#31 – Navdeep Chandel, Ph.D.: metabolism, mitochondria, and metformin in health and disease

1. 0:00 – 0:04

   Intro

   1. PAPeter Attia0:00

      [upbeat music]

2. 0:04 – 5:23

   Episode Preview and Introducing Nav Chandel

   1. PAPeter Attia0:04

      Hey, everyone. Welcome to The Peter Attia Drive. I'm your host, Peter Attia. [upbeat music] 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] Hi, everybody. Welcome to today's episode of The Drive. My guest today is my good friend, Navdeep, or Nav, as we like to call him, Chandel. Nav is a professor of medicine and cell and molecular biology at Northwestern in Chicago, which is where I actually met him to do this interview. Some of you may recall that name because Nav is one of the cast of characters that I went to Easter Island with in, uh, the fall of 2016. The other being, uh, David Sabatini and Tim Ferriss, and we actually spoke about this stuff at length on a podcast that Tim recorded while we were on Easter Island. Nav's real area of expertise is in the mitochondria and in metabolism, and in fact, he wrote a book called Navigating Metabolism, no pun intended, in 2015, which I highly recommend for anybody, especially people who, A, want to understand this stuff, and B, don't want to have to buy 17 textbooks and get into every unearthly detail. In fact, this book was written more for a general audience than a very specific audience, and I have a copy of it and love it. In this episode, we talk about a bunch of stuff, but we talk about what got Nav interested in the mitochondria. We get into ROS, or reactive oxygen species, something that I think many of you will have heard of. And then we talk about some really nuanced stuff, like this stuff about mitochondria being actual signaling organelles and ROS maybe being beneficial for that signaling. In other words, we get into this idea that reactive oxygen species may not be all bad. It might not be a black/white thing, which anyone who listened to this podcast realize we love to explore things that aren't just binary. We talk about antioxidants and whether they're harmful or not harmful, and I suspect that a lot of people will have a point of view on that. And we get into mitochondrial DNA, which in and of itself is super interesting because some of you may already know this, and if you don't, that's fine, you'll learn it on this episode, but the mitochondria have their own DNA distinct from the cell, and that DNA is of bacterial origin. It's also transmitted to us maternally, so there's a whole bunch of weird stuff going on genetically with the mitochondria that makes it super interesting. We get into a little bit of a discussion around cortisol. Nav is super interested in the role of cortisol in health. And then we talk, of course, about metformin, and I suspect that for some people listening to this, that's the only thing they're gonna care about because these days, everybody's asking me about metformin, which means it's front and center on a lot of people's minds with respect to longevity. Now, we don't even go as deep as we could on metformin. I'm saving that for another guest that's in the queue, who I'm not gonna even say too much about that, but there's a lot more coming on metformin. This, however, will be a great primer for that because you'll certainly understand how metformin works and how it may play a role in longevity. We talk about the role of the mitochondria in cancer, and again, we take a different view here from what you will have heard from other guests potentially. We talk about NAD and NAD precursors, and that again is another thing that people I think are pretty excited about. At the end, somehow Nav jujitsus me and turns the tables on me and asks me the, "So what should I eat?" question, which anybody who knows me knows I can't stand being asked that question, but because it's Nav, I humored him a little bit. Before we jump into that, please keep in mind we have an email list. Every Sunday morning, I send out an email, and that email has a whole bunch of stuff in it. It's usually pretty short though, but it's basically something I've read that's interesting that pertains to longevity, science, lipidology, performance, or just something that really interests me beyond those things. Keep in mind, we put, I would say, an ungodly amount of effort into preparing show notes. And when I say we, I'm using that term very liberally. I actually do none of that, but I have a team that does that, and that is spearheaded by Travis and Bob. So the people who do spend time on those show notes always come back to us with feedback like, "This is freaking awesome. Please keep doing this," and our intention is to keep doing that. So give us a reason to keep doing that by going and checking them out, especially when it comes to understanding some of the technical stuff that we talk about here and getting some of the references. And lastly, if you are digging this podcast, please head over to Apple Podcast reviews and leave us a review, especially if it's positive, but if it's negative, at least have the courtesy to give us some constructive feedback so we can improve upon whatever it is you don't like. So without anything further to add, please welcome Nav Chandel. [upbeat music] Hey, Nav. Good to see you again, man.

   2. NCNavdeep Chandel5:07

      Great to see you, Peter.

   3. PAPeter Attia5:08

      Yeah. The last time I saw you, me, you, and David Sabatini were hanging out, uh, near the airport in San Diego playing patty cakes.

   4. NCNavdeep Chandel5:15

      [laughs] We were.

   5. PAPeter Attia5:16

      You guys were drinking some really lame stuff.

   6. NCNavdeep Chandel5:19

      Rosés.

   7. PAPeter Attia5:20

      Rosé. [laughs]

   8. NCNavdeep Chandel5:21

      I like sparkling stuff.

3. 5:23 – 12:39

   From Math and Organ Preservation to Mitochondria: Glycolysis, the TCA Cycle and ATP

   1. PAPeter Attia5:23

      So what got you interested in mitochondria?

   2. NCNavdeep Chandel5:26

      So when I was in college, um, I was a math major. I was-- I loved math, right? I probably did math because as an immigrant, you moved from, uh, the Himalayas to Miami, got a funny accent. Math is a universal language, right? So you-- I became a math geek. But everybody's gotta make a living, and so I worked in a laboratory which was in a hospital, and it was a transplant laboratory, and the biggest thing in transplant is how do you preserve organs? I mean, you have an MD, I don't have an MD, I think that's a fair statement, and there's this Wisconsin solution that was used to-

   3. PAPeter Attia6:01

      We used it liberally.

   4. NCNavdeep Chandel6:02

      You lib-- Yeah. And so I wanted to make a better version of it as a nineteen-year-old. And if you've got to do that, then you got to think about metabolism. The first set of experiments we did, and I went to a FASEB meeting, and it's called "3-Phosphoglycerate protects against anoxia injury of hepatocytes." Anoxia is low oxygen, you know, the absence of oxygen. And then, uh, that got me interested in metabolism. If you're a mathematician and you start working metabolism and eventually, like, mitochondria, it's electrons, it's enzyme kinetics, right? There's math. And in fact, my PhD is on enzyme kinetics. And so I'm doing a PhD on a enzyme that's very critical for respiration. So, like, the enzyme that uses oxygen in every cell is what I did my PhD on, and how that enzyme works under different oxygen levels. Again, lots of math. You know, Michaelis-Menten, but much more sophisticated enzyme kinetics. And then after that, the thing that was probably the, the most influential discovery in the mitochondria field for me, and I still think this is one of the three greatest discoveries in the mitochondria field, of course, it'll be contentious because lots of people m-might take issue with this. So the first one is Hans Krebs and the TCA cycle in '37. There's the '60 paper by Peter Mitchell, how you make ATP. So those are the two big things, right? Energy, bioenergetics, and biosynthesis, because the Krebs cycle eventually makes carbon molecules, which are the backbone for lipids, nucleotides, amino acids. The third big experiment was, came out in 1996. So Xiaodong Wang, when he was at Emory, found that the protein that I used every single day to do enzyme kinetics, so I worked on cytochrome c oxidase, that's an enzyme. Already tells you cytochrome c oxidase means that it uses cytochrome c as a substrate.

   5. PAPeter Attia8:05

      What-- Let's take a step back for someone who's going to be listening to this who doesn't know everything about it. Before we get to Wang's experiment, tell us who Hans Krebs, uh, what he did, what the TCA is. A lot of people will think, "Mm, I kind of remember this from high school biology," but give me a quick refresher course. So I'll prime you a little bit for it. A cell brings glucose in, just to make it easy. It turns glucose through a number of steps, enzymatic steps, into two smaller three-carbon units called pyruvate. Assuming the demand for ATP is not extraordinary and there's sufficient cellular oxygen, what would be the most efficient way to get energy out of that?

   6. NCNavdeep Chandel8:43

      Pyruvate has two choices. It can either become lactate, and usually that happens when there's not enough oxygen.

   7. PAPeter Attia8:51

      Yeah. All right, and the other thing I always like to say to people, and/or when the demand for ATP is exceptional.

   8. NCNavdeep Chandel8:56

      Exceptional, right. But the other place where it really goes is pyruvate goes into what's called the TCA cycle, and it's really a cycle. So where glycolysis is a series of linear steps, you know, A, B, C, D, E, then you get to pyruvate, and pyruvate actually goes in a circular fashion.

   9. PAPeter Attia9:12

      And this occurs in a part of the cell called the cytoplasm.

   10. NCNavdeep Chandel9:16

       The glycolysis part does.

   11. PAPeter Attia9:17

       Yes.

   12. NCNavdeep Chandel9:17

       But the TCA happens in the mitochondria.

   13. PAPeter Attia9:19

       Which we're going to get to, yeah.

   14. NCNavdeep Chandel9:20

       So pyruvate to lactate is all in the cytoplasm, but pyruvate then gets imported through a pyruvate, a mitochondrial pyruvate carrier, and that's important because it could be a target therapeutically in certain diseases. I think most of us appreciate, and this is what you're getting to, why you're focusing on pyruvate. Pyruvate has two choices, go to lactate or the mitochondria. So clearly, the pyruvate to lactate is cytoplasmic. Pyruvate going into the mitochondria and eventually becoming acetyl-CoA, that's an important reaction. So what, where pyruvate goes and how it gets in and out is quite important, and discovery of that transporter gives you a way to maybe target that.

   15. PAPeter Attia10:02

       So now pyruvate's in the mitochondria.

   16. NCNavdeep Chandel10:04

       It's in the mitochondria, and then it's a three carbon, and it becomes acetyl-CoA. Acetyl-CoA is very important, and we can get into it later, because acetyl-CoA can acetylate.

   17. PAPeter Attia10:15

       To acetylate, the ate means you put it on, basically.

   18. NCNavdeep Chandel10:19

       Put it on, right.

   19. PAPeter Attia10:19

       Ace is an enzyme. It's the, it's the end of an enzyme.

   20. NCNavdeep Chandel10:23

       Right, to take it, take it off.

   21. PAPeter Attia10:24

       Yeah.

   22. NCNavdeep Chandel10:24

       Yeah. And then it goes through the TCA cycle, uh, which is-

   23. PAPeter Attia10:28

       Which stands for?

   24. NCNavdeep Chandel10:29

       So some people call it the Krebs cycle because Hans Krebs discovered it, so try carboxylic acid cycle. Some people call it the citric acid cycle, CAC.

   25. PAPeter Attia10:37

       So we'll use those interchangeably.

   26. NCNavdeep Chandel10:39

       And so the TCA cycle, as it's going in the mitochondria, it generates NADH and FADH. These are these reducing equivalents which then feed electrons through the electron transport chain. And the electron transport chain and can pump protons, which is basically like a battery to generate ATP, which is the currency of that makes, you know, cellular functions work.

   27. PAPeter Attia11:05

       So the way I like to explain this to people, 'cause I think it's such-- It's just so damn elegant. You look at a piece of food, and all you see is this potential energy. You see... And, and of course, within all the bonds that exist in food, which is where we get our energy from, you have carbon-carbon bonds, carbon-hydrogen bonds, carbon-nitrogen bonds, carbon-oxygen, nitrogen-oxygen. I mean, there's only a finite number of covalent bonds that exist, but the two most energy-dense, I think, are carbon-carbon and carbon-hydrogen, correct? Isn't that where the majority of the chemical energy is liberated?

   28. NCNavdeep Chandel11:39

       Right. Those electrons have to eventually be accepted by something, right?

   29. PAPeter Attia11:42

       Mm-hmm.

   30. NCNavdeep Chandel11:42

       And oxygen is the final acceptor of all of those.
4. 12:39 – 19:42

   Cytochrome c, Apoptosis and Mitochondria as Signaling Organelles

   1. PAPeter Attia12:39

      Make ATP.

   2. NCNavdeep Chandel12:40

      That's it.

   3. PAPeter Attia12:41

      And for good reason, because let's call a spade a spade. As we know, if you interrupt that cycle for even moments, it's uniformly fatal. Most people are familiar with a toxin called cyanide. Cyanide is fatal at incredibly low concentrations. There are only a handful of toxins that are more potent, more lethal at lower concentrations. Uh, but-- And, and they all tend to, you know, like botulinum toxin, I think, pr- blocks the sodium channel transporter. It might be even more lethal. But why cyanide is so lethal is it disrupts that process you just described.

   4. NCNavdeep Chandel13:15

      Indeed, but it's not clear which organ fails right away. So we'll, we'll, we'll get into that in a second. Uh, uh, the genetic experiments don't totally confirm that idea.

   5. PAPeter Attia13:26

      Interesting. I'd like to hear more about this.

   6. NCNavdeep Chandel13:27

      Yeah. Yeah. We're gonna get into that in a little bit. So in 1996, if you asked that question, it's all about ATP. And so there is this protein, cytochrome c, that's part of this energy, energy-generating system, which is ATP. And Xiaodong Wang and colleagues found that if that protein gets released from mitochondria into the cytoplasm, which had never been detected before, it can rapidly kill a cell. So now the decision for life and death is based on the localization of cytochrome c between the mitochondria and into the cytoplasm. So if it's in the mitochondria, it helps you generate ATP. If it's out, it kills you.

   7. PAPeter Attia14:15

      And I assume it only escapes when the mitochondria is under the most intense duress and destruction.

   8. NCNavdeep Chandel14:21

      Yeah. So when a cell is under some sort of toxin stress, could be low oxygen, right, complete absence of oxygen, could be a growth factor, which is telling the cell to live, is not present. Death by neglect, let's call it that. When the cell is being neglected, either by nutrition starvation, complete depletion of nu-nutrients, or complete depletion of growth factors that keep them happy, the positive signals, then cytochrome C gets released. But it's a very profound discovery because this is a protein that we were all convinced had only one role. We call it the day job now. Make ATP. It's got a moonlighting job that sometimes it leaves the mitochondria and doesn't make ATP, and bam, it starts a cascade, which is called apoptosis, cell death.

   9. PAPeter Attia15:10

      I was just about to say, i-is this part of a programmed cell death as apoptosis?

   10. NCNavdeep Chandel15:15

       Yeah. This is programmed cell death. So here, here I am in 1996. I'm twenty-six years old, very happy doing enzyme kinetics, bioenergetics, and I see this, th-this finding, and all of a sudden, I stop caring about ATP. Because in part, a lot of that, how it works, was more or less discovered. I, I didn't have the insight, 'cause obviously, why would I be still working on it? [chuckles] I still thought there was more to be discovered. But the reality was I was probably just cleaning up little side things in that field at best. Uh, and that's not hopefully to disparage the bioenergetics field, but there's still some important questions there, more at a structural level, and there's some beautiful work there. But, you know, what I was doing was-

   11. PAPeter Attia16:00

       The kinetics had been worked out now.

   12. NCNavdeep Chandel16:02

       Yeah. I mean, some of it had been and not, but this was great because this connected the mitochondria just not for energy and, you know, what the mitochondria does almost in a cell, like in an autonomous way, right? It just does ATP. But this says it starts to control cell biology and function, like the decision of life and death. So obviously, the first thing we think about is it can't be selected just for death, right? It ha- must be doing something interesting. So let's think about what else it might release. And one of the first things that we thought about, which is something that people had noticed for almost forty, fifty years before, they release superoxide and hydrogen peroxide. Reactive oxygen species, oxidants, free radicals. And most people in the mid-'90s assumed that mitochondria only release this so-called cleaning molecule or toxic molecule when the mitochondria is damaged, maybe in neurodegeneration, maybe in aging, we'll get into this, maybe when a heart failure, when there's low oxygen ischemia. So in other words, it's there almost a-as a way that the mitochondria, when it's not working well, it just spills out. Because mitochondria has all these electrons and, and they have to-- they're not working. Those electrons just spill into superoxide and eventually to hydrogen peroxide. And what we thought about is, well, maybe nature could have used that as a signaling molecule, in other words, to dictate cellular function. And so there were some papers just right b- as we were working that came out and that showed, in fact, H2O2 could be a signaling molecule, but they didn't think it was necessarily mitochondria. So there was a neat little story that there's another system in the cytoplasm that can generate H2O2, and they thought that's all about signaling. Signaling basically means it's making decisions in the cell to die, to live, to proliferate, to grow, uh, uh, if you're an immune cell, to make cytokines, to do inflammation. But the mitochondria only did it when it's not working and it's spilling all these electrons into hydrogen peroxide and it's causing damage. And we actually showed, uh, that in fact Under physiological conditions, you can make hydrogen peroxide, uh, which has a beneficial effect. And so from that point on, with the first paper was published in '98, now almost 20 years, is my group and lots of other people continue to show that mitochondrial generation of this cleaning molecule can actually cause, um, cellular functions to happen. For example, we've shown our T-cells, which are part of the adaptive immune system, right? They fight off pathogens, right? Uh, or innate immune cells as well. Just, just immunity in general, right? They fight off viral infections, bacterial infections, that H2O2 is used by those immune cells to properly function. And what's the profound implication? Which is what you're gonna get into, is antioxidants. Are they beneficial? Are they harmful? So already to the audience, it should be obvious, if I'm saying that something you think is a cleaning molecule only, then antioxidants are great. You're getting rid of this toxic molecule, cleaning molecule. You're getting rid of this bad stuff. But it, if it's also there for good purposes like immune function-

   13. PAPeter Attia19:34

       It paradoxically could be bad to have an antioxidant in your system at a time when you need enhanced, especially adaptive immunity.

   14. NCNavdeep Chandel19:42

       And

5. 19:42 – 28:43

   Antioxidants, Ferroptosis and ROS Balance

   1. NCNavdeep Chandel19:42

      so one of the clinical trials that came out was in the ICU, sepsis, that's the big disease, and which is basically on a simplistic level, tons of inflammation, and those trials failed. They made them worse, antioxidant trials. In cancer, again, in lung cancer, vitamin E trial, it didn't have a curative effect.

   2. PAPeter Attia20:04

      Yeah. Do you think it's overly simplistic to say that there ought to be a balance in the body between pro-oxidative and anti-oxidative stress, and it's never the case that one is absolutely good or absolutely bad, it depends on the state of the organism. So under perhaps a normal state, a more antioxidative, i.e. let's reduce the ROS, is the right thing to do. But to your point, when the immune system is required to take the front step, cancer and sepsis being two enormous examples, that having too much antioxidant property can actually be harmful, and that's a moment when you actually want to be able to inhibit that process.

   3. NCNavdeep Chandel20:41

      So one of the interesting antioxidant trials, now again, caveat in this experiment I'm going to tell you, is an exercise experiment. So we all agree that if you do vigorous exercise, it has benefits, and you can take a biopsy a- and look at, uh, all the genes that exercise turns on, and these are genes we think are beneficial to the host, to the rest of the body. If you give high doses of antioxidants, so that's the caveat, it's high doses, probably not the doses that most people use, it actually [laughs] turns off that beneficial response. So in other words, to your point, I think what you were making is that when the system is stressed and the mitochondria integrates that stress, how does it pass that information back to the cell? We think that perhaps it releases hydrogen peroxide. So like clearly exercise is a good example, right? That's a stress to the system, to your muscle.

   4. PAPeter Attia21:37

      Mm-hmm.

   5. NCNavdeep Chandel21:37

      And how does that muscle then turn on all these genes and blah, blah, blah? We think it does it perhaps by releasing hydrogen peroxide.

   6. PAPeter Attia21:45

      Prior to this insight, Nav, is it the case that people knew the mitochondria was signaling, but assumed there was a different molecule that was used to transmit the message? Or that people didn't actually think the mitochondria were playing any role in signaling, and this, we're still back in the ATP only paradigm?

   7. NCNavdeep Chandel22:04

      They did think about signaling only in the context of pathology. So in other words, so there are these childhood diseases like Leigh syndrome, where there's a mitochondrial mutation in a particular protein, and it's a devastating disease. The kids don't live that long. And clearly, that's a mitochondrial mutation and a protein that gets mutated, doesn't function properly in the mitochondria, and you get a childhood disease. So how does that work? So people say, "Well, probably ATP," or maybe some, maybe too much ROS." That's right. So, and so in that context, there was some idea of signaling, right? Because, but this is saying under physiological conditions. Exercise is not pathology. It's physiologic. When you get a pathogen, uh, in other words, when you get a virus-

   8. PAPeter Attia22:49

      Yeah

   9. NCNavdeep Chandel22:49

      ... or bacteria, that's, that happens. You get a cold. Your immune system has to be activated. That's not pathology. That's a good normal response. So under all those conditions, the, the mitochondria is playing a signaling role, and so I've coined this term, uh, you know, so there's the mitochondria as powerhouses. Uh, so my, my talks never talk about that. The title of every talk I give [laughs] all around the world is the same, not very original anymore, mitochondria as signaling organelles.

   10. PAPeter Attia23:19

       Mm-hmm.

   11. NCNavdeep Chandel23:20

       And H2O2 is one way. Cytochrome C is another way, right? That's prob- maybe the most original because that's for cell death. There's-

   12. PAPeter Attia23:28

       By the way, 22 years later, do we still think that that work out of Emory is... W- what has been added to that body of knowledge about the role of, in, in apoptosis, in programmed cell death?

   13. NCNavdeep Chandel23:38

       They know the whole pathway.

   14. PAPeter Attia23:40

       But it is still coming from the single enzyme?

   15. NCNavdeep Chandel23:42

       Yeah, yeah. Yeah.

   16. PAPeter Attia23:43

       Wow.

   17. NCNavdeep Chandel23:43

       There are these proteins called Bax and Bak that make these pores, es, in the mitochondria, and it releases this, uh, 13 kilodalton protein, just, it just releases that protein right out, and then it binds to a whole bunch of other proteins, Apaf-1 and caspase-9, and starts this proteolytic pathway, which eventually causes cell death. So they've worked out all the biochemistry in that.

   18. PAPeter Attia24:07

       But the main point remains, that-

   19. NCNavdeep Chandel24:09

       Conceptually, yes.

   20. PAPeter Attia24:10

       Wow. That's, that's... You don't get that all the time in biology, that 22 years later, the punchline is still the same.

   21. NCNavdeep Chandel24:14

       The punchline is the same. I mean, you know, there's a lot of details that have to-

   22. PAPeter Attia24:18

       No, there's a lot of detail. Yeah

   23. NCNavdeep Chandel24:19

       ... but conceptually, yeah.

   24. PAPeter Attia24:22

       Are there other ways, by the way, that cells can undergo apoptosis?

   25. NCNavdeep Chandel24:26

       Oh, yeah. Now, now there's a whole industry. Every day there's a new version of it. And in fact, we can talk about one new one, which I'm very excited about. So clearly we can show that H2O2 in many contexts will signal for positive responses, immune functions, as we just talked about, the exercise response. But clearly there must be cases where H2O2 or other reactive oxygen species cause cell death. How does that work? And there is a new form of cell death that was just discovered by Brent Stockwell and Scott Dixon at Columbia in '11 or so, 2011, and they... It's called ferroptosis. It's... And it's basically taking H2O2. If, if there's free iron, you can make a hydroxyl radical, an OH, and that will then make a lipid hydroperoxide. So if you have polyunsaturated fatty acids, it, it will basically, it make it into a lipid hydroperoxide, which can be very toxic. So the bottom line is there are times where hydrogen peroxide with iron and lipids, the three can come together and make something called a lipid hydroperoxide, which will cause cell death in ferroptosis. The good thing is your body's full of an enzyme called GPX4 that gets rid of it all the time. Now, if you don't have that enzyme, you're in big trouble.

   26. PAPeter Attia25:53

       Hm.

   27. NCNavdeep Chandel25:53

       So there are places where clearly H2O2 is positive, and it can become very lethal by making another form of reactive oxygen species. But again, nature has selected, you know, I can't count all of them, but at least 30 enzymes, which are constantly mopping up these reactive oxygen species, keeping them quite low so you don't get to those toxic levels.

   28. PAPeter Attia26:15

       So when we go back to apoptosis, which I didn't think we were gonna even talk about this, but it's so great to be able to bring it up because I think for many people that they're still probably thinking, "Wait, what are we talking about apoptosis?" So if a cell undergoes a genetic mutation, nuclear genetic, we'll come back to mitochondrial genes later, but if a cell undergoes a genetic mutation in the nucleus that's unrecoverable, it will, on a good day, kill itself. It will commit suicide. I mean, that would be one of the things that would drive apoptosis.

   29. NCNavdeep Chandel26:44

       You're getting to tumor suppression mechanisms, basically, right?

   30. PAPeter Attia26:46

       Yes, exactly. That's, that's where I'm going.
6. 28:43 – 45:08

   Mitochondrial DNA, Its Vulnerability and Maternal Inheritance

   1. PAPeter Attia28:43

      So, so while we're still going on history, um, I just alluded to something a moment ago that I think is an important point for the, for the listener to understand, which is, you know, everybody knows, or I guess, you know, most people who are thinking about biology would understand that the part of the cell that contains your DNA is called the nucleus, and we've got lots of genes in there, about 20,000 genes, but the mitochondria has genes too.

   2. NCNavdeep Chandel29:06

      Right.

   3. PAPeter Attia29:06

      Not that many. What, it's like 35 or something?

   4. NCNavdeep Chandel29:08

      Yeah, it's 37. And there's, the key point there is there's 13 genes that are essential for the respiratory chain to work, and the respiratory chain is where all that oxygen is being consumed. That's the one that makes that energy, that electrochemical energy we talked about that ultimately gets converted to ATP. So the key subunits of the respiratory chain, what generates that battery that we've been talking about, it holds onto those 13 genes that are critical for it. So for example, complex I, and it's one of those respiratory chains, there's these five complexes. Well, one of the complexes has 45 subunits, but a few of them, which means 45 proteins make this huge complex, but a few of them are in, uh, in the mitochondrial genome. Complex III, very important, my favorite complex. Everybody's got to have a favorite complex. And so my favorite complex-

   5. PAPeter Attia30:03

      I, I see a T-shirt here.

   6. NCNavdeep Chandel30:04

      Yeah, yeah. So my favorite complex is complex III, and it has one gene that's still in the mitochondria.

   7. PAPeter Attia30:10

      By the way, are you saying that just to be contrarian because complex I is actually the coolest?

   8. NCNavdeep Chandel30:13

      [laughs]

   9. PAPeter Attia30:15

      'Cause, like, how, how can, how can complex I not be your favorite mitochondrial complex?

   10. NCNavdeep Chandel30:20

       I'll tell you in a second.

   11. PAPeter Attia30:20

       It's just 'cause you're cool, and you're, you're too cool for school 'cause you study this. The rest of us who are in the peanut gallery, we, we default into complex I being the coolest.

   12. NCNavdeep Chandel30:31

       So you're saying I'm a mitochondrial hipster, right? [laughs]

   13. PAPeter Attia30:33

       I think you are. You're, you're leading the charge on this.

   14. NCNavdeep Chandel30:36

       No, but think of, you know, complex three is very interesting because it has 11 su- you know, one of, only one subunit is in the mitochondrial, uh, encoded by the mitochondrial genome. So, so at one point, the mitochondria... So going back in evolution, we think, uh, there was an alphaproteobacteria and an archaea, probably a methanogen, and these two prokaryotes got together and had a symbiotic love affair.

   15. PAPeter Attia31:01

       And, and just to explain to the, so we are eukaryotes.

   16. NCNavdeep Chandel31:04

       We are eukaryotes.

   17. PAPeter Attia31:05

       And what does that mean again?

   18. NCNavdeep Chandel31:06

       We've got a nucleus, we've got a bunch of organelles.

   19. PAPeter Attia31:08

       And what's a prokaryote?

   20. NCNavdeep Chandel31:10

       It doesn't have those organelles.

   21. PAPeter Attia31:11

       Got it. So bacteria.

   22. NCNavdeep Chandel31:13

       So you got a bacteria and you got an archaea, and they got together. So we think the archaea is kind of where the nucleus came from, and the alphaproteobacteria is the modern-day mitochondria. And one of the best evidences is, I remember an experiment that I did as a graduate student, and it was, I took a bacteria that somebody had discovered in the '70s, a beautiful paper in Nature, and this bacteria, if you gave it like succinate, w- like a, a mitochondrial substrate, and it'll grow on it, and it would respire very similar to modern-day bacterium, modern-day mitochondria.

   23. PAPeter Attia31:48

       Wow. A nice elegant proof of concept that the mitochondria are basically bacteria, came from bacteria.

   24. NCNavdeep Chandel31:55

       Yeah, they came from bacteria, yeah. I mean, you know, those who doubt evolution, I always tell them that every organism I know burns glucose very similarly. [laughs]

   25. PAPeter Attia32:04

       It is hard to make the, yeah, if you, if you, if you're, and not, I don't want to go down this path-

   26. NCNavdeep Chandel32:08

       Yeah, I don't want to go down this path

   27. PAPeter Attia32:08

       ... because we'll simply alienate a million people.

   28. NCNavdeep Chandel32:10

       Yeah.

   29. PAPeter Attia32:10

       But, but it is interesting to think, like, it strikes me as it's very hard to come up with an alternative explanation for why you would have this effectively foreign DNA inside every cell. And I just, I'm so intrigued by this mitochondrial DNA thing because, again, it's such a tiny number of genes on a relative scale, but yet they're so critical. And to my knowledge, is, I don't think there's any other organelle that carries its own genes with it. Is there?

   30. NCNavdeep Chandel32:39

       No, it doesn't. And, and what's interesting is that it only encodes for, like, a, a 1% of, you know, there's, I don't know, 1,000 proteins in the mitochondria.
7. 45:08 – 50:12

   Mitochondrial Decline in Aging: Adaptive or Rate-Limiting?

   1. PAPeter Attia45:08

      So, so let's shift gears a little bit to talk about some other broad mitochondrial questions because I do think that people today, and maybe it's just the bias I experience because of what I'm looking for, so this might not be the case, but it seems that the interest in mitochondria has exploded. I think people are realizing there's a lot going on here. It's more than we realize. Mitochondrial function is now a term people use all the time, but they're not just talk-- I don't think they're just talking about oxidative phosphorylation. I think they're talking about broader things. And when we talk about aging, we talk about some things changing in the mitochondria as we age. When you think of hallmarks of aging, we can debate the merits of some of them, but something's different in the mitochondria of an 80-year-old versus an eight-year-old. What are some of those changes?

   2. NCNavdeep Chandel46:00

      Well, so this is gonna get contentious now because the data suggests that you have a decrease in mitochondrial DNA. Some of that mitochondrial DNA has deletions, that the capacity to do maximal ATP generation goes down, oxidative phosphorylation. The key there is maximal. So one of the perplexing things, and this is really perplexing for me, a much more s- so I don't think much about mitochondrial DNA, and that's why I didn't have good answers for that, but this is the one that really is, and this is fundamental to the aging. When you're born, let's say, you have 100% capacity, and then as you age, that capacity, if you're giving 100% mitochondria, you get an A+, 100%. How far do you go as you age?

   3. PAPeter Attia46:55

      Just to make sure I understand what you're talking about, are you saying amount of ATP generated-

   4. NCNavdeep Chandel47:01

      Right

   5. PAPeter Attia47:01

      ... per mole of oxygen as a, as a metric so-

   6. NCNavdeep Chandel47:03

      As a metric.

   7. PAPeter Attia47:03

      Okay, okay.

   8. NCNavdeep Chandel47:04

      We could, we could use ATP generation as a simple one, right?

   9. PAPeter Attia47:06

      Okay. So-

   10. NCNavdeep Chandel47:07

       Its ability to-

   11. PAPeter Attia47:08

       For every mole of oxygen, you generate X mole of ATP, and whatever your maximum is, it declines.

   12. NCNavdeep Chandel47:13

       And you can burn it through fat, glucose, carbohydrates, proteins. It's working at its maximal efficiency. It's everything's fine. And that efficiency now declines with age. The question is, is it ever rate limiting? So you and I, I mean, again, these are loose terms, at any given point are using maybe 10 to 20% of our maximal activity.

   13. PAPeter Attia47:42

       Hey, speak for yourself, dude. [laughs] I mean, I-

   14. NCNavdeep Chandel47:44

       [laughs]

   15. PAPeter Attia47:45

       ... I, I do wind sprints every day, man. I, I, I-

   16. NCNavdeep Chandel47:48

       Okay.

   17. PAPeter Attia47:48

       No, I'm just kidding.

   18. NCNavdeep Chandel47:48

       So when you, when you do that, you might go up to 40 or 50%.

   19. PAPeter Attia47:52

       I didn't realize that.

   20. NCNavdeep Chandel47:52

       You don't hit that. And so when we knock out a protein in the mitochondria, and we knock out it completely from 100% to 0%, pathology happens. If we go from 100 to 50%, we never see any pathology.

   21. PAPeter Attia48:09

       Even under stress, you don't?

   22. NCNavdeep Chandel48:10

       Even under stress. If anything, they behave better. So-

   23. PAPeter Attia48:13

       Ooh, this is interesting.

   24. NCNavdeep Chandel48:14

       Yeah. Yeah. This is very interesting, right? Right? And so then when I look at the data on aging sometimes, you know, in some tissues it goes down by 50% of maximal, maybe 70%, 80%, but is that ever rate limiting?

   25. PAPeter Attia48:28

       Well, if what you said make, if you, what you said is true, then it would not be rate limiting-

   26. NCNavdeep Chandel48:31

       I don't think-

   27. PAPeter Attia48:32

       ... within a certain band.

   28. NCNavdeep Chandel48:33

       So I am on, and this, full disclosure again, I am in way out in outer space on this idea. I don't think mitochondrial function... And if you don't have a disease, let's be clear, normal aging we're talking about, right? Uh, you don't have cardiovascular disease, you didn't have, you know, you're just sort of, you're pretty healthy. Uh, and I don't think a healthy heart, you know, is rate limited for mitochondrial function. The implication there is That most people think, again, this is like dogma like with antioxidants, right? They're good for you. That mitochondria are declining, let's give supplements that boost mitochondrial function. Is that a fair statement?

   29. PAPeter Attia49:15

       Heck yeah.

   30. NCNavdeep Chandel49:17

       I think there's no evidence to support that. So-
8. 50:12 – 1:06:02

   How Metformin Works: Complex I, AMPK and the NAD/NADH Ratio

   1. NCNavdeep Chandel50:12

      Because we think metformin is a weak mitochondrial complex 1 inhibitor.

   2. PAPeter Attia50:18

      Yes.

   3. NCNavdeep Chandel50:18

      Uh, another, which is part of the respiratory chain. It's a weak-

   4. PAPeter Attia50:20

      That's why complex 1 is my favorite complex.

   5. NCNavdeep Chandel50:22

      That's why your complex 1 is your favorite.

   6. PAPeter Attia50:23

      But I'm a poser.

   7. NCNavdeep Chandel50:24

      [laughs]

   8. PAPeter Attia50:24

      I'm a mitochondrial poser. So, okay, 'cause, uh, what I was gonna actually ask you was on the heels of that, when you give metformin, you inhibit complex 1, you are now reducing-

   9. NCNavdeep Chandel50:36

      Mitochondrial function

   10. PAPeter Attia50:36

       ... that mitochondrial function.

   11. NCNavdeep Chandel50:37

       Right.

   12. PAPeter Attia50:38

       And if what you're saying is correct, you would need a lot of metformin to generate actual ETC toxicity.

   13. NCNavdeep Chandel50:45

       Right.

   14. PAPeter Attia50:46

       Do we ever see that?

   15. NCNavdeep Chandel50:47

       No. I mean, you do if you go to certain doses, obviously.

   16. PAPeter Attia50:50

       But, but not, not physiologically we can't, do we?

   17. NCNavdeep Chandel50:53

       The, the antidiabetic dosing that is given to people, I mean, there's some toxicity can happen due to certain patient populations, and that's, uh, but it's a very safe drug, right? It's used by almost, what, 300 million people now. Uh, it's estimated to be used by half a billion people as the diabetes epidemic explodes in China and India. So no one quite understands how metformin works. Um, we think it's, um, you know, it, it has three effects, clearly. It lowers glucose production in the liver, it has some anti-inflammatory effects, and it has some anticancer effects.

   18. PAPeter Attia51:27

       Well, let's talk more specifically about it. We were joking around when we were at Easter Island that our next trip actually needs to be to France.

   19. NCNavdeep Chandel51:33

       Uh, to see the goats? [laughs]

   20. PAPeter Attia51:35

       To see the, to see the lilac where, from where met- wasn't that in France where they, where that metformin, uh, lilac came from?

   21. NCNavdeep Chandel51:40

       Yeah. Yeah.

   22. PAPeter Attia51:41

       So two sentences on how metformin was discovered.

   23. NCNavdeep Chandel51:43

       Uh, they noticed these goats that were eating [laughs] were pretty healthy. [laughs]

   24. PAPeter Attia51:48

       I love this. I love these stories.

   25. NCNavdeep Chandel51:50

       But, you know-

   26. PAPeter Attia51:51

       Yesterday I was talking to Ted Schafer about-

   27. NCNavdeep Chandel51:53

       Yeah

   28. PAPeter Attia51:53

       ... goats as well, so I love that the two Northwestern guys, so the only two podcasts-

   29. NCNavdeep Chandel51:57

       That doesn't sound right. That doesn't sound right

   30. PAPeter Attia51:58

       ... that will ever have goats are gonna be these ones.
9. 1:06:02 – 1:16:08

   Proving Metformin's Anticancer Mechanism with Yeast Complex I

   1. PAPeter Attia1:06:02

      Well, but it's hard to have a complex I knockout-

   2. NCNavdeep Chandel1:06:04

      Exactly

   3. PAPeter Attia1:06:04

      ... because that's incompatible with life, so that would be the obvious answer that doesn't work.

   4. NCNavdeep Chandel1:06:08

      Well, so I would argue for any drug, the best experiment is to make a mutant of that particular complex.

   5. PAPeter Attia1:06:19

      That doesn't bind metformin.

   6. NCNavdeep Chandel1:06:20

      Bingo.

   7. PAPeter Attia1:06:20

      Yeah.

   8. NCNavdeep Chandel1:06:21

      So I'm not a good structural biologist, but we did something really clever. We noticed that the yeast has a protein, single protein, which will catalyze NADH to NAD.

   9. PAPeter Attia1:06:33

      Okay.

   10. NCNavdeep Chandel1:06:34

       What complex I does, in part.

   11. PAPeter Attia1:06:36

       Yes, exactly.

   12. NCNavdeep Chandel1:06:37

       It doesn't proton pump, which means it doesn't contribute to ATP generation. But we have engineered cells and mice to get rid of complex I and put back this yeast complex I, which is refractory to metformin-

   13. PAPeter Attia1:06:53

       But-

   14. NCNavdeep Chandel1:06:53

       ... to ask this question

   15. PAPeter Attia1:06:54

       ... and, but the phenotype of that cell is what? How, what is it a- what is its electron transport chain doing if it's basically losing anything at complex I? Basically, complex II through V still can't work.

   16. NCNavdeep Chandel1:07:05

       No, no, no, no. So what this protein, this yeast complex I homolog-

   17. PAPeter Attia1:07:10

       Yes

   18. NCNavdeep Chandel1:07:10

       ... the single protein-

   19. PAPeter Attia1:07:11

       Oh, oh, it does everything except the electron transport. So you-

   20. NCNavdeep Chandel1:07:14

       No, no, it does the electron transport.

   21. PAPeter Attia1:07:16

       Sorry, it doesn't do the, uh-

   22. NCNavdeep Chandel1:07:16

       The proton pump

   23. PAPeter Attia1:07:17

       ... the proton pump.

   24. NCNavdeep Chandel1:07:18

       Yeah.

   25. PAPeter Attia1:07:18

       Okay, got it. So you basically reduced your battery charge a little bit.

   26. NCNavdeep Chandel1:07:21

       A little bit.

   27. PAPeter Attia1:07:21

       But you haven't interrupted the electron transport.

   28. NCNavdeep Chandel1:07:23

       Right.

   29. PAPeter Attia1:07:24

       Oh, that's elegant.

   30. NCNavdeep Chandel1:07:25

       Thank you.
10. 1:16:08 – 1:26:58

    Mitochondria Are Necessary for Tumorigenesis: Beyond Warburg

    1. NCNavdeep Chandel1:16:08

       I think you've talked about in some other podcasts, so there was a observation made in the 1920s by a gentleman named Otto Warburg, one of the giants, uh, s- actually trained Hans Krebs, for example. He won a Nobel Prize in 1931 or '32 r- basically for discovering an enzyme w- for respiration, and so he loved measuring respiration and... But he did it in cancer, he did it in normal cells, and he noticed that cancer cells, cells at least i- on the bench top, uh, not in vivo, not in a real tumor, not in humans, just taking, uh, tissues out, that they made a lot of lactate, uh, and they didn't consume as much oxygen. And this, this didn't make sense to him because he's like, "There's plenty of oxygen. Why should it do that?" And it led him to think about perhaps that maybe the mitochondria are being suppressed in cancer. Uh, and this led to this long, long, long dogma that a very elegant, simple theory. Normal cells use a lot of mitochondrion, mitochondrial ATP, very little glycolysis, so in other words, very little glucose to lactate, uh, and tons of oxygen. Your heart does it, your brain does it. But when you become cancerous, the mitochondria sort of shuts off and you upregulate tons of lactate, and you can see that huge uptake of glucose uptake by, uh, FDG-PET that the clinicians do, and you can see lots of lactate, and that was his theory. And then you target glycolysis for cancer, uh, because it'll specifically hit cancer cells 'cause they're so glycolytic and, and spare m- all the other cells like your heart, your brain, your liver because they're all mitochondrial dependent for energy. Keep it simple, right?

    2. PAPeter Attia1:17:49

       Right.

    3. NCNavdeep Chandel1:17:49

       So far so good?

    4. PAPeter Attia1:17:50

       Absolutely.

    5. NCNavdeep Chandel1:17:51

       So-

    6. PAPeter Attia1:17:52

       And then, I mean, just to add to that story, about 10 years ago, and I've talked about this paper on the podcast, but Thompson and, uh, well, Matt Vander Heiden was the, uh, the lead author, but so, so Vander Heiden and Cantley-

    7. NCNavdeep Chandel1:18:01

       Just saw him last, just saw him last night in Madison.

    8. PAPeter Attia1:18:04

       He was here last night? I wish I'd-

    9. NCNavdeep Chandel1:18:05

       No, he was in Madison.

    10. PAPeter Attia1:18:06

        Oh, oh, you... Right.

    11. NCNavdeep Chandel1:18:07

        Uh-huh.

    12. PAPeter Attia1:18:07

        So Matthew and, and Lou Cantley and, and Craig Thompson wrote this paper in Science, uh, almost exactly 10 years ago, and it proposed a different reason for the observation. So it said the observation that Warburg put forth is what you just described, but maybe a different reason is that the cancer cell is not optimizing for energetics, because that was always viewed as an energetically very inefficient and wasteful thing to do. But the argument they put forth was, well, i- it's not doing it for energetic reasons, it's doing it for growth reasons.

    13. NCNavdeep Chandel1:18:34

        Right.

    14. PAPeter Attia1:18:34

        It's doing that to get the throughput of building blocks for cells. So same observation, different explanation.

    15. NCNavdeep Chandel1:18:40

        The one thing I will say is, for whatever reason, and in- including that beautiful review in Science, which the part that people don't highlight is what is the mitochondria really doing? So people sometimes assume, oh yeah, all that glycolysis, and it's for biomass and building blocks. Oh yeah, the mitochondria is, has a negligible contribution. It's just sort of in the background. It's, it's the potato, as we call it, right?

    16. PAPeter Attia1:19:06

        In the Sabatini world.

    17. NCNavdeep Chandel1:19:07

        Yeah, yeah. Right? It's just, it's a bystander. And we did a simple genetic experiment, said let's just test this. So we're gonna take in a mouse with a intact immune system, we g- we gave the mouse a l- uh, made it g- have, poor mouse, got lung adenocarcinoma. Lung cancer, right? The biggest cancer in the, the most prevalent cancer in the world, obviously due to smoking. And We genetically knocked out the respiratory chain, so it can't respire. So now it's 100% glycolysis. It's exactly what a tumor that Warburg would love. Do you make bigger tumors? According to him, yes, if it's all about glycolysis. Or do you make smaller tumors? We, we made very smaller tum- little, little, tiny little tumors, which told us that mitochondria are necessary, or mitochondrial respiration is necessary for tumorigenesis.

    18. PAPeter Attia1:19:59

        But Vander Heiden's hypothesis would explain that because-

    19. NCNavdeep Chandel1:20:02

        It's part of it

    20. PAPeter Attia1:20:03

        ... if you knock out the mitochondria, you don't have the biomass through which-

    21. NCNavdeep Chandel1:20:05

        Right, but he didn't say that in that paper.

    22. PAPeter Attia1:20:06

        No, no, no, I know, I know. But I'm, I'm extrapolating from what-

    23. NCNavdeep Chandel1:20:08

        Yeah, it's consistent with that. Yeah.

    24. PAPeter Attia1:20:09

        Yeah.

    25. NCNavdeep Chandel1:20:09

        No, Matt and I completely agree. It's just the way that review was written 10 years ago, it was more glycolytic centric. So I will give a cheap plug to a review that I wrote with Ralph DeBerardinis-

    26. PAPeter Attia1:20:19

        It's a very elegant review, by the way

    27. NCNavdeep Chandel1:20:21

        ... in 2016 where we updated this. It's called Fundamentals of Cancer Metabolism, and it's really simple. It just says if you go back to your biochemistry books and you ask how do you make a nucleotide? Let's keep that simple. You need to make new DNA because cancers proliferate. You make one to two daughter cells, to, to four, yeah, and there you go. So where does that nucleotide... Let's look at the structure. It has a ribose, s- as a backbone. That comes from glucose.

    28. PAPeter Attia1:20:48

        Mm-hmm.

    29. NCNavdeep Chandel1:20:48

        Bingo. It needs a, a variety of nitrogen, uh, atoms put on it. Where does that all come from? Some of it comes from, like, aspartate and glutamine. Where do they all come from?

    30. PAPeter Attia1:21:00

        They can come from glucose-
11. 1:26:58 – 1:38:15

    Targeting Mitochondria in Cancer Therapy and Nav's Contrarian Positions

    1. NCNavdeep Chandel1:26:58

       So one of them [laughs] is a complex I inhibitor that the M folks at MD Anderson have, uh, generated, and they just published two papers in Nature Medicine showing-

    2. PAPeter Attia1:27:07

       D- different from phenformin and-

    3. NCNavdeep Chandel1:27:08

       They're phenformin. Yeah, they're different from metformin, phenformin. They're much stronger, or they know the binding site. By the way, they use the same yeast NDI1 complex I that doesn't bind to metformin but doesn't bind to their drug as well as a, to show test it and, uh-

    4. PAPeter Attia1:27:25

       So how will they prevent toxicity?

    5. NCNavdeep Chandel1:27:26

       Yes, yes. Uh, so now they're, they're doing a trial in AML, and so this is a, this is the million-dollar question, and can you find a therapeutic window where maybe the drug gets taken up preferentially by, just because of the properties, by leukemic cells or prostate or lung cancer cells but spares the brain, the heart, and other organs which, where you could have toxicity? So that's the big issue. The good news is if you inhibit complex I, it will decrease tumorigenesis. The bad news is it might kill you, right? So, so we gotta find that window. And does it also work well with immunotherapy? That's an open question, right? Which is the n- the new kid on the block. Like, does it-

    6. PAPeter Attia1:28:08

       Hmm

    7. NCNavdeep Chandel1:28:08

       ... help synergize with immunotherapy, or does it prevent, uh, the immune function? So the, all of this has to be worked out, but my point is that there's some space in this area. The other one is a drug by Rafael, uh, Pharmaceuticals, and, uh, full disclosure, I sit on their scientific advisory board.

    8. PAPeter Attia1:28:26

       Thank you.

    9. NCNavdeep Chandel1:28:27

       And I'm not pitching anything here. Simply... In fact, like, they were already doing this stuff. We're just sort of giving them some, you know, my little biological insight, which is I'm trying to provide today, but, but they've already done a clinical trial, and it was... And, and I, I'll send it to you. It was published in Lancet Oncology, and it was in pancreatic cancer, just a safety trial.

    10. PAPeter Attia1:28:45

        Phase I.

    11. NCNavdeep Chandel1:28:45

        Phase I, and it targets alpha-keto, uh, TCA cycle enzymes, and so it's, it's, it's preventing the TCA cycle from functioning to build that biomass.

    12. PAPeter Attia1:28:55

        And did they generate any data on the tissue specificity of that agent?

    13. NCNavdeep Chandel1:28:59

        Not yet. So this is the kind of stuff that needs to be done, to try that drug and do the kind of experiments where you can see TCA cycle metabolites changing pre and post a drug treatment of a, of a particular tumor and then correlating that with success of, uh, remission and, you know, all the usual parameters. Now, what's interesting about that drug, again, is why would that be safe, any of this? The only way these drugs can be safe is they somehow preferentially are getting more into the tumors than-

    14. PAPeter Attia1:29:28

        Or they're just so weak that they're not bringing you below the threshold of shutting off the TCA.

    15. NCNavdeep Chandel1:29:34

        Yeah, and then maybe they combine well. So I can tell you, if you give the standard care of therapy, cisplatin, one of the chemotherapies or targeted therapies like BRAF inhibitors, is what happens, as you know, the, the primary tumor sort of debulks, right? It slows down, and slowly you get resistance, and, and then it comes back. During that slow resistance phase, at that point, they're really dependent on mitochondrial function. So there might be a window to attack it with, like, BRAF inhibitors or cisplatin, and again, like everything else, they're gonna have to find that sweet spot.

    16. PAPeter Attia1:30:07

        But that, that's... See, to me, that's where I think this has to go. I mean, I've always found immunotherapy to be the most elegant of all approaches to cancer. I'm highly biased because that's what I studied. But ultimately, I think the Swiss cheese approach has to be the approach, too, which is why would we only take one modality of therapy? If you're David and you're trying to slay Goliath in the fairy tale, one stone to the head does it. But in rea- in the real world, to take a Goliath down, I think you need to bang him at the knees, and when he bends over and complains about it, bang him in the other knee, and when he's complaining about that, whack him in the hamstring. And in other words, you've got to be able to do successive blows to a vulnerable cell, and that's gonna be, yeah, when is it most dependent on the mitochondria? Okay, well, bang, now you hit with that therapy, and then all of a sudden, uh, to your point earlier, maybe at some point you begin to weaken it even f- You, you make it more identifiable from an immune perspective, and bang, that's when you would hit with the immunotherapy.

    17. NCNavdeep Chandel1:31:04

        The last point I really like, you know, would, uh, the immune system recognize that tumor better if the mitochondria of that tumor was not working properly?

    18. PAPeter Attia1:31:12

        Yeah, see, that's... I mean, I, I'm super-

    19. NCNavdeep Chandel1:31:14

        Or maybe release that mitochondrial DNA, for example, as it's dying, you know?

    20. PAPeter Attia1:31:17

        As long as it were specific, right? As long as it could-- It didn't create a diffuse immune reaction but instead-

    21. NCNavdeep Chandel1:31:23

        A localized, yeah

    22. PAPeter Attia1:31:24

        ... allowed the body to say, "That's not self."

    23. NCNavdeep Chandel1:31:27

        Right.

    24. PAPeter Attia1:31:27

        That's... You know, and I haven't, I haven't done a podcast yet on immunotherapy. I want to have Steve Rosenberg on to talk about this-

    25. NCNavdeep Chandel1:31:32

        Yeah

    26. PAPeter Attia1:31:32

        ... because, I mean, who better to talk about this with? But anyway, so, so let's talk about another issue in cancer, right, which is, uh, I mean, I think everybody agrees that most cancers ha- involve somatic mutations. You know, there are very few cancers that involve germline mutations. That's, those are the, those are the exceptions. Uh, but the, the, the general one is these are acquired mutations. Now, some have argued, and this is a very minority opinion, but some have argued that the somatic mutations of the nuclear genome are actually the result of the mitochondrial dysfunction. I think the majority would argue no, it's the other way around, that the nuclear genomic mutations, somatic, are actually what leads to ultimately whatever's happening in the mitochondria that may be dysfunctional, may be maladaptive, may be adaptive. Y- you would be in the latter camp, correct?

    27. NCNavdeep Chandel1:32:25

        Completely, 100%. And again, this is why these clinical trials are really important. This is why the metformin trial is important, right? So I, I've told you two thing-- I've told you three points, things that are quite contrarian. We started with antioxidants, that there's no evidence that antioxidants in large scale, the dietary antioxidants, just to be clear, vitamin E, vitamin C, have had any benefit to mankind and womankind, right? There's, for human health and disease. It just hasn't worked out. So either we haven't built the right antioxidants, or the theory that ROS and oxidants are bad, that theory's off, and I would argue that theory's off because if anything, normally we use, uh, oxidants as, uh, signaling molecules. The second thing I told you about is the fact that during aging, yeah, mitochondria decline, but that correlates, and it could be adaptive, very contrarian point of view. If, if anything, if you gave an agent that decreases mitochondrial function, like metformin, that that could be a good anti-aging therapy, right? It, it's not turning on mitochondria, but turning off mitochondria. And by the way, Andy Dillin, a good friend of mine I was there with yesterday, who's done beautiful work on, uh, on worms, clearly in the worm, when you decrease complex I or III, you live longer as a worm.

    28. PAPeter Attia1:33:45

        Yeah, I don't know Andy, but David has spoken so highly of him, David Sabatini, you have as well. I need to meet Andy and hopefully interview him at some point and talk about all this stuff. Of course, it could be, going back to your point-

    29. NCNavdeep Chandel1:33:57

        Sure

    30. PAPeter Attia1:33:57

        ... that the inhibition of complex I, which inhibits mitochondrial function inside of a non-toxic range, might be, might not actually be part of why mi- metformin makes you live longer. That might just be a it survives despite that, not because of that, the organism.
12. 1:38:15 – 1:45:56

    Supplements, Vitamin C and Whether Nav Takes Metformin

    1. PAPeter Attia1:38:15

       Are there benefits, you think, to the natural quantities of antioxidants we consume in our food? So for example, berries do contain lots of antioxidants. People love to talk about those benefits. Without saying go up and take, you know, ground berry cap- capsules or something like that, do you still think there is a benefit in having... I- in other words, if a berry doesn't give you benefit in the antioxidant, there's not a hell of a lot of benefit in it, because it's basically just a vehicle to deliver fructose, which I could argue you don't need any fructose in your life. And it's a vehicle to deliver glucose, but you can get glucose in better forms or more of it elsewhere. So is there some other benefit?

    2. NCNavdeep Chandel1:38:54

       So I don't know much about berries. So the, the best one is vitamin C, right? Like, how much should you take?

    3. PAPeter Attia1:38:59

       Okay, so let's, let's talk about an orange. Is there some benefit-

    4. NCNavdeep Chandel1:39:02

       Yes

    5. PAPeter Attia1:39:03

       ... in eating an orange?

    6. NCNavdeep Chandel1:39:03

       Yes.

    7. PAPeter Attia1:39:04

       Okay, so what's the benefit in eating an orange-

    8. NCNavdeep Chandel1:39:05

       So-

    9. PAPeter Attia1:39:05

       ... from an antioxidant standpoint?

    10. NCNavdeep Chandel1:39:06

        Yeah, so there are enzymes that control DNA methylation and other reactions. So simply, uh, to maintain proper function of gene expression, so that your genes turn on and off properly, there are enzymes that are dependent on vitamin C. And you basically need about an orange a day or a glass of orange juice, you know? But-

    11. PAPeter Attia1:39:34

        Please, please, please-

    12. NCNavdeep Chandel1:39:35

        Not orange juice, okay

    13. PAPeter Attia1:39:36

        ... let's not encourage people to drink orange juice.

    14. NCNavdeep Chandel1:39:36

        Not orange juice. Fine, fine, fine.

    15. PAPeter Attia1:39:38

        [laughs]

    16. NCNavdeep Chandel1:39:38

        But, but you know, but, but what I mean is you don't need to take-

    17. PAPeter Attia1:39:40

        Non-juicing

    18. NCNavdeep Chandel1:39:41

        ... 10 oranges, right? Right? One, an orange a day is enough, right? Uh, to g- to give you enough vitamin C to make those reactions work properly. And, uh, one or two oranges, but you don't need to then go and take 400 grams.

    19. PAPeter Attia1:39:54

        But that has nothing to do with the antioxidant properties of vitamin C.

    20. NCNavdeep Chandel1:39:57

        No, no, no, no, no, no. It has nothing to do with the, nothing to do with ROS and all of this stuff we talked about. It has to do with running some enzymes that are important for controlling gene expression. I know those genes-

    21. PAPeter Attia1:40:09

        Yeah

    22. NCNavdeep Chandel1:40:09

        ... that have to get turned on and off are dependent on those, uh, those... And, and that's, so, and of course, there are some people who might not be taking, getting enough vitamin C as, and, you know, due to their diet, so that's fine. Take a, take a, take a-

    23. PAPeter Attia1:40:21

        Yeah. Pretty hard to do that

    24. NCNavdeep Chandel1:40:22

        ... pretty hard to do it. I mean, citric acid, I mean, you know, we have it a l- in a lot of places.

    25. PAPeter Attia1:40:26

        Would you be comfortable speculating that a cancer patient in particular should avoid antioxidants?

    26. NCNavdeep Chandel1:40:34

        No. No, I don't think, I don't think the dietary... Well, I guess, I guess-

    27. PAPeter Attia1:40:37

        No, no, no. I don't... Sorry, sorry.

    28. NCNavdeep Chandel1:40:37

        Yeah.

    29. PAPeter Attia1:40:38

        Let me rephrase my question. I don't mean through dietary means, but through supplemental means. Like, if any patient could actually be harmed by an antiox- antioxidant, could it be a cancer patient?

    30. NCNavdeep Chandel1:40:46

        Well, the, one of the trials, the lung cancer trial, argued that, I think it was the vitamin E trial, and they did worse. And, and in mice, you can recapitulate that. So why, why is that? It's not clear. So I personally don't take any of these supplements 'cause I think I've got a reasonable diet, so just like you, so.
13. 1:45:56 – 1:55:25

    NAD Precursors and MitoQ

    1. PAPeter Attia1:45:56

       Well, look, speaking of anti-aging, let's go back to NAD, 'cause we sort of skirted around a little bit. Obviously, one of the most popular types of supplements being offered on the market today, and there are several of them, are supplements that are aimed at delivering precursors to NAD production. So again, the logic here is, uh, it's generally well regarded that cells can't take up free NAD. They have to make their own NAD. Josh, uh, Rabinowitz and colleagues actually published a paper in June of this year that demonstrated that the NAD must be made in the cytoplasm, not in the mitochondria, and it's actually transported from the cytoplasm to the mitochondria.

    2. NCNavdeep Chandel1:46:35

       And this, these supplements mainly went to the liver first.

    3. PAPeter Attia1:46:38

       W- well, even before that, but just to explain the logic, the logic is you can make NAD from NR or NMN, and NR and NMN exist in an equilibrium, if I'm not mistaken.

    4. NCNavdeep Chandel1:46:48

       And the de novo pathway, which is from tryptophan-

    5. PAPeter Attia1:46:50

       That's right

    6. NCNavdeep Chandel1:46:51

       ... as well.

    7. PAPeter Attia1:46:51

       So by giving these precursors, the cells can take those up and presumably make NAD there and get more of that NAD into the mitochondria, where presumably it... I think the main argument, if I'm not mistaken, is actually not around the ETC, the electron transport chain, but more around having them as cofactors for the sirtuins, because the sirtuins, of course, play these two roles of, uh, acetylating, deacetylating as gene regulators. They're basically turning on and off genes. So I think the thinking is, and again, I don't want to speak out of turn, this is not my area of expertise, but more NAD should be a, uh, an important cofactor for sirtuins, which are a NAD-dependent-

    8. NCNavdeep Chandel1:47:36

       Histone

    9. PAPeter Attia1:47:36

       ... histone deacetylases, HDACs. Is that, did I get the story mostly right?

    10. NCNavdeep Chandel1:47:39

        Yeah, yeah, yeah, yeah.

    11. PAPeter Attia1:47:40

        Okay.

    12. NCNavdeep Chandel1:47:40

        I mean, that's the simplest hypothesis. NAD levels decline in aging. You lose sirtuin activity declines, which is not good.

    13. PAPeter Attia1:47:48

        Right, because you now lose the ability to-

    14. NCNavdeep Chandel1:47:50

        To control genes

    15. PAPeter Attia1:47:51

        ... b- to control gene expression-

    16. NCNavdeep Chandel1:47:52

        Right

    17. PAPeter Attia1:47:52

        ... either on or off.

    18. NCNavdeep Chandel1:47:52

        So you boost the NAD as it's declining, and, uh, you get a little bit increase in sirtuin activity.

    19. PAPeter Attia1:47:58

        Right. Right. Which so totally makes sense conceptually.

    20. NCNavdeep Chandel1:48:00

        So I think what Josh did w- is a great experiment. He basically asked, when you take these supplements, where do they go? And a lot of it goes to the liver. Eventually s- it makes its way into other tissues. Because there was this simple idea, like it's gonna get into the brain easily. It's gonna go to your heart. It's gonna go everywhere, and it's gonna do exactly what you said and therefore have all these magical properties. I think the place where NAD supplements and metformin start to crosstalk is two places. The first is it goes to the liver.

    21. PAPeter Attia1:48:29

        Mm-hmm.

    22. NCNavdeep Chandel1:48:30

        So it might be having some metabolically healthy effects on the liver like metformin and similar to like what, what metformin does. Potentially. It's a hypothesis, by the way. The second one is I think it gets into immune cells.

    23. PAPeter Attia1:48:43

        You think that NR, let's just make it simple and talk about NR 'cause that's the preparation that's more commercially available. You think that NR is being taken up by immune cells?

    24. NCNavdeep Chandel1:48:51

        Potentially.

    25. PAPeter Attia1:48:52

        But wouldn't Josh's paper contradict that?

    26. NCNavdeep Chandel1:48:54

        I don't remember if they looked at all the immune cells.

    27. PAPeter Attia1:48:56

        Well, I don't think they did, but isn't, isn't the takeaway from Josh's paper that the first pass effect-

    28. NCNavdeep Chandel1:49:00

        Yeah

    29. PAPeter Attia1:49:00

        ... is so significant that all of the NR was getting taken up by the liver?

    30. NCNavdeep Chandel1:49:05

        Yeah, but it, you know, it still circulates in the blood, right? And, and your immune cells are in the blood. So I, I don't know. And by the way, in Josh's paper, he also said that the liver, once it makes the downstream products of NR, it distributes it back into circulation to the rest of the tissue.
14. 1:55:25 – 2:02:05

    Metabolite Toxicity and L2-Hydroxyglutarate Hypothesis

    1. NCNavdeep Chandel1:55:25

       No, we're, we've, we've, we're making, you know, we've made mice and all of this. So we're, we're, we're doing that. Just to finish, uh, I know time is probably, [laughs] we've probably gone over as always. But so in my world, those ROS from mitochondria are beneficial, and you don't, you know, there's not, I'm not sure if there's a window, uh, where antioxidants get in to really scavenge them, so they're, I don't consider them harmful, Peter, right, for that reason. So generally, ROS are good. Again, very contrarian, but this is where the data's taking us. So when is metabolism bad? So my favorite new theory, which I w- this is what I'm really excited about, and, uh, I'm hoping somebody will give me lots and lots of money to test this because it's way out there. So if you think back about what causes pathologies like neurodegeneration, even diabetes, the big idea for twenty years has been that proteins get misfolded or they aggregate. The idea of what's called proteotoxicity Let's clean up bad proteins. So now they've done some trials in Alzheimer's and Parkinson's. It hasn't quite worked out, but, you know, again, maybe they caught them too late.

    2. PAPeter Attia1:56:35

       Yeah, that, that's my argument. That's-

    3. NCNavdeep Chandel1:56:36

       Yeah, yeah. So I don't have a problem with the theory. I think it's a nice theory. I still think, you know, proteotoxicity is a real phenomenon. It causes diseases, all that good stuff. But what if, which is not a mutually exclusive idea, what if there's metabolite toxicity? What does that mean? That means that certain metabolites that are normally found and at low levels and they do normal functions, if they rise, they can incur pathology. So what's the evidence for that? Well, this is where inborn errors of metabolism come in, so there, there are unfortunately people have genetic mutations in metabolic genes and, and those pathways get altered and some metabolite increases or decreases is, and that's causes major pathology. So we know that metabolites are, at a certain threshold, are sufficient to cause pathology based on inborn errors of metabolism. And so why couldn't it be that in Alzheimer's we have a particular metabolite or metabolites that increase due to the tau and all the amyloid plaques that people talk about, and those then are causing neurodegeneration?

    4. PAPeter Attia1:57:45

       Again, not mutually exclusive.

    5. NCNavdeep Chandel1:57:47

       Not mutually exclusive. It's just a different way of thinking about it. So one way you test it is, you know, someone's got to give me money to do this, but you start screening metabolites in, in mice and rats and in people and see if you see signatures. And if you see certain signatures and you say-- So I have one right now that I'm very interested in. It's called L2-hydroxyglutarate, L2HG. And I know that if a human has a mutation in a pathway that can't get rid of L2HG and it starts to accumulate, they get a, they get neuropathology. So could L2HG be elevated in Parkinson's and in Alzheimer's? What's so cool about L2HG, and this is going to wrap everything up from the start, is if mitochondria are not working, are not functional, the respiratory chain is not working, then NAD goes down and NADH goes up and it will trigger L2HG. That's the key trigger. When NADH goes up and NAD goes down, L2HG gets made.

    6. PAPeter Attia1:58:50

       So is this why you don't take metformin?

    7. NCNavdeep Chandel1:58:53

       No, because metformin is a weak, uh, uh, use-

    8. PAPeter Attia1:58:55

       So this ratio has to change a lot.

    9. NCNavdeep Chandel1:58:57

       This ratio has to change a lot. So for example-

    10. PAPeter Attia1:58:59

        Are there physiologic conditions under which that ratio changes that much?

    11. NCNavdeep Chandel1:59:02

        Hypoxia.

    12. PAPeter Attia1:59:02

        Ah.

    13. NCNavdeep Chandel1:59:03

        And under hypoxia, it's been shown that L2HG levels actually increase, and they can then function as a signaling molecule. So here is more where the organelle, uh, uh, mitochondria is completely dysfunctional. So complex I loss has been correlated with Parkinson's, uh, dopaminergic neurons are not functioning, and so is L2HG elevated there and cause pathology?

    14. PAPeter Attia1:59:26

        So have, you know, have you, have you looked at, um, you know, the other patient population you should study this in would be patients who undergo circulatory arrest in cardiac bypass. So you're gonna see-- Or even frankly, just bypass-

    15. NCNavdeep Chandel1:59:38

        Because they're so hypoxic?

    16. PAPeter Attia1:59:39

        Yeah, yeah. It'd be interesting to see, you know, quote unquote, "this idea of pump head"-

    17. NCNavdeep Chandel1:59:43

        Yeah

    18. PAPeter Attia1:59:43

        ... can it be explained through any of this stuff?

    19. NCNavdeep Chandel1:59:44

        Well, so one other thing that I like about this is, is that's an acute event, I think. We don't see it acutely. So you inhibit complex I and the NADH goes up, NAD goes down, and a real severe inhibition, it takes a long time for that to accumulate.

    20. PAPeter Attia2:00:03

        How long?

    21. NCNavdeep Chandel2:00:03

        In cell culture with complex I, not twenty-four hours, couple of days. And, uh, and you know, so you could imagine, let's just play fantasy here. Uh, you get loss of complex I slowly in a dopaminergic neuron, which causes or results in Parkinson's, and then slowly, e- over years, you get this accumulation of this particular metabolite, and that could then cause, uh, the pathology. Again, I'm very interested in just testing the broad idea that metabolites can cause pathologies. You know, like metabolite toxicity, like kind of like proteotoxicity. Probably wrong, but at least it's original. [laughs]

    22. PAPeter Attia2:00:44

        Well, I mean, it, it's just, I guess what the, the, the thing that would concern me is the ubiquity of the potential signaling molecules and trying to identify, like, what the patterns are can-- That's a... I mean, look, there, there are no problems worth solving that are easy, so, but boy, you have so many variables in so many directions. You don't just have the number of metabolomics, you have the time series in which they occur relative to an insult, and then the amount of exposure of each that's necessary to drive the disease. It can be so easy to miss something with all of those variables, right?

    23. NCNavdeep Chandel2:01:24

        Absolutely, and that's why we're being very biased and going after this one.

    24. PAPeter Attia2:01:29

        Yeah.

    25. NCNavdeep Chandel2:01:29

        Keep it simple. Test that one. But of course, we could totally miss it, uh, because there could be five other metabolites that might go up that might be causing the pathology in synchrony, right? Uh, but at least this one is tied to mitochondrial function. And so when mitochondria are really dysfunctional, uh, so we started with the powerhouse. Most people would say, well, mitochondrial dysfunction, ATP goes down. Okay, I would say mitochondrial dysfunction, guess what? L2HG goes up. It's 2-hydroxyglutarate metabolite.

    26. PAPeter Attia2:01:59

        So interesting.

    27. NCNavdeep Chandel2:02:00

        Uh, so it's a new way to think about mito dysfunction that I'm very interested in pursuing.

15. 2:02:05 – 2:09:35

    Cortisol, Stress and the Alcohol Tangent

    1. PAPeter Attia2:02:05

       So last thing I just wrote down when we were talking earlier, and I want to come back to it, is talk to me a little bit about cortisol and your views on it. How does cortisol interact with the mitochondria?

    2. NCNavdeep Chandel2:02:14

       Yeah. Well, we-- I don't know. I see another one that I would love to work on. So it's just a weird observation. I don't know if you have this. I mean, I think maybe in our circles we have a lot of- Kind of type A personalities who exercise vigorously. They watch their diet. They do all this sort of stuff.

    3. PAPeter Attia2:02:32

       I don't know anybody that does that.

    4. NCNavdeep Chandel2:02:34

       No, you don't know anybody who does that?

    5. PAPeter Attia2:02:35

       No one.

    6. NCNavdeep Chandel2:02:35

       Nobody. But I always wonder if they're stressing themselves out by being so careful about everything, you know? And you know me, I am the opposite. I eat... You've seen me eat and drink [laughs] .

    7. PAPeter Attia2:02:46

       Yeah, but you're pretty fastidious with your exercise.

    8. NCNavdeep Chandel2:02:49

       I am.

    9. PAPeter Attia2:02:49

       You play soccer every day.

    10. NCNavdeep Chandel2:02:50

        No, I do, and I don't overeat, and I do timed feedings, right? I still h- fast f- 12 to 15 hours, most days closer to 15 hours. There's no, I do watch what I eat. But what I'm saying is I know people who get very, very regimented about these things, things, and it's like the marathon runners who, who, you know the old line that they die [laughs] who don't run marathons.

    11. PAPeter Attia2:03:09

        Well, you know, yeah, I was, uh, yeah, I was with a, I was with a friend last night, and he was joking about this exact concept, and he, he was talking about his... He's a, an orthopedic surgeon, and he was talking about his partner or someone he knows, and he was like, "The guy is so into yoga, but it's become..." He's like, i- and the way he described it was really funny.

    12. NCNavdeep Chandel2:03:26

        [laughs] Right.

    13. PAPeter Attia2:03:27

        He's like, he's stuck in traffic, and he's like, "I gotta get to my fucking yoga class."

    14. NCNavdeep Chandel2:03:30

        Yes, exactly, right.

    15. PAPeter Attia2:03:30

        And it's like, yeah, no, no, of course the, there's the irony to that, right?

    16. NCNavdeep Chandel2:03:33

        Right. So, you know, your insulin levels might be fine, and everything's fine, but, you know, what's your cortisol levels? So I'm fascinated by cortisol. In fact, I'm fascinated by s- I, I would love for you to basically develop a s- very simple test that you can sell at Walgreens where you take a prick of blood, and you can do it as often as you want, and you tell me my thyroid, uh, hormones. You tell me my insulin, my glucagon, my estrogen, my testosterone, my dopamine, serotonin, and obviously cortisol, right? These five or six, seven things that I just said because it's about a lot of biology or physiology can be explained-

    17. PAPeter Attia2:04:11

        Yeah, we just, we're not gonna be able to get it that way because cortisol is mostly bound to albumin and cortisol binding protein.

    18. NCNavdeep Chandel2:04:17

        Yeah.

    19. PAPeter Attia2:04:17

        So it's the free cortisol that exerts its metabolic effects and its physiologic effects, and most of it's not free. So you can only measure the free cortisol in saliva and urine, and then the other, you know, of those other ones.

    20. NCNavdeep Chandel2:04:28

        Whatever, but do you know what I'm saying?

    21. PAPeter Attia2:04:29

        Yeah.

    22. NCNavdeep Chandel2:04:29

        Like, like, I would love to have those meta- tho- those meta... Those hormones at my disposal. You know, is my testosterone too low? Is my estrogen too high? This too high, insulin. You know what I mean? Just having that data points all the time, and then you could sort of modify your diet and your exercise. But I think the cortisol one is, uh, I, I pay more attention today to stress as than anything else. I, I'll be honest with you. Uh, I mean, I still exercise, and I watch what I eat. Those things seem now intuitive 'cause I've done it for so long. Um, but I've been wondering if myself and many of my colleagues, especially 'cause, you know, we fly, give talks. You have grand pressures. A teenager daughter, she's lovely. Lots of different pressures we all have, right? And if that somehow is being manifested metabolically through cortisol to the mitochondria, just like we think about insulin, right?

    23. PAPeter Attia2:05:20

        Yeah.

    24. NCNavdeep Chandel2:05:20

        So that's all. That's the only reason I want to talk about cortisol.

    25. PAPeter Attia2:05:23

        No, I think, uh, I agree with that wholeheartedly. I think certainly in the last three years as I've dug my heels into it, I think hypercortisolemia is, is a problem. And I, and I think I wish people would think of these hormones through more broad endocrinologic terms. You know, it's, it's very easy for people to think of hypo and hyperthyroidism. We accept those as states. You can be euthyroid, or you can have too much, or you can have too little. And yet people have such a hard time thinking of insulin in those terms. You can have too much. You can have too little. There's a range in which this hormone makes sense. And cortisol is probably equally important, if not more important, in terms of the damage that can be done, especially from too much, with respect to everything from blood pressure, which would then impact the endothelium. What it does in terms of inhibiting melatonin secretion in the brain, and melatonin obviously plays an immediate role in terms of sleep but also plays an indirect role in terms of neuroregeneration. So, and that says nothing about what we just talked about, which was the role that cortisol may even play in the mitochondria, which I'm just learning about, you know, literally in the past couple of months. So I don't disagree. I think the challenge in many ways for anyone listening to this, if we're gonna be brutally honest, I think for many people it's easier to control what they eat, how they exercise, and exert discipline around taking medications, taking supplements. But in many ways, one of the hardest things to control is our response to stress. And I think that's an important distinction to make. I don't think there's anything that's particularly troubling with being in stressful situations. I, I think the difference is, is less about the situation you're in and more about the response you have to it. And that's probably where the greatest differences lie between people, is there are some people who can be in relatively low-stress situations, and yet they're sort of, they're not reacting well to it. They're not coping with it well, and there are others who can be in-

    26. NCNavdeep Chandel2:07:18

        They have different set points where they begin from.

    27. PAPeter Attia2:07:21

        Maybe. I mean, I, I, I guess I just don't understand enough of this stuff. I mean, I, I, I think, um...

    28. NCNavdeep Chandel2:07:26

        But it's, I don't, you know, I don't hear too many people talk about it.

    29. PAPeter Attia2:07:29

        I don't know. I think it's, I think it's-

    30. NCNavdeep Chandel2:07:30

        No, people talk about stress but, but sort of... Like, we talk about insulin all the time and glucose levels, and for men testosterone, women s-
16. 2:09:35 – 2:22:36

    What Should I Eat? Mediterranean Diet, PREDIMED and Fasting

    1. NCNavdeep Chandel2:09:35

       So I have, I have one question for you-

    2. PAPeter Attia2:09:37

       Oh

    3. NCNavdeep Chandel2:09:37

       ... to sort of wrap it up.

    4. PAPeter Attia2:09:38

       Wait, I didn't think that was part of the rules.

    5. NCNavdeep Chandel2:09:40

       Well, it is, because I'll tell you why. So when I interact outside of the scientific circles, if I'm at a dinner party, if I am at a bar, if I'm on a airplane, and whoever I'm engaging with, they ask me, like, "What do you do?" Now, if I say I'm-- technically, my title is professor of medicine and cell biology. If you say that, they think, oh, you teach something. And I do, indirectly, but what we do is research. So if I just say I do research, or if I say I'm a scientist, they go, "Oh, well, that's nice." But minute I say I'm a metabolism scientist, they're like... It's like a aha. Like, they are li- they light up, and they want the next question, which is?

    6. PAPeter Attia2:10:25

       What should I eat?

    7. NCNavdeep Chandel2:10:26

       You got it.

    8. PAPeter Attia2:10:27

       But wait, can I ask you a question?

    9. NCNavdeep Chandel2:10:28

       No.

    10. PAPeter Attia2:10:29

        Given that you know that that's going to happen, when you go to parties, do you go out of your way to make sure that you don't prime people for that question? Or do you enjoy being asked that question?

    11. NCNavdeep Chandel2:10:38

        I think I enjoyed being asked that question initially as a way to tell people, look, science is cool. Metabolism is cool. You know what I mean? Sort of, of not think... There's this image that people have about scientists. Uh, as you can see, [laughs] I'm pretty flamboyant, so I figure, uh, you know, something that they can relate to as a common language. But now I, I regret it because all I hear about is, "What should I eat? What should I eat?"

    12. PAPeter Attia2:11:09

        Oh, yeah.

    13. NCNavdeep Chandel2:11:09

        "What should I eat?"

    14. PAPeter Attia2:11:09

        So here, let me give you a piece of advice on this, Nav. So first of all, I have the same problem. Whenever I'm in a situation, could be a wedding, could be a funeral, could be a party, doesn't matter. So I've learned that there are two-- I have two go-to things that I tell people I do for a living, and I know enough about each of them that I can almost never get called out. And the good news is, both of these generate almost no follow-up questions. Now, the difference is you're an extrovert and I'm an introvert. So you, at a party, would like to talk to people. I, on the other hand, don't. I don't like to go to parties. But if I'm dragged to a party-

    15. NCNavdeep Chandel2:11:47

        I love to go to parties, as you know. [laughs]

    16. PAPeter Attia2:11:49

        Oh, I don't, I don't want to be at parties. I don't want to be at happy hours. I don't want to be around anybody except two of my friends at a time sort of thing. So I just tell people... I shouldn't admit this now, because now if somebody hears this, they'll know my trick.

    17. NCNavdeep Chandel2:12:01

        Exactly. [laughs]

    18. PAPeter Attia2:12:03

        All right, I'm not gonna say it.

    19. NCNavdeep Chandel2:12:04

        Oh.

    20. PAPeter Attia2:12:04

        I'm not gonna say it.

    21. NCNavdeep Chandel2:12:05

        You're gonna leave them hanging.

    22. PAPeter Attia2:12:06

        I'm gonna leave them hanging. But I have two awesome alter egos that whenever I'm at... And I, in fact, I busted one out last night. I was at a dinner thing last night. I didn't know people, and there were a lot of doctors there, and there was a lot of butt sniffing, which always happens at doctor parties, where everybody wants to sniff everybody else's butt.

    23. NCNavdeep Chandel2:12:25

        [laughs]

    24. PAPeter Attia2:12:25

        You know, it's like kind of the dogs, you know, walking around sniffing each other's butts. And there was a lot of, "What do you do?" "Oh, I'm the chairman of this, and I'm the chairman of that, and I, I am the head of this," and blah, blah. And then they looked at me, "What do you do?" And I just said, "I'm a..." And I said it, and it was amazing. The crickets are chirping.

    25. NCNavdeep Chandel2:12:41

        [laughs]

    26. PAPeter Attia2:12:42

        Everybody is like they don't know what to say. And they said co- collectively nothing, and then the discussion just went elsewhere, and it was awesome. I didn't have to talk about anything.

    27. NCNavdeep Chandel2:12:53

        All right. So, so I do give an answer, and, and I want you to tell me if this is the right answer or the wrong answer. I still like th- I, and I know it got debunked a little bit, I still like the Mediterranean diet.

    28. PAPeter Attia2:13:06

        Y- yeah, I mean-

    29. NCNavdeep Chandel2:13:07

        I mean, I mean, not... I mean, with curry, okay? [laughs] But generally, that kind of diet with nuts and avocados, a little red wine.

    30. PAPeter Attia2:13:14

        Well, when you say debunked, I mean, I'm not even sure I would agree on that.

Episode duration: 2:22:36