Dr. Gabrielle Lyon [0:00:01]

Welcome to the Dr. Gabrielle Lyon Show, where I believe a healthy world is based on transparent conversations.

In today’s episode, I have the great privilege of sitting down with Dr. Satchin Panda. This episode was eye-opening for me. We talk all about the impact of light, both artificial and natural, on human biology and physiology. We talk about what circadian biology is and is not. We talk about how circadian biology influences a woman’s ability to get pregnant. This was just a fascinating conversation. In addition, we talk about food and meal timing; does it really matter? Does it matter when we exercise? We cover a lot of ground in this episode. I think that you’re really going to like it.

Dr. Satchin Panda is an incredible scientist. He’s a professor at the Salk Institute in California, where his research focuses on the circadian regulation of behavior, physiology, and metabolism in model organisms and, most importantly, from our perspective, in humans. How is his work being translated to human performance and human health? Dr. Panda discovered a blue light-sensing cell type in the retina that entrains our master clock, affects mood, and regulates the production of the sleep hormone melatonin. He is a world-renowned scientist. I’m so grateful that he spent time with us. I think you’re going to love this episode. As always, if you like it, please share it and rate it. We will look at all your feedback. Leave us a review. Thank you again, so much. Let’s dive in.

A special thank you to one of the sponsors of the show, which is LMNT. During the podcast and right before, people are always asking me, what are you drinking? Well, we don’t really give away water at this house, but we do give away water with LMNT in it. LMNT is an electrolyte drink with 1000 milligrams of sodium, 200 milligrams of potassium, and 60 milligrams of magnesium. It doesn’t have any fillers. It doesn’t have any sugar or color. It is formulated to help you with your electrolyte needs, whether you are eating a low-carb diet, keto diet, or paleo diet; it doesn’t even matter. We love it here; it really helps with energy and eliminates any headaches that I get from dehydration, muscle cramps, and fatigue, which are all things that can happen if you are low in electrolytes. Right now, LMNT is offering my listeners a free sample pack with any purchase. That’s eight single serving packs with any LMNT order. Get yours now. Head on over to drinklmnt.com/drlyon, and you will get to try all eight flavors. If you don’t like it, you will get a no-questions-asked refund.

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Dr. Satchin Panda, thank you so much for making the trip. I am thrilled to be talking to you. We’re going to talk all about circadian biology, circadian rhythm, and all the other things for which you are a leader in the field. Thank you so much for coming on.

Dr. Satchin Panda [0:05:07]

Thank you for having me.

Dr. Gabrielle Lyon [0:05:09]

I was thinking a lot about this prior to your coming on. There was a time when people were exposed to secondhand smoke, and nobody thought anything about it. Now there are warning labels. In fact, we’re not even around secondhand smoke anymore. Then I started thinking, what about the electrification of the world with this light, this light pollution? Now, it seems as if, potentially, with your work, maybe we’re doing the same thing that we did with secondhand smoke and its implications on health and wellness.

Dr. Satchin Panda [0:05:42]

There is a small difference. Smoke in any form is really harmful. Whereas we need light for safety, we need light to work in the evening. What is important is that now that we know which spectrum of light or which color of light is good for us in the daytime and which color is bad for us at night, we can figure out how to redesign this anthropogenic or manmade world. In this context, almost 23 years ago, three different groups, including mine, co-discovered a new light sensor called melanopsin. This light sensor senses the blue spectrum of light, cyan blue, at 480 nanometers, for those of you who are interested. This cyan blue light sensor senses light and sends that information to the brain, saying, hey, this is daytime. Be alert; reset your circadian clock to the local time zone so that you can be active.

Daylight, or sunlight, is the biggest source of that blue light. That’s why we need that blue light, or daylight, during the daytime. Then at night, the same blue light can actually confuse our brain because it tells us that evening is not here yet. It’s just been a long day. Let’s suppress your nightly hormone, melatonin, which is the hormone that makes us sleep, so that we stay awake. That’s why, during the daytime, we need more light, particularly the blue spectrum of light. At night, we need to dim that blue spectrum and then maybe crank up the orange spectrum. It’s almost like a candlelit dinner.

The point is that you are right: we designed this world with light. But now with the new LED technology, where we can change the spectrum of light and the intensity of light—all of this—we can think of light therapeutics where we can crank up, for example, those who are indoor most of the time, those who are sick and cannot go out—for them, having blue light from an electrical light source during the daytime is really awesome. Whereas at nighttime, we can also have circadian lighting so that we can tune down the blue light, give the orange light, and maybe dim down that.

Dr. Gabrielle Lyon [0:08:15]

That’s so interesting. Basically, what you’re saying is that we can use different light spectrums to potentially augment treatment and overall health. On the other hand, with fluorescent lights and the impact of light on us all the time on our skin, what kind of implications does that have on our health and wellness? Is it enough to move the needle in a negative direction, do you think?

Dr. Satchin Panda [0:08:40]

Let’s start with everybody, all of us who are living a normal life, and we go to the light to buy a light bulb, and then we get excited about this LED light because it’s super cool white, and we bring that and put it in our bedroom, in our bathroom, everywhere. In that case, what is happening is that at nighttime, of course, it gives us a lot, and we stay awake late into the night. But our day, for most of us, starts, I’d say, around 7 a.m. or 8 a.m. Even our kids have to get up and then go to school. As a result, what is happening is that people are getting less sleep. The indirect effect of putting a lot of light in our houses, particularly in the evening, is that we get sleep deprived. That’s for all of us.

Now let’s go back to two specific populations that are at very high risk of becoming ill. For example, all the hospitals also have 24/7 lighting, and that’s necessary to keep the physicians alert and everybody who is working there alert. This will not make you fall asleep. But what is interesting is that even in the ICUs and in the patient’s room, the lights are on 24/7. The lights are on because the nurses and physicians have to come and take several readings and maybe even blood samples. There are two things happening. One is that the ICU lighting is on 24/7, and that light itself disrupts sleep and circadian rhythm for the patients. Second, all the ICU practice of repeatedly waking up patients, taking their vitals, or poking needles also reduces their overall sleep and the quality of sleep. An average ICU patient gets five hours of sleep. That five-hour period is not continuous; it’s fragmented. Just imagine that if you’re healthy and you get five hours of fragmented sleep, you will be cranky.

Dr. Gabrielle Lyon [0:10:44]

I don’t know; it sounds like my routine day.

Dr. Satchin Panda [0:10:47]

It’s for most of us. That’s why it’s not surprising that nearly 1/3 of ICU patients experience delirium because they cannot figure out what time of day it is and where they are, and they become crazy. That’s one spectrum. The other spectrum where it is very well documented now in experiments is the NICU, because neonatal ICUs are extremely important to have these premature babies nurtured for sometimes several weeks before they are released. When they gain weight and are almost normal, they are released. In the US now, nearly 380,000 babies are born premature. That’s 1 in 10 babies born in this country born before full term. Almost all NICUs are also lit 24/7. People think that babies don’t have a circadian rhythm because they don’t sleep continuously. That’s wrong because almost every cell in our body has a circadian rhythm, and babies are also sensitive to light.

There was a nice experiment done in Mexico City where nearly 60 premature babies were randomized to two different groups. One group got the standard of care, and just like any other ICU, the lights were on 24/7. In the other group, the lights were on for 12 hours, producing 250 lux of light, which is average indoor light. Then in the evening between 6 p.m. and 6 a.m. or 7 p.m. and 7 a.m. for 12 hours, there is a light cotton kind of thing that is covered on the crib so that the light drops down to nearly 20 lux. 20 lux of light is equivalent to having a 40-watt old-style light bulb in your big room. That’s pretty dim enough. What is interesting is that the babies in the simulated light and dim light conditions grew much faster, so much so that they were released from the hospital’s NICU 13 days earlier than the other group.

Just imagine that one day of NICU stay in this country, in the US itself, is more than $10,000. Now, we have 380,000 premature babies in this country. The emotional burden on parents is also pretty high. This is a case where simulating the light-dark cycle can actually accelerate the growth of premature babies so that they can be released from the hospital much faster. Now, if you fast forward and think about what happens in our homes, when we have newborn babies, say four or five weeks old, they also need that simulated light-dark cycle. Whereas if we keep the lights on bright, and on top of that, if we give tablets and phones to our kids to play with, then they’re exposed to that bright light late into the night.

There is also another study showing that babies—now we’re talking about somewhere from three- to seven-year-old babies. When they have a set bedtime every evening, they’re at a lower risk of developing weight gain and obesity than babies who are put to bed at random times in the evening. There is a large study from the UK that essentially says that yes, you may see a bad effect from random bedtimes. The reason they’re going to bed at different times is not that they’re actually sitting in a dark space. They are actually being active, and they are entertained until late at night. These are some of the examples where controlling light can have a huge impact, to the extent that a few years ago, the International Space Station used to be lit 24/7. It was very difficult for the astronauts to get restorative sleep, and also, now we are in Houston.

Dr. Gabrielle Lyon [0:15:07]

It’s pretty hot and bright here.

Dr. Satchin Panda [0:15:09]

The point was that every 90 minutes, the International Space Station sees the sunrise and sunset. A few years ago, they also put simulated circadian lighting on the International Space Station. Now we can imagine that from the NICU to the ISS, the International Space Station, we are seeing the benefit of circadian lighting, or what we are losing in modern days is the darkness, or something similar to darkness, that has a huge impact.

Dr. Gabrielle Lyon [0:15:39]

It’s actually fascinating, because what I’m hearing you say is that it’s not the light exposure in and of itself, regardless of the spectrum, that is the dangerous aspect of this overexposed world. But it’s actually the disruption of the circadian cycles that has the biggest impact. Could you define a circadian cycle or circadian rhythm and also the inputs, whether it’s the suprachiasmatic nuclei or just the inputs into all of that?

Dr. Satchin Panda [0:16:09]

Circadian literally means nearly 24 hours. These are from two different Latin words circa and diem. That means these are near 24 hours timetable. Circadian rhythms are the internal timetables for every cell in every organ in our body, including our brain. Circadian rhythms constitute the master program that guides what time of the day or night every single gene out of 20,000 genes that we have become active or inactive in every cell. The result is these rhythms actually improve our immune system so that we can fight infectious disease much better. They accelerate repair so that we can recover from injury. They also optimize our brain function so that we are resilient to affective disorders, depression, anxiety, all the way to dementia. Circadian rhythms also supercharge our metabolism, detoxification, and DNA damage repair so that we stay healthy against metabolic disease, cancer, and many chronic diseases.

The circadian rhythms, as I said, are present in almost every cell in every organ. But the thing is, there is some hierarchy among these rhythms. As you mentioned, the suprachiasmatic nucleus (supra means above; chiasma is optic chiasma) means our left eye signals to the right brain and our right eye signals to the left brain. That happens because the nerve bundles from our left and right either go in crisscross at the base of the brain. This nucleus is right above the optic chiasma. What is called the nucleus is very well defined. This is nearly 20,000 neurons. 20,000 may sound like a big number, but that’s very tiny compared to the billions of cells in our brain. That means it’s smaller than a pinhead. That’s the size of the suprachiasmatic nucleus that sends signals to control all the rhythms and the rest of our body. Experimentally, almost 50 years ago, when scientists accidentally removed this part of the brain—as you can see, imagine it’s a very tiny, small head of a pin—these rats became arhythmic. That means they had no sense of their night; they would actually go to bed and get up every two to three hours.

Surprisingly, in those days in the ‘70s when they did the brain transplant, that meant they took a rat’s suprachiasmatic nucleus; the rat was running, I’d say, or the hamster was running 24 hours a day. Then the other hamster was running for 22 hours every day because that other hamster had a mutation. When they swapped the suprachiasmatic nucleus—just 20,000 neurons—they could actually swap their behavior. That was really stunning, and that’s how we established that SCN is the master regulator. Now, fast forward to nowadays, scientists are finding that in many Alzheimer’s patients and patients who have neurodegenerative disease, post mortem when they’re analyzing the brain samples, they’re finding that this suprachiasmatic nucleus may be affected in some dementia patients who actually have irregular sleep-wake cycles. It’s likely that in humans also, this is important because when the SCN is affected, many dementia patients lose the sense of day and night. We know that in severe cases of Alzheimer’s disease, people wake up in the middle of the night thinking that it’s daytime and they’re hungry, and then in the middle of the night, they’re super sleepy. That’s the hierarchy. Since SCN is right above the optic chiasma, or the tract that gets all the light information from the eyes, it’s not surprising that SCN is sensitive to the light dark cycle. Why it should be like that is because, if we think carefully about our sunrise to sunrise, that’s not exactly 24 hours. Because of the tilt of the planet, it’s slightly different. As the day gets longer in summertime, that’s different. As the day gets shorter in the wintertime, that also gradually changes.

Let’s dial back to 200,000 years, up to 150 years from now, before electrical lighting. Our body is designed to track the day-night cycle. That means every single day, as the day length changes, this morning light would reset our master clock, saying, hey, you’ve got to adjust because the sunrise is at a different time. What was surprising about that process was that there were many blind people who cannot read anything; they don’t have a sense of the visual world, but when they fly, say from the East Coast to the West Coast or vice versa, they do get jet lagged. But after three or four days, just like the rest of us, they can also reset the clock to the local time. That raises the question, what is this light signal going to the master clock? There is also the other set of blind people who might have gone to war, lost both of their eyes because of gunshot wounds, or had surgery for cancer in the eyes. When the eyes are completely removed, they don’t have any sense of day or night. That means they are, we call them the [freerun? 0:22:03] because our human circadian rhythm is roughly 24 hours, 10 minutes, or 15 minutes on average. But some people are 24, and some people can be 24 and a half. Every day, they will drift their sleep wake cycle by 10 to 15 minutes.

That led to this curiosity, what is this light sensor in the eye, and that’s where after the human genome was done, the whole sequence was determined in year 2000, then many scientists, including us, we went back and checked, hey, are there any light-sensing proteins because there is a specific signature of these proteins. We looked and we found this light-sensing protein that senses in blue light. That’s the hierarchy of how light resets SCN clock, and then SCN, these are neurons that send local connections to other parts of the brain or hypothalamus, they’d never heard of SCN. These never heards, they control our sleep wake cycle, they control osmolarity, blood pressure and also the SCN is very close to other brain centers in the hypothalamus that constitute what we call hypothalamus-pituitary-adrenal or hypothalamus-pituitary-gonadal axis. That means this brain region is a strong regulator of almost all hormones, majority of the hormones in our body that are linked to metabolism or reproduction. In that way, it also makes a good case, good framework, how circadian rhythm disruption or when we work randomly, as in case of shift work, where people do go back and forth between day and night shift, or the morning shift or night shift, their hormones get dysregulated. Their sleep wake cycle is dysregulated. Accordingly, the metabolism and also reproduction are dysregulated. That’s one way that light dark cycle, going through the SCN clock, can affect a lot of our physiology and hormones.

Dr. Gabrielle Lyon [0:24:12]

That’s so fascinating. The SCN is really only through the eye.

Dr. Satchin Panda [0:24:17]

Yeah, it receives light only through the eyes.

Dr. Gabrielle Lyon [0:24:22]

There’s no other way to affect the SCN. For the longest time, I was thinking there are skin photoreceptors, but that has no impact on the master clock.

Dr. Satchin Panda [0:24:37]

Yeah, that’s what people have shown experimentally since almost 23 years ago. There was a paper showing that maybe shining a light in the back of the knee can reset the clock. But actually, other people have tried to replicate it, and it was not replicated. That chapter is almost closed. We now know that it’s only the eyes, the blue light, and this light that go through the eyes to reset the clock. There are skin photoreceptors, and they might regulate the local skin clock. But in humans, we are still really far from getting a convincing result that these light sensors are important for the local clocks. It doesn’t mean that they don’t; the community hasn’t done the right experiment yet.

Dr. Gabrielle Lyon [0:25:31]

The eye has nothing to do with the ability to see. It has nothing to do with that. It’s solely the light sensing.

Dr. Satchin Panda [0:25:41]

Those melanopsin cells do sense light. These are not the conventional rod and cone photoreceptors because rods and cones are almost like the pixels on your iPhone. There are millions of them that constitute this visual world. But the melanopsin is present only in maybe 5000 cells. They also have a very weird characteristic because they need a lot of light to be turned on. Then, once they are turned on, they will actually stay on for several seconds. They’re not really good for the visual system.

But at the same time, there is new data showing that this melanopsin system may give us brightness perception. For example, there are many people who are very sensitive to light. When they go out into the sunlight, or even indoor light sometimes, they’re so sensitive to light that it can trigger a headache. One idea is that brightness perception in our visual world is also mediated by melanopsin. In some cases, when this pathway is superactivated, that can contribute to light-induced migraine pain or a light exacerbation of migraine pain. So there’s that other extreme end.

Historically, some experiments were done, and now I guess those are replicated, showing that those who have migraine pain that is exacerbated by light, or in other words, if your migraine pain is alleviated if you go and sleep in a dark room, then maybe wearing blue filtering glasses helps you to reduce the incidences of migraine or reduce the severity. This study was done a long time ago, in the ‘80s before even melanopsin was discovered. But hopefully, that will pan out in the future, too, for patient care.

Dr. Gabrielle Lyon [0:27:41]

Yeah, I’m curious: is there any influence on some of the phytonutrients, like lutein, that we know are good for the eyes? Do they impact the receptors?

Dr. Satchin Panda [0:27:52]

There are two things; one is a retinol derivative. Retinol is a very broad class of compounds. They constitute anywhere from things that we add to various face creams to reduce the effects of aging to even retinol and many other things. These photoreceptors, the melanopsin, also use one of the derivatives, 11-cis-Retinal, that’s the technical term. The photoreceptor is actually a combination of the protein part and the chemical part, and that chemical part is the retinol derivative. When light hits that retinol, that causes a small chemical reorganization of that molecule, and that reorganization triggers the protein to change itself. That’s how the light energy is converted to chemical energy, converted to protein change in the cell, and that triggers what we call a signaling process that essentially signals the cell that hey, there is light, and then that really just little bit of what we call neurotransmitter, or you can say brain chemical glutamate, to the SCN, and then the SCN realizes, okay, so there is light outside, and I got to reset my clock.

Dr. Gabrielle Lyon [0:29:27]

It’s fascinating. There are potentially nutritional interventions that would help with maintaining those circadian rhythms, perhaps indirectly by being able to influence sleep.

Dr. Satchin Panda [0:29:38]

There are some mouse studies done where the mice are deprived of vitamin A, and in those cases, they also reduce the sensitivity of the system to blue light. The other spectrum is that for many people, when we get older, we go through a lens transplant. We remove our natural lens and then put the artificial lens inside the eye. Our lens actually transmits a little bit of blue light. That’s why our eyes can see the blue light and reset our clock. But then, when we transplant this new lens, now you can think of lenses that will block all blue light and UV light because people want to block UV light, and ultraviolet and blue are very close to each other. Sometimes, there are some lenses, and if you remove all the blue light, then nothing goes to the eye.

Dr. Gabrielle Lyon [0:30:43]

Sounds like a really bad idea.

Dr. Satchin Panda [0:30:44]

So we had to keep that in mind what kind of lens we–

Dr. Gabrielle Lyon [0:30:49]

That’s important because there’s probably a lack of interface between the individuals that are doing the transplant surgery and then the biologists, circadian biology. There always seems to be a little bit of a lack in terms of the inflammation crossover. You mentioned something that was very interesting, and I’ve seen this in patients. When individuals age, it seems as if their circadian rhythm changes pretty dramatically; maybe they need less sleep, or they’re saying that they’re waking up earlier. Is there something that we know happens? Is it a hallmark of aging?

Dr. Satchin Panda [0:31:27]

What happens is the converse also happens when kids hit puberty.

Dr. Gabrielle Lyon [0:31:34]

So you’re giving me a heads up.

Dr. Satchin Panda [0:31:37]

As you can imagine, kids and babies usually wake up very early in the morning, and we think that’s okay, so they slept for eight to nine hours; they must be hungry. That’s why they’re getting up so early; that’s normal. But then, when they hit puberty, something happens. We don’t understand how sex hormones interact with the molecular clock in the brain. Two things happen. One is that they’re maybe slightly more sensitive to light, so the same amount of light in the evening that is not affecting their sleep might actually keep them awake for a long time. Second, their clock also changes, so they’re more likely to wake up late in the morning. As a result, teenagers, particularly high schoolers, are likely to wake up later because it’s not because they were playing video games. Of course, partly that may be true, or whatever they’re doing late at night, but biologically, they’re designed to wake up slightly later.

That’s why in another study with Horacio de la Iglesia from Seattle, he did this heroic study to delay the high school start time in two high schools in Seattle and found that when the high school start time was delayed by an hour, the kids got 34 minutes of extra sleep. The grades improved by 4.5%, and the tardiness went down. That led to this delayed school start time. But now, when we hit 50 or 60, around that time, when our sex hormone production is also reduced, we again revert back. Our circadian clock reverts back, and we are more likely to wake up earlier. That’s why we always think the old people are like babies because they’re also waking up early, and then they’re hungry. That’s one thing that happens.

The second thing that happens is that our arousal threshold goes down. What is the arousal threshold? The best example is when a mom and baby sleep together and the baby has a very high arousal threshold. Even though the mom may be accidentally putting her hand on the baby, the baby doesn’t care and will sleep through it. But if the baby kicks a couple of times, then the mom wakes up because the arousal threshold is slightly lower. Similarly, as we get older, our arousal threshold reduces so that small disturbances and small noises, like the other person turning and tossing in the bed, can wake us up.

Dr. Gabrielle Lyon [0:34:08]

Is there any evolutionary advantage to that?

Dr. Satchin Panda [0:34:11]

Well, we can’t actually go back to evolution because the average life expectancy at the turn of the last century, in 1910, was 45 years. But I think what was happening was that we do have this idea that the grandparents were taking care of the babies, and they were the caregivers. They have to wake up to those small cries from the babies to take care of them. That’s just a wild guess and hypothesis because of the grandparents’ caring for the grandkids.

Dr. Gabrielle Lyon [0:34:47]

I hope my parents are listening to this.

Dr. Satchin Panda [0:34:50]

The other thing that also happens is a thing called sleep debt. That means as we sleep less, the next day we feel more sleepy; we catch up. Our inbuilt system has this catch-up system so that we can catch up with our sleep loss. But as we get older, that catch-up system also breaks down. Even though we slept less, we cannot catch up. That means we are not feeling as sleepy as we used to, but that doesn’t mean our body doesn’t need that sleep. I guess the best example I can give you is that when we’re very young, our bodies are like self-driving cars. You don’t need much guidance; it’s all tuned. It just ignores all the external stimuli so that the babies can go to sleep early, get up early, and all that stuff. Then, as we get into middle age, it becomes the normal car, and we have to pay attention. As we get older, it’s a manual car. We have to really pay attention to everything and then try to do things that were automatically done for us.

Dr. Gabrielle Lyon [0:36:01]

As I was thinking about some of the topics that we would talk about, I looked up the ICD-10 codes, which are the diagnostic codes that we use in medicine. Circadian rhythm sleep disorder is really the overarching, the only one. I was looking at it because you talk a lot about metabolism, immune function, and other things. Again, in some of the data with shift workers, we see an increase in blood glucose, increased levels of insulin, and potentially higher levels of C-reactive protein. What was so fascinating in terms of diagnosis was that there was no mention of metabolic impairment at all.

Dr. Satchin Panda [0:36:43]

This is unfortunate, but at the same time, I think this is where we’re just at the beginning of a big change. Frankly, for many decades, people didn’t think that circadian rhythms were real. There is a nice book called Time, Love, Memory. In that book, there is a famous picture of this Nobel laureate questioning whether circadian rhythms are real. That was in 1971; that picture. But if we think about all the major discoveries in circadian rhythm—that circadian clocks regulate aspects of metabolism—that’s very relatively new. I remember in 2001, when it became easier to look at multiple genes to see what time they were going on or off, we published a landmark paper looking at only 6,000 genes. We found that many rate-limiting steps in many pathways, including cholesterol metabolism, cholesterol breakdown, making of bile acids, glucose metabolism, fat metabolism, all of these key things that the liver does are strongly circadian. That was done in mice. Typically, it takes a few years from mice to humans to come to the medical textbook.

These experiments are not easy because in circadian rhythm labs, they say that one thing that will certainly happen if you work in a circadian rhythm lab is that you will disrupt your circadian rhythm and sleep because you have to stay awake and sample things every one or two hours, which is very difficult in human studies. That’s why human studies are very difficult. There are a few, maybe a handful; actually, you can count them on one hand. That means that many labs in the entire world can actually do these human studies. When the number of labs in the world is less than the number of labs in a typical university that do metabolism, then you can see that progress is slow. But now there is another aspect to it. That is, we can go back and study shift workers who were doing shift work at the start of the Industrial Revolution.

Dr. Gabrielle Lyon [0:39:05]

Would you define shift work as overnight work from 7 p.m. to 7 a.m.? Is there a certain number that you like to think about?

Dr. Satchin Panda [0:39:13]

It’s very difficult to define. But in terms of labor organization, it compiled shift work definitions from many European countries. Their definition is that if you stay awake for two to three hours between 10 p.m. and 5 a.m. and are engaged in some kind of work, you just cannot lie in bed.

Dr. Gabrielle Lyon [0:39:34]

Lie in bed on Instagram? I’m talking to you people.

Dr. Satchin Panda [0:39:37]

Yeah. For 50 days in a year—so that’s surprising—only 50 days because if you stay awake two to three hours beyond your habitual bedtime for one night, then your circadian clock is disrupted that day because obviously you’re exposed to light because you’re working and doing something. Then it takes two to three days for that clock to reset. That means for half the week, you are working against your circadian rhythm. Then the best example is when you fly, say from one time zone to another time zone, or, for example, for all of us who are experiencing daylight saving time and then the time change, we know that even a one-hour time change can disrupt our sleep-wake cycle and our schedule for at least one or two days. Just imagine, if you’re staying awake two or three hours beyond your habitual bedtime once a week on average, that’s equivalent to shift work.

By studying shift workers, what has become very clear is that, of course, there is a lot of money and research into cancer because that’s a devastating disease. What the World Health Organization has figured out is that firefighters, certain shift workers, nurses, painters, and bakers, because these professions have been around for a long time and there is a lot of data also, shift work is like a potential carcinogen. This type of working can increase the risk for cancer.

Dr. Gabrielle Lyon [0:41:22]

Are there specific types of cancer?

Dr. Satchin Panda [0:41:24]

It’s different for different professions. For example, firefighting, which is mostly a male-dominated profession, has a different set of cancer risks. Whereas nurses, which has been traditionally women dominant, then that’s mostly breast cancer and endometrial cancer and those cancers. But now, what you’re finding is that almost all shift workers also have a very high risk for digestive system cancers that affect the digestive system, such as colon cancer. If we go back and see, they also have a high risk for other digestive system disorders or diseases. It seems like one way circadian rhythm disruption affects many of us is through the gut, which ultimately will affect the rest of the body.

Dr. Gabrielle Lyon [0:42:17]

You were talking about that before we started the podcast, about how teenagers oftentimes talk a lot about irritable bowel syndrome or have GI issues. How does that interact, and why? Why would changing the sleep-wake cycle have any kind of impact on gastrointestinal health?

Dr. Satchin Panda [0:42:35]

Well, there are two aspects. When teenagers are disrupting their sleep wake cycle, staying awake till say, one o’clock—

Dr. Gabrielle Lyon [0:42:44]

And eating Twinkies and all of that.

Dr. Satchin Panda [0:42:45]

Yeah, they’re not fasting from 6 p.m. to 1 a.m. They’re disrupting their circadian rhythm. As we discussed, circadian rhythms are present in almost every organ. There are a few aspects by which circadian disruption affects gut health. Our mouth has a circadian rhythm for saliva production. At night, it starts down so that we can sleep and we cannot drown in our saliva.

Dr. Gabrielle Lyon [0:43:15]

Yeah, that would not be good.

Dr. Satchin Panda [0:43:17]

Saliva actually neutralizes some acids. Our stomach produces a lot of acids to digest our food. There’s a circadian rhythm in acid production in the stomach. That means late at night, starting from, say, 8 p.m. onwards, the same amount of food will produce or trigger the production of more acid than the same amount in the daytime or even earlier in the evening. That’s another aspect to keep in mind. Then the third one is that our food is digested in the stomach and then goes to the intestine. The intestine has what we call peristaltic movement. Food does not go by gravity in our digestive system because we have this tube that goes back and forth, so there is some squeezing action. The muscles contract and expand, which is how the food molds. But there’s a circadian rhythm to that peristalsis movement. The intestine actually sleeps at night. It’s not doing its job of squeezing this food. As a result, when we eat late at night, we produce a lot of acid. That acid can come up to the esophagus and to our mouth and is not neutralized because our saliva production has gone down.

Dr. Gabrielle Lyon [0:44:37]

So they have more reflux.

Dr. Satchin Panda [0:44:38]

They have more reflux. After digestion, when it is going through the intestine, it’s actually sitting there. It’s not getting digested properly because the peristalsis is slow. Semi-digested food remains in the intestine for a long time. We should not forget about the gut microbiome because the microbiome is part of the digestion process. Just like in your garden, in summer and winter, you have different flowers because they prefer different types of environments. Similarly, our gut microbiome is very sensitive to pH, food, and other factors.

The gut microbiome is very different between day and night. We go to bed with a set of gut microbes, and then we wake up with a different set of gut microbes. Then, in the middle of the day, we have a slightly different diet, so diversity is very important for digesting different types of food and detoxifying some kinds of food. When we have this irregular eating pattern, that also disturbs the diversity of the gut microbiome. When we don’t have that diversity, we reduce it. This has been shown in mouse experiments where we can actually take part of the gut and examine what the gut microbiome looks like. Now you can see that there are multiple aspects of circadian rhythm disruption, particularly feeding, eating, and fasting rhythm, where now teenagers, until that time, are very regular because when the parents are setting their eating and fasting schedule, then hopefully they’re very regular. Then all of a sudden, they have sleepovers and nights out, and they’re kind of getting into a shift work schedule, essentially, because they’re staying awake two to three hours beyond their regular bedtime. They’re being active in many different ways and also eating late into the night. Just imagine, even in the first few decades of industrialization, women and children were not allowed to do shift work because, initially, I think the idea was that they were new and that was really bad for your body, and we should not do that to women and children. For a long time, women and children were not allowed to do night shift work in early industrialization.

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Dr. Gabrielle Lyon [0:47:11]

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That’s fascinating because now we’re really moving into a 24-hour life. I realized that we shouldn’t be, but people are working much later. It’s the pace at which everything is moving. The other thing is irritable bowel issues; eating on a schedule is key. You also mentioned something else. I was asking you about women and if there were differences between men and women regarding the circadian rhythm. You said something very interesting about menstrual cycles. How do circadian rhythms influence menstrual cycles?

Dr. Satchin Panda [0:50:33]

We discussed how the SCN is right next to the hypothalamus; it’s part of the hypothalamus. Then the hypothalamus signals the pituitary gland at the base of our brain, which in turn signals two different axes. One is the adrenal, and the other is the gonadal axis. In that way, circadian rhythm, or this 24-hour rhythm, is somehow connected to the estrus cycle, which we use broadly to describe both animal and human estrus cycles or menstrual cycles. The exact connection is not clear yet how this 24-hour cycle affects; for example, in mice, there’s a three- and half-day estrus cycle, whereas in humans, it’s roughly 28 days on average. But what is clear is that if we disrupt circadian rhythm in animals by putting them in constant light, or even dim light at night because that’s disruptive, or by giving them access to a high-fat, high-sugar diet where they eat at random times, then after a few days, their estrus cycle becomes very irregular.

If we look at humans, we also see some signs of circadian rhythm disruption, particularly among shift workers. When women start doing shift work, the first thing that they complain about is how they lose their menstrual cycle; they might lose a period or become very irregular. That’s something that has been known for a very long time. Now, one can say that shift work is very stressful, and the stress might be triggering that. That’s why we have to go back to animal experiments where we can give the animal stress-free care because our animals mean that in most of the high variance, the animals actually get premiere, top-level health care. Every day, there is a vet checking on them every single day, and then they get nutritious food, and everything is really well controlled. They never get heat stress, cold stress, or all that stress. In those cases, what we have found is that circadian disruption, either by tweaking the genes or tweaking the environment, will make them irregular. Second, they also have difficulty conceiving. Mice produce a lot of babies, but even they cannot conceive, or even if they do, the litter size is smaller because they do have a lot of miscarriages. These are really interesting findings in mice.

What will be interesting is to go back to humans and see whether some of these irregular cycles or missed periods can be fixed by circadian rhythm optimization. This is where there is a lot of potential. A few years ago, I think we discussed this, there was a science teacher in a high school in the San Diego area who reached out to me, saying how she heard about time-restricted eating or how to optimize your circadian rhythm by maintaining a regular eating and fasting schedule, which also helps you go to sleep better. She was in her mid- 30s. She was irregular, and she became much more regular in her menstrual cycle. She was also a counselor for many of the high school kids. These young women often complain about missing a period or being irregular and how it affects their sports and other things. She thought, why not try this? So she tried this, and then many of her students actually became regular, and that’s when she reached out to me. Unfortunately, we haven’t done a rigorous study because it’s very hard to receive funding for this study, and carrying out the study is also difficult because of the consenting process, etc. But the bottom line is that, at least in animal experiments, there is very strong evidence from multiple labs that yes, circadian rhythm disruption can lead to reduced female reproductive efficacy and also lifespan.

The other flip side of the story is that, recently, there was a study showing that if we maintain an optimum eating and fasting schedule with optimum nutrition, then these female rats and mice, even when they’re older, can still conceive. The female mice can still conceive and have babies, which is very important because we talk about longevity all the time. But we don’t talk about female reproductive longevity because that’s the test. If we can keep women in reproductive states for a longer time, that’s the true outcome of a longevity program. To put it together, now there is all this evidence in animal studies and human studies that is pointing. I think there are some studies also done in St. Louis where people looked at how irregular their eating, fasting, or sleep schedule was and whether they were regular in their menstrual cycle. That also showed some correlation between being more irregular in the sleep-wake cycle and being more irregular in the menstrual cycle. There is a lot of potential in that area. Unfortunately, there is not much funding to pursue those studies.

Dr. Gabrielle Lyon [0:56:20]

Eventually, people are going to see the importance. Looking at these ICD-10 codes, it’s all related to sleep. Are there biomarkers that someone has identified, or do you think there will be a movement towards being able to look at a lab panel and say, you know, you have early signs of circadian rhythm disruption? Where will we be able to go so we can identify this early, above and beyond just clinical questions and answers?

Dr. Satchin Panda [0:56:53]

Now this is a multi-billion-dollar question because, for example, we do have biomarkers if you’re drunk. We have a biomarker in a bust. But we don’t have a biomarker if you lost sleep. Let’s begin with that sleep disruption. Whether a pilot has really slept for eight hours or not, we don’t know that. That’s why, not only from the regular medical field but also from an industrial safety perspective, there is a huge boost even from the DOD and FAA. All these organizations are pushing to find a biomarker of sleep disruption. Just imagine if the pilot could go into the cockpit and breathe into a breathalyzer, and then it would say, no, you haven’t slept enough. Or a nuclear power plant operator just breathes or takes even test samples or pees into something that will say no, you haven’t slept enough.

There is a lot of research into that. The biggest challenge is that circadian rhythms are 24-hour rhythms. You might find some levels are up in the morning, but then that level may be down at night. For example, if somebody has traveled from six time zones away, even though the person slept for 12 hours after traveling, since the clock will take six days on average to reset, it becomes very difficult to figure out what phase it is. So this is our dream. For the last 10 years, there have been many attempts and progress. There are some studies now from Germany and also some from Japan showing that, at least from one or two blood draws, one can figure out the circadian phase, or what time of day your body is. But we are not very close to knowing whether the person has actually slept. It’s a huge challenge.

Dr. Gabrielle Lyon [0:59:02]

I think that clinically, the outcomes will be what we care about, which are issues with obesity and metabolic syndrome. I think that it would be so fascinating if we could do that and then identify it early.

Dr. Satchin Panda [0:59:16]

Yeah. But I guess right now, there are tools. For example, a lot of people wear wearables, or at least a watch that is an activity tracker. Or everybody has a cell phone as an integral part of their body; they slip with the cell phone and get up with their cell phone. As physicians, I guess the first thing they should ask is, hey, can you show me on average how many hours you’re sleeping? This means right now, I can take out my phone and it will tell you how badly I slept. This is something that any physician can do. But the question is, when they take that information, how do they interpret it? On average, the sleep researchers have come to a semi-consensus that most adults should be in bed for eight hours so that they can get six and a half to seven and a half hours of sleep. Because epidemiological studies in all continents, of course, except the north and south pole—

Dr. Gabrielle Lyon [1:00:22]

We’re going to leave those out.

Dr. Satchin Panda [1:00:24]

We have shown that even for millions of people, there is a U-curve in the amount of sleep and morbidity or even mortality. That means between six and a half and seven and a half hours of sleep, there is less comorbidity and disease, and people who habitually sleep between six and a half and seven and a half are likely to live longer. This is kind of a magic number. We do see a lot of people who don’t get that because we have a lot of human studies where we put the activity tracker on them. There are many people who don’t consistently get six and a half to seven and a half; some get five and a half. You’re in the medical profession, so you know that.

Dr. Gabrielle Lyon [1:01:12]

Yeah, I’ve just been seeing that in the military profession. If we know that it’s a known carcinogen with just 50 days or is considered a shift worker– I was telling you before, my husband is a surgical resident. It’s his first month. He’s working 100 hours a week, and he’s already done a week of overnights. He’s already seven, eight, 10 days into quote, shift work.

Dr. Satchin Panda [1:01:35]

Yeah. But that’s also another aspect that we don’t understand: how some people are so resilient and some are not. We know that even in medicine, even in many kinds of shift work, there are a lot of people who are very resilient; they can keep their mental health intact, they can plow through, and then some people are not. Understanding that will be extremely important because, just like nowadays, we’re doing genetic testing as soon as the babies are born to figure out what they are more likely to be susceptible to or resistant to so that we can design their lives. Starting with simple things like food allergies, gluten allergies, or milk allergies, we manage them.

Similarly, can we come up with a test where we can figure out whether certain people are resilient to sift work and some are not? In that way, of course, this is again on the border of whether you are affecting the employer-employee relationship or not. But at the same time, we got to think about the fact that in the future, that may be the way, or at least part of the way, where we can find out the susceptible individuals so that we can offer better care. Just like in the military, we are always looking for ways to figure out who is more likely to go through SEAL training so that we don’t take too many people and some people will fail, and that will cost taxpayers millions of dollars. So the military is already doing that. Why can’t we do that for, say, firefighters or nurses and then figure out who is at high risk? For example, those who are at high risk for breast cancer, should they be doing shift work? If they know that, okay, so I have a mutation that puts me at a high risk for breast cancer, and in animal studies, we have seen that there are many animals that carry similar kinds of mutations that put them at a higher risk for cancer. If we put them in circadian disruption, then they do actually get that cancer. Once they get it, the severity of cancer is much worse than the other.

These are some of the examples where, even now, if we can figure out what our susceptibility is and then ask, what is the contributing factor of release, shift work, or shift work-like lifestyle to increasing this risk, then we should be at least more careful. For example, for those who are at high risk for depression or something, it’s not that they should not do that work. But as soon as they know that they’re at high risk, they can take better care. For example, they can go get some daylight during the daytime so that as soon as they feel a little bit low, they can look out for support. That is one way we can actually integrate circadian rhythm into personalized professions and personalized care.

Dr. Gabrielle Lyon [1:04:43]

I definitely want to get to protocols, or at least the things that you feel would really help reregulate an individual and create circadian alignment. But before we do that, I have a few more questions. This concept of chronomedicine, how we can leverage the circadian rhythm to potentially improve health care, can you talk a little bit about where that is? Is it in its infancy? Are there things that we know?

Dr. Satchin Panda [1:05:10]

Actually, the chronomedicine history goes back almost 30, 40 years now. In the ‘80s, that’s when there is a landmark paper that examined women who are with breast cancer, and they were getting different chemo drugs. If the chemo was given in the morning versus afternoon, what is the outcome and whether it was beneficial or not. What they found was depending on the chemo type, because there are different types of chemos because different chemos affect different target, and depending on the type of chemo, some chemos were more effective if given in the morning, and some were more effective if given in the afternoon. That was a landmark paper from the ‘80s that has been cited many times that I would say is often cited as example of chronomedicine. Then starting from there, there are also studies showing even heart valve replacement surgery, which is very complicated surgery.

There was a nice study that came out I think in 2016 or 2017. They followed nearly 500 patients who went through the surgery by the same surgical team in the same hospital, and they found that those who underwent surgery in the morning had much better survival up to five years than those in the afternoon. It was not related to fatigue of the team because they actually went back and replicated an aspect of that in a mouse study and found out that one of the clock gene was actually responsible for that. Similarly, in mouse studies, they have done partial hepatectomy, which means taking out part of your liver. It is used in some cases of liver cancer, for example, surgery, and they found that the surgery in mice, it’s a different time because mice are night acting whereas we are day acting. Again, the same result that depending on what time of the day or night the surgery was done, the liver regrows much better.

Then there was another study that was done in our lab, we know that there are many cancer patients who do get radiation therapy. Radiation has many side effects, and one of the side effects is you may lose hair. We did a very simple experiment, and this experiment could have been done 50 years ago. We took mice and then gave them the same dose of irradiation that is given to humans for in-cancer treatment. Actually, mice tolerated that. We gave the dose either in the morning or in the evening. Morning would be our evening, and mouse evening is our morning. What is interesting was in the morning, when we irradiated this mice, then these mice lost 85% of their hair. In the evening, the same dose of irradiation, they retained 85% of the hair.

Dr. Gabrielle Lyon [1:08:23]

That’s wild. I know that those are mice studies, but are some of the things that they’re finding being implemented in clinical practice, because I haven’t seen that? I haven’t seen a routine implementation of any kind of chronomedicine.

Dr. Satchin Panda [1:08:37]

These are all the procedures because even for chemo, people have to come to the clinic, and scheduling the clinic becomes the overriding factor. Now if we go to medicine, really the pills, then, for example, we know that the blood pressure regulation is very circadian. In fact, for a healthy person, the blood pressure should go down at night because just like a body cools down, our breathing goes down, our blood pressure also goes down at night so that our heart can rest and recover for the next day. Even high blood pressure patients who still have lower blood pressure at nighttime, we call them dippers; they are they have much better outcomes, they are more less likely to get a cardiac event in long run than non-dippers whose blood pressure doesn’t go down at night. Now you would imagine that if you are giving a blood pressure-lowering medication in the evening to anyone, the dipper to dip more, and then the non-dippers might also dip, so that the long-term benefit will be better for everybody.

In fact, there are epidemiological studies where people have gone back and asked what time of the day did you take the blood pressure medication and then they tracked them for the next five years or 10 years. They find that any blood pressure medication irrespective of what it is treating, which target it is, irrespective of blood pressure medication type, those who took the medication in the evening had much better cardiovascular health five to 10 years in the follow up than people who took the medication in the morning. Of course, there can be many factors because people will say, well, if you’re taking them at night, then maybe you have a set routine. So you’re taking medication every day, in the morning, you might forget, all that stuff. But even in animal studies, we do see why that might work. That’s why this is one area where, among your listeners, maybe half of the US adult population are mild or severely hypertensive. That means maybe 1/4 to 1/3 of the adult population is on an antihypertensive drug. They can do the experiment themselves. If they have a blood pressure monitor at home, they can actually check whether that nighttime blood pressure is dipping before bedtime. If they take the medication in the evening, then what happens? Of course, you have to consult with your physician before you do anything. This is all hypothetical, but this is something to keep in mind, or at least people can discuss with their physicians.

Dr. Gabrielle Lyon [1:11:24]

What about hormone replacement, testosterone therapy, or even thyroid hormone therapy, things of that nature, is there really any data?

Dr. Satchin Panda [1:11:32]

In the morning, thyroid hormone has become the way to go. I think we don’t see much difference. In fact, we do have an app called My Circadian Clock. There are tens of thousands of people who have been using the app. We get a lot of medication data.

Dr. Gabrielle Lyon [1:11:54]

That’s fascinating. Anything that really surprised you?

Dr. Satchin Panda [1:11:57]

Blood pressure medication, what we see is nearly 2/3 of our users, they take blood pressure medication in the morning, only 1/3 take at night or bedtime. We hope that will whether that changes or whether that has effect. But when it comes to thyroid medication, 95% take it in the morning.

Dr. Gabrielle Lyon [1:12:16]

But just because everyone’s doing it that way, doesn’t mean that that’s probably the most effective way. Again, I don’t know. We seem to do things in medicine over and over again, whether it’s optimal or not.

Dr. Satchin Panda [1:12:27]

Yeah, so it’ll be interesting to see that.

Dr. Gabrielle Lyon [1:12:31]

You talk a lot about in some of your papers the impact, because I know you did time-restricted feeding, which obviously we’ll get into because everyone wants to hear about that. But what was so fascinating to me was this concept that circadian misalignment can really affect the utilization of certain substrates whether it’s proteins, fats, carbohydrates. I’m curious when we think about circadian rhythm, please correct me, the major influences are light, food, and activity. Is there anything else major, maybe temperature?

Dr. Satchin Panda [1:13:03]

Light and food are more direct; temperature can be indirect. For example, nighttime temperature, if it is high, then you may not sleep well. That will affect your mood and other stuff the next day.

Dr. Gabrielle Lyon [1:13:16]

Where does exercise fall into the stimulus of circadian rhythms?

Dr. Satchin Panda [1:13:21]

Exercise is both an output and also internal. That means there is an optimum time for us to do exercise.

Dr. Gabrielle Lyon [1:13:32]

We can talk about it, but everyone wants to know. But before you get there, you ready for my question? And yes, the optimal time to do exercise. This idea of changing substrate utilization; shift workers, we see increased insulin, glucose, they gain body fat. Skeletal muscle influence, while it is not a primary site for fat storage, lipid storage, triglycerides, it definitely exists right there. Of course, there’s the athlete’s paradox. But above and beyond that, in obesity, we do see this decrease in flux within skeletal muscle and increase in intramyocellular lipids. With circadian misalignment, is that utilization also affected?

Dr. Satchin Panda [1:14:18]

Yes, that’s actually affected. These are the studies we have done in fruit flies.

Dr. Gabrielle Lyon [1:14:26]

I thought that. I saw some of the studies that you published, but I didn’t quite understand how the fruit flies translate over to human skeletal muscle and how you could look at fiber type or myogenesis. I didn’t know.

Dr. Satchin Panda [1:14:43]

Fruit flies actually laid the foundation for circadian rhythm because the three scientists who got the Nobel Prize for circadian rhythm, they actually studied fruit flies and figured out how the clock works in fruit flies. The same mechanism, not exactly the same protein, but the same mechanism is also present in humans. Many of the genes are similar in humans; one thing was not similar, but that’s the minor detail. In terms of muscle, when we studied fruit fly muscle, we are not studying their hands and legs, we actually study the flight muscle because the flies have to fly and they have to flap their wings. Of course, we don’t have the same type of muscles, some of the stuff, but what is interesting is just like in human obesity, there is intramyocelluar lipid deposits. That means excessive fat inside the muscle. Similarly, these flies also store some fat in the muscle. As a result, what happens is they cannot fly enough. We do their flight test–

Dr. Gabrielle Lyon [1:16:04]

I’m never going to look at a fruit fly again. In fact, I kind of feel really guilty for killing fruit flies now.

Dr. Satchin Panda [1:16:10]

That’s okay. They’re very resilient.

Dr. Gabrielle Lyon [1:16:12]

Certainly not the ones in my kitchen. I’ll never look at a fruit fly again.

Dr. Satchin Panda [1:16:16]

In that case, what we have seen is yes, circadian rhythm disruption, particularly when these fruit flies eat randomly between day and night, then they deposit more fat, and they also cannot fly. It’s not only because they’re fat. They don’t gain that much weight, but their flight muscles just become less effective. Then the converse is if we actually do time-restricted feeding where the fruit flies have access to food for 12 hours during their wakeful time during the day, then they can reduce that intramyocellular lipid deposit, they lose that fat from the muscle. Also, they can improve their flight, so they can fly.

Dr. Gabrielle Lyon [1:17:04]

Do we know is it because of the food restriction, or is it because of the activity? Do you think one comes first? I know that’s a really difficult question. I’m just curious.

Dr. Satchin Panda [1:17:12]

I think the food restriction because what happens is we always talk about, okay, so let’s go back and think about things that people talk about longevity. For example, they talk about metformin and how it affects AMP kinase, which mimics fasting and similarly, rapamycin, all these things. What is interesting is circadian rhythm actually regulates all these pathways in a way that for example, AMP kinase becomes active for a certain number of hours when we’re fasting.

Similarly, mTOR becomes less active when we’re fasting. It’s almost like putting ourselves on two different drugs by just feeding-fasting cycle. Similarly, all of these affecting fuel utilization. Our muscles have to build muscle, have to store protein, etc. But at the same time, it also has a quality control mechanism. That means our damaged proteins from muscle or some part of the muscle protein has to turn over, has to recycle. That recycling happens when we’re fasting. Of course, people make claims that we may lose some muscle, but actually, it’s part of our natural process that we break down a little bit of protein and that amino acid comes to the liver when we’re fasting. At the same time, when we eat, now this is something that we have done in mice, and hopefully it will be done in humans too, what we’re finding is this eating followed by in mice 14 hours of fasting or 16 hours of fasting is a very strong trigger for muscle protein synthesis.

There are two things happening, the muscle protein is recycled during the fasting time. Then there is new protein synthesized when the mice ate. As a result, these two combinations are actually improving the quality of the muscle protein. That may be the reason why we have seen in mice, mice that go through this feeding-fasting cycle, they have much higher endurance. Actually, their endurance is almost double. Of course, in mice, everything is magnified except for their size. That’s one thing. When it comes to carbs also, most of the carbohydrates that we eat, it gets converted to glycogen and then that glycogen gets stored.

Then again, there is circadian rhythm in glycogen formation and also breakdown of the glycogen. In fact, one of the master regulator of that glycogen synthesis, glycogen synthase kinase, it’s a kinase that phosphorylates something. That also phosphorylates or modifies one of the clock proteins. That means there is a strong association between how we utilize carbohydrate and how that carbohydrate utilize and also talks to the clock mechanism itself. When it comes to fat, again, the AMP kinase that we talked about as target of metformin, and the AMP kinase also targets many fat metabolizing enzymes. As a result, those processes are also regulated by feeding-fasting cycle. In this way, carbohydrate, fat, and protein, all of these are linked to circadian rhythm and also circadian rhythm and feeding and fasting. When we extend that feeding period, then we disrupt many of these. Also, we should not increase the fasting period because too much of fasting can also disrupt that. Finding this optimum balance is the key to figure out.

Dr. Gabrielle Lyon [1:21:09]

I’d love to stick to exercise to start, because I think that that’s really fascinating. What would be the optimal time to train? Does it matter if it’s endurance? Does it matter if it’s weights? Is it the actual muscle contraction, or is it the increase in catecholamines or other markers or other biological compounds that make the difference?

Dr. Satchin Panda [1:21:52]

The bottom line is any exercise is better than no exercise. Let’s make it sure that that message goes across, because the median step counts in the US now is 3000 steps, which is way lower than what you’d expect. It should be at least 7000 or more. That’s just step counts. Less than 5% of people actually get the recommended level of exercise in the US. Any exercise is better than no exercise. Then we should think about, okay, so what time and why? Again, this is a field that has very rich history of what time athletic performance, for example, peaks, going back to mid-‘80s when people looked at NFL players’ performance of winning, and then they found that when West Coast team flew to East Coast and played against the home team, they had a much better chance of winning against the home team. The odds were much better than Las Vegas odds score, so does much better. If you knew when the players actually flew on Sunday, whether they flew on Sunday, and then if they played on Monday, then they had a higher chance. The reason being athletic performance or physical performance is a product of many of our organs acting together, our heart, our lungs, our skeletal muscle, even motor coordination, all of these, brain function, all of them have to work together along with fuel utilization. All of these processes are controlled by circadian rhythm. The optimum, it’s almost like all the stars align for better performance because that’s also the time when our core body temperature is slightly higher. Body temperature is higher, so that means our joints are more flexible, and we have less risk for injury. That means we can push ourselves faster, harder.

Dr. Gabrielle Lyon [unclear 1:23:51]

So what time?

Dr. Satchin Panda [1:23:52]

It’s late afternoon. Again, this is all related to your light-dark cycle and your eating-fasting cycle. But in general, it’s late afternoon, early evening. So you can say between 4pm and 7pm for an average person who is going to bed between 10pm and 11pm.

Dr. Gabrielle Lyon [1:24:11]

That’s just athletic performance, right?

Dr. Satchin Panda [1:24:13]

That’s a few things; athletic performance and also lower risk for injury because there are many elderly people who want to go to the gym, who want to perform, and they often get injured. Once you’re injured, then it becomes difficult to come. So that’s another reason. One more thing is morning exercise, of course, a lot of us, young people and healthy people can do morning exercise and there is nothing wrong or bad about that. But what happens is our heart is not prepared enough in the morning and particularly those who are waking up to an alarm clock, that means their heart or lungs is not prepared enough for a rigorous very strenuous exercise. The evidence is, if we look at the heart attack, what time of the day heart attack peaks, it’s actually early morning, that’s when heart attack increases, the incidence increases, because your heart is not ready, all of a sudden, you’re waking up, and your heart has to pump a little bit faster to make you wake up or go. Or if you’re walking, or if you’re exercising, that’s when it happens. If you talk to a lot of people who had a heart attack, and if they have a heart attack in the gym, I would say it was more likely that happened in the early morning exercise, particularly when they either came back from a trip within a few days, or they didn’t have a good night’s sleep, or they woke up to an alarm clock. Those are the things that one has to keep in mind that if you travel, then it’s okay to get up and then just pay attention, maybe not do a too strenuous exercise.

Dr. Gabrielle Lyon [1:26:02]

So it’s not really related to cortisol.

Dr. Satchin Panda [1:26:06]

The cortisol actually peaks within an hour after waking up. That’s the highest level of cortisol in the entire day, even though you may be stressed. Whatever happens in the rest of the day, the highest level is when we wake up.

Dr. Gabrielle Lyon [1:26:19]

But what you’re saying is that’s not necessarily the stimulus for a heart attack.

Dr. Satchin Panda [1:26:23]

That may be one of the stimulus, which means it’s already high, and if you’re still pushing it higher and your heart is not ready enough, that can trigger it.

Dr. Gabrielle Lyon [1:26:32]

Do we have natural sleep-wake cycles? For example, let’s say someone wants to train in the morning. Could they potentially go to bed at nine o’clock and know that they are– so you can train yourself to do it. But the evidence would suggest that over time, between 4pm and 7pm is when the body is more prepared. How do we define preparation?

Dr. Satchin Panda [1:26:56]

This is where it goes back to your biomarker of circadian rhythm. It’s really hard to define preparation. For example, if you had lunch before one o’clock, then four o’clock will be ideal time when your digestion process has slowed down and you have digested a good amount of food and you’re light enough to go start exercise. It’s a very difficult term to figure out exactly what time, that’s why in general, it’s the late afternoon. Then there is another reason why late afternoon because now, there are many controlled studies on people with hypertension or people with type 2 diabetes. Those with hypertension, it is now clearly shown that the same exercise late afternoon, again between 4pm and 7pm roughly, is more effective in reducing blood pressure than the same exercise in the morning. For type 2 diabetes, the same thing. This was a study from Karolinska Institute, Stockholm, this is a crossover study. That means the same individuals went through both the treatments. This is a study with type 2 diabetes. They were put on continuous glucose monitor so that the researchers could see 24 hours how the glucose profile is. These patients went through morning high intensity interval training, or late afternoon high intensity interval training. One group went to the morning, then after they had couple of weeks of rest, and they came back and did the afternoon, and the other group did the other way around. In both groups, what they found is the late afternoon, early evening, that exercise was much more effective in reducing 24 hours blood glucose than the same exercise in the morning.

Dr. Gabrielle Lyon [1:28:58]

So it was clinically significant.

Dr. Satchin Panda [1:29:00]

It was clinically significant. Then the question is, you might say why? There is a circadian rhythm in pancreas that produces insulin. Actually, in the first half of the day, it doesn’t mean 6am to 12 noon; what you would say roughly after waking up for the next six to eight hours, our pancreas is much more effective in producing enough insulin.

Dr. Gabrielle Lyon [1:29:28]

Irrespective of carbohydrate dose?

Dr. Satchin Panda [1:29:30]

Yes. It’s just primed to produce and release more insulin than in late afternoon, and evening, it goes to sleep almost. At the same time, we know that independent of insulin, just muscle or physical activity can also enable muscle to absorb a lot of glucose without help from insulin. This may be another reason why late afternoon, early evening exercise when our pancreas is actually slowing down, might give a boost to better absorb that glucose and maintain blood sugar level within healthy rates. So there are now all these reasons for people with peak athletic performance, or if you have a risk for heart attack or something to hypertension and high blood sugar, that covers more than half of the adults.

Dr. Gabrielle Lyon [1:30:28]

It truly is fascinating to think that we can leverage the times of when we’re doing things to support our biology, which moves us into the next question, really, food. I know you’ve worked on really some pivotal studies regarding time-restricted feeding versus calorie control. In there, I know that there is low carb diet. Can you talk about when the ideal time to eat is. I don’t know if certain macronutrients do better. You just mentioned that pancreas is more active in the morning. Again, I still wouldn’t say we front load carbohydrates, but maybe– I know that these are pretty complex topics, and we’ll do our best.

Dr. Satchin Panda [1:31:15]

I guess I always see eating and sleep as two sides of the coin. That means we have to also think about sleep and eating in terms of that relative time, when we should sleep relative to when we eat, or when we should eat relative to what time we’re waking up or going to sleep. In that context, irrespective of what time somebody is waking up, whether it’s 4am or 8am or 9am or 10am, one should wait for at least an hour or two before the first bite. The reason is that’s the hour or two when cortisol is at its peak, and we know that we should not eat during peak cortisol level, so that makes sense that we should not eat for one to two hours after waking up. Then after your first bite, one should try to eat everything within eight nine, 10, or maximum 12 hours. Again, this is where when you go to sleep matters because your last bite should be at least three hours before your bedtime. Because although you finished your last bite, your stomach will take another four to five hours to digest that food. When you’re digesting that food, your core body temperature is high because a good chunk of the blood circulation is going through the stomach and the digestive system to absorb nutrients. When your core body temperature is high, it’s difficult to fall asleep. It’s not impossible, but it’s difficult to fall asleep or to sustain that sleep. That’s why I’m not talking about and 9am to 5pm or anything; I’m talking about relative to your sleep time. Suppose you ate for 12 hours. Your first calorie and last calorie is 12 hours. After your last calorie, again, for the next five hours, your stomach is not getting rest. It’s still digesting. In fact, at the end, your stomach gets only seven hours of sleep, which is not enough for the stomach to repair itself. That’s the bottom line of when we should eat.

Now, a lot of people come back and say well, I’m not very hungry in the morning, so I can wait until noon. Some people who are even waking up at six or seven and say well, I’m not hungry, so I should wait until noon and then eat after that. There is not much study like a crossover study or something showing when they should be eating. So I’m not in favor or against people who want to wait till noon or one o’clock. But what I strongly believe is they should stop eating two to three hours before bedtime. That’s much more important.

The other thing that happens is almost two to three hours before bedtime, our melatonin level begins to build up. It begins to rise to slowly build that sleep pressure. Research only in the last 10, 15 years starting from human genetic studies showed that just like our melatonin makes our brain to sleep, it also makes our pancreas to slow down. That means melatonin inhibits, puts a break on this process where glucose triggers pancreatic islet cells to produce insulin, and melatonin puts a break on that. That means the same amount of glucose may not be enough to produce enough insulin to manage the blood glucose level. Since melatonin level begins to rise up slowly two to three hours before our bedtime, if we eat close to our bedtime, within three hours before bedtime, then there is a chance that our blood glucose level may go slightly higher than if we had the same meal a couple of hours earlier. That’s one reason why it’s important to pay attention to your sleep. The bottom line is, in the morning, wait for at least one or two hours, and in the evening, you should not eat for three hours before your habitual bedtime.

Dr. Gabrielle Lyon [1:35:46]

I think that’s really good advice. Super easy to follow. Thoughts on melatonin supplementation. Did you know I was going to ask you?

Dr. Satchin Panda [1:35:53]

When people talk about melatonin.

Dr. Gabrielle Lyon [1:35:57]

I’m just curious because it seems as if in the aging population, melatonin goes down. When I was at WashU, one of the things that we did for delirium is we gave people ramelteon, which is melatonin.

Dr. Satchin Panda [1:36:13]

Yeah, a melatonin receptor agonist.

Dr. Gabrielle Lyon [1:36:15]

Exactly. It cleared them up in a heartbeat. I looked like a very smart doctor because you have the vascular surgeons coming in and the patients are delirious, but it worked like a charm.

Dr. Satchin Panda [1:36:27]

Well, they were not getting sleep, and you don’t want to put them on a sleeping pill.

Dr. Gabrielle Lyon [1:36:34]

No Seroquel or anything like that.

Dr. Satchin Panda [1:36:36]

Actually, melatonin receptor agonist ramelteon or melatonin itself are pretty good. At the same time, as a physician, you know that they have to be taken–

Dr. Gabrielle Lyon [1:36:47]

There’s no free lunch.

Dr. Satchin Panda [1:36:51]

They have to be dosed properly. Melatonin not being controlled in the US, actually, now you can easily go to the store and get 10 milligram melatonin pill. But I remember in ’96, ’97 when I started grad school, sometimes for travel, I was looking for melatonin, and it was hard to get 3 milligram melatonin. It was mostly 1 mg or 2 mg. When we take melatonin, a good chunk of that melatonin gets metabolized by your kidney. Nearly 60%, 70%, or even 80% of it is cleared within 15 minutes. That led to the idea that we should have more melatonin or slow-release melatonin. All of these dosing formulation or research on melatonin, how it affects our sleep or how it affects cancer, for example, all of these were done before human geneticist figured out that those with a mutation in the melatonin receptor have a high risk for obesity and diabetes. That led to the effect of melatonin on pancreas. But before that, we always thought that the only role of melatonin is to make our body to sleep, and maybe it’s also good because it’s an antioxidant. So more is better, that’s what we thought.

So now if you’re taking 5 milligram of melatonin a couple of hours before bedtime, then you’re likely maintaining a pretty high level of melatonin when we wake up. For example, in the middle of our night, in the middle of our sleep, our melatonin levels go up to say 150 to 200 nanogram per ml. It sounds very low, but daytime, it’s below 10, 15 nanogram. But if somebody takes 5 milligrams of melatonin that evening, then that person is likely to have more than 100 nanogram even two hours after waking up. It’s pretty high level of melatonin that person would have. And that’s why a lot of people, they will complain that yeah, I slept well. But melatonin somehow makes me a little groggy next morning, so I need coffee to wear off the effect.

At the end, what is happening is we are beginning our day with coffee and ending with melatonin to counteract each other’s effect. In those cases, people are actually taking exogenous melatonin 3 mg or higher. Although it’s difficult to go get a melatonin test in the morning to see how much of melatonin is in your blood, of course, you can go and get that test done. But the rule of thumb is you still have pretty high level of melatonin. This melatonin that we’re exogenously taking, light has no impact on it. Because light affects the pineal gland which produces melatonin, so it puts a break on pineal melatonin production. But once it is in the bloodstream, light has barely any effect on it. That means light has no effect on how much melatonin you took. The morning light exposure will not reduce your melatonin if you have taken melatonin the previous night.

Dr. Gabrielle Lyon [1:40:24]

That’s important. Stop overdosing yourself on melatonin, otherwise, you’re going to be exhausted and you’re not going to be able to pull yourself out of it unless you’re drinking a triple espresso.

Dr. Satchin Panda [1:40:30]

For people who have type 2 diabetes, or prediabetes, if they’re taking 3 to 5 mg or higher level of melatonin the previous night, they’re more likely to have high level in the morning. For them, it becomes even more important that they should not eat a sugary, high carb breakfast early in the morning. These are some of the caveats that people are finding that melatonin is good for sleep, but it has to be taken and more regulated. Maybe the physicians can recommend few things. One is don’t take your melatonin pill with your dinner.

Dr. Gabrielle Lyon [1:41:14]

Yeah, there we go. Not ideal.

Dr. Satchin Panda [1:41:17]

At least two hours after dinner is you take your melatonin close to bedtime. People always ask me, and then I say our sensitivity for melatonin is very different. For example, I am a cheap date for melatonin. I can take 1 mg, and I’ll fall asleep. But I know people who are even more sensitive to 500 micrograms, so that means half a milligram is enough. These are people who are 250 pounds; size doesn’t matter. At the other end, I have also seen people who take 15 milligram because 10 milligram will not put them to sleep. Melatonin is a thing that people may have to titer and then figure out and play around when you’re not traveling. Also, if you’re a type 2 diabetic, then it’s more important that you play around. If you can put a continuous glucose monitor, then it’s even better that you can play around your dose.

Dr. Gabrielle Lyon [1:42:24]

That is important. I had not thought about that before. You talked about carbohydrates in the morning. Is there a time for dietary protein and fat?

Dr. Satchin Panda [1:42:34]

I think morning is good for everything. There are also studies in Japan that came out. They showed that for older women, protein intake in the morning was much better for maintaining their muscle strength and muscle mass than protein intake in the late afternoon or evening. Lifestyle is all about quality, quantity, and timing of nutrition, sleep, and activity. Of course, we are talking about timing, but we should not ignore the quality and quantity. In terms of quality, for example, the best breakfast would be a bunch of complex carb with good fiber and also protein and fat because that will help. What we see in our clinical studies is when people go through 14 hours of fast and they’re eating their first breakfast, then they’re likely to eat a bigger breakfast. Breakfast is the only meal on which we have good control if we’re eating breakfast at home.

Dr. Gabrielle Lyon [1:43:40]

You’re absolutely right, you’re absolutely right.

Dr. Satchin Panda [1:43:42]

Once you are getting out of the home, then you have very little control over what you will eat and how much you will eat. What happens is when you eat a good healthy breakfast, all the grains, for example, I eat oatmeal, and then I have some egg white or something and fruit, so that becomes very healthy. But at the same time, the big breakfast will also prevent me from eating snacks at work or wherever I’m going. So I’m less likely to pick up that doughnut or any sugary snack. There are two things, bigger breakfast, and your pancreas is much more ready, and since you have gone through that overnight fast, to recall our discussion about muscle, that’s the time when protein synthesis is also much better after overnight fast when you’re eating. In that way, having a good dose of protein also helps to build that muscle and repair.

Dr. Gabrielle Lyon [1:44:37]

I couldn’t agree with you more and also the studies are done with that first meal. Again, like you said, it’s so easy to control for. In terms of relating it to this light and light viewing and circadian entrainment, how do you recommend people do that? Is there a certain amount of time outside? Is there a certain amount of time that they should just be outside?

Dr. Satchin Panda [1:44:56]

This is becoming more and more important because light does a few things. One is biochemically, it reduces the melatonin production, so that way, it also reduces sleepiness, because even after we wake up for at least one and half hour, in some cases, two hours, the melatonin level is relatively high. Light just reduces that.

Dr. Gabrielle Lyon [1:45:20]

My kids don’t seem to have high melatonin level when they wake up. They’re just ready to go.

Dr. Satchin Panda [1:45:25]

There’s a different kind in there. They might have high cortisol level.

Dr. Gabrielle Lyon [1:45:31]

I mean, did you just drink a whole bunch of coffee or what? But for the most part, yes.

Dr. Satchin Panda [1:45:35]

The second thing that it does is it resets our clocks. Then the third one is bright light during daytime, it increases alertness. Reduction of depression doesn’t mean that you feel more alert. There is a different switch for alertness. Your executive function also improves with that. Then daytime, there was another study we just finished. Again, it’s Horacio de la Iglesia who published it. This confirmed some of the studies done from early on that daytime bright light exposure, for some reason, we don’t understand why, it increases nighttime melatonin level. Going outdoors, getting some bright light is almost equivalent to taking a melatonin pill without the adverse effect of all these things. Pineal melatonin is actually produced to a higher extent.

If we combine all of this together, then the question is how much light, for how long, and when? Studies have shown that, as a rule of thumb, 1,000 lux of light, I’ll get to what is that, for 30 to 60 minutes is enough for an average person to reduce feeling low, increase alertness. 1 lux of light is having a candle in a dark room and sitting one feet or one arm length away. 1,000 lux is typically, in Texas in a sunny day, if you just open your curtain, you have a glass window, even though the sun is not coming to your room, if you sit within a yard from that glass window, then you are getting roughly 800 to 1000 lux of light. If you’re going outdoor in a cloudy, snowy day, even in Minnesota in January, if you’re going out, you’re getting 5,000 lux of light. That’s five times more than what you need. You cannot stay outdoors in Minnesota for one hour walking. Then in the middle of the day, for example, in Texas now, it will be 200,000 lux.

Dr. Gabrielle Lyon [1:47:59]

And 200,000 degrees.

Dr. Satchin Panda [1:48:03]

That’s the rule of thumb that 1,000 lux, so that means if it is a pleasant day, then you can be even under a tree or shade outdoor for an hour, and that will be enough because you’re getting 5,000 to 10,000 lux to uplift your mood and train circadian rhythm, all this stuff.

Dr. Gabrielle Lyon [1:48:23]

Only through the eye, it’s light viewed through the eye.

Dr. Satchin Panda [1:48:26]

Light viewed through the eye, so that means you should not be sitting under the shade and wearing sunglasses, very heavy sunglasses. That defeats the purpose. Now the bottom line is Well, nowadays particularly after COVID, we are talking about how COVID changed our teenagers and many adults are feeling more depressed and all that stuff. If we see one common denominator that is we are spending more time indoors. We are also spending more time indoors away from light. It goes both ways. For example, in Texas now that it’s so sunny, so hot, people close their windows, window curtains, and then make it really cool and dark inside. In fact, we do have special watches where we track how much light people get. Even in San Diego, which is pleasant and sunny, almost 250 to 300 days in a year–

Dr. Gabrielle Lyon [1:49:26]

Yes. I don’t know how you survive that terrible weather.

Dr. Satchin Panda [1:49:29]

But what we’re finding is people spend less than an hour exposed to more than 1,000 lux of light because they’re driving from the garage to work. Then when they’re inside the car, they also have heavy sunglasses even though you don’t need for most part. Sometimes you do need sunglasses, but most of our glasses are filtering out UV light that you don’t need. The bottom line is yes, you need one hour of light. If somebody is depressed, then you need 5,000 to 10,000 lux of light for an hour. Now, we are talking about a lot of mental health crisis and teenagers and college students that are going through depression. We think about, okay, how to improve access to mental health. If you look at the number, then there is no way in the next five years we can produce enough mental health care providers. But what we can do is, if you are really concerned about somebody’s mental health, the best thing you can do is take that person out for a walk for an hour during daytime.

Dr. Gabrielle Lyon [1:50:40]

I like that. Easy fix.

Dr. Satchin Panda [1:50:41]

Yeah, that’s easy. There are a lot of people like that. I have seen people come up to me and say, well when we go out, we combine so many things. Of course, you’re exposed to light with the social aspect. Or if you’re walking in the garden or in a park then that nature walking itself, all of these uplift your mood. Why not do that? If you’re concerned about somebody’s mental health, whoever is listening, just make it a point at least once a week or twice a week, just like you would take somebody out for a tea, coffee or anything or dinner, make it a point that you do that during daytime, sit outdoor. Even if you have lunch or breakfast, or go for a walk, do that for your friend who is feeling low, and that can have a huge impact.

Dr. Gabrielle Lyon [1:51:35]

Yeah, that’s such good advice and so easy to do.

Dr. Satchin Panda [1:51:40]

That’s why I said daylight is antidepressant. It’s plentiful and free. You just have to make the effort to get out more.

Dr. Gabrielle Lyon [1:51:48]

Yes. Have you seen a lot of influx in the photobiomodulation in terms of red lights for healing? I’m sure you’ve seen a ton of that, and I’m sure people ask you about that.

Dr. Satchin Panda [1:51:58]

Yeah, I’ve seen a lot of that. Unfortunately, I haven’t done much research in that aspect.

Dr. Gabrielle Lyon [1:52:05]

Where do you feel that the field is going? What are you working on next? I’m sure that the information and the science that we’re hearing now, you’ve been aware of this for years now. And so typically, there’s something up your sleeve that’s next or where the field is going?

Dr. Satchin Panda [1:52:24]

We don’t know the mechanism for a lot of this. Even for example, we talked about chronomedicine, and based on animal works, we think that nearly 85% of FDA approved drugs might have a better time when they’re taken. But then even animal studies, with 800 plus FDA approved drugs, to do that systematically and to see whether there is in fact efficacy or not, we don’t know that. Those are some of the stuff that the field will go and address.

Then in terms of patient care, we haven’t done, and when I say we, it doesn’t mean me, but the field or community, we haven’t done systematic studies, say, lighting schedule or nutrition schedule in hospital setting. Can we improve care in a way that even if we reduce hospital stay by one day on an average, one day of hospital care is somewhere between $15,000 to $20,000.

Dr. Gabrielle Lyon [1:53:30]

Yeah, definitely reduce the burden.

Dr. Satchin Panda [1:53:32]

That will reduce the burden, so we need systematic study on that. Similarly, old age adult care, old age care, whether it’s a dementia patient, how to optimize the lighting, nutrition timing, and also medication timing, because every day they have quality day that reduces the burden on the caregivers, and also improves their quality of life, the quality of everybody’s life who care for them. Then on the babies, kids, and there also lies very little research on circadian rhythm and brain health. For example, there is a rise in autism spectrum disorder, ADHD. We don’t know because there are very few studies showing that yes, increasing light during daytime or reducing light in the evening can reduce the severity of ASD or ADHD. But those are small studies. Again, doing any study on pediatric population is extremely hard, and we need that focus. We also need support from patient advocacy group to do these kinds of studies because only when the patient advocacy groups speak up, then NIH and other funding agencies, they pay attention.

Then the other thing is sleep, how reduced sleep or sleep disruption affects our health. Those things have not been systematically studied. The bottom line is we don’t know how optimum nutrition, how optimum sleep, or how optimum exercise affects our entire body. In exercise, we’re not talking about exercise in muscle, but how exercise affects our kidney, for example, or how exercise affects our brain health. We have no idea. We just say that, yes, it does. But which part of the brain and where?

So we are doing those kinds of very systematic studies where, for example, we’ve published one in which the study was done in mice, young mice. We did time-restricted feeding where the mice were eating within nine hours. Then we asked, what is the impact of this pattern of eating on 20 plus different tissues, including brain regions. By doing this, we realized that yes, there is, by time-restricted feeding, we knew a few things would improve, for example, autophagy or self-repair improves, mitochondria function improved, and then we also saw the fat burning improve. Those we knew, but it was reassuring to see that it is happening beyond the liver; it was happening in muscle, it was happening in heart, gut, and all these other organs. But what was surprising was we found that DNA damage repair or repair of protein or quality control of protein synthesis, they improved not in the fasting phase, but when the mice refed. That was a surprise. Those are the things that we found.

Again, in the brain, we find there are certain neuro transmitters, their synthesis or their reuptake improves. Now we’ve got the gene expression signature. Now the question is, is it going to improve the health of people who are depressed? Can we improve their health by combining time-restricted feeding with light exposure? Actually, we’re starting a multi-year project with support from the Wellcome Trust, and the lead PI is in UC Berkeley. She is trying this multi-institute, multi-national study to see whether circadian rhythm optimize and will reduce the burden of depression in treatment-resistant patients. Those are the things we’re doing.

Similarly, sleep disruption, how sleep disruption affects the immune system, or how it affects the gut, whether it affects and how, and what are the implications. Similarly, on exercise, there are two aspects that we’re testing. One is how exercise affects the whole body. we also know that nearly 40% plus of athletes, they eat less and exercise more. That puts them on a negative energy balance. Particularly for women, it’s very obvious because they miss their menstrual cycle, it has become so common that the thing that being athletic, it’s normal to miss your cycle, which is not true. Common is not normal.

Dr. Gabrielle Lyon [1:58:14]

Common is not normal. That’s right.

Dr. Satchin Panda [1:58:17]

But it’s very difficult to study athletes who are eating less. First thing is they won’t admit that they’re eating less because our bodies are very different. We may be spending energy in very different rate. For me, for example, 2,000 kilocalories, maybe my maintenance kilocalorie, but when I’m exercising, I might need 2,500. Whereas another person of the same body size might need 3,000, who knows.

We are starting that relative energy deficit in sports, and we had to create a new mouse model that the mice have to exercise the same, but then we slowly reduce their calorie, and then we’re asking, is this the right model? Second, if it is the right model, then what happens in neuroendocrine system, brain? Again, we go take out at least 20 plus organs systematically, and then do a very in-depth global analysis. We look at all the genes or all the proteins or all the metabolites. Then when we do that and the regular statistical models don’t work anymore, so then we had to also bring in computer scientists to build this AI machine learning model to take the data and then give us insight. I think that will be the future not only in our field, in many fields, it will be the future.

Dr. Gabrielle Lyon [1:59:40]

Well, it’s so exciting. One of the reasons I love all the work that you’re doing is it’s applicable. There’s a lot of basic science involved, but it really is applicable to the average person, and it makes the world better. Thank you so much for doing everything that you’re doing. If you want to tell people where to find you, you have two books. I know because I have one there. I’ve already read one. But there’s a second one. Tell us a little bit about where we can find you.

Dr. Satchin Panda [2:00:08]

I have this two books, The Circadian Code that talks in general the circadian rhythm and its implication for health. That was published almost five years ago, but it has been now translated in 15 or 17 different languages. While working with patients, I also realized that circadian rhythm has a huge impact on blood pressure and blood sugar regulation. That’s why I wrote the second book, The Circadian Diabetes Code to control blood glucose, because another thing that I realized is that many people think that oh, diabetes is just a disease of this blood sugar. If we take care of it, then it’s not a big deal. But actually, diabetes, as you know, it takes you in a sliding slope, so that’s why I wrote that book. I also started a new commercial version of the app, My Circadian Clock because this is used mostly for research, and we realized that a lot of people wanted a much simpler one, so that’s why we started Ontime Health, so one can go to getontimehealth.com health.

Dr. Gabrielle Lyon [2:01:24]

We’ll link it, too.

Dr. Satchin Panda [2:01:26]

These are the places where people can get more information.

Dr. Gabrielle Lyon [2:01:29]

Thank you so much. Are you active on Twitter, Instagram?

Dr. Satchin Panda [2:01:33]

I try to be active on Twitter, once in a while I do.

Dr. Gabrielle Lyon [2:01:37]

Okay, well, we’ll link all of those. Again, thank you so much.

Dr. Satchin Panda [2:01:41]

Thank you. Thank you for doing this wonderful thing of connecting science to the bigger audience who will benefit every single day. Thank you.

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Dr. Gabrielle Lyon [2:01:51]

The Dr. Gabrielle Lyon podcast and YouTube are for general information purposes only and do not constitute the practice of medicine, nursing, or other professional health care services, including the giving of medical advice. No patient-doctor relationship is formed. The use of information on this podcast, YouTube, or materials linked from the podcast or YouTube is at the user’s own risk. The content of this podcast is not intended to substitute for professional medical advice, diagnosis, or treatment. Users should not disregard or delay in obtaining medical advice for any medical condition they may have and should seek the assistance of their health care professional for any such conditions. This is purely for entertainment and educational purposes only.