FoundMyFitness - #002 Dr. George Brooks on Lactate Shuttle Theory, Relevance for Traumatic Brain Injury, and More

Episode Date: December 2, 2014

Dr. George A Brooks Dr. George A Brooks, an expert in exercise physiology and lactate metabolism. Lactate, a once demonized molecule thought to form lactic acid and become a dead-end toxic metabolite, has been vindicated by the work of Dr. Brooks, his colleagues, and others.  In this episode, we discuss...  (00:00) Introduction (01:40) Dr. Brooks' experience as an athlete inspired his research on lactate (06:50) Lactate and its relationship to muscle fatigue is misunderstood (09:10) Adaptations to exercise improve mitochondrial functioning and lactate metabolism (14:14) How to use lactate threshold training to improve performance (23:49) Lactate improves brain health and cognitive function  (26:45) Lactate improves outcomes of traumatic brain injury via metabolism (30:00) Lactate spares glucose, increasing antioxidants such as glutathione (42:50) Early lactate administration following a traumatic brain injury is necessary, but challenging (48:20) Lactate from exercise improves Parkinson's disease  (55:00) Brain metabolism following traumatic brain injury If you're interested in learning more, you can read the full show notes here. Join over 300,000 people and get the latest distilled information straight to your inbox weekly: https://www.foundmyfitness.com/newsletter Become a FoundMyFitness premium member to get access to exclusive episodes, emails, live Q+A's with Rhonda and more: https://www.foundmyfitness.com/crowdsponsor

Dr. Ronda Patrick here. Today I'm very excited to be sitting here with Dr. George Brooks, who is a professor in the Department of Integrative Biology at the University of California, Berkeley. He is the director of the Exercise Physiology Lab, and he's really the pioneer of research that he proposed back in the early 80s that has to do with lactate that is generated from muscle during exercise, and how that lactate is used by a variety of different tissues in the body for energy, to produce energy. So we'll dive into that in a few minutes, but before we get started, I do want to mention just a couple of things about lactate,

and that is that it is something that is produced during exercise, and it's used by the heart and the brain as a preferred source of energy. I'll let Dr. Brooks get into that in a little bit. And also, we're gonna talk a little bit about lactate in the context of the brain, and how the brain also prefers to use lactate as a source of energy and how this is relevant for situations like traumatic brain injury, which is the focus of some of George's current

research and also for neurodegenerative diseases. So George, thanks for joining us. Do you mind telling us a little bit about, first of all, how you got into this research in terms of exercise, physiology, and all things lactate? Yeah. Thank you, Dr. Patrick. Rhonda, for coming here today so we can talk. talk about our lactate shuttle theory and the work we've done and the trail we've followed

to get to this point. So I was an intercollegiate athlete and very much interested in running the 440 yards and 400 meters and it wasn't quite as good as I wanted to be. And I asked my coach, what's the problem? He said I had too much lactic acid, I had an oxygen debt. And so I asked him about that and he said, well, go read about it and I did. And I read about the wonderful work done by series of investigators going back to Nobel laureates, A.V. Hileneiroz, and I tried to fit that in the context of my own performance, and it didn't

seem to make sense. Why is lactate high when there's an energy demand? People have thought that lactate is a dead-end metabolite, that it's a poison. But why is it always there? Why is the fire department always there at a fire? Is lactate the cause a problem? Or is it there to mitigate the problem? Just like the fire department.

So if you looked at a big blaze and you saw the fire engines, you would be remiss to conclude that the fire department had started the fire. You might correctly think that it was there to mitigate the problem. And so it is in nature when there's an energy crisis, there's a demand the body makes lactate. Now it can make it.

in excess and it can pile up and become a problem in and itself. But we make lactate all the time. And I don't mean to correct my lovely host here, but glycolysis, the breakdown of sugar and glycogen, happens all the time in all cells. And we use it. We use it as a fuel. We use it to support our blood sugar level.

We use it as a signaling molecule to activate certain metabolic processes. It's made in some cells and it's used in other cells. The cells which use it are cells like the heart, the liver, and we found with the brain. And our most recent work is with neurosurgery at UCLA. We have wonderful colleagues there. So my partner, my Corning and I, my partner in research, my Corning and I have worked with our colleagues at UCLA on people suffering traumatic brain injuries. injury and we think we have some really good ideas about how to mitigate the metabolic

crisis that happens after injury and we hope to be able to intervene to rescue people and improve long-term outcomes. Wow, that's fantastic. So let's step back a little bit to the lactate produced during exercise and how that, can you explain the difference between producing lactate during exercise and lactic acid and how there's this lactic acid buildup and how that may or may not cause muscle fatigue because that's something I think a lot of athletes are particularly concerned about. Yeah, so as I mentioned, the lactate builds up and causes an acidosis.

But when it builds up, there's a problem. The problem is the removal. So we produce lactate and we use it all the time. And as I mentioned, there are some really important processes that we use lactate for. So when an athlete is going all out, lactate gets really high because the energy, demand of the activity requires rapid glycolysis and glycogenalysis and people produce lactate. But we've found in our research that active muscles, the heart, the liver, and the brain are all using this stuff as a fuel.

So as long as you can make it and use it, you're fine. So is there a difference between, in order to use lactate, in order for the different organs in our body to use lactate, it needs to be taken up into the cell, and then it gets into the mitochondria. And the mitochondria use this lactate as a source of energy to produce the energetic currency of the cell, ATP. Is there a difference between... the type of exercise you do and or how hard you train and the ability to use this lactate,

which essentially has to get transported into the cell through this specific lactate transporter. Yeah, so you mentioned some really key words in our research. So we found that the lactate is produced and we found that it's oxidized. And the sites of oxidation are in the mitochondria, or this network, this reticure. of a respiratory apparatus that exists in most cells. So the lactate has to get in, and it has to have a transporter. And we were amongst the first to work on discovering the lactate transporters and where they are. And our unique contribution was to find that not only are they in the plasma membranes

of muscles and heart and other tissues, but they're also in the mitochondria. They are the lactate pyruvate transporter. So this whole field has been misunderstood historically. Going back to the first research of Otto Meyerhoff, who is one of our heroes in the study of metabolism. He had half a frog hemacorpus in a jar without oxygen, without perfusion, and he stimulated the muscles to contract. And as they needed energy to contract, they produced lactate.

Eventually those muscles fatigued and there was a lot of lactate. So this is the birth of the alpha. the idea that lactate causes fatigue and that lactic acidosis is a metabolic problem. But really, in that situation, there was no oxygen for respiration. So the only thing the muscle could do was to break down glycogen and make lactate to try to provide energy. And in the end, when the glycogen was used up and the lactate was high, well, there was a metabolic crisis.

That makes sense. So in the context of a living person that's a living person. that's using oxygen and there's lots of oxygen present, like for example, especially during exercise when we're consuming more oxygen, would you say that lactate then isn't going to build up as readily and it's going to be instead used to produce more energy? Yeah, so one of the things we found is that the classic training response that people have is to have a lower lactate at any power output. So if we would compare, I would compare myself to a young,

healthy athlete, that athlete would actually be producing more lactate than I would be, but my lactate level would be really high because I'm limited to my ability to take it up and use it, whereas the athlete is superior in terms of clearing lactate, using it as a fuel, using it as a gluconeogenic precursor. So we have discovered that lactate's produced all the time at rest and during exercise as well. And athletes actually produce more than people. who are less capable or less highly trained, but they remove it, they use it.

Okay, so the athletes can produce more and they can use it better. Is that because there's something that occurs like during exercise that makes the transporters more efficient, makes more of them? Yes, the physical activity is known to increase the mass of the mitochondrial network. Some people would say there are more mitochondria,

but we know from our own workers, there's a whole network, and the mitochondrial network buds and branches out with training. So you can actually double the amount of mitochondria you have in your muscle by training. That's really one of the most incredible adaptations we know about. And as well, you can double the amount of lactate transporters. Wow.

And so you can really upregulate the ability to do this process, we call the lactate shuttle. And again, what we mean by the lactate shuttle, some cells use it, some cells produce it, Others use it and they use it well. And when the lactate is going up, that means you you're not able to clear adequately. Okay, so here's the question that I have, which I think is probably very relevant to a lot of people out there that are listening that exercise and their athletes.

Is there a certain type of exercise that is paramount in terms of doubling the mitochondrial mass, making more mitochondria, and... making more of these transporters to transport lactate into the mitochondria to use it as energy. So for example, do you, you know, aerobic exercise like more endurance-related running, lifting weights? Is there a certain type of exercise that you found to be superior in that regard? Yeah, we haven't, you know, really even scratched the surface of this. But before we get too much into the science, I want to talk about my colleagues and friends who are coaches. They've known this since this metabolic crisis problem for decades.

And they've tried different ways to try to mitigate the problem. So they've tried endurance training. And they've tried interval training. And they've tried combinations of endurance and interval training. And we know from our work on animals and people that endurance training does increase the mitochondrial mass and does increase the number of transporters. That's all well and good. What we don't know is how to personalize it.

For you and me, what do we need to do exactly to optimize our mitochondrial mass and our lactate transport or count? What exactly, we sort of know what we need to do, which is build the aerobic base, that is do a lot of training early in the season and then as we go, if we're gonna go into competition, we need to exercise harder,

we need to work on our pace and gets really specific about our activity. But we know, from our studies that we've done with incubated muscle cells, that if we just take muscle cells and we incubate them with lactate, we'll upregulate over 600 genes, all the genes, basically, of muscle adaptation. So there are a lot of really talented people studying muscle adaptation today,

but this has, again, been overlooked because everybody believes lactate is bad, but it's really an upstream signal, which activates genes for my heart. mitochondrial biogenesis for muscle protein synthesis, basically pretty much what happens to you when you do exercise training. Wow. So that's fascinating, George. A little heavy on the biochem, so let me just recap that for those of you that may have

gotten just a little lost. Basically what George is saying is that lactate, in addition to being used as an energy source to produce energy for the cell, it also is a signaling molecule that seems to regulate, maybe even on an epigenetic level where it's upregulating, meaning increasing the transcription of a variety of genes that are related to mitochondrial function and muscle adaptation. So, and presumably probably down regulating genes as well, but essentially it's, it's, you know, regulating a variety of different physiological processes in the body. And I guess in the muscle cell specifically is what you looked at in terms of things that

are good for the mitochondria and good for the muscle to work better and harder. Also, I think that the interesting thing that you mentioned about this personalized training, I think that's a very interesting concept because you're right. There's a lot of different factors. It's not just endurance versus interval of training, there's age, there's gender, you know, there's a lot of, you know, there's how well trained people are, are they trained or untrained athletes, you know, are they novices, do they, how much, how often do they train? I presume all these factors would play a role in, you know,

a lot of these muscle adaptations and ability to produce more mitochondria and more lactate and transport lactate in the cell. So, you know, you didn't really simplify it by talking about epigenetics, but we'll come back, come back to that. But again, our colleagues who are coaches have actually used what's called the lactate threshold as a point of training. And so sometimes for endurance training, people will train below the lactate threshold, just below it.

And that seems to result in significant mitochondrial biogenesis, but then to exercise really hard, coaches know you need to exercise above the threshold occasionally. But that's too hard to do on a daily basis. So coaches and athletes have learned just empirically to measure lactate, they don't really completely understand what it's doing, but they know that when it's too high, it's bad. When it's increasing, it's too hard. And if the lactate is really low, it's probably too easy training. So coaches and athletes are using what they call threshold training quite effectively.

And you can see as people do their endurance training, their lactate level for a given power output really falls. So that allows them then to ramp up their training and ramp up their competitive pace and then be able to function effectively at a higher power output. So there are various things that people can do to attract their training. One is to measure the heart rate. Another thing is to measure their lactate. You need devices to do this. Another thing to do is to work on their breathing because as the lactate starts to rise, this acidosis goes on and often talk to people about using the talk test.

So when we were actually, if we were on two treadmills here, when we were having this conversation and got going faster and faster and we get to the point where we couldn't talk anymore, that's probably, we're acedotic now, right? So our lactate would be really high. So we can actually use our breathing as a measure of where we need to train.

That's very interesting. So because the amount of oxygen that we're able to take in and bring to our various cells, including the muscle, then really is the limiting factor in the sense where because if you don't have enough oxygen there, the lactate you produce isn't gonna get used. It's gonna pile up. It's gonna pile up.

Can you explain because when we're putting, our muscles produce lactate and all the cells. All the cells. Our red blood, our red blood cells are producing. Right, I'm talking about it in the context of exercise, because I think that's what people mostly relate it to. But when we do produce lactate, how does it get converted into lactic acid?

Well, if you look at the glycolytic pathway, it actually makes lactate. But lactate is a pretty strong acid, so it associates with water. And a certain amount of acidosis that will be associated with the lactate itself. But glycolysis actually makes lactate, not lactic acid. The acidosis,

The hydrogen ions come from other processes, like the splitting of ATP, which is our high-energy energy source. When we split that, we liberate a proton. So when you're splitting your ATP and you're not able to keep it, it's level high, you're going to develop protons. And the lactate's going to be there, and people are going to associate the proton with the lactate and call it lactic acid. This is a big misnomer and big mistake in biology.

And at physiological pH, does the lactic acid form its lactate or? Well, the PK, okay, is really about three. So if there was lactic acid, it would be completely dissociated to lactate and ion and proton. But you know, one of my inventions early on was to make what I call polylactate, which is in the sports drink, Cytomax, and sold by Sotomayor, Sotomay. Benicia, California. And this sports drink has been used by some of the world's best athletes. And it contains a lactate polymer.

And I remember from chemistry that the salt of an acid is a base. So when we take our polylactate and people consume it while they're exercising, their blood pH actually rises slightly. Oh, interesting. So you can use the salt of an acid as a base. And so the endogenous acid, um, combined with the lactate we give, is removed as lactic acid. And so it actually alkalizes the blood.

And of course, that's one of the ideas that's really, I think, one of the reasons we form this collaboration with UCLA, because when people have traumatic brain injury, there's a series of things which happen. There might be an acidosis, there might be a lack of oxygen, there's swelling which goes on. And by giving salts of lactate, we can mitigate the swelling, we can provide fuel, and we can manage the acidosis, which occurs. Yeah, so this, you know, this is a great transition into the brain.

But before we get to that, real quick, I have one question for you. Now, you were on a committee, a scientific advisory committee. Some years ago, you were asked to be on that recommends the amount of daily exercise that a person should get. And the Surgeon General of this committee, I think, recommended 30 minutes a day. But you recommended twice that. You recommended one hour a day. Can you elaborate on why that is, why we all should be exercising one hour a day? Well, we didn't say we need to exercise.

Everybody needs to exercise an hour a day. But this is a report we wrote. I was on the committee. And it's called dietary reference intakes. And this was the scientific basis behind what we're going to become the dietary recommendations. And we turned the whole thing around. So in the past, you would say, what should you eat? And you would say, you need to eat some carbohydrates, you need some lipids, you need some fats,

and so on. And then people would recommend proportions and amounts. We decided to first ask the question, what are you doing? your energy expenditure. And then you need to eat to feed that. So instead of two portions of this and three portions of that, we decided to base the whole thing on energy. And what we found by looking at the doubly labeled water database, which was generously donated by almost every investigator who ever did a study, said people who are healthy and lean and freely living, that is eating whatever they want, they're active about an hour a day.

Now it's true, there's good epidemiological research to indicate that if you do some activity like 30 minutes a day, you'll improve cardiovascular function, you'll reduce your risk of heart disease and diabetes and maybe some forms of cancer. But that's not enough activity to control your body weight. So you need to be active on the average about an hour a day. And that's not running on the treadmill for an hour. It's doing the equivalent of brisk walking, taking the stairs, going to the bus stop, walking my students between classes, the people on their jobs, perhaps standing, moving around once

in a while. So people who are active about an hour a day can manage your body weight and be healthier because of the activity. And the activity is just really incredible because physical activity, I say, works from the tip of your toes to the top of your head. It'll build your bone mass. It'll build your muscle mass. It'll help your cardiovascular, your conditioning.

It will help your endocrine functioning. And it actually goes up to the brain and is used as a fugal there. And it might stimulate what's called BDNF brain-derived neurotropic factor. So that's another whole feel we probably don't have time to talk about, but that there's There are things released from active muscles into the blood during activity that promote cell proliferation, like in the brain, with the B and DNF, or stimulate or repress cancer cells. So for instance, if somebody is regularly active, why is the incidence of colon cancer reduced? Why is the incidence of breast cancer reduced?

Well, these tissues are not really involved in the activity, per se, but there's something released from active tissues that circulates, which helps all tissues. And we think that might be lactate, but there could be cytokines, there could be micromolecules. There's probably some combination of factors released from working muscle that gets around the body. Makes people feel better and makes their tissues feel better. And of course, if you do enough activity, you can lose weight, but you can be healthier without losing weight. So depending on your day and on your schedule and what you can do, if you're active 30 minutes a day, you'll probably get some protection.

But if you are active an hour a day, you'll get a bit more protection than you can help manage your body weight. Yes, that's, I completely agree with you. In terms of the BDNF, which is a neurotrophic factor, it actually stimulates the growth of new brain cells. Lactate specifically has been shown to stimulate BDNF, which is quite interesting because it's... Lactate, like you mentioned earlier, it seems to be not only the source of energy, but it seems

to be a signaling molecule as well. So it's something that is good for the cells, it's good for many different cells, including cells in our brain. And something else that's very interesting very recently, I think it was a group in the in Netherlands, they showed that lactate actually stimulates these neurons in a brain region called the Locus Corollius, which is where all the nor epinephrine neurons are. So these neurons that make nor epinephrine. Nor epinephrine is that neurotransmitter that's involved in focus and attention.

And they've shown that actually specifically lactate stimulates the release of nor epinephrine from those locus corollus neurons. And if you think about it, I know from my own personal experience that after I exercise, I definitely have a better focus and attention. So this is something that seems very relevant for people with, for example, ADHD or people that have problem focusing, you know, and putting their attention to one thing. Get out and move, get some exercise. You know, it seems like the best medicine you can possibly have.

So the terminology we use, it connotes meaning, right? So I remember being a student and learning about the blood-brain barrier, and I thought there was this extra membrane that the brain was wrapped in. And that's not the case at all. Things get into the brain cells by transporters. And these lactate transporters are highly expressed in all the capillaries in her body, including inter-astrocytes and our neurons. So the lactate permeates through the brain when it's high it goes in, because lactate simply moves

down a concentration gradient. So the way to increase the concentration is, well, one way is like we're trying to do with our patients to infuse it, but these are people who are in a coma and they can't move around. Maybe we could try electrical stimulation and get their muscles going to fuel their brain. But the way we usually do it is we move around. Right. It goes to our brain. And you know, I know if you ever notice this, after you're exercising, you get hungry, but later.

Not right away. Yes. The lactate is crossing the broad brain barrier. It's probably going to the centers in the brain that regulate appetite, and it's mildly suppressive. Interesting. And so, but then when the lactate clears is used, you know, by the body uses it, then you get hungry.

The brain says, feed me. Feed me. So this, this concept of lactate helping with traumatic brain injury, you mentioned you're doing current research collaboration with researchers at UCLA. And I read a couple of papers recently on this topic of lactate in terms of patients that were moderate to severe, had moderate to severe traumatic brain injury. And they had higher levels of lactate in their bloodstream.

They had a better outcome. And those patients that did not have an intact blood brain barrier, that that wasn't the same for them. So can you explain why lactate would help people recover better from traumatic brain injury? Sure. But can I tell you a story first? Just in this office almost eight years ago, the chief of neurosurgery at UCLA, Dr. Neil Martin and one of his chief scientists, Dr. Tom Glenn, we had a conversation in this office about this. And they noticed that in their patients who did better, as you described, that lactate was elevated.

and the people whose brains could take it up did better. And that means that they recovered quicker and their functions, intellectual functions, were restored pretty much as they were before they were injured. And they wrote a grant and the grant went to the NIH and they said, well, you just don't understand. So they looked in the literature and they came to us because we've been dealing with this issue for decades.

People just think we're crazy because stuff obviously is bad. it can't be helpful. So we started working with patients and we have recently written two papers we call one paper the body paper and one paper the other paper the brain paper. Now we can see that after injury the whole body knows the brain injured and the whole body mobilizes its efforts to fuel the brain and part of that is lactate being produced peripherally and it does a couple of things, of course it goes to the brain and it can get across this blood brain barrier and can help fuel the brain. The other thing it does normally is the lactate goes, of course, to the liver,

it gets made into glucose, and glucose is usually used as a fuel for the brain. Now, to answer your question about why is the injured brain suffering, for some reason the breakdown of sugar or glycolysis in a brain is impaired after injury. The product of the, the disease, the product of the that is lactate. And neurons run on lactate as the preferred fuel. So in part, the brain is starving. So you can try to give more glucose by putting that in the blood, but again, the process is blocked. So our approach is to bypass that by infusing formulations containing lactate, salts and esters, and other lactate containing compounds that will get into the brain through the blood-brain barrier and get into the mitochondria and fuel the brain.

And we actually have done six patients in collaboration with our colleagues at UCLA. We show that we can increase the carbohydrate uptake that is the total of glucose plus lactate and people with brain injury by infusing lactate. Wow. Do you think that some of the glucose that is in the brain, instead of being used for an energy source, is actually being used to produce things like NADPH so that, so it's going through this different metabolic pathway called the Pentose Phosphate pathway, so that you can make things that are essentially going to be used as antioxidants by things like glutathione, perooxidase, and these

other antioxidant enzymes that are in the brain. Do you think that lactate will then allow glucose to be used for that instead of as energy for neurons? Yeah, so you're talking about sparing. You're talking about glucose sparing. And so you describe very nicely the pentose phosphate pathway and some of the things it does. So there's a limitation of the amount of glucose, but if we can fuel the brain with lactate, then the glucose that is available can do that as well as help fuel the brain.

Yeah. So... Which is very important because... Which is very important. And you know, in our approach as physiologists to this issue, we talk about the body supporting the brain. Too often in the past people get into silos. So if I'm a muscle physiologist, I don't care about the brain. And if I'm a neurosurgeon, I really want to feed the brain.

Because that's where my patients are and that's what I have to do. But we have to just step back and say, hey, the brain is in the body. We have to nourish both. We have to realize that the body is going to nourish the brain. And one of our conversations I had with one of our colleagues was Dr. Paul Vespa, who is a neurologist who really takes care of the patients after the surgery is over. Dr. Vespa, I said, you know, the body is a thief. He looked at me and he begot it right away because a person is in the intensive care unit and they're being treated by standard of care. The best physicians in the most highly advanced medical centers are concerned with bleeding

and oxygenation. And it's really hard to nourish people in these circumstances to feed them. They're unconscious they can't eat. You have to put in tubes. You have to put in things to go in the blood, things that go in nasal gastric tube into the stomach. They're repairing things. Yeah, you need to have fuel, you need to have nutrients. And so it's hard to get this aboard.

So Dr. Vesp's idea was, I'm going to deck something into the blood and it's going to go to the brain and help the person. Yes and no, because the body's going to grab it too. So then we have to find a way to nourish the whole organism, the body and the brain. We think we've done that. And we have some patents pending about how to, with a minimum of the body, of invasiveness, find out what the body energy state is. And to make formulations that will nourish the body and the brain, so the body won't

be stealing from the brain instead of reinforcing the brain. So we have this notion of the holistic approach of body and brain, and the body supports the brain that's true, and we need to accommodate both. Exactly. So this leads me to the... the supplementation with lactate. There's L lactate and there's D-lactate. Is there a difference between supplementing

with L-lactate versus D-lactate? Well, I can, with my hands here, for the camera, show the there's semic nature. We have an Lactate. I'll use my left hand and this is one configuration. The mirror image is D-lactate. And the delactate is actually neurotoxic. Okay.

Okay, so in the past, there was a solution or still used prominently called Lactated Ringer solution. And a Ringer was a 19th century physiologist, pharmacologist, maybe physician who developed formulations so cells could live in vitro in a dish. And formulations to give to a person to support. them after injury. And so what was available was lactate, and he tried it, and it seemed to work. But at that time, it was a 50-50 mixture.

So we can improve standard of care by taking out the D and just using L. And we can find different things to carry this molecule. So one of the things that I've invented in the past was original lactate to use a basic amino acid with a positive charge to bind a negative charge. And we use that in sitomax. but we could also give it to a person after injury. And of course, sodium is the major one. And sodium is good because sodium supplementation

to somebody with injury would help mitigate swelling from the injured tissue. So there are different vehicles and different ways to deliver these formulations. I wanted to talk about formulations. Realize that the lactate transporters are also transport ketones and pyruvate, as well as lactate.

So we can come up with formulations or mixtures of these things which are transportable and can be used. And in our conversation we had with Dr. Ames, just the other day, you know about ketotic diets and management of conditions in pediatrics. So they come also in by these same transporters. Now, the thing about it, and once you realize that there are transporters and you understand how they perform, they're saturateable. So if we have in all lactate, then that'll probably block ketones. And if we have all ketones, that'll block lactate.

So we don't know yet which percentage of what will work the best right now, since the MCTs of monocarboxylate transporters are more specific to lactate than pyruvate, then other monocarbosolates we can, our presumption is to give lactate compounds intravenously. But we also know that if somebody is recovering, maybe if they're on a ketotic diet, the ketones will help supplement what we deliver intravenously. We'll have to find out. Wow. So you brought up some really important points here, but first I just want to ask you then

with the D and L lactate, the D lactate is neurotoxic. Is it block lactate from being transported into the cell? Is it because they're essentially mirror images of each other? What is so toxic about the D? Yeah, I'm not sure about why it's toxic, but no, they don't share the transporter. So actually one of the tests we did early on, we showed the saturation kinetics with L lactate and D comes in in a linear fashion, so it probably comes in simply by diffusion. So fortunately it doesn't share the transporter.

which is probably why people, why it's not so neurotoxic in vivo because it's hard for it to get in. It gets disposed of probably by the liver, whereas the L can get into the brain. Because I know that certain, for example, you know, yogurt is, you know, they've got these little bugs in there that make all sorts of, you know, lactate. And some of them are L and some of them are D. Most, I think majority of them are L, but you do have some bacterial strains that make D. So, you know, that's something to keep in mind is looking at, you know, what probiotics are a big thing now also. So getting probiotics that make de-lactate may not be as good as getting probiotics that

make L-lactate. I would avoid them. You would avoid the delacta. Yeah. So, you know, with cytomax, who I realized early on that there was an intestinal transporter, the lactate transporters to a different gene family than the one that's in the cell membranes. And what's neat about it is it's sodium mediated. It's not protons.

It's not a symport for protons. It's a simport for sodium. So, of course, we put a little sodium lactate in our sports drink, and that helps to facilitate lactate uptake in the GI tract. And also, the glucose transporter in the intestinal tract is a sodium-mediated one. So, you know, it's how these sports drinks really work very well. and work better than water regardless of the brand because if you have glucose in a pinch of salt, it's going to get in faster than glucose alone.

Oh, interesting. Very interesting. So, okay, sodium lactate, good for the gut, good for the body in general. It's taken up much faster than glucose. So it was a study done some years ago by Dr. Jack Azavito at Chico State University and he did this study where he isotopically, he isotopically. label the individual components of the favorite brand, the best known brand, and also cytomax.

And cytomax contains three kinds of carbohydrates, of lactate, glucose, and pyruvate, a lactate, glucose, and a fructose transporter, so three. Whereas the most sports drinks have high fructose corn syrup, which means a lot of fructose, and probably too much fructose and not enough glucose. So in separate trials, the isotopic labeled the glucose and the fructose and the number one brand. And the lactate, the fructose, and the glucose in cytomax. Every subject had to do five trials. And you can see the lactate is the first taken up by the intestinal tract, and it's burned

and it's in a breath in five minutes. Wow. But it takes at least a half hour for glucose to get there, reach a peak. So if you want quick energy, you feed, we feed lack. He can even drink it or put it in through nasal gastric tube or put it into blood. Because of all these transporters and your abundances, they get in right away and they're used right away. It's very, very cool.

Do you think you mentioned some of the ketone bodies also, so ketone bodies are generated through beta oxidation and you, you know, it's something specifically also medium chain fatty acids can produce ketone bodies like beta hydroxybutyrate, which have also been shown to help with traumatic brain injury as well. A ketotic diet, yeah, as a treatment. Yes. Especially in kids. The question is, do you think, is that there is a competition between lactate and these

ketone bodies like beta-hydroxybutyrate, for example, in getting transported into different cells, including the brain. Do you know if, so the lactate wins, lactate can out-compete. Lactate will out-compete, it's higher. So the first studies we did in 1990 where we did isolated sarcolemma vesicles. So imagine a muscle has got a big membrane sheath and you can actually take the sheath off and it'll form vesicles. And then you can study the uptake of different things in these vesicles.

And so what goes, so it's how we describe the lactate transporter is, so we compared it to glucose and amino acids and to ketones. And so lactate is preferred to get in, right? It out-competes because it really fits the transporter configuration better than the other things do. Yeah. But, you know, in vivo, how can you deliver this stuff? Right.

Okay, can you, as I mentioned, you can put the lactate in orally or you can put it in IV. but in terms of some person's nutrition ongoing, that gets kind of complicated and somebody leaving the hospital. So maybe a ketotic diet would really work as a recommended diet for them leaving. So what about the timeframe after traumatic brain injury? Is there a certain window that delivering this lactate infusion is going to be the most beneficial in terms of preventing the brain from having more damage.

And like I said, you're sparing glucose, so you're making more antioxidant, you know, any oxidants that can be used to prevent more reactive oxygen species from further damaging your brain cells and creating this whole vicious cycle. I wish I knew the answer to that. I think it's as sooner the better. My wife, Rosemary, is a physician,

and she deals with it in the area, sports medicine and physical activity. And since concussive injuries are so frequent, especially in kids, not just pro athletes, but kids playing sports of all ages, she really wants me to develop something that she can give to her patients, right? Right.

To give on the spot. Now, our patients in the intensive care unit are studied about five days after injury. And the reason for that is we have to get permission from their legal representatives to do these procedures. Is that because they're so experimental? Well, yeah, we have to, we, for somebody to be an experiment, they have to give consent. And if they're in a coma, it's their legal representative.

So we have to find these people and they have to give consent. And you know, somebody's, in your family, just imagine somebody's in an injury and they're in a hospital and then it's going to take a few days for everybody's head to clear and to give from permission to make these measurements. So I personally think that if we instituted a lactate infusion and when the person is admitted to the intensive care unit, that would probably be more helpful. But certainly we can see that even five days out if we give lactate supplementation, the patients are going to take it up and use it. So it still helps regardless of it five days later or not.

Yeah. Now, what will probably have to do is work with the institutional review boards and try to get permission to do these right-of-way trials. Right. And, but again, the person has a right to know that they're an experiment, and if they're not capable of knowing that, then their family has to, or the legal representatives have to give permission. Do you think in the future maybe if this can become more of a standard procedure that maybe,

you know, these, the medics will have it on hand when they get to the, for the, for the For example, let's say we have car accident, the car accident is the source of the brain injury, that they immediately are infusing them intravenously with some sodium lactate. So the steps we're proposing, so right now we have an NIH grant proposed and we're going to do with animals first and see if early versus late intervention, and then we'll have the animals and they'll be given an injury and then we try to infuse them right away or later. And then if that works out the way we think it will, then maybe we'll get consent to do this. We'll get permission to have people pre-consented to do this procedure.

And then it might become standard of care. And then once it's standard of care, then it can be given widely. That would be awesome. And it would be in somebody's medical kit. Right. And think about car accidents, bike accidents, kids playing soccer football or kids playing basketball basketball and falling and bumping their head. This happens hundreds of thousands of times.

And not to mention what's happening in the military with concussive injuries. And so there's two classes of people we've fortunate to work with. One are young men, more than women. Men drive their motorcycles and cars too fast. They also play football. They play football.

But, you know, women play basketball as well and do get concussed and get bumped in ahead playing soccer. Sometimes, you know, not by the ball, but by the head of an imposing player or a teammate even. Wow. So people suffer concussive injuries. And to have something on hand to mitigate this metabolic crisis, which develops after the injury, would be really advantageous. So while there are a lot of professional football players and they need. to be protected and they need to be treated well.

There are thousands more kids and people who suffer these injuries. So in addition to young men, we have older people. All the people who lose their balance and fall and they might break their hip or they might get a concussion or they might get both. So then it was sort of a bimodal distribution of traumatic brain injury. The young men and then people of both genders later in life. So it'd be important to help everybody. Yeah, so you mentioned elderly people and that brings to mind neurodegenerative diseases

because I think traumatic brain injury is like neurodegenerative disease in real time, exponential, you know, because brain aging also has a lot of these factors that traumatic brain injury has, reactive oxygen species, these neuroinflammatory molecules and neuroinflammation, which which causes accumulation of amyloid beta plaques outside neurons and all these things, but that happens a little bit each day over many, many years. So the possible use of lactate in helping treat neurodegenerative disease is also maybe an interesting point. I know that there's a couple of studies that I've been interested in.

One has to do with exercise and Parkinson's disease. shown that Parkinson's patients that are forced to exercise beyond what they usually would, so to the point where it's uncomfortable, that they perform better on certain motor tasks and also memory tasks. And of course, I'm thinking immediately, well, of course, you're producing lactate. Lactate's going to the brain and helping fuel some of these neurons in the substantia Niagara, which are dying, these dopaminergic neurons, which are dying, but, you know, and dying. And just recently, like a few months ago, actually, a study came out in worms and also

mice. Parkinson's model, worms don't actually have a brain, but they do have Parkinson's models for worms where they have alpha synuclein, which is one of the toxic proteins that aggregates in Parkinson's disease. They have these worms making that at an accelerated rate. But they showed that feeding the worms lactate helped improve the mitochondrial function. It increased. the cell viability and also in mice. So I think that this is the next step is, well, okay, can lactate be used in the context of nerd generation to help the brain have that energy that it needs so that it can perform memory functions and also so that it can grow new brain cells.

We're talking about lactate being a signaling molecule, you know, increasing BDNF. Well, you know, Dr. Patrick, you know, you know so much about. about this and you have a good colleague at Corey, Mark Shiggenaga, who you probably work with. You know, he's been working in an animal model. He's been supplementing lactate, showing positive benefits. So maybe we've just scratched the surface. Maybe we've got the whole picture wrong from the beginning. And so thinking about fueling, supporting tissue function, signaling, cell signaling. These are all things that need to be explored.

And there are many maladies, both chronic and acute, that understanding the basic biochemistry would really help us resolve what the issues are. And it would be, of course, a huge mistake to say this works for everything all the time. But knowing this will be helpful in many circumstances, which we probably can't predict. So Parkinson's maybe that's one.

I'm not an expert in that. I really don't know that. I'll take your word from. I haven't read those papers, but we've done a lot of work, and we can see the lactate gets into the brain. And when you exercise, it goes up in the blood, and it's available to fuel, and it's preferred. And you use that word before preferred. Right. That's very interesting because we've given lactate to men during exercise, and it is preferred over glucose.

In what tissues? Ah, in muscle, and in heart. In heart. Yeah. Now, and also in brain. But here's the thing about traumatic brain injury. If lactate substitutes for glucose, that doesn't give the brain any advantage. But after traumatic brain injury, when the ability to use glucose is blocked, then we can supplement

giving lactate. So if we had somebody who was just normal healthy and we gave lactate that would spare the glucose, okay, but here in after TBI, glucose metabolism is, is impaired. So we argument, we seek to argument total carbohydrate uptake by giving lactate. Is it, it's impaired in neurons or in astrocytes? Well, we don't know that. We don't know. Because I always think about lactate being, as a source of energy, being thermodynamically

favorable because you don't need energy to convert lactate into pyruvate, but you need energy to convert glucose into pyruvate. It costs energy to make energy. So I always think about it, you know, using lactate as a source of energy to produce more energy is thermodynamics favorable. I mean, it makes sense. Yeah, it is. It's more reduced, so it actually has more energy than pyruvate.

And as you said, energy comes free. So in brain metabolism, there's a big discussion about the astrocyte neuron lactate shuttle. And it's been proposed that astrocytes, which are far more numerous than neurons, take glucose and make lactate, and they nourish the neurons that way. So if there's a shutdown in glycolysis and astrocyte that would starve neurons. But Rajah Hussain, who just poked her head in here, she has a pain. paper where she showed that all the apparatus for neurons to take glucose and make lactate are intact always.

So it might be a population thing. It might be the fact that there's so many astrocytes. If they're going to take the glucose, then they're going to make the lactate, and the neurons are going to run on lactate because the glucose has been basically swiped by astrocytes and is not really available to the neurons. But in terms of, this word preferential. Yeah. If lactate substitutes for glucose in somebody with a traumatic brain injury, we haven't gained anything,

right? Right. But if glycolysis is blocked and we can augment total energy supply by giving lactate, that's what we seek to do. Now we know if we give lactate to an exercising purpose, that will spare person that will spare glucose. And that helps the person exercise. Yeah.

Yeah, recently, earlier this year, actually a group from Amsterdam published a study showing that the brain, during physical activity, the brain also ramps up and works harder just like the muscle cells do. And it's working harder being fueled from lactate. So your brain's working harder when you're working out and lactate's allowing it to do that. Yeah. And a group from Copenhagen showed that when you exercise in your blood. the lactate rises, it substitutes for glucose in the brain.

Right. So that's perfectly predictable according to a lactate shuttle theory. But again, with the injured brain where there's a limited glucose, not availability, because the doctors are very good at supplying glucose and giving insulin, although the brain doesn't respond to insulin like other tissues do, they're very good at maintaining blood sugar level. So it's available. Yes. There's no lack of glucose for the brain.

It just doesn't get in. It's just not working. It's just not working. So, okay. So find another way. And lactate seems to be that way. So, yeah, so monocarboxylates are another way. And lactate is the major one.

People are experimenting with pyruvate. And pyruvate's not a bad metabolite to give IV. Although early on it was recognized that pyruvate degrades and solution makes toxic products. So others have tried to keep a crystalline fruct pyruvate on hand and mix it up in saline right away and give that in high levels. But the body so prefers lactate when you infuse it in one circulatory passage is all lactate. So the lungs do that and red blood cells do that. The red blood cells and the lungs are loaded with enzymes to convert pyruvate to lactate.

So even if you want to try to give pyruvate within... seconds or a minute, it's going to be lactate in here, which is fine. It's the way nature's decided to do it. Yeah. So do you think that supplementing with L lactate is something that would be beneficial to people that don't have traumatic brain injury, just people like me, for example? Well, you mentioned yogurt, you eat yogurt? Right, I do.

And some, depending on ethnicity and where people People eat sourcrow to eat kimchi. They eat cheese. These are all fermentation products that have lactate in them. And as we mentioned, there's lactate transporters in a GI tract, and it's biologically accessible. But when these things are made through fermentation, they can be kind of acidic. So the new yogurts are different than the ones I remember when I was a kid. And they're not so sour because we add sugar and we basically counteract the what goes

on naturally in these products. So yes, but putting in a lot of calories in terms of lactate compounds is pharmacologically viable. It'll be expensive compared to regular food. And when you eat carbohydrate, you make lactate anyhow. So in terms of its availability. Most foods will make lactate, the body will make it and dispose of it. And nobody actually realized this because unless you used isotopteratias, like, we did, you know, you eat carbohydrate and your blood lactate rises a little bit, but actually the

production went way up. It just was removed. By the heart, by the liver, by the brain, by all these different tissues that are using it as a source of energy. Yeah. Well, this has been so enlightening, George. Thank you so much for joining us today. I really, really learned a lot about lactate and all the different physiological roles of it

in terms of the whole body, including the brain. And if people are interested in reading about your research or things that you're doing, and you also mentioned your cytomax sports drink, where can they find you? you? Well, I've been at UC Berkeley for 43 years. So G Brooks at Berkeley.edu or George at MDFlux.com. People can find me. MDFlux?

MDFlux. So my Corning and I have tried to take this knowledge. We were encouraged by a course we took at UCSF last year called Lean Launchpad. And there was a course about how to take ideas from science to make them more widely available by developing a business and our business is called MDFlux. So MDFlux.com. People can find what's going on on MDFlux.com. Yeah, people can find out what we're doing and we're, so we've written this body paper

I told you about and a brain paper and we have a review which is being considered for publication. So PubMed, everybody should know about PubMed. It's instituted by the Library of Congress and what's published in biology and medicine is available on PubMed. And yeah, thank you for coming and letting us talk about the lactate shuttle, which started on the track and wind up in the brain. Excellent. Thank you so much, George, for joining us.

Welcome.