stay it'll stay there. But This has a profound effect on the growth of cancer has a profound effect.

on brain function, on preventing seizures. So that becomes the foundation then to apply different, different uh modalities like hyperbaric oxygen therapy. For example. It basically when you restrict glucose availability to the tumor, that inhibits the endogenous antioxidant mechanisms within the tumor. So when you hyperoxygenate the tumor, when you reverse tumor hypoxia and hyperoxygenate it, the tumor produces an overproduction of oxygen-free radicals and can kill it from the inside out.

So tumors usually they grow really fast and the oxygen supply, the vascular supply cannot keep up with the growth. So you have less vascular. So the tumor becomes hypoxic in the core. But with hyperbaric oxygen therapy, you increase the oxygenation in the body independent of hemoglobin. So hemoglobin's already saturated, you know, right? So it's like 90, 100% hemoglobin.

But the oxygen is in is dissolved into the plasma. So it's independent. Your your body's carrying the oxygen and it's dissolved in the in the plasma, in the liquid component. So it can get all into the nooks and crannies of the tumor. Right. And then that

then that makes the tumor more vulnerable to this modality that I'm talking about, which is hyperbaric oxygen. It would also make the tumor more vulnerable to radiation and chemo, to the standard of care and also immune-based therapies. So you have, you know,

ketogenic diet that can slow tumor growth. It's not going to reverse it in most cases. Some cases it will. Hyperbaric oxygen therapy. And then you have a whole toolbox of different drugs that we can talk about. So we have focused on metformin as a drug.

That seems to work pretty well.

So you have a lowering glucose and an elevation of ketones. And in that context, insulin still stays very low and it's very suppressed in that low end of normal. In that context, uh it really marginalizes, it really impacts. Cancer growth. Pretty much all cancers are dependent upon, you know, insulin, IgF1, glycolysis. I mean, that basically underlies the imaging technology. That's the gold standard, FGG PET.

So we use that technology to image tumors and also to show how aggressive the cancer is, but we don't historically use that tech use that that knowledge to target it with uh different metabolic drugs.

Until I mean I was talking about this ten years ago, until the last ten years. So now we have cancer conferences all over like cancer metabolism where drugs like metformin, drugs that are targeting like PI3 kinase inhibitors, Lou Cantley has been working on that intensive those PI3 kinase inhibitors work. primarily in the context of a ketogenic diet, because if you take a PI3 kinase inhibitor, you get a counter-regulatory effect of increasing insulin.

But if you couple it with a ketogenic diet, that will bring insulin back down and basically unleash the therapeutic effects of that PI3 kinase inhibitor. And then there's 2Doxyglucose. We've been working with that for years. lonidamine, it inhibits hexakinase, which is a glycolytic uh enzyme. Basically the cells need that to

to make energy from glycolysis. You know, and and there's different like plant-based compounds too, that like EGCG, which could help bring down glutamine. It has some effects. So there's different plant-based compounds that I'm super interested in. It's just hard to get funding for those.

types of research, but personally I'm very interested in researching many of the more natural plant-based console. Berberine is an example or dihydroberberine is is an example of something similar to metformin that's more of a natural.

Always or is it cyclical? I think last time we spoke you said you were kind of cyclical. Sometimes in the summertime you'd you'd have some more carbohydrates. I'm curious if that's still the case. And I I've heard some some conversations around like some potential acidifying effects of taking ketone supplements too often. I'm not sure if that's true.

Yeah, I incorporate like seasonally some, you know, more vegetables or more fruits in in the summer and tend to eat a little more ketogenic in the winter. And my protein on some days is is higher. Some days I'm, you know, above two hundred or but usually fluctuated about one hundred and fifty grams protein a day, which is probably not that much from your world. I mean back when I was twenty, twenty five years old, I was getting four to five hundred grams of protein a day.

Like legitimately eating pounds of steak and washing it down with metrics. Remember metrics with HMB, all at that supplement logic.

focus were on the weak points and and that's I think what really set you apart. I think you were like and you've talked about this too is just really focusing on what is not optimal and just balancing everything out.

with like one point five. But, you know, our sample size was only I think eight or ten. And we realized, hey, if we had twenty animals, we would probably have statistical significance here, but It's not as robust as using like two point five or three atmospheres of oxygen, which would require a hard shell. uh hyperbaric chamber. Keep in mind that I am talking about animal model studies for this too. So um, you know, in humans it could be a bit different, but

You know, in in comparing and contrasting low dose oxygen with high dose oxygen, the tumor suppressing effects of high dose oxygen was much more. And it's within the safe limits of hyperbaric medicine. So, you know, that's used for wound healing. And we didn't actually even do it every every day. We did it Monday, Wednesday, Friday. And we had a break. Like Tuesday would be a rest day.

And there would be adaptive processes and then we'd hit it again uh Wednesday and then hit it again Friday. So it'd be three days a week, which is more feasible to do for the patient too.

The government, you know, the NCI and and the NIH don't they don't really fund research on cancer prevention, which I think would be really important because there are animal model systems that we know that this particular animal model will have You know, fifty percent of the animals will have spontaneous tumors by the time it reaches two hundred days of age, right? And then there's

basically you could take animals and give them, you know, UV radiation to produce skin cancer. You could take you could give them certain environmental toxins that we know produce spontaneous tumors. So if we were to take these various animal models and then start prophylactically putting them on ketogenic diets, giving them hyperbaric oxygen therapy or different plant-based compounds, and then looking at spontaneous tumor formation over the life of the animal, that would have tremendous

you know, translatable consequences, actionable things that but this type of research is is not being done. And we think it's kind of important. So we hope to do some of those studies in the future. We do know that like certain things like caloric restriction, if you have

animals and calorically restrict them that, you know, it'll knock down spontaneous tumor production by like seventy percent, you know. But animals tend to just overeat when you give them ad libidum food anyway. So uh well, humans do the same thing. So uh So it would probably, you know, there'd be some translatability there. Uh, but to answer your question, which is a very good one, yeah, I do think that if someone was to put themselves into therapeutic ketosis and then use, you know,

buy like ten sessions of hyperbaric oxygen therapy or thirty sessions and use that over the course of a month and do that like maybe once a year. I think that they would be basically they're stimulating stem cells too. So we know hyperaric oxygen therapy stimulates the production and the release of stem cells.

So this could be helpful for your joints, for your brains, for your muscles, uh, help you re recovery and things like that. And it could be a prophylactic way to suppress cancer or to purge the body or kill pre-cancerous cells that you have.

But there's also this conversation around it maybe taking away from the from mitochondrial effectiveness or maybe making mitochondrial less effective. I don't know mechanistically what's happening. I assume you do. But I'm curious You know, just in general, would you say m uh metformin is a good therapy for most people looking to ultimately optimize mitochondrial function and, you know, increase longevity in the simplest format?

you know, reduction in glucose. And even some of the signaling pathways were not really uh affected that much. But what we did see was the mitochondria was causing mitochondrial stress. And that's It's part of what it you know, probably what it does maybe therapeutically too. So to answer your question, I experimented with metformin and if I'm taking two grams or more a day and I'm doing like sets of squats or really high intensity workouts, I started to become dizzy.

And actually uh it it just did not feel well. If I tested my blood with a lactate meter. my lactate was higher when I do the same amount of work if I'm taking metformin. So to me, if your body's pumping out lactate, that's a sign that your mitochondria are not keeping up with the energy demands and you're shifting some of your energy pathways to more glycolysis. So and essentially that's the Warburg effect. So the Warburg effect is

the cells are pumping out lactate and still consuming oxygen. So the mitochondria are respiring and using oxygen, but it's like a pseudo-respiration because it's not coupled to ATP production.

But whenever cells are pumping out lactate, that's a sign that the mitochondria are not efficient and that there's mitochondrial inefficiency. So this is what I observed when I took metformin. It also tends to impact and we have the livers from our metformin study, but I think it it impacts liver redox mechanisms in a way that when you work out, you generate lactate, the lactate goes back to the liver, and through the quarry cycle, that lactate then becomes glucose again.

So metformin impairs uh the cori cycle and other it shifts the redox state of the liver in a way that can decrease this cori cycle and a side effect of metformin is lactic acidosis. Right. So that's like a a well-known side effect of that. And I think it's doing that because it's essentially toxic to the liver. The liver is like shock full of mitochondria. So when we used to isolate mitochondria to to study them, we would

The easiest thing to do is actually to take the liver because it's just like chock full of mitochondria. And then you do a procedure where you isolate the mitochondria and study it. To answer your question, I I really feel that Metformin's not a good idea. Perhaps if you were gonna use it in a longevity uh scenario, you would do like you know, ketogenic diet, hyperbaric oxygen therapy for two to four weeks and then use metformin during that.

stack these different modalities together and produce a deep state of low glucose, low insulin, high ketones. That's basically going to be a huge hit to any precancerous cells. or cancer you have in your body and could potentially purge cancer out. And then uh I mean this is all theoretical, right? But I mean the basic science is there, the physiology is there.

Uh there's a lot of there'll probably never be a clinical trial that does this, although animal model studies I'm a hundred percent sure would basically demonstrate that if you have animals that are susceptible to spontaneous tumors and you were to give them a modified, you know, ketogenic diet supplement that I talk about, hyperbaric oxygen therapy, and you give them some of these.

cancer specific metabolic drugs, if you were to do that in a cohort of animals, those animals are clearly going to have less cancer. And, you know, would that translate to humans? Probably.

Right. So we're always cancering in our body. Our body's always producing precancerous cells and cancer cells, but our immune system keeps everything in check. Uh if we were to take if we have certain lifestyle things like stress, physical stress, psychological stress, or environmental toxins, and these I mean, simplest would be like alcohol.

you know, impacts the immune system. Too much well, one glass a day, maybe two glasses a day could be beneficial. High doses of you know high amounts of sugar can impair that causes a dis Dysglycemia, glycemic dysregulation. I wear a continuous glucose monitor as part of a a study with continuous. glucose monitoring and seeing how we can optimize certain metabolic parameters and non-diabetics. So I really think that's the future too using different wearables. But I mean there's

There's things in the environment that are pervasive like benzenes and c you know, these things have been shown to cause leukemias and lymphomas. I mean, that's clear. If someone has acute myeloid leukemia like AML or CML, it's The first thing you start looking at is environmental.

toxins because these things are linked uh with that. Brain cancers like glioblastomas and other forms of cancers, they have not been able to conclusively link that to different environmental toxins, but it's likely that and then there's that when we're exposed to these things, some people can mitigate it and detoxify. The liver may through first pass metabolism and different phases of detoxification, glucuronidation, for example, in the liver, which is a detoxiction.

pathway, that's impaired in a lot of people. And some people are poor methylators and they lack, you know, they have the and various genes that can disrupt endogenous antioxidant systems where it causes more oxidative stress. In in tissues when we have we're exposed to different chemicals. But there's almost too many chemicals in the environment to name, but some of them are agricultural chemicals. And another thing I think which is important to bring attention to is

infections that people have. And that could be like, you know, Lyme's disease could be one, but also uh Epstein bar virus. cytomegalovirus, various viruses that we have, the herpes simplex virus to probably makes us susceptible. We know HIV makes us susceptible to different forms of cancer.

So these viruses impair the immune system in a way that could make us more susceptible to cancer later on. The shingles, you know, virus, that's why it's probably important later on in life, if you have shingles to get uh shingles vaccination. You know, I think if you're over fifty you can get that. So these viruses that we chronically have

continue like stress our immune system out. So if we have psychological stress or physical stress, then our immune system keeps it under constraints when we're healthy, but when we're under physical or psychological stress. then these viruses basically start replicating, you have viral shedding, and then you have, you know, you starts off with like a headache and then you have maybe a shingles outbreak or a herbicimplex outbreak or Epstein bar virus if you have mono. These viruses

I I really think can be tied to different cancers. You know, I think we know that at this point. Michael Bishop, I think, won the Nobel Prize and demonstrated that viruses cause cancer. So that was like a big finding years ago.

Like are you are you able to look at variable uh variables of genetics and you know how does that influence in your ability to make decisions on who actually goes on these missions? Is that something you guys are looking into?

And even when you do like gut microbiome, that's like you're doing genetics of an astronaut, and there's a a whole nother committee. that's involved with that, like ethically. Hey, are you going to identify some kind of genetic predictor? that could exclude someone perhaps now or in the future from space flight. So there's a there's a lot of politics around that and a lot of ethics around if that's ethical to do, kind of to basically select people based upon their genetics.

can can kind of be an issue. But you bring up a really important issue and I totally I really do think that understanding genetic susceptibility to, you know Type two diabetes is is like a big one, right? I mean, that's like the low-hanging fruit. If we know there's certain families where like everybody over the age of 50 has type two diabetes and then their comorbidities are basically causing insurance companies to dump a ton of money into the management.

Of their diabetes and also all you know, you're more susceptible to dementia, cardiovascular disease, and cancer. They're the three things that kill people, right? So you're astronomically higher rates of of the three main things that kill people if you have type two diabetes and there's a genetic component there. There's an environmental component. But I think that is the future. And it could lead to

expanding nutrigenomics, expanding like cellular detoxification because people have different I would actually recommend having Dr. Sheila Dean on. She is an expert. in nutrigenomics and cellular detoxification pathways. So we're talking about detox. Not from like the pseudoscience point of view. Like she has deep information working. She does tons of labs with like uh Genova diagnostics and everything. And she's a good friend and collaborator of mine, far more insights into

knowing what tests to do on people to identify genetic susceptibility to different dietary patterns or different lifestyle patterns. So yeah, there's a lot. We're doing a little bit of that now, but it's not, you know, a huge thrust of what we're doing.

And therefore we must make our mitochondria more robust. What are some of the things you do, or maybe that you could talk about the astronauts are doing? uh that are gonna allow them to become more anti fragile, more resilient to these, you know, challenges they're facing. Cause ultimately what you know, what what can I do on a daily basis? What can I extrapolate from that to go, hey, this is how we're gonna make these mitochondria more robust.

you know, high glucose, you know, we could talk about that. But basically having a lot of lean body mass and having low body fat, that's probably the top of the chain if we're going to talk about health and longevity and brain function. And if you you feel good about your body, that's gonna be better psychology, better physiology altogether. So, you know, doctors don't really talk about that, but I think body composition is like the number one

biomarker. And then there's things, you know, blood pressure. You know, what your blood pressure is kind of like a silent killer. non-alcoholic fatty liver disease is uh I didn't realize this until we started our clinical trial and we excluded everybody that was obese, we excluded everybody that had type two diabetes. But we did, we looked for hepatic steatosis and come to find out 80% of the people that are in our trial, which are normal people.

you know, non-diabetic, non-obese, they had uh non-alcoholic fatty liver disease. And this quickly reversed with a carbohydrate restricted diet. But, you know, we didn't we didn't know that was going to be the case. Uh but that was this'll and it doesn't show up in blood work. It'll start to show up you'll have a creeping up of the ALT, AST not so much, but the ALT, the liver enzyme will start creeping up and that'll be an early. But usually once that gets out of range.

the damage has been done and you have non-alcoholic fatty liver disease and then scarring in the liver by the time your ALT gets gets high, persistently high. And then that's not gonna go back. Some of it can go back, but it's you know, it's with low carb diets, you can reverse some of the effects of non-alcoholic fatty liver. So But to, you know, get routine blood work, your C C B C, CMP, and I wear a continuous glucose monitor. I use Levels Help.

which is a CGM company that develops an app that where the the data from the biowearable, it could be the Abbott Libre device or the DEXCOM G6, goes into the app. And shows you your glycemic response to meals. And it can identify, it becomes like an AI system that could basically. if you put the information in, tell you when you've worked out, could start to understand your diet and give you a metabolic score. So having that metabolic awareness

to understand when you're a lot of people have no idea what their glucose does when they're eating. And it's hard to do if you're trying to prick your finger and time it. But if if you wear a continuous glucose monitor for even two to four weeks. that'll give you so much insight into how your nutrition is affecting your body. And that's gonna be super important. But the basic things, your blood pressure, your fasting insulin, which is not done on a routine exam.

So I use a ZRT uh cardiometabolic kit, which looks at insulin, it looks at HSCRP, high sensitivity C-reactive protein, uh hemoglobin A1C. Like a lot of these times these things are not on routine exams. And insulin should be because you could actually have normal glucose.

control, but as we age and we become insulin resistant, and Ben Bickman has written about this and I I think he was on your podcast too. Yeah. So basically what happens is that you start pumping out more and more and more insulin over time. to where and you can plot this out in non-human primate studies, which my colleague has has done that.

But your glucose stays the same, your fasting glucose, but you require three to four times more insulin. Your pancreatic beta cells are pumping out more insulin to keep that glucose in that range. You wouldn't know this, that you're going down the path of no return to become type two diabetes if you don't measure fasting insulin. So You know, uh yeah, Genova diagnostics has tests, ERT, there's different tests. And I we use a test that's like basically just blood spot. You put like

six to twelve spots of blood on a card and then it goes and analyze the same sort of methodology that Quest Labs or Lab Corps would do. Uh but you can do it in your home. You it's a kit and you send it in. So I think in addition to your C B C and C M P, Mr. General Blood Work, your blood pressure. body composition. And then another biomarker would be like a functional biomarker, like just being able to do ideally like 40 or 50 push-ups.

Right. So if you take someone and, you know, for some people it could just be walking 10 minutes. That could be a major goal. But if if you're capable of doing, you know, 20 push ups now. And then you can do 30 or 40 push-ups, that's going to translate into increased longevity, increased, I mean, there's so many, and I call that like a functional biomarker. So there's body composition.

And then there's physiological biomarkers, there's biochemical biomarkers, but it's a constellation of all these things together.

that are going to be super important for your overall energy, which will translate to productivity, which will translate into longevity. I mean, I could go really deep into other things that we do on psychological testing, on mood. general anxiety, the GAD-7 test, PHQ nine. We wear different bio biowearables like the aura ring or the whoop strap.

and look at heart rate variability and sleep. So sleep is super important. I was a mouth breather when I was sleeping, so I've been taping my mouth. I talked to James Nestor years ago and he was writing his book and then he was at our conference too. I'm really because I did my PhD on respiratory neurobiology. I've always been interested in in breathing. Tape my mouth when I when I sleep and if I'm doing cardio, try to just really focus on nasal breathing uh for that. And then

You know, I'm guilty. I have not been doing cardio. And cardio really sets the base, your recovery between sets and things like that. I noticed I invited some guys over. pretty you you know, tough guys working out with and I could train and lift really heavy, but my recovery, I was just like huffing and puffing between sets and I was like,

Man, I do farm work, but I'm not getting I really need to start doing hits. So my wife bought me uh like an assault bike or it's a Schwinn uh airdyne, like the newer Schwin airdine. So it's like, man, I really gotta start upping my cardio game. That's the big thing lacking in my life right now, uh, as far as a health standpoint, my cardio base is not very good. So

And the membrane potential is you can calculate it with like the NERST equation and the Goldman equation. This is what I teach to the Met students. But that membrane potential, the electrical potential within a cell, is actually a consequence. of ATP production. There's a sodium potassium ATPAs that maintains that membrane potential. You know, realize this even when I was an undergrad, I started doing cash clamp electrophysiology is that

the membrane potential starts to become de energized when the energy when the bioelectric uh status of the cell decreases. So that's It's all about giving the cell the proper metabolites, substrate for energy production. uh decreasing Ross production, making sure the cofactors are there, like, you know, B vitamins, B12, B, you know, another thing to look at is to do a nutritional status. You know, and I always recommend not only vitamin D, magnesium, and uh but also various B vitamins, B12, B1.

If these things are not there, the bioenergetic state of the cell and the electrical potential of the cell will be dysregulated. So we look at this, I mean, this is kind of what we do. We do use different dyes to look at membrane potential in the mitochondria and membrane potential in the cell. And then we figure out what disrupts it, and then we develop countermeasures that we ultimately move the humans.

the mitochondria and the cellular membrane potential even under really high levels of stress. So that could be dumping on glutamate, which is an excitotoxin, high pressure oxygen. different environmental chemicals and things that would typically disrupt the cellular energy. The cells were much more resilient if they were burning ketones as an energy source. So this I did not have an interest in ketones, but it just it was one of the things that I studied at the time in 2007 or eight, I guess.

that led me down the path of the ketogenic diet. And I only knew it of of a diet that was used in extreme bodybuilding for cutting, but it was like far from optimal. But I started researching and I was like, whoa, it's an anti-seizure diet. So then I went down that rabbit hole of the ketogenic diet. So when it comes to the electrical bioenergetic state of the cell. the things that I have researched that really had a high yield effect was basically, you know, burning ketones.

You know, and and I did it from a petri dish, you know, we had hippocampal neurons and we had cortex neurons. And then that got basically, you know, translated into looking at brain tissue and then mice and then rats and then ultimately humans.

ratio of electrolytes, but it binds beta hydroxybutyrate to the electrolytes. So you're giving the electrolytes and then you're giving, you know, ketones at the same time. Uh so I'll take I'll do a third of the packet in the morning.

with like creatine and acetyl-L-carnitine. So I'll mix that together. And then I drink that and just with water. So it's really no calories. And then I go out like this morning, I let the cows out. I walk around barefoot. I get a lot of bright sun as the sun's coming up. And then I jump in the pool and swim a couple laps. And then I come in, start brewing my coffee and getting my workstation, getting things up, up and running. So that's like my normal routine.

And then I'll take the rest of the packet around like two o'clock in the afternoon and then I'll mix that up and then it'll Just give me a second, a second wind. If I'm hiking or doing like extreme stuff, when I lived in the undersea environment for 10 days underwater, I was consuming a lot of exogenous ketones and looking at the effects on oxidative markers and things like that.

So yeah, I'm a big fan of you know, I have I have a whole bunch of uh ketones around the office behind me. So we have like probably thirty or more molecules. I mean, most of my research has been on ketone esters, but then as I progressed, then I realized that I was kind of not very favorable from you uh taking a big load of sodium and then I realized that sodium's actually like one of like a performance

performance enhancing substance and I kind of load on sodium before I go train, especially in Florida. So the ketone salt is actually perfect because I'm getting my electrolyte like element, but delivering beta hydroxybutyrate, which is like really a nootropic. So I think of I experiment with a lot of different nootropics and I find that beta hydroxybutyrate is probably up there with the top. And you're it's not a stimulant, although

If you use like keto start that has caffeine in it, then there's a a definitely a synergy between ketones and caffeine that have been, you know, studied and reported on. So that's something that I use also if I'm writing and I just need a lot of cognitive, you know, energy.

What happens when you boost your ketone levels to two millimolar is that you start pumping out insulin. So and then that's how we actually regulate ketones. When we go on a ketogenic diet, our ketones become elevated and then we pee out ketones. That's called ketone urea. And then as the ketones get elevated, the ketones will then stimulate the pancreas to release a little bit of insulin and that decreases fat oxidation in the liver, beta oxidation of fatty acids in the liver.

So, you know, that the insulin, as Ben Bickman talked about, the insulin will shut off the fat burning process, which is not good if you're using ketones for recomp. If you're consuming

ketone esters and getting above two millimolar, then you're shutting off your fat burning process, as evidenced by the decrease in ketones production. So if so the bottom line is that if you take a ketone supplement and you're shooting above two millimolar, maybe even 1.5, then you're decreasing fatty acid oxidation by virtue of releasing insulin and you're also decreasing ketone production.

And then what happens like if you're on a standard diet and you take a and I've done this many, many times I've taken more ketone esters than anybody on the planet. I was doing this back in back in like two thousand eight before anyone knew what ketone esters were. I had Patrick Arnold. making some actually he'd be a good guy to have on your podcast.

a disposal in tissue the insulin does. And then you get a headache after. So I kept getting these headaches. I would consume a lot and then I would have like energy, but then I would get a headache. Then I started doing a lot of blood work. Patrick started making ketone salts for me. And we were like, the only ketone salt on the market was sodium beta hydroxybutyrate. And then we were like,

Hey, why don't we just take other electrolytes and start making? So Patrick was doing this in the lab. He was sending it to me. I was consuming it, doing blood work. And we realized that the ultimate approach would really to be electrolyte supplement that would deliver the ketones. So you're getting like a twofer. So right, and then the the electrolytes basically the mineral load that you get kind of prevents you from going above 1.5 to 2 millimolar.

So every time I've measured insulin and as many times I've measured insulin with a maximum tolerable dose of a ketone salt and it's like a it's it barely moves the needle. So I can get quite a lot of ketones in my system with a ketone salt and the taste is way better. Actually it tastes pretty good.

And uh the keto star product does. It tastes pretty good. And then it gets my ketones to where I feel it. It delivers the electrolytes. I'm not dumping insulin. It's not shutting off my own ketone production. So these are what I use sort of on a daily basis for my, you know, workout. I'll take that two thirds of a pack with some creatine before I go working out.

Although for like different, you know, for cancer, for different like glucose transporter deficiency syndrome, like rare metabolic diseases and certain forms of epilepsy, I think the the ketone esters may have more potential there. because you just want to get the levels high and keep it high to manage certain serious medical disorders. So I think of like ketone esters, they're always going to taste bad. They're pr probably always going to be kind of expensive.

They're great for medical applications, but you can get a lot of like 90 to 80% of the ketone benefits from the ketone salts, and then actually avoid some of the side effects, the hyperinsulinemia that could be a result of the ketone esters.

Carnitine's a a good fat burner and a good uh with the creatine and then I go outside do my thing and then yeah, I eat I eat breakfast like an hour to when my wife wakes up, usually about two hours later, like we have breakfast and it's like a keto breakfast and then uh And then I eat a small protein rich lunch, usually like sardines or a little bit of chicken or something, but just a small amount. And then my biggest meal is probably uh dinner where I eat probably about 50% of my calories.

kind of at dinner, but we've been trying to eat it a little bit early because I don't like to eat disrupt my sleep at night. So I get a lot of calories in around like five to like six. Yeah. And then just kinda coast uh and just nibble at nighttime a little bit with like some berries or just like a little keto ice cream or something at nighttime. But I try to not disrupt my sleep.

The atherogenic risk of having a very high LDL on a ketogenic diet, which gets a lot of attention, probably more attention than it should be getting. You know, these days, uh, but mine was was really elevated and I brought it down to the upper range of normal just by incorporating, switching out.

less fatty. I was eating, you know, a lot of fatty ground meat and kind of phasing that out and just getting more fish and more chicken. Uh I still eat beef quite often, but we get beef from like a local you know, grass fed, grass finished. And maybe that makes a difference too with bringing it down. But uh the day before that I had liver and uh chicken liver. So my my wife

Uh, I grew up eating a lot of liver in Hungary and Budapest Hungary. So I have liver a couple of times a month, you know, we have that, mostly chicken liver and chicken hearts. So I think tonight we had she had balling out chicken hearts. So we eat a lot of beef liver, chicken liver, hearts, a lot of heart, a lot of all different kinds of fish and quite a lot of beef. Uh we give our dogs everything that we eat, our dogs eat too. So we have two dogs and uh

If you don't mind sharing.

Cordyceps, it's it's got L tyrosine, it's got lion's mane, uh yucapyrens, panics ginseng, cordyceps militaris extract, hooperzine A, maybe I mentioned that. So it's basically there's three products. One I'll take in the morning and that'll give you a pulse of dopamine and you'll start to feeling that and it's basically like head down, get shit done, get work done. And then they have a product that you take like in the afternoon.

That one's called Golden Hour and it's got basically it's like focus and chill and it's got a a mix of mushrooms, other interesting ingredients, including a a tiny dose of lithium. in there. So I don't know how they navigate that, but uh there's a it's

So yeah, I think there's a lot of potential in mushrooms and we can go down that scenario. But I've been talking with I visited a mushroom farm recently. Well, first person they're growing all their their lion's mane, their uh their cordyceps, their Rishi and everything. So it was really cool to see how that production happens from the ground up and the quality control. It's like pharmaceutical grade control. There's like steps to even getting into the lab and then autoclave

The vice. So and that was out in uh in Seattle, Washington, sort of the mushroom capital. Walking on the property too, there was a lot of mushrooms.

you know, developing a regenerative agricultural system and mushrooms are a big part of that. So mushrooms, mushrooms will be going to space. too. So the the mushroom conversation is super interesting and uh and I think it's not I mean we're just at the cusp of it now. I think there's so many applications to functional mushrooms.

Um, is there a way that our audience can support you down? Do you have a Patreon? Does a lab have some way where people can make um donations to the lab? Cause I think people listening, you can make a hundred dollar, a thousand dollar donation to the lab to support you in some of this amazing research. I'd love to. uh be able to contribute and ultimately g direct our audience to be able to contribute to your lab.

Uh we do I do have a website set up for some of the consulting stuff we do with the like with the space research and things like that. So I'm always looking for I'm actually very much looking for commercial partners.

that would be interesting on interested in getting their product or their device onto commercial space flight mission. So if there's anybody out there that are interested in maybe, you know, getting their company logo on a rocket or a spaceship that that's gonna go for space research, uh And then using their product too, or using their biowearable device or something like that on space missions. I'm working with groups that are sort of organizing that. So uh we do on keto ketone technologies.

dot com is a website that I have set up for consulting and more like research that we do with USF and outside USF. And I think there's a link to the USF Foundation on there. Uh and that link The money that goes is a 501c3 and that money is under tight control and that that is only used for like student research projects on metabolism, you know, uh

metabolic psychiatry uh is something I've been very interested in. So using nutrition to treat depression, using nutrition to treat bipolar disorder. So there was a had a very cool conference, the metabolic psychiatry roadmap. It was in this is just the mug from the conference. Yeah. Uh where we got together as a group of academics and clinicians and talked about. the role of nutrition and metabolism on brain function and has profound effects on depression, anxiety, like PTSD. So it's a very

This topic is emerging and now the NIH is actually funding some research. And I'm very interested.

you know, I don't say I'm neurotic, but I I'm pretty um, you know, highly aware, let's say, with my kids and like I wanna make sure they're metabolically healthy, you know, just to avoid things like that. I think it's it's something we can avoid in these young adults. Or experiencing panic disorders and anxieties and depressions, like can it all be ill eliminated? Who knows? But certainly a lot of them can, in my opinion.

So I love that you guys are doing this. And if there's a place where I can go watch the I don't know if you guys have filmed it or if you're gonna sell the the webinar and like that, if it's on YouTube, I would love to uh be a part of that and and understand what's going on.

But he gave a talk, but he also brought on a patient that had like she was obese. She had untreated like bipolar. That was crazy. And uh this this talk is actually available on Metabolic Health Summit. Website, you can download. We had a virtual component. So you can actually see all the talks. You can get CME credits and CEUs for it. So all that's downloadable on the virtual platform. That's metabolichealth summit.com.

And we had quite a few speakers on metabolic psychiatry that were just kind of mind blowing. And it kind of, you know, really, we want to elevate this. Mission more and make that a bigger part of the Metabolic Health Summit, which we'll probably have in Tampa 2023. Probably we're organizing that right now, uh, to give more attention to brain health and psychiatry and in regards to using nutrition and metabolic approaches for psychiatry.

Yeah, but that site, uh metabolic health summit dot com, all that virtual, the virtual platform will give you all the talk.

So who is uh um you know a radiation oncologist, but he is actually spearheading exercise oncology. So there's a whole field being developed right now using exercise. to mitigate cancer cachea and how the the huge effects that he has in his patients, just employing a very well designed exercise protocol

to for for outcomes. Like it's dramatically improving outcomes as you would imagine, but it's not, you know, it's not so much on the NCI or NIH radar to do research uh so much on exercise, but it's showing new data, new projects that are emerging and new science showing that if you exercise and do a well designed exercise produ it's reducing chemo brain, it's reducing the side effects from from drugs and it's just augmenting

our metabolism in ways that decrease cancer drift for one thing. It can be Obviously a preventative too, but less research is being done on

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