The Peter Attia Drive - #31 - Navdeep Chandel, Ph.D.： metabolism, mitochondria, and metformin in health and disease

00:00:00.000 Hey everyone, welcome to the Peter Atiyah Drive. I'm your host, Peter Atiyah.

00:00:10.140 The Drive is a result of my hunger for optimizing performance, health, longevity, critical thinking,

00:00:15.600 along with a few other obsessions along the way. I've spent the last several years working with

00:00:19.840 some of the most successful, top-performing individuals in the world, and this podcast

00:00:23.620 is my attempt to synthesize what I've learned along the way to help you live a higher quality,

00:00:28.360 more fulfilling life. If you enjoy this podcast, you can find more information on today's episode

00:00:33.000 and other topics at peteratiyahmd.com.

00:00:41.300 Hi everybody, welcome to today's episode of The Drive. My guest today is my good friend Navdeep,

00:00:48.020 or Nav as we like to call him, Chandell. Nav is a professor of medicine and cell and molecular

00:00:54.960 biology at Northwestern in Chicago, which is where I actually met him to do this interview.

00:01:00.100 Some of you may recall that name because Nav is one of the cast of characters that I went to Easter

00:01:06.320 Island with in the fall of 2016, the other being David Sabatini and Tim Ferriss. And we actually

00:01:12.700 spoke about this stuff at length on a podcast that Tim recorded while we were on Easter Island.

00:01:17.640 Nav's real area of expertise is in the mitochondria and in metabolism. And in fact, he wrote a book

00:01:23.460 called Navigating Metabolism, no pun intended, in 2015, which I highly recommend for anybody,

00:01:29.960 especially people who A, want to understand this stuff and B, don't want to have to buy 17 textbooks

00:01:35.880 and get into every unearthly detail. In fact, this book was written more for a general audience than a

00:01:42.860 very specific audience. And I have a copy of it and love it. In this episode, we talk about a bunch of

00:01:48.100 stuff, but we talk about what got Nav interested in the mitochondria. We get into ROS or reactive

00:01:53.600 oxygen species, something that I think many of you will have heard of. And then we talk about some

00:01:57.920 really nuanced stuff, like this stuff about mitochondria being actual signaling organelles

00:02:02.680 and ROS maybe being beneficial for that signaling. In other words, we get into this idea that reactive

00:02:07.920 oxygen species may not be all bad. It might not be a black, white thing, which anyone who listened to

00:02:13.100 this podcast realized we love to explore things that aren't just binary. We talk about antioxidants

00:02:18.420 and whether they're harmful or not harmful. And I suspect that a lot of people will have a point

00:02:22.400 of view on that. And we get into mitochondrial DNA, which in and of itself is super interesting because

00:02:26.860 some of you may already know this. And if you don't, that's fine. You'll learn it on this episode,

00:02:30.740 but the mitochondria have their own DNA distinct from the cell. And that DNA is of bacterial origin.

00:02:37.000 It's also transmitted to us maternally. So there's a whole bunch of weird stuff going on

00:02:41.860 genetically with the mitochondria that makes it super interesting. We get into a little bit

00:02:46.300 of a discussion around cortisol. Nav is super interested in the role of cortisol in health.

00:02:51.080 And then we talk, of course, about metformin. And I suspect that for some people listening to this,

00:02:55.980 that's the only thing they're going to care about because these days, everybody's asking me about

00:02:59.560 metformin, which means it's front and center on a lot of people's minds with respect to longevity.

00:03:04.140 Now, we don't even go as deep as we could on metformin. I'm saving that for another guest that's in

00:03:09.460 the queue who I'm not going to even say too much about that, but there's a lot more coming on

00:03:13.780 metformin. This, however, will be a great primer for that because you'll certainly understand how

00:03:18.280 metformin works and how it may play a role in longevity. We talk about the role of the mitochondria

00:03:23.720 in cancer. And again, we take a different view here from what you will have heard from other guests,

00:03:28.640 potentially. We talk about NAD and NAD precursors. And that, again, is another thing that

00:03:34.020 people I think are pretty excited about. At the end, somehow NAD jiu-jitsu's me and turns the tables

00:03:40.460 on me and asks me the, so what should I eat question, which anybody who knows me knows I

00:03:45.980 can't stand being asked that question. But because it's NAD, I humored him a little bit.

00:03:50.800 Before we jump into that, please keep in mind, we have an email list. Every Sunday morning,

00:03:55.260 I send out an email and that email has a whole bunch of stuff in it. It's usually pretty short though,

00:04:00.340 but it's basically something I've read that's interesting, that pertains to longevity, science,

00:04:05.720 lipidology, performance, or just something that really interests me beyond those things.

00:04:10.460 Keep in mind, we put, I would say, an ungodly amount of effort into preparing show notes.

00:04:16.520 And when I say we, I'm using that term very liberally. I actually do none of that, but I have

00:04:21.000 a team that does that and that is spearheaded by Travis and Bob. So the people who do spend time

00:04:27.360 on those show notes, always come back to us with feedback like this is freaking awesome.

00:04:32.280 Please keep doing this. And our intention is to keep doing that. So give us a reason to keep doing

00:04:37.080 that by going and checking them out, especially when it comes to understanding some of the technical

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00:04:56.780 improve upon whatever it is you don't like. So without anything further to add, please welcome

00:05:02.040 Nav Chanda. Hey Nav, good to see you again, man. Great to see you, Peter. Yeah. The last time I saw

00:05:09.760 you, me, you, and David Sabatini were hanging out near the airport in San Diego playing patty cakes.

00:05:15.600 We were. You guys were drinking some really lame stuff. Rosés. Rosés. I like sparkling stuff.

00:05:22.980 So what got you interested in mitochondria? So when I was in college, I was a math major. I loved math,

00:05:30.480 right? I probably did math because as an immigrant, you moved from the Himalayas to Miami,

00:05:36.200 got a funny accent. Math is a universal language, right? So I became a math geek,

00:05:41.720 but everybody's got to make a living. And so I worked in a laboratory, which was in a hospital,

00:05:48.180 and it was a transplant laboratory. And the biggest thing in transplant is how do you preserve organs?

00:05:54.400 I mean, you have an MD. I don't have an MD. I think that's a fair statement. And there's this

00:05:58.260 Wisconsin solution that was used to... We used it liberally.

00:06:02.320 Yeah. And so I wanted to make a better version of it as a 19-year-old. And if you've got to do that,

00:06:09.100 then you've got to think about metabolism. The first set of experiments we did, and I

00:06:13.520 went to a FACET meeting and it's called 3-phosphoglycerate protects against anoxia injury

00:06:20.460 of hepatocytes. Anoxia is low oxygen, you know, the absence of oxygen. And that got me interested

00:06:26.500 in metabolism. If you're a mathematician and you start working on metabolism and eventually

00:06:32.040 like mitochondria, it's electrons, it's enzyme kinetics, right? There's math. And in fact,

00:06:39.360 my PhD is on enzyme kinetics. And so I'm doing a PhD on an enzyme that's very critical for respiration.

00:06:47.380 So like the enzyme that uses oxygen in every cell is what I did my PhD on and how that enzyme works

00:06:54.740 under different oxygen levels. Again, lots of math. You know, Michaelis-Menten, but much more

00:07:01.360 sophisticated enzyme kinetics. And then after that, the thing that was probably the most influential

00:07:09.940 discovery in the mitochondria field for me, and I still think this is one of the three greatest

00:07:15.660 discoveries in the mitochondria field. Of course, it'll be contentious because lots of people might

00:07:19.920 take issue with it. So the first one is Hans Krebs and the TCA cycle in 37. There's the 60 paper by

00:07:26.160 Peter Mitchell, how you make ATP. So those are the two big things, right? Energy, bioenergetics,

00:07:32.460 and biosynthesis because the Krebs cycle eventually makes carbon molecules, which are the backbone for

00:07:39.300 lipids, nucleotides, amino acids. The third big experiment came out in 1996. So Zhao Dong Wang,

00:07:47.100 when he was at Emory, found that the protein that I used every single day to do enzyme kinetics,

00:07:54.720 so I worked on cytochrome C oxidase. That's an enzyme. Already tells you cytochrome C oxidase

00:08:00.920 means that it uses cytochrome C as a substrate. Let's take a step back for someone who's going

00:08:07.140 to be listening to this who doesn't know everything about it. Before we get to Wang's experiment,

00:08:11.800 tell us who Hans Krebs, what he did, what the TCA is. A lot of people will think,

00:08:17.480 I kind of remember this from high school biology, but give me a quick refresher course. So I'll prime

00:08:22.500 you a little bit for it. A cell brings glucose in, just to make it easy. It turns glucose through

00:08:27.940 a number of steps, enzymatic steps, into two smaller three-carbon units called pyruvate.

00:08:35.060 Assuming the demand for ATP is not extraordinary and there's sufficient cellular oxygen,

00:08:40.240 what would be the most efficient way to get energy out of that?

00:08:43.080 Pyruvate has two choices. It can either become lactate, and usually that happens when there's

00:08:49.780 not enough oxygen. And the other thing I always like to say to people, and or when the demand for

00:08:54.460 ATP is exceptional. Exceptional, right. But the other place where it really goes is pyruvate goes

00:08:59.820 into what's called the TCA cycle. And it's really a cycle. So where glycolysis is a series of linear

00:09:06.180 steps, you know, A, B, C, D, E, then you get to pyruvate, and pyruvate actually goes in a circular

00:09:12.440 fashion. And this occurs in a part of the cell called the cytoplasm.

00:09:15.920 The glycolysis part does, but the TCA happens in the mitochondria.

00:09:19.660 Which we're going to get to, yeah.

00:09:20.520 So pyruvate to lactate is all in the cytoplasm, but pyruvate then gets imported

00:09:25.920 through a mitochondrial pyruvate carrier. And that's important because it could be a target

00:09:31.940 therapeutically in certain diseases. I think most of us appreciate, and this is what you're getting

00:09:37.920 to while you're focusing on pyruvate, pyruvate has two choices, go to lactate or the mitochondria.

00:09:42.700 So clearly, the pyruvate to lactate is cytoplasmic. Pyruvate going into the mitochondria and eventually

00:09:49.980 becoming acetyl-CoA, that's an important reaction. So where pyruvate goes and how it gets in and out

00:09:55.720 is quite important. And discovery of that transporter gives you a way to maybe target that.

00:10:02.040 So now pyruvate's in the mitochondria.

00:10:04.220 It's in the mitochondria. And then it's a three carbon, and it becomes acetyl-CoA.

00:10:09.320 Acetyl-CoA is very important, and we'll can get into it later, because acetyl-CoA can acetylate.

00:10:15.780 To acetylate, the eight means you put it on, basically.

00:10:18.960 Put it on, right.

00:10:19.800 Ace is an enzyme. It's the end of an enzyme.

00:10:23.140 Right. To take it off.

00:10:24.260 Yeah.

00:10:24.580 Yeah. And then it goes through the TCA cycle.

00:10:28.520 Which stands for?

00:10:29.580 So some people call it the Krebs cycle, because Hans Krebs discovered it. So we'll try

00:10:32.800 carboxyl acid cycle. Some people call it the citric acid cycle.

00:10:37.060 So we'll use those interchangeably.

00:10:38.940 And so the TCA cycle, as it's going in the mitochondria, it generates NADH and FADH.

00:10:46.880 These are these reducing equivalents, which then feed electrons to the electron transport

00:10:51.780 chain. And the electron transport chain can pump protons, which is basically like a battery,

00:10:59.640 to generate ATP, which is the currency that makes cellular functions work.

00:11:05.520 So the way I like to explain this to people, because I think it's such, it's just so damn

00:11:10.460 elegant. You look at a piece of food and all you see is this potential energy you see. And of course,

00:11:16.460 within all the bonds that exist in food, which is where we get our energy from, you have carbon,

00:11:20.820 carbon bonds, carbon, hydrogen bonds, carbon, nitrogen bonds, carbon, oxygen, nitrogen, oxygen.

00:11:27.180 I mean, there's only a finite number of covalent bonds that exist, but the two most energy dense,

00:11:32.560 I think are carbon, carbon and carbon, hydrogen, correct? Isn't that where the majority of the

00:11:37.360 chemical energy is liberated?

00:11:39.060 Right. Those electrons have to eventually be accepted by something, right? And oxygen is the

00:11:43.600 final acceptor of all of those.

00:11:45.560 So in some sense, the whole purpose of eating is to take a potential energy that is in a chemical form,

00:11:53.000 turn it into an electrical potential energy inside the mitochondria, and then eventually pull a

00:12:00.580 little jujitsu and turn that back into a chemical electrical energy via the conversion of ADP to ATP.

00:12:07.140 I mean, to me, that's the simplest way to explain this.

00:12:10.360 And it's just like a battery, right?

00:12:11.780 Yeah. It's kind of amazing that we exist.

00:12:13.620 Well, that's why they call it a power plant.

00:12:15.680 Yeah.

00:12:16.140 What is the, you know, in the public domain, what do people call mitochondria?

00:12:20.680 The power plant to the cell.

00:12:21.920 Powerhouse, power plant, right? And exactly the elegant explanation you just gave.

00:12:27.320 So we're already talking about the dogma, right? Which is, it's all about ATP. So if you asked in

00:12:33.160 1996, what is the major function of mitochondria?

00:12:39.420 Make ATP.

00:12:40.240 That's it.

00:12:40.900 And for good reason, because let's call a spade a spade. As we know, if you interrupt that cycle

00:12:47.160 for even moments, it's uniformly fatal. Most people are familiar with a toxin called cyanide.

00:12:53.660 Cyanide. Cyanide is fatal at incredibly low concentration. There are only a handful of

00:12:59.700 toxins that are more potent, more lethal at lower concentrations. But, and they all tend to,

00:13:05.880 you know, like the trototoxin, I think, blocks a sodium channel transporter. It might be even more

00:13:09.900 lethal. But why cyanide is so lethal is it disrupts that process you just described.

00:13:15.140 Indeed, but it's not clear which organ fails right away. So we'll get into that in a second.

00:13:22.460 The genetic experiments don't totally confirm that idea.

00:13:26.380 Interesting. I'd like to hear more about this.

00:13:27.780 Yeah, we're going to get into that in a little bit. So in 1996, if you ask that question,

00:13:33.260 it's all about ATP. And so there is this protein, cytochrome C, that's part of this energy

00:13:39.200 generating system, which is ATP. And Jia Dong Wang and colleagues found that if that protein

00:13:46.900 gets released from mitochondria into the cytoplasm, which had never been detected before,

00:13:54.140 it can rapidly kill a cell. So now the decision for life and death is based on the localization of

00:14:03.280 cytochrome C between the mitochondria and into the cytoplasm. So if it's in the mitochondria,

00:14:10.260 it helps you generate ATP. If it's out, it kills you.

00:14:14.880 And I assume it only escapes when the mitochondria is under the most intense duress and destruction.

00:14:21.840 So when a cell is under some sort of toxin stress, could be low oxygen, complete absence of oxygen,

00:14:29.720 could be a growth factor, which is telling the cell to live, is not present. Death by neglect,

00:14:36.200 let's call it that. When the cell is being neglected, either by nutrition, starvation,

00:14:41.420 complete depletion of nutrients, or complete depletion of growth factors that keep them happy,

00:14:47.320 the positive signals, then cytochrome C gets released. But it's a very profound discovery because

00:14:53.460 this is a protein that we were all convinced had only one role. We call it the day job now,

00:14:59.580 make ATV. It's got a moonlighting job that sometimes it leaves the mitochondria and doesn't

00:15:05.660 make ATP, and bam, it starts a cascade, which is called apoptosis cell death.

00:15:10.560 I was just about to say, is this part of a programmed cell death, is apoptosis?

00:15:14.940 Yeah. This is programmed cell death. So here I am in 1996. I'm 26 years old,

00:15:20.780 very happy doing enzyme kinetics, bioenergetics. And I see this finding, and all of a sudden,

00:15:28.740 I stopped caring about ATP. Because in part, a lot of that, how it works, was more or less discovered.

00:15:36.320 I didn't have the insight, because obviously, why would I be still working on it? I still thought

00:15:41.540 there was more to be discovered. But the reality was, I was probably just cleaning up little side

00:15:47.260 things in that field at best. And that's not, hopefully, to disparge the bioenergetics field.

00:15:52.420 But there's still some important questions there, more at a structural level. And there's some

00:15:57.520 beautiful work there. But what I was doing was- The kinetics had been worked out.

00:16:01.920 Yeah. I mean, some of it had been and not. But this was great, because this connected the

00:16:06.880 mitochondria, just not for energy, and what the mitochondria does, almost in a cell,

00:16:13.520 like in an autonomous way. It just does ATP. But this says it starts to control cell biology

00:16:18.980 and function, like the decision of life and death. So obviously, the first thing we think about is,

00:16:25.540 it can't be selected just for death, right? It must be doing something interesting. So let's think about

00:16:30.200 what else it might release. And one of the first things that we thought about, which is something

00:16:35.080 that people had noticed for almost 40, 50 years before, they release superoxide and hydrogen

00:16:40.940 peroxide, reactive oxygen species, oxidants, free radicals. And most people in the mid-90s assumed

00:16:51.560 that mitochondria only released this so-called cleaning molecule or toxic molecule when the

00:17:00.660 mitochondria is damaged, maybe in neurodegeneration, maybe in aging, we'll get into this, maybe

00:17:06.420 when a heart failure, when there's low oxygen ischemia. So in other words, it's there almost

00:17:14.320 as a way that the mitochondria, when it's not working well, it just spills out. Because mitochondria has

00:17:20.720 all these electrons, and they have to, they're not working, those electrons just spill into superoxide

00:17:26.340 and eventually the hydrogen peroxide. And what we thought about is, well, maybe nature could have

00:17:33.920 used that as a signaling molecule. In other words, to dictate cellular function. And so there were some

00:17:40.600 papers just right as we were working that came out and that showed, in fact, H2O2 could be a signaling

00:17:46.340 molecule. But they didn't think it was necessarily mitochondria. So there's a neat little story that

00:17:52.520 there's another system in the cytoplasm that can generate H2O2. And they thought that's all about

00:17:57.880 signaling. Signaling basically means it's making decisions in the cell to die, to live, to proliferate,

00:18:05.180 to grow. If you're an immune cell, to make cytokines, to do inflammation. But the mitochondria only did it

00:18:12.120 when it's not working and it's spilling all these electrons into hydrogen peroxide and it's causing

00:18:17.860 damage. And we actually showed that, in fact, under physiological conditions, you can make hydrogen

00:18:25.040 peroxide, which has a beneficial effect. And so from that point on, with the first paper was published

00:18:31.980 in 98, now almost 20 years, there's my group and lots of other people continue to show that mitochondrial

00:18:39.100 generation of this cleaning molecule can actually cause cellular functions to happen. For example,

00:18:47.840 we've shown our T cells, which are part of the adaptive immune system, right? They fight off

00:18:53.500 pathogens, right? Or innate immune cells as well. Just immunity in general, right? They fight off viral

00:18:59.280 infections, bacterial infections. That H2O2 is used by those immune cells to properly function.

00:19:08.280 And what's the profound implication? Which is what you're going to get into is antioxidants.

00:19:14.060 Are they beneficial? Are they harmful? So already to the audience, it should be obvious if I'm saying

00:19:20.160 that something you think is a cleaning molecule only, then antioxidants are great. You're getting

00:19:25.080 rid of this toxic molecule, cleaning molecule. You're getting rid of this bad stuff. But if it's also

00:19:31.640 there for good purposes, like immune function.

00:19:34.580 It paradoxically could be bad to have an antioxidant in your system at a time when you need

00:19:40.220 enhanced, especially adaptive immunity.

00:19:42.660 And so one of the clinical trials that came out was in the ICU. Sepsis, that's the big disease,

00:19:49.160 and which is basically in a simplistic level, tons of inflammation. And those trials failed.

00:19:55.460 They made them worse, antioxidant trials. In cancer, again, in lung cancer, vitamin E trial,

00:20:01.720 it didn't have a curative effect.

00:20:04.660 Yeah. Do you think it's overly simplistic to say that there ought to be a balance in the body between

00:20:09.060 pro-oxidative and antioxidative stress? And it's never the case that one is absolutely good or

00:20:14.800 absolutely bad. It depends on the state of the organism. So under perhaps a normal state,

00:20:20.160 a more antioxidative, i.e. let's reduce the ROS, is the right thing to do. But to your point,

00:20:25.340 when the immune system is required to take the front step, cancer and sepsis being two

00:20:32.160 enormous examples, that having too much antioxidant property can actually be harmful.

00:20:38.500 And that's a moment when you actually want to be able to inhibit that process.

00:20:41.060 So one of the interesting antioxidant trials, now again, caveat in this experiment I'm going to tell

00:20:46.080 you is an exercise experiment. So we all agree that if you do vigorous exercise, it has benefits.

00:20:53.040 And you can take a biopsy and look at all the genes that exercise turns on. And these are genes we

00:21:00.520 think are beneficial to the host, to the rest of the body. If you give high doses of antioxidants,

00:21:06.840 so that's the caveat, it's high doses, probably not the doses that most people use,

00:21:11.020 it actually turns off that beneficial response. So in other words, to your point, I think what you're

00:21:18.060 making is that when the system is stressed, and the mitochondria integrates that stress,

00:21:24.800 how does it pass that information back to the cell? We think that perhaps it releases hydrogen

00:21:30.280 peroxide. So like, clearly exercise is a good example, right? That's a stress to the system,

00:21:36.220 to your muscle. And how does that muscle then turn on all these genes and blah, blah, blah?

00:21:41.240 So we think it does it perhaps by releasing hydrogen peroxide.

00:21:45.340 Prior to this insight, Nav, is it the case that people knew the mitochondria was signaling,

00:21:51.760 but assumed there was a different molecule that was used to transmit the message? Or that people

00:21:57.460 didn't actually think the mitochondria were playing any role in signaling, and we're still back in the

00:22:02.400 ATP-only paradigm?

00:22:03.900 They did think about signaling only in the context of pathology. So in other words, so there are these

00:22:12.480 childhood diseases like Lee's syndrome, where there's a mitochondrial mutation in a particular

00:22:16.960 protein, and it's a devastating disease, the kids don't live that long. And clearly, that's a mitochondrial

00:22:23.060 mutation, and a protein that gets mutated, doesn't function properly in the mitochondria, and you get a

00:22:29.160 childhood disease. So how does that work? So people say, well, probably ATP, or maybe too much

00:22:35.340 ROS, right? So in that context, there was some idea of signaling, right? But this is saying under

00:22:42.240 physiological conditions. Exercise is not pathology. It's physiologic. When you get a pathogen, in other

00:22:48.360 words, when you get a virus or bacteria, that happens. You get a cold. Your immune system has to be

00:22:54.880 activated. That's not pathology. That's a good, normal response. So under all those conditions,

00:23:01.560 the mitochondria is playing a signaling role. And so I've coined this term, you know, so there's the

00:23:07.180 mitochondria as powerhouses. So my talks never talk about that. The title of every talk I give all around

00:23:14.140 the world is the same. Not very original anymore. Mitochondria as signaling organelles. And H202 is one

00:23:21.980 way. Cytochrome C is another way, right? That's probably maybe the most original because that's

00:23:27.440 for cell death. By the way, 22 years later, do we still think that that work out of Emory is,

00:23:34.180 what has been added to that body of knowledge about the role of in apoptosis and programmed cell death?

00:23:38.680 They know the whole pathway. But it is still coming from the single enzyme.

00:23:42.120 Yeah, yeah. Yeah. Wow.

00:23:43.540 There are these proteins called BACs and BAC that make these pores in the mitochondria and it releases

00:23:50.500 this 13 kilodalton protein. It just releases that protein right out. And then it binds to a whole bunch

00:23:57.420 of other proteins, APAP1 and caspase 9, and starts this proteolytic pathway, which eventually causes

00:24:04.340 cell death. So they've worked out all the biochemistry. But the main point remains.

00:24:09.380 Conceptually, yes.

00:24:10.060 Wow. You don't get that all the time in biology, that 22 years later, the punchline is still the

00:24:14.540 same.

00:24:14.800 The punchline is the same. I mean, there's a lot of details that have to be. But conceptually,

00:24:21.780 yeah.

00:24:22.420 Are there other ways, by the way, that cells can undergo apoptosis?

00:24:25.720 Oh, yeah. Now there's a whole industry. Every day, there's a new version of it. And in fact,

00:24:31.020 we can talk about one new one, which I'm very excited about. So clearly, we can show that H202

00:24:37.840 in many contexts will signal for positive responses, immune functions, as we just talked

00:24:45.740 about, the exercise response. But clearly, there must be cases where H202 or other reactive

00:24:53.260 oxygen species cause cell death. How does that work? And there is a new form of cell death that

00:25:01.060 was just discovered by Brent Stockwell and Scott Dixon at Columbia in 2011 or so, 2011. And it's

00:25:07.880 called ferroptosis. And it's basically taking H202. If there's free iron, you can make a hydroxyl

00:25:15.680 radical, an OH. And that will then make a lipid hydroperoxide. So if you have polyunsaturated fatty

00:25:24.460 acids, it will basically make it into a lipid hydroperoxide, which can be very toxic. So the

00:25:30.900 bottom line is, there are times where hydrogen peroxide with iron and lipids, the three can come

00:25:37.400 together and make something called a lipid hydroperoxide, which will cause cell death and

00:25:41.920 ferroptosis. The good thing is your body's full of an enzyme called GPX4 that gets rid of it all

00:25:48.360 the time. Now, if you don't have that enzyme, you're in big trouble. So there are places where

00:25:54.920 clearly H202 is positive, and it can become very lethal by making another form of reactive oxygen

00:26:01.340 species. But again, nature has selected, you know, I can't count all of them, but at least 30 enzymes,

00:26:08.300 which are constantly mopping up these reactive oxygen species, keeping them quite low so you

00:26:14.020 don't get to those toxic levels. So when we go back to apoptosis, which I didn't think we were

00:26:17.580 going to even talk about this, but it's so great to be able to bring it up because I think for many

00:26:20.580 people that they're still probably thinking, well, what are we talking about apoptosis? So

00:26:23.880 if a cell undergoes a genetic mutation, nuclear genetic, we'll come back to mitochondrial genes later.

00:26:31.320 But if a cell undergoes a genetic mutation in the nucleus that's unrecoverable, it will, on a good

00:26:38.740 day, kill itself. It will commit suicide. I mean, that would be one of the things that would drive

00:26:43.000 apoptosis. You're getting to tumor suppression mechanisms. Yes, exactly. That's where I'm going.

00:26:48.360 Do we know if this mechanism you just described of apoptosis plays a role in the type of cancer

00:26:55.620 apoptosis that we want to see? And if so, the implication is the nuclear genome must be

00:27:02.020 communicating with the mitochondria. Yes. So there is a drug that targets that Abbott made. A good

00:27:10.320 friend of mine, Steve Fessick, was involved in it, who's now at Vanderbilt. And so in the 90s,

00:27:15.240 they figured out the structure of a particular protein that controls cytochrome C release.

00:27:21.060 And so they've made a drug against that protein, and specifically in cancer,

00:27:28.780 to make the cancer cells sensitive to chemotherapy, basically. Right? So what do cancer cells love to

00:27:35.300 do? They upregulate anti-apoptotic proteins, right? So what does that mean? That means they

00:27:41.660 turn on a whole program, which is basically an anti-death program. Right. Protects them from

00:27:48.040 everything you just described. Yeah. This release of cytochrome C and all of that stuff. And so one

00:27:52.660 idea is why don't we target those anti-epoptotic proteins, these anti-death proteins? And it's

00:27:59.120 because if we can target them and prevent them from functioning, then when we give them chemotherapy,

00:28:05.220 now the cells will die a lot quicker. The problem with chemotherapy is all these anti-death proteins

00:28:09.680 are there. So a normal cell, like, you know, so doxyurubin is a good case. A normal cell of being a

00:28:15.240 heart gets toxicity. At the same time, you're trying to kill the cancer cell. So it's not

00:28:19.720 selective. It's not selective, right? And so people have been targeting these anti-apoptotic proteins

00:28:25.580 in cancer as a mechanism to make chemotherapy more effective. Yeah. So this mechanism we were

00:28:32.680 talking from 1996, I didn't think we would get into this, but it's been a long time. This is my

00:28:37.000 previous life. I haven't thought about this in a long time. But yeah, it still applies. And it's very

00:28:42.400 important for cancer. So while we're still going on history, I just alluded to something a moment

00:28:47.420 ago that I think is an important point for the listener to understand, which is, you know,

00:28:51.580 everybody knows, or I guess, you know, most people who are thinking about biology would understand

00:28:54.700 that the part of the cell that contains your DNA is called the nucleus. And we've got lots of genes in

00:29:00.840 there, about 20,000 genes. But the mitochondria has genes too. Not that many. What is like 35 or

00:29:08.140 something? Yeah, 37. And there's the key point there is there's 13 genes that are essential for

00:29:15.420 the respiratory chain to work. And the respiratory chain is where all that oxygen is being consumed.

00:29:22.120 That's the one that makes that energy, that electrochemical energy we talked about that

00:29:27.600 ultimately gets converted to ATP. So the key subunits of the respiratory chain, which generates that

00:29:34.740 battery that we've been talking about, it holds on to those 13 genes that are critical for it. So for

00:29:40.260 example, complex one, and it's one of those respiratory chains, there's these five complexes,

00:29:45.760 well, one of the complexes has 45 subunits. But a few of them, which means 45 proteins make this huge

00:29:51.800 complex, but a few of them are in the mitochondrial genome. Complex three, very important, my favorite

00:29:59.080 complex, everybody's got to have a favorite complex. And so my favorite complex...

00:30:02.940 I see a t-shirt here. Yeah, yeah. So my favorite complex is complex three, and it has one

00:30:07.860 gene that's still in the mitochondria. By the way, are you saying that just to be contrarian

00:30:12.040 because complex one is actually the coolest? Because like, how can complex one not be your

00:30:18.260 favorite mitochondrial complex? I'll tell you in a second. It's just because you're cool and you're

00:30:22.460 too cool for school because you study this. The rest of us who are in the peanut gallery, we default

00:30:27.940 into complex one being the coolest. I know. Yeah. So you're saying I'm a mitochondrial

00:30:32.620 hipster, right? I think you are. You're leading the charge on this.

00:30:36.460 No, but think, you know, complex three is very interesting because it has 11, you know,

00:30:40.720 one of, only one subunit is in the mitochondrial, encoded by the mitochondrial genome. So at one point,

00:30:47.980 the mitochondria, so going back in evolution, we think there was an alpha proteobacteria and an archaea,

00:30:54.760 probably a metagen. And these two prokaryotes got together and had a symbiotic love affair.

00:31:01.740 And just to explain to the, so we are eukaryotes.

00:31:04.420 We are eukaryotes.

00:31:05.240 And what does that mean again?

00:31:06.180 We've got a nucleus. We've got a bunch of organelles.

00:31:08.780 And what's a prokaryote?

00:31:10.080 It doesn't have those organelles.

00:31:11.280 Got it. So bacteria.

00:31:12.920 So you got a bacteria and you got an archaea and they got together. So we think the archaea is kind

00:31:18.740 of where the nucleus came from. And the alpha proteobacteria is the modern day

00:31:22.900 mitochondria. And one of the best evidences is, I remember an experiment that I did as a graduate

00:31:29.400 student and was, I took a bacteria that somebody had discovered in the seventies, a beautiful paper

00:31:34.600 in nature. And this bacteria, if you gave it like succinate, like a mitochondrial substrate,

00:31:41.620 and it'll grow on it and it would respire very similar to modern day bacteria, modern day mitochondria.

00:31:48.140 Wow. A nice elegant proof of concept that the mitochondria are basically bacteria that came

00:31:54.600 from bacteria.

00:31:55.140 Yeah. They came from bacteria. Yeah. I mean, you know, those who doubt evolution, I always tell them

00:31:59.840 that every organism I know burns glucose very similarly.

00:32:04.540 It is hard to make that. Yeah. If you, if you, if you're not, I don't want to go down this path

00:32:07.960 because we'll simply alienate a million people. But, but it is interesting to think like

00:32:12.160 it strikes me as it's very hard to come up with an alternative explanation for why you would have

00:32:19.580 this effectively foreign DNA inside every cell. And I just, I'm so intrigued by this mitochondrial DNA

00:32:27.580 thing, because again, it's such a tiny number of genes on a relative scale, but yet they're so

00:32:33.440 critical. And to my knowledge is, I don't think there's any other organelle that carries its own

00:32:38.120 genes with it. Is there? No, it doesn't. And what's interesting is that it only encodes for

00:32:43.900 like a 1% of, you know, there's, I don't know, 1000 proteins in the mitochondria.

00:32:48.420 But it's absolutely critical. You knock those 37 genes out.

00:32:51.620 No, you knock out any one of those genes out.

00:32:54.200 You're done.

00:32:54.680 You're done. And so why did the mitochondria hold onto those? Right? So it basically gave up,

00:33:00.880 you know, if it has a thousand proteins, it said, you know what the nuclear genome?

00:33:04.620 Yeah, you take 999. I'm going to hold on. And they're all the critical catalytic subunits and

00:33:11.780 all of this. And in other words, they're really essential for the function. And I'm going to hold

00:33:16.660 onto them. It's almost like it doesn't trust its symbiotic partner, right? Right? It's like a love

00:33:22.900 affair, right? Yeah, I love you, but I'm going to hold onto a few things.

00:33:27.840 Yeah. And it's very interesting because I believe, I could be wrong, but you could make the case,

00:33:34.540 correct me if I'm wrong, that we pay a price for that lack of trust. In many ways, don't you think

00:33:40.660 the nucleus would be a better steward of those genes? Doesn't the nucleus have more ways to

00:33:46.420 protect the genome than the mitochondria? And therefore, don't we run a greater risk of disease

00:33:52.220 when the mitochondria, with its beautiful stewardship over its precious 37 genes, gets under stress?

00:33:59.240 Yeah, this is a very important point you're making. Basically, we have a lot of DNA repair

00:34:04.940 enzymes, right? That are all in the nucleus. There's these proteins called histones that cover

00:34:11.640 the double-strand DNA. So, you know, and there's many mechanisms to protect our genome. And the

00:34:18.860 mitochondrial DNA is just like this round little circle. It's so vulnerable. It's totally vulnerable

00:34:23.300 and is especially vulnerable because the site of those free radicals we've been talking about

00:34:31.620 is right there.

00:34:32.220 Exactly. That's the worst part. You put these very exposed, fragile, not protected genes in

00:34:38.280 the presence of a potential toxin.

00:34:40.640 Right.

00:34:40.780 I mean, I wish I had more time to think about it. I wish I was quicker on my feet because I think I

00:34:44.860 could think of an elegant analogy of how counterintuitive that is, right? It's like

00:34:48.520 leaving the keys to the kingdom in the hands of the guy next to the, you know, I can't even think

00:34:55.820 of it. I'm not smart enough, but like, it doesn't make sense.

00:34:58.860 It's like a hen, it's like a hen house next to where the fox is like.

00:35:01.980 Yeah, yeah, yeah. That's, that's a better. So, so what's the advantage of it?

00:35:05.140 One thing I should stress is that potential molecule that could be damaging superoxide,

00:35:14.820 hydrogen peroxide, hydroxyl radicals, the mitochondria, where the mitochondrial DNA resides

00:35:21.840 in the mitochondrial matrix, there's tons and tons of antioxidants there. So even though that the DNA

00:35:29.420 itself can't be protected, it's protected from a variety of these toxins because there's so many

00:35:36.980 proteins that clean them up, essentially. The highest level of antioxidant activity sitting

00:35:42.600 in the mitochondrial matrix, and I think that's because to protect that, that almost naked DNA.

00:35:48.620 So one other little-

00:35:49.900 If that makes sense.

00:35:50.560 Yeah, no, it, it really makes sense, Nav. Thank you. Cause I've, this has been on my mind a lot

00:35:55.140 lately because I saw a paper recently. I may have even sent it to you about another hypothesis around

00:36:00.360 inflammation. The effect that inflammation can have on the mitochondria and the mitochondria starts to

00:36:04.580 shed its DNA, which actually kicks off an immune response as it exits the cell. And that's what got

00:36:11.620 me thinking about this. I was like, wait a minute, that's a really good point. That must happen an awful

00:36:15.720 lot. And actually, what did they peg it to? They pegged it to hypercortisolemia, which we're going to come

00:36:21.680 back to because you're kind of a cortisol guy too, when it's all said and done. You're, you're a

00:36:26.740 cortisol file. If such a word exists.

00:36:28.900 No, you know, in the hormone world, I call people like you insulin profits and many of your other

00:36:37.140 former guests, uh, I'm the cortisol profit, right? And I think that's the missing link for a lot of

00:36:41.760 stuff without any real data, but it's just my own intuition.

00:36:45.160 Well, these data, these data that I saw actually suggested that the hypercortisolemia, not just

00:36:49.800 cortisol, but other glucocorticoids and including other hormones from the adrenal glands could really

00:36:55.160 become toxic to the mitochondria at high enough doses. And it was basically jettisoning broken

00:37:00.300 strands of mitochondrial DNA that basically, you know, kicked off immune responses and sort of,

00:37:05.680 you had these inflammatory responses that resulted from an immune response to mitochondrial DNA being

00:37:11.000 damaged by cortisol. So bringing it back to kind of dinner table trivia, the other thing about

00:37:17.080 mitochondrial DNA that's interesting is it comes from one parent. So tell us, yeah, tell us what

00:37:22.060 that's all about and why that's the case and what the...

00:37:24.020 Well, we don't, yeah. I mean, again, two big questions in the field. One is why we still keep

00:37:31.700 those genes that we just went over, right? You know, it's kind of like it doesn't trust.

00:37:36.220 And then the other one is why does it come from the mom?

00:37:38.940 And there's an implication there, which is you have far less dilution by generation.

00:37:42.940 You do, but why did nature select that, right?

00:37:46.760 I'm asking you.

00:37:47.500 I don't, I don't, you know, I don't have a good explanation.

00:37:50.480 Even teleologically, you don't have a good explanation?

00:37:52.840 I don't have a, I really don't. We think more about the function of mitochondria. I mean,

00:37:57.040 there's a whole group of people who think about the bottleneck of mitochondrial DNA

00:38:01.720 being passed on. But I actually, I don't have a good explanation to it. It's a fascinating,

00:38:07.740 I think lots of people have very interesting ideas around it. But to be honest with you,

00:38:13.700 why we continue to have those genes and why does it come from the mom? I think these are

00:38:18.140 still outstanding questions in the field. Something that my lab doesn't work on. And,

00:38:24.340 you know, as you know, Peter, I don't comment on things that I don't work on just because

00:38:28.460 you can speculate, but you want to have good data. But I do want to talk about one aspect of

00:38:33.060 mitochondrial DNA. And this is in my wheelhouse, which has nothing to do with those two questions,

00:38:38.100 which is a third role, but going back to signaling, right? So if you think that H202,

00:38:43.700 so what does mitochondria dump into the cytoplasm? ATP for energy? We think H202 for signaling,

00:38:50.860 you know, to do immune responses, exercise, et cetera. What else could it release? Well,

00:38:55.820 one of the things it could release is mitochondrial DNA, which would then kick off an immune response.

00:39:00.560 The only thing about that hypothesis that I struggle with is how do you release mitochondrial

00:39:08.760 DNA in a physiological way without not releasing cytochrome C?

00:39:13.860 So you're saying maybe all the damage that's, well, okay, I'll give you an answer. I'm making

00:39:18.680 this up now, but maybe you are also releasing cytochrome C. The cytochrome C results in the

00:39:23.420 apoptotic death of the cell, but the DNA gets into the plasma, which is where the immune system

00:39:30.100 begins to recognize it. So you could still have apoptosis at the cellular level, but globally,

00:39:35.980 right? So locally, apoptosis, globally, you have the immune response.

00:39:39.380 Right. So it depends on that cell dying.

00:39:41.660 Yes. Which makes sense.

00:39:43.200 That's okay.

00:39:43.740 Yeah. You're saying, I don't see a way that that could happen with an intact cell just

00:39:48.000 willy-nilly passing off its mitochondrial DNA. That makes sense.

00:39:50.760 Yeah. So that's, and people have sort of proposed that it could do that. And maybe it can. I'm open

00:39:57.940 to the idea, but someone's got to show me how you selectively release some mitochondrial DNA without

00:40:04.340 releasing everything else, you know? And where H202 and ATP get released in a much more benign

00:40:14.000 fashion without cytochrome C.

00:40:14.960 Now, ATP has an active transporter.

00:40:16.680 It has an active transporter.

00:40:17.720 H202 goes by diffusion?

00:40:19.500 We think so. Probably maybe VDAC channels, voltage-dependent anion channels could maybe

00:40:25.660 release the superoxide, which then gets converted quickly to H202 right outside the mitochondria.

00:40:31.220 So again, the mechanisms of, you know, it's kind of like water, right? Before the aquaporins,

00:40:36.100 we just thought water just went back to diffusion, right? Now there's active transport. Actually,

00:40:41.460 Pioneer was at your Institute at Hopkins, right? Got the Nobel Prize for the aquaporins.

00:40:45.940 I didn't know that.

00:40:46.480 Yeah. And so when we think about signaling, the simple idea is what gets released? ATP.

00:40:54.260 What gets released without cytochrome C getting released?

00:40:56.940 Yeah, yeah.

00:40:57.500 That's the key, right? Because when cytochrome C gets released-

00:41:00.260 It doesn't matter.

00:41:00.800 It doesn't matter. Everything is, the cell's on its way to die. So what gets released? So we

00:41:04.800 know hydrogen peroxide, ATP, and metabolites. Metabolites are always being released. So citrate-

00:41:10.600 Well, CO2.

00:41:11.860 CO2, yeah.

00:41:12.660 For obvious reasons.

00:41:14.180 But citrate, right? So citrate is a very interesting molecule. Citrate gets exported from the TCA cycle

00:41:22.220 into the cytoplasm, where it can get broken down back into acetyl-CoA, which can then be a primer for

00:41:29.060 making new lipids, new fatty acids, right? But also that acetyl-CoA can cause acetylation reactions,

00:41:36.300 like on histones, to control gene expression, the so-called chromatin modification.

00:41:41.660 Meaning it goes back to the nucleus.

00:41:43.140 Yeah. So, but that's quite- So citrate could be a signaling molecule, right?

00:41:47.280 Well, if it's doing what you just described, it would be.

00:41:49.500 It would be, right? And so there's a bunch of- So in my wheelhouse, the ones that I like to think

00:41:54.820 about, H2O2 and TCA cycle metabolites that get released. And they do. They're in constant flux

00:42:03.620 between the cytoplasm and the TCA cycle. And they can control gene expression through chromatin

00:42:10.640 modifications, through histone modifications.

00:42:13.140 So because we're going to come back to this through a totally different lens, I want to also

00:42:18.020 have you and or me explain somewhat to the listener what this idea means of histone deacetylation. And

00:42:25.640 basically, because those terms I think are largely foreign to even reasonably informed folks, but I

00:42:31.460 think the reasonably informed folk will understand what epigenome means, what a modification of a gene

00:42:37.620 means, and how genes are potentially silenced or upregulated. Is that happening often in the

00:42:44.340 mitochondrial DNA as well? Or are they pretty much just on their own?

00:42:48.600 They don't have-

00:42:49.340 So what transcription factors tell those genes when to turn on?

00:42:53.080 Again, they're all nuclear encoded and they have to be-

00:42:55.540 Oh my God. This is so staggeringly inefficient.

00:42:59.360 There has to be a reason for this that hasn't-

00:43:01.800 Yeah.

00:43:02.040 Why? You know, I mean, I know you're fascinated by mitochondrial DNA and I don't have good answers

00:43:07.040 for this. That's why we didn't want to talk about this.

00:43:08.920 I think, I'm hoping-

00:43:09.960 Which is, you know, why does it continue to have those genes?

00:43:13.200 I'm hoping there's a college student out there or a graduate student out there who's thinking,

00:43:17.280 like, I want to understand what could be the reason for this. Because if you can find,

00:43:21.680 in my sort of somewhat simplistic way of thinking about problems, I think,

00:43:25.560 when you look at something in nature and you don't have a clue why it's occurring,

00:43:30.220 if you could get a clue why it's occurring, you will unlock a whole bunch of other knowledge as well.

00:43:34.560 That might not be true, but that's like kind of a working hypothesis. And in this case,

00:43:40.240 think of like, you're one of the world's experts on this topic, and yet you're acknowledging there

00:43:45.100 are so many fundamental, obvious questions. Like a high school biology student could ask the

00:43:50.560 questions I'm asking on this topic. These are not like super nuanced questions, and yet the field

00:43:56.360 doesn't know the answer. That's really interesting.

00:43:58.880 Well, to be fair, there are people who think a lot about this and they have opinions on it,

00:44:03.320 but what I'm just simply saying is what is well established is that mitochondria generate ATP

00:44:08.780 and they generate metabolites for growth. And all of this stuff, including my signaling hypothesis,

00:44:14.840 you know, it's still a work in progress. Like everything we've talked about,

00:44:18.300 just full disclosure to the audience, it's a work in progress. So if you're a high school student,

00:44:23.960 come on and join the party. There's a lot to be discovered here.

00:44:27.020 Well, that's the beauty, right? It's not like we're ever going to run out of questions that need to be

00:44:30.600 answered. And I think the difficulty in the field historically has been the bias about ATP and

00:44:36.860 thinking about energy and solving that problem. And the great biochemists did that. They figured

00:44:41.840 out how we make ATP, fundamental to life. They figured out how we make the metabolizing TCA cycle.

00:44:47.580 But now it's getting much more challenging because those same processes can control gene expression.

00:44:54.620 Well, how does that work? I don't know. I mean, I have some reasonable hypotheses we're testing,

00:45:00.880 but I'm very careful, as you know, to not give a strong opinion on a work in progress.

00:45:08.680 So let's shift gears a little bit to talk about some other broad mitochondrial questions,

00:45:12.300 because I do think that people today, and maybe it's just the bias I experience because of what I'm

00:45:18.020 looking for. So this might not be the case, but it seems that the interest in mitochondria has

00:45:23.760 exploded. I think people are realizing there's a lot going on here. It's more than we realize.

00:45:30.920 Mitochondrial function is now a term people use all the time, but they're not just talk. I don't think

00:45:36.620 they're just talking about oxidative phosphorylation. I think they're talking about broader things. And

00:45:41.760 when we talk about aging, we talk about something's changing in the mitochondria as we age.

00:45:48.020 When you think of hallmarks of aging, we can debate the merits of some of them, but

00:45:53.240 something's different in the mitochondria of an 80-year-old versus an 8-year-old. What are some of

00:45:59.820 those changes? Well, so this is going to get contentious now, because the data suggests that

00:46:06.060 you have a decrease in mitochondrial DNA. Some of that mitochondrial DNA has deletions,

00:46:14.040 that the capacity to do maximal ATP generation goes down, oxidative phosphorylation. The key there is

00:46:24.340 maximal. So one of the perplexing things, and this is really perplexing for me, so I don't think much

00:46:33.600 about mitochondrial DNA, and that's why I didn't have good answers for that. But this is the one that

00:46:37.340 really is, and this is fundamental to the aging. When you're born, let's say, you have 100% capacity.

00:46:44.800 And then as you age, that capacity, if you're giving 100% mitochondria, you get an A+, 100%.

00:46:53.020 How far do you go as you age?

00:46:55.680 Just to make sure I understand what you're talking about, are you saying amount of ATP

00:47:00.580 generated per mole of oxygen as a metric?

00:47:03.420 As a metric. We could use ATP generation as a simple one, right?

00:47:07.120 It's ability to...

00:47:08.160 For every mole of oxygen, you generate X mole of ATP, and whatever your maximum is, it declines.

00:47:13.720 And you can burn it through fat, glucose, carbohydrates, proteins. It's working at its

00:47:18.680 maximum efficiency. Everything's fine. And that efficiency now declines with age. The question

00:47:28.100 is, is it ever rate limiting? So you and I, I mean, again, these are loose terms. At any given point,

00:47:38.060 are using maybe 10% to 20% of our maximal activity.

00:47:41.940 Hey, speak for yourself, dude. I mean, I do wind sprints every day, man.

00:47:47.500 Okay. So when you, when you do that, you might go up to 40 or 50%.

00:47:51.860 I didn't realize that.

00:47:52.780 You don't hit that. And so when we knock out a protein in the mitochondria and we knock out

00:48:01.260 it completely from 100% to 0% pathology happens, we go from 100 to 50%, we never see any pathology.

00:48:09.360 Even under stress?

00:48:10.520 Even under stress, if anything, they behave better.

00:48:13.380 So, yeah, this is very interesting, right?

00:48:16.280 And so then when I look at the data on aging sometimes, you know, in some tissues, it goes

00:48:21.500 down by 50% of maximal, maybe 70%, 80%. But is that ever rate limiting?

00:48:28.520 Well, if what you said make, if what you said is true, then it would not be rate limiting

00:48:31.820 within a certain band.

00:48:32.820 So I am on, and this full disclosure again, I am in way out in outer space on this idea.

00:48:40.080 I don't think mitochondrial function. And if you don't have a disease, let's be clear,

00:48:45.100 normal aging we're talking about, right? You don't have cardiovascular disease. You didn't have,

00:48:50.260 you know, you're just sort of, you're pretty healthy. And I don't think a healthy heart,

00:48:56.100 you know, is rate limited for mitochondrial function. The implication there is that most

00:49:01.980 people think, again, this is like dogma, like with antioxidants, right? They're good for you.

00:49:06.820 That mitochondria are declining. Let's give supplements that boost mitochondrial function.

00:49:14.320 Is that a fair statement?

00:49:15.660 Heck yeah.

00:49:16.740 I think there's no evidence to support that.

00:49:19.040 What is the most popular of said supplements? Would that MitoQ be a popular supplement?

00:49:23.500 Well, that's an anti-mitochondrial targeted antioxidant. So we can talk about MitoQ in a

00:49:27.480 second, actually. Actually, we should maybe talk about MitoQ. It's quite fascinating.

00:49:30.940 Yeah.

00:49:30.960 Let's go back to your question.

00:49:32.360 What is, well, no one's actually has, you know, people have been trying to have these,

00:49:36.800 what's called mitochondrial biogenesis activators, something that will make more mitochondria.

00:49:42.440 And I'm not quite sure what supplement people use that they think is the best one. But I would argue

00:49:48.560 the opposite, which is that they're not rate limiting. And if anything, maybe you can decrease

00:49:57.060 mitochondrial function in certain tissues a little bit to activate stress responses,

00:50:01.540 which will then fight off if you do get a disease. And this is going to go into metformin.

00:50:07.260 I was just, how do you read my mind? I didn't even start mouthing the word yet.

00:50:11.040 Why did you know I was going to bring up metformin?

00:50:12.620 Because we think metformin is a weak mitochondrial complex one inhibitor.

00:50:17.900 Yes.

00:50:18.340 Another, which is part of the respiratory chain.

00:50:20.300 That's why complex one is my favorite complex.

00:50:22.140 That's why your complex one is your favorite.

00:50:23.280 But I'm a poser. I'm a mitochondrial poser. So, okay. Because what I was going to actually ask you

00:50:28.740 was on the heels of that, when you give metformin, you inhibit complex one, you are now reducing

00:50:35.580 mitochondrial function.

00:50:36.660 That mitochondrial function.

00:50:37.680 Right.

00:50:37.920 And if what you're saying is correct, you would need a lot of metformin to generate actual ETC

00:50:44.720 toxicity.

00:50:45.640 Right.

00:50:46.140 Do we ever see that?

00:50:47.260 No. I mean, you do if you go to certain doses, obviously.

00:50:50.940 But not physiologically we can't, do we?

00:50:53.040 The anti-diabetic dosing that is given to people, I mean, there's some toxicity can happen due to

00:50:58.740 certain patient populations. But it's a very safe drug, right? It's used by almost, what, 300 million

00:51:05.040 people now. It's estimated to be used by half a billion people as the diabetes epidemic explodes

00:51:10.820 in China and India. So no one quite understands how metformin works. We think it's, you know,

00:51:18.540 it has three effects, clearly. It lowers glucose production in the liver. It has some anti-inflammatory

00:51:24.520 effects. And it has some anti-cancer effects.

00:51:27.260 Well, let's talk more specifically about it. We were joking around when we were at Easter Island

00:51:31.340 that our next trip actually needs to be to France.

00:51:33.880 To see the goats?

00:51:34.880 To see the lilac. Wasn't that in France where that metformin came from? So two sentences on

00:51:41.940 how metformin was discovered?

00:51:43.400 They noticed these goats that were eating were pretty healthy.

00:51:48.600 I love this. I love these stories.

00:51:50.540 But, you know...

00:51:51.400 Yesterday I was talking to Ted Schaefer about goats as well. So I love that the two Northwestern guys,

00:51:56.100 the only two podcasts that will ever have goats are going to be these ones.

00:52:01.280 So what's interesting about metformin, I think, is it got approved as an anti-diabetic drug.

00:52:08.240 People went back and looked at people who were taking different diabetes and epidemiologically

00:52:12.660 found that there was a lower rates of like prostate cancer. So you're probably talking to Ted Schaefer

00:52:19.120 about this, right? So, and they're lower in breast cancer. So then people started investigating as

00:52:23.700 an anti-cancer drug. Then some people started noticing, wow, it has anti-inflammatory effects.

00:52:29.020 And so I've talked to, you know, our friend David Sabutini that, isn't it interesting that rapamycin,

00:52:36.020 anti-inflammatory somewhat, anti-cancer, promotes metabolic health. So how does that all work?

00:52:42.520 Well, he'll argue, it's all mTOR. I said, well, I would argue, how can metformin do three very

00:52:48.640 disparate effects? Anti-diabetic, anti-cancer, anti-inflammatory, just like rapamycin would,

00:52:54.800 it must be hitting a node that's very important for the cell. So metformin doesn't hit mTOR.

00:53:00.840 Does though. AMPK does.

00:53:03.160 AMPK, but that's due to first hitting mitochondrial complex one, and then activating AMPK, which can

00:53:09.860 repress mTOR. But the analogy that I'm using basically is mTOR we know is the master of the

00:53:16.780 universe. So is mitochondria, right? So if you inhibit mitochondria, not to the point where you

00:53:22.080 cause toxicity, just enough, you can activate a variety of pathways, which can promote, have

00:53:28.780 anti-cancer, anti-diabetic, and anti-inflammatory effects.

00:53:31.840 Now metformin is somewhat tissue specific. It seems to have a preference for the hepatocyte.

00:53:36.160 So it gets into the kidney and the liver. I think we've talked about this before about mTOR,

00:53:42.220 right? So mTOR and rapamycin, right? Why wouldn't you use rapamycin? Well, it might get in

00:53:47.280 everywhere. I think David's arguing, you've argued, wouldn't it be great if you can get metformin to go

00:53:52.080 to the liver, but not to the skeletal muscle. So metformin already has that little bit

00:53:58.760 of that property. It only gets selectively into, it doesn't get into the heart that well,

00:54:02.620 right? So it doesn't infect your heart function, not directly. It affects your liver, your kidney.

00:54:08.040 It actually accumulates quite a bit in the gut, right? And some people get diarrhea with metformin.

00:54:12.420 And so some people think metformin is affecting your microbiome. And there's a huge literature now

00:54:18.240 thinking that's some of how it's having its effects. So I think the liver, so I think there's

00:54:24.060 three places that are important. The liver, and that can account for some of shutting down the

00:54:29.140 glucose production and having the so-called anti-diabetic effect. The colon, and affecting

00:54:34.900 your microbiome. And I think the immune cells, I think that's the big one we're missing. So that's

00:54:39.780 the one that I'm very fascinated. In other words, metformin getting into your macrophages or your,

00:54:45.220 probably maybe not your T cells, but at least your, some of your immune cells that might be causing

00:54:49.700 high levels of inflammation. And, you know, if you look at the three drugs that people like to use,

00:54:55.300 aspirin, metformin, and statins, globally use combined, maybe what, a billion people?

00:55:01.780 Probably more.

00:55:02.200 Probably more. The Venn diagram where they all overlap is inflammation.

00:55:06.460 So let's talk a little bit about the anti-inflammatory properties of metformin,

00:55:10.060 because the first thing is the one I guess we would understand the most, which is,

00:55:13.760 you've alluded to this, but I just, I want to orient the listener a little bit.

00:55:16.500 The mitochondria, you said, have these five complexes. Each of them have multiple subunits.

00:55:20.960 And what happens is these are basically the chains between the inner mitochondrial membrane and the

00:55:26.520 inner part of the mitochondria, where these reducing agents like NAD, NADH, NADP, and NADPH

00:55:33.000 are transferring the electrons and building up that gradient. So by the time you get to the end of

00:55:38.780 this thing, you've got so much potential energy and all of those electrons and you run that transfer

00:55:44.700 of phosphates from ADP to ATP and everybody wins the game. So this is essential, this electron

00:55:51.240 transport chain, like messing with that, probably not a good idea. Metformin comes along and it blocks

00:55:56.860 complex one. Now it doesn't block it completely. It blocks it partially. Now complex one, the chemical

00:56:04.320 reaction that's occurring on the inner part of the mitochondrial, uh, inner part of the mitochondria

00:56:08.300 is the transfer of NADH to NAD. Now that we're going to come back to NAD, but for totally unrelated

00:56:14.980 reasons. When you do that, what is that telling the cell by inhibiting that the cells read out is

00:56:23.280 what physiologically? Three things. First, that battery that you're talking about that generates to

00:56:30.900 make ATP. Less charged. Less charged. So then what happens? ATP goes down, ADP goes up. There's a

00:56:40.100 kinase called AMPK. Kinase. AMPK is the AMP kinase, hence AMPK. It gets activated. And in part-

00:56:49.800 That enzyme is activated is a signal that says, I'm not fed enough.

00:56:53.740 Right. Right. And one of the major things it does is it promotes autophagy.

00:56:57.160 Hmm. My favorite word. Your favorite word, right? It's one of the dominant things it does.

00:57:03.380 That's why when AMPK gets activated, we get another little benefit a la rapamycin's effect on

00:57:11.400 mTOR, which is it says, Hey man, I'm telling you from a glycolytic standpoint or from an oxfos

00:57:17.280 standpoint, energy is low. Shut things down. Right. Nutrients are scarce. Right. And this is

00:57:24.040 happening in the liver. So for example, glucose production that happens in the liver starts to

00:57:28.960 shut down in part, or lipogenesis, making new lipids in the liver. And that's why like for fatty

00:57:35.640 liver, it might have some benefits. So that's one. The other thing is what you alluded to, NAD to

00:57:41.240 NADH. Sorry, NADH2. Right. Making NAD. So that ratio also gets transmitted back to the cell.

00:57:49.620 And what's that signal? How does the low NAD to NADH get transmitted?

00:57:53.340 So the biggest one is lactate to pyruvate. Right. It's a lactate to pyruvate. It is a source of,

00:58:03.520 so there's many ways you can feed pyruvate. So we talked about glucose to pyruvate, right?

00:58:08.940 Right. So glucose to pyruvate uses NAD to NADH. And usually pyruvate to lactate will go.

00:58:21.360 Go ahead and explain what I'm doing.

00:58:24.580 So I have to tell you, and I think we're both, because we're not on camera, one of the difficulties

00:58:32.260 of really getting into the nitty gritty of metabolism is, it's so much easier to write

00:58:38.960 it in diagrams, right? I mean, when you write it in the diagram in simplistic ways, it's just like-

00:58:45.480 It's easier.

00:58:46.240 It's just easier, right? I mean, it's just-

00:58:48.000 So Nav's laughing at me because I'm closing my eyes, drawing it.

00:58:50.860 And as I'm saying it, you know, NAD, you know, it's the NADH. I mean, I'm getting confused.

00:58:55.220 I promise you, this will be one of those episodes where the show notes will be handy because we'll

00:59:03.060 have all the diagrams. Well, they can actually, you know, what they can really do, right?

00:59:08.220 There's a book I've heard. Yeah, there's a book. You want to give a plug? This is a good moment.

00:59:12.420 I'm happy to give a plug. So for all you metabolite lovers out there,

00:59:17.400 Nav wrote a book called Navigating Metabolism, wah, wah, wah. And I actually picked up a copy as soon

00:59:23.920 as we got back from Easter Island. In fact, I probably ordered it from the airport in Santiago.

00:59:28.660 And it's a fantastic resource. And we will absolutely be sure to link to that. I would

00:59:34.880 say it is, and I'm not just saying this because you're sitting here, but if you are a person who's

00:59:39.960 interested in this area, but you're not going to devote your life to it, it's a fantastic-

00:59:45.220 It's the one book you need to get. Obviously, if you're someone who's doing a postdoc in Nav's lab,

00:59:50.540 it's something you need to read, but it's not going to be sufficient to get you, you know,

00:59:54.660 to the next level of understanding. But for the knuckle-draggers amongst us, you can get pretty

00:59:59.600 far on understanding this stuff through Nav's book. And it's actually a pretty quick read. It's not,

01:00:04.800 you know, it's not like reading Stryer's Biochemistry where-

01:00:07.580 That's a very good book, by the way.

01:00:08.780 That was- Stryer was my professor.

01:00:10.800 Yeah, as is the Leninger book.

01:00:12.280 Yes, yeah. So anyway, yeah, a little digression, which is to acknowledge this is hard. Apologies

01:00:18.060 for it. But I think this topic is so important. And I just know I get asked about this stuff all

01:00:23.320 the time. I'm on a personal level, professional level, so interested in this topic that you just

01:00:29.680 have to pay the price. Like you have to be willing to get into the details. And the reason is we're

01:00:33.460 going to talk about other things. You know, people are, if I get, if I had a dollar for every time I've

01:00:37.300 been asked, should I be taking, you know, NR, NMN, and should I be going to a clinic where they do

01:00:42.140 IV, NAD, and all these things? If you want to be able to think through those things and read the

01:00:46.620 papers that are asking those questions, you have to understand how this stuff works. There's no

01:00:51.540 shortcut. Right.

01:00:52.860 So unfortunately, we have to continue doing this the way we're doing it. And that might mean that

01:00:57.400 I have to close my eyes and pretend I'm drawing a complex one.

01:01:01.280 Right. So I guess we should just talk about NAD then, right? NAD and NADH ratio.

01:01:06.900 You were, I sort of interrupted you though. Let's go back to metformin.

01:01:09.740 Right. So what metformin doesn't allow is it starts to weakly inhibit complex ones. So your

01:01:16.700 NADH to NAD is going to be slowed down. And that, how that gets transmitted to the rest of the cell is

01:01:25.660 quite, it's not fully understood. So I have many ideas around this and we can talk about one of them

01:01:32.180 later because it has to do with neurodegeneration potentially. But the big thing is that NADH to

01:01:38.700 NAD ratio is very important. And one of the important things is that when lactate, which can

01:01:45.140 come from like the muscle, the liver takes it up and the lactate becomes pyruvate and that can then

01:01:52.020 eventually become glucose. That's gluconeogenesis. It needs NAD. But if you have metformin,

01:01:59.880 you don't have as much NAD. So lactate to pyruvate slows down and therefore you don't make as much

01:02:05.060 glucose. And that's another reason why metformin has its anti-diabetic properties.

01:02:11.700 That just gave me an interesting idea. We have a friend in common, Josh Rabinowitz at Princeton,

01:02:16.700 who's a classmate of mine in medical school, a colleague of yours.

01:02:19.400 Brilliant, brilliant metabolism scientist.

01:02:20.800 Off the charts.

01:02:21.500 Incredible guy. He had a paper that came out. I've talked about it on the podcast very briefly.

01:02:26.440 I actually want to interview Josh and I just have to drag my ass down to Princeton or he has to drag

01:02:30.380 his up to New York City. But this paper in Cell Metabolism, which we'll be sure to link to,

01:02:34.560 took orally administered NR or NMN, both precursors to NAD. And it showed that the liver could take

01:02:43.860 those up in significant quantities, combine them with tryptophan and make lots of intrahepatic NAD.

01:02:52.300 But none of it made it into the cell. So the NAD wasn't making it into the cell and the NR and the

01:02:57.580 NMN were not being taken up by cells other than hepatocytes. But what you just said made me think of

01:03:02.680 something. If the liver in the presence of NR and NMN is making a lot of NAD, that means it's making

01:03:10.220 lots of substrate to enzymatically force gluconeogenesis. Or is that never rate limited

01:03:18.220 and this becomes irrelevant?

01:03:19.780 The latter, what you just said.

01:03:21.160 So we're never too low on NAD?

01:03:23.980 No, no, we are. We are the maximal amounts. And so there's two things about NAD.

01:03:29.240 One is just the quantity of NAD, which then is utilized by sirtuins, PARP, a variety of other

01:03:38.120 reactions that are important biologically, especially the sirtuins, which are NAD dependent.

01:03:43.480 But that's just simply NAD. What I'm talking about is the ratio of NAD to NADH.

01:03:49.480 And so these supplements, I don't think, they don't drastically change that redox ratio of NAD to

01:03:56.860 NADH. It's just the absolute amount of NAD, which is then utilized is by sirtuins and PARP.

01:04:03.500 And there's something to be said about this because people talk about how NAD ratios decline

01:04:08.380 in the mitochondria as we age. Does that...

01:04:12.600 Is that rate limiting?

01:04:14.000 Yeah, exactly. Does it matter if it affects the enzymatic chain at complex one?

01:04:20.700 Comes back to, is a 50% decline in NAD rate limiting for complex one activity.

01:04:27.060 Because that would mirror what metformin is doing. Metformin is lowering the ratio of NAD to NADH,

01:04:32.580 which would seem to parallel what we're told happens when we age.

01:04:36.120 Yeah.

01:04:36.480 That's a bit counterintuitive.

01:04:37.780 Exactly. Bingo. So this is my argument. Most of the people say you got to boost your mitochondria

01:04:44.580 because NAD is declining. The respiratory chain is declining. Mitochondria rate limiting. But how

01:04:50.280 does that jive with this metformin inhibiting complex one theory then? If you think that

01:04:55.500 mitochondria and NAD and everything around mitochondria is declining, you want to boost

01:05:01.620 them. If you think they're declining and maybe it's adaptive, that's why it is declining,

01:05:07.220 which is my favorite theory.

01:05:08.500 Wow. That's a little out there, man.

01:05:09.820 That's way out there that this is, there's a reason. And if you can then give something like

01:05:15.980 metformin, and it's never rate limiting really, at least for normal physiology, not maybe for stress.

01:05:21.660 And then if you can give something like metformin, you can now stress out that mitochondria at times

01:05:28.640 and turn on some adaptive responses. So that's a different theory, right? So the best evidence

01:05:34.980 for it really is we have to really nail down whether all of these effects of metformin happen

01:05:41.940 by complex one inhibition. There's wide disagreement in the literature. So just to be clear,

01:05:50.380 all these roles of metformin for cancer, for diabetes, for inflammation, does it require complex

01:05:59.460 one inhibition? So how would you test that?

01:06:02.000 Well, it's hard to have a complex one knockout because that's incompatible with life. So that

01:06:06.500 would be the obvious answer that doesn't work.

01:06:08.940 Well, so I would argue for any drug, the best experiment is to make a mutant of that particular

01:06:17.880 complex.

01:06:18.940 That doesn't bind metformin.

01:06:20.260 Bingo.

01:06:20.740 Yeah.

01:06:21.500 So I'm not a good structural biologist, but we did something really clever. We noticed that the

01:06:27.700 yeast has a protein, single protein, which will catalyze NADH to NAD.

01:06:33.760 Okay.

01:06:34.620 What complex one does in part.

01:06:36.220 Yes, exactly.

01:06:37.220 It doesn't proton pump, which means it doesn't contribute to ATP generation. But we have engineered

01:06:43.460 cells and mice to get rid of complex one and put back this yeast, complex one, which is refractory

01:06:52.500 to metformin.

01:06:53.380 But ask this question.

01:06:54.480 But the phenotype of that cell is what? What is its electron transport chain doing if it's

01:07:00.580 basically losing anything at complex one? Basically, complex two through five still can't work.

01:07:05.820 No, no, no. So what this protein, this yeast complex one homolog, a single protein-

01:07:11.660 Oh, it does everything except the electron transport.

01:07:13.880 No, it does the electron transport.

01:07:15.900 Sorry, it doesn't do the proton pump.

01:07:17.920 Yeah.

01:07:18.180 Okay, got it. So you basically reduced your battery charge a little bit.

01:07:21.300 A little bit.

01:07:21.720 But you haven't interrupted the electron transport.

01:07:23.900 Right.

01:07:24.040 Oh, that's elegant.

01:07:25.040 Thank you.

01:07:25.340 That's very elegant.

01:07:26.600 It's clever.

01:07:27.460 Yeah.

01:07:30.760 This is about the geekiest moment right now. This is like, this is, yeah.

01:07:36.260 It's one of those aha things, right? It's clever, right?

01:07:38.580 Very clever.

01:07:39.220 Very clever, right? So you put, so the first experiment we did is we did the cancer experiment.

01:07:44.180 So people had noticed, at least in laboratory settings, if you give metformin, you can reduce

01:07:49.920 tumor burden in mice, you know, the classic sort of experiments. So what we did is we took those

01:07:54.260 cancer cells and put back the yeast version.

01:07:57.860 But I want to say something here before you say, you tell us what happened, which is in fairness.

01:08:01.380 Yeah.

01:08:01.840 And we did a lit review of this in 2014. So it's very dated. I know what's going to happen. A bunch

01:08:09.800 of people are going to say, Peter, can you please link to it? It's an internal document. I may link

01:08:13.940 to it. I got to go back and look and see how ridiculous it is. But because it's now four years

01:08:18.160 old, but it was not clear at the time of this review, if the anti-cancer benefits, which seemed

01:08:24.760 real, were either due to the inhibition of complex one or due to some other mechanism by which AMPK was

01:08:33.140 activated. And to my knowledge, that is still not clear.

01:08:37.220 Oh, it's clear.

01:08:37.960 You're going to tell me it's clear.

01:08:38.900 For cancer.

01:08:40.080 Okay. Keep going.

01:08:41.220 So I'll tell you the experiment in cancers. And then I'll tell you for diabetes, there's

01:08:47.300 main effect, anti-diabetes. I think that's still up in the air.

01:08:49.760 Okay.

01:08:50.140 For inflammation, I think there's some strong evidence for complex one as well. So the simple

01:08:56.680 experiment we did was we said, let's put back in cancer cells that human cancer cells, we

01:09:06.100 put it in a mouse and it grows rapidly, right? And you can do it in colon cancer, breast cancer,

01:09:11.380 lung cancer cells, typical cancer biology experiments. And we put the yeast complex one

01:09:17.740 in. And okay. So when the yeast complex one is not there, metformin decreases tumor burden.

01:09:25.820 If the yeast complex one is there, metformin can't bind to it. So the mitochondria still continues to

01:09:32.840 work and voila, the tumors don't go down.

01:09:36.220 So what you demonstrated through that experiment, assuming we're not being fooled by some other

01:09:41.380 artifact, which is always possible, is that when you prevent metformin from this one particular

01:09:48.340 issue, which is binding to complex one and inhibiting that, its anti-cancer properties cease

01:09:54.740 to exist.

01:09:55.540 Yeah.

01:09:55.740 Did you assess the effect in that setting on AMPK? How much was AMPK activity upregulated?

01:10:04.680 Yeah. So we don't think the anti-cancer effects are due to AMPK.

01:10:09.760 Fair. But do you have an answer to the question? Do you know what happened in that setting?

01:10:13.820 Yeah. So we...

01:10:14.480 Because they should go down a little bit, but not off.

01:10:17.060 Yeah. Yeah. So we didn't think about that. We looked at other properties like NAD,

01:10:21.560 NADH ratios, which we think is the more important one.

01:10:24.100 How much did the NAD to NAD ratio...

01:10:25.700 Oh, yeah. No. So we could show clearly...

01:10:27.240 You could shut it down.

01:10:27.940 Yeah. Yeah. With metformin, you could decrease it. When the yeast complex, you can recover

01:10:32.140 that ratio, the NAD to NADH ratio, and all the metabolomics that go with it. So when you

01:10:37.880 inhibit complex one by metformin, the TCA cycle slows down, and you can capture that by mass spec,

01:10:46.060 classic, what's called metabolomics, which is basically looking at metabolite profiling.

01:10:50.140 And what's cool about that is there's a very good scientist, give him a shout out, Jason

01:10:55.360 Locasal at Duke University, again, kind of a younger version of Josh Rabinowitz. And what

01:11:01.340 Jason hooked up with the University of Chicago, ovarian cancer, very famous ovarian cancer doctor,

01:11:08.240 Ernst Lengel and his fellow Iris Romero at that point. And they were giving metformin to patients,

01:11:15.160 and then they gave these biopsies to Jason, and Jason could detect TCA cycle. He could see if...

01:11:21.520 He could ask two questions. Did the metformin get actually into the tumor?

01:11:25.320 Yes.

01:11:26.060 Yes. And the second one was, if our mechanism of complex one that we showed is correct,

01:11:33.220 then the TCA cycle metabolites should be altered. And they were in those human cancer. This is a

01:11:40.280 cell metabolism paper you can, people can link in. What year was that?

01:11:42.880 That was, so we published our metformin paper in 014. I think Jason's paper was in 016. I think we did

01:11:49.360 the simple, elegant experiment, which shows the necessity of complex one inhibition. But I think

01:11:55.500 Jason did the, as close as you can, if that mechanism is correct in the humans, he did the best,

01:12:02.040 the next best thing you could do, which is show that TCA cycle metabolites.

01:12:06.060 Clinically, it begs a question. Is that working because hepatic glucose output is going down

01:12:15.140 and insulin is going down and presumably IGF is going down? If insulin is going down,

01:12:21.080 IGF BP3 should go up. Insulin should go down, even if there's no change in the amino acids.

01:12:26.920 Those things should all, if you had a little like on-off switch, more glucose or less,

01:12:32.480 less is better, more insulin or less, less is better, more IGF, more or less, for cancer.

01:12:38.660 All of those things would move in the right direction if hepatic glucose output went down.

01:12:43.120 So do we believe that that is the vehicle through which that transduction is becoming clinically

01:12:50.320 relevant? Or do we believe that somehow inhibiting complex one in a cancer cell is

01:12:57.640 deleterious to a cancer cell? I think both mechanisms are working in concert. And so clearly

01:13:05.700 metformin, as you pointed out, lowers glucose, insulin, IGF, and insulin and IGF in certain

01:13:12.440 tumors can be a mitogen or something that promotes cancer proliferation. Right. It seems that about

01:13:17.360 two-thirds of cancers seem sensitive to insulin and IGF. So that mechanism is still in play. But

01:13:22.360 what we showed is it's equally plausible for cancers that have transporters of metformin,

01:13:29.000 and they're called organic cation transporters. Not every tumor has it. And that's why metformin

01:13:34.340 doesn't work clinically as a great anti-cancer agent, because lots of tumors just don't have them.

01:13:39.820 But if they do have them, they'll take them up, they'll inhibit complex one, and that will have

01:13:44.800 anti-cancer effects right into the cancer cell. The reason that's important, again, is our work

01:13:53.760 genetically has shown when we knock out complex one or three, tumors don't grow. If we give metformin,

01:14:00.200 we can show it's anti-cancer effects are due to complex one inhibition. So if that's right,

01:14:04.840 then could we design complex one inhibitors?

01:14:07.360 Wait, let me ask you a question. Sorry to interrupt, Nav.

01:14:09.220 When you, what you just said a moment ago, when you inhibit complex three and tumors don't grow,

01:14:16.280 that's, you have to inhibit complex three in a tumor cell or in a hepatocyte to produce that

01:14:21.100 tumor cell. And the hepatocytes are normal.

01:14:23.820 Well, the way we, these are genetically engineered where the complex threes or one is only lost in the

01:14:29.880 cancer cell. So this is the next experiment you have to do. You have to be able to separate,

01:14:34.260 listen to me telling you the experiment you have to do.

01:14:36.200 It's important, I think, to separate out how much of this is tumor specific versus global metabolic.

01:14:43.960 And the reason is the implications are profound, not just for other therapeutics, but frankly,

01:14:49.420 for a more fundamental question was what the hell should people be eating, right? If in as much as you

01:14:54.960 believe that nutrition can impact cancer therapy, the answer to this question is relevant.

01:15:01.060 So we have now generated an unpublished work. I don't know. Can you talk about unpublished work

01:15:08.080 on a podcast?

01:15:09.580 I don't know. It depends. When is it going to be published?

01:15:11.720 Not for a while, but it doesn't matter. So we've generated a mouse that contains the yeast complex

01:15:19.840 one in the liver.

01:15:21.100 Ah, okay. So that, this is, this is where you'll be able to do the experiment because there's really

01:15:25.260 a two by two that needs to be done here.

01:15:27.160 I think they're both working in concert, right? But the major thing isn't that metformin,

01:15:32.500 you know, may have some anti-cancer effects, but what it's led to, because of our work and others,

01:15:38.340 is the idea that maybe we should target mitochondria inhibition for cancer therapy.

01:15:44.740 Now that's a little counterintuitive.

01:15:46.600 Yeah. So this is, again, you know, I mean, I'm sure the audience is like,

01:15:50.280 everything this guy says is contrarian. So let's just turn them off now. But, you know,

01:15:54.980 our data is very clear. Mitochondria are necessary. Mitochondrial function is necessary

01:16:00.900 for tumor genesis.

01:16:01.740 All right. So let's take a step back and explain to the listener who hasn't heard what you just said,

01:16:05.780 why that is going to rock some people's world.

01:16:08.240 I think you've talked about it in some other podcasts. So there was a observation

01:16:12.240 made in the 1920s by a gentleman named Otto Warburg, one of the giants,

01:16:18.340 actually trained Hans Krebs, for example. He won a Nobel Prize in 1931 or 32,

01:16:23.920 basically for discovering an enzyme for respiration. And so he loved measuring respiration.

01:16:31.480 But he did it in cancer. He did it in normal cells. And he noticed that cancer cells,

01:16:36.320 at least on the benchtop, not in vivo, not in a real tumor, not in humans, just taking

01:16:43.500 tissues out, that they made a lot of lactate and they didn't consume as much oxygen. And this didn't

01:16:50.520 make sense to him because he's like, there's plenty of oxygen. Why should it do that? And it led him to

01:16:55.820 think about perhaps that maybe the mitochondria are being suppressed in cancer. And this led to this

01:17:02.200 long, long, long dogma that a very elegant, simple theory. Normal cells use a lot of mitochondria and

01:17:09.920 mitochondrial ATP, very little glycolysis. So in other words, very little glucose to lactate,

01:17:15.680 tons of oxygen. Your heart does it, your brain does it. But when you become cancerous,

01:17:21.340 the mitochondria sort of shuts off and you upregulate tons of lactate. And you can see that

01:17:25.940 huge uptake of glucose uptake by FTG PET that the clinicians do. And you can see lots of lactate.

01:17:32.940 And that was this theory. And then you target glycolysis for cancer because it'll specifically

01:17:38.700 hit cancer cells because they're so glycolytic and spared all the other cells like your heart,

01:17:44.280 your brain, your liver, because they're all mitochondrial dependent for energy. Keep it

01:17:48.400 simple. Right?

01:17:49.400 Right.

01:17:49.740 So far, so good?

01:17:50.600 Absolutely.

01:17:51.580 So.

01:17:52.020 And then, I mean, just to add to that story, about 10 years ago, and I've talked about this paper on

01:17:56.020 the podcast, but Thompson and Matt Vatterhan was the lead author. But so, so Vander Heiden and Cantley.

01:18:02.380 Just saw him last night in Madison.

01:18:04.340 He was here last night?

01:18:05.240 No, he was in Madison.

01:18:06.220 Oh, oh, you were not sure. So Matthew and Lou Cantley and Craig Thompson wrote this paper in science

01:18:11.180 almost exactly 10 years ago. And it proposed a different reason for the observation. So it said

01:18:16.060 the observation that Warburg put forth is what you just described, but maybe a different reason

01:18:20.580 is that the cancer cell is not optimizing for energetics because that was always viewed as an

01:18:25.260 energetically very inefficient and wasteful thing to do. But the argument they put forth was, well,

01:18:30.080 it's not doing it for energetic reasons. It's doing it for growth reasons. It's doing that to get

01:18:35.500 the throughput of building blocks for cells. So same observation, different explanation.

01:18:39.760 The one thing I will say is, for whatever reason, and including that beautiful review in science,

01:18:46.300 which the part that people don't highlight is, what is the mitochondria really doing?

01:18:52.440 So people sometimes assume, oh yeah, all that glycolysis, and it's for biomass and building

01:18:58.920 blocks. Oh yeah, the mitochondria has a negligible contribution. It's just sort of in the background.

01:19:04.280 It's the potato, as we call it.

01:19:06.720 In the Sabatini world.

01:19:08.180 Yeah, right? It's just, it's a bystander. And we did a simple genetic experiment,

01:19:13.580 said, let's just test this. So we're going to take in a mouse with an intact immune system.

01:19:18.900 We gave the mouse, made it have poor mouse, got lung adenocarcinoma, lung cancer, right? The biggest

01:19:24.020 cancer, the most prevalent cancer in the world, obviously due to smoking. And we genetically

01:19:30.900 knocked out the respiratory chain. So it can't respire. So now it's 100% glycolysis. It's exactly

01:19:38.180 what a tumor that Warburg would love. Do you make bigger tumors? According to him, yes. If it's all

01:19:44.480 about glycolysis, or do you make smaller tumors? We made very smaller tumors, little, little, tiny,

01:19:51.680 little tumors, which told us that mitochondria are necessary, or mitochondrial respiration is

01:19:58.320 necessary for tumor genesis.

01:19:59.840 But van der Heiden's hypothesis would explain that because if you knock out the mitochondria,

01:20:04.460 you don't have the biomass.

01:20:05.540 Right, but he didn't say that.

01:20:06.680 No, no, no. I know, I know. But I'm extrapolating.

01:20:08.720 Yeah, it's consistent with that. Yeah, no, Matt and I completely agree. It's just the way that review

01:20:12.700 was written 10 years ago. It was more glycolytic centric. So I will give a cheap plug to a review that I

01:20:18.420 wrote with Ralph Deberdinis. It's a very elegant review. 2016, where we updated this. It's called

01:20:23.740 Fundamentals of Cancer Metabolism. And it's really simple. It just says, if you go back to your

01:20:28.580 biochemistry books, and you ask, how do you make a nucleotide? Let's keep that simple. You need to

01:20:33.400 make new DNA, because cancers proliferate. You make one to two daughter cells to four. And there you go.

01:20:40.920 So where does that nucleotide? Let's look at the structure. It has a ribose as a backbone that comes

01:20:47.080 from glucose. Bingo. It needs a variety of nitrogen atoms put on it. Where does that all come from?

01:20:55.600 Some of it comes from like aspartate and glutamine. Where do they all come from?

01:20:59.840 They can come from glucose and their amino acids.

01:21:03.040 But they're amino acids, but they all come from mitochondria. Right? So in other words,

01:21:06.620 they both are, one of my favorite words, they're both necessary for tumor genesis,

01:21:12.340 but neither is sufficient. Sufficient. Can we just pause for a moment on necessary but not

01:21:17.440 sufficient? If there's one thing that I loved in medical school, when you were doing the basic

01:21:23.460 science classes before you got into the clinic, it's that when you were doing your physiology classes

01:21:29.700 and your molecular biology and things like that, these professors, they were so great at explaining

01:21:35.020 the importance of very elegant experiments that can demonstrate whether something is necessary but

01:21:39.860 not sufficient, sufficient but not necessary, neither necessary nor sufficient, you know,

01:21:43.520 all those other things. Something happens in medical school when you leave the classroom

01:21:48.060 and you start to go into clinical medicine. People start to forget that logic.

01:21:52.480 I would say the real logic people forget, everybody does. We're all guilty of this.

01:21:58.360 And this is what you and I have talked extensively about, correlation versus causality.

01:22:03.960 So, you know, my daughter can bitch all she wants about how her papa hasn't taught her any math,

01:22:10.660 but her papa has taught her one thing, correlation versus causality.

01:22:14.820 But this goes even deeper than that, right?

01:22:16.900 You got to start there.

01:22:18.040 Oh, yeah.

01:22:18.880 Fundamentally. But I think people, I mean, this is, and right now, we, even in my world where people see,

01:22:26.660 like, mitochondrial function go up or down. So, like, take your aging one. Yes,

01:22:31.100 mitochondrial function goes down. So, that's a correlation with aging. That doesn't mean

01:22:36.000 that decrease in mitochondrial function causes aging or drives aging. It's just a correlation.

01:22:43.420 It could be adaptive or maladaptive.

01:22:45.380 That's right. I mean, that's, so, see, to me, the second order point is the right point. The obvious

01:22:49.380 point is you can't infer causality. But the second order point to that is if there is causality,

01:22:55.600 it doesn't tell you if it's adaptive or maladaptive. That's the nuance. And this idea of necessary

01:23:00.860 but not sufficient to me is very important in biology. Because you can have things that are

01:23:04.800 causal, necessary, but not sufficient.

01:23:08.760 I just told you one.

01:23:09.640 Exactly. Causal, sufficient, but not necessary. And most of all, causal, neither necessary nor

01:23:17.700 sufficient. And people love to dismiss those things. I'll give you an example. Smoking and lung cancer.

01:23:26.300 There's never been a trial.

01:23:27.500 I'm going to argue smoking is causal with lung cancer. Just as I'll argue that smoking is causal

01:23:32.600 with cardiovascular disease through different mechanisms, endothelial dysfunction in the latter.

01:23:36.980 But no one in their right mind would say that smoking is either necessary nor sufficient.

01:23:42.260 Lots of smokers don't get lung cancer. Lots of smokers don't get heart disease. Lots of people

01:23:46.680 who get heart disease and lung cancer don't smoke. So, isn't it interesting that you can have

01:23:52.160 something that is neither necessary nor sufficient and yet can play a causal role in a disease?

01:23:57.220 And I, again, people might be listening going, what the hell is he making such a big deal out

01:24:00.760 of this for? I make a big deal out of this for because when you get to complex diseases like cancer

01:24:05.720 and Alzheimer's disease and atherosclerosis, it is very unlikely you will find something that is

01:24:12.580 necessary and sufficient. They're very rare to find those exceptions. These are such multifaceted

01:24:18.360 diseases. And there are so many different ways to skin a cat. You know, when you talk about

01:24:21.980 cardiovascular disease, you've got like four completely different things that have to be

01:24:26.560 going on to cause this disease. You have to have lipoproteins trafficking the sterols into the

01:24:31.880 subendothelial space. You have to have the endothelial dysfunction to enable that to get in there and get

01:24:37.860 retained. You have to have the inflammatory response. You take one of those things away, you change the

01:24:44.260 dynamic of the disease. And your other point's a great one. Even if you can infer causality,

01:24:49.760 it's not entirely clear what's adaptive and what's maladaptive.

01:24:52.860 So our experiments really would show this mitochondria is necessary tumor genesis. So

01:24:57.940 it's interesting, that paper you referred to, Vanderhand and I were graduate students together and

01:25:02.800 postdoc. When I was starting my postdoc, he was sort of finishing his graduate training with Craig

01:25:07.300 Thompson and we were in the same lab and we actually worked together. So he's an old friend of mine and

01:25:12.240 obviously Craig's a former mentor and I like Luke Antley a lot. But that paper, when it came out in

01:25:17.280 2009, right around at that point, when it came out in science, we had sent our paper to science and

01:25:24.660 showing that mitochondria and esoteric tumor genesis, they didn't send it out. They said, oh, come on,

01:25:30.620 this is, no. So then we sent it to 11 other journals. No editor sent it out. Cancer cells, cell, nature,

01:25:42.800 nature medicine, you know, nature cell biology, journal of clinical medicine, nobody sent it out.

01:25:49.040 Because the review didn't say mitochondria are not functional. It just didn't mention anything about

01:25:55.780 mitochondria. It sort of just provided an explanation of the glucose, like glucose to lactate. Why do

01:26:02.400 tumors show that? And it's for the biomass, not the energy, right? That was the point. And it didn't say,

01:26:08.400 it was sort of agnostic about mitochondria, right, in the review if you go back. But people misinterpret

01:26:14.300 that and saying, oh, yeah, mitochondria are not necessary. It's all about glycolysis. Let's target

01:26:18.720 glycolysis. So eventually the paper did get published in PNAS. And I think that sort of started,

01:26:24.580 I would argue, the revolution of looking at mitochondria and cancer. Other people were

01:26:30.440 doing it as well. But, you know, I sort of became a preacher just pointing it out. Look,

01:26:35.640 if you inhibit the respiratory chain, you can decrease tumor genesis. Ten years later,

01:26:41.300 to the best of my knowledge, and this is really important because it goes back to the clinic,

01:26:45.420 as far as I know, there are no clinical, like, drugs in the clinic that are necessarily targeting

01:26:51.520 glycolysis. Right now, there are potentially two drugs that target the mitochondria.

01:26:57.060 What do they target specifically?

01:26:58.380 So one of them is a complex one inhibitor that the folks at MD Anderson have generated,

01:27:04.440 and they just published two papers in Nature Medicine.

01:27:06.960 Different from fenformin.

01:27:08.380 They're fenformin. Yeah, they're different from metformin, fenformin. They're much stronger,

01:27:12.420 or they know the binding side. By the way, they use the same yeast, NDI1,

01:27:16.560 complex one that doesn't bind to metformin, but doesn't bind to their drug as well,

01:27:22.140 as to show, test it. And-

01:27:24.980 So how will they prevent toxicity?

01:27:26.900 Yes, yes. So now they're doing a trial in AML. And so this is a million-dollar question.

01:27:33.760 And can you find a therapeutic window where maybe the drug gets taken up preferentially by,

01:27:39.920 just because of the properties, by leukemic cells or prostate or lung cancer cells,

01:27:45.780 but spares the brain, the heart, and other organs where you could have toxicity. So that's the big

01:27:51.500 issue. The good news is if you inhibit complex one, it will decrease tumor genesis. The bad news is

01:27:58.300 it might kill you, right? So we've got to find that window. And does it also work well with

01:28:03.060 immunotherapy? That's an open question, right? Which is the new kid on the block. Does it help

01:28:08.980 synergize with immunotherapy, or does it prevent the immune function? So all of this has to be

01:28:15.540 worked out. But my point is that there's some space in this area. The other one is a drug by

01:28:21.020 Raphael Pharmaceuticals. And full disclosure, I sit on their scientific advisory board.

01:28:26.260 Thank you.

01:28:27.080 And I'm not pitching anything here. Simply, in fact,

01:28:30.000 they were already doing this stuff. We're just sort of giving them some,

01:28:33.100 you know, my little biological insight, which is I'm trying to provide today. But they've already

01:28:37.180 done a clinical trial. And I'll send it to you. It was published in Lancet Oncology. And it was in

01:28:43.560 pancreatic cancer, just a safety trial.

01:28:45.400 Phase one.

01:28:45.740 Phase one. And it targets alpha-keto, TCA cycle enzymes. And so it's preventing the TCA cycle

01:28:52.280 from functioning to build that biomass.

01:28:55.320 And did they generate any data on the tissue specificity of that agent?

01:28:59.280 Not yet. So this is the kind of stuff that needs to be done to try that drug and do the kind of

01:29:04.900 experiments where you can see TCA cycle metabolites changing pre and post drug treatment of a particular

01:29:11.080 tumor and then correlating that with success of remission and, you know, all the usual parameters.

01:29:17.500 Now, what's interesting about that drug, again, is why would that be safe? Any of this. The only way

01:29:23.380 these drugs can be safe is they somehow preferentially are getting more into the tumors.

01:29:27.940 Or they're just so weak that they're not bringing you below the threshold of shutting off the TCA.

01:29:33.700 Yeah. And then maybe they combine well. So I can tell you, if you give the standard care of therapy,

01:29:39.800 cisplatin, one of the chemotherapies, or targeted therapies like BRAF inhibitors,

01:29:45.120 is what happens, as you know, the primary tumor sort of debulks, right? It slows down.

01:29:50.020 And slowly you get resistance. And then it comes back. During that slow resistance phase,

01:29:55.640 at that point, they're really dependent on mitochondrial function.

01:29:58.780 So there might be a window to attack it with like BRAF inhibitors or cisplatin. And again,

01:30:05.020 like everything else, they're going to have to find that sweet spot.

01:30:07.780 See, to me, that's where I think this has to go. I mean, I've always found immunotherapy to be the

01:30:11.880 most elegant of all approaches to cancer. I'm highly biased because that's what I studied.

01:30:17.240 But ultimately, I think the Swiss cheese approach has to be the approach too, which is,

01:30:22.520 why would we only take one modality of therapy? If you're David and you're trying to slay

01:30:27.240 Goliath in the fairy tale, one stone to the head does it. But in the real world,

01:30:32.520 to take a Goliath down, I think you need to bang him at the knees. And when he bends over and

01:30:37.140 complains about it, bang him in the other knee. And when he's complaining about that,

01:30:40.480 whack him in the hamstring. And in other words, you've got to be able to do successive blows

01:30:44.540 to a vulnerable cell. And that's going to be, yeah, when is it most dependent on the mitochondria?

01:30:51.140 Okay, well, bang, now you hit with that therapy. And then all of a sudden,

01:30:54.680 to your point earlier, maybe at some point you begin to weaken it even, you make it more

01:30:59.080 identifiable from an immune perspective. And bang, that's when you would hit with the immunotherapy.

01:31:03.960 The last point I really like, you know, would the immune system recognize that tumor better

01:31:08.680 if the mitochondria of that tumor was not working properly?

01:31:12.260 Yeah, see, that's, I mean, I-

01:31:13.960 Or maybe release that mitochondrial DNA, for example, as it's dying.

01:31:17.760 As long as it were specific, right? As long as it could, it didn't create a diffuse immune reaction,

01:31:21.860 but instead- A localized-

01:31:24.040 Allowed the body to say, that's not self.

01:31:26.960 Right.

01:31:27.380 That's, you know, and I haven't done a podcast yet on immunotherapy. I want to have Steve Rosenberg

01:31:31.860 on to talk about this because, I mean, who better to talk about this with? But anyway, so let's talk

01:31:36.880 about another issue in cancer, right? Which is, I mean, I think everybody agrees that most cancers

01:31:42.040 involve somatic mutations. You know, there are very few cancers that involve germline mutations.

01:31:46.920 That's, those are the, those are the exceptions. Uh, but the, the, the general one is these are

01:31:51.160 acquired mutations. Now, some have argued, and this is a very minority opinion, but some have

01:31:57.460 argued that the somatic mutations of the nuclear genome are actually the result of the mitochondrial

01:32:04.600 dysfunction. I think the majority would argue, no, it's the other way around, that the nuclear

01:32:11.520 genomic mutations, somatic, are actually what leads to ultimately whatever's happening in the

01:32:17.980 mitochondria that may be dysfunctional, may be maladaptive, may be adaptive. You would be in the

01:32:24.040 latter camp, correct?

01:32:25.180 Completely. 100%. And again, this is why these clinical trials are really important. This is

01:32:31.040 why the metformin trial is important, right? So I've told you two things, I've told you three points

01:32:36.180 that are quite contrarian. We started with antioxidants, that there's no evidence that

01:32:41.500 antioxidants in large scale, the dietary antioxidants, just to be clear, vitamin E,

01:32:46.380 vitamin C have had any benefit to mankind and womankind, right? There's for human health and

01:32:53.020 disease. It just hasn't worked out. So either we haven't built the right antioxidants or the theory

01:32:58.580 that raws and oxidants are bad, that theory's off. And I would argue that theory's off because if

01:33:05.120 anything, normally we use oxidants as signaling molecules. The second thing I told you about

01:33:12.080 is the fact that during aging, yeah, mitochondria decline, but that correlates and it could be

01:33:17.880 adaptive, very contrarian point of view. If anything, if you gave an agent that decreases

01:33:24.020 mitochondrial function, like metformin, that that could be a good anti-aging therapy, right?

01:33:31.820 It's not turning on mitochondria, but turning off mitochondria. And by the way, Andy Dillon,

01:33:35.460 a good friend of mine I was there with yesterday, who's done beautiful work on worms. Clearly in the

01:33:40.800 worm, when you decrease complex one or three, you live longer as a worm.

01:33:45.160 Yeah. I don't know Andy, but David has spoken so highly of him. David Sabatini, you have as well. I

01:33:50.340 need to meet Andy and hopefully interview him at some point and talk about all this stuff. Of course,

01:33:55.280 it could be going back to your point that the inhibition of complex one, which inhibits mitochondrial

01:34:01.100 function inside of a non-toxic range might be, might not actually be part of why metformin makes

01:34:08.620 you live longer. That might just be a, it survives despite that, not because of that, the organism.

01:34:14.400 Yeah. I would argue that, you know, metformin being anti-inflammatory and-

01:34:18.700 I want to come back to anti-inflammatory in a second.

01:34:20.620 We'll come back to that. But so the third point is that glycolysis is necessary, but so is

01:34:27.080 mitochondria. That cancer cells use a robust mitochondrial function. And if that function

01:34:35.200 doesn't work, the TCS cycle or the respiratory chain doesn't work, or in most cancers, you don't

01:34:41.780 get a tumor. Now, there are these rare cancers where it has a TCS cycle mutation. And so this is

01:34:48.860 another sort of logic point, right? So they look at that rare phenomenon, the exception to the rule.

01:34:54.320 And some people say, oh, there are these rare cancers that have a TCS cycle mutation. Aha.

01:34:59.920 Therefore, cancers have TCS cycle mutations. Oh, come on. This is illogical. It's the exception to the

01:35:06.160 rule of most cancers, at least that we've studied it, whether it's in cell culture and mouse models.

01:35:12.120 And my good friend, Ralph Deberdinis, who's doing glucose, he's doing tracing experiments

01:35:17.140 like Josh Rabinowitz has done as well. They can clearly show the TCS cycle is quite robust.

01:35:23.200 And so, you know, why those cancers can arise is an interesting question, but they're the exception

01:35:29.060 to the rule. So I'm in that camp. Well, and the other, I guess, point to that-

01:35:32.260 Right, by the way. Then these drugs, if they make it in the clinic and really make a difference,

01:35:37.180 voila.

01:35:37.360 The other thing that I think would favor the genomic argument is a lot of the viral research,

01:35:43.520 because when we see viral vectors driving cancer, it's presumably nuclear DNA. I'm not aware.

01:35:51.380 Are there viruses that are causing cancer through infecting mitochondrial DNA?

01:35:54.980 I don't believe that. I think it's all nuclear, personally.

01:35:58.340 So that would be another-

01:35:59.580 Yeah. If anything, you know, so renal cell carcinomas are really-

01:36:02.500 So you know these onchocytomas?

01:36:03.980 Yep.

01:36:04.260 You know what they are? Benign tumors, essentially. If you look at in renal cancer-

01:36:09.740 Yeah, just for the listener to understand, meaning they still grow in a somewhat unregulated way,

01:36:15.040 but they don't have metastatic potential. So you're not going to die from these things,

01:36:18.700 but they're sort of benign growing tumors.

01:36:20.560 Yeah. Even those, the major mutation that they have is in the respiratory chain. So in other words,

01:36:27.260 again, they're very rare, but sometimes you do get complex one loss, but you don't get an

01:36:33.700 aggressive tumor. You get this benign tumor at best, right? So again, it's almost a barrier to

01:36:38.180 progression, and that's from human genetic data. So I'm in the camp, but ultimately, we can do all

01:36:45.420 these cute little mouse experiments, and the data is very clear in our hands, and Ralph's hand,

01:36:49.940 and Josh's hands, and lots of people's hand, that mitochondria necessary for tumor genesis,

01:36:54.060 TCA cycle activity. The ultimate proof is, well, let's inhibit the TCA cycle for prostate cancer,

01:37:01.180 for colon cancer, for pancreatic, and does it make a difference with immunotherapy or

01:37:04.940 chemotherapy? So we'll see. And by the way, the same one goes to metformin,

01:37:11.340 and which is that if metformin really does work as a potentially as an anti-aging strategy,

01:37:17.800 and we can show that those effects are due to complex one inhibition, then it's hard to think

01:37:22.340 why that, you know, this idea that mitochondria rate limiting or declining to a point during aging

01:37:30.180 that's injurious, that idea can't hold up because you're giving essentially a weak complex one

01:37:35.100 inhibitor to turn on stress responses, which means you must have enough mitochondrial activity as you

01:37:41.040 age. It's down, but not gone, right? Right, right. Enough to not be rate limiting. And of course,

01:37:47.300 the antioxidant one, we've already won that battle, right? Because the trials have all failed, so.

01:37:51.200 And for the person listening to this who's scratching their head and confused and says,

01:37:54.760 does this mean I shouldn't be taking my vitamin C or my vitamin E or my whole foods proprietary

01:38:00.640 antioxidant blend of blueberry skin? I think you're right. The answer is pretty clear that the harm of

01:38:09.520 taking those things might not be great, but the benefit seems to be negligible to nowhere.

01:38:14.200 That's a fair statement.

01:38:15.140 Are there benefits, you think, to the natural quantities of antioxidants we consume in our food?

01:38:22.980 So for example, berries do contain lots of antioxidants. People love to talk about those

01:38:28.360 benefits without saying, go up and take, you know, ground berry capsules or something like that.

01:38:33.220 Do you still think there is a benefit in having, in other words, if a berry doesn't give you benefit,

01:38:39.520 in the antioxidant, there's not a hell of a lot of benefit in it because it's basically just a

01:38:43.280 vehicle to deliver fructose, which I could argue, you don't need any fructose in your life. And it's

01:38:48.140 a vehicle to deliver glucose, but you can get glucose in better forms or more of it elsewhere.

01:38:52.680 So is there some other benefit?

01:38:54.520 So I don't know much about berries. So the best one is vitamin C, right? Like how much should you take?

01:38:59.700 Okay. So let's, let's talk about an orange. Is there some benefit in eating an orange?

01:39:03.740 Yes.

01:39:04.240 Okay. So what's the benefit in eating an orange from an antioxidant standpoint?

01:39:06.740 Yes. So there are enzymes that control DNA methylation and other reactions. So simply

01:39:14.780 that to maintain proper function of gene expressions, so that your genes turn on and off properly,

01:39:24.760 either enzymes that are dependent on vitamin C. And you basically need about an orange a day or

01:39:32.480 a glass of orange juice, you know?

01:39:34.380 Please, please, please. Let's not encourage people to drink orange juice.

01:39:36.360 Not orange juice. Fine, fine, fine. But, but you know, but, but what I mean is you don't need to take

01:39:40.920 10 oranges, right? It one, an orange a day is enough, right? That to get you, give you enough

01:39:46.800 vitamin C to make those reactions work properly. And one or two oranges, but you don't need to then go

01:39:53.180 and take 400 grams.

01:39:54.240 But that has nothing to do with the antioxidant properties of vitamin C.

01:39:57.520 No, no, no, no, no, no, no. It has nothing to do with the, nothing to do with Ross and all of this

01:40:01.020 stuff we talked about. It has to do with running some enzymes that are important for controlling

01:40:06.960 gene expression. I know those genes that have to get turned on and off are dependent on those,

01:40:11.620 those, and, and that, so, and of course there are some people who might not be taking, getting

01:40:16.760 into vitamin C and, you know, due to their diet. So that's fine. Take a, take a, take a, take a.

01:40:21.120 Yeah, but it's pretty hard to do that.

01:40:22.300 Pretty, pretty hard to do it. I mean, citric acid, I mean, you know, we have it in a lot of places.

01:40:26.300 Would you be comfortable speculating that a cancer patient in particular should avoid antioxidants?

01:40:33.860 No, no, I don't think, I don't think the dietary, well, I guess.

01:40:37.400 Sorry, sorry. Let me rephrase my question. I don't mean through dietary means,

01:40:40.460 but through supplemental means. Like if any patient could actually be harmed by an

01:40:44.500 antioxidant, could it be a cancer patient? Well, the, one of the trials, the lung cancer

01:40:49.340 trial argued that I think was a vitamin E trial and they did worse. And in mice, you can recapitulate

01:40:55.640 that. So why, why is that? It's not clear. So I personally don't take any of these supplements

01:41:02.680 because I think I've got a reasonable diet. So just like you. So why don't you take metformin?

01:41:06.920 I will not take anything unless it's done, any drug, unless it's gone through a rigorous clinical

01:41:12.880 trial. That's just my own bias. Now, some people would say, okay, you're aging now. So you're going

01:41:18.760 to, by the time they do a trial, you may not be around. So why don't, why not take a chance,

01:41:23.960 right? Lots of people argue this about NAD boosting pills, right? That you should just take

01:41:28.740 NAD boosting pill. By the time people do a clinical trial and all of that, it'll take years and years and

01:41:34.380 years. And for those people who are already later in life, you know, go ahead and take metformin.

01:41:40.140 So, so putting your bias aside, because inherent in your bias is an assumption, which is the risk

01:41:46.600 of taking it is greater than the benefit of not taking it. So either you don't think the benefit

01:41:53.360 is that much, or you think the risk is maybe greater than some do. And you're certainly somebody

01:41:59.580 who's in a position to evaluate both. So tell me where it fails. Is it a not enough benefit or a

01:42:05.840 too much risk problem? Probably. I'm not convinced about the, how much benefit for someone like me

01:42:12.380 who exercises especially, right? I mean, the best effect of metformin and it's still, it's

01:42:18.860 anti-diabetic effect. And you and I both know you lift weights, you run, you're active. You sort of

01:42:25.820 mimic the effects of metformin in many ways. Activates AMPK, you get the muscle benefits.

01:42:31.400 And so why should I take that? Now you could say, well, maybe for as an anti-cancer prevention agent,

01:42:37.480 maybe the data as an anti-cancer, we'll see where that pans out. There's a large scale trial that's

01:42:43.920 going to come out. Wait, you're not talking about TAME, are you? No, no, not. TAME is the anti-aging

01:42:48.500 trial. That won't be done for another five years. There's a breast cancer. Will that ever be done?

01:42:51.620 Yeah, I think so. I think so. But if you're healthy and you're active, it's hard to see why

01:42:57.400 you would take it. Now, of course you could argue that as you've aged, you've gotten some indication

01:43:03.600 that things aren't working as well. And therefore you should help take it as a compliment, whatever

01:43:10.600 loss you've had. Maybe you're a little diabetic, maybe. The one place I'm rethinking about metformin a

01:43:19.580 lot is whether it's a mild anti-inflammatory agent. So in other words, it sort of keeps

01:43:26.400 inflammation down all the time. And whether the effect of that over 20, 30 years, if you and I

01:43:32.540 are sort of in our 40s and that would have a benefit 20, 30 years later.

01:43:36.580 What's the mechanism by which, I'm glad you brought that up because I forgot to revisit it.

01:43:40.760 And you know, one of my favorite trials is the Cantos trial where they basically targeted IL-1 beta,

01:43:47.940 a pro-inflammatory agent directly. And it didn't change the lipid profile.

01:43:52.280 But it reduced cardiac mortality.

01:43:54.500 Exactly. Which tells you that inflammation is...

01:43:58.220 Oh yeah. And there's going to be another trial announced very soon that I think will show similar

01:44:02.620 results using low-doth and mesotrexate. Of course, I could be proved wrong and maybe that's not...

01:44:07.800 I don't know what the trial is going to show, but that's the hypothesis. Let's take as a fact,

01:44:11.880 just for the sake of time, that lowering inflammation has wonderful benefits. What's

01:44:16.260 the mechanism by which metformin will reduce inflammation?

01:44:18.580 So we think that reactive oxygen species, the free radicals, can serve as signaling molecules to

01:44:26.300 activate cytokines. And metformin, by inhibiting the respiratory chain, which is a major site of those

01:44:32.720 reactive oxygen species, decreases reactive oxygen species, and decreases cytokine

01:44:38.840 in production. And again, a little bit, right? It's not... It's a weak inhibitor of the respiratory

01:44:44.320 chain. So if you knock out the respiratory chain completely, you can never turn on the cytokines.

01:44:49.060 You've got a bigger problem.

01:44:50.140 You've got a bigger problem. You get a bacterial infection, et cetera. So this is just, again,

01:44:54.700 dampening it enough that if you get an infection, you can still respond. But just keeping the set

01:45:00.120 point where you're at a little bit lower, and whether that has good effects over 30 years,

01:45:06.040 20 years of keeping inflammation down, and then, you know, there may be some benefit to that.

01:45:12.840 So then one other place you might want to do it is if you live in Beijing or in Delhi,

01:45:17.780 because pollution increases inflammation. That's well known. It increases IL-6, right? So in those

01:45:24.500 sort of places, taking something that might decrease inflammation might be helpful.

01:45:29.840 And how robust are the data on the immune-modulating or inflammatory-modulating

01:45:35.320 benefits of metformin? Is that relatively... I mean, it's not as strong as the other stuff

01:45:39.240 we've talked about, is it?

01:45:40.080 No. No. I think it's not that many... There's not that many papers on it. It's,

01:45:45.480 you know, to be determined. But it's something that we're thinking a lot about as a mechanism

01:45:51.680 of why it might have anti-aging properties.

01:45:56.720 Well, look, speaking of anti-aging, let's go back to NAD, because we sort of skirted around a little

01:46:01.140 bit. Obviously, one of the most popular types of supplements being offered on the market today,

01:46:05.580 and there are several of them, are supplements that are aimed at delivering precursors to NAD

01:46:14.040 production. So again, the logic here is it's generally well regarded that cells can't take

01:46:19.960 up free NAD. They have to make their own NAD. Josh Rabinowitz and colleagues actually published a

01:46:26.240 paper in June of this year that demonstrated that the NAD must be made in the cytoplasm,

01:46:31.160 not in the mitochondria. And it's actually transported from the cytoplasm to the mitochondria.

01:46:35.200 And these supplements mainly went to the liver first.

01:46:38.240 Well, even before that. But just to explain the logic, the logic is you can make NAD from NR

01:46:43.780 or NMN. And NR and NMN exist in equilibrium, if I'm not mistaken.

01:46:48.240 And the de novo pathway, which is from tryptophan.

01:46:50.500 That's right.

01:46:51.000 As well.

01:46:51.680 So by giving these precursors, the cells can take those up and presumably make NAD there and get more

01:46:59.220 of that NAD into the mitochondria where presumably it, I think the main argument, if I'm not mistaken,

01:47:06.300 is actually not around the ETC, the alkaline transport chain, but more around having them

01:47:12.140 as cofactors for the sirtuins because the sirtuins, of course, play these two roles of

01:47:18.280 acetylating, deacetylating as gene regulators. They're basically turning on and off genes.

01:47:23.780 So I think the thinking is, and again, I don't want to speak out of turn. This is not my area of

01:47:26.980 expertise, but more NAD should be an important cofactor for sirtuins, which are a NAD dependent

01:47:36.020 histone deacetylases, HDACs. Is that, did I get that story mostly right?

01:47:39.800 Yeah, yeah, yeah.

01:47:40.340 Okay.

01:47:40.760 I mean, that's the simplest hypothesis. NAD levels decline in aging. You lose sirtuin activity

01:47:46.600 declines, which is not good.

01:47:48.660 Right, because you now lose the ability to control gene expression either on or off.

01:47:53.060 Boost the NAD as it's declining and you get a little bit increase in sirtuin activity.

01:47:58.020 Right, right. Which so totally makes sense conceptually.

01:48:00.260 I think what Josh did is a great experiment. He basically asked when you take these supplements,

01:48:04.900 where do they go? And a lot of it goes to the liver. Eventually it makes its way into other

01:48:09.380 tissues because there was this simple idea like it's going to get into the brain easily. It's

01:48:13.300 going to go to your heart. It's going to go everywhere and it's going to do exactly what

01:48:17.260 you said and therefore have all these magical properties. I think the place where NAD supplements

01:48:23.580 and metformin start to cross talk is two places. The first is it goes to the liver. So it might be

01:48:30.820 having some metabolically healthy effects on the liver like metformin and similar to like what

01:48:36.840 metformin does. Potentially, it's a hypothesis by the way. The second one is I think it gets into

01:48:42.000 immune cells. You think that NR, let's just make it simple and talk about NR because that's the

01:48:47.060 preparation that's more commercially available. You think that NR is being taken up by immune cells?

01:48:51.460 Potentially. But wouldn't Josh's paper contradict that? I don't remember if they looked at all the

01:48:55.380 immune cells. Well, I don't think they did, but isn't the takeaway from Josh's paper that the first

01:48:59.640 pass effect is so significant that all of the NR was getting taken up by the liver? But you know,

01:49:05.780 it still circulates in the blood, right? And your immune cells are in the blood. So I don't know.

01:49:10.680 And by the way, in Josh's paper, he also said that the liver, once it makes a downstream products

01:49:15.620 of NR, it distributes it back into circulation to the rest of the tissue.

01:49:18.860 What did it deliver? Remind me. Was it delivering NAD?

01:49:21.300 No, no.

01:49:22.320 It was delivering what downstream product?

01:49:23.820 I think it was NAM.

01:49:24.840 Okay.

01:49:25.260 Yeah, I don't remember.

01:49:26.320 And can NAM be taken up by the other cells?

01:49:29.080 Yeah, yeah.

01:49:29.460 And can NAM be worked? Can NAM work its way back?

01:49:32.460 I don't remember the paper, yeah.

01:49:34.100 I don't want to put you on the spot with something that's not in your world.

01:49:35.980 Well, no, it's not, you know, again, pathways.

01:49:38.240 I'll talk with Josh.

01:49:39.640 Talk to Josh. But I think the more simpler point is, is what I think Josh's paper is getting at,

01:49:45.940 and what you're getting at is, really, this stuff gets everywhere and has magical properties?

01:49:50.500 As in, he starts to argue, well, it goes on to the liver or only to certain tissues.

01:49:55.580 As in, I'm just arguing that a tissue, if you can call it, it's not really, but

01:49:58.980 a compartment that we don't think about enough of, whether it's with metformin or NAD supplements,

01:50:05.720 it are the inflammatory cells.

01:50:07.620 So what would an inflammatory cell, how would it benefit from having more NAD?

01:50:12.640 Well, I mean, again, for the same reasons, right?

01:50:15.200 The sirtuin reason?

01:50:16.120 Yeah, yeah.

01:50:17.560 Or some other NAD-dependent process in an immune cell that might be important.

01:50:22.100 And by the way, there is an enzyme that gets rid of NAD.

01:50:25.600 It's an NADase, basically, CD38.

01:50:27.840 It's most abundant on immune cells.

01:50:29.740 Yeah.

01:50:29.920 Yeah, so there's an immune connection there, clearly.

01:50:32.000 I didn't realize there was much CD38 off immune cells.

01:50:34.840 I mean, it depends.

01:50:35.820 Yeah, yeah.

01:50:36.140 No, I mean, I'm not disagreeing with you.

01:50:37.860 I just didn't know that.

01:50:38.420 Again, this is a little bit out of my wheelhouse, but I'm just speculating that there might be

01:50:42.760 a connection between these supplements as basically working as mild anti-inflammatory agents.

01:50:50.620 Now, of course, the other way that these things are typically delivered is through intravenous

01:50:54.920 NAD, which says, hey, you don't need to make it.

01:50:58.360 We'll give it to you.

01:50:59.320 We know you can't take NAD orally, so you have to do it intravenously.

01:51:02.640 There, I think it went everywhere in that paper, right?

01:51:04.880 But does it get into the cells?

01:51:06.880 Is there a cell that can take up NAD?

01:51:08.920 I don't think so.

01:51:10.520 But again, I don't remember, Josh.

01:51:12.640 You should, this is, I ask for the next podcast about, you know, we have stayed away from NAD

01:51:19.420 e-biology.

01:51:20.840 It's been quite a contentious field.

01:51:23.320 As you know, Josh and others are now doing really nice experiments.

01:51:27.000 We've avoided NAD.

01:51:29.440 What we haven't avoided is NAD to NADH ratio, right?

01:51:35.020 Because that's linked to complex one function.

01:51:36.920 Sure, that's what Metformin's tweaking.

01:51:38.560 And NAD to NADH ratio, to the best of my knowledge, isn't controlling sirtuins, or we don't have

01:51:43.800 great evidence for that.

01:51:45.280 NAD itself might be.

01:51:46.440 But what NAD and NADH ratio is doing biologically, or how does a cell process that ratio, is right

01:51:55.740 now probably the thing that keeps me up at night the most.

01:52:00.240 My favorite new theory of life as we know it, which is tied to that ratio.

01:52:05.700 Now, speaking of supplements, you alluded to one earlier, or I alluded to it, called MitoQ.

01:52:10.620 You, I'm getting a lot of questions from patients about this.

01:52:14.660 Should I be taking this?

01:52:15.480 Should I be taking this?

01:52:16.160 Should I be taking this?

01:52:16.900 Can you tell us what it is?

01:52:18.320 It's basically CoQ.

01:52:20.160 It's CoQ10.

01:52:21.520 So people take lots of CoQ.

01:52:22.840 What differs?

01:52:23.620 What does MitoQ differ from the regular CoQ10?

01:52:26.160 It has a cation attached to it, and because mitochondria are pumping those hydrogen ions,

01:52:34.500 they're quite negative in charge, like a battery, positive, and so it will take a molecule that

01:52:41.140 is very positively charged.

01:52:43.660 So by putting a cation on it, which is positively charged, you increase its affinity for the

01:52:47.700 cell?

01:52:48.020 Is that it?

01:52:48.360 Into the mitochondria.

01:52:49.400 Into the mitochondria.

01:52:49.920 Right.

01:52:50.060 The problem is the therapeutic window is very tight on that, because when we give MitoQ,

01:52:56.060 we can shut off a lot of ROS production, and all those beneficial stuff, gone.

01:53:01.720 So you put it on stem cell, stem cells don't renew.

01:53:04.660 You put it on immune cells, because they don't get activated.

01:53:08.480 And so I think, again, antioxidants get tough because they have normal biological roles.

01:53:15.620 And is CoQ considered an antioxidant, coenzyme Q?

01:53:18.480 The reduced form of it, which is ubiquitinol, yeah.

01:53:21.380 Yes.

01:53:21.980 And do you think, so therefore-

01:53:23.480 But they're hard, by the way.

01:53:24.800 You know this.

01:53:26.260 Super, super hydrophobic, right?

01:53:28.600 Yeah.

01:53:29.080 Most commercially available preparations don't even seem to have any bioavailability.

01:53:33.620 You can take a ton of them, and you can't measure it in the blood.

01:53:36.520 But there are potent ones that make their way into the blood, and you can measure those

01:53:40.700 levels.

01:53:41.060 I think the question is, is there benefit in that?

01:53:44.440 I, again-

01:53:46.300 Your view is no.

01:53:47.060 My view would be no.

01:53:48.520 And your view is it could be harmful?

01:53:50.020 I think a lot of these antioxidants have poor availability, so.

01:53:54.740 So when, you know, in the Peter Atiyah two by two is on the x-axis, you think about harm,

01:54:02.200 and on the y-axis, you think about benefit.

01:54:04.440 So, but to simplify it, even though these are continuous variables, you go with two categories.

01:54:09.060 So on the x-axis, which is harm, you think about picking something up in front of a tricycle

01:54:14.840 versus picking something up in front of a train.

01:54:17.480 Obviously, one has much more dire consequences.

01:54:20.760 And then in the benefit, it's picking up, you know, a Bitcoin versus a quarter.

01:54:24.540 And so do you view most of these antioxidants, CoQ10, MitoQ, as picking up quarters in front

01:54:30.740 of tricycles, where the upside, if they work, is probably not that big, but the downside

01:54:36.000 is also probably not that big?

01:54:38.200 Yeah.

01:54:38.700 And do you put a metformin in that category, or do you think metformin has more potential?

01:54:41.880 It has more potential.

01:54:43.000 But you still don't take it?

01:54:44.140 I still don't take it.

01:54:45.200 So you think metformin is potentially picking up a Bitcoin in front of a train?

01:54:48.700 Maybe.

01:54:49.640 Time will tell.

01:54:50.980 Time will tell.

01:54:51.720 I mean, you know, people are now doing clinical trials with metformin for anti-cancer.

01:54:55.980 I mean, clearly, it's still one of the first-line antidiabetic drugs.

01:55:00.060 And people are now running them through inflammation models.

01:55:03.320 We've done some interesting work around pollution and metformin, which I cannot comment on.

01:55:07.920 So there's a lot of interest beyond the antidiabetic effects of metformin.

01:55:13.140 And we'll see how it plays out.

01:55:15.780 From our point of view, we want to really nail down, is it by inhibiting mitochondrial complex

01:55:20.380 one?

01:55:20.760 Yeah, that's super elegant stuff.

01:55:22.760 So you got to go back and do the experiment we talked about with the UCA.

01:55:25.800 No, we're making, you know, we've made mice and all of this.

01:55:28.620 So we're doing that.

01:55:30.400 Just to finish, I know time is probably, we've probably gone over as always.

01:55:35.860 But so in my world, those raws for mitochondria are beneficial.

01:55:40.240 And you don't, you know, there's not, I'm not sure if there's a window where antioxidants

01:55:44.980 get in to really scavenge them.

01:55:47.520 So they're, I don't consider them harmful, Peter, right?

01:55:50.500 For that reason.

01:55:51.520 So generally, raws are good.

01:55:53.980 Again, very contrarian, but this is where the data is taking us.

01:55:57.300 So when is metabolism bad?

01:55:59.220 So my favorite new theory, which this is what I'm really excited about.

01:56:03.480 And I'm hoping somebody will give me lots and lots of money to test this because it's

01:56:08.360 a way out there.

01:56:09.360 So if you think back about what causes pathologies like neurodegeneration, even diabetes, the big

01:56:15.980 idea for 20 years has been that proteins get misfolded or they aggregate.

01:56:21.920 The idea of what's called proteotoxicity.

01:56:25.340 Let's clean up bad proteins.

01:56:27.360 So now they've done some trials in Alzheimer's and Parkinson's.

01:56:31.500 It hasn't quite worked out.

01:56:32.700 But, you know, again, maybe they caught him too late.

01:56:35.240 Yeah, that's my argument.

01:56:36.720 Yeah, yeah.

01:56:37.520 So I don't have a problem with the theory.

01:56:38.840 I think it's a nice theory.

01:56:39.840 I still think, you know, proteotoxicity is a real phenomenon.

01:56:43.280 It causes diseases, all that good stuff.

01:56:45.620 But what if, which is not a mutually exclusive idea, what if there's metabolite toxicity?

01:56:52.480 What does that mean?

01:56:53.240 And that means that certain metabolites that are normally found and at low levels and they

01:56:57.860 do normal functions, if they rise, they can incur pathology.

01:57:03.180 So what's the evidence for that?

01:57:04.720 Well, this is where inborn errors of metabolism come in.

01:57:07.660 So there are, unfortunately, people have genetic mutations and metabolic genes and those pathways

01:57:13.560 get altered and some metabolite increases or decreases is, and that's causes major pathology.

01:57:21.260 So we know that metabolites are at a certain threshold are sufficient to cause pathology

01:57:29.600 based on inborn errors of metabolism.

01:57:32.380 And so why couldn't it be that in Alzheimer's, we have a particular metabolite or metabolites

01:57:38.060 that increase due to the tau and all the amyloid plaques that people talk about, and those

01:57:43.580 then are causing neurodegeneration?

01:57:45.720 Again, not mutually exclusive.

01:57:47.240 Not mutually exclusive.

01:57:48.420 It's just a different way of thinking about it.

01:57:50.240 So one way you test it is, you know, someone's got to give me money to do this, but you

01:57:54.280 start screening metabolites in mice and rats and people and see if you see signatures.

01:58:01.080 And if you see certain signatures and you say, so I have one right now that I'm very interested

01:58:06.480 in.

01:58:06.660 It's called L2-hydroxyglutarate, L2-AG.

01:58:09.260 And I know that if a human has a mutation in a pathway that can't get rid of L2-AG and it

01:58:16.100 starts to accumulate, they get neuropathology.

01:58:19.600 So could L2-AG be elevated in Parkinson's and in Alzheimer's?

01:58:23.640 What's so cool about L2-AG, and this is going to wrap everything up from the start, is if

01:58:28.680 mitochondria are not working, are not functional, the respiratory chain is not working, then NAD

01:58:36.920 goes down and NADH goes up and it will trigger L2-AG.

01:58:43.140 That's the key trigger.

01:58:45.200 When NADH goes up and NAD goes down, L2-AG gets made.

01:58:50.960 So is this why you don't take metformin?

01:58:52.860 No, because metformin is a weak...

01:58:55.640 So this ratio has to change a lot.

01:58:57.220 This ratio has to change a lot.

01:58:58.380 So for example...

01:58:59.160 Are there physiologic conditions under which that ratio changes that much?

01:59:02.120 Hypoxia.

01:59:02.780 Aha.

01:59:03.700 And under hypoxia has been shown that L2-AG levels actually increase and they can then

01:59:08.200 function as a signaling molecule.

01:59:10.040 So here is more where the organelle mitochondria is completely dysfunctional.

01:59:14.880 So complex one loss has been correlated with Parkinson's dopaminergic neurons not functioning.

01:59:21.940 And so is L2-AG elevated there?

01:59:26.500 So have you looked at, you know, the other patient population you should study this in

01:59:31.020 would be patients who undergo circulatory arrest in cardiac bypass.

01:59:35.620 So you're going to see, or even frankly, just bypass.

01:59:38.600 Because they're so hypoxic?

01:59:39.620 Yeah.

01:59:40.020 Yeah.

01:59:40.460 It'd be interesting to see, you know, quote unquote, this idea of pump head.

01:59:43.180 Can it be explained through any of this stuff?

01:59:44.760 Well, so one other thing that I like about this is that's an acute event, I think.

01:59:50.380 We don't see it acutely.

01:59:51.240 So you inhibit complex one and the NADH goes up, NAD goes down, and a real severe inhibition.

01:59:58.240 It takes a long time for that to accumulate.

02:00:02.800 How long?

02:00:03.480 In cell culture with complex one, not 24 hours, a couple of days.

02:00:07.840 And, you know, so you could imagine, let's just play fantasy here, you get loss of complex

02:00:15.180 one slowly in a dopaminergic neuron, which causes results in Parkinson's.

02:00:20.500 And then slowly, over years, you get this accumulation of this particular metabolite.

02:00:27.200 And that could then cause the pathology.

02:00:29.760 Again, I'm very interested in just testing the broad idea that metabolites can cause pathologies.

02:00:37.200 You know, like metabolite toxicity, like kind of like proteotoxicity.

02:00:42.280 Probably wrong, but at least it's original.

02:00:44.300 Well, I mean, it's just, I guess what the thing that would concern me is the ubiquity of the potential signaling molecules

02:00:54.480 and trying to identify like what the patterns are.

02:01:00.500 Or can, that's a, I mean, look, there are no problems worth solving that are easy.

02:01:05.460 So, but boy, you have so many variables in so many directions.

02:01:10.140 You don't just have the number of metabolomics.

02:01:12.140 You have the time series in which they occur relative to an insult.

02:01:15.540 And then the amount of exposure of each that's necessary to drive the disease.

02:01:19.640 It could be so easy to miss something with all of those variables, right?

02:01:24.420 Absolutely.

02:01:25.300 And that's why we're being very biased and going after this one.

02:01:29.180 Yeah.

02:01:29.680 Keep it simple.

02:01:30.960 Test that one.

02:01:31.660 But of course, we could totally miss it because there could be five other metabolites that might

02:01:35.860 go up that might be causing the pathology in synchrony, right?

02:01:39.380 But at least this one is tied to mitochondrial function.

02:01:43.000 And so when mitochondria are really dysfunctional, so we started with the powerhouse as people

02:01:49.880 would say, well, mitochondrial dysfunction, ATP goes down.

02:01:53.600 Okay.

02:01:53.980 I would say mitochondrial dysfunction.

02:01:55.700 Guess what?

02:01:56.740 L2AG goes up.

02:01:58.040 There's two hydroxyglutarate.

02:01:59.320 So interesting.

02:02:00.400 So it's a new way to think about mitodysfunction that I'm very interested in pursuing.

02:02:05.680 So last thing I just wrote down when we were talking earlier and I want to come back to it

02:02:09.140 is talk to me a little bit about cortisol and your views on it.

02:02:11.960 How does cortisol interact with the mitochondria?

02:02:14.020 Yeah.

02:02:14.380 Well, I don't know.

02:02:15.580 I see another one that I would love to work on.

02:02:17.680 So it's just a weird observation.

02:02:19.900 I don't know if you have this.

02:02:21.300 I mean, I think maybe in our circles, we have a lot of kind of type A personalities who exercise

02:02:28.440 vigorously.

02:02:29.040 They watch their diet.

02:02:30.700 They do all this sort of stuff.

02:02:32.240 I don't know anybody that does that.

02:02:34.080 No, you don't know anybody.

02:02:35.140 No one.

02:02:35.540 Nobody.

02:02:35.980 But I always wonder if they're stressing themselves out by being so careful about everything.

02:02:42.720 And you know me, I am the opposite.

02:02:45.200 You've seen me eat and drink.

02:02:46.880 Yeah, but you're pretty fastidious with your exercise.

02:02:48.980 You play soccer every day.

02:02:50.240 No, I do.

02:02:50.440 And I don't overeat.

02:02:51.720 And I do time feedings, right?

02:02:53.240 I still fast 12 to 15 hours.

02:02:55.820 Most days closer to 15 hours.

02:02:57.800 No, I do watch what I mean.

02:02:58.820 But what I'm saying is I know people who get very, very regimented about these things.

02:03:03.520 And it's like the marathon runners who, you know, the old line that they die, don't run

02:03:09.180 marathons.

02:03:09.900 Yeah, I was with a friend last night and he was joking about this exact concept.

02:03:14.180 And he was talking about his, he's an orthopedic surgeon.

02:03:17.140 He was talking about his partner or somebody he knows.

02:03:19.640 And he was like, the guy is so into yoga, but it's become, he's like, the way he described

02:03:25.940 it was really funny.

02:03:26.560 And he's like, he's stuck in traffic and he's like, I got to get to my fucking yoga

02:03:29.720 class.

02:03:30.080 Yes, exactly.

02:03:30.740 And it's like, yeah, no, no, of course there's the irony to that.

02:03:33.220 Right.

02:03:33.520 So, you know, your insulin levels might be fine and everything's fine, but you know, what's

02:03:38.060 your cortisol levels?

02:03:39.160 So I'm fascinated by cortisol.

02:03:40.840 In fact, I'm fascinated by, I would love for you to basically develop a very simple test

02:03:47.420 that you can sell at Walgreens where you take a prick of blood and you can do it as often

02:03:52.560 as you want.

02:03:53.280 And you tell me my thyroid and hormones.

02:03:56.060 You tell me my insulin, my glucagon, my estrogen, my testosterone, my dopamine, serotonin, and

02:04:03.100 obviously cortisol, right?

02:04:04.420 These five or six, seven things that I just said, because it's about a lot of biology or

02:04:10.420 physiology can be explained.

02:04:11.560 Yeah, we're just, we're not going to be able to get it that way because cortisol is mostly

02:04:14.880 bound to albumin and cortisol bonding protein.

02:04:17.200 So it's the free cortisol that exerts its metabolic effects and its physiologic effects.

02:04:21.480 And most of it's not free.

02:04:23.780 So you can only measure the free cortisol and saliva and urine.

02:04:27.160 And then the other, you know, of those other ones.

02:04:28.820 But you know what I'm saying?

02:04:29.680 Like, I would love to have those hormones at my disposal.

02:04:34.800 I mean, is my testosterone too low?

02:04:36.580 My estrogen too high?

02:04:37.680 This too high?

02:04:39.260 Insulin?

02:04:39.800 You know what I mean?

02:04:40.120 Just having that data points all the time.

02:04:42.520 And then you could sort of modify your diet and your exercise.

02:04:46.340 But I think the cortisol one is, I pay more attention today to stress as than anything

02:04:53.720 else.

02:04:54.220 I'll be honest with you.

02:04:55.360 I mean, I still exercise and I watch what I eat.

02:04:57.960 Those things seem intuitive because I've done it for so long.

02:05:01.640 But I've been wondering if myself and many of my colleagues, especially because, you know,

02:05:05.800 we fly, give talks, you have grand pressures, a teenager daughter, she's lovely, lots of different

02:05:12.360 pressures we all have, right?

02:05:13.640 And if that somehow is being manifested metabolically through cortisol, to the mitochondria, just

02:05:19.320 like we think about insulin, right?

02:05:20.640 So that's all.

02:05:21.380 That's the only reason I want to talk about cortisol.

02:05:23.860 No, I think I agree with that wholeheartedly.

02:05:25.960 I think certainly in the last three years, as I've dug my heels into it, I think hypercortisolemia

02:05:31.240 is a problem.

02:05:33.040 And I think, I wish people would think of these hormones through more broad endocrinologic

02:05:38.920 terms.

02:05:39.380 You know, it's, it's very easy for people to think of hypo and hyperthyroidism.

02:05:43.640 We accept those as states.

02:05:45.940 You can be euthyroid or you can have too much or you can have too little.

02:05:49.540 And yet people have such a hard time thinking of insulin in those terms.

02:05:53.080 You can have too much, you can have too little.

02:05:54.640 There's a range in which this hormone makes sense.

02:05:57.060 And cortisol is probably equally important, if not more important in terms of the damage

02:06:04.020 that can be done, especially from too much with respect to everything from blood pressure,

02:06:09.060 which would then impact the endothelium, what it does in terms of inhibiting melatonin

02:06:13.700 secretion in the brain.

02:06:14.940 And melatonin obviously plays an immediate role in terms of sleep, but also plays an indirect

02:06:19.740 role in terms of neuro regeneration.

02:06:22.080 So, and that says nothing about what we just talked about, which was the role that cortisol

02:06:26.300 may even play in the mitochondria, which I'm just learning about, you know, literally in

02:06:30.000 the past couple of months.

02:06:31.360 So I don't disagree.

02:06:33.300 I think the challenge in many ways for anyone listening to this, if we're going to be brutally

02:06:37.980 honest, I think for many people, it's easier to control what they eat, how they exercise

02:06:43.660 and exert discipline around taking medications, taking supplements.

02:06:47.160 But in many ways, one of the hardest things to control is our response to stress.

02:06:51.540 And I think that's an important distinction to make.

02:06:53.420 I don't think there's anything that's particularly troubling with being in stressful situations.

02:06:57.820 I think the difference is less about the situation you're in and more about the response you have

02:07:03.320 to it.

02:07:04.020 And that's probably where the greatest differences lie between people is there are some people

02:07:07.820 who can be in relatively low stress situations, and yet they're sort of, they're not reacting

02:07:14.800 well to it.

02:07:15.800 They're not coping with it well.

02:07:17.460 And there are others who can be-

02:07:18.980 They have different set points where they begin from.

02:07:21.260 Maybe.

02:07:21.740 I mean, I guess I just don't understand enough of this stuff.

02:07:24.360 I mean, I think-

02:07:26.100 But it's, I don't, you know, I don't hear too many people talk about it.

02:07:29.440 I don't know.

02:07:30.000 I think it's-

02:07:30.720 No, people talk about stress, but sort of, like we talk about insulin all the time

02:07:35.920 and glucose levels and for men, testosterone, women-

02:07:39.180 You mean sort of in longevity circles?

02:07:40.720 Yeah, in longevity circles, like, you know, is that a variable we're missing, you know?

02:07:46.140 No, I agree.

02:07:47.340 That's all I'm saying.

02:07:47.720 You're right.

02:07:48.360 You know what it is?

02:07:49.180 I'm just pitching cortisol.

02:07:49.780 Well, part of it is we don't have a target for it, right?

02:07:52.020 No one's thinking about pharmacologic ways to manipulate this.

02:07:55.180 And we don't have great obvious ways to curb our behaviors.

02:08:00.240 Like meditation probably is the single most valuable thing I've ever found to help regulate

02:08:04.240 this.

02:08:04.600 But you also don't have the ability to measure cortisol levels that easily.

02:08:08.000 Every time you want to do one of these tests, it's, you know, you're collecting urine over

02:08:11.600 the course of a day and doing a bunch of other things.

02:08:13.700 So it's just, it's involved.

02:08:14.920 You don't have the-

02:08:15.740 Glass of wine?

02:08:16.780 Yeah.

02:08:17.200 You know, it's really funny.

02:08:18.020 I mean, I think there was a paper that came out probably about three months ago that looked

02:08:21.700 at, basically the punchline of the paper was, look, at any dose, alcohol is toxic.

02:08:26.540 But, you know, if you look at those events, it's like 950, 100,000 to 954.

02:08:31.900 The point of it is there's no dose of ethanol where the ethanol becomes valuable, but the

02:08:36.500 toxicity takes a while to kick in.

02:08:38.460 So, you know, for some people, a glass a day seems perfectly reasonable.

02:08:42.520 There's no toxicity.

02:08:44.840 But the flip side of it is, and this is where I kind of try to have this discussion with

02:08:48.560 every patient is, look, I'm not going to tell somebody not to drink.

02:08:52.020 I mean, I'm not going to tell myself not to drink.

02:08:53.460 I probably have four drinks a week.

02:08:55.340 And, you know, I pick and choose my shots.

02:08:57.480 You know, I have this rule called don't drink on airplanes because the alcohol on airplanes

02:09:00.400 sucks.

02:09:00.820 So I'm not drinking alcohol just for the sake of drinking alcohol.

02:09:03.520 But if you're sitting there and the alcohol is really great and it's something you really,

02:09:06.700 the downside of the ethanol, the hepatic toxicity of the ethanol can be offset by the

02:09:12.980 emotional benefit that could come from the enjoyment of having that glass of wine with

02:09:16.560 your buddy.

02:09:17.160 That brings me to another one of those things we should always measure, ALT, you know, the

02:09:21.160 liver enzymes.

02:09:22.800 I agree.

02:09:23.540 How well your liver function.

02:09:24.500 How's your ALT this morning, by the way?

02:09:26.400 It's pretty good.

02:09:27.580 Yeah.

02:09:28.780 I haven't checked it.

02:09:29.860 And so I think we're almost at the end.

02:09:34.180 Yeah.

02:09:34.420 Yeah.

02:09:34.780 So I have one question for you to sort of wrap it up.

02:09:38.860 Wait, I didn't think that was part of the rules.

02:09:40.500 Well, it is because I'll tell you why.

02:09:42.720 So when I interact outside of the scientific circles, if I'm at a dinner party, if I'm at

02:09:49.040 a bar, if I'm on an airplane and whoever I'm engaging with, they ask me, like, what do

02:09:56.360 you do?

02:09:57.700 Now, if I say I am technically my title is professor of medicine and cell biology.

02:10:02.280 If you say that, they think, oh, you teach something.

02:10:04.980 And I do indirectly, but what we do is research.

02:10:08.760 So if I just say I do research or if I say I'm a scientist, they go, oh, well, that's

02:10:13.200 nice.

02:10:13.740 But the minute I say I'm a metabolism scientist, it's like they light up and they want the next

02:10:23.320 question, which is?

02:10:24.400 What should I eat?

02:10:26.540 You got it.

02:10:27.480 But wait, can I ask you a question?

02:10:29.300 Given that you know that that's going to happen, when you go to parties, do you go out of your

02:10:33.320 way to make sure that you don't prime people for that question?

02:10:36.540 Or do you enjoy being asked that question?

02:10:38.480 I think I enjoyed being asked that question initially as a way to tell people, look, science

02:10:47.320 is cool.

02:10:47.960 Metabolism is cool.

02:10:49.140 You know what I mean?

02:10:49.540 Sort of not think, there's this image that people have about scientists.

02:10:55.840 As you can see, I'm pretty flamboyant.

02:10:58.640 So I figure, you know, something that they can relate to as a common language.

02:11:02.800 But now I regret it because all I hear about is what should I eat?

02:11:08.480 What should I eat?

02:11:09.100 Oh, yeah.

02:11:09.580 So let me give you a piece of advice on this now.

02:11:11.960 So first of all, I have the same problem whenever I'm in a situation, could be a wedding, could

02:11:16.480 be a funeral, could be a party, doesn't matter.

02:11:19.540 So I've learned that there are two, I have two go-to things that I tell people I do for

02:11:25.220 a living.

02:11:25.880 And I know enough about each of them that I can almost never get called out.

02:11:32.500 And the good news is both of these generate almost no follow-up questions.

02:11:37.940 Now, the difference is you're an extrovert and I'm an introvert.

02:11:40.360 So you at a party would like to talk to people.

02:11:43.180 I, on the other hand, don't.

02:11:44.540 I don't like to go to parties, but if I'm dragged to a party, I don't, I don't want to

02:11:50.220 be at parties.

02:11:50.760 I don't want to be at happy hours.

02:11:52.120 I don't want to be around anybody except two of my friends at a time sort of thing.

02:11:56.040 So I just tell people, I shouldn't admit this now because now if somebody hears this, they'll

02:12:00.740 know my trick.

02:12:02.760 All right.

02:12:03.180 I'm not going to say it.

02:12:04.180 Oh.

02:12:04.600 I'm not going to say it.

02:12:05.260 You're going to leave them hanging.

02:12:06.380 I'm going to leave them hanging.

02:12:07.000 But I have two awesome alter egos that whenever I'm at, and I, in fact, I busted one out last

02:12:13.120 night.

02:12:13.980 I was at a dinner thing last night.

02:12:15.760 I didn't know people.

02:12:17.380 And there were a lot of doctors there.

02:12:19.500 And there was a lot of butt sniffing, which always happens at doctor parties where everybody

02:12:23.460 wants to sniff everybody else's butt.

02:12:25.240 You know, it's like kind of the dogs, you know, walking around, sniffing each other's butts.

02:12:28.200 And there was a lot of, what do you do?

02:12:29.720 Oh, I'm the chairman of this and I'm the chairman of that.

02:12:32.140 And I, I am the head of this and blah, blah, blah.

02:12:33.960 And then they looked at me, what do you do?

02:12:36.040 And I just said, I'm a, and I said it.

02:12:38.300 And it was amazing.

02:12:39.760 The crickets are chirping.

02:12:42.080 Everybody is like, they don't know what to say.

02:12:45.020 And they said collectively nothing.

02:12:48.160 And then the discussion just went elsewhere and it was awesome.

02:12:51.920 I didn't have to talk about anything.

02:12:53.680 So, so I do give an answer and, and I want you to tell me if this is the right answer

02:12:59.420 or the wrong answer.

02:13:00.280 I still liked, and I know it got debunked a little bit.

02:13:04.380 I still liked the Mediterranean diet.

02:13:06.660 Yeah.

02:13:06.940 I mean, I mean, not, I mean, with curry.

02:13:09.320 Okay.

02:13:09.960 Hey, but generally that kind of died with nuts and avocados.

02:13:14.040 Well, when you say debunked, I mean, I'm not even sure I would agree on it.

02:13:16.680 No, I don't think it has.

02:13:17.560 But you know what I mean by that.

02:13:18.340 What you're referring to is the Pratamed study, which I'm guessing many people listening to

02:13:22.660 this will know what that is.

02:13:23.520 But in case somebody's not, we'll certainly link to it.

02:13:25.720 But this was a study that randomized something in the neighborhood of 7,500 patients, although

02:13:29.720 we'll come back to the word randomization.

02:13:31.340 I'll put a little asterisk beside that, uh, into three groups, about 2,500 patients per

02:13:35.340 group.

02:13:36.000 And they were randomized in a one-to-one-to-one fashion between a Mediterranean diet that was

02:13:41.120 high in extra virgin olive oil, a Mediterranean diet that was high in nuts and, and, and,

02:13:46.040 and a low fat diet.

02:13:47.540 And this was a primary prevention study, which makes it a very difficult study to do, especially

02:13:51.960 with nutritional therapeutics.

02:13:53.380 And the study was stopped early.

02:13:54.860 It was stopped at about 4.7 years, if my memory serves correctly, because the both Mediterranean

02:13:59.680 arms were outperforming the low fat arm.

02:14:01.680 Now, I used to view that as one of the more interesting studies ever done in nutrition,

02:14:06.220 because nutrition studies generally suck.

02:14:08.080 It did have one major criticism that didn't get any attention at the time of the initial

02:14:12.400 publication, which I think was 2014, maybe.

02:14:15.100 And that was the performance bias.

02:14:18.320 So the groups that were getting olive oil and nuts had those products sent to them.

02:14:24.640 The low fat group, to my knowledge, did not receive anything.

02:14:27.660 Didn't get food given to them.

02:14:29.180 Well, that creates the potential for a difference in behavior.

02:14:32.960 And that's problematic.

02:14:34.280 That's very problematic in clinical trials where you can't blind anyone.

02:14:37.940 But the more recent issue, the one that I think you're referring to, is some irregularities

02:14:44.560 popped up in their randomization.

02:14:46.640 So some people doing post hoc analyses found, hey, these numbers don't make sense.

02:14:52.020 It's very improbable that these people were all randomly assigned.

02:14:56.820 And I believe, because it's been a while since I read the correction, that what they identified

02:15:01.740 was that a number of those patients were not randomized correctly.

02:15:03.940 For example, and it wasn't nefarious, but it was done through convenience.

02:15:07.160 So if you had a husband-wife team in the study, they were immediately put on the same diet,

02:15:12.940 which, by the way, is logical.

02:15:14.900 That's actually a better study design.

02:15:16.780 But you have to then change the statistics to accommodate for that because you have no

02:15:21.760 longer randomized each of those individuals.

02:15:24.020 They would be considered one randomization, not two.

02:15:26.960 To the best of my knowledge, even when you take into account those changes or those inconsistencies

02:15:33.100 or those methodologic failures, I don't believe it changed the results or the outcome of PREDIMED.

02:15:39.260 So we're still back to the initial limitation of were those representative diets and were

02:15:45.520 those subjects, victim for lack of a better word, but the victims of a performance bias.

02:15:50.700 So all that said, look, I think the Mediterranean diet, which is unfortunately not a very descriptive

02:15:56.260 term because what the hell is a Mediterranean diet?

02:15:58.740 Is that what people eat in Italy, Egypt, Greece, Spain?

02:16:02.400 Like, I mean, so I guess the only opposition I would take to the concept is I don't, I like

02:16:08.860 to be more specific in my description of the diet.

02:16:12.160 What I dislike is high protein or a high carb or a high fat diet, like people love.

02:16:18.780 So the high protein people like is they want to look like a South Beach model essentially

02:16:21.800 as far as I can tell, because you can lose weight.

02:16:25.160 You know, the high carb, we know you've talked about it all the time, why that's bad.

02:16:28.560 And, you know, sort of the ketogenic diet, I mean, it has some benefits maybe for the

02:16:33.400 brain and other systems, but, you know, it does make you insulin resistant.

02:16:37.180 I mean, there's data in mice.

02:16:39.040 Well, I would take issue with those data though, right?

02:16:41.340 So are there data that ketogenic diet make mice insulin resistant?

02:16:45.280 I don't think there's hundreds of studies in mice that people have done.

02:16:49.000 And so my favorite one, I think you should, I sent it to you where they looked at a whole

02:16:53.860 bunch of diets.

02:16:54.740 And essentially the best one was sort of a one third, one third, like 20% protein, because

02:17:00.460 we can both agree if there's too much protein, your mTOR might be quite active if you need

02:17:05.960 enough for your muscles.

02:17:07.020 But this is, again, not in the elderly.

02:17:09.160 So again, not with the disease.

02:17:10.860 This is just primary prevention that we're talking about in healthy sort of 40 somethings

02:17:15.580 to start with.

02:17:16.140 And so it was relatively not high in protein and it had about 40, 50% carbs almost, I think.

02:17:24.680 This is a mice study.

02:17:25.840 And then the rest was sort of the good fat, you know, avocados, nuts and stuff like that.

02:17:30.320 And so I sort of liked that diet because it was a pretty good study in cell metabolism published

02:17:35.260 on these mice.

02:17:36.220 And to me, intuitively, some of this makes sense.

02:17:40.560 And so, you know, keeping protein not too high because you want to keep mTOR down.

02:17:44.440 Is that the paper that Simpson was the last author on?

02:17:47.400 Yeah.

02:17:47.800 Stephen Simpson, I think.

02:17:48.940 Maybe there was like-

02:17:49.880 He's Australian.

02:17:50.600 Yes, yes.

02:17:51.060 There was 25.

02:17:52.860 Again, I don't think there's a clear answer to this, but, you know-

02:17:57.280 Rather than answer the question, let me tell you my two cents on this topic.

02:18:00.420 One, I don't have a lot of interest in mouse studies for human nutrition.

02:18:04.340 I struggle with them because I think there are so many other issues going on that it's very

02:18:08.680 hard to make that-

02:18:09.720 That's a fair point.

02:18:10.300 The second thing is I always want to be sure that I'm distinguishing between short-term

02:18:14.960 insulin resistance and long-term insulin resistance.

02:18:16.940 So I think you're right.

02:18:17.860 In the short run, ketogenic diets in a non-trivial subset of people generate profound insulin resistance

02:18:24.720 in the muscle.

02:18:25.960 Again, I don't even know what insulin resistant means if we're going to be truthful.

02:18:29.000 Like if we were going to put me in the confession booth, I don't have a goddamn clue what that

02:18:32.300 term even means.

02:18:33.180 It's so ubiquitous.

02:18:34.220 Does it mean the failure of one type of cell but not another type of cell to respond to

02:18:40.100 insulin signaling?

02:18:40.860 I mean, all of these things.

02:18:41.440 But I think I know what you mean.

02:18:42.920 You can see huge elevations in glucose and insulin and basically a complete refusal of

02:18:48.680 the muscle to accept glucose in someone on a ketogenic diet when they first encounter a

02:18:53.460 carbohydrate.

02:18:54.860 But I think it's generally also regarded that after about three days of carbohydrate refeeding,

02:18:58.860 that effect goes away and that that effect is sort of a physiologic response to an individual

02:19:04.580 who's been so carbohydrate deprived that their muscles are basically saying any glucose in

02:19:09.880 the system we're going to preferentially save for the brain since we now have all the fatty

02:19:15.060 acids and beta-hydroxybutyrate in the world we need as metabolic substrate.

02:19:19.380 So the short answer is, I don't know.

02:19:21.160 These days I find myself far more interested in fixating less on the exact amount of this

02:19:28.440 micronutrient or this macronutrient or that micronutrient and more on the complete deprivation

02:19:32.920 of calories for more prolonged periods of time.

02:19:35.140 So, you know, people who are used to following me these days, I'm spending much more time

02:19:38.580 thinking about fasting than I am sort of sticking on one diet and sticking to it.

02:19:43.460 Yeah.

02:19:43.700 So I basically eat a third of my calories probably from fat, carbs, and protein.

02:19:50.040 And then the other thing is just the 15-hour fast every day.

02:19:53.000 But if you're getting a third from protein, that's probably quite a bit.

02:19:55.900 Probably, I think.

02:19:57.200 Probably have to lower that.

02:19:58.080 I'm going to have to check your, check your tour activity.

02:20:00.780 Well, maybe, maybe a third is too much, but yeah, I mean, I eat a fair amount of protein

02:20:06.340 probably, you know.

02:20:07.560 At the parties, tell them you're a math professor.

02:20:11.000 They won't ask you any more questions.

02:20:12.720 I don't remember any math, then we'll leave it at that.

02:20:14.800 Yeah, but hopefully they won't ask you the questions.

02:20:17.220 No, I'm an extrovert and I like talking about metabolism, but I just, I don't have a good

02:20:20.700 answer on the diet.

02:20:21.580 I have lots of answers on mitochondria and all that.

02:20:23.880 But then just tell them you're, tell them you're a mitochondrial expert, but don't use the

02:20:27.260 word metabolism.

02:20:27.960 Yeah, but then people really look at you like, oh.

02:20:32.400 Anyways.

02:20:33.060 Hey man, thank you so much for taking the time to talk about all this stuff.

02:20:36.300 I had written down a bunch of things I wanted to talk about and I think we actually got

02:20:38.860 through like half of them.

02:20:40.880 Oh, only?

02:20:42.540 Okay.

02:20:43.420 Well, but that's the nature of this stuff.

02:20:44.780 It's so fun.

02:20:45.320 There's so many rabbit holes to go down.

02:20:46.620 And in particular, I really loved the double, double click deep dive on metformin, which

02:20:50.840 is something I think a lot about myself.

02:20:52.580 Hopefully once we have some results and there's more clinical trials, we can come back and we

02:20:58.460 can really talk about some more answers.

02:21:00.640 All right, man.

02:21:01.160 Thanks.

02:21:01.640 Thank you.

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The Peter Attia Drive - December 03, 2018

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

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