Episode 66: Ketosis Fundamentals - Diet, Fasting, Exogenous Ketones, and More

If you had one hour to teach a friend all about ketosis, press the play button and sit back.

In previous conversations, host Geoffrey Woo has touched on many aspects of ketosis: The research that has been done, the metabolic pathways that are activated, how burning fat for energy affects physical performance, and the different interventions used to reach a state of ketosis.

This episode acts as the source of truth. Geoff and Dr. Brianna Stubbs sit down to lay down the fundamentals, look back at the history, and ponder over what the future will bring.

In this discussion, you will discover:

• The difference between being in a state of "ketosis" and being "ketogenic"
• How to properly implement a ketogenic diet and the common mistakes many make
• The specific metabolic processes the body undergoes to use ketones for the body and mind

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Transcription

Geoff: Hey, welcome to this week's episode of the HVMM Enhancement Podcast. This is your host, Geoffrey Woo. And this week, we're again talking to Dr. Brianna Stubbs, our research lead over at H.V.M.N. Of course, one of the most popular things that we talk to people about, and also just in internal discussions, is around ketosis. What is a ketogenic diet? How does one do it? What are tools like exogenous ketones, and how are they useful for being in ketosis? And we thought, we've touched upon a lot of these subjects through fasting, through supplementation and diet, through performance, through therapeutic.

Let's just actually set the fundamentals here. Let's clear up the misconceptions. And I couldn't think of a better partner here to talk about this than Brianna Stubbs. So just a quick overview of her background. She holds a PhD from University of Oxford on keto metabolism, co-authored a number of the human physiology studies on ketones and ketosis. I really consider her one of the best folks in the world in this space. And I would say that I have good grounds to claim that because I've talked to literally everyone in the space. So I think I have a good measure. Great to chat.

Brianna: He flatters me as ever. But I'll do my best, and we can, as you say, unpack some of the common misconceptions and just try and give people some clarity. Because I think, especially nowadays, people are getting more and more of their information on the internet. It's kind of a confusing place. So it's trying to point people to good sources of truth and providing good source of truth here ourselves, as well.

Geoff: Yeah. And I think of a lot of the internet discussion is actually quite poor in quality. Just to give some road signs on where I want this conversation to go, I think just define again what a ketogenic diet is, and I think some of the interesting applications around sport performance. I think there's a lot of misconceptions there. We can talk about some of the longevity, therapeutic potential around ketosis. And also some of the cognition-related, interesting facts and research going on in cognition and ketosis. As a rough road signs. And also just, how does one get into ketosis through diet, and how does one get into ketosis through supplementation or product?

Brianna: I think you're setting me an interesting challenge there, Geoff. That could be four or five podcasts' worth of stuff. Especially-

Geoff: Yeah, let's dive into it.

Brianna: Especially the amount I chat.

Geoff: But I think let's just set the fundamentals for everyone. So starting from the top-

Brianna: I feel like the term that confuses people the most is the term ketosis itself. And so I think it'd be really, really helpful for our listeners if we define what, in the scientific community anyway, is recognized as ketosis. So if you look at all of the papers, ketosis is normally referring to blood ketone levels. So ketosis is the state of having elevated beta hydroxybutyrate. And if you have elevated beta hydroxybutyrate, that means that you're burning it for fuel. So that is very different and distinct from the process of being ketogenic, which means that your body is using fat to make ketones. So there's a difference between being in a ketogenic state and being in ketosis. And really, until exogenous ketones came along, they weren't really ... You couldn't really separate them. So if you were in ketosis, you had to be ketogenic, because you had to have made those ketones yourself.

But now, we're advancing in the technology that people can use to get into ketosis, but that just means they have ketones in their blood, and can burn ketones as energy. It does not mean that your body has made ketones. And that is one of the things that I see tripping people up the most. So they argue that exogenous ketones don't lead to ketosis. Well, they most definitely do, because you have three to seven mM of ketones in your blood. So not only do you have ketones in the blood, but you can burn those ketones for fuel, and that's part of the reason that we think we see improved performance with ketone ester drinks, for example.

But that is completely distinct from the state of being ketogenic. In fact, as we've discussed on this podcast before, if you drink exogenous ketones, that even may slightly slow down, for a brief period of time, the process of generating your ketones. So I think that's a really, really important hook to hang the whole conversation on, the difference between producing ketones naturally and having ketones in the blood through a supplement or a food.

Geoff: Yeah. And I think that's a really important point because, again, it's a relatively novel intervention to make this actually happen in human physiology. And I just want to reiterate to the listeners out there that in normal physiology, one has to produce ketones by your own body, by your own liver. So you're ketogenic, and therefore your body is in ketosis.

Brianna: Yes.

Geoff: However, with exogenous ketones, like our ketone ester drink, H.V.M.N. Ketone, you can actually not be ketogenic in terms of your liver producing ketones, but be in a state of ketosis, which is typically defined as above 0.5mM-

Brianna: mM of BHB.

Geoff: Of BHB. And just to make sure it's super basic, beta hydroxybutyrate, or BHB, is the main ketone body that our bodies use as a fuel.

Brianna: So yeah, just to follow on from that, people might have heard of beta hydroxybutyrate. That's the one that we measure using the finger prick. Then there's also acetoacetate. That's another one that's in the blood, but it's more difficult to measure, so people don't tend to talk about it so much. But it is important as well. It's less ... If you look at the amounts of those in the blood, beta hydroxybutyrate tends to be higher than acetoacetate. And then the the third ketone that people have heard of is acetone. And that is the one that people will measure in the breath. So if you have a gas meter that you breathe into, that's measuring acetone.

Geoff: Yeah. I think that's interesting. That tees into the chemistry here. So beta hydroxybutyrate is a lot more stable than acetoacetate, as you mentioned.

Brianna: Which is part of the reason that most supplements have beta hydroxybutyrate rather than acetoacetate, because it's more stable and easier to formulate.

Geoff: But in the Krebs cycle, when it actually starts fueling the mitochondria, beta hydroxybutyrate converts into acetoacetate. So think of ... I like to think about BHB as the stable, transportable version of ketones. And then right when you actually need it for fuel, BHB converts into acetoacetate, and then breaks down further and fuels mitochondria.

Brianna: Yeah, exactly. I was worried you were going to go down a super technical rabbit hole there, but that's a good level of understanding.

Geoff: Where does acetone come in, then?

Brianna: Acetone ... The conversion of acetoacetate to acetone happens spontaneously-

Geoff: Because it's unstable-

Brianna: Because it's unstable. And then it's excreted in the breath. There are some pretty in the weeds metabolic pathways, where you can argue that acetone might hop back in and be used in metabolism, but they're not very big pathways. Most of it's excreted.

Geoff: So those are the three ketone bodies that people typically talk about, in terms of physiology. But the listeners out there might have heard of something called the raspberry ketones. And that is-

Brianna: Separate altogether.

Geoff: Can you help explain?

Brianna: To go back to the point you made initially, if we talk about the chemistry of what's going on. If we're talking about chemistry and not physiology, ketone just means carbon double bonded to an oxygen. So you can have chemically ketone compounds that are not present physiologically inside the body. So raspberry ketone has a ketone chemistry functional group, but it is not at all structurally similar to the ketones that are made by the body. I don't know whether anyone has ever seen drawing of molecules that have a hexagon or a ring of carbons. Raspberry ketones have this ring group, and then the ketone bit sticks off the side. Where as beta hydroxybutyrate and acetoacetate are straight chains. So it's very different, and it cannot be broken down and used for fuel in the same way. But another reason people get confused is that there's some very preliminary animal data looking at dropping raspberry ketones onto fat cells, that makes it look like this compound might affect fat metabolism in some way.

Geoff: It looks like it's very poor quality. I would say that most people discount that a lot. I think if you just look at the body of evidence on various compounds, which we do all day long, it's very, very speculative. Like the dose levels are crazy high-

Brianna: Yeah, the dose level, you'd never get at in people, but-

Geoff: And you would never supplement or eat that much.

Brianna: Exactly. But the reason the confusion arises is that there's the name ketone in there, and it's linked to fat metabolism, when in reality, it's structurally nothing at all like the physiologics of ketones.

Geoff: Yeah, it's thinking about it as a raspberry extract, really, is what raspberry ketone-

Brianna: Yeah. It's a plant compound. It has this specific chemical function or group that is common to ketone body, physiological ketone bodies, and it does not act as a fuel in the same way as ketone bodies.

Geoff: When you mention that, we could dive down to the rabbit hole, I think that would be an interesting conversation for a different episode. But I think there's a very interesting discussion around why ketone metabolism is different from glycolysis, glucose metabolism, how it's different from beta oxidation to fat metabolism, and how that affects metabolics in the Krebs cycle. Things like NID, NIDH, which also have been interesting across longevity research in humans.

Brianna: I think if there's anyone listening that ... If there's anything we're talking about that tickles your fancy, please comment or write into podcast@hvmn.com, and let us know, because we have these kind of conversations in the office all the time. So sometimes, maybe having a fly on the wall microphone would be-

Geoff: We can share some of the thoughts. It's just an interesting thread, starting from really, Sir Hans' Krebs back in, what, '50s? Earlier?

Brianna: '50s, '60s, yeah.

Geoff: Who won the Nobel Prize, defined what the Krebs cycle really was. And I think why we're so interested in this space of ketosis is that it's just so fundamental to metabolism, which is the fundamental creation and destruction of energy in our bodies.

Brianna: But I think another thing that is maybe going to be a teaser, maybe we'll talk about it another time, is that ketones are not only affecting metabolism and energy production, but also affecting gene expression as well. So there's a ton of ... And if we shift slightly to thinking about the ketogenic diet, when people follow this diet for a while, they have changes in gene expression that equip them to metabolize fat and ketones better, and so now, we're interested in understanding that, but also understanding how taking ketones as a food could also do similar things.

Geoff: So the buzzword is epigenetics, right?

Brianna: Epigenetics.

Geoff: How can your environment affect gene expression?

Brianna: And it's obviously a really important part of the environment.

Geoff: Yeah, which I think is a perfect segue. So okay. Ketosis, ketogenesis, different concepts.

Brianna: Raspberry ketones, not a physiological ketone.

Geoff: Right. So how does one get into ketosis, or get into a ketogenic state. So obviously, the most fundamental way to do that is eating a ketogenic diet.

Brianna: Well, actually, I'd argue the most fundamental way to do it would be fasting.

Geoff: Fasting, yeah.

Brianna: So this is all of the old studies-

Geoff: Okay, let's start with fasting first.

Brianna: Yeah, let's start with fasting first. I always like to look back at the studies that were done in the '50s, '60s, by a scientist called George Cahill. And it was cool because back then, you could get ethical approval to just starve people for days and days and days on end. There was actually one guy who, he put himself on a fast that lasted-

Geoff: Over three hundred sixty-some days.

Brianna: Yeah, like a year long. And so-

Geoff: But this was an obese man who was 400 pound, over a year-

Brianna: Lots of weight to lose, yeah.

Geoff: He had multivitamins-

Brianna: And water, as well. Salt tablets ... Anyway, we're getting super sidetracked. But what these studies done on people just fasting for medical reasons, were what gave us our early insight into natural ketone production. And so they saw that it takes maybe up to 30 to 40 days for ketone levels to reach a plateau, and they rise slowly over that time.

Geoff: How many days?

Brianna: I think the whole study was 40 days long.

Geoff: Right, right, the Cahill study was 40 days long. But the plateau-

Brianna: The plateau was maybe a little earlier. I think it was 25 to 30 days.

Geoff: The plateau for ketones is around 10, 15 days.

Brianna: That early?

Geoff: Yeah.

Brianna: And the plateau tends to be around-

Geoff: Six mM.

Brianna: Six mM. Which is interesting, because it shows that the body has a natural level of ketones that it maxes out as. I like to compare it a little bit to our blood glucose levels. So I know Americans work in milligrams per deciliter, but in Europe, we work in millimolar, and the range for glucose is about four ... Between three point five to five mM, fasted. And actually, so ketones are at a similar level once you reach that natural plateau. And so the whole point is that the body has a feedback mechanism to stop ketones getting too high, as we see in uncontrolled diabetes. So if you fast for a prolonged period of time, your carbohydrate stores in your liver and your muscles are completely depleted, and that means that the brain is ... The energy supply of the brain is at risk, because the brain really, really needs glucose to keep going, and we all know that feeling, mid-afternoon, when you're in between lunch and dinner, and you have something sugary that picks you back up and it keeps you alert. And that's because your brain needs that glucose to function. Fat is not able to cross into the blood-brain barrier and be made-

Geoff: Yeah, fatty acids are really big molecules, it doesn't transfer across.

Brianna: No. So that's a problem if you're not able to eat all of the time like we are now. Like, back our ancestors, they wouldn't have had a Starbucks on every corner. And so once they burned through their about 2000 calories' worth of carbs stored, they'd have been in trouble, because their brains, super super glucose hungry, and they'd have just passed out, fallen over. And so we evolved the ability to tap into our big old fat stores, and turn fats into something that could get across the blood-brain barrier, which is ketones, in this case. So if you look back at evolution, just as brains started to get bigger in different animal groups like mammals, that's when ketone metabolism starts to appear as a real protective mechanism for the brain during fasting.

Geoff: I think that was something that I actually have been reading a lot about. And we're one of the best animals at being ketogenic, in the sense that our brains are actually a significant portion of energy and metabolism.

Brianna: 20%.

Geoff: Yeah. And smaller-brained animals, like bears, for example, are hibernating for long periods of time. But their gluconeogenesis, the conversion of fat or protein into glucose, is enough to fuel the brain to not have to rely on ketones as much. So humans, because we have so much energy demand, our bodies can't convert enough fat ... Mainly protein, into glucose, and therefore, we really need to accelerate the level of ketones that our bodies can produce.

Brianna: Yeah. So fasting is the-

Geoff: I might have opened up a different can of worms there, of how glucose can be converted-

Brianna: Yeah, we can go into that one another time. But I think-

Geoff: But I think the summary is that fats convert into ketones, and that's ketosis.

Brianna: And the most rapid way to do it is just not eat anything, because that's the quickest way to deplete yourself of carbohydrate. And once you're depleted of carbohydrate, that's when-

Geoff: Your body is forced to revert into using ketones as fuel.

Brianna: Yeah. And another key point in the process is, the absence of insulin. So if you're not eating anything at all, insulin is released in response to a meal, so if you're not eating, then you don't trigger any insulin release. And that segues us nicely onto the ketogenic diet, because we can go into a little bit more there, but the main aim of the diet is to minimize eating foods that trigger insulin release, carbohydrate. So you can facilitate ketone production, you don't have to fast altogether. You can still eat calories, but no, or very few insulin-triggering calories.

Geoff: Right. Let's talk about some of the subjective effects around fasting, just to give a sense. I think some of the evolutionary explanations, which are somewhat hand-wavy, in storytelling, is the notion that one should be more efficient and effective if they're in a starvation state. But if one gets less effective, they'll starve and become stupid. That matched a lot of the anecdotal stories around where ... As Plato, had his students fast before entering the academy. A lot of religious figures fasted to get insight into how the world and how the universe was created. So there's interesting subjective accounts around how the notion of fasting jump-starts ketosis, which might explain some of the interesting states that humans have gone through in the past.

Brianna: And if we're going to really carry on way further down the rabbit hole, caloric restriction and fasting is linked to longevity, especially ... Clearly, in animal models, but also anecdotally in humans who regularly fast or go on hunger strike for religious reasons. They just live longer, and that could be because of the genetic effects of calorie restriction and ketosis.

Geoff: Right. And I think that's where some of the interesting research moving forward will be, is the benefits of caloric restriction from ketosis.

Brianna: They're two separate things, yeah. Subtle.

Geoff: Which I believe is still open science. So let's talk about ketogenic diet. I guess ketogenic diets really came into play as a way to treat drug-resistant epilepsy.

Brianna: Yeah, that's about in the early 1900s.

Geoff: I'm just wondering, did people just try to eat ... I guess there's been some discussion about Inuit tribes eating keto, just given they only could access to heavy protein and heavy fats, and not a lot of carbohydrates.

Brianna: And anecdotally, they would eat the fatty cuts of meat and give the lean meat to their sled dogs.

Geoff: Interesting.

Brianna: but I think, actually, whilst the ketogenic diet ... It's broadly accepted that in the early 1900s, that's when it started being used for epilepsy-

Geoff: I think that's when it was formally studied.

Brianna: Yeah, formally studied. But you know, I think it was Hippocrates that said to eat while you're sick is to feed your sickness. So fasting and using therapeutic ketosis was always ... Had a link in to disease. But yeah, I think specifically, for the ketogenic diet ... Well, and then William Banting, as well, in ... I think that was in the 1800s, he used a ... He talks about it in much-

Geoff: This was South Africa?

Brianna: No, he is not in South Africa. He was a British undertaker, and he was really overweight. And he worked with his physician. He'd been ... I identify a bit with his story, 'cause his doctor had been trying to help him lose weight to treat his gout, and he had had him rowing up and down the Thames. Being a rower, I identified with that a little bit. But then, his doctor was like, "Well, why don't you cut out all starchy foods and stop drinking beer and things like that?" And he lost a ton of weight on this very, very low carbohydrate diet. The reason you said South Africa is because now, there's a big movement of people following a low carbohydrate diet in South Africa, and-

Geoff: They call it the Banting.

Brianna: ... and they call it the Banting diet, using his name. But yeah, he was another early adopter. A very early adopter of the ketogenic diet. He published a pamphlet that was called A Letter on Corpulence that's funny to read.

Geoff: Interesting historical side factoid. But I guess it is proper to say that studied in clinics, studied clinically-

Brianna: In the early 1900s.

Geoff: ... in the early 1900s, was originally designed for treating drug-resistant epilepsy. And these diets, what was the macro ratio?

Brianna: As much fat as possible. So typically, under 25 grams of carbohydrate a day. Ideally, maximum under 50 grams of carbohydrate a day. 80 to 85 percent of the energy coming from fat. Low to moderate protein. Not a high protein diet, and a very, very low in carbohydrate.

Geoff: I want to underline there. Most people that I talk to that talk about eating a ketogenic diet are really eating an Atkins-style diet. And I think ... Let's just distinguish between what a low-carb diet is, what an Atkins-style diet is, and what a ketogenic diet is. Do you want to take a stab at it?

Brianna: I think really, the ultimate end point of a ketogenic diet is that it triggers ketone production. That's in the name. So without wanting to confuse people, if you're doing a lot of physical activity, you might be able to eat 60 grams of carbohydrate a day, and still be in ketosis. But some other people may have to eat much less carbohydrates-

Geoff: Like zero grams.

Brianna: Like zero, even, in order to be in ketosis. So if we're taking the highest level definition, a ketogenic diet is one that triggers ketone production in you, as an individual. A low carbohydrate diet, in the western community, we eat quite a lot of carbohydrate. And so there's no formal definition, but often, around 125, 100 grams of carbohydrate can be considered low. Typically, for clinically putting people on the ketogenic diet, like a formal program, people recommend starting at 50 grams for a typical ketogenic diet. So I think if we were broadly looking to define a target level of carbohydrate for it to be ketogenic, 50 would be an interesting place to start.

Geoff: Yeah, can you give a sense of how much carbohydrate that is? I've been eating very, very strictly keto-

Brianna: An apple.

Geoff: Right, is like 20-

Brianna: 20 to 25 grams, yeah.

Geoff: Right. So basically, when people say 100 grams, is that a lot or a little? Like a banana or an ounce of blueberries, is like 20, 21 grams of carbs.

Brianna: And the thing is, carbohydrates, not only in things that you'd expect to be in, but hidden in sauces and hidden in vegetables, even. You have to be careful about which different types of vegetables you choose, and how much of them you're eating. To really follow a ketogenic diet and keep your carbohydrate intake under 50 grams a day, it takes a lot of discipline. And I think the point you were making is that most people-

Geoff: I think most people are ... I don't want to say people are un-disciplined, but I think it's surprising how many carbs are in sauces or things that you don't expect.

Brianna: And vegetables as well.

Geoff: And vegetables. And then two, people overate protein. And I think that's what I was trying to get to with the difference between Atkins, low carb diets, with the ketogenic diet. So often times, people will say, I'm eating keto, I'm eating all this steak and meat, and pork and fish. And it's like, cool. But you're probably not elevating your ketone levels that much, because you're eating too much protein. And as we discussed, highlighted a little bit before, was that protein converts into glucose through gluconeogenesis.

Brianna: Yeah. I would like to put a cautionary note on this, and then maybe we can discuss this on another podcast, because I think there's also a lot of fear of protein on the keto scene, and I think the reality is a midway between people who overeat protein and trigger gluconeogenesis, and people who are afraid of protein and don't consume enough. Because without wanting to get too much into the weeds, protein has an interesting effect on glucagon, rather than just insulin. So it affects hormones differently to carbohydrates. So protein doesn't always equal gluconeogenesis, consumed at the right kind of amount. So it's nuanced. It's nuanced. I think what we're trying to say here is, protein is definitely a consideration, and it needs to be modulated, but you can't overeat protein and stay in ketosis, but you definitely need to have some protein in the diet-

Geoff: You have to maintain lean muscle mass, et cetera. And I think the hard part is getting enough fat content. So as you're saying, 80 to 85 percent of your calories from fat. So just think about that for a second. That is ... Unless you're ... One needs to be adding fat sources. So I can speak to this in experience. I've been eating very, very strict keto for the last six, seven weeks. And it's backed by also just doing finger sticks twice a day. So I'm measuring my blood ketones and confirming that I'm between one to three mM ketones. And in my fridge, one, I went from eating out a lot, because it's easier and more convenient, to cooking a lot. I basically have went from, essentially virtually eating every single meal out, to essentially cooking every single meal.

Brianna: What do you cook? What's a good example?

Geoff: So last night for dinner, I had a lot of ... I sauteed some garlic and onions, boiled it down in olive oil and butter, and then had six eggs in a six-egg omelet, and half a block of blue cheese.

Brianna: Nice.

Geoff: Like a lot of blue cheese.

Brianna: That sounds nice.

Geoff: And just melted it down.

Brianna: That sounds really good.

Geoff: Which was quite good. Often times, I'll also just cook down, you know those Costco bag sizes, or Safeway sized bag of spinach? Again, a lot of butter-

Brianna: Garlic.

Geoff: ... olive oil. And you just compress down the whole bag. This would have been a super, mega salad. And just shrinks down into a nice little bowl of steamed, oily greens.

Brianna: And I think it's interesting just to highlight that you're getting really good micronutrients through making sure that you eat leafy vegetables. And so sometimes, when people start a ketogenic diet, they end up with deficiencies because they change their diet so radically, and they don't necessarily make sure they're having a varied enough diet to get the nutrient sources that you need to stay healthy. To go back to the very, very top, it takes a lot of thought to do a ketogenic diet well, and I know that some of the leading researchers in the field, Jeff Volek and Stephen Finney, they talk ... Their buzzword is a well-formulated ketogenic diet. And whilst I feel like it gives them permission to point at anyone that gets a negative result and say, well, maybe your diet wasn't well formulated, they do raise the interesting point that it is very practical and healthful, so long as it has got the right components in it, whether calories, micronutrients, enough fat, things like that. And there's an art to it.

Geoff: Right. And I think that's one thing that a lot of people miss, is that, oh, you eat keto, that means you don't eat any vegetables. It's like, don't eat the starchy vegetables. I'm not eating potatoes, fries. Not eating beans. But I am eating a lot of leafy vegetables, which have fiber, which don't count as net carbs, because they don't break down into glucose. Your body flushes them out as a fiber-

Brianna: And I imagine you're adding a lot of salt to things as well, because eating keto can change the way that your kidneys are handling fluids and things like that as well.

Geoff: Right. Yeah. And then I think some of the interesting things, like instead of snacking on chips or something, I'll snack on pork rinds. Or these fluffed up cheese things.

Brianna: Oh yeah, those are good.

Geoff: The frozen cheese-

Brianna: Like moon cheese type things.

Geoff: Moon cheese type things. Moon cheese and pork rinds are great, go-to snacks.

Brianna: And salami, sausage, and things like that.

Geoff: A lot of cheese. I think it's a lot of cheese. And often, I'll just squirt in some MCT oil-

Brianna: Into your coffee.

Geoff: I'm not drinking any caffeine anymore.

Brianna: Oh yeah, of course.

Geoff: But that's another ... We can talk about caffeine as another discussion. But yeah. Through when I converted from a mixed diet to a ketogenic diet, a lot of heavy whipping cream, probably 500, 600 calories of heavy whipping cream with probably another 200 calories of MCT oil in cold brew, would start of my day.

Brianna: Yeah. So you're making a very conscious effort to make sure that your fat content is high.

Geoff: Yeah. And I think the first five days, it felt weird, 'cause your stomach is just not used to eating that much fat. Again, 80, 85% fat is nuts. When I'm eating steak, I used to throw away the fatty bits.

Brianna: Now you eat those bits.

Geoff: I eat the fat bits especially.

Brianna: With a slab of butter on the top. 'Cause otherwise, it's lots of protein.

Geoff: A lot of protein. Exactly. So I think one can go to this kind of extreme. I don't think it's that extreme anymore. I think I've pretty adapted to it.

Brianna: A lot of people find it impractical, though.

Geoff: You have to take a lot of thought. Yeah.

Brianna: And I think when you think about the origins of the diet, and therefore a therapeutic use, especially in children, it can be very difficult to get children to adhere to that sort of thing, and people are interested in the diet for Alzheimer's and neurodegenerative diseases, and those people also might have more trouble adhering. So there are limitations to the diet, broadly speaking. Which brings us onto exogenous ketones.

Geoff: But even before that, I think it is an important point to raise. I think ... We fast and then I've been eating keto for the last six, seven weeks. But I would say that hey, everyone in the world should be eating keto all the time. And I think that's an important notion, because I think a lot of people in the keto community are ... They get too dogmatic either way. And I think some of the limitations, or some of the concerns that I have is that I've been doing monthly blood draws to make sure my blood lipids, inflammation, insulin, and all of that are moving the right way as possible. And often times, one, a lot of people see elevated LDL cholesterol levels, which may or may not be clinically relevant given some of the emerging research out there. But what does seem to be clinically relevant is your HDL levels and your triglyceride levels. So I think make sure that you track your lipids and your bowel markers if you start doing a different diet.

Brianna: Because everyone's body responds differently. And as you say, it does not necessarily the best diet for everyone, and also, it's not necessarily the best diet for everyone all of the time. So recently, Peter Attia updated his blog post on ketosis, and he was saying how he felt like it had been a really good reset period for him, to follow it really strictly for a couple of years. And then after that, he was able to reintroduce carbohydrate and felt better on less of a strict ketogenic diet. So I think it's an interesting tool, and it'll work for people in certain contexts, but it's not necessarily for everyone.

Geoff: And I want to give air time for the people that are excited about carb-heavy diets. There's also just good longevity data around diets that are 100% carb, super low fat. So I think there is multiple ways-

Brianna: To be healthy.

Geoff: To be healthy. Metabolism is complicated. I think you're just hitting different pathways through different mechanisms.

Brianna: You hit an interesting point there. I think actually what the really bad diet is one that's high in carbs and high in fat together. That's the typical western diet, and that's not great news. But if you have really super high carb diet, low fat diet, that can work really well. And if you have a low carb, high fat diet, that also can work really, really well as well. And there's nuance to it. You can do ketogenic diet cyclically. You can fast for five days a month. There's ways of dropping in and out of these things that we're beginning to understand now. And so it doesn't have to be absolute.

Geoff: Absolutely. And I think that will be the future. And I think we've talked about that, for athletic training, for physical performance training, that one will have periodized times where you focus on getting your body keto-adapted, and then cycling out of it. 'Cause I know that for a lot of heavy lifting, anaerobic type exercises versus endurance, aerobic exercises, you need glucose. So I think there's a balance. There's no just golden, magic thing that solves everything for everyone.

Brianna: For everyone. Oh, of course not.

Geoff: So I think it is important that we actually talk about the limitations and the constraints for all types of diets, especially keto.

Brianna: Yeah. To look at the data, to bring the science lens on to it, as yet, the low carb, ketogenic diet has failed to show an outstanding benefit in terms of performance. So where we're at is we understand that people that follow this diet do have much, much higher levels of fat oxidation than people who follow a normal mixed diet. And that's been shown ... It's interesting, there's a lot of debate in this field, and it gets quite emotionally fraught, let's just say. But some people have found that these changes can happen kind of quickly, within a week of following the diet. And normally, if you measure performance after a week or so, there's normally a drop-off in performance. And the people who are pro low-carb diets say that this is because you've not had enough time to adapt.

Geoff: Keto adaptation. Takes like six months or a year.

Brianna: Which can take a very long time. And there's not been really ... There's a study that's looked at just metabolism of these athletes, but they didn't have any performance data. So really, we're relying a lot on anecdote here, and it looks to be, from the data, that there are changes in metabolism. Unclear as yet how that affects super long distance performance, but it does look like there's no clear benefit at the sort of distances that are being competed in, marathons ... By standard athletes.

One thing I suppose that is striking is that, in terms of endurance, anyway, there's often not a decrement. Sometimes people seem to lose their top end power. So if you're in a sport where you might need to sprint for the finish, like most races, let's just say, you might be a little compromised by a ketogenic diet. But you could still produce as much power for a 100 kilometer time trial and things like that. No difference. So that's a net interesting, slash positive equivalency. But the top end power, that is important for people who are competitive. And at the moment, it looks like there's no clear answer yet. And it does look, from the data, in a lot of people on that diet for a short amount of time, that their power suffers. There's a lot of anecdote out there of people who feel fine. So I don't want to rub anyone in the community up the wrong way.

Geoff: Right. So I think the way to think about it is that there's really two dimensions that people are talking about. One dimension is just strict performance. I want to be an Olympic gold medalist. I want to be the best person, best possible performance. And often times, that is contradiction, or at least orthogonal to longevity, metabolic flexibility. There's more and more data suggesting that yeah, if you're pushing your body to be a champion, that's probably not the best for you to live long. So there's trade-offs.

Brianna: You get a big heart, and people just drop dead.

Geoff: Right? So there's trade-offs. And I think that I would say that in training, or for [inaudible 00:36:07], ketosis seems to be better for the longevity maintenance of where in strict performance, you want all possible fuels at the same time, which includes glucose.

Brianna: Yeah. And as you said, you might include periods of training in ketogenic state or fasted state to boost your fat metabolism. But glycolysis and that anaerobic energy production is as important.

Geoff: It's important. It's super important. It's just part ... It's a fuel reserve and a metabolic pathway that's very efficient for what it does.

Brianna: But, this is accounting for the fact that typically, these studies have been on people using ketogenic diet, or a low carb diet, and so they either have one or the other. And so exogenous ketones are interesting because you can be in ketosis, not be ketogenic, have full carbohydrate stores, and also ketones on top, which is different again. So we've got your typical athlete, who fuels with carbohydrate, mainly. They'll be carbohydrate loading before a race, and taking on carbohydrate ... You can take on ... The recommended amount is 60 grams an hour. That's quite a lot. That's a couple of gels and hour. So it's pretty high carbohydrate intake.

Or you can be a low carbohydrate athlete, a keto athlete. And anecdotally, these guys are doing those multi-day long endurance runs, and they don't have to eat all these goo shots, and part of the reason there is upset stomach, but they're fueling on super, super low GI carbs, maybe, or fats. Nut butters, fatty shakes, things like that. And now, you've got an athlete that can have full carbohydrate stores, and also supplement with ketones on top of that, which is completely different metabolic state, because it's not just carbs or just fat and ketones. It's all three fuel sources.

Geoff: Yes, and that was a lot of your PhD work over at Oxford. The notion of a ketone ester drink. And that's what we actually introduce to the world. So not to overly promote our own products here, but that's what we're super excited about, and super knowledgeable of this space. We've really looked at all pathways to get to this point of having exogenous ketone ester, that really puts human physiology in a novel state.

Brianna: It's totally novel.

Geoff: As you mentioned, you can be in ketosis, not be ketogenic, have full carb reserves, have very, very high ketone levels, and that's my reference, when you want to win races, you want all fuels ... Replete fuels in all possible ways.

Brianna: So say you raise your ketone levels with a drink before you go and do a marathon. Say you're going to break the world record and you're on for two hours. So you have a ketone drink beforehand along with your normal carbohydrate. Your body then has ketones to burn, and it burns those in preference to the carbohydrate early on. But then, as you get an hour in, you burned through the ketones. If you don't take another drink, you're then just on carbs, which is great, as you try and start to ramp up that intensity towards the end.

Geoff: Exactly. And that does not occur naturally.

Brianna: No.

Geoff: One cannot diet or exercise into that kind of physiological state.

Brianna: No, you have to consume ketones.

Geoff: So before we dive too much into the ketone ester itself, let's talk about all the different forms and supplements that people are taking today to enhance ketosis or enhance their ketone levels. Let's say that there's three broad categories, and I'm curious to get your thoughts on it. I would say that there's a category of MCT oils. You might have heard about MCT oils from bulletproof coffee or fat coffee.

Brianna: Coconut oil.

Geoff: Coconut oil. And that's one category. So basically, medium-chain triglycerides, or fats, that are readily ... That can convert into ketones. And then you have more proper exogenous ketones, and they're in two main categories. First category is ketone salts. They have their limitations. And then there's the last category we're really excited about bringing into the world, which is a ketone ester. These are the three main ketone categories.

Brianna: So just to flesh it out a little bit more, when we've given people MCTs, you see ... It depends on how much you give people. And there are limits there because, especially to people that haven't taken them before, dosing up on MCTs rapidly can cause you GI upset.

Geoff: Which we've seen in the office, when we're doing some small case studies. I know actually, Zhill ... You were knocked out when you had an MCT C8 caprylic acid shot.

Brianna: So you take those, and you might get a blood ketone raise of between 0.5, 0.6, 0.7. A small, modest bump in ketone levels. Then the salts, those have really taken off recently. People are using them and often get between 0.5 to one mM, but interestingly enough, all of the data that's coming out around sport performance and around therapeutic uses is a bit more ... There's no improvement in performance, let's just say, with ketone salts versus ketone esters.

Geoff: I would even go as strongly and state that they make you perform worse.

Brianna: Well, yeah.

Geoff: That is what all the literature published-

Brianna: It looks like the cause, potentially, is a fluid shift thing, because they're very concentrated. And then, frequently reported, again, gastrointestinal distress.

Geoff: Yeah. But I think the data is what the data is. People are performing worse on ketone salts, which is unfortunate, 'cause a lot of the marketing around ketone salts is making people a bit better, and it's like ... You're selling something that's making people worse. They should just be drinking water.

Brianna: Yeah. I think probably the headline is that the elevations in ketones are so small that they're unlikely to be super physiologically relevant, and the co-delivery of mineral ions could well be the thing that's negatively impacting performance.

Geoff: Yeah. So one of the things that's ... I don't know if frustrating is the right word. At least ... Maybe a combination of frustrating and amusing, is that all the literature that you might have seen out there about how ketones improve performance-

Brianna: Is all the ester.

Geoff: ... is actually relating to the work at Oxford and some of the work that you were involved with, which is relating to the ketone ester. And let's talk a little bit about how the ketone ester works, and how it's different from MCT oils, which is a food supplement version, and ketone salts, which is a 1950s technology that hasn't really panned out. Why is the ketone ester so interesting?

Brianna: The ketone ester contains just pure ketone, ketone precursor. There's no mineral load with the ketone ester. And ester just means that the two parts, the two ketone parts, are joined by what's called an ester bond. But we eat esters in our diet all of the time. They're things that give our food smell, often. So our guts are really well-designed to break apart these two ketone entities. And they're absorbed really very quickly, and achieve very significant boosts in blood ketone levels. Maybe upwards of three milimals. I took it the other week, and got to seven milimal. So it's a much, much bigger rise in ketones. Much, much quicker.

Geoff: It's like five times stronger than ketone salts and MCT-

Brianna: Yeah, it's very strong and there's no mineral load. It's very easily absorbed. And because this compound, that I worked on at Oxford, we've been refining it over a long period of time, there's broadly no tolerability issues at the doses that we're giving.

Geoff: That's cool. So in a nutshell, then, I would say that the downsides are that it's still relatively expensive. We're working on bringing the cost down as quickly as we can. And it tastes kind of crazy. But other than that, cost and taste, it's five times more potent than MCTs and ketone salts. And I think the coolest part is there's actually robust body of data showing that it enhances and improves athletic performance, in the ways that are relevant.

Brianna: Yeah, I think a lot of the discussion around ketosis, generally, focuses on the whole area, and it doesn't distinguish between firstly, exogenous and endogenous ketosis, which is an important point. And then, often, it doesn't tease much into what level is needed to get the desired effect. So it just lumps everything together.

Geoff: Right. In all the cycling studies, people are up by five, six mMl.

Brianna: Yeah, exactly.

Geoff: That's what you need.

Brianna: I think they would be at five, six mM if they were at rest. During exercise, it's more like three. So you have to give more because the body's burning it. But we are starting to get a really deep understanding of how to give ketone esters alongside carbs, and as a performance thing-

Geoff: Yeah, for a lot of populations now, with military, with cyclists, with other types of sports. I think we're just building a lot of domain expertise here as we're just working with people and professionals, really world class people in all sorts of endeavors.

Brianna: Yeah. I think it has been one of the biggest challenges though, is educating people and getting people to discriminate between diet and supplements and foods, and all of these ... There's a lot of nuance there. And so education is something that we're taking really, really seriously moving forward.

Geoff: And I think a lot of the research also is just exciting. So I think something that you teased upon earlier in this conversation was that it's not just ... Beta hydroxybutyrate is not just the metabolic substrate. Not just the fuel for the Krebs cycle. It also has potential signaling effects for things associated with longevity, things with inflammation.

Brianna: Yeah. There's a lot of work to be done. And it's cool to have a tool as powerful as the ketone ester that allows us to separate ketogenesis and low carbohydrate restriction from ketosis and the effects of beta hydroxybutyrate and ketones themselves. And we're excited to see where that goes in the future.

Geoff: Yeah. I think that's why ... I think one of the interesting ways we talk about ketones and ketone ester is that we really think about it as a fourth macronutrient. So a lot of the ketogenic diet studies essentially conflate high fat diet plus the presence of ketones. And there might be some downsides or trade-offs between that kind of state, where with a ketone ester diet, you can break apart the need to eat high fat and have ketones in your system.

Brianna: Yeah, it's interesting. I was reading a paper recently, and it talked about how the mitochondria, which is the energy-producing part of our cells, how they make energy when you're on a ketogenic diet. And there are some things that improve the health of the mitochondria, and some things that make it a little less efficient. But we don't know yet what would happen if you're not eating that high fat diet, whether you just put ketones in, and we've seen in animal isolated, rat heart, that there's an improvement in efficiency of that muscle, when you just give it ketones. It's not a diet. So we wonder whether just supplementing with ketones would give you the improvements in efficiency without the negative effects of the high-fat diet in terms of-

Geoff: Which is why ... I think that opens up an interesting possibility. I think ... Can you get the benefits without the drawbacks? I think it's early, but I think what is there is that it's very, very safe, low side effect profile. It is a foodstuff, a food component. Not a supplement, not a drug. This is a food. And it really serves as a fourth macronutrient.

Brianna: And it allows people who are on a ketogenic diet to give themselves a boost in ketones, which might help them adhere to the diet, and it also allows athletes or people that are not following a ketogenic diet for performance reasons, to have this extra fuel source and maximize fuel ability during exercise.

Geoff: I was going to wrap up there, but I think you open up an interesting point, before we wrap up here, which is that a lot of our early customers are using it as an adjunct to do longer fasts, because ... You actually published this paper. Ketone ester drinks reduce grehlin, reduces appetite. And this is not insulin-genic, isn't ... So it's one of the perfect crutches, if one needs a crutch, to extend a longer fast. A lot of exciting data. It's a fascinating space, and I think we're both just super excited to play a small role in further understanding it and further educating people.

Brianna: Yeah, lots to do.

Geoff: Yeah. So hopefully, as we wrap up here, this was helpful to clarify a lot of the misconceptions or just nuances within ketosis, ketogenesis, ketogenic diets. If there's any areas that we teased upon that we didn't have enough time to dive deeply into, just send us a note. We're both on Twitter. Brianna's at Brianna Stubbs, I'm at Geoffrey Woo. But also, just email us. Podcast@hvmn.com. I think we all read every single one of your comments. We love them. And if you want to do an extra favor and show us some extra love, give us a five star review, or whatever star review that we deserve. Send us a screen shot of that and send it over to our email. And we'll send you a free SPRINT mini, which is our acute nootropic product. That's all for now.

Brianna: Great to chat again.

Geoff: Great to chat. And see you guys next week.

Brianna: Have a good one.

Geoff: Bye.

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