The Truth About Ketone Supplements | ft' Professor Dominic D’Agostino

Ketones could essentially rescue the brain from extreme hypoglycemia.

You were giving yourself exogenous hormones to artificially plummet down your blood sugar.

Basically lowered it to where the meter could not read it, and I was asymptomatic.

Ketone esters, very potent, with potential very potent benefits, but also potentially potent negative side effects. I don't know if they all taste like crap, but the ones I've tried taste pretty horrible.

Pretty clear in the literature that PUFAs are more ketogenic than saturated fats.

Hey everyone, before we get to our main interview with Professor Dominic D'Agostino, I just want to you. This one's really dense, so I hope you don't get scared away by some scientific jargon. We really go into the weeds, mostly about exogenous ketones like ketone esters, ketone salts, MCTs, etc. This was a discussion I wanted to have with Dom because he's a brilliant guy, and I don't think this is covered with enough depth and nuance elsewhere. So yes, this one gets into the weeds, but if you're interested in exogenous ketones, ketone supplements, this is something you need to watch. All the way through. Sorry if we lose you at a few points, it does get nerdy. With that, let's get into it. I think that there are select topics in the metabolic health and nutrition space that are typically covered quite poorly or with a dearth of nuance, things like ketone supplementation and fiber. So I have someone very special with me today to unpack that. My guest is Professor Dominic D'Agostino, probably a man who needs no introduction, but I'm going to give one anyway. He's a tenured professor at the University of South Florida's Morsani College of Medicine in the Department of Pharmacology and Physiology. He teaches medical neuroscience, physiology, nutrition, and neuropharmacology. I know, a mouthful. And he's a senior visiting research scientist at the Institute for Human and Machine Cognition, where he helps to advance the health and resilience of astronauts and warfighters. It's a really interesting dude. His work focuses on nutritional and metabolic-based therapies for a wide range of disease states. We have a really exciting discussion, and Just before we were getting on, he told me he was going to tell a story he's never told before about a very dangerous n 1 he did on himself that totally changed his research priorities. So I'm very excited to get into this one. Thanks for coming, Doc.

Great to be here, Nick. Thanks for having me.

All right, I want to hear about this n 1. This is divergent from the first question I had, but now I'm very curious.

Yeah, okay, right out of the gate. So yeah, briefly mentioned it to you. And, uh, yeah, I don't, I don't think I've ever talked about it, but, uh, early in my career, uh, I connected with some of the icons in, uh, ketone research, or people that I think are legitimately the icons. So Dr. Richard Veech, Dr. George Cahill, uh, Sammy Hashem, Theodore Van Italie— all these people have passed, but I had the amazing opportunity to talk to them, to meet with them. And Dr. Henri Brunengrabber, he's still alive. So these are all like people that gave me a lot of ideas for using, developing and testing exogenous ketones for very unique applications. And at some point, all of them did research on lowering blood glucose, administering ketogenic agents. And the gist in talking with them that that ketones could essentially rescue the brain from extreme hypoglycemia. So in the case of the famous Cahill study in 1967 that was published, I was kind of inspired by that. As you know, they fasted several obese individuals and administered 20 IUs of insulin and pushed their blood glucose down to as low as about 1 millimolar. And the subjects were asymptomatic for hypoglycemia. And this inspired me to pursue the idea that ketones could rescue the brain in the face of impaired glucose metabolism or hypoglycemia.

So I just want to like give numbers to a range of how remarkable that is. Um, like the standard blood glucose is generally between fasted 70 and 100, and I think people get kind of nervous when blood glucose dips below, I don't know, 60, 55. Like if you've ever worn a CGM, a Dexcom, there's an auto alarm you can't turn off for dropping below 65 because it's assumed to be dangerous. And at levels like 40 or something, we're thinking, okay, you might be going into a coma. And you're talking about literally 1 millimole and people being fine.

Yeah, 18 milligrams per deciliter, like 20 milligrams per deciliter, you know, in those units. But yes, uh, severe hypoglycemia is really under 3 millimolar. Which is, you know, right around that, you know, mid-60s mark, 70, under 70. So it becomes severe, like you need to enter, you know, you need an intervention. So without going into details about what I did, but I will say that the self-experiment that I did 15 years ago set me on a trajectory to understand, uh, exogenous ketones and the therapeutic applications. So I convinced myself, uh, I will say that I fasted for a week and did a number of things to lower my blood glucose down to ranges that were similar to what was several publications and had been published on the lowering of blood glucose. And at the time, we had just developed, uh, various exogenous ketones And I was using— I was in a state of endogenous fasting ketosis, but also had exogenous ketones at my fingertips, along with various ways to lower blood glucose. And I basically lowered it to where the meter could not read it. And I was asymptomatic for hypoglycemia. And after that, I had lowered my glucose even modestly, and the results were very, very scary and symptomatic. But I did it, you know, in a very, very titrated meticulous way. So, you know, just an N-of-1 experiment that replicated what was already in the literature. It's not like I discovered this, but— and I was really surprised that people did not pick up on this— but it validated to me the tremendous potential that we could literally save someone from insulin shock with exogenous ketones, and that, that ketones could largely replace blood glucose as an energy source and make someone essentially asymptomatic from a very life-threatening, you know, death-inducing hypoglycemia. So that really set off my trajectory of understanding, you know, what are the optimal ways to induce therapeutic ketosis and what are safe ways to do it. And like what is the dosage timing and scheduling for different disease states? I was interested in seizures, but then Alzheimer's disease and also cancer.

Yeah, that's really amazing. I want to just reiterate, you know, in simple terms, I think what you just said, and hopefully I don't disclose too much, but sometimes there's like literature out there and as a scientist and researcher, like this is amazing. I almost can't believe it. And then, so some people like you, and I've been there too, like, I'm going to test it on myself. And you were very careful not to give the exact protocol, I think, because we don't want people replicating it because we're very dangerous. But effectively, you were giving yourself exogenous hormones to artificially plummet down your blood sugar to see, hey, if the human body, and especially the human brain, is really a hybrid engine, and usually people only have access to one fuel source, glucose, if I have access to the other fuel source then if I remove the glucose basically from my bloodstream, am I okay? Which diverges from like common expectations. If you go into a hospital with a blood glucose of 1 millimolar, like 20 milligrams per deciliter, people are gonna expect you to be in a coma at the very least. And basically found that you were fine, which is metabolically remarkable from conventional standards. And then you mentioned this term exogenous ketones, which are Basically, you can go into a nutritional state of ketosis where your body is making them, but you can also supplement them. So this is probably something most people listening are aware of. Now I want to pick your brain, um, as an expert on exogenous ketones about all the different types, because it's not something I see unpacked too well generally. So we'll go through ketone esters, MCTs, ketone salts, the different forms there, 1,3-butanediol, um, Let's just start with one. Can you tell us about ketone esters, what they are and their pros and cons?

Sure. Yeah. So ketone esters can be formulated in a variety of different ways. And I would say the large majority is taking 1,3-butandiol, which we'll talk about, and adding ketones to that molecule. You can add beta-hydroxybutyrate, two forms, the D or the L enantiomers, and we could talk about that later, or acetoacetate.

Acetate.

And you can make a diester, or, uh, you can make a monoester or a diester, which we did with this acetoacetate. And you can make triesters with a gly— using a glycerol backbone similar to triglycerides. Uh, another we published a few years ago on a, uh, we've been using for years a glycerol beta-hydroxybutyrate ester, which is a triester, delivers 3 ketones, or a glycerol acetoacetate ester. And the advantage to the glycerol is that— or we can talk about it— it's, it's an alcohol-free form of exogenous ketones, and it delivers a little bit more punch. 3 ketones instead of 1 ketone for, for the monoester. So, uh, so there are— I guess we're working with it, you know, on paper we have at least 30, 32, or 34 compounds, and I would say about at least a dozen of them are very viable. And there's pharmacokinetic studies we're running now. But a ketone ester is essentially a molecule that when it's consumed orally, there's esterase that liberate the ketones from 1,3-butandiol or glycerol. So there's a transesterification to make it, and then there's a hydrolysis in the gut and in the liver, and that liberates the ketones into circulation. And each of them has a pretty different pharmacokinetic profile. Uh, with the diester you get— and we published on this over 10 years ago— you get like a spike up of acetoacetate within the hour and then another spike up. So there's like this biphasic response of the acetoacetate and then a gradual rise in beta-hydroxybutyrate from the 1,3-butandiol. And it essentially makes like a 1-to-1 ratio in the blood of beta-hydroxybutyrate to acetoacetate. So that particular molecule, the acetoacetate diester with 1,3-butandiol, has remarkable anti-seizure effects. And, uh, we chose that because originally the one— the 1,3-butandiol beta-hydroxybutyrate monoester had no seizure protection effect, actually, like there was a trend a little bit. It almost decreased the latency to seizure a little bit. 1,3-butanediol also did that. It had no anti-seizure effects. In talking with this to various investigators in the epilepsy space, Dr. Zhang Ruo was one of my mentors in this space. He said, well, you need to elevate acetoacetate and there seems to be some correlation with acetone and anti-seizure effects. Developed the monoester of acetoacetate that had remarkable anti-seizure effects, then the diester, and that essentially had double the anti-seizure effects. And then we correlated it with acetone and acetoacetate. So we had published that in a model of oxygen toxicity seizures, which is a powerful induction of tonic-clonic seizures primarily by stimulating excess glutamate. So oxygen's stimulant to the brain, and hyperbaric pressures, it's a very strong stimulant, and it's a, it's a beautiful model of seizures. So, and then, you know, after that, we've done about, you know, a half dozen other different seizure models using this particular, uh, ester, and it has a unique ability to extend ketosis for, for quite some time. So ketone esters, just simply stated, they're the most powerful exogenous ketones that we have, but I also firmly believe that they have the potential to do some harm, uh, because of their potency for one part, but also for the 1,3-butanediol esters, it is a dialcohol and we could talk about that more and what that does to metabolism and other areas, other organs.

I just want to kind of clarify what I see as the takeaway points from this since I know people aren't going to necessarily know all the biochemistry, but that like even within a subtype of exogenous ketones. There's so many different molecules with different effects. So a few terms to just unpack just at a high level for their relevances. We mentioned beta-hydroxybutyrate, acetoacetate, and acetone, which is basically the three different forms of ketone bodies that can circulate around. And depending on the ketone ester you take, you're going to get different ratios, and these are going to have different therapeutic effects. Some, something like the diester, which is increasing relatively more acetoacetate, might have more anti-seizure effects. So This is, I think, not dealt with generally with such like nuance and precision because it's so complicated and still at the forefront of what we're discovering. But the point is here, ketone esters, very potent, um, with potential very potent benefits, but also potentially potent negative side effects depending on the form you're using, the dose you're using, and then obviously the use case. And I don't know if they all taste like crap, but the ones I've tried taste pretty horrible. As well?

Yeah, so we, well, we use them, we gavage them to the animals, which means we kind of like tube feed them. And if we integrate that into the food, which is another way to administer them, we often have to add like a sweetener to ensure that we don't inadvertently produce caloric restriction because that can muddy the waters on the data interpretation. But yeah, our, my primary interest We've done some exercise studies, and I will say rats and mice, they run farther on a Rotorod device, on a treadmill, like 20 to 30% more, the Alzheimer's models especially. But most of, you know, my focus has not been on exercise, although we've studied that. My focus has been really on the therapeutic applications of these molecules.

Just to give a little history, I mean, the exercise relevancy, I think, was I saw it as a stepping stone towards the therapeutic efficacy. So my PhD was in the lab, I probably know Kieran Clarke, and they— I remember talking to her about like her pathway and you're like, look, we don't want to go through like FDA approval for a drug. So we're going to show this as efficacy. I think the original project was like some super soldier project, the $10 million DARPA grant over 2003 for enhancing soldiers' performance. And then there were some like staple papers in humans and Cox et al. was the one that really got me interested. In the area. And then that was always going to be like, okay, now we've proven this is a potent molecule in humans. Let's now see what its efficacy is for disease states. So my PhD was in Parkinson's. Just as a quick aside on the taste thing, we were doing blinded trials. So we're using the monoester because like you said, it's quite potent and I needed to blind it, which means I needed to concoct something that was the placebo that was as bad tasting So there were days in the lab where I'm just like titrating in this terrible bitter agent to try to get taste matched anyway. So, and then I give it to patients, they always hated me for it. But so that's the ketone ester, potent potential, big pros or big or potential drawbacks. And then what are MCTs? Because I think people have probably heard of those. How do they differ?

Yeah, I like to describe like MCTs as kind of like the poor man's ketone ester. I was introduced to Medium Chain Triglycerides by Dr. Mary Newport in 2008, when I just learned about ketone esters, actually from a— from actually from just going and seeing on the DARPA what was being funded. And I was exploring that for oxygen toxicity. I was like, wow, I could come up with an oxygen toxicity anti-seizure mitigation strategy that, that also enhances performance. So instead of using the anti-seizure drugs, but MCTs caught my attention because the local news here, the St. Pete Times, published a paper which later became— well, the subject, Dr. Steve Newport, he was the, the husband of Dr. Mary Newport. It became a case report using the Oxford NIH ketone ester. And it's the only case report where there's chronic administration, you know, of the ketone ester. And I was I saw the blood work and I was very— I know the dosing. I know a lot about that case because Dr. Newport is a very near and dear friend, friend of mine, and she would guest speak in my class and in other, other things. But Steve responded remarkably well to coconut oil, and coconut oil is a source of medium-chain triglycerides. And the thought was that his response in regards to cognition— he did a clock test. At the Byrd Alzheimer's Center.

He had Alzheimer's, right? I don't know if I said that.

Yeah, Steve Newport had advanced Alzheimer's disease, and Dr. Mary Newport, at the time, she was the director of the neonatal intensive care unit in St. Pete. So she was a medical doctor, she was very experienced and very knowledgeable. And she basically saw that coconut oil could enhance her husband's cognition, his He became more lucid, more animated. And I later observed this and she investigated like MCTs, like where do you get MCTs? And she found, uh, or prior to that, she was looking up things that could improve and symptomatically treat Alzheimer's disease. And she'd stumbled upon AC-1202, the patent, and within the patent it listed the ingredient of AC-1202 and it was, uh, caprylic triglyceride. So that's an MCT. So yes, I'm remembering. So then she went out and got coconut oil because MCTs are derived from coconut oil, gave that to her husband. So that's the story. And he responded remarkably well and improved on the clock test, which was sort of validated at the Byrd Alzheimer's Center at USF. And, and then later she realized, oh, well, she can just go out and buy MCT oil. So she was mixing up MCTs oil, giving it to her husband, and he improved progressively more on the Mini Mental Status Exam and on the clock test and on various objective measurements used for Alzheimer's disease. This caught my attention, and we started basically formulating our ketogenic diets with a high concentration, about 50% of the fat or 60% as MCT. So when you consume MCT, it goes directly to the liver via hepatic portal circulation. It's not packaged into chylomicrons. And the stimulation of beta oxidation in the liver contributes proportionally to much greater ketone production. In addition, unlike long-chain fatty acids, MCTs can get into circulation, and medium-chain fatty acids can cross the blood-brain barrier. So you have medium-chain fatty acids crossing the blood-brain barrier and also ketone bodies, which are generated from MCTs, uh, being able to fuel the muscles, the heart, and especially the brain. And they're very versatile, they're very stable molecules. And I think, you know, they're, they're like the, like I said, the poor man's kind of ketone ester. And they have unique ability that when they're formulated with ketone esters or with ketone salts, we'll talk about later, they enhance the efficacy, safety, and pharmacokinetic profile, shifting it to the right. So you get greater sustainment of ketosis over time.

So just to clarify, so I'm gonna take a step back a little bit and talk a little bit about digestion if people don't know. So when you eat macronutrients, say fat, protein, or carbs, generally the protein and the carbs get absorbed in the small intestine. They go into the bloodstream, portal vein, straight to the liver. Fats are a little bit different where typically these long chain fats, so they're defined by the number of carbons in the chain on the fatty acid. They get packaged into these, uh, Dom mentioned them, chylomicrons, and they circulate around your lymphatic system. But MCTs, which are like shorter chain, they have fewer carbons, they go more the path of protein and carbs. So they go straight to the liver and they have other metabolic properties like getting directly into the bloodstream, getting directly into mitochondria. They don't need the same transporter, so they're much more efficiently and quickly burned and then turned into ketones. So they can boost ketones directly, get into the blood, as you mentioned, then go straight to the brain. I'll just mention one other aside. This is a, a novel thing, but I was reading a little bit on intercell and interorgan mitochondrial transfer. So there's some new literature on cells actually trading mitochondria between them. And it's very interesting, long-chain and medium-chain fats have opposite effects on this transfer. So they might actually be changing like energy homeostasis at the level of the fat cell, which is quite incredible. So High-level point here, just the chain length on a fatty acid can radically change the metabolism. And then to double-click on something else you said, which I guess is intuitive but I never really thought about it, you can use these to boost your ketones, but you can also formulate them with other true exogenous ketones like the esters to make— you mentioned the spike earlier— less of a spike and more of a smooth like rise and steady, steady level, if I got that accurately.

Yeah, you're stimulating endogenous ketone production. MCTs also delay gastric absorption and, and the hydrolysis of like a ketone ester or the absorption of a ketone electrolyte salt. So you can also, when you combine them with a ketone salt, you can get higher ketone levels than either one used alone. So that's actually like, you know, a patent, you know, that I— that we have at USF.

So probably more tolerability too, right? Because you can't take super high doses of MCTs. They can upset your stomach and you get a huge salt burst with the salt. So you can probably combine them for more tolerability.

Yeah, that's the limitation of MCTs is that they cause— can cause gastric side effects in some, as little as a teaspoon. But what I observe over time is that the more you take MCTs, you're you're better able to absorb, transport, and use them, and they become more ketogenic the more you use it. So it's almost like training your liver. It's ramping up beta oxidation of fatty acids, and I think the transporter gets upregulated too. So over time, I was able to absorb 68— I think 100 milliliters over time, and I consumed that for like weeks on end and could stay, you know, using MCTs only within 1 to 2 millimolar of beta-hydroxybutyrate. So that's possible. Not everybody can do that.

How much is that in like, that's like 5, 6, 7 tablespoons?

Yeah, so about 30 milliliters per tablespoon. Yeah, I was getting upwards, I think about, I think I worked up to 150 milliliters of MCTs and that was spread across like 4 meals. If I take MCTs on an empty stomach, It's not pretty. But if I can— if I take MCTs and combine it with a food, for example, you can make salad dressing out of it. You could do like— I do extra virgin olive oil and, you know, MCT oil. Or you incorporate it into food when you're eating protein. That tends to slow gastric absorption in a way, and you can kind of train your body to absorb more MCTs over time. So it becomes a very cheap, effective, and safe way to produce hyperketonemia. Hence the, you know, there was even Axzerra, which was a medical food, and there's various patents on caprylic triglyceride, which is this, the 8-carbon MCT. If you buy MCTs in the store, it's usually about half C8, C10. Now there are some interesting effects of C10 and even patents on it for anti-seizure effects. Uh, and I actually—

mitochondria, right? I think I remember reading the brain versus the C8?

Yeah, yeah. Well, yeah, I think so. I think some of the literature, you know, people have patents on that molecule. So I think some of it gets a little bit commercialized and sensationalized a little bit. But I do think that there's some unique qualities to C10. It is ketogenic. I would say C8 is slightly more ketogenic. In our studies, maybe like 20% more. But I think the, the go-to would be to buy like NOW brand. I don't have any partners or anything, but a simple like NOW brand MCT would be kind of like a go-to. It's cheap, it's effective, and we've used it in our research.

Right. And people can measure if they want with Keto Mojo or something. They get their blood ketone levels. What rise do you think they should expect to see with, uh, say like a tablespoon of MCT? Let's say that they're carb but not keto.

Yeah, 20 grams of MCT on an empty stomach will produce GI upset in about 25% of people. So I would start very low with like 10 grams of MCT or 10 milliliters and then add— have that with food. And then once you get to about 20 to 30 milliliters of MCT, like in a meal, you're going to see a rise definitely above 0.5 and approaching 1 millimolar. Once you get up to about 30 milliliters, 30 to 40 in some people. But that could be a threshold for people. So yeah, there is a limitation of MCTs and I've talked to some people who just cannot tolerate it at all. And other people do really fine with 3 or 4 tablespoons a day. But I don't think these things are not mutually exclusive. And then we can talk about that, combine things. So unfortunately, pretty much all the literature is just like, you know, it studies something in isolation as a monotherapy, like the ketone mono, you know, that was just studied like in isolation. But we repeatedly show that, you know, formulation of things is when you really start to get better pharmacokinetic profile and better therapeutic effects.

And so just kind of give an example of how this could work. We're talking about a 1 millimole boost. So kind of from like a zero baseline. But if you want to like hit a threshold of say 3 millimole, which can be very difficult to do with just diet alone, rather than going like full-on extreme protein-restricted 3:1 or 4:1 keto, you could do like a, a 1.5:1. So 1.5 gram of fat for every 1 gram of protein plus carbs, and then stack on that something like MCT or formulate the diet so the fatty acids include more MCT. Before we get on to ketone salts, speaking actually about different fatty acids is I've actually found the most potent thing to increase my ketones with respect to diet composition, fatty acid composition, isn't MCTs but more polyunsaturated fats. So in particular, sesame oil, like I can get— it's a longer time frame, it's usually like next day, but something like 6 millimole having like 3 tablespoons or something of sesame oil. I know in general my impression is polyunsaturated fats are more ketogenic Because it adds into this very controversial omega-6 seed oil space, I just wanted to get your thoughts and if you'd seen other people respond like me with a very ketogenic response to a higher PUFA ketogenic diet.

Yeah, I'm one of those people too. Yeah, I do have a higher ketogenic elevation if I incorporate more, more PUFAs for sure. And I think it's There's— I've talked about this, you know, with different people. It activates PGC-1α and various fatty acid oxidation enzymes, like, over time. And, and I think just the, the transport to the liver, and they're, they're more easily oxidized, and so they're stimulating a little bit faster, greater beta oxidation in the liver. And the rate of beta oxidation in the liver dictates endogenous ketogenesis. So you kind of are deriving more ketones from the accelerated, you know, beta oxidation in the liver. And, and there's, there's a couple papers on PUFAs stimulating these fatty acid oxidation enzymes and various pathways linked to ketogenesis. So I think that's— there's a lot to— a lot that we don't know, but I think it's Pretty clear in the literature that PUFAs are more ketogenic than, than saturated fats.

And just to kind of give this a little bit more form and make a broader point, you hear this phrase, I'm gonna see how, if you agree or disagree with me, that you are what you eat. And I've always hated it. It's to me always like you are what your body does with what you eat. And when it comes to something like PUFA or seed, like seed oils, your metabolic state and your lifestyle therapies really influence the fate of, let's say, the linoleic acid omega-6. So if you have obesity and you have a high inflammatory environment, that could get turned into very harmful compounds. If you're, say, lean, active, cold plunging, ketogenic, the fate of that molecule is going to be entirely different. So it's not to say good or bad, it's to say like the metabolic context is really interacting with these molecules. And so yeah, there can be like a biohack where, you know, you use a higher PUFA ketogenic diet to get higher ketone levels. At least that works for me. So agree or disagree? I just want to throw that out there.

Yeah, especially, well, in the context of a caloric surplus, you know, high PUFAs can be potentially damaging depending upon what PUFAs we're talking about. But in the context of caloric maintenance, a eucaloric diet or a caloric deficit, I think, you know, these fats become more ketogenic. Right, because you're suppressing insulin signaling. The suppression of insulin signaling drives hepatic ketogenesis. So these molecules are directed more towards, you know, ketone production. But if you have surplus amount of calories with, you know, and that usually, you know, it requires or stimulates higher insulin levels, then these fatty acids or any macronutrient is going to be shuttled into storage pathways that that can wreak havoc to your metabolic health and create metabolic dysregulation. So, but I think in the context of like a ketogenic diet that's calorie, that's eucaloric and that is in a slight energy deficit, I think these PUFAs could be quite, have ketogenic superiority and maybe some additional benefits. So, you know, we had in the American Epilepsy Society special interest group, there was a talk about these PUFAs having, uh, sort of anti-seizure effects too. So, uh, there was a, a lot of talks were about the DHA and EPA omega-3 fatty acids, but just PUFAs in general are thought to have an anti-seizure, potentially neuroprotective effect.

There, you've heard it here. Dom's advocating for PUFAs having superiority over saturated fats. It's gonna be great.

Well, saturated fats are, are fine. You know, I, I think I'm messing with you. Yeah, yeah. And it's the ratio too.

Well, MCTs like caprylic acid is a saturated fatty acid. So is butyric acid, short-chain fatty acids, stearic acid. So, you know, one takeaway here, if the words are going over your head, is whenever you hear one of these categorical terms, ketone esters, saturated fat, polyunsaturated fat. It refers to a very diverse group of molecules whose biological impact depends on both their nature and the host who's consuming it, which is just a general truth that we often don't get into, but something I think we're teasing out here. I do want to get on to ketone salts because you've taught me some pretty interesting things about ketone salts. What is a ketone salt? Actually, I'm just gonna leave it at that. What is a ketone salt? How is it different than, like, what we've talked about so far?

Yeah, a ketone salt doesn't necessarily mean it's like, you know, sodium. When we talk about salt, we're talking about sodium chloride, right? And maybe just a little bit of a step back. Sodium chloride is associated with salt sensitivity and hypertension, right? Sodium chloride. So sodium beta-hydroxybutyrate, sodium citrate, sodium bicarb. When you ingest these things, that does not induce, uh, salt sensitivity, uh, you know, an elevation of, of blood pressure. So that's unique to— so when you're talking about, you know, getting excess sodium and that could elevate your blood pressure, that's specific to sodium chloride and something about the, the chloride too. So that's important, you know, when people are like, well, I can't take a sodium ketone salt because of the sodium overload, but because I'm salt sensitive and increased blood pressure. But, but that's unique to— not most people don't know that if they're not like renal physiologists studying hypertension. So I want to throw that out there. However, I mean, it's possible to— with the limitation of ketone salts is the mineral load, right? So it's important to you have the potential, a number of potential molecules that can be ketone salts. So you could have, you can have an amino acid salt. So there's just an ionic bond there. You can have, we've made like arginine, you know, beta-hydroxybutyrate. So that, that's kind of nasty. It's like a black tar-ish stuff. So you can make the ketone salts that I think that, you know, just to make it simple, are beta-hydroxybutyrate combined with monovalent or divalent cations. So in simple commercially available terms, that means sodium, potassium, calcium, magnesium. There's lithium salts too that we use. So you could take lithium and combine it with acetoacetate or beta-hydroxybutyrate. Uh, but the, the commercially available ones are sodium, potassium, calcium, magnesium. And you could spread the electrolytes in a way or formulate it in a way that you could have very high bioavailability, bioavailability, tolerability, and safety with these ketone salts.

Okay, it's future Nick again. We had a little bit of a file corruption. I apologize for that. So we lost a little bit here, which is why it's going to be a little bit of a jump cut. That sucks. But fortunately, we recovered almost everything. So back to our interview. I do want to get to— let's just say if you were to generate a PSA cautioned for ketones containing 1,3-butanediol, which I think are quite common commercially. What would that be?

Yeah, 1,3-butanediol is a remarkable molecule that has been studied since like the late '50s and '60s. And we've got some beautiful data with 1,3-butanediol, some of our cancer data. It is remarkably ketogenic, but it is important to appreciate that 1,3-butandiol is an alcohol. It's like an alcohol dimer, I guess you would say. It's a, it's a diol. It's in the diol. So when you consume 1,3-butandiol, it needs to be transformed and metabolized by the liver to produce beta-hydroxybutyrate. When you consume ethanol, it's metabolized in the liver and produces acetate. Acetate goes to the brain And the dependence on alcohol is actually linked to ethanol-induced acetate production, but also some of the GABAergic effects. So from the ethanol itself, and that's a whole topic that we could have a whole nother podcast on, alcohol metabolism. But 1,3-butandiol is an alcohol. Uh, it is metabolized by alcohol dehydrogenase, the first step, and the second step is aldehyde dehydrogenase, which makes 3-hydroxybutyric acid. Butanol. And, uh, so the important thing to know that enzymatic conversion in the liver of 1,3-butanediol to beta-hydroxybutyrate is a two-step reaction that consumes a lot of NAD+. So it will rapidly deplete your liver of NAD+ and it will also rapidly deplete the liver of ATP. So this is important to know. I've always known this, but— and we also take a step back. So we have inadvertently killed quite a few mice and rats, unfortunately, by administering ketone esters that are 1,3-butanediol-based and 1,3-butanediol by itself. It produces— basically, it produces ketoacidosis. So it overwhelms the body. But so a acutely. But what we did not know, uh, until maybe more recently is that when we integrated the 1,3-butandiol into food and had the animals eat it, we had a whole colony of, of mice die. And these were mice that had a genetic disorder. They were a CRISPR-generated mouse model of glycogen storage disease type 2, or POMPD, disease. So these mice don't have— they don't, uh, some the mice that are super sensitive lack NNT. So we can go into that, but NNT is sort of helps the liver regenerate NAD+. And there's the C57 black 6 mice, the line that many people use, lack this NNT. So the important thing to know is that that is like the, the canary in the coal mine. So we saw that these mice were dying, we had rats that were dying that had fine NNT, Sprague-Dawley, Fischer rats and things like And then we, when we fed food that was integrated with the 1,3-butanediol, what concerned me more is that when fed chronically, it wasn't inducing like acute ketoacidosis, but they were just, they were dying and we didn't know why. And we had, we had an, an old tech report that we kind of repackaged and add some more data and we recently published. And the gist of that tech report that looked at liver histology and also some blood biomarkers, including TNF-alpha and arginase, is that 1,3-butandiol is not benign, and that when it's consumed chronically in a high dose over time, it causes changes in liver histology that are unfavorable. Sinusoidal dilation, which is basically like occurs with alcohol, uh, it sort of backs up the The, the blood flow in the liver, uh, TNF-alpha is elevated, arginase is elevated, which is like a liver biomarker. And I observe early on, I was consuming a lot of 1,3-butanediol before we made the ketone esters. This is like more than 50 years ago. And, uh, don't do this at home, but, uh, so the— to get around the taste of 1,3-butanediol, I would make 1,3-butanediol Jell-O shots. So just basically take like a sugar-free Jell-O cherry, pour it into a pan, like mix it in with the Jell-O, and then take the Jell-O shots and, and consume it. And over time, I consumed like 80 to 100 grams of 1,3-butanediol because that's what was needed to produce and maintain a ketone level of 2 to 3 millimolar for 2 weeks. So when I did that, my transaminases popped up a little bit, and that was a little bit concerning. AST and ALT, but GGT also, like, that's a more sensitive indicator of liver stress. So GGT bumped up, bumps up quite a bit with that. And that's a very sensitive— if you're looking at blood work and you suspect someone has like a problem with alcohol, or you could direct them to get blood work and say, you know, measure GGT, and that'll be the indicator of whether or not they're like, you know, taking up too much alcohol. And just, it's important to measure, to know that just 2 glasses of wine per day could pop up your GGT. And this is kind of what I was seeing, like with the 1,3-butanediol. So, but my liver is super healthy. I take N-acetyl cysteine, I take alpha-ketoglutarate, or I take alpha-lipoic acid, which is like, you know, helps the liver. My concern with 1,3-butanediol is older people taking it chronically that have— as we age, our ability to metabolize alcohol drops sharply, sharply. And also people who have underlying metabolic problems and like who don't have healthy livers. And I think if they're consuming 1,3-butandiol or 1,3-butandiol-based ketone esters chronically, we do not have long-term data on it. There's like Steve Newport who consumed it, and I think his liver enzymes were trending a little bit high, but he was also doing a lot of other things. And then we have some data Well, I'll send you a list of the publications that suggest—

Yeah, I can add them to the notes. So just to kind of take a step back, 'cause really went into the weeds there, which is great. This 1,3-butandiol, which is very common in ketone supplements, I think commercial ketone supplements, it's cheap to produce. It's an alcohol. Chronic use can harm the liver, it sounds like, cause liver dysfunction, almost backing up of these channels so there's less outflow, inflammation, and then in humans increase markers of liver damage. So the transaminases you mentioned, if you go and get, you know, some labs done by your doctor, they're probably gonna see something called liver function tests, LFTs, AST and ALT are two of them. Those can go up, they're markers of literal damage to liver cells. And then another marker you mentioned, GGT, which is a little bit more sensitive for maybe alcohol-induced liver damage. So if you are taking a ketone supplement with 1,3-butanediol, those are probably markers you should have checked, an AST and ALT and a GGT. To see if there's any damage potentially occurring. And if they're uptrending, it's probably not a good sign.

I started seeing this, you know, I've connected with a lot of people, but looking at their blood work and also the, the red blood cell will also, the changes in the size of the red blood cells, you'll start to see that too with HIIT. So these are people that, you know, had a disorder, they're taking it for cognitive function, they're consuming quite a lot chronically, and there is a a paucity of data on high-dose chronic use of 1,3-butandiol. I mean, it just doesn't— it doesn't exist. I mean, there's one study, I think, with maybe 28 days and maybe normal AST, ALT, I think. But in our AST, ALTs actually in our rats were normal. But the take-home message, uh, is that like you could have hepatic steatosis and non-alcoholic fatty liver disease and have almost normal AST, ALT. An alcoholic that has done damage to the liver, you know, those enzymes sort of, you know, can adapt over time and can have relatively normal, uh, but could actually, you know, AST transaminases, but you could have some pretty remarkable histological effects. What we were seeing is that a lot of red blood cells and just changes in, in the, in like the the liver cytoarchitecture itself, but also we measured like TNF-alpha and arginase. And that's something that you're not going to get in bloodwork. But they were sort of early indicators that it's a liver stress and it's depleting hepatic glutathione. As you know, Dr. Lustig, Robert Lustig, he's like really big advocate of keep the liver healthy. So there's sort of some better options for ketogenic agents. You know that, and I think there's also like about at least 5 or 6 studies showing that 1,3-butanediol can sensitize the liver to other toxins, meaning that they did— I forget the— what they used, but they gave the rats like some common toxin that's like in water and maybe a half dozen other toxins and gave 1,3-butanediol, and those toxins become— became much more toxic. When the animals were eating 1,3-butandiol. So the 1,3-butandiol sort of weakened the, the body's ability to detoxify, and things that were otherwise nontoxic became toxic with the 1,3-butandiol.

And these are the antioxidant systems, presumably.

Yeah, cripples the glutathione, and it, you know, by virtue of just like the alcohol dehydrogenase and the aldehyde dehydrogenase, so it's robbing the liver of NAD, lowering ATP, but also generating that aldehyde. So that aldehyde is also— can, you know, damage, you know, proteins, nucleic acids, and things like that if it's generated. That's typically not a problem because the aldehyde, 3-hydroxybutanol, is short-lived. But if you saturate the aldehyde dehydrogenase enzyme, then that can build up and become toxic.. And you can saturate— Dr. Henri Brunengraber did studies in a dog model where they saturate that. And you know, you saturated it because you keep giving 1,3-butandiol and beta-hydroxybutyrate does not get higher. So, so I was like, I mean, that was my early kind of questions to Dr. Veech when I was trying to acquire the ester initially, I was like, well, send it to me. I was like, well, I'll just use 1,3-butandiol. And he's like, his comment was, you'll get drunk stupid. So he would always, he was kind of, um, had some articulate, you know, ways to, to, uh, he was super nice guy, super sharp, but he was like very direct. And he made it clear to me that 1,3-butandiol would make you drunk and that the ester was really the only way to safely elevate 1,3-butandiol, to safely elevate beta-hydroxybutyrate into the ranges that he thought was therapeutic. But my opinion after doing a lot of research is that higher is not better unless you're treating some kind of rare, you know, metabolic disease or like severe dementia or something like that. Once you— once the ketones get above 2, that's when you release insulin. And ketone salts, MCTs, like these do not release insulin, but ketone esters and 1,3-butandiol to some extent will increase insulin. And then essentially what you start to get is energy toxicity. Once you get into that 3, 4, 5, 6 range, you get ketones in circulation and you get spillover, right? It's just like, you know, like we're not trying to get higher glucose levels. We're not trying to get— so higher ketone levels above 2 represents too much energy in circulation that can cause reductive reductive stress rapidly—

if it's exogenous.

Exogenous. Yeah, very good distinction to make because you do not get that even in the context of fasting. If you fast for like, you know, 7 to 10 days, your ketones can be 5 millimolar, but your glucose is low and the body has a very elegant way to maintain energetic homeostasis. However, if you are taking exogenous ketones and. And that threshold, once you get above 2 millimolar, then you start to create a lot of problems, I think energetic problems and reductive stress. And there's a number of studies that were done by— not sure it was Veach, but studies that were done in the '70s, '80s, and '90s, and showed that, you know, if you increase ketones all the way up to 2 millimolar, basically you get uninhibited transport and utilization of energy. But once you get above 2 millimolar, then it starts to basically back up, then you get like spillover, and then it's contributing to processes that could be termed reductive stress, which is energy toxicity. So I'm very— and in our rats too, we never see any kind of toxicity, you know, at 2 millimolar or below. But once we get to 3, 4, 5, I mean, we start to see changes in blood pH, we start, you know, they start having signs and they look unwell.

Yeah. So we've delved into a lot. I'm going to give the Cliff Notes version quickly. Exogenous ketones, very complex area. We've gone over ketone esters, which themselves have a bunch of different profiles, but they're generally very potent, which means they can have therapeutic efficacy, but also potential risks. And they don't tend to taste that good and they're expensive. MCT oils, which are kind of the poor man's ketone. They get processed very quickly as fatty acids into ketones, and they can have direct effects on the brain and other organs because it can get transported through the blood-brain barrier and around the body. Ketone salts, which come in the just the D form or this race mix form. And I think we agree now, you've convinced me that the race mix that contains the L has particular benefits because the L has very potent signaling properties. Including on cardiovascular function and potentially in the brain too. And then you have the 1,3-butandiol, which has some potential harms, particularly on the liver. Yeah, you have to take a lot of it to get a big ketone bump. And if consumed chronically, it can potentially cause some damage. So, there's a lot more we can go into in the universe of ketones, but I want to wrap this conversation here and get on to part 2 of our conversation Before I end this part, where do you want to direct people if they want to learn more about you, follow you, advance the discussion beyond this interview about exogenous ketones?

Yeah, thanks for asking. I have an information website ketonutrition.org, ketonutrition.org, and we also have an education platform, the Metabolic Health Initiative, which is an ACCME accredited medical medical education platform that teaches practitioners and clinicians and, and anybody who wants to learn sort of the, the science and the application of metabolic-based therapies. And it's not just all ketogenic. I mean, we have— we talk about metabolic drugs and GLP-1s and fasting and exercise and things like that. Uh, so, and the Metabolic Link podcast, so, which you have been on. So that's— you'll find that link on the Metabolic Initiative platform. Awesome.

Thanks, Tom.