Ketones for Performance, Cognition, and Cardiovascular Health [transcript]

Written by Christopher Kelly

Dec. 27, 2019

[0:00:00]

Christopher:    Well, Dr. Brianna Stubbs, thank you so much for joining me once again this time in Bonny Doon.

Brianna:    I know. Well, I visited you before and I'd love to come back and be in the redwoods, so it's always a pleasure. 

Christopher:    What a difference from San Francisco. It was the last time we recorded. 

Brianna:    And in fact, we met outside the offices in the Tenderloin and that afternoon, I actually took down a would be mugger. Do you remember? That was the same day. 

Christopher:    Yeah, I do remember. You were completely bonkers. 

Brianna:    We recorded this podcast. I was walking back from recording the podcast and someone thought they're trying to steal my phone and they didn't realize that they were taking on the wrong lady and got high tackled when he tried to steal my phone and ended up in the justice system. 

Christopher:    Oh really? Did you get your phone back?

Brianna:    Oh, yeah. Well, he didn't get away. He started running and I was like, "You want to run away from me?"

Christopher:    It's completely bonkers, and in Tenderloin in San Francisco, how crazy is that? That's the thing -- 

Brianna:    But you don't think when this kind of stuff happens. You don't think. 

Christopher:    Yeah, I get that. I do.

Brianna:    The instant reaction was, "Come back, you little creep." 

Christopher:    Yeah. I think it's different though when you're British. You don't realize that American people -- 

Brianna:    That people might have a gun. 

Christopher:    Yeah. The people have guns in their freaking gloveboxes in America.

Brianna:    Yeah.

Christopher:    You can't do that. You can't flip people the birds when you're on your bike. You can't do that. 

Brianna:    I think it was just last week, there was a video that came out like a block up from where this incident happened with people opening fire and you're just like, okay, stuff works different here. 

Christopher:    Yeah, sure.

Brianna:    Yeah, so that was last time. Hopefully after this podcast, we'll part without an incident. 

Christopher:    Yes.

Brianna:    Let's hope it's not jinxed. 

Christopher:    I think you've got far less chance of having your iPhone stolen in Bonny Doon --

Brianna:    Yeah, I think it'll be alright. I think the worst that can happen to me is if one of your dogs will try to eat me. 

Christopher:    No, they're good dogs. They won't eat you.

Brianna:    Or one of your kids.

Christopher:    Yeah, that's quite possible too.

Brianna:    There's probably a high chance. 

Christopher:    Yeah. They'll take your shoes. You'll go to do the triathlon tomorrow --

Brianna:    And I'll only have one shoe.

Christopher:    Yeah, exactly, there'll only be one shoe. Tell us about your triathlon racing. You're here in Santa Cruz to race Ironman -- 

Brianna:    70.3, that's it. I did my first full Ironman in July. That was unfortunately a really fun experience. I was kind of hoping that it would be so-so so that I didn't have to do another one, but --

Christopher:    And where was that?

Brianna:    That was back in England, so I went back over there and it was in Bolton, which to American people would be like saying you're going to do an Ironman in Fresno. People are just like, "Why are you going to Bolton? Why are you going to Fresno?" but it was nice. The city was beautiful. There was a lot of support on the course. The standing on the start line was just super -- there was this great energy that kind of carried you through the day, so I really enjoyed it, feeling pretty fit, came back, and kind of regrouped a little bit. This race is just down the road from where we live and I absolutely adore Highway One. It's got to be one of the most beautiful stretches of road. 

Christopher:    Oh really? You're completely bonkers. 

Brianna:    You don't like it?

Christopher:    As a mountain biker, I'm thinking, why would anyone ride a bicycle along Highway One when you can ride in the redwoods, something like that?

Brianna:    I don't know. The redwoods is beautiful. The thing is in California, we have all the variety, so you can ride in the redwoods, but also today, I was warming up on the course and I was going with the wind, just pointing down, and there's the waves crashing on the ocean and I'm zipping along. I don't know what it is in miles per hour, but I'm not nearly 40 kph. I'm in my area of position and it just feels like you're about to take off. That's a pretty awesome feeling. There are just too many things that are good fun to do, right? It's fun to bomb down a trail on a mountain bike. It's actually kind of fun to put out a gross amount of watts on a time trial bike with a tailwind. That's fun too. 

Christopher:    And you're going to ride past Waddell Creek, which is one of the best places in the world to kiteboard, right? 

Brianna:    Yeah.

Christopher:    So you turn around Año Nuevo where all the elephant seals are. I've still never been there and seen the elephant seals. It must be quite --

Brianna:    That's cool. It's scenic. It's a scenic course. It's really nearby. With triathlon, there's so much that goes into putting a race together that it's good to get a bit more experience. I had a really interesting experience with the full Ironman swim where I got so excited on the start line and then you get in the water and I'd been typically myself and sort of seated myself with people who are a bit faster than me and actually, that was kind of claustrophobic, so people all around and people -- I wouldn't have said that -- I didn't have people swimming on top of me or battering me. It wasn't really even that, but I was breathing a bit more often than I would in swim training. I was breathing every stroke rather than every three and I feel like it was activating my deep brainstem like panic center, the breathing and not being able to see the horizon because of people. There was just a lot going on. 

Christopher:    It sounds terrible. 

Brianna:    I had to take myself out of the middle of the race and go off to the side and put my head up for a few seconds and just be like [breathes]. "Okay. This is a long day. You're not going to just freak out within the first ten minutes of the swim. You're going to swim for an hour. You'll be alright. Just stick near the edge." Once I got into my rhythm, it was fine, but you can't practice swimming with 200 or 1000 people. You can't practice swimming with that many people by yourself. I've actually done a fair bit of open water practice because I live by the San Francisco Bay and there's Shelter Cove. I felt like I've been pretty diligent and I've put in the hours in the pool with Lesley Paterson's guidance. 

Christopher:    Yeah. We've both coached with Lesley -- 

Brianna:    Yeah. She put me through my paces and I kind of felt pretty dialed in with the swimming, but you can't mimic that race situation. 

[0:05:07]

Christopher:    No.

Brianna:    So I kind of figured to get a bit of swim practice, ride on Highway One. It's kind of flat. Maybe I'll do a PR. So the aim for tomorrow -- and I feel like I've always been a little bit conservative on the bike, so I'm going to go and try and blow up on the bike and then see what I have left for the run. The race or the outcome doesn't matter so much to me, so I just want to push the envelope a little bit and see how it goes. 

Christopher:    I think that's always a good way to go into a race like you don't really give a shit about it. I've had some of my best -- and Lesley has talked about this as well that you have some of your best results when the expectation is low. I could remember a couple of years ago, I did a race in Wilder Ranch, which is where you're going to be, and the week before, I've gotten knocked off at the start and ended up with stitches in my arm. So I did the race the week after thinking, "Well, this is not going to go well, is it?" because I've got freaking stitches on my arm. Of course, I got a much better result than I thought I was going to get and I think that's a good way to go in.

Brianna:    Yeah. Set some process goals and the outcome will take care of it. I'm kind of half hoping that the whole way along this triathlon journey that I have been overconservative on the bike and that I will -- I think I'll get through the run no matter what happens, so I think it'll be good to put myself in the hurt locker a little bit and really see how it goes. 

Christopher:    What's it going to be like swimming in the open water in Santa Cruz? They've got big waves here. 

Brianna:    Because it's first in the morning, hopefully stuff won't have picked up just yet. We'll see. 

Christopher:    It won't be windy as much. The wind picks up around midday, but the waves, yeah, I didn't know about that. At the harbor, I think it'd be fine.

Brianna:    They'll be following me in. They'll be following me in on the way in, so as long as I can get out then it's fine. I'll just hold onto someone's foot. 

Christopher:    Talk about how you dose the ketone ester. That is, after all, what you're famous for. 

Brianna:    Sure, yes.

Christopher:    Everyone wants to know. 

Brianna:    I don't like -- I think partly because of that experience that I had on the Ironman UK swim, I feel like for me, the swim is like a bit of a vulnerable time, so I don't like taking anything because sometimes when I take ketone ester, I feel kind of wired and a bit like -- 

Christopher:    Over-caffeinated?

Brianna:    Well, not over-caffeinated, but I feel it's just like a bit of a different mind-body sensation, and so I don't want to throw that into the mix when I'm also a little bit like different mind-body situation because of swimming, so I don't take it before the swim. I have it in transition one before the bike. I think for -- because the swim is shorter, it's not as depletive, I take it alongside my regular carbohydrate fueling. So in the morning before, I'll have oatmeal, complex carbs like slow-release carbs a few hours before the race. Then when I get to transition one, I'll have one to maybe one and a half bottles worth, so it's 25 to 30-ish grams of ketone ester before I go onto the bike. I think I could -- for the Ironman, I would re-up again halfway through or in a couple of hours in, but for the half Ironman, I'll probably just box on. It doesn't taste great, so it depends on --

Christopher:    It still doesn't taste great even though -- 

Brianna:    Well, I think HVMN revised the flavor, so people should go try it now because I think they've got a new flavor that's apparently a little bit better. I'm waiting to try it. 

Christopher:    Oh, you haven't tried it? Okay.

Brianna:    I tried it in development, but I haven't swigged a whole bottle of it yet. 

Christopher:    Okay. What do you think might be going on with what you said about that overstimulated feeling that you can't quite put your finger on or even name? Can you give me an idea of what might be going on at the source code level there?

Brianna:    It's definitely something that other people describe when they take it, feeling like more behind their eyeballs or kind of energetic but not jittery. It's not unpleasant feeling. It's not like heart palpitations or dizziness or anything like that, not for me anyway. I think everyone has a slightly different subjective experience, but it could be a combination of the elevated ketones and the switch from glucose as an energy source in the brain specifically. There are a number of different physiological things, so you're dropping blood glucose, you're raising blood ketones. Also, you're actually giving yourself an acid load, so we see that people get mildly acidotic and that changes your pO2 and pCO2 balance, your arterial blood gasses. There are a number of fairly fundamental parameters in your basic physiology that shift a little bit. So maybe if you go from a state of balance and then the balance is shifted, maybe you experience some kind of emergent sense of that shifting. 

    Actually, recently, the group that I did my PhD in over at Oxford, they published a paper that looked at using ketone ester as a tool to deliver an acid load during exercise and look at anxiety, the feeling of discomfort in your legs and with your breathing, and then your anxiety around about that. So it was interesting because there were differences. They're not necessarily differences in discomfort or difficulty breathing, but differences in the anxiety starting to be teased out. The lead investigator, let's just say, on that paper, Dr. Olivia Faull, did her PhD looking at the periaqueductal gray, so that fear center. I'm probably butchering it and she might kill me if she hears this, but she was interested in the very, very primal parts of our brain and how that regulates anxiety.

[0:10:06]

    Then when she came and figured out that ketones could be a tool to manipulate that, she bought that expertise over and started to uncover some interesting differences there, so I think there's not much known about it, just that one paper. Maybe it's linked to that. I think there's certainly a story there. It's kind of the end of a thread when you pull it off a little bit.

Christopher:    Yeah, it's so many things. Talk about your transition to the Buck Institute. That's very exciting. I feel like I've been there at the right time to record your -- 

Brianna:    All these transitional moments. 

Christopher:    Yeah, transitional moments in both your sporting and your professional -- well, I guess they're both your professional career really. I can't really draw the distinction there. 

Brianna:    I wouldn't say I'm a professional triathlete yet.

Christopher:    But certainly, you were just recently retired in rowing when we first met. 

Brianna:    I think I was still competing when we first spoke, but definitely deciding what I was going to do next. Yeah, it's been a bit of a journey since then. I took a job as the lead translational scientist at the Buck Institute. The Buck Institute, the mission is to live better longer, so it's dedicated to aging research, about 30 PIs, all of them working on different aspects of aging, reproductive aging, brain health and metabolism, mitochondrial aging, some with disease focuses, some with more basic science and mechanistic focuses, and it's a fantastic environment. I really missed being in the center of excellence. When I was at Oxford, there were so many people working on a variety of different things. It was really interesting to be a sponge there and soaking that all up. Back at the Buck, I'm just constantly surrounded by brilliant people and I'm learning an awful lot. 

    To go back to what we were talking about at the start, it's certainly nice being in Novato halfway up a mountain in a beautiful I.M. Pei-crafted, white stone building versus the Tenderloin. I've deer pop up outside my office. I have an office overlooking a flowerbed and the mother deer come and hide their baby deers right outside my window, so rather than looking at down-and-outs doing drug deals, I'm watching the -- 

Christopher:    Yeah. It couldn't be more different, could it?

Brianna:    No.

Christopher:    I've been there. I saw it and I do know what you're talking about because I've been to the Buck Institute. I went there with Tommy to Dale Bredesen’s training for his protocols -- 

Brianna:    That's it. I believe he used to be the CEO of the Buck. 

Christopher:    I didn't know that. 

Brianna:    Yeah. They've had some fairly prestigious people be CEO there because obviously, Eric Verdin now, he's one of the leaders in NAD research and also ketone bodies as signaling metabolites as well. He's well-known for that, so they're attracting more and more really great scientist. What took me there is specifically to work on ketone biology with John and Eric, John Newman and Eric Verdin. They co-authored this fantastic review that I'd really recommend that people read. It's talked about not only ketone metabolism, but all of the different receptor interactions that there are and also the way that ketones affect epigenetics as well, and also how ketones themselves can be used as a post-translational modification and potentially affect protein function.

    It's kind of different to the sports physiology background that I came from, but I'm interested and they bought me on to help with the translation of this kind of ketone technology. What's also great is I work a little bit with the technology transfer team there. Technology transfer I think is really important. People should celebrate it a bit more, the idea that you get a scientist and they can do some fantastic research, but that's no good if you can't get it out well. It's of limited use. It's of more use if you can take that discovery and figure out a way to get it out into the world. I was thinking the other day as a scientist, you don't have those skills in legal matters, in branding and marketing, in maybe product development or software development, any discovery that you make as a scientist and you're the world-leading expert in that thing, but you need other people who are experts at all of the downstream things to actually make this a reality.

    I think in a way, [0:14:03] [Indiscernible] is a really good case study of this. We actually hosted Dr. Volek and Dr. Phinney at the Buck the other day and they're both absolutely pioneers in the field of ketogenic diet research, but they need the team of software engineers and they need -- or it was helpful for them to have Sami Inkinen, a seasoned CEO, to help with the fundraising. There's so much that goes into realizing an impactful discovery, helping it realize a full impact, and so part of what my job there at the Buck is to help scientists figure out how they can make their ideas a reality. 

Christopher:    That's very cool.

Brianna:    Which is cool. I get to speak to a number of the different PIs about the projects that they're working on -- 

Christopher:    You better explain what PI -- you just used that word again. 

Brianna:    Principal investigator. 

Christopher:    Okay, so what does a principal investigator do?

Brianna:    They're like the lab chiefs. They're the ones that will be on all of the -- or mainly on all of the NIH grants. The structure of a science lab is you might have your PI, your principal investigator. They're the one who the funding is attached to. They're generally faculty, so a professor of some kind and they'll have tenure at the institute.

[0:15:04]

    And then you might have a couple of postdocs, so they've done their PhD and they're starting to do more independent research, but they're past that internship phase. Then you might have a lab manager who's not on an academic track themselves and they might do more of the making sure supplies are stocked, but then also training people to do a certain procedure or experiment that the lab is known for. The PI will be writing grants, writing papers. The PIs are probably not doing the experiments themselves. The postdocs and the lab manager will be doing their own experiments and the lab manager will be overseeing everyone, then you have your PhD students. Depending on where they are at, their PhD and certain degrees of training with us, even more of a training position, they'll end up with their degree. Then you might have research assistants or interns or staff scientists who are -- well, we probably shouldn't bucket them altogether. Research assistants and master students would be at the very outset of their scientific career and they would need a lot of --

Christopher:    That's a very polite way of putting that. Have you made that mistake before? It was very politically correct. 

Brianna:    Yeah. I think I've had some experience when I was doing my PhD of working with a master student who I got to make up a buffer solution from, not a difficult thing. You give the kid the recipe and all he has to do is weigh it out. We did this whole experiment pipetting onto a 96-well plate four different things, a whole afternoon of experimentation and it didn't work, and I asked him to show me what he put in this recipe. He mixed up NAD and NADH, but that's important because that drives the reaction in one direction or another, and so I was just like [sighs].

Christopher:    In my world of finance, that's like the trader telling me that I should buy something and then we going ahead and selling the same amount. The side matters. 

Brianna:    I think the research assistants are master students. They need a bit more supervision. They might do tasks that are less complicated. They won't be setting their own project. You'll be telling them what to do, but they're very helpful to help with the throughput of the lab and you have to start somewhere. 

Christopher:    So this is the same John Newman that was really on STEM-Talk. 

Brianna:    Yeah, and he was the one that published the paper at this in the same issue of cell metabolism as Megan, so -- 

Christopher:    John was Episode 94 and then Megan was Episode 92, so there was this really interesting scenario that we had two people do basically the same experiment. 

Brianna:    Well, it's really interesting. In the episode of STEM-Talk recently with John, he handpicked some of the differences between his work and Megan's work, which I thought was really, really useful because it showed how the two experiments together were even more powerful than just one of them by itself and how they measured slightly different things and how that almost joint publication with slightly different methods really reinforces the findings were reproducible, which in science is not done all that often, isn't it? We have a reproducibility crisis in science, so it's kind of neat that those were done at the same time and had somewhat similar results.

    Yeah, I'm working with John Newman and his background is in ketone specifically as a signal. I think it was in 2010 or 2012, not all that long ago in science terms anyway, his group. He was at that point being mentored by Eric Verdin and they looked at BHB and its effect on histone acetylation. So their research group was the first group to publish that BHB is an endogenous, made in the body, histone deacetylase inhibitor. So when you have BHB present, you inhibit the histone deacetylases, so you get hyperacetylation of histones. Now, histones are -- whenever people draw them in diagrams, they look like little balls and their protein, structural proteins at DNA is wound around. If your DNA is unwound, it's a meter or several meters long. It's all packed on inside the nucleus and that's because it's wound around these histones. So by adding and removing these acetyle groups onto the lysine, which is an amino acid, if you add and remove these acetyle groups onto the lysines of histones then that causes them to become a little bit less tightly wound and then that means that the DNA reproducing machinery can get access to that bit of the DNA more or less depending on how tightly it's wound. In short, BHB is affecting the ability of genes to be transcribed and particularly genes associated with longevity and fat metabolism.

    There's a coordinated program of gene expression and it's terrifically interesting because it could be and it's slightly different tissue to tissue. There's a lot of nuance that goes into this. For me, it's one of the reasons why ketones are just so interesting because it's a systems-wide effect. It's not only this presence of these substances and metabolite and providing energy itself. It's not only doing that, but it also directly binds to receptors such as G Protein-Coupled Receptor 41.

[0:20:06]

    That's an actual physical receptor in the cell surface, but then also having these epigenetic effects as well. Yeah, they pioneered all of that work. It's been a great learning opportunity for me to see how they approach experimental design and to have people who can really stretch my thinking about ketones because I definitely came at it more from "Ketone is energy. I use energy," the more basic and well-established view of ketone biology. 

    I heard she got in touch with them a long time ago when I was at HVMN and the way that I operate is to try and be friends with everyone. I was in San Francisco HVMN and they were in the Buck. I think I just reached out to them via email. I was like, "Hello! I'm interested in ketones. This is what I've done in the collab, and I'm now commercializing ketone essence with HVMN. Can we meet?" and they hoisted me up at the Buck. I think that they earmarked me from them on, and so when they had an opportunity to work on ketone biology with them, they approached me. It was a tough decision to leave HVMN because I loved the company culture and it was a huge privilege to see something go from being a lab chemical to being an Amazon-able product. It's really cool. I got to work with some of the best elite athletes in the world and some very elite military operators as well, so I wouldn't change anything that I'd done. It was really tough, but I think for me, I just love learning and I'm not even a closet nerd. I'm just a nerd. I like that kind of thing. I like to be learning and stretched, and so the opportunity to go back and get my hands dirty with some science again has been really exciting. 

Christopher:    That's amazing. Well, I want to come back to that, but before we get back to that, talk about some of these epigenetic effects of ketones. Is it all to the good? I start to get a little bit suspicious. Everything they talk about is a good thing and there's this product on sale over here, by the way, right? 

Brianna:    Yeah.

Christopher:    Has anyone found any signaling effects that seem to be deleterious? 

Brianna:    That was actually something that we were discussing the other day thinking about broadly looking at ketone effects of ketone biology in an untargeted way. One of the cool things about the Buck is there's a mass spec core so we can do very broad, untargeted proteomics and metabolomics and -omics-wide looks at what's actually happening when you're in ketosis and the difference between diet and just having BHB through exogenous ketones as well, which is set up that's going to underpin a lot of our experiments going forward, the difference between endogenous and exogenous ketosis trying to isolate BHB effects. Also, another underpinning, crucial thread of the way we think about things is looking at R and S forms or D and L forms of BHB, the two optical isoforms, just tease out what's a fuel effect and what's a signal effect because in many cases, not all necessarily and it's still something that we're working out as we go, the S-form will signal in a roughly similar kind of way to the R-form. 

    Sorry. Just to confirm for your listeners, we use D and L or R and S. They kind of come as pairs and I couldn't tell you why some people use one and not another. I always used to use D and L, but now at the Buck, people call them R and S. 

Christopher:    Interesting. Somebody told me this before and I'm kicking myself in not knowing. It's one of Greek derivation and then the other is perhaps -- 

Brianna:    S is left, which is sinistral, if we're talking -- 

Christopher:    Okay, but it's the same thing. It's basically like your hands, right? They're not perfectly -- 

Brianna:    You've got four fingers and a thumb --

Christopher:    They're not mirror images. 

Brianna:    They overlay. They are equal to one another, but they don't overlay, so BHB has that property. Yeah, that's the way that we're approaching the whole field. At the moment, we don't know what's the balance of good and bad effects. I don't want to sound like a stuck record for just how we approach everything. It's going to be all depending on the context and the outcome that you're looking for, so something that may -- actually, this, I think, is a fairly well accepted paradigm right now that a performance enhancing effect is likely to be deleterious for lifespan. 

Christopher:    Okay.

Brianna:    So for lifespan, you want to slow down metabolism and not have MTOR activity and all of that, and then for performance and gain, you want rapid and efficient metabolism you get when you're fasting -- 

Christopher:    It isn't even that tissue-specific, right? You want activation in the muscle, but not necessarily -- 

Brianna:    In the muscle, but not the liver, yeah.

Christopher:    I don't want to slip up in the shower and break my hip. That would be the end of me if I'm 70 years old. 

Brianna:    Yeah. Just thinking about aging has been another really fun thing about working at the Buck especially having worked with athletes in the military. I wouldn't really necessarily have thought that much about getting old. I'm 28 myself. It's just like -- 

Christopher:    Uh-oh. Bri's mindset is starting to shift like, "Wait. Maybe I won't live forever."

[0:25:02]

Brianna:    Yeah. John Newman, the PI of my lab, he's also practicing geriatric physician at the VA in San Francisco, and so it's been really fascinating to learn about how complicated it is to manage conditions in elderly people, all of the comorbidities and also the trade-offs that you make, what's most important to this patient and how much quicker they waste away or whatever, if they're mobile for a short amount of time and all of the social things that go around it, so it's definitely given me an appreciation for that branch of medicine, but also that branch of science. It's interesting because from coming into the Buck, you can see that GeroScience, or the science of aging, is a very young field, much younger than human physiology or the kind of metabolism field, which I've been in up until this point, so it's interesting to see how rapidly everything is advancing and all of the different subfields that are emerging within that. For example, cell senescence is something that we're at the Buck very well known for. Judith Campisi, she's one of the world leaders in looking at cell senescence. She didn't publish this, but interestingly, there was a paper published in the last year or so where a group showed that BHB could affect her vascular senescence, so senescence, the balance of senescence and quiescence of cells in the cardiovascular system. There are lots of threads to pull on.

    I guess for me, I'm always asking the question like how does all of this translate because the call of it does something in a dish or in an animal model, but at what point do we start to see these things in humans? I think just to make sure I properly fully answer your question, I think we were taking an approach where we're trying to watch for good and bad effects. We haven't yet. I think the classic example of a negative ketogenic diet effect might be, say, the increase in uncoupling proteins that you get in the mitochondria that arguably make mitochondrial respiration less efficient, but that's good for some things and bad for performance. It's not all going to be gold and roses. 

Christopher:    Isn't that good for weight loss? If I'm trying to lose weight, I want to be inefficient. I want to lose -- yeah, I'll wake a bunch of protons as heat. 

Brianna:    Burn your calories in your sleep, yeah, so water space.

Christopher:    Are any of these studies going to be done in humans? I'm kind of tired of hearing about studies done in a bunch of inbred male mice and then I'm supposed to get excited about that somehow. Is there any way that any of this research I hear, John Newman, Megan Roberts and others talk about, will it ever be translated into humans? Is it even possible?

Brianna:    With some good experimental design, you can do quite a lot. I think at the Buck, they don't have a clinical center right now and I think it's something that they'd look at in the future, but it's definitely a different skill set to basic science. Yeah, it's hard. You can't take liver biopsies. You're more limited to the types of tissue you can collect and the amount of tissue that you can collect. I think some mechanistic things do really need to be proven out in animals before you can get into people, but the nature or the science papers, often they'll tell a wonderful story from the basic mechanism up into animals, up into humans. Those are the very best papers, so it can be done and I'm optimistic that we'll get there. 

Christopher:    Do you think it's a valid concern then? You could just brush me off and say, "No, Chris, you're an idiot. You don't need to do that experiment. We already know."

Brianna:    No. You definitely need to do it.

Christopher:    Okay.

Brianna:    One example, which I still don't really understand what's going on and I think we need to do more research, is there's so much or there's a very strong consensus in the ketone research community that ketones help with inflammation because BHB inactivates the NLRP3 inflammasome and I've heard that to death. That was first demonstrated in 2013 by Deep Dixit in Yale and that paper has cited a bunch of times and since then, a lot of animal experiments have shown this effect, so just assume that it would carry -- and also people in the ketogenic diet, they report less inflammation. It's like, okay, this is a thing. 

Christopher:    They report everything, weight loss, "I can hold my breath longer," "I'm winning Ironman triathlons," you name it. 

Brianna:    Yeah. That's the panacea of it. 

Christopher:    The only thing that doesn't work is cyclo-cross. 

Brianna:    Yeah. You're the outlier. I felt like this was very well demonstrated in animals. Then recently, two papers came out which seem to be suggesting the opposite. One paper came out of a group in Copenhagen and they infused -- I don't know how they got ethics to this study, but they infused a bacterial toxin called LPS into healthy, young men and then they also infused them with ketones in one arm and not --

Christopher:    Oh, is this the one where the distribution was all over the place? It wasn't anything even approaching a normal distribution. It was like a huge variable response -- 

Brianna:    To the BHB or -- 

Christopher:    Or to the LPS. I'm pretty sure. I'd have to go back and look at that -- 

Brianna:    Yeah, we'd have to go back and look at the paper. I'd be interested to look because I've started to --

[0:30:02]

Christopher:    But go on. Sorry. Sorry I've interrupted you.

Brianna:    No, no, no. I'd be interested to look at that, but they were also doing some fancy tracer stuff looking at protein synthesis and they found that having BHB present while you are giving the stress with the bacterial toxin, it's sort of somewhat protected muscle protein wasting, but they looked at cytokines and markers of inflammation that would be downstream of NLRP3 and you'd expect that they would be down, but they were actually a little bit higher in the ketone. Then six months later or within a few months after that, a paper came out of John Little's group in University of British Columbia and they were using the ketone ester, the BHB monoester that I worked on. They took a blood sample. They gave people the drink and then they took another blood sample. Once they had those blood samples out, they then stimulated them with LPS. 

Christopher:    You lost me. I understand what you said. It's just you've lost me with the utility of the test. 

Brianna:    They're now looking at how much activity, inflammatory activity goes on in the blood sample, not in the whole person, but there's some crossover because it's the same toxin. We're looking at blood cell, red/white/immune cell activation with and without ketones, and again, with the ketones, they saw a boosted inflammatory response when they put the bacteria. It's interesting because the title of the paper would lead you to believe that ketone drinks were inflammatory, but if you had a ketone drink and then I took a blood sample, in that blood sample itself, there wasn't more inflammation, but it's more active if I then stimulate it with bacteria, which you could argue is actually a good thing on the one side because you'll be like you want a big immune response to bacterial toxin, and a basal, there's no difference, but there was some interesting nuance going on there and it was clearly counter to this big, fairly well-accepted animal mechanism that had been demonstrated a bunch in animal models, so it'd be interesting to see how that shakes out, what's actually going on in those human studies, how can we get that question a little bit better, and is it just fundamentally different to animals. 

    One thing that I'm learning more and more at the Buck is that there are even differences in metabolism between different standard strains of animals. There are differences as you'd expect between rats and mice, but their more commonly used lab strains -- for example, there's a strain called C56 black-7 mouse, which is just like a cooking mouse. It's a type that everyone uses, but they have a mutation in transport called ANT, which is used in the mitochondria for part of the energy production, the ATP shuttling pathway, and that affects the metabolism profoundly and that actually might be relevant to how they respond to ketosis. You wouldn't necessarily know that if you were trying to pick a standard a model as possible. There are lots of ways Eric can come in because these animals are very, very inbred. Yeah, there are a lot of things that aren't necessarily going to mat from animals to humans, so -- 

Christopher:    Well, that's what worries me about the bottom-up approach. You start with an application that you know that works and then fiddle around with the source code later and figure out why it works, but first, make sure that it actually works.

Brianna:    Yeah. I think that actually a good way to guide basic science would be an untargeted approach in the system that you're ultimately interested in. It doesn't matter if we can make mice live longer if it's not going to help people live longer and healthier. 

Christopher:    What are the emerging applications? Is there anything that's emerged since the last time we spoke or maybe that you haven't talked about in the past? I mean there might be a different -- the Buck Institute is maybe interested in things other than winning triathlons and helping elite war fighters. 

Brianna:    Yeah. We're certainly not looking so much at physical performance in young, healthy adults. It's definitely more through the lens of aging and age-related diseases. For example, John's got a paper that's available on bioarchives where he's looked at effects on brain activity in Alzheimer's. When you have Alzheimer's disease -- in this particular model of Alzheimer's disease, the mice have what's called epileptiform spikes, so random spikes in brain activity that are present in the mice with AD, but not present in normal young mice. He saw that ketogenic diet and exogenous ketones could reduce those epileptiform spikes. He's particularly looking at brain activity in aging, protein aggregation in the brain, aging. These are all things that I guess you and I have talked about a little bit before maybe from an energy perspective, ketone -- 

Christopher:    [0:34:40] [Indiscernible] process.

Brianna:    Right, but maybe this is a multifactorial intervention here, so looking at that kind of biology. I'm interested in muscle physiology. Ken Ford from the IHMC is super interested in sarcopenia and it certainly looks that ketones evolve to be profoundly anticatabolic, so how that might affect aging. Again, to go back to what I said about John's mentorship, he's often talking about the syndrome of falls.

[0:35:09]

    Someone falls not just because there was something, a carpet, that they had a little trip. They then couldn't catch themselves. It was like a number of things that lead to a fall, and then also downstream of the fall, there's a number of reasons why it's much more serious for an old person to fall than a young person. 

Christopher:    Right. You've got to keep asking why, so five why's. Ask for "why" five times and you'll find out. 

Brianna:    Yeah, I think thinking more about aging, but I actually believe myself that a lot of the discoveries that we make that are relevant to aging will also be relevant to younger people as well because muscle metabolism and maintaining muscle mass is of interest to young people as well in the performance space, but also in the health space. Thinking about cardiovascular disease, there's been a couple of papers that's come out recently looking at ketone infusion in humans and then also a recent one from the University of Pennsylvania that looked at ketone infusions again in a paced model of cardiac failure in beagles, in dogs. They somewhat replicated Richard Vichas' findings and found an improvement in cardiac efficiency in these dogs with the heart failure phenotype, which I think is kind of interesting. 

Christopher:    What about status epilepticus? I've got an anesthesiologist friend in the UK and he sees people with status epilepticus. I hope I'm saying that right. 

Brianna:    Right. What is that?

Christopher:    You obviously haven't heard about it then. It's like a constant seizure, so you literally can't do anything -- 

Brianna:    The ketogenic diet was first used to treat seizures, so it wouldn't be a total surprise if there's an effect there. 

Christopher:    Okay. If that's the case, it's worth asking. These people have got a nasal gastric tube that they could just -- 

Brianna:    Yeah. That's actually some of what I did at Oxford. I was one of the first people to feed the BHB monoester via an NG tube and you see that you can maintain a steady state of ketone levels. 

Christopher:    Okay.

Brianna:    We're interested as well in trying to understand -- when you measure ketones in the blood, that's a really poor surrogate measure for what's actually going on inside the body. The measure in the blood is the sum of what's going in and what's going out. 

Christopher:    Right, the flux.

Brianna:    Yeah. So starting to think a little bit even about the work that I did in Oxford, if you've got ten units of ketone, arbitrary units, in your bottle of ketone ester and if it's really rapidly bioavailable and you drink that bottle of ketone ester, all ten units will appear in your blood at the same time and you get this big peak, which is what we would see with the BHB monoester, but then no more is going into the blood, and so it sort of tails off over three or four hours depending on whether you exercise or not. If you are on either a ketogenic diet or you take something that's releasing into the blood slower, you're not going to see the same high peak because if you take that ten units and you drip out two units every hour for five hours, the level is just going to be lower, but the delivery to the body is the same equivalent.

    It's interesting to us to start to try and understand flux of ketones a little bit better, but it's really difficult to do. We need some kind of isotope labeling study and those isotopes themselves are expensive and hard to work with, so I don't know how we'll get at that question, but you see this with the ketogenic diet as well. I was speaking to Dr. Volek and Dr. Phinney and they were saying that when you put people in the ketogenic diet often within the first couple of days, they might have a spike and go into ketosis quite quickly, and then they could be eating the same diet and their levels go down. This is different for different people because you definitely have some people where they take longer at a high level, but it's not always the case. That could be because they're making less or it could be because they're using more of the ketones, so it's unclear. Eric Verdin, he's been talking to me about his thoughts on this and he thinks that the presence of ketones activates BHB dehydrogenase 1, so even just the presence of ketones would somewhat expedite their clearance. So that's another interesting thing that we're thinking about a little bit, but the NG tube is kind of interesting there because we're infusing a constant rate of ketones and by the end of the nine-hour experiment, levels were starting to go down even though we were infusing a constant amount.

Christopher:    Right. They're going somewhere. 

Brianna:    Well, yeah. That begs the question whether this is even in the short-term activating increased metabolism by more exposure. We don't know. We've got to figure it out. 

Christopher:    Do you have any thoughts on the ketogenic diet and gut health? I was wondering where you'd look at butyrate, which is normally a product of colonic fermentation by carbohydrates, not necessarily the starchy type, mind you, but like lots of vegetables is good. 

Brianna:    Fiber.

Christopher:    Yeah, exactly. There are lots of things that are fermented -- 

Brianna:    It's really interesting and I think we could do a whole podcast just about what's going on in the gut with short-chain fatty acids. There are a number of things coming out recently that's tremendously interesting and I think or I feel like where we are with the gut is that we're getting better at observing what goes on and not so good at intervening and actually changing what goes on in a way that's meaningful.

[0:40:09]

    But butyrate, when we're doing screens of binding to stuff, let's just say, in the lab, butyrate is often a much more potent activator of a lot of receptors that ketones also activate or lots of things that ketones also bind to, so it's possible that butyrate itself might be a juiced up version of BHB for certain applications. I mentioned that BHB combine to receptors, and butyrate combines to those receptors. For example, D Protein-Coupled Receptor 41 and HCA2, the other receptor that we know that BHB binds to, those are found in the gut, so it's likely that there's an effect of the presence of ketones in the gut.

    In fact, there was a paper -- this will not be correct by the time this goes out, but it was published last week looking at intestinal stem cell regeneration and the balance between stemness and differentiating into a secretory phenotype. They put these mice on ketogenic diet, and then on a different condition, they also fed the mice with exogenous ketones and they were looking at what happens to the gut intestinal stem cells and they were seeing differences. They were seeing an increased stemness, less secretory. There's also an effect on maybe some kind of inflammatory response as well. It was an interesting paper. There are definitely effects of having ketones in the blood because now it appears that stuff that's in the blood can get into the gut lumen, which is kind of neat. 

Christopher:    Right. Also, that was going to be my question. If the butyrate is an essential fuel for the colonocytes and that helps to maintain the barrier function and then you change your diet such that the substrate for fermentation and hence butyrate production goes down, could beta hydroxybutyrate -- 

Brianna:    Be an alternative?

Christopher:    -- be an alternate fuel? Especially, I'm thinking about, well, if I can just raise beta hydroxybutyrate with the ester then -- 

Brianna:    I think it would be really interesting. I know that people are asking these questions and I think there'll probably be papers coming out in the next few months or -- 

Christopher:    But it makes physiologic sense to you?

Brianna:    Yes. The closest comparison that we have right now is there was a paper in nature that looked at propionate in -- 

Christopher:    Which is another short-chain fatty acid?

Brianna:    Another short-chain fatty acid and they saw that lactate from the blood could cross into the gut lumen and be metabolized by enterocytes into propionate and which could then go back into the blood and the propionate itself is having a performance effect because they could give a propionate suppository and get the same performance effect that they could with lactate. It was a very neat paper and again, another one -- they've got a lot of media at the time because they had runners that were doing the Boston marathon giving stool samples as well and they saw that propionate-producing bacteria was enriched in runners after they had run the marathon.

Christopher:    Oh yeah, I looked at that. I think you sent it to me. I haven't even heard of the bacteria. 

Brianna:    It's a neat paper. It's a really neat paper because they have the mice on the treadmills and the runners doing the Boston marathon, so it's kind of neat. If it works the same with butyrate and beta hydroxybutyrate with this model then yeah, there's definitely some interesting potential for improving gut function, gut biota function, but we do know that when people go on ketogenic diet, that causes shifts in bacterial abundance that might be deleterious, but the moment we don't know, we're just like, "Oh, it causes a shift up in this bacteria."

Christopher:    Right, and as Lucy Mailing pointed out on the podcast recently, I think a lot of what is suggested to be a healthy gut microbiota is a healthy gut microbiota in people who are eating a totally different diet and we don't know. Could there be another signature of health that occurs in people eating a ketogenic diet? It seems entirely possible. 

Brianna:    Yeah. You should go and check out the paper with the intestinal stem cells and the BHB. People need to go and they need to go into the supplementary methods on Page 1 and there's the most beautiful molecule I've ever seen in my life. They've made a cyclical ring of BHB joined together and it looks like a snowflake and it's so pretty. I saw it and I got so excited and I was like, oh, now you know you're a full nerd. You've got a crush on a cyclical BHB molecule. 

Christopher:    I hope you email them to tell them because -- 

Brianna:    I've printed it out and I have it on my office wall. 

Christopher:    So obviously, you can't tell me then, "Oh, if you're having gut problems and you've got low butyrate-producing bacteria in your gut," can I just drink the HVMN ketone ester and bring those butyrate levels back up? You can't tell me the dose -- 

Brianna:    We don't know whether -- it's so rapidly hydrolyzed. I wonder if it'd even make it. 

Christopher:    Oh, really?

Brianna:    Well, yeah, the ketone ester itself is pretty rapidly hydrolyzed, so I don't know which bit of the gut is important that it gets to if it will be getting there or if the fact that it would raise blood ketones and then that would get into -- I couldn't answer your question just yet. Who knows? We need some more science. 

Christopher:    Is there anything you've changed your mind on over the past five years specifically to ketones?

Brianna:    Well, I'm interested in this inflammation thing. I'm prepared to be wrong about that. 

[0:45:02]

Christopher:    Oh, really? 

Brianna:    Yeah.

Christopher:    I thought the data was pretty sketchy, but yeah. Oh, that's interesting. 

Brianna:    Well, you mean sketchy in which direction?

Christopher:    I thought it was just like the experiment. I think it's one of those things. You found the opposite of what the predominant theory is and it's the way that you did your experiment, not you found something the opposite.

Brianna:    I don't know. I'd have to see. That's something I'm prepared to be wrong about. What have I changed my mind about? I'm definitely changing my mind about chasing a ketone number. I'm starting to get to a point where I'm like that is not important. We need to understand the flux before -- 

Christopher:    You mean the Volek and Phinney cartoon thing? The first time I saw it, I said, "That's a cartoon." I don't think there was data that generated that optimum ketone -- 

Brianna:    No. Well, there's a difference between optimal -- I just don't think it really tells us that much, so I'm getting to a point where -- from my background as well with the exercise science, I've always been very much like we need to get to a certain level of blood BHB to have a performance effect. That does seem to be the case. It'd be interesting. I don't know how much I want to say this, but we need people to replicate the performance study result that we had with the HVMN product, the HVMN ester done in Oxford firstly because that's the only positive performance study with the monoester. Brandon Egan's group ran a running trial. The ketone levels weren't all that high and there wasn't a performance benefit. 

Christopher:    Right. 

Brianna:    So we need to start figuring out what the dose response is for performance if that is a robust performance effect. I'd still 100% hand on heart say that the metabolism exercise in physiology is very, very different in the presence of ketones, but performance, we need to replicate that more and that's what athletes are interested in, maybe look more at the difference between athletes. 

    One thing that I'm really interested in as well and I don't know whether I'd change my mind on this or maybe I just haven't made up my mind whether or not ketone ester is a good idea or not for athletes on a ketogenic diet because it does provide energy as BHB, but it also inhibits lipolysis acutely and that's a big provider of energy for the ketogenic athlete. When I was at HVMN and we had some athletes who felt like it really helped who are on a ketogenic diet and then a couple of athletes who felt like they were bonking, it wasn't consistent, so I don't really feel like even from the anecdotes that I could get a handle on that. That's something that I'm prepared to change my mind on or not made up my mind on just yet. 

Christopher:    Do you think that any applications where measuring blood levels of ketones are a valid thing to do?

Brianna:    Sport performance, it looks like it might be. Alzheimer's disease, it looks like it might be because Dr. Cunnane has done some studies looking at correlating -- again, it's only one study. It could just be a random correlation, but they're correlation between blood ketone level and changing cognitive function and brain ketone uptake.

Christopher:    What about for weight loss?

Brianna:    Weight loss, I don't think so. 

Christopher:    Okay. What do you think about these proxies for blood BHB like the breath acetone meters? They're all the rage, aren't they?

Brianna:    Yeah. People just don't want to finger-prick themselves and I understand that. It doesn't tell you what your blood BHB is, but if we think that blood BHB is in itself that useful then it's just another thing that's kind of medium useful, giving you some kind of idea into your -- 

Christopher:    Do you think the breath acetone tells you something about how much fat you're burning?

Brianna:    Yes.

Christopher:    Okay.

Brianna:    I think that that's been -- from what I've seen at the data, that's quite sensitive and has been demonstrated. I think it's more accurate at lower concentrations of acetone and it doesn't necessarily map onto what's happening in the system when you take exogenous ketones. It's not my field, so I'm perfectly happy to be proven wrong on that one, but from what I've seen of my understanding of ketone biology and acetone conversion and I've read a few of the papers and talked to a few of the companies, I'd say that's different to blood BHB butyrate. 

Christopher:    Okay. Well, I appreciate you expressing your opinions. We're totally winging it here. Bri's here for the triathlon and I agreed to give her --

Brianna:    It's the price I'd have to pay to camp at Chris' house and -- 

Christopher:    I know it causes some scientists tremendous anxiety when they don't know what they're going to be asked, and just to pull you all over the place like that, you're really a good sport. Bri's shooting from the hip here. She's got absolutely no notes or anything. I really appreciate you speaking your mind.

Brianna:    You make it sound like I don't know what I'm talking about. I actually do know what I'm talking about.

Christopher:    I know that.

Brianna:    Some of the time. I heavily caveat things I don't know about. 

Christopher:    Well, I really appreciate you taking the time to record with me, Bri. How do you think you're going to get on? Are you going to win your race tomorrow?

Brianna:    I don't know. I feel like I'm in really good shape and I've done quite well in the other ones I've done, but there are lot of triathletes in Northern California, and so there could be some other good people out there. I have to distill it down into what performance do I want to do for myself because I can't really control who else is there and where I'm going to place and it's not like a tactical thing like cyclo-cross racing where I would be following people. I wouldn't know who my oppositions are. 

[0:50:07]

Christopher:    Yeah, and even cyclo-cross, you could argue, is not super tactical with the way the conditions are right now in Northern California. It's super dry and bumpy, and so if the group goes, you have to go with them or else you're not going to see them again, but that's not true in -- I mean, the opposite is true. As we talked about last time, you'll get penalized if you jump on a wheel and fall in.

Brianna:    Yeah, we talked about that last time. I'm going to try not to get a time penalty. I have a few process goals, so I want to feel good and confident and strong in the swim. Again, it's hard to put a time goal on that because the conditions will vary a bit, but I think the feeling of being in control and confident is what I'm looking for in the swim. On the bike, I have a power goal because again, you can't -- it's quite windy today, so I can't -- 

Christopher:    You can't tell, yeah.

Brianna:    The speed, I can't really tell.

Christopher:    The speed is terrible like someone --

Brianna:    I do have a time goal that I would like to do, but if the wind is there then I'll more and more focus in on power, so I have my power goal. The run, I haven't got a specific goal for, but I think the goal is always to run as hard as I can. If I have a strong swim, screw myself over on the bike and then can hold on on the run, I think I'll probably do quite well. I think that I'm a caliber of an athlete and I hope that I'd be like top five and then we'll see. It'll be interesting to see where I shake out as everyone else. It's always a bit intimidating wandering around the village, checking in in the bike and everyone looks super athletic and everyone has got these super expensive bikes. I used to actually do these on my road bike before I had a triathlon bike and I used to go blaze past some people and that was always kind of fun. Now, I'm a nerd with a bike as well. I think that set an amount to be said for the athletic mindset and I know I can push myself. I'm excited. 

Christopher:    You've been working on your athlete identity. I think you already had an athlete identity from your rowing days.

Brianna:    Yeah, but I'm revising it, updating it, new and improved.

Christopher:    Well, I'm sure you'll do great. You're certainly very, very organized. 

Brianna:    We can update the show notes with my position --

Christopher:    Exactly, so come and find the show notes over at nourishbalancethrive.com/podcast. Also, Elaine does a really fantastic job of tracking down all of the scientific references that Bri -- 

Brianna:    Lucky Elaine, all of these ones I've been throwing out. 

Christopher:    I know. 

Brianna:    I know she does a great job. That's why I'm throwing them in because I'm trying to give her as much information as possible. 

Christopher:    Exactly. 

Brianna:    But people, go and look at that cyclical BHB. It's very beautiful. 

Christopher:    Okay. We'll find that. 

Brianna:    I'll show you later. 

Christopher:    Where can people find you online? Do you still have an online presence? 

Brianna:    I'm on Twitter. 

Christopher:    Okay.

Brianna:    Twitter is the best way to follow me and find me, and I try and respond to questions when people ask me and stuff. 

Christopher:    Good for you. Thank you.

Brianna:    Yeah. It's nice to speak to people and get challenged and think about things in a different way. It's what we're looking for. 

Christopher:    Okay. That's great. Well, thanks so much for your time, Bri. I really appreciate you. Thank you.

Brianna:    Thanks so much, Chris. 

Christopher:    Cheers!

[0:52:38]    End of Audio

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