Rhonda: Hello, everyone. Today my guest is Dr. Satchin 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.

Satchin, considering that every single living organism on the planet Earth has this internal biological clock, their 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?

Satchin: Yes, so all lives on this planet evolve 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 a 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 is 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 gonna come or when we are supposed to run, when we 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 certain time of the day, and then to rest and rejuvenate at the other time of the day.

Rhonda: 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...

Satchin: Yes. So when we are born, we, kind of…when babies are born, they actually don't have this daily 24 hours rhythm in activity or sleep. They don't to bed for six or 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 their growth phase. So, during the first 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 8 to 12 weeks, they actually begin to have some kind of consolidated sleep. So they go to sleep and wake up at the right time, wake up after a few hours, but it's not tied to light-dark cycle. So they kind of drift. So that's the 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 age, 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 age.

Rhonda: Oh, interesting. And you mentioned...so there's, there's clocks in all of our organs and there's different…your work, you've done a lot of research on what regulates these different clocks.

Satchin: Yeah.

Rhonda: There's a master regulator clock, and there's other clocks in different organs. Maybe you can explain. I read somewhere that something between 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.

Satchin: Yeah.

Rhonda: So, there's, there's a wide variety of processes that are regulated by these clocks.

Satchin: Yeah.

Rhonda: Maybe can you explain a little bit about the central master clock and...

Satchin: Yeah.

Rhonda: ...what regulates that?

Satchin: [laughs] 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 are defined like cubic millimeter area of brain that regulates something.

So we're systemically taking out parts of the brain in mouse, rodents, and different larger rodents, and then figure out that when they hit this small part of the brain called suprachiasmatic nucleus, so that means we know that our eyes send optic nerves that crisscross and there is a part of the brain called optic chiasma, so it's above the optic chiasma. So that's why suprachiasmatic nucleus. So that's...

Rhonda: Say that 10 times fast. [laughs]

Satchin: Yes [laughs]. Suprachiasmatic nucleus or SCN, it's composed of around, say, 100,000 neurons, I guess, in humans, 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 doesn't, will not have any sense of time and go to sleep at random time and will wake up after two or three hours and it continues. 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 accesses master circadian oscillator or circadian clock because it orchestrates this daily rhythm in 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 related to eating, for example, our gut, our liver, our fat, all of them are driven by this feeding behavior. Similarly, our 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 stage 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 this presents slowly, they turn into a state where they don't have a sense of day or night. They stay awake throughout the night and may be sleepy throughout the day. So that's why this master clock is so much important for our health.

Rhonda: And that might 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 feed-forward loop. But specifically with regards to the, the master clock, light is what regulates this master.

Satchin: Yeah.

Rhonda: It's what sets it.

Satchin: Yeah.

Rhonda: So can you...and this was some of your early findings.

Satchin: Yeah.

Rhonda: Can you talk a little bit about that?

Satchin: So for a long time people knew that light resets our clock, and in fact, in nature, with change of season, the sunrise and the 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 right time. So what is interesting was for a very long time, people couldn't figure out what, where is the light receptor that resets 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 to 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 go to war and lose both of their eyes because of gunshot wounds, and people who have cancer or a tumor growth in both eyes and the eyes are removed, they can't reset their clocks. So they, kind of run free. They kind of 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 a half hours, something like that. So, if we cannot entrain our clock to light-dark cycle, then every day we'll be working off 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 [inaudible 00:10:57].

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 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. And because frog skin has a light sensor that detects light, and then puts kind of a natural sunscreen.

Rhonda: Like melanin making…

Satchin: Yeah, and so it spreads melanosomes. So melanin pigments are spread. And interestingly, the same protein that spreads melanosomes in frog skin is also present in human retina and mouse retina, and only in 1000 to…sorry, 2000 to 5000 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 this suprachiasmatic nucleus or the master clock. And that's how every day, in the morning, with the first sight of light, these melanopsin cells sense light and then tell the SCN that this is morning and this is time to sync up. So that's what it is called.

Rhonda: Okay. So that first bright light exposure...

Satchin: Yeah.

Rhonda: ...sets the clock and tells your body, you know, "Okay, this is the start." So then you start to change gene expression, things are going on in the brain, you're more mentally aware of things that happen. All these little changes happen throughout the day that are on this rhythm.

Satchin: Yeah.

Rhonda: What happens, then, if you, let's say, you don't have...let's say you live in a very dark apartment or, you know, 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...

Satchin: Yeah.

Rhonda: ...someone's circadian clock?

Satchin: So you kind of use this interesting term, bright light. And actually, that's very important for melanopsin because we know we have rhodopsin 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, a clock is not sensitive to that amount of light. Just imagine, if our clock was sensitive to dim light, then we'd be completely what because even in nature, the lightning or starlight or moonlight that we can see can reset our clock.

So, one interesting thing with melanopsin, 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 1000 lux of light to fully activate melanopsin. And then another interesting part of melanopsin is it integrates light over time. So that means it actually remembers how much light exposure you previously had. So for example, if I switch on a flash, then for 100 milliseconds you see a thing and then after the flash is gone, your visual system restart, you don't see that thing. But melanopsin stays active for several seconds after lights are off. So that characteristic helps you 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 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 melanopsin because it senses light, and in diurnal organisms like us, it does know there is light, so you're not sleepy, so you stay awake.

It also indirectly connects to part of the brain that produces melatonin, and melatonin is the sleep hormone. So, when we have lot of light and also for a very long period of time, then it shuts 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 alert 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 becoming…we are learning a lot about what quality of light and how much of light do 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-shifted light during the first half of the day that may help us to stay awake, to stay alert, 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 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.

Rhonda: And modern day society is also not very conducive to that, those needs because we have artificial light, we have televisions, we have computer screens, we have iPhones and Android phones, and you know, so everything's emitting this bright light or blue light...

Satchin: Yeah. ` Rhonda:... which is what's activating the melanopsin recep-...

Satchin: Yeah.

Rhonda: ...or melanopsin 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 lux of light, upon, you know, 30 minutes of waking, so, um...

Satchin: Yeah.

Rhonda: ...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.

Satchin: Yeah, yeah.

Rhonda: 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, the circadian clock.

Satchin: Yeah.

Rhonda: And it peaks about the time we wake up...

Satchin: Yeah.

Rhonda: ...or something like that, right?

Satchin: It rises when we wake up. So that promotes alertness, and melatonin is the opposite, it [laughs] promotes sleep.

Rhonda: Right. And it also...I mean, cortisol regulates... in itself, it's regulating...

Satchin: Yeah, huge amount.

Rhonda: …you know, 20% of protein-coding genes.

Satchin: Yeah.

Rhonda: So it's doing a lot. But these people...the thing with cortisol you want it to peak when it's supposed to peak.

Satchin: Yeah.

Rhonda: And you don't want it to be active all the time. You know, things like chronic stress...

Satchin: Yeah.

Rhonda: ...that can activate cortisol and, you know, this can lead to dysregulation of, you know, 20% of the human genome...

Satchin: Yeah.

Rhonda: ...or something like that. 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.

Satchin: Yeah.

Rhonda: It's very interesting how just the bright light exposure itself...

Satchin: Yeah.

Rhonda: ...seem to regulate the stress hormone or at least keep it…

Satchin: Yeah.

Rhonda: …so it wasn't going out of control. What about people that, you know, get...so people that are exposed to bright light in the evening, so, you know, you're working late or you're, you know, watching television, and that's going to trick your brain and think, "Okay, reset." Is that kind of what's happening?

Satchin: 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 indoors and many of the indoor environments have less than 1000 lux of light and many places have actually less than 200 or 100 lux 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 it's 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 the circadian rhythm, all these rhythms and gene expression in different organs are completely desynchronized. You can imagine a car running with a bad timing belt and the spark plugs sparking at wrong time, so you can't run that car too long. So that's what happens in our body.

Rhonda: Right. I know for myself I...there's a few things, there's a couple of things that I, 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.

Satchin: Yeah.

Rhonda: So I used to have, you know, windows that were blocked by other buildings and it was not facing, you know, the west side. I mean, just no light was coming in.

Satchin: Yeah.

Rhonda: 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, so...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 Philips Hue.

Satchin: Yeah.

Rhonda: And so they're, you can program these lights to switch off blue light and only have red light.They do other colors as well than red light.

Satchin: Yeah, yeah.

Rhonda: And so I have it now where...well, now that it's summertime, I used to have it programmed with the sunset, but now that the sun's setting later, it gets too dark in my place, so about 5:30 the red lights come on.

Satchin: Yeah.

Rhonda: And then I have an app on my phone...I'm sorry on my computer called F.lux...

Satchin: Yeah.

Rhonda: ...which then blocks the, it filters the blue light...

Satchin: Yeah.

Rhonda: ...and it corresponds to the sunset...

Satchin: Yeah.

Rhonda: ...or the time zone that I'm in...

Satchin: Yeah.

Rhonda: ... or that anyone's in. So those are some of the things that I've done, and I now am very much able to go to…you know, about 10:00 at night, 10 p.m., I'm, I'm sleepy, I, you know, I brush my teeth, it's time for bed, and I wake up now probably around 7:30, 8:00. That's it. So I get a nice, a good amount of sleep...

satchin: Yeah.

Rhonda: ...but it's pretty regular and routine.

Satchin: Yeah.

Rhonda: 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 to travel to Asia at the end of next week, jet lag, you know, 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 gonna help reset me?

Satchin: Yeah, so it's a very complicated question because [laughs] there's light, and also there is food, and we'll get to that.

Rhonda: Yes.

Satchin: But one important point that you've brought up is jet lag, and although we relate to jet lag when we travel, there are nearly 15% to 20% of population in this country or in any industrial country that works in dayshift and 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 shift to morning shift to night shift, and all these shifts.

And what is interesting is most employers think that it's very stressful, so let's let them do the swing shift 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 this shift work so that these guys will go from day to night shift to swing shift without compromised fitness and with a good family life.

So we're still learning how to shift them. It's not easy for them to shift 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 1000 lux of light. So these people are continuously staying, kind of, in a dim winter environment during that 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, light does half of the job, and then the other half is done by food.

Rhonda: Right.

Satchin: You also pointed out another thing. You brought up the example of stress hormone, cortisol. Cortisol is regulated by circadian clock, 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 that time themselves. And when I say 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, right? And if you imagine if there is no light anywhere, then there will be a lot of accidents, so there will be lot of traffic congestion. So having the lights turned 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 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 are bringing in food, dividing them into different parts, and moving through this conveyor belt, the traffic. So not everything will happen at once. So there is time for protein to break down, there is time for glucose to be made, there is time for nucleotide to be made, there is time for bile acids to be made, the different hormones to be made. So these clocks actually have timed different things, and when clocks break down, then what happens is you can imagine there are traffic jam and 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 the disease.

So the point is, although we have clocks, these clocks also respond to when food is coming in. At the same time, when the food is coming in and 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 it will light up the fire and for that we prepare, 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.

Rhonda: 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 and the suprachiasmatic nucleus reaching 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.

Satchin: Yeah.

Rhonda: 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 hearts that also are regulated, but your research, and maybe we can start to talk about this, they seem to be regulated by something different.

[Stachin] Yeah.

Rhonda: By when you eat, by when you take in 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, "Well, I don't wanna eat this 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's, you know, gets dark earlier. I find it more difficult when spring and summer occur because it's lighter are out, I'm working later, you know, and therefore, you know, I eat later. But so let's talk a little bit about how food regulates...

[Stachin] Yeah.

Rhonda: ...these clocks and these different tissues.

Satchin: 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 are somewhere between 3000 to 5000 genes that are turned on at certain time of the day or night. And so that's...

Rhonda: A lot of genes.

Satchin: A lot of genes. So, that's almost 30% of expressed genome or whatever. Um, but what is interesting is, we said, "Well…" We did a very simple experiment where these are done in mice. so the night-eating mice...mice usually eat during the night time, that 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 night time, they eat. If we do that, then what happens to the liver? That all liver genes, that cycle, that take the cue 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 it's doing day, one group it's doing night. The liver takes cue from light-dark cycle then all cycling gene 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 are the same for both animals, the liver clock responds to when the mice ate. So the day-fed animals had the same 3000 genes cycling. The night fed animals had the same 3000 genes cycling. But now the genes that are turning on during daytime in the day-fed animals, now they turn on at nighttime in the night-fed animals.

So that means the time when we eat tells our liver clock when to turn on the genes and when to turn off. The light has very little impact. We cannot say no impact, very little impact on the cycling genes in the 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.

Rhonda: And you have a certain term, I guess. I don't know who coined the phrase, but it's called time-restricted feeding.

Satchin: Yeah.

Rhonda: And you've done...there's been experiments that you've done in mice where you've fed them various types of food.

Satchin: Yeah.

Rhonda: High-fat diet, high-sugar diet, normal chow 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?

Satchin: Yeah. 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'll be disease. Similarly, for 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 diseases, etc. 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, [inaudible 00:35:27]. 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, 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 condition gave 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.

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 we...to begin to with to give them a high-fat diet. So they're getting somewhere between 45% to 60% of their food from fat or 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.

Rhonda: So they're getting fat and sugar.

Satchin: So they're getting fat and sugar all this time. And then 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…and this is something that everybody, a lot of laboratories around the world do. There are 11,000 papers saying 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 we 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 and they had normal cholesterol, etc.

And then in the next set of experiments, we exposed these mice to high-fructose diet, high-carb diet, high-sucrose diet, all kinds of diets either ad libitum, whenever they can eat, or they are 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 healthy, and mice actually eat most of their food, nearly 70% of food during night time. 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 are more coordinated. So if you put them in a rotating drum, than they 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 ate constant, 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 daily 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 in 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, that quality doesn't matter, because even in our high-fat fed mice, we don't see they completely become normal just like the normal chow-fed mice. They're much healthier. So to have better health, you still have to change what and how much you eat, but timing becomes much easier to manage.

Rhonda: So you just covered so much. This experiment that you did right here, this publication, even before, you know, you've gone onto 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...

Satchin: Yeah, yeah, yeah.

Rhonda: ...so for mice, which is night within, I think, it was 12 hours...

Satchin: Yeah.

Rhonda: ...they gained…I'm sorry, they had 70% less fat mass.

Satchin: Yeah. So they had 28% less body mass total.

Rhonda: Right.

Satchin: And that change in body mass is mostly due to fat because they had 70% less fat.

Rhonda: That's amazing.

Satchin: Yeah, that's really...

Rhonda: Right there and they're eating the same crappy food, but they're eating it when their liver can process it the best, 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 eat very, very, very health-conscientious. I try to get a wide variety of vegetables and fruits, and good fats, and, you know...

Satchin: Yeah.

Rhonda: So all that stuff, omega-3s but I'm always trying to find more...the low hanging fruit to sort of delay the aging process in a way, or become, you know, as optimal as I possibly can. So, the mice that were fed a normal chow diet, you know, high in fiber and all these things, vitamins, you said they actually had more lean muscle mass.

Satchin: Yeah.

Rhonda: 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.

Satchin: Yeah, yeah.

Rhonda: And muscle mass is very important. It protects you from frailty, things like that. So, any ideas as to how just restricting your...we should probably talk about what starts that clock.

Satchin: Yeah.

Rhonda: 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?

Satchin: Yes, 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 are going for 12 to 16 hours of fasting every day. And many would think that when you go through this prolonged fasting you would 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 increased, whereas their 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 is 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 nicotinamide riboside is converted to energy, and increased amount of energy 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 energy level actually goes up slightly. So this is a natural way to boost up energy level, not only in muscle, in almost 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 gain muscle mass.

Rhonda: Okay. Can I ask you another question?

Satchin: Yeah.

Rhonda: 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 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.

Satchin: Yeah.

Rhonda: Not improved muscle strength, but improved endurance, and to me, when I read this, I thought, "Oh, well, if you think about endurance, endurance is aerobic. It requires aerobic respiration, which means it requires oxygen, which means it requires mitochondria because mitochondria are what make energy in the presence of oxygen." So have you thought about looking…and this kind of goes along with your NAD hypothesis, but had you looked at mitochondrial biogenesis, mitochondrial function? ` Satchin: 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 their 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 liver we do see increased mitochondria volume, and increased endoplasmic reticulum volume, so ER and mitochondria kind of work together. That's what we are learning these days. So the mitochondria volume increases. Another thing is we do see less damaged mitochondria in liver when they eat only from eight to nine hours.

Second thing is this mitochondrial effect is not restricted only to liver. We do see increased mitochondrial volume in brown adipose tissue, so in brown fat. As you know, these mitochondria have kind of dissipate until they are literally burning the fat. So, at least in two different organs, we have seen increased mitochondrial volume. That correlates with increased level of PGC-1alpha 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 look for the mechanism. For example, why PGC-1 level goes up and what triggers that to go up.

Rhonda: 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, you know, feeding within our active hours.

[Sachin] Yeah.

Rhonda: 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 clock. All right. That's it. So, 8:00, then you better stop eating by 8 p.m. Right? That's for 12 hours.

Satchin: Yeah, yeah.

Rhonda: Then from 8 p.m. all the way till 8 a.m. the next morning, you're fasting, right?

Satchin: Yeah, yeah.

Rhonda: You're not getting any energy.

Satchin: Yeah.

Rhonda: So, so in some ways you're getting a lot of...there are some overlap between this time-restricted feeding and intermittent fasting, for example, which has been shown to increase ketone bodies like beta-hydroxybutarate, which I know you've also shown restricted feeding does increase that as well. It takes around, I think, 10 to 12 hours...

Satchin: Yeah.

Rhonda: ...for your liver glycogen to deplete and fatty acids get immobilized, they go to the liver, you start to make beta-hydroxybutyrate 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.

Satchin: Yeah.

Rhonda: Which Eric Verdin at UCSF published. There's lots of...oh, have...can you, first of all, differentiate for people, like, the difference between intermittent fasting and time-restricted feeding? Like, what are the main differences, and maybe what some of the similarities are?

Satchin: Well, both of these depend on this idea, as 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 glycogen to deplete or maybe the fatty oxidation to begin so that we begin to use some of the fat. And you also pointed out ketone bodies and beta-hydroxybutyrate, 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 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're beginning to understand.

The reason why we coined and use 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 many people thought is difficult to achieve. So that's why we stayed away from the word caloric restriction or fasting, and we used 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 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 zoo, 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, 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-restricted feeding, we're kind of exploiting, or we're kind of bringing back that primordial physiology that's ingrained in our genome, that our genome has to respond to that fasting on a daily basis.

At the same time it syncs 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.

Rhonda: 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...

Satchin: Yeah.

Rhonda: ...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 gonna 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 gonna be as insulin-sensitive.

So, let's take someone that is doing intermittent fasting, and they wake up at 6:00 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, 7:30, 8 p.m. They've been fasting all day, so they're getting a lot of the activation of some of these...

Satchin: Yeah.

Rhonda: ...you know, stress-response pathways like AMP kinase and, you know, they're making some ketone bodies, Kreb, all these similar pathways are being activated.

Satchin: Yeah.

Rhonda: ...that, you know, time-restricting feeding also activates. But then, they take a big meal at 7:30 or 8 p.m., so 12 or 13 hours after they've already set their clock.

Satchin: Yeah.

Rhonda: 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?

Satchin: Yes, so that's a very interesting question that we get many times and we are thinking of addressing that. It's very hard to do that in experimental animal models because if you fast them, if you give them two meals, they reduce their caloric 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 as good enough as in the morning?

Rhonda: Right.

[Stachin]: Then everything you can equalize is at least insulin, which is a big thing in metabolism [inaudible 00:55:42].

So recently, what we are finding is actually the smoking gun came almost 10 years ago when people who are doing GWAS studies to find whether there are mutations in given genes that make us more diabetic or obese, surprisingly, people thought that, "Okay, so we'll find some genes that regulate metabolism." Right? So that is the common sense. But then the big surprise was they found melatonin receptor as one of their top hits.

Rhonda: Wow.

Satchin: And some of the clock genes, like cryptochromes, in the top five or ten genes. That is not only in one study. In multiple studies, they found it. So there are the smoking gun. What is melatonin doing with this obesity and diabetes? And recently, what is interesting is people are finding that melatonin receptor is present in pancreatic islet cells, beta cells, and melatonin receptors, when it's engaged with melatonin, it signals and it inhibits insulin secretion.

Rhonda: What? Really?

Satchin: Yeah. So it just came out, like, four, five weeks...

Rhonda: Wait, 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 tryptophan from dietary protein gets converted into serotonin...

Satchin: Serotonin.

Rhonda: ...and that's converted in melatonin. This is happening in the gut and...

Satchin: No, serotonin goes to pineal and then gets into...

Rhonda: So there's, so this, so the, it happens in the gut and it also happens in the brain?

Satchin: Yeah.

Rhonda: There's two separate genes that do this.

Satchin: Yeah.

Rhonda: 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.

Satchin: Yeah, so this is completely new. So that's why now it brings up...now, it helps us to connect this dot that people have. I mean, for the last 35 years clinicians know that the insulin sensitivity is very different between day and night. And then the GWAS, the human genetics people came and said, "Yes, there is some smoking gun with melatonin." And now, finally we are finally saying, "Yes, melatonin receptor can actually inhibit insulin secretion." So in that way, having an evening meal, maybe with candle light dinner, is not a good idea because you have less light, so you have more melatonin, and that can inhibit... [laughs]

Rhonda: That's fascinating. I have to get that study. It's very, very interesting.

Satchin: So that's one case where we might think that late night, even if you control food calorie, the same calorie taken in 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 were two groups of people. 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 had their lunch…in Spain, people eat lunch at 3:00. So they ate lunch earlier whereas the group that did not lose weight, two months, they ate their lunch later. So that is another piece in the puzzle saying that late-night eating might actually prevent weight loss.

Rhonda: Right. And you've now 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.

Satchin: Yeah. So one thing was we wanted to see is 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, 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 would not have time to describe everything on their plate, but we'll capture that. It will also have the timestamp. 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 would say, "Yeah, I wake up, I have my first sip of coffee and usually I eat all of my food within 12 hours." So we were very discouraged to hear that. But then we carefully selected people who don't do a shift work so they will not have to work in the nighttime, that's when they're changing their eating time, and they're also not on any medication that will change their hunger or satiety. So we 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 portion size, etc.

Rhonda: Way better compliance, I'm sure.

Satchin: Yeah. There's only three clicks, because if you think about it, open the app, take a picture, and then press the save 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 these 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 some people think, "Oh, that's normal because if they start their first sip of coffee at 6:00 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 enforce time-restricted feeding. We can't do that with humans. They have to be self-motivated.

So we 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 until we'll have 10 to 11 hours and try to stick to it every day, even on the weekend."

And surprisingly, all of these eight people, they self-selected their 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 had 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 portion 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 asked them to reduce their time, they ultimately reduced 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're 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 drink most of their coffees, 70% of their coffee, within four to five hour's interval in the morning. And people ate 70% of their alcohol in the evening, four to five hours. So now imagine if somebody's time restricting to the daytime, then he or she 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.

Rhonda: And what about the cutting out, like, the ice cream and desserts?

Satchin: Yeah, so most of the reduction in calorie was due to reduction in late night snacks.

Rhonda: Yeah.

Satchin: And after dinner, ice cream, dessert, and alcohol.

Rhonda: So this is a really cool idea, Satchin. I went to your website last night, mycircadianclock.org. Very, I really like the website in general. There's a blog section, the section explaining, you know, 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 a really great website. But I also signed up for the app.

Satchin: Yeah.

Rhonda: Because I am now on a time-restricted, you know, feeding schedule. And, you know, 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 ...

Satchin: Yeah, yeah, yeah.

Rhonda: ...because that's been shown to affect endurance. But anyways, so I went up and I signed up. It's really simple. You go to the website, you click…maybe you want to explain. Like, I clicked Sign Up or something and then...

Satchin: Yeah, and then it asks you very simple questions. 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. Or it's not even in the public health curriculum because circadian rhythm is such a new field. That's not there. So, it's hard to...

Rhonda: This is so important, and it's, like, disrupted by modern day society. I mean, it's, like, I'm gonna be talking about this now. So I'm very excited. This is definitely important.

Satchin: No, what I was saying is that if you...you brought up this modern day society. In modern day society, light is an enabler.

Rhonda: You work?

Satchin: Light enables us to stay awake throughout the night, and then we have 15% of work force who does night shift 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 work in the emergency department, they are food prepping, they are 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 and night cycle to 24 hours light cycle, and that's the biggest disruption we see. 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 five or six, top five or six 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 are the extent of circadian disruption? When do people go to sleep? When do they get up? When are they eating their food? And when 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 their lifestyle during weekday and weekend.

And then in the second phase, we can give some health information, because many of the health clubs are more geared towards losing weight, doing one thing, and it's very difficult to really guide people to do this three different things; eat, sleep, and move around on a timely basis. And it's a challenge. We are 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 9 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 knew we have some algorithm. And then we want to correlate whether this 9 hours is beneficial to you or not, or whether some people actually get the same benefit with 12 hours. Some people might go to 8 hours or 9 hours. So those information will come in the second phase that goes from second week 'til 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 their 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 the general public.

Rhonda: Yeah. Also, it's nice to feel like you're contributing to research, you know.

Satchin: Yeah.

Rhonda: So in addition to this, this myCircadianClock app which is on the AppStore.

Satchin: And also in Android.

Rhonda: Android.

Satchin: Yeah.

Rhonda: And in addition to that app, you can sync with other fitness data like MyFitnessPal, because you're gonna be measuring at all these other health parameters.

Satchin: Yeah.

Rhonda: I heard you mention something also about a light sensor thing or some...

Satchin: Yeah, so I wear a light sensor.

Rhonda: Yeah.

Satchin: It senses 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 systems, so it's already in your phone.

Rhonda: Mm, that's good.

Satchin: And that phone, that HealthKit 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 are using a special app or even the same app, if you say what do you [01:12:13] for other companies and 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 HealthKit 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 myCircadianClock. So anything, any information that you store in HealthKit gets shared with myCircadianClock, and myCircadianClock can also send some data back to HealthKit. So it kind of acts as a hub.

So similarly, various apps like MyFitnessPal, and then Nom, and many diet apps, many exercise apps, they also deposit their data to myHealthKit, sorry, HealthKit 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, and 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 myCircadianClock and we can capture all that data and we'll analyze.

Rhonda: Very cool idea. I am looking forward to contributing...

Satchin: Yeah.

Rhonda: ...to that. But I kinda, wanted to...

Satchin: Talk about the light?

Rhonda: I wanna 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...

Satchin: Yeah.

Rhonda: Heart rhythm....

Satchin: Yes.

Rhonda: ...studies. So you mentioned earlier the chronic diseases. If you look at in the United States or industrialized societies in general, the number one killer, people died in most of heart disease.

Satchin: Yeah.

Rhonda: Some sort of heart disease, you know, and obviously, lots of different things regulate our susceptibility to heart disease. Metabolism, obesity. But you found some very interesting findings doing time-restricted feeding in fruit flies.

Satchin: Yeah.

Rhonda: So can you talk a little bit about that? I'm very interested in that.

Satchin: Yeah. So fruit flies are used in science for many, many years. And they're, they have a short lifespan. They stay alive maybe 9 to 10 weeks max. So it helps us to figure out whether any intervention, like time-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 at 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 were also moving around the same distance. So, inside these bottles they could fly back and forth. And at three weeks of age, their heart is very healthy. It beats rhythmically. And although the fly heart is not like human heart, they also have...

Rhonda: Most people are probably shocked. Flies have a heart.

Satchin: Yeah. So their heart is 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 was a very interesting model.

Just like humans, the fly heart also becomes weaker with age. So, by five weeks, the hearts don't beat rhythmically. They have a little bit of arrhythmia, and then they have the same dialysis. And so then the heart gets dilated with age. The beat-to-beat distance also becomes very irregular. 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 are protected from this heart disease.

Then we said, "Okay, so if we introduce time-restricted feeding later in the lifespan, then what happens?" Because one thing we could not do in mouse study, because mice live for three to four years, we could not introduce time-restricted feeding later in life. But in flies, when we introduce later in life, they were also protected. The arrhythmia reduced in flies. And when we gave high-fat diet to flies, they also produced 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 nighttime, and they are sleepy during daytime, and that is completely prevented by time-restricted feeding. They have a good night sleep, they are very active during daytime, the heart pumps nicely.

Rhonda: Wow. Did you measure heart rate variability?

Satchin: Yeah, so we did heart rate variability. So there are seven different parameters we measured.

Rhonda: And that improved?

Satchin: Yeah, so all those seven parameters improved to some extent. And when we introduced later in life, they also improved. That was the surprise.

Rhonda: Do know what or why? What's…

Satchin: Yeah, so what we found is, again, one connection was back to mitochondria. What we found was the mitochondria were healthy, or in the sense, they did not...they may not, maybe they were not producing as much of the reactive oxygen species.

Rhonda: The mitochondria in the cardiomyocyte, in the heart cells?

Satchin: Yeah, in the heart cells.

Rhonda: Okay.

Satchin: So we took the heart cells and did gene expression for flies. We looked at all the genes, what we found is a big cluster of genes whose 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 knocked down few components of ETC and those flies also have better heart. So that was one thing.

Rhonda: Interesting.

Satchin: 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, a very newly-identified folding machinery called ATP-dependent. It's a chaperonin complex. Eight different components form this barrel-like structure to fold proteins. And this requires energy, and that CCT component has been shown to be important for various muscle, sorry, various cytoskeletal protein folding, and it make sense for heart. And in fact, in humans there is a point mutation in one of these ATP, sorry, CCT component that has been shown to predispose to some heart disease. So it's a beautiful story where found both mitochondria and this protein folding machinery are necessary for this time-restricted feeding beneficial, if beneficial effect.

Rhonda: And this time-restricted feeding was 12 hours?

Satchin: No, it's 12 hours because flies are different from us. They don't have thermoregulations, so when they fast for a longer time, they cannot, they kind of can't tolerate that.

Rhonda: Oh yeah, they'll, they'll get cold. Okay, so, you know, some of these phones also measure heart rate variability.

Satchin: Yeah, so it will be interesting.

Rhonda: That would be interesting, very interesting because that's like, you know, that's something that supposed to be very important for having a healthy heart. But if you don't mind…again, this is just, it's another reason why this time-restricted 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, you know, it's not...it's easy enough that you can do. It's like, you know, by the time it's 12 hours later, all right, that's it, you got to make sure you get all your food, your whatever it is that you consume within that 12-hour span. But something…I wanna shift gears, if you don't mind.

Satchin: Yeah, sure.

Rhonda: Another organ, the gut, because it's another 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 a mouse also seemed to, you seemed to have more of these species during certain times of the day and less during certain times of the day. And this was different in obese animals versus, you know, non-obese animals or... That is very fascinating. Can you explain that just...

Satchin: Yeah, so bacteria, they're just like us. They need their own niche, they need their own pH, temperature, nutrition, and all these factors. And now we 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-restricted 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 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 cohabit in our gut. And they also function at different time of the day. During the daytime so, for example, when we are eating we need lot of bacteria to break down starch and fibers, complex carbohydrates, and also conjugate some bile acids and etc.

So we need different players to do different things throughout day and night. And by time-restrict feeding, this alternating two different types of environment, one where there is 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 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 the diversity

There are few interesting thing that we found, which we are still working on to figure out why it happens, for example, mice that are time-restricted 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 absorbed. 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 all in the upper intestine. So in that way, by this compositional change, we can completely shift 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. Bile acids are made in liver and then they cycle back and forth between gut and liver. And bile acids are made from cholesterol. So there is an enzyme in liver that gets upregulated 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 bile acid comes to the gut and it helps absorb some fat back into the gut and there it gets conjugated by this bacteria. And for some reason we don't understand, in time-restricted 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.

Rhonda: That'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 [inaudible 01:26:01]?

Satchin: So those we are now...so short-chain fatty acids are little bit difficult to look at because they are volatile. They degrade much faster, so those are the next set of experiments we are doing.

Rhonda: Okay, okay. So does this also suggest we should time our probiotic intake? Is there...

Satchin: We haven't looked into that to see whether the probiotic...

Rhonda: Is there any data out there that has measured...so for example, I've measured my own microbiome using a company called nuBiome 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...

Satchin: Yeah, yeah. That's when…

Rhonda: ...because that's when…But it seems like the time of day is very important.

Satchin: Yeah, you can capture the compositional change by time of day.

Rhonda: Is there any data out there that has looked at how the microbiome species change from morning to evening, like,... Oh so there is?

Satchin: Yes, actually, in humans there are at least 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.

Rhonda: Right. Yeah, so, you know, very, the... I think there was study showing that microbiome gets thrown off and that leads to obesity.

Satchin: Obesity, yeah, yeah.

Rhonda: Or something. This is so much, and then of course the shift workers as well, I mean they're completely...their whole system is off whack. It will be interesting to see whether or not time-restricted feeding can help negate some of the negative effects of...

Satchin: Of shift work.

Rhonda: …of shift work. Right. That'll be very interesting.

Satchin: Yeah, so that's what we are doing now, to see whether we can put mice in shift work and give them food within shift or out of shift.

Rhonda: Do you have an option in your app for shift workers so that you could also get some human data?

Satchin: Yeah. So, people can say what they... So in the first sign of a routine, and there is a question whether you are a shift worker or a regular worker, and if they say they are shift worker, then we look at that data more carefully to see how they are changing their diet during day shift and night shift. And also, all shift works are not the same. Some employers actually put people, change shifts every week, every two weeks, every three weeks, and in some cases, every four months.

Rhonda: Yeah.

Satchin: So we'll see on the 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 there are now different variations of shift work. Many of the gig works or flexible shift work is not even fixed. So flex hours is a new trend where people can be called up any time and we want to track to them more carefully. So that's why we'll have another feature soon.

Rhonda: 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 gonna get the time zone, like...

Satchin: 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 and your home time zone, and 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 are in the same time zone. How your body is adjusting, you can see that data. We are working on it. It's, 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 daylight saving time, and all these other time changes…

Rhonda: Yeah.

Satchin: It completely...displaying data becomes a challenge. So that's another half of the challenge.

Rhonda: Yeah, I know. What you're doing, but you're off to a really good start and 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. I know you have another meeting. You are on Twitter. I follow you on Twitter. What's your Twitter handle?

Satchin: Satchin.panda.

Rhonda: Satchin.panda is your Twitter handle?

Satchin: Yeah.

Rhonda: It's S-A...

Satchin: A-T-C-H-I-N dot Panda, as in panda bear.

Rhonda: Right, okay. And your website? Um, mycircadian...

Satchin: …clock.org. Yeah.

Rhonda: And that's where people can find all things circadian clock, all fascinating research, you giving presentations, and also they can sign up...

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

Rhonda: Oh, wow.

Satchin: So that's going up this Friday. So we are very excited.

Rhonda: Yeah. I really like your blog. I was looking over it last night. It's very informative. So it's a nice, nice job. Well, thank you so much, Satchin. 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 had the opportunity to speak with you.

Satchin: That's very nice of you. Thank you so much.

Rhonda: I look forward to more research coming out of your lab. You seem to be doing some really interesting things.

Satchin: Thank you. Thank you.