Dr. Satchin Panda: Intermittent Fasting to Improve Health, Cognition & Longevity

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Andrew Huberman: Welcome to the Huberman Lab podcast, where we discuss science and science-based tools for everyday life. I'm Andrew Huberman, and I'm a professor of neurobiology and ophthalmology at Stanford School of Medicine. Today, my guest is Dr. Satchin Panda. Dr. Satchin Panda is a professor and director of the Regulatory Biology Laboratory at the Salk Institute of Biological Studies. His laboratory has made numerous important contributions that impact mental health, physical health and human performance. For instance, his laboratory discovered the neurons in the eye and neurons within the brain that regulate our so-called circadian rhythms. Circadian rhythms are 24-hour rhythms in everything from gene expression to the overall functioning of tissues, our levels of mood and alertness, our ability to sleep, appetite, and much, much more. In addition, over the last decade, Dr. Panda's laboratory has made critical discoveries in terms of how our patterns of eating over time impact our biology and our health. In particular, his laboratory pioneered discoveries related to so-called intermittent fasting, also sometimes referred to as time-restricted feeding.

Today, Dr. Panda and I discuss how our circadian behaviors — everything from when we wake up to when we view light, to when we avoid viewing light, to when we eat and what we eat and when we socialize and how we socialize — impacts our biology and our psychology and how all of that has a strong impact on our health. During today's discussion, you will learn how restricting your feeding to specific periods within each 24-hours cycle, or perhaps even exploring longer patterns of fasting and eating cycles, can impact everything from the health of your liver to your gut to your brain, and how all of that impacts things like mood and your ability to perform cognitive work.

Indeed, today's discussion goes deep into all aspects of intermittent fasting, aka time-restricted feeding. We talk about the basic science as well as the recent clinical trials that have explored time-restricted feeding in a diverse range of people, including men, women, children, people with diabetes, people who are otherwise healthy, and much, much more. I'm quite aware that intermittent fasting is a topic of much debate these days. We go deep into that debate, and by the end of today's discussion, you can be certain that you will have learned all the latest and all the details, all made very clear to you thanks to the incredible expertise, discovery and clear communication of Dr. Panda.

As some of you may already know, Dr. Panda has authored several important books on the topic of intermittent fasting and how it can benefit various aspects of health. Those books include "The Circadian Code" and a more recent book, "The Circadian Diabetes Code," both of which we've provided links to in the show note captions. In addition, if any of you are interested in learning more about Dr. Panda's work, including seeing his publications and reading those publications, or supporting his laboratory, you can do that by going to his laboratory website, which we have also linked in the show note captions.

Before we begin, I'd like to emphasize that this podcast is separate from my teaching and research roles at Stanford. It is, however, part of my desire and effort to bring zero-cost-to-consumer information about science and science-related tools to the general public. In keeping with that theme, I'd like to thank the sponsors of today's podcast.

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And now for my discussion with Dr. Satchin Panda. Satchin, Dr. Panda, so good to see you again.

Satchin Panda: Yeah, great to see you.

Andrew Huberman: We are colleagues still, but we used to be right across the street from one another.

Satchin Panda: Yeah, I remember those days.

Andrew Huberman: So I'm delighted that you're here. I think we're going to talk about a number of things, mainly intermittent fasting, time-restricted feeding and health, but also the many other things that you're doing. Just before we started recording, we were discussing your recent paper in Nature that involved recordings from postmortem human retina. So maybe if there's time at the end we can get back to that your lab has shown that it can essentially maintain or resurrect neurons from dead people in order to potentially and eventually provide transplants to rescue vision in the blind. So that's extremely exciting, but, of course, not the main focus of today's discussion. So we'll have to split it up.

The first question I have is, how am I supposed to define fasting and time-restricted feeding? Meaning when I go to sleep every night, I'm not eating. So in some sense, everybody is doing time-restricted feeding to some degree or another. At what point can we start thinking about a pattern of eating as time-restricted feeding, so-called intermittent fasting? Does it have to do with how regular one is about the start and stop times? How do you think about defining intermittent fasting? Time-restricted feeding, and maybe just to simplify the conversation, is one term more correct than the other in terms of describing this incredible pattern of feeding?

Satchin Panda: Well, you know that intermittent fasting covers many types of fasting. Actually, it started a long time ago, and it's embedded into the history of caloric restriction. Almost 100 years ago, people showed that if you reduce calorie intake in a rat, then that rat can live for a long time. And in those experiments, the calories were reduced every single day. And that led to the idea that if we cut down our calories by 20%, say, then we can potentially live longer by doing two things. One is preventing age-related disease. Or even if we fall sick, maybe we can accelerate, cure and keep the repair mechanism going so that we can live longer.

But it was very difficult to count calories every day and reduce, maintain that. I must say that it's not that calorie restriction is impossible or we are not doing it. In fact, a lot of us, we do count calories in our subconscious mind. Means every time we take out a soda bottle or something, I'm looking at it. Okay, 160 kilocalories, 30 kilocalories. Zero kilocalories. We are doing that. So the point is, we are doing, subconsciously, some kind of calorie counting. But reducing calories by 20, 30% every single day is not possible for many people. So then the idea came in mouse and rat experiments whether they can eat every other day. And in fact, this every other day feeding also led to very similar, almost equivalent health improvement as continuous calorie restriction.

So then the idea was, well, every other day is a little bit hard for humans, but just imagine, I would just get to eat only one day and then another day. Then the idea came, well, for humans, can they eat less for one or two days in the week. So that led to this five-two diet where people can eat for five days and then two days, they have to reduce calories. So, also, intermittently, people are fasting. Then, as you know, Valter Longo also came up with this idea that periodic fasting, maybe four or five days in every month or two months, three months, you can fast or reduce calories, and he also found many benefits of calorie restriction.

Andrew Huberman: Were those studies on humans?

Satchin Panda: Many of the studies started in mice. But alternate day fasting, five-two, and Valter's periodic fasting, all of them have now been done in humans. Not for longevity, of course, because we cannot do those for a long time, but for weight maintenance, for reducing some signs of aging or reversing. Those things have been done. So all of them have been done in humans, mostly healthy humans, and in some cases, people with prediabetes or some aspects of metabolic disease.

So that led to the idea that all these forms of fasting in which the total calorie intake on any given day is reduced for one or more days in a week or month, that umbrella term became intermittent fasting. So if you look up the scientific literature, most intermittent fasting involves intentionally reducing calories for at least one or two days in a week or few days in a month. So when we publish time-restricted feeding, the initial mouse experiments, and even now, most of the mouse experiments, we want to test what is the impact of time restriction versus calorie restriction.

So in these experiments, we don't reduce calories on any day of a mouse's life. So the mice eat the same number of calories as the ad libitum-fed mice, but still they see health benefit. So that's why we call it time-restricted feeding. But since it involves living without food for several hours for some people, which can be very difficult, the initial experiments were done. They were done for eight hours of feeding and 16 hours of fasting. That kind of became popular. And so that's why people use the same term as intermittent fasting. And now, if you say intermittent fasting in popular literature or popular media, then people usually refer to time-restricted eating.

So now, coming back to how do you define time-restricted feeding? So the way we have been trying to define it experimentally and also in literature is trying to confine all your energy intake from solid and liquid food combined within a consistent window of eight to 12 hours, because that's something that's doable. Of course, people have done time-restricted feeding for four hours, six hours, and some people even try to eat everything within two hours one meal a day. But the point is, those are not feasible to maintain for a very long time for a lot of people.

Andrew Huberman: One question about the six-hour versus eight-hour versus 12-hour feeding window. Is it important that the feeding window begin and end at the same time more or less? And if so, how much flexibility is there? So, for instance, I'm somebody that I am not terribly hungry in the morning. I like to drink water, usually some caffeine and electrolytes in the period before my first meal. And my first meal always lands sometime between 11 a.m. and 12 noon. There are exceptions. Occasionally I'll have a breakfast, a proper breakfast, as it's called. I guess it would be improper if you're intermittent fasting for me. But typically 11 a.m. or noon is when I first eat. And my last bite of food is typically around 8:30 and 9 p.m. That's what works for me. Is that consistency affording me any benefit? And let's just leave aside total caloric number, macronutrients, plant-based, meat, etc. But is there any benefit to shortening that feeding window that we are aware of or extending that feeding window or being even more rigid about the start and end of that feeding window?

Satchin Panda: Yeah, so the start of the feeding window, that's interesting, because the concept of time-restricted feeding, when I describe animal studies, it's feeding, for humans, it's eating. So the concept actually came from the science of circadian rhythm. So that means our body has an internal timetable that's present in every cell, in every organ, that preprograms many molecular aspects of the cells that leads to physiology and all that stuff. So that essentially there is a predetermined timetable for every cell, every organ to do certain things at certain times. And the circadian clocks, as you and I know, are more sensitive to light. Light is the most dominant time giver.

So, for example, when daylight saving time changes, or when we travel from one time zone to another time zone, we feel kind of crappy because our daily activities are out of sync with our internal clock. So that was known for a very long time. But then around the year 2000, 2002, there was a famous experiment by Ueli Schibler from Switzerland. What he did, he just fed the mice at the wrong time. Mice are nocturnal, they're night feeders, and when he fed the mice during daytime, the liver clock, instead of following its own routine, the liver clock actually started following food. So that means by changing our feeding time, we can tune our liver clock.

And subsequently the same experiment has been repeated many times. And even we repeated that in 2009 and we figured out, yes, actually outside this brain center called suprachiasmatic nucleus, or SCN, which is considered the master circadian clock, almost the rest of the brain even follows when we eat. And that came out from Pierre Chambon's lab in Europe, where they systematically looked at even places that are very close to the SCN, for those who know, dorsomedial hypothalamus, paraventricular nucleus, all of this within couple of, 4 or 5 millimeters of the SCN. But they were following food cues.

Andrew Huberman: Amazing.

Satchin Panda: So then, now if we think about it, for example, when daylight saving time changes, just one-hour change or one-hour change in alignment between our internal time and external time leads to kind of feeling groggy and feeling out of peak performance for one or two days. So the rule of thumb is when the time giver changes by one hour, then our internal clock takes at least a day to catch up. So that means if you're flying from LA to New York, you're moving through three time zones, then on an average it will take three days to catch up with the New York time. For some people it can be even slower, and for some people it can be two days. But the bottom line is, yes, there is a desynchrony.

So then what does it mean for the body? So one of the functions of the clock is to anticipate when you are going to wake up, for example. So the blood pressure slightly goes up, our heart rate goes up, our breathing goes up. Similarly for food, almost every organ that is involved in feeding or eating, digestion, all of them have clocks. So even from saliva production, that is the first phase of digestion to secretion of all the digestive juice in the stomach and then absorption of nutrients, then liver metabolism.

Everything... the whole village expects when you're supposed to eat, and they're getting ready for you to eat the first meal after fasting for a long time. So that's why it's breaking the fast or breakfast. And when that time changes, when you change it by two or three hours from one day to another, then sometimes they're like, oh, food didn't come, maybe will come at the wrong time, we were at the wrong time. And then they will track the new eating times. So suppose one day you have been eating every day at 8 a.m. I eat at 8 a.m.

Andrew Huberman: Is that when you start your feeding window? When does your feeding window shut?

Satchin Panda: Six p.m. So I eat for around 10 hours. Okay, yeah. And then one day, if I switch to 10 a.m., then what happens is a clock is thinking, well, the food didn't arrive at eight, but it arrived at 10. Maybe tomorrow the food will arrive somewhere between 8 and 10. So we'll be ready around nine. Next day. If I come back and eat at 8:00 then I may eat, but my clock is not ready to digest that food. So that's why this idea is, you have to be consistent to take advantage of this anticipatory activity of our clock in different systems to get the best out of it.

Andrew Huberman: Is there evidence that those anticipatory systems, as they relate to digestion, help us better assimilate our food? I would imagine so. I mean, if you have the gastric juices that are going to help digest the proteins, fats and carbohydrates and are already deployed at the time when you eat, I could imagine that food will be better utilized than if you don't. So in other words, what is the advantage of having these anticipatory signals in terms of potential health benefits?

Satchin Panda: The anticipatory signal is really important even from waking up. The reason why many people feel not ready completely when they wake up to an alarm clock is because the alarm clock wakes you up, but your body is not prepared. So that sleepiness after waking up to an alarm clock is due to that our body is not prepared for that. And then the best example is when the daylight saving time changes, particularly when we have to wake up one hour early. What happens? People who have an underlying heart condition when they are waking up, when the body is not ready or heart is not ready, and all of a sudden the heart has to start pumping a little bit harder. Then there is a chance of heart attack. And in fact, people have looked at hospital records and they find that on those days there is a sharp rise in heart attacks.

Andrew Huberman: And car accidents.

Satchin Panda: And car accidents too, because your brain is not coordinated, so you cannot make those fine decisions. So that's a great example of anticipatory activity. But coming back to digestion, one thing is, and this is something that many people might have experienced, there are many rhythms in our digestive system, and one of the rhythms is that our intestine has this peristaltic function. So it kind of contracts and expands and that moves. Food doesn't move due to gravity, so it goes back and forth. And that peristaltic action actually slows down at night, a few hours after our last meal. That's why when people eat late at night, for example, then that food doesn't get digested because there is not enough digestive juice first thing. And second, even if it gets digested in the stomach, it doesn't move properly. So then the next morning, people get up and think, of course, people consume some alcohol very often, and then they think that this is a hangover. But those who don't consume alcohol, then they have the food hangover because it doesn't digest. So that's one extreme example where food at the wrong time can, healthy food at the wrong time can be crap or junk.

Andrew Huberman: Yeah, I've experienced that where if I've worked late or I couldn't eat dinner or something, and then I get home, I always debate whether or not to try and sleep. But if I'm too hungry, oftentimes it's challenging. And so, for me, sometimes consuming something that at least seems easily digestible, like yogurt or something in a liquid form, is better for me than if I eat a meal. I've made the mistake of going to the refrigerator, being super hungry and eating a bunch of food at 10 or 11 p.m. and then falling asleep. And indeed, the sleep, if I'm tired enough, can be quite deep, but the next morning, I feel just completely physically and cognitively weighed down. So I think what you just described makes a lot of sense.

So if someone were to select a feeding window, regardless of whether or not it falls into classic intermittent fasting, time-restricted feeding, sounds like eating your first bite of food and eating your last bite of food at more or less the same time each day has benefits. I have this question, you mentioned feeding versus eating, and I think it's actually not just a grammatical semantic issue, and here's why. We tend to think about when you take your first bite of food and then when you take your last bite of food. But of course, foods digest at different rates. More fat in there is going to digest, make carbohydrates, digest slower, etc. I mean, there's all these adjustments to the glycemic index and so forth with foods in combination.

Is it better to think about not eating, but your fed state and blood sugar? So, for instance, I often get asked on social media, does blank break a fast? I like to think about it scientifically, like, okay, does plain water break a fast? No. Does air break a fast? No. Does one grain of sugar, of sucrose, break a fast? Well, probably not, but does one teaspoon of sugar break a fast? Well, you could say yes, but transiently, when we're talking about breaking a fast, are we talking about a rise in blood glucose, or are there molecular signals downstream of a rise in blood glucose that cannot be reversed?

In other words, if I'm going to eat my first meal every day at noon, and I'm going to eat my last bite of food at 8 p.m., and at 9 a.m., for whatever reason, I have coffee with one teaspoon of sugar in it. I suppose in the strictest sense, I've broken my fast. But maybe if I went for a hard run that morning, maybe by 9:30 a.m. I'm back in a "fasted state." So what is the fasted state really? Because when I'm eating at 8 p.m., just to give another example, I start fasting at 8:01, perhaps, but my blood glucose is elevated, so I'm not really fasted. I'm fed. It's just that I'm not "eating," the verb, right?

Okay, again, I don't want to get overly detailed just for sake of getting detailed, but I think a lot of the confusion out there about what breaks a fast is related specifically to this issue, which is if I eat a whole pizza after sitting around all day, it's very different than if I eat a whole pizza after having run a 26-miles marathon that day. Very different, metabolically speaking. So how should people think about fasted versus fed? Can we be mildly fasted versus severely fasted? Can we be fed-ish versus very fed? Anyway, I'll stop asking questions now because they all relate to the same theme.

Satchin Panda: Yeah, no, these are very interesting questions. And unfortunately, as you might have seen in life, the most obvious questions are often unanswered because it's so hard to do these damn experiments. Because if you really want to address this in humans, you have to bring humans, put them in isolation, just like you said. I can now imagine planning five or six different experiments. Each experiment should involve eight or 10 volunteers, each gender, sex, and then do it. So it's difficult.

So now let's go back to see how do we... let's dissect it in terms of, say, indirect calorimetry. So, for example, indirect calorimetry is based on this principle that whatever oxygen we breathe in and carbon dioxide we breathe out, if we can measure these two, then we can figure out whether our body, in total, we are not saying whether it's the liver, gut, or fat or muscle in total, whether it's consuming glucose or fat as energy source. The idea is when we are without food for several hours, then ideally our body will tap into glycogen first and then do a little bit of fat. And then when the body is mostly running on fat, then that ratio of CO2 to oxygen will come to 0.7.

But what is interesting is we can do these experiments in mice. So we can go to mice and ask, okay, so what happens in mice? So in mice, mice are a little bit very different, because mice are not simply little people. The metabolism is different. They store relatively less glycogen than humans do in terms of total metabolism. So overnight, within 12 to 14 hours, the RER, respiratory exchange ratio, or this ratio will go from one when they're consuming mostly glucose or carbohydrate as energy source, it will slow down, slowly go to 0.7, 0.75. So after 12 to 14 hours, they're kind of mostly running on fat. Now, as we give them food, within 10 or 15 minutes, they're not actually consuming a couple of grams of food. They might have consumed, say, 100 or 200 milligrams of that chow, which is less than, say, 5% of that food. And then the RER will immediately begin to rise as if that small amount of food stopped that fat-burning process and cranked up the carbohydrate burning process.

Andrew Huberman: When you say fat-burning process, you mean body fat stores being burned, right? Not dietary fat, correct?

Satchin Panda: Yeah. So it's all body fat. That's why I said we don't know where that fat is being burned because we are just measuring how much mice are breathing in and out. So, for example, it can be from the skin. So subcutaneous fat or belly fat--

Andrew Huberman: --But not dietary fat.

Satchin Panda: No. By that time, the dietary fat is already absorbed and digested. And hopefully it's sitting in the liver or adipose tissue somewhere. But it's the fat that's body fat. Yes, thank you.

Andrew Huberman: Yeah. The reason I ask is that nowadays I think more than half of the battles about nutrition that I see online relate to this issue where, I won't name names, but someone will come along and say, low-carbohydrate diet allows you to burn more fat. And the more nuanced people out there will say, well, that's true, but you're also talking about dietary fat. The word "fat" can confuse people. I realize you're not doing that. You are certainly not one of the people guilty of doing this, but indeed, you eat more fat, you'll burn more fat, but that doesn't mean you'll burn more body fat. In fact, I think the data say that under conditions of caloric restriction, you'll actually burn less. I hope I don't, I'll probably get pitchforks sent through the mail toward me on that one, but I think that's true. Whereas people who consume carbohydrates can still burn body fat, even though the majority of the fuel they're burning is from carbohydrates.

Satchin Panda: So here in this case, for example, for mice, we know that as soon as they start eating, the RER goes up. Coming back to your question, what would be ideal for us to do? The experiment would be, okay, so we'll go back to that, and then give the mouse maybe 100 milligrams of food and the mouse runs around in the cage, and then we'll continue to measure to see how long it takes for the mouse to come back. So that's one aspect. So now let's see, let's stay on this and then I'll come back and talk about noncaloric food and whether that is considered healthy.

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Satchin Panda: So there is a famous experiment that was published last year by Joe Takahashi's lab, and it came out in Science, and that relates to caloric restriction. And we kind of started with this idea. We started discussing that the rat experiments were done with caloric restriction, and researchers reduced calorie consumption by 20% or 30% and gave that food to the rats, and then subsequently mice, and they all lived longer. What is interesting is, in all those experiments, the researchers came and gave this bolus of food at one time. Whereas the ad libitum-fed mice or rats, they had access to food all the time. So they were eating all the time, and then these rats were given 20% less. And what happens is, these mice or rats, they're not going to take that less food, which is less for now, and just eat a little bit of lunch, and then snack after three hours. They gobble up all that food within two to three hours, maximum four hours, the food is gone.

Andrew Huberman: So they're sort of on the OMAD diet, the one-meal-a-day diet.

Satchin Panda: Yeah, they're almost like in a one meal a day, three to four hours, food is gone. Or you can say they're on four hours eating or feeding and 20 hours fasting. So then the question became, well, the benefit of caloric restriction, as we know, is it due to reduced calories or time-restricted feeding or timing? There is a timing component to it, that they are eating all of that within three to four hours, and then there is a long fasting. And this is a difficult question to answer, because now you have to ask these poor grad students or technicians to come and split that food into eight or 10 or 15 different small portions, and then give them to mice every two hours.

So, Joe Takahashi, who actually published the first paper in 2017 showing that most caloric restriction studies, I mean, he used the protocol that was used by the caloric restriction field, it actually creates a condition of time restriction. So he showed that, and then he went back and worked with engineers to come up with a smart case where he could actually tell, he could program how much food is given to mice at what time of the day or night, completely programmed. So then he took this, for example, suppose the ad libitum-fed mice eat five grams of chow in a day, and if you want to reduce calories by 20%, then the CR mouse should get four grams of food. And he divided this into nine or 10 meals and then gave them every 90 minutes.

So in this case, they are eating small meals throughout the day and night. So there is no fasting. So you can say that, well, this mouse actually is not getting into fasting because every few hours is getting some food. And then he measured how long the mouse is going to live. And he used, this is a very standard protocol. People count how many mice have died on which day and then examine them to see whether they died because there was an accident or actually there was a natural cause. And then they calculate at the end, what is the half life. So 50% survival, because that's on an average, that's a good indicator, because if there is an outlier that will live for a long time, then that can skew the data. So what was interesting was the ad libitum-fed mice. Of course, they lived a certain number of days. And then these calorie-restricted mice that never got into super fasting, but kind of eating, snacking throughout day and night, that also lived 10% extra, 10% longer. So that means caloric restriction extended lifespan by 10%.

Andrew Huberman: I wonder about this, because recently there were a bunch of news headlines about intermittent fasting, and frankly, I was frustrated. If you looked at one major news outlet, they would say time-restricted feeding affords no additional benefit beyond caloric restriction — for weight loss. Then another popular press venue, let's call it that, same study, described as time-restricted feeding — doesn't work.

Satchin Panda: Yeah, right.

Andrew Huberman: And then another one, maybe someplace even more extreme, time-restricted feeding, only beneficial because of caloric restriction or something like that. So what you've essentially got are three different interpretations of the same data, all of which are, well, two of which are true, one of which is false, in my opinion. But what I think people take away from that is, oh, time-restricted feeding isn't valuable, which is not the case. I think for many people, it's a convenient way to eat because at least for people like me, it's simpler to designate between portions of my day when I'm eating and portions of my day when I'm not eating, as opposed to portion control. For other people, portion control can work, but all of that is related to either maintenance or loss of weight. None of it deals with the potential health benefits independent of weight loss.

And so I think that if we can segment those out, obviously in humans, it's hard to know if a given treatment or experiment is extending life, because you don't really know how long people would live anyway, whereas with mice, you have some sense of when the mortality was likely to occur. So what can we say about time-restricted feeding and longevity in terms of biomarkers or in terms of any other indication that people who start and stop their feeding window at a consistent time, somewhere between eight and 12 hours per 24-hours cycle, are tilting the scales towards living longer as opposed to living shorter?

Satchin Panda: This example of this news article that you mentioned is really interesting because that relates to Joe Takahashi's study. Because I described that if you split calories and eat throughout the day, throughout day and night, then the mice lived 10% extra. But if you now give mice the same calorie restricted diet and fit them during daytime, whether within 12 hours or 2 hours, then the mice live 10% extra beyond that. Yeah.

Andrew Huberman: So 20%.

Satchin Panda: Twenty percent.

Andrew Huberman: Okay, so let me make sure I understand. So that I make sure I understand, if you take a certain number of calories and you distribute them throughout the 24-hours cycle, it's caloric restriction. The mice will live 10% longer if you, however, restrict that to the active cycle — so for humans, the daytime — then they live 20% longer.

Satchin Panda: Twenty percent longer.

Andrew Huberman: So it's not just total caloric intake, meaning it's not just important to be submaintenance in calories for sake of longevity. It also is important as to when in the 24-hours cycle you eat those calories. Do I have that right?

Satchin Panda: So now, still the story is not over because these mice were fed during daytime when they're not supposed to eat.

Andrew Huberman: That's right. So for us, it would be the equivalent of being on the night shift and only eating at night. But a subcaloric, submaintenance calorie diet, I guess, is the right way to say it.

Satchin Panda: But when he fed mice during nighttime, when they're supposed to eat and they're getting the same number of calories within 12 hours or two hours, then the mice live 35% longer than the control.

Andrew Huberman: Thirty-five percent longer. So scale to human lifespan, which we don't know, but 35% longer would mean that... And again, no one knows but humans. Now, what is the average mortality in the United States? Somewhere around 80?

Satchin Panda: Yeah, so it's around 80. It used to be 80. Now it's reduced a little bit because of COVID, but let's take 80.

Andrew Huberman: Okay, so people are then, now, living somewhere between 25 and 35 years longer. I'm putting some error bars on.

Satchin Panda: Yeah, amazing. So that was really profound. But now you pointed out biomarkers and other stuff. So now if you look at any given time within that experiment, and actually Joe went back and had a separate cohort of mice, very similar. And so that he could take tissue samples, and of course, in this case, you have to sacrifice the mouse. And he did a lot of molecular analysis with known markers, for example, hemoglobin, hemoglobin, A1C, equivalent, or glucose control, cholesterol, all this stuff, he could not find anything that predicted the benefit of caloric restriction. So that means in this experiment, whatever we know so far, the predictor of longevity, none of them could predict whether this CR-only mouse, which ate throughout day and night, that mouse is going to live less than the night-fed mouse that was going to live 25% extra.

Andrew Huberman: Does that mean that there are biomarkers related to longevity that we just haven't discovered yet?

Satchin Panda: Yeah, so that's it exactly. So that means whatever we know so far about biomarkers, those he could not use to predict, maybe there was a lot of noise, maybe he had to use more mice to get that, because biomarkers are not going to predict in every instance that there is some error. What is also very interesting is if you look at the body weight and body composition of all these mice, there is no difference in body weight and body composition.

Andrew Huberman: Across all these different groups.

Satchin Panda: Across all these groups.

Andrew Huberman: So it doesn't matter when they ate, provided they were sub... maintenance calorie intake. So less, fewer calories than is required to maintain their weight, didn't matter what pattern of eating they were, the same weight. So that in many ways seems to mimic the human studies where they say, look, it doesn't really matter whether or not you use caloric restriction, or you start your feeding window in the morning, or start your feeding window in the evening, or you portion control for sake of weight loss, because we're taking a snapshot of that.

Satchin Panda: And then another thing with the human study that we are referring to here, in that human study, people were actually already eating within a 10-hour window habitually when they selected these people to have them enroll in the study. So they were already eating for 10 hours and fasting for 14 hours. All participants had to reduce their calorie intake and they reduced by almost 25%. The CR group continued with a 10-hour eating window, and the CR-plus, time-restricted group had to eat the same number of calories within eight hours.

Andrew Huberman: So it's just a two-hour difference.

Satchin Panda: It's just a two-hours difference.

Andrew Huberman: Okay. So that people, I just want to make sure people can understand, so, in this human study, which is the one that I felt, that the popular press venues, all except one venue, got either semi wrong or badly wrong in terms of their conclusion. That was my interpretation anyway, was that either people came into the study eating basically in a 10-hour feeding window, which goes back to my first question, which is that most people are not eating in the middle of the night, or if they're on shift work and they are, then they're sleeping during the day anyway. So they're eating in a 10-to-12-hour feeding window anyway.

So you're saying they either did caloric restriction, portion control within a 10-hour window, or another group within the study ate submaintenance calories. So caloric restriction, CR, as we're calling it, the acronym CR, but restricted that to an eight-hour feeding window, and they didn't see any difference in terms of weight loss. Yeah, but it's not all that surprising, right? I mean, if it's just a two-hour difference.

Satchin Panda: Yeah, exactly. So we have done that experiment in mice and we don't see difference in not only weight loss, many other markers. And I was telling you about this Joe Takahashi's paper where I told you that he allowed these mice to eat within a two-hours or 12-hours subcaloric diet.

Andrew Huberman: Two or 12. Two or 12, yeah, that's dramatic.

Satchin Panda: But still, he did not see change in longevity even within those two. So that means when you do caloric restriction and then, at least for a mouse, and you are within 12-hours window, that is giving the mice the best benefit, the optimum benefit, and two, three or five or 12 for a mouse doesn't matter, at least for longevity.

Andrew Huberman: Can we conclude for humans that whether or not a feeding window is four hours, six hours, eight hours or 12 doesn't matter, provided the calories are similar or same?

Satchin Panda: Well, I won't go to that extent because we don't know many of these, particularly we don't know how this sort of eating window will affect both sexes, because we always think many of these mouse experiments, even that I told you about, are done only in male mice.

Andrew Huberman: But that should be changing, right? Because the NIH, I know this because I'm in the study section, which is just a bunch of people who review grants, is that every grant now has to include sex as a biological variable. It's hard to get away with. Well, rather, I should say it the way it should be stated, which is that people are required and should want to look at these phenomena in male and female mice. Yes, especially if there are differences.

Satchin Panda: So in this case, there was also another paper in time-restricted feeding that also came out, a big paper showing that the thermogenesis was accounting for loss in fat mass in time-restricted-fed mice. That was also done only in male mice. So we are paying attention to it. So we are now doing all of our studies in males and females, and we do see big differences between males and females. Coming back to humans, what typically happens is when you're trying to do four hours or six hours of time-restricted eating, people will inadvertently reduce their calorie intake just because of gut volume.

Andrew Huberman: I tried one meal per day, and I felt like I was eating so much at that one sitting that it led to a lot of gastric distress. And I get tired after the meal. And part of the reason I like to do time-restricted feeding is I have more energy. And certainly in the fasted state, I feel more energized, especially if I'm ingesting a little caffeine or something like that.

Satchin Panda: So people will reduce energy intake, and then some people who are more active, they can actually, unconsciously, they may be spending more energy in their physical activity and basal metabolic rate, all of this combined, than how much they're eating. And that can have a very adverse effect in the long term, because we know that this energy deficit, and in fact, there is a scientific term for that, it's called REDS, relative energy deficit in sports.

Andrew Huberman: Relative energy deficit in sports. Okay.

Satchin Panda: Yeah, it's because nearly 40% of athletes, not the NFL guys, but there are a lot of people who do track and field, and nearly 40% of athletes actually experience this REDS without knowing.

Andrew Huberman: Can male and female athletes both experience REDS? So it's REDS, R-E-D-S, relative energy deficit in sports. Interesting. This is the first I've heard of this acronym. We have a new acronym, folks. This is good to add to a list of other acronyms so males and females can experience it. So in females, I've heard that REDS can lead to amenorrhea. So loss of the menstrual cycle.

Satchin Panda: Yeah. So that's so common, that's so prevalent that in fact many women, many female athletes, take it for granted that, yes, if they are more active, then they will lose their menstrual cycle, which may be common, but it's not normal or optimum for health.

Andrew Huberman: Even if they don't want to get pregnant. Yeah, we had an expert on female hormones come on and say the very same thing, that regular cycling--

--is very important--

--of ovulatory menstrual cycle, is important to try and maintain.

Satchin Panda: So that's one. But then what is really concerning is it does affect bone health. And in this state, people actually, over a long period of time, they lose bone mass, and their bone also becomes more prone to injury, microfracture and fractures. So again, it's a risk, meaning if some people are trying to eat within a very short time and they're physically active, that happens. And it also has an impact on menstruation. Why, the reason why these women are losing their menstrual cycle is the HPG axis is disrupted. Hypothalamus-pituitary-gonadal axis. And it starts, it may start even upstream at the hypothalamus or pituitary. So that means the HPA axis, hypothalamus, pituitary and adrenal axis may also get disrupted. One of the symptoms of REDS is also depression, anxiety, bipolar-like symptoms. And we know that many athletes experience that.

We think that, well, this may be just peer pressure, that of always trying to compete. And we know that, unfortunately, there are a few athletes who just can't cope with it and there are many who've attempted suicide or suicide. So this is a serious issue. And there's also another new topic in the lab to come up with a mouse model of REDS and then study it. But this is one risk why we should not reduce our eating interval to one meal or a very short time, because it can have adverse side effects that we don't know now. Maybe in the future we'll figure out when we systematically study them.

There are studies that are published showing four-hours and six-hours time-restricted eating has benefits on weight loss, but those are on healthy individuals, and they were in the studies. So the study team we're already monitoring, they made sure that there was no sudden weight loss or weight loss below some safety level. So those are very different from regular people who may be even normal weight or even within the healthy range. If they do, then they can potentially, so that's why we think eight to 10 hours may be the ideal spot to begin with. And once you are physically active and you are also spending a lot of energy in physical activity or sports, you can even go up to 12 hours, because in mice we have done that experiment up to 12 hours, they do get a lot of benefits. Not all, but--

Andrew Huberman: So this is 12 hours of...?

Satchin Panda: Twelve hours of feeding, 12 hours of fasting. In humans, again, nobody has systematically done 12 hours. But there was one study in Europe from Tinhai Collette's lab and Tinhai and I, we collaborate. So they used our My Circadian Clock app. This is a research app we developed, mostly used in time-restricted eating studies. And he had nearly, I think he started with 200 Swiss participants. But then at the end, he selected and took a very small number of people who are very meticulous about recording all their food and divided them into usual feeding, whatever they wanted to eat whenever they wanted to eat. And they were given the advice of Swiss nutrition, advice that's given to improve health and reduce blood glucose, almost like the diabetes prevention program in the U.S.

And then the other group was given advice to eat within 12 hours. This was very early on in time-restricted eating, and we thought that the mice were getting some benefit. Let's try to see whether 12 hours has any benefit. The bottom line is, at the end of three months and six months, what he reported is both groups lost the same amount of body weight. And then there was not too much significant difference between groups, but both groups actually improved their health. So the bottom line is the Swiss nutritional advice that he was giving, which is the standard of care there, it achieved the same amount of weight loss as just giving people this advice that they eat within 12 hours. So one way to look at the result is like this, and then he went to more extent and actually looked at every single meal these people consumed. So there are close to, I think, close to 60 or 70,000 meal records and pictures he went through and then classified them to say whether these are good-quality food.

So they call it the Nova Classification — 1,2,3,4, one is the food that you can almost eat raw; fruits, vegetables, yogurt and dairy products that you can almost eat without any preparation. And then second, Nova Two is kind of home-cooked food that most people will prepare in a few minutes, and then Three, and Four is the food that you can never prepare at home. So, for example, biscuits or cookies that we usually purchase and a few other things. And usually the NOVA P4 are unhealthy, ultraprocessed foods, so, which we should not be eating.

So the advice is to reduce NOVA P4. And what he found was people who got all this advice to improve their nutrition quality, they actually improved their nutrition quality. They reduced their Nova 4 food, and people who were in time-restricted eating, they ate within 12 hours. They did not change their nutrition quality. But what is interesting is they both got the same modest weight loss. So that begs the question that maybe Tinhai will do this experiment again, to combine nutrition advice with time restriction and maybe reduce the time to 10 hours, and that might help. So, 12 hours is something that I say anyone from a 5-year-old to 100-year-old can do. And if you are trying to maintain weight, that might be a good way. And combine that with exercise, it'll be great.

Andrew Huberman: And people can more easily avoid REDS in that way. Women, and for nonathletes or recreational exercises, it sounds like women, if they distribute their calories across 12 hours, are less likely to lose their menstrual cycle.

Satchin Panda: Yeah. So again, this is something that we have to look at carefully. They have to be, because we do have the My Circadian Clock app that many people download and self-monitor and they share the data for researchers.

Andrew Huberman: We will provide a link to that. By the way, it's a great tool.

Satchin Panda: But once in a while we do get this input from some women saying, oh, I started doing your time-restricted eating and I am seeing all these problems. And then I ask them, okay, so what else are you doing? They typically improve their nutrition quality. So they're eating only salad and a few, and they're trying to increase their fiber intake. And it's really hard to eat so much uncooked food because cooking helps to absorb more nutrients and then at the same time they're running 5 miles every day. And of course all of this combined can lead to REDS-like symptoms. So that's why 12, I think, is a good point if you're combining physical exercise and better nutrition quality. Because in mice also, we have seen that if mice are eating healthy food and they're eating within 10 to 12 hours, then they also live longer than mice that are eating healthy food but distributing those calories over a long period of time. And this is Rafael de Cabo's finding from NIH. He has systematically done this study with two different types of diet and in mice, and he finds the same thing, that even mice that are eating within 12 hours, they do live longer than mice that eat randomly, even healthy food.

Andrew Huberman: I recall a recent study, I think it was either published in Cell Reports or Cell Reports Medicine, forgive me for not remembering which, but both, of course, Cell Press journals, excellent journals, which explored time-restricted feeding in the context of low-carbohydrate or non-low-carbohydrate diet. So it was low carbohydrate versus low carbohydrate and time restricted. So these are all caloric matched between groups and then non-low-carbohydrate diets. So more standard. I think it was somewhere in the neighborhood of 60% of calories from complex carbohydrates. And as I recall, the greatest weight loss, remember, same calories across groups, folks, was achieved with low carbohydrate plus caloric restriction.

And I wondered why all the popular news venues didn't cover that study. But that's why I'm bringing it up now. I thought, this is really interesting, and I'm somebody who's cycled a low-carbohydrate diet before I find it hard to sleep after about three or four days of being on a low-starch diet, just personally. So I like to eat some starches, especially if exercising intensely or working intensely. That's just a little editorial there. But look, I know many people who do just feel better on a low-carbohydrate diet. But what do you think of those data? Because it speaks to the idea that, okay, it's not just the total number of calories. It's not just the quality of those calories, it's the timing of those calories. And maybe carbohydrate restriction in conjunction with time-restricted feeding might be the best path for people who are looking to lose weight.

Satchin Panda: No, I totally agree that when it comes to nutrition, quality, quantity and timing, all these three matter. Nearly 40% of people who maintain healthy body weight, because 60% are overweight or obese, 40% are maintaining healthy body weight. And out of those 40%, I would say nearly a majority of them are very aware about how much they're eating and what quality of food they're eating.

Andrew Huberman: So you're really an optimist. You're looking at the 40% of the glass that's empty, or should we say not full. That was a pun intended. But it's a very interesting way of looking at, rather than saying, why are 60% of Americans obese? Saying, why are 40% not obese? That's a very interesting way to look at it.

Satchin Panda: Yeah. I mean, subconsciously, we're always making that decision. I'm sure that you are not going and eating cheeseburgers every day because you want to improve.

Andrew Huberman: Yeah, exactly. I wouldn't feel good.

Satchin Panda: Yeah.

Andrew Huberman: I enjoy a cheeseburger now and again, but no, certainly not at this stage or any stage of my life. I actually think the pandemic had a lot to do with this. I think that people started to take a look at what they were doing to support or not support their health generally. I know people gained a lot of weight during the pandemic. Other people got really into fitness. I've seen some colleagues, you've always been in good shape, actually, it's the first time I've seen you in a while, and you seem to have aged backwards. So you are a poster for your own ideas and hypotheses about time-restricted feeding. But I noticed that during the pandemic, a number of people emerged from the pandemic in better shape, other people in much worse shape. It seemed like it was like a bimodal distribution there.

Satchin Panda: Yeah.

Andrew Huberman: So, yeah, I get the sense that starting and stopping eating at more or less the same time each day, even if caloric restriction is not the main focus, has additional benefits. Can we talk about some of those benefits as they relate to the other things that impact health? So, for instance, if you're starting and stopping eating at more or less the same times each day, are you sleeping better? Are you getting more predictable shifts in alertness and sleepiness? Like, can you predict when you'll feel good enough to exercise? Maybe we could talk about that, because you, of course, are well known for time-restricted feeding and the science around that, but also other things as well, not the least of which is circadian biology generally. So I always think of the main timekeepers for our system being feeding, light, activity and social connection. Did I miss anything? And temperature.

Satchin Panda: Yeah.

Andrew Huberman: So how do these combine with one another and using timing that we begin and stop feeding as a kind of anchor point? Can we explore that a little bit?

Satchin Panda: Yeah. So we got into this beginning and end, and then you asked whether calories, how many calories will break the fast? One thing that I want the listeners and viewers to bring back to this timing of when we are breaking the fast, because we equate health with weight, body weight. And that's when we are talking about nutrition, quality and quantity, because both of them have an impact. So now let's think about mental health. Because a lot of people do struggle with mental health. They have anxiety or depression, and also gut health, because there are a lot of people who also have acid reflux or heartburn.

And we know that acid reflux or heartburn can be exacerbated by caffeine intake on an empty stomach. Those who have acid reflux or heartburn, they're prone to that. Then having black coffee in the morning before any food can upset their stomach. So that's why in those cases, it's very clear that caffeine, for them, becomes the trigger, that something, the food is supposed to come and then the stomach is not seeing the food. So it's overreacting, producing excess acid. And that comes up to the esophagus, and that's what they're experiencing.

So if people have that kind of condition, then maybe they should consider, when they drink their first coffee, is breaking their overall fast or kind of putting their health at risk for acid reflux. The other thing is people who have anxiety, panic attacks, we know that caffeine can trigger you.

Andrew Huberman: Especially on an empty stomach.

Satchin Panda: Especially on an empty stomach. So for them, again, caffeine can be a trigger. So that's why I want to kind of differentiate that there is this mental health, and other aspects of health. And these are two clear examples where anxiety, panic attack related to brain health, or acid reflux related to our gut health. In those cases, when we consume that caffeine in the morning can affect--

Andrew Huberman: --Do you avoid caffeine in the morning?

Satchin Panda: Actually, here is the interesting history about caffeine, and this is something I did not know, and I was once invited to this history of nighttime activity. And maybe we can take a little bit of detour and talk about nighttime activity, because that fascinates me as a circadian biologist, because over the last 200,000 years, we assume that humans, Homo Sapiens, evolved 200,000 years ago. So, as a species, we have been living on this planet for 200,000 years, and only in the last, you can say, a couple of thousand or 5000 years when we came to control fire, or maybe you can even go back to 100,000 years. There is some debate.

So then the question is, well, when we controlled fire, and we lighted up the fire, and we could light up whenever we wanted, we can add fuel and we can stop the fire when we don't want it. That's the key ability in humans that differentiates them from all the other species. No other species, we can always say, yes, there are signs of this intelligent decision making. For example, we know many crows can make decisions. Many animals, they kind of figure out, strategize how to get food. But controlled use of fire is something very specific to humans, and when we started controlling fire, fire did not essentially extend the day, because fire created an evening that was very different from what people did during the day and what people used to do.

During the day, they worked a lot, meaning gathering food was almost everything that we did. And so in the evening, after, we brought food, mostly tubers or maybe lentils to cook, or once in a while, animals, so that we could barbecue. All of these things happened around a fire. And the fire was so expensive that it was mostly a communal fire. So if you go back to, for example, Masai and all these populations that have no access to electricity and are still living kind of that historical life, fire is a communal event.

And they sat around, they cooked food, and then what happened? They did not talk about work, they talked about culture, they sang, they danced, they strategized. That's how politics started, philosophy started, science started. All of these things that are very unique to human civilization started around fireside chat. In that way, if we think about it, we are still doing fireside chat. The only thing is we have the microwave and the television or social media.

Andrew Huberman: And now we chat with our thumbs, right?

Satchin Panda: So we are hooked to that evening activity because that's when we are completely free from the pressure of the work and we want to express ourselves. That's our independent time. So that's why most people find it very difficult to do time-restricting and stop eating at 6 o'clock because it's ingrained even in our DNA that we want to eat and socialize in the evening.

So now let's fast-forward and see what is the role of coffee in this. If you look at coffee confabs and particularly the café, where people can come and have a little bit of coffee and socialize, it also started as an evening activity. And this is in, now we can go back to Istanbul because that's one place where coffee cafés started in the mid-16th century. So we are talking about 1540 to 1570. And that's when, I'm sorry, I'm forgetting the name of the historian who actually invited me. Okay. His name is Cemal Kafadar, and I must be butchering the name, but I'll try.

Andrew Huberman: It's okay, we will provide the spelling, and the wonderful thing about social media is somebody will tell us on YouTube the proper pronunciation. So this is a great opportunity. If you know the proper pronunciation, please put it in the comments on YouTube.

Satchin Panda: Actually, I'm even checking right now in my EndNote library. It's not picking up that.

Andrew Huberman: That's right. We'll provide a link.

Satchin Panda: So what happened was, so coffee was introduced and people came and drank coffee and talked about politics at night, at night, at evening. And it actually started with the Sufi branch of Islam because they are the ones who consumed coffee in the evening. And this is the branch of Islam where they actually sing and dance, and all that happened in the evening. So singing, dancing by the Sufis, and then here in Istanbul, people started congregating and talking about politics.

But then around the same time in Turkey, there was a good sizable number of Muslims who have to do five prayers a day, a number of prayers at set time. The first prayer is very early in the morning. And then they figured out that if they wake up and immediately have coffee, then they can stay awake for the first prayer. And in that way, they felt pretty good, they woke up. So that's how it started as a morning drink, to stay awake and kind of get on with the day. But what happened was, I don't know whether you have ever tried Turkish coffee. It's very thick.

Andrew Huberman: Yeah. A few years ago, right before the pandemic, 2019, I traveled to Turkey. First of all, the food is amazing. The coffee is indeed very thick. And I have a pretty high caffeine tolerance from drinking so much coffee and yerba mate over the years, and still do. I really enjoy it. But, yeah, it's very intense. So what you're saying is that coffee intake started as a way to extend into the night. The ability to extend into the night at all was because of the ability to harness fire. And then coffee's stimulatory properties were leveraged toward morning, which is essentially like, the way I think about it.

We did an episode on caffeine, and someone else, Michael Pollan, not I, described it this way: that you're sort of taking a loan out on your energy bank account with coffee. You're suppressing the adenosine system. Adenosine makes you sleepy, but that adenosine system will kick in later. So it's a credit card of sorts with an interest rate, and the interest being an energetic lag that you're going to experience in the afternoon.

Satchin Panda: But what happened was with the strong coffee that gave heartburn and acid reflux to a lot of people, so then they started eating something with coffee, and that's how the culture of breakfast started in Turkey.

Andrew Huberman: So coffee actually led to the development of breakfast, not the other way around. That's very heartening. Again, no pun intended for the caffeine lovers among us, which I count myself one of those.

Satchin Panda: So essentially, the food before coffee became breakfast. So you kind of give something to your stomach, so it's busy digesting that, and then when the coffee comes in, it's not reacting to coffee and creating acid reflux.

Andrew Huberman: So it wasn't, this is fascinating, so it wasn't that breakfast is necessary on its own. It was essentially a buffer against the gastric distress caused by caffeine intake.

Satchin Panda: At least in that culture. In that context, we cannot say whether the same thing happened all over the world where coffee is not consumed, but still people eat something in the morning.

Andrew Huberman: You said you start your first meal of the day at around 8. What time do you wake up?

Satchin Panda: I wake up around 6. Five thirty to 6.

Andrew Huberman: What time do you have your first caffeine?

Satchin Panda: No, actually. So that's why I brought up this story, because I have coffee after my breakfast.

Andrew Huberman: Fantastic. I'm a big proponent of delaying caffeine intake for a few hours after waking for other reasons that my listeners have heard me talk about endlessly. So I won't bother with that now. But I think allowing... suffice to say that allowing some of the natural waking up signals to occur and using light to kind of clear away adenosine. To further extent, any activity is better than using a stimulant. But until a few hours later, this is fascinating because I've never thought about the link between extension into the night socialization, or socializing, rather feeding and caffeine.

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Satchin Panda: Now, actually, I'm kind of speaking of what many other researchers have found. This fireside chat, I'm forgetting again the name of the scientist. I think she's from the University of Washington, Seattle. She went to Africa and kind of recorded what people were saying. Of course, she could not understand what they were saying.

Andrew Huberman: Twitter and whether or not Tesla's stock is going up, of course. Just kidding, folks.

Satchin Panda: And then came back and tried to translate and then figured out that what they were saying during daytime and in the evening were very different.

Andrew Huberman: What are they talking about at night?

Satchin Panda: Exactly. So this is like they're talking about matchmaking and talking about politics and strategizing to gather food or even singing and dancing. So this is, if we think about it, how we manage sunset to our bedtime. What we do between sunset and bedtime affects most of our health.

Andrew Huberman: I'm going to think about that for a moment. I totally agree. And by the way, I'm a huge believer and I'm living in great hope for the idea that right now I do think that scientists understand a lot more about the different stages of sleep, slow-wave sleep, REM sleep, etc. than we do active waking states. Like we talk about being focused or being alert. But those aren't scientific terms, as we know. But I do believe, and I've noticed a distinct difference between the first eight hours of the day in terms of cognition. And we know that the catecholamines are at much higher levels, plus cortisol. So dopamine, cortisol, epinephrine, all of that is really at much higher levels than in the later evening. And so this evening time, certainly in the context of mental health, we know that morning and evening, we are basically different creatures. Yeah, completely.

Satchin Panda: So that's why I think in the evening, if you think about it again, this is again another set of research from my good friend Horacio--

Andrew Huberman:  --de la Iglesia?

Satchin Panda: Yeah.

Andrew Huberman: Oh yeah, I'm a big fan of Horacio's. He's a fellow Argentine, so occasionally we riff about things related to that. But he's a wonderful biologist. Are you guys kind of--

Satchin Panda: --I say he's very humble and keeps a low profile, but he does amazing research.

Andrew Huberman: Totally agree.

Satchin Panda: He does research that we want to know, but nobody is ready to do it because field research is very difficult to go to the wilderness or go to the places where there is no electricity and then record when these people are eating, sleeping, or in this case, activity, exposure to light, that's what Horacio has done. And he puts on this active watch, which is kind of a modern activity tracker, but it's a little bit more refined because it also collects light information.

Andrew Huberman: So no night owls versus morning people.

Satchin Panda: Exactly. So we'll get to that.

Andrew Huberman: None of this, I get attacked for many reasons. It just goes with the business I'm in, of being public facing these days. But every time I talk about viewing sunrise or low-angle sunlight, getting some sunlight early, someone says, well, I'm a night owl. And it's almost like a protest of trying to protect identity. It's become this ideological identity-related thing. I'm a night owl, I'm a morning person, and I'm not. But you're telling me that in these cultures where there isn't electricity but there is fire, people are going to sleep within all of them, within about 15 minutes of one another.

Satchin Panda: Yeah.

Andrew Huberman: So there is no such thing as a night owl or a morning person in the context of--.

Satchin Panda: --Actually, I asked him pointedly, and then he said, no, he has not seen, has tracked hundreds of people. And if we ask, there are many sleep researchers, at least the public-facing sleep physicians or experts, they will say, yeah, we can say one-third of people are night owls, one-third are morning, and then one-third are in between.

Andrew Huberman: But they call them, like, bears, wolves. And I'm not being disparaging of that idea. I think people really do feel as if they orient towards one pattern or another.

Satchin Panda: When I was an undergrad student, I never went to bed before midnight. And actually midnight was my going to bed time. Exactly, like 11:45, I'd try to get ready to hit the bed, and then by 12 I'm in bed and I used to get up at 6, 6:15. 

Andrew Huberman: That's a pretty short sleep.

Satchin Panda: With an alarm of course. But then in daytime I used to take 45 minutes to a one-hour nap  and that was regular even if, whenever I got time. Of course in college you don't have the whole day, unlike in high school you don't have the opportunity to nap, but in college you can.

Andrew Huberman: I might have been one of those kids with his hoodie on, napping on the desk. But they come around and they wake you up.

Satchin Panda: Yeah, but in this case I just come back to the dorm and after lunch usually I used to take a nap. So then in grad school, I remember I rarely went to bed before 2 a.m. And I could have clearly said that I'm a night owl. And actually I was a night owl. I was very comfortable staying up so late. I was very productive doing experiments, writing all these manuscripts mostly. But then afterwards when I look back in postdoc, when we had our daughter, then things started changing because you have to put the baby to sleep and then after the baby sleeps it's almost, when you have a baby your life revolves around the baby. So then we have to dim down the light.

There is no caffeine and alcohol drinking or any other things after the baby sleeps because we cannot make too much noise and others. So then I realized that no, I'm actually not a night owl. And I became kind of more normal because I could go to sleep between 10 and 11. And that's how I thought, well, maybe this was very unique to me. But what is interesting is I have another colleague, good friend Ken Wright Jr.

Andrew Huberman: In Colorado.

Satchin Panda: In Colorado. And he also had grad students and postdocs like me who strongly believed that they were night owls just like everybody else. And he took the whole lab camping. And when they were camping of course there was less light and a lot of physical activity, hiking during the day. And they all went to bed between 9 and 10:30 p.m.

Andrew Huberman: I love that study.

Satchin Panda: Yeah.

Andrew Huberman: What Satchin just described was a study, I think there were two studies.

Satchin Panda: There were two, yeah.

Andrew Huberman: And what's interesting, as I recall, is that after going camping for a weekend, where people wake with more or less with the sunrise and go to sleep a few hours after sunset, their melatonin rhythms and cortisol rhythms and sleep-wake rhythms persisted on that schedule for several weeks despite returning to environments where there was a lot of artificial lighting, which I find amazing that just a weekend of consistent rising and going to bed with the sunrise and sunset more or less allowed a reset that was very long lasting.

Satchin Panda: So actually, even in Horacio's study, he found that almost all the Tobas, they wake up around sunrise time. And it's amazing, when I look at the standard deviation, it's like so tight.

Andrew Huberman: Take that night owls, so-called night owls. I also, in graduate school I would work until 2 a.m. I loved it. I would blast music in the lab. Everyone was at home, pretty much not everyone, but there was the night crew. And then I'd get in sometime around, get up sometime around 9:30-10:00 and then get in around 11. And it was no problem because I was going to stay up so very late. And then over time I noticed I'd become more locked to a standard schedule. So I think what we're saying is that our internal clocks can shift, but this idea that we are genetically biased towards one schedule or another may need revisiting.

Satchin Panda: That's the conclusion I'm taking from this couple of aspects. One is that some people are genetically so preprogrammed because the other flip side is what is called technically familial advanced sleep syndrome. So these people, you can give them caffeine or whatever, but they will fall asleep, say at 8:00, they cannot stay awake till 9 or 10. And since it's a very strong phenotype in the sleep and circadian rhythm field, they are very well studied. So in fact, Louis Ptáček and Ying-Hui Fu, they were the first ones to track one family like this. And then they figured out there was a mutation in one of the clock genes, period two, that clock gene. And that mutation allowed the clock to run in a way that these people went to bed very early.

Andrew Huberman: I guess historically, given these fireside chats, those people were probably not contributing much to the political discussion.

Satchin Panda: [LAUGHS]

Andrew Huberman: Whatever that was decided after they went to sleep is what they woke up into. That reminds me, because as you were describing the difference between nighttime discussions versus morning discussions, is there any theme to what is discussed in the morning versus in the nighttime? Or are people just eating and sipping their caffeine and just waking up? But are there any ideas about what morning discussions really consist of?

Satchin Panda: Morning discussions or daytime discussions are mostly about work, and hunting, gathering, farming, all that stuff. And even these days that's what we do. I go to work and it's mostly one meeting after another. And we're talking about how if you're in different committees and you're solving problems or your students come with questions. You have your TA or the office hours, all these things work related. We are not talking serious philosophy unless you are in a philosophy department and you are talking, or political science. And also, we are not singing and dancing. So that's why the evening activities, even these days, are very different. And typically, the evening activities are where we express ourselves. We express who we are. We feel like we are, you know, you and I, we have this academic intellectual freedom. We can talk about our work — just like we are talking now. There are a lot of people who work for, even in the tech industry, they may be working for Google and all these big tech companies. They cannot talk about their work to anybody else.

Andrew Huberman: It's all secret.

Satchin Panda: It's all secret. So just imagine. So they're spending more than half of their waking time at work thinking and doing work, but they cannot talk about that work, even sometimes to their own family members. So then what happens for them? A lot of people also do the same thing, like the person who is going and baking in a restaurant or cooking, or the person who is taking trucks and driving, or nurses and doctors.

Andrew Huberman: Can't talk about their patients, confidentiality.

Satchin Panda: Yeah. And some people just don't want to talk about it. It's so stressful. They don't want to bring that stress home. So that's why I always say that from sunset until we go to bed, during that time, we try to find time for ourselves. People say, this is "me" time. The "me" time is essentially we want to truly express who we are or we want to entertain ourselves. Because on the fireside chat, it's not that everybody was a performer. There are also some that are in the audience. So we always switch our roles. Sometimes we are performing, and sometimes we are observing. So that's what happens with "me" time.

Andrew Huberman: I love this. So maybe social media time should be restricted to just maybe a small portion of that evening time, because I would hope that people would also interact socially in the room.

Satchin Panda: Maybe in a constructive way, or maybe you use that for connection with your family members whom you love, or you can have some productive discussion or something. So it's kind of interesting.

Andrew Huberman: I think it's extremely interesting because I think, again, this conversation about time-restricted feeding is really a conversation about circadian rhythms and sleep-wake activity and human evolution, right?

Satchin Panda: So that's why, let's go back to this night owl, because we kind of made a comment that maybe it's not genetic, but this is where I'm still wrapping my head around it, because these days, there are some GWAS studies where they're trying to look at night owls to see whether there are some genetic links. And sometimes we always think, yeah, if you take half a million people, of course you'll find some on the low side. But going back to this idea, are some people more sensitive to light?

So it's likely that the same level of light, even in the same household, may make some people stay awake late into the night, whereas other people are more resistant to light so that they can go to bed early. And since light has become so prevalent these days, and this Toba story that we are talking about, or people going on camping, we have removed that light. So there is some evidence that people's light sensitivity, particularly the IPRGC, or this Intrinsically Photosensitive Retinal Ganglion Cell, or in simple speech, is the blue light sensors. In our eyes, there seems to be even one log unit change in sensitivity as measured by pupil constriction.

Andrew Huberman: So for some people, a small amount of artificial light at night could really shift their circadian clock, wake them up, essentially.

Satchin Panda: And then for some, it may not.

Andrew Huberman: Yeah, I'm very sensitive to light at night. Exquisitely sensitive to it.

Satchin Panda: So then you are like a teenager?

Andrew Huberman: Yes, in many ways I've been told this. Thank you. I think I have actually switched to using a red night-light. But I should be clear, not a fancy, high-cost red light for sake of any kind of infrared simulation, but a red party light-type light. And I find that that was based on reading one study that we covered in an episode on jet lag and shift work, which was that it seems to reduce the cortisol-releasing properties of light at night to use red-shifted light. So I just use a red light bulb. I actually travel with one. If I go to an Airbnb or hotel and I switch to red light, I find that I fall asleep and stay asleep throughout the night much more consistently, especially when I'm in new environments, which always makes it disruptive to sleep. It's made an enormous difference in the depth and duration of my sleep because oftentimes hotel lights in the bathroom, you'll turn them on, you're just getting beamed. And you're right, some people don't seem to be bothered by that. I really struggle with that.

Satchin Panda: Yeah. And in fact, in teenage, right after puberty, there seems to be, I think that's when teenagers become more sensitive to light. And it's well known that teenage boys and girls tend to stay awake late into the night and they can stay up to 12, past midnight. Although they can stay up that late, that doesn't mean that their sleep schedule is reduced. Their body still needs the same amount of sleep as other teenagers. So that's why they are more likely not to wake up at 6:30 or 7:00 when we expect them to wake up and go to school.

Andrew Huberman: I have a question and I ask every circadian-related biologist I can come into contact with this and no one has been able to give me an answer one way or the other. But I grew up hearing that every hour of sleep before midnight was of more value or potency than the hours after midnight. And Indeed I find that if I go to sleep at 9:30 or 10:00 p.m. I can wake up at 3:00 or 4:00 a.m. Feeling pretty fantastic and ready to lean into the day. But if I get the equivalent number of hours of sleep starting at midnight, I feel like complete garbage when I wake up after five, six hours. So is there any truth to the idea that going to sleep within three hours of sunset is somehow better for our circadian timing mechanisms?

Satchin Panda: Well, there are a few things. One, you said that you are very sensitive to light, so I assume that you also avoid bright light in the evening.

Andrew Huberman: As best I can.

Satchin Panda: As best as you could. And then what is happening is with absence of that bright light, your melatonin levels begin to rise. So you are prepared for sleep. Of course, this is something that we cannot measure because measuring melatonin in every one hour or 30 minutes is very difficult and there is no consumer-facing product yet. So it's likely that your body is preparing very well under this dim light to fall asleep. And when you are trying to stay awake and go to sleep at midnight, then maybe from midnight for the first three or four hours you are sleeping well.

But then after that your melatonin level might be beginning to fall. And it's not only melatonin, your core body temperature and then your heart rate and everything is changing to make you awake, but the sleep debt that you have accumulated is pushing you to be in bed. So there is this tension between the circadian aspect and your sleep debt. And unfortunately you cannot have a good night of restorative sleep for the second half of the sleep because of the tension.

Andrew Huberman: That makes good sense.

Satchin Panda: Yeah. So that's why you are not the only one, it means there are many people who experience that. And in fact a lot of people think that, well, this may be the way I sleep. Maybe I am not designed to sleep restoratively until I sleep one day, just like the camping trip.

Andrew Huberman: And then they realize what it feels like to be--

Satchin Panda: --What you're missing.

Andrew Huberman: Absolutely. I want to make sure that we talk about the other aspect of fire, which is that you had a paper that came out recently, a very interesting paper, studying firefighters and time-restricted feeding in firefighters. Would you share with us the general contour and maybe even some of the specifics of that study? Because I think it's very interesting for the sake of shift workers, but for everybody, really, to understand these results.

Satchin Panda: Yeah. So let's go back to shift workers because this also relates to all of us, because I always say that each of us is a shift worker or has lived the life of a shift worker, and we have experienced how terribly difficult it is. And now let's start with what is the definition of a shift worker, shift work-like lifestyle. There is no universal definition, unfortunately. But there are many European countries, and particularly if you go to an international labor organization, then you'll find some references. Different European countries have slightly different definitions, which essentially points to, if you stay awake for two or more hours during your habitual sleep time, and when they say habitual sleep time, they assume that we are just, like you said, we are kind of programmed to sleep somewhere between, say, 10:00 p.m. And then stay in bed and kind of wake up after 5:00 a.m.

So the idea is if you are staying awake for two or more hours between 10:00 p.m. And 5:00 a.m., and you are engaged in some activity, whether it's physical activity or intellectual activity, you are not lying in bed and wondering, worrying about something, but actually working, so that's defined as shift work. And you don't have to do it every single day. Even if you do it once a week for 50 weeks, then that itself is enough to disrupt your physiology and metabolism, behavior, brain function, like a shift worker. The reason is, as we discussed, when you change our external timing queues, so in this case, when you travel with jet lag or traveling across three days, three hours of jet lag will take three days to reset.

Similarly, if you're staying awake for two hours extra, or if you're waking up two hours before your habitual wake-up time, then we just don't wake up and then be engaged in some activity in the dark, most of us, and mice, unless you are wearing infrared goggles. We turn on light and light resets our clock. So in that way, every time we stay up for two or more hours, even for one night, then for the next two nights, our clock is kind of trying to catch up so in that way, for three days, the day of the disruption, and then two days following the disruption, our clock is trying to catch up with the outside time. So our body is not on time with our clock. So that means almost for half of the week or half of the year, our clock is trying to catch up. So that's the definition of shift work.

So now let's come back to the Department of Labor Statistics, U.S. government. They have not been tracking what percentage of people are doing shift work accurately because there are many difficulties in tracking too, but it's generally accepted that one in five working adults is a card-carrying shift worker. Card-carrying shift workers means they are nurses, doctors, firefighters and bakers, truck drivers, and many in the service industry. So that's one in five. So 20% of working adults, then, if we think about all the college students, just like I was doing, and you must have done.

Andrew Huberman: There are deadlines, grant deadlines.

Satchin Panda: Then we are also experiencing the lifestyle of a shift worker because we are delaying sleep. Even if you're delaying sleep by two hours for most of the college students for five days and then the weekend you are trying to catch up, that's kind of a circadian disruption going on. Then you take 1.5 or 1.6 million new moms in the U.S. every year. So when the child is born, then that mother is a shift worker. And actually that mother is worse than a shift worker because you don't know what time of the night the baby will wake up and how many times, and there is no weekend in motherhood. So they're also living the life of a shift worker.

We don't count many food delivery and Uber drivers, Lyft drivers as shift workers, but many of them, we know that they live this way. So in that way, we think the actual number of people who are experiencing the life of a shift worker is somewhere around 50% of the adult population at any given time. So that's why it's also another point that you might have heard from people. They will say, oh, I cannot do time-restricted eating because my schedule is messed up, or I work in a different way and that comes into play. So that's why we thought, okay, so we should try something on shift workers.

Another point is, although one in five people are shift workers, they carry disproportionately heavier burden of disease because almost all age-related disease that we can think of, whether it's high blood pressure, usually high blood pressure starts in 40s or 50s, high cholesterol, gastrointestinal problem, indigestion, chronic inflammation of the colon, and then even colon cancer in many cases, and then of course, diabetes. All of these are disproportionately more prevalent among shift workers.

But then, when you think about clinical trials, whether it's a drug or a lifestyle, often one of the top 10 exclusion factor criteria is shift work. So people who are doing shift work, we exclude them from many of these trials. One thing is most physicians and most scientists, even people who do shift work, know that their body and mind is so messed up that oftentimes even medications may not help them, and so that's why we don't try new medication. Why take the risk when we know it may not help them?

And then when it comes to lifestyle intervention, whether it's sleep extension, for example, we cannot do it, because they are supposed to stay awake and do their job, we cannot ask them to stay asleep at night. And then physical activity and exercise, some people can do, but some people are so tired after all night that they don't have the energy to do physical activity. And then nutrition. Again, most nutrition studies involve the participants to come to the clinic and get one-on-one, or attend group sessions, and they cannot come. And sometimes they cannot even come to the clinic visit when people have to draw blood.

And in fact, there is another caveat that just if, suppose I'm healthy, I have perfectly normal blood pressure, blood glucose, cholesterol, everything is normal, and I live the life of a shift worker just for five nights. That means I'm sleeping less, maybe four or five hours. And even if I don't eat at nighttime, of course, many shift workers also feel hungry. And just to keep their work, they eat. Just after five days, my blood glucose level will read almost like I'm prediabetic.

Andrew Huberman: Wow. I actually saw a study published in Proceeds of the National Academy that showed that even 100 lux dim light present in the room while people are sleeping with eyes closed can lead to disruptions in morning blood glucose levels in directions that are not good. One night. So the faint clock in the corner or even a nightlight that's too bright could be problematic. By the way, folks, these effects are reversible. So whenever I say these things, we get a lot of comments about, oh my goodness, what have I been doing for years? But kids with nightlights, this is an issue.

But what I'm hearing is that one in five people are truly shift workers in the classic sense. Their jobs require them to work at night or into the night and sleep into the day. But far more people are shift workers by virtue of the fact that they're tweeting or working or watching movies at night, even though it's not work in that they're not being paid for that time, they are essentially operating like shift workers. If we add those two groups together, would we say it's what, a third of Americans?

Satchin Panda: I would say half of Americans. Half of Americans. If you take teenagers because high school students and college students. Because again, going back to Horacio's study, Horacio also collected activity data from high school students and college students. And we have replicated that with high school students and college students in San Diego. So that's Seattle and San Diego... And this study... Now, there are many sleep researchers. They have been collecting this data. And what we find is typically the high school students, they are going to bed, say, around midnight, and college students, at least the UCSD students, we found maybe one out of 10 who went to bed before midnight.

Andrew Huberman: That reminds me that Horacio de la Iglesia just published this really nice paper showing that counter to what we believe, students, now, this is the University of Washington in Seattle, I should mention, where it's very dark in the winter, young people, see, these are people in their 20s are staying up later in the winter months compared to the summer months, which is totally counterintuitive. You think, okay, everyone stays up late in the summer and goes to bed early in the winter, but because of artificial lighting, it's the exact opposite.

Satchin Panda: Yeah. I don't know whether Horacio monitored it, but my other suspicion, I'm not saying whether it's true. In winter, we are more likely to consume more coffee, hot chocolate in the evening, and that might also be delaying sleep onset.

Andrew Huberman: Makes sense.

Satchin Panda: So in that way, again, here is another thing which can be related to policy or practice at educational institutes. So what happened during COVID was that everybody went to remote learning. The assignments became digital and assignment submission became digital. And there are many systems, online, systems that came into play, and by default, the assignment submission deadline became midnight. So now what is happening is, I don't know about Stanford, maybe when you are giving assignments, when is the deadline?

Andrew Huberman: Midnight, typically midnight.

Satchin Panda: So then most students will try to cram as much as possible, try to solve as much as possible, and submit at midnight. And it'll be really cool to go back to your system administrator to see if there are so many, the frequency plot of frequency distribution of what time people are submitting their assignment, because we know when we submit our grant.

Andrew Huberman: Yeah. You hear about the obesity crisis, the crisis of metabolic disorders, not just in the U.S., but everywhere in the world. I mean, it's really striking. I remember going to a Keystone meeting, a scientific meeting in the early 2000s, and there was a map of the United States and it showed where the obesity rates were over 30% in adults. And the entire country basically was lighting up like crazy. Now it would be the entire country, but there were these zones in the middle that were almost devoid of obesity. Colorado, namely Idaho at that time, those are now also fallen under the umbrella of rampant obesity. And everyone is speculating, okay, is it seed oils? Is it this? Is it that? Is it highly processed foods? I'm guessing it's all of those things--

Satchin Panda: --It's all of those things.--

Andrew Huberman: --including lack of activity. But one has to wonder, given everything we're talking about in terms of metabolic dysfunction, late-shifted eating, all these issues with late-shifted eating and staying up late with artificial lighting, whether or not that could be one of the major factors in the so-called obesity crisis.

Satchin Panda: It's likely we always say, "freshman 15."

Andrew Huberman: That's right,

Satchin Panda: Because these kids are gaining 15 pounds in their freshman year in college. And this is where I think as educators or professors, it'll be interesting to go back and see what we can do. Because another thing that's also becoming more and more common, for example, I give a circadian rhythm class, which means I just give two lectures. And I remember when I started 15, 17 years ago, that lecture used to be around 1:30 p.m. or 2:00 p.m. in the afternoon, and it's a two-and-a-half-hour lecture, so it's done by 5.

And for the last year, before the pandemic, I realized that they changed the timing. Now, the lecture was starting at 7:00 p.m. So I was finishing by 9-9:30 p.m. And these kids, they had to go and eat after 9:30. Study, socialize, study, socialize. Fireside chat, fireside chat, and then to express themselves, like, to feel free from assignments, when are they going to do that?

After they submit the assignment, then they're going to do that. So that's why we have to go back and revisit this issue, say, okay. So for adults, for most of us who are working a day job, our deadline is 5:00 p.m. in most cases, right? It means at least in the university system, the person who is submitting the grant or who is taking care of my IRB or I cook, they are all leaving at 5:00. So for me, everything has to end by 5.

Andrew Huberman: I think for most people out there, this raises a kind of macroscopic question, which is maybe it's not so much about restricting the feeding window, but maybe it's about feeding mostly and being active mostly in the early part of the day. I mean, I could imagine a time three, four years from now when waking up early and going to bed within three hours of sunset is the protocol which harnesses all other protocols, right? You're going to exercise, you're going to do it at that time, you're going to eat, you're going to do it at that time, you're going to socialize, you're going to do it at that time. And in doing so, you're also avoiding a lot of the issues related to disrupted sleep.

Satchin Panda: So that's why all these things, as you said, time-restricted feeding is just one aspect of the circadian health, and these are all interconnected. And going back to the comment about within three hours of sunset, yes, that's good. But then what happens in, say, Toronto or Vancouver in wintertime?

Andrew Huberman: I guess they're going to bed very early, but also waking up very early. One of the things that I hear all the time because I'm always beating on the drum of getting morning sunlight, even if through cloud cover, is people say there's no sun here this time of year. And forgive me, but there is sun. Unless you live in a cave, there's sun. It's just coming through cloud cover. No matter where you live in the world, there's sun. Unless you live in a cave, of course. So I want to make sure that we didn't overlook what was the major conclusion of the firefighter study.

Satchin Panda: We'll go back to the firefighter study. So the reason why we did this study was, as I said, there are a lot of us who are living the lifestyle of firefighters or shift workers, and shift workers are excluded from studies. So that means whatever we are learning about lifestyle or even medications that may be beneficial for people who actually have a normal schedule, but not for people who have a disrupted schedule. And if you look up clinicaltrial.gov there are more than 400,000 studies listed. And if you search how many studies are on shift workers, it's less than 1000. And then if you ask, most of them are to see what is wrong with shift workers, like, that's how we know that shift work increases our risk for metabolic disease, cancer, and even some aspects of dementia. But if you ask how many studies are done to improve the health of shift workers alone, that's less than 50. I have to go back and check the actual number, but it's less than 50.

Andrew Huberman: Wow.

Satchin Panda: So that's why we got super excited. We thought from a circadian rhythm perspective, that's something to address. So this study, again, this kind of study is only possible because I'm at Salk and we are affiliated with UCSD, and I can work with UCSD physicians to do this study. So I collaborate with Dr. Pam Taub, who is the director of Cardiac Rehab center in UCSD, and Pam has many firefighters as her patients, and we both know that the number one cause of death and disability on work for firefighters is not fighting fire, but just getting heart attack and stroke. So they have a very high incidence of heart attack and stroke. And they're also highly prone to different kinds of cancer.

And it may be difficult to ascribe cancer to disruption, circadian disruption, because they're also exposed to a lot of toxins. Anytime a fire burns, that smell of fire is essentially the smell of carcinogens. And they're breathing, even if they have the hood on and respirator, they still get it. So the idea was very simple. We know that nearly 70% of firefighters in the U.S., full-time firefighters — because there are volunteer firefighters, and then full-time firefighters — the full-time firefighters, 70% of them work 24-hour shifts. So, for example, in San Diego, their shift is from 8:00 a.m. to 8:00 a.m. the next day. And they do, at least in San Diego, they do one day on, one day off, on, off, four cycles, and then four days off. But in some fire departments, they actually do a 48-hour shift. So they come for two days, two days off, two days, two days off, and then four or five days off.

Andrew Huberman: Brutal. Thank you, firefighters.

Satchin Panda: Yeah. So then the idea was, okay, so we'll screen firefighters and then find firefighters who are metabolically unhealthy, and then we'll see whether they can actually follow 10-hours time-restricted eating. Because the point is, if firefighters can follow it, then everybody else should be with all that stress, if they can. And this is, again, where I should also acknowledge the San Diego Fire and Rescue Department, because without their help, we could not have even submitted the grant. And at that time, David Picone, who is their health-and-wellness battalion chief, he's the one who actually approached us because he's very careful. He knew that the job that they do makes them weaker in the long term and can kill them in the long term. So he was always looking for new solutions. So he approached us, and then we said, this is the idea. He said, well, I love this idea because we are not asking them to sleep more or we are not going to cut down their overtime or shift or change the work schedule. The only thing we'll be doing is ask them to eat within 10 hours. And hopefully we can do this consistently.

Andrew Huberman: Between the days that they're working and not working.

Satchin Panda: Yes.

Andrew Huberman: So that means if they're from 8:00 a.m. to 8:00 a.m., working, then they go home, then they're going to eat on the same schedule they did when they were at the firehouse, but while at home. So they're not allowing themselves to deviate from that.

Satchin Panda: Yeah. So we thought whether they can do it or not, because the number one goal or the primary outcome in this clinical trial was feasibility, can they do it? And then the second was, if they do it, then what happens to their blood sugar and weight and all this other stuff? And then we started the study and we hit the next hurdle. And that is firefighters are a very tight-knit community, and they want to make sure that you understand their culture. And the best way to understand their culture is to live the life of a firefighter.

So Emily Manoogian, who is the first author, and then we had Adina Jadorian, who is now in med school, she was a research coordinator at that time. They volunteered. They said, okay, we'll go to the busiest fire station in San Diego and we'll live the life of a firefighter. And the San Diego Fire and Rescue and the city, they all agreed. They reported for duty at 7:30 in the morning. They were assigned a bed in the station because all fire stations do have some beds for firefighters to rest. And they have assigned beds. So they were assigned a bed. Yeah. So every time a 911 call came, and if that fire station, in that fire station, that fire engine was called, then just like other firefighters, they had to run, get into the gears, just the shoes and a jacket and the helmet, and get into the seat and attend the call. Of course, they won't go to the site. They just get out of the truck, wait there and come back. So in that 24 hours, Emily got 10 calls at night that she had to run to. But there are more than 10 times, every time the 911 call comes, then there is a beep that goes out. All firefighters who are sleeping or resting, they would get up, or if they're doing something, they would look up to see which engine is called.

Andrew Huberman: Interesting. So it's not just the ones that go out. Everyone gets woken up.

Satchin Panda: Everyone gets woken up. So that means in a night, a typical night, they're waking up 10, 15, 20 times sometimes. So they're almost like, new moms are like firefighters because they don't have any idea what time the baby will cry and for what reason. Also, they don't know. So similarly, that's what Emily did. And then next morning when she came back--

Andrew Huberman: --She was like, no, grad school seems easy?

Satchin Panda: [LAUGHS] Yeah. Then we did the study, and we essentially assigned all the firefighters. We recruited 150 firefighters. We assigned half of them to a Mediterranean diet because you cannot do any harm. You have to give them something good. So that's another thing. They said, no, we want something that we know works for firefighters. And there was a Mediterranean diet study. So everybody was supposed to follow a Mediterranean diet, and then half, nearly 75 of them were supposed to eat within 10 hours. We did not fix the 10 hours because we said, you pick your own 10 hours that you can stick to.

Andrew Huberman: But it has to be consistent from day to day. So if you start eating at 9:00 a.m. You finish it at 7:00 p.m.

Satchin Panda: And then try to be, try to be consistent, because we said, yes, we understand that there will be some things, and you can take maybe half an hour here and there, and we'll see how many times you can do it. And what was interesting was, although they were all doing a 24-hour shift, they more or less chose to begin eating somewhere between 8:00 a.m. and 11:00 a.m. and they did not skip any meal. They had their first meal, or what we call breakfast, but it was several hours after waking up, because they are waking up at 5 or 6, and they're driving to come to work at 7:30 or 8, and they're eating the first meal, say, between 8 and 11, and then the final meal 10 hours later. And what we found is more or less, most of them could stick to doing this at least five days out of seven days.

And then at the end of the study, when we look at their health parameters, one thing is, as I said, we recruited everybody who came. So that means nearly one in three firefighters were completely healthy. They had no sign of any illness, no high blood pressure, high blood sugar or high cholesterol, depression or anything. So since we have one-third of the population who are already healthy, and then everybody has slightly different conditions. Some have high blood pressure, but they don't have high blood glucose. Somebody has high blood glucose but not high blood pressure. So it was kind of heterogeneous. So we did not see a big difference in weight loss or any weight change between these two groups. Another thing is the firefighters actually run almost eight to nine miles when they're at the job because that's part of their exercise routine.

But then one thing that changed significantly in the time-restricted eating group was what we call the LDL particle size and particle number, because this is something that we know. This very low-density lipoprotein, these are atherogenic, and if we can manage them much better, then we reduce the risk for atherosclerosis. So that's one parameter that changed in the time-restricted feeding group, even when we combine all healthy, unhealthy, everybody. Now, if we take firefighters who were beginning with high blood pressure, then we saw a significant reduction in their systolic as well as diastolic blood pressure. And the change in blood pressure, of course, we don't claim that in the manuscript, but when we talk about it, some physician would get up and say, wow, that looks like almost they're on a blood-pressure lowering drug. So the extent of blood pressure lowering is equivalent to somebody taking an antihypertensive drug.

Andrew Huberman: Amazing.

Satchin Panda: Yeah. And then those who started with high blood sugar, of course, we didn't have too many type 2 diabetic, but there were very few prediabetic, and they could better manage their blood glucose. And this is interesting because once shift workers become prediabetic or diabetic, they have more difficulty managing their blood sugar than nonshift workers because the work schedule itself will mess them up too much. Even if they're on many medications, they have difficulty.

Andrew Huberman: That's fascinating, and I'm really glad that you explained the study in such detail, because I would have thought from reading the abstract, and I did look at the data, but if someone were to look at the abstract, they'd say, oh, firefighters. So they're waking up in the middle of the night and they're throwing on their gear and going out to calls and doing, but if I understand correctly, all firefighters are being woken up by the signal, which makes the firefighter population a bit more similar to the more standard population who's waking up in the middle of the night to use the bathroom, getting on social media for a couple of minutes or flipping on the lights.

I mean, it's maybe not as severe as what firefighters are doing, but we know there are blood sugar regulation issues related to those multiple middle of the night wakings, especially if people are then staring at screens. So I think it's really important that people were able to hear about the deeper contours of the study. I mean, this result of regulating blood sugar better is really powerful. I get asked all the time, I've got a new kid, or I'm a shift worker, how can I do this morning sunlight viewing?

What I'm hearing is that keeping a regular meal schedule every day, at least five out of seven or as close to every day, it's sort of like sleep. I always say, try and get a really great night's sleep 80% or more of the nights of your life. And on the other 20%, hopefully it's for fun reasons, a great party or something like that, or a celebration of some sort. That seems to me a great anchor point when one can't reliably control their sleep-wake cycle. Does that mean that if somebody is coming off of shift work and they're very, very tired, that they would be better off staying awake and eating than sleeping?

Satchin Panda: Well? Yeah. So this is where we get into nuances. So here the firefighters are 24-hour shift workers. So that means, and they have been working the shift for a very long time. So they have figured out one thing is, yes, firefighters are different from nurses and healthcare workers who have to work throughout the night and they're staying awake throughout the night. Whereas firefighters get an opportunity to sleep. Even with their 10 calls, they actually have an opportunity to come back and go to sleep. And in fact, when Emily and Adina, they were in the fire station, what they observed was firefighters, after attending a call, they were not coming back and playing cards or trying to watch the news or get the score. They know they will just go back and lie in bed and switch off the light. So whenever they got any opportunity to sleep, they would try to sleep. So in that way, their sleep debt and sleep pressure during daytime is not as strong as a night shift nurse or a truck driver who is driving all night, because they are staying awake throughout the night.

So when people say, yes, you found this, and can you extend it to other shift workers? My answer is no. We have to go back and figure out, that's why we went to this station and figured out what would work for them. If I have to go and do this for some nurses, maybe even I will go, or our staff will go and figure out what is their work schedule, what happens? Do they have an opportunity to eat? Do they have an opportunity to even take a five-minute break? What do they do during break? And all of these things come into play.

But here another thing is, I always said that in other time-restricted feeding papers, we see a change in nutrition, quality and quantity. But here we also saw that somehow both groups inadvertently improved their nutrition quality because everybody was told to eat a Mediterranean diet. They increased their fruits and vegetables and olive oil intakes slightly. And when they had to stop eating early, they also reduced their alcohol intake.

And this is very significant because many shift workers, just to cope with the shift work, tend to depend on alcohol at night and caffeine in the morning. So they begin their day with caffeine and end with alcohol. And now we can relate that many normal people who are not doing shift work, we also more or less begin our day with caffeine, and many of us end with alcohol. And then when they reduce that eating to 10 hours, and then we saw a significant reduction in alcohol intake in the time-restricted eating group, but not in the standard of care or Mediterranean diet group.

Andrew Huberman: I certainly support that. We did an episode on alcohol, and I was shocked when I researched that to learn that zero to two drinks per week is essentially the threshold beyond which you start seeing health deficits, in particular, cancers and metabolic disruption, sleep disruption, and increased anxiety when people aren't under the influence of alcohol. I mean, it's pretty incredible how alcohol has kind of escaped as the opposite of caffeine, and therefore not a health hazard. Here. I'm somebody, I have a drink every once in a while. No big deal for me. I can have it or not have it.

But it's just striking how alcohol, despite extensive data that it can really disrupt health, even at three drinks per week, is just avidly consumed, as if it was kind of like food or caffeine. It's really incredible. I want to make sure that I circle back to something you mentioned earlier, because I know there are going to be a number of people that asked this. If I recall, you said that provided that the feeding window is not shorter than eight hours, that men, women and children can use time-restricted feeding.

Satchin Panda: Well, yeah. So what I say is 12 hours.

Andrew Huberman: Excuse me, 12 hours.

Satchin Panda: Thank you for that clarification, because we did a study that was published in 2015, and again, behind many of our studies, there is a story. So we are publishing all these mouse stories. And then I would go to conferences, and then, of course, some people would give me a look saying, well, you must be doing something wrong. This just breaks the second law of thermodynamics, because how come they're eating the same number of calories and not gaining weight? Of course, by that time, we figured out that, at least in mouse, time-restricted feeding also changes the gut microbiome in a way that the mice may be pooping out a little bit more fat and sugar than absorbing them.

So one thing that happens in time-restricted eating, at least in mice, is their liver cholesterol metabolism to bile acid, and bile acid's excretion in the gut changes because the gut microbiome changes. So this is a very nice study. When Amir Zarrinpar was in the lab, now he has his own lab in UCSD, and he meticulously did that. And we even did bomb calorimetry from the poop and metabolomics from the poop. And then we figured out that they excrete some calories and then their brown fat activity goes up. So they may be burning some of these extra calories.

Andrew Huberman: So they're more thermogenic.

Satchin Panda: More thermogenic. But anyway, one nice, awesome thing about Salk is if they see that your science is going well, then they will find ways to help you, and this is perfect. And this is when Bill Brody was our president. He was the president of Hopkins for 12 years, and then he was the president, and at that time he had started this innovation grant program, which was funded by Irwin Jacobs. Irwin is the founder of Qualcomm and was also on the faculty at UCSD. So he understands there are very few tech leaders who actually spend some time in academia, so he understood the pain of getting grant money. When you have some interesting idea or test some idea.

Andrew Huberman: No knock on the NIH, but I'll do it anyway because I sit in the study section for the NIH. NIH wants to see proposals for things that are so certain to work that they're mostly done. And so really groundbreaking work can happen and does happen with NIH funding. But more often than not, it is the generosity of philanthropists like Irwin Jacobs and other people that allow the really pioneering the new stuff, the cool stuff, the groundbreaking stuff, the stuff that really, no, I'm not going to say really matters. It all matters. It's all important.

Satchin Panda: It matters, but it's high risk. And NIH is not just, the government is not making money from thin air, it's taxpayers' money, so there is a little bit of responsibility to conserve that, okay, so we should not waste taxpayers' money on pie-in-the-sky kind of projects too much.

Andrew Huberman: To be clear, we're not talking about politically conservative, we're talking about scientifically conservative. You have to be so careful with language nowadays. Pretty soon we're just going to sit and stare at one another at the microphones to stay safe. So that's interesting.

Satchin Panda: So then we started this, and then what we did was I had an awesome grad student. And we got this funding from Irwin. And also, any philanthropy matters. So actually the way we say is, yes, if you give me 50 bucks, then that 50 bucks goes towards buying the gloves and a friend of tubes for one postdoc for maybe seven days.

Andrew Huberman: So true. I think a lot of people don't realize that 99% of laboratory scientists don't make any money off their discoveries. And even if there is a patentable discovery, typically the divide between the institution and the company that will eventually put that to market is so slim in favor of the others involved that scientists really do this as work of passion, labor of love.

Satchin Panda: So we came up with this app, My Circadian Clock, at that time, and we took some lessons from tech leaders, particularly from Amazon. One-click checkout, because we thought most nutrition apps actually ask people to detail, describe what they ate, go to their food library, and then portion size. We said, okay, so we'll just shortcut all of that. We just asked people to take a picture of the food, open the app, one click, take a picture, second click, and press save, third click. And when they saved, the picture actually came to our server, did not stay on their phone, and we asked 156 people who are not shift workers, just regular workers or homemakers, to be part of the study.

No student was allowed to be part of the study because we know that their lifestyle is like shift workers, and we monitor for three weeks. Here are some nuances, and I want people to understand. So suppose when somebody is starting to eat at, say, 7:00 a.m. And since they're recording everything, we caught every single thing. Even if they ate half a cookie, they had to take a picture. And they actually took a picture because it becomes second nature after three or four days that every time they ate something, even if there was a glass of water, they actually took a picture. Because we asked them to take pictures of everything. We'll figure out what it is. What is surprising was we found, so the median number of times people eat within a day, 24 hours a day, is actually seven. So it's not that we are eating three times a day. We actually snack a little bit.

Andrew Huberman: Seven times per day.

Satchin Panda: Seven times. And there are 10% of people the top decile was eating 12 times a day.

Andrew Huberman: Wow.

Satchin Panda: And it makes sense in retrospect, sometimes maybe I'll fall into that seven or eight before I did this study, because getting up, having coffee with cream and sugar is one. And then I ate my breakfast. That's two. Then I came to the lab and I found that cookie. That's three. Then I went to a meeting, and there was some cookie and something else. That's another one. Then lunch, and then afternoon, somebody asked me to go out and have a meeting. So if you think about it, it's very normal that we can go seven to eight times, ten times. But then if we look at what time, say I start breakfast, and as I said, we see that in many people, they'll start at 7:00 one day, then 7:30 another day, then 8:15 another day. Or they go back to 6:00 a.m. because they had to get up early and go to work.

So we take all these food data from three weeks and then ask, what is the time when your body system is expecting it to eat? Because it kind of averages out. It's kind of thinking, okay, maybe for you, if you're eating breakfast at, say, somewhere between 6:00 a.m. 7:30, 7:45, 8, maybe you are expecting food around 7:00. Let's forget about 6:15. That's an outlier. And then similarly, at the end of the day, if somebody is eating, finishing the last bite or the nightcap, whatever you call it, say one day at 9:00 p.m., 9:30 p.m., 10, 11, 12:30 or 1:00. Let's ignore that 1:00 and 12:30. But still, we got somewhere between 7 to 11:30 for that person over three weeks' time. So this is how we kind of figure out what is the likelihood that your body will encounter food. So when we do that, what we found was that nearly 50% of adults in our study ate for 14 hours, 45 minutes. That window when your body is expecting food. So it's easy to say that 50% of adults are eating within 15 hours or longer.

Andrew Huberman: Wow. And quite frequently throughout.

Satchin Panda: Quite frequently, too. And then if we ask what fraction of our adults were actually eating the conventional within 12 hours, three meals a day or something like that, it was 10%.

Andrew Huberman: Snacking has gone up dramatically. However you want to define snacking, the frequency of food intake throughout the day.

Satchin Panda: And outside this breakfast, lunch, and dinner, there are all these small snacks here and there. And also for a lot of people, the dinner is delayed. And we went back and looked at, okay, so what kind of food people are eating late at night and all that stuff. And what came out interesting, which is very counterintuitive, is people who prepare their own dinner, they're more likely to eat later at night because they're coming home, and then they're taking some time to prepare dinner, and then they're sitting down and eating, or maybe they're eating next to the computer, whatever it is. So it's kind of interesting that that came out. But coming back to your point, that's why I say that nearly 90% of adults are eating for more than 12 hours. So that means a lot of people can, there is scope or there is enough headspace to reduce and eat within. So as I said, all of these are interrelated. So when you think about children, most sleep researchers agree that children and teenagers should sleep somewhere between nine to 10 or 11 hours because young children, even 5-to-10-year-olds, should sleep nine to 10 hours.

Andrew Huberman: They're just pumping out growth hormones and growing, growing, growing.

Satchin Panda: And then the teenagers, actually, the recommendation is they should be sleeping nine hours because if you take teenagers, take out all the stimulatory inputs to them and then remove homework assignment and everything, and then let them kind of equilibrate to their homeostasis, how many hours they're likely to sleep. That turns out to be somewhere between eight and a half to nine and a half hours, which also means that going back to sleep, nearly 90% of high school students in this country are chronically sleep deprived because most high school students don't get nine hours of sleep on a regular basis, maybe on the weekend.

Andrew Huberman: Probably because of devices, they're on iPads.

Satchin Panda: And also, as I said, this new idea that midnight is your assignment submission time. I'll come back to that again and again.

Andrew Huberman: I'm hearing that again and again. So teachers, take note. It's a very interesting idea as a way to kind of anchor behavior earlier in the day. Yeah, learning to, I mean, public health is complicated because people are incentivized by fear. But you get more bees with honey, as they say, right? There's incentivizing people to wake earlier, not necessarily with the sunrise, but wake earlier and go to sleep earlier and eat within an eight-to-twelve-hour window. Twelve if it's children.

Satchin Panda: Yeah.

Andrew Huberman: It sounds to me like all these health benefits are what I think are going to incentivize people more than, for instance, this idea that, well, if you don't do this, you're going to get dementia or something, right?

Satchin Panda: Like every day people will feel more healthy and more productive. And so that's why I said that even if children are supposed to sleep for nine hours, of course they're not eating during those nine hours. And we are not feeding children and putting them down to sleep because their core body temperature will be high. They cannot fall asleep. So at least they should have their last meal one or two hours before going to bed, because typically parents feed them and maybe give them a shower or a bath, and then they read the bedtime story. So it's one to two hours before bedtime, they're finishing food. Similarly, on the other end, after they wake up. It's not that we are waking them up and then feeding them. Hopefully we're not doing that. So that's 12 hours, which seems to be optimum. And it's not only I'm saying that if we put all the health recommendations together from pediatrics and then it makes sense.

Andrew Huberman: Fascinating. I have a question about structuring meal intake or food intake during the eating window. I have a good friend, actually, he's the neurosurgeon at Neuralink now, but he came up through Stanford and he has a habit of eating, of skipping one meal per day within a feeding window. So it might be breakfast, lunch, skip dinner one day, then it might be breakfast, dinner the next day, lunch, and dinner the next one. So it's not in keeping with the same start time always, but the end time is either going to be earlier or there's a gate. It's never later.

What do you think about that as a strategy? In many ways it feels like that fits with the way that a lot of people's lives run. So sometimes, for instance, if I'm on a podcast, I don't tend to eat much during the middle of the day because it makes me a little bit groggy. The postprandial dip in energy. So I'll do breakfast, well again at 11. That's when I break my fast 11-ish and then dinner, maybe a snack in the middle of the day, but other days it's three meals. So does it matter overall, as long as one isn't allowing the start time and the ending time to drift out? Is it okay if you go from 12 hours to 10 to eight, eight, 10, four, 12, as long as you don't exceed the brackets? Are you okay?

Satchin Panda: So this is where the circadian aspect comes in. Because if you're moving that breakfast time or dinner time three, four hours, you're essentially causing maybe a metabolic jet lag. In the short term, in weeks, months, or maybe even a few years, you may not see any change. At the same time, we don't know the long-term consequences. One thing is we always think, I'll come back to this point again and again. We think that our body weight is a marker of health or body composition is a marker of health. It's not always true because as I said, acid reflux feeling, having some pang of depression or anxiety or LDL, like high LDL.

Andrew Huberman: High LDL. A lot of thin people or low body fat people have very high LDL.

Satchin Panda: Yeah. So those are the things that we don't connect with our habit. And since circadian rhythm and meal timing, meal structure now is a very new field, I think good studies will come out only in a few years, because right now people are just going back and retrospectively looking at some diet record, one day of diet record and trying to glean too much out of it. But I think hopefully things will improve where people become, it will become standard to at least look for one week of diet record meal time and what they're eating, all that stuff. Because now mouse studies are also showing whether front loading carbohydrate or front loading fat or protein has benefit over, so I think these studies are starting. So I should not comment whether that's good or bad.

Andrew Huberman: I think it's great to hold off until then. We'll have you back on to discuss. I have a question about fasting in the longer term. And there it's a near-infinite space we could explore of two days of fasting one day. I know people that every once in a while they just decide, I'm fasting. They've either been eating too much at parties or they're not feeling well or whatever, they just decide, I'm fasting for 24 hours, and they'll still consume water and caffeine, but they'll just fast. Is there any health benefit or detriment? You mentioned the circadian clock-shifting effects, but if somebody wakes up on Sunday and they ate too much, or they feel they ate too much, or they don't like the food they ate on Saturday, they're not really feeling it, and they're just going to fast into Monday. Is there any known benefit or health detriment to doing that kind of thing?

Satchin Panda: Yeah, there is actually a rich literature on this complete fast. And in fact, in many religions, people practiced complete fast as a way to cleanse their body. And people have seen that there are benefits to that. So in fact, the every-other-day eating in mouse model or even in humans, there are also initially some studies were done, there are many health benefits. And right now there are even fasting clinics in Germany where people check in and they're under strict supervision, and then they do a complete fast. Or maybe a small bowl of soup which has 100, 200 kilocalories. And that's all they get to eat sometimes two, three days, four days, five days even. They have gone up to three or four weeks.

Andrew Huberman: For the sake of weight loss. Is that why?

Satchin Panda: For many different things. And they come out pretty well healthy. Of course, they're under supervision to make sure that they are getting the micronutrients, vitamins and electrolytes. So those studies are pretty solid. People have observed that. And then, in fact, there are even ideas that fasting, this kind of fasting can have a huge impact on the brain, and people may come out of treatment-resistant depression or something. So those studies are very difficult to do. There are only cases of one here and there that we hear once in a while. But hopefully in future we'll see whether the depression, anxiety, the mental health aspect, will benefit from fasting. Because now, as there is more and more evidence that there's this gut-brain axis and whether the presence of food or the microbiome changes in the gut, if they can affect brain, then maybe long-term fasting, periodic fasting, a few days of low-calorie diet back-to-back, will be interesting to see how it impacts brain health.

Andrew Huberman: Very interesting. What are your thoughts on fat fasting? Where people try and limit their blood glucose by only eating mainly fats, mainly healthy... typically, they'll eat healthier fats of avocados, olive oils and nuts, and some animal fats, perhaps, but as a way to keep blood glucose low and also time restrict, this goes back to the kind of low-carbohydrate thing. What are your thoughts on that as a general strategy for health? I mean, it combines sort of two general themes that are out there, I think, both of which data are still incoming, that restricting the feeding times, it can be beneficial, as well as keeping overall blood glucose lower can be beneficial.

Satchin Panda: Yeah, I think there is too much emphasis now on blood sugar spiking, or, we don't know, this kind of eating pattern, for example, means we are essentially telling pancreas that, okay, it or the islet cells that produce insulin that is, okay, you can take a break, go on vacation for a month or two or three months. My question is, it will be interesting to see what happens to those islets, because, for example, we know that if we disuse or unuse our muscles, there is muscle atrophy, muscles will become weaker.

We don't know whether long-term consequences of this very low-carbohydrate diet, where you are not essentially engaging the islet cells periodically, what is its impact? So if there is no impact, maybe it's okay, because as you know many people who actually work on a ketogenic diet. The researchers themselves find it very difficult to stay in a true ketogenic diet because the true ketogenic diet is consuming less than 10% of calories from carbohydrates.

Andrew Huberman: And not very many from protein. A lot of people think a ketogenic diet allows them to eat massive amounts of meat, and that's not necessarily the case. Just one clarification for people. Satchin was referring to islet cells of the pancreas, which are the ones that manufacture insulin. So the question is whether or not taking in low levels of blood glucose by way of a low-carbohydrate diet, those islet cells are going to shut off their production. Very interesting. I mean, the liver is a very plastic tissue. I mean, it tends to react very dramatically to lifestyle changes.

Satchin Panda: Yeah. So that's why it will be interesting to see what happens. We know that even muscle disuse, for example, people who become bedridden, they lose some muscle mass, but when they come back and exercise, they gain it back. So it'll be interesting to see what happens in these people who are going through a long-term ketogenic diet. And of course, once in a while, because of social pressure or something else, if they don't have access to food or something happens, they may consume some sugar and blood glucose will spike. But it's not that every spike is bad. I mean, the reason why we have insulin is for good reason, to buffer that spike, to buffer that spike. And also, people always say that, well, if you have insulin produced or insulin-like growth factor, those are really bad, and you should avoid that. And I think that's a little bit extreme.

Andrew Huberman: The insulin growth factor has evolved in muscle protein synthesis, tissue repair, maybe even cognition.

Satchin Panda: And it also goes back to, say, mTOR activation and all that stuff. People get really excited about how to reduce mTOR activation, rapamycin and all that stuff. So this is where, again, from a circadian point of view, I ask people to think two very popular drug-like molecules or drugs that people think will increase longevity are metformin, which many people agree, not all will come to a consensus, that it activates AMP kinase, or the sensor in the cells that sense that your cells are fasting. So metformin kind of activates it so that you can say, although it may not be scientifically accurate, the fasting in a pill.

Andrew Huberman: So it sort of mimics fasting. And the thing I'd lump in there with metformin is that berberine is kind of the poor man's metformin. It's a tree bark extract that also dramatically lowers blood glucose.

Satchin Panda: It mimics that kind of fasting, and then rapamycin also kind of reduces mTOR activation. And people have shown that rapamycin and metformin can extend a mouse lifespan and improve health. So now let's go back to the calorie restriction study that I mentioned. In calorie restriction, people are giving food as a lump sum and they were essentially doing time restriction. The mice were doing time restriction. If we think about it, during daytime, when experimenters are coming to the vivarium, the mice should be sleeping and fasting, and they should naturally have high level of AMP kinase if they are truly fasting. And they should also have a low level of mTOR activity because mTOR responds to insulin and that should go off at night. So my suspicion is in many of these experiments where the mice were allowed to eat ad libitum, even normal standard children, now, we know that as mice get older, they actually consume a little bit more.

Andrew Huberman: Food during daytime, which is the equivalent of human night.

Satchin Panda: Humans, nighttime eating.

Andrew Huberman: This is like nighttime eating we know is an issue. I didn't realize that was more of an issue as people age.

Satchin Panda: Yeah, so we don't know. But at least in mice, because we can put the mice in a calorie metric, look at every single bite they're eating, how much they're eating. So I guess it was natural to see that researchers found that there is some mTOR activity during daytime when the mice were not supposed to have mTOR activity because they should be fasting. And since they ate a little bit, and were snacking during daytime, AMP kinase activity was not at its peak. So giving metformin kind of mimicked their fasting state and reducing mTOR activity by a drug like rapamycin also kind of mimicked some aspect of the fasting state. So my suspicion is, since these studies were done always in mice who are supposed to be in the fasting state, and both mTOR, sorry, rapamycin and AMP kinase activator metformin kind of are mimicking that fasting state. That's why we have seen those benefits.

And it'll be interesting to see if that experiment will be done in humans in the long term, because many people are very excited about if there is a long-term metformin study, and then a lot of people are actually consuming a good amount of rapamycin off level. They can get their own. So that's my curiosity.

I'm not saying whether it's good or bad or whether there is science or not. That's something that will be interesting to control for and see, because recently I saw one of my, again, close friends and colleagues at Scripps, Katja Lamia. She did a very simple, elegant study people should have done in the metformin field. She took mice and then measured their blood glucose at different times of the day. And in fact, just like human blood glucose, our blood glucose fluctuates a little bit. She saw that rhythm and then every two hours or three hours on different days, of course, she gave the same dose of metformin to mice.

And what she found was at different times of the day, metformin had a very dramatic change in glucose-reducing ability, which means that even if you take metformin and give at different time of the day for the mouse or even for humans, in a very long term, of course, in these mice, these mice were not diabetic or anything, they were healthy mice to begin with.

So in the long term we might see benefits that are very different. So this brings to this idea that, well, maybe metformin, say at the end of the day, evening metformin may trigger that fasting state much earlier than end of digestion, whereas metformin in the beginning of the day may not, at least from a longevity perspective. I'm not talking about diabetes, type 2 diabetes here. So the same thing with mTOR. Is mTOR going to have a much better impact if taken during evening, morning before meal? So these are my thoughts that go along with all this fat story that we talked about.

Andrew Huberman: Do you take metformin or berberine?

Satchin Panda: No, I haven't taken it, although I have a close friend and colleague, Reuben Shaw, who is now the director of the Cancer Center at Salk. He extensively works on AMP kinase, and so it's always fun to talk to him.

Andrew Huberman: He's a fan. Yeah, I've taken berberine before and I have had two different very distinct experiences with them. First of all, berberine when ingested with carbohydrates, in particular, carbohydrates that have a lot of simple sugars. Definitely. I know this because I measured my blood glucose.

Satchin Panda: I did.

Andrew Huberman: The experiment allows you to flatten out your blood glucose response. So in some sense there is this idea. If you're going to eat a particularly big meal or sugary meal and you don't want to get a massive blood glucose rise, you take berberine or metformin. Metformin is prescription. I went with berberine because as far as I know it works as well.

Satchin Panda: At least for healthy people.

Andrew Huberman: Yeah, for healthy people. That's right. When I took berberine and did not ingest large amounts of simple sugars or carbohydrates. Along with it, I experienced profound hypoglycemia. I felt like complete garbage for about eight hours, and I had one of the worst headaches of my life, which makes sense. You just got a blood sugar crash. So if you lower your blood sugar when you already have fairly low blood sugar, and you're not ingesting carbohydrates, you can really bottom out your blood glucose.

Satchin Panda: So just say--

Andrew Huberman: --I say that for two reasons. One is kind of a cautionary note, and the other one that when you think about the biology of these compounds, it makes perfect sense. And I did not pay attention to circadian effects.

Satchin Panda: When I joined Salk. We know Ron Evans is kind of the big leader in metabolism, and he works on nuclear hormone receptors. These are the master regulator of metabolism in normal cells, cancer cells and many others. And what was interesting was in the first few years, Ron did a very simple experiment. He just looked at what time of the day these nuclear hormone receptors are turned on at gene expression level and some at protein level. And he found that almost all of them have a circadian pattern, at least in some tissue. So he went to that length to say even that circadian is metabolism, and metabolism is circadian.

The reason why we have a circadian rhythm is to have a daily rhythm in food-seeking behavior and eating, and also go through a period of time when we should be fasting. And then on the other hand, all the metabolic regulators also have to follow that rule. And almost all metabolic regulators, everything that we can think of connected to metabolizing macronutrient protein, carb and fat, should also have a circadian rhythm or diurnal cycle to align or misalign.

So, for example, fat oxidation should be in opposite phase with feeding, you know, in retrospect, at that time, it was kind of amazing to see Ron could foresee, of course, he's smart enough to foresee and predict that this is going to happen to circadian field, because at that time, we are thinking about the suprachiasmatic nucleus sleep-wake cycle, and we are not thinking too much about metabolism. So that's the awesome thing about Salk, being at Salk, because we have 50 PIs really crammed into two awesome buildings and with an open lab structure. So you bump onto each other and talk to--.

Andrew Huberman: --And with an ocean view, yes.

Satchin Panda: Yes, it's an amazing place.

Andrew Huberman: I was lucky enough to have an adjunct position there when my lab was at UCSD. And it is an amazing place doing incredible, groundbreaking work, which, of course, includes yours. Listen, Satchin, I'm clear now that we have to have you back on for another series of discussions. Seriously speaking, if you'd be so kind and willing to do that, I want to thank you for several things, first of all, for your taking the time today to sit down and discuss these incredibly interesting ideas in detail. Much of what we talk about on the podcast is obviously grounded in science often, but not always as actionable. And so much of what we talked about today is actionable in the sense that many people are already doing certain dimensions of these things. Some are not. Some are hearing about it and considering it.

You've given us dozens, I've listed some out, dozens of tools and considerations based on whether or not people are engaging in shift work or not. I think a lot of people are going to realize that they are shift workers, even though they didn't think they were, because of the nature of their habits. Now to light and to activity and so forth. I absolutely love the firefighter study because of its relevance to the general population. Also another nod to fire fighters and shift workers everywhere. Thank you. And I think among the colleagues I've known for several decades now, you really are one of a very small few who've managed to do both animal studies and human studies, but also animal studies with a very clear eye and a pointer toward human health. And that's such a vital and rare thing, especially in this day of extremely competitive funding.

So I want to thank you for your time today, for the knowledge you share, the actionable aspects to that knowledge, the science that you're doing in your laboratory. We will provide links for people to learn more about you, and of course, to go to the app so people can engage in some of this science directly. And, of course, you have several wonderful books now that we will also link to, both of which I've read and are wonderful. In particular, the book, the first book, but also a book related to diabetes. And so for diabetics and people interested in metabolic and blood sugar regulation there. So, yeah, on behalf of myself and my team here at the Huberman Lab podcast and all the listeners, I just want to say thank you so much. Your time is valuable, and the fact that you share it with us and educate so many people is really a gift.

Satchin Panda: Yeah, thank you. And actually, likewise, there are very few scientists who have taken this leadership role that you have taken to come and communicate science to the public. It's not easy because sometimes you have to distill it down to a simple sound bite to the point where the scientists, and they'll say, oh, that may not be right, but we always have to keep in mind that we are always living in the dark age of science. Because the reason why I say that, this is not my quote, actually, this is from one of my scientific heroes, Paul Schimmel, from Scripps La Jolla, says, think about it, 10 years ago, what you thought was right and the best has already changed. But one thing is the circadian rhythm. And aligning it to our internal clock, to our habit, is very important. And as you mentioned, we have our My Circadian Clock app, which is research facing, but we have also distilled all of this down to five or six timing components. And we have a new app called Ontime Health, get Ontime Health.

Andrew Huberman: Can people access that through the standard app stores?

Satchin Panda: Yeah. So now it's available in the App Store. Sorry, the Apple App Store. And we want to see how, because people always think about fasting. But as we discussed today, feeding fasting, or eating fasting, and activity and sleep are kind of interlinked and we have to kind of balance both of these. So that was the idea behind this Ontime Health program. And thank you, Andy, because what you're doing is immensely necessary. Particularly these days when science is moving at a very fast pace. There are a lot of results coming out. Sometimes something can be very confusing, and you spending your time to communicate science is exceptional. So thank you, Andrew.

Andrew Huberman: You're most welcome. It's days like today where I get to sit down and talk to brilliant colleagues like you who are doing the important work that really matters so much. And so, as you mentioned a moment ago, there's a lot of darkness and confusion out there. But thank you for being one of those who's shining light.

Satchin Panda: Thank you.

Andrew Huberman: Thank you for joining me for today's discussion with Dr. Satchin Panda all about circadian biology and time-restricted feeding. If you're learning from and or enjoying this podcast, please subscribe to our YouTube channel. That's a terrific, zero-cost way to support us. In addition, please subscribe to the podcast on both Apple and Spotify. And on both Apple and Spotify, you can also leave us up to a five-star review.

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On various episodes of the Huberman Lab podcast, we discuss supplements. While supplements aren't necessary for everybody, many people derive tremendous benefit from them for things like improving sleep, supporting hormones, improving focus and so on. The Huberman Lab podcast is proud to have partnered with Momentous Supplements. We've done that for several reasons. First of all, Momentous Supplements are of the very highest quality and are used with various sports teams in various studies through the Department of Defense, and so on. And Momentous Supplements tend to be in single ingredient formulations. Single ingredient formulations are absolutely essential if you are going to develop the most cost-effective and biologically effective supplement regimen for you because, simply put, they allow you to adjust the dosage of individual ingredients to alternate days that you take different ingredients to cycle them, and so forth. In addition, Momentous Supplements are available internationally, which many other supplements are not. If you'd like to see the supplements discussed on the Huberman Lab podcast, you can go to livemomentous spelled O-U-S, livemomentous.com/huberman.

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Thank you once again for joining me for today's discussion with Dr. Satchin Panda. I hope you found the conversation to be as informative and actionable as I did. And last but certainly not least, thank you for your interest in science. [CLOSING THEME MUSIC]