#66 – Vamsi Mootha, MD: Aging, T2D, cancer, dementia, Parkinson’s—do all roads lead to mitochondria?

1. 0:00 – 0:04

   Intro

   1. PAPeter Attia0:00

      [upbeat music]

2. 0:04 – 20:14

   The Broad Institute and Vamsi's path from math to medicine

   1. PAPeter Attia0:04

      Hey, everyone. Welcome to The Peter Attia Drive. I'm your host, Peter Attia. The Drive is a result of my hunger for optimizing performance, health, longevity, critical thinking, along with a few other obsessions along the way. I've spent the last several years working with some of the most successful top-performing individuals in the world, and this podcast is my attempt to synthesize what I've learned along the way to help you live a higher quality, more fulfilling life. If you enjoy this podcast, you can find more information on today's episode and other topics at peterattiamd.com. [upbeat music] Hey, everybody. Welcome to this week's episode of The Drive. I'd like to take a couple of minutes to talk about why we don't run ads on this podcast and why instead we've chosen to rely entirely on listener support. If you're listening to this, you probably already know, but the two things I care most about professionally are how to live longer and how to live better. I have a complete fascination and obsession with this topic. I practice it professionally, and I've seen firsthand how access to information is basically all people need to make better decisions and improve the quality of their lives. Curating and sharing this knowledge is not easy, and even before starting the podcast, that became clear to me. The sheer volume of material published in this space is overwhelming. I'm fortunate to have a great team that helps me continue learning and sharing this information with you. To take one example, our show notes are in a league of their own. In fact, we now have a full-time person that is dedicated to producing those, and the feedback has mirrored this. So all of this raises a natural question. How will we continue to fund the work necessary to support this? As you probably know, the tried and true way to do this is to sell ads. But after a lot of contemplation, that model just doesn't feel right to me for a few reasons. Now, the first and most important of these is trust. I'm not sure how you can trust me if I'm telling you about something when you know I'm being paid by the company that makes it to tell you about it. Another reason selling ads doesn't feel right to me is because I, I, I just know myself. I have a really hard time advocating for something that I'm not absolutely nuts for. So if I don't feel that way about something, I don't know how I can talk about it enthusiastically. So instead of selling ads, I've chosen to do what a handful of others have proved can work over time, and that is to create a subscriber support model for my audience. This keeps my relationship with you both simple and honest. If you value what I'm doing, you can become a member and support us at whatever level works for you. In exchange, you'll get the benefits above and beyond what's available for free. It's that simple. It's my goal to ensure that no matter what level you choose to support us at, you will get back more than you give. So for example, members will receive full access to the exclusive show notes, including other things that we plan to build upon, such as the downloadable transcripts for each episode. These are useful beyond just the podcast, especially given the technical nature of many of our shows. Members also get exclusive access to listen to and participate in the regular Ask Me Anything episodes. That means asking questions directly into the AMA portal and also getting to hear these podcasts when they come out. Lastly, and this is something I'm really excited about, I want my supporters to get the best deals possible on the products that I love. And as I said, we're not taking ad dollars from anyone. But instead, what I'd like to do is work with companies who make the products that I already love and would already talk about for free and have them pass savings on to you. Again, the podcast will remain free to all. But my hope is that many of you will find enough value in, one, the podcast itself, and two, the additional content exclusive for members to support us at a level that makes sense for you. I want to thank you for taking a moment to listen to this. If you learn from and find value in the content I produce, please consider supporting us directly by signing up for a monthly subscription. My guest this week is Dr. Vamsi Mootha. Vamsi is a professor of systems biology at the Harvard Medical School. He has an appointment at the Broad Institute, which is actually where we met to conduct this interview, and we talk a little bit about what makes the Broad so special. He specializes in rare mitochondrial diseases as opposed to longevity per se, something that I love to talk about. But I think you'll see in this interview why it's so interesting to talk to someone who specializes in rare orphan mitochondrial diseases about longevity. His laboratory uses a blend of genomics, computational biology, biochemical physiology, and systems biology to study mitochondrial function and dysfunction. He received his bachelor's in mathematics and computer science at Stanford before going on to Harvard as part of the joint MIT Harvard program in medical school. He stayed in Boston to do his training in internal medicine, though as we discuss, he now focuses exclusively on research. He's received more honors and awards than I could name here, but it's always worth mentioning it when someone is a Genius Award recipient. So he won the MacArthur Foundation Award in two thousand and four, which, uh, obviously puts him in pretty rarefied earth. In this episode, we talk about a lot of things. We start with, at least for me, one of the best discussions I've ever had on the mitochondria. And you might think at first that some of this recapitulates things that were discussed on previous podcasts. You may recall we had a great discussion on the mitochondria with Navdeep Chandel. But we go a little bit deeper, and we talk more about some of the evolutionary pressure around the mitochondria. And even though at first you might think, "Well, gosh, this seems awfully scientific. Where's the application?" If you stick with it, you're, you're going to see where it comes and, and how understanding these rare orphan diseases that most of us have never heard of can give us an insight into aging. We do eventually start to talk about metformin, which I know many people ask about. And he provides a great insight into, or several great insights into what metformin may or may not be doing. And again, for, at least for me, this was like just the master's class in mitochondrial biogenesis, electron transport chain, et cetera. Talk about ways that we can target mitochondrial proteins and complexes to treat disease. But perhaps the single most insightful and interesting thing that we talked about that completely blew my mind was the role of hypoxia as a treatment. I want to repeat that again. The role of hypoxia, oxygen deprivation, as treatment. Now, we're going to cover this in a way that I think is very interesting, so I don't want to say any more about it. But I do want to add a disclaimer to this that Vamsi and I spoke about after the podcast, and I want to make sure it's here, right? So Vamsi emphasizes that their published research to date on the beneficial effects of hypoxia in animal models of mitochondrial disease is still in its early stages, and it's restricted to animal studies. It is not yet ready to be applied to humans. To extend these ideas to humans would be premature and irresponsible since hypoxia can have life-threatening implications. If and when the concept is extended into humans, it will need to be done so in a clinical trial setting with the appropriate ethical, regulatory, and safety measures in place. So with that caveat and without further delay, please enjoy my conversation with Dr. Vamsi Mootha. [upbeat music] Vamsi, thank you so much for, uh, making time today.

   2. VMDr. Vamsi Mootha7:37

      Oh, absolutely. Welcome.

   3. PAPeter Attia7:38

      Yeah, yeah. Sight unseen, too. I'm always impressed when people I don't know in advance agree to sit down with me. I'm kind of, uh, honored, humbled, so, so thank you very much.

   4. VMDr. Vamsi Mootha7:48

      Thank you for, uh, coming and meeting.

   5. PAPeter Attia7:50

      Yeah, the Broad is, is quite an impressive place. Tell folks a little bit about where we are right now and what makes this unique, even within the hallowed halls of, uh, Boston Biomedical Research Institutes.

   6. VMDr. Vamsi Mootha8:01

      No, I think it's a really exciting place, and I've had the pleasure of actually watching it blossom from, uh, nothing. It's really the brainchild of somebody named Eric Lander, who was one of the leaders of the Human Genome Sequencing Project. And as that was being completed in draft form in 2001, and then in quote "finished form" in 2003, he saw the need to create some sort of an entity that would take advantage of the power of genomics for improving biomedicine. So he created this institute, and it's unprecedented in a lot of ways. It's joint between Harvard and MIT. It involves all of the hospitals here in Boston, and it's basically a, uh, incredible forum where people can get together and basically pursue projects that they can't pursue on their own in their own individual laboratories. There's a big computational theme here. There's a big theme on being systematic in one's approach, not focused narrowly on the protein that they've studied in the past, but being systematic and seeing where the data takes you. And there's a very pervasive theme of collaboration as well. So Eric has always said that the Broad Institute is a bit of an experiment, but now it's been about 15, 16 years, and I think without a doubt it's been a wildly successful experiment.

   7. PAPeter Attia9:18

      Do most of you here at the Broad have an appointment elsewhere? Like, I know you spend much of your time at, uh, Mass General. Lots of people here spend-- You know, they have an appointment at MIT. Does everybody have another appointment outside of the Broad?

   8. VMDr. Vamsi Mootha9:30

      Almost. So there's almost, uh, two types of people that work at the Broad. There's some people that are actually formally employed by the Broad Institute, and there's others like myself that are employed elsewhere. In my case, I work at Mass General Hospital and Howard Hughes Medical Institute. That's my primary appointment. My paycheck comes from there. But then I spend a day a week over here working on collaborative types of projects that I can't pursue easily in my own, own lab. So there's almost two types of folks every year. I think one of the neat things about the Broad Institute is, you know, traditionally there's this grad student, postdoc, assistant professor academic track, but how about for all the other people that want to do research in a non-profit academic setting but aren't interested in applying for R1 grants or teaching? The Broad actually has an entire research scientist track as well, and so you can be employed here as a research scientist doing science.

   9. PAPeter Attia10:22

      And funded here.

   10. VMDr. Vamsi Mootha10:23

       And funded here. And I think that's a very, very different organizational model compared to any other academic organization.

   11. PAPeter Attia10:30

       Let's back up for a moment. You studied at Stanford, where you, you did, uh... Were, were you a computer science major? What was your major in undergrad?

   12. VMDr. Vamsi Mootha10:37

       I was math and computer science.

   13. PAPeter Attia10:39

       Okay. Got it. Did you know you wanted to get into biology and medicine?

   14. VMDr. Vamsi Mootha10:43

       You know, when I was a kid, I'm an Indian American. My father is a retired surgeon. As it turns out, my three older siblings would end up becoming doctors also. So I like to joke that we had the medicine gene in our family. So growing up, I was convinced I wanted to be a doctor of some sort. But then in high school, I fell in love with math. I did the high school math competitions, was pretty good at those. Did the high school science fair competitions in math, did well with those. And so I ended up going to Stanford with the goal of being a math and computer science major, and that's what I was squarely focused on. And then towards the end of college, when I was looking for a research project, my advisor told me about the work of Sam Carlin. He's a statistician that was developing some of the underlying methods for biomolecular sequence analysis. He's a fundamental mathematician and statistician.

   15. PAPeter Attia11:33

       And this is, like, early '90s?

   16. VMDr. Vamsi Mootha11:35

       Early '90s. That's right. That's right. So I ended up working on DNA sequence analysis as a college student, writing code to try to analyze DNA and protein sequences, and I fell in love with that. And then, uh, my advisor said, "Why don't you contemplate a future career in, in, in medicine? If for no other reason, going to medical school is a great way of learning physiology." You know, I thought about it from a practical perspective. I applied simultaneously to PhD programs in mathematical biology and also applied to MD-PhD programs, and then I applied to this program joint between Harvard and MIT. I actually thought that it was an MD-PhD program. This is all pre Internet.

   17. PAPeter Attia12:15

       Mm-hmm.

   18. VMDr. Vamsi Mootha12:15

       So I thought it was an MD/PhD program, but it wasn't. It was a straight MD program, but it's a joint program between the two institutions.

   19. PAPeter Attia12:22

       Yeah, they would set aside, like, a, I remember, like, 20 students for this, it, what was it called? The H-

   20. VMDr. Vamsi Mootha12:27

       HST.

   21. PAPeter Attia12:27

       HST program. That's right. [laughs]

   22. VMDr. Vamsi Mootha12:28

       That's exactly right.

   23. PAPeter Attia12:29

       Yeah, yeah.

   24. VMDr. Vamsi Mootha12:29

       That's right. So I was a part of the HST program, and it was, uh, kind of catered to students that had slightly quantitative backgrounds, math, computer science types of backgrounds. So it provided a bit of a more gentle introduction to medical school.

   25. PAPeter Attia12:43

       I could've used that program. [laughs] My first year of medical school was just unbearable. I mean, it was such a culture shock of-- I don't know if I told this story on the podcast before. The worst exam I've ever done in my life, from the point when I decided to care about school, was the first semester histology exam in medical school, because I very arrogantly and naively assumed that if I understood the concepts of histology, I didn't need to memorize anything. So I took this very pure math approach, which was I could just derive everything in my mind if I understood the fundamentals, and that got me a 53% [both laughing] on the final exam in histology, which, like, I just sat there looking at this number thinking, "How is this possible? Am I the stupidest human being that has ever walked the face of the Earth?" It was really a wake up call that said, "You know, you're gonna actually just have to start memorizing things around here."

   26. VMDr. Vamsi Mootha13:43

       It's a big culture shock, I think, when-- I know you have a background in, uh, engineering and applied math, so very similar to my background, and it made for a lot of unhappiness for me also that first semester of medical school.

   27. PAPeter Attia13:54

       [laughs]

   28. VMDr. Vamsi Mootha13:55

       At least you were in California. I was facing the Boston winter at the same time I was facing histology.

   29. PAPeter Attia14:00

       [laughs] That's a good point. I, I did have that going for me. So when you finished med school, you did a residency in internal medicine. You stayed in Boston, correct?

   30. VMDr. Vamsi Mootha14:09

       That's right.
3. 20:14 – 23:40

   How a snowy night sparked a career in mitochondria

   1. PAPeter Attia20:14

      So let's start talking about the mitochondria. When did you come to the realization that that was the area you wanted to focus on, and what is it about the mitochondria that especially drew you in?

   2. VMDr. Vamsi Mootha20:24

      So as a first year medical student, I was a little bit unhappy here in Boston. It was cold. There's a lot of memorization that first year, that first semester in particular. I wasn't sure if I'd actually made the right decision in coming to medical school from a math background. And then right in the middle of that first semester when we were taking our, uh, histology and pathology class, we had a very, very brief lecture on myopathies, muscle diseases. And there's one slide that basically indicated that there's a rare form of myopathies that are due to mutations in the mitochondrial DNA. Now, truth be told, I don't think I'd appreciated at that time that we had our own mitochondria with their own genomes, and so that immediately fascinated me. You dig a little bit deeper, you learn that these were once bacteria. They're kind of swimming around in our cells, so that's kind of cool. You see an image of mitochondria in the muscle. It's just beautiful. And there's just something that really captivated me, and I kind of got hooked on that organelle that first semester of medical school. And I've told this story to other people, Peter, but what happened was a few weeks later, my dad's cousin, who is at that time a postdoctoral fellow in the Harvard research, one of the research hospitals, she heard that I was unhappy, so she invited me over to her house in Somerville for a Friday night dinner. So it started to snow. I took the Red Line all the way to Somerville. It was a twenty-minute walk to her house. By the time I'd gotten in, my shoes were soaked. I was freezing. She immediately looked at me and said, "Oh my God, you look terrible." And so she took my coat off. She tried to dry me up, and she started cooking dinner. And then her boyfriend appeared like an hour later, and now it's about eight o'clock or nine o'clock or so. We had dinner together, and then we found out that the T had been shut down. And so not only was I an unhappy first year medical student, but now I'm spending Friday night with my dad's cousin and her boyfriend in Somerville. And so they create a makeshift bed for me in their living room. I'm spending the night there at this point. And, uh, I look at the bookshelf and there's a textbook of mitochondrial biology on the bookshelf. So just a few weeks earlier, I had this initial encounter with the organelle. I saw this book, so I just took it off the shelf and I just started reading it. I read about a hundred pages that first night. I borrowed it, and then I basically devoured that book over the course of the next few weeks, and I just fell in love with the organelle at that point and thought to myself that this is what I want to work on for the rest of my career.

   3. PAPeter Attia22:59

      That's, that's an amazing story. And I think for people listening, that's-- they shouldn't be concerned that they haven't had that eureka moment, right? I mean, I, I've, I've heard a lot of amazing scientists talk about their passion and not all of them, in fact most of them don't have such a laser moment like that. Now, of course, I can-- The stories of people that, that have those moments are even more vivid in my mind of that, "Oh my God, I can't think of anything but this." So let's talk a little bit about the mitochondria. You've already alluded to some of the really interesting features about it. So let's start with the-- Well, gosh, which one's the most interesting? Let's just start with the lineage, right? So how did these bacteria find their way into these eukaryotic cells?

4. 23:40 – 32:42

   Endosymbiosis, reductive evolution and the mitochondrial genome

   1. VMDr. Vamsi Mootha23:40

      Yeah, this is, uh, I think one of the most fascinating aspects of the organelle. So this is a process known as endosymbiosis. So the current theory is that there was an organism probably resembling a modern day gram-negative rod, something like a rickettsial species that merged-

   2. PAPeter Attia23:57

      Folks might not even know what that means, so gram-negative is just a staining that allows us to identify a type of bacteria. So you've got this bacteria that is shaped like a rod literally, and how does it get its energy prior to this encounter?

   3. VMDr. Vamsi Mootha24:12

      The thinking is that it had a full electron transport chain and was probably capable of doing aerobic metabolism using things like oxygen as a terminal electron acceptor, and one of the theories proposes that that had An electron transport chain that's not that different than modern day mitochondria. The hypothesis is that that somehow merged with something resembling modern day archaea. So there's three main domains of life. You have archaea, you have bacteria, and then you have eukaryotes, and eukaryotes have nuclei. So the hypothesis is that there's an archaeal species, there's a bacterial species, they form a union of some sort, and this is what gave rise to modern day eukaryotic cells maybe about one and a half billion years ago.

   4. PAPeter Attia25:02

      That's kind of remarkable. And is the idea, I mean, what kind of evolutionary pressure must have been placed to create an entirely new species? It's also binary. It seems somewhat binary to me. Is it? In, in other words, when you look at the difference between, I don't know, say, a chimpanzee and an ape or an ape and a human, you, you can see lots of continuous evolution, you know, Neanderthal, et cetera, et cetera. What you're describing sounds much more switched on, switched off. Is that the case? Was this a-- or were there lots of iterations that we can't even appreciate today in between the union and the current paradigm?

   5. VMDr. Vamsi Mootha25:44

      As far as we know, endosymbiosis of the mitochondrion only took place once.

   6. PAPeter Attia25:49

      Wow. [chuckles]

   7. VMDr. Vamsi Mootha25:50

      So there are lots of eukaryotes. Almost, not all, but almost all eukaryotes have a mitochondrion, and if you look at the DNA of those mitochondria that still have a genome, the phylogenetic analysis tells us that this was a monophyletic event. This took place only once. Now, that's not true for something like the chloroplast. That also arose through serial endosymbiosis, and that likely took place at least two independent times in evolution. But for the mitochondrion, it probably only took place once as far as we know.

   8. PAPeter Attia26:25

      And the chloroplast, of course, is to a plant effectively what the mitochondria is to an animal like us.

   9. VMDr. Vamsi Mootha26:31

      That's exactly right.

   10. PAPeter Attia26:32

       Yeah. So how many genes do we think that that gram-negative rod had?

   11. VMDr. Vamsi Mootha26:38

       Great question. Probably about a thousand to two thousand.

   12. PAPeter Attia26:41

       And at the time, the species that it merged with would have had how many to the best of our guessing?

   13. VMDr. Vamsi Mootha26:48

       Probably also a few thousand.

   14. PAPeter Attia26:50

       So you had two things that had comparable numbers of genes merge, and yet today you or I would have thirty thousand, twenty thousand genes inside the nucleus, and we'd have, is it thirteen genes inside our mitochondria? Thirteen preserved genes. So in other words, to a first order approximation, the mitochondria lost all of its genes, but a deeper dig says actually it somehow hung on to thirteen. Why do you think that was?

   15. VMDr. Vamsi Mootha27:22

       This is what we call reductive evolution. Modern day mitochondria actually represent a mosaic. So you need about a thousand proteins total to make our mitochondria, and so some of those are attributable to the original bacterial ancestor, and others are brand new innovations that even that original bacteria did not have. But on the reductive side, approximately a thousand genes from that original bacteria have either been lost altogether or have been transferred to the nuclear genome so that that genome today is tiny. It's only about sixteen thousand bases, and it encodes thirteen proteins. But that's only if you're looking at animals, right? There's a lot of different eukaryotes, so there's a lot of mitochondrial diversity. So you and I still retain thirteen proteins that are encoded by our mitochondrial genomes, but if you look at malaria, it's also a eukaryote. It has a mitochondrion, but its genome only encodes three proteins today, so that's additional reductive evolution.

   16. PAPeter Attia28:25

       What about things like, you know, flies, yeast? Are they also variable?

   17. VMDr. Vamsi Mootha28:29

       Flies are also animals, and so most animals-

   18. PAPeter Attia28:31

       You would put them in the category, yeah.

   19. VMDr. Vamsi Mootha28:33

       That's right. So they would have about thirteen, sometimes fourteen proteins. But if you look at something like Giardia, which causes, uh, a terrible diarrheal illness, beaver fever, that's a eukaryote. It's actually lost its mitochondrial DNA altogether.

   20. PAPeter Attia28:48

       I know we talked about thirteen proteins. Is it one-to-one mapping, or are there genes that are non-coding, or is it?...

   21. VMDr. Vamsi Mootha28:54

       Right. So the mitochondrial genome encodes two ribosomal RNAs, twenty-two tRNAs, and then thirteen proteins.

   22. PAPeter Attia29:01

       Thirteen proteins. Yep. So obviously to have thirteen, you, we pretty much have a good sense of what the function of each of these are. How many diseases that afflict humans result from genetic disorders there, inherited mutations that produce dysfunctional proteins?

   23. VMDr. Vamsi Mootha29:18

       Right. There's about two hundred and fifty different syndromes of the mtDNA, of the mitochondrial DNA. And by syndrome I mean there's a particular mutation that's associated with a particular clinical phenotype. But that's only if we're talking about the mitochondrial disorders of the mtDNA.

   24. PAPeter Attia29:37

       That's right. Is that a higher or lower frequency on a probability basis given the number of base pairs? 'Cause you said something like only what, sixteen thousand base pairs? It's relatively tiny. We have genes in our nuclear genome that are ten times that size. So from a probability basis that you could have two hundred and fifty mutations in that sixteen thousand base pair that would each lead to these distinct mitochondrial diseases, is that more or less robust from a DNA perspective than our nuclear DNA?

   25. VMDr. Vamsi Mootha30:09

       I don't think we have a good answer to that question. There's a little bit of an ascertainment bias in clinical medicine. So, you know, when I was going through residency, probably when you were also going through your clinical training, the answer to almost every single question about mitochondrial disease was maternal inheritance.

   26. PAPeter Attia30:27

       Mm-hmm.

   27. VMDr. Vamsi Mootha30:28

       And that's because The nuclear genome was sequenced in draft format in 2001, but the mitochondrial DNA was sequenced in 1981, so that was almost exactly 20 years earlier, and it's small. And so as soon as you saw patients that had a particular clinical phenotype that could be a mitochondrial disease, it was easy to sequence the mitochondrial DNA. So beginning in 1988 when two papers were published reporting the first mutations in the mitochondrial DNA, it's been relatively straightforward to sequence it and associate mutations in mtDNA with the disease phenotype. And this is why now there's about 250 of these mtDNA mutation clinical phenotype mappings. The nuclear genome has, has been a little bit slower to follow since 2001 and beginning even a little bit before the, the completion of the genome sequence. We've now as a community been able to identify about 300 different genes in the nuclear genome that underlie mitochondrial disorders, and of course, that's 300 different genes, but then there's different allelic variants as well. So I think it's gonna be a little while before we can, we can answer your question in a satisfactory way, but it's a really provocative question.

   28. PAPeter Attia31:43

       And, and one more number to sort of extract from that is do we have a sense of how many genes in the nuclear genome are required for mitochondrial function? So in other words, what's the denominator nuclear-wise?

   29. VMDr. Vamsi Mootha31:56

       Right. That's actually one of the areas that we focused on heavily in our laboratory. So beginning soon after the sequencing of the human genome, we knew that the human genome encodes about 22,000 proteins. So an important question is which of those find their way to the mitochondrion? It's gonna be more than 13.

   30. PAPeter Attia32:14

       Right.
5. 32:42 – 44:14

   Mitochondrial biogenesis, AMPK, turnover and maternal inheritance

   1. PAPeter Attia32:42

      How do they communicate? Do we, do we know how expression of mtDNA is coordinated with nuclear DNA?

   2. VMDr. Vamsi Mootha32:50

      It's a really, really interesting question. So some of the mechanisms are known, but a lot of mechanisms are not yet known. So when you exercise, for example, if you're deconditioned and if you do a combination of aerobic training and strength training, you can actually increase the number of mitochondria, and there's an entire transcriptional program that will turn on all those nuclear genes. But that same program will also turn on the replication factors that will go into the organelle and cause the mitochondrial DNA to replicate as well. So it's a really smart transcriptional program that says in response to exercise, make more of the nuclear encoded components and make more of the mitochondrial DNA and make more of the mitochondrial DNA encoded proteins.

   3. PAPeter Attia33:35

      So that increases mitochondrial density at any given cell, so you have a myocyte, a muscle cell. Do we know what the actual signals are that basically instruct the cell to make more DNA? So what is the input from the exercise? You, you mentioned two types of exercise, right? Strength training and aerobic activity. Those have very different physiologic properties. So what is it that at the physiologic level is leading to this nuclear level?

   4. VMDr. Vamsi Mootha34:03

      One of the important signals is something called AMP kinase. The change in the ATP to ADP ratio, that's known to be one of the activators of this particular transcriptional program that induces mitochondrial biogenesis.

   5. PAPeter Attia34:17

      So this would be an, a decrease in AMPK activity?

   6. VMDr. Vamsi Mootha34:22

      An increase in AMPK.

   7. PAPeter Attia34:23

      An increase, okay.

   8. VMDr. Vamsi Mootha34:24

      So that is basically sensing something like the ATP to ADP ratio.

   9. PAPeter Attia34:29

      Ratio is going down, yeah.

   10. VMDr. Vamsi Mootha34:30

       And so when we exercise, the ATP levels are usually pretty nicely defended, but then what's happening is there's another reaction that's taking two ADP molecules, making an ATP, liberating AMP. While ATP levels are defended, some of these ratios change and that can be sensed, and that's one of the inputs into this program that says, "Let's make more mitochondria."

   11. PAPeter Attia34:52

       Now we'll come back to this far down the line, but just 'cause it's-- you mention it, one of the effects of a drug called metformin that everybody loves to ask about is it activates AMPK. Does that imply that metformin administration by itself alters, uh, mitochondrial density?

   12. VMDr. Vamsi Mootha35:09

       So I think when we talk about exercise, I think AMP activation is generally regarded as one of the important signals for mitochondrial biogenesis, but I don't think it is sufficient.

   13. PAPeter Attia35:20

       It's not sufficient. It's necessary though, potentially?

   14. VMDr. Vamsi Mootha35:24

       I think it is, but I would need to review some of the older literature to really confirm that.

   15. PAPeter Attia35:28

       So what do you think some of the other signals are?

   16. VMDr. Vamsi Mootha35:30

       I think some of the other signals are things like calcium, and clearly there's other signals. There's a couple of disease states as well where we see a massive proliferation of mitochondria. They're not functioning properly, but there's a massive proliferation of malfunctioning mitochondria, so we're trying to work out some of those signals as well. So as of right now, it's a bit of an open question as to exactly how the number of mitochondria is sensed and regulated, but we know some of the inputs.

   17. PAPeter Attia35:58

       Right. We know crudely what the inputs are, right? Exercise, as you mentioned. What are some of the other things that even hormonally, for example, do nutrients play a role?

   18. VMDr. Vamsi Mootha36:09

       One of the studies that I was a part of about 10 to 15 years ago or so show that even things like androgens and testosterone can actually influence the amount of mitochondria. Disuse is a great way of rapidly eliminating mitochondria. And then in terms of nutrients, NAD is an important signal as well. This transcriptional regulator that I'm talking about, it's called PGC1alpha, and upstream of it is something called SIRT1, which of course utilizes NAD as a cofactor. So there's a couple of these inputs.

   19. PAPeter Attia36:44

       I'm having lunch with David Sinclair later today, so we'll be talking plenty about this.

   20. VMDr. Vamsi Mootha36:47

       Absolutely. Absolutely. So I think a couple of these signals are beginning to emerge, but we're not at that stage right now where in a pill we can put seven of these things, give it to a patient, and boom, we can replace exercise. We're not there yet, but it'd be remarkable if we understood the process well enough so that we could one day.

   21. PAPeter Attia37:10

       Yeah, there's been lots of claims of exercise in a pill. I remember, uh, The New York Times wrote about something called irisin. God, they wrote about it in two thousand eleven, '12, and then I saw it again recently. And, you know, it's funny, of course, you see these stories which you realize they're being written about in such a crude way that you can infer nothing. So you go back and look at the paper, and you realize [chuckles] it's kind of a ridiculous claim at this point. What is the turnover of mitochondria in a cell? So if you have-- Let's put some scale to things for folks. So I'm gonna take, I'm gonna biopsy one cell from your quadricep, one muscle cell. How many mitochondria approximately would be in it, assuming you're a relatively well-conditioned individual?

   22. VMDr. Vamsi Mootha37:49

       Talking about the number of mitochondria is a little bit ambiguous because they're not quantal units. Mitochondria will constantly undergo fusion and fission, so at any given state, you can have a different-

   23. PAPeter Attia38:02

       Hmm

   24. VMDr. Vamsi Mootha38:02

       ... quote number of mitochondria. The mitochondrial DNA is a quantal unit, so you can ask how many mitochondrial genomes are there per nuclear genome in a cell type.

   25. PAPeter Attia38:13

       Okay.

   26. VMDr. Vamsi Mootha38:13

       So a fibroblast will have a few hundred, maybe a thousand copies of the mitochondrial genome for each of its-

   27. PAPeter Attia38:19

       For each copy of its nuclear genome.

   28. VMDr. Vamsi Mootha38:21

       That's right. But there's a lot of variation.

   29. PAPeter Attia38:23

       The highest would be what? Like a cardiac myocyte or something or a neuron?

   30. VMDr. Vamsi Mootha38:27

       The unfertilized egg.
6. 44:14 – 56:09

   Mitochondria 101: batteries, electron transport and NAD

   1. PAPeter Attia44:14

      So let's talk a little bit about sort of mitochondria 101. So you're, you're a first year medical student learning about the mitochondria. Here's, here's basically what you learn, right? You've got these, you've got this inner membrane, this outer membrane. I forget what the term is. Do they call it the powerhouse of the cell or something like that?

   2. VMDr. Vamsi Mootha44:30

      Yes. [laughs]

   3. PAPeter Attia44:30

      I think there's some, there's some sort of glib term that I know that people who study mitochondria like yourself and Navdeep Chandel, who I've interviewed, sort of bristle at the simplicity of such a term. But the idea is, all things being equal, a cell takes in glucose, free fatty acid, substrate for energy, and, uh, let's start with the glucose, 'cause we'll probably spend more time talking about glucose today. Through, what is it? I can't even remember. Ten steps, we turn glucose into pyruvate, more or less.

   4. VMDr. Vamsi Mootha44:58

      Mm-hmm.

   5. PAPeter Attia44:59

      We then basically have a choice. A cell has a choice based on the availability of oxygen and the rate at which ATP is being demanded. So if oxygen is scarce relative to ATP demand, you can take a inefficient route, but at least you guarantee to get some ATP, which is you can turn the pyruvate into lactate. And lactate itself is interesting, and maybe we can talk about it, but you generate some ATP. If the demand for ATP is not as great and there's sufficient cellular oxygen, you can take that pyruvate and make acetyl-CoA, and that acetyl-CoA then becomes one of the substrates leading into this thing called the electron transport chain you alluded to. Walk us through what happens in that latter scenario.

   6. VMDr. Vamsi Mootha45:48

      I like to think of the mitochondria as being the key place where there's energy transformations. So in order for a cell to work, it needs energy, but in the same way that in order to live our lives, we need to have one type of battery for our iPhone, a different type of a battery for our laptop, a different type of a battery for our automobile. We need energy packaged in different ways. So this is sort of the charm of the mitochondria, and what it does is it's gonna take fats and carbohydrates and proteins, and it's gonna break it up almost like a Cuisinart. And as it's breaking it up, it's gonna harness the electrons, and that's what's called an electromotive force. That's one type of energy. So you're probably familiar with things like the NADH to NAD ratio. That's basically an el- electron carrier. So that's one form of energy, and certain types of enzymes can be powered directly by NADH and NAD. But then that can also be converted to a gradient, a voltage across the inner membrane, a different type of an energy form, and that energy form can be used to drive transport.

   7. PAPeter Attia46:59

      So let's explain what that means to people. So everybody knows what a battery looks like, like literally a Duracell battery that you stick into whatever, you know, your kid's toy, and that's typically about one point five volts, right? A nine volt battery gets its name because it has nine volts, but everyone recognizes it as the goofy square one. We take this, I think, for granted 'cause we sort of have these backgrounds in math or engineering and stuff, but I think for the average person, it's helpful to understand what voltage means, and you just alluded to it, right? It's a potential, it's a gradient that is created by disproportionate placement of electrons, and it's only with that that you can generate power. So why does a battery die? Why is it that, let's pretend I'm still using a Walkman, [chuckles] I, I put my two one point five volt double A batteries in my Walkman. At some point it stops working. Why?

   8. VMDr. Vamsi Mootha47:55

      At some point it's not gonna be able to hold charge, and so I'm probably more familiar with the mitochondrial battery than I am with the Duracell battery.

   9. PAPeter Attia48:03

      Right.

   10. VMDr. Vamsi Mootha48:03

       But when you have nicely functioning mitochondria, you can charge them, you can create a nice voltage that can be used for work. You can dissipate it, you can recharge it, but at some point when it gets older, when the membrane is a little bit leakier, when it can't, it, it'll stop holding charge.

   11. PAPeter Attia48:22

       So it's that ability to keep a difference in charge across the membranes that is the same reason your little one point five volt battery in your Walkman I love that I'm saying Walkman, by the way. There's half the people listening to this won't actually know what that means. Or the nine-volt battery in your smoke detector, or frankly, the fancy, I don't even know how many volts a Tesla battery is. It's like 12 volts, I'm guessing, or something like that in an electric vehicle, whatever. But there's a reason you have to keep charging these, but at some point, even when you charge them, they cease to work if it's a rechargeable.

   12. VMDr. Vamsi Mootha48:53

       That's right.

   13. PAPeter Attia48:54

       And you're basically saying, "Look, think of a mitochondria as partially being a battery."

   14. VMDr. Vamsi Mootha48:59

       That's right. That's only one form of energy, right? So-

   15. PAPeter Attia49:01

       That's taking chemical to electric.

   16. VMDr. Vamsi Mootha49:03

       That's exactly right. And so you can have an electromotor force, you can have a proton motor force, and then you can dissipate that battery to basically catalyze a formation of ATP, which most people know is the energy form that's used to power muscle when you exercise. So the mitochondrion is doing all of these elaborate energy transformations from electrical potentials to proton potentials to phosphorylation potentials, and different enzymes and processes and machines in your cells will use one or the other.

   17. PAPeter Attia49:36

       This is so exciting. Like, I've tried to have this discussion with my daughter, who's 10, and she's not quite at the point where she sees why I think this is amazing. But she's almost at that point where I guess you can look at a piece of food on the plate and explain why eating that is essential, right? Like, where is the energy in that food? So maybe we'll use this as sort of the example to go full cycle. So you are looking at a Cheerio on your plate, right? Now, that Cheerio is mostly carbohydrates, so we'll simplify this. And it's got glucose in it. It's probably got more complex carbohydrates in it. But at a molecular level, it's a lot of carbons joined to hydrogens, carbons joined to carbons, and carbons joined to oxygens, and oxygens joined to hydrogens. That's probably most of the bonds, correct? So bonds contain energy. There's chemical energy there. Which of those bonds would be the most energetic? Probably the carbon-hydrogen in total number, just given the ubiquity of it, right? That carbon-hydrogen has more energy than a carbon-carbon, I'm guessing.

   18. VMDr. Vamsi Mootha50:50

       I'm not too sure. Not sure.

   19. PAPeter Attia50:52

       I think that's the case. In the show notes, we'll list what the potential energy is in each of those bonds. But nevertheless, you go through this process of actually eating the thing. You put it in your mouth, you break it down. Mechanically, you've broken it by the time it exits your stomach. But it's really once it gets absorbed out of the bloodstream that you begin this chemical process of breaking those bonds, and then you get something for free, right? When you break those bonds, that's when you're getting the energy to create this electron gradient.

   20. VMDr. Vamsi Mootha51:20

       That's right.

   21. PAPeter Attia51:21

       Which you then use at the end to basically do this one thing you alluded to, which is phosphorylate the ATP.

   22. VMDr. Vamsi Mootha51:30

       Right.

   23. PAPeter Attia51:30

       So that energy gradient allows you to then put a phosphate back onto an ADP. That's the most obvious one from food. Now, you talked about NAD and NADH. Can you say a little bit more about what those are and how they fit into this, in particular in the mitochondria?

   24. VMDr. Vamsi Mootha51:47

       Again, the classical teaching is that NAD is an electron carrier. When you have two electrons, it's going to be in what's called the NADH form. And if you don't have those two electrons, it's in the oxidized form, which is the NAD form. That's another way of holding the energy that can catalyze reactions. What we're learning over the last few years is that in addition to this role as an electron carrier, the NAD itself can be used as a substrate for other reactions.

   25. PAPeter Attia52:18

       Outside of the mitochondria or inside?

   26. VMDr. Vamsi Mootha52:20

       Outside of its role as an electron carrier.

   27. PAPeter Attia52:23

       Okay, and the biggest role for that is in these, we'll come, I guess we'll, we'll allude to it, but there are these complexes in the mitochondria.

   28. VMDr. Vamsi Mootha52:30

       But that's still as a redox carrier. So the electrons go from the NADH are transferred to the electron transport chain, and that's basically a wire that's going to conduct the electron until they hit oxygen and make water. That's a downhill process. And during that downhill process, these protons are pumped across the inner membrane, generating about 150 millivolts, and that can then be used to, to do work, including catalyzing the conversion of ADP to ATP, and that's what we call oxidative phosphorylation.

   29. PAPeter Attia53:02

       Yep. But then talk about the other example that you were using there.

   30. VMDr. Vamsi Mootha53:05

       And this is a, a, a newer area of biomedicine, and actually David Sinclair has worked in this area quite a bit. But everything that I just told you relates to electrons coming on and off of NAD. So when we talk about the NADH to NAD ratio-
7. 56:09 – 1:02:18

   Rare mitochondrial diseases as a window into aging

   1. VMDr. Vamsi Mootha56:09

      We've historically placed a lot of emphasis on a very large collection of individually rare inborn errors of mitochondrial metabolism. These are typically single gene disorders. They can be due to recessive mutations in the nuclear genome, or they can be due to mutations in the mitochondrial genome. But at the end of the day, there's a component of the mitochondrion that's defective at birth. And so what we just spoke about is the fact that as all of us age, there's a gradual decline in the activity of mitochondria. The big question in the field is whether that's cause or consequence. These other three hundred rare monogenic disorders of mitochondria, there's no doubt, there's no question.

   2. PAPeter Attia56:53

      Right. The, the gene did the randomization for you. You know cause and effect.

   3. VMDr. Vamsi Mootha56:57

      That's exactly right. The mitochondrion is defective at birth, and now we can actually evaluate what the consequences are.

   4. PAPeter Attia57:04

      Now, you said about three hundred. What is the phenotypic spectrum? How many of these, for example, are fatal within the first year of life?

   5. VMDr. Vamsi Mootha57:11

      They tend to follow a bimodal distribution. The recessive mutations in the nuclear genome, they tend to present early in infancy within the first few weeks or months of life. The mutations in the mitochondrial genome, those tend to present a little bit later in life.

   6. PAPeter Attia57:27

      Wow. So let's focus on the latter group for a moment. I mean, un- unless you'd prefer to start with the former. Which one do you spend more time looking at?

   7. VMDr. Vamsi Mootha57:34

      We spend a little bit more time on the nuclear genes.

   8. PAPeter Attia57:36

      Okay. Because they present earlier and presumably they're more severe?

   9. VMDr. Vamsi Mootha57:39

      That's right.

   10. PAPeter Attia57:39

       Okay. So give me an example of what some of those mutations are and what their phenotype is.

   11. VMDr. Vamsi Mootha57:44

       One of the clinical syndromes that we study is something called Leigh syndrome. So there's about eighty different genes that can be mutated to give rise to this clinical syndrome, which is basically a subacute degeneration of the gray matter. It's a very rapid neurodegeneration. It's a terrible, terrible disease.

   12. PAPeter Attia58:03

       And what age are people when they start to experience this neurodegeneration?

   13. VMDr. Vamsi Mootha58:07

       So most of these kids are actually born developmentally okay.

   14. PAPeter Attia58:12

       Wow.

   15. VMDr. Vamsi Mootha58:12

       And then within the first couple of months of life, there's some sort of a stressor. Sometimes it's some sort of an infection, sometimes it's dehydration that'll put them into a neurometabolic crisis. And at that point, if you look at their brain MRIs, you'll see lesions in the brain stem, the basal ganglia, sometimes the spinal cord corresponding to regions of, uh, necrosis.

   16. PAPeter Attia58:34

       Wow. So quickly fatal. And what did you learn? I mean, you, you have one syndrome, but there are many paths that produce it. What's the c-- Are there common threads to the genetic insults that lead to this awful phenotype?

   17. VMDr. Vamsi Mootha58:48

       No, great question. That's exactly what we're trying to figure out. So thanks to genetics, we've now been able to, we as a community, I mean, have been able to map out genes in the nuclear genome. Some of these are in the mtDNA, but at the end, we get this thing called Leigh syndrome, and we're trying to figure out what exactly is it about the broken mitochondrion that gives rise to this phenotype. And honestly, we don't know what the full answer is right now, but it's a very, very active area of research right now.

   18. PAPeter Attia59:13

       It might be naive, but just listening to you describe this, I can't help but think, can we learn something about Alzheimer's disease or other forms of neurodegeneration, which I think m- many people are starting to argue are basically neuronal energy crises. So there are lots of insults, right? You can have an accumulation of toxin. You can have a insulin resistance, frankly. You can have microvascular disease. All of these things are predisposing people to neurodegeneration, and something that they could all have in common is depletion of energy to the neuron, which would be perhaps the most sensitive cell to an energy reduction. I mean, anybody can think about that for a moment. If you know somebody who's lost their ability to breathe for a period of time, usually the thing we care about the most is their brain, 'cause that's the first thing that you suffer from when you have a hypoxic event. So is that based on Leigh syndrome, is that the explanation for why you're potentially seeing it disproportionately in the brain versus skeletal muscle? Is it just the sensitivity of the brain to energy withdrawal, or do you think there's something specific about the mitochondria in neurons?

   19. VMDr. Vamsi Mootha1:00:33

       Mitochondrial disorders can actually impact almost any organ system, and so Leigh syndrome represents One type of clinical manifestation of mitochondrial disease, but there's another set of disorders that impact the skeletal muscle as well. And I think at this point we don't know why mutations in one subunit of the electron transport chain gives rise to brain disease. A mutation in the neighboring subunit of the same protein complex that's equally evolutionarily conserved will give rise to muscle disease.

   20. PAPeter Attia1:01:06

       Wow.

   21. VMDr. Vamsi Mootha1:01:06

       [laughs] There's a, a massive non-linearity over here that we simply don't understand right now.

   22. PAPeter Attia1:01:14

       So if there is one and only one silver lining in these awful diseases, it's that scientists will have no shortage of questions to ask for decades to come.

   23. VMDr. Vamsi Mootha1:01:23

       No, I think this is a super active area of, uh, research right now, in part fueled by the link between mitochondrial decline and aging.

   24. PAPeter Attia1:01:32

       Yeah.

   25. VMDr. Vamsi Mootha1:01:33

       So that's such a complicated problem. You know, trying to understand why a car breaks down after being in service for 25 years, it, it's hard. Is it, did some fan belt break? Did the battery stop charging? Did the tire deflate? It, it's kind of hard to know why an entire car breaks down after 25 years. In these rare mito disorders, we have 300 different forms of that automobile that was almost broken at birth, if that makes sense.

   26. PAPeter Attia1:02:03

       Yeah.

   27. VMDr. Vamsi Mootha1:02:04

       We study them in part because these patients need new treatments and therapies, and so that's enough of a motivation for us, but we also do expect that a subset of them, by studying them, will inform what's happening in the more common form of aging.

8. 1:02:18 – 1:22:08

   Excess unused oxygen as a mechanism of mitochondrial disease

   1. PAPeter Attia1:02:18

      Your lab studies oxygen, but not necessarily in the way that most people commonly think about it. Most people when they think of oxygen and mitochondria, something that comes to mind pretty quickly is ROS.

   2. VMDr. Vamsi Mootha1:02:30

      Absolutely.

   3. PAPeter Attia1:02:30

      I spoke with a friend of mine, Navdeep Chandel, and we spoke a lot about ROS, and Nav had a great take on it, which was, "Look, we think of ROS typically only in the negative, and they do lots of negative things, but they may also be a signaling molecule and therefore an essential thing." Talk to me about the lens through which your group looks at oxygen.

   4. VMDr. Vamsi Mootha1:02:50

      So remember a while ago you asked a very, very astute question. You have these 80 different genes. When they're mutated, they give rise to this thing called Leigh syndrome, which is a different type of a neurodegeneration. What does that pathology, pathogenesis look like? The traditional dogma for mitochondrial pathogenesis is that when the powerhouse of the cell is broken, there's not enough ATP, and there's a power failure. That's the traditional dogma, and without a doubt, there's truth to that in some instances. What we've discovered is that in addition to producing ATP, mitochondria are also consumers of oxygen. Most of the oxygen that you breathe, Peter, is being consumed by your mitochondria. When a patient has a birth defect in the mitochondrion, in addition to not being able to produce sufficient ATP, they also have excess oxygen as well. So oxygen delivery tends to be patent in these patients, but the utilization ends up being poor.

   5. PAPeter Attia1:03:59

      And oxygen, just asking for people to understand this, how does oxygen even get to the mitochondria? So we all understand that we're breathing air that has oxygen, and let's even go one step further and just take it for granted that there's a, a gradient in the lung that allows oxygen to get into hemoglobin to a red blood cell. Now that you have a fully loaded red blood cell in an arteriole that enters a capillary, how many things have to happen for oxygen to get into the mitochondria specifically, not just the cell?

   6. VMDr. Vamsi Mootha1:04:27

      Oxygen is not particularly soluble in water or fluids, and so we have an oxygen carrying protein called hemoglobin that's found in our red blood cells. And so in the lungs, all of the red blood cells and their hemoglobin get loaded with oxygen, and now these red blood cells are delivered to peripheral tissues, and the oxygen gets extracted from the fluid, and as the fluid gets depleted in oxygen, the hemoglobin will basically offload its oxygen. And so there's certain tissues that become extremely, extremely hypoxic. So the oxygen will get extracted by a tissue largely by, uh, diffusion, and the mitochondrion is basically consuming most of this oxygen.

   7. PAPeter Attia1:05:08

      So a cell that is sitting there doesn't require an active transporter to get oxygen across its outer membrane, so it just diffuses across.

   8. VMDr. Vamsi Mootha1:05:17

      That's right.

   9. PAPeter Attia1:05:17

      And then when oxygen enters the cytoplasm, how does it get over to the mitochondria?

   10. VMDr. Vamsi Mootha1:05:22

       Depending on the cell type, uh, it either diffuses, uh, uh, freely.

   11. PAPeter Attia1:05:25

       How does it know that the mitochondria is the place it needs to go?

   12. VMDr. Vamsi Mootha1:05:28

       Well, it's being consumed, so it's a little bit of a sink, basically.

   13. PAPeter Attia1:05:31

       Ah, so that, what, that's what I want to understand. There are lots of places oxygen could hang out, so what is the force that is drawing it into the mitochondria? Is it simply utilization that basically creates a vacuum?

   14. VMDr. Vamsi Mootha1:05:43

       That's right. That's right. That's right. Now, in certain tissues like skeletal muscle and heart, we have other oxygen carriers in the tissue. Things like myoglobin are oxygen carriers, so they're almost little buffers of oxygen that are in the tissue.

   15. PAPeter Attia1:05:54

       Yeah, they're more like loaders, right?

   16. VMDr. Vamsi Mootha1:05:56

       That's right.

   17. PAPeter Attia1:05:56

       They, they, I think of them as, uh, like another storage for oxygen inside.

   18. VMDr. Vamsi Mootha1:05:59

       That's right.

   19. PAPeter Attia1:05:59

       Yeah.

   20. VMDr. Vamsi Mootha1:06:00

       That's right. Yeah.

   21. PAPeter Attia1:06:00

       But that still has to get off the myoglobin and get sucked into the mitochondria effectively, right?

   22. VMDr. Vamsi Mootha1:06:06

       That's right. So it's another little storehouse, if you will. It's another buffer of oxygen so that when you're exercising, for example, you may not want to be oxygen limited, so you have a little extra oxygen in your myoglobin. But basically, your mitochondrion is where most of your oxygen is being consumed, so it's a sink, and so that's the reason that we have gradients inside of our cells.

   23. PAPeter Attia1:06:28

       It's amazing. I've never really even thought about it this way, but it's sort of interesting to think at how efficiently the body disposes of carbon dioxide because as you alluded to earlier, the end of that downhill gradient is a final path of electron acceptance generating H2O and CO2, both of which we manage to largely off gas. So somehow those things have to exit the mitochondria, weasel out of the cell. cross the gradient and go back to, well, the in the case of CO2, get back to the hemoglobin molecule and get carried back. It's like there's a lot of things going on here.

   24. VMDr. Vamsi Mootha1:07:07

       Well, so one of the things that we're discovering by studying these rare diseases, and this happened because of a CRISPR screen that we did a couple of years ago, but we've, w- what we've now discovered is that one of the consequences of mitochondrial dysfunction is excess unused oxygen.

   25. PAPeter Attia1:07:24

       So in other words, if a mitochondrion is failing to do its job, you will be failing to utilize oxygen, therefore you would see an excess accumulation of oxygen.

   26. VMDr. Vamsi Mootha1:07:37

       That's right. And we believe, this is our hypothesis now, it's that some of that excess unused oxygen is what is contributing to the pathology that we see in some of these rare diseases. It's a very, very different type of an idea. It's not all about the ATP. It's about excess unused oxygen, and we're not necessarily invoking reactive oxygen species.

   27. PAPeter Attia1:07:59

       Yeah, I was just about to say, is it through free radicals, or is it actually oxygen to oxygen, no extra electron oxygen?

   28. VMDr. Vamsi Mootha1:08:10

       This is dioxygen toxicity that we're talking about. The way that I like to think about it is that if you have an automobile that's outside and it's rusting, it's rusting in part because the oxygen is directly oxidizing iron. You may produce a radical, but that's not the phenomenon.

   29. PAPeter Attia1:08:28

       But that's not the-- Yeah.

   30. VMDr. Vamsi Mootha1:08:29

       So the car outside is not rusting because of too much superoxide or hydrogen peroxide. It's direct oxidation of iron centers by oxygen. And so one of our hypotheses is that enzymes are tuned to operate within a particular oxygen range.
9. 1:22:08 – 1:28:15

   Mitochondrial decline, inflammation and the causality question

   1. PAPeter Attia1:22:08

      You talked earlier about signatures of time, and another one of these signatures of time is inflammation within muscle cells. There was a paper that came out about a year ago that used Sting to basically block the ability of a cell to sense breakdown in mitochondrial DNA. Are you familiar with this work?

   2. VMDr. Vamsi Mootha1:22:28

      I'm a little bit familiar with the Sting pathway.

   3. PAPeter Attia1:22:31

      My understanding, it's been about a year since I read this, maybe a bit less, was that serially, if you study muscles as they age, you see more and more inflammation. So the question is, what is drawing inflammatory cells into muscle as we age? And the hypothesis was going back to something you talked about earlier. The DNA of mitochondria is bacterial in origin, and therefore, if you have a loose fragment of nuclear DNA in the cell, it shouldn't be especially immunogenic. But if you have a loose fragment of bacterial DNA in a cell, that should actually be quite immunogenic. Our immune systems would think of that as foreign. So the hypothesis was, what if the increase in inflammation we see is due to greater and greater mitochondrial damage that is leading to more and more exposure of mitochondrial DNA? And I believe to test that, it used Sting, and remind me, I think Sting actually blocks the ability of the cell to sense the mitochondrial DNA. Is that correct?

   4. VMDr. Vamsi Mootha1:23:34

      Not just mitochondrial DNA, but I think it's a general nucleic acid-

   5. PAPeter Attia1:23:37

      Okay

   6. VMDr. Vamsi Mootha1:23:37

      ... sensor. And so there could be different sources. I think-

   7. PAPeter Attia1:23:40

      It could block the sensing of DNA, period?

   8. VMDr. Vamsi Mootha1:23:42

      I think ordinarily, it's designed to sense the DNA of incoming viruses or incoming pathogens. But you could imagine that if a mitochondrion ruptures, that same DNA nucleic acids can also be sensed. And you're right, because the mitochondrion used to be a, a bacteria, a lot of the components inside of our mitochondria resemble that of modern day bacteria and can be very immunogenic. I don't know if you follow, there's a study that came out of the Beth Israel Deaconess a few years ago on sterile crush injury, and as a former surgeon, you'd probably appreciate it. But the observation was that when you had an enclosed crush injury, so the skin has not been violated -

   9. PAPeter Attia1:24:23

      Right, right

   10. VMDr. Vamsi Mootha1:24:24

       ... there's a massive inflammatory response. So this investigator was actually trying to figure out what the inflammatory nidus was, did a lot of fractionation, and ultimately figured out that there were some mitochondrial derived molecules. Um, and I believe that they found that the mitochondrial DNA, as well as something called formylated peptides, are highly inflammatory. So remember those 13 proteins that are made by the mtDNA?

   11. PAPeter Attia1:24:50

       Mm.

   12. VMDr. Vamsi Mootha1:24:51

       The translation of those 13 proteins resembles the translation of bacterial proteins. And bacterial protein translation doesn't begin with a methionyl tRNA. It begins with a formyl methionyl tRNA. Remember this FMet peptides?

   13. PAPeter Attia1:25:05

       Yeah, yeah, yeah. This is, I-- my God, I feel like I'm back in medical school. Can you just, just for no other reason than for me to remember that, let's go through that. So your, your DNA makes your messenger RNA. Your messenger RNA then moves over to be translated and to actually have the amino acids put in place to resemble the code that's being said. So talk about where the meth terminal end shows up there.

   14. VMDr. Vamsi Mootha1:25:27

       In you and I, in eukaryotes, protein translation begins with a methionine residue. In bacteria, it's not a simple methionine, but it's a, it's a modified molecule. It's called formylmethionine. And first order approximation, it's almost a signature of a bacterial-derived protein. And we actually have receptors that are designed to detect formylated peptides. It's a sign of some sort of an, an infection. Now, as it turns out, our mitochondria have bacterial origins, as we have discussed earlier. So these thirteen proteins, they still begin with the formylmethionine.

   15. PAPeter Attia1:26:03

       Presumably, they can get away with it under normal circumstances because they reside within the mitochondria.

   16. VMDr. Vamsi Mootha1:26:08

       That's right.

   17. PAPeter Attia1:26:09

       They're protected and shielded from the immune system.

   18. VMDr. Vamsi Mootha1:26:11

       That's right. So in certain injuries, right, this can actually escape, and it can basically activate the same inflammatory pathways that we have that are ordinarily designed to detect incoming pathogens.

   19. PAPeter Attia1:26:22

       I can't wait to actually find that paper. So that was who, who, who was the author on that?

   20. VMDr. Vamsi Mootha1:26:25

       I forget his name, but he's from the Beth Israel Deaconess.

   21. PAPeter Attia1:26:28

       Okay, it was like-

   22. VMDr. Vamsi Mootha1:26:29

       He's a surgeon

   23. PAPeter Attia1:26:30

       ... '02, '03-ish?

   24. VMDr. Vamsi Mootha1:26:31

       No, no, no, this was probably within the last about five years ago or so.

   25. PAPeter Attia1:26:34

       Okay, okay. Well, we'll, we'll find that paper and link to it. But basically, that paper and the paper I was referring to from about a year ago, which I think was in Science, both point to a similar conclusion, which is you can have a profound inflammatory response by simply damaging the mitochondria. And both of them would point to consistent, plausible explanations, which are the body confusing the contents for bacterial contents.

   26. VMDr. Vamsi Mootha1:27:03

       I think it's a very reasonable hypothesis.

   27. PAPeter Attia1:27:06

       Which then begs the question, if we believe that the aging inflammation phenotype is not beneficial, how do we prevent mitochondrial breakdown as we age? I mean, this becomes one of the key aging questions, right? If you believe that, and again, I don't know what the best analogy is, but spark plug failure-

   28. VMDr. Vamsi Mootha1:27:28

       Mm-hmm

   29. PAPeter Attia1:27:29

       ... plays a role more often than not in the overall picture of decline, the longer you can protect those things, preserve those things, the better.

   30. VMDr. Vamsi Mootha1:27:38

       Another way at evaluating the causality question is if we had a drug that could somehow rejuvenate mitochondria, then you could ask the question, does directly intervening on this organelle, you know, retard the aging process? And unfortunately, as of right now, we don't have that type of a magic bullet. But exercise is one of the best ways of turning over bad mitochondria and inducing the biogenesis of good mitochondria. But the challenge, of course, is exercise does lots of things.
10. 1:28:15 – 1:40:50

    Exercise, mitochondria, hysteresis and antioxidants

    1. PAPeter Attia1:28:15

       Now that said, we always, [chuckles] you know, this is one of the, the differences between, I think, being a scientist and a doctor. When you're wearing your doctor hat, you just have to know what to do for that patient in that moment, and it's a luxury to know how and why it works, right? So when we think about the importance of exercise, I've always found it ironic that I probably classify or qualify as an exercise addict, like in the true unhealthy sense of the word. You know, I probably meet all the criteria of addiction and all of that stuff. But up until recently, I don't think I really appreciated the value of exercise. I think it was honestly just something I did out of my neurotic pathology. But I actually, I think if asked, would've said that nutrition played a much greater role in health, sleep played a much greater role in health, and that exercise, you know, I mean, it's, it's great, but, you know, if you-- I'd rather you eat well than exercise a lot, or something to that effect. I'm certainly revisiting that. And of course, I also find it silly to do these sort of zero-sum games, like it has to be one or the other. Uh, you know, presumably doing all of these things well is the optimal strategy. But the deeper I look at exercise, and I'd love to know your framework for this 'cause I'm still trying to create one, I'm putting exercise very loosely into three buckets: strength training, very specific aerobic training, so this would be maximum mitochondrial output with minimal generation of lactate, and then anaerobic training, where you are basically demanding ATP at such a rate that you are really running through that lactate production pathway. Do you think that's a reasonable framework to, of buckets of exercise? Do you, do you divide them even more granularly as you think about it mechanistically?

    2. VMDr. Vamsi Mootha1:30:04

       We're really not exercise physiologists. I don't think I can comment in any particular-

    3. PAPeter Attia1:30:09

       But just personally, do you think of it in a way like that?

    4. VMDr. Vamsi Mootha1:30:11

       I think that's very reasonable. You know, just in hearing you talk, I mean, again, we're, we're not aging researchers, but... So I'll ask you a question, if that's okay. Has anyone actually-- You know, people have given metformin to mice, they've given rapamycin to mice, but has anyone given mice those three flavors of exercise to determine what the impact is on longevity?

    5. PAPeter Attia1:30:32

       Yeah, I believe those experiments have been done, and I believe all of them show benefit. I'd have to go back and look at the literature in mice. In fact, I'm in the process of just starting to work on that chapter in a book that I'm writing. The problem is I generally bias against heavy mice literature, but you at least have the advantage of control. So the short answer is definitely each of those as a medication, right? If you think of each of those as a pill, each of those produce a longevity phenotype. Where it gets challenging, I think, in humans is, well, I think there are so many ways to die when you get old that, for example, accidental death would rank in the top five causes of death for people over the age of 60. Now, the type of accident can change around, but by the time you're in your eighth or ninth decade, falling becomes such a significant cause of death due to the frailty of the individual that some of that exercise, for example, strength training, almost assuredly offers protection from that type of death. So the question is, I think it's a little hard to tease out how much of that benefit is in the cardiometabolic side versus otherwise. The other thing that's really challenging in studying humans is we don't have really good prospective studies in anything that resembles a longevity phenotype. So you are now stuck using something I think I recently described as the most servile trash ever shat into civilization, which is epidemiologic questionnaires to try to impute based on, you know, you telling me how you've exercised over the past ten years, how that's going to predict your longevity phenotype. And again, the problem there is the dose matters, the specificity, the quantity, the quality, these things matter, and they're very difficult to tease out from these retrospective views. So I think the evidence is very compelling that exercise matters, and that's maybe less the question I'm interested in. I think what I'd love to gain insights into, and we may have to rely on non-human models, is just as we now can tailor a drug to do something very specific, can we tailor our exercise to be as optimal as possible? So if you took an individual who said, "Peter, look, I'm willing to exercise five hours a week," or, "I'm willing to exercise ten hours a week, but I'm not going to be a professional athlete. How do I take those five hours a week or ten hours a week or whatever it is and make the best use of it to impact all causes of mortality?" Meaning reduction of the risk of atherosclerotic disease, cancer, neoplasm, neurodegenerative disease, and accidental death from, you know, strengthening the exoskeleton. So that's clinically the question I'm most interested in as it pertains to exercise. But I'm convinced that at the center of that question is understanding the role of exercise in mitochondrial health. I think this is a very important piece of the puzzle and, and certainly much more important than I appreciated even two years ago. I, I think what you describe about these age-appropriate or age-acknowledged declines in VO2 max, mitochondrial density, mitochondrial efficiency, uh, venous O2 concentration, I think there's something really important there. And even if exercise is affecting something upstream that is affecting that, at least we have a great proxy through which to measure.

    6. VMDr. Vamsi Mootha1:34:25

       I think there's going to end up being a lot of really interesting nonlinear dynamics of mitochondria as a function of age, as a function of exercise. There's a few vignettes I'll share. As you probably know, if you don't use your skeletal muscle, you lose lean muscle mass, you lose your mitochondria very quickly.

    7. PAPeter Attia1:34:44

       How quickly?

    8. VMDr. Vamsi Mootha1:34:45

       You have measurable defects in the VO2 max after ten days of hospitalized bed rest. And to recover the VO2 max that you lose in ten days, it takes about six weeks or so.

    9. PAPeter Attia1:34:56

       Oh my God. Yeah, I knew it was bad. I didn't know it was that bad.

    10. VMDr. Vamsi Mootha1:34:59

        So there's quite a bit of hysteresis over here, right? Quite a bit of hysteresis. So it's going to be complex and nonlinear. The programs that turn on mitochondria during exercise, they're really elaborate, and the idea of actually replacing it in a pill may end up being kind of naive. I think that exercise does so many things simultaneously. It's like seventeen different inputs into the system, and it may be the case that it's only if those seventeen inputs are provided with the right dynamics and the right off rates that you get properly functioning more mitochondria. In certain disease states, some of the muscle disorders that I study, the ragged red fiber that you may remember from your board exams, the ragged red fiber represents an accumulation of poorly functioning mitochondria. So I think that if you try to bottle up just two of these factors or three of these factors, we may be able to produce more malfunctioning mitochondria, but it could be the case that we've evolved to require seventeen inputs provided at the right time and place in order to get proper mitobiogenesis. It's a really, really smart program, this PGC-1 alpha program, because it simultaneously turns on mitochondrial biogenesis while also turning on some of the autophagy programs. And so you're actually turning over your bad mitochondria while you're turning on your good mitochondria simultaneously, and that's what happens with exercise.

    11. PAPeter Attia1:36:24

        Well, let's-- Y- you read my mind, and I don't know if you could read my little notes I'm taking over here, 'cause as we're talking, I'm making little notes of things I want to ask you, and that's exactly [chuckles] kind of where I wanted to go, which was, let's talk about what autophagy means in the context of mitochondria. So people who listen to this podcast know that I'm a big fan of fasting, periodic fasting, because even though we don't have great ways to measure autophagy clinically, I think we have pretty good evidence that periods of really strict fasting, meaning exclusively consuming water for some period of time, my hypothesis is three to seven days, produces meaningful autophagy. But how does exercise impact that based on what you've seen in the mitochondria?

    12. VMDr. Vamsi Mootha1:37:08

        So I don't know too much about fasting, but when you do have proper exercise regimes, what we observe is that there are transcriptional programs with multiple inputs, some of which we discussed earlier, but those are probably not sufficient, that will basically turn on all one thousand of those proteins to produce more mitochondria. But that same program is also saying, "Hey, let's turn over some of the previously produced mitochondria." So it's a very, very smart system. It's not going to just produce more good mitochondria in the presence of bad mitos. It'll actually cleanse the system as well.

    13. PAPeter Attia1:37:42

        And remind me what you said, uh, I know you already answered this, I apologize. When you look at cells that are not turning over quickly, so myocytes, neurons, what did you say was the approximate turnover of mitochondria?

    14. VMDr. Vamsi Mootha1:37:53

        Probably a few days.

    15. PAPeter Attia1:37:54

        A few days. Unbelievable. So [laughs] it's just-- This is at, at an unbelievable amount of work to create the new and systematically and selectively discard and recycle the old.

    16. VMDr. Vamsi Mootha1:38:07

        That's right. That's right. And the signals, given that you like exercise, I'll tell you one study that I thought was really provocative, and maybe you already know it, but it came from, I think, Michael Ristow and Ron Kahn about ten to twelve years ago in PNAS. Do you know this study?

    17. PAPeter Attia1:38:23

        I don't. I, I don't think I do, but keep going. Yeah.

    18. VMDr. Vamsi Mootha1:38:25

        It was a human study.

    19. PAPeter Attia1:38:26

        Okay.

    20. VMDr. Vamsi Mootha1:38:27

        They-- It was a two-by-two matrix. They randomized humans either to exercise or no exercise and antioxidants or no antioxidants.

    21. PAPeter Attia1:38:38

        Ah, yes. Okay. I know this study, but please keep going. No, this is great.

    22. VMDr. Vamsi Mootha1:38:41

        So which of the four quadrants do you think is best?

    23. PAPeter Attia1:38:45

        Well, I know the answer, so I want you to-- Yeah, you keep going. Yeah.

    24. VMDr. Vamsi Mootha1:38:48

        Yeah, so most people would probably guess-

    25. PAPeter Attia1:38:49

        Most people would say exercise with antioxidants must be the optimal health.

    26. VMDr. Vamsi Mootha1:38:55

        Absolutely. And, uh, what this study showed that was a little bit counterintuitive is that antioxidants on top of exercise almost prevents or erases some of the beneficial effects of exercise. And the authors concluded that things like reactive oxygen species are probably playing an important signaling role as well that helps in the adaptation. You need some of those sparks in order to turn on new programs that are net beneficial. So if you erase those sparks, yet you prevent the full benefit of exercise. So just another reason why the entire system is so complicated. I mean, I think investigating exercise, and again, we don't do that, that's not a core scientific focus of our laboratory, but so many diseases, ultimately, their risk is reduced by exercise, so studying it is, it should be a very important objective for all of us.

    27. PAPeter Attia1:39:48

        It's so interesting because that's a-- that is a great example. I'm glad you brought that up. And Nav and I, though we didn't talk about that study, we talked a lot about this issue of blocking ROS and how if one has cancer, for example, the evidence is becoming pretty clear that the last thing you want to do in a cancer patient is give them an antioxidant, as sort of anti, sort of dogmatic as that would seem, because the ROS actually play an important role in selectively targeting a cancer cell versus a non-cancer cell. Listening to these discussions makes you almost wonder, how in the world does any drug show up with a benefit in longevity? It's, it's almost a miracle that rapamycin can so ubiquitously across so many species extend life when, as you point out, most of the things that do the heavy lifting in longevity have seventeen prongs that can't be replicated by a single molecule. I mean, it just, it, it seems impossible.

11. 1:40:50 – 1:52:55

    Metformin, complex I and Attia's lactate experiments

    1. PAPeter Attia1:40:50

       The one that has me very interested right now, and again, I don't know how much you've studied this, my guess is even if you haven't, just your peripheral knowledge will exceed that of anybody's, is metformin. So again, I think most people listening to this podcast know a lot about it. I, I had a interview with Nir Barzilai, who I'm also having lunch with today, and Nir's certainly one of the world's experts on this topic. So we had a great discussion of all of the benefits of metformin. Don't think it's really disputable how big those benefits are in people who have diabetes. I think that is becoming very clear, and then by extension, in people who are insulin resistant. What I think is not entirely clear, and I think is the purpose of what Nir is hoping to study with TAME, is if you took a non-diabetic, non-insulin resistant individual and gave them metformin, will you enhance their longevity phenotype? And the one area that I'm most interested in this question is, what is the impact of metformin on the ability of exercise to improve the phenotype? And that's something that just on a personal level I've been experimenting with a lot. So doing a lot of lactate testing on myself with and without metformin and using lactate as a proxy for mitochondrial function. So, you know, we, we were talking about this a little bit before, but just for the listeners, so what I do is take a resting lactate level. I shouldn't be using any more ATP than I'm using at this moment. What is my level of lactate? Then on a bicycle that allows me to control the wattage to the nearest watt, basically move in five or ten watt increments slowly. You know, spend ten minutes at this wattage, go up by five for ten minutes, go up by five for ten minutes, and keep measuring lactate levels, and you generate a performance curve, an LPC, a lactate performance curve, and you do this with and without metformin, you see a difference.

    2. VMDr. Vamsi Mootha1:42:47

       Hmm.

    3. PAPeter Attia1:42:48

       The question is, does that difference matter clinically?

    4. VMDr. Vamsi Mootha1:42:50

       Hmm.

    5. PAPeter Attia1:42:50

       And is it possible that metformin is actually not helping in the context of exercise?

    6. VMDr. Vamsi Mootha1:42:56

       Are you saying that in the presence of metformin, if you are exercising, you're producing less lactate or more lactate?

    7. PAPeter Attia1:43:01

       I'm seeing more lactate in the presence of metformin. Now again, this is an N of one study on myself, but it makes sense that you could s-- I mean, that's a plausible-

    8. VMDr. Vamsi Mootha1:43:13

       How are you measuring your lactate?

    9. PAPeter Attia1:43:15

       Using blood in the finger.

    10. VMDr. Vamsi Mootha1:43:16

        Hmm.

    11. PAPeter Attia1:43:17

        Yeah.

    12. VMDr. Vamsi Mootha1:43:17

        We should do metabolomics on you. I mean, with our new instrumentation, we can measure not just lactate, but literally-

    13. PAPeter Attia1:43:23

        Measure everything in between, yeah

    14. VMDr. Vamsi Mootha1:43:24

        ... hundreds of metabolites. It gives a little bit more of a comprehensive snapshot of all of your metabolic pathways.

    15. PAPeter Attia1:43:30

        So could we get an IRB to do that easily?

    16. VMDr. Vamsi Mootha1:43:32

        Let's do it. Let's do it. [chuckles]

    17. PAPeter Attia1:43:33

        I'm, I'm all in. So we, we could do it. We could do an on metformin, off metformin snapshot because... So here's my crude thinking on this is if metformin is inhibiting complex one, it wouldn't be beyond the realm of possibility that the body might preferentially not shuttle pyruvate into the mitochondria. I mean, it's still doing so to a great extent, but if it's disproportionately now keeping pyruvate outside and turning it into lactate, that could drive up lactate levels. The thing that surprised me the most is how high my resting lactate levels seem to be. I mean, I remember before I started taking metformin, you would barely check a resting lactate level, but it was usually below one millimolar. Now, my resting lactate level on metformin is typically between one and two millimolar. It's about two X.

    18. VMDr. Vamsi Mootha1:44:25

        Hmm. Hmm.

    19. PAPeter Attia1:44:26

        And I'm doing this in as painful and, but hopefully valid a way as one can do it, which is I'm using two separate meters checked in duplicate on the third drop of blood. Like, I'm trying to be as systematic as possible. Anyone listening to this who wants to do this, I just wanna warn you in advance before you get started, lactate meters are upsettingly expensive, and the strips are the racket. I mean, they'll sell you the device for three hundred bucks, and each strip costs you about five dollars. So every time I do one of these dumb tests, which I typically do about once a week, it's like dinner and a movie for five people. But, yeah, it'd be amazing to see what a broader sequence of metabolomics looks like to understand is there something that's happening. And by the way, then the next question is, do that in somebody who has diabetes and see if you see an improvement or a reduction in performance.

    20. VMDr. Vamsi Mootha1:45:16

        You measured your fasting resting lactate before you started metformin. Do you know if it went up after you started metformin and then it went back down again or?

    21. PAPeter Attia1:45:28

        Well, so that's an interesting question. So before I started taking metformin, I would do lactate testing, but I was interested in a different question, so it's not an apples to apples comparison. We always had a resting lactate just 'cause you wanted to basically calibrate the machine and make sure your machine was working. But generally, when we did what the, what was called this LPC, the lactate performance curve, it was mostly geared towards identifying a different position on the curve, which is very crudely done. But you do a series of efforts at different power outputs or in a swimming pool at different speeds or on a track, different running velocities. And you'll notice that the curve is nonlinear. So it starts like this, I'm sort of drawing, it goes flat, and then it starts to asymp-- it, it starts to shoot up very quickly towards a vertical asymptote. That if can be approximated by two linear curves, and the intersection of that curve is generally a person's lactate threshold, and that's different, that's usually a higher number than two millimolar. Let's just say to make the math easy, that usually is in about the four millimolar range, and it's that point where that corresponds to on the x-axis, that output is generally about the fastest velocity or output a person can hold for a certain type of race that we're interested in studying. So I have infinite numbers of those data for myself back in the, you know, days long before I took metformin. But it was undeniable how low my lactate level started, so I at least have that data point.

    22. VMDr. Vamsi Mootha1:47:00

        I think that's really interesting. We published a paper in PNAS a couple of years ago where we placed either healthy individuals or patients with mitochondrial disease on a treadmill-

    23. PAPeter Attia1:47:10

        Mm-hmm

    24. VMDr. Vamsi Mootha1:47:10

        ... did a ten-minute exercise test, and then drew their blood at rest, peak exercise, and post-recovery just to look at the metabolome response to exercise. So of course, we get lactate, and the mito patients, some of whom have complex one deficiency, not because of metformin-

    25. PAPeter Attia1:47:26

        Yeah, yeah

    26. VMDr. Vamsi Mootha1:47:26

        ... because of a genetic deficiency, they begin with a high resting lactate, and there's a parallel rise in their lactate that, that parallels what happens to a healthy human, and it stays high parallel with the healthy individual post-recovery.

    27. PAPeter Attia1:47:40

        Do you remember offhand how high their resting lactates were relative to the, uh, non-insulted?

    28. VMDr. Vamsi Mootha1:47:47

        It was single digit millimolar. It wasn't sky high. I wanna say something like two, three, four millimolar, but we should look that up-

    29. PAPeter Attia1:47:54

        Yeah

    30. VMDr. Vamsi Mootha1:47:54

        ... just to confirm. But it'd be interesting to see, this is purely science now talking to you, is whether we could repeat that exact same study not with genetic complex one deficiency, but with-
12. 1:52:55 – 2:04:33

    Hypoxia as a preclinical therapy for mitochondrial disease

    1. PAPeter Attia1:52:55

       So changing gears around, the role of hypoxia as a therapeutic. I mean, based on what you see in the mitochondria, how do you see that as a potential therapeutic option?

    2. VMDr. Vamsi Mootha1:53:04

       This is something that we're really excited about on the preclinical level, and I really want to emphasize this, Peter, because oxygen follows the Goldilocks principle, right? I mean, too little is absolutely fatal, deadly. What we're discovering is that too much in certain instances, genetic backgrounds can be damaging as well. And so all of our work to date has been focused in preclinical models. One of the things that we are discovering in these rare mitochondrial disorders is that a lot of the ATP levels are actually nicely defended by glycolysis. And so although the textbook dogma is that a lot of these disorders are disorders of energy deficiency, under resting conditions, ATP levels are okay, but what we're observing is high unused oxygen. And the important question is: How can we now try to interdict and somehow try to reduce the delivery of oxygen? So at least in our mouse models, we're using hypoxia chambers. We actually dilute the air that the mice breathe with nitrogen. We use some of the devices that the sports industry has created, nitrogen generators, face masks, tents. We place the mice in those apparati, dilute the air with nitrogen, and then we evaluate the impact. And at least in some, not all, some of our mouse models of mito disease, the benefits are, are striking.

    3. PAPeter Attia1:54:28

       Let's explain again just why this is so profound, right? So going back to the model you described earlier, in a subset of clinical scenarios where mitochondrial function, for lack of a better word, is impaired, you're seeing a much higher level of oxygen return to the lungs despite a high output of energy, imputing that their mitochondria simply aren't working. That high amount of oxygen itself can be problematic. So you're saying, "Well, rather than putting you in an environment where the ambient oxygen concentration is twenty-one percent, we're going to lower that." How much do you lower that to, by the way, in these tents with the mice?

    4. VMDr. Vamsi Mootha1:55:09

       At sea level, we're typically breathing about twenty-one percent oxygen. We reduce it down to about eleven percent.

    5. PAPeter Attia1:55:15

       How is that-- I don't know much about my, um, altitudes, but that strikes me as really low. Is that like the top of Mount Everest low?

    6. VMDr. Vamsi Mootha1:55:22

       It's not Everest. It's probably base camp.

    7. PAPeter Attia1:55:24

       So it's 18,000 feet. Everest is what? 7% maybe?

    8. VMDr. Vamsi Mootha1:55:28

       Exactly. Exactly. So we're talking about certain parts of Bolivia. We're talking about Mont Blanc.

    9. PAPeter Attia1:55:33

       Yeah, yeah. But my brother's been to base camp, and he did something really funny, which is something only my brother would do. He typed out a series of questions for himself that at sea level, the answers to which are patently obvious, 10 questions, and at 10,000 feet and 15,000 feet, and then at base camp is 18, and then I think when he was there, they ended up not being able to cross the icefalls, but they could still get to like 21,000, and then again at 21,000 feet, he would video himself answering these questions. And it was actually quite interesting, not just the huffing and puffing that invariably goes into it, but the length of time it took him to think of the answers, which when you consider the fact that he was answering the same questions over and over again, it should've been the opposite. It should've been easier and easier and easier to come up with what year did such and such happen or whatever. That's no joke, right? I mean, that's still, for many people, quite a deficit. So how did they improve?

    10. VMDr. Vamsi Mootha1:56:26

        Earlier in the conversation, we were talking about this disease called Leigh syndrome.

    11. PAPeter Attia1:56:30

        Mm-hmm.

    12. VMDr. Vamsi Mootha1:56:30

        So we have a mouse model of Leigh syndrome. It's actually due to a loss of one of the subunits of complex I. So it's a recessive loss of one of the nuclear subunits of a complex I, and this mouse is born looking okay. It's developmentally okay. But then right around day 30, 35, it starts looking sick, and by day 55, it'll basically fulfill our hospital's euthanasia criteria. It's lost body weight. It's become hypothermic. It's very, very sick. It has lesions on brain MRI.

    13. PAPeter Attia1:57:02

        Is there anything in its periphery that looks lesioned, or is all of the insult to the brain?

    14. VMDr. Vamsi Mootha1:57:08

        This, uh, initial cause of death is probably brain driven, and if you look carefully, other tissues are affected as well. So that's what happens at 21% oxygen. There's a very stereotyped trajectory, these uniformly fatal at about day 55 or day 60. If these mice are grown at 11% instead of 21%, they now survive to about a median of one year.

    15. PAPeter Attia1:57:32

        Oh my God, so you've, you've restored them to half their normal lifespan.

    16. VMDr. Vamsi Mootha1:57:35

        That's right.

    17. PAPeter Attia1:57:36

        And what's their function level? How do they interact? Are they, do they act like normal mice up until then?

    18. VMDr. Vamsi Mootha1:57:42

        When we were doing these experiments, a, a very talented former graduate student, she's now at UCSF and our lab manager over at MGH, they were doing these experiments. They actually thought that there was a genotyping error because the mice looked so good. We actually thought that we'd misgenotyped them. And so they look, they look great. They put on body weight. They put on body temperature. So the results are striking. But again, I want to emphasize that this is all an animal model still.

    19. PAPeter Attia1:58:06

        If you're a parent who one day has a child born with this condition, to think that the answer could be your child, instead of living a few months, could live into their 40s or 50s by moving to a part of the world, which would be the easiest way to accomplish this. I don't think it would make sense to live at sea level and wear an oxygen deprivation mask for your entire life. But if the answer is, "Guess what? You're gonna go be a Sherpa," I mean, that's unbelievable to think of. I mean, that's -- I would not have predicted that at all based on what we've discussed, that it could be that strong an effect.

    20. VMDr. Vamsi Mootha1:58:40

        Well, what's interesting is in the past, people have actually proposed hyperbaric oxygen as a way of rejuvenating-

    21. PAPeter Attia1:58:47

        That, that's-

    22. VMDr. Vamsi Mootha1:58:47

        ... one's mitochondria.

    23. PAPeter Attia1:58:48

        That's what I would've stupidly suggested also, which is, "Wait a minute, we've got to try harder to get that oxygen in there. Let's go hyperbaric." So have you done that in the mice, and do, do the mice die even faster under hyperbaric conditions?

    24. VMDr. Vamsi Mootha1:58:59

        So we didn't try hyperbaric 'cause that's higher pressure, but we just tried hyperoxic.

    25. PAPeter Attia1:59:03

        Okay. Okay.

    26. VMDr. Vamsi Mootha1:59:04

        So we went up to 55%, which is what is often given in the operating room as an example. The mice will die within a few days of exposure to 55% oxygen. So there's something about having-

    27. PAPeter Attia1:59:16

        And what about hyperbaric at 21%? Has that been tried?

    28. VMDr. Vamsi Mootha1:59:19

        We haven't, we haven't tried that yet, but just hyperoxic at 55%, these mice will die within a few days of exposure. Peter, within a few days of us publishing that paper, we actually got phone calls from across the country of cases where patients that were on the outpatient had been placed in hyperbaric chambers, and then they actually ended up, you know, in some cases dying within 24 hours or going blind in a good eye within 24 hours. And so I think there's some anecdotes that suggest that super high oxygen levels on a broken electron transport chain can be very damaging in humans as well.

    29. PAPeter Attia1:59:56

        Well, this is sort of interesting, right? Because on the cancer front, people have talked about hyperbaric oxygen being a very potent tool because the mitochondria of cancer cells are gonna be defective on balance relative to the non-cancer cells. That's, again, outside of your wheelhouse, but how do you think about hyperbarics in terms of a tool to selectively target cancer mitochondria?

    30. VMDr. Vamsi Mootha2:00:18

        We're, uh, super excited about it, and in fact, we're really not a cancer biology lab, but there is a subset, a very, very rare subset of tumors where we're currently exploring that idea. I think others have thought about trying to starve cancers of their oxygen and glucose. Our idea is the exact opposite. Maybe in certain instances you want to flood them with oxygen.
13. 2:04:33 – 2:09:29

    Parkinson's and the mitochondrial role across chronic diseases

    1. PAPeter Attia2:04:33

       On the topic of cancer, and we've talked about these other chronic diseases, but it doesn't really appear that there is a chronic disease in which the mitochondria remain normal. If you look at cancer, if you look at Alzheimer's disease, if you look at atherosclerosis, and if you look at type 2 diabetes, all of these diseases have mitochondrial signatures that differ from what we would consider healthy.

    2. VMDr. Vamsi Mootha2:04:54

       Well, it gets back to the opening parts of the discussion where we said that if you take any aged tissue, it's going to be associated with dysfunctional mitochondria. And if you take diabetic muscle, if you take Alzheimer's brain, Parkinson's brain, you're going to see dysfunctional mitochondria. And this is why it gets back to, is it cause or effect, or is it going to be some complex nonlinear combination of cause and effect? And this is where using that systems biology approach or trying to gain insights from these rare diseases may inform a subset, but not, not all of these. I actually think that for Parkinson's, the, the causal hypothesis is pretty compelling out of all of these disorders.

    3. PAPeter Attia2:05:36

       Say more about that because I, I don't know anything about Parkinson's that I didn't learn in medical school, which if I recall, is more to do with dopamine secretion out of a part of the brain that the-- Substantia nigra, is that it? Where you basically lose that-

    4. VMDr. Vamsi Mootha2:05:51

       Those neurons.

    5. PAPeter Attia2:05:52

       Yeah. And so the patients that maybe start out with genetically fewer of those, 'cause there's a distribution of how many you get, may be the ones most susceptible. I'd never thought of that as a problem that shows up in the mitochondria. So expand on that.

    6. VMDr. Vamsi Mootha2:06:05

       Again, we have two classes of disorders, right? We have sort of common complex diseases, and we have monogenic diseases. And the big question is, does the pathology we see in the rare monogenic forms bear any relevance, right, to the common forms of disease?

    7. PAPeter Attia2:06:21

       It's funny. I mean, the way we're talking about it, your hands are showing it in a way that I think is, is representative, right? You had your one hand out over here, and you said, "Look, these are the very simple monogenic diseases. Most people have never heard of them. They're typically quite brutal, but they kill relatively few people." On the other hand, you have there's a divide, right?

    8. VMDr. Vamsi Mootha2:06:39

       That's right.

    9. PAPeter Attia2:06:40

       And it's like, it's, it's quite discontinuous, isn't it?

    10. VMDr. Vamsi Mootha2:06:42

        Well, also on this side, you know, the prevalence of these monogenic mitochondrial disorders is about one in four thousand. But then as you cross the continuum-

    11. PAPeter Attia2:06:51

        The, the prevalence is one.

    12. VMDr. Vamsi Mootha2:06:52

        One in one. [chuckles]

    13. PAPeter Attia2:06:53

        Yeah, exactly.

    14. VMDr. Vamsi Mootha2:06:54

        And then you have these other disorders like type 2 diabetes and Parkinson's and Alzheimer's that it's not one in one, but it's also not one in four thousand.

    15. PAPeter Attia2:07:03

        So you're saying Parkinson's may be the closest example that you, you can think of that's spanning this, these two worlds?

    16. VMDr. Vamsi Mootha2:07:09

        I think so. I think so.

    17. PAPeter Attia2:07:10

        Well, okay. I, I want to hear more about this.

    18. VMDr. Vamsi Mootha2:07:12

        Well, I think there's a couple of, couple of reasons. One is if you take, you know, the common form of Parkinson's disease and if you take some of the postmortem material, if you biopsy that or if you take postmortem material and you look, it lets you see mitochondrial lesions. You'll see an increase in the mutation burden in the mitochondrial genome. You'll see complex I deficiency. Already, we're seeing some of the molecular features of mitochondrial dysfunction. But perhaps even more compelling is that there are some toxin forms of Parkinson's. Certain types of herbicides and insecticides are actually toxic to complex one.

    19. PAPeter Attia2:07:48

        So you're saying there are people who have Pa- Parkinson's, and I apologize for my ignorance on this, where they don't actually have a dopamine deficiency in the brain, but they have a Parkinson's-like phenotype purely from an insult to their mitochondria from, say, a toxin?

    20. VMDr. Vamsi Mootha2:08:03

        Right. So in these instances, what we think has happened is that because of a environmental pesticide or insecticide, the mitochondrion has been poisoned in some of these dopaminergic neurons, and those neurons actually die, so there is a dopamine loss ultimately.

    21. PAPeter Attia2:08:17

        I see. I see. Okay.

    22. VMDr. Vamsi Mootha2:08:18

        But the root cause is the toxin.

    23. PAPeter Attia2:08:21

        The mitochondria. Okay.

    24. VMDr. Vamsi Mootha2:08:22

        That's right. That's right. So, so that's toxin evidence-

    25. PAPeter Attia2:08:25

        Mm-hmm

    26. VMDr. Vamsi Mootha2:08:26

        ... where we know that a direct toxin to the mitochondrion in humans can give rise to a Parkinsonian-like disease. In mouse models, if you give a high dose of rotenone-

    27. PAPeter Attia2:08:37

        Is that a particular-

    28. VMDr. Vamsi Mootha2:08:38

        It's a complex one poison.

    29. PAPeter Attia2:08:39

        Okay.

    30. VMDr. Vamsi Mootha2:08:40

        And this actually gets back to-
14. 2:09:29 – 2:20:25

    Optimism, protein prostheses and multi-pronged drugs

    1. PAPeter Attia2:09:29

       Are you optimistic that we are going to be able to target mitochondrial proteins as therapies? I mean, the more I listen to this, the less optimistic I am, truthfully, just because of the exceptions being exceptions and not rules.

    2. VMDr. Vamsi Mootha2:09:50

       I'm actually pretty wildly optimistic, so-

    3. PAPeter Attia2:09:52

       Okay, that's great 'cause I, I, I'm coming away, like, discouraged. Like, there are too many moving pieces to be able to use a single molecule. So are you thinking of stacking molecules or tell, tell me where your optimism comes from.

    4. VMDr. Vamsi Mootha2:10:05

       Well, it, it comes from the fact that five years ago, in some of these mouse models or cellular models, we had zero ways of alleviating mitochondrial disease in a dish or in a mouse. Now we have, in our laboratory, we can use, a- again, in a preclinical way, we can use hypoxia, and it actually helps to restore cellular function and longevity and healthspan in mouse models of mito disease. We're using other approaches that are evolutionarily inspired. We call these protein prostheses, where we take proteins from other organisms, from other kingdoms of life. We transplant them into human cells with mitochondrial disease, and we can effectively rescue the cells, and so-

    5. PAPeter Attia2:10:47

       Well, but how do you, how do you transfect all the cells? Or are you just saying that you can just, you're just do, you're doing this ex vivo?

    6. VMDr. Vamsi Mootha2:10:54

       This is all ex vivo right now.

    7. PAPeter Attia2:10:55

       Okay.

    8. VMDr. Vamsi Mootha2:10:55

       Right.

    9. PAPeter Attia2:10:55

       But still, it's a proof of concept that's very powerful.

    10. VMDr. Vamsi Mootha2:10:57

        I mean, nowadays, we have nucleic acid therapeutics, gene therapeutics, protein therapeutics, so-

    11. PAPeter Attia2:11:02

        So give me an example of one of the protein prosthetics.

    12. VMDr. Vamsi Mootha2:11:05

        Getting back to the earlier part of the conversation, we spoke about the fact that the electron transport chain was probably one of the earliest features of the early eukaryotes, probably resembling the electron transport chain of bacteria that can do oxidative phosphorylation. But then during reductive evolution, certain organisms lost parts of their electron transport chain. Now, there are certain organisms that have lost their entire electron transport chain, and we think that one of the ways that they're able to survive is that they gained a new protein that basically complements part of the activity of the electron transport chain. So we've identified some of those proteins. If we place those proteins in a human cell, you can poison the mitochondria any of five different ways, and the cell will still proliferate because it has that protein that evolutionarily, we believe, allowed that organism to lose its ETC to begin with. Does that make sense?

    13. PAPeter Attia2:12:02

        Yeah. It just seems too good to be true.

    14. VMDr. Vamsi Mootha2:12:05

        Well, this is why we call it a prosthesis. It's not 100% fix of the solution.

    15. PAPeter Attia2:12:09

        Mm-hmm.

    16. VMDr. Vamsi Mootha2:12:09

        What it does is it probably corrects part of the redox imbalance in the electron transport chain but not the full proton pumping capabilities.

    17. PAPeter Attia2:12:18

        Yeah, so, so play this forward. You, you now could argue another treatment for type 2 diabetes is in addition to making the changes we're gonna make, right? 'Cause I, I still believe deep down that you can cure type 2 diabetes with corrective exercise and nutrition and sleep. I think you, if you get those three things fully optimized, type 2 diabetes goes away, y- with, with the exception of the late stage cases where the pancreas no longer works. But what if you could add another layer to that, which is, "Oh, by the way, here's some mitochondrial prostheses"?

    18. VMDr. Vamsi Mootha2:12:51

        That's exactly right. It's not gonna fix all of the functions electron transport chain-

    19. PAPeter Attia2:12:55

        But it can become additive to other things, right?

    20. VMDr. Vamsi Mootha2:12:57

        That's right. That's right. That's one of the ideas that we're exploring right now. Can we actually, in the context of things like fatty liver and diabetes, can we use some of these mitochondrial protein prostheses to either augment or bypass some of the broken functions of mitochondria to restore function?

    21. PAPeter Attia2:13:16

        I don't know if you've ever thought of this 'cause the idea just popped into my head when you said mitochondrial protein prostheses. Have you ever thought just in sort of random sci-fi-like thinking of the opposite, which is performance-enhancing prostheses for mitochondria? I mean, if you think about the efforts that athletes can go to to enhance aerobic performance, the most obvious of these, of course, is blood doping and use of EPO, which simply deliver more oxygen to the system. But in 30 years, will people be talking about genetic cheating, where mitochondrial performance and function has been enhanced?

    22. VMDr. Vamsi Mootha2:13:53

        Well, it's funny because the sports industry is so often, I mean, the sort of underground illicit sports world of doping often is so ahead of the medical world. It's actually pretty amazing.

    23. PAPeter Attia2:14:04

        Yeah, it really is.

    24. VMDr. Vamsi Mootha2:14:05

        I mean, one of the compounds, it's like EPO, it's called FG four five nine two. It's a small molecule that blocks one of the prolyl hydroxylases. This tricks the system into thinking that it's hypoxic and you end up producing more EPO. That drug was in clinical trials, and before the drug was even approved, it was being used by cyclists, which is already amazing. But what's also even more amazing is that the anti-doping agency knew to look for drugs that were not yet even approved by the FDA in some of these athletes. And so it's like this, uh, Red Queen where everyone has to stay ahead of everybody else.

    25. PAPeter Attia2:14:43

        Yeah. [chuckles] It's an arms race. Do you think, like, theoretically, there are ways to enhance performance through, again, I'm not a huge advocate on genetic engineering. I, I still think it's so, there's so much sci-fi and the, the limitations of actually getting a virus that could be taken up ubiquitously. But, but putting that aside for a moment, could you engineer a better mitochondria? Could one, I mean, I don't want to put you on the spot, but could one engineer an even better mitochondria? How much waste is in the system? I, I, it's funny, I haven't, if I ever did this exercise, it's so long ago that I don't recall, but from an engineering perspective, how much room for improvement is there?

    26. VMDr. Vamsi Mootha2:15:21

        I think it's going to take a while before things like that are possible, and I gather from this conversation that you, like me, like automobiles. And so if you have an engine, the way to enhance it is to turbocharge it. But turbocharging it is not taking one spark plug out and replacing it with-

    27. PAPeter Attia2:15:39

        No, it's completely-

    28. VMDr. Vamsi Mootha2:15:40

        ... another spark plug

    29. PAPeter Attia2:15:40

        ... changing the way air flows through it and is recycled.

    30. VMDr. Vamsi Mootha2:15:43

        So you have like seventeen different things. You have a turbocharger, you put it on top, but there's like seventeen other things that you have to alter so that the entire system connects up. You have impedance matching, you have airflow matching, so that in the end, you have a better performing automobile. I think something analogous applies to mitochondria. It's not going to be just one thing that you can turn on. If you want to try to, the system is already pretty optimized, right? And so if you just change one thing, it's probably not going to, you can break it.
15. 2:20:25 – 2:27:49

    The dream experiment: thin air and the Indian Army data

    1. PAPeter Attia2:20:25

       We'll close with a, with a question that's admittedly kind of, kind of a tough question, so I apologize for putting you on the spot and, and no, no qualms if you, uh, can't come up with a, a good, a good or great answer. But when you think about the world you want to explore here with the questions that you want to ask, so much of what happens, even at the level that you're at, is still constrained by resources. Have you ever had the thought experiment or the, the sort of fantasy of what if you were in a totally resource unconstrained world, so you never had to apply for another grant, in fact, you were given some lump sum of money that was beyond what you could imagine, and even just from an IRB standpoint, there was nothing that stood in your way of doing kind of something that was, was still ethical, but, but maybe today would be logistically too challenging. Do you have a sense of what questions you would want to probe, but specifically what experiment or set of experiments you would, you would do if in this dream state?

    2. VMDr. Vamsi Mootha2:21:19

       It's a tough question. It sounds like you're basically asking me not to be limited by anything except my own, uh, imagination. And I think so often in, uh, biomedical research, that is what limits us, but it's a great question, Peter. One experiment that would be kind of a fun experiment to try is really motivated by our recent work on oxygen. So what we've observed is that at least in preclinical models, when you have severe mitochondrial decline, breathing thinner air appears to be beneficial. Now, how about in the common form of aging when there's a subtle decline in mitochondrial activity? Is there excess unused oxygen, and will breathing thinner air be beneficial? And given that I'm not resource limited, you know, wouldn't it be cool if we could construct a Ritz Carlton hotel or condominium at sixteen thousand feet that's extremely comfortable and perhaps another Ritz Carlton that looks identical at the plains, and we could take a very large cohort, not five, not ten, but thousands of people that live at either the plains or at the high altitude for many, many months. And we try to evaluate whether there are any biomarkers of aging, age-associated disorders that actually improve under thin air. Maybe they become worse under thin air, but it would be something like a crossover experiment that would allow us to test the idea that thin air may be beneficial for chronic diseases.

    3. PAPeter Attia2:23:07

       I love that idea [laughs] . That is elegant because one, you could do that. You answered the question right, which is in a resource unconstrained world, like that's tens of millions of dollars would allow you to do that. Call it, you know, hundreds of millions of dollars could do that longitudinally. And your intervention is elegant in that it is, it's going to touch lots of things. That's interesting. So sixteen thousand feet. So following up on that, have you done or contemplated doing the less beautiful version of that in mice where-- or, or I, I'm sort of disdainful of mice, but maybe rats or something that's less inbred, where you have models of type two diabetes, but they're genetically born with normal mitochondria. Has that experiment been done?

    4. VMDr. Vamsi Mootha2:23:50

       We're doing those types of experiments now in, uh, of course, our focus is on some of these rare genetic mitochondrial diseases, but we're going into some of these other conditions, more common conditions that are also associated with mitochondrial dysfunction. So those are currently ongoing. When we get back to that dream experiment, what is interesting, Peter, is experiments like that have actually taken place in humans, and they can be instructive.

    5. PAPeter Attia2:24:15

       Right, they're natural experiments.

    6. VMDr. Vamsi Mootha2:24:17

       And one of the experiments, there's this one paper from the early 1970s that was published by the Indian Army. It was the Indian Army reporting on the health outcomes of a huge number of their troops who India has historically had border disputes with China. I think it was in the 1960s, India deployed more than a hundred thousand troops on the Indochina border. And don't quote me on the numbers, but about twenty-five thousand of these people were at extremely high altitude and another hundred thousand or so were at, at the plains. They were there for about five to seven years or so. And of course, the food that they ate, the temperature, the activity, all of these were different between low and high altitudes. But one of the variables that was different was oxygen. And after I think it was seven years, the Indian Army actually wrote this paper. It's only been cited a few, like maybe 20 times or so. They reported the long-term health consequences, and what they showed is that death from things like infections were much higher acutely upon going to high altitude. But if you look at chronic diseases like incidence of diabetes, stroke, cardiovascular disease, they were much reduced in the high altitude arm.

    7. PAPeter Attia2:25:39

       Even after they returned to, uh, the plains?

    8. VMDr. Vamsi Mootha2:25:42

       I think the study-

    9. PAPeter Attia2:25:43

       Or only as long as they stayed at the altitude?

    10. VMDr. Vamsi Mootha2:25:45

        Only, only as long as they stayed in the altitude. I don't think they had long-term follow-up actually. But, you know, it's this type of data that actually makes me, you know, wonder whether what we're observing in some of these rare forms of mito dysfunction and the interaction of mitochondria with oxygen, perhaps some of it could bear relevance to more common conditions as well.

    11. PAPeter Attia2:26:07

        Super interesting. I could keep going on, but I, I [laughs] you've been, you've been generous with your time, especially to a total stranger. This is really helpful. I want to thank you for the work you're doing, and I want to thank you for taking the time to explain it to me and to, uh, the few people listening.

    12. VMDr. Vamsi Mootha2:26:22

        No, thank you so much. This has been a lot of fun for me. [upbeat music]

    13. PAPeter Attia2:26:26

        You can find all of this information and more at peterattiamd.com/podcast. There you'll find the show notes, readings, and links related to this episode. You can also find my blog at peterattiamd.com. Maybe the simplest thing to do is to sign up for my subjectively non-lame once-a-week email where I'll update you on what I've been up to, the most interesting papers I've read, and all things related to longevity, science, performance, sleep, et cetera. On social, you can find me on Twitter, Instagram, and Facebook, all with the ID peterattiamd. But usually Twitter is the best way to reach me to share your questions and comments. Now for the obligatory disclaimer. This podcast is for general informational purposes only and does not constitute the practice of medicine, nursing, or other professional healthcare services, including the giving of medical advice. And note, no doctor-patient relationship is formed. The use of this information and the materials linked to the podcast is at the user's own risk. The content of this podcast is not intended to be a substitute for professional medical advice, diagnoses, or treatment. Users should not disregard or delay in obtaining medical advice for any medical condition they have and should seek the assistance of their healthcare professionals for any such conditions. Lastly, and perhaps most importantly, I take conflicts of interest very seriously. For all of my disclosures, the companies I invest in and/or advise, please visit peterattiamd.com/about.

Episode duration: 2:27:53