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

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-hour 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. Our first sponsor is HVMN Ketone IQ. HVMN Ketone IQ is a supplement that increases blood ketones. I want to be clear that I am not following a ketogenic diet. Most people fall into this category. They are not following a ketogenic diet, they are omnivores, and they do eat carbohydrates. So, their standard fuel source for the brain and body is not ketones. However, I found that by taking Ketone IQ, which we know increases blood ketones, I can achieve much better focus for longer periods of time for any kind of cognitive work, and much greater energy levels for exercise, especially if I'm going into that exercise fasted and find myself a little bit hungry when I start that exercise. This is no surprise. We know that ketones are the brain's and body's preferred fuel source, even if you're not following a ketogenic diet. So, in other words, I and many other people are now starting to leverage endogenous ketones as a fuel source for the brain and body, and yet we are not following a ketogenic diet. And of course, if you are following a ketogenic diet, Ketone-IQ will further allow you to increase your blood ketones as a source of brain and body fuel. 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In fact, you can change the temperature of that environment across the night, making it a little bit cool at the beginning of the night, even cooler still a few hours into your sleep, which really helps getting into very deep sleep, and then warming it as you approach morning so that you wake up feeling most alert. I've been sleeping on an Eight Sleep mattress cover for over a year now, and it has completely transformed my sleep. If you'd like to try Eight Sleep, you can go to eightsleep.com/huberman to save up to $150 off their Pod 3 cover. Eight Sleep currently ships in the USA, Canada, UK, select countries in the EU, and Australia. Again, that's 8sleep.com/huberman. Today's episode is also brought to us by Thesis. Thesis makes custom nootropics. Now, I am not a fan of the word nootropics because it translates to smart drugs. And as a neuroscientist, what I can tell you is that you have circuits in your brain that allow you to focus. 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Again, that's takethesis.com/huberman, and if you use the code Huberman at checkout, you'll get 10% off your order. The Huberman Lab Podcast is now partnered with Momentous Supplements. To find the supplements we discuss on the Huberman Lab Podcast, you can go to livemomentous, spelled OUS, livemomentous.com/huberman. I should just mention that the library of those supplements is constantly expanding. Again, that's livemomentous.com/huberman. And now for my discussion with Dr. Sachin Panda. Sachin, Dr. Panda, so good to see you again. Yeah, good to see you. We are colleagues still, but we used to be right across the street from one another in San Diego. those days. Yeah. Yeah, so I'm delighted that you're here. Um 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, uh we were uh discussing your recent paper in nature uh that involved recordings from postmortem human retina. So, maybe if there's time at the end, we can get back to uh your lab has shown that they can uh essentially maintain or resurrect neurons from uh 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 uh split it up. Um The first question I have is how am I supposed to define fasting and time restricted feeding in 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. Yeah. 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? Um 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? Well, you know that intermittent fasting covers many types of fasting. Um So, actually, it started long time ago uh and it's embedded into the history of caloric restriction. Um 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 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. Um 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 you took out a you took out we take out a soda bottle or something. I'm looking at it. Okay, 160 kcal, 30 kcal, 0 kcal. We are doing that. So the point is it's it's we are doing subconsciously some kind of calorie uh counting. But reducing calorie by 20 30% every single day is not possible for many people. So then the idea came in mouse and rat experiment whether they can eat every other day. Um and in fact, this every other day feeding also led to very similar almost equivalent health improvement as um continuous calorie restriction. Um so then the idea was well, every other day is 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? Um so that led to this 5:2 diet where people can eat for 5 days and then 2 days they have to reduce calories. So that's also intermittently people are fasting. Um then as you know, Walter Longo also came with this idea that periodic fasting. Maybe four or five days in every month or two months, 3 months, you can fast or reduce calorie. And he also found many benefits of calorie restriction was there. Were those studies on humans? Many of the studies started in mice, but alternate day fasting, 5:2, Walter's periodic fast fasting, all of them have now been done in humans. Not for longevity, of course, because cannot do those for long time. Um but for weight maintenance, for reducing some signs of aging or reversing, those things have been done. So, all of them uh 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 that all these forms of fasting in which the total caloric intake on any given day is reduced for one or more days in a week, a month, that became 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 um few days in a month. So, when we uh published 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 calorie on any day of mouse life. So, the mice eat the same number of calories as the ad libitum fed mice, um 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 is uh it can be very difficult. The initial experiments was done they were done for 8 hours of feeding and 16 hours of fasting. That kind of become 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. Got it. So now coming back to how do you define time restricted feeding? So the way we have been trying to define experimentally and also in literature is trying to confine all your energy intake from solid and liquid food combined within a consistent window of 8 to 12 hours. Because that's something that doable of course people have done time restricted feeding with 4 hours, 6 hours and some people even try to eat everything within 2 hours, one meal a day. Um but the point is those are not feasible to maintain for very long time for a lot of people. One question about the 6-hour versus 8-hour versus 12-hour feeding window. Is it important that the feeding window begin and end at the same time? Yeah, more or less. Yeah. 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. Mhm. Usually some caffeine and electrolytes Yeah. in the period before my first meal. And my first meal always lands sometime between 11 and 11:00 a.m. and 12:00 noon. Yeah. There are exceptions. Yeah. 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 11:00 a.m. or noon is when I first eat and my last bite of food is typically around, I don't know, 8:30, 9:00 p.m. That's what works for me. Yeah. Is that consistency affording me any benefit? Sep- 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? Yeah, so the start of the feeding window, um that's interesting because it the concept of time restricted feeding when I describe animal studies, it's feeding for humans, it's eating. Uh, so the concept actually came from the science of circadian rhythm. So, that means um um our body has an internal timetable um that's present in every cell, in every organ, um that pre-programs um many molecular aspects of the cells that leads to physiology and all that stuff. So, that essentially uh there is a predetermined timetable for every cell, every organ to do certain things at certain time. And um the circadian clocks as you and I know are more sensitive to light. Light is the most dominant um time giver. Uh 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 from our internal clock. So, that was known for very long time, but then around the year 2000, 2002, um there was a famous experiment by Ueli Schibler from um 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, liver clock actually started following food. So, that means by changing our feeding time, we can change 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 rest of the brain even follows when we eat. And that came out from Urs Schibler's lab in Europe, uh where they systematically looked at even um places that are very close to the SCN. Um for those who are who know dorsomedial hypothalamus or paraventricular nucleus, all of this within couple of uh 4-5 mm of the SCN, but they were following food cue. Amazing. So, then um and now if we think about it, so for example, when the daylight saving time changes, just 1 hour change um uh 1 hour change in alignment between our internal time and external time leads to kind of feeling groggy and feeling not at our peak performance for 1 or 2 days. So, the rule of thumb is when the time giver changes by 1 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, uh you're moving through three time zones, then on an average it will take three 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 2 days, but the bottom line is yes, there is a and desynchrony. So, then what does it mean for the body? So, they one of the function of clock is to anticipate when you're going to wake up, for example, so they 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, uh all of them have clocks. So, even from saliva production, that is the first phase of uh digestion to secretion of all the digestive juice in the stomach and then absorption of nutrient and liver metabolism, everything the whole villa is expects when you're supposed to eat, and they're getting ready for you to eat the first meal after fasting for long time. So, that's why it's breaking the fast of breakfast. Um and when that time changes, when you change it by 2 or 3 hours from one day to another, then um sometimes I like, "Oh, food didn't come." Maybe um will come at the wrong time. We were at the wrong time, and then they will track the new eating times. So, suppose say one day you have been eating every day at 8:00 a.m. Um I I ate at 8:00 a.m. Is that when you start your eating window? When do you When does your feeding window shut? Uh 6:00 p.m. So, I eat for around 10 hours. Okay. Yeah. Um and then one day if I switch to 10:00 a.m., then what happens is a clock is thinking, "Well, the food didn't arrive at 8:00, but it arrived at 10:00. Maybe tomorrow the food will arrive somewhere between 8:00 and 10:00, so we'll be ready around 9:00. So, then they And 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 and different systems to get the best out of it. Is there evidence that those anticipatory systems in 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 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? The anticipatory signal is really important from even even from working up. Um The reason why many people feel not ready completely when they wake up to an alarm clock 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 our body is not prepared for that. And then the best example is when the when um the daylight saving time changes, particularly when we have to wake up 1 hour early, um what happens? People who have underlying heart condition, um when they're waking up, when the body is not ready, your heart is not ready, and all of a sudden the heart has to start pumping a little bit harder, then there is chance of heart attack. And in fact, uh people have looked at hospital records, and they they find that on those days uh there's a sharp rise in heart attacks. And car accidents, right? And car accidents, too, because your brain is not coordinated, so you cannot um, make those fine decisions. So, that's a great example of anticipatory activity. But, coming back to digestion, one thing is um, and this is something that many people might have experienced. There are many rhythms in our digestive system, and one of the rhythms is our look our intestine has this peristaltic function, so it kind of contracts and expands, and that moves food move Food doesn't move due to gravity, so it goes back and forth. And that peristaltic action actually slows down at night, um, few hours after our last meal. And, um, so that's why when people eat late at night, for example, uh, 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, um, of course, uh, people consume some alcohol very often, and then they think that this is hangover, but those who don't, uh, 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, um, so healthy food at the wrong time can be crap or junk. Yeah, I've, um, 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. Yeah. But, if I'm too hungry, often times it's challenging, and so for me sometimes consuming something that at least seems easily digestible, like yogurt or something in a liquid form, um, 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 10:00 or 11:00 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 and cognitively weighed down. So, I think that what you just described makes a lot of sense. So, is it So, if someone were to select a a feeding window regardless of whether or not it falls into classic intermittent fasting time restricted feeding, sounds like s- 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 uh grammatical uh semantic issue. Um 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 food's digested 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. I 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? So, uh and so I like to think about it scientifically like, okay, is does plain water break a fast? No. Does air break a fast? No. Um 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. Like so, I mean, when we're talking about breaking a fast, are we talking about a rise in blood glucose or are there molecular signals downstream of of a rise in blood glucose that um 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 uh bite of food at 8:00 p.m. and at 9:00 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 by if I went for a hard run that morning, maybe by 9:30 a.m. I'm back in a quote unquote fasted state. So, what is the fasted state really? Because when I'm eating at 8:00 p.m., just to give another example, I'm start fasting at 8:01, perhaps, but I have 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, so 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-mi 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 I'll stop asking questions now because they all relate to the same theme. Yeah. Now, these are um very interesting question, and then unfortunately, as you can as you have you might have seen in life, um 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 uh gut or fat or muscle in total whether it's uh consuming glucose or fat as energy source. The idea is when we fast when we are without food for several hours then ideally our body will tap onto glycogen first and then to 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. Um 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 they are the metabolism is different they store relatively less glycogen than humans do in terms of total metabolism so they 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. So now as we give them food um within 10 or 15 minutes they're not actually consuming couple of grams of food they they might have consumed say 100 or 200 mg of that chow so which is less than say 5% of that food. But then the RER will immediately begin to rise as if that small amount of food stopped that fat burning process and cranked up the um carbohydrate burning process. When you say fat burning process, you mean body fat stores being burned, right? Not dietary fat, correct? Yeah, so it's all body fat. Means that that's why I said um we don't know where that fat is being burned because we are just measuring how how much mice is breathing in and out. Um so for example, it can be from the skin, so subcutaneous fat or belly fat. Or But not dietary fat. 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 for Yeah, 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 uh low-carbohydrate diet allows you to burn more fat. Um and the more nuanced uh people out there will say, "Well, that's true, but you're also talking about dietary fat." You know, the word fat can confuse people. I realize you're not doing that. You're 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 I'll probably get um pitchforks uh sent through the mail toward me on on that one, but but I think that's true, whereas, you know, people who consume carbohydrate can still burn body fat even though the majority of the fuel they're burning is from carbohydrate. So So here in this case, for example, for mice, we know that as soon as they start eating, um 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 mg of food. And 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, and then So, that's one aspect. So, now let's say um let's stay on this, and then I'll come back and talk about non-caloric food and how whether that is considered fat. I'd like to take a quick break and acknowledge one of our sponsors, Athletic Greens. Athletic Greens, now called AG1, is a vitamin mineral probiotic drink that covers all of your foundational nutritional needs. I've been taking Athletic Greens since 2012, so I'm delighted that they're sponsoring the podcast. The reason I started taking Athletic Greens, and the reason I still take Athletic Greens, once or usually twice a day, is that it gets to me the probiotics that I need for gut health. Our gut is very important. It's populated by gut microbiota that communicate with the brain, the immune system, and basically all the biological systems of our body to strongly impact our immediate and long-term health. And those probiotics in Athletic Greens are optimal and vital for microbiotic health. In addition, Athletic Greens contains a number of adaptogens, vitamins, and minerals that make sure that all of my foundational nutritional needs are met, and it tastes great. If you'd like to try Athletic Greens, you can go to athleticgreens.com/huberman, and they'll give you five free travel packs that make it really easy to mix up Athletic Greens while you're on the road, in the car, on the plane, etc., and they'll give you a year's supply of vitamin D3K2. Again, that's athleticgreens.com/huberman to get the five free travel packs and the year's supply of vitamin D3K2. So, there's a famous experiment that was published last year by Jota 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 gave reduced calorie consumption by 20% or 30%, and gave that food the rats, and then subsequently mice, and they all lived longer. What is interesting is um in all those experiments, um 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're eating all the time. And then these rats uh were given 20% less. And what happens is these mice or rats now are going to take that less food, which is restaurant now, and just eat a little bit of uh lunch, and then snack after 3 hours, or snack after 3 hours. They gobble up all that food within 2 to 3 hours, maximum 4 hours. Food is gone. So, they're sort of on the OMAD diet, the one meal a day. Yeah. They're almost like in one meal a day, 3 to 4 hours, food is gone. Or you can say they're on 4 hours eating or feeding and 20 hours fasting. Um So, then the question became, well, the benefit of caloric restriction, as we know, is it due to reduced calorie or time-restricted feeding, or timing There is a timing component to it, that they are eating all of that within 3 to 4 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 in every 2 hours. Um so, Joe Takahashi, who actually published the first paper in 2017 showing that most caloric restriction study in I mean, he used the protocol that was used by caloric restriction field, uh 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 um 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 uh for example, suppose say the ad libitum fed mice eats a 5 g of chow in a day. And if you want to reduce calories by uh 20% then the CR mouse should get 4 g of food. And he divided this into nine or 10 meals. And then gave them in every 90 minutes. So, in this case they are eating small meals throughout day and night so there is no fasting. So, you can say that well this mouse actually is not getting into fasting because in every few hours is uh getting some food. And then he measured how long the mouse is going to live. Um and he used um a count means uh this is a very standard protocol. People count how many mice are dying on which day and then examine them to see whether they died because they there was an accident or they actually there was a natural cause. And then they calculated at the end what is the um half uh life. So, 50% survival because that's on an average that's a good indicator because if if there is an outlier that will live for a long time then that can skew. So, what was interesting was the ad libitum fed mice of course they lived certain number of days and then this caloric 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%. I've wondered about this because recently you know, there's been there were a bunch of news headlines about intermittent fasting and I and frankly I was frustrated. Uh if you looked at one major news outlet, they would say "Time-restricted feeding affords no additional benefit beyond caloric restriction for weight loss." Yeah. Then an another popular press venue, let's call it that, same study described as "Time-restricted feeding doesn't work." Yeah. Right. And then another one and maybe someplace um even more extreme. You know, time-restricted feeding um n- uh 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 is invaluable, which is not the case. It 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 day my day when I'm not eating as opposed to eat 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. Yeah. Right. So, Um and so I I think that um if we can segment those out, um 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. Yeah. Right. 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 8 and 12 hours per 24-hour cycle, are tilting the scales towards living longer as opposed to living shorter. This example of this news article that you mentioned is really interesting because that relates to those your takasis 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 mouse the same calorie restricted diet and feed them during daytime within 12 hours or 2 hours then the mice live 10% extra. Beyond that. Yeah. So 20% 20% So okay, so let me make sure I understand so that so that I make sure I understand. If you take a certain number of calories and you distribute them throughout the 24-hour cycle Yeah. it's chloric restriction the mice will live 10% longer. Yeah. If you however restrict that to the active cycle of the so for humans the daytime then 20% then they live 20% longer. 20% longer. So it's not just total caloric intake. Yeah. Meaning it's not just important to be sub maintenance in calories for sake of longevity. It also is important as to when in the 24-hour cycle you eat those calories. Do I have that right? So now that's still the story is not over because this mice were fed during daytime when they're not supposed to eat. That's right. So for us it would be the equivalent of being on the night shift and only eating at night but a sub caloric sub maintenance calorie diet I guess is the right way to say it. But when he fed mice during night time when they're supposed to eat and they're seeing this getting the same number of calories within 12 hours or 2 hours then the mice live 35% longer than the control. 35% longer. So scale to human lifespan which you know we don't know but but 35% longer would mean that and again no one knows but um now what is the average mortality in the United States? Somewhere around 80? ex- Yeah, so it's around 80. It used to be 80 now it slowed reduced a little bit because of COVID, but let's take 80. Okay, so people are then now living somewhere between 25 and 35 years longer. But I'm putting some error bars on there. yeah, yeah, yeah. Amazing. was really profound, but now you pointed out biomarker 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 looked for he did a lot of molecular analysis with known markers. For example, 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 um CR only mouse which ate throughout the end night that mouse is going to live less than the night fed mouse that was going to live 35 25% extra. Does that mean that there are biomarkers related to longevity that we just haven't discovered yet? Yeah, so that's exactly so that means whatever we know so far about biomarkers um those he could not use to predict. Maybe there was a lot of noise. Maybe he wanted he had to use more number of mice to get that because, you know, biomarkers are not going to predict in every instance so 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's no difference in body weight and body composition. Across all these different Across all these groups. So, it doesn't matter when they ate, provided they were sub 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. Yeah. 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 or you start your feeding window in the morning or start your feeding window in the evening or you um or you portion control for sake of weight weight loss." we're taking a snap sort of that. And then another thing with the human study that uh we are referring to here um that in that human study people are actually already eating within 10 hours 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 uh 14 hours. All participants had to reduce their caloric intake and they reduced by almost 25%. The CR group continued with 10 hours eating window and the CR plus time restricted group had to eat the same number of calories within 8 hours. So, it's just a 2-hour difference. It's just a 2-hour difference. Okay, so that people I just want to make sure people can understand. So, in in this human study, which is the one that I felt that the popular press venues, all except one venue um got either said me 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 sub maintenance calories, so caloric restriction, CR as we're calling it, the acronym CR, but restricted that to an 8-hour feeding window. And they didn't see any difference in terms of weight loss. Yeah, weight loss is it's not all that surprising, right? I mean, if it's just a 2-hour difference. Yeah, exactly. So, we have done that experiment in mice and we don't see um difference in not only weight loss, many other markers. And I was telling you about this um Jota Kazi's paper where I told you that he allowed these mice to eat within 2 hours or 12 hours. Subcaloric diet. 2 or 12? 2 or 12. Yeah, that's dramatic. But still, he did not see change in longevity even within those two. So, that means um when you do caloric restriction and then at least for mouse and you are within 12 hours window um that's that is giving the mice the best benefit, the optimum benefit. And um two, three, or five, or 12 for a mouse doesn't matter, at least for longevity. Can we conclude for humans that whether or not a feeding window is 4 hours, 6 hours, 8 hours, or 12 doesn't matter, provided the calories are are similar or same? Well, I won't go to that extent because we don't know many of these uh particularly we don't know how this sort of uh eating window will affect both sexes because, you know, we always think many of these mouse experiments even told you about, those are done only in male mice. But that should be changing, right? Because the NIH, I know this cuz I'm on study section, which is just a bunch of people who record who review grants, is that every grant now has to include sex as a biological variable. You It's hard to get away with a um well, rather I should say it the way it should be stated, which is people are required and should want to look at these phenomenon in male and female mice, yes, especially if there are differences. So in this case um there are many I mean there is also another paper in time restricted feeding that also came out a big paper showing that they um thermogenesis was accounting for loss in fat mass in time restricted fed mice. That was also done only in male mice. Um so this is um we are paying attention to it. So we are now doing all of our studies in male and female and we do see big differences between male and female. Coming back to humans, what typically happens is when you're trying to do 4 hours or 6 hours of time restricted eating, people will inadvertently reduce their calorie intake. Yeah, just because of gut volume. I tried one meal per day and then 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. Um so people will reduce um 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 I eating. And that can have a very adverse effect in long term because we know that this energy deficit and in fact there is a scientific term for that. It's called RED-S, relative energy deficit in sports. Relative energy deficit in sports, okay. Yeah, it's because nearly 40% of athletes not the NFL guys, but you know, there are a lot of people who do track and field um and nearly 40% of athletes actually experience this RED-S without knowing. Can male and female athletes both and female experience reds. So, it's reds, r e d s. r e d s energy relative energy deficit in sports. Interesting. This is the first I've heard this acronym. We have a new acronym, folks. This is good. To add to a list of other acronyms, but I So, males and females can experience it. So, in females, I've heard that um reds um can lead to uh amenorrhea, so loss of of mens of the menstrual cycle. Yeah. So, that's uh so common that so prevalent that in fact many women many female athletes they take it for granted that yes, if they are more active than they will lose their menstrual cycle, which is uh which may be common, but it's not normal or optimum for health. And even if they don't want to get pregnant. Yeah. Yeah. Uh we had an expert on female hormones come on and say the very same thing that regular cycling is a It's very important. of ovulatory menstrual cycle is is important to try and um maintain. Yeah. Um So, that's one, but then what is really concerning is um it does affect bone health. And um in this state people actually over long period of time they lose bone mass and the bone also becomes more prone to injury, microfracture and fractures. Um so, again, it's a risk means if some people are trying to eat within very short time and they're physically active that happens. And it also has impact on uh means the reason why these women are losing menstrual cycle is their um hpg axis is disrupted. Hypothalamus pituitary gonadal axis. And it starts it may start again upstream at hypothalamus or pituitary. So, that means that hpa axis, hypothalamus pituitary and adrenal axis may also get disrupted. One of the symptoms of RED-S is also depression, anxiety, bipolar-like symptoms, and we know that many um many athletes experience that. We think that well, this this may be just peer pressure that always trying to compete, and we know that unfortunately, there are few athletes who just can't cope it, and there are many attempted suicide or suicide. So, this is a serious issue. And um there's also another new topic in the lab to come up with a mouse model of RED-S, and then study it. Um but this is one risk why we should not reduce our eating interval to two such to one meal or very short time, um because it can have adverse side effects that we don't know now. Um maybe in future, we'll figure out when we systematically study them. There are studies that are published showing 4 hours and 6 hours time-restricted eating has benefits on weight loss, but those are on healthy individuals, and they were in the studies, so the um you know, the study team took a uh well, already monitoring, they made sure that there was no sudden weight loss or weight loss below um some safety level. Uh so, those are very different from regular people who are who may even normal weight or even weight within the healthy range, if they do, then they can potentially. So, that's why what we think is 8 to 10 hours may be the ideal spot to begin with. And um once you're 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. Um up to 12 hours, they do get a lot of benefits, not all, but So, this is 12 hours of 12 hours of eating, 12 hours of fasting. Um in humans, um again, nobody has done systematically 12 hours, but there was one study in Europe um from Tin Hai Colette Lab, and Tin Hai and I we collaborate. So, they used our myCircadianClock app. This is a research app we developed just to This is mostly used in time-restricted eating studies. And um he had nearly I think he started with 200 Swiss uh participants, but then at the end he selected and took very small number of group people who are very um 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 uh advice of Swiss nutrition advice that's given to improve health and reduce blood glucose, almost like diabetes prevention program in the US. And then the other group was given advice to eat within 12 hours. Um this is very early on in time-restricted eating, and we thought that the mice were getting some benefit. Let's try whether 12 hours has any benefit. Um the bottom line is at the end of uh 3 months and 6 months, what um he reported is both groups lost same amount of body weight. Um 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, um which is the standard of care there, it achieved the same amount of weight loss as just giving people this advice that eat within 12 hours. So, one way to look at it look at the result is like this. And um 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 um 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, um yogurt, dairy products that you can almost without any preparation. And then second uh Nova 2 is kind of home home-cooked food that most people will prepare in few minutes and then three and then fourth one is the food that you can never prepare at home. So, for example, biscuit or cookies that we usually purchase and few other things. And usually the Nova 4 are unhealthy ultra-processed food, so which we should not be eating. So, the advice is to reduce Nova 4. And what he found was people who got all this advice um to re- improve their nutrition quality, they actually improved their nutrition quality. They reduced their Nova 4 food. And people who were in time restriction eating that 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 in the maybe Tin Hai will do this experiment again to combine nutrition advice with time restriction and maybe reduce the time to 10 hours and that might help. Um so, 12 hours is something that I say anyone from 5-year-old can do. And um if you're trying to maintain weight, that might be a good way and combine that with exercise, it'll be great. And you and people can more easily avoid reds yeah in that way. Women and for non-athletes or recreational exercises, it sounds like women if they distribute their calories across 12 hours are less likely to lose their menstrual cycle. Yeah, so again, this is something that we have to look carefully. They have to be because we do have the MyCircadianClock app that many people download and self-monitor and they share the data for researchers. We will provide a link to that, by the way. It's a great It's a great tool. Yeah. 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 and quality so they're eating only salad and few and they're trying to increase their fiber intake and it's really hard to eat so much of uncooked food because cooking helps to absorb more nutrient and then at the same time they're running 5 miles every day and of course all of this combinedly can lead to RED-S like symptom. 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 that calorie over a long period of time. And this is Rafa de Cabo's um 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. I 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. Yeah. So these are all caloric matched, right? Between groups. And then non low-carbohydrate diet. So, it's sort of more standard, uh I think it was somewhere in the neighborhood of 60% of calories from complex carbohydrates. And And as I recall, the um the greatest weight loss Remember, same calories across groups, folks. Um was achieved with low-carbohydrate plus caloric restriction. Yeah. Um and I wondered why all the popular news venues didn't cover that study. Um but that's why I'm bringing it up now. I thought this is really interesting. And um And I'm somebody who's uh cycled low-carbohydrate diet um before. I find it hard to sleep after about 3 or 4 days of being on a low-starch Yeah. diet just personally. I So, I like to eat some starches, especially if exercising intensely or working intensely. That's just a little editorial there that um but Look, I know many people who do just feel better on a low-carbohydrate diet. But 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. No, I 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 majority of them are very aware about how much they're eating and what quality of food they're eating. Ah, so you're really an optimist. You're looking at the 40% of the glass that's uh or should we say not full? The That was a pun intended. But the um No, it's a very interesting way of looking at rather than saying, you know, why are 60% of Americans obese? Uh saying, why are 40% not obese? That's a very interesting way to look at it. Yeah. I mean, um subconsciously we are always making that decision. Means I know means I'm sure that you are not going and eating cheeseburger every day because you want to improve. Yeah. Right. No, yeah, exactly. I wouldn't feel good. Yeah. I enjoy a cheeseburger now and again, but I No, not certainly not this stage or any stage of my life. I think that um I think people 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 maintained You've always been in good shape. Actually, this is the first time I've seen you in a while and you seem to have aged backwards. So, you are a a poster for your own ideas and hypotheses about time restricted feeding, but but I 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 there was a It was like a bimodal distribution there. 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 Yeah. and social connection. Did I miss it? Maybe temp- and temperature. Yeah. Yeah. So, how do these combine with one another and using timing that we begin and stop feeding as kind of an anchor point? Can we explore that a little bit? Yeah. So, you know, we got into this um beginning and end and then we you asked for the calorie, how much calorie will break the fast. Um one thing that I want um the listeners and viewers to bring back to this timing of when we when you're breaking the fast because we equate health with weight, body weight. And um that's when we are talking about nutrition quality and quantity because both of them have impact. So, now let's think about mental health cuz a lot of people do struggle with mental health. They have anxiety or um depression. And also um so, gut health because um 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 in empty stomach. Um those who have acid reflux or heartburn, they're prone to that then um having black coffee in the morning before any food um can upset their stomach. So, that's why in those cases, it's very clearly that caffeine for them becomes the trigger. Um that's 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. Um 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 them putting their health at risk for acid The other thing is people who have anxiety, panic attack, we know that caffeine can judge you up. Especially on an empty stomach. 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. So, Do you avoid caffeine in the morning? No, 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 night time activity. And maybe we can take a little bit of detour and talk about night time activity because that fascinates me as a circadian biologist. Cuz over last 200,000 years, means we assume that humans, homo sapiens, evolved 200,000 years ago. So, we have been as a species, we have been living on this planet for 200,000 years. And only in the last you can say couple of thousand or 5,000 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 decision, many many animals they kind of figure out strategize how to get food, but controlled use of fire is something very specific to human. And when we started controlling fire, fire did not essentially extend the day because fire created a evening that was very different from what people did during the day. And what people used to do during the day, they walked a lot, means gathering food was almost everything that we did. And so in the evening after the after the after we brought food, mostly tubers or maybe lentils to cook or once in a while animals that we can we could barbecue. Um all of these things happened around fire. And fire was so expensive that it was mostly communal fire. So if you go back to for example Masai and all these ancest sorry um uh populations that have no access to electricity and are still living kind of that historical life. Uh 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 um culture, they talked they sang, they danced. They strategized. Um that's how politics started, philosophy started, science started. All of these things that are very unique to human civilization started around fireside chat. So um in that way if you think about it, we are still doing fireside chat. The only thing is we have the microwave and the television and our social media. And now we chat with our thumbs. So, it's still So, we are hooked to that evening activity because that's when we're 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 restriction and stop eating at 6:00 because it's ingrained in our in our even 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 consumption, particularly cafe, where people can come and have a little bit of coffee and socialize, it also started as a evening activity. And this is in Now, we can go back to Istanbul because that's one place where coffee cafes started in mid-16th century. So, if we are talking about 1540 to 1570, and that's when uh I'm sorry, I'm forgetting the name of historians who who actually invited me and Okay, his name is Cemal Kafadar, and I must be butchering the name, but I'll 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. I'm I'm actually I'm even checking right now in my EndNote library. It's not picking up that. That's right. We will provide a link. Yeah. We'll provide a link. 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 with Sufi branch of Islam because they are the ones who uh 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 and dancing um by the Sufis and then here in Istanbul people started congregating and having um uh talk about politics. But then around the same time um some you know in Turkey there was a good sizeable number of um Muslims who have to do five prayers a day. 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. And they woke up. Uh so that's how it started as a morning drink to stay awake and kind of get get on with the day. But what happened was I don't know whether you have ever tried Turkish coffee. It's very thick. Mhm. Yeah, yeah. A few years ago right before the pandemic, 2019, I traveled to Turkey. As First of all, the food is amazing. The coffee is indeed very, very thick. Yeah. Um and I have a pretty high caffeine tolerance. Yeah. Um from drinking so much coffee and yerba mate over the years and still do. I really enjoy it. But um yeah, it's it's very intense. And so what you're saying is that um 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. Uh which is essentially like the way I think about it. We did an episode on caffeine and some uh someone else, Michael Pollan, not I, described it this way. They'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, you're you're it's a credit card of sorts with an interest, right? Right. And the interest being um an energetic lag that you're going to uh experience in the afternoon. But what happened was with the uh strong coffee, um 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. Ah, so coffee actually led to the development of breakfast, not the other way around. And that uh yeah, so it does That's very heartening uh no again, no pun intended uh for the uh the caffeine uh lovers among us uh which I count myself one of those. So, essentially, the food before coffee became breakfast. So, you kind of give something to your uh to your stomach, so it's busy digesting that, and then when the coffee comes in, it's not reacting to coffee and creating um acid reflux. 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. in that culture. Means in that context. Um we cannot say that whether the same thing happened in all over the world where coffee is not consumed, but still people eat something in the morning. Um You said you start your um first meal uh of the day at around 8:00. What time do you wake up? I wake up around 6:00. I started at 6:00. What time do you have your first caffeine? No, actually, I have So, that's why I brought up this uh story because I have coffee after my breakfast. 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 um allowing uh suffice to say that allowing some of the natural waking up signals to occur and light to kind of clear away and adenosine to further extend an activity that 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. I'd like to take a brief break and thank our sponsor InsideTracker. InsideTracker is a personalized nutrition platform that analyzes data from your blood and DNA to help you better understand your body and help you reach your health goals. I've long been a believer in getting regular blood work done for the simple reason that many of the factors that impact your immediate and long-term health can only be analyzed from a quality blood test. The problem with a lot of blood and DNA tests out there, however, is that you get data back about metabolic factors, lipids, and hormones, and so forth, but you don't know what to do with those data. InsideTracker solves that problem and makes it very easy for you to understand what sorts of nutritional, behavioral, maybe even supplementation-based interventions you might want to take on in order to adjust the numbers of those metabolic factors, hormones, lipids, and other things that impact your immediate and long-term health to bring those numbers into the ranges that are appropriate and indeed optimal for you. If you'd like to try InsideTracker, go to insidetracker.com/huberman. They have a special promotion right now through Pi Day, March 14th, where you can get 31% off their ultimate plan. This is their biggest promotion of the year. Again, if you go to insidetracker.com/huberman, you can get 31% off their ultimate plan. Now, actually, I'm kind of um speaking what many other researchers have found. And this this particularly this fireside chat, I'm forgetting again the name of the scientist. I think she's from University of Washington, Seattle. Um she went to Africa and kind of recorded what people are talking. Of Of you could not understand what they were talking. Twitter and whether or not Tesla's stock is going up, of course. No, no, just just kidding, folks. And then came back and tried to translate and then figured out that what they were talking during daytime and in the evening were very different. So Um so so Uh what are they talking about at night? Do you So exactly, so this is like they're talking about matchmaking and talking about politics and strategizing to gather food or or uh even singing and dancing. Uh so this is um if you think if we think about it, how we manage sunset to our bedtime. What we do between sunset and bedtime affects most of our health. I'm going to think about that for a moment. I totally agree. Um and by the way, I'm a huge believer and and I'm in 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 that's not Those aren't scientific terms, as we know. But I do believe and I've noticed a distinct difference between the first 8 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 they this evening time it it's certainly in the context of mental health. We know that morning and evening we are basically different creatures. Yeah, completely. Yeah. So that's why I think in the evening, if you think about it, um again, this is again another set of research from um my good friend Horacio, who de Iglesias. Yeah. Oh, yeah. Yeah. I'm a big fan of Horacio's. Another uh he's a fellow Argentine, so occasionally we riff about things related to that, but he's a wonderful biologist. Are you guys collaborating? Yeah. He's a he's kind of I say he's very humble and keeps a low profile, but he does amazing amazing research. He does research that um 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 um when these people are eating, sleeping, or in this case activity exposure to light. That's what Horacio has done. And uh he puts this active watch, which is kind of a modern um activity tracker. Um but it's a little bit more refined because it also collects uh light information. What he found was most of these Argentinian tobas who have no access to electricity they consistently go to bed somewhere between 3 to 3 and 1/2 hours after sunset. So, this is very important because we always think that um our ancestors, when they didn't have electricity, as soon as the sun went down, they just went to sleep. No. The fire extended their evening. So, they were staying awake for 3 to 4 hours kind of you know, um decompressing themselves that we say and then doing all these uh activities, cooking, saying meals, and then they would go to sleep. And if you look at the sleep onset variability, it was very small. Like, they're going to bed almost within 15 to 30 minutes standard deviation. So, no night owls versus morning people. This guy Exactly. So, we'll get to that. None of this this uh the I get attacked by for many reasons. That just goes with the the business I'm in of being public-facing these days, but every time I talk about viewing sunrise or low-angle sunlight, you know, getting some sunlight early in the someone says, "Well, I'm a night owl." And they just It's almost like a a protest of trying to protect identity. It's become this ideological I I 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. Yeah. So, there is no such thing as a night owl or a morning person in the context asked him pointedly because and then I said, "No, he he has not seen." When he has tracked hundreds of people and if we ask, there are many many sleep researchers at least the public-facing sleep physicians or experts, they will say, "Yeah, we can say 1/3 of people are night owl, 1/3 are morning and then 1/3 are in between." But Yeah, they call them like bears, wolves and you know, and I'm not being disparaging of that idea. I think people really do feel as if uh as if they orient towards one pattern or another. 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'll try to get ready to hit bed and then by 12:00 I'm in bed and I used to get up at 6:00, 6:15. That's still That's a pretty short sleep. With an alarm, of course. And but then daytime, I used to take 45 minutes to 1 hour nap. And that was regular. Like even if uh whenever I got time, of course, in college, you know, you don't have the whole day unlike in high school, you don't have opportunity to nap, but in college, you can. 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. Yeah, but in in this case, just come back to the dorm and after lunch usually, I used to take nap. So, um then in grad school, I remember I rarely went to bed before 2:00 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 and but then afterwards when I look back in postdoc when I had 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 do too much noise. 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 10:00 and 11:00. 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. At Colorado. At Colorado and he also had grad students and and postdocs like me who strongly believed that they were night owls just like everybody else. And he took Ken took the whole lab for camping. And when they were camping, of course there is less light and lot of physical activity, hiking during the day and they all went to bed between 9:00 and 10:30 p.m. I love that study. Yeah. What Sachin just described was a study, I think there were two studies uh There were two, yeah. And um what's interesting as I recall is that after going camping for a weekend where people wake with the more or less with the sunrise. Yeah. And go to sleep a few hours after sunset. Yeah. 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. Yeah. So, um 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. So, take that night owl, so-called night owls. I also in graduate school I would work until 2:00 a.m. I loved it. I'd blast music in the lab. Everyone was at home pretty much, not everyone, but there were the the night crew. And then I'd get in sometime around get up or sometime around 9:30, 10:00, and then get in around 11:00, and it was no problem because I was going to stay 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 the clock can our internal clocks can shift. But this idea that we are genetically biased towards one schedule or another may need revisiting. That's what That's the conclusion I'm taking from this. couple of aspects. One is you know, some people are genetically so pre-programmed because the other flip side is what is called technically familial advanced sleep phase syndrome. So, these people you can give them caffeine or whatever, but they will fall asleep. So, at 8:00, they cannot stay awake till 9:00 or 10:00. And since it's a very strong phenotype in sleep and circadian rhythm field, they're very well studied. So, in fact, Louis Ptacek and Ying-Hui Fu, they were the first one 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 um allowed the clock to run in a way that these people went to bed very early. I guess historically, given these fireside chats, those people were probably not contributing much to the political discussion. Whatever there 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? Are people just sipping their eating and sipping their caffeine and just waking up? Um but is is there are there any ideas about what morning discussions really consist of? Morning discussions or daytime discussions are mostly about um work. Um like hunting, gathering, or farming, all that stuff. And even these days, that's what we do. We you know, you go to uh I go to work and it's mostly one meeting after another and um we're talking about how I mean if you're in different committees, then you're solving problems or your students come with questions, you have your TA or the office hours. All these things work-related. We're not talking, I mean, serious philosophy of unless you're in a philosophy department and you're talking or political science. Um and also we're not singing and dancing. So, that's why the evening activity, even these days, are very different. And typically, the evening activities uh where we express ourselves. We express who we are. We feel like we are free. And um you know, you and I, we have this academic intellectual freedom. We can talk about our work, just like we're talking now. There are a lot of people who work for even in tech industry, they may be working for Google and all these big tech companies, they cannot talk about their work to anybody else. It's all secret. It's all secret. So, just imagine they're staying So, they're spending more than half of their wake up 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 um the person who is going and baking in a restaurant or cooking or the person who is um taking trash and driving Or nurses and doctors can't talk about their patients. There's confidentiality. work. 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 audience. So, we always switch our roles. Sometimes we are performing and sometimes we are observing. So, that's what happens with me time. I love this. So, um maybe social media time should be restricted just maybe a small portion of that evening time cuz I would hope that people would also interact socially with in in the real sense. constructive way or maybe you use that for connect with your family members um whom you love or you can have some productive discussion or something. So, it's it's kind of interesting. I think it's extremely interesting because I think again this this conversation about time restricted feeding is really a conversation about circadian rhythms and sleep-wake activity and human evolution, right? Um So that's why let's go back to this uh um night owl because we we kind of made a comment that maybe it's not genetic, but uh this is where I'm still wrapping my head around because, you know, these days there's some um GWAS studies where they're trying to look at night owls to see whether there are some genetic uh linkages. And, you know, sometimes we always think, yeah, if you take half a million people, of course you'll find some loci that Um but going back to this idea that are some people more sensitive to light so that 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 Dover story that we're talking about or people going on camping, we have removed that light. Um so there is some um evidence that people's light sensitivity, particularly the IPRGC or this intrinsically photosensitive retinal ganglion cell or the simple speak is the blue light sensors in our eyes, um there seems to be even one log unit change in sensitivity as measured by pupil constriction. So for some people um a small amount of artificial light at night could really shift their circadian clock, wake them up essentially. And then for some it may not. Yeah, I'm very sensitive to light at night. Yeah. Exquisitely sensitive to it. Ah, so then you are like a teenager. Yes, in many ways. Um I've been told this. Thank you. Um yeah, I think. Um I have actually switched to using a red nightlight, 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, and I find that I fall asleep and stay asleep throughout the night much more consistently. Especially in when I'm in new environments, which always makes it disruptive to sleep. Um It's made an enormous difference in the depth and duration of my sleep. And um because oftentimes hotel lights, you know, in the bathroom, you'll turn them on and just you're just getting beamed. And you're right, some people don't seem to to be bothered by that. I I I really struggle with that. Yeah. And in fact, in teenagers, right after puberty, um there seems to be a I think that's when uh the teenagers become more sensitive sensitive to light. Uh and it's very it's well known that the teenage boys and girls, they 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. Mhm. Um 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 5 6 hours. So, um is there any truth to the idea that going to sleep within 3 hours of sunset is somehow better for our circadian timing mechanisms? Well, um there are a few things. One is said that you are very sensitive to light, so I assume that you also avoid bright light in the evening. As best I can, yeah. As best as you could. Yeah, and then uh what is happening is with absence of that bright light, your melatonin levels begin to rise, so you are prepared for sleep. Um of course, this is something that we cannot measure because measuring melatonin in every 1 hour or 30 minutes um is very difficult and there is no consumer-facing uh product yet. Uh so, it's likely that your your body is preparing very well under this dim light to fall asleep. And when you are trying to stay awake and go 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 um unfortunately, you cannot have good night of restorative sleep for the second half of the sleep because of the tension. That makes good sense. Yeah. So, that's why um you know, you are not the only one. Means uh there are many people who who experience that. And in fact, a lot of people think that well, this may be the way I sleep. Maybe I'm not um I'm not designed to sleep restoratively until you know, I sleep one day just like the camping trip. And then they realize what what it feels like to be healthy and rested. Yeah. Absolutely. Um, I I want to make sure that we talk about the other aspect of fire, which is you had a paper that came out recently, very interesting paper studying firefighters and time restricted feeding in firefighters. Would you share with us the the general contour maybe even some of the specifics of of that study cuz I think it's very interesting for for sake of shift workers, but for everybody really to understand that these results. Yeah, so let's go back to shift workers because um, this also relates to all of us because I will let's say that each of us is a shift worker or has lived the life of a shift worker um, and we have experienced how terrible difficult it is. Um, and now let's start with what is the definition of a shift worker or um, shift work like lifestyle. There is no universal definition, unfortunately, but there are many European countries and particularly if you go to International Labor Organization um, then you'll find some references. Different European countries have slightly different definition 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 um, they assume that we are just like you said, we are kind of programmed to sleep somewhere between say 10 p.m. and then stay in bed and kind of wake up after 5 a.m. So, the idea is if you stay if you're staying awake for two or more hours between 10 p.m. and 5 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 defines 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 queue, so in this case when you travel jet lag for or traveling across 3 days, 3 hours of jet lag will take um 3 days to um reset. Similarly, if you're staying awake for 2 hours extra, or if you're waking up 2 hours before your habitual wake up time, then we just don't get wake up and then be engaged in some activity in the dark. Most of us and means unless you're wearing a infrared goggles. We turn on light, and light resets our clock. So, in that way, every time we stay up for 2 or more hours, even for 1 night, then for the next 2 nights our clock is kind of trying to catch up. So, in that way for 3 days, the day of the disruption and then 2 days following the disruption, um our clock is trying to catch up with the outside time. So, our clock 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 um Department of Labor Statistics um US government, um they have not been tracking what percentage of people are doing shift work uh 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, um doctors, firefighters, um and bakers, um truck drivers, um 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, um they're also experiencing Grant deadlines. Then, we are also experiencing experiencing the lifestyle of a shift worker because we're delaying sleep. Even if you're delaying sleep by 2 hours for most of the college students for 5 days and then the weekend you're trying to catch up. That's kind of a circadian disruption going on. Then, you take 1.5 or 1.6 million new moms um in the US 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 um you know, 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. Um we don't count many food delivery and uh Uber driver, Lyft drivers as shift workers, but they many of them we know that they live. So, in that way, we think the actual number of people who are experiencing the life of a shift worker is um somewhere around 50% of the adults um 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 because my schedule is messed up Uh, I work in a different way. And um that comes into play. So, that's why we thought um okay, so we should try something on shift worker. 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, uh high cholesterol, um gastrointestinal problem, indigestion, um chronic uh inflammation of the colon, and then even uh colon cancer in many cases. And then of course diabetes, um all of these uh 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 uh trials. Uh one thing is most physicians and most scientists, even people who do shift work, they know that they are their body and mind is so messed up that often time even medications may not help them. And so, that's why we don't try any medication. Why to take the risk? We we know it may not help them. And then when it comes to lifestyle intervention, whether it's um sleep extension for example, we cannot do 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, um most nutrition studies involved the participants to come to the clinic and get one-on-one or one attend group sessions. And they cannot come. And they cannot even sometimes come to the clinic visit when people have to take draw blood. And in fact, there is another caveat that just if suppose say 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 5 nights. That means I'm sleeping less, maybe 4 5 hours. And even if I don't eat at night time, of course, many shift workers also feel hungry and just for to keep the work, they eat. Just after 5 days, my blood glucose level will read almost like I'm pre-diabetic. Wow. I actually saw a study in published in Proceedings 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. Um one night. So the the faint clock in the corner or even a nightlight that's too bright yeah, could be problematic. By the way, folks, these effects are reversible. So I whenever I say these things I we get a lot of comments about oh my goodness, what have I been doing for years? But you know, 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 they 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? Uh a third of Americans? I would say half of Americans. Half of Americans. Yeah. If you if you take teenagers because, you know, high school students and college students because again, going back to Horacio's uh study because Horacio also collected activity data from high school students and college students and we have replicated that with um 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 um 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 100 who went to bed before midnight. That um reminds me Horacio Iglesias just published this really nice paper um 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, these are people in their 20s, are staying up later in the winter months compared to the summer months. Yeah. Which is, you know, 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. Yeah, so and another um means I don't know how they 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 uh sleep onset. That makes sense. So, in that way, again, here is another thing which can be related to policy or practice at educational institute. So, what happened during COVID was everybody went to remote learning. Um 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 then now what is happening is I don't know about Stanford and maybe you are when you are giving assignment when is the deadline? Midnight typically. Midnight. So then most of us, most students they will try to cram as much as possible, try to solve as much as possible and submit at midnight. And it will be really cool to go back to your system administrator to see is there a so many frequency plot of frequency distribution of what time people are submitting their assignment because we know means when we submit our grant Yeah, so I mean you know, you hear about the obesity crisis, the crisis of metabolic disorders, not just in the US but everywhere in the world. I mean it's really striking. I remember going to a Keystone meeting, 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 kind of zones in the middle that were almost devoid of of obesity. Colorado namely, Idaho at that time. Those are now also fallen under the umbrella of of rampant obesity. And you and everyone is speculating, okay, is it you know, is it seed oils? Is it Is it this? Is it that? Is it highly processed foods? I'm I'm guessing it's all of those things 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. It's likely. You know, we all let's say freshman 15. That's right. Because these kids are getting 15 lb in their freshman year in college. And um this is where I think as educator professors um it'll be interesting to go back and see uh what can we do? Because another thing that's also becoming more and more common. Uh for example, I I give a circadian rhythm class and so I just give two lectures. And I remember when I started um 15 17 years ago, uh that lecture used to be around 1:30 p.m. or 2:00 p.m. in the afternoon and it's a 2 and 1/2 hour lecture, so it's done by 5:00. And for the last um before the pandemic, I realized that they changed the timing. Now the lecture was starting at 7:00 p.m. Mhm. So I was finishing by 9:00 9:30 p.m. And these kids, they had to go and eat after 9:30. 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? Um means at least in university system, the person who is submitting the grant or who is doing um taking care of my IRB or IACUC, they are all leaving at 5:00. So for me, everything has to end by 5:00. I think for most people out there, I so this raises a a kind of macroscopic Mhm. question, which is maybe it's not so much about restricting the feeding window, but maybe it's about feeding mostly in and being active mostly in the early part of the day. I mean, you know, I could imagine a time 3 4 years from now when it's about when waking up early and going to bed within 3 hours of sunset is the protocol which harnesses all other protocols, right? Are you going to exercise? You're going to do it in that time. You're going to eat? You're going to do it in that time. You're going to socialize? You're going to do it in that time. And in doing so, you're also avoiding a lot of the issues related to disrupted sleep. Yeah. So, that's why all these things I just said, time restricted eating is just one aspect of the circadian health and these are all interconnected. And going back to the comment about within 3 hours of sunset, yes, um that's good, but then what happens in say Toronto or Vancouver in winter time? I guess they're going to bed very very early, but also waking up very very early. Yeah. You know, one of the things that I hear all the time because I've always beating on the drum of getting morning sunlight even if through cloud cover, people say, "There's no sun here this time of year." And I I forgive me, but there is a sun unless you live in a cave, there's sun is 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, um I want to make sure that we didn't overlook What was the major conclusion of the firefighters' study? me go back to the firefighters' 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. Um but not for people who have a disrupted schedule. And if you look up clinicaltrials.gov, there are more than 400,000 studies listed and if you search how many studies are on shift workers, it's less than a thousand. 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 work alone, that's less than 50. Means I means I have to go back and check the actual number, but it's less than 50. Wow. So that's why we got super excited. We thought from 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 for 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 disruptions, circadian disruption, because they're also exposed to a lot of toxins. Anytime fire burns, that smell of fire is essentially smell of carcinogens and they're breathing, even if they have the hood on and respirator, they still get So the idea was very simple. We know that firefighters nearly 70% of firefighters in the US, full-time firefighters, because there are volunteer firefighters and then full-time firefighters. The full-time firefighters, 70% of them work 24-hour shift. So for example, in San Diego, they come in at 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. And um but in some fire departments, they actually do 48-hour shift. So, they come for 2 days, 2 days off, 2 days, 2 days off, and then 4 or 5 days off. Brutal. Thank you, firefighters. Yeah. I mean Um so, then the idea was, okay, so we'll screen firefighters and then find firefighters who are um metabolically unhealthy, and then we'll see whether they can actually follow 10-hour time-restricted eating, because the point is, if firefighters can follow it, then everybody else should be, because 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, uh David Picone, who is um the health and wellness battalion chief, he's the one who actually approached us um because he's very careful. He knew that the job that they do makes them weaker in long term and can kill them in long term. So, he was always looking for new solution. 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. So, Consistently between the days that they're working and not working? Yes. So, that means if they're from 8:00 a.m. to 8:00 a.m. working, then the next day then they go home, then they're going to eat on the same schedule they did when they were at the fire firehouse. Yeah. But while at home, so they're not allowing themselves to to deviate from that. Yeah, so we 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 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 um You know, firefighters are very 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, she and then we had Adina Jadidian, who is now in med school. She was a research coordinator at that time. Um 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 they San Diego Fire and Rescue and the city uh they all um 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 fire firefighters to rest and they have assigned beds, so they were assigned a bed. Um 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 um a jacket and a 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. Then 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 they um they got the 911. call came, then there is a beep that goes out. All firefighters were sleeping or resting, they would get up or if they're doing something, they would look up to see which engine is called. Interesting. So, it's not just the ones that go out, it's everyone gets woken up. Everyone gets woken up. So, that means in a night, typical night, they're waking up um 10, 15, 20 times sometimes. So, they're almost like uh you know, new moms are like uh 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, this fire So, that's what Emily did and then next morning once she came back, she was like, "No." Did she go to school to seem easy? Yeah. So, so we did the study and uh we essentially assigned uh all the firefighters we recruited 155 firefighters. We assigned half of them to 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 uh so, everybody was supposed to follow 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 um you pick your own 10 hours that you can stick to. But it has to be consistent from day to day. So, if you start eating at 9:00 a.m., you finish it at uh you know, at 7:00 p.m. p.m. And then try to be, yeah. More or less. 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 um what was interesting was although they were all doing 24-hour shift, they more or less chose to begin eating somewhere between 8:00 a.m. and 11:00 a.m. And um 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 5:00 or 6:00. And they're driving to come to work at 7:30 or 8:00, and they're eating the first meal, say, between 8:00 and 11:00. And then they finished meal 10 hours later. And what we found is more or less most of them could stick to doing this at least 5 days out of 7 days. Um 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 can. So, that means there are a lot nearly one in three firefighters were completely healthy. They had no sign of any any illness, no high blood pressure, high blood sugar, or high cholesterol, depression, or anything. So, since we have 1/3 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 big difference in weight loss or any weight change between these two groups. Another thing is firefighters actually run almost 8 to 9 miles when they are at the job because that's part of their exercise routine. But then, one thing that changed significantly in the time-restricted group was what we call VLDL particle size and particle number because this is something that we know is 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 are beginning with high blood pressure, then we saw 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." Um so, the extent of blood pressure lowering is equivalent to somebody taking a antihypertensive drug. Amazing. Yeah. And then those who started with high blood sugar, of course, we didn't have too many type 2 diabetic, but there are very few pre-diabetic. And they could better manage their blood glucose. And this is interesting because once shift workers become pre-diabetic or diabetic, they have more difficulty managing their blood sugar than non-shift workers because the work schedule itself will mess them up too much. Even if they're on many medication, they have difficulty. That's fascinating, and I I'm really glad that you explained the study in such detail cuz I would have thought, you know, 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, you know, 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 it's maybe not as severe as what firefighters are doing. Um 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. Yeah. Um so, I think it's really important that uh people were able to hear about the the deeper contours of the study. Uh I mean, this result of regulating blood sugar better is really powerful. I get asked all the time, you know, "I've got a new kid or um I'm a shift worker. How can I do this morning sunlight viewing?" Um what I'm hearing is that keeping a regular meal schedule every day At least five five out of seven days. 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. Um 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? Well, it's uh yeah, so this is where we get into the nuances. So, here the firefighters are 24-hour shift workers. So, that means and they have been working this 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 they get opportunity to sleep. Then even with their 10 calls, they actually have 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 they after um attending a call, they're not coming back and playing cards or trying to watch the news or get the score. They no, they will just go back and lie in the 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 have they're 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 the 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 opportunity to eat? Do they have opportunity to do even take 5 minutes 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 eating paper, we see change in nutrition quality and quantity, but here we also saw that somehow both groups inadvertently they improved their nutrition quality because everybody was told to eat Mediterranean diet. They increased fruits and vegetables and olive oil intake 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, they 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 do learn 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 group, but not in the standard of care or Mediterranean diet group. 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 Yeah. 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 the opposite of caffeine and therefore um not a health hazard. It's And And 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 um alcohol, despite extensive data that it can really disrupt health even at three drinks per week, Yeah. is um is just avidly consumed as if it was kind of like food or caffeine. It's really incredible. Um I I want to make sure that I circle back to something you mentioned earlier because I know there going to be a number of people that asked us. If I recall, you said that provided that the feeding window is not shorter than 8 hours, that men, women, and children can use time-restricted feeding. Um Well, when I say Yeah, so what I what I say is um 12 hours. For example, 12 hours, excuse me. 12 hours. Thank you for that clarification. Um because we did a study that was published in 2015. And again, um 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, they um some some people would give me a look saying, "Well, you must be doing something wrong. We This just breaks the X law of thermodynamics because how come they're eating the same number of calories and not getting weight? Of course, by that time, we figured out that uh at least in mouse, time-restricted feeding also changes the gut microbiome in a way that the mice may be pooping out a bit more fat and sugar than absorbing them. So, one thing that happens in time restricted at least in mice is the liver cholesterol metabolism to bile acid and bile acid excretion in the gut changes because the gut microbiome changes. So, this is 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 we even did bomb calorimetry from the poop and metabolomics from the poop and then we figured out that they excrete some some calories and then their brown fat activity goes up. So, they may be burning some of these extra calories. So, they're more thermogenic. More thermogenic. But anyway, so you know, one nice thing 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 yeah. And this is when Bill Brody was our president. He was the president of um um Hopkins for 12 years and then he was president. And um that time he had started this innovation grant program which was funded by Irwin Jacobs. Uh Irwin is the founder of Qualcomm. He was also a faculty at UCSD. So, he understand 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 ideas. So, Yeah, no knock on the NIH, but I'll do it anyway. And then because I sit on study section for the NIH, I mean what 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 an funding, but more often than not is it is the a generosity of philanthropists like Irwin Jacobs and other people that allow the really pioneering um the new stuff, the cool stuff. That the groundbreaking stuff. The stuff that really No, I'm not going to say really matters. It all matters. It's all important. but uh you know, it's high risk. And um and NIH means NIH is not just government is not making money from thin air. It means it's taxpayers' money. So, there is a little bit responsibility or conservative that okay, so we should not waste taxpayers' money on find this guy kind of project too much. we're not talking about politically conservative. We're talking about um scientifically conservative. We 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. Um so so that's interesting. So, they So, then we started this and then what we did was we um I had a awesome grad student and we got this funding from Irwin and also there are some Any philanthropic matters. So, actually the way we say is yes, if you give me 50 bucks, then that 50 bucks towards goes towards buying the gloves and eppendorf tubes for one postdoc for maybe 7 days. So so true. I think a lot of people don't realize that 99% of laboratory scientists just they they don't make any money off their discoveries. And even if there is a patentable discovery, typically the the divide between the institution and the company that will eventually put that to market is so slim in favor of the the others involved that you know, scientists really do this as a as work of passion, labor labor of love. So. So, we we came up with this app My Circadian Clock at that time. And we took some you know, lessons from tech leaders particularly from Amazon one-click checkout. Um because we thought most nutrition apps actually ask people to detail describe what they ate, go to the their food library, and then portion size. You say, "Okay, so we'll just shortcut all of that." We just ask 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 save, 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 worker or homemakers to be part of the study. No student was allowed to be part of the study because we know that their lifestyle lifestyle is like shift workers. And we monitor for 3 weeks. And So, here is some nuances, and I want people to understand. So, suppose say when somebody is starting to eat, let's say 7:00 a.m., and since they're recording everything, we we got every single thing. Even if they ate half a cookie, they had to take a picture, and they actually took picture because it's not It became second nature after 3 or 4 days that every time they ate something, even if there was a glass of water, they actually took a picture because we asked them, "Take picture of everything. We'll figure out what it is." What is surprising was we found the median uh so, the median number of times people eat within a day, 24-hour day, is actually seven. So, it's not it's not that we're eating three times a day. We actually snack a little bit and then Seven times per day. Seven times. And there are 10% of people, the top decile, was eating 12 times a day. Wow. Um and it makes sense in retrospect. Sometimes, maybe I'll fall into that seven or eight before um I did the study because, you know, 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. 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, and so if you think about it, it's very normal that we can go seven to eight times, 10 times. But then, if we look at what time say I start breakfast, and as I said, and we see that in many people, they'll start at 7:00 on Monday, 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. Um so we take all these food data from 3 weeks, and then ask, "What is the time when your body's system is expecting it to eat?" Because it's 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, 8:00, maybe you are expecting food around 7:00. Let's forget about 6:30, 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., 10:00, 11:00, 12:30, or 1:00. Let's ignore that 1:00 and 12:30, but still, we got somewhere between 7:00 to 11:30 for that person over 3 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 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. Wow. And and quite frequently throughout the too. And then, if we ask, "What fraction of our adults actually eating the conventional within 12 hours, three meals a day or something like that? It was 10%. So, the snacking has gone up dramatically. However, you want to define snacking, the frequency of of food intake throughout the day. 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, that's kind of interesting that came out. Um 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 this are interrelated. So, when when you think about children, most sleep researchers agree that children and teenagers should sleep somewhere between 9 to 10 or 11 hours because young children, even 5 to 10 year old, they should sleep 9 to 10 hours. They're just pumping out growth hormone and growing, growing, growing. And then the teenagers, actually they um recommendation is and they should be sleeping 9 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, what are likely How many hours are likely to sleep? That turns out to be somewhere between and 1/2 to 9 and 1/2 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 9 hours of sleep on a regular basis. Maybe in the weekend. Probably because of devices. Yeah. And also, as I said, this new idea that midnight is your assignment submission time. I'll come back to that again and again. Yeah, I'm hearing that again and again. So, teachers take note. I It's an 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 they you know, you get more bees with honey, as they say, right? You know, there's incentivizing people to wake earlier, not necessarily with the sunrise, but wake earlier and go to sleep earlier, and eat within an 8 to 12-hour window. 12 if it's Yeah, so that's why I said children. It It sounds to me like, you know, that 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 of that sort." Right? 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 9 hours, of course, they're not eating during those 9 hours. And we're not feeding children and putting them down to sleep because, you know, their core body temperature will be high, they cannot fall asleep. So, at least they should have their last meal 1 or 2 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 1 to 2 hours before bedtime they're finishing food. Similarly, on the other end, after they wake up, it's not that we're waking them up and then feeding them. Uh hopefully we're not doing that. So, that's a 12 hours seems to be optimum and it's not only I'm saying that if we put all the health recommendations together from pediatrician and then it makes sense. Um fascinating. I have a question about structuring meal intake or food intake um during the eating window. Um I have a good friend actually he's um he's the neurosurgeon at Neuralink now, but he came up through Stanford and um and he has a uh 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, um 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. It's never later. Um what do you think about that as a strategy? Um you know, 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 cuz it makes me a little bit groggy, the postprandial dip in energy. So, I'll do breakfast well but again at 11:00 and that's the first that's when I break my fast, 11:00-ish, and then dinner, maybe a snack in the middle of the day. But other days it's three meals other So, does it matter um overall as long as um 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 that the the brackets? Are you okay? Uh so, this is where the circadian aspect come in because if you're going um if you're moving that breakfast time or dinner time three, four hours, you're essentially causing maybe a metabolic jet lag. Mhm. You know, in short-term, in weeks, months, or maybe even few years, you may not see any change. Um but at the same time, we don't know what is 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, um feeling, um you know, having some pang of depression or anxiety Or LDL, like high LDL. A lot of thin people have or have very high LDL. Yeah. So, those are the things that um we don't connect with our habit. And since circadian rhythm and meal timing, meal structure now is a very new um field, um 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 out of it. But I think hopefully things will improve where people will become it will become standard to at least look for 1 week of diet record. Mealtime and what they're eating, all that stuff because um there are now mouse studies 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. No, I think it's great to hold off until we then we have you back on to discuss. Um I have a question about um fasting on the longer term. Um and there it's a near infinite space we could explore of 2 days of fasting, 1 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 um they'll still consume water and caffeine, but they'll just fast. Is there any health benefit or detriment? Um you mentioned the circadian clock shifting effects, but if somebody wakes up on Sunday and they, you know, they you know, 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 um health detriment to doing that kind of thing? Yeah, there is a actually a rich literature on um this complete fast. Um and in fact in many religion um people practice complete fast as a way to cleanse their body and um people have seen that there are benefits to that. So, in fact, the every other day eating uh in mouse model or even in humans there are also initially some studies were done. Um 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 complete fast or maybe a small bowl of soup which has 100 to 100 kcal 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. For sake of weight loss, is that why? For many different things and um they come out pretty well healthy. Of course, they're under uh supervision, make sure that they're getting macro micronutrient sorry, the micronutrients, vitamins, and um and electrolytes. Uh so, those studies are pretty solid. People have uh observed that and then in fact, there are even idea that fasting, this kind of fasting can have huge impact on brain and people may come out of treatment resistant depression or something, but you know, so those studies are very difficult to do. They're are case of one here and there that we hear once in a while. But hopefully in future we'll see um 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 um if they can affect brain then maybe long-term fasting, periodic fasting, a few days of low calorie diet back to back um will be interesting to see how it impacts brain health. Very interesting. What are your thoughts on fat fasting where people um try and limit their blood glucose by uh only eating mainly fats mainly healthy typically they'll eat healthier fats so of avocados, olive oils, and nuts and seeds, you know, and some animal fats perhaps but um as a way to keep blood glucose low and also time restrict. This goes back to the kind of low carbohydrate um thing. What What are your thoughts on that as as a general strategy for health? I mean it combines sort of two general themes that are out there. I think both of which are you know, data are still incoming that uh restricting the feeding times it can be beneficial as well as keeping overall blood glucose lower can be beneficial. Yeah, I think there's too much uh emphasis now on blood sugar spiking uh um we don't know um this kind of eating pattern for example means we are essentially telling pancreas that okay, it's it or the islet cells that produce uh insulin that is okay, you can take um take a break, go on vacation for a for a month or two or three months. Um my question is it will be interesting to see what happens to those islets because uh for example, we know that if we disuse or unuse our muscles, there's muscle atrophy. Uh, muscles will be become weaker. Uh, we don't know what the long-term consequences of this very low-carbohydrate diet where you're not essentially engaging the islet cells uh, periodically, uh, what is its impact? So, if there is no impact, maybe it's okay. Maybe because as you know, many people who actually work on ketogenic diet, the researchers themselves, they find it very difficult to stay in true ketogenic diet because the true ketogenic diet is consuming less than 10% of calories from carbohydrate. And not very many from protein. A lot of people think ketogenic diet allows them to eat massive amounts of meat, and that's not necessarily the case. Just one clarification for people, um, uh, Sachin was referring to islet cells of the pancreas, which are the ones that um, manufacture insulin. Um, so the question is whether or not uh, taking in low levels of blood glucose by way of a low-carbohydrate diet, the those islet cells are going to shut off their production. Very interesting. I mean, the liver's a very plastic tissue. I mean, it tends to um, react very dramatically to to lifestyle changes. Yeah, so that's why it would be interesting to see what happens. Means 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 uh, what happens in these people who are going through a long-term ketogenic diet, and of course, once in a while because of um, social pressure or something else, if they don't have access to food or something happens, they may consume um, some sugar, some 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, you know, 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 and I mean that's the insulin growth factor is involved in muscle protein synthesis, tissue repair, maybe even cognition. So, yeah. And it also goes back to I say mTOR activation and all that stuff people get really excited about and how to reduce mTOR activation, rapamycin, and all that stuff. So, this is where again from circadian point of view, I ask people to think. So, 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 it kind of you can say, although it may not be scientifically accurate, the you know, fasting in a pill. So, it sort of mimics fasting. And I and the 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. Yeah. Yeah. And it mimics kind of that fasting. And then rapamycin also kind of reduces mTOR activation. And people have shown that rapamycin and metformin can extend mouse lifespan and improve health. Okay. 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 AMPK is if they're truly fasting, and they should also have low level of mTOR activity because mTOR responds to insulin and that should go off at night. So, my suspicion is um in many of these experiments where the mice were allowed to eat ad libitum, even normal standard chow, now we are we know that as mice get older, they actually consume a little bit more food during daytime. Which is the equivalent of human night eating. Humans night time eating. night time eating, we know is an issue. I didn't realize that was more of an issue as people age, but Yeah, so we don't know, but at least in mice because, you know, we can put the mice in calorimetry, 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, they were snacking during daytime, AMPK is activity was not at its peak. So, giving metformin kind of mimic that fasting state. And reducing mTOR activity by drug like rapamycin also kind of mimic some aspect of the fasting state. So, my suspicion is um since these studies were done always in mice, um who are supposed to be in the fasting state and both mTOR uh sorry, rapamycin and AMPK is activator or 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 you know, there is mTOR long-term Metformin study and then a lot of people are actually consuming good amount of Rapamycin off label. They can get their own. Uh so, that's my uh curiosity. I'm not saying whether it's good or bad or whether there is science or not. That's something that'll be interesting to control for and see. Um because recently I have I saw one of my again uh close friend and colleague at Scripps, Katja Lamia. Uh she did a very simple, elegant study. People should have done it Metformin field. So, it took mice and then measured their blood glucose at different time of the day. And in fact, just like human blood glucose, our blood glucose fluctuates a little bit. Uh she saw that rhythm. And then in every 2 hours or 3 hours, um on different days, of course, she gave the same dose of Metformin to mice. And what she found was at different time of the day, Metformin had very dramatic change in glucose reducing ability. Um so, which means that even if you take Metformin and give at different time of the day for the mouse or even for humans, in very long term, of course, in these mice these mice were not diabetic or anything. They were healthy mice to begin with. So, in long term, we might see um benefits um 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. Uh whereas Metformin in the beginning of the day may not, uh at least from longevity perspective. I'm not talking about diabetes, type 2 diabetes here. So the same thing with Mtor. Is Mtor going to have much better impact if taken during evening, or morning, before meal? So These are my thoughts that go along with all this fat story that we talked about. Do you take Metformin or Berberine? No, I haven't taken. Although you know, I have close friend and colleague Reuben Shaw who is now the director of cancer center at Salk. He extensively works on MP kinase and its mechanisms and um So it's always fun to talk to him to see He's a He's a fan. Yeah, I've taken Berberine before and I've 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. I did the experiment. Allows you to flatten out your blood glucose response. So you know, in some sense if you're you know, 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 and that's why I went with Berberine because it's as far as I know it works as well. At least for healthy people. Yeah, for healthy people. That's right. Um 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. Because which makes sense. You just got a blood sugar crash. So if you lower blood your blood sugar when you already have fairly low blood sugar and you're not ingesting carbohydrates, you can really bottom out your your blood glucose. So just say it's I say that as a 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 think that and I did not pay attention to circadian effects. Yeah, yeah, yeah. I mean it's a you know, when I joined Salk and on that we know Ron Evans who is the kind of the um big leader in in metabolism and he works on nuclear hormone receptors. Um these are the master regulator of metabolism in normal cells, cancer cells and many other. And what was interesting was in the first few years Ron did a very simple experiment. Um he just looked at what time of the day this nuclear hormone receptors are turned on at gene expression level and some at protein level. And he found that almost all of them uh have a circadian pattern at least in some tissue. So uh 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 rhythms 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 they 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. And um 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 of 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're 50 PIs really crammed into two awesome buildings and with open lab structure. So you bump into each other and talk to you. So And with an ocean view. With an ocean view. Yes. It it's an amazing place. I was lucky enough to have an adjunct position there when I was when my lab was at UCSD and it is an amazing place doing incredible groundbreaking work which of course includes yours. Listen, Sachin I I'm clear now that we have to have you back on for another series of discussion. Seriously speaking, if if you'd be so 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. You know, much of what we talk about on the podcast is obviously grounded in science and and often but not always is 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 of 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 Yeah. 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 a not another nod to fighter fighters and shift workers everywhere. Thank you. And you know, I 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 shared, the actionable aspects of 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 are wonderful, and particularly the book the first book, but also 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 Human 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. 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 simple sound bite to the point where the scientist and I'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 hero, Paul Simmer from Scripts. He always says, "Think about it. 10 years ago, what 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 MyCircadianClock app, which is research facing. But we have also distilled all of this down to five or six timing component, and we have a new app called Ontime Health or Get Ontime Health. Can people access that through the standard app stores? Yeah, so now it's available in an App Store. Sorry, 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's 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, Andy. You're you're most welcome. It's um days like today where I get to sit down and and talk to brilliant colleagues like you who are doing the important work that that really matters so much. And so, as you mentioned a moment ago, that there's a a lot of darkness and confusion out there, but I thank you for being uh one of those who's shining light. Thank you. Thank you for joining me for today's discussion with Dr. Sachin Panda all about circadian biology and time-restricted feeding. If you're learning from and are 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. If you have questions for us or comments about the podcast or topics you'd like me to cover or guests that you'd like me to include on the Huberman Lab podcast, please put those in the comment section on YouTube. I do read all the comments. In addition, please check out the sponsors mentioned at the beginning and throughout today's episode. That's the best way to support this podcast. 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 and various studies through the Department of Defense and so on. 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Again, it's Huberman Lab on all social media platforms. If you haven't already subscribed to the Huberman Lab podcast Neural Network newsletter, it's a monthly newsletter that includes free toolkits for things like toolkit for sleep, how to enhance the quality and duration of your sleep, toolkit for focus, toolkit for neuroplasticity, toolkit for deliberate cold exposure, heat exposure, and summaries of podcast episodes. All of those toolkits can be found by going to hubermanlab.com. Go to the menu, scroll down to newsletter, and simply give us your email. We do not share your email with anybody, and again, the newsletters and toolkits are completely zero-cost and you will also find some PDF examples of previous toolkits. Again, that's hubermanlab.com. Thank you once again for joining me for today's discussion with Dr. Sachin 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.