WEBVTT - Every Cell in Your Body Has a Clock 0:00:15.396 --> 0:00:23.616 Pushkin Here's a thing I did not know until very recently. 0:00:24.276 --> 0:00:27.586 Every cell in your body has a 24-hour clock in it. 0:00:28.336 --> 0:00:31.636 In other words, your circadian rhythm is not just in 0:00:31.676 --> 0:00:35.436 your brain, it is everywhere in your body. And it 0:00:35.476 --> 0:00:37.276 doesn't just affect when you go to sleep and when 0:00:37.296 --> 0:00:41.146 you wake up. It affects metabolism. It affects repair of 0:00:41.226 --> 0:00:44.846 damaged cells. It affects the release of hormones. Your circadian 0:00:44.866 --> 0:00:47.246 rhythm affects all kinds of things that need to happen 0:00:47.286 --> 0:00:52.466 in your body to keep you healthy. Unfortunately, as you 0:00:52.486 --> 0:00:56.976 get older, the clocks in your cells stop regulating everything 0:00:57.476 --> 0:01:01.956 quite so well. The system gets disordered. Things fall apart. 0:01:02.836 --> 0:01:05.396 It's not all bad news, though. There are things you 0:01:05.436 --> 0:01:09.326 can do to slow the process of degradation. And scientists 0:01:09.386 --> 0:01:12.406 are learning more. They are figuring out how to keep 0:01:12.446 --> 0:01:15.566 the circadian rhythm in all your cells working better into 0:01:15.666 --> 0:01:19.146 old age so that you can stay healthier for longer. 0:01:21.336 --> 0:01:32.586 Music I'm Jacob Goldstein, and this is What's Your Problem? 0:01:32.786 --> 0:01:36.106 My guest today is Karen Esser. She's the chair of 0:01:36.146 --> 0:01:39.586 the Department of Physiology and Aging at the University of Florida, 0:01:40.046 --> 0:01:44.046 and she's a world expert on circadian rhythm in muscle cells. 0:01:44.766 --> 0:01:48.526 Karen's problem is this. What happens to the circadian rhythm 0:01:48.626 --> 0:01:51.346 in muscle cells as we age? And how can we 0:01:51.386 --> 0:01:54.186 keep the system from falling apart? Part of the answer 0:01:54.326 --> 0:01:58.526 seems to be exercise. Exercise helps keep the circadian system 0:01:58.586 --> 0:02:02.886 functioning better for longer. Now, in her research, Karen is 0:02:02.906 --> 0:02:06.126 trying to figure out why. What is going on exactly 0:02:06.326 --> 0:02:09.386 at the cellular level here? And the answer to that 0:02:09.426 --> 0:02:13.396 question could shed light on other ways to fight age-related decline. 0:02:14.296 --> 0:02:17.596 In our conversation, Karen and I discussed why muscle cells 0:02:17.736 --> 0:02:22.016 need a 24-hour clock, what the circadian rhythm in muscle 0:02:22.056 --> 0:02:26.736 cells means for when we should exercise, and Also, how 0:02:26.796 --> 0:02:29.196 your stomach and your brain can wind up in different 0:02:29.256 --> 0:02:32.696 time zones when you travel. And how Karen's research has 0:02:32.756 --> 0:02:36.296 led her to change her own habits. To start, Karen 0:02:36.316 --> 0:02:39.236 told me that she didn't set out to study circadian rhythm. 0:02:39.716 --> 0:02:42.366 She was actually looking at the effect of exercise on 0:02:42.446 --> 0:02:46.186 muscle cells. And she wound up studying circadian rhythm because 0:02:46.226 --> 0:02:49.226 of a finding that was so weird that at first 0:02:49.506 --> 0:02:50.486 she thought it was a mistake. 0:02:51.126 --> 0:02:54.606 We were looking at responses in muscle cells. in response 0:02:54.646 --> 0:02:56.996 to an exercise bout. And the clock genes came up. 0:02:57.426 --> 0:03:00.806 So that study, you know, 20 years ago was focused 0:03:00.866 --> 0:03:04.356 on that with no idea of circadian clock genes. 0:03:04.796 --> 0:03:07.676 But you found it surprising. You said, oh, after a 0:03:07.696 --> 0:03:11.376 bout of exercise, these cells are turning on genes that 0:03:11.416 --> 0:03:14.076 we associate with the sleep-wake cycle, with the circadian rhythm. 0:03:14.156 --> 0:03:15.136 And that was a surprise. 0:03:15.256 --> 0:03:17.496 Correct. But it's in the muscle. Yeah. What the heck? 0:03:17.516 --> 0:03:20.326 So, like, why does the muscle care what time it is? And. 0:03:20.936 --> 0:03:24.296 And really, is this just a technical problem? Did we 0:03:24.316 --> 0:03:27.236 make a mistake? And so, you know, as a PI, 0:03:27.276 --> 0:03:28.826 you always question your students first. 0:03:29.526 --> 0:03:32.426 You thought somebody screwed up. You're like, there's no way. 0:03:32.566 --> 0:03:35.626 No, no. And as usual, the students are fine and 0:03:35.646 --> 0:03:37.846 they did the right thing. It's just the biology is 0:03:37.886 --> 0:03:42.146 much more exciting. So that started my whole research trajectory 0:03:42.206 --> 0:03:44.326 in that. So that's a little side note. 0:03:44.346 --> 0:03:47.386 No, that's quite interesting. I mean, I think there's an 0:03:47.486 --> 0:03:50.476 idea here. Let me take a stab at it. You 0:03:50.516 --> 0:03:52.156 can tell me if it makes any sense or if 0:03:52.236 --> 0:03:56.586 I'm reaching. I feel like there's this interesting arc over 0:03:56.616 --> 0:03:59.126 the past, I don't know, few decades, I guess, of 0:04:00.166 --> 0:04:02.866 realizing that more is going on in each cell than 0:04:02.906 --> 0:04:04.586 we thought. You know, I feel like there's this old 0:04:04.646 --> 0:04:06.486 model where the brain is sort of all the action 0:04:06.526 --> 0:04:08.526 and then the body's just kind of dumb. The muscle just, 0:04:08.996 --> 0:04:11.756 you know, contracts and lifts things. But as we have 0:04:11.776 --> 0:04:14.016 looked closer, including the kind of research you're talking about, 0:04:14.036 --> 0:04:17.556 we've seen that, oh no, the cells themselves are talking 0:04:17.596 --> 0:04:19.816 to each other, are sort of Making what we might 0:04:19.856 --> 0:04:23.686 call decisions or, you know, adapting. And this seems like 0:04:23.746 --> 0:04:26.186 part of that, right? Like the fact that every cell 0:04:26.246 --> 0:04:30.406 has its own 24 hour clock is wild and really interesting. 0:04:31.106 --> 0:04:33.306 It is. It is. And I, you know, I'll be 0:04:33.346 --> 0:04:35.496 real honest. When I first started, I had some colleagues 0:04:35.536 --> 0:04:37.396 that were like, what the heck are you doing? You know? 0:04:37.786 --> 0:04:40.286 Because I had my line of research, I had NIH funding, 0:04:40.306 --> 0:04:42.396 and now I'm going over it. 0:04:42.446 --> 0:04:44.986 You mean when you started looking into circadian rhythms in 0:04:45.026 --> 0:04:47.066 muscle cells? Yeah, because they just said, oh, it's. 0:04:46.986 --> 0:04:51.476 Just noise, or, oh, it's really, the muscle clock doesn't matter, 0:04:51.676 --> 0:04:54.716 it's just a dumb clock downstream of the brain. 0:04:54.916 --> 0:04:57.816 Well, why didn't you listen? Why didn't you think that? 0:04:58.716 --> 0:05:02.316 Well, I don't know, the whole thing fascinated me. The 0:05:02.396 --> 0:05:05.276 idea that you have this clock that's an oscillator clock, 0:05:05.756 --> 0:05:08.836 regulating programs of gene expression in a cell. Yeah. 0:05:08.976 --> 0:05:11.416 And in a muscle cell, in a muscle cell, right? 0:05:11.436 --> 0:05:11.996 It's weird. 0:05:12.596 --> 0:05:17.016 Well, yes, yes. But again, I'm very influenced by evolution. 0:05:17.256 --> 0:05:18.936 Muscle cells are really. 0:05:18.806 --> 0:05:22.926 Old, okay? I mean, they're evolutionarily ancient, older than, say, 0:05:23.206 --> 0:05:25.926 eye cells or something like that. 0:05:25.946 --> 0:05:30.386 Or even a central nervous system, right? My whole training 0:05:30.446 --> 0:05:33.636 and kind of how I've thought about biology... has been 0:05:33.716 --> 0:05:36.836 more that muscle is part of this system. And so 0:05:36.876 --> 0:05:38.836 I think I was a little bit refractory to those 0:05:38.876 --> 0:05:41.096 people that were concerned about me. Yeah. 0:05:41.356 --> 0:05:44.426 I mean, the idea that muscles are sending signals to 0:05:44.446 --> 0:05:48.046 the body, right? That muscles are part of the endocrine system. 0:05:48.066 --> 0:05:51.386 Like they're not just there to move your arms and 0:05:51.426 --> 0:05:52.286 legs around. Right. 0:05:52.546 --> 0:05:54.666 Or look good when you're on the beach, right? 0:05:54.726 --> 0:05:55.486 Most importantly. 0:05:57.296 --> 0:05:58.056 So, right. 0:05:58.076 --> 0:06:02.676 So there is this broader... realization that, I mean, does 0:06:02.916 --> 0:06:06.096 every cell have a clock, have a 24-hour clock? 0:06:07.676 --> 0:06:10.676 Virtually all cells. I think it's pretty safe to say yes. 0:06:11.036 --> 0:06:15.376 And other organisms? Like, does everything, does bacteria have a 0:06:15.756 --> 0:06:16.866 circadian rhythm? It does. 0:06:17.256 --> 0:06:22.826 I mean, they do. But, you know, I think, you know, plants, bugs, insects, 0:06:23.846 --> 0:06:28.526 you know, when you look across, you know, Almost everything 0:06:28.546 --> 0:06:30.306 you're looking at is going to have a clock in it. 0:06:30.306 --> 0:06:32.206 And like every cell in everything. 0:06:32.566 --> 0:06:32.766 Yeah. 0:06:33.326 --> 0:06:35.546 What is the clock? Like we're saying there's a clock. 0:06:35.866 --> 0:06:38.346 It's not a clock. Like it's something where there's like 0:06:38.366 --> 0:06:41.626 a 24-hour cycle where things change over the course of 0:06:41.626 --> 0:06:45.066 24 hours and they go back. But like what's going on? 0:06:45.586 --> 0:06:47.416 It's a great question. And as someone that sort of 0:06:47.426 --> 0:06:50.356 came into the field from physiology, it took me, you know, 0:06:50.376 --> 0:06:51.956 it took a little while to kind of wrap my 0:06:51.996 --> 0:06:55.196 head about how to think about this. So there is 0:06:55.376 --> 0:06:58.186 what we call the core clock. And that is what 0:06:58.286 --> 0:07:02.026 I call the timer. So that's that 24-hour timer. And 0:07:02.086 --> 0:07:05.626 so there is a process of gene expression. Then the 0:07:05.666 --> 0:07:08.766 proteins are made and the proteins come back in. And 0:07:08.786 --> 0:07:12.906 then they do their function. And this takes approximately 24 hours. 0:07:13.206 --> 0:07:16.326 Is the theory that mainly what it's doing is keeping time? 0:07:16.526 --> 0:07:18.866 Is there like a set of gene kind of expression 0:07:18.926 --> 0:07:21.006 and something happens and another gene is expressed and it 0:07:21.046 --> 0:07:23.306 takes 24 hours and that's its function? 0:07:24.096 --> 0:07:25.386 That's part of its function. 0:07:25.416 --> 0:07:28.436 Yeah. Like that is rad, right? Like that is such 0:07:28.496 --> 0:07:31.376 a wild evolutionary thing. 0:07:32.076 --> 0:07:34.296 Oh, it is awesome. And I mean, part of it 0:07:34.376 --> 0:07:36.296 is I just, like I said, I didn't train in this, 0:07:36.336 --> 0:07:37.926 but when I, the more I read about it, it 0:07:37.936 --> 0:07:42.366 was just like, holy, this is really cool. And, and, 0:07:42.786 --> 0:07:46.546 and it's what we call self-sustaining, which means it doesn't 0:07:46.586 --> 0:07:49.086 need a cue. You don't need light for it to work. 0:07:49.126 --> 0:07:52.816 You don't, it is intrinsic to that genetic network inside 0:07:52.856 --> 0:07:55.746 the nucleus of that cell. So it's frigging amazing. But 0:07:55.866 --> 0:07:58.956 it has another job, and this is important from a physiology, 0:07:59.016 --> 0:08:02.416 from an aging perspective, is that these core clock factors 0:08:02.456 --> 0:08:05.936 will also sit on lots of different places. So in 0:08:06.016 --> 0:08:10.666 muscle cells, they will sit on about 4,000 to 5,000 0:08:10.666 --> 0:08:13.726 different places across the genome in a muscle, and they'll 0:08:13.786 --> 0:08:17.886 help contribute to what I call a daily program of 0:08:17.946 --> 0:08:20.486 gene expression. And so I think of it as a 0:08:20.526 --> 0:08:24.746 temporal organizer of housekeeping. And again, for a muscle cell, 0:08:25.176 --> 0:08:27.726 What you see before you wake up in your muscle 0:08:27.756 --> 0:08:32.226 cells would be genes that are important for metabolism, right? 0:08:32.346 --> 0:08:33.506 For oxidative metabolism. 0:08:33.526 --> 0:08:35.626 So this is like early morning, an hour before I 0:08:35.666 --> 0:08:38.466 get up at whatever, 6.30 every day. What's going on? 0:08:38.866 --> 0:08:40.906 Let's do a day. Can we do a day in 0:08:40.946 --> 0:08:41.566 a muscle cell? 0:08:41.586 --> 0:08:42.346 We can do a day. 0:08:42.366 --> 0:08:45.526 Okay. So it's 5.30 in the morning, an hour before 0:08:45.546 --> 0:08:47.596 I'm going to get up. If it's a good night, 0:08:47.636 --> 0:08:51.136 I sleep till 6.30. What's going on in my muscle 0:08:51.156 --> 0:08:52.096 cell at that time? 0:08:52.736 --> 0:08:55.036 So what the clock is doing at that time, so 0:08:55.196 --> 0:08:57.186 obviously your muscle cell is kind of hanging out, but 0:08:57.226 --> 0:09:00.006 the clock is regulating genes that are going to contribute 0:09:00.046 --> 0:09:03.786 to your ability to use carbohydrates and fats as fuel. 0:09:04.066 --> 0:09:06.146 So it's getting ready. It knows I'm going to get up. 0:09:06.246 --> 0:09:07.026 That's what's happening? 0:09:07.346 --> 0:09:08.846 Yeah, I think of it warming up the engine. 0:09:08.886 --> 0:09:09.276 I love it. 0:09:09.366 --> 0:09:11.756 The metabolic engine. So you get that warmed up because 0:09:11.796 --> 0:09:13.056 you don't want to start from cold. 0:09:13.176 --> 0:09:13.536 Okay. 0:09:14.736 --> 0:09:17.376 And so now you wake up and you're ready to go. 0:09:18.216 --> 0:09:20.456 And the things that are important so that, you know, 0:09:20.476 --> 0:09:23.416 your mitochondria are ready, all these things that are important 0:09:23.496 --> 0:09:30.106 for input or sensitivity to insulin or incoming glucose. They're already. 0:09:30.366 --> 0:09:32.406 So just to be clear, they're primed so that when 0:09:32.466 --> 0:09:34.606 I get up and I start using my muscles, whether 0:09:34.646 --> 0:09:37.166 it's just going downstairs to make breakfast or going for 0:09:37.186 --> 0:09:40.596 a jog, they're ready to take in sugar and make 0:09:40.656 --> 0:09:42.416 energy and do their work as muscles. 0:09:42.796 --> 0:09:46.916 Correct. Yes, exactly. So they're ready to do work because 0:09:46.936 --> 0:09:51.076 that's what muscles do. But they obviously need fuel for that. 0:09:51.296 --> 0:09:53.276 And then what happens over the course of the day? 0:09:53.586 --> 0:09:57.526 So now we're up. Is stuff changing all through the day? 0:09:58.296 --> 0:10:02.336 Absolutely. And so what you will see is that so 0:10:02.616 --> 0:10:05.086 as you start moving, as you start working, depending on 0:10:05.146 --> 0:10:08.726 how intense and that, some of your energy stores, like 0:10:08.746 --> 0:10:11.716 some of your... like glycogen, that will start declining. 0:10:11.796 --> 0:10:14.856 Yeah, which is basically stored sugar. Yeah, stored glucose. 0:10:14.876 --> 0:10:17.816 Right. So that's going to be highest in muscle at 0:10:17.856 --> 0:10:20.606 the start of the day. And then it'll start to 0:10:20.646 --> 0:10:23.136 get used as you do things. Yeah. And then you 0:10:23.176 --> 0:10:25.866 start moving into kind of the second half of the day. 0:10:26.226 --> 0:10:29.656 And it's, again, depending on your daily life patterns, then 0:10:29.726 --> 0:10:33.206 it's starting to prepare for the rest phase, which means 0:10:33.626 --> 0:10:35.126 what are you going to do during the rest phase? Well, 0:10:35.146 --> 0:10:38.066 you're going to start restoring glycogen. You're going to store 0:10:38.086 --> 0:10:42.046 other energy substrates. The way I think about it is, 0:10:42.286 --> 0:10:44.926 you know, you don't want to be repairing and replacing 0:10:44.966 --> 0:10:47.856 while you're using and contracting. I see. So you're going 0:10:47.876 --> 0:10:50.556 to send that to the rest phase. Recovery and maintenance 0:10:50.616 --> 0:10:53.336 gets done while you're in the shop, i.e. sleeping. 0:10:53.456 --> 0:10:59.326 Okay. So it's basically get ready to work, work, get 0:10:59.396 --> 0:11:01.106 ready to recover, recover. 0:11:01.706 --> 0:11:02.146 Correct. 0:11:02.246 --> 0:11:08.026 That's the basic cycle. Right. And so how does my 0:11:08.186 --> 0:11:13.546 exercise habit affect the circadian rhythm? Oh, my God. 0:11:14.886 --> 0:11:17.696 We don't have enough time for this one. Right. I'm sorry, 0:11:17.996 --> 0:11:21.196 because we're just learning some really exciting things right now. 0:11:21.256 --> 0:11:22.756 So this is a great topic. 0:11:22.816 --> 0:11:23.716 Okay. 0:11:23.956 --> 0:11:27.346 Because I also have this role within the Motorpack Consortium, 0:11:27.376 --> 0:11:27.826 which is. 0:11:28.126 --> 0:11:33.446 Love Motorpack. Molecular transducers of physical activity. Did I get it? 0:11:33.446 --> 0:11:34.226 I don't have it in front of me. 0:11:34.306 --> 0:11:37.766 Exactly. So what is it about exercise that makes us healthy? 0:11:37.806 --> 0:11:39.986 Let's just say what Motorpack is, because it's part of 0:11:40.046 --> 0:11:42.046 the reason I want to be doing these interviews, right? 0:11:42.086 --> 0:11:46.096 The big idea of like... We've known for a long 0:11:46.136 --> 0:11:48.196 time that exercise is really good for you, but we 0:11:48.236 --> 0:11:52.136 haven't really understood why at a kind of cellular level. 0:11:52.596 --> 0:11:55.276 And motor pack is this big study trying to figure 0:11:55.316 --> 0:11:56.116 that out, right? 0:11:56.676 --> 0:11:59.556 Right. And I was part of the preclinical arm of 0:11:59.636 --> 0:12:02.576 motor pack. So we worked with the animal stuff. And 0:12:02.596 --> 0:12:04.796 what I love, I will say is, you know, we 0:12:04.836 --> 0:12:08.376 studied 18 tissues in these animals. So we're looking at spleen. 0:12:08.396 --> 0:12:10.726 We're looking at small intestine, different parts of the brain. 0:12:11.476 --> 0:12:14.736 Not the usual suspects, the muscle, heart, you know, fat. 0:12:15.136 --> 0:12:18.736 So anyway, so we are currently working on a series 0:12:18.796 --> 0:12:22.456 of manuscripts to be submitted hopefully in the next six months. But, 0:12:22.616 --> 0:12:25.436 you know, in terms of the systemic effects of exercise 0:12:25.476 --> 0:12:29.096 and the way exercise or physical activity, if people don't 0:12:29.136 --> 0:12:33.466 even want to just move, the way that can communicate 0:12:33.496 --> 0:12:36.726 throughout your body to cells that you maybe didn't even realize, 0:12:36.906 --> 0:12:40.106 you know, cells in the lung, your immune cells, like 0:12:40.126 --> 0:12:43.446 I said, the spleen, The colon, the colon, you know, 0:12:43.506 --> 0:12:45.736 with training, the colon is changing as much as a 0:12:45.746 --> 0:12:49.116 muscle cell is. And so, you know, the health benefits 0:12:49.176 --> 0:12:50.716 are absolutely systemic. 0:12:51.236 --> 0:12:54.996 I'm glad to hear it. Tell me about what you're 0:12:55.016 --> 0:12:57.136 learning about the circadian rhythm in particular. And I mean, 0:12:57.156 --> 0:13:00.456 really what I'm asking, so you've talked about the kind 0:13:00.496 --> 0:13:03.686 of basic circadian rhythm. And so I'm curious, how does 0:13:03.746 --> 0:13:07.186 it change with age? And how does it change with exercise? 0:13:07.306 --> 0:13:09.786 And then what is the relationship of exercise and aging 0:13:09.926 --> 0:13:11.286 in the context of the circadian rhythm? 0:13:11.786 --> 0:13:16.436 Okay, so let's start with aging. So what we've done, again, 0:13:16.476 --> 0:13:20.096 this is all with preclinical work, but the limited clinical 0:13:20.136 --> 0:13:24.556 data with aging and circadian rhythms is very consistent. And 0:13:24.616 --> 0:13:27.856 that is the clock works as we get older. So 0:13:27.896 --> 0:13:29.876 the timer still works. So if you think about those 0:13:29.916 --> 0:13:32.806 two functions I talked about, which is the timer, and 0:13:32.846 --> 0:13:34.866 then we're going to call it the output of the clock, 0:13:35.766 --> 0:13:39.946 the output changes. And the output starts changing in middle age, unfortunately. 0:13:41.666 --> 0:13:44.506 So even though the clock's working, the types of genes 0:13:44.566 --> 0:13:48.886 it's regulating and when it's regulating those genes... Going back 0:13:48.936 --> 0:13:51.276 to your conversation with one of the other guests you 0:13:51.316 --> 0:13:54.856 had on was talking about autophagy or the ability of 0:13:55.216 --> 0:13:58.826 the cell to break down proteins. Well, at a young 0:13:58.986 --> 0:14:03.186 age in the muscle, genes involved in autophagy are under 0:14:03.286 --> 0:14:06.746 circadian control, and they are peaking just as we go 0:14:06.786 --> 0:14:09.286 into the rest phase, as we were talking about. Right. 0:14:09.316 --> 0:14:12.076 This is part of the sort of cleaning up the cells. Correct. 0:14:14.046 --> 0:14:16.866 By the time the animals are middle age, those genes 0:14:16.956 --> 0:14:20.406 involved in autophagy are now peaking toward the end of 0:14:20.456 --> 0:14:23.716 the rest phase. So now they're going to be coming 0:14:23.836 --> 0:14:25.396 on at a time you're going to want to be 0:14:25.436 --> 0:14:27.836 moving around. And so, you know, when I think about 0:14:27.856 --> 0:14:31.456 the clock, it's like you've disordered the sequence. 0:14:31.556 --> 0:14:34.996 It's not working as well. It's going to work, but. 0:14:34.936 --> 0:14:36.956 It's not going to work as well. The efficiency is 0:14:36.976 --> 0:14:38.916 going to be down and there are going to be 0:14:38.956 --> 0:14:40.136 more mistakes made. Yeah. 0:14:40.256 --> 0:14:40.616 Okay. Okay. 0:14:41.296 --> 0:14:43.156 And so then by the time you get to really 0:14:43.216 --> 0:14:48.546 old age, it's just, it's awful. It really is. When 0:14:48.586 --> 0:14:52.006 you're younger and even when you're middle age, there are 0:14:52.086 --> 0:14:55.786 categories of genes that are regulated across all 24 hours. 0:14:55.886 --> 0:14:58.546 By the time you get to, in the mouse muscle, 0:14:58.586 --> 0:15:00.956 by the time you get to old age, that gets lost. 0:15:01.096 --> 0:15:03.556 You get a peak of genes peaking around sort of 0:15:03.676 --> 0:15:09.556 rest to active phase transition. But that's it. And the overlap, 0:15:09.946 --> 0:15:13.176 So the genes that are what we call clock-controlled in 0:15:13.196 --> 0:15:15.816 the very old are not at all what you see 0:15:15.836 --> 0:15:18.256 in the younger animal, and they're not at all what 0:15:18.276 --> 0:15:20.756 you see in the middle age. So there's a loss 0:15:20.796 --> 0:15:22.896 of identity as well as a loss of timing. 0:15:26.366 --> 0:15:28.886 We'll be back in a minute with some good news. 0:15:38.396 --> 0:15:41.966 Tell me about exercise and circadian rhythms. You know, in 0:15:42.006 --> 0:15:45.006 the muscle, but throughout the body. Like, what does it do? 0:15:45.566 --> 0:15:46.226 How does it work? 0:15:46.906 --> 0:15:49.866 So, we're learning. So, again, I always, I don't want to. 0:15:49.966 --> 0:15:52.126 Well, tell me what's clear. Like, let's start with what's 0:15:52.186 --> 0:15:54.326 most clear and then move towards sort of the frontier 0:15:54.346 --> 0:15:55.246 of what you're figuring out. 0:15:56.166 --> 0:15:59.786 So, what we do know is that muscle contractions or 0:15:59.886 --> 0:16:04.266 exercise of the muscle absolutely talks with the clock system 0:16:04.326 --> 0:16:08.686 in the muscle. And so... What that means is, let's 0:16:08.706 --> 0:16:11.636 say I've been exercising in the afternoon and my work 0:16:11.656 --> 0:16:14.116 schedule changed, so now I'm going to have to exercise 0:16:14.156 --> 0:16:16.356 in the morning because of my job, right? So I'm 0:16:16.376 --> 0:16:18.976 going to start exercising in the morning. What will happen 0:16:19.056 --> 0:16:21.516 is the clocks in the muscles, it may not feel 0:16:21.556 --> 0:16:24.376 great at first, but the muscle clocks will sense the 0:16:24.416 --> 0:16:28.166 timing of exercise and they're going to shift. And in general, 0:16:28.226 --> 0:16:29.926 the way to think about it is, so if I 0:16:29.986 --> 0:16:33.526 was exercising in the afternoon, they're going to shift closer 0:16:34.086 --> 0:16:38.216 to align itself with when, you know, I am exercising 0:16:38.256 --> 0:16:41.396 in the morning. So that will happen. It doesn't require 0:16:41.456 --> 0:16:43.556 a change in the brain for that shift to happen. 0:16:43.676 --> 0:16:47.156 And so what is what's actually happening when that happens? 0:16:47.186 --> 0:16:50.386 It's sort of like they're storing energy. Like, what does 0:16:50.426 --> 0:16:51.746 that mean in practice, that shift? 0:16:52.226 --> 0:16:54.726 What we would predict is that, you know, so all 0:16:54.746 --> 0:16:56.866 the things I talked to you about, what happens to 0:16:56.886 --> 0:16:59.306 your muscle over time a day, All you're doing is 0:16:59.366 --> 0:17:02.386 shifting all those jobs to an earlier time. So you're 0:17:02.406 --> 0:17:05.786 going to prepare for your activity earlier and then the 0:17:05.836 --> 0:17:08.596 recovery will also be shifted in time. So you're going 0:17:08.616 --> 0:17:11.176 to just take your biology and shift it over. 0:17:11.196 --> 0:17:14.556 I mean, obviously, I know the main thing with exercise 0:17:14.616 --> 0:17:17.476 is just exercise. And like, I'm not really an optimizer. 0:17:17.516 --> 0:17:21.576 I just want to exercise every day. But, like, what 0:17:21.636 --> 0:17:25.056 is what you're saying about the circadian rhythm and your 0:17:25.076 --> 0:17:28.056 body adjusting if you usually exercise at a certain time? Like, 0:17:28.116 --> 0:17:30.036 what does that mean for how I should think about 0:17:30.776 --> 0:17:33.386 when I exercise if I have some control over when 0:17:33.426 --> 0:17:33.946 I exercise? 0:17:34.106 --> 0:17:37.426 So, I mean, this is a great question. What I 0:17:37.446 --> 0:17:41.506 would say is if you're thinking about performance, like, let's 0:17:41.526 --> 0:17:43.106 say you're going to be in a race or you're 0:17:43.146 --> 0:17:46.286 going to then you want to be exercising about the 0:17:46.326 --> 0:17:49.156 time you're going to be performing. So your system is 0:17:49.846 --> 0:17:52.896 I really don't believe in optimization, but it's best suited 0:17:53.076 --> 0:17:54.176 for that time. 0:17:54.196 --> 0:17:55.776 Yeah, if you want to run as fast as you 0:17:55.816 --> 0:17:58.316 can in your half marathon, then you should try and 0:17:58.336 --> 0:18:00.236 do your daily jog at the time the half marathon's 0:18:00.276 --> 0:18:01.456 going to be. Correct, correct. 0:18:01.976 --> 0:18:05.266 If you're, you know, exercising for health, that's more important 0:18:05.306 --> 0:18:08.546 than exactly when you exercise. And again, I also don't 0:18:08.586 --> 0:18:11.206 want to be too overly precise. You know, the clock 0:18:11.286 --> 0:18:13.826 is not, oh, you've got 15 minutes. If you don't 0:18:13.886 --> 0:18:16.506 exercise now, you're not going to capture it. No, it's 0:18:16.526 --> 0:18:17.086 not like that. 0:18:17.486 --> 0:18:21.276 So you've talked about aging and the circadian rhythm. And 0:18:21.356 --> 0:18:24.906 basically the circadian rhythm, just the clocks are not as 0:18:24.996 --> 0:18:27.146 effective at doing what they're supposed to do as you 0:18:27.186 --> 0:18:33.286 get older. And then exercise basically can adjust the clock. 0:18:33.366 --> 0:18:37.106 What effect does exercise have on aging in the context 0:18:37.206 --> 0:18:38.226 of circadian rhythm? 0:18:39.086 --> 0:18:41.466 So a junior faculty member in my lab has a 0:18:41.666 --> 0:18:44.126 study on that right now, and it's very exciting. 0:18:44.146 --> 0:18:45.686 So it's a secret? Can you tell me? 0:18:46.406 --> 0:18:48.906 Well, it's, you know, it's his work and I want 0:18:48.926 --> 0:18:52.416 to let him But it's good. It's very good. And 0:18:52.876 --> 0:18:57.486 so being more active improves the function of the clock 0:18:57.516 --> 0:19:00.586 and the clock output. And this was data looking at 0:19:00.646 --> 0:19:03.866 both muscle and liver. So the impact of exercise on 0:19:03.906 --> 0:19:13.996 the clock is system-wide. It's hippocampus, hypothalamus, cortex, spleen, small intestine, colon, muscle, heart, 0:19:14.116 --> 0:19:18.596 the usual suspects. But every organ in the body is 0:19:18.656 --> 0:19:22.956 responding to exercise in terms of their clock components. And 0:19:23.056 --> 0:19:26.756 so I am beginning to, well, I've been wondering about this, 0:19:26.796 --> 0:19:29.946 but I'm beginning to think about exercise as a clock 0:19:29.996 --> 0:19:34.446 improver with age. People are looking for small molecules. So 0:19:34.466 --> 0:19:37.286 there definitely are people out there looking to target the clock. 0:19:38.116 --> 0:19:42.876 Small molecules meaning drugs. Small molecules meaning drugs. Or nutraceuticals. Yeah, 0:19:42.916 --> 0:19:46.276 or supplements. Yeah. And so, I mean, as I understood 0:19:46.296 --> 0:19:50.586 it before, the problem isn't that the clock itself, it 0:19:51.026 --> 0:19:53.706 still keeps time just as well, but that it's like 0:19:53.786 --> 0:19:57.706 when the clock is telling other, well, genes basically, right, 0:19:57.746 --> 0:19:59.516 to turn on or off, that's the problem. part that 0:19:59.556 --> 0:20:01.596 gets less effective with age. Right. 0:20:01.816 --> 0:20:02.036 Correct. 0:20:02.076 --> 0:20:04.636 And so the intervention isn't to make the 24 hour 0:20:04.676 --> 0:20:08.876 thing work, keep time better. It's the relationship between the 0:20:08.916 --> 0:20:10.856 clock and all the genes it's turning on and off. 0:20:11.356 --> 0:20:12.656 Perfect. You've got it. 0:20:12.936 --> 0:20:16.316 Does it matter what time of day I exercise? Let's stipulate. 0:20:16.736 --> 0:20:19.126 Always it's better to exercise than to not exercise. And 0:20:19.166 --> 0:20:21.256 the important thing is to exercise. And, like, I'm not 0:20:21.296 --> 0:20:25.446 trying to win a race. Like, if I have some flexibility, 0:20:25.506 --> 0:20:26.026 does it matter? 0:20:26.046 --> 0:20:27.726 I don't think so. 0:20:27.906 --> 0:20:29.286 Is it better if I do it at the same 0:20:29.346 --> 0:20:30.646 time every day if I can't? 0:20:30.846 --> 0:20:33.026 That's what I'm going to come back to. I would 0:20:33.066 --> 0:20:34.926 say that, you know, so what we do know is 0:20:34.966 --> 0:20:37.026 what time you exercise can make things shift. 0:20:37.246 --> 0:20:37.426 Yeah. 0:20:37.766 --> 0:20:41.386 So probably what's not recommended is, you know— seven in 0:20:41.406 --> 0:20:43.726 the morning one day and seven at night the next day. 0:20:43.826 --> 0:20:46.726 And this is a new field, to be honest with you. 0:20:46.946 --> 0:20:50.706 And so based on what I understand with the clocks, 0:20:50.786 --> 0:20:53.966 with the clocks and exercise and health, I think just 0:20:54.106 --> 0:20:57.126 find a routine that works for you. When you're active, 0:20:57.206 --> 0:21:00.176 how you're active, if you're active, is going to be 0:21:00.216 --> 0:21:05.476