Mind & Matter
Mind & Matter
Cell Biology of Aging, Mitochondria, Metabolism, Autophagy & Stress | Andrew Dillin | #155

Cell Biology of Aging, Mitochondria, Metabolism, Autophagy & Stress | Andrew Dillin | #155

Download, watch, or listen to M&M episode #155

About the guest: Andrew Dillin, PhD is Professor of Molecular & Cell Biology at UC-Berkeley and Howard Hughes Medical Institute investigator. His lab studies mechanisms of aging, mitochondrial biology, and related subjects.

Episode summary: Nick and Dr. Dillin discuss: cell biology; mitochondria & the endoplasmic reticulum; aging & autophagy; mitochondrial biology in neurons; diet, exercise, and oxygen effects on mitochondrial health; and more.

*This content is never meant to serve as medical advice.


Full AI-generated transcript below. Beware of typos & mistranslations!

Andy Dillin 2:25

Thanks for having me. Nick.

Nick Jikomes 2:26

Can you give everyone just a brief overview of what you do? And what your lab studies?

Andy Dillin 2:32

Yeah. It's, it's a really interesting group of people that I work with. And we're we've sort of stumbled across a really interesting set of findings where we've uncovered that if you have different Seiler stress responses, if you engage them the right way, they can increase lifespan and healthspan and improve a lot of different things. And that was very exciting. But the really cool thing is you only have to engage them in the nervous system. And once they're engaged, they're the nervous system takes over and sort of coordinates this across the rest of the organism. And so for the last 20 years, we've been trying to figure out what that coordination is and what it looks like, and who's doing the coordinating. And, you know, evolutionarily, why would this evolved this way? You know, why doesn't every cell just set up its own stress response? And so on ability to do this? Why does it have a mass for cell types coordinate this?

Nick Jikomes 3:33

Yeah, so So you've studied so so the stress response, you know, in principle, you can imagine that each cell is almost like its own little island, it's going to age at its own rate, it's going to respond to whatever's happening right there to that cell. But on the other hand, you could also imagine that, you know, we are organisms with bodies, all of our cells have to be sort of aligned with a common interest in in survival and reproduction. So maybe there are mechanisms that allow full body communication across cells to coordinate stress responses and things like that. Before we get into some of the details there, I want to talk a little bit about some of the basic cell biology just to get people thinking about some of the the organelles and stuff that I think we'll talk about one very important organelle that many people have heard of, and maybe understand, you know, a slice of what these things do is the mitochondria. Can you just talk a little bit about mitochondria, what they are, and what they do, not only in terms of like, what what the average sort of biology student probably knows them for, but you know, the expanded list of important things they do?

Andy Dillin 4:40

Yeah, I think that's a great question. So first of all, I have to qualify that when I started my career. Number one, I never thought I'd work in mitochondria. And number two, I never thought I'd be labeled as a neuroscientist. But you know, it's, you just follow where the results send you and we discovered mitochondria in this pathway, and then it works in the nervous system. But to get your quote, you know, mitochondria, I mean, we all, you know, we hate saying this as mitochondrial biologists the powerhouse of the cell, that's what everyone recognizes them for, you know, the major energy producing organelle in your in your cell to produce to produce ATP, ATP, but also have a myriad of other functions. And when we think about that myriad of other functions, we need to actually go back and remember what mitochondria were. So you know, mitochondria were bacteria. And so billions of years ago, you know, one bacteria made another bacterium, and somehow the bacterium that got engulfed, figure it out to give up most of its genome to its hosts, and survive inside the host. And that happened, and it became a very symbiotic relationship. And that's how mitochondria evolved is out of that symbiotic event that happened. So,

Nick Jikomes 6:00

so one bacteria ate and other bacteria. And somehow, I imagine, we don't know exactly how this worked. But we know that the what became the mitochondria, that bacteria literally, like gave some of its genes to the host cell, and sort of that was like the deal. That's how alignment was achieved.

Andy Dillin 6:19

Yeah, the deal, you know, I think it had to be deals, plural, it had to happen over you know, over time giving up, you know, it didn't all at once give up 99% his genome, it probably did it, you know, over successive generations, but it's fascinating. You know, it's probably the most important biological event that happened on planet Earth, you know, is this ability of mitochondria to be in there, somebody, somebody else. And I was like, I would love to be able to go back in time and see how this event actually played out. Because it was probably tried many times, and it was unsuccessful, but you know, eventually became successful for for mitochondria. So in thinking about that, you know, he think about all the functions that a bacteria has, and you know, it has all of its other cellular functions. But also when it became a mitochondria, that was probably one of the first inner membranes inside of a cell. So of course, you know, you had the plasma membrane, but now you had an internal membrane structure. And so a lot of the cellular reactions that were happening inside of the free yoke you carry out before it got to mitochondria was happening in three dimensional space. But now you have a membrane to land on. Now, you can reduce those reactions down to two dimensions, because you can land on that surface and just control x and y coordinates. And so that probably like massively accelerated evolution, you know, us made reactions much more easier to attain. And so that allowed mitochondria to take on not just producing energy for the cell. But I mean, cholesterol synthesis happens there, iron biosynthesis happens. There's so many functions that mitochondria do. I mean, one of the major ones that we all know about is cell death, that organizes the death of a cell is that when things get really bad, the mitochondria recognize it first, and send out a signal to actually kill the cell. Is that actually an evolutionary thing from when it was a bacteria? Who knows? But there are all these things that mitochondria retained and gained as well when they became inside of the eukaryotes. And so I'm always just amazed, you know, we'll talk about some of the things that we've discovered that I'm still just sort of scratching my head saying, these mitochondria, you know, they were put inside of cells billions of years ago, they gave up most of their genome, but they retained 13 genes, couple T RNAs, yet they have so much control over the cell, but everyone's like, No, it's the nucleus, nucleus nucleus. But actually, the mitochondria are pretty darn important and actually drive a lot of cellular processes.

Nick Jikomes 9:00

And are they in every single cell of a multicellular animal like us? Yeah,

Andy Dillin 9:05

except for, you know, red blood cells that get rid of all the organelles? I see. But yeah, no, absolutely. And the this is also the most fascinating thing as well as that a mitochondria in your muscle cell looks very different than the mitochondria in your brain cell. So they've adapted, you know, they're adaptable to be whatever environment they're going to be in. They change the structure, they change their functions. You know, it's almost like these little aliens that are inside of us. And every single cell except for of course, the red blood cells.

Nick Jikomes 9:37

Yeah, I mean, and it is puzzling in one sense that you would see that much plasticity in something that has so few genes of its own, but I guess a lot of that is probably just coming from coordination back and forth with the nuclear genome.

Andy Dillin 9:49

Exactly. I mean, that is what everyone's begin to realize is that, you know, people always thought the mitochondria were their own entities, you know, functioning in the cytoplasm, but There's this massive communication that has these checkpoints going back and forth between the nucleus and the mitochondria. And definitely all of this stuff with the, you know, changing form and function and a cell type specific manner, is definitely coordinated by the nucleus, depending upon which energy status is required by the cell, what signaling events are happening, you know, what state the cells in what age the cell is, and, I mean, it's, I'm totally fascinated by mitochondria.

Nick Jikomes 10:29

Another I mean mitochondria, it just in the past few years, it seems they're becoming a hot topic, they're becoming way more famous than than they used to be, I think when when I was first a student, so we'll come back to mitochondria. Another organelle, that's really interesting, that I know far less about that I think is just talked about less is the endoplasmic reticulum, which we can just abbreviate to er, what is the ER, and what would be a very basic overview of what that part of a cell is doing?

Andy Dillin 11:02

Yeah, so in your cell, you're going to make new proteins. And the ones that are going to go outside of the cell, you know, to make the plasma proteins on the outside of the plasma membrane, or be secreted to talk to other cells all have to go through this structure, the endoplasmic reticulum. And that's sort of like the first processing center to know where to actually stick those proteins are they going to stay in some organelles inside the cell are they going to go actually outside. So the ER is like the, you know, the first processing center at the Amazon, you know, the big center where they sort out all the different orders, that's probably the way to think about the ER, it also has a really interesting evolutionary history, you know, it's mainly wrapped around the nucleus, it also extends out into the cytoplasm as well. And it's actually evolved to contact mitochondria and actually control mitochondrial functions. And so, you know, if you think about the nucleus, the ER, endoplasmic reticulum, and mitochondria, they're sort of working in concert, to create some form of homeostasis on energy production, protein production. And with that, which genes you're going to transcribe. So it's an interesting little trio that's working together.

Nick Jikomes 12:19

So so there's a lot of proteins that get made within a cell that actually gets shipped out to the plasma membrane of that cell, or just shipped out completely to go elsewhere to other cells or to get into the bloodstream or whatever. There is some processing that has to happen before they can do that the ER seems to be an important place for that. Can you give us a sense of like, what do we mean by processing there, what's happening to the proteins, what needs to happen to them before they can be shipped to the final destination?

Andy Dillin 12:46

Yeah, so I mean, the very first thing is they have to be imported into the Anaplasma curriculum. And they're they take on different folding states to determine if they're good enough that the soul made them good enough to send on to get further process and other organelles, such as the Golgi, to get decorated. So this is the beginning steps of, you know, we think of proteins is just the line of amino acids. But actually, what happens to the cells is that line of amino acids actually gets modified in many different ways. And in the secretory process, that getting proteins out of the cell, they get decorated with sugars, or like muscle groups. And there's a vast array of enzymes that do this, and the, I don't know enough about it. But there's enough, there's a whole set of enzymes that put on different decorations, that can signal different things to the outside of the cell, sorry about that, the signal different things the outside of the cell, and actually protect these proteins from the, you know, the bad things are on the outside of cell proteases, and things of that nature. So there's a whole bunch of modifications that actually occur.

Nick Jikomes 13:58

I see so so when our cells make proteins, you know, they're using DNA to ultimately make a sequence of amino acids. But that sequence of amino acids gets folded into a higher order structure that may or may not go perfectly. So there's quality control checkpoints built into this whole process to make sure the folding happens properly. Before these proteins, at least some of them get decorated with sugars and other things, then the reason they have all of these sugars and other things, sort of stapled or stitched to the outside of them has to do with things probably like their I would I would imagine that helps the cell know where to ship these things. It affects their longevity out in the environment, how stable they are, etc.

Andy Dillin 14:42

Yeah, absolutely. Absolutely. And then it also does structural things as well. So when they get to the outside of the cell, they actually serve structural properties. You know, there's massive sugar moieties that are added to proteins on the outside of the cell, either enormous Hyaluronic Acid is one of them. And it creates, you know, a several nanometer long fibers that actually decorate the outside of cell, which are thought, you know, to protect cells from invasion from pathogens, bacteria or viruses. So, I mean, the ear is a really important structure and, you know, over a third of the different proteins that are made actually go through the ER. So he said about a third, about a third. Yeah.

Nick Jikomes 15:25

And so what's the is the key difference there, whether they go through or not what you said before, related to whether or not they're going to be modified in order to be shipped outside the cell?

Andy Dillin 15:35

No, the first decision is made when the when the message is in the cytoplasm, and it is beginning to be translated. And if it has the right beginning amino acids, it partners with a molecule called SRP signal recognition particle, that drags it to the ER, and says, Oh, you have the right zip code, I'm going to put you into the now you're going to finish the rest of your translation, and actually be inserted into the ER.

Nick Jikomes 16:06

And so we talked about protein synthesis, the proteins can be modified with sugars. So there's, there's this is kind of one interesting part of cell biology, where are proteins and sugars are interacting? What about lipids themselves? So one thing I don't understand fully is, obviously, the cell membrane is made out of lipids, it's made out of fat molecules. Fats are, you know, they're components of other things as well. But where in the cell? are lipids being synthesized and packaged, and made and distributed? Like how does the cell you know, there must be a mechanism or mechanisms in place for it to construct its membrane and maintain its membrane? What is happening there?

Andy Dillin 16:50

I mean, that is also a major function of the ER is, you know, whether or not you're going to make a lipid droplet, that's going to stay in the state inside of the cell and be an energy source and a structural source for membranes, you know, for other cellular membranes, or if the lipid droplet actually stays inside of the ER, it becomes a Keiler micron that gets secreted out. And so, you know, you think about HDL and LDL is, you know, these lipid particles that we associate with hypercholesterolemia. You know, that's actually beginning in your EMR, making those kinds of microns.

Nick Jikomes 17:24

I see. So they're made in the cell, the ER is involved in the production of those things, and then they're secreted out. Exactly, exactly. Interesting. Okay, so well sort of keep keep some of those things in mind, I think we'll probably come back to the mitochondria in the ER in different ways. You've studied aging of the cell biology of aging. Before we sort of get into the discussion around aging, I want to ask you a vague question that I've asked many other researchers who study aging in all sorts of different ways. What exactly is aging? From your perspective as a cell biologist?

Andy Dillin 18:00

You know, that's a really interesting question. I actually just taught a class to our graduate students here yesterday about about aging. And I sort of view it, you know, I actually, we can all recognize what aging is, we all see it, we're all experts on it. You know, we're all we're all own internal experts on what aging is. But none of us really know what it is. And I've been studying it now for over 20 years. And I'm not sure I know what aging is, you know, I can recognize it, I can see it. And my best guess of what the process of aging actually is, is, you know, it's how well you built your system is that you know how well you put everything together until your time of reproduction, you know, you're sitting there maintaining your building, and then you're maintaining the structure. And once you're past reproduction, aging is really the rate at which that is probably falling apart. And, of course, you know, there's things that you can do to keep it from falling apart faster, you know, diet, exercise, sleeping, well, which we just talked about, I think are the three major things that we can do to help slow that decline. But I'm really under the feeling that it's really about how you build your system. And you know, as humans, we built our system pretty good. You know, we're in utero for nine months. And then it takes us a very long time to go through development, you know, after birth, to make a fully functional human. And so maybe that's why we live so much longer is that we've just built the system exceptionally well.

Nick Jikomes 19:42

And I would imagine so when we think about aging to you know, we already talked a little bit about how you know what the ER there's this. There are quality control mechanisms, right. So so cells are doing all sorts of things. There's a bajillion different mechanisms to do all of the things that are all of our cells are always doing But some of these mechanisms are specifically about making sure things are going right, making sure the proteins are made, right. And so I would imagine there are certain parts of cell biology, certain mechanisms that play an outsized role in things like aging, because if they break a bunch of other things that they regulate, then start braking. Right?

Andy Dillin 20:23

Yeah, I mean, it's, it's, you know, I love working on these quality control pathways. Because they're, they're ensuring the integrity of an entire system. So you know, we work on a quality control pathway for the mitochondria called the unfolded protein response. And its sole job, sole job is to monitor how well the mitochondria is functioning. And the mitochondria, you know, it's like 2000 different proteins, a bunch of membranes. And you have one system that is sitting there monitoring the integrity of all that. And so you're, you're boiling down to 1000 components to setting it as just one the stress response system. And it goes down with age, it actually goes down, right when reproduction stops. And so you know, figuring out ways to trick it to get back going again, you know, we've done this and several other people have done this, it actually is very beneficial. It's, you know, it's not the end all be all, but it makes the mitochondria function better, makes them last longer, makes them do the things they're supposed to do longer and better. But does it cause like, 100% increase in lifespan? No. But it definitely, you know, increases a little bit, and it actually delays things significantly. It's not, you know, there's probably other pathways that are required for other parts of the cell really just fixing one part, that's mitochondria.

Nick Jikomes 21:42

So there's, there's somehow some of these mechanisms are tied to reproductive viability?

Andy Dillin 21:49

Yes. That

Nick Jikomes 21:51

makes intuitive sense, right. Like, ultimately, the purpose of living things. I mean, in some sense, you could argue that the definition of a living thing is that it's, it's a, you know, a biological entity subject to, you know, Darwinian evolution. That's how a lot of people think about it anyway. And so obviously, the currency, there's going to be reproductive success. Obviously, there's lots of clear examples in nature where, you know, when you're done reproducing, the organisms done, lots of insects operate that way, you know, salmon operate that way. And then obviously, there's a window in which organisms such as ourselves, and many other things, you know, they are reproductively viable. And that window eventually closes one way or another. But in what sense is reproductive viability tied to aging? And so what I mean by that is, is it? So let's imagine two individuals in a population, they both reach reproductive maturity at the same time, then one of them engages in, you know, say several rounds of reproduction, and one of them does not. So they're both developmentally at the same stage at the same time, but one of them is engaging in reproductive acts, and one of them isn't all other things being equal, would that affect the rate of aging?

Andy Dillin 23:02

Oh, man, you're bringing it you're opening a huge can of worms. So there's this classic paper, Nature paper? Let me think about the date. Probably 99, I want to say 9899. And the title of it barren aristocrats live longer. And so they did a retro retroactive study looking at aristocratic women that gave birth versus didn't. And so they're trying to control that, when, where, and when was this just like the 1617 1800s. Okay. And so they're trying to control for environment as best they can by only looking at the aristocrats or they're living, you know, the best life possible at that time. And they look at the women there that gave birth versus the women that didn't, and the ones that didn't give birth outlive the ones that did. So it's a fascinating study, what it means and is it been revisited, you know, modern days? I don't know if it has or not, but it's a fascinating study that, you know, I think there is a lot of costs, especially to women for childbearing. It seems like there's a lot of energy, stress, you know, the other things are happening to the body that would, you know, obviously shorten our lifespan. So you could argue that that's why the barren aristocrats live longer.

Nick Jikomes 24:29

I see. And it's at least intuitive to imagine that in a sexually reproducing species, like humans, there could be very large sex differences here. Oh, absolutely. Yeah.

Andy Dillin 24:41

Yeah, I mean, the problem is, you know, men traditionally live shorter than women because of others. You know, testosterone is a pretty potent Anti Aging at certain levels. It makes us do stupid things.

Nick Jikomes 24:53

We say testosterone has an anti aging effect. No, I'm

Andy Dillin 24:56

saying that you know, as a joke, you know, it's as a you No as sad. Yeah, when you're 15 years old and all sudden you get flushed with a lot of testosterone. You know, if the first time you do some pretty crazy things that shorten your lifespan. Yeah.

Nick Jikomes 25:12

So anyways, going going back to sort of the cell biology of aging, I want to talk about this question that you've studied that I, you know, I've done a number of episodes on aging, but I've never talked about this piece, which is the coordination of aging across the cells in an individual body. So to what extent I'll just start out with a very basic question. So to what extent are each of the cells of my body independently aging? And to what extent are they being coordinated somehow?

Andy Dillin 25:40

Um, so I mean, they're definitely being coordinated. And you know, we're not the first ever I mean, insulin is probably the best coordinator there is to coordinate your glucose levels, inside of your cells and outside yourselves. So this has been known forever that, you know, there are central coordinators of these types of things. But to actually identify an aging pathway that itself coordinates across the entire organism. That's the one thing that we discovered. And that, you know, that stemmed out of this mitochondrial work where we were looking at, earlier on when I worked with Cynthia Kenyon Did you know she discovered and her and Gary Revkin that reduce insulin IGF one signaling makes animals the plot. So there's this pathway of modulating IGF signaling growth control, that's going to really factor into aging. And when I joined Cynthia's lab, I was very keen to know if that was the only pathway that could control aging. And so I went through and inactivated every single gene and this organisms body. And the vast majority of genes I uncovered were mitochondrial components, which I had never thought about mitochondria. Never thought I'd be working on it. But over and over again, our lab, Gary Ruskin's lab, many other labs uncovered the same genes, that when you inactivated, reduced mitochondrial function and made animals live long, and that was peculiar, but then the thing that was most peculiar, as you touched on this earlier, every single cell has mitochondria. And so and when we did our experiments, we were reducing mitochondrial function, every single cell, like okay,

Nick Jikomes 27:18

what exactly does that mean, reduce mitochondrial function. So

Andy Dillin 27:22

we were knocking down different nuclear encoded components of the mitochondria are the electron transport chain chain, chain, so we're reducing their function. So by and large, we're reducing mitochondrial function. And you could argue, well, which functions when we we know the electron transport chain functions, but many other functions were affected as well. And so, you know, this point about every mitochondria having every cell having mitochondria. When we did the experiments, we were knocking these down, and every single cell and seeing this great effect, this great increase in longevity. And I don't know why we did it. Well, I mean, it was sort of like a curiosity. In the beginning, as when I started my own lab were like, well, are all mitochondria equal, and contributing to the aging process? Because at the time, the reactive oxygen species theory of aging was very popular, and all mitochondria contribute to aging, and they're all giving their quanta to the aging process? And I said, Well, is that really true? And so what we did is we went and we knocked down mitochondrial function, and certain cell types, you know, not every single cell, but just a few cells at different times. And it was fascinating is that most cells, it didn't register in effect. If anything, it made the animals live shorter. There was one cell type, if we knocked it down on the nervous system, we recapitulated everything we did when we knocked it down, and all the cells I see.

Nick Jikomes 28:48

So if you knock down mitochondrial function across the board, every cell, you get this longevity effect, the animals live longer. If you do that, specifically in the nervous system, you get the same effect. Is that in all neurons? Is it in a different cell type is certain neurons? Now?

Andy Dillin 29:03

That's a great question. So when we first reported we did in all cell types, and we figured out that there's got to there, what these neurons are doing is that they're sensing mitochondrial stress, and they're sending out a signal to coordinate it with the rest of the organism. And we'll talk hopefully, we'll talk about why, why that happens. But we asked like why we started ask questions like which neurons are the responsible ones, and it really seems to be the serotonergic and the sensory neurons that are really playing a role in this. You can do other neurons, it doesn't matter. It's mainly those those sets of neurons that are doing this, and then further work and other groups did this in mice. And it's really in the you know, those neurons that control feeding the promisee AgRP in the hypothalamus, I see the same experiments, and they get this response turned on goes out in the periphery. So it's definitely conserved. Optimise we don't know about in humans in humans yet, but It is a serotonergic in the sensory neurons that are doing this. And they set up this beautiful system communicate with the rest of the organism that turn on the stress response. And what it does is it protects the animal from future stresses. So it's a, it's like an ectopic way of tricking the system is that you just touched the neurons, and then they relay the information of the rest of the organism and set up this really beneficial effect

Nick Jikomes 30:27

when these neurons are sensing mitochondrial stress elsewhere in the body under naturalistic conditions. How is that happening? How are they actually sensing the stress? What is the signal there? Yeah,

Andy Dillin 30:41

so that is a really so we've done it, we've done it with brute force genetic approaches, you know, mainly, what we do is because misfolded protein misfolding stress in the mitochondria. So John Hougen, rad discovered this in 2002, is that if you put misfolded proteins in the mitochondria, what happens is a signal gets sent to the nucleus to turn on the stress response pathway to come back and fix that challenge. And so we took advantage of John's discoveries. And, you know, we started making misfolding stress in the mitochondria. So you can do that many different ways. Put misfolded proteins in there, or there's big protein complexes, the electron transport chain, you can mess up the stoichiometry there and get that up and running, you know, get out to do it. You can mess with mitochondrial ribosomes. So you change the synthesis of proteins in there. And that causes stoichiometric imbalances. There's a lot of different ways that we can get this thing up and running, get this stress response turned on.

Nick Jikomes 31:48

And then that stress response, so that stress plants gets turned on, somehow that's detected centrally. So how do the neurons know that the stress runs has been turned on in some other cell?

Andy Dillin 32:02

So well, that we don't know yet. So all we know right now is that if we turn it on the neurons, the neurons can talk to everybody. If we turn on other cell types, those cell types don't talk to each other. And no one yet talks back to the neurons. So it seems to be a one way street. So far, I'm not ruling out that there's not these other forms of communication. We haven't uncovered them yet in our studies, and it's probably because we're limited in the way that we're looking at it. But right now, it seems like the stress has to be registered and the neurons, neurons and the glial cells, we can talk about that, but that's, but the neurons and glial cells register it and then they coordinated across the rest of the organism.

Nick Jikomes 32:46

And when so you said like, there's this involvement of the sensory neurons and the serotonergic neurons? Do we have any sense for why it's serotonergic? Neurons as opposed to some other type? Yeah,

Andy Dillin 33:00

so that's a really well, okay, so we can talk a lot about why this is originally first. I mean, a major question is, why is it originally in the nervous system? Now, Why can't every cell just determine for themselves? Why is there a master coordinator? And the nervous system seems logical, right? Because that's, that's what the nervous system is supposed to do is supposed to sense the environment and then create homeostasis internally, that's its major job. And so that makes sense. That's exactly what we're seeing. And why is it the sensory neurons and the serotonergic neurons? Well, serotonin is you know, it is a a communicator of stress. And so it makes sense, those types of neurons would actually be the Sentinels that get this response up and running. And if we knock out serotonin synthesis, we can't get this going at all. So serotonin is essential for getting this whole thing going. As long as there's also a hormone that's required as well, which is a it's called a wind lag. And, and it looks like it's also going to be conserved, at least its functions conserved in mice, and probably humans, it's gdF 15, or FGF. 21 is also a cytokine. That's what these things are called, is that when cells are stressed, especially in neurons, they will release these hormones to register with the rest of the body. So that you know, it's essential relocators like, Oh, my neurons are stressed out. Let's prepare the periphery for this impending stress that's going to happen. And so then that gets to the next question is, you know, the sensory neurons, what are they actually sensing? And so we do know that pathogens. So we're going back to remember, mitochondria are ancestral back bacteria. Yeah. Yeah. And if you give a pathogenic bacteria to an animal, it will it will turn on the stress response. Yeah. Because the mitochondria like oh my Yeah, there's somebody like me, in the environment that's trying to attack me, this pathogenic bacteria, let's protect ourselves. And so that was that's fascinating. But why sensory neurons. And so we've done this experiment where if we just have animals smell the pathogen, they're not being infected, they're not eating it, they're not touching it. They're just smelling it. They register that pathogen. And then they turn on this response to their neurons. And they communicate it to the periphery, just like all of our genetic experiments.

Nick Jikomes 35:36

So it's like a pre emptive. It's a pre emptive response.

Andy Dillin 35:38

It's a preempt so then if you take those animals that have smelt that pathogenic bacteria, and now expose them to a pathogen, have them infected, they're more resistant than the ones that didn't smell it.

Nick Jikomes 35:50

And what kind of animals are you talking about for these particular experiments?

Andy Dillin 35:53

So this is all in C. elegans, and nematode C. elegans so far that we're putting this in? So

Nick Jikomes 36:01

what's that? Little worms that can smell the bacteria? Yeah, little worms,

Andy Dillin 36:05

I can smell the bacteria. And it's only pathogenic. If they smell non pathogenic bacteria, it doesn't matter. It's only pathogenic.

Nick Jikomes 36:15

I see. So so. So these mechanisms can they're not merely reactive mechanisms, they're not, it's not like you need a stressor inside of you doing distress. They can preemptively respond based on the sensory detection of a stressor that could get into the body. Yeah, and and protect you preemptively protect the body? If that actually does happen.

Andy Dillin 36:37

Yeah, I mean, it's, you can tell I don't know if you and I've never met, but my voice right now is I'm just suffering from a little bit of cold. And I'm like, you know, this system that we have, where we let the pathogen into our body, then all sudden we're you react to it, do an innate immune response to it, and then do an adaptive response to it. I'm like that, why don't we have something that's more clever that detects it and the environment before it even infects us. And so that's where a lot of our research is going is that we're seeing that the stress response pathways are registered and sensory neurons first, and then they communicate to the rest of the body. And so what in the environment? Are they actually registering? And this first set of experiences, first set of papers that are coming out where they're registering pathogenic bacteria, I think is fascinating. Because when you want to know about a pathogen before it infects you, you're more resistant to it. So now we're trying to, you know, of course, see if this is conserved in vertebrates, and figure out what the smell is. I mean, I think the most fascinating ideas, if we can figure out what this smell that this pathogens putting off, can we actually just make a perfume and put that in the environment and make people more resistant to future pathogenic attacks.

Nick Jikomes 37:58

And when some of these stress response mechanisms turn on the protect the organism? What is that? Well, what's happening at the cellular level, what's happening that's doing the protecting? Yeah,

Andy Dillin 38:09

so. So we see that they turn on this mitochondrial stress response. But inside the cell, what happens is, we see the mitochondria divide. So they phys away from each other into small bundles. And I don't know exactly why that's a protective mechanism. Some people say that that's a way to allocate resources into smaller packets, you know, your defense mechanism is to divide and make yourself smaller, so that there's less opportunities to get, you know, destroy one giant mitochondria. If the pathogen is successful, it may just destroy one small piece of a mitochondria, not all of them, so it divides the mitochondria. The other fascinating thing that we're finding, so we're going to put another layer on top of this smelling pathogens. So if the animal is pregnant, it smells a pathogen, and then its progeny. So we take the pathogen away, the smell the pathogen away, and it only smells it, it's never infected. It's never In fact, it just smells it, let it smell it for a day or so. And then we let the animal reproduce and lay its and have its progeny. Those progeny have now turned on that stress response. And those progeny if you now expose them to the pathogen, are now resistant to the pathogen. So there's a wiring that's happening between the nervous system and the germline. That's preparing the future generation that hey, we came across a pathogen. It's more than likely that you're being born into a pathogenic environment. Let me set you up so that you can survive a little bit longer to make it to reproduction. Wow. That's pretty wild. Yeah. Is there any and so one final layer is that if you get rid of the germline, so Louisiana We'll just sterile they have no germline. If they smell the pathogen, they can't turn on the response on the periphery, in their own body in their own body. Because there has to be the impetus that, hey, I'm going to reproduce, let's protect the body. If there's no germline there, there's no point in actually setting it all up.

Nick Jikomes 40:17

Yeah, it I mean, it actually makes sense when it's time to think about it. Because, you know, from a Darwinian perspective, right, the whole purpose of mitigating stress and surviving at all, is to reproduce. And so it makes sense. There'd be something hooked up from the germline into these systems.

Andy Dillin 40:35

Yeah. Well, I'm glad to make sense to you. It was kind of a head scratcher. We're like, wow, this is really cool. And I mean, the editors loved it as well. It's like, oh, this is actually pretty fascinating with this happening.

Nick Jikomes 40:46

I mean, of course, you could imagine, right? There's obviously it would be possible to hook it up differently. It's not like you could write it's perfectly it's easy to imagine why, how you could have a stress response that's not literally hooked up to the presence of the germ line. But still, that's a that's an elegant way to really tie the end goal to these things.

Andy Dillin 41:11

Well, and also, if you're thinking about mitochondria, right, this is a mitochondrial stress response, you're detecting the pathogen, you're protecting the mitochondria in the progeny. And you have to have that germline in order to get the whole thing up and running. So there are the one cell type that cares the most about your mitochondria is your germline. So when you think so when you're when you're making your germ cells, you start out with 40,000 mitochondria. And then you eventually selected down to 40, to put into that germ cell into the O site. That's where most of all of your mitochondria come from. And as the 40 best, most pristine, you know, the best best mas Herati, Ferrari, whatever you want to use the best mitochondria, the rest gets selected out.

Nick Jikomes 41:56

I see. So there's some kind of selection mechanism there where the developing Oh site can determine the quality of the mitochondria. And then and then filter away the the bad ones.

Andy Dillin 42:06

Yep. Yeah. And that is, if it didn't, you know, your fidelity would go down dramatically. Over generations, if you weren't able to reset, you know, the germline is immortal. So it has to have the best of everything. And mitochondria is one of the major things that has to have. And if it didn't do that, you know, you may lose a minute per generation. And over successive generation, the lifespan of the organism has gone. It could do this. And so coordinating this with your sensory input from, you know, from the nervous system to now the germline I'm I mean, this is like the greatest time of my career. I mean, it's the things that the lab is discovering, and the way they're doing it, I'm just, it's just truly fascinating what they're doing. And every day, I'm like, Wait, that works that way. And it's like, oh, my gosh, wow. Really fascinating biology.

Nick Jikomes 42:58

So you mentioned mitochondrial fission. And again, I don't know a terrible amount about mitochondrial biology. But my understanding is that the the number and the size of mitochondria are important features within a cell, they tell you a lot about how old the cell is how well it's functioning at a high level, what is the size of the mitochondria? And the number of mitochondria per cell, generally tell us is that are those like good correlates of an animal's age of its ability to produce energy and so forth? Yeah,

Andy Dillin 43:30

I mean, the mitochondrial morphology is a metric. But it's not clear. How, I mean, the general theme is that if mitochondria break apart, the mitochondria aren't functioning as well. If they're fused together into a nice network, they're functioning better. But there's, you can break those correlations all the time. So it's really like, you know, the dynamics is really, there is a lot of dynamics that happens mitochondria, but it's not always accurate. And so it's, you know, we don't put a lot, you know, we're fascinated to see the dynamics happen, but I don't really understand entirely that it's always correlative to better mitochondria versus not better mitochondria. Now, the number of mitochondria that is a fascinating one is that, you know, some cells can have 1000 mitochondria, some cells can only have three mitochondria. And I mean, different cell types. I'm not saying the same cells, I want to clarify that, you know, within, you know, a certain cell type, that cell type will always have 1000, and the other cell type pillars will always have three. Now, that's a fascinating metric is like, how does the cell determine this? What is the counting mechanism? How is it known? And that is wide open space that's out there. But there is one idea out there that no matter what mitochondria are in excess, no matter what cell type it is, so with 1000 You're like, okay, yeah, of course it's an accessible The one that only has three, that actually the bioenergetics really is just that maybe only needed one. And so we have this excess of mitochondria. And that's, you know, 10 years ago, people were like we need more mitochondria. To have health, we have to increase mitochondria, we have to upregulate, this gene called PGC. One alpha that is required to make more mitochondria, we need to target that and make more mitochondria. We have a mitochondrial disease, let's just make more mitochondria. That's not actually turning out to be right, is that mitochondria are in excess. And the results that we have where we knocked down mitochondrial function, and actually get better health. Yeah, it goes against all of that. Because it's triggering the stress response, right? It's triggering this response to make the mitochondria. Yeah.

Nick Jikomes 45:46

And I Yeah, and naively, I would think, too, that more mitochondria, you know, on the one hand, you might think, Oh, more ATP, more resources. But on the other hand, more oxidative stress, more reactive oxygen species, more

Andy Dillin 45:57

oxidative stress, more, more volume taking up inside of the cell. I mean, there's lots of reasons. You know, it's kind of one of these things like when your car starts to break down, you go, you know, it's like, you go buy more cars, it's like, now you fix your car, you know, I'd rather have one really good functioning car than 10, sort of broken cars. And so making more mitochondria, as I think is not the way to go, it's actually making your mitochondria better.

Nick Jikomes 46:19

And how do we how do you guys measure that in cells? What Does better mean in terms of mitochondrial function?

Andy Dillin 46:27

I mean, we go down, we look exactly at mitochondrial function. So we look at how well they're producing ATP, how well they're utilizing oxygen. You know how well they're doing other enzymatic activities that are happening inside of the mitochondria is one of the one of the major drivers, you know, how well, you know, mitochondria have this amazing ability to pump protons across the membrane, they create this gradient to produce ATP. So just looking at that is one of the major things is, can they actually create a gradient?

Nick Jikomes 46:56

And in these sensory and serotonergic neurons, these sort of special neurons involved in this whole stress response? stuff? What are the mitochondria doing in those cells? are they behaving differently to those cells have weird mitochondria in some way? Oh, man, yeah,

Andy Dillin 47:17

this is I think I'm gonna, this is gonna be like the rest of my career. So we really want to know what those why those are, those mitochondria are more sensitive than mitochondria and dopaminergic neurons are mitochondria and other, you know, glutamatergic neurons, you know, what's the difference. And that's something that we're avidly that's like a major goal in our lab, is trying to figure this out. You know, there's one idea that the mitochondria are different. The other idea is that the stress response is dialed differently in those cells. And that those cells, you know, they're like the canary in the coal mine, like they, that stress response can be triggered, you know, just with very little change, and turn this response on. So there's two possibilities are happening there that we're actively trying to figure out. And I don't have an answer for I wish I had an answer, but I don't.

Nick Jikomes 48:13

Um, in terms of some stress response mechanisms that cells use to protect themselves. We talked about this unfolded protein response. There's also something that I know some some about, but not too much, which is the heat heat shock response. Can you talk a little bit about the heat shock response, and just the general ability of cells to respond to temperature differences from what's optimal?

Andy Dillin 48:40

Yeah, so the heat shock response is probably one of the most evolutionary ly ancient stress responses there are stemming way back from bacteria, sigma factor, sigma, 25, running, turning on the heat shock response conserved all the way up to humans. And, you know, it's sort of that that heat shock response, we talked about the mitochondrial stress response, the ER response, the heat shock response is sort of, is thought to monitor what's happening in the cytoplasm, you know, not in the other organelles, you know, all the other stuff. It's monitoring what's happening there. And it's a transcriptional response. That's when there is a stress to the cytoplasm. It turns on a bunch of repair enzymes and chaperones to come and refold that stress that's happening in the cytoplasm. Now, traditionally, it's called the heat shock response, because it's turned on by elevated heat, which, if you remember your second law of thermodynamics, that's going to actually drive free energy and actually cause proteins Miss fold. And so that's a major bases away, it's called the heat shock response. And, you know, the chaperones get turned on to refold these misfolded proteins that that turn this thing on. And let me think about What was the rest of your question?

Nick Jikomes 50:01

Yeah, just in, you know, the heat shock response, but just in general, how cells buffer themselves against deviations from the temperatures they need to maintain themselves?

Andy Dillin 50:12

To? Yeah, that's, I mean, that's a really, really good question. I mean, so it is that that you are able when you when you have the Delta and change, going from a low temperature to a high temperature, this transcription factor HSF, one can be released, and turn on the stress response to cause this buffering of the chaperones to help refold the proteins are happening.

Nick Jikomes 50:33

But it sounded like what you were starting to say maybe was, we call this the heat shock response, because that's the context in which it was first discovered, but it's not a heat shock response. It's a more general protective mechanism.

Andy Dillin 50:46

Yeah, I mean, I mean, its major response is the heat, but it also responds to other stresses as well. I mean, anything that really causes protein misfolding, you know, it should be really a protein misfolding stress response, that is responding to, and it's thought to be primarily proteins that are in the cytoplasm, that it's responding to.

Nick Jikomes 51:09

And I would imagine that, you know, at some point, you know, so a cell detect stress, there's misfolded proteins, for whatever reason, some of these mechanisms turn on, and they ensure that the proteins don't get mis folded, and then everything goes back to normal because the mechanisms work, they protected the cell. And that's great. Sometimes I would imagine that the stress is just too much. And this things go completely haywire in the cell is no longer viable, is that when we start thinking about things like autophagy?

Andy Dillin 51:39

Yeah, I mean, it's, I think there's gonna be layers of dealing with stress is that when the Challenge gets too great, there's gonna be layers that happen, you know, turn on the heat shock response, try to acutely deal with it, if you can't deal with it, you're going to form protein aggregates, and those are going to be recognized by Takuji. autophagy is going to try to catch up deal with it. And then probably by that time, it's caused so much stress inside of the cell, that mitochondria are affected, and you're going to induce apoptosis and actually just kill the cell for the benefit of the entire organism.

Nick Jikomes 52:12

Is there a link there between. So you know, if you have misfolded, proteins recycling these protein aggregates, the cell can then be digested autophagy can happen, you can get rid of that cell, that can be good if that cell can be replaced. But I imagine the nervous system is a different story, because you can't replace most of those neurons. Is there a connection here between, you know, mitochondrial health autophagy, and like neurodegenerative diseases?

Andy Dillin 52:38

Oh, there's, that is the major link is, you know, we're finding your mode, a lot of these neurodegenerative diseases are linked to defective mitochondria and defective autophagy. And so, or, or defective mitophagy. You know, to get more specific, being able to get rid of mitochondria that are defective, you can do that through a tapa G as well. And, you know, many of the disease links to me that many of the genes that are linked to Parkinson's are linked to a tapa G machinery, lysosomes, mitochondria. You know, Alzheimer's disease is becoming more prevalent, they were having defects and dealing with defective mitochondria dealing with defective autophagy. And so, but it still gets out of the question is, in all those diseases, there's select neurons that are affected, not all the neurons in your brain. And it's good to getting back this question. It's like, well, why those ones? Why not these other ones? And I think that's, you know, that's a question that everyone would love to address.

Nick Jikomes 53:44

So you have all these stress response pathways that that cells have, there are some of these very special cells that are involved in coordinating coordinating stress responses. Across all of the cells are many of the cells of an animal's body. I imagined to there's also important differences in terms of how things play out. When you talk when you distinguish between chronic stress versus acute stress, there's something that people talk about all the time. So for example, people often describe, say something like exercise as an acute stress. And because it's acute, it's generally good, it's generally beneficial for the organism. But if you were to apply stress chronically, it's generally bad for the organism overall. When we think about things like temperature, and we think about acute stressors are silly things that are becoming very popular right now. Everyone seems to be talking about ice baths. People take ice baths in the morning, they expose themselves to extremely cold water for just a short period of time, then they get out in essence, what's going on with those types of acute stressors? Are you engaging some of these mechanisms in the body and thereby making them more stress resilient overall?

Andy Dillin 54:53

Yeah, so I think one of I mean, I don't know enough about the ice bath thing sounds horrible. I mean, it's I I mean, just getting up in the morning is hard enough why jump in an ice bath? It sounds like a good way to a heart attack, actually. But I mean, let's talk about a different acute stressor that a lot of people, I mean, I actually inadvertently do this a lot. It's like intermittent fasting. Yeah. Right. So you know, you eat eight hours a day, another 16. You fast more or less, that definitely induces autophagy. It's thought to be actually beneficial, because it's inducing autophagy. And, you know, Valter Longo has this great stuff. And the late Kevin Mitchell had some, some stuff on this about, about, you know, going to surgery, people, normally glucose load you to get you through the surgery, like, oh, that's gonna be much better. And actually, they did the experiments, actually, if they fast them before, you actually have a better survival rate coming out. And so, you know, it's one of these acute stressors ideas that yeah, you're actually acutely turning on autophagy, to clear out any damages happening so that when you come out of that stress, now you're in a better state. So I, you know, I think, you know, I love exercising, I love, I love the end of the exercise that it's over with, because I know that I've stressed my body out, and now it's time to recover. And it's actually going to be a much better down the road for doing that.

Nick Jikomes 56:19

And so when you do something like intermittent fasting or time restricted feeding, so you eat and say, in our window, and then you don't eat for 16 hours, autophagy starts to happen in that 16 hour window, sometime after you stop eating. Can you give us a sense of how selective the autophagy is? Are there very specific cell types that get engulfed and digested or sort of across the board? That

Andy Dillin 56:47

is a great question. I don't know the answer that I could, I could speculate that, you know, probably the cells are, they're the most nutrient sensing or the first to start inducing autophagy. So those are probably the very first ones to start inducing it. But I don't know which which cells would do it. And, you know, there are people that do longer fasts as well. And whether or not that's going to be beneficial. I mean, it sounds miserable, but a little bit of stress in your life is good. You know, what doesn't kill you will only make you stronger, I guess. But I think there's a limit to it. I think having too much stress will be really, really bad. And it's the thing, you know, you literature, it's like chronic stress, I think that's got to be way up there with one of the number one things that are that are causing a lot of diseases. And we see this diabetes, depression, all these other things, and it's

Nick Jikomes 57:44

Has anyone done the experiment where So presumably, you want some level of autophagy, but not too much, you want to get rid of the damaged cells, the bad cells, the cancer cells, you obviously don't want to get rid of healthy cells? Have people done experiments where they just turn autophagy way down or turn it off? And if so, what generally happens?

Andy Dillin 58:04

I mean, what generally happens is that you can't survive starvation. So if you have an animal that has at the top of you turned off, and you remove food, they don't survive for very long. So it's definitely essential for that. I mean, it's definitely essential also for developing animal animals as well. So once you know if you can get them through development, then turn off a tapa G. It's really not a good scenario. It's they can't survive, you know, caloric fluctuations at all?

Nick Jikomes 58:34

I see. So So part of what the autophagy is doing is it's enabling the cell to I mean, literally eat its own cells and use that in the absence of an external food source. That's right.

Andy Dillin 58:44

Yeah. It's, it's your backup mechanism for generating resources when you're not when you're not consuming.

Nick Jikomes 58:54

So when we talk about so the nervous system in particular, and I think about mitochondria naturally, I think, you know, mitochondria, I think energy, I think energy, I think about energy, highly demanding cell types, like neurons like muscles. Are there any major differences between neurons and muscle cells in terms of how they use mitochondria? Or what the mitochondria are doing beyond just raw ATP production?

Andy Dillin 59:22

Yeah, so I mean, in the neuron, it's fascinating is that, you know, at the synapse where neurons are talking to other neurons, is, you know, they have to release a lot of ions to create electrical currents to do that neural communication. And a lot of that, you know, mitochondria massive storage is for calcium. So calcium drives a lot of that. So at the synapses, you have a lot of mitochondria built up there. And there are waves, you know, waves that are happening of ATP release and calcium release. Right happening right there. And then in the muscle, the same thing, a similar thing is happening is that with muscle contraction, you know, of course, you're gonna need ATP to do that. But also, you're gonna have to have fluctuations of calcium coming in and out. And a lot of that is actually coming from mitochondria as well. And it might have in mitochondria and muscle, it's more localized to the sarcomere, the structure of the muscle that's creating those contacts. But it's pretty fascinating that they're both they're not doing that traditionally, their ATP thing or their calcium piece functions as well.

Nick Jikomes 1:00:33

Interesting. And you know, another interesting thing to think about in terms of mitochondria instead of neurons, is neurons have a very interesting shape. Many of them are extremely long, I imagine the mitochondria have to physically move or even be transported different parts. Is there any what do we know about mitochondrial movement within something like a neuron?

Andy Dillin 1:00:54

Yeah, this is not my area of expertise. So there's a great junior faculty at Duke, Chantelle Evans, this is her body of work that she's, you know, trying to figure out how these mitochondria gets to the to the synapse, you know, how they traverse such a long period of time? Once they're there? And what if something goes bad with them? How they could actually get degraded? Because a tapa G machinery is not there. So it's really fascinating, like, what's going to happen at the synapse with these mitochondria? And, you know, she's right on this question and trying to go after it and figure it out. And I think it's, you know, it's a Pandora's box, there's gonna be so many things that are going to be learned about how mitochondria regulate in this very sub cellular localized place. And like you said, these neurons are that can be huge housing information carried from one part of the cell to the other, it's gonna be fascinating.

Nick Jikomes 1:01:49

I mean, this is sort of a big, and somewhat vague question, but any, I think anything you could say here would be interesting. In terms of dietary factors that lead to mitochondrial dysfunction. Are there any types of diets or types of macromolecules? When given an excess, say? Or when or if you're deprived certain nutrients play an outsized role in driving mitochondrial dysfunction?

Andy Dillin 1:02:13

Oh, high fat diet, of course.

Nick Jikomes 1:02:16

So, can you get more specific there? In particular? Yeah,

Andy Dillin 1:02:20

I'm not sure. You know, I don't know the literature enough, like, you know, which lipid molecule is an access, but I mean, mice, a high fat diet, I mean, their mitochondria look horrible. You know, you look at the liver, I mean, creating these large lipid droplets, and the poor mitochondria are trying to survive. I mean, it's high fat diet is really toxic for mitochondria.

Nick Jikomes 1:02:47

And we understand why, like, what the mechanisms are there?

Andy Dillin 1:02:51

Nope. I mean, I don't let's qualify that. I don't, I'm sure somebody out there has informed ideas, and maybe data that says, you know, why I fat diet is so toxic to mitochondria,

Nick Jikomes 1:03:06

but it's probably not super well worked out. You know, got it. So what, like, what are some of the things that you guys in your lab are working on today? What are some of the questions that you're asking right now that it looks like you're gonna have exciting answers to or that you think you're gonna make progress on in the near future?

Andy Dillin 1:03:26

Yeah, so we've covered a lot of this, you know, this neuronal control of mitochondrial form and function on the periphery? You know, what, and then trying to figure out, you know, why the neurons? are the ones registering this, and what are they actually picking up on? That's a major place we're going. But there's a really just basic question. You know, we've talked a lot about the stress responses. And, you know, if we go back to your idea about the heat shock response, that it's monitoring misfolded proteins in the cytoplasm, how many misfolded proteins have to be monitored, you know, which misspelled is are certain ones that monitor so you know, what, what is something as basic as that has not been answered? You know, with our mitochondrial defects that we see. And we turn this, you know, this mitochondrial stress, you know, let's say that there's a cell that has 1000 mitochondria. Is it just one bad mitochondria? All 1000 have to be bad to get the response up and running. And it's, you know, it sounds like, kind of a boring question. But it's actually fundamentally important, because it's telling you a lot about this sensing mechanism and how it's actually registered. And what it's actually responding to, you know, if you think about the heat shock response and say, well, it just monitors misfolded proteins. Well, most of the proteins in our cell are mis folded at one time or another, you know, when they're forming. And when they're relaxing. I mean, very few of our proteins in our cell are actually that crystal structure that people show us. And so why isn't the heat shock response turned on The time? Or is there something special that it's monitoring that was monitoring complexes, you know, such as the ribosomes, or, you know, the microtubules, or the actin filaments, you know, major structures, maybe that's what it's monitoring and trying to register. So we're trying to figure those questions aren't, you know, doing very quantitative experiments of just dicing and a little bit of, you know, something bad to see how much is required to turn on those responses. Because, you know, if you start thinking about trying to drug these responses, it's going to be, you know, it's going to be a bell shaped curve, is that you're going to have one a sweet spot more than likely, because if you give too much stress, you're not gonna be able to fix it. And you're cause toxicity. And if you don't give enough stress, you won't get the response turned on. So somehow, you have to figure out what that sweet spot is. And if you're trying to make a drug, that's probably, you know, people that make therapeutics and drugs, that's the worst place you want to be in, is trying to find a sweet spot for your therapeutic. Because everyone's sweetspot, maybe a little bit different. We haven't talked, you know, the heterogeneity and the human population, your heat shock response may be slightly different than mine. But we take the same dose of heat shock and deucer, you may get a benefit, and it may actually end up killing me for all the wrong spectrum. And so, you know, this has happened with diet restriction. People on different spectrum, you know, mice respond completely differently. Because they're on, you know, there's different sweet spots for different strains of mice.

Nick Jikomes 1:06:40

So you said, you know, you're, you're studying things like mitochondria in neurons today, but that's definitely not where you started. So you just start out, it's like, why did you get your start? Was it in some other aspect of cell biology?

Andy Dillin 1:06:53

Yeah, so I started out. So my history my undergraduate, I got the opportunity to work in a lab, one of my heroes, artist McCracken, at the University of Nevada, Reno, and we're working on ER stress her lab was, and she was who was really interesting is that this was in the early 90s, she was putting misfolded proteins in the ER, and they were getting degraded. And she was like, well, what's the quality mechanism there that's monitoring this. And she found out that you know, this thing called the ER unfolded protein versus the er, er associated degradation ERAD, this pathway that was discovered by her. And it was part of my undergraduate thesis, I got really turned on to genetics and cell biology. And then I came to Berkeley to do my PhD and worked with Jasper Ryan, completely changed, worked on DNA replication and transcriptional, silencing and cell cycle stuff. And yeast. And the topic was fascinating. But the education was more fascinating is that Jasper trained me to be a classic geneticists to attack every question with a genetic point of view. And, you know, try to go after it that way. So I got really rigorously trained in genetics. And armed with that, I wanted to go after a really big problem. You know, I wanted to work in schizophrenia, but it seemed a little bit too complex at the time, you know, it's one to 2% of the population multigenic. I was like, Oh, this would be great. But it seemed really complex. And so I said, oh, let's do something a little bit less complex. And that was right, when Cynthia discovered death to rail, you know, a single gene, profoundly influencing aging. I said, Oh, wow, something as complex as aging can be boiled down to a single gene, I gotta go work on that. So that's where I, I've always been a geneticist, with a little bit of cell biology, a little bit of biochemistry involved. But I've always attacked the question from genetics. And like I said, when I started with Cynthia, I went looking for a new pathway, that she was going to work on insulin IGF one signaling. That was clear, I had to find my own path. And, you know, I do this screen and I pull out all these mitochondrial genes and one of my advisors, great colleague here at Berkeley, when I was deciding on being a postdoc where I was going to do my training for postdoc after my PhD. I said, Yeah, I'm gonna go work on aging. And he said to me, that that's boring. You're just gonna be working on mitochondria metabolism. I said, No, no, no, I'm going to find this new signaling pathway. It's gonna be totally interesting. It's like find these mitochondrial genes. And I write to him and tell him he's like, Well, your career is over with, you're done. It's boring. Now there's nothing to work on. And so that's where I got it. And then when we found out the mitochondria working in neurons, then all of a sudden I got labeled as a neuroscientists, which is fantastic group of people. I'm happy that they brought me into their group and they've taught me a lot. But I'm clearly not a neuroscientist. It just happened to work on a problem that happens to be in the nervous system. I'm trying to learn neuroscience every single day and it's an upward you know, as you get older, it gets harder to learn. So I'm trying to figure it out. So that's been sort of my path of how I ended up where I never planned on being here. It just the results. That's where it took me

Nick Jikomes 1:10:17

that that first gene that you talked about DAF two, I think it was called, yeah. What was that gene doing?

Andy Dillin 1:10:23

So that is the insulin IGF one receptor. Oh, I see. Okay. Yeah. And so Cynthia is where you know, she was when she transitioned over to work on aging. In the nematode C. elegans, it goes into this alternative lifecycle, this dour face that can last. So normally, the worm only lives about three weeks. But if it goes into this alternative phase, it can live six months, and then come out and live in normal lifespan. And so she was looking, she was reasoning that the genes that control that may actually be co opted to control normal aging. And so all those genes have been discovered the DAF genes, and she started looking at those that an aging profiles. And she found that the DAF two mutation that controls entry into this thing into the diapause is actually super long lived. And it opened up but you know, and then she actually figured out that it wasn't part of its diet pause function. It actually had a normal function in aging, which was very profound. And now it's been, you know, it's been carried forward and flies and mice. And there's correlative studies in humans as well, has been a central regulator for aging.

Nick Jikomes 1:11:32

So there's lots of results out there in different organisms that show that you can, you can boost longevity, you can make animals live longer. How much longer in general, can can people make animals live? Are we talking about one or two or 10% increases? Or do you sometimes see much more dramatic increases?

Andy Dillin 1:11:55

Yeah, you definitely see. So the mitochondrial genes that I told you about when we knock them down, they're increasing by 100%.

Nick Jikomes 1:12:01

And so so how long do those organisms live normally? So

Andy Dillin 1:12:05

normally, the worm would live? Let's say 25 days now it lives 60 days.

Nick Jikomes 1:12:11

Okay. Wow. So you're doubling its lifespan, doubling its lifespan.

Andy Dillin 1:12:14

And then if we combine, you know, Cynthia's IGF one mutations with our mitochondrial perturbations, now we're looking at, you know, 100 day lifespan, tripling and quadrupling lifespan. So you can or, you know, once we've healed, there's a couple major pathways that have come out of all these aging studies over the last 20 years, IGF one pathway, the mitochondrial pathway mTOR plays some role as well. And so if you put the three of those together, you know, you can get massive lifespan extensions.

Nick Jikomes 1:12:51

And when you see those massive extensions in these model organisms, is that are they just like aging slower every single day? Or do they start aging later? Like, wow, give us a sense for what that looks like?

Andy Dillin 1:13:07

Yeah, I mean, so they, they're very healthy. They look like they're aging slower. Like they, you know, the IGF one mutant animals, very robust. And then they started declining at a normal rate, just like wild type animals, when wild type animals started planning, the mitochondrial ones are a little bit different. So when you first do it, you know, the whole body one, the animals look horrible. I mean, when I first discovered this, but when I was looking, I was like, these animals are dead, and then I'd shake them and they come back alive. Because they're, you know, they had ATP loss in their muscle, everything, but they were still alive. And that's how we found them. But then when we moved it just in the nervous system, it doesn't affect all that. So we don't have all that negative, they look like the IGF one meeting animals are moving along. totally happy and, and, you know, looking really good. So when you combine the two of those, it really does look like everything's so we see reproduction is delayed longer. There are a lot of things are thrown out to later in life, and then they, but they do that mean, the most amazing thing and aging research that no one talks about, is this stochastic decline that happens with lifespan. So let me rephrase that as if you take you know, a group of isogenic identical animals growing on the exact same environment exact same Petri plate after about 10 or 15 days, one dies 30 days later, the last one dies. So they're identical.

Nick Jikomes 1:14:40

Yeah. So they all they all sort of tank it's a different point for some reason,

Andy Dillin 1:14:43

and you can take this out to the human population, this all every population that that like you know, except for programmed death, you know, and salmon and you know, other things. They all have this like trailing curve of stochastic decline that No one can, you know, say why? And it's in their identical animals. And you're like, you can't argue that they're in different environments. You can't argue that they're genetically different. What is going on here that has played out and heterogeneous populations as well? And that would be fascinating to learn. Because if I'm that first one, I like to know, why can't I be that last one? Why can't we just wear this curve off, and it's all, you know, February 23 2080, I'm gonna die, you know? Well, I can't be that way, why they have to be this unpredictable curve happening at the end.

Nick Jikomes 1:15:36

And that's just a mystery right now.

Andy Dillin 1:15:39

So there has been funny enough, there has been some studies, I don't know if it explains the curve. But if you look earlier in life, so if you take our mitochondrial stress pathway, and we have ways to monitor and in vivo, we have a bunch of animals, current clients crawling around on a plate, totally identical. They're not experiencing, we don't give them mitochondrial stress at all, they're just normally growing. But if we look at them, we can see, you know, five to 10% of them that actually turn that on. And the 95% habit, if we take that five or 10%, they actually ended up being long lived. Naturally, we didn't do anything to them. And so maybe, you know, if you can stochastically turn on the stress responses at some time in your life, maybe that's a better predictor for you being long lived. I don't know. I mean, it's an idea that's out there, it doesn't explain all of the curve explains the last part of the curve, the long lived part, I can't explain the first, you know, the short lip part. Maybe those animals can't turn on the response. I see. So

Nick Jikomes 1:16:41

in animals where you, where you increase your longevity, you cause them to live longer. It's been done in multiple organisms, a few different ways that you've talked about. You said something that kind of triggered me earlier? Are they? are they reaching the same developmental milestones at the same time? Or is their development like delayed itself? Are they becoming mature later?

Andy Dillin 1:17:06

Well, so we can look at their early developmental stages. So you know, we classify them as adults, we rigorously identify them as just entering adulthood, and that's when they start their lifespan. So we're only looking at adult lifespan. I see. So you're not looking at developmental. But are there stages into adulthood? That we're not identifying, you know, are there gradations of adulthood that we're not identifying as possible? You know, one of the major ones we look at as reproductive timing, like, how long are they reproductive for? And, you know, the IGF one mutants extend reproduction, mitochondrial mutants extend reproduction. So maybe they are extending some parts of development and adulthood. I

Nick Jikomes 1:17:51

see. Okay. So they extend, they have a longer reproductively viable window. They're not reaching maturity necessarily at a different time. Exactly.

Andy Dillin 1:18:00

And that explains why these would never be selected for a nature. Is it as taking them longer to have their full complement of progeny? Yeah, yeah. They'd probably be predated out before they could do this. Yeah,

Nick Jikomes 1:18:12

that makes sense. Yeah. So at a high level, do you so so there's aging is sort of inherently interesting to everyone, because everyone wants to stay young, no one wants to get old, no one wants to die. It's a pretty high profile field, in the sense at least, that it's getting a lot of attention. There's a lot of really interesting results out there are a lot of really interesting claims. A lot of the claims that people get really excited about have to do with longevity, delaying the aging process, the idea of living forever, or, you know, living a ridiculously long amount of time, at least with a good health span. Like, do you think the aging process can so so I want to distinguish between lengthening life or lengthening healthspan by delaying the aging process versus say, reversing aging, so undoing some of the bad things that happen as we age? To what extent are these longevity effects, a delay of the aging process? So you know, the wear and tear is happening at a slower rate, things are breaking down at a slower rate, versus how much of it is actually coming from reversing things that have already been done?

Andy Dillin 1:19:30

Well, I mean, I don't believe in any of the reversal stuff. I don't think that there's any basis for that scientific basis for that. But the delaying parts. I mean, that is clear. I mean, that's clear and model organisms. Let's let's qualify all this. You know, we're talking nonhumans. And, I mean, I think one of the most classic experiments that we did early on in my career is let's Talking about Alzheimer's disease. So Alzheimer's disease, let's, you know, let's agree that it's caused by the formation of a beta plaques. And, you know, we can of course argue about other causes, but let's just say that that is the milestone that, you know, if you get a beta plaques you're gonna form you're gonna get Alzheimer's disease. And the argument that you know, you get it late in life is that it just takes time to make those a beta plaques enough of those actually cause ology. So if you take a long lived animal and a normal lived animal, and you engineer them both to produce a beta producing plaques, and they produce it the same way, then they should both get Alzheimer's disease exactly the same time, because it's just a matter of time, right? It's thermodynamics, if that is the argument, but what we did is we took the IGF one mutant mice that are long lived, compared to the littermates that are normal live, engineered them that have Alzheimer's disease, the IGF one long live mice didn't start getting symptoms until all the control mice were dead. So they, you know, the same amount of time happened, they're producing the exact same amount of a beta. But thermodynamically, the IGF one mice took care of it. And dealt with it like they were young, young people really, unless it's catastrophic, getting Alzheimer's, I guess there's an age component that happens. Yeah,

Nick Jikomes 1:21:35

and I don't know enough about the Alzheimer's field to know know how to think about this part of the question, but everything you just said makes sense. But it's all predicated on the A Beta plaques being the causal factor here, of course, is that is that the general consensus? Or is that a an X factor still?

Andy Dillin 1:21:54

I mean, it's an it's more, you know, Tao is a major driver of this that was not in our experiments. Also, you know, what we uncovered is that the LIGO murders were really the toxic species. And that was what was driving the pathology. And that's really what people believe now, about a beta. But not even thinking about the disease, just thinking about thermodynamics, you know, forming these aggregates. If it was just a thermodynamic process, both of these animals should have formed them at that exact same rate. They did. Yeah. So there's something inherent about being young. That can delay. I mean, they eventually did form. Yeah. And once they formed them, they formed, they didn't seem pathology as a wild type. But something about being young and youthful, you are delaying these events from happening. Now, could you actually go and reprogram this in an older animal and make them reverse those plaques? I highly doubt it. I think you have to be, you know, in the formation process in the early stages of these types of diseases to to delay that happening.

Nick Jikomes 1:23:05

So there's a lot of experimental manipulations that that you guys can engineer that extend healthspan and lifespan. So you can go into manipulate genes and things like that, setting those things aside, and just thinking about what will just go lifestyle factors, so things that can vary from individual to individual in the population that aren't artificial, in the experimental sense. You know, so you can do animals can have very different diets, one can eat more weight less, one can eat one thing, when to eat another thing. Another could be activity levels, or exercise, one could run around more than the other one. What sort of lifestyle factors are most robustly tied to increases in longevity? Is it caloric restriction?

Andy Dillin 1:23:48

That's it. So we can we can start with calorie restriction. So there's a huge misnomer here. You know, especially my research is like calorie restriction is universal. I mean, yes, of course, it's been tested in many different organisms extends lifespan, blah, blah, blah. But when you take calorie restriction across, you know, different strains of mice, that are not even nearly representing the heterogeneity in the human population, you know, rich Miller did the studies. And, you know, 20% of those strains live long. 20% actually live short.

Nick Jikomes 1:24:26

I see. So some strains of mice, if you calorically restrict them do live longer. But an equal number of strains with different genetic background will actually, you'll see the opposite result with the same

Andy Dillin 1:24:37

restriction. Absolutely. And then the others have no effect whatsoever. And the thing about calorie restriction is we talked about this a little bit earlier, you know, it's this bell shaped curve, and that there's a sweet spot, you know, too much calorie restriction, you're starvation. Too little, you're actually overfeeding and there's like this sweet spot right in the middle. And we all have a different set point for that sweet spot. And if you're as shifted to the right a little bit, and you take the same sweetspot drug that everyone else has, you're actually going to end up dying, because you're on the starvation side of things. And if your left shifted, you're gonna feel no effect. So I think that we have to be super cautious about aging and interventions of aging and applying them to whole populations. I mean, I'm all for the basic biology, you know, aging is been phenomenal for me, because I've uncovered new areas of biology. And that's where I think Aging has its greatest strengths is finding new areas of biology, but trying to actually say we're going to therapy, therapeutically change it, that might be possible in a very restricted fashion. I think it's going to be even more personalized than cancer medications or other types of diseases that are extremely personalized. Now. Aging, I think, is going to be even more personalized, especially when you start dealing with nutrient sensing pathways. Yeah.

Nick Jikomes 1:26:02

I'll just say that that makes a lot of sense. A lot of these results come from single inbred strains of mice. And it's easy to forget that. Yeah.

Andy Dillin 1:26:09

I mean, you look at you know, there's been populations of people that, you know, that lived in certain parts of the world, and all suddenly get a Western diet. And, you know, you and I can adapt to a Western diet, but then all sudden, they're, like 300 pounds, because their setpoint is completely different.

Nick Jikomes 1:26:25

Yeah, I mean, even my last episode was with SK Villar SLUB, who's a evolutionary biologist who studies based basically, human evolutionary genetics in the past few 1000 years. Even if you're talking about white Europeans, there's an incredible amount of genetic variation in fatty acid metabolism, the ability to tolerate carbohydrates that, you know, even even within that, you know, small segment of the human population, you would expect them to see very different responses to caloric restriction or different dietary compositions.

Andy Dillin 1:26:59

Yes, I fully expect it and, and the hard part that we're having is that there's this wave of, you know, diet drugs, it was limbic, these things, as well as Metformin, Metformin is being touted as an anti aging drug, which it does some of those things in model organisms, but, but really, its effects are on diabetes and obesity. Right, you're already at the extreme. And so you're dialing this back to more normal. And I think that now Healthy People will start taking that, but where are they actually on that extreme? They're already normal. So is this actually going to push them? You know, to the other side, that may actually be detrimental? Right. So um, you know, I'm really worried about this may not be any issue. You know, my hope is, you know, Metformin has been taken by billions people, it's pretty safe. It does have some serious side effects, you know, that people do talk about, but you know, I think it's, where are you on this spectrum?

Nick Jikomes 1:27:59

Right. So I think what you're saying is, you know, the Olympics and these GLP drugs that are out there, they're becoming very popular very quickly. Because they do seem to be effective at helping people lose weight, what you are basically saying is, we might want to be cautious, because it might be a good thing, if you're clearly obese, to be on one of these drugs help you lose weight. But if you're sort of a normal person, and you just want to be skinnier, that could be problematic, and there definitely are people using it who aren't morbidly obese.

Andy Dillin 1:28:30

Oh, absolutely. I mean, I was, I don't know if there's me, but Metformin is being touted this way. And I, you know, I have, I have colleagues who are totally healthy, not diabetic, taking Metformin.

Nick Jikomes 1:28:42

Because they think it's going to have a longevity benefit based on and you guys are

Andy Dillin 1:28:45

gonna have a longevity benefit. I mean, they lost, you know, they probably they lost about 10% of their weight, even though they were not overweight. And, you know, they're thinking that they're going to live longer. And I'm like, Well, I hope you're, I don't know where you're at where your setpoint is, yeah. You know, if you're obese, we know where your setpoint is, it needs to go down. So of course, yeah, you're diabetic, yes, we need to bring it down. But when you're in, when you're a healthy person, and you're taking something that we you know, I don't know, the the results for another 30 or 40 years. That really, I don't really know how to how to take that, like, you are really betting on some early stage science, you know, the aging field. You know, the molecular aging field is not very old. And, you know, we're just now getting sophisticated. And I'm really worried about some of the claims that are being made and, you know, what people are trying to do? Yeah,

Nick Jikomes 1:29:40

interesting. So, you know, a lot of the key networks that are important for aging and other things, you know, you've mentioned things like IGF mTOR insulin receptor, you know, we can, I don't know what the best way to start, think about all these things are but they're sort of very important nodes in the regulation. have energy metabolism, how much we're building up versus breaking down tissue. When we think about something like insulin resistance, so I understand why insulin resistance happens. So the cells, there's too much insulin for too long, the cell wants to decrease its sensitive activity to it. I understand why insulin resistance then leads to a decrease in the ability to regulate blood sugar levels. What actually happens after that, that causes damage? So like when a cell is insulin resistant for a long time? What goes wrong downstream?

Andy Dillin 1:30:36

Yeah, I mean, I think it's got to have a complete metabolic rewiring, right, because it's not become insulin resistant, you're not going to be taking in glucose. So you're changing your energy sources. I mean, I'm not a diabetologists. I don't study insulin that much. But I think that you're definitely changing your metabolic demands in that tissue that normally relies upon insulin to get his glucose. And so you're having to change what energy sources it's using? And if it's a cell that can adapt to that, that sounds really bad. I mean, I can't speak more authoritative ly on that, because it's not really my area.

Nick Jikomes 1:31:18

Um, one final thing, if if this is something you do know about, it's just a general thing that's been on my mind for at least the last couple of weeks. So let's see, you're talking about a healthy individual, healthy animal normal mitochondrial function. It's eating a good diet, whatever Exactly. That means. Are the mitochondria going to be preferentially using glucose versus ketones? Or do they like to have a certain mix of those things? Do we know very much about that?

Andy Dillin 1:31:48

I think it depends on which environment that cell is in. And you know, it's actually going to archery oxygen demands are going to greatly determine that how much oxygen is available of how it's actually going to do glycolysis versus oxidative phosphorylation? I think that's gonna be the major drivers of that. And beyond that, trying to think here for a minute. If there's any predictors of this? I don't. I don't know. I don't know. I don't know. Is there a right answer? Did I fail the test? No,

Nick Jikomes 1:32:25

no, I genuinely don't know. You know, I see. I don't know enough to know how much I don't know. But you see, there's a lot of stuff out there where people say, you know, our cells prefer to use glucose or ketones. I've had other people tell me that if you supply your cells with everything they could want, they actually prefer a particular mix of glucose and ketones. And you know, the ratio there shifts, depending on you know, what, you feed the cells. And so I'm just, I'm just trying to get a better handle on that. Yeah. The other, the other thing that you probably do know something about is given how mitochondria work. And given the role of oxygen and the electron transport chain, I imagine they're very sensitive to oxygen concentrations. And I'm wondering what the relationship. So I'll just, this will just be a vague question. What's the relationship between like overall mitochondrial health and oxygen levels in the environment. So if I, if I go to Denver tomorrow, what's going to start to happen to my mitochondria,

Andy Dillin 1:33:22

your mitochondria gonna be fine. I mean, the first thing that your body does is change this phosphoglycerate levels to change oxygen by anything. So that's going to your mitochondria are going to be fine. They're not going to be affected by by the oxygen levels, the only time so there's so if you have a mitochondrial disease, then you start to become sensitive oxygen levels. And there's this beautiful study, Isha Jane, who's at UCSF, when she was with Vamsi. Martha. They're working on a mitochondrial disease complex, Lee syndrome disease. And what people normally wanted to do is they're like, Oh, your mitochondria aren't functioning well. We need to give you more oxygen, to help your electron transport chain function better, to produce more ATP and alleviate symptoms, and what they uncovered it so there's not really much help and giving high oxygen, it actually may be slightly detrimental. And through a series of screens, they uncovered that oxygen sensing was central to this. And they did the reverse experiment. And they actually put these mice under hypoxia. So lower oxygen, you know, that sort of layer, the, you know, being in the lower Himalayas. And now these mice were like totally fine. Like, the mitochondrial disease was gone. And they don't know the mechanism yet of what's happening. It's probably maybe turning on the stress response. Yeah. To help these mitochondria deal with that mutation in the mitochondrial their electron transport chain coupled with lower oxygen that may be turning this thing off. But the fascinating thing is, you know, they're saying, Okay, this could you know, this be maybe a therapy for people with lace syndrome has had them live in bubbles, you know, with lower oxygen. But the second you take them out of the low oxygen, the animals can adapt back, and they die. So that's still, yeah, it's like you're stuck there. I mean, it's not immediate, you know, it takes a couple days, but they can't register back to being sick. They go from, you know, being sick, going in low oxygen being well, coming out of low oxygen not being sick being dead. You're like, and it's like, fascinating. So there it you know, the oxygen tension, syncing with mitochondria is important. But I think I mean, you're not gonna feel like going to Denver. I mean, if you went hiking in the Himalayas and stuff, you're definitely gonna go hypoxic, your mitochondria are probably going to fizz. They're not going to be happy. Denbury will probably be alright. But if you have a mitochondrial disease, you know, I think you're more sensitive, these oxygen fluctuations.

Nick Jikomes 1:36:11

What so you may or may not have a particular answer to this, but I think it's a fascinating pattern. And I'm interested to hear your take, given your background as biologist. So when you think about obesity, one of the most striking graphs I've seen is basically an overlay of obesity rates in the continental United States with a topology map showing altitude. And there's this shocking correlation, where you just see obesity rates go way down as you go up in altitude. So for some reason, Colorado has way lower obesity rates than almost anywhere else in the continental United States. What do you think could be going on there? Does this have something to do with oxygen? Does it have something to do with mitochondrial biology and just overall metabolic rate?

Andy Dillin 1:36:56

I think it's lifestyle. I mean, when you go to Colorado this weekend, why go and climb four flights of stairs and see how you feel? I think I think it's just a lifestyle thing is that, you know, put on 40 pounds of extra baggage on you and climb up and down 40 flights, four flights of stairs, you know, I don't know where you're located, if you're at sea levels can be very different than, you know, 5000 feet.

Nick Jikomes 1:37:21

So you're basically saying that the lower oxygen environment is analogous to me walking around literally with a 40 pound backpack here, or something like that. I have to work harder to do the same behavior. Oh, you're

Andy Dillin 1:37:33

gonna have to work harder in Colorado, right? Yeah. And I just think that that's a selection process is that if you're, you know, if you're obese, you're not going to want to live in Colorado. And

Nick Jikomes 1:37:42

I see. So you don't think okay, yeah, it might not be that the environment is causing this pattern to emerge. It might be that people are sorting themselves. I think people are

Andy Dillin 1:37:50

sorting themselves out. Yes. Okay. Okay. Interesting. Yeah, I think that's absolutely sorting themselves. I mean, I mean, it's such a loaded question, because, you know, there's so many outdoor activities in Colorado, you know, people are super active there. So it's sort of a social, stigmatism to be obese probably in Colorado. And so if you were obese, people want to stay there. Also, you're like, man, it's so hard for me to walk up the stairs, there's lower oxygen. So I'll just go go to lower elevations? I don't know.

Nick Jikomes 1:38:23

I see that.

Andy Dillin 1:38:24

That's an interesting. I don't think it's there. I mean, there's underlying biology, but I think there's more psychology happening.

Nick Jikomes 1:38:32

Okay. Interesting. Interesting. Well, we've already covered a lot. I don't necessarily want to dig into a whole new topic and take up too much of your time. Thank you, for this has been fascinating. Is there anything that you want to reiterate from what we discussed or any final thoughts about this general area of science you want to leave people with?

Andy Dillin 1:38:51

No, I mean, it's, I mean, if there's no future scientists are listening to this. I mean, there's so many things that are uncovered. And our lab is a prime example. I never thought I'd be working on mitochondria. Never thought I'd be working as a neuroscientist. So it's truly fascinating, you know, to see what's out there and there's so many other things happening and, you know, this whole idea of aging. It's early days, it is really early days, and it's going to be super personalized. You know, that's my personal feeling. But exercise sleep well. Try to eat as best you can. I think those are the only things we can get can't control.

Nick Jikomes 1:39:29

All right, Professor Andy Dylan, thanks again for your time.

Andy Dillin 1:39:31

Thanks so much, Nick.

Mind & Matter
Mind & Matter
Whether food, drugs or ideas, what you consume influences who you become. Learn directly from the best scientists & thinkers about how your body & mind react to what they're fed. New episodes weekly. Not medical advice.