FoundMyFitness - #025 Dr. Satchin Panda on Time-Restricted Feeding and Its Effects on Obesity, Muscle Mass & Heart Health

Episode Date: June 30, 2016

Dr. Satchidananda (Satchin) Panda is a professor in the Regulatory Biology Laboratory at the Salk Institute for Biological Studies. In this video we discuss... (00:00) Introduction (06:42) Why humans developed an internal clock (i.e., the circadian rhythm) (15:28) Light is necessary to regulate our circadian clock (25:02) Morning bright light exposure lowers cortisol levels and lifts mood, but the indoors are dim (30:25) Using light exposure to reset jet-lag and help shift workers stay healthy (36:17) Eating is an important regulator of the body's peripheral circadian clocks (40:44) Time-restricted feeding protects from the harmful effects of a Western diet (48:30) Time-restricted feeding increases muscle mass while reducing fat mass (51:03) Mice who fasted 15-16 hours-per-day gained muscle endurance due to changes in mitochondria (54:43) What's the difference between intermittent fasting and time-restricted feeding? (01:00:02) Melatonin makes us less insulin-sensitive in the evening  (01:05:56) Dr. Panda's time-restricted eating mobile app helps research participants track their food (01:20:39) Time-restricted feeding improves heart health  (01:27:31) The gut microbiota also follow a circadian rhythm (01:34:12) How to participate in Dr. Panda's research If you're interested in learning more, you can read the full show notes here. Join over 300,000 people and get the latest distilled information straight to your inbox weekly: https://www.foundmyfitness.com/newsletter Become a FoundMyFitness premium member to get access to exclusive episodes, emails, live Q+A's with Rhonda and more: https://www.foundmyfitness.com/crowdsponsor

Ladies and gentlemen of the podcast, I'm back. Welcome to another episode. I'm very excited about this one because it features a scientist whose work I have admired for quite some time. We bring to you today Dr. Sotchen Panda, a professor at the Salk Institute for Biological Studies in La Jolla, California, an institute where I actually worked and got my first taste of aging research early in my career just before the start of graduate school. Needless to say, a great place. Sotchen's work, which we talk a bit about today, deals specifically with the timing of research early in my career, just before the start of graduate school. Needless to say, a great place. Sotchen's work, which we talk a bit about today, deals specifically with the timing of of food and its relationship to our biological clocks governed by circadian rhythm. These clocks regulate thousands of genes, which is somewhere in the neighborhood of around 10 to 15% of the expressed human genome, which means that our physiology and indeed our metabolism is all meant to be tuned to behave differently depending on the time of day that it is. But what happens if it has no idea what that time of day is? Bad things. That's what. The good news is, however, that Dr. Pandas,

research and that of his colleagues has suggested a pretty straightforward solution that seems to show a lot of merit, and that is time-restricted feeding. By restricting mice to a 12-hour window in which they eat, starting at the first bite of food, but otherwise allowing them to eat the same amount of calories, they have shown that they can attain some pretty amazing benefits, including decreased fat mass, increased lean muscle mass, improved glucose tolerance, improved lipid profiles, reduced inflammation, higher mitochondrial volume, protection from mild eating. age-related fatty liver, increased production of ketone bodies, protection from obesity, and generally favorable improvements in gene expression. Some of these benefits are context-dependent.

For example, some of the largest improvements are seen in mice that are actually fed an an Obesogenic Diet or what is often called a high-fat diet for short, but is actually a 60-per-larid high-sugar diet that is the laboratory standard for causing type 2 diabetes and obesity in mice. Regardless of whether the mice are fed the same number of calories from a normal diet or the high fat diet, the results are the same. These little guys show impressive improvements by getting the timing right. But what about humans? We'll get back to that in a second. In addition to time-restricted feeding, we touch on a long list of interesting things, including the fascinating history of experimentation that ultimately elucidated the location for the region of the

brain necessary for properly timed sleep-wake cycle. The relationship between our body's master clock and its many peripheral clocks. Why infants sleep so intermittently instead of resting for a longer sustained duration like healthy young adults, and why this sustained rest also goes haywire in the elderly. The fascinating work Dr. Panda took part in that led to the discovery of a specialized light receptor in the eye that sets circadian rhythm known as melanopsin. The important relationship between the relatively light incense, of melanopsin, which requires around 1,000 lucks of light to be fully activated, and its control of

the circadian clock by means of activation of our master clock, otherwise known as the super-chaasmatic nucleus, and its consequent suppression of melatonin. The effects light exposure seem to have on next day cortisol, a glucocorticoid hormone that regulates around 10 to 20 percent of the human protein encoding genome. The clever experimental design by which Dr. Panda and his call discovered that certain circadian rhythms, especially of the liver, are entrained by when we eat instead of how much light we get. This underlines the fact that when managing our circadian rhythm, and thus our metabolism, both elements are important. Okay, now, before we dive right into the conversation, this is the part where I normally tell you to go sign up for my newsletter on my website at

foundmyfitness.com. Yes, go do that. Seriously. However, I want to take a second to go back to what I said a moment ago about the effects of time-restricted feeding and humans and how I tell you a little bit more about that. Dr. Panda is actually in the process of using crowdsourced data to do real human research on time-restricted feeding. Here's how it works. He's asked that normal people like you and me pick a time-restricted feeding window, one that we can actually commit to for a few months, and then just use our smartphones to send as many pictures of our food as we can. Pretty straightforward, right? I think this approach to science is very cool, and I'm I'm hoping he has some really amazing success with it.

You can learn more about how to participate in Dr. Panda's study by going to Mystercadianclococ.org. That's m-Y-C-I-R-C-A-D-I-A-N-C-L-O-C-K. Don't worry, you don't have to write it down right now. We'll repeat it again at the end of the podcast. A few other quick notes about jargon. If you hear something like G-W-W, which might sound like something you'd say well confused as in, gee-waw, mom, why'd you go and do that fur?

It's actually an acronym GWA. It stands for genome-wide association study. A G-WA is an examination of many common genetic variants in different individuals to see if any variant is associated with the trait. G-WAs typically focus on associations between single nucleotide polymorphisms, also known as SNPs, and traits like major diseases by comparing the DNA of participants having varying phenotypes for a particular trait or disease to those who do not. So if you've used the genetic tool that can be found on my website, I owe a lot of the information in there to these extremely valuable G-WO-W studies that have elucidated fascinating relationships between common variations in our genes and modified phenotype. The second thing to know is that when we talk about lux, for example, when we discuss the fact that offices usually have less than a thousand lux, but you actually need a thousand lux or greater in order to flip on the circadian rhythm switches in the body, we are talking about a unit that is actually lumens per square meter. That's what a unit of Lux is,

lumens per square meter. And the third thing is, in this conversation, we refer to clocks and our master clock and peripheral clocks. Most of this stuff makes sense in the context of the conversation, and I won't worry about that so much. But there is a subtle third type of clock that might be missed. This is the gene known as clock. Clock is a gene that encodes for a transcription. factor that regulates the circadian rhythm at the cellular level. Experiments have shown that if you knock that gene out in mice, their circadian rhythm becomes pretty much non-existent. Okay, I'll stop chitter-chattering.

Now on to the podcast. Hello, everyone. Today, my guest is Dr. Sachin Panda, who is a professor at the Salk Institute for Biological Studies in La Jolla, California, where he studies the body's internal circadian clock, what regulates their circadian clock and in turn how this affects a wide variety of processes, including our metabolism, our sleeping patterns, and how active we are, and so much more. Sajan, considering that every single living organism on the planet Earth has this internal biological clock, the circadian clock, can you explain to people who've never heard

what a circadian clock is, what it is and why it's so important? Yeah, so all lives on this planet evolved under a rotating Earth. So that means for 12 hours, approximately 12 hours, they had access to light. And for another 12 hours, they were in darkness. So that environment, that changing environment, put a tremendous pressure for them to come up with the timing mechanism so that they can anticipate when it's going to be evening or when it's going to be morning so that they can time their activity and sleep accordingly. So that's why almost every organism on this planet

have this internal clock that help them anticipate time. And why this is important is if you think about a diurnal organism, an animal that's active during the daytime, the animal has to anticipate when evening is going to come so that he can rush back to the cave or somewhere, some hiding place. So similarly, just before the dawn, this animal has to wake up before even light hits and then go out and get the first grub. So that's why there is this tremendous pressure to have this biological clock or internal timing

to essentially anticipate what's going to happen. So for most people, we know when we go to bed, maybe after six to eight hours, we wake up. So our clock actually tells us, yes, it's going to be morning, get up now. So similarly, almost every part of our body has clocks that help us to anticipate when the food is going to come, or when we are supposed to run, or when you are supposed to take rest. So what we are learning is almost every organ in our body has a clock, and it helps this organ to be at peak performance, peak activity at a certain time of the day, and then to rest and rejuvenate at the other time of the day. So is this internal biological clock, the circadian clock, it's not something that we're just immediately born with, right? It's not something that just... Yeah, so when you are born, we kind of...

So when babies are born, they actually don't have this daily 24 hours rhythm and activity or sleep. They don't go to bed for six, seven hours. So what we suspect is although they have a clock, those clocks are not wired together. And at the same time, babies also need a lot of food because that's the growth phase. So during the first maybe two, maybe four to six months, the babies wake up in every three to four hours, cry, eat a little bit and go back to sleep and then wake up again and do that. Then after eight to twelve weeks, they actually begin to have some kind of consolidated sleep. So they go to sleep and wake up at the right time.

So wake up after a few hours, but it's not tied to light, dark cycle. So they kind of drift. So that's a phase many parents may not notice because we now live in a very artificial environment. But that's the time when there is a clock, but it's not tied to outside light and dark cycle. So around six months of a phase, that's when the whole development process. And the clock is functional. It's tied to light dark cycle. It's wired properly, so the babies go to bed, hopefully in the evening and then sleep for nine to ten hours wake up.

So when we are born, we do have clocks, but they are not connected together until about four to six months of days. Oh, interesting. And you mentioned, so there's clocks in all of our organs. Yeah. And there's different, your work, you've done a lot of research on what regulates these different clocks. There's a master regulator clock, and there's other clocks in different organs. Maybe you can explain. But I read somewhere that something between like 10 to 15% of the entire protein-coding human genome

is actually regulated by these circadian clocks. And anywhere between around like 40 to 50% of those genes are actually involved in metabolism. Yeah. So there's a wide variety of processes that are regulated by these clocks. Yeah. Maybe can you explain a little bit about the central master clock and what regulates that? Yeah, so this is a field of study that is actually not driven by a disease, but pure curiosity. So for a long time, people thought that there might be a master clock in the brain because we always connect circadian clock to sleep wake cycle.

And fortunately, there was actually a master clock. And in fact, almost 40, 45 years ago, people who are working on different, parts of the brain because at that time, 40 years ago, people thought that different parts of the brain regulate different behavior. So they're defined like cubic millimeter area of brain that regulate something. So they were systematically taking out parts of the brain in mouse, rodents, in different larger rodents. And then figured out that when they hit this small part of the brain called supra-chaismatic

nucleus. That means we know that our eyes send optic nerves that crisscross, and that's, there is a part of the brain called optic chasm. So it's above the optic chasmus, so that's a supra-caisematic nucleus. So that's... Say that 10 times fast. Yeah, supra-chizmetic nucleus, or SCN. And it's composed of around, say, 100,000 neurons, I guess, in humans.

It's really small, maybe one millimeter by one millimeter. That's the size of this brain part. If you remove that brain part in a hamster, then this hamster will not have any sense of time. We'll go to sleep at random time and we'll wake up after two or three hours and will continue. But what is most exciting is if we take SCN from another hamster and transplant, it's like a brain transplant experiment.

then this hamster will get all the rhythms back. That's the earliest example of neural transplant transferring behavior from one animal to another animal. And that essentially established that there is part of the brain that acts as master circadian oscillator or circadian clock because it orchestras this daily rhythm and waking up and going to sleep. And just imagine, only when we are awake, we eat or we exercise. So that's why all other organs, organs related to eating, for example, our gut, a liver, our fat, all of them are driven by this feeding behavior. Similarly, a muscle is driven by when we run. So that's how the SCN acts as the master circadian oscillator.

So if we damage the SCN, then we lose all circadian rhythm. So what happens in some of the neurodegenerative disease, like very advanced days of Alzheimer's disease, dementia, if the SCN, this part of the brain is affected, then people lose their sense of time in terms of when they go to bed or when they stay awake. So these patients slowly, they turn into a state where they don't have a sense of day or night, they stay awake throughout the night and maybe sleepy throughout the day. So that's why this master clock is so much important for our health. Wow.

And that may also have a feed-forward loop because then, you know, if your master clock is thrown off and you're awake when you're supposed to be sleeping and sleeping when you're supposed to be awake, that's also been shown to affect hippocampus and long-term potentiation. So, you know, you've got this sort of, you know, feed-forward loop. But specifically with regards to the master clock, light is what regulates this master. It's what sets it. Yeah.

So can you, and this was some of your early findings. Yeah. Can you talk a little bit about that? So for a long time, people knew that a light resets our clock. And in fact, in nature with change of season, the sunrise and sunset time do change. And we have to adapt to that sunrise and sunset time. Otherwise, animals cannot go to sleep and wake up at the night time. So what was interesting was for a very long time.

people couldn't figure out what, where is the light receptor that reset the clock? Because there are many blind people out there who cannot see anything, but they can reset their clock. So if they go from east coast to west coast, they fly, then they also have typical jet lag. And after three or four days, they get used to the new time zone. And similarly, there are laboratory animals that are blind. they can't see a thing, but if you change their light dark cycle, then they readjust in six to seven days. They actually readjust the same way as mice with normal vision. So this was kind of an unanswered question in vision science for 75 years.

What is this extra light receptor in the eye? And we knew that it was in the eye because many people who got to war and lose both of their eyes because of gunshot wounds, people who have cancer, tumor growth in both eyes, and their eyes are removed, they can't reset their clock. So they kind of run free run. Because our clock is not exactly 24 hours. And our clock is very close to 24 hours, 24 hours, 15 minutes, 24 and half hours, something like that.

So if we cannot entrain our clock to light dark cycle, then every day we'll be working of 15 minutes or 30 minutes late, and then after 10 to 15 days, we'll be completely out of sync with the society. And that's what happens with this basis. If you combine these two observations, people without their eyes cannot reset their clock, and blind people can still reset their clock, then that essentially tells us that there must be some special light receptor. So almost 16 years ago, three different groups figured out that there is a new,

light sensing molecule that must be present in some of the remaining cells of the retina in blind people and our group was one among them who discovered this new light receptor called melanopsin. It's actually from frog melanosomes. So this is a clear example of how basic science actually leads to understanding human health. So if you put a frog under light, then the frog's skin will change its color. Because frog skin has a light sensor that detects light and then puts kind of a natural sunscreen.

Like melanin making? Yeah. So it spreads melanosomes. So melanin pigments have spread. And interestingly, it's the same protein that spreads melanosomes in frog skin is also present in human retina and mouse retina. And only in 2,000 to 5,000 cells. And these are special light-sensitive ganglion cells, we call them.

And these cells sense light in the blue spectrum and send that information straight to these supra-chismatic nucleus at the master clock. And that's how every day in the morning with the first sight of light, this melanopsin cells, sense light, and then tell the SCN that this is morning and this is time to sink up. So that's what it is. Okay, so that first bright light exposure sets the clock and tells your body, you know, okay, this is a start. So then you start to change gene expression.

Things are going on in the brain. You're more mentally aware. Things happen. All these little changes happen throughout the day that are on this rhythm. What happens then if you, let's say you don't have? Let's say you live in a very dark apartment or a dark apartment in the winter in Sweden or somewhere, you know, where it's like dark. You know, so you don't get that bright light exposure. How does that affect someone's circadian clock?

So you kind of use this interesting term, bright light. And actually, that's very important for melanopsin. Because we know we have rodolphin that's extremely sensitive to light. And that helps us to see the star and enjoy the moonlight. But that's very low amount of light. And actually, our clock is not sensitive to that amount of light. Just imagine if our clock was sensitive to dim light, then it would be completely worked because even in nature, the lightning or starlight or moonlight that we can see can reset our clock.

So one interesting thing with melanoxin is it's very less. sensitive to light. It's a very lousy photoreceptor. So that means you need a lot of light. For example, you may need almost a thousand locks of light to fully activate melanofsin. And then another interesting part of melanofsine is it integrates light over time. So that means it actually remembers how much light exposure you previously had. So for example, if I I switch on a flash, then for 100 milliseconds you see a scene, and then after the flash is gone, your visual system is dark, you don't see that scene. But Malanoffin stays active for several seconds after lights are off.

So that characteristic helps it to count how many minutes you had exposure to light. So in that way, not only you need bright light, you also need several minutes of bright light before it's fully active and can do all of its function, particularly to reset the clock or to do a few other functions, and I'll get to that. So when we discovered melanopsin, we thought that these cells connect only to the master clock. But what we're learning more and more is it has multiple different functions.

It also connects to part of the brain that suppresses or that regulates sleep. So that means many of us know that it's very hard to sleep in a lighted room. And that's because of melanocin. Because it senses light and in diurnal organisms like us, it tells, no, there is light. You should not sleep. You should stay awake. It also indirectly connects to part of the brain that produces melatonin. And melatonin is the sleep hormone.

So when we have a lot of light and also for a very long period of time, then it starts down melatonin, it helps us stay awake. But during daytime in the morning when we wake up, we need that big jolt of light for melanopsin to really activate and suppress the melatonin, make us more a lot, and reset the clock, and turn on hundreds of genes in the SCN, and start secretion of many neuropeptides and all that stuff. So that's why it's very, it's becoming, we have learning of the brain. lot about what quality of light and how much of light we need in the first half of

the day to keep us awake and how little light or what kind of light we need in the evening or second half of the day so that we can go to bed well so in dim environment it becomes means many people know that dim light or cloudy days make us depressed, but now we have a molecular biology explanation. Why is that? At the same time, it also tells us maybe if we have blue-sipped-light during the first half of the day, that may help us to stay awake, to stay a lot, and also to reduce depression.

But in the evening, we actually should stay away from that light. So it's a very interesting thing about our environment, because so far, everything in our environment, whether it's carbon monoxide, carbon dioxide, oxygen, temperature, everything can be set at a set point throughout 24 hours. And this is an interesting stuff about light. We need more of that in the first half of the day and as little as possible in the last half of the day or in the evening. So it's a very interesting area. And modern-day society is also not very...

conducive to those needs because we have artificial light, we have televisions, we have computer screens, we have iPhones and Android phones. So everything's emitting this bright light or blue light, which is what's activating the melanopsin receptor melanopson and inhibiting melatonin production. I remember reading some study that was published some years ago where humans that were exposed to around, I think it was around 10,000 looks of light, upon on 30 minutes of waking. So, you know, early exposure, and they were exposed to it for a number of hours, something like seven hours.

I mean, it was like bright light, you know, all day, almost like being outside. Yeah, yeah. And then their cortisol levels were measured at various points in the day. And so cortisol is one of those hormones that's regulated by this circadian clock. Yeah. It peaks about the time we wake up or something like that. It dries just when we wake up. Right.

So that promotes allotness and balatonin is the opposite. It promotes sleep. And it also, I mean, cortisol regulates, it's in itself, it's regulating, you know, 20%. Yeah, 20% of protein-coding genes. So it's doing a lot. But these people, the thing with cortisol is you want it to peak when it's supposed to peak and you don't want it to be active all the time. Things like chronic stress that can activate cortisol.

And, you know, this can lead to dysregulation of, you know, 20% of the human genome or something like. Anyways, these people that were exposed to the bright light had a 20 or 25% decrease in cortisol levels, you know, during parts of the day when it wasn't supposed to be high. Yeah. It's very interesting how just the bright light exposure itself seemed to regulate the stress hormone or at least keep it. Yeah. So, what about people that, you know, get, so people that are exposed. to bright light in the evening. So you're working late or you're watching television.

I mean, that's going to trick your brain and think, okay, reset. Is that kind of what's happening? Yeah. So what is happening is in the evening when we have that extended period of light, it's sending a wrong signal to the brain saying this might be part of the day. And that also doesn't allow melatonin level to build up. so we have trouble going to sleep. And ultimately we go to sleep,

and we wake up either sleepy or we wake up very late into the day. And in the late in the day, then our body is getting a signal, oh, this might be the morning. But at the same time, these days we spend more than 90% of our time indoor. And many of the indoor environments have less than 1,000 locks of light. And many places have actually less than 2,000. 100 locks of light. So that means even though we wake up,

we don't get that very bright light that we are designed to get in the morning. So our body gets confused completely when is day or when it's night. Although we kind of can work our way through, our body is not completely compliant, or completely is figuring out when it's day or night. So that's why all this circadian rhythm,

all these rhythms and gene expression, and different organs are completely desynchronized. You can imagine a car running with a bad timing belt and the spark flux sparking at wrong time. So you can't run that car too long. So that's what happens in our body. Right. I know for myself, there's a few things.

There's a couple of things that changes that I've made to my lifestyle within the last year or so that have made a huge difference. And that is one, I now live in a place that is not a dungeon. So I used to have windows that were blocked by other buildings, and I was not facing the west side. I mean, just no light was coming in.

And that really did affect my mood. Like, even though I was eating well, exercise, all these things, you know, that helped, but I definitely felt that my mood was affected by that. So I moved and now have bright light exposure first thing in the morning. which has really helped my circadian rhythm in addition. But also, I don't get exposed to bright or blue light in the evening. So I have these lights. I don't know if you're familiar with them.

They're Phillips Hugh. And so you can program these lights to switch off blue light and only have red light. They do other colors as well, but red light. And so I have it now where, well, now that it's summertime, I used to have it programmed with sunset. But now that the sun's setting later, It gets too dark in my place, so about 530, the red lights come on. Yeah.

And then I have an app on my phone, sorry, on my computer called Flux, which then blocks, filters the blue light, and it corresponds to the sunset or the time zone that I'm in. Yeah. it's time for bed. And I wake up now probably around 7.30, 8 o'clock. It just, that's it. So I get a nice, a good amount of sleep. But it's pretty regular and routine.

So those are some little lifestyle changes that I've made to my life that have made a big difference. What about people, like I'm getting ready to travel to Asia at the end of next week. Jet lag. So obviously when you travel to another time zone, your circadian clock can reset. Do you think the most important thing is bright light exposure when it's light? Is that what's going to help reset me? Yeah, so it's a very complicated question because there is light and also, as I said,

there is food and we'll get to that. Yes. But one important point that you brought up is jet lag. And although we led to jet lag when we travel, there are nearly 15 to 20 percent of population in this country or in any industrial country that works in day shift or night shift. So almost in every few days, they are going through that jet lag

that we dread to go through. So for them, it's very stressful to go from day shift to swing sift to morning sift to night shift and all these sifts. And what is interesting is most employers think that it's very stressful, so let's let them do the swing sift

or night shift for maybe four days in a week. And then for three days, they're again trying to be social. They're trying to catch up with their friends and families. So it's very stressful for them. And that's the biggest area where light management or lifestyle management will have a huge impact on figuring out how best to schedule the shift work so that these guys will go from day to night shift. swing sift without compromised fitness and with a good family life.

So we're still learning how to sift them. It's not easy for them to sift in every week for four days in one shift and three days in another shift. But light is a very important aspect of that, particularly individuals who work the night shift, they come home and they try to sleep throughout the day in a dark room. of course, and then if it is winter time, they barely get any light, any sunlight or bright light. And at work, you never get indoor environment. We rarely get more than thousand locks of light. So these people are continuously staying kind of in a dim winter environment

during their night shift. And so that's one area where managing light will have a huge impact on productivity, health, social life, etc. But as I said, a light does half of the job, and then the other half is done by food. Right. So you also pointed out another thing. You brought up the example of stress hormone cortisol. Cortisol is regulated by circadian clog, but at the same time, we know it's a stress hormone. So if you have stress in the middle of the night, when cortisol is not supposed to be high,

it will not just wait for the morning time. Your cortisol will go up, and we know that. So similarly, the master clock sends the signal that when it should be day, when we should be eating, and when we should be fasting. And accordingly, the liver clock, the gut clock, all these clocks, they time themselves. And when I said time themselves, what happens is just imagine there is you are kind of driving in a downtown area with a lot of stoplights and green lights. and if you imagine if there was no light anywhere then there will be a lot of accidents or there will be a lot of traffic congestion so having the lights done on and off at the right time help the traffic move similarly in our

liver if you imagine we are eating a lot of different type of food that has to be metabolized that has to be broken down sorted out then a lot of things that we don't need for our body for example the artificial sweetener the coloring agent, the flavoring agent, all of them go to the another conveyor belt, they get excreted out, and the protein gets broken down, and they build up other part of the cell. So a lot of things are going on at that time. So it's almost like you're bringing in food, dividing them into different parts, and moving through this conveyor belt or traffic. So not everything will happen at once. So there is time for protein to break down. There is a lot.

There is time for glucose to be made. There is time for nucleotide to be made. There is time for bilates to be made, different hormones to be made. So these clocks actually have time different things. And when clocks break down, then what happens is you can imagine either a traffic jam or a big pile up. So the metabolites, metabolism is not efficient anymore. There is a lot of byproducts just lying around, and that stresses the cell.

And then we get to get to the disease. So my point is, although we have clocks, these clocks also respond to when food is coming in. The same time, when the food is coming in, if the kitchen is not ready, the food is not going to stay in the garage. So our body is not built that way. It will come and then light up the fire and the food will be prepared, but then the traffic lights are not on, so there will be a traffic jam. So that's why the peripheral clocks, actually, they have a clock, but they also respond to food.

And the food tells them when to time their activity. So when we travel, our lighting changes and our food time changes. Yes. Yes. So you kind of are changing gears here, and I think it's very important to point out for people that aren't familiar with this. So we've been talking for some time about this master regulator clock, in the supra-cahazmetic nucleus region of the brain, and how light is what sets that clock,

what regulates that clock, and in turn, those are regulating a wide variety of different physiological processes. But then you just mentioned something very important, and that is that in addition to that clock, there are other clocks, for example, in our liver, in our muscle, in our heart, that also are regulated.

But your research, and maybe we can start to talk about this, They seem to be regulated by something different, by when you eat, by when you've taken food. And I know for myself, I've always, I've known, you know, about the circadian clocks in the liver and how they regulate metabolism. I know that, you know, we're most insulin sensitive, you know, during the early morning hours and most insulin insensitive in the evening. And so I've always tried to not eat too late because I'm like, well, I don't want to eat this in high carbohydrate meal when I'm the most insulin insensitive. It doesn't make any sense. It's much easier for me to do that in the winter months when it gets dark earlier. I find it more difficult when spring and summer occur because it's like lighter out.

I'm working later, and therefore, I eat later. So let's talk a little bit about how food regulates these clocks and these different tissues. Yes, a few years ago, we started looking at which genes are regulated by clock. in different organs. So if we look at liver, there might be, there are somewhere between 3,000 to 5,000 genes that are torn on a certain time of the day or night. And so that's a lot of genes. So that's almost 30% of express genome or whatever. But what is interesting is we said, well, we did a very simple experiment where these are done in mice. So the mice

night eating mice, mice usually eat during the night time. Then we asked, well, there is a master regulator in the brain that's telling the rest of the body when the timing is, when it's day or night. And let's give mice food in the middle of the day, just like the shift workers work in the nighttime, they eat. If we do that, then what happens to the liver? They're all liver genes that cycle, they take the cube from light, dark cycle, or from the food.

Because we have these two groups of mice, both groups of mice are in the same light, dark cycle. One group eats during day, one group eats during night. If the liver takes cube from light, dark cycle, then all cycling genes should be identical in two groups. If the liver clocks take cue from eating time, then the day-fed animals will have a different clock than the night-fed animals. And that's exactly what we found, that even though the light, dark cycle was the same for both animals, the liver clock responds to when the mice set. So the day-fed animals had the same 3,000 genes cycling. The night-fed animals had the same 3,000 genes cycling. But now the genes that were turning on during daytime, in the day-fed animals, now they turn on at nighttime, the night-fed animal.

So that means the time when we eat tells our liver clock when to turn on the genes and when to turn up. The light has very little impact. We cannot say no impact, very little impact on the cycling genes and liver. So that experiment has been replicated now, and what we are learning is almost every organ in our periphery outside the brain kind of follows when we eat. So then what becomes very important in the daily life is the first sight of bright light and the first bite of food. Those two determine how our body clocks work. So now we are working on how this timing of eating or timing of light affects our health in general.

And you have a certain term, I guess, I don't know who coined the phrase, but it's called time-restricted feeding. Yeah. And you've done, there's been experiments that you've done in these mice where you've fed them various types of food, high-fat diet, high-sugar diet, normal child diet. And you've restricted their time feeding, you know, during their, the nights, you know, the mouse day hours, which is actually the night because they're nocturnal. And you found, you know, some very interesting things. So can you talk a little bit about those findings? So what we have seen is when we, in experimental animals, if they don't have a clock, then their metabolism goes really weird.

So just like I said, a metabolism works like this traffic signal in downtown. And if they're not timed properly, then there will be disease. Similarly, for a very long time we knew in the field that mice that don't have circadian clock. because they lack a gene or have a mutation, they have various metabolic defect. They have obesity, diabetes, cardiovascular disease, et cetera. We also know people who do shift work for a very long period of time,

they are also highly likely to get metabolic disease, cancer, accelerated disease. So there was this idea that clocks are important if we don't have a good functioning clock, then that's bad for us. Then we went back and asked, okay, Okay, in normal circumstances, what are the conditions that can actually break down our clock? And what we found was when mice are given high fat diet or any unhealthy food, then the

food itself breaks down their clock. So they actually don't have a good eating fasting rhythm. So the mice eat throughout day and night. And we knew that high fat diet and high fructose diet, high sucrose diet, all of these diets that are used experimentally in laboratory conditions give rise to all this disease. And people always thought it's what and how much the mice ate that determined the disease. But what we found is, well, these mice are also not eating at the same time. So maybe when they eat also matters.

So we did a very simple experiment where we took two groups of mice, completely identical set of mice. No genes were changed, no drugs were given, and one group of mice ate whenever they wanted to eat. And to begin with, we give them a high fat diet. So they're getting somewhere between 45% to 60% of their food from fat, a calories from fat. So that means it will be equivalent to humans eating all of their food from cheese, nachos, ice cream, or Western diet. So they're getting fat and sugar. So they're getting fat and sugar all this stuff. And then the other group got the same number of calories and the same type of food, exactly identical food.

But they had to eat all their food within 8 to 12 hours in nighttime. So in some experiments, we have done 8 hours, 9 hours, 10 hours, 12 hours. like that. And the most surprising thing is, means this is something that everybody, a lot of laboratories around the world do, there are 11,000 papers showing high fat diet causes obesity. And we said, okay, so now we control for time. So since time was restricted,

calorie was not restricted. So that's why you call it time restricted feeding. And surprisingly, the mice that ate for 8 to 12 hours, they did not become obese, diabetic, and they had a normal liver function, they had normal cholesterol, et cetera. And then in the next set of experiments, we expose these mice to high fructose diet,

high carb diet, high sucrose diet, all kinds of diets, either ad lividum whenever they can eat or they have to eat within 8 to 12 hours. And in most cases, we see the time-restricted feeding has huge beneficial impact. Even when mice eat standard diet, normal chow, which is supposed to be very healthy,

and mice actually eat most of their food, nearly 70% of food during nighttime. They eat a little bit during daytime. But if they completely restrict that to 8 to 12 hours, then their muscle mass goes up, their fat mass decreases, and they're more coordinated. So if you put them on a rotating drum, then the coordinate on the rotating drum for a long time.

So the bottom line is this time, so in these experiments where we kept what and how much they had, The only thing that we changed is when they eat, then we see this huge beneficial impact. And that correlates with very robust clock in the liver and in other metabolic organs. And why this is important is two things. One is many of us have really bad lifestyle. I won't say bad, but we don't have much control over what and how much food we eat. As soon as we get out of our home, all the food we eat outside, we have very little control

over it. So the only control we have actually is on our time. So that's why we think this can be a good entry point to a better living by controlling time. And then the second thing is it also doesn't take away this idea that nutrition doesn't matter, the quality doesn't matter, because even in our high-being. fat-fed mice, we don't see they completely become normal, just like the normal chaffed mice. They're much healthier. So to have better health, you still have to change what and

how much we eat, but timing becomes much easier to manage. So these, you just covered like so much. This experiment that you did right here, this publication, even before, you know, you've gone on to some small human studies, but this convinced me to do a time restricted feeding schedule because, well, for a couple of reasons. But so just like to reiterate, these mice that were fed, a high fat diet, they were fed the same amount of calories, but those that ate during their waking hours, so for my sexual night within, I think it was 12 hours. Yeah.

They gained, sorry, they had 70% less fat to mass. Yeah, so they had 28% less body mass total. And that change in body mass is mostly due to fat because they had 70% less fat. That's amazing. Yeah, that's really... Right there. They're eating the same crappy food, but they're eating it when their liver can process it the best, when they're, you know, when they're, you know, able to regulate their blood sugar,

when they're able to oxidize fats, things like that. So that was really cool. And then the second thing was, you know, I don't... I eat a very, very, very health conscientious. I try to, you know, get a wide variety of vegetables and fruits and good fats and, you know, so all that stuff, omega-3s. But I'm always trying to find more with the low-hanging fruit to sort of delay the aging process in a way or become, you know, as optimal as they possibly can. So the mice that were fed in normal child diet, you know, high in fiber and all these things, vitamins,

you said they actually had more lean muscle mass. That is very interesting because for me, it's much easier to lose fat than it is to gain muscle. It's difficult to gain muscle, and as you age, it becomes even more so. And muscle mass is very important. It protects you from frailty, things like that. So any ideas as to how just restricting your – but we should probably talk about what starts that clock. What food is it, you know, it doesn't necessarily have to be a calorie, right? It can be black coffee or something like that.

But anyways, any ideas as to what, you know, is allowing you to keep on more muscle mass? Yeah, so that actually is a big mystery because in the first series of experiments, we are essentially reporting observations, what happens. The reason why we looked into muscle mass is, initially we thought that these mice, when they're going through such a prolonged period of fasting, in some experiments they're going for 12 to 16 hours of fasting every day. And many people think that when you go through this prolonged fasting,

you'll lose your muscle because muscle, the protein gets used to make glucose. That's why you measure lean mass. And surprisingly, we found that the lean mass actually, whereas the fat mass decreased. That was a big surprise. That's what we reported. But we haven't looked at exactly why the muscle mass increases. But what we are seeing recently is there are some correlation. Other people have published recently that nicotinamide riboside. This is a precursor for NAD. If that is given to mice, they also gain muscle mass or they maintain their muscle mass. And this nicotine my riboside is converted to NAD, and increased amount of NAD is always better for any cell, because that is the precursor to the energy currency of the cell, that's ATP.

And what we are seeing is, in many of our mouse experiment, we see the NAD level actually goes off slightly. So this is a natural way to boost up the NAD level, not only in muscle, in almost everything, every organ. So I think that might be one of the many different reasons why we're gaining muscle mass. But we can't explain with the current data why they can muscle mass. Can I ask you another question? So I do know that there are some genes, by the way, that are involved in nitrogen balance

that are regulated by circadian rhythm. But that's, so I also remember in your paper, I don't know if it was the same paper or a different one. I think it was the same paper. But you also found something very interesting. And it's kind of along the same lines here, and I'll tell you where I'm getting at, but you also found that animals that were fed during a nine-hour period had improved endurance, not improved muscle strength, but improved endurance. And to me, when I read this, I thought, oh, well, if you think about endurance, endurance, endurance is aerobic, requires aerobic respiration, which means it requires oxygen, which means it requires mitochondria, because with mitochondria are what make energy in the presence of oxygen.

So have you thought about looking, and this kind of goes along with your AED hypothesis, but have you looked at mitochondrial biogenesis, mitochondrial function? Yeah, so the endurance is a very interesting aspect because we see that only when mice eat for eight to nine hours. We don't see that improved endurance when they eat for 12 hours, although the body weight is maintained as nine hours. So this was interesting. So that's why, as you pointed out, clearly mitochondria might be playing a role.

And in fact, in both in liver, we do see increased mitochondria volume and increased endoplasmic reticulum volume. So ER is also ER and mitochondria kind of work together. That's what we are learning these days. So the mitochondria volume increases. thing is we do see less damaged mitochondria in liver when they eat only for 8 to 9 hours. Second thing is this mitochondria effect is not restricted only to liver. We do see increased mitochondria volume in brown adipose tissue.

So in brown fat, as you know, this mitochondria have kind of dissipate heat, really literally burning the fat. So at least in two different organs we have seen increased. mitochondrial volume, that correlates with increased level of PGC1 alpha that's involved in mitochondria biogenesis. So there is all these links that we are seeing and that are also giving us clue where to see, where to look for the mechanism. For example, why PGC1 level goes up and what triggers that to go up.

Well, this actually leads me into another area that I wanted to cover. So before we go into the flies and humans. And that is, I think people may be confused by this time-restricted feeding, which is essentially feeding within our active hours, the daylight hours, and intermittent fasting. So there's obviously some overlap between the two because if you're, let's say you're feeding within a 12-hour period. So you wake up, you have your first sip of coffee that starts your cloth.

All right. That's it. So 8 o'clock, then you better stop eating by 8 p.m., right? So that's for 12 hours. Yeah, yeah. Then from 8 p.m. all the way till 8 a.m. the next morning, you're fasting, right? You're not getting any energy. Yeah.

So in some ways, you're getting a lot of, there are some overlaps between this time-restricted feeding and intermittent fasting, for example, which has been shown to increase ketone bodies like beta-hydroxybutyrate, which I know you've also shown restricted feeding does increase that as well. Takes around, I think, 10 to 12 hours for your liver glycogen deplete and fatty acids get immobilized. They go to the liver. You start to make betahydroxybutyrate and other ketone bodies, which then get transported to other tissues and are used for energy in the brain or they act as signaling molecules. Which Eric Verdeen at UCSF published. So there's lots of, have you, can you first of all differentiate for people like the difference between intermittent fasting and

and time-restricted feeding, like what are the main differences and maybe what some of the similarities are? Well, both of these depend on this idea. The commonality is this prolonged period of fasting. When I say prolonged, that's usually longer than six to eight hours because that's how long it takes for glycosin to deplete or maybe the fat-oxidation to begin so that we begin to use some of the fat. And you also pointed out ketone bodies and beta-hydroxibouturate.

Those are also produced maybe after 8 to 10 hours. So the bottom line is this. That is when we eat, we have a type of physiology where we're using glucose and we're driving some bodily function. And at the same time, we may be also damaging some cellular components because of all the reactive oxygen species that we generate during eating, during metabolizing all of this. So all of these have to be repaired.

And for some reason, we do not know why. The repair mechanism happens only during the period of fasting. And during this period of fasting, we switch to a different kind of metabolism, just like you said, our primary energy source is not the readily available glucose from food anymore. it has to come from different sources. In some cases, it can come from a little bit of protein, that's gluconeogenesis, or from fat oxidation or just like you said, ketone bodies. So these things, this physiology, the fasting physiology, we actually know, we are just seeing the tip of the iceberg of fasting physiology.

We're just learning about a very few molecules. We don't know what happens to a lot of signaling molecules, how the mitochondria actually repair during fasting. Is it actually necessary to why some repairs happen only during fasting? Why can't they happen when we're eating? So all of these questions are out there. But what is common between this intermittent fasting and time-restricted feeding is this fasting physiology that we are beginning to understand. The reason why we coined and used the word time-restricted feeding is we are not restricting calories, at least in experimental animals.

So in that way, the intermittent fasting came from calorie restriction and every other day feeding. That had a serious component of caloric restriction that people thought, many people thought is difficult to achieve. So that's why we stayed away from the word calorie restriction or fasting. And we use the word feeding because people thought people may have a positive attitude towards it. Other than that, I think the idea of fasting is ingrained in evolution, just like in circadian rhythm, the animals have access to food only during their awake time, which can be.

be less than 12 hours. And also for diurnal animals, which are hunter-gatherers, the only time actually they have to hunt is twilight time. Because if you ever go to Savannah or any of the African countries where there is still wild animals, or if you go to even a Jew, then you know that animals are not active in the middle of the day. They're mostly active during morning and evening. So in nature, people actually, animals actually have only two chances to eat, and the rest of the time they're fasting. So this fasting physiology is a very natural response to repair and rejuvenate. And in time-restrated feeding, we're kind of exploiting or we're kind of bringing back that primordial physiology that's ingrant in our genome, that our genome has to

respond to that fasting on a daily basis. At the same time, it sinks with another aspect of the genome, that is, it helps us stay awake for 10 to 12 hours and to reduce our energy level and go into a sleep or less active state for the rest of the day. So in that way, it brings back the primordial rhythms in our physiology, metabolism, repair, and rejuvenation, whereas intermittent fasting actually helped us.

to learn various basis for this fasting physiology. That makes sense. I guess also what I was wondering is if you think about it, like so the minute you start your metabolism clocks in your liver, for example, the minute you start those metabolism clocks by your first sip of coffee and breakfast, the clock's ticking and you're insulin sensitive, you're going to be able to, you know, take glucose up into various cells after you eat, And then once you get past that time, so you're now 12 hours out, you're not going to be as insulin sensitive.

So let's say someone that is doing intermittent fasting. And they wake up at 6 o'clock or 7 a.m. They have coffee and breakfast, a big breakfast, and they're done. So then they fast for 12 hours. So now it's 7 p.m. Maybe 13 hours, 738 p.m. They've been fasting all day, so they're getting a lot of the activation of some of these, you know, stress response pathways like AMP kinase and, you know, they're making

some ketone bodies, crev, all these, all these similar pathways are being activated that, you know, time-circuiting feeding also activates. But then they take a big meal at 730 or 8 p.m., so 12 or 13 hours after they've already set their clock. Yeah. So now, in theory, then, they're, well, I don't know if this is true or not. Maybe the intermittent fasting changes some of this, but, you know, their liver wouldn't be, you know, it wouldn't be working as well at that point. Or do you think that just because they were fasting all day, that may change some of that and allow them to then eat this meal and it wouldn't have such a negative effect? Yes, that's a very interesting question that we get many times,

and we're thinking about addressing that. It's very hard to do that in experimental animal models, because if you fast, if you give them two meals, they reduce their calorie intake. but it's possible to do. But here is something that came out only in last three to four weeks. You mentioned early in our conversation that insulin sensitivity is not the same at the end of the day. And the question is, if you fast enough during the day, is your insulin sensitivity is good enough as in the morning.

Then everything you collages, at least insulin, which is a big thing in metabolism, if it is same. So recently what we're finding is, actually, this smoking gun came almost 10 years ago, when people who were doing G-WAS studies to find whether there are mutations in given genes that make us more diabetic or obese, surprisingly, people thought that, okay, so you'll find some genes that regulate metabolism, right? So that's the common sense. But then the big surprise was they found melatonin receptor as one of their top hits. and some of the clogged genes like Cryptochrome

in the top five or ten genes. It was not only in one study, in multiple studies, they found it. So there was this smoking on what is melatonin doing with this obesity diabetes. And recently, what is interesting is people are finding that melatonin receptor is present in pancreatic eyelid cells, beta cells, and melatonin receptor, when it's engaged with melatonin,

it signals and it inhibits insulin secretion. What? Really? Yeah. So it just came out like four, five weeks. So you know that I've always wondered because like most of the melatonin in the body is actually made in the gut, right? So your, so you triptophan gets converted in, so triptophan from dietary protein gets converted into serotonin, converted into melaton. This is happening in the gut.

No, serotonin goes to pineal and then gets into... So there's, so it happens in the gut and it also happens in the brain. There's two separate genes that do this. And what's really interesting, is, I don't know what melatonin, why are we making it in our gut? So I'm wondering if it's somehow signaling to the pancreas. Yeah, so this is completely new. And so that's why now it brings up, now it helps us to connect this dot that people have, for last 35 years, clinicians know that the insulin sensitivity is very different between day and night.

And then the g-was, the human genetics people came and said, yes, there is some smoking on with melatonin. And now finally we are saying, yes, melatonin deceptor can actually inhibit insulin secretion. So in that way, having an evening meal, maybe with candlelight dinner, is not a good idea because you have less light, so you have more melatonin, and that can inhibit. I have to get that study. Very, very interesting. So that's one case where we might think that late night, even if you control for, calorie, the same calorie taken late in the night versus early in the evening might have different effect.

In fact, there was one study that came out from Spain two or three years ago now, showing that in a weight loss trial, they actually found, although everybody got the same diet, they were controlled for activity. Clearly, there are two groups of people, some group, one group lost weight, significantly, a lot of weight loss. and the other group lost moderate amount of weight. And when they did post hoc analysis to see what is the difference, the only difference they found was the group that lost weight,

they actually ate their lunch. It is Spain. In Spain, people ate lunch at 3 o'clock, right? So they ate lunch earlier, whereas the group that did not lose weight too much, they ate their lunch later. So that is one, another piece in the puzzle saying, that late-night eating might actually prevent wet loss. Right.

And you've now, you've translated some of these findings into some human trials using this smartphone app that you've developed. So that's kind of neat as well. Yeah. So one thing was we wanted to see when people actually eat. And in typical nutrition studies, people are asked, when do you eat lunch, breakfast, and dinner. But that doesn't capture really they're all snacking and everything.

So that's why we thought how to capture when people eat in a very evidence-based manner. And we thought if we asked people to take a picture of their food, then the picture will speak a volume. It will have every single component. They may not have time to describe everything on their plate, but we'll capture that. It will also have the time stamp. So the whole idea was to see when do actually people eat?

Are there a lot of people who eat like mice do, that nibble throughout the day and night? And if they actually eat until, say, for more than 12 hours or 13 hours, then they are the ones who may benefit from time-restricted feeding. So when we did this experiment, when we started this project, we thought that everybody we asked, they will say, yeah, I wake up, I have my first sip of coffee, and usually I eat all of my food within 12 hours.

So I'm very discouraged to hear that. But we carefully selected people who don't do a shift work, so they will not have to work in the nighttime. That's why they're changing their eating time. And they're also not on any medication that will change their hunger or satiety. So it took really healthy people from San Diego area because we live here. And they just had to take a picture of their food. And that way it was also less stressful for them to enter what they ate and fortune size, etc.

Way better compliance, I'm sure. There's only three clicks because if you think about it, open the app, take a picture, and then press the same button. And the optional was they could actually describe what they ate. But we found very few people actually describe what they eat. So that means just typing that on your left hand when you're eating is not a very pleasant experience. What we found is out of this 156 people, nearly 50% people eat during 15 hours. So that means between their first bite, non-water bite to the last non-water bite or sip in a given day, is around 15 hours, which is some people think, ah, that's normal because if they start their first sip of

coffee at 6 o'clock in the morning. And then after dinner, they're watching their favorite show, and then had another glass of wine or chips that can go up to 9 p.m. But then we asked, well, in mice, we can actually take away food and impose time-restricted feeding. We can't do that for humans. They have to be self-motivated.

So he asked whether it's feasible for some people to at least restrict the time. So we asked eight of them to see they were eating for 14 hours or longer and they were a little bit overweight. So we asked if they can eat within 10 to 11 hours. And we said, we are not going to ask you to change what and how much you eat. The only thing you have to do is select your own time, depending on what time you go to work or what time you come back.

Select your own time interval of 10 to 11 hours and try to stick to it every day, even on the weekend. And surprisingly, all these eight people, they self-selected there 10 hours, 10 to 11 hours, and they stuck to it for 16 weeks. And at the end of 16 weeks, they came back. We saw that they lost around 4%, 3.8% body weight within the 16 weeks. They didn't have to do too many. They didn't have to read labels. They didn't have to type for some size.

But then when we asked them, why did you do it? what is surprising is they said they slept better and they felt more energetic in the morning, and that's why they did it. And since they didn't have to count calories, it was also good. But what is surprising is, in mice, if you do the same experiment, mice will chow down. They will eat the same number of calories as when they have free access to food. But in humans, these people, in our study, they actually ate 20% less calories, even though we ask them to reduce their time,

they ultimately reduce their calorie. But if you think about it, this is a much better way to control, manage their diet than to count calories. So in some way, this study is inconclusive to say whether time restriction alone was beneficial for weight loss. But what it showed is the feasibility

that some people can time restrict, and that can be an indirect way to reduce. your calorie. And since we are collecting picture of every single food, we can also ask another very simple question. What is the time of the day when people are more likely to eat certain type of food? As you can imagine, we found people eat, people drink most of their coffee, 70% of their coffee within four to five hours interval in the morning. and people ate 70% of their alcohol in the evening four to five hours. So now imagine if somebody is time restricting to the daytime than he or see is more likely

to lose on alcohol. So in that way that also improves the quality of diet. So since we humans eat different type of food at different time of the day, depending on which interval we choose, may indirectly result in change in nutrition quality and to some extent quantity. And what about the cutting out like the ice cream and desserts? Yeah, so we, most of the reduction in calorie was due to reduction in

late night snacks. Yeah. And after dinner, ice cream, dessert, and alcohol. So it's a really cool idea, Sachin. I, I went to your website last night, Meistercadiancloc.org. Very, I really like the website in general. There's a blog section, the section explaining a lot of the science behind circadian clocks and everything that we've talked about today.

There's some presentations of you there. I mean, it's just really great website. But I also signed up for the app because I am now on a time-restricted, you know, feeding schedule. Right now I'm doing 12 hours. I would like to try the nine hours to see if I can get any endurance benefits, which may possibly be mediated by beta-hydroxybutyrate because that's been shown to, I went up and I signed up. It's really simple.

You go to the website, you click. Maybe you want to explain. I clicked sign up or something. And then it asks you very simple question. So the whole idea was, if you think about it, this branch of science, circadian rhythm or circadian research came out of curiosity. So we actually don't have a traditional medical school department, which will take our results and translate to public.

It's not even in the public health curriculum because circadian rhythm is such a new field that's not there. So it's so important. And it's like disrupted by modern-day society. I mean, it's like, I'm going to be talking about this now, so I'm very excited. It's definitely important.

No, what we're saying is if you brought up this modern-day society, in modern-day society, light is an enabler. So light enables us to stay, awake throughout the night. And then we have 15% of workforce who does night-sipped work. And they are the ones who actually enable the rest of us to stay awake. They are the ones who are actually driving the truck, who are in the emergency department.

They are food prepping. They're doing all these other service jobs. And they enable the rest of us to stay awake. And then in their way, within the last 100 years, we have gone tremendously from a very natural day-night cycle to 24 hours light cycle. And that's the biggest disruption we're seeing. And that biggest disruption leads to all types of chronic diseases that we see in modern days. For example, now, out of the top 10 causes of death, if you look at the top 10 causes of

death in industrialized country, the 5 or 6 top 5 or 6 are chronic diseases. And we know circadian disruption can lead to those chronic diseases. So now the question is if we can do very simple adjustment to our lifestyle, can we prevent this chronic disease by X number of years? So to get to that, we need two different information. One is what is the extent of circadian disruption? When do people go to sleep? When do they get off?

When are they eating their food and one are they exercising? So if we can capture what, when, and how much people eat? sleep and move around. Then we have a very complete, nearly complete picture of somebody's lifestyle that will be highly useful for circadian rhythm research, for your primary care physicians, and also for public health and epidemiology. So that's the first part of the goal. To collect what when and how much people eat, sleep, and move around on a daily basis for at least a week or two weeks. So we'll know how is there a lot. lifestyle in weekday and weekend. And then in the second phase, we can give some health

information because many of the health has more geared towards losing wet, doing one thing, and it's very difficult to really guide people to do these three different things, eat, sleep, and move around on a timely basis. And it's a challenge. We're experimenting. So we are actually hoping that some people who are signing up, they will give us feedback, how to improve our science and also our education and our app. So that we'll see the benefit. In the second phase, they can self-select, just like you said, you're going to self-select 12 hours, maybe nine hours.

And when you self-select an interval and enter all of your food, and sometimes even if you forget once in a while, that's okay, because we account for that. We have some algorithm. And then we want to correlate whether this nine hours is beneficial to you or not whether some people actually get the same benefit with 12 hours some people might go to eight hours or nine hours so those information will come in the second phase that goes from second week till 16 weeks then if you want to

continue we have many users who want to continue for a year or two and they want to see how seasonally the eating pattern sleeping pattern changes that they can have the data and also we gain from that data research gains by taking that data and seeing what is the pattern in general public. Also, it's nice to feel like you're contributing to research, you know. So in addition to this Mystircadian clock app, which is on, it's on the App Store. And also in Android. Android.

And so in addition to that app, you can sync with other fitness data like My Fitness Pall. Because you're going to be measuring all these other health parameters. Yeah. I heard you mentioned something also about a lot. a light sensor thing or some. Yeah, so I wear a light sensor. Yeah.

Censor's light. But let's go back to the HealthKit and Google Fit. So most phones now have, if it is a iPhone, it has something called HealthKit that comes with your operating system. So it's already in your phone. And that phone, that health kit app is sensing every time your phone moves. So it's almost like. It's measuring your movement just like the Fitbit does, and it stores that data.

It also stores many other kind of data if you want to store. For example, your own information about your body, your height, weight, age, etc., and it can record up to, I think, 70 plus different parameters, depending on if you're using a special app or even the same app, if you say what you wait, what of the composition, it can store that. But what is interesting is that information. is not on the cloud. So it always stays on your phone.

If you lose your phone, you lose that data. But what you can do is if you want to share what is in your health kit or Google Fit, Google Fit is very similar to HealthKit, but it runs on Android. What you can do is you can sync that data with an app like MyCadion Clock. So anything, any information that you store in HealthKit

gets shared with my circadian clock. And my circadian clock can also send some data back to HealthKit. So it kind of acts as a hub. So similarly, various apps like My Fitness Ball and then Noom and many diet apps, many exercise apps, they also deposit their data to My Health Kit or Google Fit. So it's kind of a data exchange hub. So if anybody has any app where they are measuring what, when and how much, they eat, sleep, or move, or any blood parameter, any other health parameter, they are interested in sharing with researchers. They can sync that to HealthKit, and then HealthKit gets synced with my circadian clock, and we can capture all that data and we'll analyze.

Very cool idea. I'm looking forward to contributing to that. But I kind of wanted to, Talk about the light. I want to talk a little bit about your, so you've got so many awesome, so much awesome research coming out of your lab. There's also the heart rate, heart rhythm studies that you mentioned, so you mentioned earlier the chronic diseases. If you look at the United States or industrialized societies in general, the number one killer, people die the most of heart disease, some sort of heart disease.

You know, so, and obviously lots of different things. regulate our susceptibility to heart disease and metabolism, obesity. But you found some very interesting findings looking, doing time-restricted feeding in fruit flies. Yeah. So can you talk a little bit about that? I'm very interested in. Yeah. So fruit flies are used in science for many, many years, and they have a short lifespan.

They stay alive maybe nine to ten weeks max. So it helps us to figure out whether they're... any interventions on lifetime restricted feeding will have any positive or negative impact on health span or healthy lifespan or longevity etc so what we did was again a very simple experiment we took fruit flies and we gave them food only for 12 hours during daytime because fruit flies are diurnal animals they fly around during daytime eat and then nighttime they sleep or they had access to food for 24 hours and we measured that they were eating the same amount of calories, and they're also moving around the same

distance. So inside these bottles, they could fly back and forth. And at three weeks of AIDS, their heart is very healthy. It bids rhythmically, and although the fly heart is not like human heart, they also have... Those people are probably shocked flies have a heart. Yeah. So their heart has a very similar genetic program. In fact, many of the genes that are now known to be necessary for heart development in human

were discovered in flies, and vice versa. There are many diseases in humans. Those are now put into flies to see what do they do in the heart. So it's a very interesting model. Just like humans, the fly heart also becomes weaker with theirs. So by five weeks, the hearts don't beat rhythmically. They have a little bit of arrhythmia. and then they have the same dialysis, so the heart gets dilated with AIDS, the bit-to-bit

distance also because it's very regular. So what we found was when these flies eat only for 12 hours, they don't develop that arrhythmia as quickly as the normal flies do, so they're protected from this heart disease. Then we said, okay, so if we introduce time-restricted feeding later in the, in the, in the, their lifespan, then what happens? Because one thing we could not do in mouse study, because my sleep were three to four years, we could not introduce time retreating later in life. But in flies, when we introduced later in life, they were also protected, the arrhythmia

reduced in flies. And when we gave high fat diet to flies, they also produce arrhythmia and many heart conditions that we see in humans, and those were also protected in flies. And what is interesting in flies, we also saw the flies sleep better when they eat only for 12 hours. So by five weeks, flies actually are just like very old people. They have fragmented sleep at night time and they're sleepy during daytime. And that is completely prevented by time retreating. They have a good night sleep.

They're very active during daytime. The heart pumps nicely. Wow. Did you measure heart rate variability? Yeah, so we did heart rate variability, so there are seven different parameters we measure. And that improved? Yeah, so all those seven parameters improved to some extent. And when we introduced later in life, they also improved.

That was the surprise. Do you know what or why? Yeah, so what we found is, again, one connection was back to mitochondria. What we found was that mitochondria were healthier in this sense. they did not, maybe they were not producing as much reactive oxygen species. The mitochondria in the cardiomyosite? In the heart cells? Okay.

So we took the heart cells and did gene expression profile. We looked at all the genes. What we found is there was a big cluster of genes. The expression actually reduced, and those are from the electron transport chain. So that implied that maybe they have less reactive oxygen species or maybe reduced activity of ETC electron transport chain is beneficial. So then to prove that, we actually knock down few components of ETC, and those flies also have better heart.

So that is one thing that found. Second thing that we found is proteostasis of protein folding is necessary, and in many other organisms, people have shown that in different components of protein folding machinery. But here, what we found is there is a new protein folding, very newly identified folding machinery called ATP dependent. It's a chaparonean complex, eight different components form this barrel-like structure to fold proteins. And this requires energy. And that CCTV component has been shown to be important for various muscle, sorry, various cytoskeletal protein folding. And it makes sense for heart. And in fact, in humans, there is a point mutation in one

of this ATP, sorry, CCTV component that has been shown to predisposed to some heart disease. So it's a beautiful story where we found both mitochondria and this protein folding machinery are necessary for this time restricted feeding beneficial, beneficial effect. And this time restricted feeding was 12 hours? There was 12 hours because flies are different from us. They don't have thermoregulation. So when they fast for a longer time, they cannot, they kind of, they can tolerate that. Oh, yeah, they'll get cold.

Okay. So, you know, some of these phones also measure heart rate variability. Yeah, so it'll be interesting. Yeah. Very interesting because that's like, you know, that's something that's supposed to be very important for having a healthy heart. Yeah. But if you don't mind, again, this is just, it's another reason why this time restrict of feeding, it just seems like everyone should be doing it.

It's an easy lifestyle adjustment. I mean, easy enough. You have to be disciplined to some degree, but it's easy enough that you can do. It's like, you know, by the time it's 12 hours later, right, that's it. You have to make sure you get all your food, your whatever it is that you consume within that 12 hour span. But something, I do want to shift gears if you don't mind. Another organ, the gut, because it's another very area of interest of mine. And you recently published that the gut microbiome, so we'll quickly go through this, the gut microbiome is also, well, bacteria are living organisms.

And they are also on a circadian rhythm. And what I found very interesting from some of your recent work is that you showed that different bacterial species within the gut, at least in the house, also seem to have more of these species during certain times of the day and less during certain times. And this was different in obese animals versus, you know, non-obese animals. That is very fascinating. Can you explain that? Yeah. So bacteria, just like us, they need their own niche. They need their own pH, temperature, nutrition, and all these factors.

And now you can imagine that when we eat, we kind of change the gut environment, the content of the gut slightly. so that some bacteria may find it easier to grow, and then some other bacteria may find it very difficult to grow in that condition. So what happens is when we eat in a time-restrited fashion, we have a very fixed eating and fasting interval. Then during eating, that environment will promote a certain set of bacteria to bloom, and then the other bacteria kind of become quiescent, quiet. And then after a few hours of fasting,

then the second set of bacteria will bloom. So in that way, what it helps is it helps to nurture different, a wide variety of species to co-have it in our gut. And they also function at different time of the day, during the daytime. So, for example, when you're eating, we need a lot of bacteria to break down starch and fibers, complex carbohydrates,

and also conjugate some biose. bile acids and etc. So we need different players to do different things throughout day and night. And by time-restricted feeding, this alternating two different types of environment, one where there is a lot of food and the pH is very different versus one when there is fasting, there is scarcity of food and the pH is very different. By alternating between these two different environment, we promote this diversity inside the gut. And why this is important is we actually don't understand why, but research from a very

different field, from gut microbiome field, they are now finding is it's much better to have a more diverse microbiome in your gut than to have only one or two very simple species. So in some way, by having the time restricted feeding, it promotes their diversity. There are a few interesting thing that we found, which we are still working on to figure out why it happens. For example, mice that had time-restuted feeding, although the bacteria could break down the complex carbohydrate to simple carbohydrate, for some reason that simple carbohydrate could not be taken up by the gut. It actually went out in the poop. And that was a surprise because usually simple carbohydrates are the ones that get observed. So we think that

this compositional change somehow protects the complex carbohydrate in the upper intestine. So it comes back to the lower intestine where it gets degraded, but we know that the lower intestine doesn't absorb sugar. It's only in the upper intestine. So in that way, by this compositional change, we can completely sift how nutrition is even absorbed into the gut. The other thing that we also found is bile acids, which are very emerging as very important players in health, those bile acids are also better managed with time-restricted

feeding, both in the liver and also in the gut. Biolacids are made in liver, and then the cycle back and force between gut and liver, and bilacids are made from cholesterol. So there is an enzyme in liver that gets up-regulated in time-restricted feeding, and that enzyme breaks down cholesterol to bile. So you get dual benefit, you reduce cholesterol, increase bile acid. And that bilacid comes to the gut, and it helps absorb some fat back into the gut. And then it gets conjugated by this bacteria. And for some reason, we don't understand. In time-restridated feeding, they get modified in a different way than in normal feeding.

So these are some of the new research directions we are taking or trying to understand how this gut microbiome interacts with timing of food and then changes the compositional aspect of the gut. It's very interesting. Have you looked at also the short chain fatty acids that they produce and whether those get taken up by the gut? Yeah, so those, we are now, so short-chain fatty acids are a little bit difficult to look at because they're volatile. They take it much faster, so those are the next set of experiments we are doing. Okay, very, so does this also suggest we should time our probiotic intake? We haven't looked into that to see whether the probiotics.

Is there any data out there that has measured? So, for example, I've measured my own microbiome using a company called Ubiome, which allows you to send a little fecal sample, and I've done that a few times. Obviously, now it seems like the time of day is very important. I usually do it in the morning because it's a problem. But it seems like the time of day is very important. Yeah, you can capture the compositional change by time of day. Is there any data out there that has looked at how the microbiome species change?

from morning to evening? Yes. Actually, in humans, there are at least now one or two papers showing how the compositional change also changes throughout day and night. And when you have jet lag, that messes up the compositional change. Right, yeah. I think there was some study showing the microbiome

gets thrown off and that leads to obesity or something. There's so much. And then, of course, the shift workers as well. I mean, they're completely, their whole system is off whack. It'll be interesting to see whether or not time-restricted feeding can help negate some of the negative effects of shift work. Yeah, so that's what we're doing now to see whether we can put mice in shift work and give them food within shift or out of sift. Do you have an option on your app for shift workers so that you could also get some human data? Yeah, so people can say what they're, so in the first sign of, um, uh, uh,

routine and there is a question whether you are a shift worker or a regular worker and if they are they say they're shift worker then we look at the data more carefully to see how they're changing their diet during day shift and night shift and also all shift works are not the same some employers actually put people change their chance shifts every week every two weeks every three weeks and in some cases every four months yeah so we'll see all that data But we are going to introduce another aspect where they can say when they're going to work and when they're coming back, because now different variations of sift work. Many of the gig works, a flexible sift work, is not even fixed.

So flex hours is a new trend where people can be called off any time. And we want to try to him more carefully. So that's why we'll have another feature soon. Okay. And what about, so I know when I filled out the questionnaire last night, I, you know, put the city that I lived in, is it, so let's say I'm traveling and I take a picture of my food, there's a time stamp. Are you going to get the time zone? Like. Yeah, so in the new, it always tracks the new time zone because what happens is we thought about it. It's a little bit complicated to show two different time zones in your home time zone and then in the new time zone. But we'll get to that to see whether we can introduce that. feature where you can see your data as if you're in the same times on how your body is adjusting, you can see that data.

We are working on it. Time is a very, what we figured out is time is a very difficult parameter in apps because as we are moving as there is dead daylight saving time and all these other time changes. Displaying data becomes a challenge. So that's another half of the challenge. Yeah, I know what you're doing, but you're off to a really good start. I'm really excited about everything that you're doing. I have so many more things that I wish I could talk to you about,

but unfortunately we're running out of time. And I have another meeting. So you are on Twitter. I follow you on Twitter. What's your Twitter handle? Sachin. Dot Panda. Sachin.

Dot Panda is your Twitter handle? Yeah. This S-A-T-C-C. H-I-N-D-P-A-N-P-A-P-Bair. Right, okay. And your website, MyCircadian clock.org. And that's where people can find all things, circadian clock, all fascinating research, new giving presentations, and also they can sign up.

Yeah, they can sign up. And also, almost every week now we'll have a blog, either from a, actually, we are getting a first blog from a user, just like you, this person started before even our human work was done. And he just started voluntarily and did religiously did nine hours or eight hours time restricted feeding for seven months and documented everything. So that's going up this Friday. So we are very excited.

Yeah, I really like your blog. I was looking over at last night. It's very informative. So it's a nice, nice job. Well, thank you so much, Sachin. I've been a huge fan of your work for several years. and pretty much all things that I've learned about circadian rhythm, you know, I'd say 80% has come out of your lab. So I'm very excited to have the opportunity to speak with you.

That's very nice. Thank you so much. I look forward to more research coming out of your lab. You seem to be doing some really interesting things. Thank you. Thank you. All right. Wow.

That was a good one, right? Okay. So a quick correction. Dr. Panda's Twitter handle is actually Sachin Panda with NoDop. That's S-A-T-C-H-I-N-P-A-N-D-A. You can find his website and learn about participating in his smartphone-fueled human research by going to Mycircadianc.org. That's M-Y-C-I-R-C-A-D-I-N-C-L-O-C-K. Finally, this podcast is brought to you by people like you.

If you enjoy the podcast, you can commit to the financial equivalent of taking the podcast out to a coffee once a month by pledging a few bucks. This makes a meaningful difference in my ability to do this podcast and the many other fun things I have going on that I try to make the wider world beneficiaries of. Learn more about contributing by going to foundmyfitness.com forward slash crowd sponsor. That's found my fitness.com forward slash C-R-O-W-D-S-P-O-N-S-O-R. Thanks for listening and have a great day.