Effects of Fasting & Time Restricted Eating on Fat Loss & Health | Huberman Lab Podcast #41

Andrew Huberman 0:00 (uptempo music) 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, we're talking all about fasting. And anytime we're talking about fasting, we are also talking about eating, because we all need to eat sooner or later. We're going to talk about how fasting and when we eat influences a large range of aspects of our health and wellbeing, both physical and mental. So, while nowadays most people are familiar with the term intermittent fasting, also sometimes called time-restricted feeding, I think most people don't really understand how that process works. Now, it's sort of obvious that intermittent fasting, AKA time-restricted feeding, involves eating at certain periods of each 24-hour cycle, or maybe even not eating for entire days in some cases. But if you think about it, everybody sleeps eventually, and therefore, because people don't eat during their sleep, almost everybody is employing some form of intermittent fasting or time-restricted feeding. What we're going to talk about today is how particular schedules of time-restricted feeding can impact our health in different ways. And when I say different ways, I mean we are going to talk about how intermittent fasting, AKA time-restricted feeding, impacts weight loss, fat loss in particular, muscle maintenance and loss and gain, organ health, such as gut health and liver health, the genome, the epigenome, inflammation, sickness, recovery and healing from sickness, exercise, cognition, mood, and lifespan. So, we're going to cover a tremendous amount of information. I promise to make it all directly accessible, regardless of whether or not you have a background in biology and metabolic science or not. I'm also going to talk about a lot of tools. In fact, I'm going to discuss a number of tools during today's episode that actually make it such that you don't have to follow any feeding schedule or fasting schedule, same thing if you think about it, in any absolutely strict, regimented way. Meaning if you were to only eat during an eight-hour period of each day most of the time, but then occasionally eat across a 12-hour period of the day, in theory, that could actually have pretty serious detrimental health effects. And yet there are things that you can do to attenuate those negative effects. In fact, there are things that you can do and/or take that can make it as if you did not eat at all. And so we'll discuss what those tools are. And in many cases, for sake of health, weight loss, and performance, making the body think that it did not eat at all can actually be quite beneficial. So, today we're going to cover mechanism, and we're going to cover tools. Before we do that, I want to highlight a particular result that was published recently, because it serves as a useful backbone as we wade into the conversation about fasting. This is a study that was published in the journal Cell Metabolism, a Cell Press journal, excellent journal. And the title of the paper is "Fasting Blood Glucose as a Predictor of Mortality, Lost in Translation." And I'll explain what the lost in translation part means in a moment. But the basic takeaway of this study, and I should mention that the, the first author of this study is Palliyaguru, P-A-L-L-I-Y-A-G-U-R-U, guru, Palli- Palliyaguru et al. The basic finding of the study is that in humans, higher blood glucose is associated with mortality. And in fact, if you look at blood glucose, resting blood glucose across the lifespan, what you find is as people age, resting blood glucose goes up. Now, this is very interesting, because for a long time, it was thought that metabolism actually goes down as we age. And to some extent that's true, but the reductions in metabolism are not nearly as robust as we once thought that they were across the lifespan. However, unless there's something done to mitigate the increase in blood glucose associated with aging, almost everybody experiences a gradual but regular increase in resting blood glucose that predicts mortality. Now, the title, as I mentioned, is "Fasting Blood Glucose as a Predictor of Mortality, Lost in Translation," and the reason that they included lost in translation in the title is that what I just told you, that increases in resting blood glucose predict mortality or are correlated with mortality, is true for human beings and for non-human primates, monkeys. But the opposite is true in mice, and so I thought it was important to use this study as an example of where studies in mice often, but not always translate to humans and to non-human primates. So, today I'm going to be careful to distinguish when a study was performed in mice versus in humans, because it seems that at least when discussing feeding, blood glucose, and other aspects of diet as they relate to health and wellbeing, whether or not a study was performed in rodents or in humans can be very important. And in this case, the results were directly 180 degrees opposite to one another. In other words, in mice, resting blood glucose went down, and it was associated with mortality, so lower blood glucose associated with mortality, whereas in humans, higher resting blood glucose was associated with mortality. And obviously what we're mostly interested in-... is health and wellbeing of ourselves, of humans. I'm sure there are some people out there that are, um, intensely concerned about, uh, the health and wellbeing of mice, which, uh, you could imagine, uh, a few rare contexts where that's important, but obviously most of us are interested in human health. So, I'll be sure to emphasize when studies were performed in humans versus in mice.

Andrew Huberman 6:02 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 ROKA. ROKA makes eyeglasses and sunglasses that are of the absolute highest quality. I've spent a lifetime working on the visual system and how we see, and ROKA, which is a company developed by two all-American swimmers from Stanford, has developed eyeglasses and sunglasses that take into account the science of vision, and they've produced an absolutely terrific product. That product involves glasses that, first of all, are very lightweight, second of all, can be worn when performing any activity. They really are performance eyeglasses and sunglasses. So, whether or not you're sweating or running around, whether or not you're working, whether or not you're hiking, cycling, et cetera, you can wear them for essentially any activity. The nice thing is they also have a great aesthetic. So, unlike a lot of other performance sunglasses and eyeglasses out there that can make people look more or less like cyborgs, ROKA eyeglasses and sunglasses look great, whether or not you're wearing them to dinner or at work, or whether or not you're headed out for a run or a cycle or th- or something of that sort. As I mentioned before, they're extremely lightweight, they don't slip off, and that's true regardless of what activity you're engaging in. If you'd like to try ROKA glasses, you can go to roka.com, that's R-O-K-A dot-com, and enter the code Huberman to save 20% off your first order. Today's podcast is also brought to us by 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 meet your health goals. I've long been a believer in getting regular blood work done for the simple reason that many of the processes that are occurring in your body that impact your immediate and long-term health can only be assessed from a quality blood test. And nowadays, with the advent of modern DNA tests, you can also assess your genome and how that's impacting your immediate and long-term health. The problem with a lot of blood and DNA tests is you get information back, but you don't know what to do with that information, and InsideTracker has solved that problem. They have a very easy-to-use dashboard so that when you get your results back, it will tell you, for instance, if your levels of a particular metabolic factor or hormone are too high or too low, what you can do, what you can take, how you can change your nutrition in order to adjust those levels and get them where you want them to be. This is tremendously useful and takes all the guesswork out of what to do with biomarker information. If you'd like to try InsideTracker, you can go to insidetracker.com/huberman to get 25% off any of InsideTracker's plans. Just use the code Huberman at checkout. Today's episode is brought to us by Helix Sleep. Helix Sleep makes mattresses and pillows that are tailored to your unique sleep needs, and in doing so provide the best sleep possible. I started sleeping on a Helix mattress about a year or so ago and it is the best sleep that I've ever had. If you go to the Helix site, you take a brief two-minute quiz, and that quiz asks you questions such as, "Do you tend to sleep on your stomach, your side, or your back? Do you tend to run hot or cold during the night?" Maybe you don't know. And they match you to a particular mattress that's ideal for your sleep needs. In my case, I matched to the so-called Dusk mattress. I've been sleeping on a Dusk mattress, as I mentioned. It's absolutely terrific. Best sleep I've ever had. It's really key to get a mattress that's best-suited to you. If you're interested in upgrading your mattress, you can go to helixsleep.com, take that two-minute quiz, and they'll match you to a customized mattress for you. And you'll get up to $200 off any of your mattress orders, and you'll get two free pillows. If you're interested in Helix Sleep, you can go to helixsleep.com/huberman and you'll get up to $200

Andrew Huberman 9:42 off your mattress and two free pillows. I'd like to point you toward a valuable resource that's also zero-cost and is available now online. This is an event that was recorded. The event was held by Logitech, and I was fortunate enough to partake in this event, and the entire event was centered around how to be a more effective learner and teacher using the modern principles of neuroplasticity. So, at the link in the caption for this episode, you can go to what was called the Rethink Education event, and there I gave a seminar of about 20 or 30 minutes describing the modern neuroscience of neuroplasticity, the nervous system's ability to change in response to experience. I focused mainly on human studies and how different structures and different things and tools that one can implement in the classroom and outside of the classroom can lead to faster and more pervasive, longer-lasting learning of motor skills, music skills, mathematical skills, language skills, et cetera, all based on quality peer-reviewed research. So, if you'd like to check that out, you can head to that link. You'll also see an example of some of those tools in action in a music classroom of a phenomenal music teacher, Ben Eadie, who's a teacher out in Pasadena, who has applied these tools, at least to my knowledge, for the first time ever. Of course, all the tools that are there are listed out in what I call a Plasticity Super Protocol, and all those tools can be applied to learning and teaching in any format that you like. So, check it out. It's in the caption to this week's episode, and it will remain

Andrew Huberman 11:20 there. It's up on YouTube and I hope you enjoy it. Okay, so let's talk about feeding, fasting, health, and performance, and I want to just establish a few...... foundational terms so that we're all on the same page. First of all, rather than talk about fasting or time-restricted feeding, I'm largely going to talk about time-restricted feeding. But please understand that time-restricted feeding is just one side of the coin that is a two-sided coin that includes fasting on the one hand, not eating, and time-restricted feeding on the other hand. I may occasionally say fasting, but because fasting and eating establish different biological conditions in the body, time-restricted feeding is the term that I will use to describe the overall plan of restricting one's eating window, as it's called, to a particular phase of each 24-hour day, or in some cases, to particular days within the week. Because as you'll soon learn, there are aspects of time-restricted feeding, AKA fasting, that involve eating every other day or eating one way for five days and then fasting for two days and so forth. So, I'll be very precise about what I mean and why I mean it. But for the time being, I'm going to res- refer to time-restricted feeding as a way to put an umbrella over this conversation. Second of all, I am going to emphasize a lot of biological mechanism. If you've listened to this podcast before, you know that I always begin with biological mechanism. I do describe tools of how to implement those mechanisms. But I wholeheartedly believe that knowing mechanisms and understanding how these processes work gives you tremendous flexibility and understanding and control over the processes of your mental and physical health. Whereas if I were to just list off a menu of things to do and not to do, those will work, but those will not give you the kind of understanding that would allow you to navigate through life, through travel, through dinners out, through different exercise schedules, whether or not you're one age or another age, male, female, et cetera. I'm giving you mechanisms so that you can gain more control over the systems in your brain and body. Everything's timestamped, so if you want to jump to the to-dos, you can certainly do that. But I encourage you to hang in there for the mechanism bit. I will make it all very clear, because if you understand mechanism,

Andrew Huberman 13:50 you are in a true place of power and control over your biology. If ever there was a topic that is controversial, especially on the internet, it is that of diet and nutrition. So, I'm wading into this with a smile and in eager anticipation of all the "but but but" this and "but but" that, and wait, but this showed that. Here's the deal. We need to precisely define what it is that we're talking about when we talk about nutrition. I'm going to give you an example of a study that was published a few years ago, 2018, by a colleague of mine at Stanford, Chris Gardner, who's a terrific professor of nutrition and has done a, a lot of important studies on how nutrition impacts different aspects of health. This is a large-scale study. It was published in JAMA, the Journal of the American Medical Association, one of the very top-tier journals in the area of medicine, and certainly for a paper on nutrition to show up there, meant that it had to meet an exceedingly high standard. This paper, where Chris is the first author, it's Gardner et al, 2018 JAMA, looked at weight loss in people following one particular diet versus another particular diet. And this was a 12-month weight loss study, so it was focused specifically on weight loss, although they looked at some other parameters as well. And the basic conclusion of the study was that there was no significant difference in weight change between people following a healthy low-fat diet versus a healthy low-carbohydrate diet with significantly more dietary fats in them. This caused a lot of ripples in the world of nutrition and nutritional science and certainly in the general population, because anyone that understands diet and nutrition would immediately say, "But wait, there are all sorts of different implications of eating one type of diet, say low carbohydrate/higher fat, versus a higher carbohydrate/lower fat diet." And indeed there are. This study was focused specifically on fat loss and on weight loss. So, as we discuss time-restricted feeding, we need to be very precise about what are the effects of time-restricted feeding and of eating in particular ways at particular times. We are going to emphasize again whether or not the study was done in mice or in humans, in athletes, in men, in women, or both. But the study from Gardner and colleagues is a beautiful study and really emphasizes that if one's main goal is simply to lose weight, then it really does not matter what one eats, provided that the number of calories burned is higher than the number of calories ingested. However, anyone out there who understands a little bit of biology, or a lot of biology, will agree that there are many factors that impact that calories burn part of the equation. Some of those are obvious. So for instance, amount of exercise, type of exercise, basal metabolic rate, how much energy one burns just sitting there. I've talked before on this podcast about NEAT, non-exercise induced thermogenesis, where if people bounce around a lot and fidget a lot, they can burn anywhere from 800 to 2,000 calories per day. So, their quote-unquote basal metabolic rate is actually much higher simply because they're fidgeters. Whereas people who tend to be more stationary have a lower basal metabolic rate on average. There's great science to support this. Metabolic factors and hormones are also very important. Hormones such as thyroid hormone and insulin and growth hormone and the sex steroid hormones, testosterone and estrogen, those levels will also profoundly influence the calories out, the calories burned component of the calories in calories out equation. So...If out there on the internet or in listening to a particular podcast or speaker, somebody says, "This is the ideal diet." Or, "Calories in, calories out does not matter." Or, "Calories in, calories out is the only thing that matters." I think it's very important to understand that there are some foundational truths, such as calories in, calories out, but that, of course, hormone factors, and the context in which a given diet regimen is taking place, are exceedingly important. A good example of this would be puberty. At that time in life, sex steroid hormones are changing profoundly in the body, as are growth hormone and other hormones, and much of caloric intake is directed towards protein synthesis, towards the production of muscle and bone and other tissues of the body. And that's because of changes in hormones that we call puberty. So, there's no way that we can drill into every aspect of a given feeding plan or feeding schedule that would allow us to tap into every aspect of the list that I read out before, weight loss, fat loss, muscle, organ, genome, epigenome, inflammation, exercise, cognition, mood, and lifespan. But today, we're going to be very precise about how time restricted feeding, it's very clear from both animal studies and human studies, can have a very powerful and positive impact on everything from weight loss and fat loss to various health parameters. This is a beautiful literature that's emerged mostly in the last 10 or 15 years, and as we march into this literature, what you'll see is that there actually is a perfect diet for you on a given day. And that perfect diet for you on a given day is contextual, meaning it depends on what you did yesterday and what you're going to do tomorrow. So, there is a perfect diet for you, and today I'm going to arm you with the mechanisms and understanding that will allow you to define what that perfect diet is, and will allow you to eat on a schedule and w- and to eat the things that are going to best serve your goals.

Andrew Huberman 19:48 So, let's talk about eating and what happens when you eat, and let's talk about fasting, or not eating, and what happens when you fast. I did an entire episode on eating and metabolism and hormones and other factors that impact appetite. We don't have time to go into all those details now, although you're welcome to listen to that episode as well. But we can briefly describe the overall conditions that are set in the body when we eat and when we don't eat. The key word here is conditions. If I can emphasize anything today, it's that what you eat and when you eat it set conditions in your body, and those conditions can be very good for you or very bad for you, depending on when you eat. In fact, when you eat is as important as what you eat. I'll repeat that. When you eat is as important as what you eat, at least as it relates to health parameters, in particular liver health and mental health. Some simple rules about eating. First of all, when you eat, typically your blood glucose, your blood sugar, will go up. Also, insulin levels will go up. Insulin is a hormone that's involved in mobilizing glucose from the bloodstream. How much your glucose and insulin go up depends on what you eat and how much you eat. In general, simple sugars, including fructose from fruit, but also sucrose and glucose and simple sugars, will raise your insulin and blood glucose more than complex carbohydrates, things like grains and breads and pastas and so forth. And grains and breads and pastas and so forth will raise your blood glucose more than fibrous carbohydrates like lettuce and broccoli and things of that sort. Protein has a somewhat moderate or modest impact on insulin and glucose, and fat has the lowest impact on raising your blood glucose and blood insulin. So, what you eat will impact how steep a rise in blood glucose and insulin takes place, and there are a number of factors that are related to your individual health that will also dictate how steep and how high that rise in glucose and insulin will be. For the time being, I'm leaving out people who have Type 1 diabetes. These are people that don't manufacture their own insulin. And Type 2 diabetes is essentially insulin insensitivity, lack of sensitivity to insulin, which leads to high blood glucose. But when you eat, blood glucose goes up, and when you don't eat, blood glucose and insulin go down. The longer it's been since your last meal, the lower, typically, your blood glucose and insulin will be, and the higher things like GLP-1, glucagon-like peptide-1. Glucagon being a hormone that's also secreted when you are in a fasted state or a low blood glucose state. It's involved in mobilizing various energy sources from the body, including fat through what we call lipolysis, also using carbohydrates and potentially even using muscle as a source of energy. So, that's kind of a fire hose of information about what happens when you eat and don't eat, but just think of it this way, blood sugar and insulin go up when you eat, they go down when you don't eat, and other hormones go up when you don't eat. So, there are hormones associated with the fasted state, and there are hormones associated with the eating and having just eaten state. Now, the most important thing to understand is that, like everything in biology, this is a process that takes time. So, insulin and glucose go up when we eat, and it takes some period of time for them to go down. Even if we stop eating, they will remain up for some period of time and then go back down. It takes time. This is very important, because if you look at the scientific literature on fasting...... on time restricted feeding. It's absolutely clear that the health benefits, not just the weight loss benefits, but that the health benefits from time restricted feeding occur because certain conditions are met in the brain and body for a certain amount of time. And that gives us an anchor for, from which to view what eating is in terms of how it sets conditions in the body over time. And if that sounds overly analytic, I promise you, this is the simplest and best way to think about any eating schedule or any eating plan. So, I think it's fair to say that in the field of nutrition, there are few landmark studies that serve as really strong anchors for building our understanding of what to eat and what not to eat, and when to eat, depending on our goals. The Garner study that I mentioned earlier is one such study, in that it says if your goal is weight loss, it really does not matter what foods you consume, provided that you consume a sub-maintenance caloric diet. However, I want to emphasize again, that sets aside issues of adherence, meaning how easy or hard it is to adhere to a given diet. Some people find it much easier to follow a high fat, low carbohydrate diet. Some people fall, follow a different diet because it's much easier for them to follow. And some people are concerned with mental performance and athletic performance. So, that study doesn't say there's a best diet. What it says is that what you consume is less important than the amount of food that you consume, at least for sake of weight loss, not necessarily for sake of health.

Andrew Huberman 25:33 Now, the study that I'm going to refer to next is what I would consider the second major pillar of nutritional studies. This is a truly landmark study that was carried out by Satchin Panda, who is a professor at the Salk Institute of Biological Studies in San Diego, an absolutely phenomenal institution, and an absolutely phenomenal researcher. I've known Satchin for a number of years, and I want to emphasize that the current literature on intermittent fasting and time restricted feeding can largely be attributed to Satchin and the work that he's done. There are others involved too, of course. And of course, time restricted feeding and fasting has a rich history that goes back many hundreds, if not thousands of years in different cultures and religions. But the science of time restricted feeding can really mainly be attributed to the incredible work that Satchin has done. And I'm grateful to consider him a friend and a colleague, and we consulted at length in anticipation of this episode. I also hope to have him on as a guest in the future. The landmark paper that came from Satchin's lab was published in 2012. This was a paper in mice that set the basis for studies in humans that came later. And the title of this paper is Time-Restricted Feeding Without Reducing Caloric Intake Prevents Metabolic Diseases in Mice Fed A High-Fat Diet. So, the title tells us a lot. It says that what's varied in this study is not what these mice ate, it was when they ate it. And there were essentially four conditions in this study, and the results are absolutely remarkable. So, I'm going to walk you through the major results. What they did is they gave mice access to different types of food. There were four groups. One group of mice had access to just a normal mouse diet. It would not be a diet that you'd be very interested in. I confess, I've actually tasted mouse chow. If you work with mice at all, you just have to do it at least once. It doesn't taste very good. It tastes like a very bland graham cracker cookie, and I confess that I only had the tiniest little bit, but mice like that stuff. And if you allow them to eat that stuff, what's called ad libitum, whenever they want, you just keep it in their food 24 hours a day, they will eat sometimes, and then they won't eat it at other times. Or, in this case, they also had a condition where they gave them mouse chow in a time restricted way, just for a certain number of hours each day, about eight hours. Or they gave them a high fat diet, that was a separate group, got a high fat diet at any time they wanted. So, this was kind of the carnival for mice, because mice really like high fat, highly palatable foods, and so they got a lot of goodies and high fat in their food. And then there was a fourth group that had access to the high fat diet as much as they wanted to eat, but only during a restricted time period of each 24-hour cycle. Now, mice are nocturnal. Humans are what we call diurnal. Actually, we're not really diurnal, we're crepuscular, which means that we're most active in the morning and in the evening, not so much in the afternoon. But nonetheless, everything I'm going to tell you is true also for humans, and we know this now from human studies. One of the most important things to take away from this study was that mice that ate a highly palatable, high fat diet, a great tasting diet, but only during a restricted feeding window of each 24-hour cycle, maintained or lost weight over time. Whereas mice that ingested the same diet, same amount of calories, but had access to those calories around the clock, gained weight, became obese and quite sick. And as an additional second point, the mice that restricted their feeding window to a particular portion of eight hours of every 24-hour cycle actually showed some improvement in important health markers, and what was even more incredible is that mice that only ate during a particular feeding window also experienced some reversal of some prior negative health effects. So, this study really lit up the world and got people excited about time restricted eating. Again, they used an eight-hour feeding window.

Andrew Huberman 29:46 The story around that eight-hour feeding window is kind of interesting, though. Not many people know this because it wasn't included in the paper, and there was no reason to include it in the paper.Not to out anybody, but it turns out that the reason they used an eight-hour feeding window and not a nine-hour or a 10-hour feeding window is because studies of this sort are actually quite demanding to perform, and require the constant presence of the graduate student or post-doc there to ensure that the food is in the cages at particular times, and not in the cages at other times. And mice are really good at hiding food. They'll even hide food in their jowls. Um, and so y- there's a lot of work that has to be done to prepare for that eight-hour feeding window, and to make sure after that eight-hour feeding window, there's, all the- the food has been removed from the cage and from the jowls of the mice, and so forth. And it turns out that the significant other of the graduate student and/or post-doc, I won't reveal who they were, running this study forbid their significant other, the scientist, from being in the lab for periods of time that were much longer than the 10 or 12 hours that were required in order to ensure this eight-hour feeding window. So, when we hear the eight-hour feeding windows are holy, they are not holy. And later, we are going to talk about how eating for a time that's restricted to eight hours versus 10 hours versus 12 hours, for instance, how that impacts various parameters like health parameters and weight loss, et cetera. But the eight-hour feeding window was actually created because of a real world constraint on the research and the relationship with the researcher performing the research, not because there's anything holy about an eight-hour feeding window.

Andrew Huberman 31:26 Now, an important point about when the feeding window falls within the 24-hour cycle. It is very important that the feeding window fall during the more active phase of one's day. So for humans, that's typically in the early part of the day, or the later part of the day, but not at night. Put very simply, there are a lot of data now pointing to the fact that eating during the nocturnal phase of the 24-hour cycle is very detrimental to one's health. In fact, when we eat can either enhance our health or can diminish our health. When we see light can enhance our feelings of wellbeing or can diminish our feelings of wellbeing. I've talked many times before about this on the Huberman Lab Podcast, that during the daytime you want to get as much sunlight and other types of bright light in your eyes as is safely possible, and then you want to avoid light in the middle of the night. It has detrimental, dopamine-lowering effects, can cause depression, cortisol increases, et cetera. So, when you view light is as important as the light that you view, and when you eat is as important as what you eat. In this study, they saw something really interesting, which was that not only did restricting food to a particular phase of the 24-hour cycle benefit things like lean body mass, and fat loss, and a number of health parameters that I'll talk about in a moment, but it also anchored all the gene systems of the body and provided a more regular, stable, so-called circadian rhythm or 24-hour rhythm. You may be surprised to learn that 80%, 80% of the genes in your body and brain are on a 24-hour schedule. That is, they change their levels going from high to low, and back to high again across the 24-hour cycle. And when those genes are high at the appropriate times and low at the appropriate times, meaning their expression is high and low at the appropriate times, and therefore the proper RNAs and proteins are made, because DNA encodes for RNA, RNA is translated into proteins, when that happens, your health benefits. When those genes are not expressed at the right times, when they're high or low at the wrong times of each 24-hour cycle, that's when you get negative health effects. This study showed that when mice restrict their eating to an eight-hour period within the most active phase of their 24-hour cycle, many of the genes that are associated with these so-called circadian clocks, these genes have names like PER, BMAL1, CRY1, et cetera, those so-called clock genes underwent a very regular entrainment, a locking in to the proper 24-hour schedule. And while this was in mice, we now know that this also occurs in humans. I've said before on this podcast, and I'll say it again, that light, and when we view light, is the primary way in which these genes and the clock systems of our body get organized or entrained, meaning match to the outside light dark cycle. So, viewing light early in the day and in the afternoon, and as much as possible all day, great. Ideally that's sunlight. Avoiding light in the middle of the night is also great. It's great because it causes the increases in particular genes and the decreases in particular genes in every cell throughout your body at the appropriate times. The second most powerful timekeeper or zeitgeber, as it's called, is food and when you eat. And in this study, the results they saw underscore this point. What they saw is that the peaks in these clock genes became very regular, and the dips in these clock genes became very regular, and that led to a whole host of really important positive health effects. Conversely, when mice ate whenever they wanted across the 24-hour cycle, these clock genes became really out of whack, and the negative health consequences were the downstream result of these changes in these clock genes. This has now also been shown to be true for humans. So, if you want to be healthy, you want your organ health, your metabolic health to be entrained properly, one of the most important things you can do is to view light at the appropriate times of each 24-hour schedule, and to not view light at other times of that schedule, and to eat at the appropriate time of each 24-hour day. Now, again, there are rare instances that we will discuss when skipping entire days or entire 24-hour cycles...... of eating can be beneficial. But for now, we're talking about schedules of time restricted feeding that involve a window of feeding that falls during your more active phase, so during the daytime. Putting aside people that work shift work, during the daytime is when you want to eat. And this eight hour feeding window provided a very strong reinforcing signal that combines with light to ensure that these genes are expressed at the appropriate times. The short takeaway from this is you probably want to think about, and perhaps even engage in, time restricted

Andrew Huberman 36:33 feeding. So, as I mentioned earlier, when mice can eat around the clock, bad things happen, and one of the bad things that happens is that the liver suffers. The liver is involved in all sorts of things, production of important hormones and other factors related to metabolism. And when mice can eat around the clock, their livers got very sick, fatty deposits in the liver, other factors in the liver, essentially taking down the pathway of liver disease. The time restricted feeding essentially reversed that, or led in many cases to even healthier liver conditions. And that's based on this study, but also additional studies also now in humans. So, restricting your feeding to a particular window every 24 hour cycle has clearly been shown now in mice and in humans to enhance liver health, which is wonderful. How does it do this? Well, it happens because food intake, as I mentioned earlier, sets certain conditions in the body that last for a period of time. Anytime we eat, whether or not we are a mouse or a human, there's a period of time that's required for so-called digestion, but also gastric emptying and other processes related to breaking down that food and utilizing it. And that is an active process. It requires energy. And that process of breaking down food involves certain cellular functions that, if they're ongoing throughout the 24 hour cycle, or even extended too far across the 24 hour cycle, meaning you're eating across a 14 or a 16 hour, an 18 hour window, that causes serious problems. And this has now been established because of the fact that it increases the expression of different proteins and genes in the body such as TNF-alpha, IL6, IL1. What are all those things? They are pro-inflammatory markers. So, the reason that the liver gets sick when you're eating too often is because inflammatory markers are increased. These inflammatory markers are not inherently bad. They're there for a reason, but they are there in order to respond to certain challenges, immune challenges, or the ingestion of food and the breakdown of food. But then, in an ideal circumstance, they are reduced in the period in which there's no food present in the digestive tract, or in which there's very little food present in the digestive tract. So, by eating around the clock, you're making yourself sicker. By eating at restricted periods of time each 24 hour day, you're actually making yourself healthier, and you are activating certain processes that can positively impact both weight, either maintenance or loss of weight, we'll talk about weight gain a little later, and positively impacting things like liver health. Also, the expression of different things related to brown fat, the fat that increases your metabolism, we will return to this also a little bit later, and blood glucose regulation. So, the takeaway from this study, in fact there are many takeaways from this study, it's so wonderful, is that liver health, bile acid metabolism, energy expenditure, inflammation, liver metabolites, many, many aspects of our health are

Andrew Huberman 39:45 impacted by when we eat, not just what we eat. As we move forward and we talk about intermittent fasting for eight hour windows, six hour windows, 12 hour windows, for all sorts of different intents and purposes, I want to start to establish a foundational protocol that all of us, any of us can use in order to maximize your particular goals. There are some absolutes within this realm of time restricted feeding. Here are a couple of absolutes that you would want to consider. First of all, it pays off in the metabolic sense, and in the health sense, and in the weight maintenance or loss sense, to not ingest any food in the first hour after waking, and potentially for longer. So, I want to repeat that. One of the key pillars of intermittent fasting is that for the first hour after you wake up, and potentially for longer, to not ingest any food. Okay? The second major pillar that's well supported by research is that for the two, and ideally three hours prior to bedtime, you also don't ingest any food, or liquid calories for that matter. And we will talk about what it means to break a fast, and whether or not certain liquids, even coffee and tea, can break a fast, et cetera, in a few moments. But just as a foundation, it's very clear from the research in humans that not eating any food or ingesting any calories, liquid or otherwise, for the first 60 minutes after waking up each day, and for the two to three hours prior to your bedtime, that's ideal for the parameters that we've discussed earlier, all the different things like weight, and liver health, and metabolic health, and so forth. The two most common questions about intermittent fasting are

Andrew Huberman 41:35 when is the ideal time for the eating window? Is it early in the day, the middle of the day, or later in the day? And how long should that eating window be? Should it be eight hours? We already heard why the eight hour window was first established. It was because of these lab conditions and the conditions of the particular relationship of the graduate student involved. Or should it be seven hours, or six hours, or 12 hours? Turns out that there's some general frameworks that we can follow in order to answer these questions.As we move into this portion of the discussion, I want to highlight a very important reference that just came out, literally came out last week, in the journal Endocrinology Reviews. And the title of this review is Time-Restricted Eating for the Prevention and Management of Metabolic Diseases. Although the data in this paper go well beyond metabolic diseases, this is a paper from Satchin Panda's lab. It's a very lengthy review, with an enormous table that's beautifully organized, that scripts out all the studies done in humans, well over 100 studies, looking at time restricted feeding in athletes, men, women, children, diabetes, no diabetes, et cetera, with detailed references and description of the outcomes. I spent a lot of time with this review, even though it just came out recently, and is a absolute goldmine resource. It is also the major resource for everything I'm about to tell you, so if you would like to delve deeper into the material. So, let's deal with this first question of when is the ideal feeding window? And here again, we're thinking about a schedule of eating that involves eating at least once every 24 hours, not two-day or three-day or every other day fasts. So, it turns out that the answer to the question, "When is it best to eat?" is actually best answered by thinking about the other side of the coin, which is, "When is it best to fast?" So, because we are fasting during sleep, it's very clear that it's best to extend the sleep-related fast, either into the morning or to start it in the evening. Now, this might seem kind of obvious, but it's actually not so obvious. You could place that feeding window early in the day, middle of the day, or late in the day. Let's think about what happens when we sleep. When we sleep, our body undergoes a number of different processes in the brain and body in order to recover the cells and tissues. Many of you have probably heard of autophagy, which is essentially a cleaning up, a gobbling up of dead cells and cells that are injured or sick. And this is a natural process that occurs, and it occurs mainly during sleep, although not only during sleep. Fasting of any kind does tend to enhance autophagy. It is not the only way to create autophagic conditions. Autophagic conditions can be created simply by following a subcaloric diet, and there are other things that one can do in order to trigger autophagy. But fasting does trigger autophagy. So, when we're asleep, the bad cells are getting gobbled up and eaten, and the good cells also are undergoing certain repair mechanisms mainly related to or at least governed by those circadian genes that we talked about earlier, those clock genes. So, you're already fasting when you're asleep, and how deep you are into that fast depends on how long it was since your last meal. So, if you fast early in the day and you've been asleep for five, six, seven, eight hours, I would hope somewhere between six and eight hours for most people is going to be beneficial, when you wake up, I mentioned earlier that you don't want to eat for at least the first 60 minutes after waking, but were you to extend that fasting to, say, 9:00 AM, 10:00 AM, 11:00 AM, or even 12 noon or later, you are taking advantage of the deep fast that you were in during sleep and certainly toward the end of sleep. Now, why do I say deep fast? Well, because when we eat,

Andrew Huberman 45:38 the clearance of that food from our gut and the processes in our cells and organs that are related to digestion and the utilization of that food takes about five to six hours. So, if you eat a meal and that meal lasts 10 minutes, 20 minutes, or 30 minutes, or even an hour, and then you stop eating, you've stopped eating, but you are not fasting at that point. You can say you're fasting 'cause you're no longer putting food into your digestive tract, but you are not in a fasted state. You are not under conditions of fasting. Later, I'll talk about things that you can do to accelerate the transition into fasting. So, one thing is certain, that you want your eating window to be tacked or attached to your sleep-based fasting in a way that makes it easier for you to get into the fasted state for a period of time. So, we can view that point from the perspective of best, better, and worst. Okay? So, if you are like most people and you sleep at night and you're waking up somewhere around 6:30, 7:00 AM or maybe even 8:00 AM, let's say you were to push your fasting window out such that you started eating at noon, and then you stopped eating at 6:00 PM. Well, then you're not eating from 6:00 PM until, let's say, your bedtime is 10:00 PM, but from 6:00 PM to 10:00 PM, your body is not yet in a fasted state because you just ate. However, you're starting to taper into a fasted state before sleep, and then all through sleep, and until the next morning and late morning, you are actually in a fasted state. Now, most people find it very hard to only eat in the middle of the day. So, while that's best, it's ideal for sake of the fasting-related improvements in health, it is not ideal and it's not very applicable to most work and family and social situations. Most people eat breakfast with others and/or eat dinner with others. Some people eat lunch with others, but in general, it's hard to restrict your feeding window to just the absolute middle of the day. But from a purely health perspective, in a very objective way, that would be the ideal situation.Let's imagine a different pattern of eating, where the feeding window starts in the afternoon, starts around 2:00 or even 3:00 PM. Some people don't have much trouble, or they can train themselves to get their feeding window out to 2:00 or 3:00 PM, and then they will eat until 10:00 or 11:00 PM. Right? If you do the math, you realize that that feeding window is still pretty short. It still constitutes what we would call intermittent fasting or time-restricted feeding. But assuming that they go to bed around 11:00 PM or midnight, they are not actually fasted in sleep, because for the first six hours or so of sleep, maybe five, but probably more like six hours of sleep, they're still digesting the food that they consumed late in the night. It does appear beneficial to grab ahold of that sleep-related fast, meaning you don't want your feeding window to be too close to bedtime. And that's why we came up with this kind of foundational pillar that I discussed with Satchin earlier, which is at least no eating for the first hour after waking, but also no eating within two to three hours prior to bed. And because we all need to sleep, and sleep is exceedingly important for our health of all kinds, you want to prioritize sleep, but because we also have to eat, then you start to think about this, and, hmm, maybe it's not so good to push that feeding window too late in the day, because when you go to sleep, you're not actually capitalizing on the sleep-related fasting. Now, it's not just the case that it's easiest to fast while in sleep, although that's true, because when we're asleep, typically we're not hungry, or looking for food, or foraging for food, or wanting food, or trying to resist food. We're just sleeping. There is something special about the fasting that occurs during sleep, because it's associated with a number of processes that relate to the so-called glymphatic system, the movement of lymph-like fluids and other fluids through the brain, a kind of sweeping out, uh, garbage disposal, if you will, a clearing out of the metabolic debris and some of the autophagy that's associated with bad processes in the brain. So, we could do a whole episode on this, but essentially during sleep and in particular during fasted states of sleep, we are undergoing a number of automatic cellular processes that clear out debris from our brain, enhance co- cognition or at least offset dementia, this is now well-established, as well as a number of the same processes occurring in the organs of our body. So, what we're starting to see here is that there are a number of constraints on when you can eat. Now, I would be remiss if I didn't acknowledge the social constraints and the real life constraints. Some of us, because we want to eat with our family and because our family or our significant others eat around 8:00 or 9:00 PM and that's the only time we're together, you have to eat late in the day. And that's certainly not a sin. I'm not saying that's good or bad. Here, we're trying to establish, if you recall, best, better, and worst. So, from both a practical and a health perspective, and a purely objective view of how intermittent fasting works and can benefit us, starting to eat each day somewhere around 10:00 AM or around noon, and then allowing a feeding window that goes until 6:00 or maybe 8:00 PM, that seems to me, at least based on the data and what I understand about typical cultures where people eat in the daytime and in the evening, that seems to me like the kind of schedule that will allow you to get the most out of intermittent fasting, time-restricted feeding, but does not set you up to be really out of sync with the social rhythms in most cultures. If you think about it from the perspective of, say, a noon to 8:00 feeding window, what you'll find is that you're able to eat lunch with others, if you like, or by yourself. You will be able to eat dinner at a reasonable hour. At least in most countries and most cultures, eating dinner somewhere between 6:30 and 7:00 PM is typical. When you say a feeding window that goes until 8:00, that doesn't mean sitting down to dinner at 8:00. That means your last bite of food or ingestion of any liquid calories was at 8:00 PM. Assuming that you go to bed somewhere between 10:00 PM and 1:00 AM, that allows this tapering off or this transition from feeding to a fasted state and still allows you to capitalize on the special period of fasting that is sleep-related fasting. And again, I want to emphasize that the fasting that occurs during sleep is vital, and eating too close to sleep will disrupt that fasting-related sleep. Now, there are a number of caveats

Andrew Huberman 52:35 and details related to this, and there's an important caveat and detail related to people that are specifically interested in increasing or maintaining muscle mass. So first, let's talk about food volume and food type and how that relates to whether or not you quickly or slowly enter a fasted state, because clearly when we talk about a feeding window, that feeding window could include any number of different foods. It could involve cake and ice cream, pizza, hamburgers, plants, fruit, whatever it is, or it could involve just fats or just proteins, et cetera. There are at least three factors that are going to govern how quickly you transition from ingesting food to a fasted state. Remember, as you ingest your last bite or sip of calories, that's not when the fast begins. That might be when the fasting begins on your watch or on one of these apps that I'll refer to later, which can help you track your fasting and eating windows, but that's not when it actually begins, because your body is still seeing food. You're actually carrying around food inside of you. Even though you're not putting it into your mouth, you're still eating in some sense. So, it should be somewhat obvious that very large meals are going to take longer to digest than very small meals, so that will impact how slowly or quickly you migrate from a fed state to a fasted state.There's no way I can spell out what exact volume of food you should ingest, based on the size of your stomach and et cetera. But you're all familiar with being extremely full, very full, comfortably full, somewhat full, or not feeling full and feeling hungry. So, learning to gauge food volume is important. Also, foods that include some fats, or a lot of fats, will tend to slow gastric emptying time. And depending on the kind of fats, it could mean that a given meal is digested within three hours versus five hours, so more fats might be... A large meal with a lot of fats is been, can take five or six hours. A smaller meal with less fat is going to be digested more quickly. Th-, uh, consuming calories in liquid form is going to mean that gastric emptying time is going to be faster. And then of course, there's the glucose and the insulin aspect to it, which is that foods that lead to big steep rises in glucose, like pure sugars, then your glucose will drop. However, if they're combined with fats, then it tends to be a more gradual rise in glucose, and it's more sustained, et cetera. Fibrous foods will also create a more, uh, long-lasting sustained release in glucose. The important thing here is to establish a feeding window that you can comfortably manage. Okay? Meaning that, on average, you can obey a six-hour feeding window or an eight-hour feeding window or a 10-hour feeding window, and then to place that feeding window in a social and life context that you can manage on a regular basis. Now, there are two key points that have been gleaned from the scientific data about this feeding window and when to place it, and

Andrew Huberman 55:40 this is based on a really important experiment that Satchin and his colleagues have been doing. There's a website that they have, a zero-cost website called My Circadian Clock. You can go to this website, um, free of cost. There are a number of important resources there, but what they've done is they've examined the feeding behavior of thousands of people. People will take a picture of the food they're about to eat, and it enters into their account, maybe your account if you create one, on My Circadian Clock, and they do this over many days or weeks. What's great about this is it establishes what's essentially called a feedogram, a time in which people ate, and a number of important findings have emerged from these feedograms across large populations of people in different time zones with different schedules, et cetera. First of all, almost everybody underestimates their feeding window, meaning people who think that they are on an eight-hour feeding window or six-hour feeding window, when their data are analyzed, it almost is always the case that they're actually on a feeding window that's one or even two hours longer than they think, and you think, "Well, how could that possibly be?" If people are taking their first bite at noon and they're taking their last bite at 8:00 PM, well, that must mean that they are on that feeding window of eight hours. And it turns out that people cheat, but they don't cheat in any kind of obvious way. They might have, you know, a glass of wine after dinner, or they'll have a cup of tea and a little bite of a cookie, and so when people are honest, and they are honest in most cases, uh, for this, uh, experiment, what you find is that most people's eating window is actually quite a bit longer. So, in discussing this with Satchin and reviewing the literature, it's clear that if you'd like to be on a 10-hour feeding window that you should probably select an eight-hour feeding window, because there's always a little bit of a taper on either side of that eating window. Very few people are extremely strict about these eating windows. It's just hard to do in the context of life events and social gatherings and, and family and so forth. Okay, so as we build forward your ideal fasting/time restricted feeding schedule, we now have several different rules that we can list out. First, at least no food for the first hour after waking up, at least one hour. Two, no food intake for two and ideally three hours prior to your bedtime. Three, if you want to select an eight-hour feeding window, then you should probably focus on a six or seven-hour feeding window, because in reality, your feeding window is going to be longer. Reality meaning real life constraints. And if you'd like to be on a 10-hour feeding window, you should probably select an eight or a nine-hour feeding window, because the way it plays out is that people almost always eat outside of their eating window somewhat. The other nice thing about selecting a slightly shorter eating window than is comfortable for you is that it takes into account that as you take your last bite or your last sip of calories, there's this time or taper before which you are actually in a fasted state, and because you're eating different things on different days, presumably, some foods leave your gut more quickly, some things spike your insulin and your glucose more than others, sometimes you eat more fat, sometimes less fat. This allows you to fall well within the margins of the benefits of time restricted feeding that have been demonstrated in humans, which generally involve an eight-hour window or so. So, I think this eight-hour window or six-hour window is a good thing to shoot for, for most people. Some people, and we will discuss the exceptions, but some people truly are exceptions to this. They just require more food. And along

Andrew Huberman 59:30 those lines, I just now briefly want to touch on some of the studies that have looked at using a very short feeding window of about four hours. Nowadays, a number of people are doing the so-called one meal per day or are restricting their feeding window to just four hours or six hours, and that turns out to be an interesting strategy, and the data around it actually are a little bit surprising. One surprising thing to leap out of this massive literature review on time restricted feeding in humans is that relatively short feeding windows of, say, four to six hours do produce a number of positive health effects.Things like increased insulin sensitivity, which we know is good. Remember, type 2 diabetes is a reduction in insulin sensitivity. Improvements in beta cell function in the pancreas, decreased blood pressure, decreased oxidative stress, decreases in things like evening appetite, so positive health effects and psychological effects in general. However, they either produce no change in body weight or they tend to produce even increases in body weight. Now, of course, there's variation between individuals and between studies, but this is somewhat surprising. So the eight-hour feeding window seems to be very beneficial across almost all the parameters that we've discussed, inflammation, weight loss, fat loss, et cetera. And adherence, I should mention, people's ability to stick to the diet seems quite good on this eight-hour feeding windows. But when people try and undergo very short feeding windows of four to six hours, it seems that they are overeating in that four to six hours, at least overeating with respect to their metabolic needs. Now, the contrast to this is the so-called one meal per day schedule. Very few studies on one meal per day. One meal per day, unless it's a very, very long meal, a sort of feast, typically would not last four to six hours. I guess it sort of depends on how you define a meal. But when you look at the very few, I should emphasize again, very few studies on one meal per day, people typically maintain or lose weight on the one meal per day schedule. So what we can say is that the seven to nine hour feeding window produces all of the major health benefits of time restricted feeding, as well as being pretty straightforward for most people to adhere to on a regular basis. And on a regular basis turns out to be very important. I'll get back to that point in a moment. Whereas the four to six hour eating window doesn't seem to serve people as well as, say, a seven or eight hour eating window, simply because people are overeating during that eating window. And the one meal per day, while perhaps ideal for certain people's schedules, may actually cause people to undereat. And in some cases, that might be what people want. They actually want to undereat. But when we start thinking about performance in work and in sport, and when we start considering hormone health and hormone production, fertility, that's when we can really start to look at the seven to nine hour feeding window versus the four to six hour feeding window versus the one meal per day type feeding window with some different objectivity. We can start to look at it through a different lens, because it turns out that when you place the feeding window and how long that feeding window is actually will impact a number of other things, in particular hormones that can be very important for a number of things related to sex and reproduction, can be related to performance at work, performance in athleticism. And there are excellent studies on this, so let's explore those now.

Andrew Huberman 1:03:08 So let's talk about some conditions where having the feeding window early in the day would actually be very beneficial. There was a study that was published recently in Cell Reports, again, Cell Press journal, excellent journal, peer-reviewed, very stringent, from Aoyama et al., so this is A-O-Y-A-M-A et al. This was published just recently, July 2021, that looked at the distribution of protein intake in different meals delivered either early in the day or later in the day. And I'm summarizing here quite a lot, but I should mention that this study was performed in both mice and humans, same paper, mice and humans, and involved hypertrophy training, essentially increasing the weight bearing of given limbs to try and induce hypertrophy, which is the growth of muscle tissue. It does appear that muscle tissue is better able to undergo hypertrophy by virtue of the fact that there's better or enhanced protein synthesis early in the day because of the expression of one of these particular clock genes called BMAL, B-M-A-L. BMAL regulates a number of different protein synthesis pathways within muscle cells, such that eating protein early in the day supports muscle tissue maintenance and/or growth. And in this study they also looked at the effects of supplementing so-called BCAAs, branched chain amino acids, which is popular in, uh, body building circles and in strength training circles. And BCAAs are essential components of a number of different foods, but can also be supplemented. The takeaway of this study is pretty straightforward, however. The takeaway is if your main interest is maintaining and/or building muscle, then it can be beneficial to ingest protein early in the day. You would still want to obey this what we're calling a kind of foundational rule of no- not eating any food for the first hour post-waking, or at least the first hour post-waking. And the cutoff for when you would want to eat protein would be some time before 10:00 AM, and there I'm averaging across a number of different situations. But in general, this BMAL expression is such that, let's say you wake up at 7:00 AM, your main interest is in hypertrophy or maintenance of muscle, then you would want to ingest some protein sometime before 10:00 AM. But obviously, if you're interested in getting the health effects of intermittent fasting, that you wouldn't ingest any food, uh, for at least the first 60 minutes upon waking. Now, it's not as if at 10:01 AM a gate slams shut and you can't generate hypertrophy. Of course that's not the case. However, it's very interesting that it doesn't matter when the resistance training, the load bearing exercise occurs in the 24-hour cycle, so whether or not, in other words, people are training early in the day or they're training late in the day...It still appears that ingesting protein early in the day favors hypertrophy, or that y- one is better, or I should say, more easily able to access hypertrophy by way of these clock-regulated protein synthesis mechanisms by ingesting protein early in the day. In no way, shape, or form does this study say that ingesting protein later in the day is somehow bad for you. It just emphasizes the positive effects of ingesting protein early in the day for sake of muscle maintenance and/or hypertrophy. So, if you're somebody who's mainly concerned with muscle maintenance and hypertrophy, then it may make sense to move that feeding window earlier in the day. And certainly, there are people out there who are interested in muscle maintenance and hypertrophy who aren't doing intermittent fasting at all, and that's also perfectly fine. But this just so happens to be an episode about intermittent fasting and time-restricted feeding. There are, of course, modes of eating where one eats small meals spread throughout the day, or weights, meals differently, such that meals early in the day are larger than later in the day, or vice versa. There are a near infinite number of ways to organize this. But if you are somebody who's interested in deriving the many clearly established health effects of time-restricted feeding, and you are somebody who would like to maintain or build muscle, then ingesting proteins in the early part of the day would be important to you, at least on the basis of these results. And therefore, that eight-hour window that we z- we've established as more or less ideal shifted to the later part of the day might not be as beneficial for you. Now, I can just personally say that, for me, when I wake up in the morning, it's very easy for me to not eat until noon, or 1:00, or 2:00 PM. Eating early in the day is actually somewhat of a challenge. I discussed this point with Satchin because we were talking about how is it that one can move their feeding window or place themselves onto a different schedule of intermittent fasting, and it's very clear that one

Andrew Huberman 1:08:13 needs to provide a transition period in order for that to happen. You should allow yourself a transition period of anywhere from one week to 10 days in which you shift your feeding window by about an hour each day or so. And then once you establish a feeding window that feels comfortable for you and that you think you can maintain over time, that you simply maintain that feeding schedule for at least 30 days, but ideally, you would do that indefinitely. Now, this turns out to be important based on data that they've gleaned from this mice circ- (stutters) circadian clock massive experiment that they've been doing where people are entering the times that they're feeding and e- uh, and eating. Excuse me, anytime we talk about mice, I always think about feeding, because I come from a background and my lab works on both laboratory mice and on humans. Anytime I think about humans, I think about eating, but of course, they are the same thing. The interesting thing to emerge from that very large dataset in humans is that when people log their feeding times, as I mentioned before, oftentimes they think they're eating in an eight-hour window, but they are actually eating in a much broader window. However, even for people that are very good about restricting their feeding to a four, or six, or eight-hour window, if they're very strict about the start and stop times of when they ingest calories, one of the findings that's really been important to note is that almost every individual has a lot of drift in when that eating window resides in their 24-hour period. In particular, on the weekends, people are either extending or shifting their feeding window in a way that makes it seem that they've traveled to another time zone and are eating according to another time zone, and this is extremely important. As I mentioned earlier, based on the 2012 study from Satchin's lab, where eating at a particular phase of each 24-hour cycle can help enhance the expression of these clock genes, if you are eating within a very strict or semi-strict feeding window, but that feeding window is migrating around from day to day, or five days a week you're really organized about when that falls, let's say, for sake of example, from noon to 8:00 PM, noon to 8:00 PM Monday, noon to 8:00 PM Tuesday, Wednesday, noon to 8:00 PM Thursday, and so forth, but then on a Saturday it's becoming 11:00 AM and you're ending it early, or perhaps you're starting early in the day on Sunday, you're having brunch that starts at 9:30 or 10:00, and then it's extending out, still just eight hours, but it's shifting around, that can cause disruptions in these circadian clock mechanisms that cause disruptions in the downstream effects of eating that are taking at least two to three days to recover from. So, obviously we don't want to be overly neurotic about this stuff, but because this is an episode about the science of intermittent fasting and time-restricted feeding, as important as how long your feeding window is, is where that feeding window resides in each 24-hour cycle, and perhaps even more important than that is that it be fairly regular where that feeding window resides. Because even if you have a very short feeding window, if it's drifting around from day to day, that actually offsets a number of the positive health effects of intermittent fasting. So, to really just underscore the way that these different pieces of the biological puzzle fit together, if you are very strict or semi-strict about your eight-hour feeding window, but on the weekends that eight-hour feeding window is falling later than it normally would during the middle of the week, it is as if you are going to bed later, even if you're going to bed at the same time, at least from the perspective of metabolic health, because of the way that eating impacts these clock genes and impacts, or I should say, um, subtracts the sleep-related fasting that you would normally experience if you were to finish eating, say, a couple hours before bedtime. So again, we don't want to create any overly obsessive or neurotic focus on this. I think that most all people could benefit from a time-restricted feeding schedule, but they should really think hard about what they can stick to on a regular basis and understand that they tend to underestimate the feeding window that they actually are partaking in, and that they should place that feeding window...... in a portion of the 24-hour cycle that they can be consistent on most days. And I want to emphasize most, again, because we are not laboratory mice. We don't have a graduate student coming in for eight hours a day, because that's what their significant other will allow them to do and then removing the food from our jowls and from our cages. We have access to food pretty much 24 hours a day. (smacks lips) Along those lines, however, there are things that we can all do that will allow us to offset some of the drift, if you will, that we experience, or that we induce in terms of when our feeding window occurs, or that the feeding window might push out a little later and then s- therefore start a little later the next day. There are things that we can do and there are things that

Andrew Huberman 1:13:20 we can take, and so I'd like to discuss those briefly. So, throughout this episode, I've more or less been alluding to the fact that when you eat there's some period of time afterwards in which you're actually still eating, at least from the perspective of metabolism, because glucose is up, insulin is up, and you're undergoing different metabolic and digestive pro- processes that don't really speak to you being in a fasted state, right? It's not just about when you take your last bite or your last sip. However, there are things that we can do to accelerate the transition from a fed state to a fasted state. And so I'd like to discuss what those are, and I want to emphasize that the term fed state is probably a better way to think about it than eating or not eating, because we think of eating as the verb, we're eating, we're eating, okay, we're done eating, I'm fasting now, but you're not actually fasting, because you are fed. So, we should really think about fed and unfed states, because from a cellular processes perspective, and from a health perspective, that's actually what your body and your system are paying attention to, and by now with everything that we've laid out, I think that should be intuitive to understand. So, there's a fun and exciting concept related to this, which is glucose clearing. You may have heard the old adage that if you take a 20 or 30-minute walk after dinner that it accelerates the rate at which you digest that food, and indeed it does. Clearing out of glucose from your system can be accomplished through a number of different means, but light movement or exercise does increase gastric emptying time. So, for instance, if you were to eat a meal that ended at 8:00 PM and to s- and then plop to the couch, watch TV, or get on your computer, or go to sleep, it would be five or six hours until you have transitioned from a fed state to a fasted state. However, you can accelerate that considerably by taking a 20 or 30-minute just light walk. It doesn't have to be speed walking, it certainly doesn't have to be jogging, but just walking outside or moving around. So, glucose clearing is an important aspect of the transition from the fed state to the fasted state, and just a light walk can allow you to do that. Now, if you can't get outside some people will go, um, through the gymnastics literally of doing things like air squats and push-ups and things like that, and indeed those will increase the expression of things like GLUT4 and things that mobilize glucose into muscles and things of that sort, but, you know, under most conditions most people aren't doing push-ups after dinner, or certainly if you've had a big meal just taking a light walk can be beneficial. In addition, you could consider doing intense exercise. Now, you wouldn't necessarily want to do that immediately after eating, so let's take a look at what high intensity training of any kind does to blood glucose, because in this case it turns out that when you do high intensity training actually has opposite effects on blood glucose depending on whether or not you do it early or later in the day. So, a fairly recent study looked at so-called HIT training, High Intensity Interval Training, which of course can take many different forms. It can take the form of circuit training with weights, it can take the form of, you know, burpees and push-ups and sprints and all sorts of different things, but High Intensity Interval Training is typically training that gets people's heart rates up, you know, well above 70% of maximum and then brief periods of rest and then repeating, and how long the High Intensity Interval Training of course will also vary. Uh, there's, there are very brief, you know, six or 12 or 15-minute workouts, some people can, uh, carry on with High Intensity Interval Training for up to 45 or maybe even 60 minutes in extreme cases. But when you look at the studies that have explored High Intensity Interval Training and its effect on blood glucose, there are a couple studies that leap out. For instance, one that emphasized that blood glucose levels will actually increase if High Intensity Interval Training is performed early in the day and will decrease if High Intensity Interval Training is performed later in the day. Now, the purpose for this exploration was not to explore clearance of blood glucose for sake of intermittent fasting, it was mainly focused on athletic performance and whether or not that was better early in the day or later in the day, et cetera. But we can extract some information from these studies that are beneficial for sake of understanding glucose clearing. If you have ingested food throughout the afternoon and evening and late in the day and you're thinking about going to sleep and you'd like to enter sleep in a way that is less fed and more fasted, then engaging in High Intensity Interval Training in the afternoon will lower, or evening I should say, will lower blood glucose, and in that way will help you accelerate your transition into the fasted state, provided you don't ingest something after the High Intensity Interval Training. Now, is the increase in blood glucose that occurs from High Intensity Interval Training early in the day, is that detrimental? Not necessarily so. That oftentimes is associated with the shuttling of nutrients to the muscles that have just done a lot of hard work. So, it's not that High Intensity Interval Training should not be done early in the day. In fact, for many people, including myself, training early in the day i-... just for the way that my psychology and biology works, is always better for me than training later in the day. And the other important thing to mention is that high intensity interval training done late in the day can be beneficial from the perspective of glucose clearing, lowering blood glucose, and helping transition from the fed to the fasted state in preparation for sleep. However, if you're ingesting caffeine or anything to engage in that high intensity interval training in a way that prevents you from getting to sleep, well then it's going to be detrimental overall. So, the reason I mention this is, of course, because it's nice to know that light walks after dinner, or any other meal for that matter, or high intensity interval training, provided it's done in the second half of the day, can lower blood glucose and speed the transition from fed to fasted states. But I also mention it because what we are really trying to achieve when we partake in intermittent fasting, so-called time restricted feeding, is what we're really trying to do is access unfed states or fasted states. It's not really about when you eat and what you do, it's about extending the duration of the fasting period as long as you can, in a way that's still compatible with your eating, right? Not the other way around. And this gets back to this key feature of our biology, which is that what we eat, when we eat, when we exercise, when we view light, it's about setting a context or a set of conditions in your brain and body. So, it's not so much about the activities that you undergo, it's about the activities you undergo and their relationship to one another over time, and so in this way it really beautifully highlights the way that your biology is interacting all the time. Light is setting when you're going to be awake and when you're going to be asleep. When you eat is going to be determining when you're going to be awake and when you're going to be asleep. And when you eat is also going to be determining when you are able to clear out debris from your brain and body, and repair the various cells and mechanisms of your body, when you're able to reduce those inflammatory cytokines throughout your body, and this is really the beauty of time restricted feeding, which is, it's not really about restricting your feeding, it's about accessing the beauty of the fasted state. Now, there are other ways to clear out blood glucose that involve supplements or prescription drugs. These are so-called glucose disposal agents. Glucose disposal agents, such as Metformin, which is a prescription drug, or Berberine, which is an over-the-counter substance, will lead to very dramatic reductions in blood glucose, and so they shift you from a fed to a fasted state. And I know many people who take Berberine before eating meals that include a large number of carbohydrates, for instance, as a way to clear out glucose. Now, I've tried Berberine before, and what I can tell you is that if you take Berberine, which by the way is very much like Metformin, its effects are almost identical to Metformin, in fact, but it's much less expensive and it's over-the-counter. If you take Berberine and you have not ingested carbohydrates, many people, including myself, experience a splitting headache. You become hypoglycemic because it is a glucose clearing agent. So, if you're going to experiment with things like Metformin and/or Berberine or similar, you want to be very cautious that you're not clearing out blood glucose that's already low. And the dose response for this varies tremendously from one individual to the next, and there's a strong circadian component, so some people react very well to Berberine early in the day, but find that later in the day it provides extreme headaches. For some people it's the opposite. So, I caution you in exploring things like Berberine and Metformin, that you should expect to experience a number of physical and psychological effects that may work for you, might be great for you, but might also not be great for you.

Andrew Huberman 1:22:37 Nowadays there are a number of commercially available continuous glucose monitors. I've tried one of these, it involves putting, uh, a- what's essentially a patch with a little needle that goes into your skin, which is continuing, continually, excuse me, monitoring your blood glucose and you can look at it at an app on your phone, and you can learn a lot that way about how different foods impact the increases and decrease in blood glucose. If you're doing experiments with Berberine or Metformin you can see how those impact your blood glucose, you can see how exercise, HIT training, or otherwise implac- impacts blood glucose, excuse me again. It's very hard to assess blood glucose without a continuous blood glucose monitor, and if you're not using one you're mainly going to be relying on subjective things, like, "Oh, I feel like I have low blood sugar," or, "I feel, uh, shaky, like I have high blood sugar," or shaky 'cause you have low blood sugar. So, I- I have to say that glucose clearing agents that involve a walk or exercise, moderate or intense, are going to be a lot easier to titrate and adjust the levels of than things that you're going to take, where you have to ingest the dosage, and then once you ingest a certain dosage you're along for the ride, at least until the effects of that particular compound wear off. It doesn't mean those things don't have utility, it doesn't mean people aren't using them, because many people are, but they are potentially a very sharp blade that is a double-sided blade. So, I encourage you to approach those with caution if you decide to at all. It's worth thinking about what the low blood glucose state is and why it's beneficial, as well as why it might produce headaches, and in some cases can also adjust the effects of other hormones. In the fasted state a number of different proteins that are expressed in cells undergo changes in their expression. We talked about this earlier. When we are fasted we tend to reduce the activity of a particular protein called mTOR, mammalian target of rapamycin. mTOR is very active in cells while they are growing, so throughout development. It's also very active in cancers of various kinds. mTOR needs to be what's called phosphorylated. If you don't know what that means, don't worry about it, but phosphorylation is a, a manner in which certain proteins are altered so that they can actually be functional within cells.mTOR is associated with cell growth of all kinds, healthy and unhealthy. When mTOR is phosphorylated, there's a marker called PS6, so phospho-mTOR expresses PS6. If this is all escaping you, don't worry about it. Phospho-mTOR and PS6 are reduced by fasting. Now, this makes sense if you think about it, because eating and growth are associated with each other. Fasting is not necessarily anti-growth, but it is not pro-growth. And when we fast, we see increases in cells of things like AMPK, the sirtuins, things like transcription fo- factors like FOXO, ATF, and ketones or ketone bodies. You may have heard of the ketogenic diet. What's the point of all this biochemistry? It's not to just blitz you with a bunch of cellular biology and biochemistry. It's to say that we have cell growth pathways involving mTOR and PS6, and we have cell repair and cell shrinkage processes that are associated with AMPK, the so-called sirtuins, which Dr. David Sinclair from Harvard and others are famous for, uh, discovering and understanding, things like AMPK. These two different divergent pathways of cell growth and cell breakdown and repair, and by breakdown I mean actual clearance, autophagy, and repair, those can be triggered by being in either the fed or the fasted state. So, one way I'd like you to think about the fed state, not just eating, but having recently eaten, or the fasted state, meaning high blood glucose and/or you've recently eat- eaten or are currently eating or drinking calories, is that when you eat or when you don't eat, when you're fed, when you're fasted, you are either promoting cellular growth of all kinds, or you're promoting cellular repair and clearance of all kinds. And so again, this is about setting conditions in the brain and body. It's not