How Mitochondria Control Your Metabolism | Dr. Jared Rutter

1. 0:00 – 2:29

   Jared Rutter

   1. JRDr. Jared Rutter0:00

      There's a widely accepted hypothesis that mitochondria with excess energy leads to problems. Many people that li- that are listening have probably heard of reactive oxygen species. This is forms of oxygen that become reactive and end up spinning out and damaging proteins and nucleic acids. And I think it is widely accepted that one of the contributors to that is mitochondria that have too much energy. Basically, the form that energy takes when it's extracted from the food we eat and before it's converted to ATP is powering the mitochondria. And when that mitochondria is overpowered, that leads to a state that is very susceptible to generation of these reactive species that end up damaging our genome, creating mutations, and damaging proteins, and creating many of the problems that we see.

   2. AHAndrew Huberman0:51

      Welcome to the Huberman Lab Podcast, where we discuss science and science-based tools for everyday life. I'm Andrew Huberman, and I'm a professor of neurobiology and ophthalmology at Stanford School of Medicine. My guest today is Dr. Jared Rutter. Dr. Jared Rutter is a professor of biochemistry at University of Utah and an investigator with the Howard Hughes Medical Institute. He is one of the world's top experts in the biology of mitochondria and metabolism. Mitochondria are known as the powerhouse of the cell, but as you'll learn today, they do far more than just power our cells. They also determine how much energy goes into making new cells, to making sure that cells stay healthy, and to fighting off disease. Today's conversation explains how mitochondria do that and clarifies what your metabolism really is. And in doing so, you will learn that you don't have one metabolism. Your metabolism, as it's called, is actually a reflection of the constellation of all the metabolisms of all the cells in your body. So today's conversation will teach you the real biology of mitochondria, and it will provide a framework for you to make better decisions on the behalf of your health. So what follows is a conversation about mitochondria and metabolism unlike any that you've heard from one of the world's premier experts in this topic. Before we begin, I'd like to emphasize that this podcast is separate from my teaching and research roles at Stanford. It is, however, part of my desire and effort to bring zero cost to consumer information about science and science-related tools to the general public. In keeping with that theme, today's episode does include sponsors. And now for my discussion with Dr. Jared Rutter.

2. 2:29 – 8:36

   Metabolism, Cells; Aging

   1. AHAndrew Huberman2:29

      Dr. Jared Rutter, welcome.

   2. JRDr. Jared Rutter2:31

      Thank you. Thanks for having me on.

   3. AHAndrew Huberman2:32

      I have many questions about metabolism, mitochondria, and I know many people do as well. Most people hear the word metabolism and they think calories in, calories out. They hear the word mitochondria and they probably think the powerhouse of the cell, and that's all great. People are becoming more educated about cells and their bits and pieces and what they do. You have a very different perspective that is very important, I believe, for people to understand. Maybe we could start off by talking about how the metabolism of any one cell in our body relates to what we call our metabolism-

   4. JRDr. Jared Rutter3:09

      Right

   5. AHAndrew Huberman3:09

      ... the collective metabolism of all those cells. And as you go, if you could take any liberties you want to tell us what we probably don't know about the, quote-unquote, "powerhouses of the cell."

   6. JRDr. Jared Rutter3:19

      Yeah, yeah. You know, when we think about metabolism, as you say, I think all of us think about metabolism in terms of our body's metabolism, our metabolic rate. As you say, calories in, calories out. What that is really, our body's metabolism is basically the, the sum total of what we ingest. You know, what we eat, what we drink, what we breathe. That enters our body and gets processed, and the results of that processing are individual molecules, amino acids, and sugars and so forth, that then distribute throughout the body, go into id- individual cells, and enter this process that we call metabolism and we call cellular metabolism. And I think it's reasonable to think of cellular metabolism as almost like a map. There's an entry point, a molecule of glucose or sugar comes into a cell, and that sugar can be chemically modified in a variety of ways to fulfill the needs of that cell. And then that cell does whatever it needs to do with the molecules it takes in to fulfill its particular functions. And then that leads to the, um, release of waste products that we eliminate from our body, and that is sort of the organismal metabolism, the metabolism of our body. And as you allude to, I think something that maybe many people don't understand is that cellular piece of it. The metabolism of our body is really the sum total of the metabolism of each one of our 30 trillion cells or so. That's really where my passions lie, are those individual cells and how they choose to take up certain nutrients, how they choose how to process them, turn them into other things, how they use them to fulfill their particular functions, and how that's regulated. The masterful coordination of each of those cells working together to allow us to be sitting here talking to one another and go out and run or whatever we do, it's a beautiful orchestration. But that happens at the level of, of individual cells, and I think that's one of the fascinating things that is maybe a little bit less understood.

   7. AHAndrew Huberman5:36

      If we were to, uh, just take the single cell view for a moment, and I know that aging isn't a pr- like, your specific area of interest. But one thing that's always intrigued me, because my postdoc advisor once came down the hall and said, "Why do I have so much less energy than I used to?" And he had a ton of energy, so that-

   8. JRDr. Jared Rutter5:53

      [laughs]

   9. AHAndrew Huberman5:53

      ... was like, "I wonder what he used to be like." But it's a great question. He used to do this every once in a while, like just ask these very basic questions that No one else on our halls at Stanford could really answer. Why does a kid have so much energy, and when we're older, we don't? W- people say, "Well, people are moving less. The tissues are wearing out." But at the level of energy production, are we aware, as biologists at this point in history, as to why a young cell, could be muscle cell, could be neuron, whatever, versus an older version of that cell, why it, it either produces less energy, I don't know if it does, I'm guessing it might, but why the whole body just seems to have less get up and go? Do we have an answer for that?

   10. JRDr. Jared Rutter6:36

       I think we have a partial answer for that. I think that's a, that's definitely a frontier of science, is trying to understand exactly what goes wrong during aging. There's many aspects to it. As you alluded to, one of my passions also is the mitochondria, and I think it's almost universally the case that mitochondria become less energized, less effective, let's say, as we age. And the reasons for, for that are, to some extent, clear, but I think largely unclear, but that is definitely a feature of the aging process. You know, there, there is this sort of aspect of accumulation of damage. You know, living in the world we live in, as I alluded to before, this orchestration of metabolism that happens throughout the body, that's hard. It's expensive, and it's expensive not only in terms of what we need to eat to fuel it, but it's e- expensive in terms of the damage that can come as a side effect of that. And the accumulation of that damage over time is certainly correlated strongly with aging, and I think there's some really nice evidence in models where we can do genetics, you know, in, in animal models, that suggest that that accumulation of damage is a big part of the aging process, and it's a huge area of interest in the field is trying to understand how you can decrease the onset of damage, how you can reverse damage that comes. One thing that I like about how you ask that question is thinking about that in the context of the cell. Which again, I don't think we t- tend to think of aging as a cellular phenomenon, but I think fundamentally it almost has to be. We are made up of cells.

   11. AHAndrew Huberman8:15

       Mm-hmm.

   12. JRDr. Jared Rutter8:15

       And the processes that lead to aging are the accumulation of processes that happen at the level of individual cells. And I think in a way we're at the precipice of understanding a lot of this because of the tools that we are, um, starting to have access to that will help us better understand cause and effect and the specific molecular features of, of the aging process.

3. 8:36 – 13:07

   Mitochondria, Origin & Cell Complexity

   1. AHAndrew Huberman8:36

      Let's talk about mitochondria. Perhaps surprisingly, I'm gonna ask you why you study them, with the caveat that they are incredibly interesting. They are involved in energy production and metabolism. But what, what specifically drew you to mitochondria versus all the other pieces of cells or parts of the body or organs that you could have worked on? Why the mitochondria? What, what's so sticky about those-

   2. JRDr. Jared Rutter9:00

      Yeah

   3. AHAndrew Huberman9:00

      ... as a place to... I mean, you devote a significant a-

   4. JRDr. Jared Rutter9:02

      Yeah

   5. AHAndrew Huberman9:02

      ... a fraction of your life to them.

   6. JRDr. Jared Rutter9:04

      Yeah. It's an area of cell biology, an area of sort of the details of how life works. One of these things that is, in my view, just a brilliant example of taking in chemistry of incredible complexity and making it work effectively inside of a, a living cell. Mitochondria are believed to have been the result of an endosymbiotic event where a bacterium, a free-living bacterium, was engulfed by another cell, and in a way kind of domesticated-

   7. AHAndrew Huberman9:42

      So wild to think about

   8. JRDr. Jared Rutter9:43

      ... by that cell. Totally wild.

   9. AHAndrew Huberman9:44

      I'm sure people are following, but in case there's somebody who's not, what Jared is saying is that our cells basically were invaded by a bacterium, and then that bacterium became part of our stable genome going forward. It went into the w- what we call the germline, and therefore was propagated from parents to kids. And so now mitochondria live in us, but they didn't start off living in us.

   10. JRDr. Jared Rutter10:09

       That's right.

   11. AHAndrew Huberman10:10

       And I, and we hear that about the gut microbiome. Like we have these trillions of bacteria that live in us and we colonize and we can recolonize, take antibiotics, and then you need to replenish, eat your yogurt and so on. But, but the fact that the mitochondria made it stably into our genome and are transmitted from one generation to the next, we think of them as us. But you're saying there is solid evidence that they came from outside of humans.

   12. JRDr. Jared Rutter10:32

       I think that's the only model that I think any of us as scientists have any good reason to believe. And, you know, that's fascinating history, right? That there was a bacteria in another cell that got together and, and together that combination could do things that, that any one of either of them on their own could not do, and that they worked together in, in some way to enable the evolution of complex life. You know, eukaryotes, which are the, the type of cell that resulted from that combined situation that we were just talking about, these are all the organisms that we see around us. Plants, animals, fungi even, are all the result of these two cells getting together and making peace, so to speak, and, uh, teaming up to make this synergistic cell.

   13. AHAndrew Huberman11:24

       Is it synergistic? Forg- forgive me for interrupting, but-

   14. JRDr. Jared Rutter11:27

       Yeah

   15. AHAndrew Huberman11:27

       ... when I think about viruses, I think viruses have their own sort of intelligence. They kind of h- they hijack the genomes of cells, and they either kill those cells or if they're really smart, they keep them, those cells alive and use those cells to continue to live, and then propagate through like the behavior of an animal-

   16. JRDr. Jared Rutter11:42

       Mm-hmm

   17. AHAndrew Huberman11:42

       ... like a rabies virus.

   18. JRDr. Jared Rutter11:43

       Yeah.

   19. AHAndrew Huberman11:43

       Like, "Oh, let's get this animal aggressive-

   20. JRDr. Jared Rutter11:44

       Yeah

   21. AHAndrew Huberman11:44

       ... so that it bites," and then... I mean, viruses don't think, but they have an intelligence.

   22. JRDr. Jared Rutter11:49

       Yeah, yeah, yeah.

   23. AHAndrew Huberman11:49

       Do we know that the mitochondria were benefiting the cells and the cells were benefiting the mitochondria, or could have this been a takeover by the-

   24. JRDr. Jared Rutter11:56

       Yeah

   25. AHAndrew Huberman11:57

       ... by the mitochondria?

   26. JRDr. Jared Rutter11:58

       I mean, this is a, a bit of a philosophical question. Of course, we don't have a record of, of what exactly happened when and who benefited in real time. But one thing we do know is all of complex life resulted From cells that underwent that event, one time or multiple times, but all of complex life evolved from that. And I think that tells us that more than likely, complex life could not result from a bacterium on its own or the archaea, the, the s- the, the cell that became the host for that bacteria. So I think you can make a compelling argument that this was beneficial, and one reason it was beneficial because it enabled a form of metabolism that wasn't possible before, and enabled now a more complex cell to be able to do things metabolically, to be more metabolically efficient and, and, and diversified, that it could enable, you know, again, complex life to evolve. And totally fascinating history, but I think, as you alluded to, also has very interesting implications for life today.

4. 13:07 – 15:16

   Sponsors: Joovv & BetterHelp

   1. AHAndrew Huberman13:07

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5. 15:16 – 18:18

   Mitochondria Genome, Inheritance

   1. AHAndrew Huberman15:16

      Could we explore a little bit of how mitochondria getting into these cells were able to make it stably into their genome and propagate? This isn't gonna be a conversation about genetics per se, but, uh, may- maybe as a just two points of background for people, like if any of our cells have something put into them, let's say a physical object like a splinter, little tiny piece of splinter stays in the cell, and then you procreate with somebody. You don't expect-

   2. JRDr. Jared Rutter15:40

      Yeah

   3. AHAndrew Huberman15:40

      ... that child will have that-

   4. JRDr. Jared Rutter15:41

      Yeah

   5. AHAndrew Huberman15:41

      ... those little bits of splinter-

   6. JRDr. Jared Rutter15:42

      Yeah

   7. AHAndrew Huberman15:42

      ... in their cells. But if the germline, right? So the, the eggs or the sperm have something incorporated into them, then potentially it could propagate. That's why they call germline-

   8. JRDr. Jared Rutter15:52

      Yeah

   9. AHAndrew Huberman15:52

      ... as opposed to somatic cells. I, I think most people aren't aware of that.

   10. JRDr. Jared Rutter15:55

       Yeah.

   11. AHAndrew Huberman15:55

       It makes perfect sense once you hear it.

   12. JRDr. Jared Rutter15:56

       Yeah.

   13. AHAndrew Huberman15:57

       But you're talking about many, many, many years ago, a cell having this bacterium go into it, and then it was somehow able to stably represent itself in the genome so that that propagated forward. And eventually, it has to be in the germline of whatever, you know, primordial Homo sapiens-

   14. JRDr. Jared Rutter16:15

       Yeah

   15. AHAndrew Huberman16:15

       ... were there. Otherwise, your kids-

   16. JRDr. Jared Rutter16:18

       Yeah

   17. AHAndrew Huberman16:19

       ... I, you, wouldn't have mitochondria in us. How do we think that might have happened?

   18. JRDr. Jared Rutter16:23

       The main genome of the cell, the cellular genome, it's DNA contained typically in the nucleus of the cell. Mitochondria exist in the cytosol outside the nucleus. One of the interesting things about mitochondria, which I think is totally fascinating and has really interesting disease implications and worthy of talking about, we may or may not come back to it, is that mitochondria have their own separate genome that is sort of a relic of the bacterium that they are the descendants of. It's in a circle like the bacterial genomes, whereas the nuclear genome of a eukaryotic cell is linear chromosomes. And that genome performs very essential functions and codes very important proteins that enable our mitochondria to function as the powerhouse of the cell, which we, uh, know them to be, to enable the extraction of usable energy from the food that we eat. So as you alluded to, those cytoplasmic mitochondria somehow make it from generation to generation and one of the interesting features of them being cytoplasmic is they're completely inherited from the mom, from the egg. 'Cause as you know, when the sperm invades the egg, the, the genome from the sperm gets into the, the egg, fertilizes it. The cytoplasm of the sperm does not. So the mitochondrial genome of you came completely from your mother. Mine came completely from my mother. And again, that has interesting implications for the inheritance of, uh, diseases that are mitochondrial on origin. But that's sort of how we think it works. It basically propagates from the egg upon fertilization, then it gets distributed to all the cells, including the, the germline that, that- fertilized embryo will have and then gets passed on to the next generation in the

6. 18:18 – 25:59

   Mitochondria & Spatial Distribution; Cell-Specific Metabolism

   1. JRDr. Jared Rutter18:18

      same way

   2. AHAndrew Huberman18:18

      Ratcheting toward, uh, the actual functioning of mitochondria, maybe, um, you gave a beautiful picture of the mitochondria not, uh, in the nucleus of the cell but in the cytoplasm, so still inside the cell. And most people probably remember from their high school biology, a picture of a cell always looks round.

   3. JRDr. Jared Rutter18:35

      Mm-hmm.

   4. AHAndrew Huberman18:36

      I'm guessing you're gonna tell us that the mitochondria can be distributed lots of places in the cell 'cause a lot of cells aren't round. A lot of them look hairy or they have long extensions like neurons. Is it fair to say that you can find mitochondria everywhere in a cell? So no matter what shape it is, it's got mitochondria everywhere, and if so, what is the importance of having mitochondria distributed spatially through the cell?

   5. JRDr. Jared Rutter18:58

      Yeah.

   6. AHAndrew Huberman18:58

      So maybe we go ... So that people know where we're going, we'll, we'll talk about the spatial distribution 'cause it turns out that's very important, we'll talk about the functioning, and then I wanna talk about time as a factor, and that can be a little bit abstract for people so we'll come to that.

   7. JRDr. Jared Rutter19:10

      Yeah. Yeah, spatially, uh, you know, I, I ... one of my scientist colleagues might call me on this, but to mine all, I can't think of a place that exists in cells where there aren't mitochondria. And I think as you alluded to, I ... it's a little bit dangerous for me to talk about neurons with a neuroscientist. I am not a neuroscientist but one of the brilliant bodies of work that's been done on mitochondria has been done in neurons. It's fascinating these, these neurons that have one meter long projections and mitochondria transit from the cell body down those projections. And as best we can tell, those mitochondria play essential roles at the ends of those rejections, typically being able to generate, again, usable energy. They're extracting the energy from the food that we eat and powering the neurotransmission, the, the functions of those nerve, nerve terminals and I think that's true of virtually every cell in our body. The extraction of energy and turning it into u- a usable form, typically in the form of ATP, adenosine triphosphate, obviously that is the energy currency that's used by almost every cell in our body and that is a key function of mitochondria. We'll probably come to functions of mitochondria that are outside of just extracting energy, but that is a critical function of mitochondria and that ATP is needed in virtually every place of every cell, and by having local production that makes it more efficient. So I think spatial distribution is a key part of that. It's fascinating. There's been beautiful work that's shown that when a cell is crawling, as cells sometimes do, you know, like an immune cell that sees something it's chasing. There will be a distribution of mitochondria towards that leading edge of the cell-

   8. AHAndrew Huberman21:00

      Mm

   9. JRDr. Jared Rutter21:00

      ... which is very energetically expensive to crawl for a cell. It use ... it requires a lot of ATP. And mitochondria will congregate at that leading edge where that ATP is being consumed to make ATP right there so it can be used. I think it's a fascinating example of that local, uh, demand for energy.

   10. AHAndrew Huberman21:19

       I'm asking some high-level questions, I realize, but is there any reason to believe that a m- a given mitochondria knows what cell it belongs to?

   11. JRDr. Jared Rutter21:28

       Mm-hmm.

   12. AHAndrew Huberman21:29

       Like, the ... Like, are they different? Is, is ... Are the mitochondria in one cell type so very different than the mitochondria in another cell type? And are the mitochondria between, like, let's say a neuron of the eye ver- let's get at it r- since you're saying-

   13. JRDr. Jared Rutter21:41

       Yeah

   14. AHAndrew Huberman21:41

       ... you don't wanna talk neurons as a per se. Like is, is-

   15. JRDr. Jared Rutter21:43

       We can do it

   16. AHAndrew Huberman21:44

       ... you know, two adjacent skin cells, they're both skin cells, they have mitochondria in them, but do they know which cell they belong to? And do your mitochondria, I'm guessing 'cause they came from your mom's genome, they know that they're different than my mitochondria-

   17. JRDr. Jared Rutter21:57

       Yeah

   18. AHAndrew Huberman21:57

       ... but how much identity do they have?

   19. JRDr. Jared Rutter21:59

       Yeah. I would say this is a topic that is at the frontier of what we know. You're, you're asking some questions that are right at the edge of our current knowledge. Yeah, mitochondria are different. To a first approximation you could say that virtually every cell in our body has slightly different mitochondria that are particularly suited to the demands of that cell. A heart muscle cell, a cardiomyocyte, that cell kinda has one job and that's to contract every second of every minute of every hour of every day for our entire life, and when it coordinates that contraction with the other cells in the heart, that enables our heart to beat. That's what its job is.

   20. AHAndrew Huberman22:43

       Is there any turnover of those cells? We know neurons don't tend to turn over.

   21. JRDr. Jared Rutter22:46

       Very little. Very little.

   22. AHAndrew Huberman22:47

       Well, that's reassuring.

   23. JRDr. Jared Rutter22:48

       Very, very little.

   24. AHAndrew Huberman22:50

       I'm glad to hear that actually.

   25. JRDr. Jared Rutter22:51

       You, you can imagine that it-

   26. AHAndrew Huberman22:52

       Yeah

   27. JRDr. Jared Rutter22:52

       ... it would be hard to replace that-

   28. AHAndrew Huberman22:54

       Yeah, yeah, yeah

   29. JRDr. Jared Rutter22:54

       ... in real time, right? That's a-

   30. AHAndrew Huberman22:55

       Yeah
7. 25:59 – 31:13

   Nutrient Energy, Hormones, Fat Cells

   1. JRDr. Jared Rutter25:59

      cell.

   2. AHAndrew Huberman25:59

      Okay, so I eat some food and, uh, that food's absorbed, and I get glucose circulating in my bloodstream. I've got some stored energy in the form of glycogen, et cetera. And I'm curious, how greedy are the different mitochondria? Is the name of the game that every cell is trying to get as much energy as it can to produce as much ATP as possible? Or are they communicating and is it energy being allocated in some way that's a little bit more, um, democratic?

   3. JRDr. Jared Rutter26:25

      Yeah.

   4. AHAndrew Huberman26:25

      That's one question. Then framed within that, um, I could imagine two scenarios. One, non-mutually exclusive, where like the vasculature just distributes the glucose very well to everything. So everybody, every cell gets, gets access to some of this glucose and, and then is just greedily trying to make as much ATP as possible and the whole system works beautifully. I could also imagine a situation where there's some shuttling to important structures like the brain.

   5. JRDr. Jared Rutter26:51

      Right.

   6. AHAndrew Huberman26:51

      You know what I... Like keeping you alive, like breathing, heart, the, th- there's a prioritization of, of organs. I'm talking about under non-stressful conditions.

   7. JRDr. Jared Rutter26:58

      Yeah.

   8. AHAndrew Huberman26:58

      So yeah, so how is energy allocated to cells and then how are cells divvying up the, the goods?

   9. JRDr. Jared Rutter27:04

      Yeah. It's a brilliant question and a fascinating area of physiology. As you allude to, when we eat, our digestive system starts extracting the constituents of what we eat. Again, sugars, amino acids, fats from that food. That then triggers signals of different kinds. GLP-1 being one, insulin being another. Those signals then are hormones. They get secreted and they go to many cells throughout the body, and that tells each individual cell, "We just ate." And the implications of that are different from each cell. Some cells don't care. Some cells don't pay attention to that and they just keep on doing what they were doing. Some cells care a lot. Adipocytes, for example. These are the fat cells, the cells that make up our fat tissue. They care a great deal about that, and when they see insulin, what they do is they turn on a protein, they start making a protein that will cause glucose to be taken up into that adipocyte, that fat cell. And that glucose will then be converted through a series of chemical reactions into a fat molecule, and then that fat molecule will be stored away in a way that is very safe and enabled to be stored for potentially a very long time. And again, it's a beautiful way for the organism to coordinate, "I just ate. Our energy status as an organism, as a body is great. It's very good. So let's squirrel away some of that energy in the form of fat that can be stored in our adipocytes," again, very safely, "and can be then used when we go through a period of prolonged fasting," which doesn't happen for us all that frequently, but happened for our ancestors probably much more frequently. And those adipocytes full of fat from when we ate probably kept our ancestors alive when they went through the periods of prolonged fasting. Insulin has other effects on muscle and, and other cells throughout the body that, again, this is the brilliance of this coordination. The response of different cells to the fed state is different depending on the, the, the needs and, and functions of that cell. Again, some cells don't care at all. They're gonna just go about and do their business. And some cells completely rewire their function depending on the, the metabolic state, the fed/fasted state of the organism.

   10. AHAndrew Huberman29:38

       So the picture you just described leads me to conclude that basically every cell obviously knows its job and is not greedily but is, um, diligently fulfilling that role.

   11. JRDr. Jared Rutter29:51

       Yeah.

   12. AHAndrew Huberman29:52

       And somehow The whole thing is orchestrated so that like we work

   13. JRDr. Jared Rutter29:57

       Yeah

   14. AHAndrew Huberman29:57

       Which I know, I think for some people it might be like, "Duh," but like just like think about that

   15. JRDr. Jared Rutter30:01

       It's crazy

   16. AHAndrew Huberman30:02

       Like a liver cell isn't really talking to the brain cell in any kind of direct way about how much glucose it has access to. What you describe makes me really understand for the first time the brilliance of having this hormone signal insulin, not just as a shuttle, 'cause I think most people, we think of like insulin sens- most people listening to this podcast-

   17. JRDr. Jared Rutter30:18

       Yeah

   18. AHAndrew Huberman30:19

       ... or just existed in the world today, they're like, "Oh, you want to be insulin sensitive. You want your cells to recognize this signal." But we've never actually talked on this podcast about what exactly that signal is.

   19. JRDr. Jared Rutter30:28

       Yeah.

   20. AHAndrew Huberman30:28

       We think about insulin as a shuttle.

   21. JRDr. Jared Rutter30:29

       Yeah.

   22. AHAndrew Huberman30:30

       But the size of that signal is saying what's likely to be there, and I realize has all sorts of cool implications that can prepare the cell to like, "Oh, I'm gonna go to work hard now-

   23. JRDr. Jared Rutter30:41

       Wow

   24. AHAndrew Huberman30:41

       ... to be the little squirrel that I am-

   25. JRDr. Jared Rutter30:42

       Yeah

   26. AHAndrew Huberman30:42

       ... of a fat cell.

   27. JRDr. Jared Rutter30:43

       Yeah.

   28. AHAndrew Huberman30:43

       I'm gonna squirrel away as much as I can, or be a brain cell that's like, "Let's go. I'm ready to fire action potentials-

   29. JRDr. Jared Rutter30:48

       Right

   30. AHAndrew Huberman30:48

       ... if I need to."
8. 31:13 – 36:41

   Glucose, ATP Conversion, Pyruvate

   1. JRDr. Jared Rutter31:13

      Yeah.

   2. AHAndrew Huberman31:13

      So if you could walk us through what happens as glucose gets into the cell and, and, and really what we've not done ever on this podcast, and I, I don't think I've heard elsewhere on any podcasts, uh, maybe it's out there, but is how you go from ATP to actually the cell being able to perform its roles.

   3. JRDr. Jared Rutter31:31

      Yeah.

   4. AHAndrew Huberman31:31

      And I realize there's a lot of biochemistry there, but you've worked on some really linchpin molecules in that pathway that perform very specific roles. And so, like maybe we could really talk about what basically gets us from ATP to pyruvate, which might scare some people away.

   5. JRDr. Jared Rutter31:46

      Mm-hmm.

   6. AHAndrew Huberman31:46

      But you'll, you'll educate us as to why it's not scary.

   7. JRDr. Jared Rutter31:49

      Yeah.

   8. AHAndrew Huberman31:49

      It's just super cool, and why it's so important to have these signals that, that aren't just like chemicals. They actually mean something-

   9. JRDr. Jared Rutter31:55

      Yeah

   10. AHAndrew Huberman31:55

       ... for the cell. 'Cause for me, forgive me for going a little long here, but then I'll shut up, I think if people can really internalize this idea that, yeah, like hormones go up, hormones go down. Cortisol goes up with stress, it goes down. You wake up, cortisol goes up. Melatonin when you're sleepy. It's not just that it's there, but that the size of the signal says a lot more than just be sleepy. It's saying what once happened is different than what's happening now. It sets a stage for what happens next, and this is really like the verbs of biology-

   11. JRDr. Jared Rutter32:25

       Yeah

   12. AHAndrew Huberman32:25

       ... that are harder to communicate even in video.

   13. JRDr. Jared Rutter32:27

       Yeah.

   14. AHAndrew Huberman32:28

       So take us from glucose to ATP, and ATP to this thing that we call energy.

   15. JRDr. Jared Rutter32:34

       Yeah. There's a l- obviously a lot to unpack there. Glucose is the dominant, let's say, carbohydrate, the dominant sugar that most our cells are consuming. And when glucose is brought into a cell, it goes through, again, a series of chemical reactions that we call glycolysis. And I, I'm going to simplify 'cause there's obviously-

   16. AHAndrew Huberman32:55

       Sure

   17. JRDr. Jared Rutter32:55

       ... this is the subway map of New York. There's a lot of branches going all over the place that we're gonna ignore for right now.

   18. AHAndrew Huberman33:00

       We just need to north, north or south.

   19. JRDr. Jared Rutter33:02

       Yeah. North and south. Yeah.

   20. AHAndrew Huberman33:03

       Which is pretty much the only direction-

   21. JRDr. Jared Rutter33:04

       Yeah

   22. AHAndrew Huberman33:04

       ... you can go on the subway.

   23. JRDr. Jared Rutter33:05

       [laughs] That's right.

   24. AHAndrew Huberman33:05

       I'm just... I'm not a New Yorker. I'm kidding.

   25. JRDr. Jared Rutter33:06

       [laughs]

   26. AHAndrew Huberman33:06

       I realize you can go across the, across the island.

   27. JRDr. Jared Rutter33:08

       Yeah, don't insult the New Yorkers, Andrew.

   28. AHAndrew Huberman33:09

       Well, yeah.

   29. JRDr. Jared Rutter33:10

       So glucose comes into a cell, goes through a series of chemical reactions, and you mentioned it gets to pyruvate. That's the endpoint of glycolysis, this set of chemical reactions. And then pyruvate, there's a decision that has to be made by that cell. It can either take that pyruvate into the mitochondria and burn it, essentially, oxidize it, which is essentially burning it, combining it with oxygen, and that is a very effective way to extract all the energy that can be extracted from that glucose via pyruvate.

   30. AHAndrew Huberman33:46

       Tell us a little bit about pyruvate.
9. 36:41 – 46:02

   Cell Choice: Energy or Growth, Cancer; Virus

   1. AHAndrew Huberman36:41

      So we are probably like seven, I'm insulting the cell biologists, but probably seven steps away from sandwich.

   2. JRDr. Jared Rutter36:47

      [laughs]

   3. AHAndrew Huberman36:47

      So sandwich goes in the mouth, into the gut, gets absorbed, right? Correct, we get glucose, glucose gets into the cell. We got some important biochemistry that, you know, is in this, uh, ATP generation pathway, and we get to this like key node that you're describing as pyruvate. And pyruvate is either gonna say, "Let's make more," you called it biomass, but stuff of cells.

   4. JRDr. Jared Rutter37:08

      Yeah.

   5. AHAndrew Huberman37:09

      Sort of like you have lumber arriving, maybe might be a decent enough analogy.

   6. JRDr. Jared Rutter37:13

      Right, right.

   7. AHAndrew Huberman37:13

      You're either gonna use it to build more house or you're gonna burn it for heat energy.

   8. JRDr. Jared Rutter37:17

      Great analogy, yeah.

   9. AHAndrew Huberman37:19

      Um, and let's look, m- make a, add a condition where you need to burn some of that lumber for heat energy to keep the construction project going. [laughs]

   10. JRDr. Jared Rutter37:26

       Exactly.

   11. AHAndrew Huberman37:27

       Okay, so we're at this key bifurcation, this key split point. Is it just as metabolically demanding for a cell to use pyruvate to keep itself going, like a cardiomyocyte, versus making biomass, or is one more costly? I'm thinking, again, as you beautifully pointed out at the beginning about thinking about that our metabolism as a whole body, as a person is, is the sum total of all these, these things. Is it equivalent in terms of, like, how much sandwich, relatively speaking, is going into maintaining us-

   12. JRDr. Jared Rutter37:59

       Yeah

   13. AHAndrew Huberman37:59

       ... and rebuilding us?

   14. JRDr. Jared Rutter38:00

       Yeah.

   15. AHAndrew Huberman38:01

       What you call biomass.

   16. JRDr. Jared Rutter38:02

       Yeah.

   17. AHAndrew Huberman38:02

       What I'm calling building, you know, allocating lumber for the, for the house itself versus to, uh, fuel the fire so to speak.

   18. JRDr. Jared Rutter38:09

       Yeah. That's hard math to do. There's a lot of nuance in that.

   19. AHAndrew Huberman38:12

       Rough percentages.

   20. JRDr. Jared Rutter38:13

       Yeah, yeah.

   21. AHAndrew Huberman38:13

       I won't hold you to it.

   22. JRDr. Jared Rutter38:14

       Yeah, no. I mean, one way to think about that, many of us are probably unfortunately aware of PET imaging, right? This is, this is something that happens. It's often used to diagnose cancer.

   23. AHAndrew Huberman38:23

       Positron emission tomography.

   24. JRDr. Jared Rutter38:24

       Yeah.

   25. AHAndrew Huberman38:24

       Yeah.

   26. JRDr. Jared Rutter38:24

       Positron emission tomography. And FDG-PET, which is the most common form of PET, is basically you're giving cells a form of glucose that can then be visualized with this PET scan that many people are aware of. And the reason we do that is because tumors take up a lot of glucose. An FDG-PET is fluorodeoxyglucose. This is a, a labeled version of glucose. So the reason we do FDG-PET is to see the cells, where in the body is taking up a lot of glucose, and tumors take up a lot of glucose.

   27. AHAndrew Huberman39:00

       Mm.

   28. JRDr. Jared Rutter39:00

       So FDG-PET is used to diagnose cancer frequently, very effectively. So that is one metric for this. A cancer cell is, again, a cell that is making a resource allocation decision all the time, but in the context of, of that cell when it transforms into a cancer cell, that resource allocation becomes very much about building more cells. That's why a tumor is a tumor is because that one cell that was the first bad actor decided instead of doing the thing it was supposed to be doing, decided to duplicate itself and duplicate itself again and build a cluster of cells that then become a tumor.

   29. AHAndrew Huberman39:41

       Okay, I have a pseudo-philosophical question-

   30. JRDr. Jared Rutter39:45

       Yeah
10. 46:02 – 48:36

    Sponsors: AG1 & Eight Sleep

    1. AHAndrew Huberman46:02

       I'd like to take a quick break and acknowledge our sponsor, AG1. AG1 just launched their newest formulation called AG1 Pro, and right now you can get an extra 20% off your first subscription. AG1 takes the clinically backed AG1 formula, which is a blend of vitamins, minerals, probiotics, and adaptogens, and adds three important new ingredients, creatine monohydrate, calcium HMB, and zinc carnosine. It has five grams of creatine monohydrate to support muscle strength and performance, along with brain health, calcium HMB to support muscle recovery and reduce muscle breakdown, and zinc carnosine to support and improve the lining of your gut. Some of these ingredients I personally was already taking separate from the AG1 formula, so it's great to see all three of them now in the new AG1 Pro. As you may know, I've been taking AG1 every single day for about 14 years now. That means I discovered it and started taking it daily long before I even knew what a podcast was. I continue to take it and back it here on the podcast because it is an excellent formula, and it's now even better with the AG1 Pro formula. For a limited time, you can get an extra 20% off your first subscription to AG1 Pro by going to drinkag1.com/huberman and using the code Back2Routine. So that's with a numeral two, Back, numeral two, Routine. Just go to drinkag1.com/huberman. Today's episode is also brought to us by Eight Sleep. Eight Sleep makes smart mattress covers with cooling, heating, and sleep tracking capacity. One of the best ways to ensure you get a great night's sleep is to make sure that the temperature of your sleeping environment is correct, and that's because in order to fall asleep and stay deeply asleep, your body temperature actually has to drop by about one to three degrees, and in order to wake up feeling refreshed and energized, your body temperature actually has to increase by about one to three degrees. Eight Sleep automatically regulates the temperature of your bed throughout the night according to your unique needs. I've been sleeping on an Eight Sleep mattress cover for nearly five years now, and it has completely transformed and improved the quality of my sleep. The latest Eight Sleep model is the Pod 5. This is what I'm now sleeping on, and I absolutely love it. It has so many incredible features. For instance, the Pod 5 has a feature called Autopilot, which is an AI engine that learns your sleep patterns and then adjusts the temperature of your sleeping environment across different sleep stages. It'll even elevate your head if you're snoring, and it makes other shifts to optimize your sleep. If you'd like to try Eight Sleep, go to eightsleep.com/huberman to get up to $350 off the new Pod 5. Eight Sleep ships to many countries worldwide, including Mexico and the UAE. Again, that's eightsleep.com/huberman to save up to $350.

11. 48:36 – 51:44

    Microbiome, Role of Humans

    1. AHAndrew Huberman48:36

       I'll take us down one more estuary, then we are actually gonna talk about mitochondria and pyruvate again, and your contributions-

    2. JRDr. Jared Rutter48:42

       Yeah

    3. AHAndrew Huberman48:42

       ... to this critical node of where pyruvate puts its efforts, building more stuff of the cell or using energy. Anytime I have, like, a serious cell biologist, which isn't that often on this podcast, or somebody who thinks about the pieces that make up us, I try and ask this. I'm bothered by this one thing I heard once, which is that, like, it's so easy to think about evolution as like, okay, we're all adaptively trying to make more of ourselves, care for our young, and go forward. That's, like, what every spec- most every-

    4. JRDr. Jared Rutter49:12

       Mm-hmm

    5. AHAndrew Huberman49:12

       ... you know, mammalian species-

    6. JRDr. Jared Rutter49:13

       Yeah, yeah

    7. AHAndrew Huberman49:13

       ... does. That all makes sense until I learned about the gut microbiome from my colleague Justin Sonnenburg, and he said, you know, every time you shake hands, like, we exchange a microbiome today.

    8. JRDr. Jared Rutter49:24

       Mm-hmm.

    9. AHAndrew Huberman49:24

       And we're sharing in the air and skin. We shook hands, you see. And, like, there is this one model of, like, all of this that's very purely biological that we are just shuttles for the microbiota.

    10. JRDr. Jared Rutter49:37

        Hmm.

    11. AHAndrew Huberman49:37

        And everything that we're doing-

    12. JRDr. Jared Rutter49:39

        [laughs]

    13. AHAndrew Huberman49:39

        ... like building electric cars and, uh, holding, uh, debates and protests and, um, sending kids to school and all of that we think is about us.

    14. JRDr. Jared Rutter49:48

        [laughs]

    15. AHAndrew Huberman49:49

        But the microbiota are just like they've h- hijacked this process and, like, they're not sitting there going, [laughs] "Ah, you see all this?"

    16. JRDr. Jared Rutter49:55

        [laughs]

    17. AHAndrew Huberman49:55

        They think this is all about them, and we're just trying to spread and make sure that we continue, and maybe long after they're gone we're just gonna keep going. And I can't poke any holes in this.

    18. JRDr. Jared Rutter50:04

        [laughs]

    19. AHAndrew Huberman50:04

        It's, like, too good a theory.

    20. JRDr. Jared Rutter50:05

        No.

    21. AHAndrew Huberman50:06

        But I keep hoping somebody's gonna tell me, at least from a purely biological perspective, that, like, that's not true. But it kinda scares me. Every once in a while I think, like, "Maybe I'm just a bunch of microbiota."

    22. JRDr. Jared Rutter50:17

        Yeah. You're, you're just the vehicle. Okay, yeah.

    23. AHAndrew Huberman50:18

        I'm a shuttle. We're just a shuttle, but we got this brain-

    24. JRDr. Jared Rutter50:20

        Yeah

    25. AHAndrew Huberman50:20

        ... which is very convenient for them, right?

    26. JRDr. Jared Rutter50:22

        Yeah.

    27. AHAndrew Huberman50:22

        'Cause it makes me wanna go out and do things, and I think about failures and successes and how I wanna do better and what I wanna do at different stages. And, like, maybe it's just all about them getting as far and wide as they can.

    28. JRDr. Jared Rutter50:33

        Well, unfortunately, Andrew, I'm not sure I'm gonna be able to provide you the concrete proof that that's not true. It's a fa- it's a fascinating hypothesis.

    29. AHAndrew Huberman50:39

        And kind of eerie, right?

    30. JRDr. Jared Rutter50:40

        Yeah, very eerie.
12. 51:44 – 59:42

    Molecule Discovery Process, MPC1, MPC2

    1. AHAndrew Huberman51:44

       Tell us about MPC1 and 2. I'm asking about biochemical steps in a key process of energy production and, and allocation, and normally when people hear acronyms, they don't understand.

    2. JRDr. Jared Rutter51:55

       Yeah.

    3. AHAndrew Huberman51:55

       They kind of go, "Oh my goodness, like, what are we doing here?" But, like, I think it's so important that people understand, like, this business of us, of this metabolism, having energy, whether we're young or old, have a lot of it or less of it, healthy or dealing with cancer, like, this is a key node. And what I wanna know truly is how do you actually discover something like this? Because... And this is where I think we, we can really illustrate the scientific process in a way that, like, most people just don't understand. So you need cells, first of all. You need to be able to find the mito- mitochondria. You need to be able to know what's ATP and what's pyruvate. And then you know they're going to two different pathways 'cause someone else said that.

    4. JRDr. Jared Rutter52:34

       Yeah.

    5. AHAndrew Huberman52:34

       And you can observe it down a microscope.

    6. JRDr. Jared Rutter52:36

       Yeah.

    7. AHAndrew Huberman52:37

       But then how do you find this thing?

    8. JRDr. Jared Rutter52:39

       Yeah.

    9. AHAndrew Huberman52:39

       And then tell us what it's doing.

    10. JRDr. Jared Rutter52:40

        Yeah.

    11. AHAndrew Huberman52:40

        Perhaps. Or tell us what it's doing. But, like, I think it would be very useful for people to get a picture of how this is done.

    12. JRDr. Jared Rutter52:46

        Yeah.

    13. AHAndrew Huberman52:46

        Because we hear this stuff, like, oh, this molecule-

    14. JRDr. Jared Rutter52:48

        Yeah

    15. AHAndrew Huberman52:48

        ... MPC... And people go, "Oh, is there a peptide for that?"

    16. JRDr. Jared Rutter52:50

        Yeah.

    17. AHAndrew Huberman52:50

        It's like, hold off. Let's think about how we come to understand these, these essential aspects of ourself I think would be so useful.

    18. JRDr. Jared Rutter52:59

        I appreciate you asking about that. It allows me to reminisce a little bit about the process of discovering that, which was, you know, a fun time in my career and was fueled by the brilliant people in the lab that did it. So MPC, this is a case where the acronym actually makes sense. It's the mitochondrial pyruvate carrier.

    19. AHAndrew Huberman53:16

        Oh, thank you.

    20. JRDr. Jared Rutter53:17

        So you don't have to be a scientist.

    21. AHAndrew Huberman53:18

        Did you name it?

    22. JRDr. Jared Rutter53:19

        Uh, we did not name it. That wa- it was named before. I'll, I'll tell you that when I tell you about the story.

    23. AHAndrew Huberman53:22

        Well, thank you whoever named it.

    24. JRDr. Jared Rutter53:23

        Yeah.

    25. AHAndrew Huberman53:23

        'Cause I don't like acronyms that aren't informative.

    26. JRDr. Jared Rutter53:25

        Yeah. MPC, aptly named-

    27. AHAndrew Huberman53:28

        Yep

    28. JRDr. Jared Rutter53:28

        ... is the carrier that enables pyruvate to get into the mitochondria. Mitochondrial pyruvate carrier, that's what it does. Sits in the mitochondria and basically provides a very specific hole in the membrane to enable pyruvate to get in so that it can then be burned by the mitochondria to, again, extract all the energy to make ATP. That's, that's basically what it does. The history of this is really interesting. It's been known for 60 or 70 years that mitochondria must have a carrier to enable pyruvate to get in, but it was not identified what that protein was, how it worked. And fast-forward to 2008 or '09 or so, and our laboratory had just recently become, again, fascinated with mitochondria. I would say the motivating piece of, of information that convinced us to start working on mitochondria was the realization that many of the proteins that make up mitochondria, that do the stuff that mitochondria do, we don't know what their functions are. And that suggested that this organelle powerhouse of the cell We kind of, I at least, felt like we knew a lot about what mitochondria do. There's mysteries there that we don't have answers for. And so we started just taking some of these proteins that we know are in mitochondria, we don't know what they do, and trying to figure out what they do. And two of those turned out to be MPC1 and MPC2.

    29. AHAndrew Huberman55:02

        Way back when, uh, I observed and was taught, I didn't do a ton of this, that like if you want to figure out what proteins are in a cell, you get a bunch of those cells, which you can do.

    30. JRDr. Jared Rutter55:12

        Mm-hmm.
13. 59:42 – 1:07:03

    Cell Resource Sensing, Fasting, Glucagon, Fat Cells; Neurons, Heart

    1. AHAndrew Huberman59:42

       How do they ensure that they, these cardiomyocytes make sure that they make just enough to maintain themselves so they, they're not so busy burning up all the lumber that they end up going, "Oh my goodness," and the house fell apart?

    2. JRDr. Jared Rutter59:55

       Yeah.

    3. AHAndrew Huberman59:55

       Do they consistently devote 90% of, of their ATP to energy utilization and th- they just know 10%?

    4. JRDr. Jared Rutter1:00:02

       Yeah.

    5. AHAndrew Huberman1:00:02

       Like how quantitative-

    6. JRDr. Jared Rutter1:00:03

       Yeah, yeah

    7. AHAndrew Huberman1:00:04

       ... are these, these, these pathways?

    8. JRDr. Jared Rutter1:00:05

       This clearly-

    9. AHAndrew Huberman1:00:05

       'Cause you can't, you can't have the walls fall down.

    10. JRDr. Jared Rutter1:00:07

        Exactly.

    11. AHAndrew Huberman1:00:07

        It doesn't matter how much energy-

    12. JRDr. Jared Rutter1:00:08

        Exactly

    13. AHAndrew Huberman1:00:08

        ... you produce, right?

    14. JRDr. Jared Rutter1:00:09

        It's a brilliant question and, and it's definitely not programmed like, like there's a s- a spigot with a diverter valve that 90% goes this way and 10% goes that way. What actually happens, and this doesn't just happen in cardiomyocytes, it happens in every cell, is that basically the cell is measuring the outputs. Again, to anthropomorphize, and I have to s- say there are some scientists that hate us when we anthropomorphize cells.

    15. AHAndrew Huberman1:00:35

        I'm talking about-

    16. JRDr. Jared Rutter1:00:35

        But I'm doing it anyways

    17. AHAndrew Huberman1:00:36

        ... humans having an intelligence-

    18. JRDr. Jared Rutter1:00:37

        Yeah, exactly

    19. AHAndrew Huberman1:00:37

        ... or an adaptive logic, so it's okay. Yeah.

    20. JRDr. Jared Rutter1:00:39

        So I think you've provided cover for me to do it on, for cells then.

    21. AHAndrew Huberman1:00:42

        Plenty, yeah.

    22. JRDr. Jared Rutter1:00:43

        Cells basically are measuring- their resources all the time.

    23. AHAndrew Huberman1:00:49

        Hmm.

    24. JRDr. Jared Rutter1:00:50

        I think you could make a compelling argument that every cell, almost all cells know how much usable energy, ATP they have all the time. And when it gets low, they will initiate a series of reactions to that, responses to that to bring it back up. They'll turn off processes that use ATP. They'll start pulling glucose out of the circulation to make more ATP. There's this really profound response to ATP depletion, and I think that's true for many of the end products of our metabolic map. Again, these are the, the, the products of the metabolic map are the amino acids that make proteins and the nucleotides that are required to make DNA and RNA, our genome.

    25. AHAndrew Huberman1:01:38

        There's a greediness to all these cells. Uh, if the fat cells are greedy, you could really see a problem. Like, if we're not ingesting enough glucose... Let's, let's hold off on ketosis for a second-

    26. JRDr. Jared Rutter1:01:46

        Yeah

    27. AHAndrew Huberman1:01:46

        ... and alternate-

    28. JRDr. Jared Rutter1:01:47

        Yeah

    29. AHAndrew Huberman1:01:47

        ... metabolic pathways.

    30. JRDr. Jared Rutter1:01:48

        Yeah.
14. 1:07:03 – 1:11:46

    Cell Resource Allocation, MPC, Heart Failure; Disease

    1. AHAndrew Huberman1:07:03

       What is the consequence of eliminating the M- MCP?

    2. JRDr. Jared Rutter1:07:07

       Mm-hmm.

    3. AHAndrew Huberman1:07:07

       A shuttle? Like, do you get-- Like, if you take a mouse, you're at the University of Utah. Let's give a shout-out to Mario Capecchi-

    4. JRDr. Jared Rutter1:07:13

       Yeah, yeah

    5. AHAndrew Huberman1:07:13

       ... whose life story is amazing-

    6. JRDr. Jared Rutter1:07:14

       Yeah

    7. AHAndrew Huberman1:07:15

       ... who won a Nobel Prize for essentially developing what are called knockout mice-

    8. JRDr. Jared Rutter1:07:19

       Yeah

    9. AHAndrew Huberman1:07:19

       ... a- among other things. Um, you can eliminate genes to test the role of a particular protein downstream of that gene.

    10. JRDr. Jared Rutter1:07:25

        Yeah.

    11. AHAndrew Huberman1:07:25

        If you make a mouse that lacks these proteins, do you get a dead mouse?

    12. JRDr. Jared Rutter1:07:28

        Mm-hmm.

    13. AHAndrew Huberman1:07:28

        They, so they don't-

    14. JRDr. Jared Rutter1:07:29

        They do not survive to birth, yeah.

    15. AHAndrew Huberman1:07:31

        You can get sperm, egg in a, in the -- Somehow the-

    16. JRDr. Jared Rutter1:07:34

        It will still, yeah

    17. AHAndrew Huberman1:07:34

        ... it, it can become a, a mouse.

    18. JRDr. Jared Rutter1:07:36

        Yeah. It'll start to develop, and then I think if I remember right, it's about 12 or 13 days of development-

    19. AHAndrew Huberman1:07:41

        Mm-hmm

    20. JRDr. Jared Rutter1:07:41

        ... which is, you know, two-thirds of the way from-

    21. AHAndrew Huberman1:07:44

        Mm-hmm

    22. JRDr. Jared Rutter1:07:44

        ... fertilization to birth of the mouse. It will die-

    23. AHAndrew Huberman1:07:47

        Mm-hmm

    24. JRDr. Jared Rutter1:07:47

        ... and, and you won't get a live mouse. But what has been done, and, and obviously you're probably getting there, is because of the technologies that Mario developed and then others following after him, we can now make mice that lack the MPC only in the liver or only in the heart or only in the muscle or only in the brain, and many of these things have been done.

    25. AHAndrew Huberman1:08:08

        Sorry, I should have been giving credit.

    26. JRDr. Jared Rutter1:08:09

        Yeah.

    27. AHAndrew Huberman1:08:09

        He developed a technology that would allow for organ and cell type-specific deletions-

    28. JRDr. Jared Rutter1:08:13

        Yeah

    29. AHAndrew Huberman1:08:13

        ... or additions of genes. For- forgive me.

    30. JRDr. Jared Rutter1:08:15

        Yeah, yeah.
15. 1:11:46 – 1:13:24

    Sponsor: Function

    1. AHAndrew Huberman1:11:46

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16. 1:13:24 – 1:20:43

    Cell Size vs Fuel Balance, Cell Identity & Disease

    1. AHAndrew Huberman1:13:24

       So is it fair to say that the allocation of energy, which is made pathologic in this mutant mouse, but also in people who have these, uh, cardiac conditions and die of heart attack essentially, it's almost like the, the identity of the cells is screwed up. They're still a cardiomyocyte-

    2. JRDr. Jared Rutter1:13:41

       Yeah

    3. AHAndrew Huberman1:13:42

       ... but they're devoting too much energy to making more of themselves and not enough to, to doing what they're supposed to do. I have, like, two analogies that I wanna throw out there and, and maybe they're, they're too much of a reach, but I, I love dogs. I have a now a medium-sized dog. I used to have a large dog. The larger breeds of dogs live much shorter lives than the smaller ones. And, and we actually know that's because of dosing of IGF-1-

    4. JRDr. Jared Rutter1:14:03

       Right. Mm-hmm

    5. AHAndrew Huberman1:14:03

       ... which is a growth pathway thing.

    6. JRDr. Jared Rutter1:14:05

       Mm-hmm.

    7. AHAndrew Huberman1:14:05

       So there is this, like, story-

    8. JRDr. Jared Rutter1:14:07

       Mm-hmm

    9. AHAndrew Huberman1:14:07

       ... about larger animals within a given species tend to live much shorter lives than the smaller variety of that same species. There's some exceptions to this, but there does seem to be a sort of rule that, like, you can either be big and live a short life-

    10. JRDr. Jared Rutter1:14:22

        Mm-hmm

    11. AHAndrew Huberman1:14:22

        ... or you can be small and live a longer life-

    12. JRDr. Jared Rutter1:14:24

        Mm-hmm

    13. AHAndrew Huberman1:14:24

        ... within certain species. But there's also this thing about heartbeats, right? Like, this theory that you only get so many heartbeats in your life. The, the reason I, I like these higher level, perhaps, uh, appropriate comparisons, a lot of caveats there, is that, like, ultimately when I think about life and evolution and a propagation of species and health versus pathology, it's all about energy, right? It's like, how are you devoting energy? It can get into the kind of mystical, spiritual piece. Uh, that's not our purpose or it's not my purpose in-

    14. JRDr. Jared Rutter1:14:54

        Mm-hmm

    15. AHAndrew Huberman1:14:55

        ... in, in bringing this up now. But it seems like at the cellular level and at the sub-cellular level, which is what you're describing, the allocation of energy i- in this case is the difference between life and death. But, but this, this decision, you're not telling us, like, oh, you know, these pathways I discovered along with others-

    16. JRDr. Jared Rutter1:15:12

        Yeah

    17. AHAndrew Huberman1:15:13

        ... are really, like, there's a, a fan out of, like, 50 different options. You're saying make more biomass, more of self or use energy to be self.

    18. JRDr. Jared Rutter1:15:22

        Mm-hmm.

    19. AHAndrew Huberman1:15:23

        And there seems to be a, like, a critical balance there, and I have another story I could tell about how, like, if you look at the data on longevity in different athletes, like the gymnasts, the sprinters seem to live three to six l- years longer on average than, than others. And the endurance runners are somewhere in the middle. And you, you look at very large athletes like the powerlifters and the, um, moving aside all things of, like, use of drugs in sports and everything, you go, like, the, the sports where there's just a lot more of somebody-

    20. JRDr. Jared Rutter1:15:47

        Mm-hmm

    21. AHAndrew Huberman1:15:47

        ... that's not good for longevity.

    22. JRDr. Jared Rutter1:15:49

        Hmm.

    23. AHAndrew Huberman1:15:49

        And it really isn't.

    24. JRDr. Jared Rutter1:15:50

        Yeah.

    25. AHAndrew Huberman1:15:51

        So there does seem to be this balance between size and the use of fuel to, to build more of oneself a- and the use of fuel to just be oneself. And that self could be a cell.

    26. JRDr. Jared Rutter1:16:03

        Yeah.

    27. AHAndrew Huberman1:16:03

        That self could be an organ.

    28. JRDr. Jared Rutter1:16:05

        Yeah.

    29. AHAndrew Huberman1:16:05

        That self could be a whole organism. And I find that, like, not incidental, but maybe I'm taking too many liberties here.

    30. JRDr. Jared Rutter1:16:13

        Yeah. I mean, that's a, that's a complex analogy and, and, but I think one thing that is very clear about, about what you're talking about is this sense of, of, of identity in a cell. I mean, that's a fundamentally important phenomenon that, again, we've known about for a long time, and there's been under- an understanding in some cell types in some ways about how that identity is established and maintained. But I think your question is a really interesting one. To what extent is disease associated with loss of that cell identity? And, and cell identity is a bit of a squishy-
17. 1:20:43 – 1:24:29

    MPC Discovery, Genetics, Model Systems

    1. AHAndrew Huberman1:20:43

       What I didn't get was how you actually found it. So was it that you knew there was a gene there that coded for this thing of a certain size, so you started making some, what we call recombinant-

    2. JRDr. Jared Rutter1:20:52

       Yeah

    3. AHAndrew Huberman1:20:52

       ... version of that and, like, throwing it on cells, seeing what happened? Is that kind of the, the steps that went through?

    4. JRDr. Jared Rutter1:20:56

       We knew the protein was there. What we didn't know is what it did.

    5. AHAndrew Huberman1:20:59

       Mm-hmm.

    6. JRDr. Jared Rutter1:21:00

       And I would say the key discoveries of that came from genetics. Basically, Carl's lab made flies that lacked the MPC. And we could then-

    7. AHAndrew Huberman1:21:12

       Dead fly?

    8. JRDr. Jared Rutter1:21:12

       They were actually alive. There's an interesting story there that's probably too in the weeds, but they live.

    9. AHAndrew Huberman1:21:16

       Uh-huh.

    10. JRDr. Jared Rutter1:21:17

        But they had specific manifestations-

    11. AHAndrew Huberman1:21:20

        Yeah

    12. JRDr. Jared Rutter1:21:20

        ... that we could analyze using chemistry, and I'll tell you about the results of that. We were studying in other, in other cell types, in yeast cells and in human cells, and studying the results of losing these genes. You know, again, this is what's enabled by doing genetics. You know, Mario Capecchi figured out how to do this in mice, and his colleagues. That gave us the ability to do knockout mice. Other people have enabled it in other species. And by doing that and studying the results, we could then deduce, oh, what's happening in these yeast cells, these fruit flies, and these human cells grown on a dish is they aren't able to take their pyruvate into the mitochondria. You know, by analyzing them using sophisticated chemical tools, we could see that they were basically, their metabolic pathway from glucose to pyruvate to pyruvate in the mitochondria to ATP, that was being blocked, and it was being blocked specifically at that level of the pyruvate.

    13. AHAndrew Huberman1:22:25

        Mm-hmm.

    14. JRDr. Jared Rutter1:22:26

        So that then gave us the initial hypothesis, maybe that's what these proteins are doing, and we could then go and validate that hypothesis in multiple experiments and that, uh, like I said, been validated by many other people over the ensuing decade or so. So those were the experiments-

    15. AHAndrew Huberman1:22:42

        Got it

    16. JRDr. Jared Rutter1:22:42

        ... that enabled us to, to figure it out. It was really, um, genetics that enabled us to do it.

    17. AHAndrew Huberman1:22:47

        Very satisfying when a discovery comes about in yeast flies and mammalian inclu- including human cells. Uh, what year span was all of that happening? If you had to really tighten it to-

    18. JRDr. Jared Rutter1:22:58

        We pub- yeah, we published the paper in 2012. It probably was going on from 2008 or '09 to 2012, something, something like that.

    19. AHAndrew Huberman1:23:06

        This is a actually an important moment, I think, for people to understand. Like, when they hear about yeast or flies, they're probably like, like, "Why, why are we doing this stuff?"

    20. JRDr. Jared Rutter1:23:13

        Yeah.

    21. AHAndrew Huberman1:23:13

        And I'm not here to, like, plug federal funding for research. I think that just happens naturally as a consequence of the podcast, or at least I hope so. But my graduate advisor told me that yeast, like, they have a very quick turnover, so that's why they're good to-

    22. JRDr. Jared Rutter1:23:25

        Mm-hmm

    23. AHAndrew Huberman1:23:25

        ... use. And, and she said that, um, she was a wine drinker. She said, "And they are much smarter than us 'cause they know how to make their own alcohol."

    24. JRDr. Jared Rutter1:23:30

        [laughs]

    25. AHAndrew Huberman1:23:31

        So now we know why you, biologists use yeast.

    26. JRDr. Jared Rutter1:23:33

        [laughs]

    27. AHAndrew Huberman1:23:33

        Fruit flies, it's because of the short generation time.

    28. JRDr. Jared Rutter1:23:36

        Yeah.

    29. AHAndrew Huberman1:23:36

        You can get a lot of experiments done.

    30. JRDr. Jared Rutter1:23:37

        Yeah.
18. 1:24:29 – 1:31:32

    Lactate, Oxygen, Exercise; Energy Prioritization Hierarchy

    1. AHAndrew Huberman1:24:29

       Let's talk about lactate.

    2. JRDr. Jared Rutter1:24:30

       Mm.

    3. AHAndrew Huberman1:24:31

       Every time lactate's come up on this podcast before, it's been, like, in the context of exercise physiology. We had the, the great Andy Galpin, whose name I don't expect you to recognize, but he's, he's really one of the, like, preeminent public educators. He's a professor of physiology and exercise physiology, and he told us and he told the world, like, everyone talks about lactic acid. Like, we don't actually make lactic acid.

    4. JRDr. Jared Rutter1:24:50

       Mm-hmm.

    5. AHAndrew Huberman1:24:50

       We make this thing called lactate. But within the cell, lactate plays a very crucial role in this metabolic pathway. I know you've spent some time with lactate.

    6. JRDr. Jared Rutter1:24:58

       Mm-hmm.

    7. AHAndrew Huberman1:24:58

       So when you think about lactate- What do you think about?

    8. JRDr. Jared Rutter1:25:03

       I mean, so pyruvate, we talked about pyruvate extensively. To a first approximation, again, it's a little more complicated than this, but I think this is a good way to think about it. When pyruvate is made, simplistically has two fates. It can go into the mitochondria, we talked about. What we didn't talk about is the other major fate is to be converted to lactate and exported, and that decision, burn it, make lactate, I think you could make a very strong argument is one of the most important metabolic decisions that cells are making all the time.

    9. AHAndrew Huberman1:25:32

       Why would it not burn it or make more of itself? 'Cause it's just got it in excess?

    10. JRDr. Jared Rutter1:25:36

        Yeah. There's something about that production of lactate that enables ongoing production of biomass. So again, a little more complicated than this. If you burn the pyruvate, that turns into carbon dioxide, we breathe it out, that the stuff is gone. We breathe it out. There's no stuff. There's just the energy. If you don't burn it, that stuff doesn't get eliminated as carbon dioxide and can turn into a protein, can contribute to protein production or carbohydrate production or, you know, fatty acids that can be used to make, make new cells. And so that really is the, uh, that resource allocation decision, uh, we talked about many times, building or burning, and lactate is one of the mediators in a way of that building decision. And so lactate, I think historically has been thought of as a waste product when our cells can't burn, typically because of lack of oxygen. We haven't talked so much about the role of oxygen in all this. When I talk about burning, what I really mean is taking that pyruvate or fatty acids or other things and oxidizing them using oxygen and ex- by so doing, extracting the energy and doing this unbelievably amazing chemistry that the mitochondria do to basically very effectively capture all that energy and make it usable in the form of ATP. When oxygen isn't available, that pyruvate cannot be burned, and then it essentially has to be converted to lactate. That's why when we exercise and our muscle becomes hypoxic or doesn't have adequate oxygen, we make lactate, and that lactate is what causes the burn that we feel. And we've thought about it traditionally as a waste product. There's been beautiful experiments done in the last five or 10 years. Josh Rabinowitz, a friend of mine and professor at Princeton, has done some of these that have demonstrated that lactate is a very important fuel on its own. The heart, for example, is quite good at consuming lactate and burning it.

    11. AHAndrew Huberman1:27:40

        The heart can... It seems like it's kind of like a... It's got, it's consuming a sort of like dog's breakfast of fuels.

    12. JRDr. Jared Rutter1:27:46

        [laughs]

    13. AHAndrew Huberman1:27:46

        It likes lipids. It'll take glucose. It likes lactate.

    14. JRDr. Jared Rutter1:27:50

        Anything. Anything.

    15. AHAndrew Huberman1:27:50

        Well-

    16. JRDr. Jared Rutter1:27:50

        That's good for us 'cause that, that keeps it beating no matter what the metabolic status of, uh, uh, you know, as long as we're alive, we have something that it can burn, and lactate is just an important mediator of carrying tho- that energy around.

    17. AHAndrew Huberman1:28:03

        It can be a fuel. It can be a shuttle.

    18. JRDr. Jared Rutter1:28:05

        Mm-hmm.

    19. AHAndrew Huberman1:28:06

        In the context of exercise and brain, and I know this is, uh, we're not talking about actionables here, but like I've mentioned before on this podcast, like if we do like an intense, typically it's aerobic exercise, we get like enough lactate generated, that does seem to be a signal to the brain for this brain-derived neurotrophic factor, which now kind of makes sense in this context because the whole purpose of BDNF is to build more stuff, more connections typically, uh, rather than break connections. So it's amazing that we think of these things as like a waste product, just like we used to talk about like junk DNA.

    20. JRDr. Jared Rutter1:28:38

        Mm-hmm.

    21. AHAndrew Huberman1:28:38

        Nobody does that anymore.

    22. JRDr. Jared Rutter1:28:39

        Yeah.

    23. AHAndrew Huberman1:28:39

        But to be very careful with language in biology, I'm realizing.

    24. JRDr. Jared Rutter1:28:42

        Yeah. Yeah.

    25. AHAndrew Huberman1:28:43

        Like w- the moment we, we label something conceptually-

    26. JRDr. Jared Rutter1:28:46

        [laughs]

    27. AHAndrew Huberman1:28:46

        ... you like shut down a field-

    28. JRDr. Jared Rutter1:28:48

        [laughs]

    29. AHAndrew Huberman1:28:48

        ... a, like a line of discovery that almost always ends up being like super important.

    30. JRDr. Jared Rutter1:28:52

        Yeah. We joke all the time in the mitochondria field about the powerhouse of the cell, right?
19. 1:31:32 – 1:36:18

    Cancer, Mutations, Metabolism Changes & Warburg Effect

    1. JRDr. Jared Rutter1:31:32

       good at it.

    2. AHAndrew Huberman1:31:32

       We had a colleague of yours on the podcast, uh, who studies hypoxia and spleen function.

    3. JRDr. Jared Rutter1:31:37

       Mm-hmm.

    4. AHAndrew Huberman1:31:37

       And, and we were talking about how everyone hears the word mutation and they think like, "Oh, mutations are just always damaging."

    5. JRDr. Jared Rutter1:31:43

       Mm-hmm.

    6. AHAndrew Huberman1:31:43

       But, you know, these mutations that afford a m- more life, that are adaptive essentially-

    7. JRDr. Jared Rutter1:31:47

       Mm-hmm

    8. AHAndrew Huberman1:31:47

       ... are... People can't hear that un- enough.

    9. JRDr. Jared Rutter1:31:49

       Yeah.

    10. AHAndrew Huberman1:31:50

        Mutations are the reason we're here.

    11. JRDr. Jared Rutter1:31:52

        That's right.

    12. AHAndrew Huberman1:31:52

        Yeah, so the X-Men had it right.

    13. JRDr. Jared Rutter1:31:54

        Yeah, exactly. [laughs]

    14. AHAndrew Huberman1:31:54

        Like, that's a, that's a good series to watch. On the other side of the coin, the maladaptive, um, situation, could you tell us about the Warburg effect-

    15. JRDr. Jared Rutter1:32:01

        Yeah

    16. AHAndrew Huberman1:32:01

        ... and its role in cancer? And, and I do wanna frame this properly because nowadays we're, we're living in a weird time around this topic of cancer. There are these corners of the internet that, like, don't actually believe in cancer or germ theory. They, they, they just, like, don't believe it. And some of that is actually kind of catching on. I believe cancer exists and I believe that cancers can come about through a variety of mechanisms. So only if you believe that to be true, that it can come about through a variety of mechanisms-

    17. JRDr. Jared Rutter1:32:30

        Mm-hmm

    18. AHAndrew Huberman1:32:30

        ... uh, would I ask you to, like-

    19. JRDr. Jared Rutter1:32:31

        Yeah

    20. AHAndrew Huberman1:32:32

        ... agree. Uh, if you disagree-

    21. JRDr. Jared Rutter1:32:34

        Yeah

    22. AHAndrew Huberman1:32:34

        ... please disagree. But it's true, right? That there are a lot of paths to cancer.

    23. JRDr. Jared Rutter1:32:38

        Yeah.

    24. AHAndrew Huberman1:32:38

        Right?

    25. JRDr. Jared Rutter1:32:38

        Uh, there's no question that there are some fundamental features of cancer. All cancers, to my knowledge, have mutations in the genome.

    26. AHAndrew Huberman1:32:46

        Mm-hmm.

    27. JRDr. Jared Rutter1:32:47

        And those mutations are many, but tend to cause, again, work together to cause that cell to divide-

    28. AHAndrew Huberman1:32:55

        Mm-hmm

    29. JRDr. Jared Rutter1:32:55

        ... to replicate itself more rapidly, to ev- evade the immune system, which is patrolling, looking for misbehaving cells and to eliminate them, and somehow cancer cells can avoid that. Critically important and, you know, one of the most, um, exciting developments in cancer therapy over the last 10 or 15 years has been these checkpoint inhibitors, PD-1, PD-L1, that, uh, inhibitors that basically reverse that... You know, cancer cells are very good at cloaking themselves, let's say, from the immune system-

    30. AHAndrew Huberman1:33:26

        Mm-hmm
20. 1:36:18 – 1:43:00

    Cancer Challenges & Therapies

    1. AHAndrew Huberman1:36:18

       Of the, uh, modern treatments for cancer, radiation, chemotherapy, and immunotherapies, and what's of happening now, had someone on talking about, you know, CAR T cells and, um, things of that sort. But is there anything that, um, you kind of sense on the horizon, it might be 5, 10 years out or 2 years out, that, like, if, if we could just solve that, that we would be in a position to treat and cure many more cancers? Like, like-

    2. JRDr. Jared Rutter1:36:46

       Mm-hmm

    3. AHAndrew Huberman1:36:46

       ... what's the, what's the kind of linchpin thing here? Is it being able to reallocate the use of pyruvate? Like, if we could do that, if that was a druggable thing or you could do a gene therapy but... or you could use non-invasive tools like ultrasound or light.

    4. JRDr. Jared Rutter1:37:02

       Yeah.

    5. AHAndrew Huberman1:37:02

       But these are all just forces, right?

    6. JRDr. Jared Rutter1:37:04

       Yeah.

    7. AHAndrew Huberman1:37:04

       Chemical or mec-

    8. JRDr. Jared Rutter1:37:05

       Yeah.

    9. AHAndrew Huberman1:37:05

       I always, I would like to simplify things, like, for people if possible.

    10. JRDr. Jared Rutter1:37:07

        Yeah.

    11. AHAndrew Huberman1:37:07

        Like, there are two ways to change things in the body, healthy or unhealthy. You have mechanical choices and chemical choices.

    12. JRDr. Jared Rutter1:37:12

        Yeah.

    13. AHAndrew Huberman1:37:12

        Right? You can feel more full by having your gut distend. You can feel more full 'cause your hypothalamus says-

    14. JRDr. Jared Rutter1:37:16

        Right

    15. AHAndrew Huberman1:37:16

        ... you're full.

    16. JRDr. Jared Rutter1:37:17

        Right.

    17. AHAndrew Huberman1:37:17

        And there's a bunch of other stuff-

    18. JRDr. Jared Rutter1:37:18

        Yeah

    19. AHAndrew Huberman1:37:18

        ... involved, but, like, that's all we've got-

    20. JRDr. Jared Rutter1:37:19

        Yeah

    21. AHAndrew Huberman1:37:19

        ... is mechanical and chemical forces.

    22. JRDr. Jared Rutter1:37:21

        Yeah.

    23. AHAndrew Huberman1:37:21

        So let's assume you had the tool. Is there some place where, like, you feel like if we could just Turn that bolt-

    24. JRDr. Jared Rutter1:37:29

        Yeah

    25. AHAndrew Huberman1:37:30

        ... we would be in a much better position to treat a lot of cancers or cure them.

    26. JRDr. Jared Rutter1:37:33

        Let's maybe take a step back from that and then get to that question in a second and talk about cancer, you know, what it is and why it's so difficult. If a bacteria invades us, it's very easy for our immune system to say, "Hey, that's not us. Let's go kill that thing."

    27. AHAndrew Huberman1:37:51

        Mm-hmm.

    28. JRDr. Jared Rutter1:37:52

        If a cancer cell starts hyper-proliferating, it's us, right? It's our cells. It doesn't have antigens, which are the technical term for the molecules, the features that are recognized by the immune system. It doesn't necessarily have antigens that are recognized as not us, non-self. So that's one of the big challenges of cancer. The challenge for us is to figure out a way to kill those cells, which again, are our cells, they are us, is to kill those cells without killing the rest of our cells, 'cause if we kill the rest of our cells, we kill us, right? That's the challenge of cancer therapy, in my view. Again, I'm oversimplifying, but that's, that's a big challenge. And many of the features of cancer cells are not completely new things that that cancer just invented. It's using the functions that our normal cells have. For example, one of the things that's common, not universal, but common in cancer cells is to become more like a stem cell. Has many features of stem cells. So okay, we can find a way to target a specific stem cell pathway and kill all the cells that have that. Well, then we're killing many of our stem cells too, and now the lining of our gut doesn't regenerate, t- which we talked about. That's driven by stem cells.

    29. AHAndrew Huberman1:39:15

        Hair falls and hair falls out.

    30. JRDr. Jared Rutter1:39:16

        Exactly.
21. 1:43:00 – 1:48:31

    Therapy Combinations, Unique Cancer Mutations & Metabolism

    1. AHAndrew Huberman1:43:00

       That's very encouraging. We had a guy on the podcast named David Fajgenbaum. He's a medical doctor.

    2. JRDr. Jared Rutter1:43:05

       Mm.

    3. AHAndrew Huberman1:43:05

       Are you familiar with his work? He's at University of Pennsylvania. He had Castleman's disease-

    4. JRDr. Jared Rutter1:43:08

       Mm

    5. AHAndrew Huberman1:43:08

       ... and he was able to cure his own Castleman's disease, 'cause he was basically on his deathbed, and he basically just started taking different combinations of already approved drugs-

    6. JRDr. Jared Rutter1:43:17

       Mm

    7. AHAndrew Huberman1:43:17

       ... in a kind of desperate attempt to save his life, and he, he found things that would extend his life.

    8. JRDr. Jared Rutter1:43:22

       Mm.

    9. AHAndrew Huberman1:43:22

       And he's been alive 11 years now.

    10. JRDr. Jared Rutter1:43:24

        Mm.

    11. AHAndrew Huberman1:43:24

        And he runs a lab, serious scientist, as we say, but he also has this, uh, not-for-profit called Every Cure, which has been successfully using AI and cell assays and things to take tumor biopsies and trying to figure out like, okay, in this tragedy of a kid who's dying of a particular cancer, like let's just throw a bunch of not random drugs, but already approved drugs at this tumor-

    12. JRDr. Jared Rutter1:43:47

        Yeah

    13. AHAndrew Huberman1:43:47

        ... in a dish. And if some of them work, like if the parents agree and there's no other hope, do it. And like the, in some cases they're curing.

    14. JRDr. Jared Rutter1:43:55

        Yeah.

    15. AHAndrew Huberman1:43:55

        And in many cases they're extending life.

    16. JRDr. Jared Rutter1:43:57

        Yeah.

    17. AHAndrew Huberman1:43:57

        It matches up well with what you're describing. It requires this AI piece to run iterations 'cause there's a huge catalog of drugs that even oncologists might not be aware of.

    18. JRDr. Jared Rutter1:44:06

        Yeah.

    19. AHAndrew Huberman1:44:06

        One particular highlight of his work is that we know now that in breast cancers where they use lidocaine during the surgery, the incidences of recurrence are significantly lower.

    20. JRDr. Jared Rutter1:44:17

        Hmm. Mm-hmm.

    21. AHAndrew Huberman1:44:18

        And it turns out that lidocaine has some effect on the local environment. I'm not, this isn't my area.

    22. JRDr. Jared Rutter1:44:22

        Yeah.

    23. AHAndrew Huberman1:44:22

        But you know, David talks about this.

    24. JRDr. Jared Rutter1:44:24

        Yeah.

    25. AHAndrew Huberman1:44:24

        And I'm encouraged by things like that and what you're describing that w- we're not necessarily gonna have like the miracle drug, but the, the miracle cocktail for that individual, that cancer. Yeah.

    26. JRDr. Jared Rutter1:44:34

        That's the key thing is that-

    27. AHAndrew Huberman1:44:36

        Yeah

    28. JRDr. Jared Rutter1:44:36

        ... you know, David's situation is very specific to David.

    29. AHAndrew Huberman1:44:40

        Right.

    30. JRDr. Jared Rutter1:44:40

        And, and every tumor is a little bit different.
22. 1:48:31 – 1:56:34

    Technology to Visualize Metabolism; Disease, Metabolism & Scents

    1. AHAndrew Huberman1:48:31

       How far are we from a, a world where, um, I drink a fluid, and it's a safe fluid 'cause we do this for like other types of imaging, and I step into a tube, and I do it when I'm like five.

    2. JRDr. Jared Rutter1:48:42

       Mm-hmm.

    3. AHAndrew Huberman1:48:43

       And I do it when I'm 50.

    4. JRDr. Jared Rutter1:48:44

       Mm-hmm.

    5. AHAndrew Huberman1:48:45

       And I get a picture of red and green in every cell, right? So I get like an image of like the proportion of my metabolism in different organs, and you could zoom in to a single cell. This is not like science fiction at the level of like it couldn't be done.

    6. JRDr. Jared Rutter1:48:58

       Mm-hmm.

    7. AHAndrew Huberman1:48:59

       Where you say, okay, like this is a healthy cardiomyocyte, and it's using 65% of its energy to just keep pumping, and then it like puts aside a little bit to make sure it can make more of its stuff, so it stays around. And a little bit, it's like going to this other pathway, and like that's a healthy cardiomyocyte. We know this from the population of-

    8. JRDr. Jared Rutter1:49:18

       Mm-hmm

    9. AHAndrew Huberman1:49:18

       ... of age-matched data. And then when I'm, you know, 40, 50, you go, "Yeah, I don't know, like the, your heart's looking a little more green than red or something like that."

    10. JRDr. Jared Rutter1:49:28

        Mm-hmm.

    11. AHAndrew Huberman1:49:28

        We can kind of turn the dial back. Like, like we have druggable, you know, targets inside of cells, and you can like kind of like adjust the, the energy allocation. Like is what I'm describing like so crazy? Because I can imagine a mouse experiment or paper would probably come out on that next week-

    12. JRDr. Jared Rutter1:49:43

        Yeah

    13. AHAndrew Huberman1:49:43

        ... if it hasn't already.

    14. JRDr. Jared Rutter1:49:45

        Yeah.

    15. AHAndrew Huberman1:49:45

        And like that's kind of what you want. You want subcellular resolution.

    16. JRDr. Jared Rutter1:49:48

        Yeah.

    17. AHAndrew Huberman1:49:48

        'Cause I feel like we've gone from this place where like I was around when the first, uh, MR-- like functional magnetic resonance-

    18. JRDr. Jared Rutter1:49:54

        Yeah

    19. AHAndrew Huberman1:49:54

        ... imaging stuff was kind of like, here's a person looking at a banana.

    20. JRDr. Jared Rutter1:49:57

        Yeah.

    21. AHAndrew Huberman1:49:57

        Here's a person hearing a joke. And like now you can see dynamics and you can see axon pathways, but if we get down to the cells, cool. It's a lot of salt and pepper.

    22. JRDr. Jared Rutter1:50:06

        Mm-hmm.

    23. AHAndrew Huberman1:50:07

        Then you get down to the inner workings of the cells and you can't see everything. If you look at everything, it's gonna look like chaos.

    24. JRDr. Jared Rutter1:50:12

        Yeah.

    25. AHAndrew Huberman1:50:12

        Someone put on X this morning, actually, a AI rendering of all the proteins in a cell in one tiny patch of cell, and it's just like overwhelming.

    26. JRDr. Jared Rutter1:50:20

        Yeah.

    27. AHAndrew Huberman1:50:20

        You're just like, oh my God, like there's so much here. But if you could just say like, let's just look at metabolism at this key node, and we know what healthy should be, here's where you're at.

    28. JRDr. Jared Rutter1:50:29

        Yeah.

    29. AHAndrew Huberman1:50:29

        And you're just trying to tilt that balance, I mean, that to me feels like a -- that could be done.

    30. JRDr. Jared Rutter1:50:34

        Yeah.
23. 1:56:34 – 2:01:12

    Excess Energy & Mitochondria, Reactive Oxygen Species

    1. AHAndrew Huberman1:56:34

       We were talking, uh, a few moments ago about excess energy toxicity.

    2. JRDr. Jared Rutter1:56:38

       Yeah.

    3. AHAndrew Huberman1:56:38

       This is something that Dr. Layne Norton brought up on this podcast. He's a serious biochemist, nutrition, exercise science guy, public educator, loves randomized control trials and meta-analyses. That's like his... If it's not there, he's not interested, or he, uh, he's perfectly interested in, in tossing away everything else, so that's kind of his hallmark. So that should feel good to you-

    4. JRDr. Jared Rutter1:56:57

       Mm-hmm

    5. AHAndrew Huberman1:56:58

       ... just knowing that.

    6. JRDr. Jared Rutter1:56:58

       Mm.

    7. AHAndrew Huberman1:56:59

       But he talks about this energy toxicity. You know, like excess calories leads to problems, not just because of the presence of excess body fat, but because of just too much energy at the front end creates downstream biochemical issues across the body. How does this relate to some of what we've been discussing?

    8. JRDr. Jared Rutter1:57:18

       Yeah. There's a, a widely accepted hypothesis that mitochondria with excess energy leads to problems. You know, many people that li- that are listening have probably heard of reactive oxygen species. This is, you know, forms of oxygen that become reactive and end up spinning out and damaging proteins and nucleic acids. And I think it is, uh, again, widely accepted, not universally, but widely accepted, that one of the contributors to that is mitochondria that have too much energy. Basically, the form that energy takes when it's extracted from the food we eat and before it's converted to ATP is powering the mitochondria. And when that mitochondria is overpowered, that leads to a state that is very susceptible to generation of these reactive species that end up damaging our genome, creating mutations, and damaging proteins, and creating many of the problems that we see. And I think there's been a number of studies that have suggested they might contribute to various pathologies, including aging. So I think that idea of excess energy is one that is really important to consider from the level of the organism down to the level of individual cells and even the mitochondria within those cells.

    9. AHAndrew Huberman1:58:36

       Once again, uh, it... I'm thinking about the, this notion like no individual or collection of individuals or cell or collection of cells can really get away with... Or what's the saying? Like, you pay the piper somehow.

    10. JRDr. Jared Rutter1:58:50

        Yeah.

    11. AHAndrew Huberman1:58:50

        Like, cells really get punished for cheating themselves-

    12. JRDr. Jared Rutter1:58:54

        Yeah

    13. AHAndrew Huberman1:58:54

        ... by taking too much energy or not allocating it correctly. Like, you can level up from this, like, single cell analysis all the way to, to societies, I actually think.

    14. JRDr. Jared Rutter1:59:04

        Mm-hmm.

    15. AHAndrew Huberman1:59:04

        This is fascinating I- for a variety of reasons. First of all, again, we've never had a serious discussion about what mitochondria actually do besides just create, help create energy. So first of all, thank you so much for telling us how they actually allocate their resources towards things other than just making more energy for usage to build more of oneself. Also, for framing that in the context of, of disease and health, and also for shining a light on the fact that, like, while we might be right here now, that I do think, I'll just say what maybe you were trying to say but are too humble to say, that I think as long as we're looking at things just like, "Oh, this is a cancer of this tissue," and not actually asking what specifically is happening to the cells there that might be common to other cancers elsewhere, and, like, changing our nomenclature and boundaries of how we classify things, opening up our minds to it-

    16. JRDr. Jared Rutter1:59:56

        Mm

    17. AHAndrew Huberman1:59:56

        ... as well as really thinking about the whole body as a, like a constellation of these little microfactories that is us.

    18. JRDr. Jared Rutter2:00:04

        Mm.

    19. AHAndrew Huberman2:00:04

        I am certain that people hearing this will no longer think about, like, metabolism just as them, my metabolism, but this, um, constellation of metabolisms and, and the health status of, of all the different cells. So it goes without saying that it's a, a really unique opportunity for the general public to hear from, like, like, a world-class biologist working on these specific issues and related issues for decades now, right? And so... And you're a very busy person, so I'm very grateful to, to you, to the University of Utah for l- allowing, uh, and encouraging public education, uh, to Howard Hughes. No, they didn't tell me to say this.

    20. JRDr. Jared Rutter2:00:38

        [laughs]

    21. AHAndrew Huberman2:00:38

        But I think people really need to understand what an amazing opportunity it is to learn from people, and there are others in the field, you're so good at attribution, who are, who are really f- trying to figure out these really hard problems in biology that are crucial to health and to disease, and therefore to curing disease, and really trying to move things forward in your workshop that you call-

    22. JRDr. Jared Rutter2:00:58

        Yeah

    23. AHAndrew Huberman2:00:58

        ... a laboratory.

    24. JRDr. Jared Rutter2:00:58

        Yeah.

    25. AHAndrew Huberman2:00:59

        So you don't have to do this sort of thing, but I greatly appreciate it, and I speak on behalf of many, many people who really appreciate it. There's information, and then there's superb information, so thank you so much.

    26. JRDr. Jared Rutter2:01:08

        Thanks, Andrew. It's been a lot of fun.

    27. AHAndrew Huberman2:01:09

        Uh, we'll do it again.

    28. JRDr. Jared Rutter2:01:10

        Anytime.

    29. AHAndrew Huberman2:01:11

        Cheers.

    30. JRDr. Jared Rutter2:01:11

        Thank

24. 2:01:12 – 2:03:45

    Zero-Cost Support, YouTube, Spotify & Apple Follow, Reviews & Feedback, Sponsors, Protocols Book, Social Media, Neural Network Newsletter

    1. JRDr. Jared Rutter2:01:12

       you.

    2. AHAndrew Huberman2:01:12

       Thank you for joining me for today's discussion with Dr. Jared Rutter. To learn more about his work, please see the links in the show note caption. If you're learning from and/or enjoying this podcast, please subscribe to our YouTube channel. That's a terrific zero-cost way to support us. In addition, please follow the podcast by clicking the follow button on both Spotify and Apple. And on both Spotify and Apple, you can leave us up to a five-star review. And you can now leave us comments at both Spotify and Apple. Please also check out the sponsors mentioned at the beginning and throughout today's episode. That's the best way to support this podcast. If you have questions for me or comments about the podcast or guests or topics that you'd like me to consider for the Huberman Lab Podcast, please put those in the comments section on YouTube. I do read all the comments. For those of you that haven't heard, I have a new book coming out. It's my very first book. It's entitled Protocols: An Operating Manual for the Human Body. This is a book that I've been working on for more than five years, and that's based on more than 30 years of research and experience, and it covers protocols for everything from sleep, to exercise, to stress control, protocols related to focus and motivation, and of course, I provide the scientific substantiation for the protocols that are included. The book is now available by pre-sale at protocolsbook.com. There you can find links to various vendors. You can pick the one that you like best. Again, the book is called Protocols: An Operating Manual for the Human Body. And if you're not already following me on social media, I am Huberman Lab on all social media platforms. So that's Instagram, X, Threads, Facebook, and LinkedIn. And on all those platforms, I discuss science and science-related tools, some of which overlaps with the content of the Huberman Lab Podcast, but much of which is distinct from the information on the Huberman Lab Podcast. Again, it's Huberman Lab on all social media platforms. And if you haven't already subscribed to our Neural Network Newsletter, the Neural Network Newsletter is a zero-cost monthly newsletter that includes podcast summaries as well as what we call protocols in the form of one to three-page PDFs that cover everything from how to optimize your sleep, how to optimize dopamine, deliberate cold exposure. We have a foundational fitness protocol that covers cardiovascular training and resistance training. All of that is available completely zero cost. You simply go to hubermanlab.com, go to the Menu tab in the top right corner, scroll down to Newsletter, and enter your email. And I should emphasize that we do not share your email with anybody. Thank you once again for joining me for today's discussion with Dr. Jared Rutter. And last but certainly not least, thank you for your interest in science. [outro music]

Episode duration: 2:03:46