#05 - Dom D'Agostino, Ph.D.: ketosis, n=1, exogenous ketones, HBOT, seizures, and cancer

Foreign. Hey everyone. Welcome to the Peter Attia Drive. I'm your host, Peter Attia. The Drive is a result of my hunger for optimizing performance, health, longevity, critical thinking, along with a few other obsessions I've gathered along the way. I've spent the last several years working with some of the most successful, top performing individuals in the world, and this podcast is my attempt to synthesize what I've learned along the way to help you live a higher quality, more fulfilling life. If you enjoy this podcast, you can find more information on today's episode and other topics@peterattiamd.com. In this episode I interview my good friend Dominic d'. Agostino. Dom, as he is known by, is a professor at the University of south Florida. His PhD is in neuroscience and that's where he got his background. But Dom is probably most recognizable to people listening to this because he is certainly one of the experts on ketosis and that's in in all variants of it. So starvation, ketosis, nutritional ketosis, and in particular the use of exogenous ketones. Gosh, Dom and I go way back. We met probably a little over five years ago and instantly formed a friendship around our obsessive N of 1 experiments. Although I will say he is closer to winning a Darwin Award on the basis of his N of one's than I am. A couple notes about this podcast first, this is highly technical at times, and in fact we'll timestamp it in the show notes, but I would say roughly the first hour is even a little more technical than I had intended to go. I think part of the issue is just once I get talking with Dom about this stuff, I couldn't stop asking him questions. And I think there were times when I guess we forgot we were recording a podcast and it was just us getting really technical. I don't think it's too technical to follow if you have some background understanding of biochemistry, but we'll do our best in these shownotes to make sure that we're given even the recreational user the necessary tools to follow this. Now that said, if you get 20 minutes into this thing and you're like, I don't understand what the hell these guys are talking about, do not hesitate to skip ahead. There's a lot of stuff that gets later on into the podcast and this is a long podcast, it's nearly three hours. There's a lot of stuff we get into at the end that I think will be kind of the stuff people really want to know, even if they don't want to get in the gory details. So in particular, we talk very specifically about all of the ketones. And I'm getting a lot of questions about Peter, what's the difference between a ketone ester, a ketone salt? What are the monoesters, what are the diesters? Where does MCT fit into this? What about the caprylic acid? And, you know, how many should we be using? This one versus this one? And what are the advantages and disadvantages? This is going to be your dissertation level course in that subject matter. The other thing that we get into at the very end, and we almost end on this, but again, look to the timestamps for exactly where it is, is we get into what I consider one of the most interesting discussions I've ever had on what I sort of loosely describe as a metabolic oncologist playbook. So when I asked Dom about this, he had just some of the most interesting insights. And I was really impressed by the breadth and the organization of his thinking around this. Now, I want to point out something here and I say it in the show, but it's really important for me to caveat this here. This cannot be construed as medical advice. Dom is not a medical doctor. He doesn't pretend to be one on tv. He is a research scientist who focuses on basic and translational research. He collaborates with lots of physicians. He is involved in a number of clinical trials. But ultimately, Dom is not offering medical advice and frankly, nor is anybody or nor should anybody be on a podcast. So this information I asked, because I get asked this stuff a lot, and frankly, I don't know enough about this sort of outreaching and outlying metabolic therapies out there. But I hope that if people are listening to this and they're afflicted by cancer, which statistically speaking, is obviously going to happen, given that one in six people are going to get cancer in their lifetime. I hope that if some of this stuff does scratch someone's sort of desire to understand more, that they can use some of the resources we're going to link to to potentially identify the right places where either a clinical trial will be taking place, or they could at least pursue some of these things under the appropriate medical guidance. I could go on and on about other nits and gnats in here, but honestly, I think the best thing to do right now is probably pay a little bit of attention, maybe more than usual, to the show notes, treat this a little bit like a buffet. Go to the places you want to go to. Of course, I would recommend the entire thing if you really have an interest in this subject matter. And I hope that this podcast is going to answer many of the questions that I see people asking out there. I actually learned quite a bit on this, and I tend to know the subject matter reasonably well. So without any further delay, welcome to the podcast with Dominic d'. Agostino. Hey, Dom.

Hey, Pete.

How are you, man?

I'm doing well. How are you?

I'm. I'm doing really well. And I'm really grateful for you making the trip all the way up here. I know that, in part, you're visiting family, but it's great that you've carved out time to come from New Jersey all the way up to the lovely city of Manhattan.

I appreciate the invite and love being here. Yeah. Love to visit.

Well, there's going to be a number of people listening to this today who are already incredibly familiar with who you are, the work you've done. I certainly consider you probably one of the two most authoritative persons on the subject we're going to get into today. But for anybody who's listening to this who is not entirely familiar with you, I suspect by the end of today, they're going to want to get a lot more familiar with you. So I actually remember the day we met, and it's kind of funny. I was in Florida giving that talk at ihmc, and I knew of you by name, but I didn't know who you were or what you looked like, so I wouldn't have recognized you. And I gave a talk. This would have been 2011, maybe. Maybe 2012. And at the end of the talk, there was like a Q and A, and, you know, it was a long Q and A, and it just went on and on and on. And then you asked a question. Now, I wish I could say I remember the question, but I knew from the question that that guy knows what he's talking about. And then, of course, Ken Ford, who knew us both, had basically arranged for us to all have dinner that night. And so that was the night we met. And it was really, at least from my standpoint, not to embarrass you, it was like a love at first sight. Like, I was like, I was just so giddy to be able to sit there and have dinner with you.

Same. Same here. Yeah, I knew who you were, so. And I was looking forward to that talk. I made the drive up there, and I felt like we were connected before we even connected. You know, we're definitely on the same wavelength on. On this stuff.

Yeah, you've got such an interesting history that we're going to get into about how you got interested in this space. But also I think one of the things that many people might not appreciate fully, that I appreciated just because of the, you know, the convenience and luxury of how we met, was just your interest in self experimentation as well. And sometimes when you're studying something or interested in something that is not entirely mainstream yet, you have to bootstrap it and you have to look at like, limited amounts of animal data, limited amounts of in vitro data, and then sometimes combine it with insights that you get through early experimentation on, you know, yourself.

Absolutely. So I immerse myself in what I'm doing. I think that's sort of why that's how we learn. Yeah, that's really. That's the best way to learn.

So you did your PhD in neuroscience, correct?

Yeah.

So what? Physiology and physiology. So you're finishing your Ph.D. and you're, what, planning to do a postdoc?

Yep. I did it in the neural control of autonomic regulation. So the brainstem mechanism sort of sense O2, oxygen and CO2 and modulate respiratory rhythm generation and also cardiovascular sympathetic tone to the heart, like those neurons and how they sense oxygen. During my PhD, I got interested in diving physiology. And it was amazing to me that we don't really understand how our brains and our physiology functions in extreme environments. As it pertains to elevated hyperbaric pressure, elevated oxygen, CO2 anesthetic gases, for example. We know the anesthetic potency of a gas is proportional to its lipid solubility, but we don't really know what that means. Like, why, what's happening at the level of the membrane of the mitochondria. So my postdoctoral fellowship was actually developing technologies to study that. And that would be hyperbaric atomic force microscopy. And that was like, that's what I just delved into for.

So how does that work? So I know what hyperbaric means. I know what microscopy means. Tell me about the part about the force.

The first term for atomic force microscopy was scanning probe microscopy.

Okay.

And instead of using light or electrons, it uses a very sharp tip probe that can be so sharp it's monoatomic, and it essentially raster scans across the sample and can detect very subtle changes in the topography of the sample that you're scanning. Right. So it actually spawned the whole nanotechnology world. So this particular instrument was used to characterize materials and really help develop Silicon Valley in many ways. And it's a microscope that we took basically an off the shelf atomic force microscope that gives you the scanning resolution of an electron microscope, but also has the capacity to image living cells, and took this technology and put it inside an environmental chamber, a hyperbaric chamber. And part of my project was doing the electrical, the fluid and the gas penetrations to make the thing functional, and also doing a series of studies and calibration tests to determine that we could reliably make hyperbaric atomic force microscopy measurements inside this chamber. And with this technology, it gives us insight at the nanoscopic level of what's happening to the mitochondria, to the cell membrane. So I got a grant through the Department of Defense, which they give these equipment grants to develop this technology, and also a grant to use it. And then later another grant to put a confocal microscope, you might have heard of a laser scanning.

I actually used a confocal microscope in my undergrad thesis to do optical sectioning of no, because I was an engineer. So we were, I was interested in a question of did the direction of extrusion that you put on a tibial plateau. So when you do joint replacements, does the direction in which you extrude what's called ultra high molecular weight polyethylene, does that predict its fracture? And it turned out it did. But the tool to help us measure that was this confocal microscope. So that was my introduction to high end microscopy.

It's an amazing tool. Yeah. So the second everyone should have one, really. Yeah. You got it through the toys that we have in the lab. So that was the next phase of the sort of my experiments was installing a laser scanning confocal so we could optically section individual cells and look at the mitochondria inside the cells under graded levels of oxygen and hyperbaric pressure, essentially pressure of an inert gas like helium nitrogen. So to simulate, for example, a Navy seal dive or a deep sea dive, and in the context of developing this technology and imaging a wide variety of cells, from primary neurons to glioblastoma cells, to human dermal fibroblasts, smooth muscle cells, I noticed that cancer cells would produce proportionally more superoxide anion, which is the precursor oxygen free radical that comes from the mitochondrial electron transport chain as a consequence of normal metabolism. And the cancer cells looked to have what appeared to be they're chock full of mitochondria and they were moving around very dynamic structures. And under normal levels of oxygen, they kind of produced a normal level of superoxide anion or oxygen free radicals. But when we Hit the cancer cells with hyperbaric oxygen, the superoxide production went off the charts. And it was very apparent to me that they were producing excess free radicals. And as we made measurements over time, it was very apparent that it was accelerating membrane lipid peroxidation, which we use a variety of tests. One is a T bars test where we look at malan dialehyde production. The technology, the atomic force microscopy, allows us to look at very subtle changes of the surface of the membrane. You measure the perturbations on the surface of the membrane in nanoscopic changes and we look at membrane roughness and you could look at the roughness of the membrane and calculate that. And that can correlate to membrane lipid peroxidation and it correlates. The numbers correlate well. So what you're looking at is the physical correlate of membrane lipid peroxidation. When you capture that data with atomic force microscopy. Is that clear?

Yeah, let me, let me back up and make sure I can disaggregate this into steps. So the first thing that you notice is lots of mitochondria in cancer cells.

Chock full of mitochondria.

And these are what types of cancer lines?

The main one that I was working with that I ended up publishing the paper neuroscience with was U87 glioblastoma cells. And they're taken out of a like a 44 year old patient.

So human cell line.

Human cell line, yeah. A lot of people use it, you know.

And these are astrocytes, right? These are not neurons.

Yeah. Of a glial origin. Yes, yes.

So observation one, lots of mitochondria. Okay, good to know. Because obviously there's an understanding that Warburg pointed out that says, hey, like, you know, these things largely are anaerobic, not aerobic, so they shouldn't really need much mitochondria.

Yeah.

And then what you're saying is you put them into a hyperbaric environment. And how hyperbaric, how many times atmospheric pressure would you need?

I saw the observation at. So normal oxygen is 0.2 Ata. We say atmosphere is absolute. And I saw a big jump up in superoxide anion production at 0.95. So carbon.

So that's almost five times atmospheric pressure.

That's almost five times, yeah. And actually 0.95 if your breathing produces a PO2 in the brain, if similar to breathing, 2.5 atmospheres of oxygen. And then I actually went up to, I did the experiment with 3.25 atmospheres of oxygen. And then that Basically was cooking the cells from the inside out. The mitochondria were producing so much oxidative stress through reactive oxygen species. So superoxide anion can go to hydroxyl radical through the fenton reaction through hydrogen peroxide, and that can be driven in different ways. And I basically saw the mitochondria exploding under hyperbaric oxygen conditions. And I had never seen that before.

You have a control in this of non cancerous glial cells that are not doing the same thing.

Yeah. So most of my experiments prior to this, this with like smooth muscle cells, I was looking at in primary cortical neurons, primary hippocampal neurons. At the time, I was just basically looking at. I was doing these experiments to validate the tool that we had just built. So no one actually had imaged living cells under hyperbaric conditions because no one had a hyperbaric microscope before. So I didn't actually know what I was even looking at. I was not a cancer biologist. I knew that cancer cells were recognized rapidly proliferating, so they probably had amped up metabolism. But it was just a very interesting observation to me. It was very interesting that they were also dying. And I figured cancer cells should be hardy and you should be able to throw everything but the kitchen sink at them, and they should live. And then when I saw them, basically the mitochondria exploding and the membrane starting to become permeable and necrotic cell death, I became more and more interested in that. We ended up publishing the observation, but I didn't actually know what it meant. Like, I published it more like here I built this cool tool and we did this experiment. And I was actually just looking at the cell line as a model system to study reactive oxygen species and oxygen toxicity seizures. Because part of the military was funding me to understand the cellular and molecular mechanisms of oxygen toxicity seizures. And it's thought that high levels of oxygen creates oxidative stress, and that perturbs the brain in a way that causes these grand mal tonic clonic seizures. And we were developing tools. You can't understand it unless you know fundamentally what's happening at the level of the cell and the mitochondria.

So I want to come back to that, because that now makes sense for why diving could increase that risk. Because if you're using an oxygen rebreather, you're getting a higher concentration of oxygen, and then you're under multiple atmospheres of pressure. You've now basically replicated in a person what you were seeing, a cell. But going back to the cell Thing for a sec. Do the free radicals that get generated destroy other cells beyond the cell that is generating the free radical? Or is the problem largely contained to the cell?

It's a dose dependent phenomenon. Right. And we were studying cells in this particular experiment in a petri dish or on a coverslip. So you have sort of like an intact neural network or cellular network. So the cells are literally connected to one another. Unlike a tissue slice where you have an intact cytoarchitecture, which that's a little bit different. But the oxygen free radicals and the substances that the cells produce do actually influence other cells adjacent to it or juxtaposed to it. That's obvious from some of the experiments we do in cell signaling. You know, if one cell becomes permeable and we could detect cell death with various molecules like ethanium homodimer 1, when that cell dies, it can stimulate excitotoxic events in the surrounding cells. Same thing happens with the cancer cells. It's obvious that cancer cells use reactive oxygen species for growth and proliferation. And I know this is something that may be contradicting to many people. We view free radicals as something that's damaging that the cell needs to get rid of. But they're very powerful signaling molecules, especially for cancer cells in growth and proliferation and in normal tissues.

And you mean nuclear signaling?

In nuclear signaling and activation of transcription factors. Basically, there are many. I study as neuroscientists, I study redox sensitive ion channels. So the redox state of an ion channel can dictate the permeability and the gating functions of that ion channel, which is intimately linked to cellular excitability by influencing the resting membrane potential. So as a neuroscientist, you know, you can study a very particular. And cells have hundreds of thousands of ion channels, specific ion channels that are redox from regulated. But what was obvious is that cancer cells have elevated rates of reactive oxygen species that they use for growth and proliferation, and also fuels metastasis and invasiveness of cancer cells. And because they overproduce oxygen free radicals in the context of high oxygen, you can push the cells above their antioxidant potential and then trigger apoptosis. So it's like a double edged sword.

It's basically a U shaped curve or inverted depending on how you want to think about it, where exactly the cancer cell is not only optimized to survive, it's optimized to thrive at a certain.

Level of elevated reactive oxygen.

Elevated level. But if you go too far, it becomes counter.

Yeah. So they have elevated Endogenous antioxidant capacity. Right. But because their mitochondria are defective in many ways. And there's. That term is kind of controversial. Some people think the Warburg effect definitely endows the cells many benefits. But the aberrant activity of the mitochondria is creating this excess free radicals. And hyperbaric oxygen and chemotherapeutic drugs that augment oxidative stress are therapeutic modalities that can be used. It was very apparent to me seeing that in a hyperbaric chamber, looking at a microscope, looking at these cells and no one had seen it before because no one had hyperbaric microscope.

Nobody had the tool.

Yeah. And that kind of stimulated. At the same time, I was growing these cells under different conditions. I was very interested in lactate and I became interested in ketones too, just not for this reason. I was not yet interested in the ketogenic diet. I was looking at it for a different reason actually. But I noticed that the cancer cells were not growing as rapidly as they should in the context of 1, 2 and 5 millimolar of beta hydroxybutyrate, which I was growing them in. And I thought the lab tech may have been doing something that was influencing, but she assured me it wasn't. So we would pull the media off and put regular media on without the ketones and the cancer cells would start growing rapid.

Why were you using ketones in the media?

Well, I was looking at a variety of different substrates back in 2008 and 9.

I see, so you were just saying lactate, glucose, BHB.

Yeah. 2 deoxyglucose. Yeah. Lactate. I was using a variety of different. And ketones were like, well, let's just see what ketones do. You know, that ketones were something that the body would produce in fasting. But I didn't even know the anti seizure properties of the ketogenic diet. I just thought of it as like, what do brains. And a couple odd papers that came out like ketones could be used as fuel. I was very interested in alpha L polylactate, various forms of lactate that could be used to preserve brain energy metabolism in the face of oxidative stress. And the ketones just, they sort of shined. So basically what they were able to do was allow the neurons to preserve their membrane potential and normal cellular function, even in the context of extreme oxidative stress. And it made sense. Right, because the ketogenic diet, you know, I started looking more into this and discovered that the ketogenic diet was a Very effective anti seizure strategy. Even when drugs fail, about two thirds of patients respond favorably. You get, you know, 10 or 15% are super responders that never have seizures again. You can get them off your meds. And it was probably working through, through a mechanism independent of any anti seizure compound. Because the ketogenic diet worked when drugs failed, suggesting it was working through a different mechanism or many mechanisms, kind of in synchrony. So the tools that we developed really sort of started to allow us to understand from a cellular and molecular mechanism how ketones were working. And I was looking at other compounds at the time, but it's just as I kept studying. I was looking at sigma receptor agonists, I was looking at other antioxidants, many different antioxidants and combinations of antioxidants that were catalase mimetics, superoxide dismutase mimetics, you know, all these things that were, in theory, they should work really well, but nothing was really working as well as ketones. And it also motivated me because when I discovered the ketogenic diet was a grossly underutilized anti seizure strategy, I was like, wow, I could go back to my nutrition roots because when I was undergrad I majored in nutrition science, but I didn't pursue a PhD in nutrition because nutrition was not like a real science. Like there was no jobs in Nutrition and the 90s was a decade of the brain. So it was like, let me try to get into a cellular neuroscience program. So I kind of just left nutrition and this was my opportunity to bring nutrition back into my research projects, into the lab.

Going back to that BHB in the media? Yeah. Did you have the same amount of glucose in as you had in the BHB free media?

Yeah. So we did everything in the context of the same amount of glucose.

In other words, the benefit was from the addition of bhb, not the reduction of glucose.

Absolutely. Absolutely. Yep. And as I started to get into the literature and read into this a little bit more, we started doing glucose subtraction and adding ketones and saw that normal healthy neurons functioned and thrived in a low glucose environment. If the ketones were present, but the cancer cells would die. And this was also replicated and published in various neuroblastoma cell lines. And I think Skinner was one a person that published. And I found that he was at University of Florida, but he was a, he was a fellow and just had left the school at the time. And then I went up there and gave a talk, I think in 2010. And that further that got me more and more interested in studying cancer, even though it was not funded to do so. It was like this pet project that was completely very intellectually stimulating to me and something that I could not just shelf and come back to at a later time. I had to. I felt like the environment was kind of hot for this. So I just kept reaching out to different scientists and showing them my data and asking them to explain it, like top level cancer biologists. And then I stumbled across Tom Seyford.

Actually speculating why do you think Tom was one of the few people that latched onto this? Was it simply because he'd already been thinking the same things or because it's really. It is interesting when you think about how many really interesting and impressive people in cancer have not sort of come around to thinking about this stuff. Now in 2009, I think it was 2009, I'm sure, you know, have read this paper a thousand times. It's sort of. I think it was the first obvious mainstream view of this was the Matt Vanderheiden, Luke Cantley, Craig Thompson science paper.

Yeah.

Was that 09? That sound about right?

Which reminded me of. They had a couple papers around that time. Which one was.

Well, this is the one that offered an explanation for the Warburg effect.

Yeah, yeah, yeah. It was more than an energy biosynthetic.

That's right.

Directing or expanding the biomass, directing metabolites to do that.

Yeah, yeah. And that was interesting because that's a different explanation than presumably Tom would offer. Right.

It's accepting the Warburg effect is a very powerful. But the question that Tom has really set out to address. No one is arguing the Warburg effect is present. Present. But the initiation of the Warburg effect, that damaged mitochondrial respiration causes an energetic crisis that kicks on the oncogenes that basically turn on the genes that are the essence of the Warburg effect.

Well, let's describe. I should. I want to take for granted that everyone listening knows what the Warburg effect is. So for someone who doesn't know, how would you explain the Warburg effect?

The Warburg effect, simply stated, is insufficient mitochondrial oxidative phosphorylation, or what we call respiration with compensatory fermentation in the form of establishing the cell, establishes its energy, its production of ATP, our energy currency through glycolysis and substrate level phosphorylation. And it's well recognized that cancer cells, 90% of them, I would say, have a Warburg phenotype, meaning that they have highly accelerated Glycolysis and substrate level phosphorylation.

So let me simplify that a little bit more. Our cells can turn glucose into something called pyruvate, and that occurs outside of the mitochondria. And that's not a highly energy efficient process. It doesn't generate much ATP. You then have a decision to make as a cell, which is basically how quickly does the body want ATP? And as a general rule, when it wants it quickly, it's an anaerobic environment, if you think about things that drive quick ATP requirement. And so then it will just say, look, we're just going to turn this pyruvate into lactate. That's a glycolytic pathway, which is not particularly efficient either. It doesn't generate that much more ATP. But it has the luxury of saying, I can guarantee to do this quickly and I don't need to be limited by cellular oxygen. Under ideal circumstances, you would want to generate the most ATP. You would shuttle that pyruvate into the mitochondria as acetyl Coa, and you have this other process. So what you're saying is the Warburg effect is, hey, even under conditions at rest, a cancer cell seems to disproportionately do this glycolytic thing and it generates its ATP that way as opposed to going into the mitochondria.

Exactly. Even in the presence of normal oxygen, it utilizes glycolysis and pumps out lactate. So under no other conditions do normal cells ferment and pump out lactate. So that's now Warburg.

Did he win a Nobel Prize for this observation?

He won a Nobel Prize, yeah. For his work in metabolism of cancer cells. Yeah. And it was. Is more kind of appreciated a little bit later what the implications of this was. But it was part of his Nobel Prize. Yeah.

You know, I remember reading an article about this once that has since escaped me, but. And maybe I'm wrong, so correct me, but one of the reasons that the hypothesis was because this was in the 1920s, if I recall.

Yeah.

Warburg was. Yeah. So one of the reasons that this sort of got discarded, for lack of a better word, or at least ignored, was people tended to focus on the exceptions. And there were exceptions. Right. Certain lung cancers certainly seem to pose an exception to the Warburg effect. And so the idea was, well, look, if you have an exception, then the rule is not so much a rule anymore. And is there another reason why the Warburg effect was largely ignored for, you know, a generation and a half to two generations?

Travis Christopherson Wrote a book called Tripping over the Truth that nicely sums that up. I think there's a lot of reasons for that, but I think the big focus was on understanding the gene pathways that were associated with carcinogenesis, and that if we can understand the gene etiology of cancers and different types of cancers, then that would explain cancer in a much more fundamental level. And that is the case. There is a dynamic interplay between metabolism and genetics. So now we have an appreciation that metabolites, you could call them oncometabolites, are epigenetic drivers. And metabolism is just not something. It's just not producing ATP. There are so many different intermediates and redox signaling and so many different signaling molecules from metabolism that have epigenetic genetic regulation. And I think that has become. When I got into this, there was no cancer metabolism conferences, you know, and now there's a dozen or more where Lou Cantley is a keynote speaker and Craig Thompson is. And this has all sort of exploded shortly after some of these observations that I made. And it's just, you know, it's. I don't think it's coincidence. I think.

Do you remember that night? Yeah, yeah. Remember when we had that dinner in D.C. at that conference?

Georgetown. Yeah.

I still look back at that as one of the most remarkable rooms to be sitting in as a fly on the wall, because there was only about 12 people there.

Yeah.

And, you know, you had Luke Cantley, you had Michael Bishop, Steve Rosenberg, David Sabatini. Who else was there?

Michael Pollock, Evander Heyden. Yeah, yep.

Matthew Vander Heyden. I mean, you basically have some of the most thoughtful cancer scientists in the. In the world, certainly in the United States, in one room. And that was an amazing evening conversation. Yeah, yeah.

That was.

If I could go back in time. Exactly.

That was golden.

We'll talk those guys into getting in a room again.

Yeah.

I mean, I think what you're basically saying is, look, part of its reason for being discarded, or at least forgotten about, was a new, sexier idea emerged, which is, hey, we started to understand the role of the genome. And there's this weird sort of debate you hear, and.

And the observation that things like viruses, you know, which could, you know, encode and change our DNA, but the viruses that cause cancer are the very same viruses that damage the mitochondria, that damage the DNA and the mitochondria, and causing respiratory insufficiency, which triggers an energetic crisis, which can trigger the activation of oncogene through retrograde response. So that needs to be appreciated, too. But There is this. This explosion of technologies that allowed us to understand genetics, and that was sort of being leveraged to really delve into cancer. I think there was some politics influencing that too.

So was the first thing you did from that point, because there's really two separate problems that you're talking about. The first is, why are these seizures occurring? And I'm referring very specifically to your DARPA funded work, which was, why is it that when these special forces guys are doing their ultra secret dives which require rebreathers, why are a subset of them having these fatal seizures?

Well, it's at the Office of Navy Research.

Oh, it was. There's also darpa. Okay. DARPA was doing that separately.

They were doing war fighter performance. Got it. With ketone esters just prior to, you know, what I was doing.

So that's one problem. And the other problem that's that you've also articulated is, hey, what's going on with cancer?

Yes, yes. So oxygen toxicity seizures are a limitation for Navy SEAL divers, and we don't know how to predict them or prevent them. It's also a limitation of hyperbaric oxygen therapy. Right. So if you have carbon monoxide poisoning, right. And you need to live, essentially, you need to get that. That carbon monoxide off your hemoglobin. You need to Basically increase the PO2 in your tissues, do that as fast as possible.

Carbon monoxide has a much higher effect affinity than oxygen for hemoglobin. So you have to basically out compete it.

Yes. So if you were to take a ketone ester, which we know now, increase your resistance to oxygen toxicity by like 600%, and take a ketone ester and then get inside a hyperbaric chamber, you have a much greater chance of living if you have wounds. There's 14 different applications for hyperbaric oxygen therapy. We think that therapeutic ketosis strategy would make it much safer and more efficacious. So in the context of an oxygen rebreather, the advantage is that there's a stealth component because you don't produce bubbles. You can dive in a quiet lake and go all the way across and surprise your enemy. But at just 50ft of seawater, within 10 minutes at 50ft of seawater, you run the risk of getting oxygen toxicity seizures. That's pretty shallow.

Wait, say that again. At 50ft, 50ft of seawater, 10 minutes.

If you're on a Draeger rebreather, according to the oxygen dive tables, that has been enough to trigger a seizure in many guys. So that produces a PO2 in your brain of about roughly 2,000 times higher than what your oxygen level in your brain would be right now. 2000% higher percent, not higher percent. So that needs to be sort of appreciated. And of course, this could all be averted if you just stick to the dive tables, right? But if you have enemy fire with 50 caliber machine guns coming down on you and you want to stay down, if the water's clear, you got to go down deeper. If you have a plant a mine and get to the bottom of a ship or a bridge, you might be underwater for three or four hours and the enemy's still up there. And you got to get down there and do your job and dive deep and avoid that. And then, you know, after a time, you have pulmonary oxygen toxicity, too, if you're down there long enough. But generally speaking, these rebreathers are for shallow diving, but situations where they need to go down deeper.

Do you have an estimate of how many Navy divers just in the United States, both in training or combat, would die in a given year from this or be injured?

It's pretty rare, fortunately. It's pretty rare. And if they do get hit with oxygen, you know, our friend Kurt Parsley will tell you that Navy SEALs notorious about not telling what their issues are with their health, right? So if they do have a seizure, they would be kicked out, you know, a lot of these guys, because that may make them a weak link that they're vulnerable. So we know recreational divers that push the limit, who have been hit a couple times, you know, with this, and we're doing some studies right now, recreational divers. So it's very underreported, but studies have shown. I always show a video in one of my talks of a guy in a chamber where he has a mask on, and the mask is breathing 100% oxygen, and the guy inside the chamber is breathing hyperbaric air. And within, at 2.7 atmospheres of oxygen, he gets hit with a seizure and has a really violent tonic clonic seizure. And it stopped as soon as you remove the oxygen mask and start breathing air, you. Even if it's at the same barometric pressure, the seizures stop. So one of the beneficial things of these seizures, if there's a beneficial component to it, is that they quickly stop as soon as you remove the hyperbaric oxygen source or you go from breathing 100% oxygen to hyperbaric air. So what's happening is that the high levels of oxygen are creating oxidative stress and. And actually impeding various metabolic processes in the brain. And the brain is becoming hyper excitable and the neurons are firing so many action potentials that the cells essentially can't maintain their membrane potential. And you get excitotoxicity that causes mass firing in the neurons and a seizure. Right.

And this is obviously under a very supraphysiologic.

Supraphysiologic. It only happens, happens in these extreme environments of pressures. And the reason for it now is kind of you have s nitrosylation of glutamic acid decarboxylase, there's two different isozymes. And then what we think now is that you have more glutamate to GABA ratio. So the enzyme that converts our gamma aminopteric acid is actually created from glutamate. Right, I got it.

So you have much more excitatory than inhibitory neurotransmitters.

So that ratio changes and it's a redox dependent reaction. Actually it's a. You have s nitrosylation of this enzyme that converts more glutamate to gaba. So you have increased neuronal firing and increased release of glutamate and also less conversion of the glutamate to gaba, which has a brain stabilizing effect.

So this is going off topic for just a second. But we know that as people age we see greater and greater oxidative damage. So we see, you know, the susceptibility to ROS going up. Does any of what you learned in this supraphysiologic environment where in a very short period of time you're going to generate a ton of Ross by exposing someone to high pressure and high O2. Does anything you learned in that environment offer an insight into non superphysiologic or normal aging and disease progression?

Yeah, I think in many different ways. So it's almost like exercise, right? If you exercise intensely, your reactive oxygen species are going to go up, inflammation, all these things kick on. So high pressure oxygen increases oxidative stress and that kicks on many different processes that can endow the cell with greater cellular protection. So it can, for example, cause an increase in superoxide dismutase. It can enhance, enhance our antioxidant defenses. So the oxidative stimulus is a trigger for adaptive processes that can allow our systems to be more resilient against the same level of oxidative stress. This happens very robustly in a young animal and is significantly attenuated in an older animal. And I think that needs to be appreciated. So the adaptive response to the stimulus is. Varies genetically, probably between the individual. There's a lot of individual variability between people. And even if you take the same person under different conditions, whether it be if they're sleep deprived, what they ate that day, maybe if they're dealing with a little viral illness or something, their susceptibility to oxygen toxicity, seizures can be greatly affected by a lot of different variables. But that adaptive response. So we know hyperbaric oxygen stimulates the production of stem cells as much as something like GM csf, like neupogen or leukine, like it's that powerful. It causes the production and the release of stem cells which kind of hone in on sites of injury and aid in repair. So that's why it's. Its most utilized application is actually for enhancing wound wound production or wound healing effects.

I see you mentioned that there were 14 approved applications. I wasn't aware that there were that many.

I certainly, I think it's 15 now.

So what are some of the others? Not to put you on the spot to rattle off all 15, but we can look it up. But sure. Just off the top of your head, what other ones do you know?

Yeah. Radiation necrosis. So for cancer, if you are getting radiation therapy for cancer, it is FDA approved for that. So if you have patients, you know who's had radiation therapy, of course there's decompression sickness. So we're recreational diving. If you get bent, another term for bent is decompression.

You know, it's the same deal. It's basically get the nitrogen out by basically punching nitrogen out, beating it out with oxygen.

Yep. Carbon dioxide, carbon monoxide. Obviously diabetic wounds, all the hyperbaric, the uhms. So Hyperbaric Medicine Society approves the facilities and I would say 90 plus percent of their revenue generated from that is diabetic wounds, which is a huge problem. Like you probably in your practice, you probably see people with wounds that just don't heal.

Well, I don't see it in my practice, but I certainly cut my teeth on it during residency. No pun intended. Significant problem.

Yep. So that's, I mean that's a few different applications. And there's a lot of sort of rare things. There's noise induced hearing loss if used. That's one of the newer applications that could be. So some things that are kind of counterintuitive. So when we think of high pressure oxygen, a lot of times you think of retinopathy of prematurity. Right. If you put a newborn and give them high levels of oxygen, you could cause them to go blind. Right. A newborn so that's an interesting meaning.

A newborn is more.

More susceptible, More susceptible to oxygen. It was very common, I guess you could say, to put newborns on high levels of oxygen if they were born premature.

And why? What is it about the newborn that.

Makes them more development of their lungs?

Is it the angiogenic component of this?

Yes, yes, that could be a component too. And maybe they just don't have the robust endogenous antioxidant capacity, but probably it might be the angiogenic component too.

Do you know off the top of your head if elevated mercury or mercury toxicity is an indication for hyperbaric? Because I've heard of a lot of people doing this, but it strikes me as a little bit off label.

There's so much off label stuff being done. So one of the things that I'm really interested in testing is for traumatic brain injury. And I do think that low levels of hyperbaric oxygen therapy, if used shortly after a traumatic brain injury, I think the faster you restore oxygenation, the more likely you are to salvage those neurons. So ideally, you want to treat with something that's going to re establish energy in neurons, decrease inflammation, and increase oxygenation to hypoxic pockets. And I think from my perspective, giving something like a ketone ester with lower levels of hyperbaric oxygen therapy would probably work. That's probably the by far the most controversial application because there are some remarkable responses from people who have even a regeneration of brain cells after the hypoxic injury, for example, in kids who are very resilient. Anyway, I know Dr. Paul Harch, you know, has been on pretty much all the major news networks with a girl that sustained an incredibly severe hypoxic injury and brain death and regenerated some of her brain, brain function and brain tissue.

How old was the girl?

She was pretty young, I think, five or six, I believe. And I met her actually one of the conferences, and it's very clear that nothing was working for her until she did hyperbaric oxygen therapy. So. But kids are completely. Could be another story. You know, we don't know if we could replicate that, but there are a lot of stories out there, anecdotal reports, but it just has not been studied appropriately. And those studies need to be done.

What do you see as the resistance? I mean, when you look at what's happened in the last five years in the NFL that has brought along with, I think, just the returning vets, TBI is. I mean, I don't think you could walk down Madison Avenue and hit Someone with a rock who hadn't at least heard the term tbi. So everybody knows what it is. We've got, you know, these two completely different demographics who are highly affected by it, athletes and soldiers. What's the hang up? I mean, you and I have spent a lot of time behind the scenes trying to get organizations like the NC2A interested in studying this. I'm struggling to understand what the hang up is.

You know, they're looking for devices to, you know, quantify TBIs and concussions. So that's a lot of funding is going into that. That area. At least when we talk about the NFL hit challenge and something that, you know, we submitted to, you know, I don't really know. I don't really know. I think the scientific rationale for a metabolic based therapy for the brain makes a lot of sense in restoring oxygenation. I think the waters are very muddy though when it comes to hyperbaric oxygen with tbi because I mean, we even did some rat studies where repeated doses of hyperbaric oxygen in a concussion or a brain injury model, a rat caused more injury can exacerbate the effects. Whereas a single dose of hyperbaric oxygen ra right after, at least in our rat model, decreased the infarct size by maybe 30%, something like that.

So this is dangerous. I mean, we don't want someone listening to this who's suffered a TBI thinking I'm going to go to some off label clinic and just max, you know, repeatedly expose myself to hyperbarics. I mean, the point here is this has to be studied. It has to be studied rigorously. It has to be studied empirically. And then we haven't even got into something we will get into later, which is the potential augmentation of the exogenous ketone.

Yeah, yeah. I would not do hyperbaric oxygen therapy if people are going to do it with and without, you know what I say? I would definitely do hyperbaric oxygen therapy if you're going to do it in strong nutritional ketosis. Because a consequence of hyperbaric oxygen therapy is could be CNS oxygen toxicity. So you do not. The last thing you want if you have a brain injury is to have a seizure. And we know 85% of all penetrating traumatic brain injuries lead to seizures in people who've had penetrating.

What about blunt? I mean, it's less than that. But how much less?

Yeah, so I don't know. I guess you would have to quantify the blunt.

The severity.

Yeah, but when it comes to penetrating. But it's it's, it's upwards. About 85% of penetrating traumatic brain injury injuries have seizures. And that's because you have excess glutamate, you know, and that's the very thing that's actually contributing to oxygen toxicity, seizures. Right. So I think the biggest thing to do is to augment your brain energy metabolism to burn energy more efficiently. The ketones do that and lower neuroinflammation. And I think there's a variety of ways to do that, but you don't want to throw more fuel on the fire. And I think high levels of hyperbaric oxygen therapy could be doing that. I think maybe these soft chambers that go to like 1.41 5 may be a better means to implement that.

Let's get into ketosis a little bit. I want to come back and talk about cancer. I want to come back and talk about the exogenous ketones, both the salts, the esters, and even different molecules. But one of the most interesting experiments we've seen in the physiology of ketones, like, you know, as far as old school experiments, was the George Cahill starvation experiments. Right.

I was highly motivated by that study.

We're going to link to it here. But let's. Why don't you give people the Reader's digest version of what George Cahill did that could probably never be done again.

Yeah, yeah. And I was. I was very lucky to connect with him before he died. He passed away in 2012. I connect with him a few years before that, and just to figure out, you know, did he really do this studies? And there was a lot of studies that also that didn't get published that were pretty remarkable too, that somehow they got past ethics review at Harvard Medical School. But essentially what he did, a very elegant study to look at brain energy metabolism, the AV difference in blood and metabolites in subjects that fasted for 40 days. And most of the subjects were divinity students, I believe, or maybe conscience and subjectors to the war or something like that. But each person had like a different story behind it. And he fasted these subjects for 40 days.

And just to be clear, this is water and mineral.

Only water, no calories.

Yeah, but they took minerals. Right? They had magnesium and sodium.

They did. I think they took a mineral supplement. And they also were. They weren't lean subjects, so they were subjects who, from their perspective, were overweight, if they not obese subjects. So they had some weight to lose. And it was a very well documented and well controlled study where they monitored free fatty acids, insulin, glucose Beta hydroxybutyrate, acetoacetate and acetone. And.

And let's. I'll just pause you there for a moment for the listener. We'll come back to this because I want you to explain the difference between beta hydroxybutyrate or BHB acetoacet tonight, or ACAC and acetone, how they're produced, which ones are metabolically active, which ones aren't. But hopefully, by me just saying this between the two of us, we'll remember to come back to that. Okay.

Yeah. So, yeah, essentially three ketone bodies, beta hydroxybutyrate being the primary ketone that's elevated and more stable in the blood and probably more likely to be a brain fuel. And if we just focus on that ketone body, after 70 days, it reached the level to where it was at or above the level of glucose in the subject. So glucose came down from 5 to 6 millimolar, down to 3, and stayed at 3 millimolar throughout the duration of the experiment, throughout the duration of the fast, from day seven, essentially, to the remainder of the 40 days.

So for the Yankees listening to this, who aren't familiar with the metric system, 3 millimolar is about. About 55 milligrams per deciliter.

Yeah. Yep.

Okay. So that's pretty darn low.

Yeah.

But what's interesting is it gets down there. I think it was between day 7 and day 10, it hit 3 millimolar and then it just never went down again.

Yeah, yeah.

What the heck is going on? These people don't eat any glucose. How are. How do they sell? And what that tells you, by definition is their liver still had glycogen because that. You have to be putting that glucose out. Out from the liver.

Yep. So the maintenance of glucose is under very powerful homeostatic mechanisms. So we have. We're hardwired from an evolutionary perspective to maintain glucose. And the glucose can be coming from gluconeogenic amino acids. So we are breaking down some muscle. And then the glycerol backbone of triglycerides, too, also contributes to the production of.

So triglycerides being the storage form of fatty acids. You have a three carbon backbone that's called a glycerol backbone. It has three of these free fatty acids that are. Well, they become free once they're cleaved. They become the substrate that you're going to explain to us in a few minutes is how you make BHB or beta hydroxybutyrate. But you don't just throw that glycerol out. You can actually. The liver can turn that back into glycogen within itself to then.

Yeah.

Slowly trickle out into the bloodstream.

Exactly. Yep.

So when Cahill did this, if I recall, insulin levels also got very low. By day seven, the insulin levels were, you know, at rock bottom and sort of stayed there.

Yeah, yeah, they're really low.

One of the interesting things about the experiment, in addition to the stuff I want to hear about, which is the brain metabolism and how did the brain partition those fuels, is was it this experiment or a different one where he was able to give insulin lower glucose levels but not generate CNS trauma through that?

Yeah. So the subjects were asymptomatic for hypoglycemia, and they felt really fine. And in another.

Down to what level? Like 1 millimolar.

Yeah. So they infused IV infusion of 20ius of insulin and pushed glucose from 3 millimolar or thereabouts down to roughly 1 millimolar, which is like less than 20 milligrams per deciliter.

Yeah. Which would be 50 fatal. That would be universally fatal.

Level of glucose, even 2. 2 becomes like coma and essentially fatal if it's maintained.

I hit two very briefly.

Yeah.

During an insulin suppression test I had at Stanford, and I was no longer in ketosis because I was doing this insulin suppressant test. So I started at about two and a half or three millimolar, but 90 minutes later, my ketones had withered down to, like, 0, 3.3.4.

Yeah.

And then my glucose hit about 38 milligrams per deciliter. And. Yeah, I really. I. That was the day I thought I was gone.

Dangerous area.

Oh, yeah. No, I thought I was gone.

I have a little self experiment I can mention after this, but essentially what they did, which was a very bold and gutsy demonstration, they injected insulin, which facilitated glucose disposal in the patients, essentially, and brought blood glucose down to roughly 1 millimolar, which is universally fatal. And the subjects were relatively asymptomatic for hypoglycemia, which was remarkable. Their ketones were maintained at about above 5 to 6 millimolar.

That is out freaking rageous when you just stop to think about how you could take a normal, normal, healthy volunteer and do something. I mean, we're all in the spirit of learning, but when you just think about that from an ethical standpoint, like.

I can't do that in mice. I'm not allowed to do that in mice. The iacuc, the Institute for Animal Care and Use Committee, you know, would not Approve. Fasting for more than 48 hours. I think it's for 24 at our institution. Yeah. So that's for mice and maybe rats. Might be 48, but yeah. And the use of insulin to further, you know, that would. I'm. I serve on the iacuk. I mean, these things would be quickly rejected.

I mean, this is. This was the wild, wild west. Yeah. And then just the last thing on this topic that I remember, which I'd love you to expand on, is what did we learn about how the brain partitioned? Fuel. How much of the brain's energy once you were in that steady state after about 10 days, came from glucose? Beta hydroxybutyrate and acetoacetate.

Yeah. So beta hydroxybutyrate accounted for approximately 60% of the energy and probably 10% acetoacetate. And roughly at that point, after about 10 days, only about a third of the energy was coming from glucose. Right. And basically what's in your blood as far as ketones and glucose is what your brain is utilizing, you know, your brain's utility in a hungry state, and it's effectively utilizing and clearing those. Those metabolites. You can do that. It was. It was very elegant demonstration, and it kind of changed our understanding of brain energy metabolism as glucose being exclusive predominant fuel. So in a fed state, they were consuming 100 of their brain energy metabolism was from glucose.

Right.

But only after being fasted did that change. And he went on to write a note, number of reviews, and went on with Dr. Veach, who actually created and developed some of the. They published together.

Veech was a postdoc with Cahill, wasn't he?

A postdoc? Yeah, he was a student of Hans Kreb, actually. And then. Yeah, he was one of my. I forgot that fact. Yeah, he was one of his best students, from my understanding. Yeah. From word of mouth. Yeah. They went and they worked together in different capacities. Yeah. I think he might have been a fellow with him.

Him. I think most people listening to this, if they can dig back to high school biology, that that name, Krebs will sort of ring a bell. Right, so you mentioned that. That Cahill shared with you stuff that wasn't even published. Do you remember anything that that was. That struck you as super interesting? That was unpublished?

Yeah. You know, some things maybe not worth talking about. Well, yeah, I don't know if he. There was some stories, and then I heard some stories. Stories through other people to.

Well, I don't want to make you say anything that you're not comfortable saying.

Publicly, I would say some of the work that was done in animals definitely suggested that glucose could go lower, even lower, and that you could really transition your metabolic physiology to be fueled off fats and ketones. And that was against what we knew. These were remarkable observations that changed the whole context of what we knew about metabolic physiology and brain energy metabolism.

Do we know today if the brain can use lactate directly as a fuel without it having to go through the CORI cycle?

Yeah, it most certainly can, I think. I think lactate's actually a great fuel, and that's one of the first fuels I got interested in when I was studying hypoxia, and then later even hyperoxia, was thinking about using lactate. Different forms of orally available lactate, like poly L lactate, I think it's in the product Cytomax, if you remember, for cycling, I used to use Cytomax.

Yeah.

So I was actually interested in that and that actually led me to ketones. And then once I got more into studying ketones and discovered somehow it slipped past me. All the years I thought I knew what a ketogenic diet was, but then when I read about the history of the ketogenic diet being used for almost a century, and I realized that it was like the standard of care for seizures. And then understanding that these ketones can largely replace glucose as the energy source, and then they have these signaling properties that are even independent of metabolism that are remarkable. Over the last five years, a lot of these big labs are looking at the epigenetic effects of ketones functioning as class 1, class 2 histone, functioning as a suppressor of the NLRP3 inflammatome, producing less inflammation in a metabolic independent way.

So you obviously pretty quickly come to this idea that these ketones are interesting molecules. And they're interesting for a couple of reasons. At the very least, what you just said, which is they have signaling properties that make. Make them kind of unique. Outside of the exogenous ketones, though, you have to also undergo a pretty extreme physiologic change, at least in a Western culture, to make enough of these to matter. And you have to restrict carbohydrates and protein to get there. So did you first personally get interested in this from a nutritional standpoint, and then eventually through this exogenous pathway or vice versa?

Yeah. So ketone esters, to my knowledge, in 2008, eight didn't exist. They actually did, but I didn't know of them. I discovered them on a DARPA website as some work that was being Funded and developing of the ketone esters for war fighter performance. But at the time when I just decided to go down the route of the ketogenic diet, I reached out to Johns Hopkins and the crew there.

Which is where the anti seizure therapy was pioneered, right?

Yeah. Mayo Climb Clinic first and then they worked together with Hopkins. I would say the bulk of the work that was done to develop the protocols for the ketogenic diet which are in use today, was developed at Johns Hopkins. And I got Eric Kossoff books, his book published with John Freeman, which was. I just went out and did the classical ketogenic diet. The 4 to 1 ratio. So 4 parts fat and 1 part being protein and core carbohydrates, it equates out to 87 to upwards of 90% fat, maybe 10% protein and like 1 or 2% carbohydrate. So I mean it's like basically eating super low carb and then adding mountains of fat on top of that plate, making like a super low carb meal with protein restrict and then add some butter and a couple cups of heavy cream with that. And that's. I started weighing everything out.

What year did you start that?

2008 I think. And nine. I think it was 2008 or nine that Eric Kossoff published the modified ketogenic diet which was more liberal in protein and increasing protein from 10% to 25 and 30% or 25% is a huge difference. Like you can. That's actually a diet that I mostly adhere to now. And I followed the ketogenic diet and I bought the STR strips were very expensive at the time. There was a couple different kits that I got to measure my own ketones and you know, I immersed myself in it. I got obsessed with it and I wanted to know what it felt like to have a brain that ran on.

Ketones and how high did your levels get measured in the blood.

I kind of struggled to get up there even with the classical ketogenic diet 2 and 2.5. I would typically with the classical kidney. This is before MCTS. So I wasn't quite using MCTS yet. In 2009 I started incorporate the same time I discovered the modified ketogenic diet was the same time I started using mcts. And a modified ketogenic diet with mcts got my ketone levels up probably higher than the classical ketogenic diet, which was just mostly a dairy based long chain fat sort of derived diet.

So let's tell everybody how we make ketones and then we'll tell Them what an MCT is for those.

Yeah.

So let's talk about starvation, ketosis and then if there's differences between that that are worth highlighting with nutritional, that would be great. But evolutionarily, I'm going to deprive you from eating for a few days. How do you survive?

Well, you start burning up your liver glycogen.

Okay. So 24 hours later, you've got that down to about half of its. Yeah, have to let about a quarter of its supply.

Through the suppression of the hormone insulin, we start mobilizing fat from adipose tissue, which are cells. Pretty much all cells in the body, especially muscle and heart cells, burn fat. Like a superior energy source, Long chain fatty acids don't effectively cross the blood brain barrier. So through accelerated fat oxidation, beta oxidation, oxidation of fats in the liver, that stimulates the accumulation of acetyl CoA, which forms acetoacetate and ultimately beta hydroxybutyrate. So you start spilling these ketone bodies through accelerated fat oxidation in the liver. The liver lacks succinyl COA transferase, so it does not actually use the ketone bodies for fuel. And they become available for your brain, central nervous system and peripheral system.

So the liver is secreting the beta hydroxybutyrate.

Yeah. And to some extent.

Okay, so is the BHB being made and then being converted into acetoacetate or is the liver making both acetoacetate first.

And then beta hydroxybutyrate? And it's interesting that some people have a ratio beta hydroxybutyrate to acetoacetate of 2 to 1 and some people 5 to 1, generally speaking, about 4 to 1. So acetoacetate is unsettling, stable in that it can spontaneously decarboxylate to acetone, which is volatile, and we blow it off in our breath.

Does it have metabolic activity? Can we.

It was thought that it didn't. But more recent work is suggesting that the carbons of acetone do find their way into sort of lipid biosynthesis and some other things. But it's kind of rare for that.

But it's not a great ATP source.

Not. No, not, not really. It has some effect on neurons, so it has an anticonvulsant effect through, I believe, opening a potassium channel, which could hyperpolarize the membrane potential and actually help attenuate some hyperexcitability in the brain. So there are people that study, you know, the effects of acetone as a sub. Narcotic levels of acetone. Right. Acetone can be pretty narcotic and be problematic. But acetone levels that are 0.5 millimolar and even upwards of 1 millimolar can have a neuroprotective effect. Once you get above 1 millimolar you start to dissolve some of the membranes and you can have sort of.

It doesn't sound.

Yeah, you have problematic. You know, acetone is a, is a pretty powerful solvent. Right. It's a nail polish remover. But small levels of acetone are neuroprotective and that's actually something that we study.

So how do acetoacetate and beta hydroxybutyrate enter the Krebs cycle? In other words, where do we get ATP from them?

It depends on the cells. So different cells have different, we're looking at this now, different ketolytic enzymes. Right. So they can feed in through a number of different pathways. Like I said, the liver is the production site of beta hydroxybuty. And when it comes to skeletal muscle, they have a range of ketolytic enzymes that can allow them to enter the Krebs cycle at different areas. So succinate, for example, so you can replenish TCA cycle intermediates. With succinate acetoacetate can break down and provide acetyl COA for the Krebs like. So what we're finding is that the Krebs cycle is not the simple cycle that we thought it was, especially as it relates to cancer cells. So it's almost like we can't even look at the biochemistry book and kind of pinpoint different pathways with substrate level phosphorylation. There are a number of different pathways like the malate aspartate shuttle that are associated, associated with cancer cells. If we go back to those pathways.

Did you see that paper that came out in Nature two days ago about aspartate being a rate limiting step in cancer metabolism in the mitochondria?

I didn't see that.

I haven't. Bob and I were just talking about it today. It's interesting because the paper was part of. It was written through a lens of hey, this might be how metformin can exert some of its anti cancer benefits by interfering with aspartate. I think it was to interfering with degradation of aspartate. But again, I haven't read the paper yet. Just sort of the abstract. But it was yet another. Like I didn't know that. Wow.

Yeah.

Every day I feel like I'm feel like I'm getting dumber because the rate at which I'm being exposed to new information is exceeding the rate at which I'm assimilating it. So it's just. It feels like I'm on a downward spiral to stupidity.

There are textbook pathways that I used to just rattle off, and it all seems so simple. And then, you know, I read three or four papers and I realize that I probably shouldn't talk about it in simplistic terms like that. I mean, we're kind of going down the rabbit hole of glutamine lysis. Right. So glutamine is the fermentable fuel. So ketones are a non fermentable fuel, whereas cancer cells. We use glucose and glutamine as the two primary fermentable fuels.

You know, it's funny, I. I mean, I know that biochemically I'd never thought of it in those terms, though.

Yeah.

Yeah. It's not fermentable. That's interesting.

So that's kind of what I'm thinking about, you know, in terms of. Of ketone metabolism with glutamate, so. Or glutamine. Glutamine can make glutamate. Right. And alanine and aspartate and lactate. And glutaminolysis is kind of driven by the malate aspartate short shuttle. And that has become a major focus now of many cancer researchers are looking to target glutamine. And it's not. It's not easy, I mean, because you have. If you have a glutaminase inhibitor that has tremendous side effects, huge toxicity. Right? Yeah. So we need to approach this in a very nuanced sort of way when it comes to targeting glutamine.

Yeah. So let's go back to the MCT. So you talked about how you started out on 4 to 1 ratio, which is interesting. I started out 4 to 1. I spent three years on just 4 to 1. I never deviated from 4 to 1. But then you mentioned you went to 2 to 1, which is obviously much easier to do, but you augmented with mct. So mct, of course, stands for medium chain triglyceride. They're a type of saturated fat, and they're of a certain length. And I don't even remember anymore. Is it 8 to 14 carbons is what we define as MCT.

Yeah. 8 to 10, I think 8 to 14 from. In that. But when we talk about the ketogenic ones, the.

They're more close. They're closer to caprylic acid, which is the C8.

Yep.

So why does. Why does taking those make this process easier?

When you consume them orally, they are transported to the liver via hepatic portal circulation. And they're not packaged into chylomicrons and, you know, long chain fatty acids. When we eat them, they're packaged in the chylomicron and they go through, essentially enter the lymphatic system and have a different route of entry. They're metabolized totally differently. Whereas medium chain fats go directly to the liver through hepatic portal circulation. It's like a bolus of fat going to the liver, and it's a type of fat that's rapidly oxidized. The liver is chock full of mitochondria. So if I want to study mitochondria, I'll take out a chunk of the liver and isolate it from that because that's the easiest thing to do. So the mitochondria really burn up medium chain triglycerides very quickly. And there's very high rates of fat oxidation in the liver from an oral bolus of medium chain triglycerides. So they're much less likely to be stored as fat. They're a source of calories, and they can be incorporated into meals and into foods to further enhance and boost the ketone. Ketone levels of the ketogenic diet. Or even if you're not on a ketogenic diet, they can be consumed with a high carbohydrate diet and actually elevate ketones in the blood.

Yeah, I mean, I've heard that, but I've never actually measured it, probably because I've only done this with liquid mct, which you end up getting to sort of GI tolerance becomes an issue probably before you get a high enough level. But if you're on a high carb diet and you consume, I don't know, 2 to 3 tablespoons of MCT, how high could you reasonably expect your BHB to get?

Depending on your absorption? Anywhere between 0.5 to 1 millimolar max high, say. Yeah, even on a high. Yeah, if it's pure C8, maybe. So with C8, you get about a 20, maybe 30% elevation above, like a mix of the C10, C8, which is generic. There's some work being done that C10 may actually have some beneficial effects. I mean, that's kind of the idea behind the product Exona, that was on the market, you know, a while back. I don't know if it's still on the market.

I don't know. I don't know what it is.

Yeah, It's a basically C8.

It's powdered C8 that used to sold as pure C8.

Yeah, you can order.

I ordered, like from Sigma or something like that.

Yeah, well, I. Dave Asprey's brain. Octane is caprylic triglyceride. And perillo nutrition makes captree, which is a C8 oil. So if you buy pure C8, not in triglyceride form, caprylic. If you just. Yeah, just straight acid.

Yes.

That'll kill you. I mean, you consume that. I bought. I made the mistake early on and bought from Sigma. Caprylic acid, but not. You need to buy.

How did you catch that mistake before ingesting it?

I bought it from Sigma and I think I was going to use it in experiments and we were going to make. Mix it, you know, with our rat child. And I wanted to go through a legitimate source and I put a little bit on my finger and it kind of burnt my tongue off. And I realized, wait a second. I think I need the triglyceride form of caprylic acid. I need the caprylic triglyceride. Yeah. I almost killed myself.

You almost won a Darwin award.

Dump it. Yeah. Yeah. You know, I never looked at. Someone probably did that before.

Accidentally kills himself.

Yeah.

Have you had any experience with the powdered MCTs?

Yeah. Yeah. So powdered MCTs allow me to increase my ketone levels higher than. And I use the Quest powdered MCT formula. There's a couple on the market now maybe.

Yeah, I. I have vats of this stuff at home because I feel like anyone who's ever made a ketone product just somehow figures out my address and sends them to me. So I have a pantry full of every type of ketone you can imagine.

I do too, but I haven't.

Yeah, you probably get more than me. I just haven't got around to trying any of the MCT powder, but I'm getting ready to do a long fast in a couple of weeks. And I was thinking I really ought to get. Make sure I'm back in ketosis the week before I deprive myself of food for a week.

Yeah.

So I was actually just thinking about this last week, which is I gotta fire up those powdered MCT and kickstart this thing because I don't have like a couple months to get fully adapted.

Yeah, they are great. I mean, MCTs are kind of like the poor man's ketone ester. Right. So they are. They're. They're found in nature, they're versatile. You can.

I would even call them the middle classes, man.

Yeah.

Given how Expensive ketone esters are now.

That's right, that's right. Yeah. So I tinkered a lot with MCTS early on and increased my tolerability from maybe 30ml a day to 150ml a day.

Hang on a second. That, that's ridiculous. Yeah. When anytime I went to 30 in one sitting.

10 tablespoonfuls.

Yeah, yeah, that's, that's hard to fathom.

You need to incorporate it with food. So I was spreading it. What I found I needed to do was instead of doing intermittent fasting now, which I pretty much do now, I incorporate, I spread it out over like four meals and maybe would have a little bit of MCT in the coffee too, and not including that in a meal. So I was eating a modified ketogenic diet, but spreading that MCT out with salad dressings, putting it on vegetables and things like that. And I was able to, because if.

Anybody'S listening to this and is trying to, like they're just sitting there thinking, what could I do to do it? To have a bowel prep? Like the answer is just, just, just drink mct. It's, you know, it's, it's better than Fleets phosphor soda. You will, you will spend the day in the bathroom and you'll, you'll have a great coma, but you can work.

Your way up to it. So there's a number of transporters obviously that are upregulated and you are enhancing the breakdown and transport of these fat and mcts actually do cross the blood brain barrier. So we did studies in rats where we.

But if they're getting absorbed portally, how do we know?

Oh, okay, some of them, I forget the percentage, but I think, and some people say it's like 50% of MCTs converted to ketones, but I think it's something like about 20% of MCTs. And it depends on the energetic state of the liver, you know, which is the master regulator and your, your physiology in general. But you have a, a fairly significant portion of the MCTs being converted to ketones. But the MCTs do enter the blood and they can cross the blood brain barrier, unlike the long chain fats. And they. For example, if you take out the hippocampi of rats that are eating an MCT based ketogenic diet, you'll find MCT levels are significantly elevated. So they're crossing, they're getting into the brain and the brain is utilizing mcts as fuel.

And do we know if that has any anti seizure effect independent of the ketone that might be produced alongside it.

That's a big area of research. Right. Right now that MCTs as functional fats.

I've never heard that term before. Functional fats.

Yeah, well, fats with drug like properties. So I think there's a number of patents around C10 actually that I know they have in the UK. I think it might be a pharmaceutical now. So C10 actually has anti seizure properties. So there's some people argue that the effects of the ketogenic diet, at least with mcts is not due to ketones, but actually due to the mcts and not the ketones. So there's a little bit. There's a couple groups out there that are sort of arguing that and I think they have a case, but I think it's probably a common, definitely a combination of the ketones and the mcts. So mcts do have interesting properties.

Do you know Elizabeth Thiel at Boston Children's? So I remember having breakfast with her about six years ago and asking her a question that at the time I don't think she knew the answer to and she was gracious enough to explain that and she was there with someone else in her lab. So it was a very spirited, awesome discussion. But I wonder if the answer is known today. The question was basically do you believe that the anti seizure properties of a ketogenic diet are more the result of the brain having another feature, fuel to displace glucose or due to the reduction in glucose that invariably accompanies ketogenesis. And at the time she shared with me very compelling data that would could argue either of those points, potentially suggesting it was the combination of them. Do you have a point of view on this or is there more information today that steers you one way or the other?

Well, I know she's done some work with the low glycemic index diet and.

So carbohydrate reduction but without the production of ketones.

Yeah. So a reduction, it's carbohydrate restriction, but only to the effect of maybe 20 or 25%, you know, and then carbohydrates that are low glycemic index.

And what are the results of that intervention?

For different types of seizures it can have a positive effect. And for certain, certain types of seizures, that's not the first line of thickness therapy for, you know, very powerful tonic clonic seizures. And pediatrics you want to go right to the classical ketogenic diet, but it does have a number of applications for different types of seizure disorders.

And what about if you Take someone on a fully carved diet who's having recalcitrant seizures and you give them ketone, exogenous ketone. Does that have anti seizure benefit?

Yeah. So those studies have not been done yet. And there's a study being recruiting right now for something called Angelman syndrome, which is a rare genetic disorder that has seizures where the exogenous ketones are the therapy independent of the diet. So they're just being added on top of the diet. There are people out there because exogenous ketones are commercially available that are using this in place of the ketogenic diet. Because, because the families are either unwilling or for various reasons unable to use the ketogenic diet and they, you know, use, are using exogenous ketones. And the feedback that I'm getting could be biased, but it does seem to have an effect. It obviously has an effect in animal models. The animal models that we work with, we give exogenous ketones on top of a standard rat chow, which is high carbohydrate chow. And it, it works, works very well for CNS oxygen toxicity, but also for things like phenylan tetrazole seizures, PZT seizures. Even for absence seizures, we use a particular animal model with absence seizures or absence seizures, which works for that. So it works for a variety of different seizure models. Independent. We are circumventing sort of the dietary restriction that's typically associated with getting into therapeutic ketosis and just simply giving exogenous ketones and elevating exogenous ketones. But a consideration is that exogenous ketones lower blood glucose. So you have, and in some cases it lowers it really low. Like the high dose ketone esters that we do in our rat models. It pushes. And rats typically maintain a glucose of around 140 to 150 and it'll push it down to 40. So milligrams per deciliter. Yeah. And that's approaching the maximum tolerable dose of the ketone ester. And it's interesting, when we go above the maximum tolerable dose, we actually see glucose levels spike up. And this is a phenomenon that we see. It's almost like it's stressing out the liver or dysregulating the liver in some way. It's the data we're trying to figure out. But if you titrate in ketone salts or ketone salt, MCT combination or, or various ketone esters, it's inversely proportional to, as you elevate ketones, you have a very predictable Reliable decrease in blood glucose that's above and beyond the decrease in blood glucose that you'd observe with something like metformin. And we use metformin for many, many studies in the lab. I mean, we've have a lot of experience with it.

So what do we think? You know, it's funny, I was up in San Francisco like a month ago and I was talking with Steve Phinney, who, you know, at the outset I said, you're one of the people who I would say knows more about ketosis than anyone alive and certainly Steve would have to be in that category. So I would, if I were going to just guess, I would say between you and Steve Phinney, if the answer isn't really known on ketosis, the answer might not be known.

Yeah, yeah.

So, but, and Steve and I were having this really fun discussion with a few other folks about why is it that the ketones are driving down the glucose levels and conversely, and maybe this is a different question, of course, but why is it that when we do these experiments of you take somebody in nutritional ketosis and you make them do really, really aggressive exercise, you know, do a two minute all out effort on the rowing machine, that the ketones go way down and the glucose goes way up, Is it solely a consumption and hepatic glucose output issue? Is there something else going on? You know, and, and I was like, well, I kind of always assumed that we knew the answer to that and that it was the explanation I had. But, you know, it wasn't. At the end of that discussion, I was like, actually, I pretty much now don't think I know the answer to this question.

I don't think we do. I have three potential explanations. One could be an exogenous ketone induced release in insulin that facilitates glucose disposal. So where that happens, you do get, I mean, it's not like consuming a protein bolus or a carbohydrate bolus, but you do get an elevation of ketones. That's, that's how we moderate our ketone levels. Right. So as our ketone levels, if we're on the ketogenic diet and our ketones become elevated, there's ketoneuria, we pee out some ketones and there's a number of products, but one is a ketone induced release of insulin, which then feeds, feeds back on the liver to like a rheostat really, and lowering beta oxidation, which.

Totally makes sense because that's the reason that someone with type 1 diabetes can get ketoacidosis. They lose the checkpoint Yep, yep.

And other researchers, like, if you ask Richard Veech, he'll tell you that insulin sensitivity is increased. So the insulin that you have available and associated signaling is being enhanced in the presence of keto ketones.

So is that an immediate change or is that a change that takes place over a long period of time? That. That sounds like a long standing issue.

I think there's a number of regulatory things that happen. I know in his study where rats were fed standard rodent chow, but 30 to 20% ketone ester, I think within that chow, their baseline insulin levels went down like 50%. So that's just simply by, you know.

Just the addition of the ketone.

Addition of the ketone over time, over. I think it was like maybe a three week. I gotta look to see the study. But it was, it was consuming ketone ester that was integrated into the rat chow over a number of weeks decreased baseline levels of insulin significantly. I mean, it was like a huge effect. And the implications of that, you know, as a rat study, you know, you can argue rat study, but I can tell you experimentally that, or just, you know, testing on myself that the same observation happens. I can actually, if I get a significant amount of my calories from exogenous ketones and I do that over several weeks and I measure my insulin, it gets below the reference range. Whereas if I get back to a regular ketogenic diet, I'm always on the low end of the reference range. But I did find, if I. If I consume the maximum tolerable dose of a ketone ester or ketone salt, and then I measure insulin an hour or two after that, I do get a little bump up in insulin, but it's nowhere near the bump I would get up if I ate an equivalent amount of calories from protein or carbohydrates, which would shoot me up to 8 or 10 or something like that with a big dose. But it's usually somewhere around. I bump it up from 1.5 to 2.5 or 3 or something like that.

Wow, those are still super low.

And that's my baseline. It's usually between 1 and 2.

So has your IGF level changed in the years that you've been on ketosis? Have you tracked it much?

I have not. I've gotten it measured a few times, but not, not reliably. Like, I do insulin quite often, like every, every two months or so, Like, I'm doing that. And if I'm doing an experiment, I may do multiple measurements of insulin, like throughout the week. Week But I haven't measured IGF1 recently. I did a while back and I was just in the normal range, but I wasn't fasting. I didn't. That's the one variable I wish I would have tried. Insulin was low, so I can assume IGF1 might have been a little bit low.

Yeah. So just for listeners and stuff, how do we measure ketones? I mean, people talk about urine strips versus blood. What are you measuring in each? And breath, for that matter. You've got three ways to theoretically measure these things. Which one do we prefer and why?

For a newbie getting into this, I think the urine ketone strips will at least tell you if you're in ketosis or not in ketosis.

What is it measuring a urine strip, peeing on it. And what does it tell you?

Urine acetoacetate is measured. And now there's a urine beta hydroxybutyrate kits that are available, so you could do that. So the Abbott Labs Precision Extra and the Keto Mojo are two devices that will measure basically an assay, a home assay kit for beta hydroxybutyrate. And we have used both of those things and kind of measured it against various assays in the lab and blood that we send out for analysis. And it's pretty close. Pretty close. Plus or minus, maybe 10 or 15%.

What does the urinary level? Even though it's a qualitative assay, but everybody says, hey, my urinary ketone thing lit up bright purple. Can we infer anything from that about the blood level of BHB or acetoacetate?

Usually, you know, unless you're running kind of dehydrated, you know, if you have a normal hydration state and your urine acetoacetate is 40 milligrams per deciliter or above, you're probably hitting 1 millimolar or above. If you're anywhere between 40 and 80 to, I think, 160 milligrams per deciliter. So you're in a state of ketosis. I would. If you're at 15, that's like light pink or something, you're usually probably not in a state what I would say, keto, that might be a normal state. If you wake up in the morning in sort of a fasted state, you might be hitting that. But generally speaking, you need to be at about 80 milligrams per deciliter on the urine ketone strip.

And the one thing I didn't do do, rather, when I was doing my sort of long foray, into ketosis is I didn't use the urine meters at all. I was just, you know, I was. Yeah, I was keeping Abbott in business basically with how many of those precision extra strips I was going through. So I don't know if my urinary excretion actually declined over time when my body became better and better at retaining this potentially preferred fuel. Have you done anything on that, either personal, personally, or in the lab?

So what we use in the lab is the clinitech status device. And that device takes the Siemens 10 SG kit, so the multi stick. So you can buy for a similar cost as the keto stick. You could buy the Siemens 10 SG multi stick and that measures 10 things including urine acetoacetate. And you could take that urine strip and stick that in a device that will give you more of a quantified number.

I see. So that's how you were giving me quantitative information on the urine, Because I've only seen the qualitative stuff.

Well, it's a color change on the strip that's measured, right?

The device tells you.

Yeah. So over the years I rejected urine ketone strips as something that just wasn't very accurate. And the more I use them, making hundreds, if not thousands of measurements, the more I gain an appreciation that it can be a pretty useful device. But I think it's, it's kind of useful for the individual. Your hydration status definitely changes it. I mean, I've been in situations where I'm dehydrated, where I've come out of the water after like a six hour dive and I've peed on those things and it's like, it's like screaming. And I knew, I mean, I did some dives where I purposely went. I wasn't in ketosis for some of the research that we do. And I was deep into. Into ketosis just because I was, you know, very, very dehydrated.

I didn't know someone could dive for six hours.

I was on the NASA NEMO extreme environment mission operations trip. So I was a crew member on that, where I maintained I was lived in saturation for 10 days in a hyperbaric environment. And that that involves like an 18, 19 hour decompression to come out. So it's a NASA sort of a Mars analog mission where you, where you work with astronauts underneath the sea. And I maintained a state of ketosis throughout that whole mission and did lots and lots of measurements on myself down there. And I saw, really, when I one time I got out after maybe it was a six Hour eva. So essentially, you're in a hyperbaric habitat on the bottom of the ocean, and then you go out into the water. Water. And then you come back inside the hyperbaric habitat. But when you're out in the water, even though you're down in the Keys, the water, water pulls heat from you like, 200 times faster than air. So even though it's like, you know, upper 80s, I come out of that hypothermic and dehydrated. My blood glucose always was in, like, the 30s, sometimes in the 40s. When I was on Akita, I was testing some of the ketone supplements.

Wow.

Yeah.

What were the other people experiencing under those circumstances?

Well, we'll find out with this. My wife actually was selected as a crew member for NASA NEEMO 23. I was on 22, and I did not get the IRB protocol approved to do all the metabolic studies that I wanted to do, but I became an n of 1 on that, and I collect a lot of data on myself. So with this new mission, we have the NEEMO NASA NEEMO 23. We'll be able to make some pretty comprehensive metabolic measurements, including things like hemoglobin H1C. We're going to measure inflammation, HSCRP, glucose ketones, all these things on all the crew members. Interestingly, this year, it's a. It's an all female crew. So you have, like, Samantha Cristoforetti, the famous European Tracy Caldwell Dyson, who I've known at NASA and my wife. And it's all female. So we'll have. We'll have some female data to go along with this.

What surprised you the most in Your N of 1? What did you see that you least expected?

I saw why. Predicted that the habitat would really trigger inflammation. That was probably from the elevated CO2 levels and the elevated oxidative stress. I chose to stay in a state of ketosis with the idea that that was my baseline state. We're doing studies on sleep. We're using the OURA ring, you're probably familiar with that on sleep, and also the Polar V800 to collect heart rate variability data, gut microbiome, we're doing body composition measurements, we're doing stress. So we use the NIH toolbox and, and joggle to look at cognitive psych parameters. So that data has not been shared to me. So I don't know. My wife collected some of that data and that's being analyzed, you know, later on for publication. But from a metabolic perspective, from a hormone perspective, some of the things living in that environment for 10 days. Decrease my testosterone.

How much?

At a 25% decrease in testosterone from the time. And so we're fairly, maybe fairly sleep deprived. I average about six hours of sleep per night, but I was getting like two and a half hours of deep sleep, which is more deep sleep than typically. Yeah, I was like, I don't know if it's a.

It might be an artifact of how the sleep is being estimated. In other words, you know, if you think you're assuming you're giving that off the Oura ring, right?

Yeah, that was aura.

So the Oura ring is measuring, but.

I usually get about 90, 80 minutes sometimes like last last night, I got one hour and 53 minutes of deep sleep, but I usually get about one hour, one and a half hours of deep sleep. But I got over two hours every night. And instead of seven hours sleep a night, I was getting consistently just, you know, five to six hours sleep a night.

So where were you getting mostly shortchanged? On rem?

Yeah, on rem, but my REM was even not that bad. Usually I was getting about an hour, you know, an hour around, which is not as much as I. Yeah, that's too low. Usually 2 is optimal for me. I think. So. Yeah. We measured sleep. The things that really stood out were being in the water really pushes my body into. And being hypothermic really turns me into a fat burning machine. My ketones go off the chart and my glucose goes way down. It almost looks like a six hour eva. When I came back into the habitat, looked like I fasted for a week. So I have all that data for that too, that, that I need to compile and analyze.

Should we be looking at that? We meaning people, as a potential way to replicate fast under a more stressful state?

Looking at what? Just underwater immersion?

Yeah. Do you think it was a combination of temperature and pressure primarily that was driving that effect?

So over the holidays we went to Thailand and we did. I did a lot of nitrox dives, something like 30 nitro nitrox dives. And I, I made these measurements too, and I did see trends for decreased glucose and nitrox dives were doing like an hour, maybe hour, hour and a half dives at the most. And I saw trends, but nothing like the trends I saw in the saturation environment when we did these long EVAs.

So do you think that the temperature was the difference or the duration?

The temperature really has to have a difference because you come out and you're. You're kind of shaky you know, even though you feel very comfy when you're down there, the first two or three hours and then by the end, the last, you know, four, five, six hours for a longer eva, you start like shaking a little bit uncontrollably, you know, but it's kind of subtle. Even though the water is kind of warm, like it feels warm, but it's just, you know, your body temperature is going down. And they were on the days maybe I wasn't getting as much calories as I as I needed. I came out of that mission lighter than I've ever been before. I came out, when we got back to mainland and I stepped on the scale, I was 2:07, which is super low for me. I ended up losing about maybe I went in kind of late because I was training for it. I'm not a very good swimmer like you. I had to really train to meet like you. It would be like a total day in the park for you to, to meet all the criteria for that. But I had to train really hard to, to meet the swim requirements. So I ended up losing a little bit of weight. But when I came out, I, I would definitely mission. I lost 9 pounds and it came out 7. So I went in 2:16. So I went in pretty late. I'm like 2:21 now. So last year I entered the mission at 2:16 and I came out like 2:07, which was like, I thought the scale was wrong. So even though I ate a lot of calories during that mission, your metabolic rate. Yeah, my metabolic rate was really high, you know, and that, that was a consequence of that is so interesting because it's.

Those are two completely contradictory concepts to me. On the one hand you're saying, hey, my glucose levels went down, my ketone levels went up. It looked like I had fasted for a week. But of course if you fasted for a week, your metabolic rate would be going down and not up. In fact, you would expect to see autophagy skyrocket. Whereas I'm sitting here as I'm listening to you thinking, would autophagy have increased during that period of time or decreased?

I think anything that pushes glucose that low and ketones that high, and I think not really without knowing it, we're pretty task loaded. So you don't have all the time, you know, that much time to eat. I mean, part of the mission is that they're training. This is part of. It's the only NASA analog where astronauts are actually part of the crew members. Like other things like high seas Mission or NASA Hero mission actually uses everyday folks and they push them to the limits to see how they, they can break them. But the NASA Nemo mission is actually training sort of astronauts so they task load you to see what you're doing and you don't have a whole lot of time to eat. But I was, I was consuming what my normal calories would be, but I was under, I underestimated my calories for this and I think it put me in a calorie deficit which probably decreases, decreased my testosterone may have, my cortisol level increased, but it was still within the normal range. And you're away from the light, so your circadian is probably a bit screwed up too. Being in the industry, you're only at like 60ft, so you do see some of the light come down. But it's probably a little bit different than I'm a very light sort of sun worshiper. Like I always try to get some light in the middle, you know, in the beginning of the day and that, that's part of something that I always do. So it was a bit disruptive in that sense.

So let's talk about ketone, esters, salts, et cetera. So to your knowledge, what's the first exogenous ketone that was ever manufactured?

Is that Vitaly1 or exogenous ketone manufactured? So 13 butanediol has been around a long time, since the 1950s actually. MIT did some research as a space fuel. So that got. There was a publication in 1975 where they were trying to identify an alternative energy fuel for long duration spaceflight. And the best candidate was 13 butanediol, which is sort of a synthetic compound that breaks down completely to beta hydroxybutyrate.

Meaning the liver is not required to transform it into bhb.

The liver is required, yeah, through a couple simple steps. So sodium beta hydroxybutyrate would be the first sort of ketone, exotic ketone that was used clinically and that there was a number of papers that utilized that for rare metabolic disorders actually. So that would be the first one. And a lot of the IP and sort of patents that came out were sodium beta hydroxybutyrate.

And then maybe explain for people what the difference is between a salt and an ester. So we'll leave acetoacetate out of that for a moment. Yeah, but if you talk about beta hydroxybutyrate, but you can have aceto acetate.

Salt too, so I can mention that.

So I didn't know that. I thought it was Only a diester. So that's. We'll definitely want to hear about that. So on the BHB front, people are sort of inundated with ketone salts, ketone esters, and then a whole bunch of complete, like, weird stuff, like raspberry ketones and stuff. But, yeah, let's just leave the nonsense off the table. Yeah. But if you just talk about comparing a ketone, a BHB ester to a BHB salt, what's the chemical difference?

Yeah, So a salt is just an ionic bond, Right. Between the ketone molecule, beta hydroxybutyrate, a monovalent or a divalent cation, or an alkaline amino acid like arginine, citrulline, histidine, lysine. So you can literally ionically bond beta hydroxybutyrate to a number of different things. The easiest thing to do is to bond it with sodium, potassium, calcium and magnesium.

Now, calcium and magnesium have two positive charges.

You could put two BHBs on them. That's the advantage. Sort of an advantage. A disadvantage, I guess, with magnesium bhb, which is actually is very bioavailable. Magnesium. I measured my magnesium after taking it. It went up quite high. But disadvantage is that your GI tolerability to something like magnesium beta hydroxybutyrate may be only somewhere between 1 to 3 grams, 3 grams max per dose. Wow.

Which is not that much.

One gram, three times a day, at least for me, had no issues. I could probably tolerate two or three grams per day. So it's nice. I mean, it's something that's contributing. But ideally, what you want to do is with a ketone salt is because salt has a stigma. I call them ketone electrolyte formulations, is to spread the beta hydroxybutyrate out across monovalent and divalent cations, and they're the four that have the most utility.

And then an ester, of course, is a covalent bond, not an ionic bond, Right?

Yeah. So you can take 13 Butane Diol and you could create a mono ester ester with beta hydroxybutyrate. Right. And just add it, do a transesterification reaction and combine that beta hydroxybutyrate to 13 butane diol or acetoacetate you can combine with 13 butane. Or you could take glycerol. So with glycerol, you can come up with a triester of glycerol, which we have.

Basically, you're creating a triglyceride, that is, instead of three fatty acids, you put three BHBs.

It's pretty cool molecule. Yeah. So we have some experience using. Using that.

So, yeah, I told a story, like, many, many years ago, probably four or five years ago on Tim Ferriss's podcast about how I drank this jet fuel and almost thought I was going to go blind. Of course, what I may have. What I may or may not have omitted from that story was that you gave it to me. And so the ketones today taste a heck of a lot better than that earlier gen stuff. And I. Even when I told you that I just took the 50ml vial, you said, and chugged it in one sitting, even you were sort of horrified. You're like, wait, wait, wait, you didn't read the note I wrote you explaining how to dilute it and mix it.

We had talked about it.

We had assuredly talked about it.

Very. You're very enthusiastic about getting started.

Yeah, Yeah. I couldn't resist.

I was, too.

So that stuff's unbearably bad.

Yeah.

So what. I mean, whereas the ketone salts actually don't taste bad.

They're formulated, but they're awesome.

Yeah. Yeah. So why does the ester. Is there an obvious reason from an olfactory slash taste perspective, why they are so staggeringly horrible?

Yeah.

Or at least they were. And I mean, I'm told they're better today.

Yeah. I would say the ketogenic potency is inversely proportional to taste. So it just seems like, you know, the more. The more potent these compounds get. Even the triester of beta hydroxybutyrate, you know, is pretty nasty stuff.

Meaning that glycerol triglyceride that.

Yeah, it's a great molecule. I mean, it has, like, lots of, you know, tremendous utility. Well, making a ketone ester with 13 butane diol is really cool because the 1,3 butane dial broken down. Yeah. So that goes into another question. The whole enantiomer. So if you use the R beta hydroxybutyrate with The R are 1, 3 butane diol, then you can really get ketone levels up pretty high. And that would be sort of the delta G or the human, you know, ketone ester that's out there.

It's the R enantiomer.

That would be the R. Yeah, the R. It's R. So you have. You can get racemic 13 butane dial, but that's the R enantiomer of 13 butane dial with the R beta hydroxych.

Can we explain to everybody what R versus l mean in the enantiomer world.

So beta hydroxybutyrate, not acetoacetate, but beta hydroxybutyrate has a stereoisomer. So if you put your hands together, the R beta hydroxybutyrate or let's do D and L. Let's do that. So the D would be equivalent to the R. Beta hydroxybutyrate would be the mirror image of the L beta hydroxybutyrate. And the predominant form of beta hydroxybutyrate in the body body is D beta hydroxybutyrate. We do have a racemase enzyme that in various tissues that can convert the D to the L. So but when.

You'Re in nutritional ketosis or starvation ketosis, you are making D an antimer of the bhb.

Predominantly. Yeah. So we do have the capacity to make the L, but it's, it's pretty, pretty minimal. So that brings up the question. I think 99% of all the ketones salts being sold right now are racemic. So they are the D and the L when you give equal. Yeah, yeah, they're equal amount. And there may be a concern there, but we don't know. So most of my research has actually been with the racemic compounds and they work great therapeutically.

In pharmacology, there's a sordid history of getting the enantiomer wrong. I mean, one of the, one of the most famous stories I know of is fen. Phenomenal.

Yeah.

Oh, thalidomide as well. Yeah, so, so that's right. Thalidomide and fen phen were both examples of using the wrong enantiomer.

Many pharmaceuticals, like I think ibuprofen and I know like ephedrine, you know, is, is racemic and many of the drugs out there, so. And things like Ringer's lactate, I think, you know, lactate is, is it D now? It used to be racemic.

Oh, really?

I think, yeah, I think, I think.

You can get both. Okay, so you're saying, look, physiologically exist at 9010 d to l and then you're buying something racemic. You at least have to entertain the question, hey, am I ingesting something that might have a negative side effect?

Yeah.

And so the ketone esters, they're, they're mirroring the physiology or they're just going mostly D, presumably.

Well, the human ketone ester from my understanding is completely D. So it's produced a D beta hydroxybutyrate, interestingly, elevating just beta hydroxybutyrate in Our seizure models, even with the D does not have an anti seizure effect. So that's actually why we went to the 13 butanediol.

Sorry, say that again. Did you say that if you use.

A pure D salt, D salt or de ester.

Pure D salt or pure D ester, no anti seizure benefits, no anti seizure.

Effect with beta hydroxybutyrate. We needed. And the animal models even suggest that this. If you just look, even studies beyond our study is that you need to elevate acetoacetate has the anti seizure effect and we don't know exactly why that happens. The ketone ester that we work with, which is 1:3 butanediol acetoacetate diester elevates beta hydroxybutyrate and acetoacetate in approximately a one to one ratio.

Is that what you used to give me or was I just getting.

I gave you a bunch of things.

What was the one in the capsule that tasted even worse than the BHB ester?

Actually, that. Yeah, that was the diester of acetoacetate. Yeah. And that's really potent.

And it was bound to what it 13 butane dial.

Yep.

That was from another planet of bad. I still have some because I've done shots of that. I like to just give it.

I put many gallons of that through me and done quite a bit of blood work and, and know pretty reliably, at least in my body, that it's not toxic. And pretty much all the biomarkers go in a remarkably positive direction. But even though I know that it's not enough for me to. Even though it has that, and that's. No matter how great a substance can be, if it doesn't taste good, you know, even me, I'm not going to take it, you know, even in a capture.

I just think it's an aftertaste. Exactly. Well, I also remember you telling me because you sent them and I was like, oh, sweet, it'll be capsules. Because I had seen your animal data and I was like, I want that. And then you said, okay, well I'll send it to you in capsules because you can't drink it. It's too bad. And I was like, perfect, situation resolved. And you said, not entirely. You'll still taste it through the capsule. And I actually find it to be a great dinner party trick. Like. Like, who's the biggest, you know, tough guy here that just wants to show me how much of this stuff they can enjoy?

Yeah, yeah. I mean, we've done a lot of Work with that, Esther. And it has remarkable effects, but we think it's probably more suited for like a medical food and something that could be sort of a parenteral, you know, IV therapy.

So who first synthesized that?

So I reached out to Henri Bruningraber at Case Western, who was the director of the metabolomics NIH funded, I think, metabolomics core at Case Western. And I reached out to everybody who had any experience either researching with ketone esters or synthesizing them, and he kindly gave me the recipe on how to synthesize it that was above and beyond the patent. It was actually a detailed recipe on how to use a Kugel row distillation apparatus where to get the vaccine pressure.

You didn't already know how to do that?

I knew it was short past it. Well, actually. So Patrick Arnold, as you know, kind of helped me with the art. So an organic chemistry really is an art, you know, to be able to do this.

And Patrick is an artist.

Patrick is. Is an artist. And he was. He thought this was like shady stuff in the beginning, and I kept sending him papers and. And then he realized that this could be something big. You know, he realized that the science was there and there was a lot of big players in this field who had done remarkable research, but just didn't really have what it took to like actually make it a product, like synthesize it in the stuff that you actually consume.

I became obsessed with Patrick after all of this stuff happened and actually introduced him to Tim. And in the show, notes to this, I'll make sure that we link to Tim's podcast with Patrick with Patrick, which I'd love to have Patrick on the show at some point too, to talk about this should this show end up persisting. But that episode with Tim and Patrick is so interesting. It's like if you have any interest in endocrinology, in sort of like how the hormones work, how steroids work, it's. Yeah, yeah. It's just what a character.

I owe a lot to Patrick. I don't think. I probably wouldn't have gotten tenure without I owe so much to him. So I need to acknowledge him for that. That there were academic icons out there who could not do what. What Patrick did for me. And he was pretty persistent in doing it too. So he synthesized first the monoester, and then it was a mix of monoester and diester. But he nailed it down to, you know, ultimately getting the art of the organic chemistry to. Whereas pretty much pure diester.

He's such a wonderful human Being anytime I email Patrick a question which invariably I do have, like clinically I'll have a question about a hormone or they'll be like there's no textbook that knows the answer, there's no paper that knows the answer. I'm like Patrick, I got a crazy question for you. And it's like even if he doesn't know the answer, I mean he'll have a more thoughtful insight than you can get anywhere. And it's. Yeah, it speaks to his capabilities. So first of all you've shared with me something I didn't actually know today that's really interesting, which is this notion that if you are purely using the D enantamer you do not get any of the anti seizure benefits whereas if you're at 9010 presumably you're getting them. So you don't need a lot of the L but you need some of.

The L. Yeah, I don't think there's any studies that show using an exogenous ketone in the form of pure beta hydroxybutyrate is beneficial. So what we do know is that when you deliver exogenous ketones in a beta hydroxybutyrate to acetoacetate ratio of one to one, that has pretty remarkable anti seizure effects. And there was some studies that were done with acetoacetate and also some studies that were done with acetone showing anti seizure effects. So I do think acetoacetate is necessary. So what we don't know. I don't think think that racemic salts or racemic esters or esters that produce both D and L beta hydroxybutyrate are a concern. I have not seen data to suggest that these would be a health concern. There are companies out there that are selling 8 million sort of doses per month of salts that are racemic in nature and there have been sort of no consequences from that that have been reported.

So how are so many companies able to do this? Is there no IP in the salt world anymore?

I don't think there is IP for the key. I think some of the early patents may expired so I don't think there's actually there's, there's some intellectual property with formulations of a ketone salt and a ketogenic fat and mct and that's some of the stuff that my university has and there's some, some composition matter patents and maybe some use patents around the D salts I think and maybe the D ketone esters.

So at this point in time do you think that the ketone salts have more physiologic benefit than the ketone esters, just as a function of having a higher amount of the L enantiomer.

So I think when it comes to purely a metabolic fuel, I think the D beta hydroxybutyrate has some advantages. Right. So we also know that in regards to some of the signaling effects, especially the inflammation, the NLRP3 inflammasome is suppressed by beta hydroxybutyrate, both the D and the L form. And we know that when we consume racemic ketone salts in the D and L form, the L form tends to stick around longer and gets metabolized slightly slower. So conceivably that could be having a stronger anti inflammatory effect because you have a ketone body, an endogenous metabolite that's functioning as a very powerful signaling molecule that's suppressing an inflammatory pathway. So the concentration just tends to get higher. You know, that's my view of it. So we haven't really studied that in detail, but the lab that did some of the work on showing the Nature Medicine paper that showed the NLRP3 inflammasome was suppressed by beta hydroxybutyrate, it occurred both in the D and the L form. We do know that the L form gets metabolized slower, so the concentrations in the tissue may actually reach higher levels. So what we have observed is that the racemic beta hydroxybutyrate has a glucose lowering effect. So we're trying to figure out. But we also see big effect.

We also see that in the pure enantiomer. I've seen that with the human product, which is obviously a pure D BHB. I think they're seeing about a 20 to 30% reduction in glucose. Do you see more than the racemic?

It tends to be the case. Yeah, it tends to be the case, especially with 1,3 butanediol. You see it and maybe it's a redox shift in the liver. That's what Henri Brunengraber thought. But it's pretty remarkable. And when we compare. So I have some products in my bag. I'll give you. I have, I've been doing a lot of work with D salts. So I've been consuming D salts and pretty high levels that bring my ketone levels up pretty close to an ester. So you can formulate sort of which.

In you is how high.

If the elevation of my ketones gets more than 3 millimolar, I just start feeling, feeling a little bit weird, you.

Know, which is interesting because you've Experienced naturally occurring ketones at much higher than that level.

Yeah, but I don't actually I'm a pretty good ketone burner. So you could do a glucose tolerance test. I do a ketone tolerance test. A ketone tolerance test is consuming a known amount of ketones and looking at that pharmacokinetic curve.

So you measure, so you'll do fasting level of bhp, glucose, insulin, fetal fatty acid. Ingest your ketone and then measure it 30, 60, 90, 120 minutes.

And athletes have, when you challenge them with a ketone tolerance test, I'm creating like a new test here. They actually dispose of ketones and utilize it. Remarkably effective. When you take a couch potato and this is the same as the couch potato rats, you could push a couch potato rat into ketoacidosis. If they're older, their tissues are not effectively utilizing the ketones for fuel. And I've seen that in some individuals and some people. I get hundreds of emails and people will show me their data. And one packet of even a commercial ketone product on the market can shoot some people up to like 5 or 6, which is like that.

And just to be clear, in that ketone tolerance test, which by the way, I freaking love this idea. How have you not told me that until today? Holding out on your best.

It's just materialized in my brain. What am I going to call it? You know, I don't know.

But next time you get one of these ideas, just pick up the phone, you know my number, you call me and you tell me this stuff. This is your. It's like you're holding out on me. Just kidding. I want to make sure I understand something. Is this independent of whether or not that athlete was in ketosis before or after? In other words, how much of that utilization is a function of the metabolic machinery in the muscle to utilize ketone versus having? Hey, athletes are just better at oxidation to begin with.

Fat adapted athletes are very good ketone utilizers and have a hard time elevating their ketone levels with the ketogenic diet.

Now if you take a high carb athlete who's still fit as a fiddle.

Yep.

And you do this test.

Yep.

How do they behave?

Not as well. And I do think that high performing athletes probably are bouncing in and out of ketosis. Right. You have post exercise ketosis just from the energy depletion that you get during exercise. So their bodies are probably used to seeing ketones using them as fuel. But if you take someone who's a real keto adapted fat burning ketone machine and you hit them with high doses of ketones, they tend to dispose of them very quickly. So they've upregulated ketone transport across membranes, across the blood brain barrier, through the MCT transport, which are upregulated.

And this of course is not the same MCT that we talked about earlier.

No, these are monocarboxylic acid transporters. It also transport things like lactate and pyruvate. And because the MCT transporters are much higher and more dense in the membrane, you could probably clear lactate faster. So I think that may contribute in part to why keto adapted athletes produce less lactate.

It's funny you say that, I hadn't thought of that. Actually I didn't realize that in ketosis you upregulate mct. I've always suspected that that might play a role in the genetic differences between athletes. Why do some athletes seem virtually unparalyzed by anaerobic activity? And it's like, look, if you can shut a lactate out of the cell quick enough, you can recycle it and reuse it. We actually tried to get an IRB of an N of 1, a guy named Ryan Flaherty. Who, I don't know if you know Ryan.

Uh huh. I know the name.

You'll know of him. Yeah. So Ryan and I and a couple of other guys tried to get an n of 1 IRB at UCSD to do muscle biopsies on ourselves pre and post. A certain type of nutrition exercise routine we wanted to implement that Ryan has sort of pioneered with a number of endurance athletes. And that was one of our end points was could we see an upregulation of mct? Because the hypothesis was the certain type of training stress was going to, was going to lead to that, which would obviously increase our performance at a certain level of output. But super interesting to think about that through the level of the ketone potentially enhancing that signaling.

Yeah, it is a lot of things to think about there.

So I'm going to caveat my next question with a really serious caveat, but it's also a very serious question and I was sort of on the fence about whether I'd ask you this or not, but I, I'm going to say screw it and I'm going to ask you anyway. I'm going to caveat this by giving the disclaimer, which is you're a PhD scientist, you do basic research, you are not an MD, you are not an oncologist, and nothing you say is going to be construed as medical advice. So with that said, I still have to ask you a question, which is if tomorrow, you, your wife, someone you cared about deeply, was diagnosed with cancer, and it was a cancer for which all standard therapies had been exhausted and you were now left to the best insights you, you have with respect to your knowledge of cancer metabolism. Tell me what pulling out all the stops looks like. And again, what I'm. This is in the context of you've taken and you are complying with all chemotherapeutic radiation therapy, hormonal therapy, surgical therapy, et cetera. But you're losing, right. So something else needs to be done. What. What does that combination of that something look like?

So I guess, I mean, when we think about the worst cancer, worst case scenario, scenario, who'd have pancreatics pretty bad, but probably glioblastoma would top the list of things. Right.

And would your answer be different if I was asking you about pancreatic adenocarcinoma versus gbm?

I think, you know, it would be. There's things like with pancreatic cancer can make it hard for someone to follow the ketogenic diet. Right. Because. And liver cancer and things like that. So they need to approach it a little bit different. And you can have a lot of unexpected expected consequences, metabolic consequences by someone with liver cancer if they have heavy liver mets or. So let's make it simpler, brain cancers.

Let's talk about GBM and metastatic breast cancer.

Okay.

Okay. So start with gbm, your loved one or you have gbm.

Yeah, I would say it would be useful, not necessarily, you know, absolutely necessary to ask for an FDG PET scan, do a PET ct and especially, I mean, with gbm, it's going to light up like there's no tomorrow.

Right. So just for the listener, so FDG PET means you take glucose, you label glucose with a molecule. Yeah. And then when you do the PET scan shows by lighting up anything that absorbs that and the most rapidly metabolizing tissues of glucose, light that up, which is almost always any cancer. And then a brain normally lights up. So a brain with cancer takes that to another level.

Yeah.

So you're doing that to document that this is a high glycolytic tumor.

Yeah.

Okay.

So even now there's a lot of experimental things going on for gbm, but pretty much the standard of care is not offering any survival advantage when it comes to this. So we did.

GBM is uniformly fatal. I believe the five, the five year survival is almost zero.

Yeah. Yep. And the mutation rate in GBM is they're very, very heterogeneous in regards to the number of mutations. So many of the standard of care therapies that target specific pathways just are not efficacious because you have grossly mutated cells throughout the tumor. So I'd probably. My answer would default back to this press pulse idea that we published in Nutrition Metabolism.

Is that the one in 2017?

No, actually. So the 2017 paper was in seminars in cancer, and that was with oncologists at the Moffitt Cancer center where we discuss how the ketogenic diet essentially targets the Warburg effect and in doing so really targets all the hallmarks of cancer. So any cancer biologist you know is writing a review on paper like, you know, you talk about the hallmark marks of cancer. There's enhanced proliferation, evasion of immune system angiogenesis, all these different things, evasion of apoptosis, the ketogenic diet, nutritional ketosis, actually targets all those things and even the aberrant metabolism and the increase in inflammation that is now a hallmark of cancer. So from the press pulse, the simplest way to describe it, at least it's implementation, which I think is probably most important for the listeners, is to achieve a glucose ketone index. So press essentially means you're providing metabolic stress to the cancer cells that can stop their rapid growth and proliferation. It's like taking your foot off the gas pedal of cancer cell growth. And there's a number of things that we could do to slow down cancer growth and proliferation and, and metabolically stress those cancer cells, and that can be done continuously. And pulse protocols, you have a wide expanding toolbox of modalities that can be used in an intermittent fashion, that can be sort of tactically used at different time points to kill off the cancer cells that you have applied the press stress to. So press protocols, which are done continuously, would be something like a calorie restricted ketogenic diet, perhaps with intermittent fasting, perhaps a low dose metformin.

And what was the ketone to glucose ratio that you want to see?

I would want to see anywhere between a maintenance of 1 to 2, meaning.

That'S the glucose to ketone ratio, daily.

Maintenance of 1 to 2. Yeah.

So glucose should never be more than twice the ketone level when both are measured in millimolar.

Yeah. Ideally in a perfect scenario, 3 millimolar ketones, 3 millimolar glucose. So that's kind of hard to achieve, but not, not with a number of tools. So there's a number of tools that you can use to achieve that. And that needs to. And there are things that we could talk about too. So the fastest way to get to a glucose ketone index of and maintain that of 1 to 2 would be what I would call supplemented ketogenic intermittent fasting. Right. So when you eat within a restricted time window, say of like six hours a day, you start eating at 2pm and finish at 8pm seems relatively easy to do. And within that fasting window, if needed, you could consume calories in the form of perhaps exogenous keto ketones and that would further lower glucose and elevate ketone levels like within a range. And they are commercially available ketone products on the market. Millions are being consumed and there's no kind of adverse effects. You know, when you compare it to something like a Red Bull, which you'll find lots of adverse effects. So there's fairly good safety data, but this needs to be.

But the difference is Red Bull sponsors a Formula one team so it's got to be better.

Yeah. So these things are relatively safe and their utility are that, you know, they can help you achieve a glucose ketone index. And when you do have a glucose ketone index of 1 to 2, you are limiting fermentable fuels to the cancer cells and also most likely suppressing the hormone insulin tremendously to get there.

And because I'm sure you'll be asked, or I'll be asked, is the reason you are applying an intermittent or tight time restricted feeding algorithm to this because during the fasted time you increase ketogenesis or because there was something specific about having complete liver and gut rest. In other words, is there a reason that an individual should or should not consume exogenous ketones and or MCT during the fasting window?

Yeah, I think if it's difficult for them to achieve a glucose ketone index of 1 to 2, one of the tools in the toolbox could be to consume exogenous ketones during that fasting period. I think it can be help. And you can also consume them during the feeding period too. And they provide an extra source of calories that's a non fermentable fuel and I think have a benefit in and of itself. You could just talk about the anti inflammatory benefits. You know, I think there are a number of different benefits.

So that press protocol is pretty aggressive. Yeah.

And it could also things like meditation and yoga. I mean and exercise of course, low intensity exercise I think. But the most important thing from my perspective of the press, so we're just talking about the Press is to get that glucose ketone index two to one or better.

Or one to two or better.

Yeah, yeah, one to two or better. And then once that is achieved or concurrently, so you could think about different modalities for the pulse protocol. So changing your metabolic physiology with what we just described will have a huge effect on targeting the Warburg effect and also will be already targeting all the hallmarks of cancer. So you have a different person, you have just changed that person's metabolism. You know, I mean, the glucose ketone index of the average Joe out on the street is probably something like 25 or 50. It's like nowhere near that.

Right, right.

So you are literally changing the metabolic physiology of that person. So modalities that they may be resistant to or completely failed may have an effect now. So chemo radiation, maybe immune based therapies may be working.

Now that's an important point. Right.

We view this as an, as an adjuvant. So you could do a neoadjuvant concurrent, Concurrent or adjuvant approach. So, and I think that what I just described can be used as a neoadjuvant concurrent and an adjuvant approach.

Yeah. So people talk about cancer approaches as, look, you want to think about the legs of a stool, so you take a chemotherapeutic approach, you take a radiation approach, you take an immune based approach, and you take a surgical approach. Those are really the four pillars of cancer treatment today. You're basically saying, look, there needs to be be a new type of oncologist, which is the metabolic oncologist. So you have a surgical oncologist, you have a radiation oncologist, you have a medical oncologist, you now have an immuno oncologist. Why don't we have a metabolic oncologist?

Yeah, things will lead that way just by the research that's being done now, the huge amount of research being done, even on oncometabolites and all the genetics, people are now focusing on the how metabolism is influencing genetics. Metabolism is a driver for our biology and influencing epigenetic expression. So, you know, the work. I'd like to also point to the work of a friend of mine and colleague, Adrienne Scheck, who did her work at the Barrow Neurological Institute, which demonstrated in a mouse model, GL261, I think, model of glioblastoma, that using temozolomide and also radiation, with really focusing on radiation, that being in a state of nutritional ketosis made radiation therapy many, many times more efficacious in that mouse. Model, which is kind of a gold standard model for gbm. It actually cured the GBM in that mouse model using the ketogenic diet combined with whole brain radiation. So that was a pretty significant finding that actually spearheaded some of the ketogenic diet clinical research that's been done.

In her research, this was done with dietary or nutritional ketosis, not exogenous supplementation.

She went on to do some work with exogenous ketones and looking at how ketones can reprogram the metabolism. And ketones can actually have. They are like Cox channel inhibitors. They inhibit reactive oxygen species, which is driving growth and proliferation. So that work spawned research just on ketones by themselves in her animal model.

So what is in your pulse protocol, then?

Pulse protocol can be varied. So hyperbaric oxygen therapy at what frequency? Three, generally speaking. So with gbm, you have to. So a consequence of a GBM could be seizures. Right. So getting hyperbaric oxygen therapy with a GBM is tricky. So, yes, you have to start very low, probably like somewhere around 1.5 ATA, and then work up gradually from there based on the individual person. But generally speaking, the research that we did showed that not five days a week, which is typically used for wound healing. But I do think there needs to be a day off for adaptive effects to happen. So three days a week, 2.5 atmospheres for 60 minutes, three times a week. And that produces, well, reverse tumor hypoxia, for one thing. So hyperbaric oxygen increases tissue oxygenation not by hyperoxygenating hemoglobin, but it actually gets oxygen into the plant plasma. And that's a very important thing because.

Meaning you solubilize oxygen within the plasma. Yes, because you can't really supersaturate the hemoglobin that much more. You're at the top of the curve.

Yeah. You and I are sitting here, I don't know this air here, but your hemoglobin is essentially saturated, probably 96, 98%. But the hyperoxygenation that occurs with hyperbaric oxygen therapy. And this is why oxygen therapy does not not work independent of an increase in pressure. Right. So the increase in pressure is needed to drive the oxygen into the plasma. And once it's in the plasma, tumors have erratic vasculature. Right. And then the red blood cells get caught inside the capillaries and the vascular, and the oxygen doesn't get into the tissue inside the tumor. But if the oxygen is in the plasma, it can get past and all into the. The nooks and crannies of the tumor and then reverse tumor hypoxia, which is tumor hypoxia, is driving HIF1 Alpha and VEGF and causing.

So ironically, you're taking something that is initially a deficit of cancer, which is its hypoxia, but then it utilizes it as it's an advantage by saying, hey, I'm going to work around this. It's going to make me more resilient, it's going to allow me to increase my vasculature. Boom. And you're saying, hey, buddy, that little advantage you had, that was a disadvantage. We're going to reverse it. We're going to hyper oxygenate you now. We're going to take away your hypoxia.

And you also turn off free radicals. Yes. So you have a dual effect. Right. So you are silencing the oncogenes, you're turning off some of the oncogenes and also by hyperoxygenating a tumor, which its baseline is to be in a state of hypoxia, by supersaturating the tumor with oxygen. And that tumor tissue has damaged mitochondria because hypoxia damages the mitochondria. So basically you're hyperoxygenating a whole bunch of damaged mitochondria. And essentially what that does is skyrockets superoxide anion, which then through Fenton chemistry. So when you have a lot of free iron and all, you got a whole bunch of heme and stuff that's being broken down the tumor. So you have a lot of free iron driving the fish Fenton reaction, which is producing hydroxyl radicals and that causes a massive oxidative stress specifically to the tumor. And you're delivering a massive oxidative stress to the tumor while it's relatively non toxic to healthy cells that have normal metabolism. Right. Because the tumor is thriving in a low oxygen environment. And you're reversing tumor hypoxia and horizontal hyper oxygenating it. And you have this environment which is just fueling redox stress. You can then trigger apoptosis and necrosis, really driving necrosis in these tumor cells. So hyperbaric oxygen delivered at the maximum tolerable dose three times per week. And you could further enhance the oxidative stress of the tumor by something that's. A lot of people haven't heard of this, but IV vitamin C. So vitamin C, if given intravenously, you can give.

Up to about a hundred grams at that.

You could. Yeah, 25 to 100 grams is kind of pushing it. But vitamin C, ascorbic acid also functions as a glucose antagonist.

So you got to make sure you have dextrose on hand if patients, but.

Not if you're in a state of ketosis. Right. So if you're in a state of ketosis. So I did a pretty high dose vitamin C C. But being in a state of ketosis, you can tolerate higher amounts. Right.

Do you know what your glucose dropped to?

So when you measure your glucose, when you're getting vitamin C, you get a false positive on the meter.

Falsely high.

You get falsely high. Well, at least the Abbott Precision Extra. Yes. Yeah, it just, you know, when you measure that meter, that assay on the meter is also sensitive to the PH of your blood too. And there's a redox shift and ascorbic acid is a powerful reducing agent and that might be altering the assay. So I was not able to get my glucose, like skyrocket. I know I went into it hypoglycemic, but my ketones were elevated and I took a pretty big hit of vitamin C. And I was just doing it just for the self experimentation thing.

Right. But what's the thought here? So lots of people oxidative stress.

So vitamin C driving the fentany reaction to produce more oxidative stress. So vitamin C is a pro oxidant. When you get blood levels of vitamin C in the millimolar concentration, then it becomes a pro oxidant. It's not an antioxidant. So we're not using antioxidants or definitely you don't want to use.

I was going to come back to that, but the next thing is, I'm sure somebody listening to this is going to say, well, I don't have access to IV vitamin C if I wanted to do that.

You could. You can't do it orally.

You can't do it orally because of what it's not. You can't get it out of the gut enough.

Yeah, you can't. You can only get like a very small amounts and then, you know, your gut autoregulates it too.

So you just. Let's get to the next thing you said, which is again, highly counterintuitive to most people. We're hardwired to think that there's nothing better for you than antioxidants.

Yeah.

But paradoxically, once you have cancer, that might not be the case.

Yeah. So I think antioxidants may be blocking some of the efficacy of some of the things. Some of the therapies too. Right. Because many chemotherapeutic drugs Their function works through enhancing oxidative stress. Radiation sure does. So radiation, maybe 20% of the cancer killing effects of radiation are due to damaging the DNA with double, you know, double strand nicks. But 80% of the tumor killing effect of radiation is by the generation of reactive oxygen species.

Now does that mean you can't have blueberries and things that have low levels of antioxidants?

I would say no, but you don't want to kind of saturate your body with a cocktail of antioxidants. Like you don't want to do a glutathione push right after you do.

Same with nac. So you wouldn't have nac?

I personally would not. I don't, I don't think that none of the cancer studies in animal models or humans are supportive of the use of anti acquisition. And that was a big focus of me. I mean, during my PhD, I wanted to do a postdoc research in antioxidant cocktails that were going to save the world. And none of the research on antioxidants really panned out in my mind. There's a couple things, you know, maybe for mitochondrial antioxidants for like Friedreich's ataxia and maybe ALS and some research there, but it's pretty subtle benefits. But in the context of cancer, no, I don't, I think antioxidants should be avoided.

Anything else in your pulse protocol?

Yeah, I mean there's a lot of things that you could add. So with the press protocol, I think a low dose of metformin could be helpful too. So that will activate AMP kinase, maybe decrease insulin a little bit, maybe increase ketones a little bit too. And it's just a readily available cheap drug that has a very good safety profile. 500 milligrams to 2,000 milligrams a day are usually well tolerated, probably starting with 500 milligrams and working up. But when it comes to the pulse protocol, hyperbaric oxygen, iv, vitamin C. And there are a number of drugs that we're working with now. One would be two deoxyglucose, which in and of itself from a seizure world. And I've, I've been a reviewer in for the government for different grants and stuff. Stuff. And this is in the context of epilepsy. 2D G is sort of like the ketogenic diet in a drug. So by inhibiting glycolysis it has. This gets back to the question, right, you have no ketones, but you inhibit glycolytic pathways, perhaps even like Reduce sort of MTOR signaling or some glycolytic signaling and that may have anti seizure effects. So 2 DG is something that we're working on with now, I think.

What was 2Dg originally developed for pharmacologically? It's been around for a long time.

For a long time. I think maybe it was just in the realm of experimental compound. But I know there's phase two trials in cancer. The problem is it becomes cardiotoxic above say 50 milligrams per kilogram. I know can be. I know there's some evidence that cardiotoxicity, but at 25 milligrams per per kilogram at least on some of the grants that I reviewed that was, had a pretty good safety profile for epilepsy. So, you know, not making any recommendations out there, But I think 25 milligrams per kilogram seems to be within the realm of therapeutic efficacy and safety.

And this is being studied in humans and they're out of phase one. So this.

You have phase one data to support that epilepsy world. Yeah, and I think there's some cancer cancer trials going on too. And I do think that synergizes really well. Once you create the environment where you put the press protocol into action, then the cancer cells become even very selectively vulnerable to other things. Like 2D G will inhibit a glycolytic pathway that drives the pentose phosphate pathway. And that pentose phosphate pathway is responsible for, for enhancing the endogenous antioxidant capacity of cells. So it makes the cancer cells even more vulnerable to oxidative stress the more you can inhibit the glycolytic pathways. So 2 DG dichloroacetate is something that we've worked with too, inhibits PDH complex. And that can also is DCA, a.

Drug that's been on the market for a long time.

It's a small molecule. Yeah, it's been on the market for a very long time.

And what's its normal use?

Its normal use is lactic acidosis actually. So one of the side effects of metformin, right. Is once you start increasing the dose of metformin and escalating the dose, the problem that you run into. It's a very powerful activator of AMP kinase. Its effects are primarily through the liver, you know, inhibiting gluconeogenesis and it's a mitochondrial toxin throw. We published a paper that it increases ROS production from the complex one of the mitochondria.

So it's inhibiting complex one Correct.

It's inhibiting, yeah, mildly inhibiting complex one. And it's triggering what the cell experiences as an energetic crisis. And that, you know, it has an activation of amp kinase 2. So you are creating, creating a scenario where that's putting a lot of persistent metabolic stress on the tumor cells. And then you come in here with different modalities that have overlapping but independent mechanisms at producing oxidative stress. So hyperbaric oxygen, IV vitamin C, and then cancer specific glycolytic inhibitors 2 deoxyglucose, 3 bromopyruvate and lonidamine. Lodinomine is also a hexokinase 2 inhibitor. And those three drugs that I mentioned right there, they are very powerful and they need to probably be used in two weeks on, two weeks off.

And if somebody's listening to this and they're thinking, well, how the heck could I ever do this? Are there physicians out there who are obviously doing this under the full and legal umbrella of ethical medical practice? Is everything you're talking about purely theoretical or are there ways to actually have these things implemented?

I think there are some physicians out there that are probably not making it public, but I think they are getting success with doing 25% of what I just talked about. You know, they're not doing all these things, but everything that I just mentioned is readily available. I mean you could most of the compounds, even IV vitamin C. Hyperbaric oxygen therapy can be costly if you don't have a hard shell chamber. But I like that with radiation. If you're giving radiation to your body or it's like going in there with a flamethrower and you have a lot of collateral damage. Whereas hyperbaric oxygen naturally elevates the precursor for oxygen free radicals and the cancer cells selectively produce more oxygen free radicals. So it's a very gentle approach. And instead of thinking that we should just go in there and eradicate the tumor, I think it's more appropriate to give sort of a gentle stress to the tumor. So the therapy that I'm describing, if the patient goes into it, they're going to come out of it stronger than they were going into it. When you fat adapt and keto adapt your body, so many metabolic biomarkers start to go in the right direction. When you go in for chemotherapy and radiation and you measure things after your body, you're a big inflammatory mess. I mean, you're metabolically deranged, you're insulin resistant, you are pushing things and you have chemo brain on top of that. That may not be reversible. The suppression of your immune system with chemo is setting you up for more cancers, potentially other cancers. So the scenario that we envision is a comprehensive metabolic based therapy where you go into it and it's a more gradual approach and you start adding these modalities sort of as you go, you know, get the patient acclimated, you know, with that glucose ketone index of 1 to 2, and then start utilizing some of these other therapies. You could potentially put someone on an iv, right, and pulse a low dose of insulin to make them hypoglycemic, even 1 or 2 millimolar, and then deliver some of these agents where you've really restricted the fermentable fuels. So I was, you know, I'm a reviewer on different manuscripts that are coming in, and some of these academic and clinical oncologists are actually suggesting this and, you know, medical hypothesis, his papers now.

And that's kind of counterintuitive because you'd think, well, we don't. The last thing you want to do for a tumor is give it insulin, because this is so. Because this is pulsatile and it's acute.

And the amount of insulin, it's not like 20 IUs, it's something like one or two IUs. So the patient comes in fasted and you give them just a little bit, and that's facilitating mostly facilitating glucose uptake in the skeletal muscle, so making it less available for the tumor. Right. And that creates a scenario where you produce severe, what would typically be fatal hypoglycemia. And you could deliver ketones, you know, as an insurance and, and also deliver some of these agents that would. You'd probably dramatically sensitize that tumor tissue to the other modalities and. I know. So I mean, what I didn't talk about when I did this seven day fast, like years ago, I brought my glucose levels down really low and I got to a glucose ketone index of one or maybe even a little bit lower than one.

So you were about what, three to four on each of them?

Yeah, well, my ketones were about four or five and my glucose got down to three. So that was the lowest I ever captured.

And that was just a seven day fast.

Yeah, after seven day fast, you know, after a brisk walk at the end. So I never got like ketone seven or eight. Like, I got it like four, you know, after like a long fast. But then I did, inspired by the Cahill study, I used various strategies to bring my glucose level down, you know, Pharmacological strategies. And I, I did it slowly and.

Just do me a favor, Dom, I really would be kind of pissed off if you like offed yourself doing dumb shit because I think the world kind of needs you to stick around. So. So see if you can just maybe get an IRB to do this in the mice or something. Nothing that would break my heart more than getting a call from your wife saying, yeah, Dom died of some freak hypoglycemic crazy accident. What's the longest fast you've ever done?

Well, that was it actually seven days. So yeah. And I was pretty adapted. And the point I was kind of getting to that I brought my glucose down to where it was not even measurable, but with exogenous ketones I was the meter didn't even read it. So that to me, and I did that years ago, that motivated me more to basically focus on this area of research as sort of like my life research because it validated to me that this should not be happening. And ketones are an alternative energy source that can be utilized in these metabolic basis therapies that can be game changers for, for bear. And we also study glucose transporter type 1 deficiency syndrome. Right. Which is the inability. And people who have GLUT1D don't get cancer to my knowledge. I've talked to the doctors and they've never came across anyone with glucose transporter. So that's kind of motivating too to that you can create a therapy for that that could sort of be a magic, magic bullet.

Well, what's interesting is this is sort of in many ways old school science. Right. Where scientists would begin by sort of experimenting on themselves, identifying unnatural or extreme physiologic conditions that are not predicted by the current understanding.

Yeah.

And then that sort of provokes further investigation. Remind me again, at the end of that seven day fast, how much did you deadlift?

Yeah, I did £500 for 10 and then I did sort of a one repper at the end with six plates or 585. But that's below my, you know, normal. But it was, it was amazing to me that, you know, I didn't want to push my body too hard, but it was amazing that that amount of fasting does not really impact your.

How much of a ridiculous. So what was your max at that time?

At that time? Well, I was tinkering around with like, you know, ketogenic diet and fasting a lot, but within a year of that time, I forget if it was, was before or after I did 675 for 5 and maybe 5, I did 555 for an 8 to 10. So. So I did, you know, an extra plate for 8 to 10, but I went into this basically. I felt like I did more, I could have done more, but I just wanted to stop. I didn't want to hurt myself because I knew I was pushing the limits at that point and I didn't get sore at all. So I did that. And it was, it wasn't like my body was broken down and sort of in a depleted state where I was wasted the next day. I felt I didn't even have to recover from that. Like I had no lower back soreness the next day after that. So I probably was like, I probably could have went heavier. But it was just validation to me that if you're in a keto adapted state, your body is very resilient. And from a military standpoint too, which we work pretty closely with the military, I'm trying to sort of, of get them to understand this idea that if you are fat and keto adapted and you're faced in austere conditions with limited food availability, you could maintain your physical and cognitive resilience in those, in those conditions, which is pretty clear to me. I was pretty much obsessed with eating like six meals a day for many years and it was very liberating not to have to do that now. And I'm amazed at how little I can eat. Once you're keto adapted and maintain your size and your strength. I'm not trying to be big anymore or anything or try to do any records in the gym, but it's amazing how easy it is to maintain once your body is adapted.

You've been so generous with your time. I want to let you get on your way. I know you've got a long drive potentially tonight, but I want to ask you a question or a couple maybe. What do you believe today to be true that five years ago you did not believe to be true? Let's keep it within the purview of your ketogenic life. What today do you think?

Things that really, I would say when I got into this field, I was really fascinated and immersed in this idea as ketones as an alternative energy source, so as even like space food, you know, and we're still working on that front. But then over the last five years, the observation that beta hydroxybutyrate is a powerful endogenous metabolite that's also a signaling molecule through its HDAC activity, histone deacetylase activity. More recently, we've been working with an organization that. The name of the organization is called All Things Kabuki. So there's a. There's a rare genetic disease called Kabuki syndrome, which is a gene defect in. In the KMT2D, which is essentially an acetylase enzyme. And a defect in that gene or that protein creates an imbalance between gene expression and gene repression. Right. And in the mouse model of Kabuki syndrome, two things have worked in this mouse model. One is a histone deacetylase inhibitor, HDAC inhibitor called AR42, which, which restores neurons in the dentate gyrus and kind of silences the pathological features in this mouse model. And another thing is nutritional ketosis. So nutritional ketosis functioning as a histone deacetylase inhibitor basically salvages or rescues the phenotype of this and circumvents this gene mutation, the KMT2D mutation. The animals have a normal neuronal density in the dentate gyrus. And even from a behavioral characteristic, it enhances sort of learning and memory. So this idea that an endogenous metabolite can epigenetically sort of control gene transcription. So I believe it's probably not unique to beta hydroxybutyrate. I think metabolites, we know that's true for acetyl, coa and other things are epigenetic drivers. And I think they are really, they call the shots. So you can even take a step back and say the mitochondria kind of call the shots too. Right. Because I think mitochondrial health and mitochondrial vitality would be the ultimate tumor suppressor. So if the bioenergetic capacity of a cell in tissues are maintained to a high degree, that bioenergetic efficiency is going to preserve genome stability and be far less likely to trigger oncogenes at the level of the DNA. So when it comes to something like Kabuki syndrome, you have a persistent molecular genetic pathology that's silenced by the elevation of beta hydroxybutyrate functioning in a metabolic intake. Yeah, through their. It's HDAC activity. So that to me is like, mind blowing. And I think that's the direction kind of our lab is going into now. I'm always fascinated with developing alternative energy substrates and alternative fuels as a form of nutrition for tactical applications, space applications maybe. But this idea that you could develop and even engineer nutrition to have powerful effects on gene transcription and epigenetic regulation is something I would have never predicted.

That's an amazing answer, actually, because And I know that was probably a little hard for some people to follow. So what you're basically saying is, look, five years ago you were completely intrigued and blown away by the metabolic properties of these ketones primarily as an alternative energy source. And with that comes a lot of interesting stuff we've talked about. But at this HDAC pathway, this inhibition of something that can result in epigenetic change or activation of, in this case you can basically take a germline acquired mutation and silence it with an epigenetic overlay that seems to be signaled by something as simple as ketones. And Dr. Virdin at the Buck Institute has spoken quite a bit about this as well. I mean this really is one of those moments where you think, holy cow, we are really at the just at the cusp of learning about this stuff. And if there's one reason to make sure we don't off ourselves with self experiments, it's to make sure we can stick around long enough to do this. Dom, where can people follow you socially and then maybe more importantly, see what you're doing from a research perspective.

Sure. So the site I maintain for informational purposes would be ketonutrition.org it's a.org not.com and on that website I have a list of, you know, podcasts, there's nutrition consultants, resources like the Charlie foundation which is an incredible resource that I've helped them do some educational work and Jim Abrams of the Charlie Foundation Foundation. It's really created an amazing resource there. I have a blog and we test various ketone supplements, ketogenic foods. I'm self experimenting and have collected a lot of data and we'll be putting some of that data in the blog. So I think that would be sort of like the One Stop Shop website for anyone interested in hearing more about what I talked about. I'd also like to mention that our lab in collaboration with EPI Genics foundation is sponsoring the Metabolic Health Summit that's occurring in January 30th to February 3rd in Long Beach, California. And it's going to have an amazing array of basic scientists. For example, like Luke Cantley will be there, be a keynote speaker, Thomas Seyfried, there's going to be clinicians there, influencers there, and a lot of entrepreneurs, entrepreneurial people will be there representing companies that are really changing the shape of this industry. So I'm very interested in technologies and foods and supplements that can make nutritional ketosis accessible for people that want to use it not only therapeutically for metabolic management of a disorder but maybe also for prevention or longevity or just as a lifestyle. So you're going to find there's something for everybody at the Metabolic Health Summit. From basic science will be sort of what our lab is focused on. But from clinical application to moving the science into human application is really the theme of that.

And can people register for that already?

Yes, I think you can go to the website and register. If you want to be a sponsor, I think you can sort of download the sponsorship package. There's going to be a lot of high profile representation there that would bring sort of more awareness and more reach to your product, if you have a product there. So we're looking for sponsors and I think we've nailed down most of our speakers. But if you're interested in speaking too, it might be good to contact us through the website.

Got it. And on Twitter you're pretty active. What's your handle?

Yeah, before I realize how important is to have a, A like a handle you can Remember, it's Dominic Dagosti 2.

We'll link to it.

Yeah, we'll yeah, link to it. It's not the easiest to remember. And also Facebook, I'm Fairly active. Dominic D' Agostino 1. I think that's my handle on Facebook too. So I kind of cross post on each and try to use Instagram a little bit more because they tell me I got to use it more. But not too active on that.

But all right, well we'll make sure we link to all of those things. I want to thank you again. I owe a lot of what I know in this space to you and.

I can say the same. Thank you. Yeah, incredible blog. It's been a great resource for many.

You are arguably one of the most generous people I've ever met when it comes to his insights. Dom, I don't know that you get enough credit for not only the work you've done, but for how much work you do behind the scenes as far as sharing your knowledge with people. I'll just share one very quick anecdote personally. One of my best friends from medical school, his wife has breast cancer and you know, without any hesitation, you were more than happy to speak with them about some of these things that they could do above and beyond what she was already doing, which was participating in a clinical trial where by the way, she's the only woman to still be alive in this clinical trial. So the trial has closed. That agent will likely not be approved though she will have a couple compassionate exemption. But you know, she is someone who has been on a ketogenic diet now for six years and has and remains incredibly indebted to the work that you've done. And her oncologists in Boston are sort of amazed that she's alive. Interestingly, next year Lou Cantley will be explaining a very plausible mechanism for why she is still alive. It's a paper that I'm sure you're aware of that was just approved and will be out in May Nature very soon. So anyway, I could sit here and spend another hour thanking you for everything, but I know nobody really wants to hear that, so I'll be quick about it and just tell you again that Dom, you're an amazing guy. You really are one of those people that I think fits in the category of just being kind of a treasure. And so on behalf of many people I want to thank you and thank.

You, thank you for giving me this platform. I know your podcast will be an amazing resource for so many people. Always great to catch up with you, always very stimulating in so many ways. So thank you Peter for having me. Appreciate it.

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