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

00:00:00.000 Hey everyone, welcome to the Peter Atiyah Drive. I'm your host, Peter Atiyah.

00:00:10.140 The Drive is a result of my hunger for optimizing performance, health, longevity, critical thinking,

00:00:15.600 along with a few other obsessions I've gathered along the way. I've spent the last several years

00:00:19.860 working with some of the most successful, top-performing individuals in the world,

00:00:23.440 and this podcast is my attempt to synthesize what I've learned along the way to help you

00:00:27.840 live a higher quality, more fulfilling life. If you enjoy this podcast, you can find more

00:00:32.100 information on today's episode and other topics at peteratiyahmd.com.

00:00:41.220 On this episode, I interview my good friend Dominic D'Agostino. Dom, as he is known by,

00:00:48.440 is a professor at the University of South Florida. His PhD is in neuroscience, and that's where he

00:00:55.140 got his background, but Dom is probably most recognizable to people listening to this because

00:00:59.640 he is certainly one of the experts on ketosis, and that's in all variants of it. So starvation

00:01:05.380 ketosis, nutritional ketosis, and in particular, the use of exogenous ketones. Gosh, Dom and I go way

00:01:11.900 back. We met probably a little over five years ago and instantly formed a friendship around our

00:01:17.660 obsessive N of 1 experiments, although I will say he is closer to winning a Darwin Award on the basis of

00:01:24.600 his N of 1's than I am. A couple notes about this podcast. First, this is highly technical at times,

00:01:31.000 and in fact, we'll timestamp it in the show notes, but I would say roughly the first hour is even a

00:01:36.840 little more technical than I had intended to go. I think part of the issue is just once I get talking

00:01:42.100 with Dom about this stuff, I couldn't stop asking him questions, and I think there were times when I

00:01:47.120 guess we forgot we were recording a podcast, and it was just us getting really technical. I don't think

00:01:52.180 it's too technical to follow if you have some background and understanding of biochemistry,

00:01:55.580 but we'll do our best in these show notes to make sure that we're given even the recreational user

00:02:01.220 the necessary tools to follow this. Now, that said, if you get 20 minutes into this thing and you're

00:02:06.180 like, I don't understand what the hell these guys are talking about, do not hesitate to skip ahead.

00:02:10.040 There's a lot of stuff that gets later on into the podcast, and this is a long podcast. It's nearly

00:02:14.380 three hours. There's a lot of stuff we get into at the end that I think will be kind of the stuff

00:02:18.960 people really want to know, even if they don't want to get in the gory details. So in particular,

00:02:24.160 we talk very specifically about all of the ketones, and I'm getting a lot of questions about

00:02:29.040 Peter. What's the difference between a ketone ester, a ketone salt? What are the mono esters?

00:02:33.180 What are the diesters? Where does MCT fit into this? What about the caprylic acid? And how many should

00:02:38.900 we be using this one versus this one? And what are the advantages and disadvantages? This is going to be

00:02:43.020 your dissertation level course in that subject matter. The other thing that we get into at the very

00:02:48.140 end, and we almost end on this, but again, look to the timestamps for exactly where it is, is we get

00:02:53.300 into what I consider one of the most interesting discussions I've ever had on what I sort of loosely

00:02:58.840 described as a metabolic oncologist playbook. So when I asked Dom about this, he had just some of the

00:03:06.420 most interesting insights, and I was really impressed by the breadth and the organization of his thinking

00:03:11.800 around this. Now, I want to point out something here, and I say it in the show, but it's really

00:03:16.460 important for me to caveat this here. This cannot be construed as medical advice. Dom is not a medical

00:03:21.820 doctor. He doesn't pretend to be one on TV. He is a research scientist who focuses on basic and

00:03:28.800 translational research. He collaborates with lots of physicians. He is involved in a number of clinical

00:03:33.680 trials, but ultimately, Dom is not offering medical advice, and frankly, nor is anybody, or nor should

00:03:39.480 anybody be on a podcast. So this information I asked because I get asked this stuff a lot, and

00:03:45.980 frankly, I don't know enough about this sort of outreaching and outlying metabolic therapies out

00:03:50.580 there, but I hope that if people are listening to this and they're afflicted by cancer, which

00:03:57.000 statistically speaking is obviously going to happen given that one in six people are going to get

00:04:00.060 cancer in their lifetime, I hope that if some of this stuff does scratch someone's sort of desire

00:04:04.840 to understand more, that they can use some of the resources we're going to link to to potentially

00:04:09.100 identify the right places where either a clinical trial will be taking place, or they could at least

00:04:14.460 pursue some of these things under the appropriate medical guidance. I could go on and on about other

00:04:20.440 nits and gnats in here, but honestly, I think the best thing to do right now is probably pay a little

00:04:25.000 bit of attention, maybe more than usual, to the show notes. Treat this a little bit like a buffet.

00:04:29.620 Go to the places you want to go to. Of course, I would recommend the entire thing if you really have an

00:04:34.200 interest in this subject matter. And I hope that this podcast is going to answer many of the questions

00:04:39.840 that I see people asking out there. I actually learned quite a bit on this, and I tend to know

00:04:44.680 the subject matter reasonably well. So without any further delay, welcome to the podcast with Dominic

00:04:50.640 D'Agostino. Hey, Dom. Hey, Pete. How are you, man? I'm doing well. How are you? I'm doing really well,

00:04:59.920 and I'm really grateful for you making the trip all the way up here. I know that in part you're

00:05:04.760 visiting family, but it's great that you've carved out time to come from New Jersey all the way up to

00:05:09.900 the lovely city of Manhattan. I appreciate the invite and love being here. Yeah, love to visit.

00:05:16.280 Well, there's going to be a number of people listening to this today who are already incredibly

00:05:19.740 familiar with who you are, the work you've done. I certainly consider you probably one of the two

00:05:25.140 most authoritative persons on the subject we're going to get into today. But for anybody who's

00:05:30.660 listening to this who is not entirely familiar with you, I suspect by the end of today they're

00:05:34.780 going to want to get a lot more familiar with you. So I actually remember the day we met, and it's kind

00:05:40.140 of funny. I was in Florida giving that talk at IHMC, and I knew of you by name, but I didn't know who

00:05:48.640 you were or what you looked like, so I wouldn't have recognized you. And I gave a talk. This would have

00:05:52.240 been 2011, maybe? Maybe 2012. And at the end of the talk, there was like a Q&A. And, you know, it was a

00:06:00.180 long Q&A, and it just went on and on and on. And then you asked a question. Now, I wish I could say I

00:06:04.180 remember the question, but I knew from the question that that guy knows what he's talking about. And then, of

00:06:11.060 course, Ken Ford, who knew us both, had basically arranged for us to all have dinner that night. And so that was the

00:06:18.600 night we met. And it was really, at least from my standpoint, not to embarrass you, it was like a

00:06:23.700 love at first sight. Like I was like, I was just so giddy to be able to sit there and have dinner with

00:06:29.040 you. Same, same here. Yeah, I knew who you were. And I was looking forward to that talk. I made the

00:06:34.680 drive up there. And I felt like we were connected before we even connected. You know, we're definitely

00:06:39.140 on the same wavelength on this stuff. Yeah, you've got such an interesting history that we're going to get

00:06:44.420 into about how you got interested in this space. But also, I think one of the things that many people

00:06:50.020 might not appreciate fully that I appreciated just because of the, you know, the convenience and luxury

00:06:54.540 of how we met was just your interest in self experimentation as well. And sometimes when you're

00:07:00.280 studying something or interested in something that is not entirely mainstream yet, you have to bootstrap

00:07:05.940 it and you have to look at like limited amounts of animal data, limited amounts of in vitro data,

00:07:10.820 and then sometimes combine it with insights that you get through early experimentation on,

00:07:15.320 you know, yourself. Absolutely. So I immerse myself in what I'm doing.

00:07:19.560 I think that's sort of why we connected. That's how we learn. Yeah, that's really,

00:07:22.700 that's the best way to learn. Yeah. So you did your PhD in neuroscience, correct? Yeah.

00:07:27.780 So what were you? And physiology. And physiology. So you're finishing your PhD and you're what,

00:07:32.740 planning to do a postdoc? Yep. I did it in the neural control of autonomic regulation. So the brainstem

00:07:38.760 mechanism sort of sense O2, oxygen and CO2 and modulate respiratory rhythm generation and also

00:07:46.080 cardiovascular sympathetic tone to the heart, like those neurons and how they sense oxygen.

00:07:50.700 During my PhD, I got interested in diving physiology and it was amazing to me that we don't really

00:07:58.240 understand how our brains and our physiology functions in extreme environments as it pertains

00:08:04.420 to elevated hyperbaric pressure, elevated oxygen, CO2, anesthetic gases, for example. We know the

00:08:11.260 anesthetic potency of a gas is proportional to its lipid solubility, but we don't really know what

00:08:16.740 that means. Like why, what's happening at the level of the membrane of the mitochondria. So my

00:08:21.340 postdoctoral fellowship was actually developing technologies to study that. And that would be

00:08:26.540 hyperbaric atomic force microscopy. And that was like, that's what I just delved into for three or

00:08:32.520 years. So how does that work? So I know what hyperbaric means. I know what microscopy means.

00:08:36.600 Tell me about the part about the force. The first term for atomic force microscopy was scanning probe

00:08:42.960 microscopy. Okay. And instead of using light or electrons, it uses a, a very sharp tip probe that's

00:08:50.760 can be so sharp, it's monoatomic and that it essentially raster scans across the sample and can

00:08:58.080 detect very subtle changes in the topography of the sample that you're scanning, right? So it actually

00:09:04.840 spawned the whole nanotechnology world. So this particular instrument was used to characterize

00:09:11.340 materials and really help develop Silicon Valley in many ways. And it's a microscope that we took

00:09:19.040 basically an off the shelf atomic force microscope that gives you the scanning resolution of an electron

00:09:24.600 microscope, but also has the capacity to image living cells and took this technology and put it

00:09:31.000 inside an environmental chamber, a hyperbaric chamber. And part of my project was doing the

00:09:37.200 electrical, the fluid and the gas penetrations to make the thing functional and also doing a series

00:09:43.380 of studies and calibration tests to determine that we could reliably make hyperbaric atomic force

00:09:49.960 microscopy measurements inside this chamber. And with this technology, it gives us insight at the

00:09:56.040 nanoscopic level of what's happening to the mitochondria, to the cell membrane. So I got a grant

00:10:02.520 through the department of defense, which they give these equipment grants to develop this technology and

00:10:07.960 also a grant to use it. And then later, another grant to put a confocal microscope. You might've heard

00:10:13.720 of a laser scanning. I actually used a confocal microscope in my undergrad thesis to do optional

00:10:21.080 optical sectioning of, uh, no, cause I was an engineer. So we were, I was interested in a question

00:10:26.360 of did the direction of extrusion that you put on a tibial plateau. So when you do joint replacements,

00:10:32.720 does the direction in which you extrude what's called ultra high molecular weight polyethylene,

00:10:37.720 does that predict its fracture? And it turned out it did, but the tool to help us measure that

00:10:43.600 was this confocal microscope. So that was my introduction to high end microscopy.

00:10:47.820 It's an amazing tool. Yeah. So the second, everyone should have one. Yeah, you got it.

00:10:52.320 They're the toys that we have in the lab. So that was the next phase of sort of my experiments was

00:10:57.640 installing a laser scanning confocal. So we could optically section individual cells and look at the

00:11:03.380 mitochondria inside the cells under graded levels of oxygen and hyperbaric pressure, essentially pressure

00:11:11.440 of an inert gas, like helium, nitrogen. So to simulate, for example, an AV seal dive or a deep

00:11:16.340 sea dive. And in the context of developing this technology and imaging a wide variety of cells from

00:11:23.480 primary neurons to leoblastoma cells, to human dermal fibroblasts, smooth muscle cells, I noticed that

00:11:31.740 cancer cells would produce proportionally more superoxide anion, which is the precursor oxygen free

00:11:39.580 radical that comes from the mitochondrial electron transport chain as a consequence of normal

00:11:44.080 metabolism. And the cancer cells look to have what appeared to be their chock full of mitochondria.

00:11:50.760 And they were moving around very dynamic structures. And under normal levels of oxygen, they kind of

00:11:56.280 produced a normal level of superoxide anion or oxygen free radicals. But when we hit the cancer cells

00:12:03.300 with hyperbaric oxygen, the superoxide production went off the charts. And it was very apparent to me that

00:12:09.520 they were producing excess free radicals. And as we made measurements over time, it was very apparent

00:12:17.340 that it was accelerating membrane lipid peroxidation, which we use a variety of tests. One is a T-MARS

00:12:24.220 test where we look at malandialdehyde production. And the technology, the atomic force microscopy allows us

00:12:31.140 to look at very subtle changes of the surface of the membrane. You measure the perturbations on the

00:12:37.800 surface of the membrane and nanoscopic changes. And we look at membrane roughness. And you could look

00:12:44.720 at the roughness of the membrane and calculate that. And that can correlate to membrane lipid

00:12:51.020 peroxidation. And it correlates, the numbers correlate well. So what you're looking at is the

00:12:55.880 physical correlate of membrane lipid peroxidation when you capture that data with atomic force microscopy.

00:13:01.840 Is that clear? Let me let me back up and make sure I can disaggregate this into steps. So the first

00:13:05.960 thing that you notice is lots of mitochondria in cancer cells and chock full. And these are what

00:13:12.380 types of cancer lines? The main one that I was working with that I ended up publishing the paper

00:13:16.900 neuroscience with was U87 glioblastoma cells. And they're taken out of a like a 44 year old

00:13:22.980 patient. So human cell line. Human cell line. Yeah. A lot of people use it, you know,

00:13:27.440 these are astrocytes, right? These are not neurons. Yeah. Of a glial origin. Yes. Yes.

00:13:32.580 So observation one, lots of mitochondria. Okay. Good to know. Cause obviously there's a

00:13:37.480 understanding that Warburg pointed out that says, Hey, like, you know, these things largely are

00:13:42.660 anaerobic, not aerobic. So they shouldn't really need much mitochondria. And then what you're saying

00:13:47.160 is you put them into a hyperbaric environment and how hyperbaric, how many times atmospheric pressure

00:13:51.660 would you need? I saw the observation at, so normal oxygen is 0.2 ATA. We say atmosphere is

00:13:59.340 absolute. And I saw a big jump up in superoxide anion production at 0.95. So that's almost five

00:14:08.100 times atmospheric pressure. That's almost five times. Yeah. And actually 0.95, if you're breathing

00:14:14.720 produces a PO2 in the brain, if similar to breathing 2.5 atmospheres of oxygen. And then I actually went up

00:14:20.940 to, I did the experiment with 3.25 atmospheres of oxygen. And then that basically was cooking

00:14:27.080 the cells from the inside out. The mitochondria were producing so much oxidative stress through

00:14:33.880 reactive oxygen species. So superoxide anion can go to hydroxyl radical through the fenton reaction

00:14:39.580 through hydrogen peroxide. And that can be driven in different ways. And I basically saw the mitochondria

00:14:44.500 exploding under hyperbaric oxygen conditions. And I had never seen that before.

00:14:50.160 And I'm sorry, did you have a control in this of non-cancerous glial cells that are not doing

00:14:54.820 the same thing? Yeah. So most of my experiments prior to this with like smooth muscle cells I was

00:15:00.800 looking at and primary cortical neurons, primary hippocampal neurons. At the time, I was just basically

00:15:07.180 looking at, I was doing these experiments to validate the tool that we had just built. So no

00:15:13.800 one actually had imaged living cells under hyperbaric conditions because no one had a hyperbaric

00:15:18.860 microscope before. So I didn't actually know what I was even looking at. I was not a cancer

00:15:23.180 biologist. I knew that cancer cells were rapidly proliferating, so they probably had amped up

00:15:28.080 metabolism. But it was just a very interesting observation to me. It was very interesting that

00:15:32.300 they're also dying. And I figured cancer cells should be hardy. And you know, you should be able to throw

00:15:36.740 everything but the kitchen sink at them and they should live. And then when I saw them, basically

00:15:41.420 the mitochondria exploding and the membranes starting to become permeable and, you know,

00:15:47.740 necrotic cell death, I became more and more interested in that. And we ended up publishing

00:15:51.800 the observation, but I didn't actually know what it meant. Like I published it more like here,

00:15:56.740 I built this cool tool and we did this experiment. And I was actually just looking at the cell line

00:16:02.740 as a model system to study reactive oxygen species and oxygen toxicity seizures. Because part of the

00:16:11.960 military was funding me to understand the cellular and molecular mechanisms of oxygen toxicity seizures.

00:16:17.580 And it's thought that high levels of oxygen creates oxidative stress and that perturbs the brain in a way

00:16:25.180 that causes these grand mal tonic clonic seizures. And we were developing tools. You can't understand it

00:16:31.180 unless you know fundamentally what's happening at the level of the cell and the mitochondria.

00:16:36.000 So I want to come back to that because that now makes sense for why diving could increase that risk.

00:16:41.740 Because if you're using an oxygen rebreather, you're getting a higher concentration of oxygen and then

00:16:46.380 you're under multiple atmospheres of pressure. You've now basically replicated in a person what you were

00:16:54.320 seeing a cell. But going back to the cell thing for a sec, do the free radicals that get generated

00:16:58.560 destroy other cells beyond the cell that is generating the free radical? Or is the problem

00:17:05.240 largely contained to the cell? It's a dose dependent phenomenon, right? And we were studying cells in this

00:17:13.560 particular experiment in a petri dish or on a cover slip. So you have sort of like an intact neural network

00:17:21.180 or cellular network. So the cells are literally connected to one another. Unlike a tissue slice where you have

00:17:26.680 an intact cytoarchitecture, which that's a little bit different. But the oxygen free radicals and the

00:17:32.340 substances that the cells produce do actually influence other cells adjacent to it or juxtaposed

00:17:38.140 to it. That's obvious from some of the experiments we do in cell signaling. You know, if one cell becomes

00:17:44.320 permeable and we could detect cell death with various molecules like athenium homodymer one, when that

00:17:50.540 cell dies, it can stimulate excitotoxic events in the surrounding cells. Same thing happens with the

00:17:56.860 cancer cells. It's obvious that cancer cells use reactive oxygen species for growth and proliferation.

00:18:02.700 And I know this is something that may be contradicting to many people. We view free radicals as something

00:18:09.720 that's damaging that the cell needs to get rid of. But they're very powerful signaling molecules,

00:18:14.000 especially for cancer cells and growth and proliferation and in normal tissues.

00:18:17.220 And you mean nuclear signaling? In nuclear signaling and activation of transcription factors,

00:18:24.240 basically there are many. I study as neuroscientists, I study redox sensitive ion channels.

00:18:30.460 So the redox state of an ion channel can dictate the permeability and the gating functions of that ion

00:18:37.360 channel, which is intimately linked to cellular excitability by influencing the resting membrane

00:18:42.460 potential. So as a neuroscientist, you know, you can study a very particular and cells have hundreds

00:18:49.740 of thousands of ion channels, specific ion channels that are redox regulated. But what was obvious is

00:18:56.060 that cancer cells have elevated rates of reactive oxygen species that they use for growth and proliferation

00:19:01.720 and also fuels metastasis and invasiveness of cancer cells. And because they overproduce oxygen-free

00:19:09.020 radicals in the context of high oxygen, you can push the cells above their antioxidant potential

00:19:17.060 and then trigger apoptosis. So it's like a double-edged sword.

00:19:21.060 So it's basically a U-shaped curve or inverted, depending on how you want to think about it,

00:19:25.260 where the cancer cell is not only optimized to survive, it's optimized to thrive at a certain level

00:19:30.560 of elevated reactive oxygen species. Yeah, an elevated level. But if you go too far,

00:19:35.240 it becomes counter. Yeah. So they have elevated endogenous antioxidant capacity, right? But because

00:19:41.720 their mitochondria are defective in many ways, and that term is kind of controversial. Some people

00:19:48.660 think the Warburg effect definitely endows the cells many benefits, but the aberrant activity of

00:19:55.700 the mitochondria is creating this excess-free radicals. And hyperbaric oxygen and chemotherapeutic

00:20:01.880 drugs that augment oxidative stress are therapeutic modalities that can be used. It was very apparent

00:20:07.620 to me seeing that in a hyperbaric chamber, looking at a microscope, looking at these cells. And no one

00:20:14.000 had seen it before because no one had hyperbaric microscopy. Nobody had the tool.

00:20:17.060 Yeah. And that kind of, at the same time, I was growing these cells under different conditions.

00:20:23.260 I was very interested in lactate. And I became interested in ketones too, just not for this

00:20:29.820 reason. I was not yet interested in the ketogenic diet. I was looking at it for a different reason

00:20:34.220 actually. But I noticed that the cancer cells were not growing as rapidly as they should in the

00:20:41.140 context of one, two, and five millimolar of beta-hydroxybutyrate, which I was growing them

00:20:46.940 in. And I thought the lab tech may have been doing something that was influencing, but she assured me

00:20:51.540 it wasn't. So we would pull the media off and put regular media on without the ketones and the cancer

00:20:57.180 cells would start growing rapid. Why were you using ketones in the media? Well, I was looking at a

00:21:01.520 variety of different substrates back in 2008 and 2009. I see. So you were just saying lactate,

00:21:07.560 glucose, BHB. Yeah. 2-deoxyglucose. Yeah. Lactate. I was using a variety of different.

00:21:12.620 And ketones were like, well, let's just see what ketones do. You know, that ketones were something

00:21:17.200 that the body would produce in fasting. But I didn't even know the anti-seizure properties of

00:21:24.080 the ketogenic diet. I just thought of it as like, what do brains? And a couple odd papers I came out

00:21:29.260 like ketones could be used as fuel. I was very interested in alpha-L polylactate, various forms of

00:21:34.780 lactate that could be used to preserve brain energy metabolism in the face of oxidative stress.

00:21:41.400 And the ketones just, they sort of shined. So basically what they were able to do was allow

00:21:48.820 the neurons to preserve their membrane potential and normal cellular function, even in the context

00:21:55.420 of extreme oxidative stress. And it made sense, right? Because the ketogenic diet, you know,

00:22:02.620 I started looking more into this and discovered that the ketogenic diet was a very effective

00:22:06.940 anti-seizure strategy, even when drugs fail. About two thirds of patients respond favorably.

00:22:13.240 You get, you know, 10 or 15% are super responders that never have seizures again. You can get them

00:22:18.280 off your meds. And it was probably working through a mechanism independent of any anti-seizure compound

00:22:24.400 because the ketogenic diet worked when drugs failed, you know, suggesting it was working through

00:22:29.100 a different mechanism or many mechanisms kind of in synchrony. So the tools that we developed really

00:22:35.640 sort of started to allow us to understand from a cellular and molecular mechanism, how ketones are

00:22:42.420 working. And I was looking at other compounds at the time, but it's just, as I kept studying,

00:22:47.440 I was looking at sigma receptor agonists. I was looking at other antioxidants, many different

00:22:52.720 antioxidants and combinations of antioxidants that were catalase memetics, superoxide dismutase

00:22:59.400 memetics, you know, all these things that were in theory, they should work really well, but nothing

00:23:05.200 was really working as well as ketones. And it also motivated me because when I discovered the ketogenic

00:23:12.400 diet was a grossly underutilized anti-seizure strategy, I was like, wow, I could go back to my

00:23:18.680 nutrition roots. Cause when I was undergrad, I majored in nutrition science, but I didn't pursue

00:23:23.980 a PhD in nutrition because nutrition was not like a real science. Like there was no jobs in nutrition.

00:23:28.960 And, and the nineties was a decade of the brain. So it was like, let me try to get into a cellular

00:23:33.420 neuroscience program. So I kind of just left nutrition and this was my opportunity to bring

00:23:39.780 nutrition back into my research projects into the lab. But my going back to that BHB in the media,

00:23:48.080 did you have the same amount of glucose in, as you had in the BHB free media?

00:23:52.660 Yeah. So we did everything in the context of the same amount of glucose, usually about five

00:23:58.220 millimolar. In other words, the benefit was from the addition of BHB, not the reduction of glucose.

00:24:03.720 Absolutely. Yep. And as I started to get into the literature and read into this a little bit more,

00:24:10.640 we started doing glucose subtraction and adding ketones and saw that normal, healthy,

00:24:17.620 healthy neurons functioned and thrived in a low glucose environment. If the ketones were present,

00:24:23.800 but the cancer cells would die. And this was also replicated and published in various neuroblastoma

00:24:30.880 cell lines. And I think Skinner was one, a person that published, and I found that he was at University

00:24:36.000 of Florida, but he was a, he was a fellow and just had left the school at the time. And then I went up

00:24:42.020 there and gave a talk, I think in 2010. And that further, that got me more and more interested in

00:24:48.660 studying cancer, even though it was not funded to do so. It was like this pet project that was

00:24:55.760 completely very intellectually stimulating to me and something that I could not just shelf and come

00:25:01.120 back to at a later time. I had to, I felt like the environment was kind of hot for this. So I just

00:25:06.440 kept reaching out to different scientists and showing them my data and asking them to explain

00:25:11.720 it like top level cancer biologists. And then I stumbled across Tom Seaford actually speculating.

00:25:17.540 Why do you think Tom was one of the few people that latched onto this? Was it simply because he'd

00:25:21.320 already been thinking the same things or because it's really, it is interesting when you think about

00:25:27.060 how many really interesting and impressive people in cancer have not sort of come around to thinking

00:25:32.240 about this stuff. Now in 2009, uh, I think it was 2009 and I'm sure you know, have read this paper

00:25:38.200 a thousand times. It's sort of, I think it was the first obvious mainstream view of this was the Matt

00:25:44.060 Vander Heiden, Lou Cantley, Craig Thompson science paper. Was that 09? Does that sound about right?

00:25:49.520 Yeah, which reminded me of, they had a couple of papers around that time. Which one was it?

00:25:53.200 Well, this is the one that offered an explanation for the Warburg effect.

00:25:56.340 Yeah, yeah, yeah.

00:25:57.260 It was basically an energy synthetic. That's right. It was expanding the biomass directing

00:26:02.580 metabolites to do that. Yeah. And that was interesting because that's a different explanation

00:26:07.460 than presumably Tom would offer, right? It's accepting the Warburg effect is a very powerful,

00:26:11.820 but the question that Tom has really set out to address, no one is arguing the Warburg effect is

00:26:20.520 present, present, but the initiation of the Warburg effect and that damaged mitochondrial

00:26:28.340 respiration causes an energetic crisis that kicks on the oncogenes that basically turn on

00:26:35.680 the genes that are the essence of the Warburg effect. It's metabolic program.

00:26:40.320 Well, let's describe the effect. I should, I want to take for granted that everyone listening knows

00:26:43.120 what the Warburg effect is. So for someone who doesn't know, how would you explain the Warburg effect?

00:26:48.020 The Warburg effect simply stated is insufficient mitochondrial oxidative phosphorylation or what

00:26:55.100 we call respiration with compensatory fermentation in the form of establishing the cell establishes

00:27:04.500 its energy, its production of ATP, our energy currency through glycolysis and substrate level

00:27:12.180 phosphorylation. And it's well recognized that cancer cells, 90% of them, I would say have a Warburg

00:27:21.300 phenotype, meaning that they have highly accelerated glycolysis and substrate level phosphorylation.

00:27:27.880 So let me simplify that a little bit more. Our cells can turn glucose into something called pyruvate

00:27:33.640 and that occurs outside of the mitochondria. And that's not a highly energy efficient process. It

00:27:39.260 doesn't generate much ATP. You then have a decision to make as a cell, which is basically how quickly

00:27:47.540 does the body want ATP? And as a general rule, when it wants it quickly, it's an anaerobic

00:27:53.920 environment. If you think about things that drive quick ATP requirement. And so then it will just say,

00:27:59.160 look, we're just going to turn this pyruvate into lactate. That's the glycolytic pathway, which is not

00:28:02.820 particularly efficient either. It doesn't generate that much more ATP, but it has the luxury of saying,

00:28:07.840 I can guarantee to do this quickly and I don't need to be limited by cellular oxygen. Under ideal

00:28:14.340 circumstances, you would want to generate the most ATP. You would shuttle that pyruvate into the

00:28:19.060 mitochondria as acetyl-CoA and you have this other process. So what you're saying is the Warburg effect

00:28:24.880 is, hey, even under conditions at rest, a cancer cell seems to disproportionately do this glycolytic

00:28:32.200 thing. And it generates its ATP that way, as opposed to going into the mitochondria.

00:28:38.980 Exactly. Even in the presence of normal oxygen, it utilizes glycolysis and pumps out lactate.

00:28:45.280 So under no other conditions do normal cells ferment and pump out lactate.

00:28:50.960 Now Warburg, did he win a Nobel prize for this observation?

00:28:54.540 He won a Nobel prize, yeah, for his work in metabolism of cancer cells. Yeah. And it was,

00:29:00.200 is more kind of appreciated a little bit later what the implications of this was,

00:29:05.060 but it was part of his Nobel prize. Yeah. You know, I remember reading an article about this

00:29:08.860 once that has since escaped me, but then maybe I'm wrong. So correct me. But one of the reasons

00:29:13.080 that the hypothesis was, cause this was in the 1920s, if I recall. Yeah. So one of the reasons that

00:29:19.600 this sort of got discarded for lack of a better word, or at least ignored was people tended to focus on

00:29:25.220 the exceptions. And there were exceptions, right? Certain lung cancers certainly seem to pose an

00:29:29.200 exception to the Warburg effect. And so the idea was, well, look, if you have an exception, then the

00:29:33.380 rule is not so much a rule anymore. And is there another reason why the Warburg effect was largely

00:29:38.020 ignored for, you know, a generation and a half to two generations?

00:29:42.060 Travis Christopherson wrote a book called Tripping Over the Truth that nicely sums that up. I think

00:29:46.480 there's a lot of reasons for that. But I think the, the big focus was on understanding

00:29:51.960 the gene pathways that were associated with carcinogenesis. And that if we can understand

00:29:59.620 the gene etiology of cancers and different types of cancers, then that would explain

00:30:04.880 cancer in a much more fundamental level. And that is the case. There is a dynamic interplay

00:30:11.240 between metabolism and genetics. So now we have an appreciation that metabolites, you could call

00:30:18.040 them oncometabolites, are epigenetic drivers. And metabolism is just not something, it's just not

00:30:25.500 producing ATP. There are so many different intermediates and redox signaling and so many

00:30:33.440 different signaling molecules from metabolism that have epigenetic regulation. And I think that has

00:30:40.680 become, when I got into this, there was no cancer metabolism conferences, you know, and now there's a

00:30:46.320 dozen or more where Lou Cantley is a keynote speaker and Craig Thompson is, and this has all sort of

00:30:52.680 exploded shortly after some of these observations that I made. And it's just, you know, it's, I don't

00:30:58.900 think it's coincidence. I think.

00:31:00.280 Do you remember that night? Yeah. Yeah. Remember when we had that dinner in DC at that conference?

00:31:04.120 Yeah. Georgetown conference. Yeah.

00:31:05.820 I still look back at that as one of the most remarkable rooms to be sitting in as a fly on the

00:31:10.980 wall. Cause there was only about 12 people there and you know, you had Lou Cantley, you had

00:31:16.080 Michael Bishop, Steve Rosenberg, David Sabatini. Um, who else was there? Michael Pollack.

00:31:23.440 Vanderheiden. Yep. Matthew Vanderheiden. I mean, you basically had some of the most

00:31:28.740 thoughtful cancer scientists in the, in the world, uh, certainly in the United States in

00:31:33.540 one room. And that was an amazing conversation. Yeah. Yeah. That's if I could go back in time,

00:31:38.440 exactly. That was golden. We'll talk those guys into getting in a room again. Yeah. I mean,

00:31:44.160 I think what you're basically saying is look, part of its reason for being discarded or at least

00:31:48.120 forgotten about was a new sexier idea emerged, which is, Hey, we started to understand the role

00:31:52.900 of the genome and there's this weird sort of debate you hear. And the observation that things

00:31:58.240 like viruses, you know, which could, you know, encode and change our DNA, but the viruses that cause

00:32:03.940 cancer are the very same viruses that damage the mitochondria that damage the DNA and the

00:32:09.240 mitochondria and causing respiratory insufficiency, which triggers an energetic crisis, which can

00:32:14.800 trigger the activation of oncogene through retrograde response. So that needs to be appreciated too.

00:32:21.180 But there was this explosion of technologies that allowed us to understand genetics. And that was

00:32:27.820 sort of being leveraged to really delve into the cancer. I think there was, there was some politics

00:32:33.380 influencing that too. So it was the first thing you did from that point. Cause there's really two

00:32:39.000 separate problems that you're talking about. The first is why are these seizures occurring? And

00:32:45.740 I'm referring very specifically to your DARPA funded work, which was, why is it that when these special

00:32:50.660 forces guys are doing their ultra secret dives, which require rebreathers, why are a subset of them

00:32:58.020 having these fatal seizures? Well, it's the, at the office of Navy research. So there's also DARPA.

00:33:04.000 Okay. DARPA was doing a separate, uh, they were doing warfighter performance actually with

00:33:08.560 ketone esters just prior to, you know, what I was doing. So that's one problem. And then the other

00:33:14.100 problem that's, that you've also articulated is, Hey, what's going on with cancer? Yes. Yes. So oxygen

00:33:19.920 toxicity seizures are a limitation for Navy SEAL divers, and we don't know how to predict them or

00:33:26.100 prevent them. It's also a limitation of hyperbaric oxygen therapy, right? So if you have carbon monoxide

00:33:31.040 poisoning, right. And you need to live essentially, you need to get that, that carbon monoxide off your

00:33:36.060 hemoglobin, you need to basically increase the PO2 in your tissues. Oh, because carbon monoxide

00:33:41.160 has a much higher affinity than oxygen for hemoglobin. So you have to basically outcompete it.

00:33:47.420 Yes. So if you were to take a ketone ester, which we know now increase your resistance to oxygen

00:33:55.040 toxicity by like 600% and take a ketone ester and then get inside a hyperbaric chamber, you have a much

00:34:00.520 greater chance of living. If you have wounds, there's 14 different applications for hyperbaric oxygen

00:34:05.580 therapy. We think that therapeutic ketosis strategy would make it much safer and more

00:34:10.300 efficacious. So in the context of an oxygen rebreather, the advantage is that there's a

00:34:16.760 stealth component because you don't produce bubbles. You can dive in a quiet lake and go all the way

00:34:21.720 across and surprise your enemy. But at just 50 feet of seawater within 10 minutes at 50 feet of seawater,

00:34:28.420 you run the risk of getting oxygen toxicity seizures. That's pretty shallow.

00:34:31.680 Say that again. At 50 feet, 50 feet of seawater, 10 minutes, you're on a drag or rebreather,

00:34:37.460 according to the oxygen dive tables, that has been enough to trigger a seizure in many guys. So that

00:34:43.620 produces a PO2 in your brain of about roughly 2000 times higher than what your, your oxygen level in

00:34:51.100 your brain would be right now. 2000% higher. So that needs to be sort of, sort of appreciated. And

00:34:59.000 of course this could all be averted if you just stick to the dive tables, right? But if you have,

00:35:04.440 you know, enemy fire with 50 caliber machine guns coming down on you and you want to stay down,

00:35:09.180 if the water's clear, you got to go down deeper. If you have a plant of mine and get to the bottom

00:35:13.020 of a ship or a bridge, you, you might be underwater for three or four hours and the enemy's still up

00:35:19.300 there. And it's, uh, you, you got to get down there and do your job and dive deep and avoid that.

00:35:25.240 And then, you know, after a time you have pulmonary oxygen toxicity too, if you're down there long

00:35:28.860 enough, but generally speaking, these are breathers are for shallow diving, but situations where they

00:35:33.340 need to go down deeper. Do you have an estimate of how many Navy divers just in the United States,

00:35:39.100 both in training or combat would, would die in a, in a given year from this or be injured?

00:35:44.500 It's pretty rare. Fortunately, it's pretty rare. And if they do get hit with oxygen, you know,

00:35:49.400 our friend Kurt Parsley will tell you that Navy SEALs, uh, notorious about not telling what their

00:35:55.600 issues are with their health. Right. So if they do have a seizure, they would be kicked out. You

00:36:00.940 know, a lot of these guys, because that may make them a weak link that they're vulnerable. So we know

00:36:07.000 recreational divers that push the limit who have been hit a couple of times, you know, with this,

00:36:11.440 and we're doing some studies right now, recreational divers. So it's very underreported,

00:36:16.180 but studies have shown, I always show a video in one of my talks of a guy in a chamber where he has

00:36:22.800 a mask on and the mask is breathing 100% oxygen. And the guy inside the chamber is breathing hyperbaric

00:36:29.560 air. And within at 2.7 atmospheres of oxygen, he gets hit with a seizure and has a really violent

00:36:37.560 tonic-clonic seizure. And it stopped. As soon as you remove the oxygen mask and start breathing air,

00:36:42.880 even if it's at the same barometric pressure, the seizure stop. So one of the beneficial things of

00:36:49.660 these seizures, if you want to, if there's a beneficial component to it is that, uh, they

00:36:54.120 quickly stop as soon as you remove the hyperbaric oxygen source, or you go from breathing 100% oxygen

00:37:01.280 to hyperbaric air. So what's happening is that the high levels of oxygen are creating oxidative stress

00:37:08.920 and actually impeding various metabolic processes in the brain. And the brain is becoming hyper

00:37:14.980 excitable. And the neurons are firing so many action potentials that the cells essentially can't

00:37:21.120 maintain their membrane potential. And you get excitotoxicity that causes mass firing in the

00:37:27.620 neurons and a seizure, right?

00:37:29.700 And this is obviously under a very supra-physiologic condition.

00:37:33.940 Supra-physiologic. It only happens, you know, in these extreme environments of pressures. And,

00:37:38.880 and the reason for it now is kind of, you have S-nitrosylation of glutamic acid decarboxylase.

00:37:46.260 There's two different isozymes. And then what we think now is that you have more glutamate to

00:37:52.180 GABA ratio. So the enzyme that converts our gamma immunopatric acid is actually created from

00:37:59.280 glutamate, right?

00:38:00.180 I got it. So you have much more excitatory than inhibitory neurotransmitter.

00:38:03.760 So that ratio changes and it's a redox dependent reaction. Actually it's a,

00:38:08.840 it's, you have S-nitrosylation of this enzyme that converts more glutamate to GABA. So you have

00:38:15.460 increased neuronal firing and increased release of glutamate and also less conversion of the glutamate

00:38:21.260 to GABA, which has a brain stabilizing effect.

00:38:24.480 So this is going off topic for just a second, but we know that as people age,

00:38:29.280 we see greater and greater oxidative damage. So we see, you know, the susceptibility to ROS going

00:38:36.180 up. Does any of what you learned in this super physiologic environment where in a very short

00:38:41.620 period of time, you're going to generate a ton of ROS by exposing someone to high pressure and high O2,

00:38:47.960 does anything you learned in that environment offer an insight into non-super physiologic or normal

00:38:54.120 aging and disease progression?

00:38:55.540 Yeah, I think in many different ways. So it's almost like exercise, right? If you exercise intensely,

00:39:00.940 your reactive oxygen species are going to go up, inflammation, all these things kick on.

00:39:05.080 So high pressure oxygen increases oxidative stress. And that kicks on many different processes that can

00:39:14.720 endow the cell with greater cellular protection. So it can, for example, cause an increase in superoxide

00:39:22.620 dismutase. It can enhance, it can enhance, enhance our antioxidant defenses. So the oxidative stimulus

00:39:28.360 is a trigger for adaptive processes that can allow our systems to be more resilient against the same level

00:39:35.940 of oxidative stress. This happens very robustly in a young animal and is significantly attenuated

00:39:44.940 in, in an older animal. And I think that needs to be appreciated. So the adaptive response to the

00:39:53.020 stimulus is varies genetically, probably between the individual. There's a lot of individual variability

00:39:59.920 between people. And even if you take the same person under different conditions, whether it be if they're

00:40:06.740 sleep deprived, what they ate that day there, maybe if they're dealing with a little viral illness or

00:40:12.280 something, their susceptibility to oxygen toxicity seizures can be greatly affected by a lot of different

00:40:18.860 variables. But that adaptive response, so we know hyperbaric oxygen stimulates the production of stem cells as

00:40:26.420 much as something like GMCSF, like neupogen or leukine. Like it's that powerful. It causes the production and the

00:40:34.060 release of stem cells, which kind of hone in on sites of injury and aid in repair. So that's why it's, it's most

00:40:40.520 utilized application is actually for enhancing wound, wound production or wound healing effects.

00:40:47.420 I see. You mentioned that there were 14 approved applications. I wasn't aware that there were that

00:40:52.200 many. I certainly, I think it's 15 now. So what, what are some of the others? Not to put you on the

00:40:56.140 spot to rattle off all 15, but we can look it up, but just off the top of your head, what other ones do

00:41:00.520 you know? Yeah. Uh, radiation necrosis. So for cancer, if you are getting radiation therapy for cancer,

00:41:05.840 it is FDA approved for that. So if you have patients, you know, who's had radiation therapy,

00:41:10.600 of course there's decompression sickness. So we're recreational diving. If you get bent,

00:41:16.080 another term for bent is decompression, you know, it's the same deal. It's basically get the nitrogen

00:41:20.940 out by basically, you know, just nitrogen out. Yeah. Beating it out with oxygen. Yep. Carbon monoxide

00:41:27.100 obviously diabetic wounds, all the hyperbaric, the UHMS. So hyperbaric medicine society approves

00:41:35.060 the facilities. And I would say 90 plus percent of their revenue generated from that is diabetic

00:41:43.700 wounds, which is a huge problem. Like you probably in your practice, you probably see people with

00:41:48.500 wounds that just don't heal. Well, I don't see them in my practice, but I certainly cut my teeth on it

00:41:52.740 during residency. Yeah. No pun intended. Significant problem. Yep. So that's, I mean, that's a few

00:41:57.800 different applications and there's a lot of sort of rare things. There's noise induced hearing loss.

00:42:02.880 If you use, that's one of the newer applications that could be, so some things that are kind of

00:42:07.740 counterintuitive. So when we think of high pressure oxygen, a lot of times you think of retinopathy

00:42:13.340 or prematurity, right? If you put a newborn and give them high levels of oxygen, you could cause

00:42:18.460 them to go blind, right? A newborn. So that's an interesting. Meaning a newborn is more susceptible.

00:42:24.720 More susceptible to, to oxygen. It was a very common, I guess you could say, to put newborns

00:42:31.180 on high levels of oxygen if they were born premature. And why, what is it about the newborn

00:42:35.780 that makes them more susceptible? The development of their lungs. Is it the angiogenic component of

00:42:39.520 this? Yes. Yes. That could be a component too. And maybe they just don't have the robust endogenous

00:42:45.040 antioxidant, you know, capacity, but probably it might be the angiogenic component too. Do you know

00:42:50.460 off the top of your head if elevated mercury or mercury toxicity is an indication for hyperbaric?

00:42:54.520 Because I've heard of a lot of people doing this, but it strikes me as a little bit off-label.

00:42:57.940 Probably not. There's so much off-label stuff being done. So one of the things that I'm really

00:43:02.960 interested in testing is for traumatic brain injury. And I do think that low levels of hyperbaric

00:43:10.540 oxygen therapy, if used shortly after a traumatic brain injury, I think the faster you restore

00:43:18.460 oxygenation, the more likely you are to salvage those neurons. So ideally you want to treat with

00:43:25.860 something that's going to reestablish energy in neurons, decrease inflammation and increase

00:43:31.340 oxygenation to hypoxic pockets. And I think from my perspective, giving something like a ketone ester

00:43:38.600 with lower levels of hyperbaric oxygen therapy would probably work. That's probably the, by far the

00:43:45.680 most controversial application because there are some remarkable responses from people who have

00:43:52.600 even a regeneration of brain cells after the hypoxic injury, for example, in kids who are very

00:44:00.620 resilient anyway. I know Dr. Paul Harch, you know, has been on pretty much all the major news networks

00:44:06.600 with a girl that sustained a incredibly severe hypoxic injury and brain death and regenerated some of her

00:44:14.200 brain, brain function and brain tissue. How old was the girl? She was pretty young, I think five or six,

00:44:21.000 I believe. And I met her actually, uh, one of the conferences and it's very clear that nothing was

00:44:26.020 working for her until she did hyperbaric oxygen therapy. So, but kids are completely, could be

00:44:31.660 another story. You know, we don't know if we could replicate that, but there are a lot of stories out

00:44:36.540 there anecdotal reports, but it just has not been studied appropriately and those studies need to be

00:44:43.620 done. And what do you see as the resistance? I mean, when you look at what's happened in the last

00:44:48.460 five years in the NFL that has brought along with, I think just the returning vets TBI is, I mean,

00:44:56.080 I don't think you could walk down Madison Avenue and hit someone with a rock who hadn't at least heard

00:45:01.860 the term TBI. So everybody knows what it is. We've got, you know, these two completely different

00:45:07.500 demographics who are highly affected by it, athletes and, uh, soldiers. What's the hangup? I mean, you

00:45:15.200 and I have spent a lot of time behind the scenes trying to get organizations like the NC2A interested

00:45:21.480 in studying this. I'm struggling to understand what the hangup is. You know, they're looking for devices

00:45:28.380 to, you know, quantify TBIs and concussions. So that's a lot of funding is going into that,

00:45:34.960 that area, at least when we talk about the NFL head challenge and something that, you know, we,

00:45:39.700 we submitted to, you know, I don't really know. I don't really know. I think the scientific rationale

00:45:45.560 for a metabolic based therapy for the brain makes a lot of sense in restoring oxygenation. Uh, I think

00:45:52.020 the waters are very muddy though, when it comes to hyperbaric oxygen with, uh, TBI. Cause I mean,

00:45:58.180 we even did some rat studies where repeated doses of hyperbaric oxygen in a concussion or a brain

00:46:06.620 injury model, a rat caused more injury can exacerbate the effects. Whereas a single dose

00:46:15.000 of hyperbaric oxygen right after, at least in our rat model decreased the infarct size by maybe a 30%,

00:46:20.880 something like that. So this is dangerous. I mean, we, we don't want someone listening to this

00:46:24.680 who's suffered a TBI thinking I'm going to go to some off label clinic and just max, you know,

00:46:31.000 repeatedly expose myself to hyperbarics. I mean, we, the point here is this has to be studied.

00:46:36.500 It has to be studied rigorously. It has to be studied empirically. And then we haven't even got

00:46:40.160 into something we will get into later, which is the potential augmentation of the exogenous ketone.

00:46:46.580 Yeah. Yeah. I would not do hyperbaric oxygen therapy. If people are going to do it with and

00:46:52.020 without, you know, what I say, I would definitely do hyperbaric oxygen therapy. If you're going to do

00:46:56.840 it in strong nutritional ketosis, because a consequence of hyperbaric oxygen therapy is could

00:47:04.580 be CNS oxygen toxicity. So you do not, the last thing you want, if you have a brain injury is to have

00:47:10.320 a seizure and we know 85% of all penetrating traumatic brain injuries lead to seizures and

00:47:18.300 people who've had penetrating. What about blunt? I mean, it's less than that, but how much? Yeah.

00:47:23.120 So I don't know. I guess you would have to quantify the blunt, the severity. Yeah. But when it comes to

00:47:28.500 penetrating, but it's, it's, it's upwards about 85% of penetrating traumatic brain injuries have

00:47:33.340 seizures and that's because you have excess glutamate, you know, and that's the very thing that's

00:47:37.880 actually contributing to oxygen toxicity seizures. Right? So I think the biggest thing to do is to

00:47:44.320 augment your brain energy metabolism to burn energy more efficiently. The ketones do that and lower

00:47:50.480 neuroinflammation. And I think there's a variety of ways to do that, but you don't want to throw

00:47:55.700 more fuel on the fire. And I think high levels of hyperbaric oxygen therapy could be doing that.

00:48:01.720 I think maybe these soft chambers that go to like 1.4, 1.5, maybe a better means to implement that.

00:48:09.320 Let's get into ketosis a little bit. I want to come back and talk about cancer. I want to come back

00:48:13.340 and talk about the exogenous ketones, both the salts, the esters, and even different molecules. But

00:48:20.020 one of the most interesting experiments we've seen in the physiology of ketones, like, you know,

00:48:25.000 as far as old school experiments was the George Cahill starvation experiments, right?

00:48:29.200 I was highly motivated by that study. We're going to link to it here, but why don't you give people

00:48:33.920 the Reader's Digest version of what George Cahill did that could probably never be done again?

00:48:38.260 Yeah. Yeah. And I was very lucky to connect with him.

00:48:41.780 Before he died.

00:48:42.420 He passed away in 2012. I connect with him a few years before that. And just to figure out,

00:48:48.420 you know, did he really do these studies? And there was a lot of studies that also didn't get

00:48:52.580 published that were pretty remarkable too, that somehow they got past ethics review at Harvard Medical

00:48:58.600 School. But essentially what he did, a very elegant study to look at brain energy metabolism,

00:49:05.740 the AV difference in blood and metabolites in subjects that fasted for 40 days. And most of

00:49:12.580 the subjects were divinity students, I believe, or maybe conscientious objectors to the war or

00:49:19.120 something like that. But each person had like a different story behind it. And he fasted these

00:49:24.340 subjects for 40 days. And just to be clear, this is water and mineral only water, no calories.

00:49:30.200 Yeah. Yeah. But they took minerals, right? They had magnesium and sodium.

00:49:33.380 They did. I think they took a mineral supplement and they also were, they weren't lean subjects. So

00:49:38.960 they were subjects who from their perspective were overweight, if not obese subjects. So they had

00:49:45.120 some weight to lose. And it was very well documented and well controlled study where they monitored

00:49:53.140 free fatty acids, insulin, glucose, beta-hydroxybutyrate, acetoacetate, and acetone.

00:50:00.600 And let's, I'll just pause you there for a moment for the listener. We'll come back to this because I

00:50:04.920 want you to explain the difference between beta-hydroxybutyrate or BHB, acetoacetate or

00:50:09.240 ACAC and acetone, how they're produced, which ones are metabolically active, which ones aren't. But

00:50:13.840 hopefully by me just saying this between the two of us, we'll remember to come back to that.

00:50:17.820 Okay. Yeah. So yeah, essentially three ketone bodies, beta-hydroxybutyrate being the primary

00:50:23.060 ketone that's elevated and more stable in the, in the blood and probably more likely to be a brain

00:50:28.500 fuel. So, and if we just focus on that ketone body after seven days, it reached the level to where

00:50:36.780 it was at or above the level of glucose in the subject. So glucose came down from five to six

00:50:43.000 millimolar down to three and stayed at three millimolar throughout the duration of the

00:50:48.020 experiment, throughout the duration of the fast from day seven, essentially to the remainder of

00:50:53.320 the 40 days. So for the Yankees listening to this, who aren't familiar with the metric system,

00:50:58.180 three millimolar is about 55 milligrams per deciliter. Yeah. Yep. Okay. So that's pretty darn low.

00:51:05.560 Yeah. But what's interesting is it gets down there. I think it was between day seven and day 10,

00:51:10.880 it hit three millimolar and then it just never went down again. Yeah. Yeah. What the heck is

00:51:15.400 going on? These people don't eat any glucose. How are the, how do they sell? And what that tells you

00:51:19.560 by definition is their liver still had glycogen because you have to be putting that glucose out

00:51:25.880 from the liver. Yep. So the maintenance of glucose is under very powerful homeostatic mechanisms. So we

00:51:35.120 have, we're hardwired from an evolutionary perspective to maintain glucose and the glucose can be coming

00:51:40.820 from gluconeogenic amino acids. So we are breaking down some muscle and then the glycerol backbone of

00:51:46.880 triglycerides too also contributes to the production of, um, so triglycerides being the storage form of

00:51:53.700 fatty acids. You have a three carbon backbone that's called a glycerol backbone. It has three of these

00:51:59.740 free fatty acids that are, well, they become free once they're cleaved, they become the substrate that

00:52:05.600 you're going to explain to us in a few minutes is how you make BHB or beta hydroxybutyrate,

00:52:09.880 but you don't just throw that glycerol out. You can actually, the liver can turn that back into

00:52:14.860 glycogen within itself to then slowly trickle out into the bloodstream. Exactly. Yep. So when Cahill did

00:52:21.640 this, if I recall, insulin levels also got very low by, with about by day seven, the insulin levels

00:52:26.780 were, you know, at rock bottom and sort of stayed there. Yeah. Yeah. They're very low. One of the

00:52:31.000 interesting things about the experiment, what, in addition to the stuff I want to hear about,

00:52:34.860 which is the brain metabolism and how did the brain partition those fuels is, was it this experiment or

00:52:40.460 a different one where he was able to give insulin lower glucose levels, but not generate CNS trauma

00:52:48.080 through that? Yeah. So the subjects were asymptomatic for hypoglycemia and they felt really fine.

00:52:53.600 And in another report, down to what level? Like one millimolar? Yeah. So they infused IV infusion

00:53:00.440 of 20 IUs of insulin and pushed glucose from three millimolar or thereabouts down to roughly one

00:53:08.400 millimolar, which is like less than 20 milligrams per deciliter. Yeah. Which would be fatal. That would

00:53:14.100 be a fatal level of glucose. Even two, two becomes like coma and essentially fatal if it's maintained.

00:53:21.340 I hit two very briefly during an insulin suppression test I had at Stanford and I was no longer in

00:53:28.840 ketosis because I was doing this insulin suppressant test. So I started at about two and a half or three

00:53:33.520 millimolar, but 90 minutes later, my ketones had withered down to like 0.3, 0.4. Yeah. And then my

00:53:40.860 glucose hit about 38 milligrams per deciliter. And I really, I, that was the day I thought I was

00:53:47.460 dangerous area. Oh yeah. No, I thought I was gone. I have a little self-experiment I can mention after

00:53:52.940 this, but essentially what they did, which was a very bold and gutsy demonstration. They injected

00:54:01.560 insulin, which facilitated glucose disposal in the patients essentially, and brought blood glucose down

00:54:08.640 to, you know, roughly a one millimolar, which is universally fatal. And the subjects were relatively

00:54:13.800 asymptomatic for a hypoglycemia, which was remarkable. Their ketones were maintained at

00:54:19.720 about, uh, above five to six millimolar. That is out freaking rageous. Like that, when you just

00:54:27.140 stop to think about how you could take a normal, healthy volunteer and do something, I mean, we're

00:54:34.820 all in the spirit of learning, but when you just think about that from an ethical standpoint, like

00:54:38.480 I can't do that in mice. I'm not allowed to do that in mice. The IACUC, the Institute for Animal

00:54:43.400 Care and Use Committee, you know, would not approve, uh, fasting for more than 48 hours. I think it's

00:54:49.660 for 24 at our institution. Yeah. So that's, uh, for mice and maybe rats might be 48, but yeah. And the

00:54:55.360 use of insulin to further, you know, that would, I'm, I serve on the IACUC. I mean, these things would

00:55:00.100 be quickly rejected. I mean, this is, this was the wild, wild West. Yeah. And then, uh, just the last

00:55:05.720 thing on this topic that I remember, uh, which I'd love you to expand on is what did we learn about

00:55:11.080 how the brain partitioned fuel, how much of the brain's energy, once you were in that steady state

00:55:16.140 after about 10 days came from glucose, beta hydroxybutyrate and acetoacetate. Yeah. So

00:55:22.800 beta hydroxybutyrate accounted for approximately 60% of, of the energy and probably 10% acetoacetate.

00:55:31.660 And roughly at that point, after about 10 days, only about a third of the energy was coming from

00:55:39.420 glucose, right? And basically what's in your blood as far as ketones and glucose is what your brain

00:55:45.600 is utilizing. You know, your brain's in a hungry state and it's effectively utilizing and clearing

00:55:50.560 those, those metabolites. You can do that. It was, it was very elegant demonstration and it kind of

00:55:56.740 changed our understanding of brain energy metabolism as glucose being exclusive predominant fuel. So in a

00:56:03.980 fed state, they were consuming 100% of their brain energy metabolism was from glucose, but only after

00:56:09.840 being fasted did that change. And he went on to write a number of reviews and went on with Dr. Veach who

00:56:16.180 actually created and developed some of the, they published together. Veach was a postdoc with Cahill,

00:56:21.920 wasn't he? A postdoc. Yeah. He was a student of Hans Krebs actually. And then, uh, yeah, he was one

00:56:26.940 of the, I forgot that fact. Yeah. He was one of his best students from my understanding. Yeah. From

00:56:31.840 word of mouth. Uh, yeah, they went and they worked together in different capacities. Yeah. I think he

00:56:37.200 might've been a fellow with him. I think most people listening to this, if they can dig back to high

00:56:41.660 school biology, that, that name Krebs will sort of ring a bell, right? Yeah. Yeah. So you mentioned

00:56:47.880 that, that Cahill shared with you stuff that wasn't even published. Do you remember anything

00:56:51.740 that, that was, that struck you as super interesting that was unpublished?

00:56:55.580 Yeah. You know, some things may be, uh, not worth talking about. Well, yeah, I don't know if he,

00:57:01.460 I, there was some stories and then I heard some stories through other people too.

00:57:06.060 Well, I don't want to make you say anything that you're not comfortable saying publicly.

00:57:09.360 I would say that some of the work that was done in animals definitely suggested that glucose could go

00:57:14.560 lower, even lower, and that, uh, you could really transition your metabolic physiology to be fueled

00:57:23.100 off fats and ketones. And, and that, that was against what we knew. These were remarkable observations

00:57:33.280 that changed the whole context of what we knew about metabolic physiology and brain energy metabolism.

00:57:39.400 Do we know today if the brain can use lactate directly as a fuel without it having to go through

00:57:44.140 the Cori cycle? Yeah, most certainly can. I think, I think lactate's a actually a great fuel. Okay.

00:57:50.100 And that's one of the first fuels I got interested in when I was studying hypoxia and then later even,

00:57:55.640 uh, hyperoxia was thinking about using lactate, uh, different forms of orally available lactate,

00:58:00.940 like poly L lactate, you know, I think it's in the product Cytomax, if you remember for cycling.

00:58:06.480 I used to use Cytomax. Yeah. So, uh, so I, I was actually interested in that and that actually led me to

00:58:12.000 ketones. And then once I got more into studying ketones and discovered somehow it slipped past me

00:58:17.720 all the years, I thought I knew what a ketogenic diet was. But then when I read about the history

00:58:21.580 of the ketogenic diet being used for almost a century, and I realized that it was like the

00:58:27.320 standard of care for seizures. And then understanding that these ketones can largely replace glucose as

00:58:34.300 the energy source. And then they have these signaling properties that are even independent of

00:58:38.380 metabolism that are remarkable. Over the last five years, a lot of these big labs are looking at

00:58:46.060 the epigenetic effects of ketones functioning as class one, class two histone, the functioning as a

00:58:53.880 suppressor of the NLRP three inflammasome producing less inflammation in a metabolic independent way.

00:59:01.020 So you obviously pretty quickly come to this idea that these ketones are interesting molecules and

00:59:08.060 they're interesting for a couple of reasons at the very least, what you just said, which is they have

00:59:12.740 signaling properties that make them kind of unique outside of the exogenous ketones though, you have

00:59:17.700 to also undergo a pretty extreme physiologic change, at least in a Western culture to make enough of these

00:59:24.360 to matter. And you have to restrict carbohydrates and protein to get there. So did you first personally

00:59:30.740 get interested in this from a nutritional standpoint and then eventually through this exogenous pathway

00:59:35.800 or vice versa? Yeah. So ketone esters, to my knowledge in 2008, didn't exist. They actually

00:59:43.120 did, but I didn't, I didn't know of them. I discovered them on a DARPA website as some work that was being

00:59:49.080 funded, you know, in developing of the ketone esters for warfighter performance. But at the time,

00:59:55.680 when I just decided to go down the route of the ketogenic diet, I reached out to Johns Hopkins and

01:00:01.600 the crew there. Which is where the anti-seizure therapy was pioneered, right? Yeah. Mayo Clinic

01:00:06.740 first, and then they worked together with Hopkins. I would say the bulk of the work that was done to

01:00:12.860 develop the protocols for the ketogenic diet, which are in use today, was developed at Johns Hopkins.

01:00:17.680 And I got Eric Kossoff books, his book with published with John Freeman, which was, I just went out and

01:00:25.120 did the classical ketogenic diet, the four to one ratio. So four parts fat and one part being protein

01:00:31.760 and carbohydrates. It equates out to 87 to upwards of 90% fat, maybe 10% protein and like one or 2%

01:00:41.060 carbohydrate. So, I mean, it's like basically eating super low carb and then adding mountains

01:00:48.160 of fat on top of that plate, making like a super low carb meal with protein restricted and then add

01:00:53.800 some butter and a couple cups of heavy cream with that. And that's, I started weighing everything out.

01:00:59.260 And what year did you start that? 2008, I think in nine, I think it was 2008 or nine that Eric Kossoff

01:01:06.940 published the modified ketogenic diet, which was more liberal and protein and increasing protein

01:01:13.240 from 10% to 25 and 30% or 25% is a huge difference. Like you can, that's actually a diet that I mostly

01:01:22.280 adhere to now. And I followed the ketogenic diet and I bought the strips were very expensive at the time.

01:01:28.160 There was a couple of different kits that I got to measure my own ketones and, you know, I immersed

01:01:33.580 myself in it. I got obsessed with it and I wanted to know what it felt like to have a brain that ran

01:01:38.720 on ketones. And how high did your levels get measured in the blood? I kind of struggled to

01:01:44.200 get up there even with the classical ketogenic diet, two and 2.5. I would typically with the

01:01:51.040 classical ketogenic, and this is before MCTs. So I wasn't quite using MCTs yet. In 2009, I started

01:01:58.280 incorporate the same time I discovered the modified ketogenic diet was the same time I started using

01:02:03.560 MCTs and a modified ketogenic diet with MCTs got my ketone levels up probably higher than the

01:02:12.380 classical ketogenic diet, which was just mostly, you know, a dairy based long chain fat sort of

01:02:19.080 derived diet. So let's tell everybody how we make ketones and then we'll tell them what an MCT is for

01:02:23.800 those that don't know. So let's talk about starvation ketosis. And then if there's differences between

01:02:28.400 that that are worth highlighting with nutritional, that would be great. But evolutionarily, I'm going to

01:02:33.060 deprive you from eating for a few days. How do you survive? Well, you start burning up your liver

01:02:39.400 glycogen. Okay. So 24 hours later, you've got that down to about half of its half to about a quarter of

01:02:45.960 its supply. Through the suppression of the hormone insulin, we start mobilizing fat from adipose tissue,

01:02:52.740 which are cells pretty much all cells in the body, especially muscles and heart cells,

01:02:57.600 burned fat like a superior energy source. Long chain fatty acids don't effectively cross the

01:03:04.520 blood brain barrier. So through accelerated fat oxidation, beta oxidation of fats in the liver,

01:03:10.800 that stimulates the accumulation of acetyl CoA, which forms acetyl acetate and ultimately beta

01:03:18.220 hydroxybutyrate. So you start spilling these ketone bodies through accelerated fat oxidation in the

01:03:24.580 liver. The liver lacks succinyl CoA transferase. So it does not actually use the ketone bodies for fuel

01:03:30.540 and they become available for your brain, your central nervous system and peripheral tissues.

01:03:35.640 So the liver is secreting beta hydroxybutyrate.

01:03:38.400 Yeah. And acetyl acetate to some extent.

01:03:40.640 Okay. So is the BHB being made and then being converted into acetyl acetate or is the liver making

01:03:46.220 both? Acetyl acetate first and then beta hydroxybutyrate. And it's interesting that some people have a ratio

01:03:53.220 beta hydroxybutyrate to acetyl acetate of two to one and some people five to one, generally speaking

01:03:58.680 about four to one. So acetyl acetate is unstable in that it can spontaneously decarboxylate to

01:04:06.580 acetone, which is volatile. And we blow it off in our breath. Does it have metabolic activity? Can we,

01:04:12.860 it was thought that it didn't, but more recent work is suggesting that the carbons of acetone do find

01:04:19.760 their way into sort of lipid biosynthesis and some other things, but it's kind of rare for that to

01:04:26.500 happen. But it's not a great ATP source. Not, no, not, not really. It has some effect on neurons. So it

01:04:33.160 has an anticonvulsant effect through, I believe, opening a potassium channel, which could hyperpolarize

01:04:39.920 the membrane potential and actually help attenuate some hyperexcitability in the brain. So there are

01:04:45.860 people that study, you know, the effects of acetone as a sub-narcotic levels of acetone,

01:04:53.100 right? Acetone can be pretty narcotic and be problematic, but acetone levels that are 0.5

01:05:00.880 millimolar and even upwards of one millimolar can have a neuroprotective effect. Once you get above

01:05:06.900 one millimolar, you start to dissolve some of the membranes and you can have sort of,

01:05:11.140 that doesn't sound, yeah, you have problematic, you know, acetone as a pretty powerful solvent,

01:05:16.700 right? It's a nail polish remover, but small levels of acetone are neuroprotective. And that's

01:05:21.200 actually something that we study. So how do acetoacetate and beta hydroxybutyrate enter the

01:05:26.740 Krebs cycle? In other words, where do we get ATP from them? It depends on the cells. So different

01:05:32.340 cells have different, and we're looking at this now, different ketolytic enzymes, right? So they can feed

01:05:38.280 in through a number of different pathways. Like I said, the liver is the production site of beta

01:05:44.940 hydroxybutyrate. And when it comes to skeletal muscle, they have a range of ketolytic enzymes

01:05:52.400 that can allow them to enter the Krebs cycle at different, different areas. So succinate,

01:05:58.500 for example, so you can replenish TCA cycle intermediates with succinate. You can, acetoacetate

01:06:05.360 can break down and provide acetyl-CoA for the Krebs cycle. So what we're finding is that

01:06:11.480 the Krebs cycle is not the simple cycle that we thought it was, especially as it relates to cancer

01:06:17.420 cells. So it's almost like we can't even look at the biochemistry book and kind of pinpoint

01:06:25.440 different pathways. With substrate level phosphorylation, there are a number of different

01:06:32.040 pathways like the malate-aspartate shuttle that are associated with cancer cells if we go back

01:06:38.880 to those pathways. Did you see that paper that came out in Nature two days ago about aspartate

01:06:44.400 being a rate-limiting step in cancer metabolism in the mitochondria? I didn't see that. I haven't,

01:06:49.320 Bob and I were just talking about it today. It's interesting because the paper was, part of it was

01:06:54.080 written through a lens of, hey, this might be how metformin can exert some of its anti-cancer

01:06:58.200 benefits by interfering with aspartate. I think it was interfering with degradation of aspartate,

01:07:04.340 but again, I haven't read the paper yet, just sort of the abstract, but it was yet another like,

01:07:09.120 I didn't know that. Wow. Every day I feel like I'm, I feel like I'm getting dumber because the rate at

01:07:14.900 which I'm being exposed to new information is exceeding the rate at which I'm assimilating it.

01:07:19.040 So it's just, it feels like I'm on a downward spiral to stupidity.

01:07:22.620 There are textbook pathways that I used to just rattle off and it's all seems so simple. And then,

01:07:27.980 you know, I read three or four papers and I realized that I probably shouldn't talk about it

01:07:33.980 in some simplistic terms like that. I mean, we're kind of going down the rabbit hole of glutamine

01:07:39.540 lysis, right? So glutamine is the fermentable fuel. So ketones are a non-fermentable fuel,

01:07:47.320 whereas cancer cells will use glucose and glutamine as the two primary fermentable fuels.

01:07:53.680 You know, it's funny. I, I mean, I know that biochemically, I'd never thought of it in those

01:07:57.220 terms though. Yeah. Yeah. It's not fermentable. That's interesting. So that's kind of what I'm

01:08:02.460 thinking about, you know, in terms of, of ketone metabolism with glutamate. So, or glutamine,

01:08:08.200 glutamine can make glutamate, right? And alanine and aspartate and lactate and glutamine lysis is kind of

01:08:16.240 driven by the malay aspartate shuttle. And that has become a major focus now of many, um, cancer

01:08:24.800 researchers are looking to target glutamine and it's not, it's not easy. I mean, cause you have,

01:08:29.240 if you have a glutaminase inhibitor that has tremendous side effects, huge toxicity, right?

01:08:34.160 Yeah. So we need to approach this in a very nuanced sort of way when it comes to targeting glutamine.

01:08:40.680 Yeah. So let's go back to the MCT. So you talked about how you started out on a four to one ratio,

01:08:45.360 which is interesting. I started out four to one. I spent three years on just four to one. I never

01:08:49.520 deviated from four to one, but then you mentioned you went to two to one, which is obviously much

01:08:53.900 easier to do, but you augmented with MCT. So MCT of course stands for medium chain triglyceride.

01:09:00.080 They're a type of saturated fat and they're of a certain length. And I don't even remember anymore.

01:09:04.840 Is it eight to 14 carbons is what we define as MCT? Yeah. Eight to 10, I think eight to 14 from

01:09:11.200 in that. But when we talk about the ketogenic ones, the, uh, they're more close, they're closer

01:09:15.660 to caprylic acid, which is the C eights. Yep. So why does, why does taking those make this process

01:09:22.500 easier? When you consume them orally, they are transported to the liver via hepatic portal

01:09:28.360 circulation and they're not packaged into chylomicrons and, you know, long chain fatty acids. When we eat

01:09:34.300 them, they're packaged into chylomicrons and they go through essentially enter the lymphatic system

01:09:40.200 and have a different route of entry. They're metabolized totally differently. Whereas medium

01:09:45.220 chain fats go directly to the liver through hepatic portal circulation. It's like a bolus of fat going

01:09:50.680 to the liver. And it's a type of fat that's rapidly oxidized, right? The liver is chock full of

01:09:56.960 mitochondria. So if I want to study mitochondria, I'll take out a chunk of the liver and isolate it from

01:10:02.300 that. Cause that's the easiest thing to do. So the mitochondria really burn up medium chain triglycerides

01:10:08.800 very quickly. And, uh, there's very high rates of fat oxidation in the liver from an oral bolus of

01:10:15.300 medium chain triglycerides. So they're much less likely to be stored as fat. They're a source of

01:10:19.700 calories and they can be incorporated into meals and into foods to further enhance and boost the

01:10:27.960 ketone levels of the ketogenic diet. Or even if you're not on a ketogenic diet, they can be consumed

01:10:33.340 with a high carbohydrate diet and actually elevate ketones in the blood. Yeah. I mean,

01:10:37.420 I've heard that, but I've never actually measured it probably because I've only done this with liquid

01:10:41.800 MCT, which you end up getting to sort of GI tolerance becomes an issue probably before you

01:10:47.020 get a high enough level. But if you're on a high carb diet and you consume, I don't know,

01:10:52.980 two to three tablespoons of MCT, how high could you reasonably expect your BHB to get?

01:10:59.140 Uh, depending on your absorption, anywhere between 0.5 to one millimolar.

01:11:03.180 That high?

01:11:04.320 I would say. Yeah. Even on a high. Yeah. If it's pure C8, maybe, uh, so with C8, you get about a 20,

01:11:10.800 maybe 30% elevation above like a mix of the C10, C8, which is generic. There's some work being done

01:11:17.480 that C10 may actually have some beneficial effects. I mean, that's kind of the idea behind the product

01:11:23.540 Exona that was on the market, you know, a while back. I don't know if it's still on the market.

01:11:27.060 I don't know. I don't know what it is. Yeah. It's a basically C8. It's powdered C8.

01:11:31.520 Oh, I used to just order pure C8. Yeah. You can order it.

01:11:35.020 I ordered like from Sigma or something like that. Yeah. Well, I, Dave Asprey's Brain Octane is,

01:11:40.640 is caprylic triglyceride and Perillo Nutrition makes CapTree, which is a C8 oil. So if you buy pure C8,

01:11:49.260 not in triglyceride form, uh, caprylic, if you just, uh, just straight acrylic acid,

01:11:54.940 that'll kill you. I mean, you, you consume that. I bought, I made the mistake early on and bought

01:11:59.980 from Sigma caprylic acid, but not yet. You need to buy caprylic triglyceride. How did you catch that

01:12:05.540 mistake before ingesting it? I bought it from Sigma and I think I was going to use it in experiments

01:12:11.340 and we were going to mix it, you know, with our rat child. I wanted to go through a legitimate source

01:12:15.520 and, uh, I put a little bit on my finger and it kind of burnt my tongue off. And I realized,

01:12:22.580 wait a second, I think I need the triglyceride form of caprylic acid. I need the caprylic

01:12:28.180 triglyceride. Yeah. I almost killed myself. I almost won a Darwin award. Yeah. Yeah. You know,

01:12:33.500 I never looked at someone probably did that before accidentally, uh, kills himself. Yeah. Have you

01:12:40.700 had any experience with the powdered MCTs? Yeah. Yeah. So powdered MCTs allow me to

01:12:46.440 increase my ketone levels higher than, uh, and I use the quest powdered MCT formula. There's a couple

01:12:52.480 on the market now maybe. Yeah. I have vats of this stuff at home because I feel like anyone who's ever

01:12:58.540 made a ketone product just somehow figures out my address and sends them to me. So I have a pantry

01:13:04.060 full of every type of ketone you can imagine. I do too, but I haven't. Yeah. You probably get more

01:13:09.580 than me. I just haven't got around to trying any of the MCT powder, but I'm getting ready to do a long

01:13:15.240 fast in a couple of weeks. And I was thinking I really ought to get, make sure I'm back in ketosis

01:13:20.700 the week before I deprive myself of food for a week. Yeah. So I was actually just thinking about

01:13:25.360 this last week, which is I got to fire up those powdered MCT and kickstart this thing. Cause I

01:13:30.000 don't have like a couple months to get fully adapted. Yeah. They are great. I mean, MCTs are kind of like

01:13:36.240 the poor man's ketone ester, right? So they are, they're, they're found in nature. They're

01:13:41.080 versatile. You can incorporate them in the food. I would even call them the middle classes, man.

01:13:44.460 Yeah. Given how expensive ketone esters are now. That's right. That's right. Yeah. So I tinkered a

01:13:50.480 lot with MCTs early on and increased my tolerability from maybe 30 milliliters a day to 150 milliliters a

01:13:58.580 day. Hang on a second. That's ridiculous. Yeah. And when, anytime I went to 30 in one sitting,

01:14:05.700 it's 10 tablespoons. Yeah. Yeah. That's, that's hard to fathom. You need to incorporate it with

01:14:12.000 food. So I was spreading it. What I found I needed to do was instead of doing intermittent fasting

01:14:18.800 now, which I pretty much do now, I inquire, I spread it out over like four meals and maybe would

01:14:24.340 have a little bit of MCT in the coffee too, and not including that in a meal. So I was eating a

01:14:29.380 modified ketogenic diet, but spreading that MCT out with salad dressings, putting it on vegetables

01:14:35.180 and things like that. And I was able to, cause if anybody's listening to this and is trying

01:14:39.080 to like, they're just sitting there thinking, how, what could I do to do it to have a bowel

01:14:42.580 prep? Like the answer is just, just, just drink MCT. It's, you know, it's, it's better than

01:14:48.260 fleet's phosphosoda. You will, you will spend the day in the bathroom and you'll, you'll have

01:14:53.280 a great, but you can work your way up to it. So there's a number of transporters obviously

01:14:58.600 that are upregulated and you are enhancing the breakdown and transport of these fat and

01:15:04.320 MCTs actually do cross the blood brain barrier. So we did studies in rats where we took out

01:15:09.860 the hippocampus.

01:15:10.100 But if they're getting absorbed portally, how do we know? Oh, okay.

01:15:13.020 Some of them, I forget the percentage, but I think, and some people say it's like 50% of

01:15:18.000 MCTs converted to ketones, but I think it's something like about 20% of MCTs. And it depends

01:15:24.380 on the energetic state of the liver, you know, which is the master regulator and your, your

01:15:28.520 physiology in general, but you have a fairly significant portion of the MCTs being converted

01:15:34.740 to ketones, but the MCTs do enter the blood and they can cross the blood brain barrier, unlike

01:15:39.720 the long chain fats. And they, for example, if you take out the hippocampi of rats that are

01:15:46.460 eating an MCT based ketogenic diet, you'll find MCT levels are significantly elevated. So they're

01:15:51.600 crossing, they're getting into the brain and the brain is utilizing MCTs as fuel.

01:15:56.200 And do we know if that has any anti-seizure effect independent of the ketone that might

01:16:00.540 be produced alongside it?

01:16:01.840 That's a big area of research right now that MCTs is functional fats.

01:16:07.300 I've never heard that term before, functional fats.

01:16:09.860 Yeah. Like, well, fats with drug-like properties. So I think there's a number of patents around

01:16:14.740 C10 actually that I know they have in the UK. I think it might be a pharmaceutical now.

01:16:20.160 So C10 actually has anti-seizure properties. So there's some people argue that the effects of

01:16:27.460 the ketogenic diet, at least with MCTs, is not due to ketones, but actually due to the MCTs and

01:16:33.980 not the ketones. So there's a couple of groups out there that are sort of arguing that. And I think

01:16:40.280 they have a case, but I think it's definitely a combination of the ketones and the MCTs. So MCTs

01:16:48.160 do have interesting properties.

01:16:50.020 Do you know Elizabeth Thiel at Boston Children's?

01:16:52.260 Yeah.

01:16:52.440 So I remember having breakfast with her about six years ago and asking her a question that at the

01:16:59.000 time I don't think she knew the answer to. And she was gracious enough to explain that. And she

01:17:03.980 was there with someone else in her lab. So it was a very spirited, awesome discussion. But I wonder

01:17:08.980 if the answer is known today. The question was basically, do you believe that the anti-seizure

01:17:14.280 properties of a ketogenic diet are more the result of the brain having another fuel to displace glucose

01:17:22.160 or due to the reduction in glucose that invariably accompanies ketogenesis? And at the time she

01:17:31.380 shared with me very compelling data that could argue either of those points, potentially suggesting

01:17:37.520 it was the combination of them. Do you have a point of view on this? Or is there more information

01:17:41.580 today that steers you one way or the other? Well, I know she's done some work with the low

01:17:45.720 glycemic index diet. And so, so carbohydrate reduction, but without the production of ketones.

01:17:50.940 Yeah. So a reduction, it's carbohydrate restriction, but only to the effect of maybe 20 or 25%,

01:17:58.820 you know, and then carbohydrates that are low glycemic index.

01:18:03.140 And what are the results of that intervention?

01:18:04.900 For different types of seizures, it can have a positive effect. And for certain,

01:18:09.240 certain types of seizures, that's not the first line of therapy for, you know, very powerful tonic

01:18:15.120 clonic seizures and pediatrics. You want to go right to the classical ketogenic diet, but it does

01:18:20.220 have a number of applications for different types of seizure disorders. And what about if you take

01:18:25.840 someone on a fully carb diet, who's having recalcitrant seizures and you give them ketone,

01:18:32.380 exogenous ketone? Does that have anti-seizure benefit?

01:18:36.100 Yeah. So those studies have not been done yet. And there is a study being recruiting right now for

01:18:43.480 something called Angelman syndrome, which is a rare genetic disorder that has seizures where

01:18:47.980 the exogenous ketones are the therapy independent of the diet. So they're just being added on top of

01:18:54.440 the diet. There are people out there because exogenous ketones are commercially available that are using

01:19:00.320 this in place of the ketogenic diet because the families are either unwilling or for various

01:19:07.060 reasons, unable to use the ketogenic diet. And they, you know, use argue using exogenous ketones and

01:19:13.440 the feedback that I'm getting could be biased, but it does seem to have an effect. It obviously has an

01:19:18.720 effect in animal models. The animal models that we work with, we give exogenous ketones on top of a

01:19:25.640 standard rat chow, which is high carbohydrate chow. And it, uh, it works very well for, uh, CNS oxygen

01:19:32.200 toxicity, but also for things like phenyl and tetrazole, uh, seizures, uh, PZT seizures, even for

01:19:38.320 absence seizures. We use a particular animal model with absence seizures or absence seizures, which are,

01:19:44.520 it works for that. So it works for a variety of different seizure models independent. We are circumventing

01:19:50.760 sort of the dietary restriction that's typically associated with getting into therapeutic ketosis and

01:19:56.300 just simply giving exogenous ketones and elevating exogenous ketones. But a consideration is that

01:20:03.380 exogenous ketones lower blood glucose. So you have, and in some cases it lowers it really low, like the

01:20:10.360 high dose ketone esters that we do in our rat models, it pushes and rats typically maintain a glucose of

01:20:16.020 around 140 to 150 and it'll push it down to 40. So milligrams per deciliter. Yeah. And that's approaching

01:20:23.360 the maximum tolerable dose of the ketone ester. And it's interesting when we go above the maximum

01:20:29.740 tolerable dose, we actually see glucose levels spike up. And this is a phenomenon that we see. It's almost like

01:20:35.460 it's stressing out the liver, just regulating the liver in some way. It's the data we're trying to figure out.

01:20:40.320 But if you titrate in ketone salts or ketone salt MCT combination or various ketone esters, it's inversely

01:20:49.540 proportional to, as you elevate ketones, you have a very predictable, reliable decrease in blood glucose that's

01:20:58.300 above and beyond the decrease in blood glucose that you'd observe with something like metformin. And we use

01:21:04.380 metformin for many, many studies in the lab. I mean, we've, we've had a lot of experience with that.

01:21:09.340 What do we think? You know, it's funny. I was up in San Francisco like a month ago and

01:21:12.440 I was talking with Steve Finney who, you know, at the outset, I said, you're one of the people who

01:21:16.600 I would say knows more about ketosis than anyone alive. And certainly Steve would have to be in

01:21:21.200 that category. So I would, if I were going to just guess, I would say between you and Steve Finney,

01:21:26.480 if the answer isn't really known on ketosis, the answer might not be known.

01:21:31.080 Yeah. Yeah. Yeah. So, but, and Steve and I were having this really fun discussion with a few other

01:21:36.560 folks about why is it that the ketones are driving down the glucose levels and conversely, and maybe

01:21:43.560 this is a different question, of course, but why is it that when we do these experiments of you take

01:21:48.000 somebody in nutritional ketosis and you make them do really, really aggressive exercise, you know,

01:21:52.820 do a two minute all out effort on the rowing machine that the ketones go way down and the glucose

01:21:58.940 goes way up. Is it solely a consumption and hepatic glucose output issue? Is there something else going

01:22:05.480 on? You know, and, and I was like, well, I kind of always assumed that we knew the answer to that

01:22:10.800 and that it was the explanation I had, but you know, it wasn't at the end of that discussion. I was

01:22:14.880 like, actually, I pretty much now don't think I know the answer to this question. I don't think we do.

01:22:19.640 I have three potential explanations. One could be an exogenous ketone induced release in insulin

01:22:26.640 that facilitates glucose disposal. So we're, that happens. You do get, I mean, it's not like

01:22:32.920 consuming a protein bolus or a carbohydrate bolus, but you do get an elevation of ketones. That's

01:22:39.180 where, that's how we moderate our ketone levels, right? So as our ketone levels, if we're on the

01:22:43.460 ketogenic diet and our ketones become elevated, there's ketone urea. We pee out some ketones and

01:22:49.600 there's a number of products, but one is a ketone induced release of insulin, which then feeds back on the

01:22:56.220 liver to like a rheostat really and lowering beta oxidation, which totally makes sense. Cause that's

01:23:01.480 the reason that someone with type one diabetes can get ketoacidosis. They, they lose the checkpoint.

01:23:07.280 Yep. Yep. And other researchers, like if you ask Richard V, she'll tell you that insulin sensitivity

01:23:13.540 is increased. So the insulin that you have available and associated signaling is being enhanced in the

01:23:20.240 presence of ketones. So is that an immediate change or is that a change that takes place over a long

01:23:25.440 period of time? That, that sounds like a longstanding issue. I think there's a number of regulatory things

01:23:30.860 that happen. I know in his study where rats were fed standard rodent chow, but 30 to 20% ketone

01:23:38.220 ester, I think within that chow, their baseline insulin levels went down like 50%. So that's just

01:23:45.640 simply by, you know, just the addition of the ketone, just the addition of the ketone over time over,

01:23:52.140 I think it was like maybe a three week. I got to look to see the study, but it was, it was consuming

01:23:57.400 ketone ester that was integrated into the rat chow over a number of weeks, decreased baseline levels

01:24:04.720 of insulin significantly. I mean, it was like a huge effect and the implications of that, you know,

01:24:10.180 as a rat study, you know, you can argue rat study, but I can tell you experimentally that, or just,

01:24:15.820 you know, testing on myself that the same observation happens. I can actually, if I get a significant

01:24:21.080 amount of my calories from exogenous ketones and I do that over several weeks and I measure my insulin,

01:24:27.640 it gets below the reference range. Whereas if I get back to a regular ketogenic diet, I'm always on

01:24:35.100 the low end of the reference range. But I did find if I consume the maximum tolerable dose of a ketone

01:24:41.520 ester or a ketone salt, and then I measure insulin, you know, an hour or two after that, I do get a

01:24:47.540 little bump up in insulin, but it's nowhere near the bump I would get up if I ate an equivalent amount

01:24:52.980 of calories from protein or carbohydrates, which would shoot me up to like, you know, eight or 10

01:24:57.740 or something like that, you know, with a big dose. But it's usually somewhere around, I bump it up from

01:25:01.580 like 1.5 to like 2.5 or three or something like that. Wow. Those are still super low. Yeah. And that's

01:25:07.440 my baseline is usually between one and two. So how has your IGF level changed in the years that you've

01:25:13.320 been on ketosis? Have you tracked it much? I have not. I've gotten it measured a few times,

01:25:17.400 but not, not reliably. Like I do insulin quite often, like every, every two months or so,

01:25:23.740 like I'm doing that. And if I'm doing an experiment, I may do multiple measurements of

01:25:27.600 insulin like throughout the week, but I haven't measured IGF-1 recently. I did a while back and I

01:25:33.040 was just in the normal range, but I wasn't fasting. I didn't, that's the one variable I wish I would

01:25:38.120 have tried. Insulin was low, so I can assume IGF-1 might've been a little bit low. Yeah. So

01:25:42.940 just for listeners and stuff, how do we measure ketones? I mean, people talk about urine strips

01:25:47.340 versus blood. What are you measuring in each and breath for that matter? You've got three ways to

01:25:51.920 theoretically measure these things. Which one do we prefer and why? For a newbie getting into this,

01:25:56.860 I think the urine ketone strips will at least tell you if you're in ketosis or not in ketosis.

01:26:01.760 What is it measuring? A urine strip, you're peeing on it and what does it tell you?

01:26:05.060 Urine acetoacetate is measured. And now there's a urine beta-hydroxybutyrate kits that are available,

01:26:10.880 so you could do that. So the Abbott Labs Precision Extra and the Keto Mojo are two devices that will

01:26:19.100 measure basically an assay, a home assay kit for beta-hydroxybutyrate. And we have used both of

01:26:26.500 those things and kind of measured it against various assays in the lab and blood that we send

01:26:33.560 out for analysis. And it's pretty close, pretty close plus or minus maybe 10 or 15%.

01:26:38.820 What does the urinary level, even though it's a qualitative assay, but you know, everybody says,

01:26:43.900 hey, my urinary ketone thing lit up bright purple. Can we infer anything from that about the blood

01:26:50.880 level of BHB or acetoacetate? Usually, you know, unless you're running kind of dehydrated,

01:26:56.980 you know, if you have a normal hydration state and your urine acetoacetate is 40 milligrams per

01:27:03.100 deciliter or above, you're probably hitting one millimolar or above. If you're anywhere between

01:27:10.220 40 and 80 to, I think, 160 milligrams per deciliter. So you're in a state of ketosis.

01:27:16.520 If you're at 15, that's like light pink or something, you're usually probably not in a state,

01:27:23.100 what I would say, keto. That might be a normal state. If you wake up in the morning in sort of a

01:27:28.340 fasted state, you might be hitting that. But generally speaking, you need to be at about 80

01:27:32.220 milligrams per deciliter on the urine ketone strip. And the one thing I didn't do rather when I was

01:27:38.360 doing my sort of long foray into ketosis is I didn't use the urine meters at all. I was just,

01:27:44.000 you know, I was, I was keeping Abbott in business basically with how many of those precision extra

01:27:48.560 strips I was going through. So I don't know if my urinary excretion actually declined over time

01:27:55.920 when my body became better and better at retaining this potentially preferred fuel.

01:28:01.620 Have you done anything on that either personally or in the lab?

01:28:04.560 So what we use in the lab is the Clinitec status device. And that device takes the Siemens 10SG kit.

01:28:13.020 So the multi-stick. So you can buy for a similar cost as the keto stick, you could buy the Siemens

01:28:20.500 10SG multi-stick and that measures 10 things, including urine acetoacetate. And you could take

01:28:27.740 that urine strip and stick that in a device that will give you more of a quantified number.

01:28:33.340 I see. So that's how you were giving me quantitative information on the urine because I've only seen

01:28:38.180 the qualitative stuff.

01:28:39.740 Well, it's a color change on the strip that's measured in the device.

01:28:44.680 Yeah. So over the years I rejected urine ketone strips as something that just wasn't very accurate.

01:28:52.440 And the more I use them making hundreds, if not thousands of measurements, the more I gain an

01:28:57.260 appreciation that it can be a pretty useful device. But I think it's, it's kind of useful for the

01:29:04.260 individual. Your hydration status definitely changes it. I mean, I've been in situations where

01:29:09.040 I'm dehydrated, where I've come out of the water after like a six hour dive and I've peed on those

01:29:15.040 things. And it's like, it's like screaming. And I knew, I mean, I did some dives where I purposely

01:29:20.180 wasn't in ketosis for some of the research that we do. And I was deep into, into ketosis just because

01:29:26.440 I was, you know, very, very dehydrated.

01:29:28.660 I didn't know someone could dive for six hours.

01:29:30.740 I was on the NASA Nemo Extreme Environment Mission Operations trip. So I was a crew member on that where I

01:29:36.540 maintained, I lived in saturation for 10 days in a hyperbaric environment. And, uh, that, that involves

01:29:42.760 like an, uh, 18, 19 hour decompression to come out. So it's a NASA sort of a Mars analog mission

01:29:49.300 where you, where you work with astronauts underneath the sea. And I, I maintained a state of ketosis

01:29:55.200 throughout that whole mission and, uh, and did lots and lots of measurements on myself down there.

01:30:00.700 And I saw really, when I, one time I got out after maybe it was a six hour EVA. So essentially

01:30:07.240 you're in a hyperbaric habitat on the bottom of the ocean and then you go out into the water and

01:30:13.620 then you come back inside the hyperbaric habitat. But when you're out in the water, even though you're

01:30:18.120 down in the keys, the water, water pulls heat from you like 200 times faster than air. So even though

01:30:25.480 it's like, you know, upper eighties, I come out of that hypothermic and dehydrated, my blood glucose

01:30:31.720 always was in like the thirties, sometimes in the forties when I was on the key to, I was testing some

01:30:37.340 of the ketone supplements. Wow. Yeah. What were the other people experiencing under those circumstances?

01:30:42.940 Well, we'll find out with, uh, this, my wife actually is, uh, was selected as a crew member for

01:30:48.620 NASA NEMO 23. I was on 22 and I did not get the IRB protocol, uh, approved to do all the metabolic

01:30:57.400 studies that I wanted to do, but I became an end of one on that. And I collected a lot of data on

01:31:02.880 myself. So with this new mission, we have the NEMO, NASA NEMO 23, we'll be able to make some pretty

01:31:11.400 comprehensive metabolic measurements, including things like, uh, hemoglobin H1C. We're going to measure

01:31:17.240 inflammation, HSCRP, glucose, ketones, all these things on all the crew members. Interestingly this

01:31:24.060 year, it's a, it's an all female crew. So you have like Samantha Christopheretti, the famous, uh,

01:31:29.540 European Tracy Caldwell Dyson, who, uh, I've known at NASA and, and my wife and it's all female. So

01:31:36.520 we'll have, we'll have some female data to go along with this. What surprised you the most in your N of

01:31:41.680 one? What did you see that you least expected? I saw why predicted that the habitat would really

01:31:48.980 trigger inflammation that was probably from the elevated CO2 levels and the elevated oxidative

01:31:55.780 stress. I chose to stay in a state of ketosis with the idea that that was my baseline state. We're doing

01:32:02.720 studies on sleep. We're using the aura ring. You're probably familiar with that on sleep and also the

01:32:08.180 polar V800 to collect heart rate variability data, gut microbiome. We're doing body composition

01:32:14.480 measurements. We're doing, uh, stress. So we use the NIH toolbox and, and joggle to look at cognitive

01:32:22.420 psych parameters. So that data has not been shared to me. So I don't know my wife collected some of that

01:32:29.260 data and that's being analyzed, you know, later on for publication, but from a metabolic perspective and

01:32:34.940 from a hormone perspective, some of the things living in that environment for 10 days, decrease

01:32:40.080 my testosterone at a 25% decrease in testosterone from, uh, the time. And so we're fairly, maybe

01:32:48.020 fairly sleep deprived. I average about six hours of sleep per night, but I was getting like two and a

01:32:53.240 half hours of deep sleep, which is more deep sleep than I typically. Yeah. I was like, I don't know if

01:32:58.140 it's a, it might be an artifact of how the sleep is being estimated. In other words, you know, if you

01:33:04.300 think you're assuming you're giving that off the aura ring, right? Yeah, that was the aura ring. So

01:33:07.560 the aura ring is measuring, but I usually get about 90 minutes sometimes like last, last night I got

01:33:14.760 one hour and 53 minutes of deep sleep, but I usually get about one hour, one and a half hours of deep

01:33:19.380 sleep, but I got over two hours every night. And instead of seven hours sleep a night, I was getting

01:33:23.840 consistently just, you know, five to six hours sleep a night. So where were you getting mostly

01:33:28.380 shortchanged on REM? Yeah. On REM, but my REM was even not that bad. Usually I was getting about an

01:33:34.320 hour, you know, an hour REM, which is not as much as I'd like. Yeah, that's too low. Usually two is

01:33:39.980 optimal for me, I think. So yeah, we measured sleep. The things that really stood out were being in the

01:33:47.060 water really pushes my body into, and being hypothermic really turns me into a fat burning

01:33:53.540 machine. My ketones go off the chart and my glucose goes way down. It almost looks like

01:33:57.720 a six hour EVA. When I came back into the habitat, it looked like I fasted for a week.

01:34:02.820 So I have all that data for that too, that I need to compile and analyze.

01:34:06.800 Should we be looking at that? We meaning people as a potential way to replicate fast under a more

01:34:14.400 stressful state? Looking at what, just underwater? Yeah. Do you think it was a combination of

01:34:19.520 temperature and pressure primarily that was driving that effect? So over the holidays,

01:34:24.400 we went to Thailand and we did, I did a lot of nitrox dives, something like 30 nitrox dives. And

01:34:31.460 I made these measurements too. And I did see trends for decreased glucose and nitrox dives. We're doing

01:34:37.720 like an hour, maybe hour, hour and a half dives at the most. And I saw trends, but nothing like the

01:34:43.120 trends I saw in the saturation environment when we did these long EVAs.

01:34:47.100 So do you think that the temperature was the difference or the duration?

01:34:50.400 The temperature really has to have a difference because you come out and you're, you're kind of

01:34:55.200 shaky, you know, even though you feel very comfy when you're down there the first two or three hours.

01:34:59.980 And then by the end, the last, you know, four or five, six hours for a longer EVA, you start like

01:35:07.140 shaking a little bit uncontrollably, you know, but it's kind of subtle, even though the water's kind

01:35:11.800 of warm, like it feels warm, but it's just, you know, your body temperature is going down and they

01:35:17.240 were on the days, maybe I wasn't getting as much calories as I, as I needed. I came out of that

01:35:22.480 mission lighter than I've ever been before. I came out when we got back to mainland and I stepped on

01:35:29.380 the scale, I was 207, which is super low for me. I ended up losing about maybe I went in kind of

01:35:36.240 light cause I was training for it. I'm not a very good swimmer like you. I had to really train to

01:35:41.600 meet like you. It would be like a total day in the park for you to, to meet all the criteria for that.

01:35:46.500 But I had to train really hard to meet the swim requirements. So I ended up losing a little bit

01:35:51.840 of weight. But when I came out, I would definitely did the whole mission. I lost nine pounds and I

01:35:58.080 came out seven. So I went in two 16. So I went in pretty late. I'm like two 21 now. So, uh, last year

01:36:03.660 I entered the mission at two 16 and I came out like two 07, which was like, I thought the scale

01:36:09.740 was wrong. So even though I ate a lot of calories during that mission, your metabolic rate, my

01:36:14.960 metabolic rate was really high, you know, and that, that was a consequence of, that is so

01:36:19.900 interesting because it's, those are two completely contradictory concepts to me. On the one hand,

01:36:24.220 you're saying, Hey, my glucose levels went down. My ketone levels went up. It looked like I had fasted

01:36:29.940 for a week. Yep. But of course, if you fasted for a week, your metabolic rate would be

01:36:33.480 going down and not up. In fact, you would expect to see autophagy skyrocket. Whereas I'm sitting

01:36:40.140 here as I'm listening to you thinking, would autophagy have increased during that period of

01:36:43.980 time or decreased? I think anything that pushes glucose that low and ketones that high. And I think

01:36:51.180 not really without knowing it, we're pretty task loaded. So you don't have all the time, you know,

01:36:56.460 that much time to eat. I mean, part of the mission is that they're training. This is part of,

01:37:01.260 it's the only NASA analog where astronauts are actually part of the crew members, like other

01:37:05.780 things like high seas mission or NASA hero mission actually uses everyday folks and they push them to

01:37:11.480 the limits to see how they, they can break them. But the NASA NEMO mission is actually training

01:37:15.880 sort of astronauts. So they task load you to see what you're doing and you don't have a whole lot of

01:37:21.140 time to eat. But I was, I was consuming what my normal calories would be, but I was under,

01:37:26.620 I underestimated my calories for this. And I think it put me in a calorie deficit,

01:37:32.040 which probably decreased my testosterone may have, my cortisol level increased, but it was still

01:37:37.500 within the normal range and you're away from the light. So your circadian is probably a bit screwed

01:37:44.240 up to being in the industry. You're only at like 60 feet. So, uh, you do see some of the light come

01:37:50.860 down and, but, uh, but it's probably a little bit different than I'm a very light sort of sun

01:37:56.720 worshiper. Like I always try to get some light in the middle, you know, in the beginning of the day.

01:38:01.300 And that that's part of something that I always do. So it was a bit disruptive in that sense.

01:38:06.080 So let's talk about ketone, esters, salts, et cetera. So to your knowledge, what's the first

01:38:10.460 exogenous ketone that was ever manufactured? Is that Vitaly one or?

01:38:14.460 Exogenous ketone manufactured. So one, three butane dial has been around a long time since

01:38:20.680 the 1950s. Actually, MIT did some, uh, research as a space fuel. So that got, there was a publication

01:38:28.440 in 1975 where they were trying to identify an alternative energy fuel for long duration space

01:38:36.220 flight. And the best candidate was one, three butane dial, which is sort of a synthetic compound

01:38:43.360 that breaks down completely to beta hydroxybutyrate, meaning the liver is not required to transform it

01:38:49.380 into BHP. The liver is required. Yeah. Through a couple of simple steps. So sodium beta hydroxybutyrate

01:38:57.440 would be the first sort of ketone, exogenous ketone that was used clinically. And that there was a

01:39:03.140 number of papers that utilize that for rare metabolic disorders actually. So that would be the first one.

01:39:09.240 And a lot of the IP and sort of patents that came out were sodium beta hydroxybutyrate.

01:39:15.980 And then maybe explain for people what the difference is between a salt and an ester. So

01:39:20.420 we'll leave acetoacetate out of that for a moment. Yeah. But if you talk about beta hydroxybutyrate,

01:39:25.220 but you can have acetoacetate salt too. So I can mention that. So I didn't know that. I thought it

01:39:29.080 was only a diester. So that's, we'll definitely want to hear about that. So on the BHP front, people are

01:39:34.160 sort of inundated with ketone salts, ketone esters, and then a whole bunch of complete like weird stuff

01:39:39.480 like raspberry ketones and stuff. But yeah, let's just leave the nonsense off the table. Yeah. But

01:39:44.000 if you just talk about comparing a ketone, a BHP ester to a BHP salt, what's the chemical difference?

01:39:48.880 Yeah. So a salt is just an ionic bond, right? Between the ketone molecule, beta hydroxybutyrate,

01:39:55.900 a monovalent or a divalent cation or an alkaline amino acid like arginine, citrulline, histidine,

01:40:03.300 lysine. So you can literally ionically bond beta hydroxybutyrate to a number of different things.

01:40:09.360 The easiest thing to do is to bond it with sodium, potassium, calcium, and magnesium.

01:40:16.040 Now, calcium and magnesium have two positive charges.

01:40:18.920 You could put two BHPs on them. That's the advantage, sort of an advantage. A disadvantage,

01:40:25.100 I guess, with magnesium BHP, which is actually is very bioavailable magnesium. I measured my

01:40:31.400 magnesium after taking it. It went up quite, quite high. Disadvantage is that your GI tolerability

01:40:37.320 to something like magnesium beta hydroxybutyrate may be only somewhere between one to three grams,

01:40:44.420 you know, three grams max per dose.

01:40:47.080 Wow. Which is not that much.

01:40:48.780 One gram, three times a day, at least for me, has no issues. I could probably tolerate two or

01:40:55.620 three grams per day. So it's nice. I mean, it's something that's contributing, but ideally what you

01:41:00.380 want to do with a ketone salt is, because salt has a stigma, I call them ketone electrolyte

01:41:05.460 formulations, is to spread the beta hydroxybutyrate out across monovalent and divalent cations. And

01:41:12.980 they're the four that have the most utility.

01:41:15.940 And then an ester, of course, is a covalent bond, not an ionic bond, right?

01:41:20.000 Yeah. So you can take one, three butane diol and you could create a monoester with beta hydroxybutyrate,

01:41:28.500 right? And just add it, do a trans esterification reaction and combine that beta hydroxybutyrate to

01:41:34.860 one, three butane diol or acetoacetate. You can combine with one, three butane, or you could take

01:41:40.320 glycerol. So with glycerol, you can come up with a triester of glycerol, which we have.

01:41:46.200 Basically, you're creating a triglyceride that is, instead of three fatty acids, you put three

01:41:50.460 BHBs.

01:41:51.200 It's a pretty cool molecule, yeah. So we have some experience using that.

01:41:55.700 You know, I told a story like many, many years ago, probably four or five years ago on Tim

01:41:59.440 Ferris's podcast about how I drank this jet fuel and almost thought I was going to go blind.

01:42:04.500 Of course, what I may or may not have omitted from that story was that you gave it to me.

01:42:10.000 And so the ketones today taste a heck of a lot better than that earlier gen stuff.

01:42:14.940 And I, even when I told you that I just took the 50 ml vial you sent and chugged it in one

01:42:19.900 sitting, even you were sort of horrified. You're like, wait, wait, wait, you didn't read the note

01:42:24.460 I wrote you explaining how to dilute it and mix it.

01:42:27.160 I thought we had talked about it.

01:42:28.300 We had assuredly talked about it.

01:42:30.740 I know you're very, you're very enthusiastic about getting started.

01:42:33.300 Yeah, yeah. I couldn't resist.

01:42:35.080 I was too.

01:42:35.820 That stuff's unbearably bad.

01:42:38.020 Yeah.

01:42:38.320 So what, I mean, whereas the ketone salts actually don't taste bad.

01:42:41.840 They're obviously strong, but they're awesome.

01:42:44.080 Yeah, yeah.

01:42:44.580 So why does the ester, is there an obvious reason from an olfactory slash taste perspective

01:42:50.320 why they are so staggeringly horrible?

01:42:53.760 Yeah.

01:42:54.380 Or at least they were.

01:42:55.380 And I mean, I'm told they're better today.

01:42:57.160 Yeah.

01:42:57.500 I would say the ketogenic potency is inversely proportional to taste.

01:43:03.200 So it just seems like, you know, the more, the more potent these compounds get, even the,

01:43:08.660 the triester of beta hydroxybutyrate, uh, you know, is pretty nasty stuff.

01:43:14.220 Meaning that glycerol triglycerol.

01:43:16.200 That.

01:43:16.480 Yeah.

01:43:16.940 It's a great molecule.

01:43:18.300 I mean, it has like lots of, you know, tremendous utility.

01:43:21.240 Well, making a ketone ester with one, three butane diol is really cool because the one,

01:43:26.120 three butane diol itself gets more substrate broken down.

01:43:28.900 Yeah.

01:43:29.580 So that goes into another question, the whole anantomer.

01:43:32.300 So if you use the R beta hydroxybutyrate with the R one, three butane diol, then you can really

01:43:37.840 get ketone levels up pretty high.

01:43:39.760 And that would be sort of the Delta G or the human, you know, ketone ester that's out there.

01:43:45.320 It's the R anantomer.

01:43:46.620 Uh, that would be the R.

01:43:48.060 Yeah.

01:43:48.280 The R it's R.

01:43:49.780 So you have, you can get racemic one, three butane diol, but that's the R anantomer of

01:43:55.120 one, three butane diol with the R beta hydroxybutyrate.

01:43:58.340 Can we explain to everybody what a R versus L means in the, in the anantomer world?

01:44:03.320 So beta hydroxybutyrate, not acetoacetate, but beta hydroxybutyrate has a stereoisomer.

01:44:09.760 So if you put your hands together, the R beta hydroxybutyrate, or let's do D and L let's

01:44:15.420 do that.

01:44:15.880 So the D would be equivalent to the R beta hydroxybutyrate would be the mirror image of

01:44:21.920 the L beta hydroxybutyrate and the predominant form of beta hydroxybutyrate in the body is

01:44:29.160 D beta hydroxybutyrate.

01:44:31.320 We do have a racemase enzyme that in various tissues that can convert the D to the L.

01:44:37.620 So, but when you're in nutritional ketosis or starvation ketosis, ketosis, you are making

01:44:42.020 D anantomer of the BHB.

01:44:45.500 Predominantly.

01:44:46.180 Yeah.

01:44:46.580 So we do have the capacity to make the L, but it's, it's pretty, pretty minimal.

01:44:50.640 So that brings up the question.

01:44:53.000 I think 99% of all the ketone salts being sold right now are racemic.

01:44:58.360 So they are the D and the L when you give equal, yeah, yeah, they're equal amount and there

01:45:05.880 may be a concern there, but we don't know.

01:45:08.900 So most of my research has actually been with the racemic compounds and they work great

01:45:13.100 therapeutically.

01:45:14.300 In pharmacology, there's a sordid history of getting the enantomer wrong.

01:45:17.720 I mean, one of the, one of the most famous stories I know of is fen-fen.

01:45:21.800 Yeah.

01:45:22.000 Oh, fen-fen as well.

01:45:22.920 Yeah.

01:45:23.580 So, so that's right.

01:45:24.780 Felidomide and fen-fen were both examples of using the wrong enantomer.

01:45:28.780 Many pharmaceuticals, like I think ibuprofen and I know like ephedrine, you know, is, is

01:45:33.920 racemic and many of the drugs out there.

01:45:36.760 So, and things like ringer's lactate, I think, you know, lactate is, is it D now?

01:45:42.420 It used to be racemic.

01:45:43.600 Oh really?

01:45:44.060 I think, yeah.

01:45:44.680 I think you can get both.

01:45:46.140 Okay.

01:45:46.420 So you're saying, look, physiologically exist at 90-10, D to L, and then you're buying something

01:45:53.020 racemic.

01:45:53.740 You at least have to entertain the question, hey, am I ingesting something that might have

01:45:59.580 a negative side effect?

01:46:00.580 Yeah.

01:46:00.960 And so the ketone esters, they're, they're mirroring the physiology or they're just going

01:46:04.660 mostly D presumably.

01:46:06.080 Well, the human ketone ester, from my understanding, is completely D. So it's produced a D beta

01:46:10.760 hydroxybutyrate.

01:46:11.660 Interestingly, elevating just beta hydroxybutyrate in our seizure models, even with the D does

01:46:18.060 not have an anti-seizure effect.

01:46:19.800 So that's actually why we went to the 1,3-butane diol.

01:46:24.520 Sorry, say that again.

01:46:25.600 Yeah.

01:46:25.760 Would you say that if you use a pure D salt?

01:46:28.500 A D salt or D ester.

01:46:30.540 Pure D salt or pure D ester.

01:46:32.440 No anti-seizure benefit.

01:46:33.720 No anti-seizure effect with beta hydroxybutyrate.

01:46:35.800 We needed, and the animal models even suggest this if you just look even studies beyond our

01:46:41.040 study, is that you need to elevate acetoacetate has the anti-seizure effect.

01:46:46.420 And we don't know exactly why that happens.

01:46:50.100 The ketone ester that we work with, which is 1,3-butane diol, acetoacetate diester, elevates

01:46:55.400 beta hydroxybutyrate and acetoacetate in approximately a one-to-one ratio.

01:46:59.300 Is that what you used to give me?

01:47:00.780 Or was I just getting...

01:47:01.800 I gave you a bunch of things.

01:47:03.640 What was the one in the capsule that tasted even worse than the BHB ester?

01:47:09.700 Actually, yeah, that was the diester of acetoacetate.

01:47:13.440 Yeah.

01:47:13.840 And that's really potent.

01:47:15.080 And it was bound to what?

01:47:16.760 1,3-butane diol.

01:47:18.540 Yep.

01:47:18.880 That shit was from another planet of bad.

01:47:22.020 I still have some because...

01:47:24.240 I've done shots of that.

01:47:25.640 I like to just give it to people.

01:47:26.640 I put many gallons of that through me and done quite a bit of blood work and know pretty

01:47:31.920 reliably, at least in my body, that it's not toxic.

01:47:35.140 And pretty much all the biomarkers go in a remarkably positive direction.

01:47:40.660 But even though I know that, it's not enough for me to...

01:47:44.300 To consume it.

01:47:44.760 Even though it has that.

01:47:45.760 And that's...

01:47:46.380 No matter how great a substance can be, if it doesn't taste good, even me, I'm not going

01:47:51.640 to take it.

01:47:52.520 Even in a capsule.

01:47:53.500 I just think it's an aftertaste.

01:47:54.640 Exactly.

01:47:55.140 Well, I also remember you telling me...

01:47:57.440 Because you sent them and I was like, oh, sweet.

01:47:59.200 It'll be capsules.

01:47:59.980 Because I had seen your animal data and I was like, I want that.

01:48:03.220 And then you said, okay, well, I'll send it to you in capsules because you can't drink

01:48:05.900 it.

01:48:06.060 It's too bad.

01:48:06.760 And I was like, perfect situation resolved.

01:48:08.760 And you said, no, not entirely.

01:48:10.180 Yeah.

01:48:10.700 You'll still taste it through the capsule.

01:48:12.600 Yeah.

01:48:13.080 And I actually find it to be a great dinner party trick.

01:48:16.120 Like, who's the biggest tough guy here that just wants to show me how much of this stuff

01:48:21.500 they can ingest?

01:48:22.400 Yeah.

01:48:23.520 Yeah.

01:48:23.960 I mean, we've done a lot of work with that, Esther, and it has remarkable effects, but

01:48:29.160 we think it's probably more suited for like a medical food and something that could be

01:48:35.320 sort of a parenteral, you know, IV therapy capsule.

01:48:38.460 So who first synthesized that?

01:48:39.980 So I reached out to Henri Bruningrabber at Case Western, who was the director of the

01:48:48.040 metabolomics.

01:48:49.200 NIH funded, I think, metabolomics core at Case Western.

01:48:52.300 And I reached out to everybody, but I, who, who had any experience, you know, either researching

01:48:59.240 with ketone esters or synthesizing them.

01:49:01.680 And he kindly gave me the recipe on how to synthesize it.

01:49:06.160 That was above and beyond the patent.

01:49:07.760 It was actually a detailed recipe on how to use a Kugel Road distillation apparatus, where

01:49:13.520 to get the vacuum pressure.

01:49:14.740 You didn't already know how to do that?

01:49:16.640 I knew it was short past it.

01:49:18.080 I'm teasing.

01:49:18.300 So like, well, actually, so Patrick Arnold, as you know, kind of helped me with the art.

01:49:24.900 So an organic chemistry really is an art, you know, to be able to do this.

01:49:28.520 And Patrick is an artist.

01:49:30.100 Patrick is, is an artist.

01:49:31.480 And he was, he thought this was like shady stuff in the beginning.

01:49:34.260 And I kept sending him papers and, and then he realized that this could be something big.

01:49:39.200 You know, uh, he realized that the science was there and there was a lot of big players

01:49:43.680 in this field who had done remarkable research, but just didn't really have what it took to

01:49:49.020 like actually make it a product, like synthesize it in the stuff that you would actually consume.

01:49:54.120 I became obsessed with Patrick after all of this stuff happened and, um, actually introduced

01:49:59.660 him to Tim and in the show notes to this, I'll make sure that we link to Tim's podcast

01:50:05.600 with Patrick, um, which I'd love to have Patrick on the show at some point too, to, to talk

01:50:10.460 about this should, should this show end up persisting.

01:50:12.840 But that episode with Tim and Patrick is so interesting.

01:50:17.600 It's like, if you have any interest in endocrinology in sort of like how the hormones work, how steroids

01:50:24.400 work, it's yeah.

01:50:26.100 Yeah.

01:50:26.260 It's just what a character.

01:50:27.360 I owe a lot to Patrick.

01:50:28.560 I don't think I probably wouldn't have gotten tenure without, I owe so much to him.

01:50:33.320 So I need to acknowledge him for that, that there were academic icons out there who could

01:50:40.380 not do what, what Patrick did for me.

01:50:42.580 And he was pretty persistent in doing it too.

01:50:44.940 So he synthesized first the monoester and then it was a mixed of monoester and diester,

01:50:50.700 but he nailed it down to, you know, ultimately getting the art of the organic chemistry to

01:50:57.020 where it's pretty much pure diester.

01:50:58.920 He's such a, he's such a wonderful human being.

01:51:01.080 Anytime I email Patrick a question, which invariably I do have like clinically, I'll have a question

01:51:06.200 about a hormone or they'll be like, there's no textbook that knows the answer.

01:51:09.380 There's no paper that knows the answer.

01:51:10.760 I'm like, Patrick, I got a crazy question for you.

01:51:13.920 And it's like, even if he doesn't know the answer, I mean, he'll have a more thoughtful

01:51:17.420 insight than you can get anywhere.

01:51:19.920 And it's, yeah, it speaks to his, his capabilities.

01:51:22.340 So first of all, you've shared with me something I didn't actually know today.

01:51:25.280 That's really interesting, which is this notion that if you are purely using the D and

01:51:29.900 antimer, you do not get any of the anti-seizure benefits.

01:51:32.800 Whereas if you're at 90, 10, presumably you're getting them.

01:51:35.520 So you don't need a lot of the L, but you need some of the L.

01:51:37.940 Yeah, I don't think there's any studies that show using an exogenous ketone in the form

01:51:43.160 of pure beta-hydroxybutyrate is beneficial.

01:51:46.900 So what we do know is that when you deliver exogenous ketones in a beta-hydroxybutyrate

01:51:53.020 to acetoacetate ratio of one to one, that that has pretty remarkable anti-seizure effects.

01:51:59.680 And there was some studies that were done with acetoacetate and also some studies that were

01:52:04.160 done with acetone showing anti-seizure effects.

01:52:07.400 So I do think it's, acetoacetate is necessary.

01:52:11.880 So what we don't know, I don't think that racemic salts or racemic esters or esters that produce

01:52:22.960 both D and L beta-hydroxybutyrate are a concern.

01:52:27.440 I have not seen data to suggest that these would be a health concern.

01:52:32.940 There are companies out there that are selling 8 million sort of doses per month of salts that

01:52:38.860 are racemic in nature.

01:52:40.960 And there have been sort of no consequences from that that have been reported.

01:52:44.900 So how are so many companies able to do this?

01:52:46.540 Is there no IP in the salt world anymore?

01:52:49.100 I don't think there is IP for the key.

01:52:51.980 I think some of the early patents may expire.

01:52:54.780 So I don't think there's actually, there's some intellectual property with formulations

01:52:59.260 of a ketone salt and a ketogenic fat and MCT.

01:53:03.900 And that's some of the stuff that my university has.

01:53:06.220 And there's some composition matter patents and maybe some use patents around the D salts,

01:53:10.740 I think, and maybe the D ketone esters.

01:53:13.740 So at this point in time, do you think that the ketone salts have more physiologic benefit

01:53:19.000 than the ketone esters just as a function of having a higher amount of the L enantomer?

01:53:25.740 So I think when it comes to purely a metabolic fuel, I think the D beta-hydroxybutyrate has

01:53:31.480 some advantages, right?

01:53:33.240 So we also know that in regards to some of the signaling effects, especially the inflammation,

01:53:41.100 the NLRP3 inflammasome is suppressed by beta-hydroxybutyrate, both the D and the L form.

01:53:48.620 And we know that when we consume racemic ketone salts in the D and L form, the L form tends

01:53:55.540 to stick around longer and gets metabolized slower.

01:53:59.060 So conceivably, that could be having a stronger anti-inflammatory effect because you have a ketone

01:54:06.100 body and endogenous metabolite that's functioning as a very powerful signaling molecule that's

01:54:12.860 suppressing an inflammatory pathway.

01:54:15.820 So the concentration just tends to get higher.

01:54:18.760 You know, that's my view of it.

01:54:20.540 So we haven't really studied that in detail, but the lab that did some of the work on showing

01:54:26.920 the nature medicine paper that showed the NLRP3 inflammasome was suppressed by beta-hydroxybutyrate,

01:54:34.000 it occurred both in the D and the L form.

01:54:36.540 We do know that the L form gets metabolized slower.

01:54:39.200 So the concentrations in the tissue may actually reach higher levels.

01:54:44.260 So what we have observed is that the racemic beta-hydroxybutyrate has a glucose lowering

01:54:50.300 effect.

01:54:51.080 So we're trying to figure out, and that's a pretty big effect.

01:54:55.580 But we also see that in the pure D enantomer.

01:54:58.320 Yep.

01:54:58.440 But I've seen that with the human product, which is obviously a pure D-BHB.

01:55:03.400 I think they're seeing about a 20% to 30% reduction in glucose.

01:55:06.360 Do you see more in the racemic?

01:55:08.240 It tends to be the case.

01:55:09.920 Yeah.

01:55:10.180 It tends to be the case, especially with 1,3-butanediol.

01:55:12.700 You see it.

01:55:14.180 And maybe it's a redox shift in the liver.

01:55:16.940 That's what Henri Brunengrabber thought.

01:55:19.340 But it's pretty remarkable.

01:55:20.420 And when we compare, so I have some products in my bag I'll give you.

01:55:24.840 I've been doing a lot of work with D-salts.

01:55:27.580 So I've been consuming D-salts in pretty high levels that bring my ketone levels up

01:55:32.520 pretty close to an ester.

01:55:34.240 So you can formulate sort of a D-salts.

01:55:36.320 Which in you is how high?

01:55:38.340 If the elevation of my ketones gets more than 3 millimolar, I just start feeling a little

01:55:43.220 bit weird.

01:55:44.580 Which is interesting because you've experienced naturally occurring ketones at much higher

01:55:48.900 than that level.

01:55:49.740 Yeah.

01:55:50.320 But I don't.

01:55:50.960 Actually, I'm a pretty good ketone burner.

01:55:52.640 So you could do a glucose tolerance test.

01:55:56.080 I do a ketone tolerance test.

01:55:58.020 A ketone tolerance test is consuming a known amount of ketones and looking at that pharmacokinetic

01:56:02.420 curve.

01:56:03.740 So you measure.

01:56:05.240 So you'll do fasting level of BHP, glucose, insulin, fatty acid, ingest your ketone, and

01:56:11.060 then measure it 30, 60, 90, 120 minutes.

01:56:14.300 And athletes have, when you challenge them with a ketone tolerance test, I'm creating like

01:56:19.480 a new test here, they actually dispose of ketones and utilize it remarkably effective.

01:56:26.040 When you take a couch potato, and it's the same as the couch potato rats, you could push

01:56:30.720 a couch potato rat into ketoacidosis if they're older.

01:56:35.060 Their tissues are not effectively utilizing the ketones for fuel.

01:56:38.360 And I've seen that in some individuals and some people, I get hundreds of emails and people

01:56:43.340 will show me their data.

01:56:44.920 And one packet of even a commercial ketone product on the market can shoot some people

01:56:49.440 up to like five or six, which is like that.

01:56:51.640 And just to be clear, in that ketone tolerance test, which by the way, I freaking love this

01:56:56.680 idea.

01:56:57.240 How have you not told me that until today?

01:56:59.580 Holding out on your best stuff.

01:57:01.220 It's just materialized in my brain.

01:57:02.840 What am I going to call it?

01:57:03.780 You know?

01:57:03.920 I don't know, but next time you get one of these ideas, just pick up the phone, you know

01:57:07.500 my number, you call me and you tell me this stuff.

01:57:09.380 This is your, it's like you're holding out on me.

01:57:11.520 I'm not just kidding.

01:57:12.100 I want to make sure I understand something.

01:57:13.240 Is this independent of whether or not that athlete was in ketosis before or after?

01:57:16.760 In other words, how much of that utilization is a function of the metabolic machinery in

01:57:20.820 the muscle to utilize ketone versus, hey, athletes are just better at oxidation to begin

01:57:28.420 with?

01:57:28.740 So fat adapted athletes are very good ketone utilizers and have a hard time elevating their

01:57:34.880 ketone levels with a ketogenic diet.

01:57:36.760 So if you take a high carb athlete who's still fit as a fiddle and you do this test, how do

01:57:43.060 they behave?

01:57:43.600 Not as well.

01:57:44.620 And I do think that high performing athletes probably are bouncing in and out of ketosis,

01:57:50.420 right?

01:57:50.660 You have post-exercise ketosis just from the energy depletion that you get during exercise.

01:57:56.000 So their bodies are probably used to seeing ketones, using them as fuel.

01:58:00.920 But if you take someone who's a real keto adapted fat burning like ketone machine and

01:58:06.780 you hit them with high doses of ketones, they tend to dispose of them very, very quickly.

01:58:11.240 So they've upregulated ketone transport across membranes, across the blood brain barrier through

01:58:17.160 the MCT transporters, which are upregulated.

01:58:19.760 And this of course is not the same MCT that we talked about earlier.

01:58:22.940 No, these are monocarboxylic acid transporters that also transport things like lactate and

01:58:27.640 pyruvate.

01:58:28.340 And because the MCT transporters are much higher and more dense in the membrane, you could probably

01:58:34.500 clear lactate faster.

01:58:35.940 So I think that may contribute in part to why keto adapted athletes produce less lactate.

01:58:42.280 It's funny you say that.

01:58:43.100 I hadn't thought of that actually.

01:58:44.740 I didn't realize that in ketosis you upregulate MCT.

01:58:47.480 I've always suspected that that might play a role in the genetic differences between athletes.

01:58:52.560 Why do some athletes seem virtually unparalyzed by anaerobic activity?

01:58:59.540 And it's like, look, if you can shut a lactate out of the cell quick enough, you can recycle

01:59:04.380 it and reuse it.

01:59:06.180 We actually tried to get an IRB of an N of one, a guy named Ryan Flaherty, who I don't

01:59:10.860 know if you know Ryan.

01:59:11.720 Yeah, I know the name.

01:59:13.080 You'll know of him, yeah.

01:59:14.020 So Ryan and I and a couple of other guys tried to get an N of one IRB at UCSD to do

01:59:19.260 muscle biopsies on ourselves pre and post a certain type of nutrition exercise routine

01:59:26.140 we wanted to implement that Ryan has sort of pioneered with a number of endurance athletes.

01:59:31.920 And that was one of our endpoints was, could we see an upregulation of MCT?

01:59:37.240 Because the hypothesis was the certain type of training stress was going to lead to that,

01:59:41.640 which would obviously increase our performance at a certain level of output.

01:59:45.460 But super interesting to think about that through the level of the ketone potentially

01:59:49.300 enhancing that signaling.

01:59:51.020 Yeah, it is a lot of things to think about there.

01:59:53.320 So I'm going to caveat my next question with a really serious caveat, but it's also a very

01:59:57.800 serious question.

01:59:58.520 And I was sort of on the fence about whether I'd ask you this or not, but I, I'm going

02:00:02.080 to say, screw it.

02:00:02.760 I'm going to ask you anyway.

02:00:04.060 I'm going to caveat this by giving the disclaimer, which is you're a PhD scientist.

02:00:08.420 You do basic research.

02:00:10.380 You are not an MD.

02:00:11.680 You are not an oncologist and nothing you say is going to be construed as medical advice.

02:00:15.920 So with that said, I still have to ask you a question, which is if tomorrow you, your

02:00:22.080 wife, someone you cared about deeply was diagnosed with cancer and it was a cancer for which all

02:00:26.960 standard therapies had been exhausted.

02:00:28.800 And you were now left to the best insights you have with respect to your knowledge of

02:00:36.340 cancer metabolism.

02:00:37.860 Tell me what pulling out all the stops looks like.

02:00:40.760 And again, what I'm, this is in the context of you've taken and you are complying with

02:00:44.840 all chemotherapeutic radiation therapy, hormonal therapy, surgical therapy, et cetera, but you're

02:00:50.600 losing, right?

02:00:51.660 So something else needs to be done.

02:00:53.100 What, what is that combination of that something look like?

02:00:55.440 So I guess, I mean, when we think about the worst cancer, worst case scenario, who'd have

02:01:00.680 pancreatic is pretty bad, but probably glioblastoma would top the list of things, right?

02:01:06.940 And would your answer be different if I was asking you about pancreatic adenocarcinoma versus

02:01:11.040 GBM?

02:01:11.860 I think, you know, it would be, there's things like with pancreatic cancer can make it hard

02:01:16.720 for someone to follow the ketogenic diet, right?

02:01:19.840 Cause, and, and liver cancer and things like that.

02:01:22.120 So they need to approach it a little bit different and you can have a lot of unexpected consequences,

02:01:27.200 metabolic consequences by someone with liver cancer.

02:01:30.040 If they have heavy liver mets or brain cancers, let's talk about GBM and metastatic breast

02:01:36.180 cancer.

02:01:37.020 Okay.

02:01:37.540 Okay.

02:01:37.900 So start with GBM, your loved one or you have GBM.

02:01:41.380 Yeah.

02:01:41.780 I would say it would be useful, not necessarily, you know, absolutely necessary to ask for an

02:01:48.160 FDG PET scan, do a PET CT.

02:01:50.720 And especially, I mean, with GBM, it's going to light up like there's no tomorrow.

02:01:54.220 Right.

02:01:54.280 So just for the listener.

02:01:55.420 So FDG PET means you take glucose, you label glucose with a molecule.

02:02:01.060 Yeah.

02:02:01.420 And then when you do the PET scan shows by lighting up anything that absorbs that and

02:02:07.160 the most rapidly metabolizing tissues of glucose light that up, which is almost always any cancer.

02:02:12.520 And then a brain normally lights up.

02:02:14.840 So a brain with cancer takes that to another level.

02:02:17.100 Yeah.

02:02:17.480 So you're doing that to document that this is a high glycolytic tumor.

02:02:21.320 Yeah.

02:02:21.780 Okay.

02:02:22.120 So even now there's a lot of experimental things going on for GBM, but pretty much the standard

02:02:26.960 of care is not offering any survival advantage when it comes to this.

02:02:31.180 So we did.

02:02:32.220 GBM is uniformly fatal.

02:02:33.860 I believe the five, the five year survival is almost zero.

02:02:37.420 Yeah.

02:02:38.060 Yep.

02:02:38.420 And the mutation rate in GBM is, they're very, very heterogeneous in regards to the number

02:02:46.780 of mutations.

02:02:47.320 So many of the standard of care therapies that target specific pathways just are not efficacious

02:02:53.480 because you have grossly mutated cells throughout the tumor.

02:02:58.540 So I'd probably, my answer would default back to this press pulse idea that we published

02:03:06.280 in Nutrition and Metabolism.

02:03:08.300 Is that the one in 2017?

02:03:10.800 Uh, no, actually.

02:03:13.080 So the, the 2017 paper was in seminars in cancer.

02:03:16.980 And that was with oncologists at the Moffitt Cancer Center, where we discuss how the ketogenic

02:03:23.040 diet essentially targets the Warburg effect.

02:03:26.340 And in doing so really targets all the hallmarks of cancer.

02:03:31.180 So any cancer biologist, you know, is writing a review on paper.

02:03:34.680 Like, you know, you talk about the hallmarks of cancer.

02:03:36.880 There's enhanced proliferation, evasion of immune system, angiogenesis, all these different

02:03:43.320 things, evasion of apoptosis, the ketogenic diet, nutritional ketosis actually targets all

02:03:49.680 those things and even the aberrant metabolism and the increase in inflammation that's, you

02:03:54.740 know, is now a hallmark of cancer.

02:03:56.900 So from the press pulse, the, the simplest way to describe it, at least its implementation,

02:04:02.600 which I think is probably most important for the listeners is to achieve a glucose ketone

02:04:07.420 index.

02:04:08.040 So press essentially means you were providing metabolic stress to the cancer cells that can

02:04:15.660 stop their rapid growth and proliferation.

02:04:17.880 It's like taking the, your foot off the gas pedal of cancer cell growth.

02:04:22.100 And there's a number of things that we could do to slow down cancer growth and proliferation

02:04:27.420 and metabolically stress those cancer cells.

02:04:30.860 And that can be done continuously.

02:04:32.840 And pulse protocols, you have a wide expanding toolbox of modalities that can be used in an

02:04:41.280 intermittent fashion that can be sort of tactically used at different time points to kill off the

02:04:49.540 cancer cells that you have applied the press stress to.

02:04:53.580 So press protocols, which are done continuously would be something like a calorie restricted ketogenic

02:05:01.240 diet, perhaps with intermittent fasting, perhaps a low dose metformin.

02:05:07.260 And what was the ketone to glucose ratio that you want to see?

02:05:11.340 I would want to see anywhere between a maintenance of one to two.

02:05:15.580 Meaning that's the glucose to ketone ratio.

02:05:18.500 A daily maintenance of one to two.

02:05:19.800 Yeah.

02:05:20.120 So, so glucose should never be more than twice the ketone level when both are measured in millimolar.

02:05:25.480 Yeah.

02:05:26.120 Ideally in a perfect scenario, three millimolar ketones, three millimolar glucose.

02:05:30.580 So that's kind of hard to achieve, but not, not with a number of tools.

02:05:35.140 So there's a number of tools that you can use to achieve that.

02:05:38.220 And that needs to, and there are things that we could talk about too.

02:05:41.520 So the fastest way to get to a glucose ketone index of, and maintain that of one to two would

02:05:49.140 be what I would call supplemented ketogenic intermittent fasting, right?

02:05:54.100 So, uh, when you eat within a restricted time window, say of like six hours a day, you start

02:05:59.100 eating at, you know, 2 PM and finish at 8 PM seems relatively easy to do.

02:06:05.000 And within that fasting window, if needed, you could consume calories in the form of perhaps

02:06:12.940 exogenous ketones.

02:06:13.920 And that would further lower glucose and elevate ketone levels, like within a range.

02:06:19.420 And they are commercially available ketone products on the market.

02:06:23.820 Millions are being consumed and there's no kind of adverse effects.

02:06:28.100 You know, when you compare it to something like a Red Bull, which you'll find lots of

02:06:31.400 adverse effects.

02:06:32.060 So there's fairly good safety data, but this needs to be said.

02:06:35.220 But the difference is Red Bull sponsors a formula one team.

02:06:37.820 So it's, it's gotta be better.

02:06:39.020 So these things are relatively safe and their utility are that, you know, they can help you

02:06:43.940 achieve a glucose ketone index.

02:06:46.520 And when you do have a glucose ketone index of one to two, you are limiting fermentable

02:06:53.180 fuels to the cancer cells and also most likely suppressing the hormone insulin tremendously to

02:06:59.880 get there.

02:07:00.360 And, and because I'm sure you'll be asked, or I'll be asked, is the reason you are applying

02:07:04.820 an intermittent or time restricted feeding algorithm to this because during the fasted

02:07:10.180 time you increase ketogenesis or because there was something specific about having complete

02:07:15.580 liver and gut rest?

02:07:16.640 In other words, is there a reason that an individual should or should not consume exogenous ketones

02:07:22.280 and or MCT during the fasting window?

02:07:24.860 Yeah.

02:07:25.420 I think if it's difficult for them to achieve a glucose ketone index of one to two, one of the

02:07:31.420 tools in the toolbox could be to consume exogenous ketones during that fasting period.

02:07:36.920 I think it can be helped.

02:07:38.000 And you can also consume them during the feeding period too.

02:07:41.640 And they provide an extra source of calories.

02:07:43.620 That's a non-fermentable fuel.

02:07:45.860 And I think have a benefit in and of itself.

02:07:49.180 You could just talk about the anti-inflammatory benefits.

02:07:51.780 You know, I think there's a number of different benefits.

02:07:54.840 So that press protocol is pretty aggressive.

02:07:57.520 Yeah, and it could also include things like meditation and yoga.

02:08:02.000 I mean, and exercise, of course, low intensity exercise, I think.

02:08:06.080 But the most important thing from my perspective of the press, so we're just talking about the

02:08:11.520 press, is to get that glucose ketone index to one to two.

02:08:15.080 A two to one or better, or one to two to better.

02:08:16.660 Yeah, yeah, one to two or better.

02:08:17.960 And then once that is achieved or concurrently, so you could think about different modalities

02:08:24.100 for the pulse protocol.

02:08:26.600 So changing your metabolic physiology with what we just described will have a huge effect

02:08:34.120 on targeting the Warburg effect and also will be already targeting all the hallmarks of cancer.

02:08:39.500 So you have a different person.

02:08:41.940 You have just changed that person's metabolism.

02:08:44.860 You know, I mean, the glucose ketone index of the average Joe out on the street is probably

02:08:49.220 something like 25 or 50.

02:08:50.820 It's like nowhere near that.

02:08:51.840 You know, so you are literally changing the metabolic physiology of that person.

02:08:57.820 So modalities that they may be resistant to or completely failed may have an effect now.

02:09:04.840 So chemo, radiation, maybe immune-based therapies may be working now.

02:09:09.660 That's an important point, right?

02:09:10.980 We view this as an adjuvant.

02:09:12.820 So you could do a neoadjuvant, concurrent, or adjuvant approach.

02:09:15.900 So I think that what I just described can be used as a neoadjuvant, concurrent, and an

02:09:21.580 adjuvant approach.

02:09:22.900 Yeah.

02:09:23.080 So people talk about cancer approaches as, look, you want to think about the legs of

02:09:28.480 a stool.

02:09:29.180 So you take a chemotherapeutic approach.

02:09:31.300 You take a radiation approach.

02:09:32.720 You take an immune-based approach.

02:09:34.340 And you take a surgical approach.

02:09:35.640 Those are really the four pillars of cancer treatment today.

02:09:38.960 Yeah.

02:09:39.280 You're basically saying, look, there needs to be a new type of oncologist, which is the

02:09:42.480 metabolic oncologist.

02:09:42.900 So you have a surgical oncologist, you have a radiation oncologist, you have a medical

02:09:47.760 oncologist, you now have an immuno-oncologist.

02:09:51.040 Why don't we have a metabolic oncologist?

02:09:53.060 Yeah.

02:09:53.440 Things will lead that way just by the research that's being done now.

02:09:57.220 The huge amount of research being done, even on oncometabolites.

02:10:01.420 And all the genetics people are now focusing on how metabolism is influencing genetics.

02:10:09.340 Metabolism is a driver for our biology and influencing epigenetic expression.

02:10:15.140 So, you know, the work, I'd like to also point to the work of a friend of mine and colleague,

02:10:19.780 Adrienne Scheck, who did her work at the Barrow Neurological Institute, which demonstrated

02:10:25.100 in a mouse model, GL261, I think, model of glioblastoma, that using temozolamide and

02:10:33.980 also radiation with really focusing on radiation, that being in a state of nutritional ketosis

02:10:39.980 made radiation therapy many, many times more efficacious.

02:10:45.580 And that mouse model, which is kind of a gold standard model for GBM, it actually cured

02:10:50.960 the GBM in that mouse model using the ketogenic diet combined with whole brain radiation.

02:10:57.680 So that was a pretty significant finding that actually spearheaded some of the ketogenic

02:11:03.880 diet clinical research.

02:11:05.420 And in her research, this was done with dietary or nutritional ketosis, not exogenous supplementation?

02:11:10.920 Not.

02:11:11.260 She went on to do some work with exogenous ketones and looking at how ketones can reprogram

02:11:18.560 the metabolism and ketones can actually have, they are like COX-2 inhibitors.

02:11:24.460 They inhibit reactive oxygen species, which is driving growth and proliferation.

02:11:29.440 So that work spawned research just on ketones by themselves in her animal model.

02:11:35.820 So what is in your pulse protocol then?

02:11:38.040 The pulse protocol can be varied.

02:11:39.740 So hyperbaric oxygen therapy.

02:11:41.360 At what frequency?

02:11:42.760 Three, generally speaking.

02:11:45.100 So with GBM, you have to, so a consequence of a GBM could be seizures, right?

02:11:49.900 So getting hyperbaric oxygen therapy with a GBM is a bit tricky.

02:11:54.460 So yes, you have to start very low, probably like somewhere around 1.5 ATA and then work

02:12:01.900 up gradually from there based on the individual person.

02:12:06.440 But generally speaking, the research that we did showed that not five days a week, which

02:12:11.580 is typically used for wound healing, but I do think there needs to be a day off for adaptive

02:12:16.860 effects to happen.

02:12:18.060 So three days a week, 2.5 atmospheres for 60 minutes, three times a week.

02:12:25.240 And that produces, well, reverse tumor hypoxia for one thing.

02:12:30.620 So hyperbaric oxygen increases tissue oxygenation, not by hyperoxygenating hemoglobin, but it actually

02:12:39.540 gets oxygen into the plasma.

02:12:41.980 And that's a very important thing because-

02:12:44.100 Meaning you solubilize oxygen within the plasma.

02:12:47.100 Yes.

02:12:47.640 Because you can't really supersaturate the hemoglobin that much more.

02:12:50.640 You're at the top of the curve.

02:12:51.800 Yeah.

02:12:52.000 You and I are sitting here.

02:12:53.600 I don't know what this air here, but your hemoglobin is essentially saturated, probably

02:12:58.580 96, 98%.

02:13:00.160 But the hyperoxygenation that occurs with hyperbaric oxygen therapy, and this is why oxygen therapy

02:13:07.020 does not work independent of an increase in pressure, right?

02:13:10.740 So the increase in pressure is needed to drive the oxygen into the plasma.

02:13:15.660 And once it's in the plasma, tumors have erratic vasculature, right?

02:13:20.500 And then the red blood cells get caught inside the capillaries and the oxygen doesn't get into

02:13:26.100 the tissue inside the tumor.

02:13:27.540 But if the oxygen is in the plasma, it can get past and all into the nooks and crannies

02:13:34.300 of the tumor and then reverse tumor hypoxia, which is tumor hypoxia is driving HIF-1-alpha

02:13:40.460 and VEGF and causing oncogenic activation.

02:13:43.260 Oh, that's so interesting.

02:13:43.940 So ironically, you're taking something that is initially a deficit of cancer, which is its

02:13:49.320 hypoxia, but then it utilizes it as its advantage by saying, hey, I'm going to work around this.

02:13:54.960 It's going to make me more resilient.

02:13:56.280 It's going to allow me to increase my vasculature, boom.

02:13:58.340 And you're saying, hey, buddy, that little advantage you had that was a disadvantage,

02:14:02.580 we're going to reverse it.

02:14:03.540 We're going to hyperoxygenate you now.

02:14:05.320 We're going to take away your hypoxia.

02:14:07.160 Do you also increase free radicals?

02:14:09.360 Yes.

02:14:09.800 So you have a dual effect, right?

02:14:11.340 So you are silencing the oncogenes.

02:14:14.200 You're turning off some of the oncogenes.

02:14:16.380 And also by hyperoxygenating a tumor, which its baseline is to be in a state of hypoxia

02:14:26.320 by supersaturating the tumor with oxygen.

02:14:29.800 And that tumor tissue has damaged mitochondria because hypoxia damages the mitochondria.

02:14:34.500 So basically, you're hyperoxygenating a whole bunch of damaged mitochondria.

02:14:38.400 And essentially, what that does is skyrockets superoxide anion, which then through fenton chemistry,

02:14:45.380 so when you have a lot of free iron and all, you've got a whole bunch of heme and stuff

02:14:49.580 that's being broken down the tumor.

02:14:51.080 So you have a lot of free iron driving the fenton reaction, which is producing hydroxyl radicals.

02:14:56.800 And that causes a massive oxidative stress specifically to the tumor.

02:15:02.420 And you're delivering a massive oxidative stress to the tumor while it's relatively non-toxic

02:15:10.440 to healthy cells that have normal metabolism, right?

02:15:13.800 Because the tumor is thriving in a low-oxygen environment, and you're reversing tumor hypoxia

02:15:18.620 and hyperoxygenating it, and you have this environment which is just fueling redox stress,

02:15:24.540 you can then trigger apoptosis and necrosis, really driving necrosis in these tumor cells.

02:15:30.140 So hyperbaric oxygen delivered at the maximum tolerable dose, three times per week.

02:15:36.200 And you could further enhance the oxidative stress of the tumor by something that's a lot of people

02:15:43.840 who haven't heard of this, but IV vitamin C.

02:15:46.020 So vitamin C, if given intravenously at about—

02:15:50.200 You could give, what, up to about 100 grams at that?

02:15:52.620 You could, yeah.

02:15:53.340 Yeah, 25 to 100 grams is kind of pushing it, but vitamin C, ascorbic acid, also functions

02:15:59.380 as a glucose antagonist.

02:16:00.980 Yes, you've got to make sure you have dextrose on hand if patients—

02:16:04.460 Yeah, but not if you're in a state of ketosis, right?

02:16:07.160 So if you're in a state of ketosis—so I did a pretty high dose of vitamin C, but being

02:16:11.960 in a state of ketosis, you can tolerate higher amounts, right?

02:16:14.980 Do you know what your glucose dropped to?

02:16:16.440 So when you measure your glucose, when you're getting vitamin C, you get a false positive

02:16:23.060 on the meter.

02:16:24.740 Falsely high?

02:16:25.460 You get falsely high.

02:16:26.720 Well, at least the Abbott Precision Extra.

02:16:28.380 Yes.

02:16:29.020 Yeah.

02:16:29.800 It's just, you know, when you measure that meter, that assay on the meter is also sensitive

02:16:35.720 to the pH of your blood, too, and there's a redox shift.

02:16:39.480 And ascorbic acid is a powerful reducing agent, and that might be altering the assay.

02:16:44.540 So I was not able to get—my glucose, like, skyrocket.

02:16:46.880 I know I went into it hypoglycemic, but my ketones were elevated, and I took a pretty

02:16:51.800 big hit, you know, of vitamin C. And I was just doing it just for the, you know, the

02:16:56.420 self-experimentation thing.

02:16:58.020 Right.

02:16:58.420 But what's the thought here?

02:16:59.720 So lots of people have talked about—

02:17:01.300 Oxidative stress.

02:17:01.960 So vitamin C driving the fentanyl reaction to produce more oxidative stress.

02:17:06.840 So vitamin C is a pro-oxidant.

02:17:08.860 And when you get blood levels of vitamin C in the millimolar concentration, then it becomes

02:17:14.680 a pro-oxidant.

02:17:15.680 It's not an antioxidant.

02:17:17.140 So we're not using—antioxidants are definitely—you don't want to use antioxidants for cancer

02:17:20.800 therapy.

02:17:21.000 Yeah, I was going to come back to that.

02:17:21.460 But the next thing is, I'm sure somebody listening to this is going to say, well, I

02:17:24.400 don't have access to IV vitamin C if I wanted to do that.

02:17:27.180 You can't do it orally.

02:17:28.060 You can't do it orally because of what?

02:17:29.700 It's not—you can't get it out of the gut enough.

02:17:31.520 Yeah, you can't.

02:17:32.180 You can only get, like, very small amounts.

02:17:34.980 And then, you know, your gut auto-regulates it, too.

02:17:38.320 So you just—let's get to the next thing you said, which is, again, highly counterintuitive

02:17:42.020 to most people.

02:17:42.820 We're hardwired to think that there's nothing better for you than antioxidants.

02:17:47.060 Yeah.

02:17:47.420 But paradoxically, once you have cancer, that might not be the case.

02:17:50.940 Yeah.

02:17:51.280 So I think antioxidants may be blocking some of the efficacy of some of the therapies,

02:17:57.240 too, right?

02:17:57.840 Because many chemotherapeutic drugs, their function works through enhancing oxidative stress.

02:18:03.540 Radiation sure does.

02:18:04.980 So radiation, maybe 20% of the cancer-killing effects of radiation are due to damaging the

02:18:11.920 DNA with double-strand nicks.

02:18:14.260 But 80% of the tumor-killing effect of radiation is by the generation of reactive oxygen species.

02:18:21.520 Now, does that mean you can't have blueberries and things that have low levels of antioxidants?

02:18:25.300 I would say no.

02:18:26.820 But you don't want to kind of saturate your body with a cocktail of antioxidants.

02:18:33.540 Like, you don't want to do a glutathione push, right, after you do IV vitamin C.

02:18:37.960 Same with NAC, so you wouldn't have NAC?

02:18:40.180 I personally would not.

02:18:41.600 I don't think...

02:18:42.760 None of the cancer studies and animal models or humans are supportive of the use of antioxidants.

02:18:49.600 And that was a big focus of me.

02:18:51.080 I mean, during my PhD, I wanted to do a post-doc research in antioxidant cocktails that were

02:18:57.980 going to save the world.

02:18:59.040 And none of the research on antioxidants really panned out in my mind.

02:19:03.740 There's a couple things, you know, maybe for mitochondrial antioxidants, for like Friedrich's

02:19:08.100 ataxia and maybe ALS and some research there.

02:19:11.460 But it's pretty subtle benefits.

02:19:13.680 But in the context of cancer, no, I don't...

02:19:16.180 And I think antioxidants should be avoided.

02:19:18.220 Anything else in your Pulse protocol?

02:19:19.980 Yeah.

02:19:20.360 I mean, there's a lot of things that you could add.

02:19:22.200 So with the PRESS protocol, I think a low dose of metformin could be helpful, too.

02:19:27.140 So that will activate AMP kinase, maybe decrease insulin a little bit, maybe increase ketones a

02:19:34.420 little bit, too.

02:19:35.400 And it's just a readily available, cheap drug that has a very good safety profile.

02:19:41.860 500 milligrams to 2,000 milligrams a day are usually well-tolerated, probably starting

02:19:47.600 with 500 milligrams and working up.

02:19:49.940 But when it comes to the Pulse protocol, hyperbaric oxygen, IV vitamin C, and there are a number

02:19:56.340 of drugs that we're working with now.

02:19:58.080 One would be 2-deoxyglucose, which in and of itself, from a seizure world, and I've been

02:20:05.340 a reviewer for the government for different grants and stuff.

02:20:08.880 And this is, in the context of epilepsy, 2-DG is sort of like the ketogenic diet in a drug.

02:20:16.240 So by inhibiting glycolysis, it has...

02:20:19.160 This gets back to the question, right?

02:20:20.600 You have no ketones, but you inhibit glycolytic pathways, perhaps even reduce sort of mTOR

02:20:27.560 signaling or some glycolytic signal, and that may have anti-seizure effects.

02:20:31.800 So 2-DG is something that we're working with now, I think has...

02:20:35.900 What was 2-DG originally developed for pharmacologically?

02:20:39.360 It's been around for a long time.

02:20:41.040 Yeah, it's been around for a long time.

02:20:41.740 I think maybe it was just in the realm of experimental compound.

02:20:45.280 But I know there's phase two trials in cancer.

02:20:49.400 The problem is it becomes cardiotoxic above, say, 50 milligrams per kilogram.

02:20:56.280 I know there's some evidence that's cardiotoxicity, but at 25 milligrams per kilogram, at least

02:21:03.400 on some of the grants that I reviewed, that had a pretty good safety profile for epilepsy.

02:21:08.420 So, you know, not making any recommendations out there, but I think 25 milligrams per kilogram

02:21:14.100 seems to be within the realm of therapeutic efficacy and safety.

02:21:19.100 And this is being studied in humans?

02:21:21.180 And they're out of phase one.

02:21:22.640 So you have phase one data to support that.

02:21:24.820 Yeah, like in the epilepsy world.

02:21:25.760 Yeah, and I think there's some cancer trials going on too.

02:21:28.540 And I do think that synergizes really well.

02:21:31.340 Once you create the environment where you put the PRESS protocol into action, then the

02:21:37.960 cancer cells become even very selectively vulnerable to other things.

02:21:42.480 Like 2-DG will inhibit a glycolytic pathway that drives the pentophosphate pathway.

02:21:49.040 And that pentophosphate pathway is responsible for enhancing the endogenous antioxidant capacity

02:21:55.960 of cells.

02:21:56.640 So it makes the cancer cells even more vulnerable to oxidative stress, the more you can inhibit

02:22:03.400 the glycolytic pathways.

02:22:05.060 So 2-DG, 2-dichloroacetate is something that we've worked with too, inhibits PDH complex.

02:22:12.700 And that can also-

02:22:13.660 Is DCA a drug that's been on the market for a long time?

02:22:16.020 It's a small molecule.

02:22:17.660 Yeah, it's been on the market for a very long time.

02:22:19.560 And what's its normal use?

02:22:21.060 Its normal use is lactic acidosis, actually.

02:22:24.560 So one of the side effects of metformin, right, is once you start increasing the dose of metformin

02:22:32.900 and escalating the dose, the problem that you run into, it's a very powerful activator

02:22:39.560 of amp kinase, its effects are primarily through the liver, you know, inhibiting gluconeogenesis.

02:22:45.660 And it's a mitochondrial toxin through, we published a paper that it increases Ross production

02:22:50.780 from the complex one of the mitochondria.

02:22:55.060 So it's inhibiting complex one, correct?

02:22:56.600 It's inhibiting, yeah, mildly inhibiting complex one, and it's triggering what the cell experiences

02:23:02.880 as an energetic crisis, and that, you know, it has an activation of amp kinase too.

02:23:08.240 So you are creating a scenario where that's putting a lot of persistent metabolic stress

02:23:13.580 on the tumor cells, and then you come in here with different modalities that have overlapping

02:23:20.160 but independent mechanisms at producing oxidative stress.

02:23:24.140 So hyperbaric oxygen, IV vitamin C, and then cancer-specific glycolytic inhibitors, 2-deoxyglucose,

02:23:32.180 3-bromopyruvate, and lonitamine.

02:23:34.840 Lonitamine is also a hexokinase 2 inhibitor.

02:23:37.360 And those three drugs that I mentioned right there, they are very powerful, and they need

02:23:43.300 to probably be used in two weeks on, two weeks off.

02:23:47.260 And if somebody's listening to this and they're thinking, well, how the hell is it?

02:23:50.160 How the heck could I ever do this?

02:23:52.560 Are there physicians out there who are obviously doing this under the full and legal umbrella

02:23:59.440 of ethical medical practice?

02:24:01.300 Is everything you're talking about purely theoretical, or are there ways to actually have these things

02:24:05.580 implemented?

02:24:06.000 I think there are some physicians out there that are probably not making it public, but

02:24:11.320 I think they are getting success with doing 25% of what I just talked about.

02:24:18.040 You know, they're not doing all these things.

02:24:20.600 But everything that I just mentioned is readily available.

02:24:25.320 I mean, you could, most of the compounds in IV vitamin C, hyperbaric oxygen therapy can be

02:24:30.920 costly if you don't have a hard shell chamber.

02:24:32.660 But I like that with radiation, if you're giving radiation to your body, it's like going in there

02:24:39.760 with a flamethrower, and you have a lot of collateral damage, whereas hyperbaric oxygen

02:24:44.780 naturally elevates the precursor for oxygen-free radicals, and the cancer cells selectively produce

02:24:53.000 more oxygen-free radicals.

02:24:54.380 So it's a very gentle approach.

02:24:57.120 And instead of thinking that we should just go in there and eradicate the tumor, I think

02:25:02.020 it's more appropriate to give sort of a gentle stress to the tumor.

02:25:07.500 So the therapy that I'm describing, if the patient goes into it, they're going to come

02:25:11.480 out of it stronger than they were going into it.

02:25:14.160 When you fat adapt and keto adapt your body, so many metabolic biomarkers start to go in the

02:25:19.520 right direction, when you go in for chemotherapy and radiation, and you measure things after,

02:25:26.120 your body, you're a big inflammatory mess.

02:25:29.300 I mean, you're metabolically deranged.

02:25:31.240 You're insulin resistant.

02:25:32.680 You are pushing things, and you have chemo brain on top of that that may not be reversible.

02:25:38.260 The suppression of your immune system with chemo is setting you up for more cancers,

02:25:42.320 potentially other cancers.

02:25:43.340 So the scenario that we envision is a comprehensive metabolic-based therapy where you go into it

02:25:51.400 and it's a more gradual approach, and you start adding these modalities sort of as you go.

02:25:56.660 Get the patient acclimated with that glucose ketone index of one to two, and then start utilizing

02:26:03.480 some of these other therapies.

02:26:05.200 You could potentially put someone on an IV and pulse a low dose of insulin to make them

02:26:14.080 hypoglycemic, even one or two millimolar, and then deliver some of these agents where you've

02:26:20.420 really restricted the fermentable fuels.

02:26:23.340 So I'm a reviewer on different manuscripts that are coming in, and some of these academic

02:26:29.920 and clinical oncologists are actually suggesting this in medical hypothesis papers now.

02:26:36.500 And that's kind of counterintuitive because you'd think, well, we don't want the last thing

02:26:39.560 you want to do for a tumor is give it insulin because this is so, because this is pulsatile.

02:26:43.640 And it's acute, and the amount of insulin, it's not like 20 IUs.

02:26:47.100 It's something like one or two IUs.

02:26:48.860 So the patient comes in fasted, and you give them just a little bit, and that's facilitating,

02:26:54.520 mostly facilitating glucose uptake in the skeletal muscle.

02:26:57.480 So making it less available for the tumor, right?

02:27:01.000 And that creates a scenario where you produce severe, what would typically be fatal hypoglycemia,

02:27:09.180 and you could deliver ketones as an insurance, and also deliver some of these agents that would,

02:27:15.880 you'd probably dramatically sensitize that tumor tissue to the other modalities.

02:27:21.120 And I know, so, I mean, what I didn't talk about when I did this seven-day fast, like,

02:27:26.940 years ago, I brought my glucose levels down really low, and I got to a glucose ketone

02:27:32.840 index of one, or maybe even a little bit lower than one.

02:27:35.760 So you were about, what, three to four on each of them?

02:27:38.000 Yeah, well, my ketones were about four or five, and my glucose got down to three.

02:27:43.460 So that was the lowest I ever, like, captured.

02:27:46.060 And that was just a seven-day fast?

02:27:48.200 Yeah, after a seven-day fast, you know, after a brisk walk at the end.

02:27:51.660 So I never got, like, ketone seven or eight.

02:27:54.200 Like, I got it, like, four, you know, after, like, a long fast.

02:27:57.580 But then I did, inspired by the Cahill study, I used various strategies to bring my glucose level down,

02:28:05.940 you know, pharmacological strategies.

02:28:07.700 And I did it slowly.

02:28:09.080 Just do me a favor, Dom.

02:28:11.640 I really would be kind of pissed off if you, like, offed yourself doing dumb shit,

02:28:16.560 because I think the world kind of needs you to stick around.

02:28:19.640 So see if you can just maybe get an IRB to do this in the mice or something.

02:28:24.840 There'd be nothing that would break my heart more than getting a call from your wife saying,

02:28:28.860 yeah, Dom died of some freak hypoglycemic crazy accident.

02:28:33.920 What's the longest fast you've ever done?

02:28:36.380 Well, that was it, actually.

02:28:37.620 Seven days?

02:28:37.800 So, yeah, and I was pretty adapted.

02:28:40.000 And the point I was kind of getting to that I brought my glucose down to where it was not even measurable.

02:28:45.060 But with exogenous ketones, I was, the meter didn't even read it.

02:28:50.160 So that, to me, and I did that years ago, that motivated me more to basically focus on this area of research

02:28:59.960 as sort of like my life research, because it validated to me that this should not be happening.

02:29:04.320 And ketones are an alternative energy source that can be utilized in these metabolic-based therapies

02:29:11.320 that can be game changers.

02:29:13.580 And we also study glucose transporter type 1 deficiency syndrome, right, which is the inability.

02:29:19.640 And people who have glut 1D don't get cancer, to my knowledge.

02:29:23.460 I've talked to the doctors, and they've never came across anyone with glucose transporter.

02:29:28.220 So that's kind of motivating, too, that you can create a therapy for that that could sort of be a magic bullet.

02:29:36.440 Well, what's interesting is this is sort of, in many ways, old-school science, right,

02:29:40.800 where scientists would begin by sort of experimenting on themselves,

02:29:44.760 identifying unnatural or extreme physiologic conditions that are not predicted by the current understanding.

02:29:51.760 And then that sort of provokes further investigation.

02:29:55.520 Remind me again, at the end of that seven-day fast, how much did you deadlift?

02:29:58.500 Yeah, I did 500 pounds for 10, and then I did sort of a one-repper at the end with six plates or a 585.

02:30:07.680 But that's below my, you know, normal.

02:30:10.180 But it was amazing to me that, you know, I didn't want to push my body too hard,

02:30:15.560 but it was amazing that that amount of fasting does not really impact your strength.

02:30:19.700 How much of a verdict?

02:30:20.560 So what was your max at that time?

02:30:22.320 At that time, well, I was tinkering around with, like, you know, ketogenic diet and fasting a lot.

02:30:26.800 But within a year of that time, I forget if it was before or after, I did 675 for 5.

02:30:32.480 And maybe 5, I did 555 for an 8 to 10.

02:30:38.960 So I did, you know, an extra plate for 8 to 10.

02:30:42.360 But I went into this, basically, I felt like I did more.

02:30:45.920 I could have done more, but I just wanted to stop.

02:30:48.340 I didn't want to hurt myself because I knew I was pushing the limits at that point.

02:30:52.440 And I didn't get sore at all.

02:30:54.200 So I did that, and it wasn't like my body was broken down and sort of in a depleted state where I was wasted the next day.

02:31:00.760 I felt I didn't even have to recover from that.

02:31:02.700 Like, I had no lower back soreness the next day after that.

02:31:06.200 So I probably was like, I probably could have went heavier.

02:31:07.980 But it was just validation to me that if you're in a keto-adapted state, your body is very resilient.

02:31:15.380 And from a military standpoint, too, which we work pretty closely with the military, I'm trying to sort 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,

02:31:32.760 you could maintain your physical and cognitive resilience in those conditions, which is pretty clear to me.

02:31:38.600 I was pretty much obsessed with eating like six meals a day for many years.

02:31:42.780 And it was very liberating not to have to do that now.

02:31:45.880 And I'm amazed at how little I can eat once you're keto-adapted and maintain, you know, your size and your strength.

02:31:52.820 I'm not trying to be big anymore or anything or try to do any records in the gym.

02:31:56.600 But it's amazing how easy it is to maintain once your body is adapted.

02:32:01.360 You've been so generous with your time.

02:32:02.600 I want to sort of let you get on your way.

02:32:04.780 I know you've got a long drive potentially tonight.

02:32:06.520 But I want to ask you a question or a couple maybe.

02:32:09.620 What do you believe today to be true that five years ago you did not believe to be true?

02:32:15.400 Let's keep it within the purview of your ketogenic life.

02:32:18.600 What today do you think?

02:32:19.900 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.

02:32:32.540 So it's even like space food, you know, and we're still working on that front.

02:32:36.540 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.

02:32:53.180 More recently, we've been working with an organization that the name of the organization is called All Things Kabuki.

02:32:59.840 So there's a rare genetic disease called Kabuki syndrome, which is a gene defect in the KMT2D, which is essentially an acetylase enzyme.

02:33:12.640 And a defect in that gene or that protein creates an imbalance between gene expression and gene repression, right?

02:33:20.380 And in the mouse model of Kabuki syndrome, two things have worked in this mouse model.

02:33:26.700 One is a histone deacetylase inhibitor, HDAC inhibitor, called AR42, which restores neurons in the dentate gyrus and kind of silences the pathological features in this mouse model.

02:33:40.380 And another thing is nutritional ketosis.

02:33:42.340 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.

02:33:57.760 The animals have a normal neuronal density in the dentate gyrus and even from a behavioral characteristic, it enhances sort of learning and memory.

02:34:09.020 So this idea that an endogenous metabolite can epigenetically sort of control gene transcription.

02:34:19.140 So I believe it's probably not unique to beta-hydroxybutyrate.

02:34:22.920 I think metabolites, we know that's true for acetyl-CoA and other things, are epigenetic drivers.

02:34:30.520 And I think they are really, they call the shots.

02:34:32.780 So you can even take a step back and say the mitochondria kind of call the shots too, right?

02:34:38.320 Because I think mitochondrial health and mitochondrial vitality would be the ultimate tumor suppressor.

02:34:43.940 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.

02:35:00.040 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 independent way.

02:35:15.560 Yeah, through their, it's HDAC activity.

02:35:17.480 So that to me is like mind-blowing.

02:35:20.060 And I think that's the direction kind of our lab is going into now.

02:35:23.420 I'm always fascinated with developing alternative energy substrates and alternative fuels as a form of nutrition for tactical applications, space applications maybe.

02:35:33.600 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.

02:35:48.540 That's an amazing answer, actually, because, and I know that was probably a little hard for some people to follow.

02:35:54.560 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.

02:36:06.660 And with that comes a lot of interesting stuff we've talked about.

02:36:09.260 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.

02:36:31.280 And Dr. Virdin at the Buck Institute has spoken quite a bit about this as well.

02:36:35.320 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.

02:36:44.100 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.

02:36:51.380 Dom, where can people follow you socially?

02:36:54.460 And then maybe more importantly, see what you're doing from a research perspective.

02:36:58.320 Sure.

02:36:58.960 So the site I maintain for informational purposes would be ketonutrition.org.

02:37:07.040 It's a .org, not .com.

02:37:09.340 And on that website, I have a list of, you know, podcasts.

02:37:14.260 There's nutrition consultants, resources like the Charlie Foundation, which is an incredible resource that I've helped them do some educational work.

02:37:22.580 And Jim Abrams of the Charlie Foundation has really created an amazing resource there.

02:37:26.520 I have a blog and we test various ketone supplements, ketogenic foods.

02:37:31.920 I'm self-experimenting and I've collected a lot of data and will be putting some of that data in the blog.

02:37:38.340 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.

02:37:45.100 I'd also like to mention that our lab in collaboration with Epigenics Foundation is sponsoring the Metabolic Health Summit that's occurring in January 30th to February 3rd in Long Beach, California.

02:38:00.880 And it's going to have an amazing array of basic scientists, for example, like Lou Cantley will be there, be a keynote speaker, Thomas Seyfried.

02:38:10.860 There's going to be clinicians there, influencers there, and a lot of entrepreneurial people will be there representing companies that are really changing the shape of this industry.

02:38:23.540 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.

02:38:41.600 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.

02:38:51.480 But from clinical application to moving the science into human application is really the theme of that.

02:38:59.140 And can people register for that already?

02:39:00.960 Yes.

02:39:01.240 I think you can go to the website and register.

02:39:03.520 If you want to be a sponsor, I think you can sort of download the sponsorship package.

02:39:07.380 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.

02:39:18.660 So we're looking for sponsors.

02:39:20.100 And I think we've nailed down most of our speakers.

02:39:22.660 But if you're interested in speaking, too, it might be good to contact us through the website.

02:39:26.680 Got it.

02:39:26.980 And on Twitter, you're pretty active.

02:39:28.800 What's your handle?

02:39:30.000 Yeah.

02:39:30.300 Before I realize how important it is to have a handle, you can remember.

02:39:34.660 Or it's Dominic D'Agosti 2.

02:39:38.240 We'll link to it.

02:39:39.440 Yeah.

02:39:39.460 We'll link to it.

02:39:40.560 It's not the easiest to remember.

02:39:41.680 And also Facebook.

02:39:42.740 I'm fairly active.

02:39:43.900 Dominic D'Agostino 1.

02:39:45.780 I think that's my handle on Facebook, too.

02:39:48.240 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.

02:39:54.380 But I'm not too active on that.

02:39:56.400 All right.

02:39:56.860 Well, we'll make sure we link to all of those things.

02:39:58.940 I want to thank you again.

02:40:00.000 I owe a lot of what I know in this space to you.

02:40:03.860 I can say the same.

02:40:04.860 Thank you.

02:40:05.500 Yeah.

02:40:06.060 Incredible blog.

02:40:07.080 It's been a great resource for many.

02:40:08.880 You are arguably one of the most generous people I've ever met when it comes to his insights.

02:40:12.740 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.

02:40:20.480 I'll just share one very quick anecdote.

02:40:22.960 Personally, one of my best friends from medical school, his wife has breast cancer.

02:40:26.620 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 is the only woman to still be alive in this clinical trial.

02:40:44.680 So the trial has closed.

02:40:46.480 That agent will likely not be approved, though she will have a compassionate exemption.

02:40:51.360 But, you know, she is someone who has been on a ketogenic diet now for six years and remains incredibly indebted to the work that you've done.

02:40:59.240 And her oncologist in Boston are sort of amazed that she's alive.

02:41:04.420 Interestingly, next year, Lou Cantley will be explaining a very plausible mechanism for why she is still alive.

02:41:11.540 It's a paper that I'm sure you're aware of that was just approved and will be out in nature very soon.

02:41:17.160 So anyway, I could sit here and spend another hour thanking you for everything, but I know nobody really wants to hear that.

02:41:22.480 So I'll be quick about it and just tell you again that, Dom, you're an amazing guy.

02:41:26.620 You really are one of those people that I think fits in the category of just being kind of a treasure.

02:41:31.580 And so on behalf of many people, I want to thank you.

02:41:33.980 And thank you.

02:41:34.400 Thank you for giving me this platform.

02:41:36.120 I know your podcast will be an amazing resource for so many people.

02:41:39.560 Always great to catch up with you.

02:41:41.020 Always very stimulating in so many ways.

02:41:43.720 So thank you, Peter, for having me.

02:41:45.700 Appreciate it.

02:41:48.340 You can find all of this information and more at peteratiamd.com forward slash podcast.

02:41:53.420 There you'll find the show notes, readings, and links related to this episode.

02:41:57.720 You can also find my blog and the nerd safari at peteratiamd.com.

02:42:02.220 What's a nerd safari, you ask?

02:42:03.820 Just click on the link at the top of the site to learn more.

02:42:06.700 Maybe the simplest thing to do is to sign up for my subjectively non-lame once a week email where I'll update you on what I've been up to, the most interesting papers I've read, and all things related to longevity, science, performance, sleep, etc.

02:42:18.560 On social, you can find me on Twitter, Instagram, and Facebook, all with the ID Peter AtiyahMD.

02:42:24.900 But usually Twitter is the best way to reach me to share your questions and comments.

02:42:28.620 Now for the obligatory disclaimer.

02:42:30.180 This podcast is for general informational purposes only and does not constitute the practice of medicine, nursing, or other professional healthcare services, including the giving of medical advice.

02:42:40.460 And note, no doctor-patient relationship is formed.

02:42:42.780 The use of this information and the materials linked to the podcast is at the user's own risk.

02:42:48.480 The content of this podcast is not intended to be a substitute for professional medical advice, diagnoses, or treatment.

02:42:54.720 Users should not disregard or delay in obtaining medical advice for any medical condition they have and should seek the assistance of their healthcare professionals for any such conditions.

02:43:03.460 Lastly, and perhaps most importantly, I take conflicts of interest very seriously.

02:43:08.560 For all of my disclosures, the companies I invest in and or advise, please visit PeterAtiyahMD.com forward slash about.

The Peter Attia Drive - July 16, 2018

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

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