[Transcript] – The Latest Research On Ketones & Ketosis For Performance & Recovery, Do Ketones Break A Fast, Using Ketones For 45 Days Of Crossfit Murph, Ketone Esters vs. Ketone Salts & More With Geoffrey Woo of H.V.M.N.

Affiliate Disclosure


For podcast: https://bengreenfieldfitness.com/podcast/supplements-podcasts/ketone-esters/

[00:00:00] Introduction

[00:01:04] Podcast Sponsors

[00:03:29] Guest Introduction

[00:05:40] Using Ketone Esters In CrossFit “Murph”

[00:12:58] Why Ketogenesis Is Not A Physiologically Typical State

[00:16:11] The Role Ketones Play When It Comes To Recovery

[00:24:13] Pros And Cons Of Endogenous And Exogenous Ketosis

[00:30:51] Podcast Sponsors

[00:33:38] The Difference Between Ketone Esters And Salts

[00:38:32] The Ketone Esters Developed By The DARPA Program

[00:44:43] Gold Standard Usage For Dosage And Frequency Of Ketone Esters

[00:53:11] Whether Or Not Ketones Break A Fast

[00:57:09] Lactylation And The Expression Of Longevity Genes

[01:02:12] Parallels Between Lactate And Ketones

[01:07:03] Stacking Sodium Bicarbonate With Ketone Esters Pre-Workout

[01:10:14] Ketones Used In Place Of Alcohol In Cocktails

[01:15:17] Closing the Podcast

[01:16:56] End of Podcast

Ben:  On this episode of the Ben Greenfield Fitness Podcast.

Geoffrey:  It does look like that a lot of the longevity reasons why people do intermittent fasting are doubled down through exogenous ketones. They seem to have some central nervous system effect that isn't yet studied in the academic or the clinic just yet. When you have ketones stacked with availability of protein and carbohydrate, that's where you see the divergence between endogenous ketosis and exogenous ketosis.

Ben:  Health, performance, nutrition, longevity, ancestral living, biohacking, and much more. My name is Ben Greenfield. Welcome to the show.

Alright, keto freaks, or people who want to know more about ketones, ketone esters, ketone salts, got Geoffrey Woo on the podcast today. This cat is super smart. We had a ton of fun geeking out on all things keto.

Now, as a part of, of course, the fat loss and the metabolic efficiency that can often accompany a ketogenic diet, another real cool trick is cold thermogenesis, and it just so happens conveniently enough that on August 3rd, which is coming up very soon, we are starting a Cold Thermogenesis Challenge at Kion. We're providing you with all of the support, exclusive content on how to set up cold exposure practices no matter where you live, access to a bunch of video content from cold thermogenesis experts, a chance to enter an epic giveaway with premium cold thermogenesis gear. You're going to learn everything you need to know about cold showers, cold baths, cold soak, how long, how cold, exactly how to do it, what to eat before, what to eat after if you're going to eat, everything cold exposure and a ton of accountability and support from a bunch of people who are going to be doing this Cold Thermo Challenge with you. Now, the opt-in to get on this closes on August 2nd. So, get in while the getting's good. You go to getkion.com, getK-I-O-N.com/coldthermo, getkion.com/coldthermo.

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Well, folks, it is keto time, it's keto time on today's show, and not just keto time, but a real dive into a lot more of some of the concepts around ketosis that involve these ketone esters, and ketone salts, and a lot of the more kind of advanced things people are doing with exogenous ketones for recovery, for performance, some of the latest studies, some of the latest research on all things ketosis because a lot has happened since the last episode that I've really devoted to ketosis and ketones. So, I figured that it was high time we visited this topic in detail. So, I decided to bring on a guy who is a real, real wizard in the realm of all things ketones and ketosis. His name is Geoffrey Woo. He actually has a podcast himself, the H.V.M.N. Podcast, and is the co-founder and CEO of H.V.M.N., which stands for Health Via Modern Nutrition.

You may have seen these little like pinkish, red bottles for sale online or elsewhere chock-full of this ketone ester, and he's responsible for bringing that to market, and therefore, has looked into, followed up on, and studied a lot of what's going on in the realm of ketones. He himself is a pretty avid self-experimenter, too. He does things like seven-day waters only fasts and he just did CrossFit Murph for 45 days in a row, which I'm very curious about, and he has a background in computer science, but really has been immersed in the whole biohacking sector for a while. And I respect Geoffrey because he doesn't just sit behind his computer and blog about this stuff. He's out there trying things out himself and doing a lot of voracious self-experimentation so to speak.

So, Geoffrey, first of all, welcome to the show, and of course second of all, I got to hear about doing Murph 45 freaking days in a row because that sounds like a recipe for rhabdomyolysis. So, fill me in, man.

Geoffrey:  First of all, thank you so much for the kind words. That's too generous. I mean, it's just been a wild, insane time for everyone. I know that's just catching up a little bit before the call. It sounds like you've been able to focus and be heads down and just now, but just over the last two, three months really. So, the Murph story, over the last few years, gotten to know a number of folks in the Navy SEAL community and always heard super highly of this Murph thing. It's named after Lieutenant Mike Murphy, who won the Medal of Honor and fell in combat in Afghanistan. And it's just exercise, which is a one-mile run, 100 pull-ups, 200 push-ups, 300 squats, wrapped up by a mile run.

I think the first second week of shelter-in-place of quarantine, I think that first week I was, like I think many of us, just confused what the hell is happening in the world. Were we all going to die of COVID in the next two months? But quickly just got back on my horse in terms of being more proactive in setting the tone of what I wanted to live my life like over the next–at the time of foreseeable future, decided to get down and do my first Murph, one of the things that I wanted to do at some point. And each of those individual activities I've done, all of those never did it together and made it a challenge to our community to say, “Hey, let's be proactive, run COVID. Let's do a challenge.” It's probably reasonable to do some exercise and not just sit on our couch, watch Netflix, and eat a bunch of junk food.

Ben:  Yeah. And honestly, Murph fits into the equation pretty well because you don't need that much equipment for it aside from a weighted vest, if you choose to use one, which you–I mean, some people who are more entry-level don't, and then some running shoes and a pull-up bar, and maybe some callous cream or hand cream for 45 days in a row. My buddy Hunter McIntyre actually has been doing very similar Murph training. He actually went for the world record and I think he got it. This was last week at the time we're recording this. I believe he did something like 34 minutes in change. And I guess, I don't know how you–and I promise folks, for those of you listening in, we won't spend the whole time talking about freaking push-ups and squats and pull-ups, but he–I think did the 300 squats, 200 push-ups, and 100 pull-ups all in a row, meaning, all 300 squats, all 200 push-ups, all 100 pull-ups, sandwiched in between the run. But you can break it up. You could do like 30, 20, 10, 10 times through and then do the run, right?

Geoffrey:  Yeah. So, that's what I did. I started with 10, 20, 30 pull, push, squat, and then I ramped it up to sets of 50, 75, 100s. I think it just depends on what your permutation is. I think, yeah, you definitely want to be rotating your muscle groups. But yeah. I mean, I think it was one of those things where we challenged community and I felt like once I put it out there, I got to just keep doing it until the end of the challenge here. So, I ended up doing 45 of those Murphs in a row.

Ben:  Geez.

Geoffrey:  Which is pretty brutal. I mean, my times range from 45 minutes, some days when I'm just feeling crappy, hour plus. It wasn't necessarily for time. I was just wanting to be consistent. And I think the plus side of it was just getting back a routine. I think that's what has been helpful for a lot of folks in the community that were inspired by this challenge, which is that once shelter-in-place happened, a lot of people didn't have to go to the office, they couldn't go to their gym, they didn't have their CrossFit or peloton or whatever class that they had to go to. And just like reinstalling one anchor totem practice a day seemed to be helpful, at least for myself, and a bunch of folks did their own versions of the challenge. Not everyone could do a Murph or wanted to do a Murph, but everyone at least did some sort of exercise that was a good anchor for their day.

Ben:  Yeah.

Geoffrey:  So, overall, I think a good idea for folks considering something like that.

Ben:  Okay. And this begs the question and is a perfect segue into the topic at hand, and that is, did you implement the use of ketone esters or any other of the type of biohacks that you're immersed in as your pre-post during workout nutrition or as a recovery protocol or anything like that?

Geoffrey:  Yeah. So, in general, I eat pretty low carb, fairly carnivorous on the side of low carb. And I think we like the larger discussion of what a normal healthy diet looks like. I think that's like a default decent state. But I would say that I'm not dogmatic or religious like some folks are in the nutrition Twitter community where carbs are evil, proteins are good, fats are great, or fats are evil, it's going to give you a heart attack. I think it's really context-specific and application-specific. So, as I was doing that third, fourth, fifth Murph in a row, I realized that you're doing pretty anaerobic movements, right? Like, doing a bunch of pull-ups, push-ups, and a mile run is not a big endurance run. I felt like I needed additional carbohydrates.

Ben:  Right. There's some definite glycolytic throughput and even more when you're doing it for 45 days sequentially. You're looking at some hefty needs for liver and muscle glycogen repletion if you actually want to not be out there for two hours.

Geoffrey:  Yeah, 100%. So, I started adding carbohydrates pre and post, and then I would have either ketone esters or other exogenous ketones like MCT oil powder or something along those lines to increase the ketone plus protein-carbohydrate recovery benefits that some of the more recent literature has shown to be effective. So, I was mainly using a ketotic approach for the recovery side rather than a performance side because one, this was not for an acute one-time maximal effort, this was a marathon if you will.

Ben:  Right, right. And by the way, the simultaneous elevation of blood ketones and blood glucose is something I experimented with a few times when I was doing obstacle course racing, and it is like rocket fuel. It is admittedly, from an evolutionary or ancestral standpoint, probably not a physiologic condition, and I don't know if you agree with me on this that humans would have frequently experienced elevated levels of ketones, which normally would be listed by carbohydrate restriction, and physical activity, and fasting, but instead are brought on by the ingestion of something like ketone esters or ketone salts, which are then combined, in the case of the way that I was doing it, with either a dextrose-based fuel or a maltodextrin and fructose-based fuel.

So, you've got an incredible amount of glucose uptake based on the high glycemic index of the dextrose or the multiple glucose transporters being used by the combination of maltodextrin and fructose. You essentially are kind of like hyperglycemic and hyperketotic, and it's like rocket fuel for exercising. But I in no way would argue that it's, from an ancestral standpoint, a physiological norm as far as a place for the human body to be in.

Geoffrey:  That is correct. It is not a physiologically normal or typical state, and that's because if you think about why ketogenesis exists, it's really sort of a backup metabolic process in carbohydrate-restricted states. So, in a typical metabolism, you either have high availability of glucose. Therefore, not carbohydrate restriction. So, there's a lack of need for upregulated lipolysis and upregulated ketogenesis. So, the interesting thing with ketone esters or exogenous ketones, in general, is it really was conceptualized as a research tool. And I think a lot of the discussion about ketogenic diets or ketosis has always been conflated around a high-fat, low-carb diet. And with exogenous ketones, you can finally have a tool that does not require a high-fat, low-carb diet to induce ketosis.

So, I think one of the refrains that you hear different researchers talk about is that ketones can be thought of as a fourth macronutrient. So, as opposed to looking at ketones as an endpoint to reach to or a ketosis as an endpoint to reach to, one can now start thinking about ketones as almost equivalent to carbohydrate, or protein, or MCT, or fat as a starting point in terms of nutrition and input into metabolism. So, I think that's where the paradigm shift is interesting from a research perspective. And exactly, in terms of an applications perspective, I think what you're referencing has been a very interesting last couple of years where there's a lot of uses in the top levels of sport and military where you just unlock this novel physiological state that does not occur in nature.

Ben:  Right, right. Exactly. Now, I want to quickly visit something that you mentioned when you were talking about your 45 days of Murph. And then, by the way, for those of you listening in who might be somewhat new to ketones and ketone esters and ketosis in general, we're not going to spend a lot of time on ketosis 101, but I will, in the shownotes, put links to a lot of previous podcasts I've done, kind of walking you through the basics of ketosis. And so, if you want that as a foundation, just go to BenGreenfieldFitness.com/woo, as in W-O-O, which is Geoff's last name. And at BenGreenfieldFitness.com/woo, I'll link to other podcasts that I've done on ketosis if you need to get a refresher, folks like Jason Fong, and Jimmy Moore, and Dominic D'Agostino, and a host of other people I've interviewed on the basics of ketosis because we're really going to delve into some more specialty areas on today's show.

But you mentioned, Geoffrey, the use of ketone esters or ketosis in general for recovery and some of the new literature around that. It's not really a topic I've talked about much versus, say, performance or cognition. So, what role do ketones play when it comes to recovery?

Geoffrey:  I would say that a lot of the early research, but early as in sort of mid-2010, so 2016, 2018, has been focused on acute performance benefits. So, using ketone esters or exogenous ketones as a pre-fuel, do a time trial. Usually, a lot of these studies are done on cyclists or runners because these are very simple quantitative sports. It's much easier to measure the performance of someone on a bike versus someone playing soccer where there's a lot more technique and strategy involved in winning.

In 2018, 2019, 2020, a research group based in Belgium, KU Leuven, by Professor Peter Hespel, who's also, interesting enough, a consultant in some of the Belgian Tour de France teams, started looking at the application and dosing protocols for ketone esters. So, there's been a lot of anecdotal–I hate to use the word anecdotal, but I would say like the craft of sports performance. I think this is something that you, I think, Ben, know a lot about, which is that the practitioners oftentimes are the leading signals, or the experimenters are the leading signals for academic research or the randomized clinical trials. So, one of the observations in some of the early Tour de Frances was that people felt better recovery or “fresher legs” if they were using ketones more for the recovery aspect versus the pre-performance acute pre-bout use cases.

So, Hespel did a great study that was published in 2019 summer right ahead of the 2019 Tour de France showing that when people mimicked or cyclists mimicked a Tour de France style training protocol, which is around 13 hours of training a week, which had two workouts per day over that week period, and using ketone esters plus protein and carbohydrate versus a calorie equivalent protein and carbohydrate drink alone, after a three-week training period of that regimen, folks that had the ketone ester plus intervention had a 15% increase in overall training volume, and at the last 30-minute time trial, a 5% increase in performance.

So, this is one of those interesting study points where the anecdote or the practitioners who were actual athletes experimenting pushing what was possible actually informed what the academics did in the clinic. That's an interesting point. I think there's a lot of speculation of why ketones would do this. And one of the interesting mechanisms that I really liked from that study, or was informed by a previous Peter Hespel study was that ketones plus protein and carbohydrate actually upregulates mTORC1. So, mTOR, which is the muscle synthesis, protein synthesis pathway that has been interesting in some of the longevity discussions.

Ben:  So, they're upregulating an anabolic pathway?

Geoffrey:  Exactly. So, I think that's one of the interesting things with ketones where you can talk about them in terms of anabolism or anti-catabolism, which does make sense from an evolutionary perspective because when would the ancestral human go into ketosis? Well, they would go into ketosis in a starvation state. So, having anti-catabolic effects is consistent from an evolutionary perspective.

Ben:  Okay. Got it. Now, that's interesting because in the past, one of the benefits that has been highlighted in terms of being in a ketogenic state is the blockage of mTOR via the increased activity of AMPK, meaning that when AMPK is increased, then it would be a signal that ATP stores would be in a state of depletion. And you'd see an inhibition of things like uncontrolled cell growth, or proliferation, or oxidative stress. Therefore, a lot of people would associate ketosis with a non-anabolic state if it blocks mTOR. So, what was different in this study, or what's occurring from a pathway standpoint that this would actually activate mTOR? Because there's even studies on PubMed that say that a ketogenic diet would inhibit mTOR.

Geoffrey:  That's exactly the right question. I think that's something that I've been really focused on, which is there's application-specific and context-specific use cases for something that is like a macronutrient. So, the difference here is that, yes, in an ancestrally consistent state of a ketogenic diet or fasting, you will not have the presence of carbohydrate and protein. So, when there are ketones through a ketogenic diet, it is exactly correct that you would expect to see mTOR being downregulated, and AMPK being downregulated as well because there's that lower available energy substrates from glycolysis, and then you see upregulation of lipolysis and fat mobilization.

But the difference with exogenous ketones is that now you can have exogenous ketones plus external substrates of protein and carbohydrate. So, that's where that's interesting piece of research or a new field where when you have ketones stacked with availability of protein and carbohydrate, that's where you see the divergence between endogenous ketosis and exogenous ketosis. I think that's an understudied area or area that will be a major field of study I would say in the next two, five, ten years.

Ben:  Okay. So, to clarify for folks then, what you're saying is that if you are interested in using a ketogenic state for recovery, what you would actually want to do is have adequate nutrient availability with adequate calorie intake, and arguably, even enough carbohydrate to allow for liver and muscle glycogen levels to be full. And you would achieve that via feeding as you normally would, but then including ketone esters, and that would induce an anabolic pathway that would be over and above what you'd see in the absence of the same approach without ketone esters. However, if you wanted to instead trigger pathways of autophagy, enhance fasting, or decrease mTOR, then what you would do is use a similar approach, but instead use nutritional ketosis and/or the use of ketone esters, but in the presence of a lower amount of carbohydrate and overall calorie availability. So, there's kind of like two different ways that you could use ketosis.

Geoffrey:  A hundred percent. I think that's a nice summary.

Ben:  Okay.

Geoffrey:  And I think that opens up an interesting mini topic around why calorie restriction works and how autophagy is triggered. And I think the consensus is that ketosis or the ketone beta-hydroxybutyrate itself may at least partially mediate that response. So, I think there's an open research question, does beta-hydroxybutyrate itself be the signaling molecule that triggers HDAC inhibition, FOXO3, some of these longevity pathways, or is it the calorie restriction itself? That's an open field of study. So, basically, the way to study this is that if you just have an exogenous ketone without calorie restriction, how much of the calorie restriction benefits do you see? That is a good question.

Ben:  Okay. Got it. So, we know though thus far that, especially based on this recent study in cyclists, that if you throw ketone esters into a recovery fueling based equation, you're going to see enhanced recovery, upregulation of mTOR, and activation of anabolic pathways over and above what you'd see in the absence of ketone esters.

Geoffrey:  Correct.

Ben:  Okay. Got it. Now, kind of backpedaling just a little bit here, let's talk about the difference between what's happening in the body if–and we talked a little bit about this, but I'd like a little bit more thorough explanation. If someone were to achieve ketosis via what might be called endogenous ketosis, carbohydrate restriction, calorie restriction, fasting, et cetera, versus entering into ketosis simply via the use of what many people call cheating or the use of exogenous ketones, what's the difference there as far as pros versus cons of each?

Geoffrey:  I'll just start off what's happening physiologically. So, endogenous ketosis, necessarily, there's some sort of carbohydrate restriction, which could be calorie-restricted or not. Ketogenic diet is not calorie-restricted, but there is definitely a carbohydrate restriction. So, what happens there is that the brain senses–especially the brain, but other tissues also care about energy sensitivity, it starts detecting like a lowered AMPK because there's a lack of glucose. So, what happens? The body responds by increasing lipolysis, increasing fat mobilization. And the interesting thing about the brain is that there's a blood-brain barrier that prevents fat directly entering the brain to provide fuel or substrate for neurons.

So, what do animals–and a number of animals have this metabolic pathway of ketosis. What happens? Well, they evolve this pathway of ketogenesis or ketosis where it converts fat into ketone bodies, and ketone bodies are small molecules that do cross the blood-brain barrier. So, what's the tl;dr of the summary there? Usually, in endogenous ketosis, you see an increase in free fatty acids because you mobilize more fat, you see fat burning lipolysis, and this is why a lot of people in the weight loss or weight management field talk about keto as this fat-burning state because–yes, that is true, you have energy deficit from carbohydrate restriction, you start mobilizing more fat.

So, that's what's happening physiologically. What happens when you have exogenous ketones? You're simply eating calories in the form of ketones. So, again, I think the macronutrient analogy works really well here. You can eat calories in the form of fat, protein, carbohydrate. You can also eat calories in the form of ketones. So, what happens there is, yes, exogenous ketones will elevate beta-hydroxybutyrate very, very aggressively. So, ketone esters can make you look like you've been fasting for seven days and 30 minutes. Other exogenous ketones do some spectrum of that. But the difference is that you actually inhibit or block fat burning. You actually inhibit lipolysis, and you actually see free fatty acids go down, and you actually see glucose go down.

And that makes sense again from a homeostatic perspective because our bodies are essentially energy balancing machines and you have energy from the form of ketones that you consume directly. It makes sense the body starts blunting other sources that are stored. So, that's what's happening physiologically. And I would say that the two interesting implications of that is ketones can then be used as a metabolic fuel, meaning that they can be used as a precursor into the Krebs cycle, so being used directly, and what I think is the more interesting research area, which is ketones can be used as a signaling metabolite. How does ketones in your blood signal things like mTOR, AMPK, sirtuins, NAD ratios, and all the things that are buzzwords in the longevity health span research areas today?

Ben:  So, a question for you based on this then. So, what you would say–and I'm curious to hear your take on this, especially for people who might be trying to, say, lose weight or increase metabolic efficiency by training their bodies how to burn fatty acids more efficiently. With the use of exogenous ketones since you are, if you consume exogenous ketones as you've just stated, going to decrease the amount of free fatty acids that you would burn, would you actually blunt some amount of your own adipose tissue conversion into fatty acids for use as energy if you were supplementing with exogenous ketones?

Geoffrey:  Yes. So, this is actually very interesting. So, intramuscular triglycerides are upregulated. So, the use of the fat within muscle tissue is increased, but lipolysis of adipose tissues is actually inhibited. But I think the broader question of how this plays is that there's been studies showing that ketones directly mediate ghrelin or the appetite hormone. So, that would be the mechanism that's also consistent with a lot of the, again, anecdotal kind of community discussion around feeling more full on a ketogenic diet. And perhaps that's because ketones signal ghrelin, which signals satiety.

So, the more interesting question is, are ketone esters [00:29:18] _____  these magic drinks that make you melt fat off your body? And the answer is no. These are calorie-containing substances. If you have energy surplus or a calorie surplus, ketones aren't some magic thing that breaks the second law of thermodynamics that disappears calories. But that doesn't say that there aren't appetite-controlling effects that are second order from just the calories themselves. I guess that's just like maybe a little bit of a complicated nuanced answer to–there's multiple ways these things work. If I were to use ketones for a weight loss protocol, I would think about using them as a way to make fasting easier.

Ben:  Right. As an appetite suppressant strategy. And I see where you're going here, basically, even though you might be burning fewer of your own fatty acids as a fuel when you acutely ingest these ketone esters, the long-term effects of appetite suppression. And the subsequent decrease in calorie intake that's likely going to occur as a response to that is probably going to support fat loss and may actually–the fat loss that you're supporting may exceed any blunting of fatty acid burning that you might experience by using exogenous ketones as a dietary strategy to, for example, suppress appetite, enhance fasting, and increase fat loss.

Geoffrey:  Exactly. So, that's on the community side is how a lot of folks have been using exogenous ketones who aren't necessarily Navy SEALs or elite athletes.

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That's been my own personal experience, like we were chatting about even before we began recording, my wife and boys are out of town for five days. And I told my wife when she left, I'm like, “Don't go grocery shopping. Don't leave anything in the refrigerator.” I got some ribeye steaks that I'm going to have with a little bit of a liver pate that I make and some homemade sprouts for dinner every night. And sometimes I'll throw in a little bit of like organic pumpkin mash. And then, I'm just planning on jamming through breakfast and lunch on ketones, MCTs, and liquid calories, and a little bit of bone broth because if my wife's out of town, I go into hyper-productive, work 14 to 16 hours a day, and that works very well. I don't get hungry at all when I'm doing that even–and you could see, oh, well, you're burning fewer of your own fats, Ben. And actually, I'm probably burning more of my own fats because once I added up at the end of the day, probably consuming fewer calories than I would normally consume. So, I would not necessarily throw out the idea of not using, or I would not throw out the idea of using exogenous ketones if you're trying to lose weight. I think the pros outweigh the cons in that respect.

Now, you've mentioned ketone esters, and I know that's the particular flavor or form of ketones that you guys specialize in implementing in your H.V.M.N. product. And just briefly, and again, I've unpacked this in detail on previous podcasts. You don't need to spend too much time on this because again, I'll link to everything we discussed you guys at BenGreenfieldFitness.com/woo, W-O-O.

But these ketone esters that you're using are remarkably different than ketone salts. And, A, I'm wondering if you can just briefly describe the difference between the two. And then, in terms of your product at H.V.M.N., how you're using ketone esters, like what form of ketone esters, and why?

Geoffrey:  Yeah. It's an interesting history and I've been spending a lot of time talking to the principals, the folks who've been part of this area of research for the last 40, 50 years. So, to answer the easy part, which is, what is a ketone salt versus what are ketone esters? Well, they really describe two classes of exogenous ketones, and then you have things like MCT, butanediol, [00:36:00] _____ ketogenic agents or ketogenic precursors, things that readily convert into beta-hydroxybutyrate or ketones in your system, but aren't actually directly ketones.

Okay. So, what is a ketone salt? It's simply beta-hydroxybutyrate bound to a mineral, a salt. So, a lot of common ketone salts are sodium, magnesium, calcium. The pros and cons there, pros, relatively cheap, relatively available. The potential cons is that if you actually look at the percentage of salt versus beta-hydroxybutyrate, you're eating a lot of mineral when you're eating a ketone salt product. So, if you look at the label, oftentimes you're seeing like 100%, 200% of your daily recommended value for salt. Not necessarily a bad thing, but something that is just part of the molecular construction of a ketone cell.

So, what are ketone esters? In general, there's also a whole family of compounds that are ester forms of ketones. What is an ester? An ester is just an organic molecule that has an oxygen double bond in between different components. So, there's monoesters with one ester bond, there's diesters with two ester bonds, and there's a whole swath of folks looking at ketone esters and different types of ketone esters, which I think we can talk a little bit about later, which is that I think in the future, there will be a whole family of potential exogenous ketones just like there's a whole family of carbohydrates from dextrose, to maltodextrin, to starches, just like there's omega-3 and omega-6 fats.

I think in the future, how you see this industry will evolve or this notion of nutrition evolves is that there will be a whole family of exogenous ketone variants with pros and cons. But to talk about what is focused on today and something that we focus on H.V.M.N. is a specific ketone monoester that is beta-hydroxybutyrate esterified with R1,3-butanediol, which is, as I referenced before, a ketogenic agent that readily converts into beta-hydroxybutyrate in your liver. Why does this matter? Well, it's pretty cool that a ketone ester basically delivers 100% BHB equivalent versus something like a ketone salt, which delivers over half of its molecular weight in minerals. There's another ketone ester that Dom D'Agostino has done a lot of workaround, which is an acetoacetate diester, and that's acetoacetate which is a derivative form of beta-hydroxybutyrate bound to butanediol. And there's two acetoacetates to that. So, a little bit of different configuration.

Ben:  Okay. Now, I was looking at the H.V.M.N. ketone bottle, and on there, it says DeltaG as the active ingredient in the ketone ester, and then it says, “Invented by Oxford and NIH scientists as part of the DARPA metabolic dominance program.” So, a lot to detail there, but what is DeltaG and what is this ketone ester that was invented as part of the DARPA program?

Geoffrey:  Yeah. It's a fascinating story. So, back in the '60s and '70s, there was a general–this is a popular study that's been referenced a lot. I think we've talked about this fasting study where they starved Harvard Divinity students for over a year. And that study was actually conducted by a Harvard Medical School Professor by the name of George Cahill, and he was friends with Dr. Richard Veech, who I know you've also spoken to. And he, I would say, was one of the earliest folks looking at ketones and understanding the metabolic implications of ketones. And I think in the early 1900s and 1950s post-ketogenic diet, I think a lot of people thought of ketones as a metabolic waste product for type 1 diabetics. But people didn't realize the broader implications as a fuel substrate, as well as a signaling metabolite.

So, as people realize that beta-hydroxybutyrate could be a useful molecule, there was a lot of research around, “Okay, can we do exogenous ketones in different formulations?” So, there's a lot of studies on intravenous ketone salts, other earlier versions of ketone esters. But what happened was in the early 2000s, there was a DARPA program stood up by Dr. Joseph Bielitzki. He actually, before his DARPA program management spot, was actually the chief veterinarian officer for NASA. So, a very interesting guy with an interesting career. He had the purvey to set up a program to enhance the human factor side of warfighting.

So, there's a number of different research projects that we're looking at, things like quercetin, which I think is interesting given the COVID recent conversation. They also had things like the cooling glove that came out of Stanford, which showed enhanced recovery. It was also part of that program. And of course, ketone esters was also a part of that program. So, Dr. Veech recruited and brought onboard Oxford professor, who is a specialist in cardiac metabolism by the name of Professor Kieran Clarke, who I work closely with on the commercialization side of ketone esters, and they kicked off a research program to synthesize and scale up DeltaG, which is the trade name or the commercial name for the keto monoester, which is that beta-hydroxybutyrate, butanediol monoester.

Long story short, you had to prove out the human safety. Could you actually feed this stuff to people and does it actually work? Does it actually elevate ketone levels effectively? And then, I would say within the last four or five years was when a lot of the publications came out for the ergogenic or performance-enhancing aspects of ketones. And it's been an interesting journey being a part of the ecosystem that's working a lot with the scientists for therapeutic use cases, for performance enhancement use cases, as well as working a lot with the end-users, which are professional athletes, military applications, as well as folks that are experimenting using this for weight management or longevity, or potential therapeutic use cases.

So, it's a very fast-growing evolving field, but really interesting historical story with how everything came together. The way I see it is that we're all standing on top of shoulders of giants. I think Veech had a cool story where he actually studied under Hans Krebs, who the Krebs cycle is named after. And I think a lot of that training with metabolism, understanding all the intermediates, all the ratios I think informed him of why ketones were interesting from a fueling perspective.

Ben:  Yeah. And I know that you actually, on your own podcast, had an interview with Joseph Bielitzki, the chief program manager that oversaw that decade-long ketone ester development as part of this metabolic dominance program that was initiated by DARPA to basically enable superior physical and physiological warfighter performance by controlling energy metabolism on demand. That was a fascinating podcast that you did I think a couple years ago. And I'll link to that in the shownotes for those of you who want to hear that.

And so, these ketone esters, you've developed them and you guys at H.V.M.N. have kind of packaged them in a liquid form as a couple other companies on the market have done, these liquid ketone esters, which admittedly, and of course, I know this isn't news to you, are not considered to be the tastiest supplement that exists because it is very difficult to get ketone esters, which have a little bit of a bitterness to them to actually be palatable. I haven't really found much of a way around them. You can add a little stevia and put them in some coconut water or toss them in a smoothie. I found they impart a mild kind of like acidic taste even when added to a smoothie.

But for me, it is what it is. I'm so used to testing supplements and formulating supplements and getting random powders sent to my house that I must just dump straight into my mouth and taste that I may have killed off some taste buds. And so, for me, I could be jaded and I have no problem just drinking the stuff and continuing on throughout the day. But these liquid ketone esters that one would drink when it comes to actual dosage, what's kind of like the gold standard scenario in terms of how the typical person is using these throughout the day? And I'm fine if you break this out into the person who might be using it for–the executive using it for cognition versus the athlete using a performance during events.

But what's the general gold standard use case for these type of things in terms of dosage and frequency?

Geoffrey:  Yeah. That's a good question. And yeah, the taste is the taste. I think we've all seen, yeah, your conversations, as well as folks have written blog posts in the early, early days eating sort of like the rocket fuel versions of ketone esters. Yeah. They are not the most pleasant thing, but I like to say it tastes like it works. So, I'll start with what's been studied in clinical academic research. So, typically, the dosage is, if you want to be very, very precise, based on body weight. So, the clinical gold standard is around 600 milligrams per bodyweight kilogram for acute performance use cases. So, if that's a 70-kilogram man, 154 pounds, that's 42-ish grams of ketone ester, which is almost two bottles of the H.V.M.N. ketone ester product. So, you actually need pretty high doses for acute pre-bout, pre-exercise use cases.

Ben:  And would the–I mean, because I began to use ketones back in 2013 for Ironman triathlon, and obviously, there's a big difference between an Ironman and let's say, whatever, a 45-minute Murph. So, what kind of level of exercise are we talking about here when you're taking two full bottles of this stuff in terms of volume?

Geoffrey:  This was primarily geared towards Tour de France athletes. So, very high volume.

Ben:  Yeah. So, these are pretty serious athletes that would be doing two full bottles of something like ketone esters prior to performance?

Geoffrey:  Exactly. So, there's been a number of studies on a number of different applications, right? Like you've seen studies where ketone salts either no difference, some ketone ester studies showing some difference, some showing not. And it sounds like really the threshold is one by bodyweight, or two, which I think is actually more applicable, you need to hit a threshold of beta-hydroxybutyrate in your blood. And it looks like that number is that you want to at least have 2.0 millimole beta-hydroxybutyrate. In some of the best performing studies, people are showing blood levels of three to five millimole as they're going into the most critical parts of their race or competition.

Ben:  Right, which is very–it's surprisingly difficult unless you've been fasting or consuming low carbohydrate or ketogenic diet for quite some time to achieve that level of blood millimole, at least in my own personal experience, without the use of ketone esters. And yet someone who is not even fat-adapted who can be eating 70% to 80% carbohydrate can achieve that level acutely upon consumption of these esters. For me being relatively fat-adapted and keto-adapted, if I were to do two bottles, I would be up around seven millimolar easily for ketone values.

Geoffrey:  Yeah. I think that's something that I think is again like–I think a lot of people just entering the keto community are just chasing ketones, and I think you're exactly right, there's a lot of adaptation whereas you get more keto-adapted, your body's just more efficient. You just never want extra substrate floating around. So, yeah, when you're dumping that much exogenous ketones in your system, I would expect something that high. If you see a lot of athletes, we've seen people uptake ketones so quickly that even if they're dumping ketone esters in, their blood levels correct very, very quickly. So, it's interesting to see again the application of the context where some athletes who are very, very well-trained will uptake very, very quickly. So, to answer your initial question, for acute use cases or application, I would target–like the most professional customers, blood BHB is the most important thing to dial in, and that depends on your body weight, and also your personal metabolism, and how fat or keto-adapted you might be.

Ben:  What do you use to measure your own state of ketosis? And this could lead to a deeper discussion in ketone measurement technology. So, if you want to, you could finish that thought. I just interrupted you, I realized. And then, I'd love to touch briefly on how to actually measure these values you're talking about.

Geoffrey:  Yeah, 100%. And just wanted to follow up the last step, which is the more casual use cases. A lot of people will use ketones for cognitive use cases, and there's been some early studies relating to military, as well as relating to sports decision making in terms of preservation of cognitive function in stressful or extreme environments. And that's an exciting area where it looks like there's some early signals showing that brains that are fueled by ketones preserve cognitive function or preserve executability better than on placebo.

So, again, some of the anecdotal consumer use cases are using this for jet lag, using this for focus. And I think the mechanisms aren't super defined or super clear. I think it's not necessarily a solid thing, but I think what we do know is that ketones do cross the blood-brain barrier and ketones have a very different metabolic pathway than glucose fueling the brain. So, there seems to be something there and it's been interesting to hear folks on Olympic weightlifting teams using ketone esters, I think partly for the weight loss or the weight cutting because it's a weight cutting sport, but also, they seem to have some central nervous system effect that isn't yet studied in the academic or the clinic just yet. A lot of experimentation to be honest on different protocols. Again, some of the other interesting use cases using ketone esters ahead of fasts to basically kick start your fasting routine or helping transition into a ketogenic diet where sometimes there's like that keto flu, which essentially is you have low carbs and low ketones at the same time and you feel really bad because you just have low energy. Can you bridge that with exogenous ketones?

Ben:  Right. And so, I think in summary, a few things to bear in mind here would be for very hefty amounts of performance such as Ironman triathlete, or a marathoner, or a Spartan athlete, or a serious CrossFit or someone like that listening in, you may be up to two bottles prior to a really hard work out, but ideally for this, and any of these other use cases, you should just test, and we'll get to that momentarily, and try to shoot for three-plus millimolar to really feel the performance-enhancing effects of ketones. If you're using this for cognitive throughput on a demanding day that might be mentally demanding, but not as physically demanding, you could probably get by on a little less than that yet if you test, and you can get your levels and determine how many ketones you need to get your levels at three millimolar above. That's the sweet spot where you're really going to feel a hefty cognitive effect.

And then, if you are, for example, wanting to go into a fast or you are shifting into carbohydrate mitigation, shifting in a low-carb diet or ketogenic diet, then using these for several days even as little as a bottle but perhaps two bottles a day going into that fast or going into that shift to a low-carb diet, that would significantly ease the transition, that would be kind of like a few use cases for something like this.

Geoffrey:  That's a good summary, yup.

Ben:  Got it.

Geoffrey:  And then, to answer that second part, which is, what do I use to measure? Simple fingerstick, FreeStyle Neo, or some of those things where you have a little strip, finger prick, get a little bit of blood and good to go. I think there's been some folks looking at breath meters, which measures acetone or urine stick. I prefer blood because that's what academics use in the clinic and it's just the most consistent.

Ben:  Yeah, yeah. And are you doing any type of urinary measurements or anything like that?

Geoffrey:  I've done in the past, but I think what you've seen, I would suppose that this is what you see is that as people get very, very keto-adapted, you don't excrete as much ketones because it's basically your body's adapting to holding on to beta-hydroxybutyrate, acetoacetate as fuel substrates. So, as you get more efficient at utilizing and producing ketones, you excrete less of it. So, I think that's one of the subtle things around the urine test. It needs to be captured.

Ben:  Yeah. So, basically, you're going to wind up with fewer ketones in your urine as you become more efficient at using ketone bodies. Therefore, as you're testing with urine, you could be in a pretty good state of ketosis yet your urine is not showing that you're increasing in ketosis because you're simply becoming more efficient using the ketone bodies.

Now, I want to talk about some of these more sexy areas of research, but there's one other probably more basic question that I want to make sure that I address, and that is, for someone who is, say, intermittent fasting for the purposes of autophagy or longevity, or someone who is concerned about glycemic variability or insulin resistance, what's the state of ketones when it comes to any research on whether or not they are insulinogenic in any appreciable way or whether they “break a fast,” since I'm asked if gum breaks a fast, if coffee breaks a fast, if meditating breaks a fast, do ketones break a fast?

Geoffrey:  Yeah. That's an interesting discussion. Maybe another way to phrase the question is, what is the purpose or what is the goal of the fast, and which metabolic pathways do we care about? Ketones themselves are not insulinogenic or mildly insulinogenic at best if you're eating a lot of ketones. But the interesting thing is that, does it directly trigger mTOR? No. Does it directly trigger some of the pathways that we think are antithetical to a fast? Not that we know of. But the benefits of what ketones —

Ben:  Wait. You just said earlier that it did trigger the mTOR pathway though.

Geoffrey:  When you stack it with protein and carbohydrate.

Ben:  Okay. When you stack it, yeah, I'm sorry.

Geoffrey:  Then you upregulate it beyond just normal levels —

Ben:  That's right, but by themselves of course if you're in a fasted state, yeah. Thanks for correcting me. They actually would downregulate that pathway.

Geoffrey:  Yes, exactly. So, I think the interesting research questions now is there is more data showing that ketones are HDAC inhibitors, which control the unfolding and expression of different proteins or genes. And one of the popular pathways to target is FOXO3, which is associated with fasting. Beta-hydroxybutyrate also shifts to NAD+ and NADH ratios. So, I think there's been a lot of discussion on NAD precursors, and I think that's half the equation. You need to have enough NAD substrate, of course, but I think another important part of that conversation is, what is NADH? It's a coenzyme as part of the Krebs cycle, and that balance of NADH and NAD+ is actually affected by the substrate going in.

So, the NAD+, NADH ratio is different if it's being fueled by glucose, it's different when it's filled by beta-oxidation or fat, and it's different when it's filled by ketosis or ketones. They all produce Acetyl-CoA and go into the Krebs cycle, but the actual equilibrium of those coenzymes are different. So, it looks like ketosis actually shifts the NAD+, NADH ratio in a way that's beneficial for sirtuin activation. That's the interesting areas that is converging a lot of the research on the longevity health span side around sirtuins, NAD+ boosters, mTOR, and it's like folding into how we understand ketosis to work. So, these are very powerful multifaceted targets, ketosis fasting. Specifically, I think ketones have an interesting research role for how these longevity benefits are mediated. So, the quick tl;dr on that is that it does look like that a lot of the longevity reasons why people do intermittent fasting are doubled down through exogenous ketones.

Ben:  Okay. Got it. Tl;dr, by the way, is–does that mean too long to–was it too long to read?

Geoffrey:  Yeah. Too long, didn't read.

Ben:  Too long, didn't read, that's right, that's right. It was a newer phrase to me a couple of months ago. I had to look it up. Yeah, too long, didn't read. I love that. Okay. So, we know that we can manipulate histones for longevity and in gene expression, particularly in a favorable way. And it appears that ketones are actually able to affect histone and histone acetylation in a manner that is favorable to longevity.

And in my understanding, there's some pretty recent research on lactic acid being able to do something similar when it comes to something called lactylation, actually also somehow enhancing the expression of some of these longevity or anti-aging genes. Is that true? Like, where does lactate fit into the picture here?

Geoffrey:  Yeah. I think that's an interesting and good point, which is that, typically, when we think about controlling of gene expression, we hear a lot about methylation and acetylation. These are just methyl groups or acetyl groups tying to histones and those are kind of like literally physical molecules that block the unfolding and folding of your DNA. So, interestingly, and this is like literally being discovered in the last year or two, it looks like beta-hydroxybutyrate can actually bind the histones through a process called beta-hydroxybutyrylation. And the same thing can actually happen with lactate. So, you have actually lactate bind the histones, controlling the folding and unfolding of DNA, which then controls protein expression.

So, I think lactate is one of those–and it reminds me of, very similar to the story, of ketones, which is that lactate was thought of as this metabolic waste product. And George Brooks over at UC Berkeley has been doing a lot of work around lactate showing how it's actually potentially not just a metabolic waste product. And I think the key concept that I've realized and been thinking a lot about is biology for better or for worse has been a study of snapshots, meaning that when I take a finger prick of my beta-hydroxybutyrate or I take a finger prick of my glucose, you get a snapshot in one time of what my metabolic state looks like.

But what's actually happening is that there's a flux or a turnover of all these metabolic [00:59:03] _____ happening all at the same time. And we just don't have the technical measurement tools to actually measure flux really easily. So, we have to use a simpler mathematical understanding to model out what's going on, but I think what was done really interesting by George Brooks is that lactic acid, when you're exercising, does build up. That's why you see lactate going up, and that's why people say they get sore. But the interesting thing is that there's a ton of turnover. It's not just lactate sitting there, it's actually getting recycled and used as fuel.

So, while the end snapshot looks like it's building up, all that lactate is being turned over again and again and again. And if you look at lactate, it also crosses the blood-brain barrier. And the Berkeley group has shown that lactate like ketones could be useful for concussion, TBI. It reminds me of a lot of the same characteristics of why people think ketones are interesting. There seems to be a similar story at play with lactate.

Ben:  Well, I agree and I have a couple of thoughts on that. First of all, I have measured my level of ketosis after a difficult workout, but a difficult workout that was not performed in a fasted state per se, like a 4:00 p.m. workout that occurred after having had a breakfast and a lunch. And despite not being in a state of appreciable ketosis anywhere near that three millimolar mark, I have suppressed appetite and a feeling of mental superiority that I sense is due to the availability of lactate as a substrate for neurons. And I think that there's some definite benefits to lactate that are similar to what one might experience with ketones. And so, I haven't experimented too much with how that might be amplified if I throw ketone esters into the mix, but I would imagine it could probably enhance that process even more.

And you briefly touched on lactic acid and soreness, and that's just an annoying old-school theory that drives me nuts when I hear people say, “Oh, this supplement or this tactic is going to reduce lactic acid, therefore, make you less sore,” when in fact, as you've just alluded to, lactate turnover, specifically via something called the Cori cycle, allows for lactate to be converted back into glucose or to do things like enter the brain for use as a fuel, and you don't have much lactate hanging around in your body post-workout. And by the next day, none there at all dictating that it's definitely not lactic acid that's making you sore. And in fact, it's more likely that it's a release of intracellular calcium that is contributing to soreness more than anything else along with just microtrauma to muscles, the influx of white blood cells, and other inflammatory markers, and the subsequent swelling, and even pressure against nerves and pressure against muscles that would occur as a result of that, and not lactic acid. Lactic acid really is barely even around the next day. That's not what makes you stiff and sore so to speak.

So, that's interesting regarding lactate. Anything else we should know about the parallels between lactate and ketones?

Geoffrey:  I would say that the interesting things to me are that lactate and ketones are not insulin-mediated. So, I think the interesting substrates for metabolic health, and I think that goes down that whole trajectory of insulin resistance, insulin sensitivity, all that whole story. And I think on the other side, on the performance side, there's been some work on lactate supplementation and on the cognitive TBI side of house–

Ben:  Right. You mean using like a magnesium or calcium lactate pre-workout to enhance the activity of lactic acid, buffering enzymes before like a really anaerobic workout to allow you to get less burn pre-workout the same way that you might use like sodium bicarbonate loading pre-workout?

Geoffrey:  Yeah. Sodium buffering is–yeah, it's like bicarbonate or buffering is an interesting topic, and I think that actually ties into use of exogenous ketones for acute workout. There's actually a really, really recent study just published around looking at potentially the flow of electrolytes when you're in ketosis versus not, right? And I think this might make sense to people that have done a lot of fasting or ketogenic diet whereas your insulin reduces, you excrete out more sodium, you actually need more sodium, for example.  So, there's also an interesting parallel to how you actually use that in conjunction of ketone esters, for example.

The last point I wanted to touch on was the interest, and I think an important area of research, which is cognitive impairment or TBIs. What happens when the brain has a TBI or Traumatic Brain Injury or a concussion is that there's a catecholamine release a lot of adrenaline everything dumps, you have a hypermetabolic state where all the sugar is used up. And then, one important enzyme, pyruvate dehydrogenase, which is the enzyme that converts glucose into PDH or pyruvate, and then pyruvate goes into acetyl CoA as a Krebs cycle. That enzyme, that's the gating factor of glucose uptake in the brain that is actually inhibited through all that oxidative stress. And, an area that I'm excited about is what happens in that post-traumatic brain injury brain state.

Obviously, the acute damage is there, you can't repair things that are just shattered, but what happens is that if you actually look at the brain after a TBI, there's very, very, low energy because no glucose can be utilized in the brain. So, if you'd actually look at the post-TBI brain versus the pre-TBI brain, there's literally huge fractions of difference between the amount of energy being consumed in the brain. So, it's interesting, can you go around PDH, can you go around the glucose pathway to feed these starving neurons with other substrates like ketones, like lactate, and again, they work in kind of similar ways where they're not PDH limited. And that also has interesting implications for neurological conditions like Alzheimer's, dementia, I know that there's researchers like Stephen [01:05:14] _____ in Canada have been looking at ketogenic agents for this use case, as well as efforts at the NIH looking at this application as well. So, very interesting early, but promising research threads.

Ben:  Yeah, I have a few little anecdotes to throw in there. I can definitely attest to the fact that, in terms of, not just management of TBI, but overall clear-headedness on a busy day. I've been experimenting quite a bit with hyperbaric oxygen therapy. As a matter of fact, during this coronavirus quarantine, I have been in my own little soft shell hyperbaric chamber every single day. And, I have experimented with dosing with ketone esters prior, and you come out of the hyperbaric chamber with a great deal of clear-headedness compared to what you would achieve with doing HBOT in the absence of ketone esters, and more clear-headedness than what you get from the ketone esters used by themselves. So, some definite interplay between this hyperbaric oxygen therapy and the use of ketone esters dictating that, I would imagine the two would be a pretty useful combination for management of something like TBI, even though neither of us are physicians and no one should misconstrue this as medical advice.

The other interesting thing, just to close the loop on the lactic acid piece, is that we touch briefly on the use of these lactate supplements pre-workout. And I should note that the prevailing amount of research shows that they do indeed not seem to work for buffering, to an extent where an athlete is able to perform better with high-intensity bursts of exercise. However, sodium bicarbonate or baking soda, still stands out as the best way to buffer lactate. Now, that being said, I know that there's good evidence out there that the supplementation of ketone esters lowers blood lactic acid. And so, what I'm curious about based on this then, Geoff, is have you come across anyone who has done something like stacked sodium bicarbonate and ketone esters pre-workout?

Geoffrey:  You're a smart man, Ben. People are exploring that, and I would say that some people consider that kind of trade secret or proprietary, “This is how we have an advantage to our competitors.” What I will say is that you're exactly right, there's actually an interesting effect of ketone esters on blood pH, blood acidity, and we'll see if there's published research coming in the next couple of months that describe that. But, you're exactly thinking the right way. You're controlling a system, ketone esters offer a novel tool into that system, there's pros and cons but can be using something like bicarbonate balance out some of the acidity when you have high ketones in your blood.

Ben:  Yeah.

Geoffrey:  We'll start seeing published literature on that very, very shortly.

Ben:  Yeah. And just so you guys know, the problem that researchers always run into when using sodium bicarbonate as something that you would dose with pre-workout is that it can cause a steep intake of fluid volume into the bowels and result in diarrhea and diaper pants pre-workout. And so the trick, and this is what most people have found through experimentation and is now being used in some research studies, is you do little microdoses. Let's say, you plan on doing a workout at 6:00 pm, and this would be a tough workout, maybe you're like Geoff, and you will go crush Murph, or you've just got some super intense coming up, or even a race, or a competition, what you do is for the two hours leading up to that competition, every 20 minutes or so, have a little bit of water. Four ounces or so of water and just put a tip of a teaspoon of baking soda into each glass of water. It probably comes out to somewhere close to a gram or so. And, that actually mitigates a lot of those effects of doing a large bolus of baking soda like 20 to 30 minutes pre-workout. So, that's a strategy that seems to work and I would imagine that combining that with a dose of ketone esters, then 20 to 30 minutes prior to that workout as part of that scenario would actually be a pretty good lactate buffering strategy. The only thing I could think of throwing in if we're going to stack these type of things would be there's a lot of evidence now on carnosine, in carnosine's lactate buffering effects. And there are companies, like LactiGo, is one that comes to mind that are now producing really absorbable transdermal carnosine applications that you would put on the arms, or the legs, and so this could be like a pre-suffer fest type of workout stack would be ketone esters, sodium bicarbonate, microdosing, and then the topical application of carnosine. And this would be something that for you, super-competitive athletes out there, would probably serve you well and be kind of like a tool in your in your back pocket for lactate buffering.

Now, there's actually one other thing, kind of a fun topic I wanted to ask you about, Geoff. Fun for some people, I suppose, and that would be that there's this rumble in the biohacker community about using ketones as an alternative to alcohol in cocktails. Particularly, one ketone known as 1,3-Butanediol, as a way to kind of get an alcoholic buzz without the toxic acetaldehyde that would normally be produced by ethanol metabolism. And, you would actually just use ketones in a cocktail that would normally call for gin or vodka or anything like that, and you'd use a small amount, like 10 to 20 milliliters or something like 1,3-Butanediol, or a ketone ester in a cocktail. Do you have any experience with that or have you looked into that at all?

Geoffrey:  Yeah, I mean, you got to experiment. I think that's one of the things that, again,  just being in the space in the interesting position, one foot on the practitioner athlete side of house who are really just actually on the front lines with personal experience developing signal. And on the research side which is very kind of cut and dry and we got to do everything in RCTs. This has been a fun area to play around with. Can you stack ketones with other fun compounds? I know there's been, we've experimented mixing this with actual alcohol. Can you do ethanol plus ketones? Yeah, I think it's been one of those fun things where–I can imagine a world where you have ketones replace ethanol as a fun going out drink. There's definitely a cognitive impact, and I think it's still being unpacked exactly how the brain is impacted with ketones. But there seems to be an anxiolytic effect or an anti-anxiety effect primarily demonstrated in animal models. We haven't yet seen or replicated that in humans just yet. But I would say, from a mechanistic approach, just like ethanol or alcohol reduces anxiety, ketones seem to do the same thing. And in terms of like a bitter flavoring elements, ketones and ethanol, I'm sure that a ketone ester drink doesn't taste as bad as Everclear or something. So, I think you're going to be in a good spot if you're mixing a cocktail.

Ben:  I've experimented with it quite a bit, and as a matter of fact, probably three to four times a week now because I love to have a cocktail with dinner. I'm using ketones instead of alcohol and I find it to be pretty pleasant, I mix it with little lemon juice, I'll throw some stevia in there. If I'm going to make, let's say, a Moscow Mule, I'll do lime juice, some of the Zevia Zero carbohydrate ginger beer, some ketones, usually a pinch of sea salt, I'll muddle some mint in there sometimes, and, it's actually not too bad. And, the only warning I should give people is that the combination of these Butanediols with alcohol is not advisable at all, and as a matter of fact, can simulate something very similar to GHB, which is commonly known as a “date rape” drug. Because Butanediol can get converted into gamma-hydroxybutyrate, which is GHB, especially 1,4-Butanediol. So, I wouldn't go near 1,4-Butanediol. For this, 1,3-Butanediol seems to be a little bit more safe. And I've taken that on its own instead of something like the H.V.M.N. ketone ester to add to a cocktail as a substitute for alcohol, and it works pretty well.

I have also tried combining something like 1,3-Butanediol or ketone ester with the alcohol, and you're pretty much just face down in your play, and so I do not recommend combining ketones with alcohol but as a substitute for alcohol. My own experimentation actually seems to work pretty well. And again, you don't see any of the sleep disruption or any other issues that you would get with alcohol, so it's actually a pretty cool hack if you want to have a nice cocktail and use ketones not in addition to the alcohol but as a substitute for it. Especially this 1,3-Butanediol, it seems to work pretty impressively.

Geoffrey:  Yeah, I think one thing to add is that I've been experimenting with CBD and ketones, and that's been an interesting combination where CBD, it's not necessarily supposed to be psychoactive, but some people report definitely kind of a feeling of relaxation. So, I think there's definitely anxiolytic compounds whether they're adaptogens and whatnot, that I think stacking with ketones will be a fun place to experiment on the biohacker or the hobbyist side of house. I think it's still very early in terms of what kind of these combinations could kind of look like. And yeah, you're exactly right, the GHB, gamma hydroxybutyrate, very, very different molecule than Beta-Hydroxybutyrate, 1,4-Butanediol is very, very different from 1,3-Butanediol. But yes, don't accidentally date rape yourself with GHB or 1,4-Butanediol.

Ben:  Exactly. Well, I feel like we could talk for a really long time about all this stuff and I did want you to know, because if you want to see what Geoff looks like in a fun little flick. I watched this on an airplane coming back from Japan a few months ago, and there's this movie called “Smart Drugs,” and Geoff is in that. And it was actually a really good movie, I thought, or documentary on smart drugs which is another topic that Geoff specializes in that we didn't get a chance to visit much today. But, this little movie, “Smart Drug,” is actually a fun flick and you can see Geoff featuring that movie. So, congratulations on being a big Hollywood star, Geoff.

Geoffrey:  I haven't yet watched it myself, still too embarrassed. But I hope that's entertaining.

Ben:  Yeah, it's not bad, really. And I'll link to that, I'll link to everything we talked about. Geoff's H.V.M.N. ketones, his own company's formulation, they're giving all of us a 10% discount over at their website. Just use code BEN over there, and I'll put a link to that in the show notes as well. Or, you can just go to GoHVMN.com/Ben, that's GoHVMN.com/Ben and get yourself some exogenous ketone esters. If you want to experiment with them and see what they feel like, that should be a little bit easier on your pocketbook with that 10% discount. And again, I'll link to everything at BenGreenfieldFitness.com/Woo. And, Geoff, thanks for coming on the call, man. It's been a ton of fun geeking out with you.

Geoffrey:  Yeah, this is great. Thanks so much, Ben.

Ben:  All right, folks, that's Ben Greenfield along with Geoffrey Woo of H.V.M.N. If I can spit it out, H.V.M.N. Signing out from BenGreenfieldFitness.com. Have an amazing week.

Well, thanks for listening to today's show. You can grab all the shownotes, the resources, pretty much everything that I mentioned over at BenGreenfieldFitness.com, along with plenty of other goodies from me, including the highly helpful “Ben Recommends” page, which is a list of pretty much everything that I've ever recommended for hormone, sleep, digestion, fat loss, performance, and plenty more. Please, also, know that all the links, all the promo codes, that I mentioned during this and every episode, helped to make this podcast happen and to generate income that enables me to keep bringing you this content every single week. When you listen in, be sure to use the links in the shownotes, use the promo codes that I generate, because that helps to float this thing and keep it coming to you each and every week.




It's time for a serious geek out on all things ketones, ketosis, ketone esters, and more!

My guest on today's show, Geoffrey Woo, is co-founder and CEO of H.V.M.N. – Health Via Modern Nutrition. He is also the host of the Health Via Modern Nutrition Podcast, a health & performance podcast that recently broke 4 million downloads. H.V.M.N. helped popularize ketones as a food group beyond fats, proteins, and carbohydrates and makes foods & supplements for metabolic performance and health—fueling some of the world's top performers, athletes, and military service members.

Geoff is an avid self-experimenter who like to do 7-day water fasts, has inspired thousands under the COVID-19 lockdown to push themselves with positive challenges by completing the Crossfit Murph workout for 45 days in a row, and studies the optimization of human performance—at the individual scale, the team scale, the organization scale, and at the civilizational scale. He holds a BS with honors and distinction in computer science from Stanford University.

During this discussion, you'll discover:

-How Geoffrey used ketone esters while doing a Crossfit “Murph” for 45 consecutive days…5:45

  • Named after Michael Murphy, a Navy SEAL killed in Afghanistan
  • Consists of a 1-mile run, 100 pullups, 200 pushups, 300 squats, then another mile run
  • Staying with a routine when COVID-19 became a serious issue
  • Low carb diet overall
  • Need for muscle and liver glycogen repletion
  • Added carbs to the diet, as well as ketone esters and exogenous ketones
  • Used ketones more for recovery than for performance

-Why ketogenesis is not a physiologically typical state…13:00

-The role ketones play when it comes to recovery…16:15

  • Research thus far has been focused on acute performance benefits
  • Trials performed on runners and cyclists; much easier to quantify than other sports
  • Tour de France cyclists reported exogenous ketones were better for recovery than for pre-race fuel
  • 2019 study on mimicking Tour de France training regimen with ketone esters
  • Ketones plus carbs and protein upregulates mTORC1
  • Anti-catabolic effects are consistent from an evolutionary perspective
  • Ketogenic diet inhibits mTOR
  • If you want to use a ketogenic state for recovery:
    • Have adequate nutrient availability, caloric intake, and carbs (allows liver and muscle glycogen levels to be full)
    • Include ketone esters with regular meals (induces anabolic pathway not present without ketone esters)
  • To trigger autophagy, decrease mTOR, and enhance fasting:
    • Use nutritional ketosis and/or ketone esters
    • Lower amount of carb intake and calorie availability
  • Open question of inquiry: Is β-hydroxybutyrate (BHB) itself the signaling molecule that triggers HDAC inhibition, FOXO3, other longevity pathways, or is it the caloric restriction itself?

-Pros and cons of endogenous and exogenous ketosis…24:18

  • What's happening physiologically:
    • Endogenous includes carb restriction by default (not necessarily calorie restriction)
    • The brain senses lower AMPK due to a lack of glucose
    • Increases lipolysis and fat mobilization
    • Blood-brain barrier prevents fat from entering to provide substrate for neurons
    • Increase in free fatty acids
    • Fat burning lipolysis
  • Exogenous ketosis: eating calories in the form of ketones
  • Exogenous ketones will elevate BHB aggressively
  • Inhibit lipolysis (fat burning) and free fatty acids go down
  • Ketones can be used a metabolic fuel as well as a signaling metabolite
  • Ketones mediate ghrelin (the appetite hormone) which signals satiety

-The difference between ketone esters and salts…35:15

  • Ketone salt: BHB bound to a mineral (a salt)
  • Pros and cons of salts:
    • Cheap and available
    • Often too much mineral in a ketone salt product
  • Ketone esters: Organic molecule that has an oxygen double bond between different components (monoesters and diesters)
  • Future research will reveal a “family” of esters, similar to carbohydrates, fats, etc.
  • H.V.M.N. focuses on a monoester: BHB esterified with R1,3-butanediol
  • This ketone ester delivers 100% of BHB vs. ~50% with ketone salts
  • Another ketone ester is acetoacetate diester, that Dom D'Agostino has worked on.

-The ketone esters developed by the DARPA program…38:45

  • Beginning in the 1960s, various studies conducted to determine the efficacy of ketones
    • Fasting study at Harvard by George Cahill – studies on starvation
    • Dr. Richard Veech, one of the earliest researchers of ketones and understanding the metabolic implications of ketones
    • At the start, a lot of people thought of ketones as metabolic waste products for type 1 diabetics, did not realize the broader implications as a fuel substrate as well as a signaling metabolite
  • Early 2000s, DARPA program headed by Dr. Joseph Bielitzki initiates project to determine the human factor in fighting wars
  • Quercetin, cooling glove out of Stanford and ketone esters were part of the program
  • DeltaG is the code name for a ketone monoester developed in the program
  • Last 4-5 years, performance-enhancing aspects of ketones have been studied as part of the program
  • Geoffrey's podcast with Dr. Joseph Bielitzki of the DARPA program

-Gold standard usage for dosage and frequency of ketone esters…44:45

  • Dosage is based on body weight
  • High amounts needed for pre-exercise (for Tour de France cyclists)
  • Aim for a threshold of BHB in the blood
  • Body becomes more efficient when more adapted to ketones
  • Blood BHB is the most important variable—dependent on body weight, metabolism, and keto adaptability
  • Ketones uses:
    • Cognitive use (military and sports decision making)
    • Used prior to and after fasting
    • Transition to ketogenic diet minus the “keto flu”
  • Blood is the best way to measure ketone levels
  • You don't excrete as many ketones when you become keto-adapted

-Whether or not ketones break a fast…53:35

  • What is the purpose of the fast
  • Which metabolic pathways do we care about
  • Ketones are mildly insulinogenic at best
  • They do not upregulate the mTOR pathway (only happens when stacked with carbs and protein)
  • Ketosis shifts NAD+ and NADH ratio to enhance sirtuin activation

-How a process called lactylation enhances the expression of longevity genes…57:11

  • BHB binds histones through process called β-hydroxybutyrylation
  • Same thing happens with lactate
  • “Biology is a study of snapshots”
  • Lactic acid builds up during exercise
  • Lactate crosses the blood-brain barrier
  • Possible use in treating TBI, concussions, etc.

-Parallels between lactate and ketones…1:02:15

  • Not insulin-mediated; substrates for metabolic health
  • Cognitive and TBI repair
    • No glucose can be utilized by the brain after a concussion or TBI
  • Potential for use treating Alzheimer's, Parkinson's, etc.
  • HBOT chamber (use code BEN to save $500)
  • Sodium bicarbonate (baking soda) is the best way to buffer lactate

-Stacking sodium bicarbonate with ketone esters pre-workout…1:07:15

  • Water, tip of teaspoon (microdosing) leading to the workout helps with potential diarrhea
  • Lactigo transdermal carnosine applications (use code BEN to save 20%)

-Ketones used in place of alcohol in cocktails…1:10:15

  • 1,3-butanediol can give the buzz minus the toxicity of alcohol
  • Anti-anxiety effect demonstrated in animal models
  • Butanediols combined with alcohol is highly discouraged
  • Minimal sleep disruptions with use of ketones rather than alcohol
  • CBD and ketone combinations

-And much more…

Resources from this episode:

– Geoffrey Woo:

– BGF podcasts and articles on ketones and ketosis:

– Gear and supplements:

– Other resources:

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