312 - A masterclass in lactate: metabolic fuel, implications for diseases, and therapeutic potential

1. 0:00 – 0:12

   Intro

   1. PAPeter Attia0:00

      [upbeat music] Hey, everyone. Welcome to "The Drive" podcast. I'm your host, Peter Attia. [upbeat music] Hey, George. Thank you so much

2. 0:12 – 15:02

   Our historical understanding of lactate and muscle metabolism: early misconceptions and key discoveries

   1. PAPeter Attia0:12

      for making time to sit down with me today. This is, uh, this has been a long time coming. As you know, your, uh, your, your colleague and, and partner in crime on much of the work you've done, Inigo San Millán, has been a, a multiple time guest on this podcast. Uh, and of course, your name has come up many times. I've referenced you and your work in my book. Um, so it's great to be sitting down with you and, uh, to talk about lactic acid, um, which is something that I, I think, uh, you know, I think it would be safe to say at the outset is probably a misunderstood molecule. Is that a-- would that be a safe statement to start this out?

   2. GBGeorge A. Brooks0:49

      Yes, it is. And thank you, Peter, for having, having me on. Uh, you really, uh, really helped make my career, because my physician wife's friends, uh, know my name, but after reading your book, they say, "That's George." [chuckles]

   3. PAPeter Attia1:04

      [chuckles]

   4. GBGeorge A. Brooks1:05

      So that's really great. So not to be difficult, but, uh, you did mention lactic acid.

   5. PAPeter Attia1:11

      Yeah. I was just about to say we-- A-a-and I'm glad you brought that up, but I assume you're going to say, should we really think about this as lactate or lactic acid? And let's, let's have you get the semantics right out of the gate for us.

   6. GBGeorge A. Brooks1:22

      We can say lactate.

   7. PAPeter Attia1:24

      Yeah.

   8. GBGeorge A. Brooks1:24

      The body does not make lactic acid.

   9. PAPeter Attia1:28

      Right. Makes lactate, and then there's a hydrogen ion, and presumably, if there's a hydrogen ion near the lactate, it's lactic acid. Is that the-

   10. GBGeorge A. Brooks1:35

       That's been a historical mi-mistake. It's a hundred years-

   11. PAPeter Attia1:38

       Oh, interest-

   12. GBGeorge A. Brooks1:38

       ... a hundred-year mistake. It's like lactate is not just an innocent bystander. It's a participant in the process of powering muscle and, in fact, all cells.

   13. PAPeter Attia1:52

       So, so let's go back in time a hundred years, right? 'Cause it was about a hundred years ago that Otto Meyerhof, uh, made a, made a seminal discovery. Um, can, can you tell us a little bit about what that was and, and, um, and w-you know, how that sort of, uh, started a chain of, uh, of understanding that brought us to where we are today?

   14. GBGeorge A. Brooks2:15

       Yeah. So the, the early twentieth centuries, people were trying to unite what was known from fermentation technology to what was coming out of, um, studies of muscle metabolism. And Meyerhof is was a, was a great man, a great investigator, and one of the things he did was to quantify how much glycogen, uh, is in muscle and how it-- when it degrades, it produces lactate, uh, at that time thought to be lactic acid. So, uh, um, we're projecting now a picture of the seminal kind of experimental, um, setup that Meyerhof and colleagues used, and they had a half a frog in a jar without oxygen supplementation, without any perfusion, that is blood flow. And this half a frog, the muscles were made to contract, and they contracted until they couldn't contract anymore. And then quantitatively, um, Meyerhof could say, "Well, there was X amount of glycogen, and there was a l-X amount of lactate produced." And so that was, uh, really instrumental in developing this pathway. But if you look at this, this is really not what we are. Uh, these muscles are made in nature to contract once or twice. The frog hops, it gets away or gets eaten. Um, so it doesn't-- the muscle doesn't-- is not representative of us. But in this situation, uh, they stimulated the muscle to contract. It, um, stimulated glycolysis to produce ATP, and at the end, the muscle fatigued, and at the end, there was a lot of lactate, and there was also a lot of acid. So this is how we came to associate, um, lactate or lactic acid production and oxygen lack, 'cause there was no oxygen around here, so it, it had to happen. It was a fait accompli, and this led to the idea of lactic acidosis and the anaerobic threshold and the oxygen debt. But if you just look at this simple, simple apparatus where we have a half a frog made to contract, this is really the aegis of our understanding of how carbohydrate is used in the body. All textbooks, most textbooks, well, not mine, talks about-- talk about, um, glycolysis going to make pyruvate, and when there's no oxygen, uh, lactic acid. So this has been a problem, and this spills over not only into muscle physiology, but it spills over into pulmonary medicine. It, it spills over into cardiology. It spills over, uh, into nutrition. Uh, now we know, uh, a lot of things that were not known or not-- could not be known at that time. And, um, right now, I think I'm gonna stop sharing the screen to talk more directly about our, our new research.

   15. PAPeter Attia5:11

       W-well, l-I wanna go back to that for a second, though, before we get there, George, to make sure everybody kind of understands the experiment and the, um, uh, interpretation. So, um, again, uh, some folks couldn't see that image, but, but basically, you were showing a schematic of an experiment. So let's, let's just kind of explain what was going on there and, and maybe try to understand the interpretation. So, um, the, the musculature of, uh, of part of a frog is put into an anaerobic chamber. This is a chamber that has no oxygen, and it's not perfused, so there was no, uh, blood to carry hemoglobin to carry oxygen to the muscles. Presumably, electrodes were placed, uh, somewhere on the musculature within the chamber, and the electrodes provided the stimulation for muscle contraction? And then the question became: What is it that fueled the contraction? Well, obviously, it's the glycogen within the muscle, but if glycogen or glucose is being used to fuel contraction without oxygen, it somehow must be happening in the absence or exclusion of the mitochondria. And so what they were measuring was the consumption of glycogen, the production of lactate, um, and you're, and presumably they could measure the pH in the solution, and I'm assuming that the pH, which is a measure of acidity, was going down. Is that all correct?

   16. GBGeorge A. Brooks6:44

       That's all correct.

   17. PAPeter Attia6:46

       Okay.

   18. GBGeorge A. Brooks6:46

       That was the observation.

   19. PAPeter Attia6:48

       And so the interpretation of that observation was what at the time?

   20. GBGeorge A. Brooks6:55

       Well, first of all, that was important in terms of quantifying glycolytic pathway.

   21. PAPeter Attia6:59

       Yep.

   22. GBGeorge A. Brooks6:59

       Pre- precursor and product.

   23. PAPeter Attia7:01

       Yep.

   24. GBGeorge A. Brooks7:01

       You start out with a certain amount of precursor and you wind up with a certain amount of product. Um, but since then, people have associated the appearance of lactate with oxygen lack.

   25. PAPeter Attia7:13

       Yep.

   26. GBGeorge A. Brooks7:14

       And that's, that's a mistake. There was no oxygen there. And s- it's a s- stress strain kind of relationship. The muscle is stressed to perform. It uses what it has. It uses glycogen. It produces lactate. And there's also an acidosis, so there's association with lactate and lactic acid, uh, acidosis and fatigue. So this whole thing was all boiled up into one knot. So when I learned exercise physiology, it was all those same things, fatigue, acidosis, um, lactic acid.

   27. PAPeter Attia7:51

       So George, in the experiment that Meyerhof did almost exactly 100 years ago, at some point, I assume the frog's leg stopped contracting in the presence of the stimulus. And is it believed that that was due to a depletion of glycogen, or was it believed that the degree of acidosis had become so significant that the acidosis crippled, in some way, the actin and myosin filaments of the muscle and prevented either further contraction or relaxation?

   28. GBGeorge A. Brooks8:30

       Exactly. So at that, at that time, people were trying to understand why muscles contracted, and it was just a simple kind of thing, like, "Let's have tea, and, uh, would you like tea with, uh, cream, or would you like it with lemon?" "Oh, I would like it with both." So right then, you get this curdling.

   29. PAPeter Attia8:49

       [laughs]

   30. GBGeorge A. Brooks8:50

       The acidosis. And so, uh, one idea of muscle contraction was that the, actually the actin and myosin kind of curdle, and then they-
3. 15:02 – 23:49

   Fundamentals of metabolism: how glucose is metabolized to produce ATP and fuel our bodies

   1. PAPeter Attia15:02

      Uh, George, I w- I wanna go back to some fundamentals, and I, and I, I was a lit- little delinquent in not doing this out of the gate 'cause I wanted to sort of jump right in. But it, it occurs to me as we're talking now that I, I don't wanna take for granted that our listeners really, um, might be as familiar as, as you and I are with metabolism and, um, and, and frankly, you know, the, the, the breakdown of a carbohydrate into what ultimately becomes ATP. So, so I, I'd like for you to spend a moment explaining the following. So, so at a high level, this is what I s- will typically tell a patient if I'm talking about this or if they express an interest. I say, "Look, food is chemical energy, right? So you ha-- you eat these things, and they have bonds in them. They have, you know, especially hydrocarbons, right? They're incredibly rich in stored potential energy within the carbon-carbon and carbon-hydrogen bonds in particular. These are the most energy-rich bonds." Metabolism is a fancy word for taking the chemical energy that is stored within the bonds, again, primarily between carbon and hydrogen and carbon and carbon, and turning that into electrical energy. And that electrical energy is used to turn back into chemical energy. So you take the electrical energy in the electron transport chain, for example, and then you shuttle it back into chemical energy in the form of ATP. So basically, food to ATP is just changing the form of energy, but obviously energy is conserved in this process. And that's just kind of like a hand-waving, high-level explanation. But I think for the purpose of this discussion, we should go a little deeper and explain just-- And we c-- we don't have to even get into fatty acid at this point. We'll probably come to it later. But even just through the lens of glucose, uh, which of course we'll treat as synonymous with glycogen. So when a molecule of glucose is being used by a cell and that cell needs to make ATP, can you walk through, in a little bit of detail, how it does it and what are the different, uh, nodes or paths that it can go down?

   2. GBGeorge A. Brooks17:18

      Yeah. Uh, well, that was a very good explanation. I don't think this, [chuckles] what I'm about to say is gonna advance this, uh, understanding much more. So when glucose is activated to break down, and we can also talk about getting glucose into the cell. Um-

   3. PAPeter Attia17:33

      Yes

   4. GBGeorge A. Brooks17:33

      ... and there are barriers to that, and-

   5. PAPeter Attia17:36

      Well, l- actually, go ahead and do that, George, because I know lactate is going to come and figure into insulin. So why don't you do that? Why don't you start at getting glucose into the cell, and then we'll keep going?

   6. GBGeorge A. Brooks17:47

      Yeah. So, um, glucose is a molecule that can be quite high in the blood, but it, it can't get into the cells. It, it meets a transporter, and some of the transporters are constitutive. Th-they're in all cells. Uh, for like the brain has a, uh, the first one, uh, transporter discovered was named one, and then two and three and four. And four is important because four is expressed in, um, most of our body, in our muscles and, uh, in our fat cells. So we need to have these glucose transporters at the cell surface. And, uh, depending on the various kinds of signaling, insulin is, is the typical signal. Also, muscle contraction will move these transporters to the cell surface. Now glucose can come in. So, um, when I teach glycolysis to my class and I use one of the textbook figures where it starts out with glucose, I put the brakes on and say, "No, we need to put a membrane barrier in here. We need to get glucose into the cell, and then it can be metabolized." And it's usually once the glucose is in the cell, then there are two things that can happen. It can be stored as glycogen, but if there's an energy need, it will enter the glycolytic pathway and be de- de- degre- be degraded. There are a couple of important regulatory steps which are involved, phosphate level and redox, but I'll just say that the glucose splits into two. And so we have a six carbon molecule that makes two three-carbon molecules. And depending on who you are and how you drive, uh, right this pathway, the last step is either pyruvate or it's lactate. And what we found, uh, recently, uh, because we traced the glucose to see what, what it makes, glycolysis basically goes to lactate. So it's a series of steps. One, um, reactant, um, it, it... One product is a reactant for the next step and will... and there's a splitting of a six carbon molecule to two three-carbon molecules that progress to, uh, lactate. And so the process itself, uh, is basically pH neutral.

   7. PAPeter Attia20:05

      L- let's just, let's just make sure people understand that. So what you're saying is, if I heard you correctly, George, um, the glucose comes into the cell. Let's just ass- let's just assume we're not in a storage state, we're in a utilization state. The six carbon ring is split into two three-carbon halves.

   8. GBGeorge A. Brooks20:22

      Mm-hmm.

   9. PAPeter Attia20:23

      Now, a second ago you said you have two f- potential fates there, right? You could make pyruvate or you could make lactate. Is that, is that correct?

   10. GBGeorge A. Brooks20:30

       Yeah.

   11. PAPeter Attia20:30

       Or did you say that it's all... Okay. And you said that either choice is pH neutral. Is that correct?

   12. GBGeorge A. Brooks20:37

       Well, actually, if you get to lactate, it's actually an alkalizing step. But the whole process it- itself is basically pH neutral. And for our discussion of muscle, so we're, we're embedded in muscle now. That's been our thinking for... my thinking, my career-

   13. PAPeter Attia20:52

       Uh-huh

   14. GBGeorge A. Brooks20:52

       ... 50 years in this, and for the whole field, it's all muscle. But we'll, we'll get to what happens, you know, when we take carbohydrate as we go, go through this. Yeah, so, um, we're gonna split this molecule, and as, as you described, it's potential carbon energy. So one way to think about metabolism is the flow of c- of energy, and carbohydrate... carbon energy, c- carbon-derived energy. And at some point we could talk about its integration with fatty acid, maybe amino acid metabolism. But we're really in a basic biological sense talking about the energy highway-

   15. PAPeter Attia21:32

       Mm-hmm

   16. GBGeorge A. Brooks21:32

       ... which is, uh, uh, carbon based, and it's, it's, uh, reduced, so chemically then when it can be oxidized, a lot of energy is released, and we can capture that as ATP. Now, actually, when we're doing just glycolysis in a muscle, and I need to say that when our muscles are working, oh, about 80% of that carbon flow comes from previously stored carbohydrate glycogen. So that's our carbohydrate energy s- source. And we, we have done numerous experiments looking at carbohydrate oxidation in exercise and the use of, uh, glucose. And really, the body protects, um, its glucose pool because there are certain cells that really need glucose, like our brain. And if we got our muscles going, they could suck up all the glucose and leave us really hypoglycemic, and we would crash. Uh, so actually just the active muscles, uh, um, are gonna take up glucose. But it's not gonna be a major part of the energy. It's a significant part, maybe 20, 25%. Most of that carbon is gonna come from previously, uh, stored glucose, which we call glycogen.

   17. PAPeter Attia22:45

       And for the listener who might not be as familiar with that, about 80% of the body's total glycogen or stored glucose is found within the skeletal muscles, while the remaining 20 to 25% would be in the liver. And, um, the way I think about it is that the, the liver's primary responsibility is regulating blood glucose for the brain, whereas having all of that stored glycogen in the muscle is, as you said, an important source of fueling the muscle so that the muscle doesn't have to, you know, for lack of a better word, steal glucose that... from the circulation that would otherwise be imperative to keep the brain happy. But of course, one of the very important things I am sure we will discuss is the role the lactate plays in replenishing the liver, uh, which if I'm not mistaken, was another Nobel Prize probably now somewhere in the, in the mid to, to late '40s, if memory serves correctly, uh, vis-à-vis the Cori cycle. Um-

4. 23:49 – 31:30

   The critical role of lactate in energy production within muscles

   1. GBGeorge A. Brooks23:49

      Yeah, I think 1947 was the year.

   2. PAPeter Attia23:52

      Um, well, let's, let's talk a little bit about that. I mean, I think we're kind of marching our way through history, but that, that was another big seminal, uh, involvement and, and, um- So, so yeah. So let, let's talk about what happens to lactate when it is produced in the, um, uh, i- in the metabolic process of, of, of breaking down glucose? And, and but-- And, and I guess the other question I would have, George, just for the listener, what determines that path choice? Let's not talk about a cancer cell, for example, but let's just talk about a normal muscle cell that needs ATP. It's got its glucose. It splits it in half. It's got its two three-carbon units. What, what are the physiologic pressures that drive towards gluco-- uh, t- uh, pardon me, towards pyruvate versus lactate?

   3. GBGeorge A. Brooks24:40

      Yeah. So we, we, we have a couple of steps that depend on redox. But, um, one of the things that's been noticed by our colleagues who really have done a lot of muscle biopsies is that it's not the ATP level that falls, 'cause the whole system is set up to maintain homeostasis of ATP. But we get changes in what NAD, NADH ratio or redox, but we get changes in ADP, adenosine diphosphate. So when we have this ATP molecule, there are three phosphates, and we get energy by splitting one off, and it gives us ADP. Turns out that's a big signal to activate these enzymes of processing glucose. So, uh, and we, we know that in a lot of ways. If we just take an iso- isolated mitochondria, I take a muscle, isolate the mitochondria, and we want to turn them on and make them start doing something, we add ADP, and away they go, and they start to phosphorylate that ADP and make ATP by the chemiosmotic process, which you described as electrical energy. So yes, the muscle mitochondrial network work, works like a big battery, and it's a battery. Uh, it's just not, um... I don't know if we'll talk about mitochondrial functionality or about its arrangement. It, it's a network. It's not-- They're not just little capsules. This whole network, I call it the energy highway. Uh, other people have called it the cellular energy power grid. Anyhow, that's where the ATP is gonna be generated. And to do that, you need this chemical energy fuel, which is pyruvate or lactate. People have assumed that it's pyruvate that goes into the mitochondria, and that's true, that happens. But most of that chemical energy comes in the form of lactate that goes into the mitochondrial reticulum or network, and that's the fuel to run, uh, the apparatus of oxidative phosphorylation and make ATP.

   4. PAPeter Attia26:40

      And George, I just have to stop you there because that is such a, um... Again, people who are listening to this who are physicians or have studied this are gonna say, "Wow, hang on a second. That is the biggest departure from everything we ever learned." Right? So-

   5. GBGeorge A. Brooks26:58

      Yeah

   6. PAPeter Attia26:58

      ... I just wanna restate what every single textbook on this subject says to paint the backdrop for why this discussion is so interesting, right? So the textbook, every textbook says the following: when you make pyruvate out of glucose, the pyruvate gets shuttled into the mitochondria, and there we undergo the, uh, Krebs cycle, where we very, very efficiently produce massive amounts of ATP, and the only byproduct is carbon dioxide and water. And so as we are undergoing, uh, aerobic respiration, we're consuming oxygen and pyruvate, generating, again, i- incredibly efficient amounts of high volume ATP, [clears throat] and out comes carbon dioxide and water, which is what we're breathing out. Conversely, when you take that glucose and you make lactate, you do generate ATP, but very, very little amounts, and that lactate now needs to escape the cell, make its way into the circulation, where it can go back to the liver and be turned back into glucose via the Cori cycle to begin again. But unless I missed, I don't know, like a couple months of my education in medical school, I do not remember any discussion of lactate going into the mitochondria directly from the cytoplasm as a substrate for, uh, ATP production under aerobic respiration. Um, so, so is-- it's possible I just missed that. But is it, is it more likely the case that most people would believe my belie-- uh, what, what I just said?

   7. GBGeorge A. Brooks28:49

      We've been teaching glycolysis wrong for a hundred years. And, uh, probably, uh, you learned that in junior high school or high school, and physicians and scientists are smart people. Uh, and, uh, if you hear it a- at the high school level and you hear it in college and you hear it in medical school, well, that's what you think it is. That's, that's an assumption that's really deli- deleterious. Uh, so that lactate, uh, that's formed enters the mitochondria, and we have shown that there's a mitochondrial carrier for the lactate to get in. And we've shown, uh, this, it's-- and we call it the mitochondrial lactate oxidation complex. And we have electron micrographs, we have light micrographs to show, uh, how this process works, and the enzymes are there for lactate oxidation. But lactate is important, uh, as a fuel, and as you describe, uh, really the first articulation of a lactate shuttle was by the Coris. And they showed that a dog muscle made to contract with a- adrenaline or otherwise will release pyruvate and lactate, which will recirculate to the liver and become glucose. So that's a way to support, supply blood glucose, uh, during exercise. So the muscles are actually, uh, f- not only fueling themselves, they're, they're fueling adjacent tissues and they're fueling the brain, uh, by, by this lactate shuttle or Cori cycle.

   8. PAPeter Attia30:21

      I- is that a rate-dependent or... Rate's the wrong word. Is it a velocity or a demand-dependent process? In other words, if ATP is being demanded at a very high rate, is the body that, in that scenario preferentially taking the lactate back to the Cori cycle, back to the liver to make glucose? Um, versus if the body has the, quote-unquote, "the time," it can make the long-term investment in getting more ATP per unit carbon by putting lactate into the mitochondria. Because again, the traditional thinking on this is we go down the lactate pathway when we are demanding ATP faster than oxygen can be supplied to the mitochondria, and that's why it's referred to as this anaerobic pathway. And if we, you know, if we have the time, if the ATP demand is low enough that we can afford to get oxygen to the mitochondria, well, then we would always preferentially go down the oxidative phosphorylation

5. 31:30 – 45:55

   Lactate as a preferred fuel during high-energy demands: impact on fat oxidation, implications for type 2 diabetes, and more

   1. PAPeter Attia31:30

      pathway. So i- in, in the discovery that you're talking about, which again, I, I just, I can't overstate how, um, how, how sort of mind-boggling that is. Uh, w- what determines the path?

   2. GBGeorge A. Brooks31:46

      Well, it's this ADP to ATP ratio. That's t- that's what accelerates glycolysis.

   3. PAPeter Attia31:53

      So if ADP is... If the ADP to ATP ratio is low-

   4. GBGeorge A. Brooks31:58

      Mm-hmm

   5. PAPeter Attia31:58

      ... which tells us ATP is being consumed quickly, does that drive lactate into the mitochondria or out to the liver?

   6. GBGeorge A. Brooks32:07

      Yeah. So recently, actually, not us, but others have shown that lactate activates the mitochondria. We have shown that, uh, lactate is a preferred fuel.

   7. PAPeter Attia32:18

      So s- tell, tell me what that means. What do you mean by lactate activates the mitochondria?

   8. GBGeorge A. Brooks32:22

      Uh, it activates, uh, lactate dehydrogenase, the enzyme, uh, in mitochondria, which allows the carbon flowed to go into the mitochondria and for oxidation.

   9. PAPeter Attia32:33

      Does that mean that it also amplifies other substrates flow through? So in other words, if you have a bunch of acetyl-CoA hanging around-

   10. GBGeorge A. Brooks32:42

       Mm-hmm

   11. PAPeter Attia32:42

       ... from fatty acid breakdown, is that also being stimulated to run through the mitochondria at an accelerated rate?

   12. GBGeorge A. Brooks32:49

       Good point. To the contrary. So lactate is not only-- If we c- we have compared glucose to lactate to fatty acids.

   13. PAPeter Attia32:57

       Yes.

   14. GBGeorge A. Brooks32:57

       So lactate's preferred over glucose in, in the brain and muscle w- wherever. But when you, um, the path of degradation of lactate is to generate this acetyl-CoA, and that inhibits the enzymes of-- that transport acetyl-CoA or fatty acids into the mitochondria. So lactate basically shuts the door, blocks fatty acid metabolism. So it inhibits, and Inio's and I have shown this-

   15. PAPeter Attia33:28

       Hmm

   16. GBGeorge A. Brooks33:28

       ... uh, blocks the CPT one and two, the, uh, carnitine palmityate transporters. These are transporters that get-- allow fatty acids to get into the mitochondria for oxidation. So yes, uh, there is a competition among substrates, and lactate shuts the door for fatty acid metabolism.

   17. PAPeter Attia33:49

       I'm struggling to understand teleologically why that makes sense, which just tells me I'm missing something, 'cause I would never for a second suggest my intuition should be better than a billion years of evolution.

   18. GBGeorge A. Brooks34:00

       [laughs]

   19. PAPeter Attia34:01

       But w- why is it that we would ever want to shut down a substrate for which we have an infinite supply, right? 'Cause we, you know, again, we're carrying around more than 100,000 kilocalories of fatty acid. Why wouldn't we always want to maximize our ability to utilize that substrate at the expense of something relatively finite as glycogen, which of course is necessary to even make the lactate?

   20. GBGeorge A. Brooks34:35

       Well, that's part of the fight and flight mechanism. So in terms of our survival, uh, what are we gonna save the, uh, the fats for? The tiger?

   21. PAPeter Attia34:47

       Okay, I understand. Good, good point. Thanks for catching that. Uh, thanks for correcting my stupidity. No, no. So, so you're saying the reason, Peter, is if you are in a lactate dependent state, there's so- something has gone wrong from a... You, you, you're basically in a sympathetic state, and you don't have the luxury of slow-burning fat.

   22. GBGeorge A. Brooks35:07

       Exactly.

   23. PAPeter Attia35:08

       Yeah. Okay.

   24. GBGeorge A. Brooks35:08

       So but fats are really important. Uh, you can see this play out in, in the, in, uh, the natural world. So we, we fight, we, we hunt, uh, we escape, and this is really glycogen glucose dependent. Now, um, our energy stores are depleted. That's, in recovery, is when we're gonna use these fats.

   25. PAPeter Attia35:33

       Well, this is very interesting, and now it actually makes more sense with something we're gonna talk about later, but I'll plant the seed right now. Um, we discussed this previously with Inigo, but I know we're gonna talk about it again. You look at lactate levels in... You look at lactate levels, uh, in individuals at rest who have type 2 diabetes versus lactate levels at rest in world-class athletes. There's a significant difference. And the great irony of that is the very low levels of resting lactate in the athlete mean that at rest they're quite capable of oxidizing fatty acids when sympathetic drive is low and demand is low, and yet paradoxically, the individual with type 2 diabetes, who would most benefit from fatty acid oxidation, is presumably now inhibited in doing so because of those elevated levels of lactate. Is that- Probably a fair assessment?

   26. GBGeorge A. Brooks36:31

       Yeah, that, that, that basically, uh, shuts down the fat metabolism. But think about this. This is my, my old thinking. That lactate there is elevated because of lack of disposal, not necessarily production.

   27. PAPeter Attia36:50

       Mm-hmm.

   28. GBGeorge A. Brooks36:50

       It's there because of failure to dispose. So what the new thinking, my new thinking is, the body, uh, has a, in a diabetic situation, has a hard time taking up glucose because of those, uh, insulin signaling and the GLUT4 mechanism is not working very well. So think about lactate not as a stress, but as a strain. So now we're gonna bypass this inhibition of glucose uptake. We're gonna provide actually the preferred carbohydrate. So, uh, and we see that not only in diabetes, we see that in, in the heart after MI. Lactate is a preferred fuel. Well, you think that what... We had an MI because we had ischemia and we had a blockage. Why would the heart prefer a fast-acting fuel versus a slow-acting fuel? Because it needs energy, 'cause it needs to survive.

   29. PAPeter Attia37:55

       How does one measure, um, the kinetics by which one mole of lactate versus one mole of glucose versus one mole of fatty acid can produce ATP? Um, what are the tools that allow you to make the observation, um, that one fuel is preferred over the others, or that the kinetics of one fuel are faster than that of another?

   30. GBGeorge A. Brooks38:24

       Yeah, we've used i- thank you for that question. We use isotope tracers to do that. So when our first experiments to give, uh, with rats, to give carbon-14 labeled lactate, uh, then we would go into the tissues and try to measure it. It's all gone. It's been burned. It's, it's out into the atmosphere.
6. 45:55 – 53:51

   How the infusion of lactate could aid recovery from traumatic brain injuries (TBI)

   1. PAPeter Attia45:55

      And would it be roughly equal amounts of, of those two in an uninjured brain?

   2. GBGeorge A. Brooks45:59

      Roughly. Probably.

   3. PAPeter Attia46:01

      Okay.

   4. GBGeorge A. Brooks46:02

      So we know. We've published on it. We worked with the UCLA Neurosurgery. We did these experiments with, uh, deuterio glucose and s- uh, thirteenc lactate. So probably about the same. Yeah.

   5. PAPeter Attia46:14

      Okay. And then in an, in an... N- now let's talk about the injured brain. So now you have a, a TBI patient, and you're doing the exact same thing. You're infusing equal concentrations, uh, of, of glucose, lactate, and, and BHB. What would you think... We've already... You already... You know, everybody knows clinically that glucose is gonna be suppressed. How much of that is made up for by the lactate versus the BHB?

   6. GBGeorge A. Brooks46:36

      Yeah. So if lactate's around, it's gonna suppress the BHB.

   7. PAPeter Attia46:41

      So lactate could be the dominant fuel in the injured brain.

   8. GBGeorge A. Brooks46:44

      Yep.

   9. PAPeter Attia46:45

      So the implication of this, at the risk of stating the obvious, is we should be giving brain-injured people intravenous lactate round the clock to heal their brains.

   10. GBGeorge A. Brooks46:57

       I think so.

   11. PAPeter Attia46:59

       How, how many people are aware of that, agree with that? I mean, that's a-

   12. GBGeorge A. Brooks47:04

       So we, uh, s- for various reasons, we lost our collaboration with UCLA Neurosurgery, but they were in the Stage 2 clinical trial of infusing lactate. Uh, and they weren't the only, only ones. There's a group in Switzerland who, uh, preferentially gives hypertonic lactate to TBI patients, and they s- they appear to do better. But, uh, we were hoping to have a clinical trial, multi-center trial demonstrating, you know, the use of lactate as, as an augmentation to glucose in the TBI state. But, um, I don't know what the status of those studies are. But there was a Stage 2 clinical trial that had started at UCLA.

   13. PAPeter Attia47:48

       George, has anybody labeled lactate with FDG so that... Like, or, or, you know, some, some, like the equivalent of an FDG so that you could do a PET scan and actually demonstrate significant uptake of lactate in a brain and then actually do that experiment in an injured brain? So 'cause, 'cause what I'm imagining is you... Everybody has seen the images of the injured brain under standard FDG PET where you have the hypoperfusion in the area. And by the way, this is relevant in diseases like Alzheimer's disease. This is relevant in dementia where we see hypoperfusion of glucose. Um, but it would be interesting if, if it hasn't already been done, to see what the uptake of lactate is if you can put an F-18 onto lactate, which I assume is a trivial task, right?

   14. GBGeorge A. Brooks48:36

       Uh, I don't know about that. But, uh, our, our colleague here at Berkeley, Tom Budinger, really h- helped develop PET and, um, helped make NMR clinically relevant. Uh, he did w- experiments with carbon-11 lactate. So it gave, in the PET scanner it gives a signal as does fluorodeoxyglucose. So that way, uh, you could see lactate taken up by the brain. The difficulty with those experiments, I think the half-life of carbon th- carbon, uh, 11 is on the order of minutes, 20 minutes. So the first experiments involved somebody in the cyclotron making carbon 11 lactate, putting it in a lead-lined s- station wagon, driving it down, running it through a column to remove the strontium 82, and then infusing it into a, a brain and, and imaging the brain. So it's possible with carbon 11 to do that experiment.

   15. PAPeter Attia49:37

       But any reason not to just put F18 onto lactate? Is that chemically not feasible?

   16. GBGeorge A. Brooks49:43

       I haven't thought about that.

   17. PAPeter Attia49:44

       It, it seems like that would be a very interesting experiment though, right? I mean, uh, it, it, or at, at, at a minimum just to generate a hypothesis, right? That says we can fill an energetic gap by using lactate and simply observing a difference in profusion p- pre and post lactate infusion.

   18. GBGeorge A. Brooks50:03

       Oh, I'm making a note. [laughs]

   19. PAPeter Attia50:05

       [laughs] Okay. I, I, I, yeah, it's possible. It, it, if, if it hasn't been done, I'm sure I'm missing something obvious about the, the chemistry of it.

   20. GBGeorge A. Brooks50:13

       Budinger would do when he would do the experiments with glucose or lactate, he also would give rubidium-82, which is a, uh, a, an, a marker of flow. So you would want to do exactly what you described. You would want to know the uptake relative to the flow. So if the flow is depressed in an area, then you would expect the uptake to be less.

   21. PAPeter Attia50:35

       Yeah.

   22. GBGeorge A. Brooks50:36

       Uh, and so you would, we, in the Budinger method, you need to do two isotopes, uh, simultaneously, and that's really tricky and hard to do clinically. It's really, as you described, could be a great experiment. But getting it to, um, work in, uh, clinical centers would be a real trick, a real head-banger.

   23. PAPeter Attia50:57

       Yeah. Uh, w- what about just in, in sort of rodent studies of hypoperfusion? Um, uh, I, I assume that would be an easier place to look at, you know, a TBI model where you ask if lactate can rescue the animal.

   24. GBGeorge A. Brooks51:12

       Well, we could just do that even without a tracer, right?

   25. PAPeter Attia51:15

       Exactly. That's my point. Yeah, you can, you could get around the whole tracer component by just doing that. Uh, is there any issue with, um, infusing lactates at higher concentrations? Is four millimole sufficient, or is there any reason you couldn't put in six or eight millimole?

   26. GBGeorge A. Brooks51:33

       Yeah. I think our friends in, in Switzerland have got it up to eight millimole. But then, you know, you're using hypertonic lactate. So what you can give vascularly, people need to understand it can't be too concentrated to make the blood, uh, really affected poorly.

   27. PAPeter Attia51:50

       When, when we give patients like an intravenous bag of lactated ringers, what's the concentration of lactate in that-

   28. GBGeorge A. Brooks51:56

       It's really pretty low

   29. PAPeter Attia51:57

       ... in that solution? Yeah. Okay.

   30. GBGeorge A. Brooks51:58

       Yeah. So, uh, what they do is they do half molar sodium lactate.
7. 53:51 – 56:35

   The effects of exercise-induced lactate

   1. PAPeter Attia53:51

      the highest lactate I've ever measured in myself, uh, is about 18 millimole, uh, obviously after a very intense bout of exercise. Um, not surprisingly, anybody who's measured lactate in themselves, a- anything over 10 is a very, very uncomfortable situation to be in. Let's go back and talk about what's going on and where my discomfort comes from, because it's not the lactate that's causing me discomfort, correct?

   2. GBGeorge A. Brooks54:22

      No. Lactate is there to, um, moderate. It's a strain response. It's helping to protect you. But you probably are d- d- uh, have a severe acidosis.

   3. PAPeter Attia54:36

      I'm feeling like I'm about to die because my pH is probably 7.05 or something like that.

   4. GBGeorge A. Brooks54:43

      Yeah, yeah. And can I ask you a question? Are you ever hungry after one of these episodes?

   5. PAPeter Attia54:48

      Not at all. In fact, it's usually you're about to vomit if you don't actually vomit.

   6. GBGeorge A. Brooks54:54

      Yeah. So actually, lactate crosses the blood-brain barrier and works in the brain, in the dentate... not in the dentate gyrus, in the hypothalamus to inhibit your appetite. So those of us, you know, who run f- four 40 yards or 400 meters, we're not hungry for three hours, right, until that lactate level's, is cleared, which is a g- really a good reason. People have written about this recently. It inhibits appetite. Lactate suppresses ghrelin. It works directly in the CNS. So an advantage of doing an exercise, not like that one you did, Peter, but getting lactate up to maybe three or four millimolar would actually help satiate people. I know there are people who say, "Well, I exercise and, uh, I, I'm really so hungry afterwards." Well, you're not exercising hard enough. But if you do raise lactate, it will cross the blood, blood-brain barrier. It'll inhibit ghrelin secretion, and it will suppress the appetite.

   7. PAPeter Attia55:55

      That's a very interesting point, and, and I know that people who are listening to this who are familiar with lactate testing, um, which I know is, is a bit esoteric, um, but there is a fundamental difference between having your lactate at 1.5 millimole or one millimole, which is where it might be if you go for kind of a, a brisk walk, versus being at four millimole, which is, you know, not a level you can sustain indefinitely, but it's, um, it's, it's not, you know... it's also not so strenuous that you could only do it for a few minutes. I mean, that's sort of, uh, you know, uh, a fit person could hold that, that level of exertion for 30 to 40 minutes.

8. 56:35 – 1:04:21

   Metabolic differences between highly-trained athletes and insulin-resistant individuals

   1. GBGeorge A. Brooks56:35

      I think your li- listen- listeners will know that four millimolar is, is talked about a lot.

   2. PAPeter Attia56:42

      Let's talk a little bit about, um, differences between athletes and non-athletes, uh, which again, I, I think, uh, becomes very illustrative because they're simply different metabolically, right? So the-- it's not just that the athletes are stronger and the non-athletes are not. Um, but, but what's happening in terms of fuel partitioning that differentiates, uh, a highly, highly trained aerobic athlete, like a cyclist, uh, with, you know, someone who's got insulin resistance? What, what, what are the differences in their ability to utilize fuels?

   3. GBGeorge A. Brooks57:20

      Great. So let's back up just a little bit and go back to the mitochondria. Mitochondria are the sinks or the disposal units. So when anything fluxes, as you described, in the body, like carbon flux, it has to go from a production or entry site and has to go to a removal site, and the mitochondrial network is the removal site. Now, when, uh, a highly trained athlete exercises, and here we need to talk about relative or absolute power output, so let's say 65% of VO2 max or 65% of effort. For an untrained person, well, that's not very much exercise really. They'll get to 65% of VO2 max at a very low power output. Now we take the trained athlete, put him or her at their 65%. They're generating a lot of lactate, but they're burning it, and as you described earlier, it's recirculating to the Cori cycle to support blood glucose. So even if you just measure the concentration, you don't have the whole story. You don't have the-

   4. PAPeter Attia58:28

      That's right

   5. GBGeorge A. Brooks58:28

      ... flow. You don't have the flux rate. You don't have the partitioning, uh, sensation. Now, if you take that same athlete now and you push him to a lactate that elicits maybe six or eight millimolar, there are gonna be really, uh, a lot of differences there, and now you've exceeded their capacity of the mitochondria to clear lactate, and also you're probably gonna have shunting away from the gut. This goes back to something we, we mentioned in passing. So gluconeogenesis, the making of glucose from lactate, depends on good liver blood flow. When you start going really, really hard, all your, your blood's gonna go to your muscles basically, and you're gonna clamp down. You're not gonna perfuse the liver. So now the gluconeogenesis goes down regardless of who you are when you sort of take the liver and the kidneys out of circulation. Now... And of course, those are major organs of lactate disposal as well. I said 20, 25% earlier. If you eliminate those by basically clamping them off, then the lactate level's gonna be higher.

   6. PAPeter Attia59:40

      I want to go back to something I asked you earlier, but I want to make sure I re- I, I, I captured what you said. As the individual is increasing, um, the energy demand, they're making more and more lactate. Um, is ADP or ADP to ATP helping to determine when the lactate is going in the mitochondria versus back to the liver? Because in the scenario you described where energy demand is going up and up and up, and therefore perfusion is going down in the organs that are able to recirculate lactate, you would think that the body would just say, "Okay, no problem. I'm gonna shovel more lactate into the mitochondria. I've got a perfect engine here to generate more ATP." In other words, why is that a problem that the lactate now can't be cleared as efficiently through the gluconeogenic pathways?

   7. GBGeorge A. Brooks1:00:41

      Yeah. So go, again, to your example of the athlete. When we train, we increase our mitochondrial mass maybe 100%. And if we train, we'll raise our VO2 max maybe 10, 15%. So the c- there's more plasticity in the muscle to increase the mitochondrial mass, and I think really that's the key to Inigo's success with his athletes. He trains them so they increase their mitochondrial mass.

   8. PAPeter Attia1:01:08

      Wait, how... Did you say y- how much did you say you increase mitochondrial mass by?

   9. GBGeorge A. Brooks1:01:12

      Well, you can double it.

   10. PAPeter Attia1:01:14

       Over what period of time?

   11. GBGeorge A. Brooks1:01:16

       Well, as far as the first study on this appeared in 1967 in the Journal of Biological Chemistry, was in rats, was by John Halasz. Uh, and you could, uh, over the perios- period of several weeks of training rats, you could do that. Uh, after that, we, uh, extended those studies a bit with Kelvin, Kelvin Davies when he was here, and we were, again, saw a doubling of the mitochondrial mass. Um, uh, others have looked into the, the muscles of athletes and find, found that, uh, they have more than twice the mitochondrial mass of the average person. And that, of course, is a lot selection.

   12. PAPeter Attia1:01:56

       S- sorry, just to be clear, this is mitochondrial density. So for a, for one gram of vastus lateralis in an athlete versus one gram of vastus lateralis in a non-athlete, you'll see 2X the mitochondria?

   13. GBGeorge A. Brooks1:02:12

       You'll, you'll see 2X the mitochondrial mass. So I, I don't talk about-

   14. PAPeter Attia1:02:19

       Yeah, not necessarily the number of mitochondria-

   15. GBGeorge A. Brooks1:02:21

       Yeah

   16. PAPeter Attia1:02:21

       ... because the vol- yeah. And, and how is that, um, conveyed? Is that larger mitochondria plus more mitochondria that amounts to that doubling?

   17. GBGeorge A. Brooks1:02:30

       We talk about the mitochondrial reticulum.

   18. PAPeter Attia1:02:33

       Mm-hmm.

   19. GBGeorge A. Brooks1:02:33

       So think about a t- tree budding and branching out, leaves.

   20. PAPeter Attia1:02:38

       Yep.

   21. GBGeorge A. Brooks1:02:39

       So if you do a thin section, you'll see, and you do point counting, one mitochondrion, two mitochondrion, three mitochondrion, a thousand mitochondrion, but they're all part of a network. Uh, so what you have is a bigger, bigger energy delivery system that goes from the cell surface deep within the fiber through this network.

   22. PAPeter Attia1:03:05

       Yeah.

   23. GBGeorge A. Brooks1:03:05

       And again, some people call it the cellular energy power grid.

   24. PAPeter Attia1:03:09

       And to your point, which is, you know, has the experiment been done to demonstrate the causality of exercise there? In other words, do we have the ex- experiment where you take untrained individuals, do the muscle biopsy, c- compute mitochondrial density, mass of mitochondria per unit mass of muscle, train them for four to six months, repeat the biopsy, and see if the training is leading to the doubling, rather than just saying, "Well, athletes are athletes because they have more mitochondria"?

   25. GBGeorge A. Brooks1:03:42

       Yeah, well, it works both ways. If you're, if you're, if you're, uh, born with that and you go into athletics, you're successful. And then-

   26. PAPeter Attia1:03:51

       That's right, yeah

   27. GBGeorge A. Brooks1:03:52

       ... and then if you're not, then you become a professor. [laughs]

   28. PAPeter Attia1:03:55

       [laughs] That's sort of something I'm curious about. I, yeah.

   29. GBGeorge A. Brooks1:03:59

       It, it goes up proportionally. And interesting, all the enzymes that are, as far as we can tell, all the constituents that make up this mitochondrial network go up proportionally. So you get twice as much Krebs cycle enzymes, twice as much electron transport cycle enzyme. You basically activate the whole, the whole system.

   30. PAPeter Attia1:04:20

       S-

9. 1:04:21 – 1:12:44

   How training enhances lactate utilization and facilitates lactate shuttling between fast-twitch and slow-twitch muscle fibers

   1. PAPeter Attia1:04:21

      so George, I was taught the following, which I'm now almost assuming is going to be, at best, an oversimplification, and at worst, I might just be abjectly wrong.

   2. GBGeorge A. Brooks1:04:30

      [laughs]

   3. PAPeter Attia1:04:32

      Um, you, you mentioned something called MCTs a moment ago. Do you wanna tell folks what an MCT is?

   4. GBGeorge A. Brooks1:04:37

      Oh, yeah, I, I, I had to explain this to my wife, Rosemary, the sports medicine doctor. What's an MCT? Well, we were looking for the lactate transporter protein, and, uh, said, "Ah, we got scooped. Somebody found it." And, and she called it, and it was Dr. K- Christine Kim Garcia in the Goldstein lab in, in Dallas, and we're, that's a Nobel Prize lab. And she found, they were looking for transporters of, um, um, things that contributed to cholesterol metabolism. And she found this protein, and she didn't know what it was, and she found out it was a lactate transporter. And so they were called monocarboxylate transporters, and now it, it's like the glucose transporter field where we have the first isoform and the second one and the third and the fourth. There are actually more, more than four now that have been discovered.

   5. PAPeter Attia1:05:35

      When was the first one?

   6. GBGeorge A. Brooks1:05:37

      About 2000.

   7. PAPeter Attia1:05:39

      Okay. So, so what I was taught, uh, again, uh, we'll see, we'll see how far off base I am, was that one of the benefits of training was increasing the density of MCTs. So in other words, the harder I trained, the more I increased the density of these MCTs-

   8. GBGeorge A. Brooks1:06:04

      Mm-hmm

   9. PAPeter Attia1:06:05

      ... in my muscle cells, and what that allowed me to do was produce more lactate, but get it out of the cell and back to the liver. So, you know, you t- imagine a little cartoon where I've got a muscle cell, I'm untrained, and I've got 50 MCTs, and after training, I've now got 100 MCTs, after a period of time, not acutely, but you know, years of training or whatever, and therefore, I can now make twice as much lactate and get that lactate out. Now, of course, all of this was predicated on the model that said more lactate in the muscle is bad because with lactate goes hydrogen, and hydrogen inhibits performance. So, so again, that was all viewed through that lens, but was there any truth to the idea that as we train more, we increase the density of MCTs, which, if nothing else, I assume would give us more flexibility in this, uh, lactate flux game?

   10. GBGeorge A. Brooks1:07:03

       Yes, we've done this in animals and we've done it in, uh, looking at trained and untrained people, and we can see an increase in the abundance of the MCTs. Now that, that, that helps two ways, because getting lactate into the mitochondrial network requires an MCT.

   11. PAPeter Attia1:07:23

       Mm.

   12. GBGeorge A. Brooks1:07:24

       So we were bold enough to look in the mitochondria and, and find MCTs. So people think, well, it's just on the cell me- membrane and it's good for ex- uh, export, and that's true. But, uh, in, um, oxidative muscle fibers with a abundance of transporters, many of them are in the mitochondria, so the lactate will move into the mitochondria as well as can be exported. So then we see a difference between fiber type. Um, fast glycolytic fibers will be pale in color, and they're-

   13. PAPeter Attia1:08:02

       Mm

   14. GBGeorge A. Brooks1:08:03

       ... they're, uh, pale because of less heme oxygen compounds. They'll have less blood flow through capillaries per fiber, they'll have less myoglobin, and mitochondria are the color of liver or vice versa. Liver is the color of mitochondria. So, uh, those fibers, when they're made to contract, they have lesser mitochondrial density, they will export lactate. But they can export it to a neighboring, neighboring red fiber. So we call this the cell-cell lactate shuttle, where a fast glycolytic fiber produces lactate and it's consumed by an adjacent fiber and never even appears in the venous blood except as CO2.

   15. PAPeter Attia1:08:48

       I'd never heard that, George, so just to make sure the listeners are following and that I'm following, uh, we've had many podcasts where, of course, we discuss type one and type two muscle fibers, uh, colloquially referred to as fast twitch and slow twitch fibers. Um, so the, the, the slow twitch fiber, the type one fiber is the red fiber. It's the fiber that is, uh, dense in mitochondria. It is the one that has the capacity for oxidative phosphorylation. It is less powerful, but much slower to fatigue, right? Then you have these type two fibers, and I'm oversimplifying a little bit because there are subtypes of them, I understand, but the type two fiber, you know, it's a more contractile, it's a more powerful fiber.

   16. GBGeorge A. Brooks1:09:35

       Mm-hmm.

   17. PAPeter Attia1:09:35

       Uh, twitches a little faster, but it's very fast to fatigue. It's the white fiber because it is lacking in the mitochondria. Does it outright lack mitochondria? Uh, and, and basically it's just a pure glycolytic fiber, correct?

   18. GBGeorge A. Brooks1:09:47

       No, there are mitochondria in there.

   19. PAPeter Attia1:09:49

       There are, just a much lower density.

   20. GBGeorge A. Brooks1:09:50

       Lower density, yeah.

   21. PAPeter Attia1:09:52

       Yeah. So what you just said a second ago was, as those cells, uh, accumulate lactate, they realize that their neighboring type one cells can make even more use of the lactate, given that they have a greater conc- or a greater density of mitochondria, so they'll shuttle the lactate from the twos to the ones?

   22. GBGeorge A. Brooks1:10:13

       Mm-hmm.

   23. PAPeter Attia1:10:13

       Is that correct?

   24. GBGeorge A. Brooks1:10:13

       Yeah.

   25. PAPeter Attia1:10:15

       Wow.

   26. GBGeorge A. Brooks1:10:16

       Yeah, so that's, that's actually part of the discovery of, uh, the lactate shuttle. Uh, so early on when we started doing the studies on rats and using C14 lactate and tritiated glucose and comparing the flux rates of the, of the two and looking at the various fates of where the carbon goes, um, uh, we knew that there was a h- with an exercise was a large flux. But from the tracer itself, you can't tell where. So a colleague of mine at UC Irvine, Ken Baldwin, did his studies on rats, and he made them exercise hard, then he measured the lactate levels in blood, in red muscle, and in white muscle. So a rat made to run hard has a very high level of lactate in the fast glycolytic type two fibers.

   27. PAPeter Attia1:11:12

       Can you give me the approximate concentrations in that type of an experiment between blood type one and type two?

   28. GBGeorge A. Brooks1:11:19

       Yeah, so w- but let's... I'll give you this just to finish the analogy. We can put some numbers on it. So [clears throat] then he measured the lactate level in, in the arterial blood, and of course it was lower. And, and the red muscles, the lactate level was lower than in arterial blood, and that gave rise to the idea that the fast fibers were sharing lactate, not just to the venous blood, but to the red fibers that were adjacent. So the numbers, I'm trying to remember, this is back 30 years, what the numbers were. It would be something like in the fast fibers, it would be something like 10 to 12 milliequivalents. In the blood it would be four, and in the red fibers it would be three.

   29. PAPeter Attia1:12:05

       And then in the arterial... And then the, but the four was in venous blood, correct?

   30. GBGeorge A. Brooks1:12:10

       In blood? No.
10. 1:12:44 – 1:16:21

    The growing recognition of lactate and monocarboxylate transporters (MCT)

    1. PAPeter Attia1:12:44

       Got it. This is just... So, so, so when, when did you first find, uh, MCTs on mitochondrial membranes? What year did you first publish that?

    2. GBGeorge A. Brooks1:12:55

       About '95.

    3. PAPeter Attia1:12:58

       So what percentage of the relevant scientific community acknowledges that now? Uh, again, am I just taking this... Is it, is it taken for granted within your world that that is completely, uh, settled? And is it just that it, I mean, that hasn't made it out to any of the textbooks yet?

    4. GBGeorge A. Brooks1:13:16

       Oh, well, Tom Fay and I are revising our textbook. We're gonna get it right. But yes, there's been a stonewall silence. For instance, in Science magazine, they published papers on the mitochondrial pyruvate transporter, two papers simultaneously about this discovery of the pyruvate transporters. Previously, we had shown the mitochondrial lactate transporter wasn't even cited. Neither the editors nor the reviewers knew about it. So now things are changing, Peter. So actually right now, there is a lot of interest in lactate.

    5. PAPeter Attia1:13:50

       So, so this is interesting. Why, why... I mean, I, I know this is kind of a, uh, these are difficult questions to answer, so I'm, I'm sensitive to that. But, but why do you think that something that was discovered 30 years ago, uh, that appears quite germane to the physiology of everything, but if nothing else, just through the physiology of exercise, but it clearly extends beyond that, um, why, why do you think that this isn't more widely understood even in the, the, the, the, the physiologic circles that you, you travel in?

    6. GBGeorge A. Brooks1:14:23

       Yeah. I think I said it earlier. People who do science a- and medicine are smart people. They've learned it a certain way, and that's what they... It's their set point.

    7. PAPeter Attia1:14:35

       But I tend to differ between scientists and physicians, and, and I say this as no disrespect to my profession, but I, I think that that makes more sense at the physician level where, look, you know, medical school is drinking from a fire hose. You don't... It, it's sort of... It's almost beat out of you to question things because you, you frankly don't have the time, right? You've got two years to learn so much. Um, but I, I, I would have to think that that's quite different for people who choose, uh, a scientific pathway where discovery, uh, questioning orthodox beliefs, you know, that is the name of the game. Uh, I'm... I- is, is there something I'm missing here?

    8. GBGeorge A. Brooks1:15:15

       So maybe there is a, a difference between science and medicine in this regard. So when I'm given the opportunity, I will talk to, for instance, the Washington S- Thoracic Society and go to a meeting and, and talk to the docs and... Because when they see lactate, they start infusing bicarbonate. Uh.

    9. PAPeter Attia1:15:37

       Right.

    10. GBGeorge A. Brooks1:15:38

        And, uh, or they give oxygen. So, uh, in the medical field, there's a, a character maybe someday you would really enjoy meeting this. His name is Ronaldo Belomo. He's a world-renowned, uh, uh, physician, r- emergency r- room physician, and he's written about the fact that pulmonologists need to be more like exercise physiologists with regard to understanding lactate metabolism. He challenges his, his colleagues to, to do that, and Belomo is a, Belomo is a big name in the field. So there's, has been a lot of inertia in this, but I think we're getting some momentum.

11. 1:16:21 – 1:33:40

    The intricate pathways of lactate metabolism: isotope tracer studies, how exceptional athletes are able to utilize more lactate, and more

    1. PAPeter Attia1:16:22

       So I want, I want to use an example, a, a real-life example to have you explain the difference in metabolism between two people, me and one of my friends. So this is, this is... I, I, I'm not gonna name him, but, but I, but, but I already talked with him about the, you know, maybe potentially telling his story. So, so there's a friend of mine who is really an exceptional cyclist, okay? He is probably in the top... Uh, he would, he would easily be in the top 10, uh, amateur cyclists in the country, okay? So, um, again, for people who y- y- you would understand these numbers, but I should just throw out some numbers so people understand what we're talking about. So this is a guy who's in his late 40s, and he can still put out 5.3 watts per kilogram for an hour, so that's what we would call his functional threshold power. So when he is on a bike, he can put out 420 to 430 watts for 60 minutes. Um, and you know, whatever. He weighs about 80 kilos. Um, so a- again, uh, for, for... I understand that people listening to us might not understand what 430 watts feels like, uh, let alone what it would feel like for an hour, but I know you understand this, and I think there are enough people listening to us that understand this that we can still justify the time on this topic. So I just want to explain to you, here he is, this incredible cyclist, uh, and, and, and actually a great triathlete as well, so great swimmer and runner, but really on the bike is where he shines. And these are, you know, these are numbers that at his age are almost unheard of and frankly would still be at the levels of a low-level professional cyclist. Okay. Contrast that with me. I'm a very mediocre cyclist. Uh, even at my best, I was... my FTP was lower than his, right? At my very best.

    2. GBGeorge A. Brooks1:18:30

       Mm-hmm.

    3. PAPeter Attia1:18:30

       Um, and today, I don't know, my FTP, if I'm lucky, might be three to three and a half watts per kilo. Very low. Okay. Um, he was over at my house last week, George, and we were lifting weights together. Now, he doesn't lift weights anymore. He is... All of his energy goes into, uh, cycling, and I do everything. I'm kind of a, a, a jack of all trade, master of nothing. And so he was lifting weights with me. We were doing some leg exercises, and 80 kilos is pretty big for a cyclist, so he doesn't look like a tiny little cyclist, especially in the legs. And so I put him on a machine where I was doing some, some squats, right? And, um, I just assumed he would start at a weight very close to what I was doing, a little bit less. I maybe had him at 20% less weight than me. And I said, "Tell me how this feels." And he said, "Oh, there's no way in hell I could move this." We ended up having to take it down to half the weight that I move for him to be able to do the exercises. And I was really thinking to myself, "This is a very interesting lesson in physiology," right? Because his legs are so superior to mine in generating absurdly high wattage for a long period of time, yet when I'm, you know, asking him to do this different type of task, which is clearly more recruiting of a type two muscle fiber, um, he doesn't have the contractile force. So we... And he and I ended up having a great discussion about this, uh, because it was like, "Oh, that's so interesting that, you know, you're not as strong in this regard as I would've expected, and yet you're so superior in this other way." And what we got talking about was the differences in our metabolism, right? Which is clearly he is able to do something... 'Cause again, what's more interesting to me is not that he's not as strong as me on a, you know, a squat, it's how much stronger he is than me on a bike, right? So that's a long-winded background, but now I want you to imagine you had muscle biopsies of both of us, right? So you, now you've got his quads and my quads. What is it about him that is allowing him to hold 430 watts per kilo f- uh, pardon me, 430 watts for an hour? What is happening at the level of fuel utilization that allows him to be so different from the rest of us, regardless of how strong we are? And that's really the point I'm trying to make, right? What is it that he is doing that is so special and, and that which all, you know, exceptional athletes can do?

    4. GBGeorge A. Brooks1:21:22

       Well, not all. That, it's, uh, sport specific, so-

    5. PAPeter Attia1:21:26

       Yeah. All, all exceptional cyclists, right?

    6. GBGeorge A. Brooks1:21:28

       Yeah. You-

    7. PAPeter Attia1:21:28

       Or endurance athletes

    8. GBGeorge A. Brooks1:21:29

       ... you, you described it earlier as the flow of energy. And so I would guess that he had, was mostly type one fibers, these red fibers that are highly perfused, that have the mitochondrial reticulum really highly expressed, so he can have a h- high carbon flux, um, and sustain it. He can generate large amounts of lactate and clear it, and some of the lactate probably goes into his blood and helps maintain his blood su- sugar level. So the fact that he can't exert a, a real, as great a force as you probably, um, means that, uh, he's a, he's got the slow red fiber type, and he, he also hasn't learned how to do it. You probably could work with him a couple times, he might improve s- you know, just jump up a little bit by learning.

    9. PAPeter Attia1:22:30

       Well, that, that... Yeah, by the way, that, I wanna make that point. I am totally confident that in three weeks he would be leg- he would be squatting as... He, he would be doing as, you know, the same amount of weight than me. This, again, the point is not so much that he w- yeah, I don't wanna suggest that he wouldn't be as strong. It's more that if you gave me the rest of my life, I would not be able to get to five watts per kilo.

    10. GBGeorge A. Brooks1:22:56

        Yeah.

    11. PAPeter Attia1:22:57

        That's, that's the bigger point, even though ostensibly I'm stronger.

    12. GBGeorge A. Brooks1:23:02

        Yeah. Because it's different... You, you were talking about different metabolic systems, or a metabolic system s- surfeit surplus versus a contractile, uh, entity that coexist together in the same muscle. And of course, one feeds the other. So in his case of cycling, his, his muscle power output is limited by the carbon flow that he can sustain.

    13. PAPeter Attia1:23:27

        Ah, okay. So thank you. That's exactly where I want to go with this. How much is he limited by carbon flux input versus, uh, metabolic byproduct output? In other words, why isn't he at six watts per kilo, which would make him among the best cyclists on planet Earth?

    14. GBGeorge A. Brooks1:23:49

        Yeah, I would... Well, I think it's a, a matter of degree. I think if we looked at really top cyclists, we would find that they could clear lactate more efficiently than he could, and a lot has, of that would have to do with his, the fiber type and the mitochondrial mass that they had.

    15. PAPeter Attia1:24:07

        I see. So in the final analysis, you think that what differentiates the absolute best performers on planet Earth is going to be lactate clearance?

    16. GBGeorge A. Brooks1:24:21

        Yeah. It's gonna c- uh, or w- we're talking about carbon flux, 'cause that glycolytic flux goes to lactate, and nobody knew that until we traced it. And, and that, that gets oxidized, so what he, what you have is this, um, production versus disposal capacity, and he's got a great disposal capacity for carbohydrate carbon-

    17. PAPeter Attia1:24:48

        So when he, when he is on that bike for 60 minutes at 430 watts, if you had to guess, if you could sample his arterial blood, his venous blood, his type one and his type two fibers for lactate concentration, what would be your prediction?

    18. GBGeorge A. Brooks1:25:07

        So we've, we haven't done this with trained athletes, but we've done it with some people who are physically fit and, uh, recreation, re- recreationally competent. So you can see, um, lactate, uh, very high in the venous effluent of a working muscle I'm gonna just make up some numbers here.

    19. PAPeter Attia1:25:28

        Mm-hmm.

    20. GBGeorge A. Brooks1:25:29

        10 to 12. And, uh, at the same time, we-- since we had arterial sampling versus femoral venous sampling, when the blood goes around the body, not even one complete passage, it's down to four millimolar. So there are lactate pyruvate conversions happening in the blood, in part by the red blood cells and in part by the lung parenchyma, 'cause all the blood goes through the lungs.

    21. PAPeter Attia1:26:01

        Yeah, I was about to say, when you sample that venous, uh, blood at 10 to 12 millimole, um, it wouldn't matter if you're doing that pre or post portal vein because y- I would think that the... I- if, if you-- I mean, you could not do that easily, but just, you know, i- if you, if you were sampling it above the liver, wouldn't it be significantly lower given that the liver is also going to be a huge sink for lactate?

    22. GBGeorge A. Brooks1:26:29

        That's a good point. We-- it's, it, it's, it wasn't a mixed venous sample, but we had a femoral sample, so in part dilution.

    23. PAPeter Attia1:26:38

        So, so you're doing it pre-liver, obviously, so you're getting the absolute peak level of lactate. This is very interesting, George. I never thought of this. All those times I'm sitting there poking my finger in my earlobe, I'm probably underestimating the venous concentration of lactate because it's already had a hepatic pass, right?

    24. GBGeorge A. Brooks1:26:58

        It hasn't had a hepatic pass. It's had a hepatic dilution, and it's gone, gone through the lungs.

    25. PAPeter Attia1:27:06

        So that's potentially a double reduction in lactate.

    26. GBGeorge A. Brooks1:27:08

        Yeah.

    27. PAPeter Attia1:27:10

        Well, that's interesting. So you're saying if you're measuring 16 millimole in your finger or earlobe, and assuming you're generating this on a bike, and someone had a femoral transducer in you, y- you could be more than 20 millimole in the, in the femoral blood supply as it's exiting the muscle, correct?

    28. GBGeorge A. Brooks1:27:29

        It hasn't been explored much. We just have a couple of papers on it. Uh, one is by, um, Matthew-- both are by M-Matthew Johnson and another by Greg Henderson. Matt is, uh... Y- y- you know Matt Johnson? There's two, actually. [laughs]

    29. PAPeter Attia1:27:48

        I don't.

    30. GBGeorge A. Brooks1:27:49

        Okay. Uh, so Matt is-- works at Descom, Dexcom. He's a, uh, research scientist at De-Dexcom. They, they make the glucose analyzers.
12. 1:33:40 – 1:41:24

    The role of lactate in cancer

    1. PAPeter Attia1:33:40

       bit about, um, cancer. Um, we alluded to it at the outset with the Warburg or Warburg effect, where cancer cells seemingly in the presence of unlimited oxygen still seemingly choose a metabolic pathway that avoids the mitochondria, although I'm gonna come back and ask you about that now because we're gonna call everything into question. But again, uh, let's just go through the traditional thinking. Traditional thinking is you take cancer cells in a dish, you give them unlimited access to every substrate under the sun, and what do they do? They, they don't want to use fatty acids. They just want to use glucose, and they just want to make lactate. Um, I know that the first hypothesis put forward there was, "Oh, well, cancer cells must have defective mitochondria. That's why they can't use anything else, and that's why they have to make so much lactate." Um, that hypothesis doesn't seem to be the case. Uh, and it seems that there are other reasons. Um, famously, Lou Cantley, Craig Thompson, and I think, uh, at least one other, uh, colleague wrote, uh, it was Matt Vander Heiden, if I'm not mistaken, that, well, this, the cancer cell is not optimizing for ATP, and it doesn't care that it's being inefficient in making lactate. It's optimizing for cellular building blocks because it's a cell that has to replicate, uh, without stopping, and that's why it's, it's doing that. It's, it's making... It's going down the lactate pathway to generate more carbon, nitrogen, whatever else it needs to actually build a cell. Um, tell me a little bit now about where your, uh, your discoveries kind of fit into this hypothesis around why a cancer cell would follow the principle of the Warburg effect.

    2. GBGeorge A. Brooks1:35:38

       Yeah. Well, um, maybe that's a Nobel Prize, right? [laughs] Understand that?

    3. PAPeter Attia1:35:43

       Yeah.

    4. GBGeorge A. Brooks1:35:43

       'Cause I, I do... Uh, to, to rephrase that, I think the answer has been staring us in the face. Cancer is a, is a problem of glycolysis, unrestrained gly- gly- gly- glycolysis. And Inio and I have some papers together, and in fact, he was kind enough to put my name on a, his most recent paper, which is now being reviewed for publication, and has to do with, um, the expression of certain glycolytic enzymes, and I don't want to spill any of his, uh, beans here, um, about this. Uh, it has to do with the expression of glycolytic enzymes, and it looks at, as if that in all the various stages of cancer progression, lactate, um, stimulates those. So, uh, and he- Inio is now looking at sort of the mitochondrial basis for that. So my-- so to repeat what you said, cancer cells do have mitochondria. We've seen that, other people have seen that, and they're capable of oxidizing, uh, different substrates inc- including lactate. But the lactate is generated, uh, the, the high lactate production seems to stimulate a lot of things that are, uh, untoward in cancer. And one of the papers that Inio and I first wrote was to look at all the adaptations in muscle to training, and look at, uh, where cancer cells differ from the norm, and then look at those points of difference between training and cancer, and it has to do in part with lactate clearance. So those, uh, cancer cells do generate a lot of lactate, and the lactate is injurious in those cells

    5. PAPeter Attia1:37:40

       So I, I w- you know, the, it would be easy to listen to that statement and say a cancer patient should never be exercising, but it, it... And that might be one implication, although another implication might be cancer patients need to be exercising because they need a sink for all that lactate.

    6. GBGeorge A. Brooks1:37:58

       Yeah.

    7. PAPeter Attia1:37:58

       So which of those two do you think is more accurate?

    8. GBGeorge A. Brooks1:38:01

       So I, I used to believe the first one. Oh my gosh, we don't want to generate lactate. But then I, we thought more about it. Well, lactate's low because you clear it, and when you do regular exercise, you increase your clearance capacity. And so in that sense, uh, if lactate is carcinogenic, by removing it, you lessen the chance for carcinogenesis.

    9. PAPeter Attia1:38:37

       Yeah, I mean, that, that, that, that's just s- simply kind of remarkable statements, right? I mean, uh, if, um... First of all, that lactate is, is carcinogenic is, is kind of remarkable. Um, and then it feeds to the difference between concentration and flux or flow.

    10. GBGeorge A. Brooks1:38:55

        Mm-hmm.

    11. PAPeter Attia1:38:55

        This is the most... I, I think in physiology, one of the hardest things for people to wrap their mind around. I'll give you another example, but it's, it's something near and dear to my heart, right? Which is you look at intramyocellular fatty acids. Why is it-- I mean, you know the answer, but I'm leading you down the path for the listener. Why is it that both the best athletes in the world and the most metabolically unhealthy people with type 2 diabetes both have high amounts of intramyocellular fat?

    12. GBGeorge A. Brooks1:39:25

        Yeah.

    13. PAPeter Attia1:39:25

        Well, of course, the difference is in the person with type 2 diabetes, it's static. It's stagnant. It sits there, and it is one of the causative drivers of insulin resistance. Uh, yet in the athlete, it's just a fl- it's a carbon flow. It's just, it's moving. It's, it's not... You know, it's the difference between a stagnant pond and a flowing river.

    14. GBGeorge A. Brooks1:39:45

        Yeah.

    15. PAPeter Attia1:39:46

        Um, and I think we get into this trap with lactate, don't we? Where we measure concentrations, and we just assume high is high, low is low, high is bad, low is good. But we can't measure flux without, you know, the complex instrumentation you use in a lab.

    16. GBGeorge A. Brooks1:40:02

        Yeah. That's true. And just to elaborate more on sort of the, uh, the marathoner paradox, if you do an EM and you find a mitochondrial net- network, you'll see a fat, a globule right next to it. So the potential for fat oxidation is great.

    17. PAPeter Attia1:40:20

        Yeah.

    18. GBGeorge A. Brooks1:40:20

        Uh, in our work, we've done some, uh, MR- MRS and MRI, and we've looked at athletes, and, um, they don't use much fat during exercise. But in the recovery period, you know, when glycogen is low, that's the period of fat burning. So those, those fats there are, um, preconditioning, pre-positioning-

    19. PAPeter Attia1:40:46

        Mm

    20. GBGeorge A. Brooks1:40:46

        ... fuel supply in recovery when glycolysis switches off and people start to relax. So you're right about this whole idea of flux. Also, in diabetes, glucose is high. Why? Was it produced too much or not cleared?

    21. PAPeter Attia1:41:05

        Right. Yep.

    22. GBGeorge A. Brooks1:41:06

        Well-

    23. PAPeter Attia1:41:06

        Yeah. It's, it's a great point

    24. GBGeorge A. Brooks1:41:08

        ... a bit of both, really.

    25. PAPeter Attia1:41:08

        Yeah.

    26. GBGeorge A. Brooks1:41:09

        So that's easier to explain with glucose than with lactate. People more readily ex- understand the dynamics of appearance versus disappearance, and the hi- the level just tell, is informative, but it's not the whole story.

    27. PAPeter Attia1:41:23

        So we've talked

13. 1:41:24 – 1:50:15

    The role of lactate in the pathophysiology of various diseases, and how exercise could mitigate lactate's carcinogenic effects and support brain health

    1. PAPeter Attia1:41:24

       a little bit about... well, quite a bit about lactate in athletic performance. I have a much better understanding of that. You, you've talked about something very, very tantalizing with respect to brain health and TBI, and I'm very much hoping that, that this is being investigated. I mean, again, TBI is something where, uh, fortunately, people are so much more aware of it today, but yet we still seem relatively, um, poor in therapies. And if we had a tool, a metabolic tool, to aid following a concussion... I mean, I mean, imagine if there was a concussion protocol that said every time a person got a concussion, they were to receive intravenous lactate, you know, for X number of consecutive days, four hours a day at four millimole. Um, a- again, very testable hypotheses here. It's, it's a little, uh, frustrating to think that, that this type of work isn't being funded given, uh... I mean, heck, I would have the NFL, uh, Players Association be, you know, uh, to, you know, look into this, right? Because you clearly have a high volume, uh, of individuals who are susceptible to concussions, and it would be easy to test that. We've talked a little bit about the role of lactate in cancer, although we'll, we'll save that for maybe the next time I have Inigo back on and let him, uh, be the one to talk about that. But the big takeaway there is, yes, lactate may be carcinogenic, but the bigger problem is not the accumulation of lactate, it's the accumulation of lactate in the absence of an effective clearance mechanism. And if one thing has become demonstrated over and over in our discussion today, it is that if you want to increase lactate flow and you want to increase la- lactate clearance, you must exercise.

    2. GBGeorge A. Brooks1:43:06

       Yes.

    3. PAPeter Attia1:43:07

       Are there other disease states besides these conditions we've discussed where lactate plays an important role in the pathophysiology?

    4. GBGeorge A. Brooks1:43:17

       Well, you, you suggested earlier on brain health-

    5. PAPeter Attia1:43:21

       Mm-hmm

    6. GBGeorge A. Brooks1:43:21

       ... dementia, Alzheimer's, so it, it's really looking at ex- exercise as protect- protective, not just card game kind of mental exercises, but physical exercise, and people talking about, uh, brain blood flow and the delivery of substrates. And in fact, uh, some people are talking about the role of lactate in stimulating neurogenes- neurogenesis in the dentate gyrus, uh, looking at, uh, development of new brain cells. Um, which is, uh, [clears throat] which used to be a, a really heretical idea. The, uh, the original idea was that when we're born, we have a certain number of brain cells. Now we know that there's a turnover of brain cells, and they're renewed, and we know that the pro- uh, problems can c- occur when the progenitor cells are damaged or injured or not stimulated in some way. So I think there's a big future for investigators to be working in the field of, uh, physical activity and aging, um, and the, the healthspan.

    7. PAPeter Attia1:44:31

       We talked very briefly about the role of lactic, uh, well, we-- of lactate specifically in, as a precursor-

    8. GBGeorge A. Brooks1:44:38

       Right

    9. PAPeter Attia1:44:38

       ... um, or a canary in the coal mine around sepsis.

    10. GBGeorge A. Brooks1:44:42

        Yeah.

    11. PAPeter Attia1:44:42

        Do you believe that that is still a valuable tool?

    12. GBGeorge A. Brooks1:44:45

        Oh, yes, definitely. But so the, uh, so to follow Bellomo's argument, okay, show me where there's an anoxic area in your patient. He challenges his colleagues, "Show me where there's hypoxia." And so then the attitude becomes, well, it's not the cause, it's a response, and it's a, it's a strain and understanding stress and strain.

    13. PAPeter Attia1:45:15

        Sorry, just, just to back up for a second. He's saying this to ask the question, if you're telling me that lactate is the response to anoxia or hypoxia, why when we see lactate going up in a septic patient, can you not point to the area of anoxia? Is that, is that the question he's posing?

    14. GBGeorge A. Brooks1:45:36

        That's what I'm saying. Yeah.

    15. PAPeter Attia1:45:37

        Okay. And then tell me what the response is to that res- uh, question.

    16. GBGeorge A. Brooks1:45:40

        [laughs] I don't know what the response is to that. Nobody can identify it. But my own, and I've written about this, uh, anticipating this kind of general question, where is this lactate coming from? I think it might be coming from the gut, um, personally.

    17. PAPeter Attia1:45:58

        That's, that's what we were taught, George. When I was in the ICU, we were taught when you see these rising lactate levels in patients, it is hypoperfusion of the gut. Um, now, okay, so I measured a lactate level in a patient, and it's up to 10 millimole. That's bad news, but am I supposed to take that patient to the operating room and look for ischemic bowel? Like it, there's still a bit of a... That tells you that that's a lot of smoke, but it doesn't tell you where the fire is-

    18. GBGeorge A. Brooks1:46:30

        Yeah

    19. PAPeter Attia1:46:30

        ... even if you believe it's a gut perfusion issue.

    20. GBGeorge A. Brooks1:46:33

        Well, I think the, part of it is because the microbes w- uh, are producing racemic lactate. They're producing L lactate and D lactate. And most of our body runs on the, the form of lactate that's i- identified as L lactate. But I think i- in sepsis, there's a lot of D lactate going on that is formed in the lower bowel, uh, as opposed to the upper bowel.

    21. PAPeter Attia1:47:01

        Is that-- How, how, uh, how easy is it to distinguish between those two? What, uh... I-- It's been so long since I've done organic chemistry. I don't remember how we distinguish. I, I, I understand the difference between a D and an L-

    22. GBGeorge A. Brooks1:47:11

        Mm-hmm

    23. PAPeter Attia1:47:11

        ... but I don't remember how one measures it.

    24. GBGeorge A. Brooks1:47:14

        Oh, so m- most of, most of all the analyzers we have hospital elsewhere measure the L form, and these are like f- I'm holding up my hands here, uh, on purpose. Say one is the mirror image of the other.

    25. PAPeter Attia1:47:27

        Mm-hmm.

    26. GBGeorge A. Brooks1:47:27

        And, uh, the L is the form we usually, um, make and utilize. But if we make this other form, now we have this stuff which is neurotoxic and, and pro-inflammatory. And I think that in, in large part, people can't really see the extent of, um, lactatemia that occurs in sepsis.

    27. PAPeter Attia1:47:53

        Wait a minute. You're saying that when we measure the 10 millimole in the septic patient, the 10 millimole is only the L lactate concentration 'cause that's all the assay measures, but there could be 20 millimole of D lactate there-

    28. GBGeorge A. Brooks1:48:07

        Mm-hmm

    29. PAPeter Attia1:48:07

        ... that is actually causing a problem.

    30. GBGeorge A. Brooks1:48:10

        Yeah.
14. 1:50:15 – 2:06:41

    George’s current research interests involving lactate

    1. GBGeorge A. Brooks1:50:15

       generation.

    2. PAPeter Attia1:50:17

       So what is the most interesting question that you are asking today that you still don't have an answer to in your mind with respect to lactate metabolism?

    3. GBGeorge A. Brooks1:50:27

       Yeah. Thank you for that. Our most recent paper touches on this. So for 100 years, everybody, including us, have been thinking about muscle and related tissues, tissues that can use lactate, but it's, it's all been a muscle thing. So we did a very simple test. We used our isotopes as we, uh, usually do. We had aboard a carbon-13 labeled lactate, and then a deutero glucose and a D5 glycerol, so we could measure lactate, glycerol, and glucose all at the same time. And then we gave, uh, people an oral glucose tolerance test. And the first thing that came out in the arterial blood, and this is arterial blood, not venous blood, the first thing that came out after taking glucose is lactate. So there's an int- enteric glycolysis that takes place. And this is the way the body participates in distributing carbohydrate energy to make lactate. So that's-- So this just changes our mind completely.

    4. PAPeter Attia1:51:48

       But sorry, George, did we not know before this that when you consume glucose, lactate goes up?

    5. GBGeorge A. Brooks1:51:54

       We know that, and nobody would understand why. It's part of the lactate shuttle. I presented this, uh, inf- our most recent studies at, last year at the American Diabetes Association. There was a doc there from NIH, and he said, "Well, we feed carbohydrate, we get two millimolar lactate." So what's the deal? [chuckles] That's, that's the way the body's working. In sports, we would say it's hiding the ball. In baseball, we hide the ball. In football, we try to hide the ball. Here the body's trying to minimize the glucose load, but still deliver carbohydrate energy, and it starts with the enterocytes in the gut. So there, there are plenty of studies where people would incubate enterocytes under air, give glucose immediately. You have lactate.

    6. PAPeter Attia1:52:49

       And, and just give me a sense of scale, right? So when you give, uh, somebody an oral glucose tolerance test, this is 75 grams of glucose. You gave a standard dose, I'm assuming?

    7. GBGeorge A. Brooks1:52:59

       Yeah.

    8. PAPeter Attia1:53:00

       Okay. So plasma glucose in these subjects will easily double, right? It'll easily go from 75, uh, gr- milligrams per deciliter to 150 milligrams per deciliter, correct?

    9. GBGeorge A. Brooks1:53:14

       Yeah.

    10. PAPeter Attia1:53:15

        And lactate might double, maybe go from 0.6 to 1.2 millimole, correct?

    11. GBGeorge A. Brooks1:53:24

        Correct.

    12. PAPeter Attia1:53:25

        From a mass balance perspective, I, I'm not smart enough to remember how to do this. [chuckles] Can you remind me how much carbon went in each of those two paths?

    13. GBGeorge A. Brooks1:53:36

        Yeah, so, uh, good point. We're just talking about the concentration, but earlier we talked about the flux.

    14. PAPeter Attia1:53:43

        Yeah.

    15. GBGeorge A. Brooks1:53:44

        Okay? So, [clears throat] so it looks like the liver is really, really important in this whole thing, and we did touch on the liver and its importance. It's really underestimated, and you're asking about what I think I wanna do next is to really explore this problem, which you are articulating. How does the body, uh, shuttle carbohy- carbohydrate energy? So you said the blood glucose will rise, and it will go, will double. But it doesn't get, uh, that high until 30 minutes after the test. Whereas if I give the glucose, the lactate is spiking in five minutes, reaching a peak at 15 minutes, then subs- subs- uh, subsiding. And now the glucose is starting to become the carbohydrate energy form.

    16. PAPeter Attia1:54:39

        But, but just so that listeners understand something you and I take for granted, when a person's blood glucose goes from 80 to 150 milligrams per deciliter, that's a s- that's still a trivial amount of absolute glucose difference concentration. It's a difference of five grams of glucose in the entire circulation that would explain that delta. You still gave the person 75 grams. In other words, we have to account for 70 more grams of glucose. And my thinking was that most of that's in the muscle, right? That's... When we, we do oral glucose tolerance tests on everybody, George. I mean, we, we are, you know, uh, we, we just really believe that that is a great functional test of glucose disposal. But truthfully, you know, we're not measuring lactate when we do this. Maybe we should be. But we're basically asking the question, how sensitive are your muscles to insulin, and how much of a reservoir do you have to dispose of glucose? Because we're also measuring insulin every 30 minutes as well as glucose. Um, but now I'm wondering, because we haven't measured lactate, there's another pathway we're not accounting for, which is how much of the glucose are those enterocytes turning into lactate as an alternative fuel source?

    17. GBGeorge A. Brooks1:56:06

        Yeah. So that's, that's the first part of what happens. We s- we saw it and we're s- we were, uh, lucky, uh, to b- have arterialized blood, so we could see the spike in lactate that comes out after taking glucose way before the glucose starts to rise. And then from our, our isotope, uh, t- technology, we could see that when-

    18. PAPeter Attia1:56:29

        Hmm

    19. GBGeorge A. Brooks1:56:29

        ... glucose is rising, it's giving rise to lactate. That's the... That's been seen before. It's called, uh, the indirect pathway. But to go back to an earlier point you raised about the importance of the liver, and this is, uh, in our paper, we reference the work of Stender, who gave 13C, uh, glucose in an OGT. The liver, the liver picks up most of it, and the liver is basically sequesters about 80% of the glucose load, and then doles it out over time, and it starts to release this glucose after about, uh, I'm trying to remember their study, 30 minutes. Meanwhile, lactate has a big role. It plays a role, and meanwhile, the glucose is still in the liver, and now it starts to be doled out. It's being m- released as glucose, and that's getting, uh, converted to lactate in the muscles, and that's what's called the sort of indirect pathway, uh, of glucose metabolism. So the liver is really key. So what I would hope to be able to do in the near future is to really revisit all this, these dietary nutritive aspects of, okay, glucose gets taken up or, and lact- uh, lactate is... Glucose is taken up, made into lactate. Well, what if we have fats there, like a real meal, not, not just an OG-

    20. PAPeter Attia1:57:59

        Yeah

    21. GBGeorge A. Brooks1:57:59

        ... GT.

    22. PAPeter Attia1:58:00

        Yeah.

    23. GBGeorge A. Brooks1:58:00

        Maybe a meal tolerance test that we would, um, we would do this. A version of this was done by somebody named Schlacher in Germany, and they did this really incredible study. They did make a mistake 'cause they forgot about the liver. They grew grain in a high carbon 13C O2 environment, and plants, as I think most people know, take CO2 from the air when they make sugar. So they did an oral glucose tolerance test with 13C, and also they harvested this grain, and they did a, a, a meal test. They made porridge out of this stuff, and they looked at the appearance of, um, lactate and glucose in the blood, and they saw the same thing we did. Right away, there's a spike in lactate, and they said, "Well, lactate's the whole story." But they forgot about the liver.

    24. PAPeter Attia1:58:57

        So you're saying in most... In a standard oral glucose tolerance test, your belief is that most of the glucose that is being disposed of is actually being disposed of initially by the liver, and then the liver starts doling that back out. The muscle picks it up, and then the muscle is the... Your s- your secondary production of lactate is by the muscle. Your primary production is by the enterocyte on immediate... And then that's why you get two peaks of lactate, right? You get the first fast peak in response to the enterocyte making lactate, and then you get a second delayed slower peak when the muscles get it from... get the glucose from the liver and start making lactate.

    25. GBGeorge A. Brooks1:59:36

        Yeah. And one of our core investigators is Umesh Mashirani. He's a diabetologist at UCSF.

    26. PAPeter Attia1:59:43

        Mm-hmm.

    27. GBGeorge A. Brooks1:59:43

        And he said, "Well, maybe that's how metformin works." So, um, for our, uh, our listeners, your listeners, uh, metformin is p- the most popularly prescribed drug for high blood sugar, and one of the concerns is that when you give that drug, lactate rises. And Umesh is very comfortable saying, "Well, the body's making lactate." So metformin is encouraging enterocytes to make lactate. That's why the lactate's high, and that's a good thing.

    28. PAPeter Attia2:00:18

        Very interesting. Um, as you know, there's a, a body of literature suggesting that metformin may enhance exercise performa- uh, pardon me, may impede exercise performance. Um, and again, the problem with metformin is for the f- you know, despite the fact that this drug's been around, it's almost as old as God, um, it seems to have so many points of action that it's very difficult to know what it's doing or how much of its net outcome, which is, you know, reducing hepatic glucose output, can be attributed to what, right? So the... I guess the conventional thinking on metformin is it's inhibiting complex one of the mitochondria, correct?

    29. GBGeorge A. Brooks2:01:00

        Mm-hmm. Yeah.

    30. PAPeter Attia2:01:02

        And if you inhibit complex one, you're... God, you're activating AMP kinase. That should reduce hepatic glucose output, correct?
15. 2:06:41 – 2:20:55

    Questions that remain about lactate: role in gene expression, therapeutic potential, difference between endogenous and exogenous lactate, and more

    1. PAPeter Attia2:06:41

       get to. But again, it seems to me that if what you're saying is correct, George, there's a lot we're, we're misinterpreting from, for example, sepsis literature, right? Where you get that patient in the ICU who's got high lactate, well, they also have a low pH. But those two things could be dif- d- driven by, given by-- driven by different processes.

    2. GBGeorge A. Brooks2:07:05

       Yeah. Exactly. So when you s- when you s-- uh, uh, it's-- we addressed this earlier. I, I, I think if you see a low pH, yeah, you need to do something. If you see a higher lactate in the absence of a change in pH, I would be very, uh, inclined not to do much.

    3. PAPeter Attia2:07:25

       Very interesting. You, you've, you've, you've given me and, and everybody listening a, a lot to think about here, George. Um, so it seems to me that, that understanding the, the, the full flux, the full mass balance of lactate, both exogenous and endogenous, is a necessary step to, to, to, to ful- fulfill our understanding of metabolism, uh, in a more complete manner, correct?

    4. GBGeorge A. Brooks2:07:54

       Yeah. Thank you. I think so.

    5. PAPeter Attia2:07:57

       All right.

    6. GBGeorge A. Brooks2:07:58

       Oh, and you mentioned endogenous versus exogenous. So when we inf-- Exogenous means we're gonna infuse lactate or-

    7. PAPeter Attia2:08:07

       Yeah

    8. GBGeorge A. Brooks2:08:07

       ... put it in the body s- some way. Um- Well, I learned in organic chemistry the salt of an acid is a base, so it's not unexpected that, uh, when you give it, pH will rise slightly, and maybe part of that also is sodium. Uh, so, uh, yeah, what, what does it m- mean to, to use this exogenous stuff? So lactate, uh, is distinguished from pyruvate, and lactate is, um, reduced. It has more hydrogen on it. It has one more hydrogen than pyruvate.

    9. PAPeter Attia2:08:47

       Mm-hmm.

    10. GBGeorge A. Brooks2:08:48

        So that double-- that keto bond on pyruvate, the double bond to oxygen, uh, becomes, uh, hydrogen.

    11. PAPeter Attia2:08:56

        Yep.

    12. GBGeorge A. Brooks2:08:56

        So it's more reduced. Now, when you start putting in this reduced equivalent into the blood, it's gonna go around the whole body and change redox in a number of tissues, all the tissues, basically, to which it's gonna-- where the lactate's gonna go. So lactate is, is a powerful signal, and it works in diverse ways to activate various pathways, including by changing cell redox.

    13. PAPeter Attia2:09:24

        What does lactate do in terms of gene expression? We haven't talked about that, but given how potent a signaling molecule it is in both metabolism, uh, directly and vis-a-vis redox, what do we know about, uh, other forms of, of signaling and expression of genes?

    14. GBGeorge A. Brooks2:09:43

        So there's a new field now. So we used to think genes are re- regulated in part epigenetically by acetylation or methylation. Now we realize they're also lactylated. So, uh, we've done some of those experiments here in our lab. We haven't pub- published it, but the, the lactate is a predominant, uh, um, metabolite, and it can bind to, uh, genes, and it, it can affect gene expression.

    15. PAPeter Attia2:10:11

        Mean- meaning it, it can covalently bind?

    16. GBGeorge A. Brooks2:10:14

        Mm-hmm. Acetylation, methylation-

    17. PAPeter Attia2:10:17

        Yeah

    18. GBGeorge A. Brooks2:10:17

        ... lactylation. That's actually a term, and I was gonna compliment you on your reading of the literature because you can w- look that up in PubMed, and you can see that people are starting to look at lactylation of histones by, uh, raising lactate.

    19. PAPeter Attia2:10:34

        Hmm. So it's not through histone acetylation. It's direct lactate binding.

    20. GBGeorge A. Brooks2:10:41

        Lac-- Yeah, and it's called lactylation.

    21. PAPeter Attia2:10:44

        Yeah.

    22. GBGeorge A. Brooks2:10:45

        Dr. Attia, you've got us off into the, into the stratosphere here of where science needs to go, starting with the premise exercise is healthful. Uh, how can it affect the body corpus, promote healthful living? Well, probab- uh, possibly in part by, uh, lactylation of histones promoting mitochondrial biogenesis.

    23. PAPeter Attia2:11:13

        It's very interesting because we, we, we, we've talked about all of these benefits of exercise, right? We talk about how, you know, my friend clearly has more mitochondria than I do, and he's-- he has more MCTs, and he's so much better at clearing lactate and all of these things. But of course, what we're missing in that is the how and the why. Why is he doing that? What is it about his training stimulus that does that? And what you're suggesting, at least as a hypothesis, is what if the lactate itself is signaling the gene expression that leads to the more favorable phenotype seen in the athlete?

    24. GBGeorge A. Brooks2:11:50

        Yeah, well, with Takeshi Hashimoto, we published a paper. Um, if you just take muscles, put them in a, a, a muscle cells in a dish, you add lactate, you activate 500 genes.

    25. PAPeter Attia2:12:02

        But here's the thing. There has to be something... If I'm just thinking about this perhaps a bit too quickly, I would, I would have to believe it, it also must involve something favorable with consumption. It can't just be infu-- like, in other words, I have a hard time believing. If you took my friend and you took me, right?

    26. GBGeorge A. Brooks2:12:24

        Mm-hmm.

    27. PAPeter Attia2:12:24

        And you would argue based on his training and based on my training, you know, I'm on a bike three or four hours a week. He's on a bike 15 to 20 hours a week. Um, he's clearly making more lactate in any given week than I am, and he's clearly using more lactate in any given week than I am. But if you, if you came up with an experiment that you-- imagine you could do this, where you could give-- you could pair feed us lactate, okay? So in other words, for every millimole of lactate he produces endogenously, you exogenously deliver the same lactate to me. I still don't think we'd end up the same, even though we have the same input of lactate because he's using it during exercise, whereas I'm sitting around on my butt while you're giving me all of that lactate.

    28. GBGeorge A. Brooks2:13:18

        Mm-hmm.

    29. PAPeter Attia2:13:18

        So it's hard for me to imagine that lactate by itself would be the signal. I, I have to think there's something associated with the benefits of how lactate is consumed during exercise.

    30. GBGeorge A. Brooks2:13:31

        So yeah, this is a, this is of interest in the literature now. People are doing lactate clamps, uh, on people and, uh, looking for increases in mitochondrial protein expression. And-

Episode duration: 2:20:55