ZOE Science & Nutrition - The best exercise routine, according to your muscle clocks with Professor Karyn Esser

Episode Date: April 4, 2024

Our bodies naturally follow a roughly 24-hour cycle, called our circadian rhythm. And every cell has a rhythm. As we get older, we tend to lose muscle, making us more prone to falls and less able to live independently. Though we can't stop aging, staying active helps keep our muscles strong and our bodies healthy for longer. Prof. Karyn Esser is a specialist in how the body's natural rhythms affect muscles. Today, she guides us through the latest research and shows that it's always possible to harness the power of your muscles to enhance your quality of life. She is a professor in the Department of Physiology and Aging at the University of Florida, where she’s also the co-director of the University of Florida Older Americans Independence Center. In today's episode of ZOE Science & Nutrition, Jonathan and Karyn explore the body's internal clocks and ask: why do our muscles have their own schedule, and is there an ideal time of day to exercise? 🌱 Try our new plant based wholefood supplement - Daily 30 *Naturally high in copper which contributes to normal energy yielding metabolism and the normal function of the immune system Learn how your body responds to food 👉 zoe.com/podcast for 10% off Timecodes 00:00 Introduction 00:18  Quickfire questions 02:01  Why are muscles important, particularly as we get older? 08:45  Why we all lose strength as we age 11:07  What type of exercise do we need to maintain our muscle strength as we age? 14:55  What is a circadian clock? 19:25  Everything has a circadian rhythm 21:32  Why do our muscles work on a 24-hour cycle? 24:20  Humans are stronger in the afternoon 30:24  Is there a best time to exercise? 35:01  Can exercise before or after work help shift workers with jet lag? 37:33  Is there a difference between men and women’s responses to circadian rhythms?   41:44  What are the effects of time-restricted eating on muscle mass? 53:42  Summary Mentioned in today's episode: Defining the age-dependent and tissue-specific circadian transcriptome in male mice from Cell Reports Related studies:  Timing is everything: Circadian clocks set the rhythm for vital functions in bacteria from the University of Chicago Effects of resveratrol on in vitro circadian clock gene expression in young and older human adipose-derived progenitor cells in Aging Age is associated with dampened circadian patterns of rest and activity: The Study of Muscle, Mobility and Aging (SOMMA) in medRxiv Have feedback or a topic you'd like us to cover? Let us know here Episode transcripts are available here.

Welcome to ZOE Science and Nutrition, where world-leading scientists explain how their research can improve your health. In today's episode, you'll learn how to stay strong as you age. Now, you're probably unsurprised to hear that strength is important in later life. Losing it can lead to frailty, fractures, and ultimately death. But you may be surprised by what's impacting our ability to maintain strength. According to today's guest, it has something to do with the time of day when we're active. Karen Esser is a professor of physiology and aging at the University of Florida

and co-director of the Alder Americans Independence Center. She's a truly world-leading expert on this topic, and her groundbreaking new research focuses on the muscles' own circadian rhythms and how they affect strength and health. Karen, thank you for joining me today. Well, it's great to be here, Jonathan. All right. Well, Karen, we have a tradition here at Zoe where we always start with a quick fire round

of questions from our listeners. And we have some very strict rules. You can say yes or no, or if you absolutely have to, you can give us up to a sentence. Now, we know this is very difficult for professors, but are you willing to give it a go? Sure. Brilliant. All right. I like that you're game for this. Okay. Am I likely to lose a lot of my muscles as I get older? The amount varies, but yes. If I lose muscle as I age, is this going to be bad for my long-term health? Yes. Do our muscles have their own body

clock? Yes. There you go. You see, it's not so bad. If I exercise at the wrong time of day, could this mess with my body clock? It depends. Is there a best time in the day for someone to exercise? Yes. So we've spoken to a number of different experts on the podcast in the past about how important exercise is, particularly sort of if you want to stay healthy over time and how important it is, in fact, to keep those muscles. We've had no conversations whatsoever about when to exercise. And I think this is information that most people have not only never heard of, but never even thought that it could possibly matter. So I'm really excited. This is like, you're basically leading the world in this area, which you've said seems sort of obvious to you,

but I think most people listening are going to be like, oh, that's really surprising. But before we dive into that, I'd really like to sort of start at the first level, which is why is staying strong so important to our health at all? What I will say is the data for muscle strength and maintenance of muscle strength with aging or, you know, in conditions of some, a variety of different chronic diseases is really quite stunning. So there's about 20 plus years of epidemiological data that make very clear that loss of strength and secondarily loss of muscle mass increases your probability of bad outcomes, i.e. death. In many ways, to me as someone that's been studying muscle my whole career, it's sort of a little frustrating

that our clinical colleagues don't always recognize the importance of strength. I mean, so there's lots of data in the epidemiological field where the more basic science and translational science is coming in is the why. So what is it about maintaining muscle strength that actually helps our system be more resilient and be more healthy? Right. So there is there's one area in which metabolic health. So muscles are your primary sore site in the body where you store glucose. Which is sort of blood sugar. Yes. And so, you know, there are estimates that vary,

but let's just say about 80% of the sugar that you store in your body is in skeletal muscle. 80% of the sugar, I just want to make sure I got that, 80% of the sugar that you're storing in your body is actually in your muscle, which I think most people are like, I didn't realize I stored anything in my muscles. I thought it was just this thing I remember, you know, like learning at school. It's just a thing that sort of contracts to lift things. So have we always known that we were storing all of this sugar in our muscle? Yeah, yeah. It's another one of those pieces of information that's been around for quite a long time.

So when you think about systemic sugar control or glucose control, your muscle is part of that equation. Now your pancreas with insulin is also part of that and the liver is important, but muscle is a big player in that network that helps keep you metabolically healthy. Okay. And I'm not talking about weight loss. I'm not talking about that. I'm just talking about management of blood sugar, management of metabolic health. Okay. So this is avoiding things like diabetes? Correct. So I think it's important for everybody to understand that healthy muscle is part of the equation for everybody to have, you know, healthy metabolism, healthy blood sugar management. So there is that property.

The other thing, you know, obviously, again, thinking about aging, maintenance of muscle strength is going to be really important as we think about getting out of the chair, maintaining independent living, and also breathing, right? So coughing, breathing, these things that we take for granted require muscle and require muscle to work and generate proper amounts of force. And so to handle the cough or to handle the inspiration and expiration required with breathing. So it's not just your leg muscles that matter, it's the other muscles in your body, and they are everywhere. So things like coughing, obviously, if you've, you know, eaten something or swallowed something and it's gone, as we say, down the wrong tube,

so you want to cough, you know, you don't want to be putting liquids into your lungs, so you cough to keep it from going down the wrong tube, right? Well, if you're not strong enough to get that out, there's an increased probability that some of the stuff you don't want going down will go down. I think we've heard some people even on the show talking about the importance of doing exercise to maintain the independent living that you're describing. Nobody's talked to me about the exercises for coughing. Do you just get this for free if you continue to do some exercise? Well, it's a great question, but I have to say, I don't think we have data that directly demonstrates that. I think there are many,

many in the field that would say if you're exercising, there is that systemic benefit of exercise. And again, when you're exercising, you're breathing. So, you're working the muscles of inhalation, exhalation. So, those are going to get exercise trained. And is there anything else that muscles are doing? Because I understand that there has been a shift to think about muscles as sort of a more active, complex sort of organ in our body than, again, the sort of model that I grew up with, which is it's literally, it sort of, you know, it opens and closes. I'm just putting my hands backwards and forwards to demonstrate the simplicity of understanding the muscle. But I've heard of

some suggestion that we now think it's doing more. Oh, absolutely. I think so. So the other very somewhat, I guess you'd call it hot area is muscle is an endocrine organ. So people coin the term myokines. These are very fancy words. Could you help me understand what that means, Karen? The term is called myokine. So myo is a muscle prefix, kine being like endocrine. The concept here is there are things that get made in muscle that can be released into the blood

that can work at remote sites like the brain, like the heart, like the liver, the kidney, etc., in ways that support systemic health. Got it. So just to play that back, make sure I understood it. You're saying that the muscle's a bit like we know that our liver creates things that go around in our blood elsewhere in our body. You're saying actually our muscles are also creating some sort of chemicals that are then going around the body, which is very different from thinking about them as just being acted upon as sort of like these springs or something like that. Is that pretty robust science? Is the evidence for that strong now?

Yes, there actually are, you know, strong now? Yes. It's very robust. I mean, I think we're actually at the tip of the iceberg, as they say. There are some known factors, IL-6 being one of them that was identified many years ago. And the most recent one is something called irisin. But I think, like I said, I think we're just starting to understand that. And so that is another example where you're saying that having like strength and muscles as we age is going to be really important for supporting our health. And I think what I also understand from talking to some people in this podcast is in general, we're all much weaker in later life than our

ancestors would have been. I think a lot about evolution when I think about science. So yes, one might say that, you know, if you look at muscle strength of a, let's say an 80 year old, it's less than maybe somebody we would have seen, you know, 100 years ago. But most people didn't live to 80. So, so I would say that, you know, 100 years ago, but most people didn't live to 80. So, I would say that, you know, what we're realizing is as we've been able to, you know, with our medications and stuff and our healthy living, we're living longer. But the reality is, I don't care whether you're a master's athlete or whether you're just a regular person, no matter what, you're going to lose strength with age. We have not

figured out how to stop that process. So what you're saying is, well, actually, in the past, almost everybody died before they got to 70. So frankly, there are more people who are strong age 70 than before, because in the past, most of them were dead. Maybe to put it a different way is that if you want to be having a really high quality of life as you're older, then you in fact do need to have this muscle strength in the same way that we might think about, you know, having a, you know, healthy immune system or whatever else. I feel that's very different from even what I was, what I was being taught, you know, when I was a teenager, that there's been this big shift where I didn't hear anyone discuss the idea that you needed to have any muscles at all,

really, when you were 70. That was not viewed as relevant in the mainstream. Right. You just sort of needed a brain and a heart and you're okay. Correct. So I feel like that's a big shift, at least in terms of public understanding of this. Is that fair, Karen? Yeah, no, I would. I agree completely. And what I think is a very strong argument is that people consider, you know, consider thinking about strength related exercises, not, you know, as we get older.

And, you know, the cardiovascular stuff is still important. Don't get me wrong. But inclusion of some things that help maintain, let's say, upper body strength, shoulders, back, and is going to help improve quality of life and health as we age. Hi, I'm Zoe's U.S. Medical Director, Dr. Will Bolsowitz, and I'm excited to tell you about a free resource that's going to kickstart your journey to better gut health. If you're a regular listener, you probably already know how a healthy gut microbiome is important for digestion, immune support, and mental well-being, and that a high-fiber diet is a great way to improve your gut health. But where to start? And what exactly does a high-fiber shopping list look like? With 95% of US adults deficient in fiber, clearly this is not common knowledge.

Zoe's Gut Guide has the answers. To get yours for free, simply go to zoe.com slash gut guide and start feeling the benefits of a healthier gut today. Practical question, therefore, what do you think that people need to do in order to maintain muscle? Not in order to be an Olympic athlete at the age of 80, but maybe to say, I'd like in my 70s, for example, to have really high quality of life, or indeed, in my 80s, I'd like to have really high quality of life. What level and what sort of activity you feel is required in order to maintain the muscles for that? There are layers, right? So if you're not active, just be active. So if that means walking around the block, I mean, walking is a fantastic activity.

The other thing, and I'm saying this a little bit from my own personal experience, you know, just bringing a little bit more resistance type exercises into your life. So whether that's doing things like pushups, you know, doing a little bit of strength exercises, you know, to make sure your shoulders stay healthy so I can pick up my grandchildren, carry the groceries, go to the airport, carry my bag. Those are the kind of activities I think about that I want to be able to keep going as I get older and older. And at this stage, it needs a little reminder. It needs a little training. It needs a little more attention than it did when I was, let's say, in my 40s or 50s. And there's a little bit of reversal, isn't there, about also our societal views of this, where therefore I shouldn't immediately take the bag away necessarily from my mother or father is what you're saying, right? Like actually, them carrying that is actually a really good thing. I just want to check that that's correct. If they want to carry that stuff, by all means, let them. If they want to work around the yard, I mean, yard work's another good thing.

You know, carrying a bag of mulch, carrying, you know. So, again, it doesn't have to be anything sophisticated or fancy. But the idea is you need to put load, which you probably have had for some of the exercise. You want to put some loading on the muscle groups. And the ones we load the least, again, depending on your lifestyle, but for some of us that sit around working on a computer most of the time, is sort of back, shoulder, upper body, core, core exercises. And I think it's really easy to forget they're kind of there, but you know, once you start paying attention to them, I think most people will notice the benefit. That's brilliant. And I think it's a, it's a brilliant setup for why these muscles are so important and why they're not just,

you know, in order to, you know, look good when you're young. I have a 16 year old, um, son who's like very excited by the fact that he's just grown taller than me. Literally every day he wakes up and his muscles have grown and he's discovered that he can go to the gym and he's getting this great pleasure, which I love from it. And based upon podcasts like this, I'm very supportive of, but he's definitely not worrying about his long-term health, right? He basically just is totally focused on the day that he's stronger than me. That is basically, that's clearly the objective. So I think explaining that actually this is really important for your long-term health is a huge shift. And Pat, and again, you can say patterns

that we all set in our younger years and your younger, depending on where you are, your younger years can be anywhere, right? So it can be the 16 yearyear-old, it can be the 30-year-old, it can be the 50-year-old. And, you know, that will all help, right? So it doesn't go astray, I guess is the point I want to make. You can start being active at any age. Obviously, there are certain ages you need to be a little bit more aware of any kind of clinical issues. But for the most part, making an effort to be active is only, as far as all the research I've ever seen, is only going to help you. That's brilliant. Can I go from generically muscles and now start to talk about this circadian clot, which I know is the area of your own research? And we've had one or two podcast guests talking about this broadly, but maybe you could just do a quick introduction about what is a circadian clock? And then how do

you know that our muscles have one of these? Okay. Circadian rhythms are things that people, I think, widely understand. We all have what we call our sleep-wake cycles. So you have a part of the day that you sleep, you have another part of the day that you're active. And so that's kind of a great place to start. The fact is there's an intrinsic mechanism, there's a part of biology inside every single person that is a timer. And that even if we didn't have light and dark cycles, we would still have sleep and wake cycles that would be regularly maintained. And again, there's research for this, right? So, there was a really neat sort of study. It wasn't published, but there was a faculty member at the University of Chicago, somewhere around the 1930s or 40s. And he and his graduate student went down to a place in

the middle of the United States called Mammoth Cave. And what was special about Mammoth Cave is there was no light and the temperature was constant. And so they went down there and they lived there for about 40 days and just asked what their bodies did under these conditions. That's a brilliant experiment. I love it. And as usual, he took his graduate student, who was like, you have no choice. Yes, probably, I'm guessing the ethics restrictions on things back then. Okay. So they went down and lived in a cave for 40 days. What did they discover? They could not control their sleep-wake cycle. They tried to put themselves, I think, on a 28-hour day. They said, okay, let's work for 14 hours. Let's sleep for 14 hours. And it just never worked for them. That was at a time

we were understanding, obviously, plants have rhythms to them. Other animals exhibit rhythms. But this is a nice little story where people actually tried to test that in themselves. So if it was something we could control, then there'd be no problem. You could do a 14-hour, 14-hour day. Who cares that the Earth is on 24 hours? But actually, even in complete darkness, they are locked onto this, they were still locked onto this 24-hour rhythm.

24-hour clock, right. And these are all these little clocks in all, sort of across our body. Right, so there is this clock that exists in us, and I call it a timer. It's an approximate 24-hour timer. And the big discovery, which was awarded a Nobel Prize in 2017, was to the group that identified that the molecules or the biological things that are involved in that

timing mechanism, right? Historically, the sort of behaviors, these 24-hour repeating behaviors, were all identified to be controlled by a site in your brain, which is referred to as the central clock. And that is located in the hypothalamus. It's just a small part of the brain. And it's that part of the brain that gets the signals from light each day. And then historically, as I said before, the argument was then that part of your brain controls all the other circadian processes in the rest of the body. So just to play that back, it was sort of like, you get the light to your eyes, it triggers a special part of your brain, which is like, oh, okay, it's the morning,

it's, you know, I'm making sure that I've set it as 730 or whatever it is. And then I'm going to pass a message to everywhere else in the body. I'm thinking about people setting their watches in the past next to each other, making sure they're all like 7.30 before they go off to do their tasks. Absolutely. I think that was a really good way to put it. And because the one thing I also, I mean, I guess I want to make sure people understand is the clock runs, right? So the light doesn't turn the clock on. So that's why these people can go be living in darkness on 24 hours. Their clocks just run. What all the light's doing is saying, oh, you're about a minute or two off here. You're a minute or two off this way. Let me adjust you based on the information we're getting from the light. So now you move forward a few years and all of a sudden people are identifying that these clock, these timers are actually

existing in virtually every single cell in our body, right? So they're not just in the brain, it's found in heart cells, it's found in liver cells, it's found in muscle cells. Now, all of a sudden, we have a whole bunch of timers around our body. And again, the idea is that the brain is controlling. So, as you noted, if the brain goes, oh, we're going to shift about five minutes this way, then the rest of the body finds out and that goes along. Now, one of the things I think most people can identify with is something called jet lag. So, if anybody's traveled across time zones, they realize that, you know, when you first get somewhere, you don't feel great. Right.

I have definitely experienced that. Yeah. And so jet lag is a circadian syndrome. You know, so when you feel off, I mean, there's a variety of ways people feel off, but when people feel less than 100%, the problem is the brain clock is on one time, I call it time zone. It's on one time zone. Your liver clock is slightly different, your muscle clock, your heart clock. So everything is out of what we call alignment. So your brain's thinking at 7 a.m., your liver thinks it's maybe, I don't know, 3 a.m., and your muscle clock maybe thinks it's midnight, you know, so depending on how many time zones you shifted.

And they're doing different things at these different times. So systemically, you don't, I mean, you don't feel great. Okay. And so I use that as an example, because the obviously the connection between the brain clock and the system clocks takes more than a, you know, a few hours to get conveyed. And so they can end up out of out of alignment with each other. Absolutely. So Karen, we had a conversation with Sachin Panda recently, and he was talking a little bit about this specifically with the gut. And his explanation, at least as I took it away, was, well, it makes sense to have a clock with your gut because during the daytime, it needs to know there's going to be all this food

and you're going to have to be ready for all of that sort of activity. And it needs to know that nighttime, I'm going to have to do all of this repair work and you really want to do that repair work when there gonna be all this food, and you're gonna have to be ready for all of that sort of activity. And it needs to know that nighttime, I have to do all of this repair work. And you really want to do that repair work when there isn't all this food coming through. So this was sort of his explanation, as I understood it, which made a lot of sense. I could see how you would want that body clock. And I can also see, therefore, that if that all got misaligned, because you were doing night work or something like that, that this could cause mayhem. Help me to understand why my muscles need a circadian rhythm, because that doesn't immediately seem as obvious. It's not like food running through it or anything. Why is there a circadian rhythm there and what happens as a

result? The clocks are just part of the cell. They're a fundamental part of cell biology. So all the way back to like the first like single-celled creatures, they already have a clock, do they? Virtually everything on planet Earth has something that has an approximate 24-hour timer. Why do muscle cells need clocks? Well, you know, I think my analogy would be sort of similar to Sachin's. It would be that you have periods of rest inactive. And so in the active phase, you need to have, you know, you want to make sure your metabolic pathways are primed and ready to go.

So that includes oxidative metabolism. That also includes, you know, glucose metabolism in the cell. Those processes have time of day variances. So, and then when we're resting, again, you don't want to be repairing your cell in the middle of your run, right? You want, you know, you want to, you'd rather do the repair and also restoration. So, like I told you before, muscle cells store sugar. So, you know, they're not going to be starting to store sugar at the start of the day. They're going to be starting to store sugar at the end of the active phase and during the rest phase after you've eaten. So all these things are all, again, sort of taking into account the timing of feeding,

the timing of activity. And so tell me what happens. Let's say that somebody wakes me up at three in the morning. I'm not normally awake at three in the morning, just to be clear. And then I need to run away from a lion or whatever. Are my muscles, in fact, less capable because of this body clock? I'm curious what that means for us. Yeah. So there are a couple of things. The clock is not turning things on or off. Think of the clock more like a thermostat,

sort of warmer, colder, just changing those kinds of things. So a fire in your house, you wake up at three in the morning, you're going to run. Now, that said, there is quite a lot of data now that humans are stronger in the afternoon. All right? In the are stronger in the afternoon. All right. And so in the afternoon, so four or five o'clock in the afternoon, um, you are going to be stronger.

And that doesn't end. And the impressive part about this, it's men, it's women, a variety of different ages. Uh, the exercises range from things like grip strength to sort of leg extension kinds of things. And it's tremendously consistent, which isn't always true in human research, that strength is better in the afternoon. And at this stage, people have, you know, looked at, is it the nerve? And there's no indication it's how the nervous system is recruiting the muscles. It seems to be something locally at the level of the muscle. And so that's one example where we have some evidence that likely the clock is playing a role and sort of, you know, under regular conditions, you are stronger. You're going to be stronger in the afternoon.

Now, why? I don't, you know, we don't have a why for that, but that's how it works. The other one that some of my colleagues from the Netherlands have shown is that, you know, the mitochondria in the muscle cells, so the powerhouses, the things that make all the energy, they have a higher capacity in the afternoon. Just to make sure I've got this, this is your body clock through 24 hours changing the way that your muscles work. And interestingly, you're saying like across men and women, and it sounds like you said a lot of different studies,

you can actually see that this strength is peaking surprisingly late in the day. You're saying sort of four to five in the afternoon, which I rather think is like sort of the day is sort of... Yeah, I don't want to be too precise here because, you know, but I'd say afternoon. So I'd say, let's just say from two on. Okay. Depends when you wake up, I guess, is what you're saying, is that when my afternoon and your afternoon might be different. But that's really fascinating. Is that also constant as we age? We don't know. If I had to make a prediction,

I would say we'd lose our day-night difference based on what I understand with the timer. But that actually hasn't been tested. I mean, it's been looked at maybe up to about 30 years old. But again, I don't think we've actually moved those studies into sort of the over 50 crowd. So in general, do we see our circadian rhythms become weaker as we age? What is it that makes you think that that's what's likely to be happening? We talked about the clock mechanism, which is the same in every single cell, right?

So you have this timer where my research has been and where people don't really talk about it in terms of trying to apply it to the physiology is that beyond timekeeping, it has another job. All right. So it actually has a second job that from a physiological perspective is critically important, and that is to regulate a set of genes at different times of day. Can you help us to understand that? Because I think most people listening to this will be like, hang on, my genes are just this fixed thing. What does that mean to regulate a set of genes at a different time of day? Could you just help us to understand what you just said? So you have this timer that has sort of gears on it, right? And those gears touch different parts, different sets of genes at different times of day. There are some genes that are constant, but there are a number of genes. So let's say over a thousand genes in a muscle cell are expressed in a pattern

where they're higher at sometimes and lower at others. And does this mean like, because genes are sort of a bit like instructions, aren't they, to do something? So is this sort of saying you're basically this muscle cell is being told, hey, at four in the afternoon, do all the things that are going to set you up to be the strongest you possibly can. But at three in the morning, you should be working, switch on all the repair, switch off all of the special turbocharging stuff, switch on different functions that you want to be happening in this cell at different time of day. Absolutely. So one way to think about the clock or the way we, you know, is that it is a anticipatory timer. So it's based on, you know, the fact that we have these changes in what we do at different times of day. And so what you will see is before you wake up in your muscle, you will see sets of genes that are getting turned on and those will make for

proteins. And those things are going to be involved in metabolism or breakdown of like fats and carbohydrates that will provide the energy for you to use your muscle. Your muscle is basically getting ready to be used. You know, you're still lying in bed, but it knows that you're going to be waking up in an hour and it's going to start doing these things so that it's ready because you're gonna have to get up and you have to get the kids ready for school and you're going to walk them to school or whatever it is. You can start doing a bunch of stuff and it doesn't just get turned on instantly. It's not like we're a bit used to our phones can do anything instantly, but actually this is more like these machines need to be warmed up and ready and with all the

right things. And so this is doing that in over quite to be warmed up and ready and with all the right things. And so this is doing that in over quite a long period, right? You're not talking about just minutes here. Correct. Your idea of the warm up is perfect, right? So what the clock is doing is it is changing things without you having to think about it. It's changing things in your muscle that get your muscle ready for once you get out of bed and do all those things you're going to do. Right. And then at a different time of the day, it's going to be doing something different.

And that will be related to storage of sugar, storage of replacement of proteins that may be damaged. So it knows you're going to be resting or, you know, it assumes you're going to be resting. And so it's getting those specific genes expressed to do the jobs it wants to be doing during that rest phase. Hi, I have a small favor to ask. We want this podcast to reach as many people as possible as we continue our mission to improve the health of millions. And watching this show grow is what motivates the whole team at Zoe to keep up the really hard work of creating new episodes each week. So right now, if you could share a link to the show with one friend who would benefit from today's information, it would mean a great deal to me. Thank you. So Karen, I'd love to take that very sort of cutting edge research that you're

doing about literally what's going on inside our muscle cells and then step back and say, well, somebody is listening to this. What might it imply for how they think about their life and how they might think about doing exercise? There'll be a lot of people listening to this show who have become convinced a bit like me that they need to do more exercise, even if they don't necessarily really love it very much, but they're like, you know, it's a bit like brushing your teeth, you need to do this. So, I mean, why don't we start with me? I'm in my late forties.

Um, what does this tell you about both? What is like good in terms of how I would think about the timing of my exercise or being physically active, but also I guess what would be suboptimal. With what we understand about the natural rhythms of the clocks in our muscles, then, you know, if you are able to, I mean, exercising in the afternoon is probably when your body and when your muscles are best set for doing that, right? You're stronger, you know, based on the mitochondrial measures, you know, the endurance should be good. It's a very nuanced question. And so I'm trying, I'm struggling with trying to find the way. Not at all. Karen, one of the things I love about

this show always is whenever you speak to the people who are like the absolute world experts in something, they're always much more cautious about the advice than when you talk to somebody who's like a long way away from it, hasn't maybe done the research themselves. It's where they tend to make very strong statements. So I think we are used to the fact that this is cutting edge science, that the results may in fact be reinterpreted. And so I understand the caution. If I play it back, what I think you're saying is that, you know, right now the evidence is that there is a change during the day, that you are stronger starting from the afternoon, and that that implies that that's a better time to exercise. And I think you're also saying that you haven't carried out all the randomized control trials

to sort of prove this yet. Is it, would that be a... That would be correct. And then the other part that we haven't talked about is what time you exercise actually feeds into the muscle clock. So talk about,

help me to understand what you're saying. So just like light adjusts the clock in the brain. Right. What time you exercise adjusts your muscle clocks. People often talk about the fact that if you do have jet lag, then sort of doing exercise in the place that you go to can be helpful. And I just assumed that that was something to do with just being more active or something. But you're saying that actually that might contribute to adjusting in the same way that the light is supposed to help you adjust. Absolutely. And feed. And again, I love that you say that. Like it's, if you're on audio,

you won't see Karen looking at me as I'm a complete idiot because it's obvious that this is going to change the time zone. But I'm quite surprised. So to explain a little bit what happens, you're saying? You can perform exercise at different times of day. And depending on when you exercise, it will change the settings or the phase of the muscle clock independent. So the clock in the brain does not change, but the muscle clocks will shift sort of directionally toward, I call it sort of toward the time of the exercise. What we now understand is that there is information that's coming from that exercise at that particular time that's telling the muscle clock, hey, this might be something we're going to be doing more often. Let's adjust so we're going to be ready for this, right? So if we think about the clock being an anticipatory mechanism, if all of a sudden you start exercising at six in the morning, the clocks in your muscles are going to shift more there. It's learning. It's in training. It's adapting to that time. So you are going to be better prepared or your muscles are going to be better prepared

to perform that activity at that time. And Karen, does that affect your body clocks elsewhere as well? So if I'm doing this exercise, does that start to drag all my other body clocks also in that direction? Well, it can. It's not a simple answer. It's not like all the other peripheral tissues come along. No.

But we have evidence that the clocks in your fat will change. The clocks in your lungs will change. So it's definitely not just the muscles. There is this. Correct. Hence you saying it's obvious that if you are jet lagged, you should do exercise. It's going to help you to move.

Absolutely. It makes me suddenly think, because we talk about jet lag as traveling to somewhere else, but there will be a lot of people listening to this who do shift work. So there might be nurses or doctors or whatever it is who have to go through effectively this massive jet lag for themselves where there is no light. In fact, they're fighting against the light. What does this imply about anything to do with exercise being able to be helpful to manage that moving on to shift and moving off?

Yeah, again, it's an area. It's a great question. There's very little data in that area. But I think, I mean, you know, this would be one of those things where I'd talk to the people who do exercise on shift and they could help the scientists design the experiment in some ways. Because a lot of times people figure out what makes them feel best and, you know, when the exercise makes them feel best. You know, there's data out with sleep deprivation and exercise and the benefits that come with that. Aspects of sleep deprivation are circadian in nature. And so, the prediction is that it will

be beneficial. And again, it will vary depending on whether you're a swing shift type person or if you're a very consistent shift type person. I think hopefully there are people in that area now figuring these things out. And based upon what you know now, so someone's listening and saying like, that's great, you're gonna have better answers in five years time. But Karen, are you saying you should be trying to do some exercise therefore in the shift because that's going to help to make the, let's say you're doing this for some long period of time right so it's not just for a day or two but it's a a week are you saying that you you know you don't want to sit in your you know somehow like the activity levels would help what do you i mean you know based on what we understand

right now i i would suggest exercising before you start your work before you start your shift rather than at the end of the shift but that's's, you know, again, my caution is that, you know, there's still much to be learned. But I think having that exercise before you start will be more beneficial than at the end. Because it might actually help to sort of kick your body more towards the right internal body clock with what you're living. Absolutely. That's fantastic. And thank you, Karen, for letting me push you a little bit past your comfort zone. We heard the proviso, which is, I think, always what's fun of looking at this stuff that's

really cutting edge. Now, is there anything, you know, if my wife was listening to this, is there any difference that you see between men and women in terms of these responses, either at particular times or over time periods? So not terribly much. I mean, to be honest, I think everything we've seen sort of, at least I've looked at in terms of the circadian physiology and muscle would say like a variety of things. Women tend to be more resilient and their rhythmicity tends

to be more resilient. When you say more resilient, I just want to make sure I understand, does that mean that they're more, help me to understand what you mean by that? Yeah. So what I mean by that is the rhythms are more robust. So when, you know, so you can kind of perturb them, but they, they stay on track a bit better when we were talking about that sort of time of day differences in gene expression, they have a little bit stronger gene expression changes based on time of day. So does that mean that actually your advice on time of day might even be potentially more important for them because the differences are stronger or no? No, I think what we're learning with at least studies in women, studies in female animals is that they can handle a challenge, right? So they can handle whether it's a jet lag,

whether it's something that interferes with the circadian clock or the timer function. The females handle that better than males. I wish you told me this five years ago, because I remember when our little girl was really small, I felt that I was definitely struggling worse than Justine to deal with like all the interrupted nights. And now I'd be like, well, you know, science has proven that you're better able to cope with this is I think what I'm hearing from you. It's just your biology. It's just your biology. But is that an example of what you're saying that that would potentially be more robust to these sorts of interruptions of, you know, the rhythm that you might get by being woken up by a small child sort of three times in a night?

Absolutely. Do you see that robustness continue later in life? Because I think one of the things we see in a lot of the things that we study, and Zoe's really interested in this personalization, is that often as we get older, some of these different systems, maybe they're not as good as they were when you're 15. Do you see also that there's a difference between men and women over time in terms of how well these circadian systems continue? Yes. And so I think the challenge to understand right now is that the clocks continue to work as we get older. So the timer works, but it's like the, so when I talked about that, maybe this, you know, the gears have rubbed off and they don't,

that part doesn't work. So it doesn't get translated into the sort of physiological output like it did when you were younger. And so it slips. It just doesn't, you know, just stuff just doesn't work as well as we get older is sort of the analogy, I think, in my head. So the evidence for the timer continuing to work is great. It looks wonderful. But, you know, the output, you know, the power of looks wonderful. But, you know, the output, you know, the power of your car or the, you know, whatever, however you want to think about that, that output is greatly diminished. And it's actually, unfortunately, starting to diminish by your age, for example. It just continues to go as we get older. And so, this is an area we're

very interested in trying to identify. And so does that mean that, you know, at my age and as I get older, like the timing of the day doesn't necessarily matter so much because actually I'm not managing to switch the right things on and off in the same way? Well, I mean, that's possible.

That's possible. Or, you know, the other side of it is it becomes more important to maintain regular behaviors like when you eat, when you exercise, to reinforce the clock function when we age. So it could be that actually you need to be more regimented because you need to support this because your body is not quite doing the same. You're just depressing me with yet another thing that is already not working so well inside me, even though I can't see it. Karen, I do want to cover one other related thing to do with this circadian rhythm before we finish, because I know that what you call chrononutrition,

so look at the time of when people are eating something also that your research is interested in. And it's a topic that we're very interested in. Zoe is one of the things that you can change and where I think there's been a lot of really interesting advice about, particularly I think about time-restricted eating, this idea that maybe narrowing the number of hours that you eat might in fact be really good for your health. And I think you've done some specific research looking at, as we get older, how the length of

time that we're eating might actually have an impact on our muscles. Could you tell me about that? We actually haven't published some of this yet, but we do have some really nice data, again, in a preclinical setting where restricting time of eating with an older animal actually helps maintain muscle, lean body mass, muscle mass, and also helps maintain our ability to store sugars. And so our systemic metabolic parameters are improved. No difference in the amount of food, just decrease the amount of time that they were allowed to eat. We decreased it to about eight to nine hours versus sort of, you know, letting them eat any time. And so it was really quite striking. And this effect occurred over sort of a five to six week window of time. So it wasn't

like they had to be doing this their whole lifetime. It was something, you know, they took up for a month and they already had. Did you say that this was this was testing animals, not in humans? Is that correct? Correct. Correct. And so is there any evidence about time periods in humans? And I think one of the questions that actually the team here were really interested to ask is, is there also a view on how there might be too short a window for people to be able to get everything they need in order to support their muscles, which I think is not often what people are. There's been a lot of focus on time-restricted eating, for example, for people trying to manage their weight. And clearly, I think everyone's actually

really interested in making sure they're maximizing their health. What does your research and other research tell us? I mean, that's really important. And I think, I mean, that's one of the things, you know, sort of been a number of clinical trial, randomized clinical trials in younger adults with time feeding. But the impact of this on older people is not well understood. And I think it is an issue that one has to take into account. As far as I know, there's no data on that right now. The nuance is, you know, sometimes appetite goes down as people get older. And so, you know, trying to get them to eat a whole big meal is probably a much harder challenge. And so thinking about, you know, if it requires 12

hours, by all means, 12 hours. And so, or, you know, 14. There's a paper that was met several years ago. It was specifically dealing with people that have liver disease and are really challenged. And then they get what we call cachectic, or they get, you know, they lose muscle mass. They also will lose fat mass to some extent. And for reasons not related to circadian rhythms, this group gave them snacks at night, and they found that to be helpful. And so, again, very consistent with the idea that they're eating at a time that the body's set to store. And so they're more efficient at storage when they eat there. So if you have a population that is actually potentially challenged in terms of lean body mass, what I would say is if you're going to play with time of feeding, you're going to want them to be eating more of their food

at the later part of the day when the muscles are actually going into more of a storage phase to take advantage of that efficiency. So what we know about the muscle clock is that it actually partitions, you know, sort of use of fuels and storage of fuels. And so if you're older and you're concerned about losing muscle mass, then, you know, if you're going to think about what time you eat, then I would shift things later in the day so that you are eating more and making sure you're getting enough protein. So you probably have people talking about that as well, because that's another area older people tend not to do. And then but sort of target more of the afternoon, evening eating. Got it. And would that mean, so I think you're really distinguishing between

maybe people who are younger and people who are quite a lot older, where you're starting to worry about them losing muscle. Maybe you're also worrying about their bones, it sounds like as well. And there, I think you're describing at that point, I think both saying that shifting later the eating time may be helpful. I think you're also saying that you're quite cautious about having a really short eating window. So saying I'm only going to eat for six hours or eight hours, but I want to make sure I understand, is that what you're saying? Yes, you're correct. I think, again, so just to make sure I'm really clear that what you're saying? Yes, you're correct. I think, you know, again,

so just to make sure I'm really clear, what I'm working with is thinking about an older person. So I'm thinking sort of over 70 that is not worried about metabolic disease. So let's take metabolic disease off the table, but is just thinking about their health, thinking about maintaining their lean body mass. And so the, you know, discussing sort of making sure you have a big enough window. So if, you know, your appetite might be challenged, you have plenty of time and you're not trying to force feed yourself. And then maybe, you know, making sure that the end of your day, you're getting the kind of nutrition and an amount of food that you really need to sort of support the muscle health. Got it. So I think there's a real personalization you're describing

here because it sounds like you're also saying there might be somebody else who has maybe, you know, real metabolic problems and therefore perhaps you might reduce the time frame. So this is obviously a really interesting area of research, it sounds like. I'm guessing that there's going to be a lot more research looking at how this actually works in, you know, in humans, which we know, and I've learned through this, often behave differently from, you know, mice or whatever else, in order to understand how these time periods might really, you know, be optimized for people at, you know, particular stages of life. Yeah. And just to follow up, just a quick quick follow-up, because muscle clocks give us an inability to actually compare between the mouse and the human. And so what I will say is that the muscle clock in mice and

human look very much the same. And so not that anybody wants to be a mouse, but just what we're learning from these preclinical models is translating quite well into the human condition. That's really interesting. So, you're saying that actually, if I play that back, you're quite confident about how this will translate to human beings because of the similarity between, you know, the muscle in a mouse and the muscle in a person. Is that fair, Karen? Correct. Yes. I mean, muscle is one of the few things we can get from humans in kind of a time series, right? So, you know, you're obviously not going to be getting, you know, heart or brain or any of these organs, but muscle, getting, obtaining muscle biopsies every four hours for 24 hours has been done a few times now. And so we have real

data that we can compare side by side with the mouse. And it's really quite impressive. So you're describing that like, basically, you're taking bits of muscle out of me every four hours to see what's changing during this 24 hour clock. I want to make sure I've understood that, Karen, is that what you're saying? Correct. And then you're saying that looks a lot like a Karen. Is that what you're saying? Correct. And then you're saying that looks a lot like a mouse. Is that what you're saying? Correct. Got it.

And hence, when you do these studies on mice, where you see what happens with, for example, time-restricted eating, it's actually making you feel really quite confident that that's going to work also in human beings. Correct. Yeah, yeah, yeah. And so if I play that back, just to conclude, because I think we focus a lot on the much older people,

I think you're saying for this not yet published research that restricting the time of eating in these mice down to about eight hours actually really helped them to maintain muscle with nothing else changed. So actually for, and that your carry over, I think therefore to human beings is that if you were, you know, below 70, as you were describing, actually time-restricted eating could actually be really helpful in terms of maintaining muscle and

therefore supporting health, independent of the things you do about changing what you eat and what exercise you do. Correct. What I think about a lot these days is, you know, how we can use scheduled exercise of time of exercise or time of feeding to actually leverage the benefits of what the clock is doing to sort of, so it is a very personalized approach to how we think about this. And last question for me, Karen, just to understand how that carries over. What would be the sort of time-restricted eating?

What would be the period of eating in 24 hours that you would therefore guess you would be applying to a human being under 70 who's listening to this show right now? I think just trying to eat primarily during the hours that you're the sort of active daylight phase of the day. So I think about, I mean, honestly, and just trying to be a human being who might like for me, I like good like good food. But but, you know, just minimizing. So like a 10 hour window is great. Then to some extent, you find what works for you. So there are people that are morning people, they may want to eat breakfast earlier, but that means they're going to finish during that, you know, earlier in the afternoon versus those people that wake up

later, will finish later and and, you know, try to minimize those, you know, snacks while watching TV. I find it really hard, Karen, to be honest. So I was really hoping you were going to say a longer number than that because, you know, my colleagues like Tim Spector will be like, oh, you see, I told you, Jonathan. So I am notorious for having to eat dark chocolate while watching TV on the sofa late at night. So I'm really not very good. And it's interesting to me that you said, you know, 10 hours, which is still, I think, much shorter period of time for eating than most people do. Particularly if you accept that it includes, for example, a glass of wine or a beer would also count as, you know, eating in

this definition, right? So a lot of us are like, oh, but I ate my breakfast at eight in the morning and you know, it's nine o'clock or 930 or whatever, and I'm still doing something and you're suddenly eating for 14 hours. But I think you're saying when we're thinking also for these muscles here, your guess is that we should be eating more in a sort of 10 hour period and giving our body more like 14 hours to recover. Is that? This is a great question. It's important and it's important for us to figure this out. But I think, you know, and the other part of this is, you know, what you've brought up, how do we eat or how do we exercise to help maintain muscle mass as we aging? Now, that may be different than if I am pre-diabetic or I'm diabetic and what are the

kind of patterns I want to use to help my health. You know, once you start working with a patient population, they have circadian rhythm issues just by the fact that they have a disease. So we are way too early to actually give hard and fast rules on some of these things. Karen, thank you so much.

I really enjoyed this conversation. I'm going to try and do a little summary, and please correct me if I got any of this wrong. So we started just saying, like, why are muscles important? And I think what you talked about is that there's been a lot of things that we have been learning over the last few decades that show that they play a much bigger role than just helping to sort of, you know, pick things up. And that critically, there's very clear data that says that if you lose strength, this directly increases your probability of death. And I think everyone on this call is like, well, I would like to reduce my probability of death.

But also, I think everyone on this call was to increase the number of healthy years that they have, right? It's not how long you live, it's how many healthy years you live. And I think there again, you're saying that your muscles have this huge impact on your ability to live independently, but also we now understand, I think you use this word myokine, that our muscles are actually creating chemicals that are going around to the rest of our body, to our brain. So they're really affecting our overall health. So we need to do something about that. And I think you said in the same way that a number of our other guests that in particular, we need to think about putting more resistance exercise into our life. So, you know, walking is good, but you need to be doing some stuff that loads your muscles.

And I think interestingly, you were saying, you know, for a lot of people listening to this, we're not maybe really big into exercise. It's going to be particularly sort of the upper body, sort of back and shoulder core, which you need to maintain. And that's what's going to give out. Then we talked about really your own area of research, which is talking about, you know, these body clocks that are, it turns out in every single cell in our body. And apparently you said ever since we were like a one cellcelled creature, whenever that was, a billion years ago, we've had these. So this is very deep inside us. And they're in our muscles because our muscles also need to have times in the day when they rest and times when they need to be ready to be active. And you said that, in fact, before we even wake up, they're sort of getting

ready over a period which is sort of hours rather than minutes. So there is this whole getting ready, being active and resting. That interestingly, your exercise can help to shift when your body clock is. So if, for example, you're in shift work, you should think about doing exercise at the beginning of your shift is going to help you to shift your body clock the same that you can use it if you're traveling on holiday somewhere to another time zone, that this has an effect on therefore when you should think about exercising. That interestingly, you're saying for almost all of us, we are strongest in the afternoon. You said sort of after 2 p.m. So I need to stop all of my 8 a.m. training. I should be doing it at 2 in the afternoon. And Karen is like, no, no, no, no. Okay. So I should continue my training. But if

I could switch it to 2 in the afternoon instead of eight o'clock, that would be better. If you like exercising at eight in the morning, the clocks in your muscle are going to learn that and they're going to shift. And so it probably will be that your time of strength and your time of endurance will shift with it. So what I'm saying is if you're going to train, try to be consistent with when you train. So if you're going to train at six or eight in the morning, train that time. Don't do eight in the morning one day and eight in the evening one day. So my current schedule, which is bouncing all around to fit in with being CEO of Zoe is terrible is what you're basically saying. So if I like it in the morning, then that's probably okay. My body will adjust to it.

But if I'm bouncing around, then I'm not really up, which is interesting because I do find that when I do the sessions that are quite off my normal session that I'm always like not up for it. But it's interesting. I hadn't thought about the consistencies. That's really interesting because you're saying the body clock is just going to be set to support this. And then we talked about how the body clock and muscles is related to the time of eating. And you shared this very exciting new research that says that actually restricting the time of eating, it helps to maintain muscle in mice, and that you believe the evidence for that being applicable to human beings is really strong. And therefore, this is another argument for why time-restricted

eating could really help with our health, given how much you've explained about the importance of muscles, that exactly what's right to you is likely to be very personalized, I think you said. So this is one of the areas where you see a lot of variation. So understanding exactly when you want to eat is important. But you did say like a 10-hour window is great. So if people, and most people listening to this probably are eating for more than 10 hours based upon actually, you know, the studies that we've done at Zoe, and I can see you nodding here. So like reducing this is likely to be helpful with one sort of caution that for people who are older and you said, you know, sort of over 70, when you start to maybe have concerns

around having enough muscle and bones and where potentially people's appetites are shrinking, it's much more important to extend the period of eating and make sure you're getting enough protein and enough nutrition rather than starting to say, well, no, it's more important to have this short window. That sounds good. Karen, thank you so much for that. I thought that was absolutely fascinating. And I hope we can get you back on in the future as we hear about the ongoing results of this research. Well, thank you very much, Jonathan.

It was wonderful. And yeah, we look forward to what we learn in the next year or so. Brilliant. I really enjoyed it. Thank you very much. I think it's been incredible to learn all about staying strong as we age with Professor Karen Esther today and all of this amazing new research about how even our muscles have their own circadian rhythms. And I think one of the takeaways is physical activity is one of the key pillars of a long and healthy life. And of course, nutrition is another.

Now, if you'd like to take your nutrition to the next level with personalized advice and support, you'll want to learn more about becoming a Zoe member. And as a podcast listener, you can get 10% off your membership by going to zoe.com slash podcast. I'm your host, Jonathan Wolfe. Zoe Science and Nutrition is produced by Yellow Hewins Martin, Richard Willen, and Sam Durham. As always, the Zoe Science and Nutrition podcast is not medical advice. It's for general informational purposes only. If you have any medical concerns, please consult your doctor. See you next time. Bye.